18 Liver and biliary tract disease 831-888

Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 831xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease
18 Liver and biliary tract disease
P.C. HAYES
K.J. SIMPSON
O.J. GARDEN
page 831

page 832

page 832

page 833
page 833

page 834
The liver is one of the heaviest organs in the body (1.2-1.5 kg) and serves the principal function of maintaining the body's internal milieu. The anatomical position of the liver is key to fulfilling this function, as almost all absorption of foreign material into the body takes place in the gut and the portal blood draining the gut flows to the liver, which subsequently controls the release of absorbed nutrients into the systemic circulation. In addition to its function in metabolising nutrients, the liver is able to store and release a variety of substrates, vitamins and minerals, and plays a crucial role in drug and bilirubin metabolism. The liver is also the largest reticulo-endothelial organ in the body and its situation is important in removing infecting bacteria and bacterial products, which often enter the body from the gut.

pages 831 - 834


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=C01870350


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com




Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease > FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
FUNCTIONAL ANATOMY, PHYSIOLOGY AND INVESTIGATIONS
MAJOR HEPATIC FUNCTIONS
The liver performs a wide variety of functions (see Fig. 18.1). Following a meal, more than half the glucose absorbed is taken up by the liver and stored as glycogen or converted to lactate and released into the systemic circulation. Amino acids are used for hepatic and plasma protein synthesis and excess amino acids are catabolised to urea. In contrast, during fasting the liver releases glucose, derived either from the breakdown of glycogen or from gluconeogenesis using amino acids released from extrahepatic tissues such as muscle (see p. 644). Synthesis of urea, and endogenous protein and hepatic amino acid release are suppressed during fasting. In both the fed and fasting state the liver plays a central role in lipid metabolism, producing very low-density lipoproteins and further metabolising low- and high-density lipoproteins (see p. 306).


Figure 18.1 Important liver functions.
The liver plays a central role in the metabolism of bilirubin and bile salts, drugs and alcohol (see pp. 843 and 881, 868 and 866 respectively). Some vitamins, such as A, D and B12, are stored by the liver in large amounts, while others, such as vitamin K and folate, are stored in smaller concentrations and disappear rapidly if dietary intake is deficient. The liver is also able to metabolise vitamins to more active compounds, e.g. tryptophan and vitamin D. Vitamin K is essential for the hepatic synthesis of coagulation factors II, VII, IX and X (see p. 898). The liver stores minerals such as iron, in ferritin and haemosiderin, and copper.
Approximately 15% of the liver is composed of cells other than hepatocytes (see Fig. 18.2). Foremost among these are the Kupffer cells, derived from blood monocytes. These cells constitute the largest single mass of tissue-resident monocytes in the body and account for 80% of the phagocytic capacity of this system. Kupffer cells remove aged and damaged red blood cells, bacteria, viruses, antigen-antibody complexes and endotoxin. In addition, these cells are able to produce a wide variety of inflammatory mediators that may act locally or may be released into the systemic circulation. Stellate cells are found in the space of Disse and play an important role in regulating blood flow through the liver. Following liver injury cytokines produced by Kupffer cells and hepatocytes activate the stellate cells. Activated stellate cells become transformed into a myofibroblast phenotype and are an important source of extracellular matrix components such as collagen during the genesis of cirrhosis. Endothelial cells line the hepatic sinusoids. These capillary vessels of the liver differ from other capillary beds in the body. There is no basement membrane visible by electron microscopy and the endothelial cells have large fenestrae (0.1 microns), allowing free flow of fluid and particulate matter across to the hepatocytes and other cells lining the space of Disse.


Figure 18.2 Function of non-parenchymal liver cells.
page 834

page 835
FUNCTIONAL ANATOMY


Figure 18.3 Schematic representation of the liver.
The liver has traditionally been divided into the left and right lobes, by the falciform ligament, fissure of the ligamentum teres and fissure of the ligamentum venosum. Advances in hepatic surgery, however, have indicated a more useful division into right and left hemilivers based on the hepatic blood supply (see Fig. 18.3). The right and left hemilivers are further divided into a total of eight segments in accordance with subdivisions of the hepatic and portal veins. Each segment is made up of multiple smaller units known as lobules, comprised of a central vein, radiating sinusoids separated from each other by single liver cell (hepatocyte) plates and peripheral portal tracts. However, the hepatic lobule has no functional significance. The functional unit of the liver is the hepatic acinus (see Fig. 18.4), which is anatomically almost the reverse of the hepatic lobule. Blood flows into the hepatic acinus via the single terminal branches of the portal vein and hepatic artery located in the portal tracts, and along the hepatic sinusoids; it then drains into several hepatic venous tributaries at the periphery of the acinus. In contrast, the flow of bile is in the opposite direction along the biliary canaliculi into terminal bile ductules (cholangioles) and subsequently into the interlobular bile ducts located in the portal tracts. The hepatocytes in each acinus can be divided functionally into three different zones, in accordance with their position relative to the terminal portal tract. The hepatocytes in zone 1 are closest to the terminal branches of the portal vein and hepatic artery and therefore are supplied firstly with oxygenated blood, and secondly with blood containing the highest concentration of nutrients and toxins. The hepatocytes in zone 3 are furthest from the portal tracts andclosest to the hepatic veins and are therefore relatively hypoxic compared with the hepatocytes in zone 1.


Figure 18.4 Hepatic acinus. Functional unit of the liver.
INVESTIGATION OF HEPATOBILIARY DISEASE
The aims of investigation in patients with suspected liver disease are shown in Box 18.1. When investigating patients with suspected liver disease various testing modalities are integrated along the pathways presented in the algorithm (see Fig. 18.5).
DETECTION OF HEPATIC ABNORMALITY
page 835

page 836


Figure 18.5 Investigative procedures in liver disease. Suggested sequence for identifying structural lesions in the liver and biliary tract. (ERCP = endoscopic retrograde cholangiopancreatography; PTC = percutaneous transhepatic cholangiography; MRI = magnetic resonance imaging)
18.1 AIMS OF INVESTIGATIONS IN PATIENTS WITH SUSPECTED LIVER DISEASE
Detect hepatic abnormality
Measure the severity of liver damage
Define the structural effects on the liver
Identify the specific cause
Investigate possible complications


The clinical suspicion of liver disease usually leads to the measurement of the liver function tests or 'LFTs' (see Box 18.2). The LFTs are not truly function tests, provide little prognostic information and do not indicate a specific diagnosis, although they may point to an underlying pathological process and direct further investigation. Several serum enzymes are measured in these widely available biochemical tests.
The activities of one or two transaminase enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), are often measured. These enzymes function normally to transfer the amino group from an amino acid, alanine in the case of ALT and aspartate in the case of AST, to a ketoacid, producing pyruvate and oxaloacetate respectively. Both ALT and AST are located in the cytoplasm of the hepatocyte; an alternative form of AST is also located in the hepatocyte mitochondria. Although both transaminase enzymes are widely distributed in other tissues of the body, the activities of ALT outside the liver are low and therefore this enzyme is considered more specific for hepatocellular damage.
Alkaline phosphatase is a group of enzymes that are capable of hydrolysing phosphate esters at alkaline pH and are widely distributed in the body, with significant activities in the liver, gastrointestinal tract, bone and placenta. Translational and post-translational modification of alkaline phosphatase results in the production of several different isoenzymes; the relative concentration of these isoenzymes differs in different tissues. The alkaline phosphatase enzymes are found in greatest concentration in membranes associated with absorptive or secretory functions; in the liver they are therefore localised in the sinusoidal and biliary canalicular membrane.
18.2 LIVER FUNCTION TESTS USED TO ASSESS LIVER DISEASE
Measurement Fluid Assessment
Bilirubin1 Plasma
Urine Transport
Aminotransferases2 Plasma Hepatocellular damage
Alkaline phosphatase Plasma Biliary obstruction
Gamma-glutamyl transferase Plasma Enzyme induction
Proteins (total and albumin) Plasma Synthesis
Coagulation tests Plasma Synthesis

1Bilirubin detected in the urine identifies conjugated hyperbilirubinaemia and indicates hepatobiliary disease.
2Alanine aminotransferase is more specific for liver damage than aspartate aminotransferase.
Gamma-glutamyl transferase (GGT) is a microsomal enzyme found in many cells and tissues of the body; however, the largest concentrations are found in the liver, localised in the hepatocytes and epithelium of the small bile ducts. GGT functions normally to transfer glutamyl groups from gamma-glutamyl peptides to other peptides and amino acids.
The transaminase, GGT and alkaline phosphatase concentrations should be considered together. Large increases of aminotransferase activity associated with small increases of alkaline phosphatase activity favour hepatocellular damage; small increases of aminotransferase activity and large increases of alkaline phosphatase and GGT activity favour biliary obstruction (see Box 18.3). Unfortunately, these patterns do not absolutely separate the two diagnostic groups and further investigation with hepatic imaging is essential. Isolated elevation of the serum GGT is relatively common and may occur during ingestion of microsomal enzyme-inducing drugs (see Box 18.4).
page 836

page 837
18.3 BIOCHEMICAL TESTS IN DIFFERENT CAUSES OF JAUNDICE
Enzyme combination Diagnostic likelihood
Aminotransferase Alkaline phosphatase Hepatocellular jaundice Biliary obstruction
> × 6 < × 2.5 90% 10%
< × 6 > × 2.5 10% 80%
Other combinations No clear separation

18.4 DRUGS INCREASING PLASMA GAMMA-GLUTAMYL TRANSFERASE
Barbiturates
Carbamazepine
Ethanol
Glucocorticoids
Griseofulvin
Isoniazid
Meprobamate
Phenytoin
Primidone
Rifampicin


Other widely available biochemical tests may become altered in patients with liver disease. Hyponatraemia occurs in severe liver disease and is multifactorial in aetiology. Serum urea may be reduced due to impaired hepatic synthesis. Increased urea may occur following gastrointestinal haemorrhage, but when associated with a high serum creatinine and low urinary sodium excretion is indicative of hepatorenal failure, which carries a grave prognosis.
Haematological investigations are also commonly abnormal in patients with liver disease and may suggest the underlying diagnosis. The haemoglobin concentration, and white cell and platelet count may be normal. A normochromic normocytic anaemia can reflect acute upper gastrointestinal haemorrhage from oesophago-gastric varices or peptic ulcer disease, the latter being more common in liver disease than among the general population. Chronic blood loss from peptic ulcers or portal hypertensive gastropathy may produce a chronic hypochromic microcytic anaemia secondary to iron deficiency. A high erythrocyte mean cell volume (macrocytosis) is associated with alcohol misuse, but target cells in any jaundiced patient also result in a macrocytosis. Rarely, an erythrocytosis occurs in hepatocellular carcinoma due to ectopic secretion of erythropoietin. Leucopenia and thrombocytopenia may complicate portal hypertension and hypersplenism. In contrast, leucocytosis may occur with cholangitis, alcoholic hepatitis and hepatic abscesses. Atypical lymphocytes are seen in infectious mononucleosis, which may be complicated by an acute hepatitis. Thrombocytosis may occur in those with active gastrointestinal haemorrhage and, rarely, in association with hepatocellular carcinoma.
TESTS TO DETERMINE THE SEVERITY AND ACTIVITY OF LIVER DISEASE
Simple and widely available biochemical and haematological investigations can give important information on the severity of both acute and chronic liver failure and provide prognostic information in these clinical situations.
Biochemical tests
Requesting the liver function tests also routinely involves measurement of the serum bilirubin and albumin concentrations. These measurements are truly tests of liver function. Bilirubin metabolism is discussed on page 843. Albumin is one of the most important proteins involved in maintaining the normal colloidal oncotic pressure of the blood and is a major carrier of low molecular weight substances such as bilirubin, hormones and drugs. The liver produces 8-14 g of albumin per day, but the reduction in serum albumin observed with liver diseases involves changes in the volume of distribution of albumin, inaddition to reduction in synthesis.
Coagulation tests
The liver synthesises most coagulation factors, and requires vitamin K to activate factors II, VII, IX and X. Severe liver damage and prolonged biliary obstruction, the latter reducing vitamin K absorption, are associated with a reduced plasma fibrinogen concentration and prolongation of the prothrombin time. The prothrombin time depends on factors I, II, V, VII and X, and is prolonged when the plasma concentration of any of these factors falls below 30% of normal. The normal half-lives of the vitamin K-dependent coagulation factors in the blood are short (5-72 hours). Therefore changes in the prothrombin time occur relatively quickly following liver damage, and provide valuable prognostic information in patients with both acute and chronic liver failure. An increased prothrombin time is evidence of severe liver damage in chronic liver disease, provided that vitamin K (10 mg by slow i.v. injection) is given to exclude deficiency. Hypercoagulation can cause hepatic venous thrombosis and the Budd-Chiari syndrome (see p. 875).
Specific aetiological investigations
A variety of blood tests are available to determine the aetiology of hepatic disease (see Box 18.5), and are discussed under specific diseases. In certain clinical situations these blood tests may require further assessment by performing a liver biopsy.
LIVER BIOPSY
page 837

page 838
18.5 SPECIFIC AETIOLOGICAL INVESTIGATIONS
Disease Test
Haemochromatosis Serum ferritin
Serum iron, iron-binding capacity,
saturation
Polymerase chain reaction (PCR) for genetic abnormality
Wilson's disease Serum ceruloplasmin
Serum, urine, liver copper estimations
Hepatitis A infections IgM anti-hepatitis A virus
Hepatitis B infections Hepatitis B surface antigen (HBsAg)
Hepatitis Be antigen (HBeAg)
Hepatitis B viral DNA (HBV-DNA)
Anti-hepatitis B core (anti-HBc)
Anti-hepatitis B surface (anti-HBs)
Anti-hepatitis Be (anti-HBe)
Hepatitis C Anti-hepatitis C virus antibodies (various)
PCR for hepatitis C viral RNA
Hepatitis D Anti-hepatitis D (IgM and IgG)
Hepatitis E Anti-hepatitis E (anti-HEV)
Autoimmune chronic active hepatitis Serum immunoglobulins
Serum antinuclear factor, anti-smooth muscle and liver, kidney, microsomal (LKM) antibodies
Primary biliary cirrhosis Serum immunoglobulins
Serum antimitochondrial antibodies

18.6 CONDITIONS REQUIRED FOR SAFE LIVER BIOPSY
Cooperative patient
Prothrombin time < 4 seconds prolonged
Platelet count > 100 × 109/l
Exclusion of bile duct obstruction, localised skin infection, advanced chronic obstructive pulmonary disease, marked ascites and severe anaemia


A liver biopsy can confirm the severity of liver damage and provide aetiological information; it is performed with a Trucut or Menghini needle, usually through an intercostal space, using local analgesia. Liver biopsy is a relatively safe procedure if the conditions detailed in Box 18.6 are met, but should never be undertaken lightly as the mortality rate is about 0.05%. The main complications are abdominal and/or shoulder pain, bleeding and, rarely, biliary peritonitis which usually occurs when a biopsy is performed in a patient with obstruction of a large bile duct. Liver biopsies can be carried out in patients with defective haemostasis if the defect is corrected with fresh frozen plasma and platelet transfusion, if the biopsy is obtained by the transjugular route, or if the procedure is conducted percutaneously under ultrasound control and the needle track is then plugged with procoagulant material. In patients with potentially resectable malignancy, biopsy should be avoided due to the potential risk of bleeding and tumour dissemination. Operative or laparoscopic liver biopsy may sometimes be valuable, as in the staging of lymphoma.
Histological assessment of hepatic biopsies
Histological assessment of liver biopsy tissue is enhanced by discussion between clinicians and pathologists. Although the pathological features of liver disease can be diverse and variable, with several features occurring together, liver disorders can be broadly classified histologically into fatty liver (steatosis), hepatitis and cirrhosis. The use of special histological stains can sometimes help in determining the aetiology of liver disorders. The clinical features and prognosis of these changes are dependent on the underlying aetiology, and are discussed in the relevant sections.
Steatosis
Hepatic steatosis results from accumulation of fat within hepatocytes. The accumulating lipid depends on the aetiology; for example, alcoholic steatosis is associated with increased cellular triacylglycerol. Mild steatosis involving less than 10% of hepatocytes is normal; more severe steatosis is seen in a number of disorders. Steatosis may be macrovesicular where a single fat globule fills the liver cell and pushes the nucleus to the periphery, or microvesicular where small fat vacuoles give the liver cell a foamy appearance and the nucleus remains central (see Fig. 18.6). In some patients macrovesicular steatosis occurs with associated neutrophilic infiltrate, liver cell death and, rarely, Mallory's hyaline. This histological change has been termed steatohepatitis.
Hepatitis
In this disorder there is inflammation of the liver which results in damage to hepatocytes, with subsequent cell death. Acute injury is generally followed by complete recovery. Prolonged inflammation may be accompanied by fibrosis and progression to cirrhosis. The most common causes of hepatitis are listed in Box 18.7. The histological appearances in hepatitis are generally classified as acute or chronic but they are not always readily separable and areas of overlap occur.
Acute hepatitis. The pathology of acute hepatitis depends on the cause of the damage. Lesions in acute viral hepatitis and most instances of acute damage due to drugs are similar. Cell damage occurs throughout the liver, particularly in centrilobular areas, though individual lobules are variably affected. Damaged hepatocytes are swollen and granular, while dead ones become shrunken and deeply stained acidophilic bodies. These changes, originally described in yellow fever (Councilman bodies), are strong indicators of acute hepatitis. The lobules may be infiltrated with mononuclear cells (lobulitis). Polymorphonuclear leucocytes and fatty change are features of alcoholic hepatitis or amiodarone hepatotoxicity. The portal tracts are enlarged and contain a predominantly mononuclear cell infiltrate (triaditis). More severe damage is accompanied by collapse of the reticulin framework, particularly between the central veins and portal tracts, which become linked to one another; this is known as bridging or subacute hepatic necrosis. Very severe damage destroys whole lobules (massive necrosis) and is the lesion underlying most instances of acute hepatic failure. Cholestasis is occasionally prominent.
18.7 CAUSES OF HEPATITIS
Viral infections
Hepatitis A virus
Hepatitis B virus
Hepatitis C virus
Hepatitis D virus
Hepatitis E
Epstein-Barr virus (EBV)
Cytomegalovirus (CMV)
Herpes simplex

Toxins
Alcohol
Drugs, e.g. methyldopa, isoniazid, halothane, amiodarone, herbal drugs

Miscellaneous
Autoimmune hepatitis
Wilson's disease
a1-antitrypsin deficiency
Haemochromatosis


page 838

page 839






Figure 18.6 Liver histology. A Normal liver. This van Gieson stain shows normal liver appearances. Columns of hepatocytes 1-2 cells thick radiate from the portal tracts to the central veins. The portal tract contains a normal intralobular bile duct branch of the hepatic artery and portal venous radical. There is little fibrous tissue which stains pink with this particular stain. B A cirrhotic liver. This van Gieson stain shows disruption of the liver architecture. The normal arrangement of portal tracts and hepatic veins is lost and nodules of proliferating hepatocytes are broken up by strands of pink-staining fibrous tissue. C Hepatitic steatosis. Haematoxylin and eosin-stained liver section shows expansion of hepatocytes with clear globules of fat. These globules are large enough to distort the hepatocytes, a change which is termed macrovesicular steatosis. D Hepatitis. This haematoxylin and eosin-stained section shows expansion of a normal portal tract with inflammatory cells. The majority are lymphocytes which are spilling over from the portal tract into the hepatic lobules surrounding single liver cells and destroying them by apoptosis. This change is known as interface hepatitis. There are also foci of inflammatory cells surrounding individual hepatocytes within the lobules (lobulitis). E Haemochromatosis. This Perls stain shows accumulating iron within hepatocytes which is stained blue. There is also accumulation of large fat globules in some hepatocytes (macrovesicular steatosis). As well as accumulating in hepatocytes, the iron is also found in Kupffer cells and biliary epithelial cells. F a1-antitrypsin deficiency. Accumulation of periodic acid-Schiff-positive granules within individual hepatocytes is shown in this section from a patient with a1-antitrypsin deficiency.
page 839

page 840
Chronic hepatitis. Chronic hepatitis is characterised by a mononuclear inflammatory cell infiltrate of the portal tracts (see Fig. 18.6). When this infiltrate is confined to the portal tract (a condition previously known as chronic persistent hepatitis) and is associated with a normal lobular architecture, the condition is regarded as mild, and progression to cirrhosis is uncommon. Invasion of inflammatory cells into the periportal parenchyma with loss of definition of the portal-periportal interface (limiting plate), damage to the periportal hepatocytes and formation of hepatocyte 'rosettes' is termed interface hepatitis (previously described as chronic active hepatitis). Interface hepatitis is often associated with progressive parenchymal damage and fibrosis leading to cirrhosis. Histological or immunohistochemical staining of liver tissue may help in confirming the specific aetiology of a chronic hepatitis, such as with hepatitis B.
Cirrhosis
Common causes of cirrhosis are listed in Box 18.8. The changes in cirrhosis affect the whole liver but not necessarily every lobule (see Fig. 18.6). They include progressive and widespread death of liver cells associated with inflammation and fibrosis, leading to loss of the normal lobular liver architecture. Destruction of the liver architecture causes distortion and loss of the normal hepatic vasculature with the development of portal-systemic vascular shunts, and the formation of nodules rather than lobules due to the proliferation of surviving hepatocytes. The evolution of cirrhosis is gradual and progressive, and consequently cirrhotic livers have an infinitely variable appearance, limiting the usefulness of anatomical classifications. The current classification includes micronodular cirrhosis, characterised by regular connective tissue septa, regenerative nodules approximating in size to the original lobules (1 mm in diameter), and involvement of every lobule; and macronodular cirrhosis, in which the connective tissue septa vary in thickness and the nodules show marked differences in size, with large ones containing histologically normal lobules. Micronodular cirrhosis tends to evolve gradually into macronodular cirrhosis, and intermediate mixed forms are seen. Hepatic cirrhosis contrasts histologically with congenital hepatic fibrosis and partial nodular transformation. In the former condition extensive fibrosis occurs in the absence of hepatocyte injury and nodular regeneration; in the latter nodular regeneration occurs without hepatic fibrosis.
18.8 CAUSES OF CIRRHOSIS
Any cause of chronic hepatitis
Alcohol
Primary biliary cirrhosis
Primary sclerosing cholangitis
Secondary biliary cirrhosis (stones, strictures)
Haemochromatosis
Wilson's disease
a1-antitrypsin deficiency
Cystic fibrosis


18.9 INVESTIGATION OF COMPLICATIONS OF HEPATIC CIRRHOSIS
Complication Investigations
Hepatic encephalopathy Investigation for any precipitating cause
Psychometric tests
Electroencephalogram (EEG)
Sensory evoked potentials
Portal hypertension Upper gastrointestinal endoscopy
Barium swallow and meal
Liver ultrasound
Abdominal computed tomography (CT)
Wedged hepatic venous pressure
Venography of hepatic veins
Ascites Ascitic fluid sampling (for protein concentration, white blood cell count, bacterial culture, cytological examination)
Liver ultrasound
Laparoscopy
Renal failure Urine analysis
Renal ultrasound
Central venous pressure recording
Renal biopsy
Hepatocellular carcinoma a-fetoprotein
Liver ultrasound
Abdominal CT
Hepatic angiogram
Laparoscopy

INVESTIGATION OF THE POTENTIAL COMPLICATIONS OF LIVER DISEASE
Investigation of patients for specific complications is especially important in those who have cirrhosis of the liver. The investigations employed are summarised in Box 18.9 and are discussed in more detail in the relevant sections.
IDENTIFICATION OF STRUCTURAL LESIONS WITHIN THE LIVER (IMAGING TECHNIQUES)
page 840

page 841


Figure 18.7 Ultrasound showing stone in the gallbladder. Stone (arrow) with acoustic shadow (S).
Several complementary imaging techniques can be used to determine the site and general nature of structural lesions in the liver and biliary tree. Ultrasound requires a skilled operator but is safe and comfortable for the patient. Its most frequent use is the identification of gallstones (see Fig. 18.7) and biliary obstruction. Ultrasound is often used in the initial assessment of patients with liver disease to determine further investigation. However, it is often difficult to identify diffuse parenchymal diseases; moreover, focal lesions, such as tumours or metastatic disease, may not be resolved unless they are more than about 2 cm in diameter and have echogenic characteristics sufficiently different from normal liver tissue. The advent of colour Doppler ultrasound has allowed blood flow in the hepatic artery, portal vein and hepatic veins to be investigated. Endoscopic and laparoscopic ultrasound provides high-resolution images of the pancreas, biliary tree and liver. Computed tomography (CT) can be used for the same purposes as ultrasound, but detects smaller focal lesions in the liver, especially when combined with contrast injection.


Figure 18.8 ERCP showing normal biliary and pancreatic duct system.
Cholangiography can also be undertaken via an endoscopic (endoscopic retrograde cholangiopancreatography, ERCP) or percutaneous (percutaneous transhepatic cholangiography, PTC) approach (see Fig. 18.8). The latter does not allow the ampulla of Vater or pancreatic duct to be imaged. Both endoscopic and percutaneous approaches allow therapeutic interventions such as the insertion of biliary stents across malignant bile duct strictures.
Magnetic resonance imaging (MRI) is increasingly used for the investigation of the liver and biliary tree. Magnetic resonance cholangiopancreatography (MRCP) is as good as ERCP at imaging the biliary tree and is less invasive, but does not allow therapeutic intervention (see Fig. 18.9).
Hepatic arteriography is most useful for localising focal liver lesions, particularly primary and secondary tumours, and is necessary in planning hepatic surgery. Hepatic portal venography is rarely performed, but imaging of the hepatic veins is necessary in patients with suspected Budd-Chiari syndrome (see Fig. 18.27, p. 876).
Plain abdominal radiographs, oral cholecystography and radionucleotide liver scanning are now rarely employed to investigate liver diseases.


Figure 18.9 A magnetic resonance cholangiopancreatogram (MRCP) showing a cholangiocarcinoma in the distal common bile duct (arrow). The proximal common bile duct is dilated but the pancreatic duct is normal.
ISSUES IN OLDER PEOPLE
INTERPRETATION OF LIVER FUNCTION TESTS
There is a reduction in liver size and a decline in liver blood flow with age.
Older people are more prone to drug hepatotoxicity, partly because of increased exposure to drugs. Up to a third of acute hepatitis in old age is drug-induced.
There are no clinically relevant changes in liver function tests in older adults.
Minor transient changes in liver function tests are not uncommon during acute infective illnesses or heart failure in old age.
Persistent abnormalities of liver function in older patients are therefore a sign of possible liver disease.



pages 834 - 841


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC018002


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com




Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease > MAJOR MANIFESTATIONS OF LIVER DISEASE
MAJOR MANIFESTATIONS OF LIVER DISEASE
Liver disease produces a wide range of clinical manifestations. Jaundice is the main manifestation of acute liver disease, usually in association with systemic features of an acute illness. Severe acute liver disease can give rise to neuropsychiatric symptoms (encephalopathy) which characterise the rare syndrome of fulminant or acute hepatic failure. Chronic liver disease causes manifestations resulting from damage to the liver itself and from portal hypertension. Fluid retention (ascites and oedema) and hepatic encephalopathy are due mainly to a combination of these two processes and are features of chronic liver failure (or hepatic decompensation). The main manifestation of portal hypertension is bleeding from varices or gastropathy. In most countries the dominant cause of portal hypertension is hepatic cirrhosis and, although the underlying liver disease is always advanced, liver failure may or may not be present.
'ASYMPTOMATIC' ABNORMAL LIVER FUNCTION TESTS
The almost universal availability of automated biochemical analysis and the frequency of insurance, employment and health screening examinations have led increasingly to the identification of abnormal biochemical liver tests in asymptomatic people. Whilst the finding of abnormal biochemical liver tests may be indicative of a severe underlying liver disease, it is important to note that chronic liver disease may be associated with normal liver function tests; hence approximately 10% of patients with cirrhosis are identified unexpectedly at laparotomy or autopsy.
Investigation of patients with abnormal liver function tests starts with a clinical history and physical examination. Non-specific symptoms such as fatigue and weakness are common in patients with chronic liver disease. Clinical features of jaundice, pruritus, ascites, gastrointestinal bleeding and hepatic encephalopathy should be sought. The patient should be questioned regarding alcohol intake and previous drug exposure, including 'over the counter' or illegal drugs and herbal medicines. The physical examination specifically addresses whether or not there are cutaneous manifestations of chronic liver disease such as palmar erythema, spider telangiectasia and other skin changes. Abdominal examination may reveal hepatosplenomegaly and ascites. Features of hepatic encephalopathy, such as flapping tremor (asterixis) and constructional apraxia, should be sought. Measurement of height and weight allows calculation of the body mass index (BMI, see p. 298).
Often patients are truly asymptomatic or at most suffer from the non-specific symptoms described above. This situation is becoming more frequent in clinical practice and fatty liver related to obesity is one of the most common causes. The pattern of abnormality of the liver function tests may suggest a specific disorder (see p. 837). Isolated elevation of the bilirubin is seen in Gilbert's disease (see p. 844). Significant elevation of the alkaline phosphatase and GGT occurs in cholestatic disorders such as primary biliary cirrhosis and primary sclerosing cholangitis (see p. 874) or gallstones (see p. 882). Isolated elevation of the GGT occurs in alcohol misuse and with some forms of drug therapy (see Box 18.4, p. 837). Predominant increases in the serum transaminases are suggestive of hepatitis which has many causes (see Box 18.3, p. 837 and Box 18.7, p. 838).
Raised transaminases have been reported in 2.4-8.8% of healthy blood donors and 0.5% of US military recruits. In approximately 33% of cases the elevated transaminases will resolve spontaneously, 33% resolve but subsequently recur, and 33% remain elevated. In the latter two groups a careful alcohol history, calculation of the BMI and specific aetiological blood tests as discussed above will usually identify the cause without recourse to liver biopsy, which is rarely necessary or helpful in investigating such patients.
JAUNDICE
Jaundice refers to the yellow appearance of the skin, sclerae and mucous membranes resulting from an increased bilirubin concentration in the body fluids. It is usually detectable clinically when the plasma bilirubin exceeds 50 µmol/l (3 mg/dl) but recognition of jaundice is often dependent on the ambient light available. Internal tissues and body fluids are coloured yellow but not the brain, as bilirubin does not cross the blood-brain barrier other than in the immediate neonatal period. Mechanisms leading to jaundice are shown in Box 18.10.
18.10 MECHANISMS PRODUCING JAUNDICE
Increased production of bilirubin
Haemolysis

Impaired excretion of bilirubin
Congenital non-haemolytic hyperbilirubinaemia
Gilbert's syndrome
Crigler-Najjar type I and type II
Dubin-Johnson syndrome
Rotor's syndrome
Hepatocellular jaundice
Acute parenchymal liver disease
Chronic parenchymal liver disease
Cholestasis

page 842

page 843
18.11 SOURCES OF UNCONJUGATED BILIRUBIN
Haemoglobin breakdown
Catabolism of other haem-containing proteins, e.g. myoglobin and cytochrome enzymes
Ineffective erythropoiesis


Bilirubin metabolism
Unconjugated bilirubin is produced (425-510 mmol, 250-300 mg daily) from the catabolism of haem after removal of its iron component. The sources of unconjugated bilirubin are detailed in Box 18.11. Bilirubin in the blood is normally almost all unconjugated and, as it is not water-soluble, it is bound to albumin and does not pass into the urine. Further metabolism of bilirubin is shown in Figure 18.10. Unconjugated bilirubin is conjugated by the endoplasmic reticulum enzyme, glucuronyl transferase, into bilirubin mono- and diglucuronide. These bilirubin conjugates are water-soluble and exported into the bile via specific carriers on the hepatocyte membrane. Conjugated bilirubin is metabolised by colonic bacteria to form stercobilinogen, which may be further oxidised to stercobilin. Both stercobilinogen and stercobilin are then excreted in the stool. A small amount of stercobilinogen (4 mg/day) is absorbed from the bowel, passes through the liver and is excreted in the urine, where it is known as urobilinogen or, following further oxidisation, urobilin.
HAEMOLYTIC JAUNDICE
This results from increased destruction of red blood cells, or their precursors in the marrow, causing increased bilirubin production. Jaundice due to haemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma. However, this does not apply to the newborn, in whom the hepatic bilirubin transport mechanism is immature, or to patients with liver disease.
Clinical features
There are often no stigmata of chronic liver disease other than jaundice. Increased excretion of bilirubin and hence stercobilinogen leads to normal-coloured or dark stools, and increased urobilinogen excretion causes the urine to turn dark on standing as urobilin is formed. Pallor due to anaemia and splenomegaly due to excessive reticulo-endothelial activity are usually present.
Investigations


Figure 18.10 Pathway of bilirubin excretion.
The plasma bilirubin is usually less than 100 µmol/l (6 mg/dl) and the liver function tests are otherwise normal. There is no bilirubinuria because the hyperbilirubinaemia is predominantly unconjugated. The blood count and film may show evidence of haemolytic anaemia (see p. 921).
CONGENITAL NON-HAEMOLYTIC HYPERBILIRUBINAEMIA
Gilbert's syndrome is the only common form of congenital non-haemolytic hyperbilirubinaemia. All other forms are very rare (see Box 18.12). Familial cases of Gilbert's syndrome have been linked to a mutation in the promoter region of the UDP-glucuronyl transferase enzyme leading to reduced enzyme expression. This results in decreased conjugation of bilirubin, which accumulates as unconjugated bilirubin in the blood. The levels of unconjugated bilirubin increase during fasting and fall during treatment with phenobarbital (and can be used as confirmatory tests in difficult cases). The hyperbilirubinaemia is mild (< 100 µmol/l), and other liver function tests and hepatic histology are normal. The condition has an excellent prognosis, needs no treatment, and is clinically important only because it may be mistaken for more serious liver disease.
page 843

page 844
18.12 CONGENITAL NON-HAEMOLYTIC HYPERBILIRUBINAEMIA
Syndrome Inheritance Abnormality Clinical features/treatment
Unconjugated hyperbilirubinaemia
Gilbert's Autosomal ? Glucuronyl transferase Mild jaundice, especially with fasting
dominant ? Bilirubin uptake No treatment necessary
Crigler-Najjar
Type I Autosomal recessive Absent glucuronyl transferase Rapid death in neonate (kernicterus)
Type II Autosomal dominant ? ? Glucuronyl transferase Presents in neonate Phenobarbital, ultraviolet light or liver transplant as treatment
Conjugated hyperbilirubinaemia
Dubin-Johnson Autosomal recessive ? Canalicular excretion of organic anions including bilirubin Mild No treatment necessary
Rotor's Autosomal
dominant ? Bilirubin uptake
? Intrahepatic binding Mild
No treatment necessary

HEPATOCELLULAR JAUNDICE
Hepatocellular jaundice results from an inability of the liver to transport bilirubin into the bile, occurring as a consequence of parenchymal liver disease. Bilirubin transport across the hepatocytes may be impaired at any point between uptake of unconjugated bilirubin into the cells and transport of conjugated bilirubin into the canaliculi. In addition, swelling of cells and oedema resulting from the disease itself may cause obstruction of the biliary canaliculi. In hepatocellular jaundice the concentrations in the blood of both unconjugated and conjugated bilirubin increase, perhaps because of the variable way in which bilirubin transport is disturbed. The severity of jaundice, the other clinical features, and the investigation and treatment vary with the underlying disease and are considered later in this chapter.
CHOLESTATIC JAUNDICE
In unrelieved cholestasis jaundice tends to become progressively more and more severe because conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood, and also because there is a failure of clearance of unconjugated bilirubin arriving at the liver cells.
Aetiology
The causes of cholestatic jaundice are listed in Box 18.13. Cholestasis may be due to failure of the hepatocytes to generate bile flow, to obstruction of bile flow in the bile ducts in the portal tracts, or to obstruction of bile flow in the extrahepatic bile ducts between the porta hepatis and the papilla of Vater. Causes of cholestasis can operate at more than one of these levels. Those confined to the extrahepatic bile ducts may be amenable to surgical correction.
18.13 CAUSES OF CHOLESTATIC JAUNDICE
Intrahepatic
Primary biliary cirrhosis
Primary sclerosing cholangitis
Alcohol
Drugs
Viral hepatitis
Autoimmune hepatitis
Severe bacterial infections
Post-operative
Hodgkin's lymphoma
Pregnancy
Idiopathic recurrent cholestasis

Extrahepatic
Choledocholithiasis
Carcinoma
Ampullary
Pancreatic
Bile duct (cholangiocarcinoma)
Secondary
Cystic fibrosis
Parasitic infection
Traumatic biliary strictures


Clinical features
Clinical features in cholestatic jaundice include those due to cholestasis itself and those due to the development of infection (cholangitis) consequent to biliary obstruction (see Box 18.14). Other clinical features may point to a likely cause for the condition (see Box 18.15) and are discussed in greater detail in the relevant sections; none of these is pathognomonic of a particular cause, but each is more likely in some diseases than in others.
Investigations
The history and clinical findings determine investigations in individual patients. Usually, biochemical tests show greater elevation of the alkaline phosphatase and GGT compared with the aminotransferases, and an ultrasound is performed to identify any biliary dilatation. Subsequent investigation is shown in Figure 18.5, page 836.
page 844

page 845
18.14 CLINICAL FEATURES IN CHOLESTATIC JAUNDICE
Cholestasis
Early features
Jaundice
Dark urine
Pale stools
Pruritus

Late features
Xanthelasma and xanthomata
Malabsorption
Weight loss
Steatorrhoea
Osteomalacia
Bleeding tendency

Cholangitis
Fever
Rigors
Pain
Hepatic abscess


18.15 CLINICAL FEATURES SUGGESTING AN UNDERLYING CAUSE OF CHOLESTATIC JAUNDICE*
Clinical feature Causes
Jaundice
Static or increasing Carcinoma
Fluctuating Stone
Stricture
Pancreatitis
Choledochal cyst
Abdominal pain Stone
Pancreatitis
Choledochal cyst
Cholangitis Stone
Stricture
Choledochal cyst
Abdominal scar Stone
Stricture
Irregular hepatomegaly Hepatic carcinoma
Palpable gallbladder Carcinoma below cystic duct (usually pancreas)
Abdominal mass Carcinoma
Pancreatitis (cyst)
Choledochal cyst
Occult blood in stools Papillary tumour


* Each of the diseases listed here can give rise to almost any of the clinical features shown. The more likely causes of each clinical feature are given.
Management
This depends on the underlying cause of the cholestasis and is discussed in detail in the relevant sections.
UNUSUAL FORMS OF CHOLESTASIS
Cholestasis of pregnancy
This is probably caused by an inherited susceptibility of the patient's liver cells to oestrogens; the condition may also be precipitated by oral contraceptives. Pruritus is the dominant symptom and jaundice occurs in about half of the patients. Itching almost always starts in the third trimester of pregnancy and remits within about 2 weeks of delivery. Some patients experience steatorrhoea. Pruritus can be relieved with colestyramine (see p. 874). There is an increased risk of premature delivery, fetal distress during delivery and stillbirth. Careful obstetric surveillance during the third trimester is essential and treatment with ursodeoxycholic acid may reduce the incidence of fetal complications.
Benign recurrent intrahepatic cholestasis
This is a rare condition in which episodes of cholestasis lasting from 1-6 months occur, starting in adolescence or early adult life. Genetic factors are probably important, as more than one family member may be affected. Episodes start with pruritus, and painless jaundice develops later. Liver function tests show the pattern of cholestasis; liver biopsy shows cholestasis during an episode but is normal between episodes. Treatment is required to relieve pruritus and the long-term prognosis is good.
ACUTE (FULMINANT) HEPATIC FAILURE
Acute or fulminant hepatic failure is a rare syndrome in which hepatic encephalopathy, characterised by mental changes progressing from confusion to stupor and coma, results from a sudden severe impairment of hepatic function. The syndrome is defined further as occurring within 8 weeks of onset of the precipitating illness, in the absence of evidence of pre-existing liver disease, to distinguish it from those instances in which hepatic encephalopathy represents a deterioration in chronic liver disease.
Aetiology
Any cause of liver damage can produce acute hepatic failure, provided it is sufficiently severe (see Fig. 18.11). Acute viral hepatitis is the most common cause world-wide; paracetamol toxicity (see p. 170) is the most frequent cause in the UK. Otherwise acute liver failure occurs occasionally with other drugs, or from Amanita phalloides (mushroom) poisoning, in pregnancy, in Wilson's disease, following shock (see p. 195) and, rarely, in extensive malignant disease of the liver.
Pathogenesis
page 845

page 846


Figure 18.11 Causes of acute liver failure in the UK. The relative frequency of different causes of liver failure varies according to geographical area.
Traditionally, cell death (including that of hepatocytes) has been described, mainly on morphological appearances, as occurring by apoptosis or necrosis. Apoptosis results in cell shrinkage, nuclear and cytoplasmic condensation, and cellular fragmentation into apoptotic bodies, which are phagocytosed by the surrounding immune and parenchymal cells. Cell membrane integrity is maintained during apoptosis and therefore inflammation is minimal. In contrast, necrosis of cells leads to cellular swelling and rupture of the plasma membrane. The consequent release of cytoplasmic contents provokes an inflammatory response in the surrounding cells. Hepatocyte apoptosis can be induced by receptor-mediated (e.g. tumour necrosis factor, Fas, TRAIL) or mitochondrial (e.g. cellular stress and reactive oxygen intermediates) pathways which result in the activation of cytoplasmic caspase enzymes. These proteolytic enzymes exist as inactive zymogens but become activated during apoptosis and induce cellular destruction and the histological features of apoptosis. In contrast, necrotic stimuli lead to extensive mitochondrial damage and reduction in cellular adenosine triphosphate (ATP) levels. (ATP is required for the apoptotic process.)
However, this strict division of the types of cell death into either necrotic or apoptotic is now no longer appropriate; many types of injurious stimuli can lead to both forms of cell death. Although liver biopsy is often contraindicated by the severe coagulopathy, liver transplantation has allowed examination of liver tissue from patients with acute hepatic failure. These studies have shown that the histological and electron microscopic features of both hepatocyte apoptosis and necrosis occur in patients with acute hepatic failure. Activation of both receptor and mitochondrial apoptotic pathways has been implicated in the pathogenesis of acute hepatic failure induced by paracetamol overdose, viral hepatitis, Wilson's disease and other causes.
Clinical features
18.16 CLINICAL GRADING OF HEPATIC ENCEPHALOPATHY
Clinical grade Clinical signs
Grade 1 Poor concentration, slurred speech, slow mentation, disordered sleep rhythm
Grade 2 Drowsy but easily rousable, occasional aggressive behaviour, lethargic
Grade 3 Marked confusion, drowsy, sleepy but responds to pain and voice, gross disorientation
Grade 4 Unresponsive to voice, may or may not respond to painful stimuli, unconscious

page 846

page 847
Cerebral disturbance (hepatic encephalopathy) is the cardinal manifestation of acute hepatic failure, but in the early stages this can be mild and episodic. The initial clinical features are often subtle and include reduced alertness and poor concentration, progressing through behavioural abnormalities such as restlessness, aggressive outbursts and mania, to drowsiness and coma (see Box 18.16). Confusion, disorientation, inversion of sleep rhythm, slurred speech, yawning, hiccup and convulsions may also occur. A flapping 'hepatic' tremor (asterixis) of the extended hands is characteristic but may be absent. Cerebral oedema can produce increased intracranial pressure causing unequal or abnormally reacting pupils, fixed pupils, hypertensive episodes and bradycardia, hyperventilation, profuse sweating, local or general myoclonus, focal fits or decerebrate posturing. Papilloedema occurs rarely and is a late sign. More general symptoms include weakness, nausea and vomiting. Right hypochondrial pain is only an occasional feature.
Examination shows jaundice, which develops rapidly and is usually deep in subsequently fatal cases. Jaundice is not seen in Reye's syndrome, and death in other causes of acute hepatic failure occasionally occurs before jaundice develops. Fetor hepaticus can be present. The liver may be enlarged initially but later becomes impalpable. Splenomegaly is uncommon and never prominent. Ascites and oedema are late developments and may be a consequence of fluid therapy. Other features are related to the development of complications, which are considered below in the management of the condition.
Investigations
18.17 INVESTIGATIONS TO DETERMINE THE CAUSE OF ACUTE HEPATIC FAILURE
Toxicology screen of blood and urine
IgM anti-HBc
IgM anti-HAV
Anti-HEV, HCV, CMV, herpes simplex, EBV
Ceruloplasmin, serum copper, urinary copper
Autoantibodies: ANF, AMA, ASMA, LKM
Ultrasound of liver and Doppler of hepatic veins
See 'Investigation of hepatobiliary disease' (pp. 835-841) for abbreviations.

18.18 ADVERSE PROGNOSTIC CRITERIA IN ACUTE HEPATIC FAILURE
Paracetamol overdose
pH < 7.3 at or beyond 24 hours following the overdose
or
Serum creatinine > 300 µmol/l, prothrombin time > 100 seconds and encephalopathy grade 3 or 4
Non-paracetamol cases
Prothrombin time > 100 seconds
or
Any three of the following:
Jaundice to encephalopathy time > 7 days
Age <> 40 years
Indeterminate or drug-induced causes
Bilirubin > 300 µmol/l
Prothrombin time > 50 seconds


Investigations are used to determine the cause of the liver failure and the prognosis (see Boxes 18.17 and 18.18). The prothrombin time rapidly becomes prolonged as coagulation factor synthesis fails; this is the laboratory test of greatest prognostic value and it should be carried out at least twice daily. The plasma bilirubin reflects the degree of jaundice. Plasma aminotransferase activity is particularly high after paracetamol overdose, reaching 100 to 500 times the normal activity, but falls as liver damage progresses and is not helpful in determining prognosis. Plasma albumin concentration remains normal unless the course is prolonged. Percutaneous liver biopsy is contraindicated because of the severe coagulopathy, but biopsy can be undertaken by the transjugular route. Liver biopsy is particularly helpful in patients with suspected malignancy.
Management
18.19 OBSERVATIONS IN FULMINANT HEPATIC FAILURE
Neurological
Conscious level
Pupils-size, equality, reactivity
Fundi-papilloedema
Plantar responses
Cardiorespiratory
Pulse
Blood pressure
Central venous pressure
Respiratory rate
Fluid balance
Input-oral, intravenous
Output
Hourly urine output, 24-hour sodium output
Vomiting, diarrhoea
Blood analyses
Arterial blood gases
Peripheral blood count (including platelets)
Creatinine, urea
Sodium, potassium, HCO3-, calcium, magnesium
Glucose (2-hourly in acute phase)
Prothrombin time
Infection surveillance
Cultures-blood, urine, throat, sputum, cannula sites
Chest radiograph
Temperature


18.20 COMPLICATIONS OF ACUTE HEPATIC FAILURE
Encephalopathy
Cerebral oedema
Respiratory failure
Hypotension
Hypothermia
Infection
Bleeding
Pancreatitis
Renal failure
Metabolic
Hypoglycaemia
Hypokalaemia
Hypocalcaemia
Hypomagnesaemia
Acid-base disturbance


page 847

page 848
A patient with acute hepatic damage should be observed in a high-dependency or intensive care unit as soon as a progressively prolonging prothrombin time or hepatic encephalopathy is identified (see Box 18.19) so that prompt treatment of complications can be initiated (see Box 18.20). Conservative treatment aims to maintain life in the hope that hepatic regeneration will occur, but early transfer to a specialised transplant unit should always be considered. N-acetylcysteine therapy may improve outcome, particularly in patients with acute liver failure due to paracetamol poisoning (see EBM panel). Liver transplantation is an increasingly important treatment for acute hepatic failure, and criteria have been developed to identify patients unlikely to survive without a transplant. Patients should, wherever possible, be transferred to a transplant centre before these criteria are met to allow time for assessment of the patient and to maximise the time for a donor liver to become available. Survival following liver transplantation for acute liver failure is improving with increasing experience and 1-year survival rates of about 60% can be expected. Survival without transplantation is under 10%.
EBM
PARACETAMOL-INDUCED ACUTE LIVER FAILURE-role of N-acetylcysteine therapy
'In an RCT N-acetylcysteine (NAC) treatment in patients with paracetamol-induced acute liver failure was associated with a significant improvement in survival, less cerebral oedema and fewer episodes of hypotension requiring inotropic support.'
Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol-induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991; 303:1026-1029.


CIRRHOSIS AND CHRONIC LIVER FAILURE
Cirrhosis and chronic liver failure are not synonymous terms, although the former can eventually lead to the latter. Chronic liver failure develops when the functional capacity of the liver can no longer maintain normal physiological conditions. The term 'hepatic decompensation' or 'decompensated liver disease' is often used when chronic liver failure occurs. Chronic liver failure is a syndrome complex that can occur as a consequence of insidious destruction of hepatocytes, but is more commonly precipitated by a number of events such as variceal haemorrhage or infection. It is characterised by a variety of clinical and laboratory features which may occur alone or more commonly in combination (see Box 18.21) and include hepatic encephalopathy, ascites and peripheral oedema, renal failure, jaundice, and hypoalbuminaemia and coagulation abnormalities due to defective protein synthesis.
Aetiology and pathogenesis
18.21 CLINICAL FEATURES OF HEPATIC CIRRHOSIS
Hepatomegaly (although liver may also be small)
Jaundice
Ascites
Hepatic (portosystemic) encephalopathy
Circulatory changes
Spider telangiectasia, palmar erythema, cyanosis
Endocrine changes
Loss of libido, hair loss
Men: gynaecomastia, testicular atrophy, impotence
Women: breast atrophy, irregular menses, amenorrhoea
Haemorrhagic tendency
Bruises, purpura, epistaxis, menorrhagia
Portal hypertension
Splenomegaly, collateral vessels, variceal bleeding, fetor hepaticus
Other features
Pigmentation, digital clubbing, low-grade fever


Hepatic cirrhosis can occur at any age and often causes prolonged morbidity. It frequently manifests itself in younger adults and is an important cause of premature death. Causes are listed in Box 18.8 on page 840. Any condition leading to persistent or recurrent hepatocyte death may lead to hepatic cirrhosis, e.g. viral hepatitis and alcohol. Prolonged biliary damage or obstruction, as can occur in primary biliary cirrhosis, sclerosing cholangitis and post-surgical biliary strictures, will also result in cirrhosis. Persistent blockage of the venous return from the liver, e.g. veno-occlusive disease and Budd-Chiari syndrome, will eventually result in liver cirrhosis. World-wide, the most common causes of cirrhosis are viral hepatitis and prolonged excessive alcohol consumption.
Common to all causes of liver cirrhosis is an activation of the hepatic stellate cells. These cells are widely distributed throughout the liver in the space of Disse. Following activation the quiescent fat-storing stellate cells become transformed into multifunctional cells, capable of collagen production, contraction and cytokine synthesis. This process is dependent on interaction with other cells in the liver, such as hepatocytes and Kupffer cells, and both paracrine and autocrine cytokine stimulation (see Fig. 18.12).
Chronic liver failure occurs when the functional capacity of the liver is exceeded. This situation may result following an increase in liver injury such as may occur in viral hepatitis or following an alcoholic binge. Alternatively, it may occur when certain clinical situations lead to increased metabolic demands on the liver, e.g. infection or gastrointestinal haemorrhage. Factors leading to the development of the clinical features of chronic liver failure, ascites, hepatic encephalopathy and jaundice are discussed under the appropriate sections.
Clinical features
These vary greatly and include any combination of the manifestations described below. Autopsy series have highlighted the fact that cirrhosis may be entirely asymptomatic, and in life may be found incidentally at surgery or may be associated with minimal features such as isolated hepatomegaly. Frequent complaints include weakness, fatigue, muscle cramps, weight loss and non-specific digestive symptoms such as anorexia, nausea, vomiting, upper abdominal discomfort and gaseous abdominal distension. Otherwise, clinical features are due mainly to hepatic insufficiency and portal hypertension.
page 848

page 849


Figure 18.12 Pathogenic mechanisms in hepatic fibrosis. The activation of hepatic stellate cells from a quiescent fat-storing cell into an activated myofibroblast-like cell occurs during the pathogenesis of hepatic fibrosis. Stellate cell activation occurs under the influence of cellular factors (cytokines) released from several different cell types within the liver. Injured hepatocytes release lipid peroxide products, insulin-like growth factor (IGF) and transforming growth factor-a (TGF-a); activated platelets release platelet-derived growth factor (PDGF), transforming growth factor-ß1 (TGF-ß1) and epidermal growth factor (EGF). Activated Kupffer cells also release PDGF and TGF-ß1 as well as an as yet uncharacterised 5000 mw factor which activates stellate cells. Once stellate cells become myofibroblast-like they can perpetuate their own activation by the synthesis of PDGF and TGF-ß1 in a series of autocrine activation loops. Activated stellate cells lose their fat-storing vesicles and become able to synthesise collagen matrix and inhibitors of collagen breakdown. They can migrate towards appropriate stimuli (chemotaxis) and contract under appropriate stimuli, as well as being able to synthesise cytokines.
Hepatomegaly is common, but progressive hepatocyte destruction and fibrosis gradually reduce liver size as the disease progresses. A reduction in liver size is especially common if the cause of cirrhosis is viral hepatitis. The liver is often hard, irregular and painless. Jaundice is usually mild when it first appears and is due primarily to a failure to excrete bilirubin. Mild haemolysis occurs in cirrhosis but is not important in the development of jaundice. Palmar erythema (see p. 832) can be seen early in the disease, but it is of limited diagnostic value as it occurs in many other conditions associated with a hyperdynamic circulation as well as in some normal people. Spider telangiectasia (see p. 832) are due to associated arteriolar changes and comprise a central arteriole (which occasionally raises the skin surface) from which small vessels radiate. They vary in size from 1-2 mm to 1-2 cm in diameter, are usually found only above the nipples, and can occur early in the disease. One or two small spider telangiectasia are found in about 2% of healthy people and they can occur transiently in greater numbers in the third trimester of pregnancy, but otherwise they are a strong indicator of liver disease. Florid spider telangiectasia, gynaecomastia and parotid enlargement are most common in alcoholic cirrhosis. Pigmentation is most striking in haemochromatosis and in any cirrhosis associated with prolonged cholestasis. Pulmonary arteriovenous shunts also develop, leading to hypoxaemia and eventually to central cyanosis, but this is a late feature.
page 849

page 850
Endocrine changes are noticed more readily in men, who show loss of male hair distribution and testicular atrophy. Gynaecomastia is infrequent and can be due to drugs such as spironolactone. Easy bruising becomes more frequent as cirrhosis advances, and epistaxis is common and sometimes severe; it can mimic upper gastrointestinal bleeding if the blood is swallowed. Splenomegaly, collateral vessel formation and fetor hepaticus are features of portal hypertension, which occurs in more advanced disease (see p. 850). Haemorrhoids are often said to be more common in patients with portal hypertension but there is no evidence for this. Ascites is due to a combination of liver failure and portal hypertension (see p. 856) and signifies advanced disease. Evidence of hepatic encephalopathy also becomes increasingly common with advancing disease. Non-specific features of chronic liver disease include pigmentation, clubbing of the fingers and toes, and low-grade fever. Dupuytren's contracture is traditionally regarded as being associated with cirrhosis, especially that due to alcohol, but the evidence for this association is weak.
Management
This includes the treatment of any known cause (discussed below), the maintenance of nutrition, and treatment of the complications of cirrhosis (see below). Chronic liver failure due to cirrhosis can also be treated by orthotopic liver transplantation, which currently accounts for about three-quarters of all liver transplant operations. Liver transplantation is most commonly undertaken in patients with cholestatic forms of cirrhosis, especially primary biliary cirrhosis, alcoholic cirrhosis and cirrhosis due to hepatitis C virus. Patients with alcoholic cirrhosis need to show a capacity for abstinence. Rarer indications include metabolic diseases such as a1-antitrypsin deficiency and haemochromatosis. Signs of liver failure pointing to the need for transplantation include sustained or increased jaundice (bilirubin > 100 mmol/l in cholestatic diseases such as primary biliary cirrhosis), ascites or hepatic encephalopathy not responding readily to medical therapy, and hypoalbuminaemia (< 30 g/l). Fatigue and lethargy affecting the quality of life, intractable itching in cholestatic disease, and recurrent variceal bleeding are additional indications. The main contraindications to transplantation are sepsis, the acquired immunodeficiency syndrome (AIDS), extrahepatic malignancy, active alcohol or other substance misuse, and marked cardiorespiratory dysfunction. Survival at 1 year after transplantation is about 80%, and the prognosis thereafter is good.
EBM
LIVER TRANSPLANTATION FOR CHRONIC LIVER FAILURE
'RCTs of liver transplantation for chronic liver failure have not been reported. However, a survival benefit of transplantation has been shown in patients with liver failure secondary to primary biliary cirrhosis or alcoholic cirrhosis when compared with a simulated control population.'
Markus BH, Dickson ER, Grambsch PM, et al. Efficacy of liver transplantation in patients with primary biliary cirrhosis. N Engl J Med 1989; 320:1709-1713.
Poynard T, Naveau S, Doffoel M, et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999; 30:1130-1137.
Further information: www.bsg.org.uk

Prognosis
18.22 CHILD-PUGH CLASSIFICATION OF PROGNOSIS IN CIRRHOSIS
Score 1 2 3
Encephalopathy None Mild Marked
Bilirubin (ímol/l) <> 50
In primary biliary cirrhosis and sclerosing cholangitis <> 170
Albumin (g/l) > 35 28-35 < 28
Prothrombin time (seconds prolonged) <> 6
Ascites None Mild Marked
Add the individual scores: < 7 = Child's A
7-9 = Child's B
> 9 = Child's C

18.23 SURVIVAL IN CIRRHOSIS
Survival (%)
Child-Pugh grade 1 year 5 years 10 years Hepatic deaths* (%)
A 82 45 25 43
B 62 20 7 72
C 42 20 0 85

*Include hepatic failure, gastrointestinal bleeding and hepatocellular carcinoma.
The overall prognosis in cirrhosis is poor. Many patients present with advanced disease and/or serious complications that carry a high mortality. Overall, only 25% of patients survive 5 years from diagnosis but, where liver function is good, 50% survive for 5 years and 25% for up to 10 years. The prognosis is more favourable where the underlying cause of the cirrhosis can be corrected, as in alcohol misuse, haemochromatosis and Wilson's disease.
Laboratory tests give only a rough guide to prognosis in individual patients. Deteriorating liver function, as evidenced by jaundice, ascites or encephalopathy, indicates a poor prognosis unless a treatable cause such as infection is found. Increasing plasma bilirubin, falling plasma albumin or an albumin concentration < 30 g/l, marked hyponatraemia (< 120 mmol/l not due to diuretic therapy) and a prolonged prothrombin time are all bad prognostic signs (see Boxes 18.22 and 18.23). The course of cirrhosis is uncertain, as unforeseen complications such as variceal bleeding may lead to death unexpectedly.
PORTAL HYPERTENSION
Portal hypertension is characterised by prolonged elevation of the portal venous pressure (normally 2-5 mmHg). Patients developing clinical features or complications of portal hypertension usually have portal venous pressures above 12 mmHg.
Aetiology and pathogenesis
page 850

page 851
Portal venous pressure is determined by the portal blood flow and by the portal vascular resistance. Increased vascular resistance is usually the main factor producing portal hypertension, irrespective of its cause, and consequently the causes of portal hypertension are classified in accordance with the main sites of obstruction to blood flow in the portal venous system (see Fig. 18.13 and Box 18.24).


Figure 18.13 Classification of portal hypertension according to site of vascular obstruction.
Extrahepatic portal vein obstruction is frequently the cause of portal hypertension in childhood and adolescence, while cirrhosis causes 90% or more of portal hypertension in adults in Western countries. Schistosomiasis is the most common cause of portal hypertension world-wide but it is infrequent outside endemic areas. Increased portal vascular resistance leads to a gradual reduction in the flow of portal blood to the liver and simultaneously to the development of collateral vessels, allowing portal blood to bypass the liver and enter the systemic circulation directly. Increased portal blood flow may contribute to portal hypertension but is not the dominant factor. Collateral vessel formation is widespread but occurs particularly in the gastrointestinal tract, especially the oesophagus, stomach and rectum, in the anterior abdominal wall, and in the renal, lumbar, ovarian and testicular vasculature. Normally, virtually all the portal blood flows through the liver but, as collateral vessel formation progresses, half or more (and occasionally almost all) of the portal blood flow can be shunted directly to the systemic circulation.
Clinical features
18.24 CAUSES OF PORTAL HYPERTENSION ACCORDING TO SITE OF ABNORMALITY
Extrahepatic post-sinusoidal
Budd-Chiari syndrome
Intrahepatic post-sinusoidal
Veno-occlusive disease
Sinusoidal
Cirrhosis
Cystic liver disease
Partial nodular transformation of the liver
Metastatic malignant disease
Intrahepatic pre-sinusoidal
Schistosomiasis
Sarcoidosis
Congenital hepatic fibrosis
Vinyl chloride
Drugs
Extrahepatic pre-sinusoidal
Portal vein thrombosis due to sepsis (umbilical, portal pyaemia) or procoagulopathy (thrombotic diseases, oral contraceptives, pregnancy, secondary-cirrhosis)
Abdominal trauma, including surgery
Malignant disease of pancreas or liver
Pancreatitis
Congenital


page 851

page 852
The clinical features of portal hypertension result principally from portal venous congestion and from collateral vessel formation. Splenomegaly is a cardinal finding, and a diagnosis of portal hypertension is unlikely when splenomegaly cannot be detected clinically or by ultrasonography. The spleen is rarely enlarged more than 5 cm below the left costal margin in adults, but more marked splenomegaly can occur in childhood and adolescence. Hypersplenism is common and frequently results in thrombocytopenia. Platelet counts are usually around 100 × 109/l; values below 50 × 109/l are rare. Leucopenia occurs occasionally, but anaemia can hardly ever be attributed to hypersplenism. Collateral vessels may be visible on the anterior abdominal wall and occasionally several radiate from the umbilicus to form a caput medusae. Rarely, a large umbilical collateral vessel has a blood flow sufficient to give a venous hum on auscultation (Cruveilhier-Baumgarten syndrome). The most important collateral vessels occur in the oesophagus and stomach, where they can cause severe bleeding. Rectal varices also cause bleeding and are often mistaken for haemorrhoids, which are no more common in portal hypertension than in the general population. Fetor hepaticus results from portosystemic shunting of blood, which allows mercaptans to pass directly to the lungs.
Investigations
Radiological and endoscopic examination of the upper gastrointestinal tract can show varices. This establishes the presence of portal hypertension but not its cause (see Fig. 18.14). Imaging, particularly ultrasonography, can show features of portal hypertension, such as splenomegaly and collateral vessels, and can sometimes indicate the cause, such as liver disease or portal vein thrombosis. Portal venography demonstrates the site and often the cause of portal venous obstruction and is performed prior to surgical intervention. Portal venous pressure measurements are rarely needed but can be used to confirm portal hypertension and to differentiate sinusoidal and pre-sinusoidal forms.
Complications
Gastrointestinal bleeding from varices or from congestive gastropathy is the main complication (see Box 18.25). Hypersplenism is rarely severe enough to be clinically significant and portal hypertension is only one factor contributing to the development of ascites (see p. 855), renal failure (see p. 847) and hepatic encephalopathy (see p. 858).


Figure 18.14 Varices: endoscopic views. A Oesophageal varices at the lower end of the oesophagus. B Gastric varices.
18.25 COMPLICATIONS OF PORTAL HYPERTENSION
Variceal bleeding
Oesophageal, gastric, other (rare)
Congestive gastropathy
Hypersplenism
Ascites
Renal failure
Hepatic encephalopathy


VARICEAL BLEEDING
Variceal bleeding occurs from oesophageal varices that are usually located within 3-5 cm of the oesophago-gastric junction or from gastric varices. The size of the varices, endoscopic variceal features such as red spots and red stripes, high portal pressure and liver failure are all general factors that predispose to bleeding. Drugs capable of causing mucosal erosion, such as salicylates and other non-steroidal anti-inflammatory drugs (NSAIDs), can also precipitate bleeding. Variceal bleeding is often severe, and recurrent bleeding occurs if preventative treatment is not given. Bleeding from varices at other sites is comparatively uncommon but most often occurs from varices in the rectum or intestinal stomas.
Management of acute variceal bleeding
The differential diagnosis and diagnostic approach in patients with acute upper gastrointestinal haemorrhage are detailed on page 764.
page 852

page 853
The priority in acute bleeding from oesophageal varices is to restore the circulation with blood and plasma, not least because shock reduces liver blood flow and causes further deterioration of liver function. Even in patients with known varices, the source of bleeding should always be confirmed by endoscopy because about 20% of such patients are found to be bleeding from some other lesion, especially acute gastric erosions. Several treatments are available to stop acute variceal bleeding and to prevent its recurrence (see Box 18.26). Sclerotherapy and banding are the preferred initial means for treating variceal bleeding.
Reduction of portal venous pressure
Pharmacological reduction of portal pressure is less important than sclerotherapy or banding, is expensive and is not always used. Transjugular intrahepatic portosystemic stent shunts (TIPSS) are increasingly being used for reducing portal pressure (see below).
Pharmacological treatment. Vasopressin constricts the splanchnic arterioles and reduces portal blood flow and hence portal pressure. It is best given by intravenous infusion 0.4 U/min until bleeding stops or for 24 hours, and then 0.2 U/min for a further 24 hours. Vasoconstriction also occurs in other vascular beds and can cause angina, arrhythmia and even myocardial infarction. Glyceryl trinitrate should be given transdermally or intravenously to combat these side-effects. Vasopressin should not be used in patients with ischaemic heart disease. Terlipressin is the current drug of choice because vasopressin is released from it over several hours in amounts sufficient to reduce the portal pressure without producing systemic effects. It is given in a dose of 2 mg i.v. 6-hourly until bleeding stops and then 1 mg 6-hourly for a further 24 hours.
Octreotide, the synthetic form of somatostatin, reduces the portal pressure and can stop variceal bleeding. It has few side-effects and is given in a dose of 50 µg intravenously, followed by an infusion of 50 µg hourly.
TIPSS and shunt surgery. TIPSS, described below, can be used for acute bleeding not responding to sclerotherapy or banding. Emergency portosystemic shunt surgery has a mortality of 50% or more and is now virtually never used for treating active variceal bleeding.
18.26 TREATMENTS TO STOP OESOPHAGEAL VARICEAL BLEEDING AND TO PREVENT RECURRENT BLEEDING
Local measures
Sclerotherapy
Banding
Balloon tamponade
Oesophageal transection

Reduction of portal venous pressure
Somatostatin (octreotide)
Vasopressin
Terlipressin

Prevention of recurrent bleeding
Sclerotherapy/banding
Transjugular intrahepatic portosystemic stent shunt (TIPSS)
Portosystemic shunt surgery (unselective or selective)
Propranolol


Local measures
The measures used to control acute variceal bleeding include sclerotherapy, banding, balloon tamponade and oesophageal transection.
Sclerotherapy or banding. This is the most widely used initial treatment and is undertaken if possible at the time of diagnostic endoscopy. It stops variceal bleeding in 80% of patients and can be repeated if bleeding recurs. Active bleeding at endoscopy may make sclerotherapy difficult; in such cases bleeding should be controlled by balloon tamponade prior to sclerotherapy. Banding can be used to stop acute variceal bleeding but it is less easy to apply than sclerotherapy in this situation (see Fig. 18.15).
Balloon tamponade. This technique employs a Sengstaken-Blakemore tube possessing two balloons which exert pressure in the fundus of the stomach and in the lower oesophagus respectively. Current modifications, such as the Minnesota tube, incorporate sufficient lumens to allow material to be aspirated from the stomach and from the oesophagus above the oesophageal balloon. The tube should be passed through the mouth and its presence in the stomach should be checked by auscultating the upper abdomen while injecting air into the stomach and by radiology. Gentle traction is used to maintain pressure on the varices. Initially, only the gastric balloon should be inflated as this will usually control bleeding. Inflation of the gastric balloon must be stopped if the patient experiences pain because inadvertent inflation in the oesophagus can cause oesophageal rupture. If the oesophageal balloon needs to be used because of continued bleeding, it should be deflated for about 10 minutes every 3 hours to avoid oesophageal mucosal damage. Balloon tamponade will almost always stop oesophageal and gastric fundal variceal bleeding, but only creates time for the use of more definitive therapy.


Figure 18.15 Appearances of oesophageal varices following application of strangulating bands (band ligation, arrow).
page 853

page 854
Oesophageal transection. Transection of the varices can be performed with a stapling gun, although it carries some risk of subsequent oesophageal stenosis, and is normally combined with splenectomy. The operation is used when TIPSS is not available and when bleeding cannot be controlled by the other therapies described. The operative morbidity and mortality are considerable as hepatic failure is normally well established when other interventions have failed to control haemorrhage.
Prevention of recurrent bleeding
Recurrent bleeding is the rule rather than the exception in patients who have previously bled from oesophageal varices, and treatment to prevent this is needed.
EBM
VARICEAL BLEEDING IN PATIENTS WITH CIRRHOSIS-role of secondary prophylaxis
'Following control of active variceal bleeding, varices should be eradicated using endoscopic methods, with band ligation the current method of choice. While TIPSS is more effective than endoscopic treatment in reducing variceal rebleeding, it does not improve survival and is associated with more encephalopathy.'
Jalan R, Hayes PC. UK guidelines on management of variceal haemorrhage in cirrhotic patients. Gut 2000; 6:1-15.
Laine L. Ligation: endoscopic treatment of choice for patients with bleeding esophageal varices? Hepatology 1995; 22:663-665.
Further information: www.bsg.org.uk/guidelines.html

Sclerotherapy
This is the most widely used method for preventing recurrent oesophageal variceal bleeding. Varices are injected with a sclerosing agent as soon as practicable after bleeding, and injections are repeated every 1-2 weeks thereafter until the varices are obliterated. Regular follow-up endoscopy is necessary to allow treatment of any recurrence of varices. The treatment is not free of risk as injections can cause transient chest or abdominal pain, fever, transient dysphagia and occasionally oesophageal perforation. Oesophageal strictures may develop. However, mortality is low even in those with poor liver function, and recurrent bleeding is largely prevented. Prolongation of life has been claimed but this remains to be proven.
Banding
This is a technique in which varices are sucked into an endoscope accessory, allowing them to be occluded with a tight rubber band. The occluded varix subsequently sloughs with variceal obliteration. The technique is applied in the same way as sclerotherapy, is generally more effective, has fewer side-effects and is becoming the treatment of choice.
TIPSS
This is a technique in which a stent is placed between the portal vein and the hepatic vein in the liver to provide a portosystemic shunt to reduce portal pressure (see Fig. 18.16). The procedure is carried out under radiological control via the internal jugular vein; prior patency of the portal vein must be determined angiographically, coagulation deficiencies may require correction with fresh frozen plasma, and antibiotic cover is provided. Successful shunt placement stops and prevents variceal bleeding. Further bleeding necessitates investigation and treatment (e.g. angioplasty) because it is usually associated with shunt narrowing or occlusion. Hepatic encephalopathy may occur following TIPSS and requires that the shunt diameter be reduced. The long-term value of the technique remains to be assessed.


Figure 18.16 Transjugular intrahepatic portosystemic stent shunt (TIPSS). A Radiograph showing placement of TIPSS within the portal vein, allowing blood to flow from the right hepatic vein into the inferior vena cava. Note contrast within the superior mesenteric vein but not the splenic vein, which has collapsed with the reduction in portal pressure. B Explanatory diagram.
page 854

page 855
Portosystemic shunt surgery
This used to be the treatment of choice because it effectively prevented bleeding, provided the shunt remained patent. However, the mortality associated with the procedure was high, especially in patients with poor liver function, and follow-up of patients showed that troublesome hepatic encephalopathy often supervened. Non-selective portacaval shunts can divert the majority of the portal blood away from the liver. This diversion of blood renders patients liable to post-operative liver failure and hepatic encephalopathy. This led to the development of more selective shunts (such as the distal splenorenal (Warren) shunt) to decompress the oesophageal varices and preserve portal blood flow to the liver. Such shunts are associated with less post-operative encephalopathy, but with the passage of time liver portal blood flow falls and later encephalopathy may occur. Furthermore, survival is not prolonged, as death from liver failure occurs. In practice, portosystemic shunts are now reserved for patients in whom other treatments have not been successful and are offered only to those with good liver function.
Propranolol
Propranolol (80-160 mg/day) reduces the portal venous pressure in portal hypertension and has been used to prevent recurrent variceal bleeding; however, it is not widely used in secondary prevention and compliance may be poor.
Primary prophylaxis of initial variceal bleeding
In view of the mortality and morbidity associated with variceal haemorrhage, portosystemic shunts, sclerotherapy and propranolol have all been used to try to prevent initial bleeding from varices. Propranolol in a dose of 80-160 mg daily has given beneficial results and can be used for primary prevention (see EBM panel).
EBM
PRIMARY PREVENTION OF VARICEAL BLEEDING
'Meta-analysis of RCTs of propranolol versus no therapy has demonstrated a 47% reduction in variceal bleeding (p = 0.0001), a reduction of 45% in deaths from bleeding (p = 0.017) and a 22% overall reduction in mortality (p = 0.052).'
Hayes PC, Davies JM, Lewis JA, Bouchier IA. Meta-analysis of value of propranolol in prevention of variceal haemorrhage. Lancet 1990; 336:153-156.
Further information: www.bsg.org.uk/guidelines.html

CONGESTIVE GASTROPATHY
Long-standing portal hypertension causes chronic gastric congestion recognisable at endoscopy as multiple areas of punctate erythema. Similar lesions occur rarely more distally in the gastrointestinal tract. These areas may become eroded, causing bleeding from multiple sites. Acute bleeding can occur, but repeated minor bleeding causing iron-deficiency anaemia is more common. Anaemia may be prevented by oral iron supplements but repeated blood transfusions can become necessary. Reduction of the portal pressure using propranolol 80-160 mg/day is the best initial treatment; if this is ineffective, a TIPSS procedure can be undertaken.
ASCITES
Ascites refers to the accumulation of free fluid in the peritoneal cavity. While cirrhosis is a common cause of ascites, there are many other causes, and these need to be considered even in a patient with chronic liver disease (see Box 18.27).
18.27 CAUSES OF ASCITES
Common causes
Malignant disease
Hepatic
Peritoneal
Cardiac failure
Hepatic cirrhosis

Other causes
Hypoproteinaemia
Nephrotic syndrome
Protein-losing enteropathy
Malnutrition
Hepatic venous occlusion
Budd-Chiari syndrome
Veno-occlusive disease
Pancreatitis
Lymphatic obstruction
Infection
Tuberculosis
Spontaneous bacterial peritonitis
Rare
Meigs' syndrome
Vasculitis
Hypothyroidism
Renal dialysis


Pathogenesis
Liver failure and portal hypertension in cirrhosis cause general sodium and water retention in the body, and localisation of fluid in the peritoneum due to the high venous pressure in the mesenteric circulation. The mechanism of sodium and water retention is unknown, but two general theories have been put forward. One explanation postulates that following the loss of fluid into the peritoneum there is compensatory renal retention of sodium and water ('underfilling theory'), while the other postulates a primary renal retention of sodium and water with eventual overspill of fluid into the peritoneum ('overflow theory'). The most important pathogenic factor is probably splanchnic vasodilatation causing a reduction in effective circulating volume ('vasodilator theory'). This leads to activation of the renin-angiotensin system with secondary aldosteronism, increased sympathetic nervous activity, alteration of atrial natriuretic hormone secretion and altered activity of the kallikrein-kinin system (see Fig. 18.17).
page 855

page 856


Figure 18.17 Pathogenesis of ascites.
Clinical features
Ascites causes abdominal distension with fullness in the flanks, shifting dullness on percussion, and a fluid thrill when the ascites is marked (see Fig. 18.18). These signs do not appear until the ascites volume exceeds a litre even in thin patients, and much larger volumes can be hard to detect in the obese. Associated features of ascites include distortion or eversion of the umbilicus, herniae, abdominal striae, divarication of the recti and, occasionally, meralgia paraesthetica (see p. 1182) and scrotal oedema. Pleural effusions can be found in about 10% of patients, usually on the right side. Most are small and only identified on chest radiographs, but occasionally a massive hydrothorax occurs. Pleural effusions, particularly those on the left side, should not be assumed to be due to the ascites.
Investigations


Figure 18.18 Abdominal swelling in ascites.
18.28 APPEARANCES AND CAUSES OF ASCITES
Cause Appearance
Cirrhosis Clear, straw-coloured or light green
Malignant disease Bloody
Infection Cloudy
Biliary communication Heavy bile staining
Lymphatic obstruction Milky-white (chylous)*

*Milky-white chylomicrons pass into supernatant on centrifugation.
Ultrasonography is the best means of confirming ascites, particularly in the obese and those with small volumes of fluid. Abdominal radiographs can show ascites, but they are insensitive and non-specific. Paracentesis can also be used to confirm the presence of ascites, but is most useful in obtaining ascitic fluid for analysis, if necessary under ultrasonic guidance. The appearance of the ascites may point to the underlying cause (see Box 18.28). The ascites protein concentration and the serum-ascites albumin gradient are used to separate ascites due to transudation from ascites due to exudation. Ascites with protein concentrations below 25 g/l or serum-ascites albumin gradients above 1.5 (transudates) are usually due to cirrhosis. Exudative ascites (ascites protein concentration above 25 g/l or serum-ascites albumin ratio below 1.5) raises the possibility of infection (especially tuberculosis), malignancy, hepatic venous obstruction, pancreatic ascites or, rarely, hypothyroidism. Ascites amylase activity above 1000 U/l identifies pancreatic ascites, and low ascites glucose concentrations suggest malignant disease or tuberculosis. Cytological examination can reveal malignant cells, and polymorphonuclear leucocyte counts above 250/mm3 strongly suggest infection (spontaneous bacterial peritonitis). Laparoscopy can be valuable in detecting peritoneal disease.
Diagnosis
page 856

page 857
In the great majority of patients ascites is caused by malignant disease, cirrhosis or cardiac failure; however, the presence of cirrhosis does not necessarily mean that this is the cause of the ascites. This is particularly so when liver function is good or when there is no evidence of portal hypertension, and in such patients a complication of cirrhosis, such as hepatocellular carcinoma or portal vein thrombosis, should be sought or an independent cause of ascites considered.
Management
Successful treatment of ascites relieves discomfort but does not prolong life, and if over-vigorous can produce serious disorders of fluid and electrolyte balance and precipitate hepatic encephalopathy (see p. 858). Conventional treatment aims to reduce body sodium and water by restricting intake, promoting urine output and, if necessary, removing ascites directly. The rate of loss of sodium and water is most easily measured by regular weighing. No more than 900 ml can be mobilised from the peritoneum daily so the body weight should not fall by more than 1 kg daily if fluid depletion in the rest of the body is to be avoided.
Sodium and water restriction
Restriction of dietary sodium intake is essential to achieving negative sodium balance in patients with ascites. Restriction to 80 mmol/day ('no added salt diet') may be adequate, but restriction to 40 mmol/day is necessary in more severe ascites and this requires close dietetic supervision. Drugs containing relatively large amounts of sodium and those promoting sodium retention such as non-steroidal analgesic agents must be avoided (see Boxes 18.29 and 18.30). Restriction of water intake to 0.5-1.0 litre/day is necessary only if the plasma sodium falls below 125 mmol/l. A few patients can be managed satisfactorily on this treatment alone.
Diuretic drugs
18.29 SOME DRUGS CONTAINING RELATIVELY LARGE AMOUNTS OF SODIUM OR CAUSING SODIUM RETENTION
High sodium content
Antacids
Alginates
Antibiotics (see Box 18.30)
Aspirin
Phenytoin
Sodium valproate
Effervescent preparations
e.g. Aspirin
Calcium
Paracetamol
Sodium retention
Carbenoxolone
Corticosteroids
Diazoxide
Metoclopramide
NSAIDs
Oestrogens


18.30 SOME ANTIBIOTICS WITH A HIGH SODIUM CONTENT
Note Significant increases of sodium intake due to antibacterial therapy usually occur only during parenteral therapy when large (gram) amounts of drug are used. Maximum parenteral doses of the above drugs increase daily sodium intake by about 20-50 mmol. Drugs that do not themselves contain sodium increase sodium intake if they are infused in sodium-containing fluids. Oral antibacterial therapy rarely increases sodium intake but can occur with fucidin and para-aminosalicylate.
Amoxicillin
Ampicillin
Benzylpenicillin
Cefotaxime
Cefoxitin
Cefradine
Ceftazidime
Cefuroxime
Chloramphenicol
Flucloxacillin
Piperacillin
Ticarcillin


Most patients require diuretic drugs in addition to sodium restriction. Spironolactone (100-400 mg/day) is the drug of choice for long-term therapy because it is a powerful aldosterone antagonist, but it can cause painful gynaecomastia and hyperkalaemia. Some patients will also require powerful loop diuretics (e.g. furosemide (frusemide)), though these can cause fluid, electrolyte and renal function disorders. Diuresis is improved if patients are rested in bed while the diuretics are acting, perhaps because renal blood flow increases in the horizontal position.
Paracentesis
Paracentesis of 3-5 litres over 1-2 hours has always been used for immediate relief of cardiorespiratory distress due to gross ascites. Large-volume paracentesis alone has been regarded as a hazardous treatment; however, paracentesis to dryness or the removal of 3-5 litres daily is safe, provided the circulation is supported by giving a colloid such as human albumin solutions (6-8 g per litre of ascites removed) or another plasma expander. Total paracentesis can therefore be used as an initial therapy or when other treatments fail.
LeVeen shunt
The LeVeen shunt is a long tube with a non-return valve running subcutaneously from the peritoneum to the internal jugular vein in the neck, which allows ascitic fluid to pass directly into the systemic circulation. It is effective in ascites resistant to conventional treatment, but complications including infection, superior vena caval thrombosis, pulmonary oedema, bleeding from oesophageal varices and disseminated intravascular coagulopathy limit its use.
TIPSS
TIPSS (see p. 854) can relieve resistant ascites but does not prolong life. It can be used where liver function is reasonable or in patients awaiting liver transplantation. It should not be used in the terminally ill.
Prognosis
Ascites is a serious development in cirrhosis as only 10-20% of patients survive 5 years from its appearance. The outlook is not universally poor, however, and is best in those with well-maintained liver function and where the response to therapy is good. The prognosis is also better where a treatable cause for the underlying cirrhosis is present (see p. 850) or where a precipitating cause for ascites, such as excess salt intake, is found.
page 857

page 858
Complications
Ascites may be complicated by infections which are spontaneous (see below) or, more commonly, precipitated by invasive investigations or treatment, such as upper gastrointestinal endoscopy and injection sclerotherapy. Ascites can also be complicated by renal failure. Both of these complications have adverse prognostic significance and may prompt referral for transplantation.
SPONTANEOUS BACTERIAL PERITONITIS (SBP)
Patients with cirrhosis are very susceptible to infection of ascitic fluid as part of their general susceptibility to infection. SBP usually presents suddenly with abdominal pain, rebound tenderness, absent bowel sounds and fever in a patient with obvious features of cirrhosis and ascites. Abdominal signs are mild or absent in about one-third of patients, and in these patients hepatic encephalopathy and fever are the main features. Diagnostic paracentesis may show cloudy fluid, and an ascites neutrophil count above 250/mm3 almost invariably indicates infection. The source of infection cannot usually be determined, but most organisms isolated from ascitic fluid or blood cultures are of enteric origin and Escherichia coli is the organism most frequently isolated. Ascites culture in blood culture bottles gives the highest yield of organisms. SBP needs to be differentiated from other intra-abdominal emergencies, and the finding of multiple organisms on culture should arouse suspicion of a perforated viscus.
Treatment is started immediately with broad-spectrum antibiotics such as cefotaxime. Recurrence of SBP is common and may be reduced by norfloxacin (400 mg daily). Infections of other fluid collections that may occur in patients with cirrhosis, such as pleural and pericardial effusions, have been reported.
EBM
SPONTANEOUS BACTERIAL PERITONITIS (SBP)-treatment and prophylaxis
'Empirical antibiotic therapy improves outcome in patients with an ascitic fluid neutrophil count of greater than 250/mm3. Cefotaxime (> 2 g/12 hrs, 5 days' minimum duration), other cephalosporins or amoxicillin-clavulanic acid at standard doses are the recommended antibiotics. In patients with a previous episode of SBP norfloxacin 400 mg/day can prevent recurrence in patients with continued ascites.'
Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000; 32:142-153.
Bernard B, Grange JD, Khac EN, et al. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. Hepatology 1999; 29:1655-1661.


HEPATIC (PORTOSYSTEMIC) ENCEPHALOPATHY
Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver disease. It occurs most often in patients with cirrhosis but also occurs in acute hepatic failure.
Aetiology
Hepatic encephalopathy is thought to be due to a biochemical disturbance of brain function because it is reversible and does not cause marked pathological changes in the brain. Liver failure and portosystemic shunting of blood are two important factors underlying hepatic encephalopathy and the balance between these varies in different patients. Some degree of liver failure is a constant factor as portosystemic shunting of blood hardly ever causes encephalopathy if liver function is normal. Little is known of the biochemical 'neurotoxins' causing the encephalopathy, but they are thought to be mainly nitrogenous substances produced in the gut, at least in part by bacterial action, which are normally metabolised by the healthy liver so that they do not enter the systemic circulation. Ammonia has long been considered an important factor but much interest has centred recently on gamma-aminobutyric acid. Additional putative culprit substances include other false neurotransmitters such as octopamine, amino acids, mercaptans and fatty acids. Some factors appear to precipitate hepatic encephalopathy by increasing the availability of these substances; in addition, the brain in cirrhosis may be sensitised to other factors such as drugs that are able to precipitate hepatic encephalopathy (see Box 18.31). Disruption of the function of the blood-brain barrier is a feature of acute hepatic failure and may lead to cerebral oedema.
18.31 FACTORS PRECIPITATING HEPATIC ENCEPHALOPATHY
Uraemia
Spontaneous, diuretic-induced
Drugs
Sedatives, antidepressants, hypnotics
Gastrointestinal bleeding
Excess dietary protein
Constipation
Paracentesis (volumes > 3-5 litres)
Hypokalaemia
Infection
Trauma (including surgery)
Portosystemic shunts
Surgical, spontaneous (large)


Clinical features
page 858

page 859


Figure 18.19 Number connection test used in assessing encephalopathy. These 25 numbered circles can normally be joined together within 30 seconds. Serial observations may provide useful information as long as the position of the numbers is varied to avoid the patient learning their pattern.
These include changes of intellect, personality, emotions and consciousness, with or without neurological signs. When an episode develops acutely a precipitating factor may be found (see Box 18.31). The earliest features are very mild but, as the condition becomes more severe, apathy, inability to concentrate, confusion, disorientation, drowsiness, slurring of speech and eventually coma develop. Convulsions sometimes occur. Examination usually shows a flapping tremor (asterixis, see p. 833), inability to perform simple mental arithmetic tasks (see Fig. 18.19) or draw objects such as a star (constructional apraxia, see p. 833), and, as the condition progresses, hyper-reflexia and bilateral extensor plantar responses. Hepatic encephalopathy rarely causes focal neurological signs, and if these are present, other causes must be sought. Fetor hepaticus, a sweet musty odour to the breath, is usually present but is more a sign of liver failure and portosystemic shunting than of hepatic encephalopathy. Rarely, chronic hepatic encephalopathy (hepatocerebral degeneration) gives rise to variable combinations of cerebellar dysfunction, Parkinsonian syndromes, spastic paraplegia and dementia.
Investigations
The diagnosis can usually be made clinically, but when doubt exists an electroencephalogram (EEG) shows diffuse slowing of the normal alpha waves with eventual development of delta waves. The arterial ammonia is usually increased in patients with hepatic encephalopathy. However, increased concentrations can occur in the absence of clinical encephalopathy so this investigation is of little or no diagnostic value. Other clinical conditions that may be confused with hepatic encephalopathy are listed in Box 18.32.
18.32 DIFFERENTIAL DIAGNOSIS OF HEPATIC ENCEPHALOPATHY
Subdural haematoma
Drug or alcohol intoxication
Delirium tremens
Wernicke's encephalopathy
Primary psychiatric disorders
Hypoglycaemia
Neurological Wilson's disease


Management
EBM
TREATMENT OF HEPATIC ENCEPHALOPATHY
'Studies in small numbers of patients have shown lactulose to be of benefit in both acute and chronic hepatic encephalopathy but large RCTs are lacking.'
'Neomycin treatment is not significantly better than placebo in treating acute hepatic encephalopathy.'
'Current evidence does not support the use of branched-chain amino acid solutions in either acute or chronic hepatic encephalopathy.'
Simmons F, Goldstein H, Boyle JD. A controlled clinical trial of lactulose in hepatic encephalopathy. Gastroenterology 1970; 59:827-832.
Elkington SG, Floch MH, Conn HO. Lactulose in the treatment of chronic portal-systemic encephalopathy. A double-blind clinical trial. N Engl J Med 1969; 281:408-412.
Strauss E, Tramote R, Silva EP, et al. Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 1992; 39:542-545.
Morgan MY. Branched chain amino acids in the management of chronic liver disease. Facts and fantasies. J Hepatol 1990; 11:133-141.


Episodes of encephalopathy are common in cirrhosis and are usually readily reversible until the terminal stages occur. The principles of management are to treat or remove precipitating causes (see Box 18.31), to reduce protein intake, and to suppress production of neurotoxins by bacteria in the bowel. Dietary protein is reduced to less than 20 g/day, and glucose (300 g/day) is given orally or parenterally in severe cases. As encephalopathy improves, dietary protein is increased by 10-20 g/day every 48 hours to an intake of 40-60 g/day, which is usually the limit in cirrhotic patients. Lactulose (15-30 ml 8-hourly) is a disaccharide which is taken orally and reaches the colon intact to be metabolised by colonic bacteria. The dose is increased gradually until the bowels are moving twice daily. It produces an osmotic laxative effect, reduces the pH of the colonic content, thereby limiting colonic ammonia absorption, and promotes the incorporation of nitrogen into bacteria (see EBM panel). Lactitol is a rather more palatable alternative to lactulose, with a less explosive action on bowel function. Neomycin (1-4 g 4-6-hourly) is an antibiotic which acts by reducing the bacterial content of the bowel. It can be used in addition or as an alternative to lactulose if diarrhoea becomes troublesome. Neomycin is poorly absorbed from the bowel but sufficient gains access to the body to contraindicate its use when uraemia is present. It is less desirable than lactulose for long-term use; ototoxicity is the main deleterious effect. Chronic or refractory hepatic encephalopathy is one of the main indications for liver transplantation.
HEPATOPULMONARY SYNDROME
Many patients with cirrhosis are hypoxaemic due to a variety of factors including pulmonary hypertension, pleural effusions and the hepatopulmonary syndrome. The latter is characterised by resistant hypoxaemia and intrapulmonary vascular dilatation. Clinical features include digital clubbing, cyanosis, spider naevi, and a characteristic reduction in arterial oxygen saturation on standing. The hepatopulmonary syndrome is now considered an indication for liver transplantation.
page 859

page 860
HEPATORENAL FAILURE
Renal failure consequent on liver failure can occur in cirrhosis. The kidneys themselves are intrinsically normal and renal failure is thought to result from altered systemic blood flow including diminished renal blood flow. The condition is called 'functional renal failure of cirrhosis' or the 'hepatorenal syndrome'. It occurs in advanced cirrhosis, almost always with ascites, and is characterised by the absence of proteinuria or abnormal urinary sediment, a urine sodium excretion below 10 mmol/day and a urine/plasma osmolality ratio greater than 1.5. It is important to exclude hypovolaemia by measuring the central venous pressure and giving colloidal solutions such as human albumin solutions to maintain a pressure of 0-5 cm of water. The treatment of hepatorenal syndrome includes giving dopamine (1-2 µg/kg/min) to maximise renal blood flow, and thereafter diuretics. Uraemia and endogenous protein breakdown should be limited by restricting protein intake to 20 g/day and giving 300 g of carbohydrate daily. Recovery depends ultimately on improvement of liver function but in chronic liver disease this seldom occurs. Accordingly, the prognosis is very poor unless liver transplantation can be undertaken.

pages 842 - 860


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC018018


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com




Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease > SPECIFIC CAUSES OF PARENCHYMAL LIVER DISEASE
SPECIFIC CAUSES OF PARENCHYMAL LIVER DISEASE
VIRAL HEPATITIS
18.33 CAUSES OF VIRAL HEPATITIS




Integration link: Main viruses causing hepatitis in humans

Taken from Medical Microbiology 3e




Hepatitis A virus (HAV)
Hepatitis B virus (HBV)
Hepatitis C virus (HCV)
Hepatitis D virus (HDV)
Hepatitis E virus (HEV)
Non-A-E viral hepatitis
Cytomegalovirus
Epstein-Barr virus
Herpes simplex virus
Yellow fever virus


18.34 FEATURES OF THE MAIN HEPATITIS VIRUSES
Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E
Virus
Group Enterovirus Hepadna Flavivirus Incomplete virus Calicivirus
Nucleic acid RNA DNA RNA RNA RNA
Size (diameter) 27 nm 42 nm 30-38 nm 35 nm 27 nm
Incubation (weeks) 2-4 4-20 2-26 6-9 3-8
Spread
Faeces Yes No No No Yes
Blood Uncommon Yes Yes Yes No
Saliva Yes Yes Yes ? ?
Sexual Uncommon Yes Uncommon Yes ?
Vertical No Yes Uncommon Yes No
Chronic infection No Yes Yes Yes No
Prevention
Active Vaccine Vaccine No Prevented by No
Passive Immune serum globulin Hyperimmune serum globulin No hepatitis B vaccination No


Note All body fluids are potentially infectious, though some (e.g. urine) are less infectious.
Viral hepatitis is almost always caused by one of the specific hepatitis viruses; hepatitis due to other viruses accounts for only about 1-2% of cases (see Box 18.33). All these viruses give rise to illnesses which are similar in their clinical and pathological features and which are frequently anicteric or asymptomatic. The features of the major hepatitis viruses are summarised in Box 18.34.
Clinical features
Prodromal symptoms usually precede the development of jaundice by a few days to 2 weeks. They are the common manifestations of an acute infectious disease and include chills, headache and malaise. Gastrointestinal symptoms may be prominent; anorexia and distaste for cigarettes are frequent, and nausea, vomiting and diarrhoea may follow. A steady upper abdominal pain, occasionally severe, occurs as a result of stretching of the peritoneum over the enlarged liver. Initially, physical signs are scanty; the liver is usually tender though not readily palpable, enlarged cervical lymph nodes may be found, and splenomegaly may occur, particularly in children. Patients with HBV infection often have arthralgia during the prodrome, and occasionally a 'serum sickness syndrome' with skin rashes (including urticaria) and polyarthritis occurs.
page 860

page 861
Dark urine and a yellow tint to the sclerae herald the onset of jaundice. As obstruction to the biliary canaliculi develops, the jaundice deepens, the stools become paler, the urine darker and the liver more easily palpable. At this time the appetite often improves and gastrointestinal symptoms diminish in intensity. Thereafter the jaundice recedes, the stools and urine regain their normal colour, the liver enlargement regresses, and in the course of 3-6 weeks the majority of patients recover. Mild illnesses may run an anicteric course recognised only because of known contact with a definite case or by the association of vague gastrointestinal complaints or malaise with bilirubinuria and biochemical evidence of hepatic dysfunction.
Investigations
A plasma aminotransferase activity exceeding 400 U/l, even before jaundice develops, is the most striking abnormality. The plasma bilirubin reflects the severity of the jaundice. The alkaline phosphatase activity rarely exceeds 250 U/l unless marked cholestasis develops, and the albumin concentration is normal. Prolongation of the prothrombin time is a reliable indication of severe liver damage. Bilirubinuria is an early finding, occurring in the prodromal phase and usually continuing into the convalescent period. Mild proteinuria may be present. The white cell count is normal or low in uncomplicated cases, sometimes with a relative lymphocytosis; this is of some value in differentiation from Weil's disease (see p. 20). Serological tests can identify HAV, HBV, HEV, cytomegalovirus and Epstein-Barr infection but are unreliable in acute HCV infection. Differential diagnosis is discussed on page 838.
Complications
18.35 COMPLICATIONS OF ACUTE VIRAL HEPATITIS
Acute hepatic failure
Relapsing hepatitis
Biochemical
Clinical
Cholestatic hepatitis
Post-hepatitis syndrome
Hyperbilirubinaemia (Gilbert's syndrome)
Aplastic anaemia
Connective tissue disease
Renal failure
Henoch-Schönlein purpura
Papular acrodermatitis
Chronic hepatitis
Cirrhosis (hepatitis B, C)
Hepatocellular carcinoma


While many complications of acute viral hepatitis are recognised (see Box 18.35), in practice serious complications are uncommon. Fatalities are rare and are usually attributable to acute hepatic failure (see p. 845). The return of symptoms and signs of acute hepatitis during recovery is characteristic of relapsing hepatitis and occurs in 5-15% of patients. Asymptomatic 'biochemical' relapses with increases of plasma aminotransferase activity are even more common. Relapsing hepatitis resolves spontaneously and does not imply a worse prognosis. Cholestasis can develop at any stage during the course of the illness, causing more severe jaundice of a clinically and biochemically obstructive type. Liver biopsy shows the features of hepatitis with prominent cholestasis and no evidence of chronic liver damage. This cholestatic illness may continue for many months; however, the prognosis is good.
Debility for 2-3 months is common following clinical and biochemical recovery. Sometimes, particularly in anxious patients, there may be prolonged malaise, anorexia, nausea and right hypochondrial discomfort without clinical or biochemical evidence of liver disease. This phenomenon is known as the post-hepatitis syndrome.
Chronic HBV infection, with or without HDV superinfection, can cause chronic hepatitis and cirrhosis. Chronic HCV infection can also cause chronic hepatitis and cirrhosis. These chronic viral infections also predispose to hepatocellular carcinoma. Unconjugated hyperbilirubinaemia is sometimes found after acute viral hepatitis. Most instances are probably due to pre-existing Gilbert's syndrome.
Systemic complications are rare but include aplastic anaemia. This seems most common after non-A-E infection and may not become apparent for up to a year after the hepatic illness. Other complications are mostly related to HBV and HCV infection and include connective tissue disease, particularly polyarteritis nodosa (see p. 1042), and renal damage such as glomerulonephritis (see p. 612). Henoch-Schönlein purpura and papular acrodermatitis have been reported in children.
General management
Only the more severely affected patients require care in hospital, principally to allow early detection of developing acute hepatic failure. The post-hepatitis syndrome is treated by reassurance. Specific treatments are discussed below for the different viruses.
Diet
A nutritious diet containing 2000-3000 kcal daily is given. This is often not tolerated initially owing to anorexia and nausea, in which case a light diet supplemented by fruit drinks and glucose is usually acceptable. The content of the diet is dictated largely by the patient's wishes; however, a good protein intake should be encouraged. If vomiting is severe, intravenous fluid and glucose may be required.
Drugs
Drugs should be avoided if possible, especially in severe hepatitis, because many are metabolised in the liver. This applies especially to sedative and hypnotic agents. Alcohol must be avoided during the illness but can be taken once clinical and biochemical recovery have occurred. Oral contraceptives may be resumed after clinical and biochemical recovery.
Surgery
Surgery during acute viral hepatitis carries a significant risk of post-operative liver failure. Only life-saving operations should be carried out.
Liver transplantation
Liver transplantation may be required for acute or chronic liver failure due to hepatitis viruses.
page 861

page 862
Prognosis
This varies depending on the cause of the hepatitis (see below). The overall mortality of acute viral hepatitis is about 0.5% in otherwise well patients under 40 years of age, but mortality reaches about 3% in patients over 60 years and may be much higher in patients with other serious diseases, such as chronic liver disease, carcinoma or lymphoma.
VIROLOGY
The hepatitis viruses (A-E) all cause primarily hepatic illness in humans but otherwise are quite distinct and belong to separate virus groups.
Hepatitis A
The hepatitis A virus (HAV) belongs to the picornavirus group of enteroviruses and, although it can be cultured, this is only done for research purposes. HAV is highly infectious and is spread by the faecal-oral route by persons incubating or suffering from the disease. Infected persons excrete viruses in the faeces for about 2-3 weeks before the onset of the illness and for up to 2 weeks thereafter. Children are most commonly affected and conditions of overcrowding and poor sanitation facilitate spread. In occasional outbreaks water, milk and shellfish have been the vehicles of transmission. Though faeces are the usual source, a transient viraemia in the incubation period occasionally allows infection to be spread by blood and by homosexual activity, especially in men. A chronic carrier state, analogous to that for hepatitis B virus, does not occur.
Investigations
Only one HAV antigen has been found; individuals infected with HAV make an antibody to this antigen (anti-HAV). Anti-HAV is important in diagnosis as HAV is only present in the blood transiently during the incubation period. Excretion in the stools occurs for only 7-14 days after the onset of the clinical illness and the virus cannot be grown readily. Anti-HAV of IgM type, indicating a primary immune response, is already present in the blood at the onset of the clinical illness and is diagnostic of an acute HAV infection. Titres of this antibody fall to low levels within about 3 months of recovery. Anti-HAV of IgG type is of no diagnostic value as HAV infection is common and this antibody persists for years after infection, but it can be used to measure the prevalence of HAV infection. Its presence indicates immunity to HAV.
Prevention
Infection in the community is best prevented by improving social conditions, especially overcrowding and poor sanitation. Individuals can be given substantial protection from infection by active immunisation with an inactivated virus vaccine (Havrix). Immunisation should be considered for individuals with chronic hepatitis B or C infections. Immediate protection can be provided by immune serum globulin if this is given soon after exposure to the virus. This can be considered for those at particular risk such as close contacts, the elderly, those with other major disease and perhaps pregnant women. Immune serum globulin can be effective in an outbreak of hepatitis, in a school or nursery, as injection of those at risk prevents secondary spread to families. Persons travelling to endemic areas are best protected by vaccination, but where time is limited vaccine and immune serum globulin can be injected in separate sites to provide immediate and longer-term protection. The protective effect of immune serum globulin is attributed to its anti-HAV content; those with anti-HAV in the blood are protected naturally.
Prognosis
Acute hepatic failure is rare in HAV infection and chronic infection does not occur. However, HAV infection in patients with chronic hepatitis B or C may cause serious or life-threatening disease.
Hepatitis B


Figure 18.20 Schematic diagram of hepatitis B virus. Hepatitis B surface antigen (HBsAg) is a protein which makes up part of the viral envelope; hepatitis B core antigen (HBcAg) is a protein which makes up the capsid or core part of the virus (found in the liver but not in blood); hepatitis B e antigen (HBeAg) is part of the HBcAg which can be found in the blood and indicates infectivity.
page 862

page 863
The hepatitis B virus (HBV) is the only hepadna virus causing infection in humans. It cannot yet be grown but can be transmitted to certain primates, such as the chimpanzee, in which it replicates. It comprises a capsule and a core containing DNA and a DNA polymerase enzyme (see Fig. 18.20). The virus, known as Dane particles, and an excess of its capsular material, hepatitis B surface antigen (HBsAg), circulate in the blood. Humans are the only source of infection. Individuals incubating or suffering from acute hepatitis are highly infectious for at least as long as the HBsAg is in the blood. Patients with chronic infections may be asymptomatic or have chronic liver failure. These individuals are most infectious when markers of continuing viral replication such as HBeAg, HBV-DNA or DNA polymerase are present in the blood, and are least infectious when these are absent and only anti-HBe is present. Chronic hepatitis B affects about 300 million people around the world; infection is associated with cirrhosis and primary hepatocellular carcinoma. Chronic carrier rates of the virus following infection vary from 10-20% in Asia, Africa, the Middle East and the Pacific Islands, where most infections are acquired in infancy, to 2% in Europe and North America.
Blood is the main source of infection; spread may follow transfusion of infected blood or blood products, or result from injections with contaminated needles, a mode of spread most common among parenteral drug misusers who share needles or other injecting paraphernalia. Blood and blood products used for transfusion are no longer a major source of infection, provided that donor blood is tested for the virus, and less than 10% of all post-transfusion hepatitis is now attributable to HBV. However, only products such as albumin solutions and gamma-globulin which are pasteurised are wholly free of risk. Tattooing or acupuncture can also spread this disease if inadequately sterilised needles are used.
HBV can also cause sporadic infections which cannot be attributed to parenteral modes of spread. The means of non-parenteral transmission are uncertain, but the discovery of HBsAg or HBV-DNA in body fluids such as saliva, urine, semen and vaginal secretions suggests many mechanisms. Close personal contact seems necessary for transmission, and sexual intercourse, especially in male homosexuals, is an important route of infection. The virus may also be spread vertically from mother to child in the immediate perinatal period; this represents the chief source of infection globally.
Investigations
HBV contains several antigens to which infected persons can make immune responses (see Fig. 18.21); these antigens and their antibodies are important in identifying HBV infection (see Box 18.36).


Figure 18.21 Serological responses to hepatitis B virus infection. (HBsAg = hepatitis B surface antigen; anti-HBs = antibody to HBsAg; HBeAg = hepatitis B e antigen; anti-HBe = antibody to HBeAg; anti-HBc = antibody to hepatitis B core antigen)
In acute infection the hepatitis B surface antigen (HBsAg) is a reliable marker of HBV infection, and a negative test for HBsAg makes HBV infection very unlikely but not impossible (see Fig. 18.21). HBsAg appears in the blood late in the incubation period and before the prodromal phase of acute type B hepatitis; it may be present for only a few days, disappearing even before jaundice has developed, but usually lasts for 3-4 weeks and can persist for up to 5 months. Antibody to HBsAg (anti-HBs) usually appears after about 3-6 months and persists for many years or perhaps permanently. Anti-HBs implies either a previous infection, in which case anti-HBc (see below) is usually also present, or previous vaccination if anti-HBc is not present. The hepatitis B core antigen (HBcAg) is not found in the blood, but antibody to it (anti-HBc) appears early in the illness and rapidly reaches a high titre which then subsides gradually and persists. Anti-HBc is initially of IgM type with IgG antibody appearing later. Anti-HBc (IgM) can sometimes reveal an acute HBV infection when the HBsAg has disappeared and before anti-HBs has developed (see Fig. 18.21 and Box 18.36). The hepatitis Be antigen (HBeAg) appears only transiently at the outset of the illness and is followed by the production of antibody (anti-HBe). The HBeAg reflects active replication of the virus in the liver.
Chronic HBV infection (see p. 864) is marked by the presence of HBsAg and anti-HBc (IgG) in the blood. Rarely, anti-HBc (IgG) alone is the sole evidence of chronic infection. Usually, HBeAg or anti-HBe is also present; HBeAg indicates continued active replication of the virus in the liver while anti-HBe implies that replication is occurring at a much lower level or that HBV-DNA has become integrated into host hepatocyte DNA. Polymerase chain reactions (PCR) can show HBV-DNA in the blood, implying that viral replication is occurring. This is rarely needed for diagnosis but can be useful in selecting for, and measuring response to, therapy. Some rare mutant forms of the virus cannot synthesise the 'e' antigen and HBV-DNA is necessary for their detection.
18.36 INTERPRETATION OF MAIN INVESTIGATIONS USED IN THE SEROLOGICAL DIAGNOSIS OF HEPATITIS B VIRUS INFECTION
Anti-HBc
Interpretation HBsAg IgM IgG Anti-HBs
Incubation period + + - -
Acute hepatitis
Early + + - -
Established + + + -
Established (occasional) - + + -
Convalescence
(3-6 months) - ± + ±
(6-9 months) - - + +
Post-infection
> 1 year - - + +
Uncertain - - + -
Chronic infection
Usual + - + -
Occasional - - + -
Immunisation without infection - - - +


+ = positive; - = negative; ± = present at low titre or absent.
page 863

page 864
Management
Treatment of acute hepatitis B is supportive with close monitoring for acute liver failure. The role of lamivudine is currently unclear. Treatment of chronic hepatitis B is limited, with interferon and lamivudine being licensed drugs. Interferon is most effective in patients with high serum transaminase concentrations and active hepatitis on biopsy, who have not acquired infection at birth, and in those who are HIV-negative. Treatment consists of 5 MU daily or 10 MU three times per week for 16 weeks. Side-effects include influenza-like symptoms (fever and myalgia), depression, neutropenia, thrombocytopenia and thyroid abnormalities. Sustained loss of markers of viral replication (HBeAg and HBV-DNA) leads to biochemical, clinical and histological remission. A response to interferon is characterised by an increase in serum aminotransferases after 6-8 weeks of therapy. Great care is necessary, therefore, in treating patients with cirrhosis as liver failure may be induced. Long-term follow-up studies are scanty but indicate a significant improvement in survival among responders. Individuals with pre-core mutant virus, who lack HBeAg, respond poorly. Other unfavourable prognostic markers include high pre-treatment levels of HBV-DNA, male gender, cirrhosis on liver histology and origin in the Far East.
A number of anti-HBV nucleoside drugs are currently under evaluation; all these agents are inhibitors of HBV-DNA polymerase. The most promising at present is lamivudine which is now licensed and is used in a daily dose of 100 mg for 1 year. It has a low incidence of side-effects and causes complete suppression of serum HBV-DNA in 93-100% of patients, with significant improvements in liver histology. Seroconversion from HBeAg to anti-HBeAg is approximately 17% compared with 8% in controls, and this figure rises if therapy is prolonged. However, HBV replication recurs in many patients when treatment is stopped. Prolonged use leads to the emergence of a lamivudine-resistant strain of virus which is rapidly replaced by wild-type when treatment is withdrawn. There is evidence that lamivudine therapy may reduce or even reverse fibrosis.
EBM
CHRONIC HEPATITIS B INFECTION-role of antiviral therapy
'A meta-analysis of over 15 RCTs of interferon-alpha treatment of patients with chronic hepatitis B infection showed a significant response in the treated patients: HBeAg loss among 33% of those treated, compared with 12% of controls; HBV-DNA loss among 37% of those treated compared with 17% of controls. Randomised trials of lamivudine (100 mg/day for 52 weeks) showed significant response rates in both American and Chinese patients. An RCT of interferon and lamivudine therapy showed no additional benefit over interferon therapy alone.'
Wong DK, Cheung AM, O'Rourke K, et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993; 119:312-323.
Lai CL, Chien RN, Leung NW, et al. A one-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998; 339:61-68.
Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999; 341:1256-1263.


18.37 AT-RISK GROUPS MERITING HEPATITIS B VACCINATION IN LOW ENDEMIC AREAS
Parenteral drug users
Homosexuals (male)
Close contacts of infected individuals
Newborn of infected mothers
Regular sexual partners

Patients on chronic haemodialysis
Medical/nursing personnel
Dentists
Surgeons/obstetricians
Accident and emergency departments
Intensive care
Liver units
Endoscopy units
Oncology units

Laboratory staff handling blood

Prevention
A recombinant hepatitis B vaccine containing HBsAg is available (Engerix) and is capable of producing active immunisation in 95% of normal individuals. The vaccine gives a high degree of protection and should be used particularly in those at special risk of infection who are not already immune, as evidenced by anti-HBs in the blood (see Box 18.37). The vaccine is ineffective in those already infected by HBV. Type B hepatitis can be prevented or minimised by the intramuscular injection of hyperimmune serum globulin prepared from blood containing anti-HBs. This should be given within 24 hours, or at most a week, of exposure to infected blood in circumstances likely to cause infection; these include accidental needle puncture, gross personal contamination with infected blood, oral ingestion or contamination of mucous membranes, or exposure to infected blood in the presence of cuts and grazes. Vaccine can be given together with hyperimmune globulin (active-passive immunisation).
Prognosis
Full recovery occurs in 90-95% of adults following acute HBV infection. The remaining 5-10% develop a chronic infection which usually continues for life, although later recovery occurs occasionally. Infection passing from mother to child at birth leads to chronic infection in the child in 95% of cases and recovery is rare. Chronic infection is also common in immunodeficient individuals such as those with Down's syndrome or human immunodeficiency virus (HIV) infection. Recovery from acute HBV infection occurs within 6 months and is characterised by the appearance of antibody to viral antigens. Persistence of HBeAg beyond this time indicates chronic infection. Combined HBV and HDV infection causes more aggressive disease. Most patients with chronic hepatitis B are asymptomatic and develop complications such as cirrhosis and hepatocellular carcinoma only after many years. Cirrhosis develops in 15-20% of patients with chronic HBV, over 5-20 years. This proportion is higher in those infected in childhood.




Integration link: Hepatitis B - serum antigens

Taken from Medical Microbiology 3e




Hepatitis C
page 864

page 865


Figure 18.22 Schematic diagram of hepatitis C virus: RNA coding regions. (C = core protein; E = envelope proteins; NS = non-structural proteins)
The hepatitis C virus (HCV) is an RNA-containing flavivirus which cannot yet be grown but which can infect primates (see Fig. 18.22). Humans seem to be the sole source of infection, and inoculation with blood or blood products is the best-recognised mode of transmission. HCV caused over 90% of post-transfusion hepatitis before serological tests allowed the screening of blood donors, and accounted for the high incidence of chronic hepatitis in patients with haemophilia. Screening of blood donors and heat treatment of coagulation factor concentrates should prevent infection in future. Parenteral drug users continue to be at high risk of HCV infection. Sporadic HCV infection also occurs but the modes of transmission are unknown. Sexual and vertical spread may occur but are less common than in HBV infection. Chronic infection occurs in about 70-80% of patients and this is usually life-long. Most never suffer an acute illness. Patients with chronic infection are often asymptomatic or complain of mild fatigue. Extrahepatic manifestations include cryoglobulinaemia, vasculitis, arthritis and glomerulonephritis. Without treatment life-long preventative measures are required to limit infection of other individuals.
Investigations
HCV contains several antigens giving rise to antibodies in infected individuals and these are used in diagnosis. Previously, diagnosis depended on identifying antibody to a single viral antigen (c 100-3), but this test gave false-positive reactions, especially in conditions such as autoimmune hepatitis associated with hyperglobulinaemia, and false-negative reactions. Current laboratory diagnosis depends on identifying antibodies to several viral antigens. These tests generally identify chronic HCV infection, as the diagnostic antibodies appear irregularly in the blood during the first 3 months of illness. PCR can show HCV-RNA in the blood, and is used increasingly to confirm the diagnosis where antibody tests give equivocal results and in selecting for, and measuring response to, therapy.
Management
Interferon used alone has only limited efficacy. Approximately 50% of patients will respond but relapse is common and only 10-20% show a long-term response. The treatment of choice for chronic hepatitis C infection is now a combination of interferon and ribavirin. The latter is a synthetic nucleoside analogue which resembles guanosine. Ribavirin's main toxicity is haemolytic anaemia and the drug should be avoided in patients with pre-existing anaemia or cardiopulmonary disease. It also causes abortion when given to women or their male partners; adequate contraception is therefore essential. Combination therapy with interferon 3 million Units thrice weekly and ribavirin 1000 or 1200 mg produces a sustained response (elimination of HCV-RNA from the blood 6 months after completing therapy) in 40% of cases. Patients infected with HCV genotype 1 require therapy for 12 months. The new, longer-acting, pegylated interferons show promise in recent studies.
EBM
HEPATITIS C-efficacy of combined ribavirin and interferon-a
'RCTs indicate that the sustained virological response rates are 33% (95% CI 29-37%) for patients on combination therapy compared with 6% (95% CI 3-10%) on interferon monotherapy, based on 24 weeks' treatment. The corresponding 48-week results are 41% (CI 36-45%) for combination therapy compared with 16% (CI 13-19%) for monotherapy. For relapsed patients (who responded to interferon alone but relapsed in the 6 months following initial treatment) sustained virological response rates were 49% (95% CI 42-57%) on combination therapy compared with 5% (95% CI 2-9%) on monotherapy, for 24 weeks' treatment.'
NICE Technology Appraisal Guidance 2000: no. 14.
Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998; 352:1426-1432.
Further information: www.nice.org.uk

Prevention and prognosis
There is no available active or passive protection against HCV infection. Most patients acquiring HCV infections (80%) develop a chronic infection. Chronic HCV usually remains asymptomatic for years and is not associated with an early increase in mortality. However, many patients eventually develop cirrhosis and some progress to hepatocellular carcinoma. Approximately 20% of chronically infected patients will develop cirrhosis after 20 years of infection, and around 50% after 30 years. This is more likely if patients are misusing alcohol as well. Once cirrhosis is present, 2-5% per year will develop hepatocellular carcinoma.




Integration link: Hepatitis C

Taken from Medical Microbiology 3e




Hepatitis D
page 865

page 866
The hepatitis D virus (HDV) is an RNA-defective virus which has no independent existence; it requires HBV for replication and has the same sources and modes of spread as HBV. It can infect individuals simultaneously with HBV, or it can superinfect those who are already chronic carriers of HBV. Simultaneous infections give rise to acute hepatitis which is often severe but is limited by recovery from the HBV infection. Infections in individuals who are chronic carriers of HBV can cause acute hepatitis with spontaneous recovery, and occasionally simultaneous cessation of the chronic HBV infection occurs. Chronic infection with HBV and HDV can also occur, and this frequently causes rapidly progressive chronic hepatitis and eventually cirrhosis. HDV has been reported recently in the absence of HBV following liver transplantation; how HDV maintains itself in such instances is unknown.
HDV has a world-wide distribution. It is endemic in parts of the Mediterranean basin, Africa and South America where transmission is mainly by close personal contact, and occasionally by vertical transmission from mothers who also carry HBV. In non-endemic areas, transmission is mainly a consequence of parenteral drug misuse.
Investigations
HDV contains a single antigen to which infected individuals make an antibody (anti-HDV). Delta antigen appears in the blood only transiently, and in practice diagnosis depends on detecting anti-HDV. Simultaneous infection with HBV and HDV followed by full recovery is associated with the appearance of low titres of anti-HDV of IgM type occurring within a few days of the onset of the illness. This antibody generally disappears within 2 months but persists in a few patients. Superinfection of patients with chronic hepatitis B virus infection leads to the production of high titres of anti-HDV, initially IgM and later IgG. Such patients may then develop chronic infection with both viruses, in which case anti-HDV titres plateau at high levels.
Prevention
Hepatitis D is effectively prevented by preventing hepatitis B.
Hepatitis E
The hepatitis E virus (HEV) is an RNA virus which is excreted in the stools and spreads by the faecal-oral route. It is found in countries where sanitation is poor and causes large epidemics of water-borne hepatitis. Occasional cases are recognised in patients in developed countries following a visit to an area where infection is endemic. The clinical illness resembles acute HAV infection and recovery is the rule. Chronic infection does not occur. Pregnant women with HEV infection are particularly liable to acute hepatic failure which is associated with a high mortality, but again chronic infection does not occur.
Investigations
Individuals infected with HEV produce anti-HEV which is used in diagnosis. Routine assays for the serological identification of HEV infection should be available in the near future.
Prevention
There is no available active or passive protection against HEV infection.
Other (non-A, non-B, non-C and non-E) hepatitis
Non-A, non-B (NANB) or non-A-E hepatitis is the term used to describe hepatitis thought to be due to a virus but not HAV, HBV, HCV or HEV. Other viruses which affect the liver do exist, but the hepatitis viruses described above now account for the majority of hepatitis virus infections. Cytomegalovirus and Epstein-Barr virus infection causes abnormal liver function tests in most patients, and occasionally icteric hepatitis occurs. Herpes simplex is a rare cause of hepatitis in adults, and most of these patients are immunocompromised. Yellow fever virus causes hepatitis in parts of the world where it is endemic. Abnormal liver function tests are also common in chickenpox, measles, rubella and acute HIV infection.
ALCOHOLIC (ETHANOLIC) LIVER DISEASE
In many societies alcohol is the most common cause of chronic liver disease.
Aetiology and pathology
Alcohol is metabolised almost exclusively in the liver. It is first converted to acetaldehyde, mainly by the mitochondrial enzyme alcohol dehydrogenase but also by the mixed-function oxidase enzymes of the smooth endoplasmic reticulum. Alcohol is a powerful inducer of the mixed-function oxidases, specifically cytochrome P4502E1, thereby increasing the ability of the liver to metabolise alcohol and other drugs, toxins or carcinogens metabolised by these enzymes. Acetaldehyde is converted to acetate by acetaldehyde dehydrogenase, and acetate is metabolised by the Krebs cycle enzymes.
The hepatic lesions of alcoholic liver disease (see below) are attributable directly to alcohol. The risk of developing alcoholic liver disease is related directly to the amount of alcohol (of any kind) ingested but is more likely to be clinically apparent at daily intakes above 30 g (3 units) in men and 20 g (2 units) in women. More than 5 years of drinking, and usually more than 10 years, are required to produce alcoholic cirrhosis, and a steady daily intake is more hazardous than intermittent drinking.
The mechanism or mechanisms underlying the ability of alcohol to produce individual liver lesions are poorly understood. Fatty change is attributed to an impaired excretion and enhanced synthesis of triacylglycerol by hepatocytes. The development of alcoholic hepatitis, fibrosis and cirrhosis is much more obscure. Biochemical mechanisms involving the production of toxic metabolites, called adducts, during the conversion of acetaldehyde to acetate and an immune reaction to liver cells altered by alcohol may be involved in these forms of liver damage. Release of proinflammatory cytokines, such as tumour necrosis factor and interleukin-1, and chemoattractant chemokines, such as interleukin-8, have been implicated in the pathogenesis of both alcoholic hepatitis and cirrhosis. Alcohol-induced liver injury, particularly hepatitis, is more common in women, and other genetic factors have been implicated in the genesis of alcoholic liver disease (see Fig. 18.23).
Alcohol causes several different pathological lesions in the liver which can occur together in any combination (see Box 18.38).
page 866

page 867


Figure 18.23 Factors involved in the pathogenesis of alcoholic liver disease.
18.38 PATHOLOGICAL FEATURES OF ALCOHOLIC LIVER DISEASE
Mitochondrial swelling
Proliferation of endoplasmic reticulum
Macrovesicular steatosis
Lipogranulomas
Mallory's hyaline
Siderosis
Autoimmune (interface) hepatitis
Central hyaline sclerosis
Fibrosis
Cirrhosis
Hepatocellular carcinoma


Clinical features
Alcoholic liver disease manifests as a clinical spectrum ranging from non-specific symptoms, with few or no physical abnormalities, to advanced cirrhosis. The ready availability of laboratory investigations can reveal alcoholic liver damage in patients with other diseases or in asymptomatic people undergoing medical examination. This spectrum is often divided into four syndromes (see Box 18.39), but in reality these overlap considerably and the various pathological changes can coexist in the same liver.
Investigations
18.39 CLINICAL SYNDROMES OF ALCOHOLIC LIVER DISEASE
Fatty liver
Non-specific symptoms
Hepatomegaly
Cholestasis
Jaundice
Abdominal pain
Hepatomegaly (often tender)
Hepatitis
Severe illness
Malnutrition
Jaundice
Hepatomegaly
Ascites
Encephalopathy
Cirrhosis
Stigmata of cirrhosis
Varices
Ascites
Encephalopathy
Hepatocellular carcinoma
Hepatorenal syndrome


Investigations aim to establish alcohol misuse, exclude alternative causes of liver disease and assess the severity of liver damage. The clinical history from the patient, relatives and friends is most important in establishing alcohol misuse, its duration and, in particular, its severity. Biological markers suggest and support a history of alcohol misuse; the most universally used indicators are a peripheral blood macrocytosis in the absence of anaemia and increased plasma gamma-glutamyl transferase. Absence of these markers does not exclude alcohol misuse. Unexplained rib fractures on a chest radiograph are also associated with alcohol misuse. Investigation of the extent of liver damage often requires a liver biopsy (see Fig. 18.24).
Management
page 867

page 868


Figure 18.24 Histology of alcoholic fatty liver. The fatty change (steatosis) is evident as fat globules within the cytoplasm of the liver cells.
Cessation of alcohol intake is the single most important treatment and without this all other therapies are of limited value. Life-long abstinence is the best advice and is essential for those with more severe liver damage. Good nutrition is also important and feeding via a fine-bore nasogastric tube may be needed in severely ill patients. Treatment for complications such as encephalopathy (see p. 858), ascites (see p. 855) and variceal bleeding (see p. 852) may be required. Corticosteroid therapy may be of some value in patients with severe alcoholic hepatitis. The role of liver transplantation in the management of patients with alcoholic liver disease is controversial. However, in most centres alcoholic liver disease is a common indication for considering transplantation. The challenge is to identify patients with an unacceptable risk of returning to harmful levels of alcohol consumption. Many programmes require a 6-month period of abstinence from alcohol before a patient is considered for transplantation, but this relates poorly to the incidence of alcohol relapse after transplantation. Discussion or assessment by a psychiatrist with a particular interest in substance misuse may be invaluable in differentiating harmful alcohol use from alcohol misuse, as patients falling into the former category are much more likely to maintain abstinence. Continuous input from psychiatric services may also prevent relapse.
Prognosis
EBM
ALCOHOLIC HEPATITIS-role of glucocorticoid therapy
'A single blind RCT showed that prednisolone (40 mg/day for 28 days) resulted in a significant improvement in short-term mortality. However, a subsequent meta-analysis of all available trial data showed no significant beneficial effect of glucocorticoids.'
Ramond MJ, Poynard T, Rueff B, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med 1992; 326:507-512.
Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables. Gut 1995; 37:113-118.


The most important prognostic factor is the patient's ability to stop drinking alcohol. General health and longevity are improved when this occurs, irrespective of the form of alcoholic liver disease. Alcoholic fatty liver generally has a good prognosis and usually disappears after about 3 months of abstinence. Alcoholic hepatitis has a significantly worse prognosis because about one-third of patients die in the acute episode if liver function is poor, as evidenced by hepatic encephalopathy or a prothrombin time sufficiently prolonged to preclude liver biopsy. Patients may progress to cirrhosis after recovery, particularly if drinking continues. Alcoholic cirrhosis often presents with a serious complication such as variceal bleeding or ascites, and only about one-half of such patients survive 5 years from presentation. However, most who survive the initial illness and who become abstinent will survive beyond 5 years.
DRUGS, TOXINS AND THE LIVER
18.40 MANIFESTATIONS OF DRUG HEPATOTOXICITY
Liver histology Examples
Acute hepatic damage
Acute hepatitis Paracetamol, halothane, rifampicin, isoniazid
Cholestatic hepatitis Chlorpromazine, ethambutol
Cholestasis Oral contraceptives, anabolic steroids
Abnormal liver function tests Statins, NSAIDs
Hepatic fibrosis and cirrhosis Methotrexate, vitamin A
Chronic hepatitis Amiodarone, penicillamine
Hepatic vascular damage
Budd-Chiari syndrome Oral contraceptives
Veno-occlusive disease Azathioprine, cyclophosphamide
Neoplasia
Adenoma Oral contraceptives, danazol
Hepatocellular carcinoma Oral contraceptives, diethylstilbestrol
Haemangioma/haemangiosarcoma Oral contraceptives, anabolic steroids

18.41 THE DIAGNOSIS OF ACUTE DRUG-INDUCED LIVER DISEASE
N.B. Challenge tests with drugs should virtually never be performed.
Consider the possibility of a drug-induced problem
Tabulate drugs taken
Prescribed
Self-administered
Relate drugs to the onset of the illness
Look for pre-existing liver disease
Clinical examination
Previous liver investigations
Consider alternative causes
Viral hepatitis-serological tests
Biliary disease-ultrasound
Observe the effects of stopping the suspected drugs
Consider liver biopsy
Suspected pre-existing liver disease
Failure to improve


page 868

page 869
The liver is the main organ in which drugs are metabolised and consequently is important in determining the effects of drugs in the body. Liver disease may alter the capacity of the liver to metabolise drugs and unexpected toxicity may occur when patients with liver disease are given drugs in normal doses (see p. 155).
Drugs themselves can damage the liver and there is increasing recognition of the many forms of hepatic damage attributable to them (see Boxes 18.40 and 18.41).
FATTY LIVER AND NON-ALCOHOLIC STEATOHEPATITIS
Fatty liver is a common and generally benign condition. The majority of obese patients (60-90%) and up to 50% of type II diabetics have fatty liver. In general the lipid accumulation is characterised by macrovesicular steatosis. In a minority of cases hepatic steatosis is associated with an inflammatory infiltrate. This histological appearance, described as steatohepatitis, may be caused by alcohol misuse; however, in some patients with other causes there is no history of excessive alcohol consumption (see Box 18.42). This is known as non-alcoholic steatohepatitis (NASH), and may progress to cirrhosis in a small proportion of patients. With the increasing frequency of obesity in the Western population it is likely that this clinical condition will become much more common. Microvesicular steatosis occurs in more serious conditions and can be associated with mitochondrial damage, which causes impaired fatty acid beta-oxidative metabolism.
18.42 CAUSES OF STEATOSIS (FATTY LIVER) AND STEATOHEPATITIS
Macrovesicular steatosis/steatohepatitis
Alcohol
Obesity
Diabetes mellitus
Rapid weight reduction
Starvation (kwashiorkor)
Malabsorption
Parenteral nutrition
Intestinal bypass operations
Drugs (amiodarone, minocycline, iron)

Microvesicular steatosis
Fatty liver of pregnancy
Reye's syndrome (aspirin)
Drugs (e.g. sodium valproate, ketoprofen, didanosine)
Inherited metabolic disorders (e.g. urea cycle defects, fatty acid oxidation defects, lysosomal acid esterase deficiency)


The pathogenesis of hepatic steatosis induced by these diverse clinical conditions is unknown. However, in all cases there is an imbalance in hepatocyte triacylglyceride synthesis and export. Many of the conditions are characterised by relative insulin deficiency, which has multiple effects on lipid metabolism in the liver, adipose tissue and muscle. It has been suggested that a second insult such as oxidative stress or endotoxin-mediated cytokine release is necessary for the progression of steatosis into steatohepatitis.
Clinical features and management
Macrovesicular steatosis is often asymptomatic or is associated with the clinical features of its cause, such as diabetes mellitus or obesity. It is therefore often found incidentally. Hepatomegaly, sometimes with hepatic tenderness, is the only clinical feature. Liver function tests usually show mild increases in the GGT in particular. Elevation of the transaminases suggests the development of steatohepatitis. Ultrasonography shows generally increased echogenicity (bright liver). The treatment is that of the underlying disorder.
Microvesicular steatosis may be associated with the acute onset of fatigue and vomiting, progressing if severe to encephalopathy and coma. Jaundice is typically absent in Reye's syndrome but may be present with other causes of steatosis or steatohepatitis. Acute hepatic failure due to microvesicular steatosis may require intensive care support or emergency liver transplantation.
Prognosis
The outlook for most patients with steatosis is excellent, although a few deaths have been reported. In patients with alcoholic steatosis, the severity of the fatty change can predict the eventual progression to cirrhosis. Previously, the prognosis of patients with acute fatty liver of pregnancy was considered poor. However, milder forms of this condition are now more frequently recognised.
AUTOIMMUNE HEPATITIS
This form of chronic hepatitis occurs most often in women, particularly in the second and third decades of life.
Aetiology and pathology
Several subtypes of this disorder have been proposed with differing immunological markers. Classical (type I) autoimmune hepatitis is characterised by a high frequency of other autoimmune disorders such as Graves' disease. Type I autoimmune hepatitis is associated with HLA-DR3 and DR4, particularly HLA-DRB3*0101 and HLA-DRB1*0401. These patients have high titres of antinuclear and anti-smooth muscle antibodies but none of these antibodies is cytotoxic. A suggested hypothesis for the development of type I autoimmune hepatitis is the aberrant expression on the hepatocyte of HLA antigen, influenced by viral, genetic and environmental factors. Type II autoimmune hepatitis is characterised by the presence of anti-LKM (liver-kidney microsomal) antibodies and lack of antinuclear and anti-smooth muscle antibodies. Anti-LKM antibodies recognise cytochrome P450-IID6, which is expressed on the hepatocyte membrane. The pathological features of both forms of autoimmune hepatitis are similar and are described on pages 838-840.
Clinical features
page 869

page 870
The onset is usually insidious, with fatigue, anorexia and jaundice. In about one-quarter of patients the onset is acute, resembling viral hepatitis, but resolution does not occur. Other features include fever, arthralgia, vitiligo and epistaxis. Amenorrhoea is the rule. On examination, general health may be good. Jaundice is mild to moderate or occasionally absent, but signs of chronic liver disease, especially spider telangiectasia and hepatosplenomegaly, are usually present. Sometimes a 'Cushingoid' face with acne, hirsutism and pink cutaneous striae, especially on the thighs and abdomen, are present. Bruises may be seen. Though liver disease usually dominates the clinical syndrome, many associated conditions occur in florid autoimmune hepatitis, emphasising its essentially systemic nature (see Box 18.43).
18.43 CONDITIONS ASSOCIATED WITH AUTOIMMUNE HEPATITIS
Migrating polyarthritis
Urticarial skin rashes
Lymphadenopathy
Hashimoto's thyroiditis
Thyrotoxicosis
Myxoedema
Coombs-positive haemolytic anaemia
Pleurisy
Transient pulmonary infiltrates
Ulcerative colitis
Glomerulonephritis
Nephrotic syndrome


Investigations
Liver function tests vary with the activity of the disease. Active inflammation is reflected by the plasma aminotransferase activity, and the severity of liver damage by the plasma albumin concentration and prothrombin time. Aminotransferase activity is often increased more than 10-fold during relapses in patients with florid disease, and hypoalbuminaemia and marked hyperglobulinaemia are common. Hyperglobulinaemia is polyclonal and due mainly to marked increases in IgG. The plasma bilirubin reflects the degree of jaundice but usually does not exceed 100 µmol/l (6 mg/dl). The plasma alkaline phosphatase activity reflects the degree of intrahepatic cholestasis.
18.44 FREQUENCY OF AUTOANTIBODIES IN CHRONIC NON-VIRAL LIVER DISEASES AND IN HEALTHY PEOPLE
Disease Anti-nuclear antibody (%) Anti-smooth muscle antibody (%) Anti-mitochondrial antibody* (%)
Healthy controls 5 1.5 0.01
Autoimmune hepatitis 80 70 15
Primary biliary cirrhosis 25 35 95
Cryptogenic cirrhosis 40 30 15

* Patients with antimitochondrial antibody frequently have cholestatic liver function tests and may have primary biliary cirrhosis (see text).
Serological testing for specific autoantibodies may suggest autoimmune hepatitis (see Box 18.44). However, these autoantibodies are all heterogenous and can be found in apparently healthy people, particularly in women and in older people. Antinuclear antibodies occur in about 5% of healthy people and anti-smooth muscle antibody in 1.5%, but antimitochondrial antibody is rare, being found in about 0.01%. Autoantibody titres in such healthy people are usually low. Antinuclear and antimitochondrial antibodies also occur in connective tissue diseases and in autoimmune diseases, including various thyroid disorders and pernicious anaemia, while anti-smooth muscle antibody has been reported in infectious mononucleosis and a variety of malignant diseases. Frequencies of antibodies are shown in Box 18.44. Antimicrosomal antibodies (anti-LKM) occur particularly in children and adolescents.
Liver biopsy shows interface hepatitis (see p. 840) with or without cirrhosis.
Management
Treatment with corticosteroids is life-saving in autoimmune hepatitis, particularly during exacerbations of active and symptomatic disease. Initially, prednisolone 30 mg/day is given orally and the dose reduced gradually as the patient and liver function tests improve. Maintenance therapy is required for at least 2 years after liver function tests have become normal, and withdrawal of treatment should not be considered unless a liver biopsy is also normal. Side-effects from prednisolone are uncommon at a maintenance dose of 10 mg/day or less; azathioprine 50-100 mg/day orally may be added to the therapy to allow the dose of prednisolone to be reduced to this level (see EBM panel). Corticosteroids treat and prevent acute exacerbations rather than prevent cirrhosis and are less important in asymptomatic autoimmune hepatitis with mild biochemical and histological activity.
EBM
AUTOIMMUNE HEPATITIS-role of immunosuppressive therapy
'In patients with autoimmune hepatitis treatment with prednisolone ± azathioprine results in a significant improvement in serum biochemistry, hepatic histology and survival compared with placebo or azathioprine alone.'
'In patients that have been in remission for longer than 1 year, increasing the dose of azathioprine (from 1 to 2 mg/kg) and withdrawal of prednisolone are associated with loss of steroid side-effects and no increase in the relapse of the hepatitis.'
Soloway RD, Summerskill WH, Baggenstoss AH, et al. Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis. Gastroenterology 1972; 63:820-833.
Summerskill WH, Korman MG, Ammon HV, et al. Prednisone for chronic active liver disease: dose titration, standard dose, and combination with azathioprine compared. Gut 1975;16:876-883.
Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med 1995; 333:958-963.


Prognosis
The disease occurs in exacerbations and remissions, and most patients eventually develop cirrhosis and its complications. Hepatocellular carcinoma is uncommon. About half of patients with symptoms die of liver failure within 5 years if no treatment is given, but this falls to about 10% with therapy.
HAEMOCHROMATOSIS
Haemochromatosis is a condition in which the amount of total body iron is increased; the excess iron is deposited in and causes damage to several organs including the liver. It may be primary, or secondary to other diseases.
page 870

page 871
HEREDITARY (PRIMARY) HAEMOCHROMATOSIS
This is a disease in which the total body iron reaches 20-60 g (normally 4 g). Iron is deposited widely in the body. The important organs involved are the liver, pancreatic islets, endocrine glands and heart. In the liver, iron deposition occurs first in the periportal hepatocytes, extending later to all hepatocytes. The gradual development of fibrous septa leads to the formation of irregular nodules, and finally regeneration results in macronodular cirrhosis. An excess of liver iron can occur in alcoholic cirrhosis but this is mild by comparison with haemochromatosis.
Aetiology
Hereditary haemochromatosis is caused by an increased absorption of dietary iron. This inability to limit iron absorption is inherited as an autosomal recessive gene located on chromosome 6. Approximately 90% of patients have a single-point mutation resulting in a cysteine to tyrosine substitution at position 282 (C282Y) in a protein with structural and functional similarity to the HLA proteins, designated HFE. The exact function of the HFE protein in regulating iron absorption is not known. However, it is believed that HFE is absent from the basolateral membrane of intestinal epithelial cells where it normally interacts with the transferrin receptor. This defect in uptake of transferrin-associated iron may lead to up-regulation of enterocyte iron-specific divalent metal transporters and excessive iron absorption. A histidine to aspartic acid mutation at position 63 (H63D) in HFE can also result in haemochromatosis but the disease is less severe and is most commonly found in patients who are compound heterozygotes also carrying a C282Y mutated allele. Perhaps fewer than 50% of C282Y homozygotes will develop clinical features of genetic haemochromatosis; therefore other factors must also be important. Iron loss in menstruation and pregnancy may protect females, as 90% of patients are male.
Clinical features
The disease usually presents in men aged 40 years or over with signs of hepatic cirrhosis (especially hepatomegaly), diabetes mellitus or heart failure. Leaden-grey skin pigmentation due to excess melanin occurs, especially in exposed parts, axillae, groins and genitalia; hence the term 'bronzed diabetes'. Impotence, loss of libido, testicular atrophy and arthritis with chondrocalcinosis secondary to calcium pyrophosphate deposition are also common. Early clinical features, particularly tiredness, fatigue and arthropathy, are increasingly recognised.
Investigations
The serum ferritin is greatly increased; the plasma iron is also increased, with a highly saturated plasma iron-binding capacity. Computed tomography may show features suggesting excess hepatic iron. The diagnosis is confirmed by liver biopsy, which shows heavy iron deposition and hepatic fibrosis which may have progressed to cirrhosis. The iron content of the liver can be measured directly. Both the C282Y and H63D mutations can be identified.
Management
Treatment consists of weekly venesection of 500 ml of blood (250 mg iron) until the serum iron is normal; this may take 2 years or more. Thereafter, venesection is continued as required to keep the serum ferritin normal. Other therapy includes that for cirrhosis and diabetes mellitus. First-degree family members should be investigated, preferably by genetic screening and also by checking the plasma ferritin and iron-binding saturation. Liver biopsy is indicated in asymptomatic relatives if the liver function tests are abnormal and/or the serum ferritin is greater than 1000 µg/l because these features are associated with significant fibrosis or cirrhosis. Asymptomatic disease should also be treated by venesection once the serum ferritin rises above normal.
Prognosis
Hereditary haemochromatosis has a good prognosis compared with other forms of cirrhosis, as three-quarters of patients are alive 5 years after the diagnosis. This is probably because liver function is usually well preserved at diagnosis and improves with therapy. Given that hepatocellular carcinoma is the main cause of death and occurs in about one-third of patients with cirrhosis irrespective of therapy, screening of this patient population is imperative (see p. 877).
ACQUIRED IRON OVERLOAD (SECONDARY HAEMOCHROMATOSIS)
Many conditions, including chronic haemolytic disorders, sideroblastic anaemia, other conditions requiring multiple blood transfusion (generally over 50 litres), porphyria cutanea tarda, dietary iron overload and occasionally alcoholic cirrhosis, are associated with widespread secondary siderosis. The features are similar to haemochromatosis, but the history and clinical findings point to the true diagnosis. Some patients are heterozygotes for the primary haemochromatosis gene and this may contribute to the development of iron overload.
WILSON'S DISEASE (HEPATOLENTICULAR DEGENERATION)
This is a rare but important condition in which the total body copper is increased, with excess copper deposited in, and causing damage to, several organs.
Aetiology and pathology
page 871

page 872
Wilson's disease is inherited as an autosomal recessive disorder that results in abnormal copper accumulation. Normally, dietary copper is absorbed from the stomach and proximal small intestine and is rapidly taken into the liver, where it is stored and incorporated into ceruloplasmin, which is secreted into the blood. The accumulation of excessive copper in the body is ultimately prevented by its excretion, the most important route being via the bile. In Wilson's disease, there is almost always a failure of synthesis of ceruloplasmin; however, some 5% of patients have a normal circulating ceruloplasmin concentration and this is not the primary pathogenic defect. The amount of copper in the body at birth is normal, but thereafter it increases steadily and the organs most affected are the liver, basal ganglia of the brain, eyes, kidneys and skeleton.
The gene responsible for Wilson's disease is located on chromosome 13 and has been designated ATP7B. This gene encodes a member of the copper-transporting P-type ATPase family, which functions to export copper from the various cell types. At least 200 different mutations have been described. Although most of the mutations are rare, their relative frequency differs in different populations. The histidine to glucine single-base mutation at position 1069 is most common in Polish and Austrian patients, but rare in Asia, India and Sardinia. In contrast, approximately 60% of Sardinian patients have a 15 nucleotide deletion in the 5' untranslated region of the Wilson's gene. Most cases are compound heterozygotes with two different mutations in the Wilson's gene. Attempts to correlate the genotype with the mode of presentation and clinical course have not shown any consistent patterns.
Clinical features
Symptoms usually arise between the ages of 5 and 30 years. Hepatic disease occurs predominantly in childhood and early adolescence, while neurological damage causes basal ganglion syndromes and dementia in later adolescence. These manifestations can occur alone or simultaneously. Other manifestations include haemolysis, renal tubular damage and osteoporosis, but these are virtually never presenting features.
Kayser-Fleischer rings


Figure 18.25 Kayser-Fleischer rings at the junction of the cornea and sclera (arrow) in a patient with Wilson's disease.
These are the most important single clinical clue to the diagnosis and they can be seen in most patients presenting in or after adolescence, albeit sometimes only by slit-lamp examination. Kayser-Fleischer rings are characterised by greenish-brown discoloration of the corneal margin appearing first at the upper periphery (see Fig. 18.25). They eventually disappear with treatment. Appearances indistinguishable from Kayser-Fleischer rings are found rarely in other forms of chronic hepatitis and cirrhosis.
Liver disease
This can manifest in many ways which are not specific. Episodes of acute hepatitis which are sometimes recurrent can occur, especially in children, and may progress to acute hepatic failure. Chronic hepatitis and steatohepatitis can also develop, and eventually cirrhosis with liver failure and portal hypertension may supervene. Recurrent acute hepatitis of unknown cause, especially accompanied by haemolysis, or chronic liver disease of unknown cause in a patient under 40 years old suggests Wilson's disease.
Neurological disease
Clinical features include a variety of extrapyramidal features, particularly tremor, choreoathetosis, dystonia, parkinsonism and dementia (see Ch. 22).
Investigations
A low serum ceruloplasmin is the best single laboratory clue to the diagnosis. However, advanced liver failure from any cause can reduce the serum ceruloplasmin, and occasionally the serum ceruloplasmin is normal in Wilson's disease. Other features of disordered copper metabolism should therefore be sought; these include a high serum copper concentration, a high urine copper excretion and a very high hepatic copper content. Patients with Wilson's disease fail to incorporate radioactive copper into ceruloplasmin, but this test is almost never needed. Genetic testing is limited by the existence of multiple genetic defects, but may be useful in screening families once the abnormality has been identified in an affected individual.
Management
The copper-binding agent penicillamine is the drug of choice in Wilson's disease. The dose given must be sufficient to produce cupriuresis and most patients require 1.5 g/day (range 1-4 g). The dose can be reduced once the disease is in remission, but treatment must continue for life and care must be taken to ensure that reaccumulation of copper does not occur. Abrupt discontinuation of treatment must be avoided because this may precipitate acute liver failure. Serious toxic effects of penicillamine are rare in Wilson's disease. If they do occur, trientine dihydrochloride (1.2-2.4 g/day) or zinc is an alternative effective therapy. Liver transplantation may be needed for acute hepatic failure or for advanced cirrhosis with liver failure.
Prognosis
The prognosis of Wilson's disease is excellent provided treatment is started before there is irreversible damage; hepatocellular carcinoma does not occur. Siblings and children of patients with Wilson's disease must be investigated and treatment should be given to any who have the disease even if it is asymptomatic.
page 872

page 873
ALPHA1-ANTITRYPSIN DEFICIENCY
Alpha1-antitrypsin (a1-AT) is a serine protease inhibitor (Pi) produced by the liver. The form of a1-AT is genetically determined, and one of these forms (PiZ) cannot be secreted into the blood by the liver cells owing to polymerisation within the endoplasmic reticulum of the hepatocyte. Homozygous individuals (PiZZ) have low plasma a1-AT concentrations, although globules containing a1-AT are found in the liver, and this form of a1-AT deficiency is also associated with hepatic and pulmonary disease (see p. 509). Liver disease includes cholestatic jaundice in the neonatal period (neonatal hepatitis) which can resolve spontaneously, chronic hepatitis and cirrhosis in adults, and in the long term the development of hepatocellular carcinoma. There are no clinical features distinguishing liver disease due to a1-AT deficiency from other causes of liver disease, and the diagnosis is made from the low plasma a1-AT concentration and the PiZZ genotype. Alpha1-AT-containing globules can be demonstrated in the liver but this is not necessary to make the diagnosis. Occasionally, patients with liver disease and minor reductions of plasma a1-AT concentrations have a1-AT phenotypes other than PiZZ, such as PiMZ or PiSZ, but the relationship of these genotypes to liver disease is uncertain. No specific treatment is available; the concurrent risk of severe and early-onset emphysema means that all patients should be advised to abandon cigarette smoking.
BILIARY CIRRHOSIS
Biliary cirrhosis results from destruction of intrahepatic bile ducts in cases of primary biliary cirrhosis or primary sclerosing cholangitis, and may also be the result of prolonged obstruction.
PRIMARY BILIARY CIRRHOSIS
Primary biliary cirrhosis (PBC) predominantly affects women who usually present clinically in middle age. The ready availability of diagnostic tests has revealed asymptomatic disease which can remain quiescent for years, and has shown that PBC is a relatively common form of cirrhosis.
Aetiology and pathology
The cause of PBC is unknown but immune reactions causing liver damage are suspected. Autoantibodies and immune complexes are found in the blood, cellular immunity is impaired, and abnormal cellular immune reactions have been described. The primary pathological lesion is a chronic granulomatous inflammation damaging and destroying the interlobular bile ducts; progressive inflammatory damage with fibrosis spreads from the portal tracts to the liver parenchyma and eventually leads to cirrhosis.
Clinical features
Non-specific symptoms such as lethargy, fatigue and arthralgia are common and may precede diagnosis for years. Pruritus is the most common initial complaint pointing to hepatobiliary disease and it may precede jaundice by months or years. Bile acids have been suggested as the cause of pruritus but this remains unproven. Jaundice is occasionally a presenting feature but usually pruritus is also present. Although there may be abdominal discomfort, the abdominal pain, fever and rigors which are often features of large bile duct obstruction do not occur. Diarrhoea from malabsorption of fat, and pain and tingling in the hands and feet due to lipid infiltration of peripheral nerves occasionally occur. Bone pain or fractures resulting from osteomalacia from malabsorption or osteoporosis (hepatic osteodystrophy) can be prominent and distressing features in advanced disease.
Initially patients are well nourished but considerable weight loss can occur as the disease progresses. Scratch marks may be found. Jaundice is only prominent late in the disease and can become intense. Xanthomatous deposits occur in a minority, especially around the eyes, in the hand creases and over the elbows, knees and buttocks. Hepatomegaly is virtually constant, and splenomegaly becomes increasingly common as portal hypertension develops. Liver failure and portal hypertension arise as the disease progresses.
Associated diseases
Autoimmune and connective tissue diseases occur with increased frequency in primary biliary cirrhosis, particularly in patients with the sicca syndrome (see p. 1038), coeliac disease (see p. 792) and thyroid diseases. Hypothyroidism should always be considered in patients with fatigue.
Investigations
Liver function tests show the pattern of cholestasis (see p. 836). Hypercholesterolaemia is common and worsens with disease progression; however, it is often of no diagnostic value. The antimitochondrial antibody is present in over 95% of patients, and when it is absent diagnosis should not be made without obtaining histological evidence and performing cholangiography (ERCP, see p. 841) to exclude other biliary disease. Antinuclear and anti-smooth muscle antibodies may be present (see Box 18.44, p. 870), and autoantibodies found in associated diseases may also be found. Ultrasound examination shows no sign of biliary obstruction. As has already been noted, liver biopsy is required only in doubtful cases.
Management
page 873

page 874
EBM
PRIMARY BILIARY CIRRHOSIS (PBC)-role of ursodeoxycholic acid
'In PBC ursodeoxycholic acid (UDCA) therapy (13-15 mg/kg/day) is associated with significant improvement in biochemical markers of cholestasis and jaundice. Some randomised trials have shown that UDCA treatment significantly slows disease progression. Overall, UDCA has not been shown to affect mortality or transplantation rates significantly.'
Poupon RE, Lindor KD, Cauch-Dudek K, et al. Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis. Gastroenterology 1997; 113:884-890.
Corpechot C, Carrat F, Bonnand AM, et al. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology 2000; 32:1196-1199.
Further information: www.update-software.com

No specific therapy is available. Corticosteroids, azathioprine, penicillamine and ciclosporin have all been tried, but none is effective and all may have serious adverse effects. Ursodeoxycholic acid improves liver function tests, may slow down histological progression and has few side-effects (see EBM panel). Transplantation should always be considered once liver failure has developed and may be indicated in patients with intractable pruritus. Treatment may be needed for the consequences of cholestasis, particularly for pruritus and malabsorption.
Pruritus
This is the main symptom demanding relief and is best treated with the anion-binding resin colestyramine, which reduces the concentration of bile acids in the body by binding them in the intestine and increasing their excretion in the stool. A dose of 4-16 g/day orally is used. The powder is mixed in orange juice and the main dose (8 g) is taken with breakfast when maximal duodenal bile acid concentrations occur. Colestyramine may bind other drugs in the gut (e.g. anticoagulants), which should therefore be taken 1 hour before the binding agent. Colestyramine is sometimes ineffective, especially in complete biliary obstruction. Rifampicin or ultraviolet light may help in these patients.
Malabsorption
Prolonged cholestasis is associated with steatorrhoea and malabsorption of fat-soluble vitamins and calcium. Steatorrhoea can be reduced by limiting fat intake to 40 g/day. Monthly injections of vitamin K (10 mg), vitamin D (calciferol 1 mg/day; alfacalcidol 1 mg/day orally) and calcium supplements should also be given, the last as effervescent calcium gluconate (2-4 g/day). The effervescent preparation of calcium gluconate contains significant amounts of sodium, and where there is fluid retention calcium gluconate alone should be used. Associated coeliac disease requires exclusion.
SECONDARY BILIARY CIRRHOSIS
This develops after prolonged large duct biliary obstruction due to gallstones, bile duct strictures or sclerosing cholangitis (see below). Carcinomas rarely cause secondary biliary cirrhosis because few patients survive long enough. There is chronic cholestasis with episodes of ascending cholangitis or even liver abscess (see p. 878). Digital clubbing is common and xanthomata and bone pain may develop. Cirrhosis, ascites and portal hypertension are late features. Cholangitis requires treatment with antibiotics, which can be given continuously if attacks occur frequently.
SCLEROSING CHOLANGITIS
This condition, which is being increasingly diagnosed, is characterised by fibrotic obliteration of the intrahepatic and/or extrahepatic bile duct system, and may be primary or secondary in type. Primary sclerosing cholangitis has no known cause but is often associated with ulcerative colitis and occasionally with retroperitoneal fibrosis, HIV infection and a variety of autoimmune disorders. There is an association between primary sclerosing cholangitis and the HLA haplotypes B8, DR2 and DR3. In secondary sclerosing cholangitis there is an underlying disorder of the biliary tree causing the fibrotic state: for example, retained bile duct stones or strictures following surgery (both of which may be difficult to differentiate from bile duct tumours).
Clinical features
The patient presents with jaundice, which may fluctuate, intermittent fever, pruritus and right upper quadrant pain. Secondary biliary cirrhosis may result. There is a strong association with cholangiocarcinoma, and progressive jaundice, anorexia and weight loss are suggestive of this complication.
Investigations


Figure 18.26 A percutaneous cholangiogram in sclerosing cholangitis showing the irregularity in the biliary tree.
page 874

page 875
Liver function tests demonstrate cholestasis with elevation of the serum bilirubin, GGT and alkaline phosphatase. These abnormalities may fluctuate. The prothrombin time may be prolonged if cholestasis is long-standing or if hepatic cirrhosis and liver failure have developed. Perinuclear antineutrophil cytoplasmic antibodies (p-ANCA, see p. 1040) have been found in this disease, especially when it is associated with ulcerative colitis. Ultrasonography may not show biliary abnormality as the thickened fibrotic ducts are not dilated, and diagnosis is best made by cholangiography, which typically shows narrowed irregular obstruction and 'beading' of the extra- and intrahepatic bile ducts (see Fig. 18.26). The disease may affect the whole of the biliary system or may be confined to the extrahepatic or intrahepatic portion of the bile ducts. The typical whorled appearance of fibrosis around the bile ducts may be seen if liver biopsy is undertaken. Bile duct tissue obtained at laparotomy may demonstrate the characteristic lymphocytic cell infiltrate with plasma cells and giant cells. The main differential diagnosis is cholangiocarcinoma.
Management
There is no specific treatment, but antibiotics are needed during episodes of cholangitis. Ursodeoxycholic acid has been used but its efficacy is in doubt. Corticosteroids and other immunosuppressive drugs are of no value. Biliary drainage may be attempted using stents placed at ERCP, but this is only reasonable where a single dominant stricture is present. Such strictures may be resected if there is doubt about the presence of an underlying malignancy. Liver transplantation is the only effective therapy in patients with advanced disease.
VASCULAR DISEASE OF THE LIVER
HEPATIC ARTERIAL DISEASE
Hepatic arterial disease is rare and difficult to diagnose, but it can cause serious liver damage. Hepatic artery occlusion may result from inadvertent injury during biliary surgery or be caused by emboli, neoplasms, polyarteritis nodosa, blunt trauma or radiation. It usually causes severe upper abdominal pain with or without signs of circulatory shock. Liver function tests show a high transaminase activity as in other causes of acute liver damage. Patients usually survive if the liver and portal blood supply are otherwise normal.
Hepatic artery aneurysms are extrahepatic in three-quarters of cases and intrahepatic in one-quarter. Atheroma, vasculitis, bacterial endocarditis, and surgical or biopsy trauma are the main causes. They usually cause bleeding into the biliary tree, peritoneum or intestine and are diagnosed best by arteriography. Treatment is surgical. Any of the vasculitides can affect the hepatic artery, but this rarely causes symptoms.
PORTAL VENOUS DISEASE
Portal venous thrombosis is rare but can occur in any condition predisposing to thrombosis. It also occurs with local intra-abdominal inflammatory or neoplastic disease and is a recognised complication of portal hypertension. Acute portal venous thrombosis causes abdominal pain and diarrhoea, and may lead to bowel infarction. Treatment is surgical but patients will require anticoagulation if an underlying thrombotic condition is diagnosed. Less acute thrombosis can be asymptomatic and may later give rise to extrahepatic portal hypertension (see p. 850).
HEPATIC VENOUS OUTFLOW OBSTRUCTION
Obstruction to hepatic venous blood flow can occur in the small central hepatic veins, in the large hepatic veins, in the inferior vena cava or in the heart. The clinical features depend on the cause and on the speed with which obstruction develops, but congestive hepatomegaly and ascites are features in all patients.
BUDD-CHIARI SYNDROME
Aetiology and pathology
This is an uncommon condition in which obstruction occurs in the larger hepatic veins and sometimes the inferior vena cava. The cause cannot be found in about half of patients. In the others, thrombosis may be due to haematological diseases including primary proliferative polycythaemia, paroxysmal nocturnal haemoglobinuria and antithrombin III, protein C or protein S deficiencies (see pp. 953-954). Pregnancy and oral contraceptive use, obstruction due to tumours, particularly carcinomas of the liver, kidneys or adrenals, congenital venous webs and occasionally inferior vena caval stenosis are the other main causes. Hepatic congestion affecting the centrilobular areas is the initial consequence; centrilobular fibrosis develops later and eventually cirrhosis in those who survive long enough.
Clinical features
Sudden venous occlusion causes the rapid development of upper abdominal pain, marked ascites and occasionally acute hepatic failure. More gradual occlusion causes gross ascites and often upper abdominal discomfort. Hepatomegaly, often with tenderness over the liver, is almost always present. Peripheral oedema occurs only when there is inferior vena cava obstruction. Features of cirrhosis and portal hypertension develop in those who survive the acute event.
Investigations
Liver function tests vary considerably depending on the presentation and can show the features of acute hepatitis (see p. 836) when the onset is rapid. Ascitic fluid analysis typically shows a protein concentration above 25 g/l in the early stages; however, this is often lower later in the disease. Doppler ultrasound examination may reveal obliteration of the hepatic veins and reversed flow or associated thrombosis in the portal vein. CT may show enlargement of the caudate lobe, as it often has a separate venous drainage system not involved in the disease. Hepatic venography shows occlusion of the hepatic veins and any inferior vena cava involvement (see Fig. 18.27), and liver biopsy demonstrates centrilobular congestion with fibrosis depending upon the duration of the illness.
Management
Predisposing causes should be treated as far as possible; where recent thrombosis is suspected, treatment with streptokinase followed by heparin and oral anticoagulation should be considered. Ascites is treated medically initially but this often has limited success. LeVeen shunts are rarely performed. Some patients may be managed successfully by insertion of a TIPSS. Occasionally, a web can be resected or an inferior vena caval stenosis dilated. Progressive liver failure is an indication for liver transplantation.
page 875

page 876


Figure 18.27 Flush venogram showing Budd-Chiari syndrome. This injection of contrast into the inferior vena cava shows an indentation caused by caudate lobe enlargement. Ordinarily, the diameter of the inferior vena cava is uniform, as shown by the broken line. This flush venogram also shows little backflow of contrast into the hepatic veins (arrow). This can be confirmed by attempted selective catheterisation of the hepatic veins.
Prognosis
The prognosis is generally poor, particularly when the onset is sudden; up to two-thirds of patients die within a year and few live more than 5 years. Some patients survive to develop cirrhosis.
VENO-OCCLUSIVE DISEASE
Widespread occlusion of central hepatic veins is the characteristic of this condition. Pyrrolizidine alkaloids in Senecio and Heliotropium plants used to make teas, cytotoxic drugs and hepatic irradiation are all recognised causes. The clinical features, investigation and management of veno-occlusive disease are similar to those of the Budd-Chiari syndrome (see above).
CARDIAC DISEASE
Hepatic damage due primarily to congestion may develop in cardiac failure from any cause, but the clinical features are usually dominated by the cardiac disease. Occasionally, the hepatic features are more prominent.
Acute hepatitis
Rapidly developing cardiac failure sometimes causes a syndrome suggesting an acute hepatitis. This often follows an acute reduction in hepatic perfusion and is termed 'shock liver' (see p. 208); it is sometimes seen following myocardial infarction, decompensation of any chronic myocardial disease or respiratory condition associated with cor pulmonale, or rapidly developing cardiac tamponade. The patient is generally very ill with an enlarged tender liver, with or without jaundice, and liver function tests showing an acute hepatitis. The correct diagnosis is made by recognising that the cardiac output is low, that the jugular venous pressure is high and that other signs of cardiac disease are present.
Ascites
Cardiac failure sometimes causes hepatomegaly and ascites disproportionate to the degree of peripheral oedema, and hence can mimic ascites due to liver disease. A high ascites protein concentration may suggest hepatic venous outflow obstruction. Constrictive pericarditis (see p. 478) is particularly likely to mislead, as a normal heart size points away from heart disease. A raised jugular venous pressure is the most important single clue to the diagnosis. Rarely, long-standing cardiac failure and hepatic congestion cause cardiac cirrhosis, and this is suggested by hard irregular hepatomegaly or a palpable spleen due to portal hypertension.
Management
The treatment of these patients is that of the underlying causative disease.

pages 860 - 876


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC018092


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com




Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease > TUMOURS OF THE LIVER
TUMOURS OF THE LIVER
HEPATOCELLULAR CARCINOMA (HEPATOMA)
Hepatocellular carcinoma is the principal primary malignant liver tumour. Its incidence shows great geographic variation, the tumour being common in Africa (especially Mozambique) and South-east Asia but rare in temperate climates.
Aetiology
Chronic hepatitis B virus infection has emerged as the most important cause world-wide, but chronic hepatitis C virus infection is becoming increasingly important. Aflatoxin contamination of foods may be important in tropical countries. Cirrhosis and male sex are the main risk factors for hepatocellular carcinoma in temperate climates. Cirrhosis is present in 80% of cases and may be of any type; however, hepatocellular carcinoma appears most commonly in haemochromatosis and alcoholic cirrhosis, predominantly male diseases, and rarely in primary biliary cirrhosis, which mainly affects women. Exposure to toxins such as thorotrast and arsenic has in the past been shown to produce angiosarcomas and rarely hepatocellular carcinomas. Oestrogens, androgens and anabolic steroids may cause adenomas or, exceptionally, hepatocellular carcinomas.
Pathology
page 876

page 877


Figure 18.28 Histology of hepatocellular carcinoma (left) arising within cirrhotic liver (right).
Macroscopically, the tumour may comprise a single mass or multiple nodules and can occasionally be diffusely invasive. Microscopically, the tumour is made up of trabeculae of well-differentiated malignant cells resembling hepatocytes (see Fig. 18.28). Bile secretion by tumour cells is diagnostic. Intravascular invasion and growth are often features and may result in tumour spread into the portal vein or inferior vena cava. The tumour metastasises mainly to regional lymph nodes, the peritoneum, the lungs and bones.
Clinical features
These include weakness, anorexia, weight loss, fever, abdominal pain, a large irregular liver or an abdominal mass, and ascites. Hepatocellular carcinomas are vascular; a bruit may be heard over the liver and intra-abdominal bleeding may occur. Clinical deterioration in a patient with cirrhosis should always lead to suspicion of hepatocellular carcinoma.
Screening
Hepatocellular carcinoma is most common in patients with cirrhosis, especially if associated with HCV infection, haemochromatosis or alcohol. Treatment can only be curative if small asymptomatic tumours are removed by resection or liver transplantation. Such tumours can be detected by regular serum a-fetoprotein measurements and ultrasound examinations undertaken at 6-monthly intervals.
Investigations
A greatly increased or rising serum a-fetoprotein is virtually diagnostic. Imaging usually reveals one or more filling defects, laparoscopy may reveal the tumour, and the diagnosis can be confirmed by liver aspiration or biopsy, which does, however, risk 'seeding' the tumour along the biopsy tract (see Fig. 18.29). Liver function tests give variable non-specific results. Metabolic abnormalities include polycythaemia, hypercalcaemia, hypoglycaemia and porphyria cutanea tarda.
Management


Figure 18.29 CT showing a large hepatocellular carcinoma (arrows).
Surgical removal is only appropriate if the tumour is confined to one lobe in the absence of cirrhosis and is rarely feasible; however, the possibility should always be considered before injudicious biopsy is undertaken. Arterial embolisation with or without local installation of chemotherapeutic agents (chemoembolisation) can provide palliation of hepatic pain. Chemotherapy has been disappointing. Percutaneous ethanol injection may have a place if the tumour is small. Liver transplantation can be considered for small tumours not amenable to local resection.
EBM
TREATMENT OF HEPATOCELLULAR CARCINOMA
'Controversy exists regarding the relative role of hepatic resection or liver transplantation in patients with small single (< 5 cm) or small multiple (3 nodules each less than 3 cm) hepatomas. No RCTs are available.'
'In patients with larger tumours, arterial embolisation ± chemoembolisation or tamoxifen treatment has not resulted in improved survival.'
DeMatteo RP, Fong Y, Blumgart LH. Surgical treatment of malignant liver tumours. Baillieres Best Pract Res Clin Gastroenterol 1999; 13:557-574.
Heneghan MA, O'Grady JG. Liver transplantation for malignant disease. Baillieres Best Pract Res Clin Gastroenterol 1999; 13:575-579.
Llovet JM, Bruix J. Early diagnosis and treatment of hepatocellular carcinoma. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(6):991-1008.


Prognosis
The outlook is very poor. Surgery alone gives prolonged survival, but only about 10% of patients are suitable for this therapy. Few patients survive beyond a year. Liver transplantation in selected cases improves survival.
FIBROLAMELLAR HEPATOCELLULAR CARCINOMA
This rare variant differs from other hepatocellular carcinomas in that it occurs in young adults, equally in males and females, and is not associated with either cirrhosis or hepatitis B or C virus infection. It may present with pain due to bleeding into the tumour, which may later cause intrahepatic or intraperitoneal calcification. The serum a-fetoprotein is usually normal, and biopsy shows large polygonal malignant hepatocytes in a dense fibrous tissue stroma. Two-thirds of tumours are resectable and transplantation may be considered where there is no spread beyond the liver. Two-thirds of patients survive beyond 5 years.
page 877

page 878
OTHER PRIMARY MALIGNANT TUMOURS
These are rare but include haemangio-endothelial sarcomas and cholangiocarcinoma (see p. 886).
SECONDARY MALIGNANT TUMOURS
These are common and usually originate from carcinomas in the lung, breast, abdomen or pelvis. They may be single or multiple. Peritoneal dissemination frequently results in ascites.
Clinical features
The primary neoplasm is asymptomatic in about half of patients. Hepatomegaly may suggest cirrhosis, but splenomegaly is rare. There is usually rapid liver enlargement, with weight loss and jaundice.
Investigations
A positive faecal occult blood test may point towards the presence of primary gastrointestinal malignancy. A raised alkaline phosphatase activity is the most common biochemical abnormality but the liver function tests may be normal. Ascitic fluid has a high protein content and may be blood-stained, and cytology sometimes reveals malignant cells. Imaging (see p. 840) usually reveals filling defects (see Fig. 18.30), laparoscopy may reveal the tumour (see Fig. 18.31), and the diagnosis can be confirmed by liver aspiration or biopsy.
Management
Every effort should be made to detect resectable secondary tumours, as hepatic resection can improve survival for slow-growing tumours such as colonic carcinomas. Patients with hormone-producing tumours, such as gastrinomas, insulinomas and glucagonomas, and those with lymphomas may benefit from chemotherapy. Unfortunately, palliative treatment to relieve pain is all that is available for most patients; this may include arterial embolisation of the tumour masses.


Figure 18.30 CT showing multiple liver metastases (arrows).


Figure 18.31 Laparoscopic appearance of a hepatic metastasis (arrows) from colonic carcinoma.
BENIGN TUMOURS
Hepatic adenomas are rare vascular tumours which may present as an abdominal mass or with abdominal pain or intraperitoneal bleeding. They are more common in women and may be caused by oral contraceptives, androgens and anabolic steroids. Haemangiomas are the most common benign liver tumours and rarely cause sufficient symptoms to merit resection (see Fig. 18.32).


Figure 18.32 MRI showing a haemangioma (arrows) in the liver.

pages 876 - 878


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC018194


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com




Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease > MISCELLANEOUS LIVER DISEASES
MISCELLANEOUS LIVER DISEASES
LIVER ABSCESS
Liver abscesses are pyogenic, hydatid or amoebic.
PYOGENIC ABSCESS
Pyogenic liver abscesses are uncommon but important because they are potentially curable, inevitably fatal if untreated, and readily overlooked.
page 878

page 879
18.45 CAUSES OF PYOGENIC LIVER ABSCESSES
Biliary obstruction (cholangitis)
Haematogenous
Portal vein (mesenteric infections)
Hepatic artery (bacteraemia)
Direct extension
Trauma
Penetrating or non-penetrating
Infection of liver tumour or cyst


Aetiology and pathology
Infection can reach the liver in several ways (see Box 18.45). Abscesses are most common in older patients and usually result from ascending infection due to biliary obstruction (cholangitis), or contiguous spread from an empyema of the gallbladder. Abscesses in young adults consequent on suppurative appendicitis were previously common but are now rare. Immunocompromised patients are particularly likely to develop liver abscesses. Abscesses vary greatly in size; single lesions are more common in the right liver, and multiple abscesses are usually due to infection secondary to biliary obstruction. E. coli and various streptococci, particularly Strep. milleri, are the most common organisms; anaerobes including streptococci and Bacteroides can often be found when infection has been transmitted from large bowel pathology via the portal vein, and multiple organisms are present in one-third of patients.
Clinical features
Patients are generally ill with fever, sometimes rigors, and weight loss. Abdominal pain is the most common symptom and is usually in the right upper quadrant, sometimes with radiation to the right shoulder. The pain may be pleuritic in nature. Hepatomegaly is found in more than half the patients and tenderness can usually be elicited by gentle percussion over the organ. Mild jaundice may be present but is severe only when large abscesses cause biliary obstruction. Abnormalities are present at the base of the right lung in about one-quarter of patients. Atypical presentations are common and explain the frequency with which the diagnosis is made only at autopsy. This is a particular problem in patients with gradually developing illnesses or pyrexia of unknown origin which may not include abdominal pain or prominent clinical features pointing to an underlying cause such as colonic diverticular disease. Necrotic colorectal metastases can be misdiagnosed as hepatic abscess.
Investigations
Liver imaging is the most revealing investigation and shows 90% or more of symptomatic abscesses. Needle aspiration under ultrasound guidance confirms the diagnosis and provides pus for culture. A leucocytosis is frequent, plasma alkaline phosphatase activity is usually increased, and the serum albumin is often low. The chest radiograph may show a raised right diaphragm and lung collapse or an effusion at the base of the right lung. Blood culture should always be carried out as it may reveal the causative organism.
Management
This includes prolonged antibiotic therapy and drainage of the abscess. Pending the results of culture of blood and pus from the abscess, treatment should commence with a combination of antibiotics such as ampicillin, gentamicin and metronidazole. Aspiration or drainage with a catheter placed in the abscess under ultrasound guidance may be required if the abscess is large or if it does not respond to antibiotics. Surgical drainage is rarely undertaken, although hepatic resection may be indicated for a chronic persistent abscess or 'pseudotumour'.
Prognosis
The mortality of liver abscesses is 20-40%; failure to make the diagnosis is the most common cause of death. Older patients and those with multiple abscesses also have a higher mortality.
HYDATID CYSTS
Hydatid cysts are caused by Echinococcus granulosus infection (see p. 879). They have an outer layer derived from the host, an intermediate laminated layer and an inner germinal layer. They can be single (see Fig. 18.33) or multiple. Chronic cysts become calcified. The cysts may be asymptomatic but may present with abdominal pain or a mass. There may be a peripheral blood eosinophilia, radiographs may show calcification, imaging shows the cyst(s), and serological tests are positive in 50% of cases. Rupture or secondary infection of cysts can occur, and a communication with the intrahepatic biliary tree is invariable. Surgical removal of the intact cyst is the preferred treatment under mebendazole prophylaxis.


Figure 18.33 Hydatid cyst of the liver on CT (arrows).
AMOEBIC LIVER ABSCESSES
page 879

page 880
Amoebic liver abscesses are caused by Entamoeba histolytica infection. Up to 50% of cases do not have a previous history of intestinal disease. Although amoebic liver abscesses are most often found in endemic areas, patients can present with no history of travel to these places. Abscesses are usually large, single and located in the right lobe, although multiple abscesses may occur in advanced disease. Fever and abdominal pain or swelling are the most common symptoms. Diagnosis may depend on cyst aspiration revealing the classic anchovy sauce appearance of the cyst fluid. Treatment is described on page 66.
HEPATIC NODULES
Liver diseases characterised primarily by hepatic nodules which are not neoplastic are rare, and three types are usually recognised. Hepatic adenomas (see p. 878) and nodules occurring in cirrhosis are not included with these diseases.
NODULAR REGENERATIVE HYPERPLASIA OF THE LIVER
This disease is characterised by small hepatocyte nodules throughout the liver without fibrosis. It occurs in older people and has been associated with many conditions such as connective tissue disease, haematological diseases and with immunosuppressive and corticosteroid drugs. The condition usually presents as an abdominal mass or occasionally because of portal hypertension. Diagnosis is made by liver biopsy. Liver function is good and the prognosis is very favourable; however, hepatocellular carcinoma occurs occasionally.
FOCAL NODULAR HYPERPLASIA OF THE LIVER
This usually takes the form of a single subcapsular liver nodule, yellow-brown in colour and with central fibrosis. It is almost always asymptomatic and found by chance on ultrasound imaging for other pathology. Intraperitoneal bleeding is an exceptional complication.
PARTIAL NODULAR TRANSFORMATION OF THE LIVER
Nodules in this condition are restricted to the perihilar region of the liver where they can cause portal hypertension. The rest of the liver is normal and liver function is excellent. Needle liver biopsy is often normal.
CYSTIC AND FIBROPOLYCYSTIC DISEASE
Fibropolycystic diseases of the liver and biliary system constitute a heterogeneous group of rare disorders, some of which are inherited. They are not distinct entities, as combined lesions occur.
SOLITARY HEPATIC CYSTS
Isolated hepatic cysts may be discovered by chance; rarely, they give rise to complications, including pain or jaundice from cyst enlargement, haemorrhage or infection. Portal hypertension and bleeding from varices are exceptional.
Diagnosis is best made by ultrasonography. Resection of a large cyst or groups of cysts is only required if symptoms are troublesome, and the prognosis is excellent.
ADULT HEPATORENAL POLYCYSTIC DISEASE
The kidneys are predominantly affected in this condition (see Fig. 18.34), which is inherited as an autosomal dominant trait (see p. 621). Hepatic cysts which do not communicate with the biliary system are present in over half of patients with renal cysts, and cysts can also be found in other organs. Cerebrovascular aneurysms may develop. Cysts restricted to the liver constitute a separate rare genetic disorder.


Figure 18.34 MRI showing multiple cysts in the liver and kidneys in polycystic disease. Note the dilated common bile duct.
CAROLI'S SYNDROME
This is very rare and is characterised by segmental saccular dilatations of the intrahepatic biliary tree. The whole liver is usually affected, and extrahepatic biliary dilatation occurs in about one-quarter of patients. Recurrent attacks of cholangitis (see p. 885) occur and may cause hepatic abscesses. Complications include biliary stones and cholangiocarcinoma. Antibiotics are required for episodes of cholangitis, and occasionally localised disease can be treated by segmental liver resection.
CONGENITAL HEPATIC FIBROSIS
page 880

page 881
This is characterised by broad bands of fibrous tissue linking the portal tracts in the liver, abnormalities of the interlobular bile ducts, and sometimes a lack of portal venules. The renal tubules may show cystic dilatation (medullary sponge kidney, see p. 622), and eventually renal cysts may develop. The condition can be inherited as an autosomal recessive trait. Liver involvement causes portal hypertension with splenomegaly and bleeding from oesophageal varices that usually presents in adolescence or in early adult life. The prognosis is good because liver function is preserved. Treatment may be required for variceal bleeding and occasionally cholangitis (see p. 885). Patients can present during childhood with renal failure if the kidneys are severely affected.
CHOLEDOCHAL CYSTS
This term applies to cysts anywhere in the biliary tree (see Fig. 18.35). The great majority cause diffuse dilatation of the common bile duct (type I), but others take the form of biliary diverticula (type II), dilatation of the intraduodenal bile duct (type III) and multiple biliary cysts (type IV). The last type merges with Caroli's syndrome (see above). In the neonate they may present with jaundice or biliary peritonitis. Recurrent jaundice, abdominal pain and cholangitis may arise in the adult. Liver abscess and biliary cirrhosis may develop, and there is an increased incidence of cholangiocarcinoma. Excision of the cyst with hepaticojejunostomy is the treatment of choice.
ISSUES IN OLDER PEOPLE
LIVER DISEASE
10% of alcoholic liver disease presents over the age of 70 years, when it is more likely to be severe at presentation and has a worse prognosis than in younger people.
Hepatitis A causes more severe illness in older people and runs a more protracted course.
One-third of cases of primary biliary cirrhosis are over 65 years and age is an adverse prognostic factor.
More than 50% of all cases of liver abscess in the UK are over 60 years.
Approximately 50% of cases of hepatocellular carcinoma present over the age of 65 years in the UK.
Older people are less likely to survive liver surgery (including transplantation) because comorbidity is more prevalent than in younger patients.




Figure 18.35 Classification and frequency of choledochal cysts.

pages 878 - 881


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC018211


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com




Home > 2 SYSTEM-BASED DISEASES > 18 Liver and biliary tract disease > GALLBLADDER AND OTHER BILIARY DISEASE
GALLBLADDER AND OTHER BILIARY DISEASE
FUNCTIONAL ANATOMY
BILIARY SYSTEM
The biliary tract begins in the biliary canaliculi, which are formed by the arrangement of hepatocytes, and the intrahepatic bile ducts derived from them join progressively to form the right and left hepatic ducts. These ducts join as they emerge from the liver to form the common hepatic duct, which forms the common bile duct after joining the cystic duct (see Fig. 18.36). The common bile duct is approximately 5 cm long; it has a thin-walled wide-lumened proximal part and a thick-walled narrow-lumened distal part surrounded by the choledochal sphincter. The distal common bile duct usually joins the pancreatic duct before it enters the duodenum. The gallbladder is a pear-shaped sac lying under the right hemiliver, with its fundus located anteriorly behind the tip of the 9th costal cartilage. Its body and neck pass posteromedially towards the porta hepatis, and the cystic duct then joins it to the common hepatic duct. The cystic duct mucosa has prominent crescentic folds (valves of Heister), giving it a beaded appearance on cholangiography.
BILE
page 881

page 882


Figure 18.36 Functional anatomy of the biliary tree.
The liver secretes 1-2 litres of bile daily. The hepatocytes provide the driving force for bile flow by creating osmotic gradients of bile acids, which form micelles in bile (bile acid-dependent bile flow), and of sodium (bile acid-independent bile flow). Common bile duct pressure is maintained by rhythmic contraction and relaxation of the ampullary sphincter; this pressure exceeds gallbladder pressure in the fasting state so that bile normally flows into the gallbladder where it is concentrated some 10-fold by resorption of water and electrolytes. Cholecystokinin released from the duodenal mucosa during feeding causes gallbladder contraction and reduces sphincter pressure so that bile flows into the duodenum. Vagal activity maintains gallbladder tone, but sympathetic activity has little or no effect on the gallbladder.
GALLSTONES
Gallstone formation is the most common disorder of the biliary tree and it is unusual for the gallbladder to be diseased in the absence of gallstones.
Pathology
Gallstones are conveniently classified into cholesterol or pigment stones, although the majority are of mixed composition. Cholesterol stones are most common in industrialised countries, whereas pigment stones are more frequent in developing countries. Gallstones contain varying quantities of calcium salts, including calcium bilirubinate, carbonate, phosphate and palmitate, which are radio-opaque.
Epidemiology
In Western countries gallstones are common and occur in 7% of males and 15% of females aged 18-65 years, with an overall prevalence of 11%. In those under 40 years there is a 3:1 female preponderance, whereas in the elderly the sex ratio is about equal. Gallstones are common in North America, Europe and Australia, and are less frequent in India, the Far East and Africa. In developed countries the incidence of symptomatic gallstones appears to be increasing and they occur at an earlier age.
18.46 RISK FACTORS AND MECHANISMS FOR CHOLESTEROL GALLSTONES
? Cholesterol secretion
Elderly
Female
Pregnancy
Obesity
Rapid weight loss
Impaired gallbladder emptying
Pregnancy
Gallbladder stasis
Fasting
Total parenteral nutrition
Spinal cord injury
? Bile salt secretion
Pregnancy


18.47 COMPOSITION AND RISK FACTORS FOR PIGMENT STONES
Black Brown
Composition Polymerised calcium bilirubinates* Calcium bilirubinate crystals*
Mucin glycoprotein Mucin glycoprotein
Calcium phosphate Cholesterol
Calcium carbonate
Cholesterol Calcium palmitate/stearate
Risk factors Haemolysis Infected bile
Age Stasis
Hepatic cirrhosis
Ileal resection/disease

* Major component.
page 882

page 883
The most important risk factors for cholesterol and pigment gallstones are shown in Boxes 18.46 and 18.47. There has been much debate over the role of diet in cholesterol gallstone disease; an increase in dietary cholesterol, fat, total calories and refined carbohydrate or lack of dietary fibre have all been implicated. At present the best data support an association between simple refined sugar in the diet and gallstones. There is a negative association between a moderate alcohol intake (2-3 units daily) and gallstones.
Aetiology
Gallstone formation is multifactorial, and the factors involved are related to the type of gallstone.
Cholesterol gallstones
Cholesterol is held in solution in bile by its association with bile acids and phospholipids in the form of micelles and vesicles. Biliary lipoproteins may also have a role in solubilising cholesterol. In gallstone disease the liver produces bile which contains an excess of cholesterol either because there is a relative deficiency of bile salts or a relative excess of cholesterol. Such bile, which is supersaturated with cholesterol, is termed 'lithogenic'. Disorders with the potential to induce the production of lithogenic bile are shown in Box 18.48. Factors initiating crystallisation of cholesterol in lithogenic bile (nucleation factors) are also important; patients with cholesterol gallstones have gallbladder bile which forms cholesterol crystals more rapidly than equally saturated bile from patients who do not form gallstones. Factors favouring nucleation (mucus, calcium, fatty acids, other proteins) and antinucleating factors (apolipoproteins) have been described.
Pigment stones
Brown crumbly pigment stones are almost always the consequence of bacterial or parasitic infection in the biliary tree. They are found commonly in the Far East where infection of the biliary tree allows bacterial ß-glucuronidase to hydrolyse conjugated bilirubin to its free form, which then precipitates as calcium bilirubinate. The mechanism of black pigment gallstone formation in developed countries is not satisfactorily explained. Haemolysis is important as these stones occur in chronic haemolytic disease.
Biliary sludge
The term 'biliary sludge' describes bile which is in a gel form that contains numerous crystals or microspheroliths of calcium bilirubinate granules and cholesterol crystals as well as glycoproteins. It is an essential precursor to the formation of gallstones in the majority of patients. Biliary sludge is frequently formed under normal conditions, but then either dissolves or is cleared by the gallbladder; only in about 15% of patients does it persist to form cholesterol stones. Fasting, parenteral nutrition and pregnancy are also associated with sludge formation.
Clinical features
The majority of gallstones are asymptomatic and remain so. Only about 10% of those with gallstones develop clinical evidence of gallstone disease.
18.48 PATHOGENIC FACTORS LEADING TO THE PRODUCTION OF LITHOGENIC BILE
Defective bile salt synthesis
Excessive intestinal loss of bile salts
Over-sensitive bile salt feedback
Excessive cholesterol secretion
Abnormal gallbladder function


18.49 CLINICAL FEATURES AND COMPLICATIONS OF GALLSTONES
Clinical features
Asymptomatic
Biliary colic
Acute cholecystitis
Chronic cholecystitis
Complications
Empyema of the gallbladder
Porcelain gallbladder (see p. 884)
Choledocholithiasis
Pancreatitis
Fistulae between the gallbladder and duodenum or colon
Pressure on/inflammation of the common bile duct by a gallstone in the cystic duct (Mirizzi's syndrome)
Gallstone ileus
Cancer of the gallbladder


Symptomatic gallstones (see Box 18.49) manifest either as biliary pain ('biliary colic') or as a consequence of cholecystitis (see p. 884). If a gallstone becomes acutely impacted in the cystic duct, the patient will experience pain. The term 'biliary colic' is a misnomer because the pain does not rhythmically increase and decrease in intensity as in colic experienced in intestinal and renal disease. Instead the pain is typically of sudden onset and is sustained for about 2 hours; its continuation for more than 6 hours suggests that a complication such as cholecystitis or pancreatitis has developed. Pain is felt in the epigastrium (70% of patients) or right upper quadrant (20% of patients) and radiates to the interscapular region or the tip of the right scapula, but other sites include the left upper quadrant, the epigastrium and the lower chest; the pain can be confused with intrathoracic disease, oesophagitis, myocardial infarction or dissecting aneurysm.
Combinations of fatty food intolerance, dyspepsia and flatulence not attributable to other causes have been referred to as 'gallstone dyspepsia'. These symptoms are not now recognised as being caused by gallstones and are best regarded as non-ulcer dyspepsia (see p. 788).
Investigations
A plain abdominal radiograph will demonstrate calcified gallstones in less than 20% of patients. Ultrasonography is the method of choice to diagnose gallstones (see Fig. 18.7, p. 841) but oral cholecystography and CT can also be used (see Fig. 18.37). Oral cholecystography shows whether or not the gallbladder is functioning, and this is useful if oral dissolution therapy is being considered (see under Management below). MRI is becoming increasingly available and may demonstrate gallstones or their complications.
Complications
page 883

page 884


Figure 18.37 CT showing gallstone within gallbladder (arrow).
Occlusion of the cystic duct for any prolonged period of time results in acute cholecystitis. Other complications include chronic cholecystitis, and a mucocoele of the gallbladder, in which there is slow distension of the gallbladder from continuous secretion of mucus. If this material becomes infected, an empyema develops. Calcium may be secreted into the lumen of the hydropic gallbladder, causing limy bile, and if calcium salts are precipitated in the gallbladder wall the radiological appearance of 'porcelain' gallbladder results.
Gallstones in the gallbladder (cholecystolithiasis) migrate to the common bile duct (choledocholithiasis) in approximately 15% of patients and cause biliary colic, but they may be asymptomatic. Rarely, fistulae develop between the gallbladder and the duodenum, colon or stomach. Air will be seen in the biliary tree on plain abdominal radiographs. If a stone larger than 2.5 cm in diameter has migrated into the gut it may impact either at the terminal ileum or occasionally in the duodenum or sigmoid colon. The resultant intestinal obstruction may be followed by 'gallstone ileus'. Rarely, gallstones impacted in the cystic duct cause stricturing in the common hepatic duct (Mirizzi's syndrome), resulting in obstructive jaundice.
Cancer of the gallbladder is uncommon, although it is recognised more frequently in an ageing population and in a 'porcelain' gallbladder. In over 95% of patients with gallbladder cancer there are accompanying gallstones. Cancer is usually diagnosed as an incidental histological finding following cholecystectomy for gallstone disease.
Management
18.50 TREATMENT OF GALLSTONES
Cholecystectomy-open or laparoscopic
Oral bile acids-chenodeoxycholic or ursodeoxycholic
Contact dissolution
Lithotripsy
Endoscopic sphincterotomy


Asymptomatic gallstones found incidentally are not usually treated because the majority will never give symptoms. Symptomatic gallstones are best treated surgically, and minimal access techniques have largely replaced non-surgical treatment. Gallstones can be dissolved and fragmented in the gallbladder or removed mechanically from the common bile duct (see Box 18.50).
Medical dissolution of gallstones can be achieved by oral administration of the bile acid ursodeoxycholic acid. Radiolucent gallstones, a gallbladder that opacifies on oral cholecystography, stones not larger than 15 mm in diameter, moderate obesity and no or at most mild symptoms are the features which suggest that drug therapy may be feasible. Success can be expected in approximately 75% of patients who fulfil these criteria. Occasionally, direct contact dissolution therapy is attempted via percutaneous catheters or catheters placed at ERCP. Extracorporeal shock-wave lithotripsy is expensive and not widely available. Bile salt therapy is necessary following lithotripsy to dissolve the gallstone fragments within the gallbladder. As in the case of oral bile salt therapy, only 30% of all patients with gallbladder disease are suitable for lithotripsy. All therapeutic regimens which retain the gallbladder have a 50% recurrence of stones after 5 years.
CHOLECYSTITIS
ACUTE CHOLECYSTITIS
Aetiology and pathology
Acute cholecystitis is almost always associated with obstruction of the gallbladder neck or cystic duct by a gallstone. Occasionally, obstruction may be by mucus, parasitic worms or a tumour. The pathogenesis is unclear, but the initial inflammation is possibly chemically induced. This leads to gallbladder mucosal damage which releases phospholipase, converting biliary lecithin to lysolecithin, a recognised mucosal toxin. At the time of surgery approximately 50% of cultures of the gallbladder contents are sterile. Infection occurs eventually and in elderly patients or those with diabetes mellitus a severe infection with gas-forming organisms can cause emphysematous cholecystitis. Acalculous cholecystitis can occur in the intensive care setting.
Clinical features
The cardinal feature is pain in the right upper quadrant but also in the epigastrium, the right shoulder tip or interscapular region. It usually lasts for more than an hour but differentiation between biliary colic (see p. 883) and acute cholecystitis may be difficult; features suggesting cholecystitis include severe and prolonged pain, fever and leucocytosis.
Examination shows right hypochondrial tenderness, rigidity worse on inspiration (Murphy's sign) and occasionally a gallbladder mass. Fever is present but rigors are unusual. Leucocytosis is common, except in the elderly patient where the signs of inflammation may be minimal. Jaundice occurs in less than 10% of patients and may be due to the presence or recent passage of stones in the common bile duct. Minor increases of plasma transaminase and amylase activity may be encountered.
page 884

page 885
Cholecystitis usually resolves with medical treatment, but the inflammation may progress to an empyema or perforation and peritonitis.
Investigations
Plain radiographs of the abdomen and chest may show radio-opaque gallstones, and rarely intrabiliary gas due to fistulation of a gallstone into the intestine, and are important in excluding lower lobe pneumonia and a perforated viscus. Ultrasonography detects gallstones and gallbladder thickening due to cholecystitis. The plasma amylase should be measured to detect pancreatitis (see p. 802), which may be a complication of gallstones. The peripheral blood count often shows a leucocytosis.
Management
Medical
This consists of bed rest, pain relief, antibiotics and maintenance of fluid balance. Severe pain is relieved using morphine, and the increased tone of the sphincter of Oddi may be minimised by the concurrent use of atropine. Less severe pain can be relieved by pethidine, pentazocine or diclofenac. Antibiotics are required. A cephalosporin (such as cefuroxime) is the antibiotic of choice, and metronidazole is usually added in severely ill patients. Fluid balance is maintained by intravenous therapy and nasogastric aspiration is only needed for persistent vomiting. Any cause of stones (e.g. haemodialysis) should be treated.
Surgical
Urgent surgery is required when cholecystitis progresses in spite of medical therapy and when complications such as empyema or perforation develop. Operation should be carried out within 5 days of the onset of symptoms. Delayed surgery after 2-3 months is no longer favoured. Recurrent biliary colic or cholecystitis is frequent if the gallbladder is not removed.
CHRONIC CHOLECYSTITIS
Chronic inflammation of the gallbladder is almost invariably associated with gallstones. The condition may be asymptomatic. The usual symptoms are those of recurrent attacks of upper abdominal pain, often at night and following a heavy meal. The clinical features are similar to those of acute calculous cholecystitis but milder. The patient may recover spontaneously or following analgesia and antibiotics. Patients are usually advised to undergo elective laparoscopic cholecystectomy.
ACUTE CHOLANGITIS
Acute cholangitis is caused by bacterial infection of bile ducts and occurs in patients with other biliary problems such as choledocholithiasis (see below), biliary strictures or tumours, or after ERCP. Jaundice, rigors and abdominal pain are the cardinal presenting features. Treatment is with antibiotics and removal (if possible) of the underlying cause.
CHOLEDOCHOLITHIASIS
Stones in the common bile duct (choledocholithiasis) occur in 10-15% of patients with gallstones (see Fig. 18.38). These stones account for more than 80% of common bile duct stones; they migrate from the gallbladder, and are similar in appearance and chemical composition to the stones found elsewhere. Primary bile duct stones may develop infrequently within the common bile duct many years after a cholecystectomy or represent the accumulation of biliary sludge consequent upon dysfunction of the sphincter of Oddi. In Far Eastern countries, where bile duct infection is common, primary common bile duct stones are thought to follow bacterial infection secondary to parasitic infections with Clonorchis sinensis, Ascaris lumbricoides or Fasciola hepatica. Common bile duct stones can cause partial or complete bile duct obstruction and may be complicated by cholangitis due to secondary bacterial infection, septicaemia, liver abscess and biliary stricture.
Clinical features


Figure 18.38 ERCP showing common duct stones.
page 885

page 886


Figure 18.39 Ultrasound showing dilated bile ducts (between arrows) in obstructive jaundice secondary to obstruction of the common bile duct.
Choledocholithiasis may be asymptomatic, may be found incidentally by operative cholangiography at cholecystectomy, or may manifest as recurrent abdominal pain with or without jaundice. The pain is usually in the right upper quadrant and fever, pruritus and dark urine may be present. Rigors may be a feature; painless jaundice is uncommon. Physical examination may show the scar of a previous cholecystectomy; if the gallbladder is present, it is usually small, fibrotic and impalpable.
Investigations
Liver function tests show a cholestatic pattern and bilirubinuria is present. If cholangitis is present, the patient usually has a leucocytosis. The most convenient method of demonstrating obstruction to the common bile duct is by ultrasonography; this shows dilated extrahepatic and intrahepatic bile ducts together with gallbladder stones, but it is not always successful in indicating the cause of the obstruction in the common bile duct (see Fig. 18.39). Endoscopic retrograde cholangiography can be used to diagnose obstruction and its cause, and to remove bile duct stones. If ERCP fails, percutaneous transhepatic cholangiography may be undertaken.
Management
Cholangitis requires analgesia for pain, intravenous fluids and broad-spectrum antibiotics such as cefuroxime and metronidazole. Blood cultures should be taken before the antibiotics are administered. Patients require urgent decompression of the biliary tree and stone removal either surgically or by endoscopic sphincterotomy via ERCP. Endoscopic sphincterotomy and stone extraction is the treatment of choice, particularly in patients over the age of 60, and is successful in about 90% of patients. Less commonly used techniques include extracorporeal lithotripsy.
Surgical treatment of choledocholithiasis is carried out less frequently than ERCP because it carries higher morbidity and mortality. Before exploring the common bile duct an accurate diagnosis of choledocholithiasis should be confirmed by intraoperative cholangiography. If gallstones are found, the bile duct is explored, all stones are removed, stone clearance is checked by cholangiography or choledochoscopy, and a T-tube is inserted into the common bile duct. It is now possible to achieve these goals in specialist centres by laparoscopic means.
RECURRENT PYOGENIC CHOLANGITIS
This disease occurs in South-east Asia. Biliary sludge, calcium bilirubinate concretions and stones accumulate in the intrahepatic bile ducts, with secondary bacterial infection. The patients present with recurrent attacks of upper abdominal pain, fever and cholestatic jaundice. Investigation of the biliary tree demonstrates that both the intrahepatic and extrahepatic portions are filled with soft biliary mud. Eventually, the liver becomes scarred and liver abscesses develop. The condition is difficult to manage and requires drainage of the biliary tract with extraction of stones, antibiotics and, in certain patients, partial resection of damaged areas of the liver.
TUMOURS OF THE GALLBLADDER AND BILE DUCT
CARCINOMA OF THE GALLBLADDER
This is an uncommon tumour occurring more often in females and is usually encountered above the age of 70 years. More than 90% of such tumours are adenocarcinomas; the remainder are anaplastic or, rarely, squamous tumours. Gallstones are usually present and are thought to be important in the aetiology of the tumour.
The condition is usually diagnosed incidentally, following surgery for gallstone disease. Occasionally, it may manifest as repeated attacks of biliary pain and later persistent jaundice and weight loss. A gallbladder mass may be palpable in the right hypochondrium. Liver function tests show cholestasis, and gallbladder calcification (porcelain gallbladder) may be found on radiograph. The tumour may be diagnosed on ultrasonography and can be staged by CT. The treatment is surgical excision but local extension of the tumour beyond the wall of the gallbladder into the liver, lymph nodes and surrounding tissues is invariable and palliative management is usually all that can be offered. Survival is generally short.
CHOLANGIOCARCINOMA
page 886

page 887


Figure 18.40 Cholangiocarcinoma. A ERCP showing malignant biliary stricture (bottom arrow) and dilated intrahepatic bile ducts above (top arrow). B Post-ERCP stenting showing plastic endobiliary stent (arrow) which will draw bile from the dilated ducts above the stricture into the duodenum.
This uncommon tumour arises anywhere in the biliary tree from the small intrahepatic bile ducts to the papilla of Vater, but it is the tumour involving the confluence of the right and left hepatic ducts (Klatskin tumour) which is the most challenging to manage. The cause is unknown but it is associated with gallstones, primary sclerosing cholangitis and choledochal cysts (see p. 881). Primary sclerosing cholangitis is associated with ulcerative colitis, and cholangiocarcinoma may occur some years after proctocolectomy or as a presenting feature, with ulcerative colitis being discovered only subsequently. Tumours typically invade the lymphatics and adjacent vessels, with there being a predilection for spread within perineural sheaths.
The patient presents with jaundice, which may be intermittent. Half the patients have upper abdominal pain and weight loss. The diagnosis is made by ultrasound and cholangiography, but can be difficult to confirm in patients with sclerosing cholangitis. Cholangiocarcinomas can occasionally be excised or palliated surgically, but most patients are treated by inserting drainage stents across the tumour, using endoscopic or transhepatic techniques (see Fig. 18.40).
CARCINOMA AT THE PAPILLA OF VATER
Nearly 40% of all adenocarcinomas of the small intestine arise in relationship to the papilla of Vater and present with pain, anaemia, vomiting and weight loss. Jaundice may be intermittent or persistent. Diagnosis is made by duodenal endoscopy and biopsy of the tumour. Ampullary carcinoma must be differentiated from carcinoma of the head of the pancreas and a cholangiocarcinoma because both these latter conditions have a worse prognosis.
Curative surgical treatment can be undertaken by pancreaticoduodenectomy and the 5-year survival may be as high as 50%. When this is impossible a palliative bypass or insertion of a drainage stent is performed.
BENIGN GALLBLADDER TUMOURS
These are uncommon, often asymptomatic and usually found incidentally at operation or autopsy. Cholesterol polyps, sometimes associated with cholesterolosis, papillomas and adenomas are the main types.
MISCELLANEOUS BILIARY DISORDERS
POST-CHOLECYSTECTOMY SYNDROME
Dyspeptic symptoms following cholecystectomy (post-cholecystectomy syndrome) occur in about 30% of patients depending on how the condition is defined, how actively symptoms are sought, and the original indication for cholecystectomy. Post-cholecystectomy symptoms occur most frequently in women, in patients who have a history longer than 5 years prior to cholecystectomy, and in patients in whom the operation was undertaken for non-calculous gallbladder disease (see Box 18.51). Severe post-cholecystectomy syndrome occurs in only 2-5% of patients.
page 887

page 888
18.51 CAUSES OF POST-CHOLECYSTECTOMY SYMPTOMS
Immediate post-surgical
Bleeding
Biliary peritonitis
Abscess
Fistula
Biliary
Common bile duct stones
Benign stricture
Tumour
Cystic duct stump syndrome
Disorders of the ampulla of Vater
Extrabiliary
Non-ulcer dyspepsia
Peptic ulcer
Pancreatic disease
Gastro-oesophageal reflux
Irritable bowel syndrome
Functional abdominal pain


The usual complaints include right upper quadrant abdominal pain, flatulence, fatty food intolerance, and occasionally jaundice and cholangitis. Liver function tests may be abnormal and sometimes show cholestasis. Ultrasonography is used to detect biliary obstruction, and ERCP or MRCP is usually needed to detect common bile duct stones. Other investigations which may be required include upper gastrointestinal endoscopy, barium examination of the small intestine, pancreatic function tests, cholescintigraphy and a liver biopsy. The question of a functional illness should also be considered (see p. 254).
BILIARY MOTOR DISORDERS
Some patients with right upper quadrant discomfort do not have gallstones and the term 'biliary dyskinesia' has been introduced to describe this condition. The dyskinetic disorder may affect either the gallbladder or the sphincter of Oddi. Patients complain of recurrent epigastric or right upper quadrant pain.
The diagnosis is established by excluding gallstones and undertaking tests to demonstrate that contraction of the gallbladder is associated with pain and abnormal liver analytes or that the papilla is stenosed. ERCP, endoscopic manometry and radiomanometry are all used in an attempt to define this disorder more clearly. Identification of biliary dyskinesia remains difficult and the treatment is uncertain. Some patients with evidence of sphincter dysfunction derive benefit from sphincterotomy.
CHOLESTEROLOSIS OF THE GALLBLADDER
In this condition lipid deposits in the submucosa and epithelium appear as multiple yellow spots on the pink mucosa, giving rise to the description 'strawberry gallbladder'. The condition is usually asymptomatic but may occasionally present with right upper quadrant pain. Radiologically the features are those of small, fixed filling defects on cholecystography or ultrasonography, and the radiologist can usually differentiate between gallstones and cholesterolosis. The condition is usually diagnosed at cholecystectomy; if the diagnosis is made radiologically, cholecystectomy is indicated, depending on symptoms.
ADENOMYOMATOSIS OF THE GALLBLADDER
In this condition there is hyperplasia of the muscle and mucosa of the gallbladder. The projection of pouches of mucous membrane through weak points in the muscle coat produces Rokitansky-Aschoff sinuses. There is much disagreement over whether adenomyomatosis is a cause of right upper quadrant pain or other gastrointestinal symptoms. It may be diagnosed by oral cholecystography when a halo or ring of opacified diverticula can be seen around the gallbladder. Other appearances include deformity of the body of the gallbladder or marked irregularity of the outline. Localised adenomyomatosis in the region of the gallbladder fundus causes the appearance of a 'Phrygian cap'. Most patients are treated by cholecystectomy but it is advisable first to exclude other diseases in the upper gastrointestinal tract.
ISSUES IN OLDER PEOPLE
GALLBLADDER DISEASE
By the age of 70 years, the prevalence of gallstones is around 30% in women and 19% in men.
Acute cholecystitis in older people tends to be severe, may have few localising signs, and is associated with a high frequency of empyema and perforation. If such complications supervene, the mortality rate in this group may reach 20%.
Mortality after urgent cholecystectomy for acute uncomplicated cholecystitis is not significantly higher than in younger patients.
Endoscopic sphincterotomy and removal of common duct stones is well tolerated by older patients and has a substantially lower mortality than surgical common bile duct exploration.
Cancer of the gallbladder is a disease of old age, and has a 1-year survival of 10%.


FURTHER INFORMATION
Bacon BR. Hemochromatosis: diagnosis and management. Gastroenterology 2001; 320:718-725.
Blei AT. Diagnosis and treatment of hepatic encephalopathy. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(6):959-974. Medline Similar articles Full article
Fernandez J, Bauer TM, Navasa M, Rodes J. Diagnosis, treatment and prevention of spontaneous bacterial peritonitis. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(6):975-990. Medline Similar articles Full article
Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal haemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology 2001; 320:726-748.
Haydon GH, Neuberger J. Liver transplantation of patients in end-stage cirrhosis. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(6):1049-1073. Medline Similar articles Full article
Llovet JM, Bruix J. Early diagnosis and treatment of hepatocellular carcinoma. Baillieres Best Pract Res Clin Gastroenterol 2000; 14(6):991-1008. Medline Similar articles Full article
Pratt DS, Kaplan MM. Evaluation of abnormal liver enzyme results in asymptomatic patients. New Engl J Med 2001; 342:1266-1271.
Walsh K, Alexander GJ. Update on chronic viral hepatitis. Postgrad Med J 2001; 910:498-505.
www.aasld.org
www.bsg.org.uk
www.unos.org

pages 881 - 888


Link to this page: http://www.studentconsult.com/content/default.cfm?ISBN=0443070350&ID=HC018231


Copyright © 2005 Elsevier Inc. All rights reserved. Read our Terms and Conditions of Use and our Privacy Policy.
For problems or suggestions concerning this service, please contact: studentconsult.help@elsevier.com