Graeme Alexander
Synopsis
The liver is the most important organ for structural alteration and disposal of drugs, generating metabolites which may be biologically active or inactive (or toxic). The liver is exposed to drugs at higher concentrations than most organs because most agents are administered orally and absorbed from the gastrointestinal tract, so the whole dose passes through the liver to the systemic circulation, rendering the liver vulnerable to injury from chemicals and drugs. Conversely, disordered hepatic function is an important cause of abnormal drug handling and responses.
• Drugs and the liver.
Pharmacodynamic and pharmacokinetic changes
Prescribing in liver disease
Drug-induced liver injury
Aspects of therapy.
Effects of liver disease
Pharmacodynamic changes in liver disease
Patients with advanced liver disease have increased prothrombin time (INR) and serum bilirubin and require particular care when prescribing because they exhibit abnormal end-organ responses to drugs. Sensitivity of the central nervous system (CNS) to opioids, sedatives and antiepilepsy drugs is increased; the effect of oral anticoagulants is increased because synthesis of coagulation factors and thrombotic factors is impaired; fluid and electrolyte balance are altered; sodium retention is induced more readily by non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids; ascites and oedema become diuretic resistant.
Pharmacokinetic changes in liver disease
The liver has large metabolic reserve and important changes in drug handling occur only with hepatic decompensation. Parenchymal liver disorders, including chronic viral hepatitis or alcohol-related liver disease, have more impact on hepatic drug-metabolising enzyme activity than cholestatic conditions, such as primary biliary cirrhosis, where elimination via biliary excretion may be impaired. Hepatocellular injury leads to decreased activity of drug-metabolising enzymes, reflected in diminished plasma clearance of drugs with hepatic metabolism. There is variation between patients and overlap with healthy subjects.
Hepatic blood flow and metabolism
Complex changes in blood flow occur with liver disease. Increased resistance to portal blood flow in cirrhosis and portosystemic/intrahepatic shunts reduce drug delivery to hepatocytes, while increasing delivery direct to the systemic circulation. The pattern of change caused by disease relates to the manner in which the healthy liver treats a drug; there are two general classes:
• Drugs metabolised rapidly with high extraction in a single pass through the liver. Clearance is limited normally by hepatic blood flow, but in severe liver disease less drug is extracted from blood passing through the liver because of poor hepatocyte function and portosystemic shunts that allow blood to bypass the liver. The predominant kinetic change for drugs given orally is increased systemic availability. The initial and maintenance doses of such drugs should be reduced. With severe liver impairment the t½ of drugs in this class may lengthen.
• Drugs metabolised slowly with poor extraction in a single pass through the liver. The rate-limiting factor for elimination of this type of drug is metabolic capacity and the major effect of liver disease is prolongation of t½. Consequently, the interval between doses may need to be lengthened and the time to reach steady-state concentration in the plasma (5 × t½) is increased.
Plasma protein binding of drug
Binding of drugs to albumin is reduced when plasma concentrations of albumin fall with defective synthesis. These changes provide scope to enhance the biological activity of drugs, but assume importance only with extensive protein binding (> 90%).
Other considerations
Patients with severe decompensated liver disease develop renal impairment, with consequences for drugs with significant renal elimination. Where possible, dosing should be guided by measuring plasma concentrations (e.g. vancomycin).
Prescribing for patients with liver disease
Prescribing of most drugs is safe in well-compensated liver disease. If in doubt, check the prothrombin time and serum bilirubin. Take particular care with:
• Impaired hepatic synthetic function (hypoalbuminaemia, increased INR).
• Current/recent hepatic encephalopathy.
• Fluid retention and renal impairment.
• Drugs with:
high hepatic extraction
high plasma protein binding
low therapeutic ratio
CNS depressant effect.
For drugs with significant hepatic metabolism, a reasonable approach is to reduce the dose to 25–50% of normal and monitor responses. Specific examples include:
CNS depressants
Sedatives, antidepressants and antiepilepsy drugs should be avoided or used with extreme caution in advanced liver disease, particularly with current/recent hepatic encephalopathy. Enhanced CNS sensitivity to such drugs is well documented. Treatment of alcohol withdrawal in patients with established liver disease is hazardous; reducing doses of chlordiazepoxide over 5–10 days is recommended (with high-dose thiamine).
Analgesics
Opiates can precipitate hepatic encephalopathy in decompensated liver disease. If required to control postoperative pain, doses should be reduced to 25–50%. Intravenous infusions risk accidental overdose. Codeine can precipitate hepatic encephalopathy through constipation alone and accumulates with renal impairment. Avoid aspirin and other NSAIDs whenever possible, as they exacerbate impaired renal function and fluid retention by inhibiting prostaglandin synthesis and precipitate gastrointestinal bleeding.
Gastrointestinal system
Antacids that contain large quantities of sodium can precipitate fluid retention and cause ascites. Aluminium- or calcium-based preparations and antimotility drugs cause constipation and may precipitate hepatic encephalopathy.
Drug-induced liver damage
The spectrum of hepatic abnormalities caused by drugs is broad (Table 34.1). Drugs tend to injure specific hepatocyte components, e.g. plasma membrane, biliary canaliculi, cytochrome P450 enzymes or mitochondria.
Table 34.1 Idiosyncratic drug reactions and the cell components that are affected
|
Type of reaction |
Effect on cells |
Examples of drugs |
|
Hepatocellular |
Direct effect on production by enzyme–drug combination leads to cell and membrane dysfunction |
Isoniazid, trazodone, diclofenac, nefazodone, venlafaxine, lovastatin |
|
Immune mediated |
Cytotoxic lymphocyte response directed at hepatocyte membranes altered by drug metabolite ± additional autoimmune component |
Nitrofurantoin, methyldopa, lovastatin, minocycline, halothane |
|
Cholestasis |
Injury to canalicular membrane and transporters |
Chlorpromazine, oestrogen, erythromycin and its derivatives |
|
Granulomatous |
Macrophages, lymphocytes infiltrate hepatic lobule |
Diltiazem, sulfa drugs, quinidine |
|
Microvesicular fat |
Altered mitochondrial respiration, β-oxidation leads to lactic acidosis and triglyceride accumulation |
Didanosine, tetracyclines, acetylsalicylic acid, valproic acid |
|
Steatohepatitis (fatty liver) |
Multifactorial |
Amiodarone, tamoxifen |
|
Fibrosis |
Activation of stellate cells |
Methotrexate, excess vitamin A |
|
Vascular collapse |
Causes ischaemic or hypoxic injury |
Nicotinic acid, cocaine, methylenedioxymethylamfetamine (MDMA) |
|
Oncogenesis |
Encourages tumour formation |
Oral contraceptives, androgens |
|
Mixed |
Cytoplasmic and canalicular injury, direct damage to bile ducts |
Amoxicillin–clavulanic acid, carbamazepine, herbs, ciclosporin, methimazole, troglitazone |
Certain drugs interfere with bilirubin metabolism and excretion without causing hepatic injury. Jaundice is induced selectively with minimal or no disturbance of other liver function tests; recovery follows stopping the drug.
Examples are:
• C-17α-substituted steroids impair bilirubin excretion into hepatic canaliculi. These include synthetic anabolic steroids and oestrogens in oral contraceptives; jaundice due to the latter is rare with current formulations. Many have genetic susceptibility with mutations in ABC cassette biliary transporter proteins.
• Rifampicin impairs hepatic uptake and excretion of bilirubin; unconjugated and conjugated bilirubin levels may be raised within 3 weeks.
• Fusidic acid interferes with hepatic bilirubin excretion, causing conjugated hyperbilirubinaemia, particularly with sepsis.
Diagnosis and management of drug-induced liver injury
• Always consider the possibility. Take careful drug histories, including over-the-counter, complementary, illicit and alternative medicines.
• Consider a viral aetiology with hepatitis.
• Consider other causes of cholestatic disease.
• Underlying liver disease can cause diagnostic confusion.
• Liver biopsy is often helpful, but eosinophil infiltration, often thought to be specific for drug reaction, has many causes.
• Diagnostic challenge is dangerous, may precipitate life-threatening liver disease and is never justified.
• Monitoring liver function in the early weeks of therapy is wise in detecting early reactions to drugs with hepatotoxic potential, e.g. isoniazid. Minor abnormalities (serum transaminase levels less than twice normal) are often self-limiting and progress should be monitored. For increases exceeding three-fold, consider drug withdrawal, even in asymptomatic patients.
Aspects of therapy
Complications of cirrhosis
Variceal bleeding
Varices are dilated vessels, linking the portal and systemic venous systems, which return blood from the splanchnic circulation to the systemic circulation, bypassing the liver, decompressing the portal venous system and reducing portal pressure. Varices can be large, and haemorrhage, sometimes catastrophic, occurs from any of these vessels when intravascular pressures reach a threshold. Lower oesophageal or gastric varices, which are thin-walled and submucosal, are most prone to haemorrhage because intravascular pressures rise beyond that threshold with everyday physiological processes.
Portal pressure is a function of portal venous resistance and blood flow. In cirrhosis, both portal venous resistance and splanchnic blood flow are increased, the latter by a combination of splanchnic vasodilatation and increased cardiac output. Variceal bleeding is more likely once the pressure gradient between the portal and systemic venous systems rises above 12 mmHg (measured as the wedged hepatic venous pressure).
Fifty per cent die from hypovolaemia or associated complications after a first oesophageal or gastric variceal haemorrhage, manifest as melaena or haematemesis. Correct hypovolaemia promptly with plasma expanders and blood transfusion. The use of central venous access and monitoring is recommended; correction of coagulopathy with platelets and clotting factors appears logical. The relation between bacterial infection and haemorrhage is intriguing; bacterial infection is often found at presentation and 60% have evidence of infection within 7 days of haemorrhage. It is unclear whether infection increases the risk of haemorrhage or is a consequence. Bacterial infection should be treated, or anticipated, using broad-spectrum antibiotics with Gram-negative cover in line with local prescribing policy. Proton pump inhibitors are also recommended. Many patients cease bleeding spontaneously, but over half re-bleed within 10 days. Conservative management is rarely acceptable.
Acute variceal haemorrhage
The first step is always resuscitation. If bleeding varices are suspected, give terlipressin, as it reduces splanchnic blood flow, increases systemic blood pressure and reduces haemorrhage, which aids diagnostic endoscopy.
Oesophageal band ligation is the treatment of choice for bleeding varices identified at endoscopy. Varices are obliterated by application of small elastic bands under direct vision by an experienced operative. This has supplanted injection sclerotherapy, which involved injecting sclerosant into and around varices but which carried a higher rate of complications (oesophagitis, oesophageal stricture/perforation and distant sclerosant embolisation). Direct injection of superglue into the varix, the treatment of choice for bleeding gastric varices, requires considerable expertise. Bleeding is controlled in 90% of patients after oesophageal band ligation in conjunction with terlipressin. Obliteration of oesophageal varices requires repeated band ligation over a prolonged period.
Pharmacological reduction of portal pressure
Vasopressin, in addition to its action on renal collecting ducts (through V2 receptors), constricts smooth muscle (V1 receptors) in the cardiovascular system and particularly in splanchnic blood vessels, reducing splanchnic blood flow. Systemic, cerebral and coronary artery vasoconstriction are predictable complications necessitating treatment withdrawal in 20% of older patients. In patients with cardiovascular disease and uncontrolled haemorrhage that precludes definitive endoscopic therapy, simultaneous administration of glyceryl trinitrate (transdermally, sublingually or intravenously) allows continued use of vasopressin, reducing cardiac risk, and also reduces portal venous resistance and pressure directly.
Vasopressin is cleared rapidly from the circulation so is given by continuous intravenous infusion; with concerns about distant ischaemia, the short t½ of vasopressin is advantageous.
The synthetic analogue, terlipressin (triglycyllysine-vasopressin) has supplanted vasopressin. This prodrug is converted in vivo to vasoactive lysine vasopressin, which has biological activity for 3–4 h, and is effective as bolus injections 4-hourly for 2–5 days, reducing the risk of re-bleeding.
Somatostatin and the synthetic analogue octreotide reduce portal pressure by decreasing splanchnic blood flow. Octreotide has the advantage of a longer duration of action and is given as bolus injection. It can be used as an alternative to terlipressin, with similar efficacy and indications, but does not carry a risk of cerebral or cardiac ischaemia.
When endoscopic therapy proves impossible or ineffective and bleeding continues despite pharmacotherapy, the next step is placement of a transjugular intrahepatic portosystemic shunt (TIPS), linking systemic and portal circulations with a covered expandable stent. With this in mind, patients should have early ultrasound assessment of the portal vein after variceal haemorrhage, as patency is usually a prerequisite for TIPS insertion by interventional radiologists. Covered stents are recommended for long-term patency. Long-term complications of TIPS include loss of patency with recurrent portal hypertension, stent infection and portosystemic encephalopathy.
Direct pressure on varices can be applied with an inflatable triple-lumen tube that abuts the gastro-oesophageal junction providing temporary control of bleeding in 90%. Re-bleeding is common when the tube is withdrawn and use is often complicated by aspiration, oesophageal ulceration or perforation. Advantages of this approach are safer transfer of patients to units with expertise or as a temporary measure before definitive therapy. Patients who continue to bleed or are unsuitable for TIPS have a high mortality and should be considered for surgery.
Prevention of variceal haemorrhage
Endoscopic oesophageal band ligation repeated at regular intervals until varices are obliterated is the treatment of choice for secondary prevention of variceal haemorrhage and substantially reduces the incidence of re-bleeding. Endoscopic band ligation is also the preferred approach for primary prevention of variceal haemorrhage for those at high risk, defined by endoscopic criteria.
Pharmacological therapy
Non-selective β-blockers, e.g. propranolol or nadolol, are also used as primary or secondary prophylaxis against variceal haemorrhage. They reduce cardiac output via β1-receptor antagonism and induce splanchnic vasoconstriction via β2-receptor antagonism, allowing unopposed α-adrenergic vasoconstriction. Propranolol is extracted extensively in a single pass through the liver so systemic availability is less predictable in cirrhosis with portal hypertension due to variations in hepatic blood flow and portosystemic shunts. Ideally, the dose of propranolol (given twice daily) should be adjusted by measuring the wedged hepatic venous pressure since haemorrhage is rare if this is below 12 mmHg. This is often not possible. As an alternative, monitor the resting pulse rate, aiming at a 25% reduction as a measure of adequate β-blockade, although this is a poor surrogate marker of efficacy and many patients are under-treated. Nadolol, with a longer duration of action, is given once daily.
Ascites
Fifty per cent of patients with cirrhosis develop ascites within 10 years. Ascites is an important milestone, since 50% will die within 2 years. The process by which ascites forms in cirrhosis is not understood fully but involves activation of the renin–angiotensin–aldosterone system (causing renal retention of sodium and water) and the production of antidiuretic hormone (causing hyponatraemia due to dilution of plasma sodium). Hypoalbuminaemia and portal hypertension favour formation of ascites.
Management of ascites
Perform an ascitic tap to confirm the presence of a transudate before initiating therapy. Ultrasound assesses portal vein patency and the presence of hepatocellular carcinoma. Treatment targets induction of natriuresis with consequent loss of water. Salt restriction is effective; fluid restriction is unnecessary unless the plasma sodium falls below 125 mmol/L. Measurement of urinary sodium before treatment and changes in therapy is helpful, indicating if dietary restriction of sodium has been achieved, helping time the introduction of diuretics, guiding dose changes and indicating when therapy has ceased to be effective.
Bed rest (reduces plasma renin activity) with dietary sodium restriction is effective, but diuretics are needed eventually. Spironolactone is most useful, although maximum efficacy is seen at 2 weeks, following metabolism to products with long duration of action, e.g. canrenone (t½ 10–35 h). If renal function is conserved, loop diuretics, e.g. furosemide, may be added, counteracting hyperkalaemia induced by spironolactone. A ratio of spironolactone 100 mg to furosemide 40 mg works well and under careful supervision can be increased weekly to a maximum of spironolactone 400 mg + furosemide 160 mg. It is rare for patients to tolerate these doses for long.
Monitor body-weight, as patients with oedema and ascites may exhibit rapid weight loss, which should not exceed 0.5 kg/day; extreme negative fluid balance runs the risk of hypovolaemia, electrolyte disturbance, renal impairment and hepatic encephalopathy.
Patients lose weight if the urinary sodium excretion exceeds intake; those who do not respond despite a high urinary sodium are almost certainly receiving additional dietary sodium (sometimes iatrogenic, e.g. antacids). Unwanted effects of diuretic use are very common; in addition to electrolyte disturbances and renal impairment, cramps are unpleasant and if spironolactone causes painful gynaecomastia, amiloride is an alternative (10–40 mg/day). Those without natriuresis should have diuretic therapy withdrawn.
Abdominal paracentesis was once shunned because of the risk of circulatory failure, but administration of albumin at the time of paracentesis has led to its safe re-introduction. Drainage leads to prompt relief of discomfort of tense, painful ascites and improves circulatory dynamics; it can be undertaken as other measures to control ascites are introduced. Alternatively, paracentesis is the treatment of choice for patients unresponsive to diuretic therapy or with complications of diuretic treatment, especially renal impairment. Planned procedures at intervals of 2–3 weeks restore a degree of quality of life. It is essential to assess subacute bacterial peritonitis at each paracentesis, limit the duration of paracentesis (6 h) and ensure that each litre of ascites removed is matched by 6–8 g albumin given before or with paracentesis. Paracentesis carries a risk of perforation of abdominal contents and abdominal wall varices.
Patients with ascites should receive prophylaxis against subacute bacterial peritonitis. Quinolones, for example ciprofloxacin or norfloxacin, are effective.
Subacute bacterial peritonitis
This medical emergency has high mortality and should be suspected in any patient with liver disease and ascites who develops pain or clinical deterioration. A white cell count > 500 cells/mL or > 250 neutrophils/mL of ascitic fluid confirms the diagnosis. Culture of ascites is often negative and treatment should be triggered by the leucocyte count. Infection of ascites is a manifestation of severe liver disease and attributed to translocation of Gram-negative organisms across the gut wall. Antibiotic use is guided by local hospital preferences, but quinolones are effective unless the patient has been on antibiotic prophylaxis, when a switch to meropenem is recommended. Treatment is for 7–14 days, with an ascitic tap at completion of therapy.
Hepatorenal syndrome
This occurs in 10% of patients with advanced cirrhosis and ascites and is attributed to intense renal vasoconstriction (Fig. 34.1). It is defined by the urinary sodium under 5 mmol/L with euvolaemia. Three-month mortality is high. Some patients respond to vasoconstrictor agents, particularly terlipressin, while maintaining volume with albumin, over a 14-day interval. Dopamine is ineffective.
Fig. 34.1 Haemodynamic abnormalities in decompensated cirrhosis.
Hepatic encephalopathy
Infection, gastrointestinal bleeding, injudicious use of sedatives and diuretics can precipitate hepatic encephalopathy in cirrhosis. The pathophysiology is complex but ammonia is a key player. Diagnosis is confirmed by elevated plasma ammonia and/or typical EEG appearances. Ammonia is derived from the action of colonic urease-containing bacteria and normally undergoes hepatic extraction from portal blood, but with portal/systemic shunting and impaired hepatic metabolism, it reaches high systemic concentrations, affecting the brain adversely.
Lactulose acts as an osmotic laxative to expedite clearance of potentially toxic substances from the gastrointestinal tract. In addition, colonic bacteria metabolise it to lactic and acetic acids, which inhibit the growth of ammonia-producing organisms and by lowering pH, reduce non-ionic diffusion of ammonia from the colon into the bloodstream. The correct dose is that which produces two to four soft acidic stools daily (usually 30–60 mL daily). Exceeding this dose causes dehydration.
Dietary restriction of protein reduces ammonia production, but any clinical benefit is outweighed by exacerbating malnutrition characteristic of cirrhosis and it is not recommended.
Neomycin and metronidazole inhibit urease-producing bacteria, but their use is limited by toxicity. The non-absorbed antibiotic rifaximin is effective over a prolonged period without significant toxicity.
Hepatocellular carcinoma (HCC)
Patients with cirrhosis face a substantial lifetime risk of HCC, which is higher in men, increased age and the cause of liver injury. Surveillance with liver ultrasound and serum α-fetoprotein estimation allows early tumour detection. Liver transplantation is curative for 75% with smaller tumours. Surgical resection, radiofrequency ablation and transarterial embolisation (with or without chemotherapy) have beneficial effects that usually fall short of cure. Recent clinical trials show sorafenib extends life by a few months in patients with compensated cirrhosis, but with significant toxicity.
Immune-mediated liver disease
Autoimmune hepatitis (AIH)
This chronic inflammatory disease is associated with circulating antinuclear and smooth muscle antibodies and high serum immunoglobulin concentrations (serum IgG above 20 g/L). The presentations include jaundice with ill-health, relapsing/remitting jaundice and, less commonly, subacute liver failure. A third of patients have cirrhosis at presentation and untreated cases progress to cirrhosis. Corticosteroids are first-line therapy (prednisolone 20 mg daily). Faced with subacute liver failure (increased INR and hepatic encephalopathy) the choice is between corticosteroids (with a risk of sepsis) or liver transplantation. Rituximab, to deplete B cells, may have a role in this unusual scenario but data are preliminary.
The majority of patients improve substantially with corticosteroids and a fall in serum bilirubin occurs usually within 2 weeks. Azathioprine (1 mg/kg daily) should be introduced when jaundice improves and is an effective steroid-sparing agent. In the long term corticosteroid doses should be adjusted according to liver function. Elevated IgG levels settle with successful therapy; a rise in serum IgG predates relapse. Remission can be maintained in the first 2 years by azathioprine with prednisolone (5–10 mg/day). If there is evidence of biochemical remission with a normal IgG after 2 years then withdrawal of corticosteroids can be considered. A liver biopsy to confirm remission is recommended before reducing the dose of corticosteroids. Long-term remission maintained by azathioprine is the goal. There are no clear criteria to determine whether azathioprine can be stopped safely. Corticosteroids often cause steatosis, increasing liver enzymes, which may be mistaken for active AIH.
Mycophenolate mofetil (500 mg twice daily orally) appears useful when patients are intolerant of azathioprine. Patients intolerant of prednisolone respond to budesonide (3–9 mg daily orally). Budesonide is unproven as induction therapy. Some patients never achieve good control with the prednisolone and azathioprine. Mycophenolate with tacrolimus (trough level 5–10 ng/L) may be effective. All causes of liver injury are associated with accelerated bone loss and the use of calcium, vitamin D and bisphosphonates in AIH is recommended.
Primary biliary cirrhosis (PBC)
PBC is a chronic cholestatic liver disease affecting women predominantly from middle age onwards with a heritable component. Fatigue and pruritus are common, early symptoms that usually predate jaundice. The natural history was thought to be inexorable progress to liver failure over a period of 10 years from presentation, but that view is unduly pessimistic. Once jaundice is present, the course of the illness is predictable.
The aetiology of PBC is unknown but high titres of antimitochondrial antibody in almost all and elevated IgM levels with clustering of ‘autoimmune disorders’ in many suggest immune involvement. There is no role (yet) for immune modulation. Corticosteroids are ineffective; methotrexate is ineffective; azathioprine has marginal benefit. Curiously, patients with PBC treated with ciclosporin after transplantation are less likely to suffer PBC in the grafted liver than those prescribed tacrolimus.
The pruritus of cholestasis can be debilitating and has been attributed to autotaxin. Cholestyramine, which binds bile salts in the gut, has proved effective, but it is unpleasant to swallow, affecting compliance. Ursodeoxycholic acid 10–15 mg/kg daily, which improves liver function tests and pruritus, is free from unwanted effects other than dose-related diarrhoea. Long-term studies indicate ursodeoxycholic acid is associated with a reduced risk of liver decompensation and need for liver transplantation
Chronic cholestasis leads to malabsorption of fat-soluble vitamins, particularly vitamin D, and deficiency should be corrected to avoid osteomalacia. The use of calcium, vitamin D and bisphosphonates for bone loss in PBC is recommended.
Primary sclerosing cholangitis (PSC)
PSC is a progressive disease characterised by remitting/relapsing jaundice that affects predominantly non-smoking men of working age. There is inflammation and stricturing of the larger intrahepatic and extrahepatic bile ducts leading to persistent jaundice and biliary cirrhosis. There is a significant lifetime risk of cholangiocarcinoma. An association with ulcerative colitis, clustering with other autoimmune disorders and a heritable component, suggest this is an autoimmune condition. There is no effective therapy and no role (yet) for immune modulation. There may be a role for ursodeoxycholic acid 10–15 mg/kg daily. Recurrent episodes of bacterial cholangitis may respond to cyclical antibiotics that are concentrated in bile and target Gram-negative organisms, e.g. ciprofloxacin.
Alcoholic hepatitis
The sudden onset of jaundice in a patient consuming alcohol to excess heralds the onset of alcoholic hepatitis. Men are admitted to hospital more often than women, but the latter develop the syndrome after a lower lifetime consumption of alcohol (corrected for body weight). The biochemistry is characteristic, with conjugated bilirubinaemia but a normal ALT and alkaline phosphatase. Liver ultrasound shows no evidence of biliary tract disease. Several scoring systems based on INR, bilirubin and age predict mortality, which is substantial. Liver biopsy shows intense inflammation with a neutrophil infiltration. The presence of bacterial infection is a poor prognostic sign; serum markers of inflammation suggest bacterial infection, which is not necessarily present and related to elevated plasma cytokine levels.
The inflammatory features led to investigation of immune modulation. Randomised controlled trials of corticosteroids (prednisolone tapered from 40 mg/ day for up to 4 weeks) have rendered diverse results. There may be a role for early corticosteroids in patients without active sepsis or bleeding. High serum levels of tumour necrosis factor-α (TNFα) pointed clinical investigators in the direction of pentoxifylline, which inhibits TNFα production. Limited data suggest significant survival benefit with this agent, which has fewer unwanted effects.
Metabolic disease
Wilson's disease
This recessive genetic disorder (most are compound heterozygotes) predisposes to copper accumulation. Clinical presentations are diverse and include movement disorder, psychiatric illness, haemolysis or liver disease, often advanced. Many pre-symptomatic patients are identified following family screening. Confirmation of the diagnosis can be difficult and relies on a combination of serum copper and caeruloplasmin concentrations, urinary excretion of copper (comparing pre- and post-D-penicillamine excretion), a search for Kayser–Fleischer rings by slit lamp examination and diagnostically, an elevated liver copper concentration. Genetic analysis is too difficult for routine practice.
D-penicillamine, a copper chelating agent, is the treatment of choice for which there is the greatest experience, but since treatment for Wilson's disease is lifelong there have been concerns about short- and long-term toxicity. Trientine is an alternative and effective chelating agent, but there are also long-term concerns. Zinc also reduces total body copper content and probably represents the least toxic long-term option.
Haemochromatosis
Haemochromatosis is a homozygous genetic disease of iron storage affecting numerous organs including the liver, most commonly due to a mutation in the HFE gene. Treatment is by iron depletion, managed most easily, and without toxicity, by venesection. Iron chelation is ineffective.
Non-alcohol related fatty liver disease
The triad of hypertension, obesity and diabetes mellitus is found commonly in conjunction with abnormal liver function tests. Liver biopsy is almost always abnormal and patients can be separated into those with steatosis alone or those with steatohepatitis. The latter carries a high risk of progressive liver injury with fibrosis, cirrhosis and eventually HCC, especial in older men. Management is directed at control of weight, hypertension, hyperlipidaemia and diabetes mellitus. Metformin and insulin sensitisers such as piaglitazone and rosiglitazone improve liver function tests and some histological features, but have no effect on fibrosis, progression or survival.
Viral hepatitis
Hepatitis A virus (HAV)
Changing standards of hygiene and an effective vaccine have altered the pattern of illness associated with HAV infection. Symptomatic infection is uncommon in Western countries but more common than it was in the developing world, because infection now occurs at a later age. Significant disease following HAV infection is confined to those over 40 years. Active immunisation against HAV is recommended before travel; protective antibody takes about 2 weeks to develop and lasts for at least 10 years. Passive immunity, using antibody prepared from pooled plasma from immune donors confers temporary protection, but is no longer recommended.
Hepatitis B virus (HBV)
Exposure to HBV results usually in an acute resolving infection which may be asymptomatic or unrecognised. There is no evidence that intervention in acute infection is helpful, but antiviral therapy (below) should be considered for the tiny proportion that develops acute liver failure with detectable HBV replication. Acute infection in an immune suppressed host, where there is a high risk of serious disease or chronic infection, however, should be treated.
Chronic, usually lifelong, infection follows exposure to HBV in infants; the rate of chronic infection falls throughout childhood, affecting the sexes equally, to 5–10% in adults and men much more than women. Chronic infection is more common in the immune suppressed and the elderly.
Viral load falls with each decade to low levels and HBV protein production (HBsAg and HBeAg) falls in parallel. Treating all patients is neither practical nor appropriate and careful assessment of the stage of the disease is critical to successful management. Natural history studies reveal that viral replication is associated with progressive liver injury, cirrhosis, liver failure and HCC, all more common in men. Successful antiviral therapy is associated with improved survival, a reduced risk of liver failure, a reduced need for liver transplantation and less HCC.
Interferon-α is available in a pegylated formulation allowing weekly administration by subcutaneous injection. A 6-month course in those with active liver disease, with increased liver enzymes, inflammatory changes on the liver biopsy and a low viral load achieves cure in 25%. Young females fare best. A ‘flare’ with marked increase in liver enzymes during treatment anticipates elimination of HBV-DNA and HBsAg and development of anti-HBs. Interferon-α should not be used if there is evidence of hepatic decompensation as the ‘flare’ can precipitate liver failure.
Only a small number of patients are suitable for interferon-α. The majority of patients treated currently receive long-term therapy with an oral nucleot(s)ide analogue. Agents include lamivudine, telbivudine clavudine, emtricitabine, adefovir, tenofovir and entecavir. Some basic points merit mention. HBV has a high rate of spontaneous mutation and both immune responses to HBV and antiviral therapy select for mutations. Lessons from other infectious diseases (HIV and tuberculosis) suggest that long-term combination therapy reduces the chance of treatment failure. Long-term control rather than cure of HBV replication is the pragmatic goal with oral therapy. The duration of treatment is uncertain. Loss of HBsAg from the blood is one situation when treatment can be curtailed with less concern. Patients on therapy should be monitored to assess viral load. Liver function tests should fall to normal in line with the drop in viral load. A failure to control viral replication may be due to the evolution of mutations, inadequate dosing or poor compliance. Mutations should be sought if HBV-DNA is detected after a reasonable period of treatment and for some agents compliance can be assessed by measurement of drug levels in serum. Because the majority of patients will not develop life-threatening liver disease, treatment needs to be targeted at those with, or at risk of, fibrosis. Some women are reluctant to embark on antiviral therapy while pregnancy is possible; lamivudine, which has been used for years, appears safe in pregnancy, but newer agents cannot yet be regarded as safe although there is no evidence yet to raise concern. Some patients have a high risk of HCC and should also be considered for treatment. Many patients will have been treated, often with lamivudine and may have developed mutations as a result. Pre-treatment mutation profiles are not undertaken routinely but a strong case can be made that they should. Confirmation that a mutation is present during therapy necessitates a change in strategy. The notion that HBV with mutations is less likely to cause liver injury is incorrect.
Perhaps the most important issue in determining which drugs to use first is the clinical context. Those at greatest immediate risk include those with recrudescent HBV post-chemotherapy or subsequent to immune suppression (when the clinical course is accelerated) and with decompensated liver disease. In these scenarios the drugs with the most rapid and potent antiviral effects should be used (tenofovir and entecavir). Where there is less urgency, a combination of agents such as lamivudine with adefovir/tenofovir can be considered.
Tenofovir (even as monotherapy) is associated with the lowest rate of mutations to date (close to zero in large series) but clinical experience is limited to 5 years so far. Lamivudine and similar agents are associated with the highest rate of mutations, with adefovir in an intermediate position. As first line therapy, entecavir has a low level of breakthrough but mutations are much more likely in those with past use of lamivudine, which may not be recorded.
Hepatitis B vaccination
The hepatitis B vaccine (inactivated HBsAg adsorbed on aluminium hydroxide adjuvant) is effective and provides long-lasting immunity against HBV. Response rates fall with increasing age and are lower in the immune compromised. Protection lasts from years to decades and it is unclear if booster vaccination is ever required. Escape mutants with heterogeneity in the A epitope, driven by immune responses, are described and coexist with ‘humoral immunity’ but are fortunately very rare; thus it is possible to be ‘immune’ and HBV-DNA positive.
Targeting and screening mothers for HBV in order to protect their children is effective. Babies born to carrier mothers should be vaccinated at birth and after 1 and 6 months and thereafter tested for evidence of immunity and infection beyond 12 months. Concurrent use of hepatitis B immunoglobulin (pooled plasma from highly selected donors with high titre antibody to HBsAg) as passive prophylaxis is also recommended when the mother has high-level HBV replication, but as a human product, it carries an unquantifiable risk of infection.
Hepatitis B immunoglobulin also has a role in providing passive immunity for post-exposure prophylaxis, e.g. after accidental needle stick injury. Conventional vaccination is also important in such cases.
Hepatitis D virus (HDV)
This virus displaces HBV core replacing it with HDV core, but retaining the outer envelope of HBV. HDV infection is rare in clinical practice and occurs either as a simultaneous infection with HBV or as a superinfection in a patient already HBV-positive. Long-term treatment with pegylated interferon-α, i.e. for more than 1 year, controls HDV replication (measured as HDV-RNA in serum) in about 50% of cases.
Hepatitis C virus (HCV)
Exposure to HCV is most often a consequence of injecting drug use; vertical transmission (mother to child) occurs in 5%. Historically, HCV infection was associated with transfusion of blood/blood products, but that risk is close to zero with reliable tests for HCV in donors. Acute HCV infection is usually asymptomatic. Chronic infection follows exposure in 85% of cases and is more likely at extremes of age or with immune suppression. Genetic variation, such as polymorphism of IL28B, underlies spontaneous resolution in some patients. Some 5% develop cirrhosis and 25% of those develop HCC. The rate at which liver disease progresses to cirrhosis varies markedly between individuals, but can be rapid in those acquiring infection over the age of 60 years. Age over 40 years at infection, male sex, a raised body mass index, insulin resistance, immune suppression, HIV infection and alcohol abuse all increase the chance that fibrosis will progress. Significant fibrosis at liver biopsy predicts progression at subsequent biopsy.
Treatment is considered for all with viraemia. Interferon-α was the first agent to show efficacy in chronic HCV infection, with 10% responding with long-term elimination of HCV-RNA from serum. Response rates increased using pegylated interferon-α, given weekly, increasing both compliance and efficacy. Combining the weak antiviral agent ribavirin with interferon-α led to an unexpected but marked increase in permanent loss of HCV-RNA. The mode of action is not known. Successful treatment is defined as HCV-RNA negative at completion of treatment and 6 months after completion. Response rates to combination therapy are influenced by several factors, of which age is the most critical. The chances of long-term elimination of HCV with combination treatment fall with every decade to 10% or less in those over 60 years, an important reason not to delay therapy. Other host factors influencing elimination of HCV with therapy include male sex, elevated body mass index, insulin resistance, excessive alcohol consumption, immune suppression and HIV infection. Ribavirin is a known mutagen and men or women planning to have children should delay conception until 6 months after treatment is completed. The magnitude of change in viral load soon after starting treatment gives an indication of long-term efficacy. Further critical issues are that HCV genotypes influence response rates. Those with genotype 2 or 3 have higher response rates than those with other genotypes; consequently, treatment is for 6 months for those with a favourable genotype and 12 months for those with less favourable genotypes. Unfortunately, the severity of disease also influences the treatment response rates such that those most in need have the lowest response rates; treatment is extended by 6 months in cirrhosis.
Side-effects are frequent and many patients curtail therapy early. A clinical decision may be made to stop treatment early if it appears likely to be ineffective, based on early changes in viral load and marked adverse effects.
Adverse effects of ribavirin include rash and haemolysis, which can be severe. Close monitoring is required and the dose adjusted to maintain the haemoglobin above 10 g/L. The use of serum trough ribavirin levels reduces the risk of anaemia. Blood transfusion may be required and some advocate erythropoietin to maintain the haemoglobin concentration. Interferon-α also causes significant toxicity. Pyrexia, muscle ache and headache are likely. Fatigue and depression are common and often debilitating. Interferon-α must be used with caution and regular supervision be given to those with a history of psychiatric disease, especially depression. Anticipating and/or treating depression with agents such as citalopram is effective. Interferon-α may have profound effects on neutrophil, lymphocyte and platelet counts. Careful supervision is required, with dose reductions when those counts reach critical levels. Some clinicians use GCSF with neutropenia and eltrombopag in those with thrombocytopenia.
Interferon-α is cleared rapidly, mainly by the kidney (t½ 4 h) and increasing the molecular weight of the drug by conjugation with polyethylene glycol (pegylation) prolongs the t½ to 40 h, allowing single weekly injections. Pegylation probably improves compliance. Dose reduction may be needed in renal impairment. Ribavirin is also cleared by the kidney and dose reduction is essential in those with renal impairment (guided by serum ribavirin).
A number of agents that target specific HCV enzymes will be available soon, increasing response rates further.
Gallstones
Ursodeoxycholic acid can dissolve cholesterol gallstones, as it supplements the bile acid pool and improves the solubility of cholesterol in bile. It is used rarely, if at all, for this indication but may have a role in patients with disease due to biliary sludge or microcrystals identified at endoscopic ultrasound of the biliary tree; it is often used in patients with biliary tract disease ‘prophylactically’ to prevent stone formation within the biliary tree. The dose is 8–12 mg/kg daily orally.
Pancreas
Digestive enzymes
In pancreatic exocrine insufficiency the aim of therapy is to prevent weight loss and diarrhoea and in children to maintain growth. The problem of getting sufficient enzyme to the duodenum concurrently with food is not as simple as it might appear. High fat, calories and protein delay gastric emptying, while gastric acid destroys pancreatic enzymes taken by mouth. Only one-tenth of normal pancreatic output is sufficient to prevent steatorrhoea. Acid suppression by proton pump inhibitors improves the efficacy of pancreatic enzyme supplements.
Preparations are of animal origin and variable potency. Pancreatin, as Cotazym and Nutrizym, is satisfactory. Start patients on the recommended dose of a reliable formulation and vary this according to clinical need, the size and composition of meals. Enteric-coated formulations (pancreatin granules, tablets) are available. High-potency pancreatic enzymes should not be used in patients with cystic fibrosis as they cause ileocaecal and large bowel strictures.
Acute pancreatitis
Many drugs have been tested for specific effect, but none has shown convincing benefit. The main requirements of therapy are:
• To provide adequate analgesia. Opioids are generally satisfactory; analgesic efficacy outweighs the potential disadvantage of contracting the sphincter of Oddi (and retarding the flow of pancreatic secretion); buprenorphine is often preferred.
• To correct hypovolaemia due to the exudation of large amounts of fluid around the inflamed pancreas. Plasma may be required, or blood if the haematocrit falls; in addition, large volumes of electrolyte solution may be needed to preserve renal function.
• To achieve biliary drainage (by endoscopic retrograde cannulation of the pancreas) early in the illness if gallstones are suspected.
• The value of additional interventions, including nutritional support and antibiotic prophylaxis, is as yet unproven.
Drugs and the pancreas
Adverse effects are most commonly manifest as acute pancreatitis. The strongest association is with alcohol abuse. High plasma calcium concentration, including that caused by hypervitaminosis D and parenteral nutrition, also increases the risk. Corticosteroids, didanosine, azathioprine, diuretics (including thiazides and furosemide), sodium valproate, mesalazine and paracetamol (in overdose) are causally related.
Guide to further reading
Liver disease, Adams D.H., Haydon G., eds., Clin. Med. (Northfield Il). 2006;6. 19–46
American Association for the Study of Liver Disease practice guidelines Available online at: http://www.aasld.org/practice guidelines/
European Association for the Study of the Liver. Available online at: http://www.easl.eu/_clinicalpractice-guidelines/
Johnson C.D. UK guidelines for the management of acute pancreatitis. Gut. 2005;54(Suppl. iii):1–9.
Kingsnorth A., O'Reilly D. Acute pancreatitis. Br. Med. J.. 2006;332:1072–1076.
Krawitt E.L. Autoimmune hepatitis. N. Engl. J. Med.. 2006;354:54–66.
Lee W.M. Drug-induced hepatotoxicity. N. Engl. J. Med.. 2003;349:474–485.
Navarro V.J., Senior J.R. Drug-related hepatotoxicity. N. Engl. J. Med.. 2006;354:731–739.
NHS evidence for gastroenterology and liver disease Available online at: http://www.library.nhs.uk/gastroliver/