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The liver is the most important organ in which drugs are structurally altered. Some of the resulting metabolites may be biologically inactive, some active and some toxic (see Chapter 7).The liver is exposed to drugs in higher concentrations than are most organs because most are administered orally and are absorbed from the gastrointestinal tract.Thus the whole dose must pass through the liver to reach the systemic circulation. Because of this the liver is a vulnerable target for injury from chemicals and drugs, and disordered hepatic function is an important cause of abnormal drug handling and response. ...

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  1. 33 Liver, biliary tract, pancreas SYNOPSIS Effects of liver disease The liver is the most important organ in which drugs are structurally altered. Some of the resulting metabolites may be biologically PHARMACODYNAMIC CHANGES IN inactive, some active and some toxic (see LIVER DISEASE Chapter 7).The liver is exposed to drugs in Patients with severe liver disease characteristically higher concentrations than are most organs show abnormal end-organ response to drugs. For because most are administered orally and are example: absorbed from the gastrointestinal tract.Thus the whole dose must pass through the liver to • CNS sensitivity to opioids, sedatives and reach the systemic circulation. Because of this antiepilepsy drugs is increased. the liver is a vulnerable target for injury from • The effect of oral anticoagulants is increased chemicals and drugs, and disordered hepatic because synthesis of coagulation factors is function is an important cause of abnormal impaired. drug handling and response. • Fluid and electrolyte balance are altered. Sodium Drugs and the liver retention may be more readily induced by NSAIDs or corticosteroids; ascites and oedema • Pharmacodynamic and pharmacokinetic become more resistant to diuretics. changes • Prescribing in liver disease • Drug-induced liver injury • Aspects of therapy PHARMACOKINETIC CHANGES IN LIVER DISEASE Bile salts and gallstones Pancreas and drugs The liver has a large metabolic reserve, and it is only when disease becomes decompensated that 651
  2. 11 LIVER, BILIARY TRACT, PANCREAS important changes in drug handling occur. Paren- PLASMA PROTEIN-BINDING OF DRUG chymal liver disease e.g. chronic viral or alcoholic Binding of drugs to albumin is reduced when liver disease, has more impact on hepatic drug- plasma concentrations of the latter are low due to metabolising enzyme activity than primarily defective synthesis. Additionally, endogenous sub- cholestatic conditions, e.g. primary biliary cirrhosis, stances produced in liver disease may displace drugs although clearance of drugs eliminated mainly by from plasma protein binding sites. These changes biliary excretion will be impaired in the latter. provide scope to enhance the biological activity of Hepatocellular injury (toxic, infectious) leads to drugs, but assume importance only for those that decreased activity of drug-metabolising enzymes, are extensively (> 90%) protein bound. which is reflected in diminished plasma clearance of drugs that are metabolised. There is much variation between patients, and often overlap with OTHER CONSIDERATIONS healthy subjects. Patients with severe decompensated liver disease usually have associated renal impairment, with obvious consequences for drugs eliminated pre- HEPATIC BLOOD FLOW AND dominantly by the kidney. Where facilities exist, METABOLISM dosing should be guided by plasma concentration Complex changes in blood flow occur with liver monitoring, e.g. of theophylline, lidocaine and disease. Resistance to hepatic portal blood flow rises phenytoin. in cirrhosis, and portasystemic and intrahepatic These changes in drug response (in particular) shunts reduce drug delivery to hepatocytes. The and in disposition affect prescribing, as is now pattern of change caused by disease relates to the discussed. manner in which the healthy liver treats a drug and there are two general classes: • Drugs that are rapidly metabolised and highly extracted in a single pass through the liver. Prescribing for patients Clearance of such compounds is normally limited by hepatic blood flow but in severe liver with liver disease disease less drug is extracted from the blood as it If liver disease is stable and well compensated, passes through the liver due to poor liver cell prescribing of most drugs is safe. Particular care function, and portasystemic shunts allow a should attend evidence of: proportion of blood to bypass the liver altogether. Therefore the predominant change in • Impaired hepatic synthetic function the kinetics of drugs that are given orally is (hypoalbuminaemia, impaired blood increased systemic availability. Accordingly the coagulation) initial and maintenance doses of such drugs • Current or recent hepatic encephalopathy should be smaller than usual. When liver • Fluid retention and/or renal impairment function is severely impaired the t\ of drugs in • Drugs with this class may also be lengthened. • high hepatic extraction • Drugs that are slowly metabolised and are poorly • high plasma protein binding extracted in a single pass through the liver. The rate- • low therapeutic ratio limiting factor for elimination of this type of • CNS depressant effect. drug is metabolic capacity, and the major change caused by liver disease is prolongation of t1/2. When a drug undergoes significant hepatic Consequently the interval between doses of such metabolism, a reasonable approach is to reduce the drugs may need to be lengthened, and the time dose to 25-50% of normal and monitor the response to reach steady-state concentration in the plasma carefully. The following are comments on specific (5 x t1/,) is increased. examples: 652
  3. DRUG-INDUCED LIVER DAMAGE 11 CNS depressants. Sedatives, antidepressants and antiepilepsy drugs should be avoided or used with Drug-induced liver extreme caution in patients with advanced liver disease, and particularly those with current or recent damage hepatic encephalopathy. Enhanced sensitivity of the CNS to such drugs is well documented and adds to The spectrum of hepatic abnormalities caused by the pharmacokinetic changes. Treatment of alcohol drugs is broad, and encompasses the whole range withdrawal in patients with established liver disease of liver lesions from other causes. Adverse hepatic using chlormethiazole is hazardous, especially given effects of drugs, classified as elsewhere in this book i.v. The temptation to give initial large doses to (see Chapter 8) include: control agitation must be avoided because this drug, which normally has a high hepatic extraction, can readily accumulate to toxic concentrations. TYPE A (Augmented) Chlordiazepoxide is preferred. Liver injury or abnormal function occurs as the dose of some drugs is increased, causing: Analgesics. Opiates can precipitate hepatic en- • Interference with bilirubin metabolism and excretion. cephalopathy in patients with decompensated liver Jaundice is induced selectively with minimal or disease. If required to control postoperative pain, no disturbance of other liver function tests; doses should be reduced to 25-50% of normal. recovery ordinarily occurs on stopping the drug. Constant intravenous infusions should be avoided Examples are: if the patient is not to be insidiously overdosed. Codeine can precipitate hepatic encephalopathy by • C-17ot-substituted steroids impair bilirubin its constipating effect alone. Aspirin and other excretion into the hepatic canaliculi; the block NSAIDs may exacerbate impaired renal function is biochemical not mechanical. These include and fluid retention by inhibiting prostaglandin synthetic anabolic steroids and oestrogens synthesis and may also precipitate gastrointestinal used in oral contraceptives; jaundice due to bleeding. the latter is rare with the low dose formulations now preferred. • Rifampicin impairs hepatic uptake and Cardiovascular drugs. Propranolol (to prevent excretion of bilirubin; plasma unconjugated variceal bleeding) and diuretics (to treat ascites), see and conjugated bilirubin may be elevated below. during the first 2-3 weeks of dosing. • Fusidic acid interferes with hepatic bilirubin excretion to cause conjugated Gastrointestinal system. Antacids that contain hyperbilirubinaemia, particularly in patients large quantities of sodium can precipitate fluid with sepsis. retention to cause ascites. Aluminium- and calcium- based preparations cause constipation and may • Centrilobular necrosis due to production of thereby precipitate hepatic encephalopathy, as can reactive metabolites, from paracetamol in antimotility drugs. overdose and also carbon tetrachloride (used in dry-cleaning) and other nonmedicinal chemicals. Hormone preparations. Use of contraceptives • Hepatocellular necrosis with salicylates, should be monitored carefully in patients with particularly in patients with collagen diseases, cholestatic liver disease, because jaundice may be when > 2 g/d are taken. exacerbated; continued use of oral contraceptives • Fatty change in liver cells and hepatic failure during an attack of acute hepatitis can have the with tetracyclines with high doses; this is same effect. Low oestrogen preparations carry less avoided if < 2 g/day is given orally and risk of this complication. < 1 g/day i.v. 653
  4. 33 LIVER, BILIARY TRACT, PANCREAS TYPE B (Bizarre) • Chronic active hepatitis may develop with prolonged use of methyldopa, isoniazid, Many drugs can cause hepatic damage at thera- dantrolene and nitrofurantoin. peutic doses, although the incidence with any single • Hepaticfibrosisor cirrhosis may be caused by agent is very low. Pathogenesis probably involves therapeutic use of methotrexate, e.g. for stimulation of metabolic pathways leading to pro- psoriasis; in the latter case the risk is lessened by duction of hepatotoxic reactive metabolites. For giving a large dose weekly rather than a smaller some reactions immune mechanisms directed dose daily and by monitoring progress by liver against drug metabolite-altered liver cell antigens biopsy after every 1.5-2 g of methotrexate. are also likely to be involved. Patterns include: Chronic exposure to amiodarone may lead to • Acute hepatocellular necrosis. This reaction varies cirrhosis; this drug can also cause an alcoholic from a transient disturbance of liver function hepatitis-like picture. tests to acute hepatitis. It can be induced by several drugs including general anaesthetics DIAGNOSIS AND MANAGEMENT OF (halothane), antiepileptics (carbamazepine, DRUG-INDUCED LIVER INJURY phenytoin, sodium valproate, phenobarbital), antidepressants (MAO inhibitors), anti- • Always bear in mind the possibility. Take a inflammatory drugs (indomethacin, ibuprofen), careful drug history, including over-the-counter antimicrobials (isoniazid, sulphonamides, and alternative complementary medicine nitrofurantoin) and cardiovascular drugs remedies. (methyldopa, hydralazine). • In patients with hepatitis a viral aetiology should • Cholestatic hepatitis. The picture is of obstructive be excluded. jaundice with a variable component of • Cholestatic lesions, which may resolve only slowly hepatocellular damage. This pattern is on drug withdrawal, have to be differentiated particularly associated with the phenothiazine from other causes of obstructive jaundice, both neuroleptics, especially chlorpromazine. The intrahepatic and extrahepatic. jaundice generally occurs within the first month • Underlying liver disease can cause diagnostic of therapy, its onset may be insidious or acute confusion, e.g. the alcoholic patient receiving with abdominal pain, and can be accompanied antituberculosis drugs. It is wise to measure liver by features suggesting allergy (see above). function tests before starting treatment with any Recovery is usual but occasionally a picture drug which has documented hepatotoxic resembling primary biliary cirrhosis (see below) potential. may develop. Cholestatic hepatitis can also be • Liver biopsy is of only limited use in diagnosis, caused by antidiabetic drugs (tolbutamide, although certain features, e.g. eosinophil glibenclamide, carbimazole, erythromycin and infiltration, may provide a pointer to drug- gold, chlorpropamide). induced liver disease. • Diagnostic challenge is extremely dangerous for hepatic reactions because it may precipitate fulminant hepatic failure; the procedure is safer TYPE C (Continued use) for cholestatic reactions. • Benign liver tumours may develop when synthetic • Monitoring liver function tests in the early C17-cx-substituted gonadal steroids (e.g. anabolic weeks of therapy is useful in detecting an steroids usually in high dose, and oral impending reaction to some drugs e.g. contraceptives) are used for more than 5 years; isoniazid. Minor abnormalities (serum there is also increased risk of hepatocellular transaminases less than twice normal) are often carcinoma, although the absolute risk of either self-limiting and progress can be monitored. complication is very low. These liver tumours are Elevations greater than three-fold should be an highly vascular and may cause recurrent or acute indication for drug withdrawal, even if the abdominal pain if they rupture and bleed. patient is asymptomatic. 654
  5. DRUG-INDUCED LIVER DAMAGE 33_ COMPLICATIONS OF CIRRHOSIS Direct pressure on varices can be applied by inserting an inflatable triple-lumen (Sengstaken) Variceal bleeding tube which abuts the gastro-oesophageal junction, and controls bleeding in 90%; rebleeding is common Varices are dilated anastamoses between the portal when the tube is withdrawn and its use may be and systemic venous systems which form in an accompanied by aspiration, oesophageal ulceration attempt to decompress the portal venous system or perforation. when the pressure within undergoes sustained elevation. Those in the lower oesophagus or gastric body are prone to rupture because they are thin- Reduction of portal pressure. Vasopressin (anti- walled and lie just below the mucosa. duiretic hormone, see p. 711), in addition to its Portal pressure is a function of resistance in the action on the renal collecting ducts (through V2 portal venous system and the/low of blood through receptors), constricts smooth muscle (Va receptors) it. In cirrhosis, portal venous resistance is increased, in the cardiovascular system (hence its name), and and inflow of blood is increased by splanchnic particularly in splanchnic blood vessels, so reducing vasodilatation and elevation of cardiac output. blood flow in the portal venous system. Unfortunately, Variceal bleeding is increasingly likely as the coronary vasoconstriction can also occur, and pressure gradient between the portal and systemic treatment has to be withdrawn from 20% of patients venous systems rises beyond 12 mmHg. because of myocardial ischaemia. Glyceryl trinitrate Up to 50% of patients with portal hypertension (transdermally, sublingually, or intravenously) reduces bleed from oesophageal or gastric varices and the cardiac risk and, advantageously, further reduces half die from complications of their first bleed. portal venous resistance and pressure. Hypovolaemia must be corrected with plasma ex- Vasopressin is rapidly cleared from the circu- panders and blood transfusion. Sepsis is common; lation and must be given by continuous i.v. infusion. the incidence rises from 20% at 48 hours to over The synthetic analogue, terlipressin (triglycyl-lysine- 60% at 7 days and antimicrobial prophylaxis should vasopressin) is now preferred. This prodrug (or be given with ciprofloxacin (1 g/day). Some 70% hormogen) is converted in vivo to the vasoactive will stop bleeding spontaneously but over half re- lysine Vasopressin which has biological activity for bleed within 10 days. 3-4 hours, and is effective by bolus injections 4- hourly, usually for 48-72 hours. It is a useful adjunct to endoscopic therapy and reduces rebleeding. Acute variceal bleeding Somatostatin and its synthetic analogue octreotide Management involves measures directed at the reduce portal pressure by decreasing splanchnic varices and also to reduce portal pressure by blood flow. Octreotide has the advantage of a pharmacological methods and blood shunting longer duration of action so that it can be given as a procedures. bolus injection rather than the constant intravenous infusion needed for administration of somatostatin. Its can be used as an alternative to terlipressin, Direct treatment of varices by endoscopy is having similar efficacy and indications for use. preferred. Band ligation, in which the varices are Patients who continue to bleed despite the above strangulated by application of small elastic bands measures require surgery (ligation or transection of has fewer complications than sclerotherapy, which varices) or placement of a stent between intrahepatic involves injecting sclerosant into and around the branches of the portal and (systemic) hepatic veins varices but may lead to oesophagitis, stricture or under radiological control. The latter is now the embolisation of sclerosant. Either technique can technique of choice for the 10-15% of patients with control bleeding in about 90% of patients, and acute bleeding resistant to conventional treatment, rebleeding is reduced if this direct treatment is and also for long-term management of patients combined with reduction of portal pressure (see who are difficult to help by other methods (see below). below). 655
  6. 11 LIVER, BILIARY TRACT, PANCREAS Prevention of variceal bleeding A combination of bed-rest (which lowers plasma renin activity) and dietary sodium restriction are Endoscopic therapy as (above), preferably by band effective in about 10% of patients but diuretic therapy ligation, and repeated at weekly intervals until all is usual. The most useful drug is spironolactone but varices are obliterated, is currently the treatment of its maximum effect can take up to 2 weeks to choice; it reduces the incidence of rebleeding by develop as it is metabolised to products with long 50-60%. duration of action, e.g. canrenone t1// 10-35 h. A loop diuretic, e.g. frusemide (furosemide), is therefore given Pharmacological therapy. Nonselective |3-blockers, in combination, which also helps to counteract e.g. propranolol or nadolol, reduce cardiac output hyperkalaemia induced by spironolactone. A dose (P1 receptor antagonism) and induce splanchnic ratio of spironolactone 100 mg and frusemide 40 mg vasoconstriction (P2 receptor antagonism allowing o.d. works well, and can be increased every 3-4 unopposed oc-adrenergic vasoconstriction). Recurrent days to a maximum of spironolactone 400 mg + bleeding is reduced by about 40%. As propranolol frusemide 160 mg. is extensively extracted in a single pass through the Body weight and urinary sodium excretion liver, its systemic availability may be unpredictable should be monitored. Patients who have oedema as in patients with cirrhosis and portal hypertension well as ascites exhibit rapid weight loss. When due to variations in hepatic blood flow and portal/ ascites only is present weight loss should not exceed systemic shunts. Ideally, the dose of propranolol 0.5 kg/day, which is the maximum rate that fluid (given b.d.) should be adjusted by measuring the can move from the peritoneal cavity into the circu- portal/systemic venous pressure gradient; if this is lation. Creating a negative fluid balance runs the not feasible, the resting pulse rate is monitored, risk of hypovolaemia, electrolyte disturbance, renal aiming at a 25% reduction. Decreased cardiac out- impairment and eventually hepatic encephalopathy. put can exacerbate impaired renal function and Patients should lose weight if their urinary sodium fluid retention. Nadolol, having a longer duration excretion exceeds that provided by the diet; those of action, is given only once daily. who do not respond despite high urinary sodium outputs are almost certainly receiving additional sodium in their diet or medications, e.g. antacids. ASCITES Should spironolactone cause painful gynaecomastia, amiloride is a useful substitute (10-40 mg/day) with About 50% of patients with cirrhosis develop a more rapid onset of action. ascites within 10 years of diagnosis and 50% of Abdominal paracentesis is useful particularly these will die within 2 years. The process by which when ascites is tense; rapid drainage of 5 litres leads ascites forms in cirrhosis is not fully understood but to prompt relief of discomfort and improves circu- appears to involve the accumulation of vasodilator latory dynamics. Provided renal function is not com- substances, activation of the renin-angiotensin- promised, extensive paracentesis is safe and can be aldosterone system (causing renal retention of sodium used as an adjunct to diuretic therapy to shorten and water), and the production of antidiuretic hospital stay. When more than 5 litres are drained it hormone (causing hyponatraemia due to dilution, is customary to infuse colloid or albumin (6-8 g per not deficiency, of plasma sodium). litre of fluid removed) to prevent hypovolaemia. Management of ascites HEPATIC ENCEPHALOPATHY The aim is to induce natriuresis with consequent Infection, gastrointestinal bleeding or injudicious loss of water. Fluid restriction is unnecessary unless use of sedatives and diuretics can precipitate hepatic the plasma sodium falls below 120mmol/l. The encephalopathy in cirrhotic patients. The patho- initial management must include a diagnostic tap of physiology is complex but ammonia appears to hold the ascitic fluid as spontaneous bacterial peritonitis a central role. Derived mainly from the action of complicates up to 25% of patients on presentation. colonic urease-containing bacteria, ammonia is 656
  7. VIRAL HEPATITIS 11 normally extracted from the portal blood by the pressives. Some 80% will benefit from prednisolone liver, but when there is portal/systemic shunting which should be continued in the long term, as and impaired hepatic metabolism, it reaches high most patients relapse if the drug is withdrawn. concentration in the blood and adversely affects the Azathioprine (1 mg/kg daily) is effective as a steroid brain. Theraputic measures that limit production of sparing agent, and usually permits reducing of ammonia have therefore been developed. prednisolone to 5-10 mg/d. Increasing azathioprine to 2 mg/kg allows further reduction in prednisolone Lactulose acts as an osmotic laxative to expedite dose but haematological toxicity may result and the clearance of potentially toxic substances from the blood count must be monitored every 2 months. gastrointestinal tract. In addition, colonic bacteria metabolise it to lactic and acetic acids which inhibit PRIMARY BILIARY CIRRHOSIS (PBC) the growth of ammonia-producing organisms and, by lowering pH, reduce nonionic diffusion of This chronic cholestatic liver disease affects 1 in ammonia (a basic substance) from the colon into the 4000 people in the United Kingdom. Pruritus is a bloodstream. The correct dose is that which pro- common early symptom, and can be helped by duces 2-4 soft acidic stools daily (usually 30-60 ml colestyramine. Chronic cholestasis leads to mal- daily). Exceeding this dose can dehydrate the absorption of fat-soluble vitamins, particularly vit- patient. As lactulose is intended for long-term use, amin D, and deficiency of which must be corrected there is no rational basis for giving it to patients to avoid osteomalacea. after paracetamol overdose, as prophylaxis against The aetiology of PBC is unknown but high hepatic encephalopathy. titres of antimitochondrial antibody in the majority suggest involvement of immune mechanisms. There Reduction of dietary protein reduces ammonia is no effective treatment. Adverse effects outweigh production and has long been used to prevent benefits from prednisolone, but budesonide is cur- hepatic encephalopathy. Any potential benefit rently under assessment as it is highly extracted by against encephalopathy must be tempered by the the liver and thus poorly available to the systemic knowledge that most patients with severe liver circulation. Ursodeoxycholic acid 10-15 mg/kg/d disease are malnourished. Protein from vegetable improves biochemical liver function tests, but appears sources is often better tolerated than animal-derived not to lengthen survival or prevent complications. protein, at least in part due to its higher fibre con- tent which accelerates transit through the gut. Neomycin and metronidazole both inhibit urease- producing bacteria and are useful, but their long- Viral hepatitis term use is limited by toxicity. HEPATITIS A Passive immunity can be obtained by i.m. injection Immune-mediated liver of globulin containing antibody to the virus (normal immunoglobulin; prepared from pooled plasma from disease known immune donors) which confers temporary protection for travellers visiting areas where the virus is endemic. Active immunisation with Hepatitis AUTOIMMUNE ACTIVE CHRONIC A vaccine is now preferable; protective antibody HEPATITIS takes about two weeks to develop. This chronic inflammatory disease of the liver is characteristically associated with circulating auto- HEPATITIS B antibodies and high serum immunoglobulin con- centrations. Untreated, it progresses to cirrhosis, Chronic carriage in the UK occurs in about 5% of but the condition responds well to immunosup- those infected but is more common in the immuno- 657
  8. 11 LIVER, BILIARY TRACT, PANCREAS compromised and in other high-risk groups including HEPATITIS D male homosexuals and intravenous drug abusers. This virus replicates only in the presence of hepatitis In parts of Asia and Africa, chronic carriage occurs B. Interferon alfa is less effective than in other forms in up to 50% of the population. Worldwide there are of viral hepatitis, giving sustained responses in about 300 million chronic carriers of hepatitis B about 15% of patients. virus and it is the most important cause of primary hepatocellular carcinoma. Interferon alfa (see p. 263) given for 4-6 months HEPATITIS C gives long-term clearance of hepatitis B virus from Most individuals infected with the hepatitis C virus the plasma in 25-40% of patients. The effect is become long-term carriers. Chronic infection with characteristically preceded by elevations in serum hepatitis C virus affects an estimated 170 million transamininases which reflects immune-mediated individuals worldwide. Up to one-third of these destruction of virus-infected hepatocytes; if liver will progress to cirrhosis with its attendant compli- function is impaired prior to therapy use of cations including hepatocellular carcinoma, over interferon alfa should be monitored carefully a period of 30-40 years. In the western world because it may precipitate hepatic failure. hepatitis C infection arises mainly from intravenous Lamivudine, a nucleoside analogue, inhibits repli- drug abuse. cation of hepatitis B virus DNA and reduces hepatic Treatment with interferon alfa leads to suppression inflammation. The serum of about 17% of patients of circulating hepatitis C viral RNA and improve- converts from positive to negative for antibodies to ment in hepatic inflammation in about 40%, but at hepatitis B after one year of therapy. Long-term least half relapse on cessation of treatment. Com- treatment is probably necessary and the drug is bination of interferon alfa with ribavirin greatly well tolerated. enhances the response, achieving sustained re- mission in up to 70%; age, duration of infection and viral genotype are among the factors that determine Hepatitis B immunisation the response. Interferon alfa is cleared rapidly, mainly by the kidney (tV2 4 h), and must be given Hepatitis B vaccine (inactivated B virus surface by s.c. injection three times per week. Increasing the antigen adsorbed on aluminium hydroxide adju- molecular weight of the drug by conjugation with vant) provides active immunity against hepatitis B polyethylene glycol (pegylation) prolongs the t1/, to infection, and in countries of low endemicity it is 40 h, allowing single weekly injections. Pegylation given to individuals at high risk, including health- also appears to enhance the efficacy of interferon care professionals. Immunity is conferred for at alfa, possibly by increasing exposure time to the least 5 years and can be supplemented by booster virus. injections. Treatment should last 6-12 months but should cease after 3 months if any virus RNA persists. Hepatitis B immimoglobulin (pooled plasma Depression, agitation, headache and malaise may selected for high titres of antibodies to the virus) limit treatment. Its use is currently restricted to provides passive immunity for post-exposure pro- patients with severe necroinflammatory changes on phylaxis e.g. after accidental needlestick injury. liver biopsy (who are thought to be most at risk of In countries with high prevalence of hepatitis B progressing to cirrhosis). the virus is transmitted vertically (from mother to baby). Passive immunoprophylaxis with immune globulin given to the baby at birth, followed by vaccination, is effective at preventing chronic car- riage. Mass vaccination should lead to a reduction Gallstones in the incidence of primary hepatocellular carcinoma, but cannot yet be implemented in third world Ursodeoxycholic acid can be used to dissolve choles- countries for want of funding. terol gallstones; it supplements the bile acid pool 658
  9. PANC RE AS 11 and thus improves the solubility of cholesterol in analgesic efficacy; buprenorphine is often bile. Its use is limited to patients with a functioning preferred. gallbladder who have small stones that are not To correct hypovolaemia due to the exudation of calcified. The dose is 8-12mg/kg/day p.o., treat- large amounts of fluid around the inflamed ment takes up to 2 years and recurrence is common. pancreas. Plasma may be required, or blood if the haematocrit falls; in addition large volumes of electrolyte solution may be needed to maintain urine flow. Pancreas DRUGS ANDTHE PANCREAS DIGESTIVE ENZYMES Adverse effects are most commonly manifest as acute pancreatitis. The strongest association is In pancreatic exocrine insufficiency, the aim of with alcohol abuse. High plasma calcium, including therapy is to prevent weight loss and diarrhoea that caused by hypervitaminosis D, and parenteral and, in children, to maintain adequate growth. The nutrition also increase the risk. Corticosteroids, problem of getting enough enzyme to the duo- didanosine, azathoipurine, diuretics (including thia- denum concurrently with food is not as simple as it zides and frusemide), sodium valproate, mesalazine might appear. Gastric emptying varies with the com- and paracetamol (in overdose) have also been position of meals, e.g. high fat, calories or protein causally related. cause delay, and the pancreatic enzymes taken by mouth are destroyed by gastric acid. On the other hand, only one-tenth of the normal pancreatic output is sufficient to prevent steatorrhoea. Acid GUIDETO FURTHER READING suppression by proton pump inhibitors improves the efficacy of pancreatic enzyme supplements. Dusheiko G 1999 A pill a day, or two, for hepatitis B? Preparations are of animal origin and variable Lancet 353:1032-1033 potency. Pancreatin, as Cotazym and Nutrizym, Jalan R, Hayes P C 1997 Hepatic encephalopathy and appears to be satisfactory. A reasonable course is to ascites. Lancet 350:1309-1315 start the patient on the recommended dose of a Krige J E J, Beckingham IJ 2001 Portal hypertension reliable formulation and to vary this according to — 1: varices. British Medical Journal 322: 348-351; the individual's needs, and the size and composition also Portal hypertension — 2: ascites, of meals. Enteric-coated formulations (pancreatin encephalopathy, and other conditions. 322: 416^18 granules, tablets) are available. High-potency pan- Koff R S 1998 Hepatitis A. Lancet 351:1643-1649 creatic enzymes should not be used in patients with Lauer G M, Walker B D 2001 Hepatitis C virus infection. cystic fibrosis as they may cause ileocaecal and New England Journal of Medicine 345: 41-52 large bowel strictures. Lee W M 1997 Hepatitis B virus infection. New England Journal of Medicine 337:1733-1745 Martin P-Y et al 1998 Nitric oxide as a mediator of ACUTE PANCREATITIS haemodynamic abnormalities and sodium and water retention in cirrhosis. New England Journal Many drugs have been tested for specific effect, and of Medicine 339: 533-541 none has shown convincing benefit. The main Mas A, Rodes J 1997 Fulminant hepatic failure. Lancet requirements of therapy are: 349:1081-1085 • To provide adequate analgesia. Opioids are Ryder S D, Beckingham IJ 2001 Chronic viral generally satisfactory; their potential hepatitis. British Medical Journal 322: 219-221 disadvantage of contracting the sphincter of Sharara A I, Rockey D C 2001 Gastroesophageal Oddi (and retarding the flow of pancreatic variceal haemorrhage. New England Journal of secretion) appears to be outweighed by their Medicine 345: 669-681 659
  10. 33 LIVER, BILIARY TRACT, PANCREAS Schafer D F, Sorrell M F 1999 Hepatocellular Tilg H, Diehl A M 2000 Cytokines in alcoholic and carcinoma. Lancet 353:1253-1257 non-alcoholic steatohepatitis. New England Steer M L et al 1995 Chronic pancreatitis. New Journal of Medicine 343:1467-1476 England Journal of Medicine 332:1482-1490 Trauner M et al 1998 Molecular pathogenesis of Steinberg W, Tenner S 1994 Acute pancreatitis. New cholestasis. New England Journal of Medicine 339: England Journal of Medicine 330:1198-1210 1217-1227 660
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