• Viral hepatitis (Table 6.1) is caused by hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV) and hepatitis E virus (HEV).

• In addition, 1–2% of viral hepatitis is due to non-A–E viruses, i.e. so far unidentified viruses, and occasionally is a feature of a recognized viral illness such as infectious mononucleosis (Epstein–Barr virus, EBV), cytomegalovirus (CMV), yellow fever or herpes simplex. Toxoplasmosis can also produce a similar picture to infectious mononucleosis.

• Hepatitis B, C and D may progress to chronic viral hepatitis, which implies the presence of persistent liver inflammation for at least 6 months.

• Co-infection of HBV and/or HCV with HIV is common — see p. 115.

Table 6.1 Some features of hepatitis viruses

Hepatitis A

This is the most common viral hepatitis worldwide, often occurring in epidemics, usually caused by the ingestion of contaminated food or water (e.g. shellfish). Overcrowding and poor sanitation facilitate spread (faeco-oral transmission), the virus being present in the faeces for up to 3 weeks from onset of the disease.

The main symptoms are general malaise and anorexia, followed by jaundice with raised serum transferases. It usually settles in 3–6 weeks. Less than 1% develop acute fulminant hepatitis.

An anti-HAV IgM in the serum confirms an acute infection; IgG antibody develops later and provides lifelong immunity.

Management

• Supportive treatment. If illness is not resolving, repeat bilirubin, AST, ALT, albumin and PT.

• Vaccination. Vaccination is recommended to all people travelling to endemic areas. Patients with chronic liver disease, people with haemophilia and workers in frequent contact with hepatitis cases should also be vaccinated. A formaldehyde-inactivated HAV vaccine is available and 0.5 mL is given into the upper arm, followed by a booster dose 6–12 months later. Immunity can then last for up to 10 years.

• Hepatitis A immunoglobulin. A single IM dose of immunoglobulin 0.02 mL/kg is given to anyone recently exposed to HAV who has not previously been vaccinated. If the patient has been vaccinated more than once prior to exposure, no treatment is required. This dose gives protection for 3–4 months.

Hepatitis B

HBV is present worldwide, with an estimated 360 million carriers. The UK and the USA have a low carrier rate (0.5–2%), but this rises to 10–20% in parts of Africa, the Middle East and the Far East.

Vertical transmission from mother to child in utero, during parturition or soon after birth, is the usual means of transmission worldwide. This is related to the HBV replicative state of the mother (90% are HbeAg+, 30% HbeAg−ve) and is uncommon in Africa, where horizontal transmission (sibling to sibling) is common. HBV is not transmitted by breast feeding.

Horizontal transmission occurs particularly in children, through minor abrasions or close contact with other children, and HBV can survive on household articles, e.g. toys or toothbrushes, for prolonged periods so transmission may be possible.

Hepatitis D

HDV is an incomplete RNA particle enclosed in a shell of HBsAg. It is unable to replicate on its own but is activated by the presence of HBV. Active HBV synthesis is reduced by HDV infection and patients are usually negative for HBeAg and HBV DNA.

Co-infection of HDV and HBV is clinically indistinguishable from an acute icteric HBV infection, but a biphasic rise of serum aminotransferases may be seen. Diagnosis is confirmed by finding serum IgM anti-D in the presence of IgM anti-HBc.

Superinfection results in an acute flare-up of previously quiescent chronic HBV infection. A rise in serum transferases occurs and the diagnosis is made by finding serum IgM anti-D in the serum.

Treatment

Peginterferon-alfa2a for 48 weeks produced a sustained clearance of HDV RNA in 25%.

Hepatitis C

HCV is transmitted by blood and blood products. Prevalence of infection is less than 0.02% in Northern Europe, 1–3% in Southern Europe and up to 6% in Africa. Incidence is high in IV drug users but sexual transmission is uncommon. Vertical transmission is rare. In 20% of cases, the exact mode of transmission is unknown.

Acute HCV infection is usually subclinical but a mild illness with jaundice may occur. HCV antibody is not detected for 6–8 weeks, although HCV RNA measured by PCR can be detected at 2 weeks.

Chronic hepatitis occurs in 80% of patients. It is often found in an asymptomatic individual who is discovered to have a mild rise in the serum transferase on routine screening. The diagnosis is confirmed by detecting antibody to HCV in the serum, and qualitative and quantitative PCR for HCV RNA would indicate the viral load. HCV genotype is useful to predict the success of treatment.

Treatment

• Acute. In cases due to needlestick injury, interferon is used to prevent chronic disease.

• Chronic. Treatment is appropriate for patients with chronic hepatitis on liver histology who have HCV RNA in their serum and who have raised serum aminotransferases for more than 6 months. Patients with persistently normal aminotransferases are also treated if they have abnormal histology. The presence of cirrhosis is not a contraindication but therapeutic responses are less likely. The aim of treatment is to eliminate the HCV RNA from the serum in order to:

• stop the progression of active liver disease

• prevent the development of hepatocellular carcinoma.Patients with decompensated cirrhosis should be evaluated for possible transplantation.

Trends are now going towards specifically targeted therapy (STAT). For example, patients with genotype 1 with a mutation in anti-viral IL-28B are targeted with telaprevir in addition to peg-INF and ribavirin.

Antiviral agents

Current treatment is combination therapy with pegylated interferon, which is interferon with a polyethyleneglycol tail (α2a 180 mcg/week or α2b 1.5 mcg/kg/week) and ribavirin (1000–1200 mg/day for genotype 1, 800 mg/day for genotype 2 or 3) in daily divided doses for 12 months for genotype 1, and 6 months for other genotypes. Efficacy is also determined by viral load, with HCV RNA ≥ 6 000 000 U/L less likely to respond. For the side-effects of interferon, see p. 184. Ribavirin is usually well tolerated but side-effects include a dose-related haemolysis, and pruritus and nasal congestion occur. Pregnancy should be avoided, as ribavirin is teratogenic. Taribavirin is a new alternative with less anaemia being reported.

Telaprevir is a specific inhibitor of the HCV protease. It is showing efficacy in clinical trials but a major adverse effect is rash.

Monitoring results

An early virological response is defined as becoming HCV RNA-negative or having at least a 2 log reduction in RNA following treatment in the first 12 weeks. This occurs in about 80% of patients tolerating full dosage. If this is not achieved, they are unlikely to respond and treatment should be stopped. If HCV RNA is undetectable at 4 weeks, treatment for patients with genotype 2 can be stopped at 12–16 weeks, and for genotype 1 (if HCV RNA < 600 000 U/mL at baseline) at 6 months.

A sustained response is clearance of HCV RNA at 6 months. It is a good surrogate marker for the resolution of the hepatitis. This is achieved in 40–50% of patients with genotype 1 and 80% in genotype 2 or 3. In sustained responders relapse is unlikely and histological progression is halted. For non-responders and relapsers, longer duration of therapy is being assessed.

Hepatitis E

HEV is enterally transmitted, usually by contaminated water, with 30% of dogs, pigs and rodents carrying the virus in many developing countries. Clinical features are similar to HAV hepatitis. There is no carrier state and it does not progress to chronic liver disease. An ELISA for IgG and IgM anti-HEV is available, although not always reliable. HEV RNA can be detected in the serum or stools by PCR. There is a high mortality, particularly in pregnant women (10–20%).

Prevention of hepatitis

Avoiding the risk factors is still necessary despite the availability of vaccination for HAV and HBV. Standard safety precautions in laboratories and hospitals must be enforced strictly. HAV and HEV infection in the community should be prevented by improving sanitation and overcrowding.

Fulminant hepatic failure (See Emergencies in medicine p. 708)

This is defined as severe hepatic failure in a patient with a previously normal liver in whom encephalopathy develops in under 2 weeks. It can occur from any cause of acute hepatitis, the commonest (worldwide) being viral hepatitis; paracetamol overdosage is commonly implicated in the UK.

Histologically there is multi-acinar necrosis involving a substantial part of the liver. The patient is encephalopathic and jaundiced; gastrointestinal haemorrhage, sepsis, hypoglycaemia and worsening of the encephalopathy occur. Patients require 10% glucose infusion, correction of any coagulopathy (with IV vitamin K, platelets, blood or fresh frozen plasma) and any electrolyte abnormality with potassium, calcium, phosphate and magnesium as appropriate. A proton pump inhibitor should be given intravenously to prevent stress ulcers. Prophylaxis against bacterial and fungal infections is not routine but given if there is advanced encephalopathy, refractory hypotension or the development of SIRS. Suspected infections should be treated with an appropriate antibiotic. Raised intracranial pressure requires 20% mannitol intravenously. Patients should be managed in a specialized unit (Box 6.2), as liver transplantation may be required. Prognostic variables are shown in Box 6.3.

Box 6.2 Transfer criteria to specialized units for patients with acute liver injury

• INR > 3.0

• Presence of hepatic encephalopathy

• Hypotension after resuscitation with fluid

• Metabolic acidosis

• PT above normal (secs) > interval (hours) from overdose (paracetamol cases)

Cirrhosis and its complications

Cirrhosis results from the necrosis of liver cells followed by fibrosis and nodule formation. The liver architecture is diffusely abnormal and this interferes with liver blood flow and function. This derangement produces the clinical features of portal hypertension and impaired liver cell function. Serum albumin and PT are indicators of liver function, and the outlook is poor with a serum albumin level < 25 g/L. The PT is prolonged as the disease becomes more severe. Liver biochemistry is variable and not helpful in assessing function. Serum α-fetoprotein should be measured routinely every 6 months; a level > 400 ng/mL suggests hepatocellular carcinoma.

Prognosis

There are a number of prognostic classifications based on modifications of Child’s grading (A, B and C). This is based on the presence of jaundice, ascites and encephalopathy, the level of serum albumin and the PT. Patients with good liver function (Child’s grade A) do better than patients with poor liver function (Child’s grade C: albumin < 30 g/L, bilirubin > 50 µmol/L and ascites).

The Model of End-Stage Liver Disease (MELD) score is widely used as a predictor of mortality in transplant centres.

(LN = natural log)

To convert µmol/L to mg/dL: for bilirubin, divide by 17; for creatinine, divide by 88.4.

With a MELD score < 10, 1-year survival is 97%; with a score of 30–40, it is about 70%.

Complications

Variceal haemorrhage

Approximately 90% of patients with cirrhosis will develop gastro-oesophageal varices over 10 years and one-third of these patients will bleed from them. This is discussed in upper gastrointestinal haemorrhage, p. 149.

Ascites

Ascites is the presence of fluid within the peritoneal cavity and is a common complication of decompensated liver cirrhosis. Ascites occurs due to portal hypertension, low serum albumin and sodium retention.

• Diagnosis. Diagnostic aspiration should always be performed to exclude infection and to eliminate other causes of ascites.

• Management. The aim is both to reduce sodium intake and to increase renal excretion of sodium.

• Sodium and fluid restriction. Dietary sodium restriction to 40 mmol (1 g in 24 hours) will still maintain an adequate protein and calorie intake with a palatable diet. Fluid restriction is not necessary unless the serum sodium is < 120 mmol/L.

• Diuretic therapy. The aim should be to produce a net loss of fluid approaching 700 mL in 24 hours (0.7 kg of weight loss or 1.0 kg if peripheral oedema is present), and 60% of patients respond with this regimen. The aldosterone antagonist spironolactone, starting at 100 mg daily and increasing every 7 days to a maximum of 500 mg daily, is used. Chronic administration produces gynaecomastia. Eplerone does not have this side-effect. Amiloride 5–15 mg daily is also used. A loop diuretic, such as furosemide 20–40 mg or bumetanide 1 mg daily, may be added if response is poor. These loop diuretics have several disadvantages, including hyponatraemia, hypokalaemia and volume depletion. Ascitic fluid is mobilized more slowly than interstitial fluid and diuretic dosage is lower in those without peripheral oedema.

• Monitoring. Check serum electrolytes and creatinine at the start and every other day of treatment; weigh patients and measure urinary output daily.

• Electrolyte problems. Diuretics should be temporarily discontinued if a rise in serum creatinine level occurs, representing over-diuresis and hypovolaemia. Hyponatraemia occurring during therapy almost always represents haemodilution secondary to failure to clear free water (usually a marker of reduced renal perfusion) and should be treated by stopping the diuretics if the sodium level falls below 120 mmol/L, as well as introducing water restriction. Diuretics should also be stopped if there is hyperkalaemia or the development of encephalopathy.

• Paracentesis is used to relieve symptomatic tense ascites and can also serve as a means of rapid therapy. Hypovolaemia can occur and IV albumin is infused (8 g per L of ascitic fluid removed).

Spontaneous bacterial peritonitis (SBP)

SBP is due to Escherichia coli, Klebsiella and enterococci. It should be suspected in any patient with ascites with evidence of clinical deterioration. Features such as pain and pyrexia are frequently absent.

• Diagnosis. Diagnostic aspiration shows a raised neutrophil count > 250 cells × 10⁹/L in the ascitic fluid and is sufficient to start treatment immediately.

• Treatment. Cefotaxime IV 1 g twice daily, or ceftazidime IV 1 g 3 times daily, is used and modified on the basis of culture results. SBP has a mortality of 25% and recurs in 70% of patients. An oral quinolone, e.g. norfloxacin 400 g daily, prevents recurrence and prolongs survival. Patients are referred for possible liver transplantation.

Portosystemic encephalopathy (PSE)

PSE refers to a chronic neuropsychiatric syndrome secondary to chronic liver disease. PSE is seen in patients with cirrhosis, with portal hypertension that is due to spontaneous ‘shunting’, or in patients following a portosystemic shunt procedure, e.g. transjugular intrahepatic portosystemic shunting (TIPS). Encephalopathy is potentially reversible.

• Management consists of restriction of protein intake. Any precipitating cause, such as drugs, infection or electrolyte imbalance, is corrected. Lactulose, an osmotic purgative given 10–30 mL 3 times daily, and rifaximin, an unabsorbed antibiotic, are given to evacuate and sterilize the colon.

Hepatorenal syndrome

This occurs in a patient with advanced cirrhosis, jaundice and ascites. The urine output is low, with a low urinary sodium concentration due to a functional failure of the kidneys.

• It is precipitated by over-vigorous diuretic therapy, diarrhoea or paracentesis.

• Diuretic therapy should be stopped and hypovolaemia corrected. The prognosis is poor and liver transplantation is the best option.

Liver transplantation

This is performed in patients with fulminant hepatic failure of any cause, the commonest being acute viral hepatitis and following paracetamol (aminophen) overdose. All patients with chronic liver disease and Child’s grade C cirrhosis or MELD score > 15 should be assessed for transplantation.

• Transplantation in primary biliary cirrhosis is indicated when the serum bilirubin rises > 100 µmol/L.

• Patients with chronic hepatitis B with HBV DNA can be transplanted but recurrence of the hepatitis occurs despite the use of hepatitis B immunoglobulin and lamivudine.

• In chronic hepatitis C, the 5-year prognosis of the graft is good, although universal HCV reinfection occurs.

• Patients with alcoholic liver disease should have stopped drinking before being offered a transplant.

Prognosis

In low risk patients the 5 year survival is 70–80%.

Chronic liver disorders

Autoimmune hepatitis

This disease is seen mainly in women in middle age presenting with fatigue and elevated levels of serum aminotransferases. The immunoglobulins are raised and antinuclear and anti-smooth muscle antibodies are present in the serum.

A younger group of women often present with an acute hepatitis and jaundice. The group may well have the clinical features of cirrhosis with hepatosplenomegaly, spider naevi and liver palms. They have similar biochemical features but anti-liver/kidney microsomal (anti-LKM1) antibodies are often present.

In both groups there may be features of other autoimmune diseases, such as pernicious anaemia, thyroiditis and Coombs-positive haemolytic anaemia.

• Diagnosis requires a liver biopsy, which shows variable interface hepatitis with plasma cell infiltration.

• Treatment is with prednisolone 30 mg daily for 2 weeks, reducing to a maintenance dose of 10–15 mg daily as the biochemical parameters improve. Budesonide is an alternative with less steroid side effects. Azathioprine 2 mg/kg is added as a steroid-sparing agent. This therapy induces remission in 80% of cases but relapses occur after stopping the therapy. Liver transplantation may be required.

Primary biliary cirrhosis (PBC)

This usually affects middle-aged women, with pruritus being the commonest symptom. There is progressive destruction of bile ducts with granuloma formation, eventually leading to fibrosis and cirrhosis.

• Diagnosis. Serum antimitochondrial antibodies are present in almost all cases. Of the mitochondrial proteins involved, the antigen M2 is specific to PBC. A high serum alkaline phosphatase is often the only abnormality in the liver biochemistry but the serum IgM may be very high with a raised serum cholesterol. US shows diffuse liver involvement with normal extrahepatic bile ducts.

• Treatment:

• Ursodeoxycholic acid 10–15 mg/kg improves serum bilirubin and aminotransferase values, but it is not clear whether prognosis is altered.

• Vitamin supplementation is required because of malabsorption of fat-soluble vitamins (A, D and K); when deficiency is detected, they should be given prophylactically in the jaundiced patient.

• Bisphosphonates are required for osteoporosis. Hyperlipidaemia should be treated, usually with a statin.

• Colestyramine 1 4 g sachet 3 times daily can be helpful for pruritus but this can be difficult to treat.

• Liver transplantation is often necessary and should be performed when the bilirubin is 100 µmol/L.

Alcoholic liver disease

Ethanol is metabolized in the liver and 10–20% of people who drink heavily will develop serious liver damage.

Fatty change

The metabolism of alcohol invariably produces fat; this is minimal with small amounts of alcohol but with large amounts the hepatocytes become swollen with fat. Liver biochemistry shows mild abnormalities with elevation of the serum aminotransferases. The γ-GT is usually raised, and US or CT will demonstrate fatty infiltration. An elevated MCV indicates heavy drinking.

Alcoholic hepatitis

In addition to fatty change, there is an infiltration by polymorphonuclear leucocytes with hepatocyte necrosis. The clinical features vary from a few symptoms to an ill patient with jaundice and ascites. There is often a high fever and abdominal pain associated with the liver necrosis. In severe cases the mortality is at least 50%.

• Diagnosis. The serum bilirubin may be raised but there is always a rise in the serum transferases and serum alkaline phosphatase. The PT may be prolonged with a low serum albumin, indicating diminished liver function. A liver biopsy will confirm the diagnosis.

• Treatment. See below. This is often influenced by the discriminant function (DF):

Bilirubin µmol/L divided by 17 to convert to mg/dL.A high DF of ≥ 32 suggests severe liver disease and the prognosis is poor.

Alcoholic cirrhosis

The symptoms are often related only to the complications. There is frequently hepatosplenomegaly with deranged liver biochemistry. Diagnosis is usually made with US or CT and is confirmed by biopsy if necessary.

Management and prognosis of alcoholic liver disease

All patients must stop drinking. A slow (over 30 mins) IV infusion of thiamine 100 mg, in a combined preparation with other vitamins, should be given to prevent Wernicke–Korsakoff encephalopathy. Side-effects include serious allergic reactions.

• Alcoholic hepatitis.

• Good nutrition is necessary and this may need to be given via a fine-bore naso-gastric tube.

• Corticosteroids improve outcome in severe cases (see above). The mortality is approximately 50% with a PT twice normal.

• Pentoxifyllene 400 mg × 3 daily, an inhibitor of TNF synthesis, has been used with variable efficacy.

• Alcoholic cirrhosis. Management is that of the complications (p. 188).

Abstinence from alcohol results in an improvement in prognosis with a 5-year survival of 90%, as opposed to 60% in those who continue drinking. Liver transplantation is being used more widely in those who have stopped drinking.

Non-alcoholic fatty liver disease (NAFLD)

This is the term used for patients who are found to have a fatty liver, either on US or on liver biopsy, and who do not drink alcohol to excess. It is often seen in the obese, patients with diabetes and those with raised serum lipids. If there is evidence of inflammation on the liver histology, as well as fatty change, the term non-alcoholic steatohepatitis (NASH) is used. The prognosis of a fatty liver on its own appears to be good but some patients with NASH and raised serum aminotransferases go on to develop chronic liver disease, with a few having cirrhosis and occasionally hepatocellular carcinoma.

Treatment

There is no specific effective therapy.

• Weight loss; strict control of diabetes and lipid levels.

• Thiazolidinediones, e.g. pioglitazone, these have shown improvement in fatty change and inflammation but benefits in the long term are unclear.

• Metformin has been used.

Hereditary haemochromatosis (HH)

HH is a common inherited disease characterized by excess iron deposition in various organs, leading to eventual fibrosis and functional organ failure. Diabetes, arthritis, hypogonadism and cardiomyopathy are seen; the classic bronzed skin colour is rare. There is hepatomegaly with deranged liver biochemistry.

Diagnosis

• Serum iron is elevated (> 30 µmol/L), with a reduction in the total iron binding capacity (TIBC) and complete or almost complete transferrin saturation (> 60%).

• Serum ferritin is elevated (usually > 500 mcg/L or 240 nmol/L).

• Heterozygotes may have normal biochemical tests or only modest increases in serum iron or serum ferritin (usually > 400 mcg/L), with a transferrin saturation of > 50%. All patients and first degree relatives should be checked for a mutation in the HFE gene, which is strongly associated with HH.

Treatment

• Venesection prolongs life and may reverse tissue damage; the risk of hepatic malignancy still remains if cirrhosis is present and patients should be monitored with US and serum α-fetoprotein every 6 months. All patients should have excess iron removed as rapidly as possible, with venesection 500 mL (1 unit) performed twice weekly for up to 2 years, i.e. 160 U containing 250 mg of iron per U = 40 g of iron removed. During venesection, serum iron and ferritin and the mean corpuscular volume should be monitored. These fall only when available iron is depleted. Three or four venesections per year are required to prevent reaccumulation of iron, which is checked with a serum ferritin.

• Liver biopsy is useful to ensure removal of iron and to assess progress of hepatic disease.

Wilson’s disease

This is a rare error of copper metabolism, which results in copper deposition in various organs, including the liver and the basal ganglion of the brain.

• Children usually present with hepatic problems, whereas young adults have neurological features such as tremor, dysarthria, involuntary movements and eventually dementia. A specific sign is the Kayser−Fleischer ring caused by copper deposition in Descemet’s membrane in the cornea.

• The liver disease varies from an acute hepatitis, that can go on to fulminant hepatic failure, to chronic hepatitis or cirrhosis.

Treatment

• Lifetime treatment with penicillamine 1–1.5 g daily is effective in chelating copper but must be started early to prevent permanent damage.

• Trientine 1.2–1.8 g/day and zinc acetate 150 mg/day are used for maintenance therapy.

• Relatives should be screened for the ATP7B mutation.

α₁-Antitrypsin deficiency

This deficiency is sometimes associated with liver disease but more commonly causes pulmonary emphysema, particularly in smokers.

• The serum α₁-antitrypsin is low, and on electrophoresis most patients have the PiZZ phenotype. Liver biopsy shows the positive periodic acid–Schiff (PAS) globules in the liver, with fibrosis and cirrhosis.

• Liver transplantation is required for severe chronic liver disease.

Primary sclerosing cholangitis

This is a chronic disease due to fibrosing inflammation of intra- and extrahepatic bile ducts. Seventy per cent of patients have associated inflammatory bowel disease, usually ulcerative colitis. Primary sclerosing cholangitis is progressive and complicated by episodes of bacterial cholangitis and cholangiocarcinoma (20%).

• Diagnosis is supported by a raised alkaline phosphatase, a positive antineutrophil cytoplasmic antibodies (ANCA) and typical findings of strictures on ERCP or MRCP.

• Treatment. Episodes of cholangitis are treated with antibiotics. Ursodeoxycholic acid 250 mg 4 times daily has been used but liver transplantation is the only proven therapy.

Budd–Chiari syndrome

There is obstruction to the venous outflow of the liver due to occlusion of the hepatic vein. This occurs in hypercoagulability states and presents with abdominal pain, hepatomegaly and sometimes evidence of liver failure.

• Diagnosis. US (with Doppler), CT or MRI show the abnormalities in blood flow in hepatic vein.

• Treatment. Liver transplantation is the treatment of choice for chronic and fulminant cases.

Liver abscesses

Pyogenic abscess

These abscesses are uncommon but may be single or multiple. Aetiology is often unclear. The most common organism is E. coli but often the infection is mixed. Some patients are ill with fevers, rigors, anorexia, vomiting and abdominal pain, while others present only with malaise. US is the most useful initial investigation but a CT scan is diagnostic. Aspiration is usually attempted to obtain material for culture and broad-spectrum antibiotics such as IV cefotaxime 1 g every 12 hours are given and surgical drainage is not usually necessary.

Amoebic abscess

Entamoeba histolytica is carried from the bowel to the liver, producing inflammation and multiple microabscesses, which can develop into single or multiple large abscesses. An amoebic complement fixation test is always positive.

• Treatment

• Metronidazole 800 mg 3 times daily for 10 days.

• Aspiration is used in patients failing to respond, in multiple and large abscesses, and in those with abscesses in the left lobe of the liver.

• Diloxanide furoate 500 mg 8-hourly for 10 days should be given subsequently to remove amoebae from the bowel.

Drugs and the liver

• Many drugs are metabolized by liver enzymes and cause mild liver biochemical abnormalities.

• Some drugs can cause acute liver failure or chronic liver disease.

• Hepatotoxicity can be:

• direct and dose-dependent; this is predictable, e.g. paracetamol

• idiosyncratic and non-dose-dependent (Table 6.3): hypersensitivity; metabolic — due to altered drug clearance or increased hepatotoxic metabolics, e.g. ketoconazole.

Table 6.3 Liver damage produced by some drugs

Types of liver damage	Drugs
Zone 3 necrosis	Amanita mushrooms Carbon tetrachloride Cocaine Paracetamol Piroxicam Salicylates

Zone 1 necrosis Ferrous sulphate Microvesicular fat

Nucleoside reverse transcriptase inhibitors

Steatohepatitis

Fibrosis

Other cytotoxic agents

Retinoids

Vitamin A

Vascular Sinusoidal dilatation

Anabolic steroids

Oral contraceptives

Peliosis hepatis

Anabolic steroids, e.g. danazol

Azathioprine

Oral contraceptives

Veno-occlusive

Cytotoxics — cyclophosphamide

Pyrrolizidine alkaloids (Senecio in bush tea)

Acute hepatitis

Paracetamol (acetaminophen) overdose

Volatile liquid anaesthetics, e.g. halothane

Chronic hepatitis

Fenofibrate

Infliximab (autoimmune)

Isoniazid

Methyldopa

Nitrofurantoin

General hypersensitivity

Allopurinol

Anticonvulsants, e.g.

Ampicillin

Co-trimoxazole

Canalicular cholestasis

Azathioprine

Chlorpromazine

Ciclosporin

Cimetidine/ranitidine

Biliary sludge Ceftriaxone Sclerosing cholangitis Hepatic arterial infusion of 5-fluorouracil Hepatic tumours Pills with high hormone content (adenomas) Hepatocellular carcinoma

Danazol

Oral contraceptives

The ‘predictability’ of drugs to produce damage can be affected by metabolic events preceding their ingestion. For example, chronic alcohol users may become more susceptible to liver damage because of the enzyme-inducing effects of alcohol, or ill or starving patients may become susceptible because of the depletion of hepatic glutathione produced by starvation. Many other factors, such as environmental or genetic effects, may be involved in determining the ‘susceptibility’ of certain patients to certain drugs.

• The incidence is 14 per 100 000 population, with a 6% mortality.

• It is the most common cause of acute liver failure in the USA.

• Liver transplantation is used.

N.B. In any patient with liver dysfunction, ALWAYS ask about drugs taken (prescribed or unprescribed).