-IBIS-1.7.6-
tx
digestive system
cirrhosis
Nutrition

dietary guidelines

eating principles:
• Protein intake should generally be reduced with an emphasis on increasing the proportion of vegetable sources. Daily consumption of 400 g carbohydrates will allow restriction of protein to 45 g per day without increasing the risk of negative nitrogen balance.
• 3-5 day alkaline fasts (see Fasting in materia medica)

therapeutic foods:
• foods that soothe the Liver, clear Heat
• foods rich in Vitamins A, E, C, and B-complex

fresh juices:
• carrot, beet, and cucumber (Jensen. 52.)
• black cherry concentrate mixed with liquid chlorophyll (Jensen. 52.)
• carrot (Walker. 131.)
• carrot and spinach (Walker. 131.)
• carrot, celery, parsley (Walker. 131.)

specific remedies:
• take 2-3 plums with pits and crush them. Add one cup of boiling water, mix and obtain the juice. Drink in the morning and evening (Yin-fang, Cheng-jun. 36.)
• take 250 g soybean sprouts and 250 g adzuki beans, cook into a light soup and eat three times daily (Chao-liang, Qing-rong, Bao-zhen. 73.)
ascites: cook a head of peeled garlic in peanut oil and eat at meals. Continue for 2-3 months (Chao-liang, Qing-rong, Bao-zhen. 87.)

avoid:
• meat, alcohol, hot sauces, spicy foods, fried foods, fatty foods, rich foods, salty foods, coffee, caffeine


supplements

Antioxidants: A wide range of researchers and clinicians have postulated that oxygen-derived free radicals may contribute to the development of chronic liver damage. In their investigation of 105 patients with chronic cholestasis, Floreani et al recently reported that both primary biliary cirrhosis and primary sclerosing cholangitis patients had significantly lower levels of retinol, alpha-tocopherol, total carotenoids, lutein, zeaxanthin, lycopene, alpha- and beta-carotene than controls.
(Pratico D, et al. J Investig Med. 1998 Feb;46(2):51-57; Yamamoto Y, et al. Biochem Biophys Res Commun. 1998 Jun 9;247(1):166-170; Nalini G, et al. Indian J Med Res. 1999 Dec;110:200-203; Watson JP, et al. J Gastroenterol Hepatol. 1999 Oct;14(10):1034-1040; Floreani A, et al. Aliment Pharmacol Ther. 2000 Mar;14(3):353-358.)
• Vitamin A, 50-100,000 IU per day, for anti-oxidant effect.
Vitamin B-complex: Vitamins B1 (50-100 mg), B2 (50-80 mg), B3 (50-75 mg - other than niacin), Pantothenic acid (100 mg), B6 (50-100 mg), B12 (250-1,000 mcg), and Folate (400 mcg) daily will counter the deficiencies commonly associated with liver disease.
Caution: Avoid Niacin as it can damage the liver.
Vitamin C, 500-1,500 mg three times daily, to prevent fatty acid oxidation, reduce inflammation, and facilitate detoxification functions, especially involving glutathione peroxidase enzyme activities. Vitamin C may be helpful for some individuals in the prevention or treatment of hepatitis.
Vitamin E, 400 IU, one to three times daily, to prevent fatty acid oxidation and reduce inflammation. Vitamin E levels are usually low among individuals with hepatitis and those who develop liver cancer due to chronic infections. One study involving children with viral hepatitis found no significant benefit from a daily dose of 300 IU. Further research will be necessary to determine whether this dose was inadequate or whether Vitamin E supplementation might be more appropriate for other causes of cirrhosis. In their investiagtion of thirty cirrhotic patients and thirty controls Ferro et al found that 300 mg of vitamin E twice daily reduced both lipid peroxidation and clotting activation in liver cirrhosis. Recent studies led by Andiran and Canturk involving rats found that alpha-tocopherol helped protect liver cells against chemically-induced cirrhosis and improved the rate of regeneration in cirrhotic rats whose livers were mostly (70%) removed.
(Mezes M, et al. Int J Clin Pharmacol Res 1986;6:333-338; Yurdakok M, Kanra G. Mikrobiyol Bul 1986;20:91-94; Pan WH, et al. Ann Epidemiol 1993;3:217-224; Houglum K, et al. Gastroenterology 1997;113:1069-1073; Canturk Z, et al. East Afr Med J. 1999 Apr;76(4):223-227; Ferro D, et al. Blood. 1999 May 1;93(9):2945-2950; Andiran F, et al. J Surg Res. 2000 Apr;89(2):184-188.)
• Vitamin K: Supplementation can benefit those with cirrhosis against the common tendency to deficiency and thus prevent inadequate clotting.
(Kowdley KV, et al. Am J Gastroenterol. 1997 Nov;92(11):2059-2061.)
• Selenium, 200 mcg per day, to prevent fatty acid oxidation and reduce inflammation.
(Michelson AM. J Environ Pathol Toxicol Oncol. 1998;17(3-4):233-239.)
L-Carnitine, 300 mg per day, protects liver against fatty degeneration.
• Catechin, 500-700 mg three times daily. This bioflavonoid may be beneficial for some individuals with hepatitis; research findings have been mixed.
(Bar-Meir S, et al. Gut 1985;26:975-979; Suzuki H, et al. Liver 1986;6:35-44; Munoz Torres E, et al. An Med Interna. 1989 Apr;6(4):189-191..)
Essential Fatty Acids, 1,000-1,500 mg (or one Tbsp) of combined omega-3 (flaxseed) and omega-6 (evening primrose) oils daily may provide beneficial anti-inflammatory action. Researchers, however, have come to mixed conclusions.
(Jenkins AP, et al. Aliment Pharmacol Ther. 1996 Aug;10(4):665-668; Miyamoto A, et al. J Gastroenterol Hepatol. 1997 Oct;12(9-10):644-652.)
Glutathione, 500 mg two to three times daily. This important anti-oxidant plays a key role in liver detoxification processes; it specifically helps reduce circulating ammonia, a serious risk factor to the brain in cirrhosis.
(Bianchi G, et al. J Hepatol. 1997 Mar;26(3):606-613; Michelson AM. J Environ Pathol Toxicol Oncol. 1998;17(3-4):233-239; Pena LR, et al. JPEN J Parenter Enteral Nutr. 1999 Jan-Feb;23(1):1-6; Purucker E, et al. Res Exp Med (Berl). 1998 Dec;198(4):167-174.)
Lecithin (Phosphatidyl Choline): A wide array of animal, in vitro and human studies have investigated the value of phosphatidyl choline in the treatment of liver disease, especially hepatitis, cirrhosis and accompanying gastritis, and reported generally positive findings. One study involving individuals with chronic hepatitis B showed significant reduction in liver damage among those who took three grams of phosphatidyl choline per day.
(Jenkins PJ, et al. Liver 1982;2:77-81; Aleynik SI, et al. J Hepatol. 1997 Sep;27(3):554-561; Podobed OV, et al. Biull Eksp Biol Med. 1997 Sep;124(9):311-314; Miyamoto A, et al. J Gastroenterol Hepatol. 1997 Oct;12(9-10):644-652; Brady LM, et al. Biochem Biophys Res Commun. 1998 Jul 9;248(1):174-179; Chawla D, et al. Biochem Soc Trans. 1998 May;26(2):S147; Hayashi H, et al. Curr Med Res Opin. 1999;15(3):177-184.)
Lipotropic factors (Choline, Methionine and Inositol): These substances provide general liver support. However, supplemental methionine may be of limited value for individuals with significant cirrhosis since it needs to be activated to S-adenosylmethionine (SAMe), a process impaired by the disease.
SAMe (S-adenosylmethionine): SAMe has been found to attenuate mitochondrial lesions in baboons, replenish glutathione, and significantly reduce mortality in some patients with cirrhosis.
(Kakimoto H, et al. Gastroenterol Jpn. 1992 Aug;27(4):508-513; Muriel P. J Appl Toxicol. 1993 May-Jun;13(3):179-182; Mato JM, et al. J Hepatol. 1999 Jun;30(6):1081-1089; Lieber CS. J Hepatol. 1999 Jun;30(6):1155-1159.)
• Liver tissue: Dessicated liver tissue has been used for decades as a nutritional support for liver repair and regeneration.
Thymus tissue: 200 mg three times daily (crude extract) or 40 mg three times daily (purified proteins). Numerous studies have found that thymus tissue extracts, usually from young cows, can provide significant benefit in the treatment of hepatitis, particularly chronic hepatitis B and possibly hepatits C. Measurable improvements in markers of liver damage are among the findings that have been reported.
(Juszczyk J. Pol Tyg Lek. 1984 Aug 13;39(33):1085-1089; Cianciara J, et al. Pol Tyg Lek. 1984 Aug 13;39(33):1097-1101; Galli M, et al. Drugs Exp Clin Res 1985;11:665-669; Bortolotti F, et al. Curr Ther Res 1988;43:67-72; Skotnicki AB. Med Oncol Tumor Pharmacother 1989;6:31-43; Civeira MP, et al. Aliment Pharmacol Ther 1989;3:395-401; Zeman K, et al. Immunol Invest. 1991 Dec;20(7):545-55.)

» Interactions:
• Alcohol and beta-carotene: Ahmed et al found that plasma beta-carotene is relatively increased by heavy alcohol consumption, whereas in patients with liver damage, especially cirrhosis, due to alcohol, it is lowered.
(Ahmed S, et al. Am J Clin Nutr. 1994 Sep;60(3):430-436.)

footnotes

Ahmed S, Leo MA, Lieber CS. Interactions between alcohol and beta-carotene in patients with alcoholic liver disease. Am J Clin Nutr. 1994 Sep;60(3):430-436.
Abstract: We found lower plasma beta-carotene concentrations in alcoholics than in control subjects, but heavy drinkers (> or = 200 g/d) had about twice the beta-carotene of those drinking less (P < 0.01), with a significant correlation between plasma beta-carotene and alcohol intake (r = 0.6, P < 0.001). When beta-carotene beadlets (30-60 mg/d) were administered to hospitalized alcoholics given controlled diets, those with cirrhosis had a much lower plasma beta-carotene response than those without; the latter in turn responded with lower beta-carotene concentrations than did control subjects. Plasma retinol, alpha-tocopherol, and other carotenoids, such as lycopene, did not differ significantly. We concluded that plasma beta-carotene is relatively increased by heavy alcohol consumption, whereas in patients with liver damage, especially cirrhosis, it is lowered. In these patients, beta-carotene supplementation may be justified, but this should be coupled with control of drinking because of possible hepatotoxic alcohol-beta-carotene interactions.

Aleynik SI, Leo MA, Ma X, Aleynik MK, Lieber CS. Polyenylphosphatidylcholine prevents carbon tetrachloride-induced lipid peroxidation while it attenuates liver fibrosis. J Hepatol. 1997 Sep;27(3):554-561.

Andiran F, Ayhan A, Tanyel FC, Abbasoglu O, Sayek I. Regenerative capacities of normal and cirrhotic livers following 70% hepatectomy in rats and the effect of alpha-tocopherol on cirrhotic regeneration. J Surg Res. 2000 Apr;89(2):184-188.

Bar-Meir S, Halpern Z, Gutman M, Shpirer Z, Baratz M, Bass D. Effect of (+)-cyanidanol-3 on chronic active hepatitis: a double blind controlled trial. Gut. 1985 Sep;26(9):975-979.
Abstract: Forty patients with biopsy proven chronic active hepatitis were studied, 22 received (+)-cyanidanol-3 in a dose of 3 g daily and 18 placebo. Side effects related to cyanidanol were fever (four patients), haemolysis (one patient) and urticaria (one patient). All side effects subsided on discontinuation of the medication. Cyanidanol had an effect no better than placebo on symptoms, laboratory tests, and histological findings on liver biopsy.

Baur H, Staub H. Treatment of hepatitis with infusions of ascorbic acid: Comparison with other therapies. JAMA 1954;156:565. (Abstract)

Bianchi G, Bugianesi E, Ronchi M, Fabbri A, Zoli M, Marchesini G. Glutathione kinetics in normal man and in patients with liver cirrhosis. J Hepatol. 1997 Mar;26(3):606-613.
Abstract: BACKGROUND/AIMS: The dynamics of glutathione in plasma has always been studied by bolus injections. Data are available suggesting that the low plasma levels of cirrhosis are due to decreased production in glutathione-producing tissues, mainly the liver. We aimed to measure the kinetics of glutathione during controlled steady-state conditions, and to determine the reasons for its reduced plasma levels in advanced cirrhosis. METHODS: The plasma clearance of glutathione was measured in six control subjects and in ten patients with cirrhosis during a 2-step infusion study, producing steady-state levels approximately 5 and 10 times basal values. The plasma disappearance curve after infusion stop was used to determine the apparent volume of distribution and half-life of glutathione, and the estimated basal appearance rate. RESULTS: The clearance of glutathione did not reject 1st-order kinetics, i.e., it was concentration-independent, and was nearly doubled in cirrhosis. The half-life of exogenous glutathione was not different, whereas the volume of distribution was larger in cirrhosis, in the same range as extracellular water. The endogenous basal appearance rate of glutathione was reduced by 50%, and correlated with liver function, measured by routine and dynamic tests. CONCLUSIONS: The data confirm that the primary defect responsible for reduced glutathione in liver disease is a reduced production, possibly related to hepatocyte dysfunction and a block along the pathway of methionine metabolism.

Bortolotti F, et al. Effect of an orally administered thymic derivative, thymomodulin, in chronic type B hepatitis in children. Curr Ther Res 1988;43:67-72.

Brady LM, Fox ES, Fimmel CJ. Polyenylphosphatidylcholine inhibits PDGF-induced proliferation in rat hepatic stellate cells. Biochem Biophys Res Commun. 1998 Jul 9;248(1):174-179.

Burk RF, Early DS, Hill KE, Palmer IS, Boeglin ME. Plasma selenium in patients with cirrhosis. Hepatology. 1998 Mar;27(3):794-798.

Campbell RE, Pruitt FW. The effect of vitamin B12 and folic acid in the treatment of viral hepatitis. Am J Med Sci 1955;229:238.

Campbell RE, Pruitt FW. Vitamin B12 in the treatment of viral hepatitis. Am J Med Sci 1952;224:252-262.

Canturk Z, Canturk NZ, Ozbilim G, Yenisey C. Experimental cirrhosis of the liver and cytoprotective effects of alpha tocopherol. East Afr Med J. 1999 Apr;76(4):223-227.

Chawla D, Malik AM, Lima VL, Owen JS. Immunoaffinity-isolation of plasma lecithin-cholesterol acyltransferase (LCAT) from patients with hepatic cirrhosis. Biochem Soc Trans. 1998 May;26(2):S147.

Cianciara J, Babiuch L, Gorska E, Kassur B. [Immunotherapy of chronic active hepatitis (HBsAg+) with calf thymus extract (TFX-Polfa). Clinical evaluation]. Pol Tyg Lek. 1984 Aug 13;39(33):1097-1101. [Article in Polish]

Civeira MP, Castilla A, Morte S, et al. A pilot study of thymus extract in chronic non-A, non-B hepatitis. Aliment Pharmacol Ther 1989;3:395-401.

Corrales FJ, Ruiz F, Mato JM. In vivo regulation by glutathione of methionine adenosyltransferase S-nitrosylation in rat liver. J Hepatol. 1999 Nov;31(5):887-894.

de la Maza MP, Petermann M, Bunout D, Hirsch S. Effects of long-term vitamin E supplementation in alcoholic cirrhotics. J Am Coll Nutr. 1995 Apr;14(2):192-196.

Denda A, Endoh T, Tang Q, Tsujiuchi T, Nakae D, Konishi Y. Prevention by inhibitors of arachidonic acid cascade of liver carcinogenesis, cirrhosis and oxidative DNA damage caused by a choline-deficient, L-amino acid-defined diet in rats. Mutat Res. 1998 Jun 18;402(1-2):279-288.

Ferro D, Basili S, Pratico D, Iuliano L, FitzGerald GA, Violi F. Vitamin E reduces monocyte tissue factor expression in cirrhotic patients. Blood. 1999 May 1;93(9):2945-2950

Filaci G, Pelli N, Sacco T, Contini P, Lanza L, Picciotto A, Scudeletti M, Puppo F, Castiglioni G, Indiveri F. S-adenosil-L-methionine is able to reverse the immunosuppressive effects of chenodeoxycholic acid in vitro. Int J Immunopharmacol. 1997 Mar;19(3):157-165.

Floreani A, Baragiotta A, Martines D, Naccarato R, D'odorico A. Plasma antioxidant levels in chronic cholestatic liver diseases. Aliment Pharmacol Ther. 2000 Mar;14(3):353-358.
Abstract: BAKCGROUND: A predictable consequence of cholestasis is malabsorption of fat-soluble factors, (vitamins A, D, E, K) and other free radical scavengers, such as carotenoids. It has been suggested that oxygen-derived free radicals may be involved in the pathogenesis of chronic liver damage. AIMS: (i) To evaluate retinol, alpha-tocopherol and carotenoid plasma levels in two groups of patients with chronic cholestatic liver disease (primary biliary cirrhosis and primary sclerosing cholangitis); (ii) to compare the respective plasma levels with those of the general population; (iii) to correlate the plasma levels with disease severity. METHODS: A total of 105 patients with chronic cholestasis were included in the study: 86 with primary biliary cirrhosis (81 female, five male, mean age 55.5 +/- 11 years), 19 with primary sclerosing cholangitis (seven female, 12 male, mean age 35 +/- 11 years; six patients had associated inflammatory bowel disease); 105 sex- and age-matched subjects from the general population in the same geographical area (88 female, 17 male, mean age 51.3.5 +/- 10 years) served as controls. Carotenoids (lutein zeaxanthin, lycopene, beta-carotene, alpha-carotene, beta-cryptoxanthin), retinol and alpha-tocopherol were assayed by high-pressure liquid chromatography. A food frequency questionnaire was administered to each subject to evaluate the quality and the quantity of dietary compounds. Data were processed by analysis of variance and linear regression analysis, as appropriate. RESULTS: Both primary biliary cirrhosis and primary sclerosing cholangitis patients had significantly lower levels of retinol, alpha-tocopherol, total carotenoids, lutein, zeaxanthin, lycopene, alpha- and beta-carotene than controls (P < 0.0001). Among the cholestatic patients, no significant difference in the concentration of antioxidants was observed between primary biliary cirrhosis and primary sclerosing cholangitis subjects. Anti-oxidant plasma levels were not affected by the severity of the histological stage in primary biliary cirrhosis, but a negative correlation was found between total carotenoids and both alkaline phosphatase (ALP) and gammaglutamyl transpeptidase (GGT) (P < 0.013 and P < 0.018, respectively). Within the primary sclerosing cholangitis group, no correlation was found between total carotenoids and cholestatic enzymes. Nutritional intake in cholestatic patients was comparable to controls, including fruit and vegetable intake. CONCLUSIONS: Although no clinical sign of deficiency is evident, plasma levels of antioxidants are low in cholestatic patients even in early stages of the disease. This is probably due to malabsorption of fat-soluble vitamins, as well as other mechanisms of hepatic release, suggesting the need for dietary supplementation.

Galli M, Crocchiolo P, Negri C, Caredda F, Lazzarin A, Moroni M. Attempt to treat acute type B hepatitis with an orally administered thymic extract (thymomodulin): Preliminary results. Drugs Exp Clin Res 1985;11(9):665-669.
Abstract: A double-blind trial with thymomodulin (TM) was performed in a consecutive series of 50 inpatients affected with acute type B hepatitis. Twenty-six randomly selected patients received TM (Leucotrofina, Ellem), 1 ampoule b.i.d. per os for 30 days, and 24 patients received the same amount of placebo for the same period. TM-treated patients showed accelerated AST and ALT decrease and an earlier HBsAg clearance. However, only the difference in ALT decrease was statistically significant in comparison with the controls (p less than 0.02). Before the treatment was started, lymphocyte subsets, as determined by monoclonal antibodies, showed a different pattern in the two groups despite strict randomization. Nevertheless, by the end of the trial, mean T4+/T8+ ratios were increased in the treated group, but remained unchanged in the control group. The trends in the two groups were significantly different (p less than 0.005). Further information is expected from a long-term follow-up.

Hadi Yasa M, Kacmaz M, Serda Ozturk H, Durak I. Antioxidant status of erythrocytes from patients with cirrhosis. Hepatogastroenterology. 1999 Jul-Aug;46(28):2460-2463.

Hayashi H, Tanaka Y, Hibino H, Umeda Y, Kawamitsu H, Fujimoto H, Amakawa T. Beneficial effect of salmon roe phosphatidylcholine in chronic liver disease. Curr Med Res Opin. 1999;15(3):177-184.
Abstract: Phosphatidylcholine (PC), especially dilinoleoyl-PC, has been reported to be effective in preventing hepatic fibrosis in chronically alcohol-fed baboons. Continuous hepatic inflammation predisposes the structure of the liver to fibrosis. Since n-3 polyunsaturated fatty acids (PUFA) have been shown to exhibit an anti-inflammatory effect, we tested the hypothesis that n-3 PUFA PC as a dietary supplement has a beneficial effect on chronic liver disease susceptible to fibrosis. Salmon roe phospholipids, 90% of which are PC, were extracted and encapsulated. Almost a third of the PC fatty acids were docosahexaenoic acid (22:6 n3) and 10% were eicosapentanoic acid (20:5 n3). About 1600 mg/day of the phospholipids was administered for six months to six chronic liver disease patients, four with hepatitis B infection (three with cirrhosis, one with chronic hepatitis), one with hepatitis C virus cirrhosis and one with alcoholic cirrhosis. There was no change in the results of blood chemistry studies related to liver function, except in globulin, which decreased from 3.80 g/dl to 3.67 g/dl (p < 0.05). Among the lipid parameters, HDL-cholesterol, apolipoprotein A-I and apolipoprotein E increased significantly. Although this was a small trial, n-3 PUFA PC may be beneficial in the treatment of chronic liver diseases.

Holm E, Sedlaczek O, Grips E. Amino acid metabolism in liver disease. Curr Opin Clin Nutr Metab Care. 1999 Jan;2(1):47-53. (Review)

Houglum K, Venkataramani A, Lyche K, Chojkier M. A pilot study of the effects of d-alpha-tocopherol on hepatic stellate cell activation in chronic hepatitis C. Gastroenterology 1997;113:1069-1073.

Jenkins AP, Green AT, Thompson RP. Essential fatty acid supplementation in chronic hepatitis B. Aliment Pharmacol Ther. 1996 Aug;10(4):665-668.
Abstract: BACKGROUND: Dietary supplementation with essential fatty acids and polyunsaturated lecithin may improve biochemical and histological parameters in liver disease. METHODS: Ten patients with serological and histological evidence of chronic hepatitis B received capsules of the polyunsaturated fatty acid-rich evening primrose oil in a dose of 4 g daily for 12 months, while a matched group received liquid paraffin capsules as a placebo. RESULTS: Compared to the placebo group, the patients receiving evening primrose oil showed no improvement in either biochemical or histological indices of liver damage, or in the rate of loss of circulating e antigen. CONCLUSIONS: Dietary, supplementation with this dose of essential fatty acids is unlikely to be of benefit in chronic hepatitis B.

Jenkins PJ, Portmann BP, Eddleston AL, Williams R. Use of polyunsaturated phosphatidyl choline in HBsAg negative chronic active hepatitis: results of prospective double-blind controlled trial. Liver. 1982 Jun;2(2):77-81.
Abstract: In a prospective double-blind trial, polyunsaturated phosphatidyl choline therapy (3 g/day) was given in addition to normal maintenance immunosuppressive therapy to 15 patients with HBsAg negative chronic active hepatitis. Histological evidence of disease activity was significantly reduced in the phospholipid-treated group. The results indicate that polyunsaturated phosphatidyl choline is of value as additional treatment in the management of patients with HBsAg negative chronic active hepatitis whose disease is inadequately controlled with conventional doses of immunosuppressive therapy.

Juszczyk J. [Preliminary evaluation of the results of treatment of chronic active hepatitis (HBsAg+) with calf thymus extract (TFX-Polfa)]. Pol Tyg Lek. 1984 Aug 13;39(33):1085-1089. [Article in Polish]

Kakimoto H, Kawata S, Imai Y, Inada M, Matsuzawa Y, Tarui S. Changes in lipid composition of erythrocyte membranes with administration of S-adenosyl-L-methionine in chronic liver disease. Gastroenterol Jpn. 1992 Aug;27(4):508-513.

Keeling PW, Viola L, Anderson MG, Marigold JH, Macartney JC, Paradinas FJ, Murray-Lyon IM, Thompson RP. Trial of (+)-cyanidanol-3 in patients with hepatitis B chronic liver disease. J R Soc Med. 1986 Aug;79(8):460-461.

Knodell RG, Tate MA, Akl BF, Wilson JW. Vitamin C prophylaxis for posttransfusion hepatitis: lack of effect in a controlled trial. Am J Clin Nutr 1981;34:20-23.

Kowdley KV, Emond MJ, Sadowski JA, Kaplan MM. Plasma vitamin K1 level is decreased in primary biliary cirrhosis. Am J Gastroenterol. 1997 Nov;92(11):2059-2061.

Lieber CS. Pathogenesis and treatment of liver fibrosis in alcoholics: 1996 update. Dig Dis. 1997 Jan-Apr;15(1-2):42-66. (Review)

Lieber CS. Alcoholic liver disease: new insights in pathogenesis lead to new treatments. J Hepatol. 2000;32(1 Suppl):113-128. (Review)

Lieber CS. Prevention and treatment of liver fibrosis based on pathogenesis. Alcohol Clin Exp Res. 1999 May;23(5):944-949. (Review)

Lieber CS. Role of S-adenosyl-L-methionine in the treatment of liver diseases. J Hepatol. 1999 Jun;30(6):1155-1159.

Loguercio C, Nardi G, Argenzio F, Aurilio C, Petrone E, Grella A, Del Vecchio Blanco C, Coltorti M. Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease. Alcohol Alcohol. 1994 Sep;29(5):597-604.

Loguercio C, Blanco FD, De Girolamo V, Disalvo D, Nardi G, Parente A, Blanco CD. Ethanol consumption, amino acid and glutathione blood levels in patients with and without chronic liver disease. Alcohol Clin Exp Res. 1999 Nov;23(11):1780-1784.

Look MP, Reichel C, von Falkenhausen M, Hahn C, Stockinger K, von Bergmann K, Rao GS, Spengler U, Sauerbruch T. Vitamin E status in patients with liver cirrhosis: normal or deficient? Metabolism. 1999 Jan;48(1):86-91.
Abstract: The study aim was to compare the ratio of vitamin E to serum cholesterol with the serum vitamin E level alone as a measure of vitamin E status in patients with different degrees of liver dysfunction. Assessment of serum vitamin E and total serum cholesterol was performed in 85 patients with liver cirrhosis at Child's stage A (n = 26), B (n = 26), and C (n = 33) and 50 patients with noncirrhotic liver disease. As surrogate markers of liver function, 7alpha-hydroxycholesterol and prealbumin concentrations and the plasma prothrombin time were determined. Mean serum vitamin E concentrations in Child A, B, and C patients were 27.4%, 36.9%, and 37.3% lower, respectively, than in healthy controls (P<.01). Twelve of 26 Child A, 14 of 26 Child B, and 14 of 33 Child C patients had vitamin E deficiency with respect to the absolute values, i.e., serum levels less than 13.76 micromol/L (5% percentile of healthy controls). In contrast, only two of 26 Child A, five of 26 Child B, and five of 33 Child C patients (P<.01 for Child A/B and P<.05 for Child C) were vitamin E-deficient according to the serum vitamin E to cholesterol ratio, i.e., less than 2.86 micromol/mmol. Serum vitamin E was correlated significantly with prealbumin, 7alpha-hydroxycholesterol, and the plasma prothrombin time, but the vitamin E to cholesterol ratio was not. Correcting serum vitamin E for total serum cholesterol in patients with liver cirrhosis leads to the phenomenon of reduced serum vitamin E levels inadvertently shifted toward normal values. In patients with liver cirrhosis, the absolute vitamin E concentration correlates better with the typical clinical and biochemical findings of the disease than the vitamin E to cholesterol ratio. Therefore, a considerable number of patients with advanced liver cirrhosis might actually be vitamin E-deficient.

Marra F, Riccardi D, Melani L, Spadoni S, Galli C, Fabrizio P, Tosti-Guerra C, Carloni V, Gentilini P, Laffi G. Effects of supplementation with unsaturated fatty acids on plasma and membrane lipid composition and platelet function in patients with cirrhosis and defective aggregation. J Hepatol. 1998 Apr;28(4):654-661.

Mato JM, Alvarez L, Ortiz P, Pajares MA. S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol Ther. 1997;73(3):265-280. (Review)

Mato JM, Camara J, Fernandez de Paz J, Caballeria L, Coll S, Caballero A, Garcia-Buey L, Beltran J, Benita V, Caballeria J, Sola R, Moreno-Otero R, Barrao F, Martin-Duce A, Correa JA, Pares A, Barrao E, Garcia-Magaz I, Puerta JL, Moreno J, Boissard G, Ortiz P, Rodes J. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999 Jun;30(6):1081-1089.
Abstract: BACKGROUND/AIM: The efficacy of S-adenosylmethionine (AdoMet) in the treatment of liver cell injury has been demonstrated in several experimental models. The aim of this study was to investigate the effects of AdoMet treatment in human alcoholic liver cirrhosis. METHODS: A randomized, double-blind trial was performed in 123 patients treated with AdoMet (1200 mg/day, orally) or placebo for 2 years. All patients had alcoholic cirrhosis, and histologic confirmation of the diagnosis was available in 84% of the cases. Seventy-five patients were in Child class A, 40 in class B, and 8 in class C. Sixty-two patients received AdoMet and 61 received placebo. RESULTS: At inclusion into the trial no significant differences were observed between the two groups with respect to sex, age, previous episodes of major complications of cirrhosis, Child classification and liver function tests. The overall mortality/liver transplantation at the end of the trial decreased from 30% in the placebo group to 16% in the AdoMet group, although the difference was not statistically significant (p = 0.077). When patients in Child C class were excluded from the analysis, the overall mortality/liver transplantation was significantly greater in the placebo group than in the AdoMet group (29% vs. 12%, p = 0.025), and differences between the two groups in the 2-year survival curves (defined as the time to death or liver transplantation) were also statistically significant (p = 0.046). CONCLUSIONS: The present results indicate that long-term treatment with AdoMet may improve survival or delay liver transplantation in patients with alcoholic liver cirrhosis, especially in those with less advanced liver disease.

Mezes M, Par A, Nemeth P, Javor T. Studies of the blood lipid peroxide status and vitamin E levels in patients with chronic active hepatitis and alcoholic liver disease. Int J Clin Pharmacol Res 1986;6:333-338.

Mezey E. Dietary fat and alcoholic liver disease. Hepatology. 1998 Oct;28(4):901-905. (Review)

Michelson AM. Selenium glutathione peroxidase: some aspects in man. J Environ Pathol Toxicol Oncol. 1998;17(3-4):233-239

Miyamoto A, Wakabayashi H, Watanabe A. Abnormality in fatty acid composition of gastric mucosal phospholipids in patients with liver cirrhosis and its correction with a polyunsaturated fatty acid-enriched soft oil capsule. J Gastroenterol Hepatol. 1997 Oct;12(9-10):644-652.
Abstract: The abnormal composition of the fatty acids in gastric mucosal phospholipids was examined in 11 patients with non-alcoholic liver cirrhosis accompanied by gastritis and in 10 healthy subjects without liver disease and gastritis. The cases positive for serum anti-Helicobacter pylori immunoglobulin G antibody were excluded. The arachidonic acid (AA, C20:4n-6) contents of the two main components of phospholipid, the phosphatidylcholine (PC) and phosphatidylethanolamine (PE) fractions, in gastric biopsy specimens were significantly lower in the cirrhosis group, although PC and PE contents in gastric biopsy specimens were not altered. In the cirrhosis group, AA contents of the PC fractions in gastric biopsy specimens were significantly correlated with AA contents of plasma PC fractions and serum albumin levels. Soft oil capsules containing polyunsaturated fatty acid (PUFA) such as AA, eicosapentanoic acid (EPA, C20:5n-3) and docosahexanoic acid (DHA, C20:6n-3) were administered after each meal daily for 4 weeks to six cirrhotic patients and four control subjects, who were randomly selected from the patients and control subjects. After administration of PUFA-enriched oil capsules, gastric mucosal AA contents of PC and PE fractions were significantly improved almost to the control levels. In three cirrhotic patients with severe or mild gastritis whose gastric mucosal lesions were endoscopically shown to have responded to PUFA-enriched oil capsules, AA contents of plasma PC and PE fractions before administration were much lower than in the remaining three cirrhotics that did not respond to the PUFA-enriched oil capsules, but significantly improved to the control levels after administration of oil capsules. The results demonstrate that administration of PUFA-enriched soft oil capsules increased AA contents of the phospholipids in gastric mucosa and thus improved gastric mucosal lesions endoscopically in cirrhotic patients with gastritis.

Morishige F, Murata A. Vitamin C for prophylaxis of viral hepatitis B in transfused patients. J Int Acad Prev Med 1978;5:54.

Munoz Torres E, Abad Hernandez MM, Lopez Bravo A, Alonso Martin MJ, Paz Bouza JI. [Effect of (+) cyanidanol-3 on experimental liver cirrhosis induced by carbon tetrachloride]. An Med Interna. 1989 Apr;6(4):189-191. [Article in Spanish]
Abstract: Liver cirrhosis is a very common illnesses and currently its treatment remains unpromising. In a research line devoted to studying the hepatotoxicity of certain substances we have evaluated the lesions that appear prior to the occurrence of cirrhosis and hepatocarcinoma in order to test, in different assays liver-protecting substances such as cyanidanol-3 that have been seen to lead to an improvement in morphological alterations in the liver and even to reverse such lesions. The mechanisms of action of this compound are discussed. The authors believe that considerable work remains to be carried out but that some day some liver-protecting substances that yield good experimental results may be applied to clinical situations.

Muriel P. S-adenosyl-L-methionine prevents and reverses erythrocyte membrane alterations in cirrhosis. J Appl Toxicol. 1993 May-Jun;13(3):179-182.

Nagita A, Ando M. Assessment of hepatic vitamin E status in adult patients with liver disease. Hepatology. 1997 Aug;26(2):392-397.

Nalini G, Hariprasad C, Narayanan VA. Oxidative stress in alcoholic liver disease. Indian J Med Res. 1999 Dec;110:200-203.

Navder KP, Baraona E, Leo MA, Lieber CS. Oxidation of LDL in baboons is increased by alcohol and attenuated by polyenylphosphatidylcholine. J Lipid Res. 1999 Jun;40(6):983-987.

Naziroglu M, Cay M, Ustundag B, Aksakal M, Yekeler H. Protective effects of vitamin E on carbon tetrachloride-induced liver damage in rats. Cell Biochem Funct. 1999 Dec;17(4):253-259.

Pan WH, Wang CY, Huang SM, et al. Vitamin A, Vitamin E or beta-carotene status and hepatitis B-related hepatocellular carcinoma. Ann Epidemiol 1993;3:217-224.

Parola M, Leonarduzzi G, Robino G, Albano E, Poli G, Dianzani MU. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis. Free Radic Biol Med. 1996;20(3):351-359.

Pena LR, Hill DB, McClain CJ. Treatment with glutathione precursor decreases cytokine activity. JPEN J Parenter Enteral Nutr. 1999 Jan-Feb;23(1):1-6.

Podobed OV, Fedorova LM, Abakumova OIu, Iakusheva IV, Tsvetkova TA, Gavril'chak AV, Shekhter AB, Kariakin AV. [A study of hepatoprotective effect of the preparation phospholiv containing phosphatidylcholine from sunflower seeds and glycyrrhizic acid in the model of liver cirrhosis in rats]. Biull Eksp Biol Med. 1997 Sep;124(9):311-314. [Article in Russian]

Poniachik J, Baraona E, Zhao J, Lieber CS. Dilinoleoylphosphatidylcholine decreases hepatic stellate cell activation. J Lab Clin Med. 1999 Apr;133(4):342-348.

Pratico D, Iuliano L, Basili S, Ferro D, Camastra C, Cordova C, FitzGerald GA, Violi F. Enhanced lipid peroxidation in hepatic cirrhosis. J Investig Med. 1998 Feb;46(2):51-57.
Abstract: BACKGROUND: Lipid peroxidation is thought to play a role in the evolution of liver damage, based on evidence in experimental models. However, evidence that lipid peroxidation occurs in patients with liver disease remains to be provided. We addressed the hypothesis by measuring levels of 8-epi Prostaglandin F2 alpha a bioactive prostaglandin isomer produced by free radical catalyzed peroxidation of arachidonic acid, in patients with liver cirrhosis. METHODS: In 42 patients with hepatic cirrhosis 8-epi Prostaglandin F2 alpha, factor VII activity, endotoxemia, carotenoids and alpha-tocopherol were measured. In 10 patients 8-epi Prostaglandin F2 alpha was also measured before and 30 days after 300 mg b.i.d. vitamin E administration. RESULTS: Cirrhotic patients had significant higher 8-epi Prostaglandin F2 alpha, excretion than controls [median (range): 199.2 (60.0-812) vs 85.9 (55.6-160.0) pg/mg creatinine, p < 0.0001]. Patients with urinary 8-epi Prostaglandin F2 alpha above the range in controls were more likely to have moderate or severe than mild liver failure (p < 0.004). They also had lower factor VII activity (62 +/- 19 vs 74 +/- 15%, P < 0.02) than patients with normal levels of the isoprostane. Urinary excretion of 8-epi Prostaglandin F2 alpha correlated directly with endotoxemia (Rho = 0.56, p < 0.0002) and inversely with factor VII (Rho = -0.39, p < 0.02). Cirrhotic patients given vitamin E showed a significant decrease of urinary 8-epi Prostaglandin F 2 alpha [median (range): 342.5 (170 - 812) vs 292.5 (142-562) pg/mg creatinine, p < 0.04]. CONCLUSION: This study demonstrated that lipid peroxidation is increased in vivo in patients with cirrhosis and suggests that oxidant stress might contribute to the deterioration of liver disease.

Purucker E, Winograd R, Roeb E, Matern S. Glutathione status in liver and plasma during development of biliary cirrhosis after bile duct ligation. Res Exp Med (Berl). 1998 Dec;198(4):167-174.

Rahman MM, Suzuki M, Unno M, Endo K, Takeuchi H, Kakita T, Matsuno S. Hepatic phosphatidylcholine hydroperoxide content in noncirrhotic, cirrhotic, and antioxidant-treated rats with endotoxemia. Surg Today. 1999;29(10):1047-1052.

Schomerus H, Wiedmann KH, Dolle W, Peerenboom H, Strohmeyer G, Balzer K, Goebell H, Durr HK, Bode C, Blum AL, et al. (+)-Cyanidanol-3 in the treatment of acute viral hepatitis: a randomized controlled trial. Hepatology. 1984 Mar-Apr;4(2):331-335.

Shirahata A. [Hepatobiliary and pancreatic disorders as risk factors for fat-soluble vitamin deficiencies]. Nippon Rinsho. 1999 Oct;57(10):2371-5237. (Review) [Article in Japanese]

Skotnicki AB. Therapeutic application of calf thymus extract (TFX). Med Oncol Tumor Pharmacother 1989;6:31-43. (Review)

Stanciu L. [Immunomodulator therapy in chronic viral hepatitis]. Rev Med Interna Neurol Psihiatr Neurochir Dermatovenerol Med Intern. 1989 Nov-Dec;41(6):491-502. (Review) [Article in Romanian]

Suzuki H, Yamamoto S, Hirayama C, et al. Cianidanol therapy for HBs-antigen-positive chronic hepatitis: A muticentre, double-blind study. Liver 1986;6:35-44.

Suzuki H. [Treatment of hepatitis B]. Nippon Naika Gakkai Zasshi. 1990 Aug 10;79(8):1032-1036. [Article in Japanese]

Tietge UJ, Boker KH, Bahr MJ, Weinberg S, Pichlmayr R, Schmidt HH, Manns MP. Lipid parameters predicting liver function in patients with cirrhosis and after liver transplantation. Hepatogastroenterology. 1998 Nov-Dec;45(24):2255-2260.

Von Herbay A, Stahl W, Niederau C, et al. Diminished plasma levels of vitamin E in patients with severe viral hepatitis. Free Radic Res 1996;25:461-466.

Watson JP, Jones DE, James OF, Cann PA, Bramble MG. Case report: oral antioxidant therapy for the treatment of primary biliary cirrhosis: a pilot study. J Gastroenterol Hepatol. 1999 Oct;14(10):1034-1040.
Abstract: BACKGROUND: The symptoms of the chronic cholestatic liver disease primary biliary cirrhosis (PBC), in particular fatigue and chronic pruritus, adversely affect quality of life and respond only poorly to treatment. Recent studies have suggested that oxidative stress may play a role in tissue damage in cholestatic liver disease and may contribute to symptoms, such as fatigue. We have, therefore, examined, in an open-label pilot study, the therapeutic effects of antioxidant medication on the biochemistry and symptomatology of PBC. METHODS: Patients were randomized to 3 months treatment with a compound antioxidant vitamin preparation (Bio-Antox), four tablets daily (n = 11, group 1), or the combination of Bio-Quinone Q10 (100 mg) with Bio-Antox (n = 13, group 2). Biochemical and symptomatic responses were assessed at 3 months. RESULTS: Significant improvement in both pruritus and fatigue was seen in the patients in group 2. Mean itch visual analogue score improved from 2.4 +/- 3.0 to 0.4 +/- 0.7 post therapy (P < 0.05) while mean night itch severity score improved from 2.6 +/- 1.9 to 1.3 +/- 0.7 (P < 0.05). Nine of 13 of these patients reported less fatigue, while 10/13 showed an improvement in at least one domain of their Fisk Fatigue Severity Score. No significant improvement in itch and only limited improvement in fatigue were seen in the patients in group 1. No change in biochemical parameters was seen in either group. CONCLUSIONS: Antioxidant therapy, as a combination of Bio-Antox and Bio-Quinone Q10, may improve the pruritus and fatigue of PBC. This combination of therapy should be investigated further in a double-blind, placebo-controlled trial.

Yamamoto Y, Yamashita S, Fujisawa A, Kokura S, Yoshikawa T. Oxidative stress in patients with hepatitis, cirrhosis, and hepatoma evaluated by plasma antioxidants. Biochem Biophys Res Commun. 1998 Jun 9;247(1):166-170.
Abstract: We have applied our method for the simultaneous detection of plasma ubiquinol-10 (reduced form) and ubiquinone-10 (oxidized form) (S. Yamashita and Y. Yamamoto, Anal. Biochem. 250, 66-73, 1997) to plasmas of normal subjects (n = 16) and patients with chronic active hepatitis (n = 28), liver cirrhosis (n = 16), and hepatocellular carcinoma (n = 20) to evaluate the pressure of oxidative stress in these patients. The average ubiquinone-10 percentages (+/- S.D.) in total ubiquinone-10 and ubiquinol-10 in the four groups were 6.4 +/- 3.3, 12.9 +/- 10.3, 10.6 +/- 6.8, and 18.9 +/- 11.1, respectively, indicating a significant increase in ubiquinone-10 percentage in patient groups in comparison to normal subjects. These results and a significant decrease in the plasma ascorbate level in patient groups indicate that oxidative stress is evident after the onset of hepatitis and the subsequent cirrhosis and liver cancer.

Yurdakok M, Kanra G. Vitamin E therapy in viral hepatitis. Mikrobiyol Bul 1986;20:91-94. [Article in Turkish]

Zeman K, Dworniak D, Tchorzewski H, Pokoca L, Majewska E. Effect of thymic extract on allogeneic MLR and mitogen-induced responses in patients with chronic active hepatitis B. Immunol Invest. 1991 Dec;20(7):545-55.

Zhang M, Song G, Minuk GY. Effects of hepatic stimulator substance, herbal medicine, selenium/vitamin E, and ciprofloxacin on cirrhosis in the rat. Gastroenterology. 1996 Apr;110(4):1150-1155.
Abstract: BACKGROUND & AIMS: Cirrhosis is a potentially lethal condition for which there is no proven effective therapy. The aim of this study was to compare the effects of hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin treatment on biochemical and histological features of fibrosis in rats with carbon tetrachloride (CCl4)/ethanol-induced cirrhosis. METHODS: One hundred twenty adult Wistar rats were divided into six study groups (20 rats/group): healthy controls, CCl4/ethanol-injured rats left untreated, and CCl4/ethanol-injured rats treated for 4 weeks with either hepatic stimulator substance, traditional Chinese herbal medicine, a combination of selenium plus vitamin E, or ciprofloxacin. After the 4-week treatment, rats were killed and the following parameters of hepatic fibrosis were determined: hepatic hydroxyproline and proline levels, serum hyaluronic acid concentrations, and histological staining of hepatic tissue. RESULTS: Hepatic fibrosis was significantly improved in all four treated groups compared with the untreated CCl4/ethanol-injured controls. Improvements were most striking in the groups treated with traditional Chinese herbal medicine and ciprofloxacin. CONCLUSIONS: The data indicate that hepatic stimulator substance, traditional Chinese herbal medicine, selenium plus vitamin E, and ciprofloxacin significantly decrease the amount of hepatic fibrosis caused by CCl4/ethanol injury in rats.