CLINICAL PHARMACOLOGY 2003 (PART 34)

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.. Drugs

Liver, biliary tract, pancreas

SYNOPSIS

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.

Drugs and the liver

• Pharmacodynamic and pharmacokinetic

changes

• Prescribing in liver disease

• Drug-induced liver injury

• Aspects of therapy

Bile salts and gallstones

Pancreas and drugs

Effects of liver disease

PHARMACODYNAMIC CHANGES IN LIVER DISEASE

Patients with severe liver disease characteristically show abnormal end-organ response to drugs For example:

• CNS sensitivity to opioids, sedatives and antiepilepsy drugs is increased

• The effect of oral anticoagulants is increased because synthesis of coagulation factors is impaired

• Fluid and electrolyte balance are altered Sodium retention may be more readily induced by NSAIDs or corticosteroids; ascites and oedema become more resistant to diuretics

PHARMACOKINETIC CHANGES IN LIVER DISEASE

The liver has a large metabolic reserve, and it is only when disease becomes decompensated that

important changes in drug handling occur

Paren-chymal liver disease e.g chronic viral or alcoholic

liver disease, has more impact on hepatic

drug-metabolising enzyme activity than primarily

cholestatic conditions, e.g primary biliary cirrhosis,

although clearance of drugs eliminated mainly by

biliary excretion will be impaired in the latter

Hepatocellular injury (toxic, infectious) leads to

decreased activity of drug-metabolising enzymes,

which is reflected in diminished plasma clearance

of drugs that are metabolised There is much

variation between patients, and often overlap with

healthy subjects

HEPATIC BLOOD FLOW AND

METABOLISM

Complex changes in blood flow occur with liver

disease Resistance to hepatic portal blood flow rises

in cirrhosis, and portasystemic and intrahepatic

shunts reduce drug delivery to hepatocytes The

pattern of change caused by disease relates to the

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.

Clearance of such compounds is normally

limited by hepatic blood flow but in severe liver

disease less drug is extracted from the blood as it

passes through the liver due to poor liver cell

function, and portasystemic shunts allow a

proportion of blood to bypass the liver

altogether Therefore the predominant change in

the kinetics of drugs that are given orally is

increased systemic availability Accordingly the

initial and maintenance doses of such drugs

should be smaller than usual When liver

function is severely impaired the t\ of drugs in

this class may also be lengthened

• Drugs that are slowly metabolised and are poorly

extracted in a single pass through the liver The

rate-limiting factor for elimination of this type of

drug is metabolic capacity, and the major change

caused by liver disease is prolongation of t1/2.

Consequently the interval between doses of such

drugs may need to be lengthened, and the time

to reach steady-state concentration in the plasma

(5 x t1/,) is increased

PLASMA PROTEIN-BINDING OF DRUG

Binding of drugs to albumin is reduced when plasma concentrations of the latter are low due to defective synthesis Additionally, endogenous sub-stances produced in liver disease may displace drugs from plasma protein binding sites These changes provide scope to enhance the biological activity of drugs, but assume importance only for those that are extensively (> 90%) protein bound

OTHER CONSIDERATIONS

Patients with severe decompensated liver disease usually have associated renal impairment, with obvious consequences for drugs eliminated pre-dominantly by the kidney Where facilities exist, dosing should be guided by plasma concentration monitoring, e.g of theophylline, lidocaine and phenytoin

These changes in drug response (in particular) and in disposition affect prescribing, as is now discussed

Prescribing for patients with liver disease

If liver disease is stable and well compensated, prescribing of most drugs is safe Particular care should attend evidence of:

• Impaired hepatic synthetic function (hypoalbuminaemia, impaired blood coagulation)

• Current or recent hepatic encephalopathy

• Fluid retention and/or renal impairment

• Drugs with

• high hepatic extraction

• high plasma protein binding

• low therapeutic ratio

• CNS depressant effect

When a drug undergoes significant hepatic metabolism, a reasonable approach is to reduce the dose to 25-50% of normal and monitor the response carefully The following are comments on specific examples:

CNS depressants Sedatives, antidepressants and

antiepilepsy drugs should be avoided or used with

extreme caution in patients with advanced liver

disease, and particularly those with current or recent

hepatic encephalopathy Enhanced sensitivity of the

CNS to such drugs is well documented and adds to

the pharmacokinetic changes Treatment of alcohol

withdrawal in patients with established liver disease

using chlormethiazole is hazardous, especially given

i.v The temptation to give initial large doses to

control agitation must be avoided because this

drug, which normally has a high hepatic extraction,

can readily accumulate to toxic concentrations

Chlordiazepoxide is preferred

Analgesics Opiates can precipitate hepatic

en-cephalopathy in patients with decompensated liver

disease If required to control postoperative pain,

doses should be reduced to 25-50% of normal

Constant intravenous infusions should be avoided

if the patient is not to be insidiously overdosed

Codeine can precipitate hepatic encephalopathy by

its constipating effect alone Aspirin and other

NSAIDs may exacerbate impaired renal function

and fluid retention by inhibiting prostaglandin

synthesis and may also precipitate gastrointestinal

bleeding

Cardiovascular drugs Propranolol (to prevent

variceal bleeding) and diuretics (to treat ascites), see

below

Gastrointestinal system Antacids that contain

large quantities of sodium can precipitate fluid

retention to cause ascites Aluminium- and

calcium-based preparations cause constipation and may

thereby precipitate hepatic encephalopathy, as can

antimotility drugs

Hormone preparations Use of contraceptives

should be monitored carefully in patients with

cholestatic liver disease, because jaundice may be

exacerbated; continued use of oral contraceptives

during an attack of acute hepatitis can have the

same effect Low oestrogen preparations carry less

risk of this complication

Drug-induced liver damage

The spectrum of hepatic abnormalities caused by drugs is broad, and encompasses the whole range

of liver lesions from other causes Adverse hepatic effects of drugs, classified as elsewhere in this book (see Chapter 8) include:

TYPE A (Augmented)

Liver injury or abnormal function occurs as the dose of some drugs is increased, causing:

• Interference with bilirubin metabolism and excretion.

Jaundice is induced selectively with minimal or

no disturbance of other liver function tests; recovery ordinarily occurs on stopping the drug Examples are:

• C-17ot-substituted steroids impair bilirubin excretion into the hepatic canaliculi; the block

is biochemical not mechanical These include synthetic anabolic steroids and oestrogens used in oral contraceptives; jaundice due to the latter is rare with the low dose

formulations now preferred

• Rifampicin impairs hepatic uptake and excretion of bilirubin; plasma unconjugated and conjugated bilirubin may be elevated during the first 2-3 weeks of dosing

• Fusidic acid interferes with hepatic bilirubin excretion to cause conjugated

hyperbilirubinaemia, particularly in patients with sepsis

• Centrilobular necrosis due to production of reactive metabolites, from paracetamol in overdose and also carbon tetrachloride (used in

dry-cleaning) and other nonmedicinal chemicals

• Hepatocellular necrosis with salicylates,

particularly in patients with collagen diseases, when > 2 g/d are taken

• Fatty change in liver cells and hepatic failure

with tetracyclines with high doses; this is avoided if < 2 g/day is given orally and

< 1 g/day i.v

TYPE B (Bizarre)

Many drugs can cause hepatic damage at

thera-peutic doses, although the incidence with any single

agent is very low Pathogenesis probably involves

stimulation of metabolic pathways leading to

pro-duction of hepatotoxic reactive metabolites For

some reactions immune mechanisms directed

against drug metabolite-altered liver cell antigens

are also likely to be involved Patterns include:

• Acute hepatocellular necrosis This reaction varies

from a transient disturbance of liver function

tests to acute hepatitis It can be induced by

several drugs including general anaesthetics

(halothane), antiepileptics (carbamazepine,

phenytoin, sodium valproate, phenobarbital),

antidepressants (MAO inhibitors),

anti-inflammatory drugs (indomethacin, ibuprofen),

antimicrobials (isoniazid, sulphonamides,

nitrofurantoin) and cardiovascular drugs

(methyldopa, hydralazine)

• Cholestatic hepatitis The picture is of obstructive

jaundice with a variable component of

hepatocellular damage This pattern is

particularly associated with the phenothiazine

neuroleptics, especially chlorpromazine The

jaundice generally occurs within the first month

of therapy, its onset may be insidious or acute

with abdominal pain, and can be accompanied

by features suggesting allergy (see above)

Recovery is usual but occasionally a picture

resembling primary biliary cirrhosis (see below)

may develop Cholestatic hepatitis can also be

caused by antidiabetic drugs (tolbutamide,

glibenclamide, carbimazole, erythromycin and

gold, chlorpropamide)

TYPE C (Continued use)

• Benign liver tumours may develop when synthetic

C17-cx-substituted gonadal steroids (e.g anabolic

steroids usually in high dose, and oral

contraceptives) are used for more than 5 years;

there is also increased risk of hepatocellular

carcinoma, although the absolute risk of either

complication is very low These liver tumours are

highly vascular and may cause recurrent or acute

abdominal pain if they rupture and bleed

• Chronic active hepatitis may develop with

prolonged use of methyldopa, isoniazid, dantrolene and nitrofurantoin

• Hepatic fibrosis or cirrhosis may be caused by

therapeutic use of methotrexate, e.g for psoriasis; in the latter case the risk is lessened by giving a large dose weekly rather than a smaller dose daily and by monitoring progress by liver biopsy after every 1.5-2 g of methotrexate Chronic exposure to amiodarone may lead to cirrhosis; this drug can also cause an alcoholic hepatitis-like picture

DIAGNOSIS AND MANAGEMENT OF DRUG-INDUCED LIVER INJURY

• Always bear in mind the possibility Take a

careful drug history, including over-the-counter

and alternative complementary medicine remedies

• In patients with hepatitis a viral aetiology should

be excluded

• Cholestatic lesions, which may resolve only slowly

on drug withdrawal, have to be differentiated from other causes of obstructive jaundice, both intrahepatic and extrahepatic

• Underlying liver disease can cause diagnostic

confusion, e.g the alcoholic patient receiving antituberculosis drugs It is wise to measure liver function tests before starting treatment with any drug which has documented hepatotoxic potential

• Liver biopsy is of only limited use in diagnosis, although certain features, e.g eosinophil infiltration, may provide a pointer to drug-induced liver disease

• Diagnostic challenge is extremely dangerous for hepatic reactions because it may precipitate fulminant hepatic failure; the procedure is safer for cholestatic reactions

• Monitoring liver function tests in the early weeks of therapy is useful in detecting an impending reaction to some drugs e.g

isoniazid Minor abnormalities (serum transaminases less than twice normal) are often self-limiting and progress can be monitored Elevations greater than three-fold should be an indication for drug withdrawal, even if the patient is asymptomatic

COMPLICATIONS OF CIRRHOSIS

Variceal bleeding

Varices are dilated anastamoses between the portal

and systemic venous systems which form in an

attempt to decompress the portal venous system

when the pressure within undergoes sustained

elevation Those in the lower oesophagus or gastric

body are prone to rupture because they are

thin-walled and lie just below the mucosa

Portal pressure is a function of resistance in the

portal venous system and the/low of blood through

it In cirrhosis, portal venous resistance is increased,

and inflow of blood is increased by splanchnic

vasodilatation and elevation of cardiac output

Variceal bleeding is increasingly likely as the

pressure gradient between the portal and systemic

venous systems rises beyond 12 mmHg

Up to 50% of patients with portal hypertension

bleed from oesophageal or gastric varices and

half die from complications of their first bleed

Hypovolaemia must be corrected with plasma

ex-panders and blood transfusion Sepsis is common;

the incidence rises from 20% at 48 hours to over

60% at 7 days and antimicrobial prophylaxis should

be given with ciprofloxacin (1 g/day) Some 70%

will stop bleeding spontaneously but over half

re-bleed within 10 days

Acute variceal bleeding

Management involves measures directed at the

varices and also to reduce portal pressure by

pharmacological methods and blood shunting

procedures

Direct treatment of varices by endoscopy is

preferred Band ligation, in which the varices are

strangulated by application of small elastic bands

has fewer complications than sclerotherapy, which

involves injecting sclerosant into and around the

varices but may lead to oesophagitis, stricture or

embolisation of sclerosant Either technique can

control bleeding in about 90% of patients, and

rebleeding is reduced if this direct treatment is

combined with reduction of portal pressure (see

below)

Direct pressure on varices can be applied by inserting an inflatable triple-lumen (Sengstaken) tube which abuts the gastro-oesophageal junction, and controls bleeding in 90%; rebleeding is common when the tube is withdrawn and its use may be accompanied by aspiration, oesophageal ulceration

or perforation

Reduction of portal pressure Vasopressin

(anti-duiretic hormone, see p 711), in addition to its action on the renal collecting ducts (through V2 receptors), constricts smooth muscle (Va receptors)

in the cardiovascular system (hence its name), and particularly in splanchnic blood vessels, so reducing blood flow in the portal venous system Unfortunately, coronary vasoconstriction can also occur, and treatment has to be withdrawn from 20% of patients because of myocardial ischaemia Glyceryl trinitrate (transdermally, sublingually, or intravenously) reduces the cardiac risk and, advantageously, further reduces portal venous resistance and pressure

Vasopressin is rapidly cleared from the circu-lation and must be given by continuous i.v infusion

The synthetic analogue, terlipressin

(triglycyl-lysine-vasopressin) is now preferred This prodrug (or hormogen) is converted in vivo to the vasoactive

lysine Vasopressin which has biological activity for

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

Somatostatin and its synthetic analogue octreotide

reduce portal pressure by decreasing splanchnic blood flow Octreotide has the advantage of a longer duration of action so that it can be given as a bolus injection rather than the constant intravenous infusion needed for administration of somatostatin Its can be used as an alternative to terlipressin, having similar efficacy and indications for use Patients who continue to bleed despite the above measures require surgery (ligation or transection of varices) or placement of a stent between intrahepatic branches of the portal and (systemic) hepatic veins under radiological control The latter is now the technique of choice for the 10-15% of patients with acute bleeding resistant to conventional treatment, and also for long-term management of patients who are difficult to help by other methods (see below)

Prevention of variceal bleeding

Endoscopic therapy as (above), preferably by band

ligation, and repeated at weekly intervals until all

varices are obliterated, is currently the treatment of

choice; it reduces the incidence of rebleeding by

50-60%

Pharmacological therapy Nonselective |3-blockers,

e.g propranolol or nadolol, reduce cardiac output

(P1 receptor antagonism) and induce splanchnic

vasoconstriction (P2 receptor antagonism allowing

unopposed oc-adrenergic vasoconstriction) Recurrent

bleeding is reduced by about 40% As propranolol

is extensively extracted in a single pass through the

liver, its systemic availability may be unpredictable

in patients with cirrhosis and portal hypertension

due to variations in hepatic blood flow and portal/

systemic shunts Ideally, the dose of propranolol

(given b.d.) should be adjusted by measuring the

portal/systemic venous pressure gradient; if this is

not feasible, the resting pulse rate is monitored,

aiming at a 25% reduction Decreased cardiac

out-put can exacerbate impaired renal function and

fluid retention Nadolol, having a longer duration

of action, is given only once daily

ASCITES

About 50% of patients with cirrhosis develop

ascites within 10 years of diagnosis and 50% of

these will die within 2 years The process by which

ascites forms in cirrhosis is not fully understood but

appears to involve the accumulation of vasodilator

substances, 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,

not deficiency, of plasma sodium)

Management of ascites

The aim is to induce natriuresis with consequent

loss of water Fluid restriction is unnecessary unless

the plasma sodium falls below 120mmol/l The

initial management must include a diagnostic tap of

the ascitic fluid as spontaneous bacterial peritonitis

complicates up to 25% of patients on presentation

A combination of bed-rest (which lowers plasma renin activity) and dietary sodium restriction are

effective in about 10% of patients but diuretic therapy

is usual The most useful drug is spironolactone but

its maximum effect can take up to 2 weeks to develop as it is metabolised to products with long duration of action, e.g canrenone t1// 10-35 h A loop

diuretic, e.g frusemide (furosemide), is therefore given

in combination, which also helps to counteract hyperkalaemia induced by spironolactone A dose ratio of spironolactone 100 mg and frusemide 40 mg o.d works well, and can be increased every 3-4 days to a maximum of spironolactone 400 mg + frusemide 160 mg

Body weight and urinary sodium excretion should be monitored Patients who have oedema as well as ascites exhibit rapid weight loss When ascites only is present weight loss should not exceed 0.5 kg/day, which is the maximum rate that fluid can move from the peritoneal cavity into the circu-lation Creating a negative fluid balance runs the risk of hypovolaemia, electrolyte disturbance, renal impairment and eventually hepatic encephalopathy Patients should lose weight if their urinary sodium excretion exceeds that provided by the diet; those who do not respond despite high urinary sodium outputs are almost certainly receiving additional sodium in their diet or medications, e.g antacids Should spironolactone cause painful gynaecomastia, amiloride is a useful substitute (10-40 mg/day) with

a more rapid onset of action

Abdominal paracentesis is useful particularly when ascites is tense; rapid drainage of 5 litres leads

to prompt relief of discomfort and improves circu-latory dynamics Provided renal function is not com-promised, extensive paracentesis is safe and can be used as an adjunct to diuretic therapy to shorten hospital stay When more than 5 litres are drained it

is customary to infuse colloid or albumin (6-8 g per litre of fluid removed) to prevent hypovolaemia

HEPATIC ENCEPHALOPATHY

Infection, gastrointestinal bleeding or injudicious use of sedatives and diuretics can precipitate hepatic encephalopathy in cirrhotic patients The

patho-physiology is complex but ammonia appears to hold

a central role Derived mainly from the action of colonic urease-containing bacteria, ammonia is

normally extracted from the portal blood by the

liver, but when there is portal/systemic shunting

and impaired hepatic metabolism, it reaches high

concentration in the blood and adversely affects the

brain Theraputic measures that limit production of

ammonia have therefore been developed

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 nonionic diffusion of

ammonia (a basic substance) from the colon into the

bloodstream The correct dose is that which

pro-duces 2-4 soft acidic stools daily (usually 30-60 ml

daily) Exceeding this dose can dehydrate the

patient As lactulose is intended for long-term use,

there is no rational basis for giving it to patients

after paracetamol overdose, as prophylaxis against

hepatic encephalopathy

Reduction of dietary protein reduces ammonia

production and has long been used to prevent

hepatic encephalopathy Any potential benefit

against encephalopathy must be tempered by the

knowledge that most patients with severe liver

disease are malnourished Protein from vegetable

sources is often better tolerated than animal-derived

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-term use is limited by toxicity

Immune-mediated liver

disease

AUTOIMMUNE ACTIVE CHRONIC

HEPATITIS

This chronic inflammatory disease of the liver is

characteristically associated with circulating

auto-antibodies and high serum immunoglobulin

con-centrations Untreated, it progresses to cirrhosis,

but the condition responds well to

immunosup-pressives Some 80% will benefit from prednisolone

which should be continued in the long term, as most patients relapse if the drug is withdrawn

Azathioprine (1 mg/kg daily) is effective as a steroid

sparing agent, and usually permits reducing of prednisolone to 5-10 mg/d Increasing azathioprine

to 2 mg/kg allows further reduction in prednisolone dose but haematological toxicity may result and the blood count must be monitored every 2 months

PRIMARY BILIARY CIRRHOSIS (PBC)

This chronic cholestatic liver disease affects 1 in

4000 people in the United Kingdom Pruritus is a common early symptom, and can be helped by

colestyramine Chronic cholestasis leads to

mal-absorption of fat-soluble vitamins, particularly vit-amin D, and deficiency of which must be corrected

to avoid osteomalacea

The aetiology of PBC is unknown but high titres of antimitochondrial antibody in the majority suggest involvement of immune mechanisms There

is no effective treatment Adverse effects outweigh benefits from prednisolone, but budesonide is cur-rently under assessment as it is highly extracted by the liver and thus poorly available to the systemic circulation Ursodeoxycholic acid 10-15 mg/kg/d improves biochemical liver function tests, but appears not to lengthen survival or prevent complications

Viral hepatitis

HEPATITIS A

Passive immunity can be obtained by i.m injection

of globulin containing antibody to the virus (normal

immunoglobulin; prepared from pooled plasma from

known immune donors) which confers temporary protection for travellers visiting areas where the

virus is endemic Active immunisation with Hepatitis

A vaccine is now preferable; protective antibody

takes about two weeks to develop

HEPATITIS B

Chronic carriage in the UK occurs in about 5% of those infected but is more common in the

immuno-compromised and in other high-risk groups including

male homosexuals and intravenous drug abusers

In parts of Asia and Africa, chronic carriage occurs

in up to 50% of the population Worldwide there are

about 300 million chronic carriers of hepatitis B

virus and it is the most important cause of primary

hepatocellular carcinoma.

Interferon alfa (see p 263) given for 4-6 months

gives long-term clearance of hepatitis B virus from

the plasma in 25-40% of patients The effect is

characteristically preceded by elevations in serum

transamininases which reflects immune-mediated

destruction of virus-infected hepatocytes; if liver

function is impaired prior to therapy use of

interferon alfa should be monitored carefully

because it may precipitate hepatic failure

Lamivudine, a nucleoside analogue, inhibits

repli-cation of hepatitis B virus DNA and reduces hepatic

inflammation The serum of about 17% of patients

converts from positive to negative for antibodies to

hepatitis B after one year of therapy Long-term

treatment is probably necessary and the drug is

well tolerated

Hepatitis B immunisation

Hepatitis B vaccine (inactivated B virus surface

antigen adsorbed on aluminium hydroxide

adju-vant) provides active immunity against hepatitis B

infection, and in countries of low endemicity it is

given to individuals at high risk, including

health-care professionals Immunity is conferred for at

least 5 years and can be supplemented by booster

injections

Hepatitis B immimoglobulin (pooled plasma

selected for high titres of antibodies to the virus)

provides passive immunity for post-exposure

pro-phylaxis e.g after accidental needlestick injury

In countries with high prevalence of hepatitis B

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

in the incidence of primary hepatocellular carcinoma,

but cannot yet be implemented in third world

countries for want of funding

HEPATITIS D

This virus replicates only in the presence of hepatitis

B Interferon alfa is less effective than in other forms

of viral hepatitis, giving sustained responses in about 15% of patients

HEPATITIS C

Most individuals infected with the hepatitis C virus become long-term carriers Chronic infection with hepatitis C virus affects an estimated 170 million individuals worldwide Up to one-third of these will progress to cirrhosis with its attendant compli-cations including hepatocellular carcinoma, over

a period of 30-40 years In the western world hepatitis C infection arises mainly from intravenous drug abuse

Treatment with interferon alfa leads to suppression

of circulating hepatitis C viral RNA and improve-ment in hepatic inflammation in about 40%, but at least half relapse on cessation of treatment

Com-bination of interferon alfa with ribavirin greatly

enhances the response, achieving sustained re-mission in up to 70%; age, duration of infection and viral genotype are among the factors that determine the response Interferon alfa is cleared rapidly, mainly by the kidney (tV2 4 h), and must be given

by s.c injection three times per week Increasing the molecular weight of the drug by conjugation with polyethylene glycol (pegylation) prolongs the t1/, to

40 h, allowing single weekly injections Pegylation also appears to enhance the efficacy of interferon alfa, possibly by increasing exposure time to the virus

Treatment should last 6-12 months but should cease after 3 months if any virus RNA persists Depression, agitation, headache and malaise may limit treatment Its use is currently restricted to patients with severe necroinflammatory changes on liver biopsy (who are thought to be most at risk of progressing to cirrhosis)

Gallstones

Ursodeoxycholic acid can be used to dissolve

choles-terol gallstones; it supplements the bile acid pool

and thus improves the solubility of cholesterol in

bile Its use is limited to patients with a functioning

gallbladder who have small stones that are not

calcified The dose is 8-12mg/kg/day p.o.,

treat-ment takes up to 2 years and recurrence is common

Pancreas

DIGESTIVE ENZYMES

In pancreatic exocrine insufficiency, the aim of

therapy is to prevent weight loss and diarrhoea

and, in children, to maintain adequate growth The

problem of getting enough enzyme to the

duo-denum concurrently with food is not as simple as it

might appear Gastric emptying varies with the

com-position of meals, e.g high fat, calories or protein

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

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,

appears to be satisfactory A reasonable course is to

start the patient on the recommended dose of a

reliable formulation and to vary this according to

the individual's needs, and the size and composition

of meals Enteric-coated formulations (pancreatin

granules, tablets) are available High-potency

pan-creatic enzymes should not be used in patients with

cystic fibrosis as they may cause ileocaecal and

large bowel strictures

ACUTE PANCREATITIS

Many drugs have been tested for specific effect, and

none has shown convincing benefit The main

requirements of therapy are:

• To provide adequate analgesia Opioids are

generally satisfactory; their potential

disadvantage of contracting the sphincter of

Oddi (and retarding the flow of pancreatic

secretion) appears to be outweighed by their

analgesic efficacy; 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 maintain urine flow

DRUGS ANDTHE PANCREAS

Adverse effects are most commonly manifest as

acute pancreatitis The strongest association is

with alcohol abuse High plasma calcium, including

that caused by hypervitaminosis D, and parenteral nutrition also increase the risk Corticosteroids, didanosine, azathoipurine, diuretics (including thia-zides and frusemide), sodium valproate, mesalazine and paracetamol (in overdose) have also been causally related

GUIDETO FURTHER READING

Dusheiko G 1999 A pill a day, or two, for hepatitis B? Lancet 353:1032-1033

Jalan R, Hayes P C 1997 Hepatic encephalopathy and ascites Lancet 350:1309-1315

Krige J E J, Beckingham IJ 2001 Portal hypertension

— 1: varices British Medical Journal 322: 348-351; also Portal hypertension — 2: ascites,

encephalopathy, and other conditions 322: 416^18 Koff R S 1998 Hepatitis A Lancet 351:1643-1649 Lauer G M, Walker B D 2001 Hepatitis C virus infection New England Journal of Medicine 345: 41-52 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 haemodynamic abnormalities and sodium and water retention in cirrhosis New England Journal

of Medicine 339: 533-541 Mas A, Rodes J 1997 Fulminant hepatic failure Lancet 349:1081-1085

Ryder S D, Beckingham IJ 2001 Chronic viral hepatitis British Medical Journal 322: 219-221 Sharara A I, Rockey D C 2001 Gastroesophageal variceal haemorrhage New England Journal of Medicine 345: 669-681

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