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Home , Alcoholic hepatitis, Alcoholic liver disease

280 Postgrad Med J 2000;76:280–286

Alcoholic disease Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from

Kevin Walsh, Graeme Alexander

Abstract is a major cause of liver Box 1: Safe limits for alcohol intake in the Western world and accounts for the x Males = 21 units per week (1 unit = majority of cases of liver cirrhosis seen in glass or half pint) district general hospitals in the UK. The x Females = 14 units per week three most widely recognised forms of alcoholic are alcoholic fatty liver (), acute alcoholic , and alcoholic cirrhosis. The exact patho- genesis of alcoholic liver injury is still not Box 2: Factors increasing susceptibility clear but immune mediated and free to ALD radical hepatic injury are thought to be x Lifetime intake of alcohol important. There is increasing interest in genetic factors predisposing to hepatic x Female sex injury in susceptible individuals. Diagno- x Genetic factors sis is based on accurate history, raised x Drinking without food serum markers such as ã-glutamyl- transferase, mean corpuscular volume, x and IgA and liver histology when x High concentration alcoholic drinks—for obtainable. Abstinence is the most example, spirits important aspect of treatment. Newer x Drinking multiple diVerent alcoholic drugs such as and naltrex- beverages one are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while have a role in acute where there Danish subjects found that ALD was increased is no evidence of gastrointestinal above a threshold of 7–13 drinks per week in haemorrhage or sepsis. Liver transplan- females and 14–27 drinks in males.2 There was tation has excellent results in abstinent a steep dose dependent increase in ALD risk patients with end stage liver disease but above this threshold with increasing alcohol there are concerns about recidivism after intake. Women had greater susceptibility to http://pmj.bmj.com/ transplant. ALD at any given level of intake. Kwo have (Postgrad Med J 2000;76:280–286) et al recently shown that men and women have 3 Keywords: cirrhosis; liver disease; alcohol equivalent alcohol elimination rates. The gen- der diVerences in susceptibility to liver injury may be due to pharmacokinetic reasons such as (ALD) is one of the diVerences in absorption or alterna- major medical complications of . tively diVerences in the response of the liver to Alcohol is the major cause of liver cirrhosis in alcohol induced injury such as that caused by on September 25, 2021 by guest. Protected copyright. the Western world, with schistosomial infec- oxidative by-products of ethanol metabolism in tion being the major cause of portal hyper- the liver. tension in the developing countries. Alcohol The pattern of drinking was also important as accounts for 80% of all liver cirrhosis cases ALD is increased in those who drink without seen in district general hospitals in the UK. accompanying food and also in those who drink Alcoholic cirrhosis is increasingly seen in multiple diVerent alcoholic beverages.1 It is well countries such as Japan and India which known that food delays gastric emptying and traditionally had a low prevalence of the intestinal absorption of alcohol and thus intake disease. of food before drinking will decrease the rise of The safe limits for alcohol intake are contro- blood alcohol concentrations. The absorption of versial. Guidelines recommended by the Royal alcohol is lower when consuming low concentra- Department of College of Physicians advise a weekly limit of tion beverages such as compared with high Medicine, University 21 units (210 g) of alcohol in men and 14 units concentration spirits. of Cambridge, Box in women. The 1994 OYce of Population A recent study in 12 687 subjects showed 157, Addenbrooke’s Censuses and Surveys’ General Household that coVee consumption protected males from Hospital, Cambridge Survey found that 27% of men and 13% of the induction of ã-glutamyltransferase by alco- CB2 2QQ, UK women in the UK were exceeding these limits. hol and may possibly protect against liver cell K Walsh 4 G Alexander A recent prospective Italian study in 6534 sub- damage caused by alcohol. jects showed the risk threshold for developing Correspondence to: ALD is 30 g ethanol/day and this risk increases Spectrum of liver disease Dr Alexander with increasing daily intake.1 Women had The three most widely recognised forms Submitted 3 June 1999 greater susceptibility to ALD in the range of of ALD are alcoholic fatty liver (steatosis), Accepted 6 September 1999 3–8 drinks daily. A previous study in 13 285 acute alcoholic hepatitis, and alcoholic Alcoholic liver disease 281

cirrhosis. At least 80% of heavy drinkers Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from develop steatosis, 10%–35% develop alcoholic Box 3: Major classification of ALD hepatitis, and approximately 10% will develop x Alcoholic fatty liver (steatosis) 5 cirrhosis. x Acute alcoholic hepatitis x Alcoholic cirrhosis ALCOHOLIC FATTY LIVER (STEATOSIS) Steatosis is invariable if consumption exceeds 80 g of alcohol per day. A large proportion of the cytoplasm of aVected is Box 4: Histological features of ALD occupied by a single large triglyceride occlu- sion but liver function is often normal. It is x Steatosis (fatty liver) reversible with abstinence but may progress to x Mallory’s hyaline bodies cirrhosis if excess alcohol intake persists.6 x due directly to fatty liver are rare and x Liver fibrosis are usually caused by acute or fat embolism. x Micronodular cirrhosis

ACUTE ALCOHOLIC HEPATITIS system, is increased by induction and In alcoholic hepatitis, ballooning is also responsible for production of acetalde- occurs due to increased intracellular water hyde. accumulation. Mallory’s hyaline bodies are is increased in zone 3 (also the perinuclear eosinophilic inclusion bodies and maximal site of action of alcohol dehydro- are probably condensed and disorganised genase). This is also the site of the terminal fragments of the cytoskeletal framework of the veins making this zone the most hypoxic hepatocyte. They are not specific for alcoholic and therefore highly susceptible to hypoxic hepatitis as they are also seen in Wilson’s injury. Oxygen derived free radicals may disease and primary biliary cirrhosis. It has cause direct hepatocyte injury by lipid peroxi- been estimated that 15–20 years of excessive dation. drinking is necessary to develop alcoholic Acetaldehyde binds covalently to proteins hepatitis. There is prominent cholestasis. forming adducts that are antigenic. Humans It is more severe in females and also in and animals exposed to long term alcohol Northern Europeans and is unrelated to excess develop persistent circulating antibod- pattern of drinking or type of alcohol drink. ies that recognise acetaldehyde protein High mortality rates are seen (30%–60%). adducts.7 Acetaldehyde modified self proteins Patients often deteriorate after hospital may serve as neoantigens, initiating harmful admission despite abstinence. This latter phe- humoral and/or cellular immune responses, nomenon may be due to reperfusion liver which leads to tissue injury.8 The expression of

injury. the proinflammatory , tumour necro- http://pmj.bmj.com/ sis factor-alpha (TNF-á), transforming ALCOHOLIC CIRRHOSIS growth factor-beta (TGF-â), interleukin (IL)- Cirrhosis is the most severe form of alcoholic 1â, and IL-6 are increased in alcoholic liver liver injury and is usually of the micronodular injury while the anti-inflammatory , type. The risk is increased in continuous IL-4 is decreased.9 These cytokines stimulate drinkers compared to binge drinkers. stellate cells which produce collagen leading to deposition can be pericellular, in the space of liver fibrosis. A study by Neuman et al suggests Disse, and around central veins (central hyaline that it is TNF-á that is the main candidate on September 25, 2021 by guest. Protected copyright. sclerosis). The latter is often associated with accounting for as addition of an rapid progression to cirrhosis and commoner equivalent amount of IL-6 seen in ALD did and more severe in women. Collagen bridges not produce injury in a normal rat liver eventually develop between central veins and whereas equivalent amounts of TNF-á did portal tracts isolating groups of hepatocytes produce injury.10 Removal of toxic reactive which form the regeneration nodules. Survival oxygen species is achieved via three major for patients is 60%–70% at one year and 35%– antioxidant : catalase, superoxide dis- 50% at five years. mutase, and glutathione peroxidase. The gen- eration of high concentrations of free radicals Pathogenesis during the metabolism of alcohol may exceed There are a number of hypotheses regarding the capacity of the antioxidant defence mecha- the pathogenesis of alcoholic liver injury. nisms and contribute to the development of Ethanol metabolism usually takes place in alcohol induced liver injury. Polavarapu et al the mitochondria. Ethanol is oxidised to have shown that in rats with alcohol induced acetaldehyde by , which injury, these antioxidant enzymes are reduced in turn is oxidised to acetate by acetaldehyde and levels are inversely correlated with severity dehydrogenase. These oxidation reactions are of liver injury.11 Alcohol reduces alkaline associated with the formation of NADH and protease activity in rats resulting in failure to NAD and alter the redox state of the cell. This clear hepatocytes of oxidatively damaged has harmful eVects on lipid and carbohydrate proteins.12 This results in oxidative liver metabolism—for example, steatosis. In ha- damage. bitual drinkers, a microsomal mixed function Soluble fatty acid synthase (FAS) and oxidase, the microsomal ethanol oxidising FAS ligand are increased in patients with 282 Walsh,Alexander

acute alcoholic hepatitis and alcoholic Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from cirrhosis while they are normal in chronic Box 5: Putative pathogenic .13 These soluble mediators could mechanisms be produced in hepatocytes, Kuppfer cells, or x Lipid peroxidation polymorphonuclear cells in the liver. Their x Reduced antioxidant defences exact role in alcoholic liver injury needs to be determined. x Immunological Twin studies suggest a genetic component to x Iron deposition disease susceptibility.14 In white people, asso- ciations between ALD risk and polymorphisms of the genes encoding the P-450 CYP2E115 and TNF-á16 have been shown. The frequency of an alcohol dehydrogenase 3 allele Box 6: Clinical features has been found to diVer in alcohol related liver x 17 disease and controls. IL-10 polymorphism is x Abdominal discomfort associated with an increased risk (× 1.8) of x Diarrhoea ALD. Hepatitis C viraemia and alcohol have an x additive eVect on the risk of liver injury.18 Alco- x hol may impair the immune system’s response x Encephalopathy to the virus or increased hepatic iron secondary x Upper gastrointestinal bleeding to alcohol may modify the clinical course of hepatitis C virus. There is significant iron deposition in alcoholic .19 A recent study found no link between simple heterozygotes of either HFE jaundice, ascites, encephalopathy, or upper gene and risk of ALD.20 Comparing 257 gastrointestinal bleeding. patients with ALD and 117 healthy controls, ALD may be detected when patients present 15.7 % of fibrotic/cirrhotic patients were voluntarily for detoxification. Patients may C282Y heterozygote compared with 13.7% of present with other sequelae of such controls. Of chromosomes without the C282Y as pneumonia, rib fractures, or head injury. mutation, 15.4% of ALD and 16.6% of Liver damage may be detected when patients controls were H63D heterozygote. Significant present with alcoholic damage to other organs iron staining was found in 6/23 C282Y hetero- such as the pancreas, heart, brain, and periph- zygotes versus 4/26 H63D heterozygotes versus eral nerves. 4/23 controls. Simple heterozygotes are not Patients with fatty liver usually look well and more susceptible to developing iron catalysed often have only mild with no

during ethanol consumption. other stigmata of . http://pmj.bmj.com/ Patients with ALD have increased iron accu- In alcoholic hepatitis patients usually look mulation, independent of HFE genotype. This very unwell, are malnourished, and often may be because of folic acid deficiency increas- pyrexial. Patients are often deeply jaundiced 21 ing iron absorption. Oxidative stress increases and cutaneous features of chronic liver disease the activity of iron regulatory proteins which are common. There is often marked bind to iron response elements in the messen- hepatomegaly which is tender on palpation. ger RNAs of iron regulating genes such as the Hepatic may be heard. Splenomegaly is 22 transferrin receptor and ferritin. This results uncommon. Ascites and hepatic encephalopa- on September 25, 2021 by guest. Protected copyright. in an increase in free iron in the hepatocyte. thy are common but varices are not common. Hepatic siderosis in an alcoholic may identify Upper gastrointestinal bleeding does occur those most susceptible to oxidative stress— but is usually due to gastric erosions or peptic because of genetic or environmental reasons. ulceration on a background of . There is an inverse correlation between liver Infections are very common during the iron staining and survival in alcoholic illness. cirrhosis.23 The clinical features of alcoholic cirrhosis Alcohol increases portal blood flow and also are similar to non-alcoholic cirrhosis. It is hepatic vascular resistance leading to an thought that spider telangiectasia, parotid increase in portal pressure and collateral blood enlargement, gynaecomastia, and hepatome- flow.24 This increases the risk of variceal bleed- galy are more common in alcoholic cirrhosis. ing in patients with alcoholic cirrhosis and por- tal hypertension. Investigations The most important part of the diagnostic Clinical presentation work-up is obtaining a reliable history of Alcohol can cause significant liver damage prolonged alcohol abuse. Patients are often not without producing any symptoms or signs of forthcoming until they gain the trust of their liver disease. Many people are diagnosed when doctor and so their general practitioner may be they have routine as part of in the best position to make the diagnosis. a medical check-up. Patients may present with Various questionnaires such as the CAGE test non-specific features such as nausea, vomiting, are useful in screening for alcohol abuse. A col- abdominal discomfort, or diarrhoea. Patients lateral history from spouses, family members, with advanced liver disease may present with and friends is very important. Alcoholic liver disease 283

The two commonest laboratory indices in Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from detecting excessive alcohol consumption are a Box 7: CAGE questionnaire raised serum ã-glutamyltransferase and mean C. Have you ever felt the need to cut down corpuscular volume. Individually these test your drinking? have a sensitivity of 30%–40% but combining A. Have you ever felt annoyed by criticism the tests is much more informative. A moder- of your drinking? ately raised ã-glutamyltransferase can be found in non-alcoholic fatty liver and also in patients G. Have you ever felt guilty about your taking drugs which induce hepatic enzymes drinking? such as phenytoin. An isolated raised E. Have you ever taken a drink (eye ã-glutamyltransferase in a heavy drinker with opener) first thing in the morning? otherwise normal liver function tests is usually Score 1 for each positive response. A score associated with only mild histological liver of 2 or more suggests alcohol excess. damage which is reversible. Many clinicians therefore feel a to assess liver injury is unnecessary in this situation. Serum carbohydrate deficient transferrin is a Box 8: Investigations specific and sensitive test of alcoholism but is x ã-Glutamyltransferase not widely available and many feel that a com- bination of ã-glutamyltransferase and mean x Mean corpuscular volume corpuscular volume is just as useful. x Carbohydrate deficient transferrin Serum transaminase levels are often not x (markedly raised in acute greatly raised in ALD and values greater than alcoholic hepatitis) five times the upper limit of the normal reference range should lead to consideration of x Serum transaminases: if greater than five other diagnoses such as viral or autoimmune times normal suspect other liver hepatitis. Hyperbilirubinaemia reflects the se- pathology verity of the hepatitis and is greatly increased in x Prothrombin time alcoholic hepatitis. x Albumin Prolongation of the prothrombin time and x Serum fibrosis markers: procollagen III hypoalbuminaemia reflect poor hepatic syn- propeptide, laminin, type IV collagen thetic function. A score based on prothrombin time (sec- x Liver ultrasound: also detect onds) and serum bilirubin (mmol/l) is used to splenomegaly and ascites determine short term prognosis in alcoholic x Liver biopsy hepatitis.25 The discriminant function (DF) is calculated from the equation DF = 4.6 (prothrombin time − control time) + serum

bilirubin/17.1. A score >32 denotes severe dis- riskier procedure, which may necessitate using http://pmj.bmj.com/ ease with a two month mortality of 50% and the transjugular venous route for performing these patients should be given a trial of the biopsy. corticosteroids. Portal pressure measurements taken at Leucocytosis is common in alcoholic hepa- hepatic venography may be superior to the titis as is thrombocytopenia, which occurs sec- Child-Pugh score in predicting mortality and ondary to direct alcohol toxicity or to bleeding risk in patients with alcoholic cirrhosis hypersplenism found in . but no previous bleeding.27 Electrolyte abnormalities commonly found are on September 25, 2021 by guest. Protected copyright. hyponatraemia and hypokalaemia and less Treatment commonly hypocalcaemia and hypomagnesae- The most important aspect of treatment is mia. abstinence from alcohol. This should be Ultrasound scanning can reveal the presence encouraged with help from the patient’s family of fatty liver and hepatitis through changes in and friends, psychiatric intervention, and also the reflectivity of the liver parenchyma. An support groups such as Alcoholics Anony- irregular shrunken liver suggests severe cirrho- mous. Despite these measures, many patients sis while additional pointers to liver disease continue to abuse alcohol and this has led to such as ascites, varices, and splenomegaly can great interest in pharmacological agents to be identified. Doppler studies can demonstrate treat . The opiate antago- changes in hepatic artery and portal vein flow. nist, naltrexone has been licensed in the USA Newer radiological tools such as magnetic for treatment of alcoholism since 1994. This is resonance spectroscopy are being evaluated.26 used in patients who are actively drinking, A number of serum markers of fibrosis have where it has been shown to reduce craving and been shown to reflect severity of alcoholic liver the level of drinking over several months. It has injury such as procollagen III propeptide, lam- no role in enhancing abstinence. A newer opi- inin, and type IV collagen. However they lack ate antagonist, nalmefene, has the advantage enough sensitivity and specificity to be used in of not being toxic to the liver and having no individual cases. first-pass metabolism but data are insuYcient Liver biopsy is necessary to confirm the at present to recommend its clinical use. extent of liver injury and to provide a prognos- Acamprosate is the other agent which has also tic guide. The coagulopathy accompanying been shown to reduce drink frequency but its alcoholic hepatitis and cirrhosis makes this a eVect on abstinence is unclear. The mode of 284 Walsh,Alexander

action of acamprosate is unknown but it Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from appears to interact with glutamate receptors Box 9: Management and calcium channels. A recent meta-analysis x Abstinence: support groups, opiate has confirmed the clinical benefits of naltrex- antagonists, acamprosate one and acamprosate but has cast doubt on the x Vitamins: thiamine, folic acid, and benefits of disulfiram which has been tra- other B vitamins ditionally used to promote abstinence.28 The meta-analysis also showed that serotonergic x Nutrition supplements: nasogastric drugs and lithium have no clinical benefit in feeding in malnourished managing alcohol misuse. x Corticosteroids for severe acute Vitamin B deficiency is common in ALD, in alcoholic hepatitis particular thiamine, , pyridoxine, and x Standard treatment for riboflavine. Parenteral vitamin B supplemen- decompensation features such as tation is preferred due to lower absorption of hypoglycaemia, ascites, varices, oral preparations in alcoholism and malnutri- infections, encephalopathy, renal tion. Wernicke’s encephalopathy has occurred failure, and coagulopathy despite high dose vitamin B supplementation orally.29 Concerns exist regarding use of x parenteral vitamin B preparation after the publication in 1989 by the Committee on Safety of Medicines of a warning about serious Box 10: Research treatments adverse reactions relating to Parenterovite. Parenterovite was later withdrawn world wide x in 1992 due to manufacturing problems. A x Malotilate new intravenous preparation, Pabrinex, was x S-adenosyl-L-methionine introduced in 1993. In reality, Parenterovite caused a serious reaction in only one in x Saturated fatty acids 250 000 cases in the UK and no serious reac- x tions were described in 300 000 patients x Soya bean lecithin treated with intravenous thiamine in the x Thalidomide USA.30 These figures pale in comparison with reported allergic reactions in 1%–10% of x Monoclonal anti-TNF antibodies penicillin administrations and 1%–18% of streptokinase administrations. We routinely administer Pabrinex I and II ampoules diluted in 50–100 ml 5% dextrose given over 30 min- beneficial in improving short term survival in utes. This is given twice daily for three days patients with severe alcoholic hepatitis.31 32 and then patients are switched to oral thiamine This was confirmed in a randomised, double

300 mg daily and multivitamins (two daily). blind trial comparing 28 days of http://pmj.bmj.com/ One important consideration is that thiamine 40 mg daily with placebo in 61 patients with should be administered before a glucose load alcoholic hepatitis. At 66 days, mortality in the in alcoholics with hypoglycaemia as the placebo group was 84% compared with 12.5% glucose load may deplete already borderline in the prednisolone treated group.33 Cortico- thiamine stores and thus precipitate Wer- steroids should not be given if patients have nicke’s encephalopathy. gastrointestinal bleeding, active infection, pan- Patients should be assessed by a dietitian and creatitis, or decompensated diabetes. Other- receive nutritional supplements while very wise, if patients have severe alcoholic hepatitis on September 25, 2021 by guest. Protected copyright. malnourished patients may benefit from na- in terms of encephalopathy, coagulopathy, leu- sogastric or nasojejunal feeding. cocytosis, hyperbilirubinaemia or ascites, we Patients often require a reducing dose of treat them with prednisolone 40 mg daily for chlormethiazole or chlordiazepoxide to prevent 28 days. We often judge the severity clinically alcohol withdrawal phenomena. Intravenous rather than adhering rigidly to Maddrey’s dis- chlormethiazole is occasionally used in very criminant function score as mentioned previ- agitated patients but should only be used where ously. Even if short term mortality is reduced, close cardiorespiratory monitoring is available. the long term benefits on mortality and As with other types of liver disease, therapy is prevention of progression to cirrhosis are still indicated for the complications such as hy- unknown. poglycaemia, ascites, encephalopathy, variceal Propylthiouracil has been proposed as a bleeding, infection, coagulopathy, and renal treatment for ALD because it abolishes the impairment. When considering encephalopa- ethanol induced increase in liver oxygen thy in an alcoholic patient, it is important to consumption that follows long term ethanol diVerentiate this from subdural haematomata, administration.34 Initial trials in alcoholic , and Wernicke’s encepha- hepatitis produced conflicting results.35 36 How- lopathy. ever, a study in 310 patients with chronic liver There is great debate regarding the benefits disease showed that those receiving propylth- of corticosteroids in acute alcoholic hepatitis. iouracil (300 mg daily) had a 50% reduced They inhibit immune mechanisms that cause mortality rate compared with placebo.37 Fur- liver damage as a result of the formation of ther studies are awaited to confirm these data antibodies to acetaldehyde products. Two and therefore the drug is not routinely used in meta-analyses suggest that corticosteroids are a clinical setting at present. Alcoholic liver disease 285

Malotilate has been used in the treatment of 4 Tanaka K, Tokunaga S, Kono S, et al.CoVee consumtion Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from and decreased serum gamma-glutamyltransferase and ALD because it inhibits CYP2E1 induced by aminotransferase activities among male alcohol drinkers. Int alcohol.38 39 J Epidemiol 1998;27:438–43. 5 Grant BF, Dufour MC, Harford TC. Epidemiology of alco- S-adenosyl-L-methionine dietary supple- holic liver disease. Semin Liv Dis 1988;8:12–25. ment therapy has been used in ALD as it 6 Teli MR, Day CP, Burt AD, et al. Determinants of progres- sion to cirrhosis or fibrosis in pure alcoholic fatty liver. Lan- replenishes liver mitochondrial glutathione 1995;346:987–90. 40 41 cet levels. A defect in transporting glutathione 7 Koskinas J, Kenna JG, Bird GL, et al. Immunoglobulin A from cytosol into mitochondria caused by antibody to a 200 kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis. 1992;103:1060–7. ethanol depletes the mitochondrial pool of glu- 8 Xu D, Thiele GM, Beckenhauer JL, et al. Detection of tathione. This renders ethanol fed hepatocytes circulating antibodies to malondialdehyde-acetaldehyde adducts in ethanol-fed rats. Gastroenterology 1998;115:686– more susceptible to the cytotoxic eVects of 92. inflammatory cytokines such as TNF-á by 9 Fang C, Lindros KO, Badger TM, et al. Zonated expression of cytokines in rat liver: eVect of chronic ethanol and the amplifying the generation of reactive oxygen cytochrome P450 2E1 inhibitor, chlormethiazole. Hepatol- species within mitochondria. ogy 1998;27:1304–10. 10 Neuman MG, Shear NH, Bellentani S, et al. Role of Saturated fatty acids are protective against cytokines in ethanol-induced cytotoxicity in vitro in hep G2 ALD. Polyunsaturated fatty acids potentiate cells. Gastroenterology 1998;115:157–66. 11 Polavarapu R, Spitz DR, Sim JE, et al. Increased lipid alcohol induced liver injury by inducing peroxidation and impaired antioxidant enzyme function is cytochrome P-450 2E1. Fatty acid saturation associated with pathological liver injury in experimental alcoholic liver disease in rats fed diets high in corn oil and decreases CYP2E1 activity and lipid peroxida- fish oil. 1998;27:1317–23. tion in rat studies. Nanji et al showed that when 12 Fattaccioli V, Andraud E, Gentil M, et al.EVects of ethanol administration on rat liver protease activities: relationship alcohol feeding was stopped in rats and the with oxidative stress. Hepatology 1999;29:14–20. dietary fat was switched from fish oil rich in 13 Taieb J, Mathurin P, Poynard T, et al. Raised plasma soluble Fas and Fas-ligand in alcoholic liver disease. Lancet polyunsaturates to palm oil rich in saturated 1998;351:1930–1. fatty acids, the alcohol induced liver injury was 14 Hrubec Z, Omenn GS. Evidence of a genetic predisposition reversed to normal.42 When rats were fed fish to alcoholic cirrhosis and psychosis; twin concordances for alcoholism and its biological endpoints by zygosity among oil continuously before and after alcohol with- male veterans. Alcohol Clin Exp Res 1981;9:306–9. drawal, the liver injury persisted. The role of 15 Grove J, Brown AS, Daly AK, et al. The RSAI polymor- phism of CYP2E1 and susceptibility to alcoholic liver fatty acids needs to be explored in human disease in caucasians: eVect on age of presentation and ALD. dependence on alcohol dehydrogenase genotype. Pharmaco- genetics 1998;8:335–42. Long term oxandrolone has been used 16 Grove J, Daly AK, Bassendine MF, et al. Association of a because of its anabolic eVects (improved nitro- tumor factor polymorphism with susceptibility to alcoholic . Hepatology 1997;26:143–6. gen balance) and its ability to accelerate the 17 Day CP, Bashir R, James OF, et al. Investigation of the role reversal of the fatty liver of ALD.43 It has shown of polymorphisms at the alcohol and aldehyde dehyrogenase loci in genetic predisposition to alcohol-related end-organ benefit only in moderate disease. damage. Hepatology 1991;14:798–801. Soya bean lecithin is also a possibility 18 Wiley TE, McCarthy M, Breidi L, et al. Impact of alcohol on the histological and clinical progression of hepatitis C infec- because it can restore phosphatidyl choline tion. Hepatology 1998;28:805–9. levels and inhibit fibrosis in baboons who are 19 Ludwig J, Hashimoto E, Porayko MK, et al. Hemosiderosis 44 in cirrhosis: a study of 447 native livers. Gastroenterology fed alcohol. 1997;112:882–8. Thalidomide has been considered in alco- 20 Grove J, Daly AK, Burt AD, et al. Heterozygotes for HFE http://pmj.bmj.com/ holic hepatitis because it has anti-TNF proper- mutations have no increased risk of advanced alcoholic liver disease. Gut 1998;43:262–6. ties. 21 MacDonald RA, Jones RS, Pechet GS. Folic acid deficiency and haemochromatosis. Arch Pathol 1965;80:153–60. 22 Rouault TA, Klausner RD. Iron-sulfur clusters as biosensors Liver transplantation of oxidants and iron. Trends Biochem Sci 1996;21:174–7. Survival after liver transplant for alcoholic cir- 23 Ganne-Carrie N, Christidis C, Chevret S, et al. Predictive value of liver iron content for survival in 229 prospectively rhosis is similar to or even better than for other followed patients with cirrhosis. J Hepatol 1996;25(suppl end stage liver diseases. Because of the limited 1):95.

24 Luca A, Carles Garcia-Pagan J, Bosch J, et al.EVects of etha- on September 25, 2021 by guest. Protected copyright. availability of liver transplants, using this nol consumption on hepatic hemodynamics in patients with option in the management of ALD has alcoholic cirrhosis. Gastroenterology 1997;112:1284–9. 25 Maddrey WC, Biotnott JK, Bedine MS, et al. Coricosteroid become highly emotive because the disease is therapy of alcoholic hepatitis. Gastrenterology 1978;75:193– self inflicted. Most centres demand that 9. 26 Menon DK, Harris M, Sargentoni J, et al. In vivo hepatic patients be abstinent for six months before 31P magnetic resonance spectroscopy in chronic alcohol transplantation. Many candidates are deemed abusers. Gastroenterology 1995;108:776–88. 27 VorobioV J, Groszmann RJ, Picabea E, et al. Prognostic unsuitable because of socioeconomic reasons, value of hepatic venous pressure gradient measurements in psychiatric problems, or coexistent alcoholic alcoholic cirrhosis: a 10-year prospective study. Gastroenter- ology 1996;111:701–9. damage to other organs such as cardiomyopa- 28 Garbutt JC, West SL, Carey TS, et al. Pharmacological thy. A major worry is the recidivism rate after treatment of alcohol dependence. JAMA 1999;281:1318– 25. transplant. A recent study from Birmingham 29 Chataway J, Hardman E. Thiamine in Wernicke’s noted a significant recidivism rate with pa- syndrome—how much and how long? Postgrad Med J 1995; 71:249. tients often returning to alcohol intake in the 30 Wrenn KD, Slovis CM. Is intravenous thiamine safe? Am J first year after transplant.45 These patients Emerg Med 1992;10:165. 31 Imperale T, McCullough A. Do corticosteroids reduce mor- rapidly developed histological liver injury tality from alcoholic hepatitis? Ann Intern Med 1990;113: including fibrosis. 299–303. 32 Reynolds T, Benhamou J, Blake J. Treatment of acute alco- holic hepatitis. Gastroenterol Int 1989;2:208–16. 1 Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as 33 Ramond M-J, Poynard T, RueV B, et al. A randomized trial cofactors of risk for alcohol induced liver damage. Gut of prednisolone in patients with severe alcoholic hepatitis. N 1997;41:845–50. Engl J Med 1992;362:507–12. 2 Becker U, Deis A, Sorensen TIA, et al. Prediction of risk of 34 Carmichael FJ, Orrego H, Saldivia V, et al.EVect of liver disease by alcohol intake, sex and age: a prospective propylthiouracil on the ethanol-induced increase in liver population study. Hepatology 1996;23:1025–9. oxygen consumption in awake rats. Hepatology 1993;18: 3 Kwo PY, Ramchandani VA, O’Connor S, et al. Gender dif- 415–21. ferences in alcohol metabolism: relationship to liver volume 35 Orrego H, Kalant H, Israel Y. EVects of short term therapy and eVect of adjusting for body mass. Gastroenterology 1998; with propylthiouracil in patients with alcoholic liver disease. 115:1552–7. Gastroenterology 1979;76:105–15. 286 Walsh,Alexander

36 Halle P, Pare P, Kaptein E, et al. Double blind 41 Garica-Ruiz C, Morales A, Colell A, et al. Feeding Postgrad Med J: first published as 10.1136/pmj.76.895.280 on 1 May 2000. Downloaded from controlled trial of propylthiouracil in patients with severe S-adenosyl-L methionine attenuates both ethanol-induced acute alcoholic hepatitis. Gastroenterology 1982;82: depletion of mitochondrial glutathione and mitochondrial 925–31. dysfunction in periportal and perivenous rat hepatocytes. 37 Orrego H, Blake JE, Blendis LM, et al. Long-term treatment Hepatology 1995;21:207–14. of alcoholic liver disease with propylthiouracil. N Engl J Med 42 Nanji AA, Sadrzadeh SM, Yang EK, et al. Dietary saturated 1987;317:1421–7. fatty acids: a novel treatment for alcoholic liver disease. Gas- 38 Takase S, Matsuda Y, Yasuhara M, et al.EVects of maloti- troenterology 1995;109:547–54. late treatment on alcoholic liver disease. Alcohol 1989;6: 43 Mendenhall CL, Moritz TE, Roselle GA, et al. A study of 219–22. oral nutritional support with oxandrolone in malnourished 39 Kim SG, Kwak JY, Lee JW, et al. Malotilate, a hepatopro- patients with alcoholic hepatitis: results of a Department of tectant, suppresses CYP2E1 expression in rats. Biophys Res Veterans AVairs. Hepatology 1993;17:564–76. Commun 1994;200:1414–20. 44 Lieber CS, Robins SJ, Li J, et al. Phosphatidylcholine 40 Collell A, Garcia-Ruiz C, Miranda M, et al. Selective protects against fibrosis and cirrhosis in the baboon. Gastro- glutathione depletion of mitochondria by ethanol sensitizes enterology 1994;106:152–9. hepatocytes to . Gastroenterology 1998; 45 Tang H, Boulton R, Gunson B, et al. Patterns of alcohol con- 115:1541–51. sumption after liver transplantation. Gut 1998;43:140–5.

Royal Medical Benevolent Fund

St Bartholomew’s Hospital Choral Society St Bartholomew’s Hospital Choral Society celebrates the millennium and their 35th anniver- sary with a concert at the Royal Albert Hall on 21 November 2000 in support of their chosen charity for 2000/2001, the Royal Medical Benevolent Fund. The choir will perform Mahler’s Symphony No 8, “Symphony of a Thousand” with the Royal Philharmonic Orchestra. Six hundred singers are needed for this monumental work so contact the Barts Choir Honorary Secretary on 01628 664157 to participate. To support the Royal Medical Benevolent Fund contact the Fund at 24 King’s Road, Wimbledon, London SW19 8QN (tel: 020 8540 9194, fax: 020 8542 0494, e-mail: [email protected]). http://pmj.bmj.com/ on September 25, 2021 by guest. Protected copyright.