Review Nutrition and Alcoholic Liver Disease LUIS MARSANO, M.D. From the
AND
CRAIG J.
MCCLAIN, M.D.
and Nutrition, University of Kentucky Medical Center and Administration Medical Center, Lexington, Kentucky
Department of Medicine, Division of Digestive Diseases
Lexington Veterans
ABSTRACT. While the rate of malnutrition is relatively modest in alcoholic patients without alcoholic liver disease, the rate of malnutrition is virtually 100% in patients with alcoholic hepatitis and/or alcoholic cirrhosis. The reasons for malnutrition in the alcoholic hepatitis patient include various factors such as anorexia, poor diet, malabsorption, and altered metabolic state. When the patient is hospitalized, the malnutrition frequently worsens because of fasting for tests, continued anorexia, and complications such as gastrointestinal bleeding. Patients with severe acute hepatitis appear to be both hypermetabolic and hypercatabolic, whereas data are much more conflicting concerning patients with more stable liver disease.
Most studies suggest that patients with alcoholic liver disease require at least 60 g of protein per day to maintain positive nitrogen balance. Consistent alterations in plasma amino acid profiles occur in alcoholic liver disease, and specialized nutritional formulations have been devised to correct this amino acid profile with the intent of improving overall nutritional status, hepatic encephalopathy, and mortality. The effects of nutritional support (including use of specialized products) on outcome, on acute hepatic encephalopathy, and on chronic or latent portal systemic encephalopathy are reviewed. ( Journal of Parenteral and Enteral Nutrition 15 :337-344, 1991)
PREVALENCE OF MALNUTRITION
Many physicians and other alcohol-treatment personnel erroneously applied information obtained from these studies to the chronic alcoholic population in general. However, in six separate studies evaluating alcoholics without liver disease, nutritional status (as determined by visceral proteins, anthropometric measurements, immune function, and dietary history) was relatively well
Alcoholism Without Liver Disease
Nutritionists traditionally have been interested in alcohol for its high level of calories while being a source of &dquo;empty&dquo; calories.1-3 Regular alcohol intake can be a major source of calories, with beer having approximately 150 maintained.5-1O calories per 12-ounce can and bourbon or scotch with a mixer having approximately 130 calories per drink. Thus, a social drinker can easily consume 500 calories per day Alcoholic Hepatitis in alcohol. Chronic alcoholics without liver disease usually take In opposition to the above-noted alcoholics without in 1/3 or more of their total calories as ethanol.4 Although liver disease are the patients with alcoholic hepatitis, ethanol generally lacks nutritional value, it is important who regularly suffer malnutrition. Indeed, every patient to note that most of the better studies suggest that the entered into the recent Veterans Administration (VA) majority of alcoholics without major liver disease are not Cooperative Study on Alcoholic Hepatitis had some deseverely malnourished.5-lo Thus, it is a misconception gree of malnutrition. In this study, 363 patients with held by many health care providers that just because a alcoholic hepatitis were evaluated at six VA Medical patient is an alcoholic, he/she also is severely malnour- Centers, and 284 of these subjects had complete nutritional assessments.4 Patients were categorized as having ished. In the context of this manuscript, we have used the mild, moderate, or severe alcoholic hepatitis. The mean term, malnutrition, to indicate a pathologic state in alcohol consumption for these patients was 228 g of which an individual fails to ingest adequate calories and/ ethanol per day. Patients with mild disease took in a or protein to meet his needs, causing a series of functional mean of 45% of their calories as alcohol, whereas patients changes which result in changes in body composition with severe disease consumed 50% of calories as alcohol. and eventually in clinical and biochemical abnormalities. Anorexia was present in 46% of patients with mild disThe original studies dealing with nutritional deficiencies ease and 66% of patients with severe disease. Creatinine/ in chronic alcoholics evaluated only hospitalized patients height index was 76% in mild disease and 64% in severe with liver disease who were often indigent and who had disease. Triceps skin fold, arm-muscle circumference, severely decompensated liver disease with cirrhosis. and responsiveness to skin testing were abnormal in these patients, and the severity of liver disease generally correlated with malnutrition. This is by far the most detailed study of nutritional status in alcoholic hepatitis. Luis of Marsano, MD, Department Reprint requests: Medicine, Other studies also have reported a high rate of malnutriDivision of Digestive Diseases and Nutrition, MN654, University of tion in alcoholic hepatitis, although many studies did not Kentucky Medical Center, Lexington, KY 40536-0084. 337 Downloaded from pen.sagepub.com at DARTMOUTH COLLEGE on January 2, 2015
338 evaluate
a
relationship between severity of disease and
malnutrition.ll-1~
nutritional status often does not improve with ization. METABOLIC
Stable Cirrhosis with Ascites A limited number of studies have evaluated stable alcoholic cirrhotics without superimposed alcoholic hepatitis. We investigated 25 alcoholic cirrhotics who were not actively drinking, who had no clinical evidence of alcoholic hepatitis, who had serum bilirubin levels 1 year before study and were tested postprotocol 14.5 ± 8 months. =
=
=
=
=
=
=
=
=
progression of cirrhosis,51 and methylprednisolone (for the subgroup of patients with severe alcoholic hepatitis by either markedly elevated discriminant function or spontaneous hepatic encephalopathy).5’ Thus, the hepatologist regularly is faced with patients for whom there is no universally accepted form of therapy. Therefore, it is clear why the concept of specialized nutritional support as a form of therapy for alcoholic hepatitis might be attractive to both the physician and the patient. Major questions need
to be addressed
=
=
concerning nutritional
=
=
=
=
=
=
=
support in alcoholic liver disease. Specifically, does nutritional support affect outcome including nutritional status, liver function, mental status, morbidity/compli-
cations, hospital stay,
or
mortality?
.
Several studies indicate that aggressive nutritional support of varying types improves nutritional status. Various studies have used high caloric density enteral feedings, oral BCAA supplementation, standard total parenteral nutrition (TPN) solutions, TPN solutions high in BCAA, and a &dquo;nutritious diet. &dquo;16,17,53-59 Thus,
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341
data from many different groups using different products support the concept that nutritional support improves nutritional status in patients with alcoholic liver disease. One of the more recent studies is a VA Cooperative Study on Alcoholic Hepatitis. Thirty-four patients with alcoholic hepatitis served as &dquo;controls&dquo; and 23 were &dquo;treatment&dquo; patients. The control patients were given a routine hospital diet consisting of 2500 kcal with protein content individualized for hepatic encephalopathy. Food consumption was determined. In the treatment group, 1000 kcal or greater as a hospital diet was provided as well as 2240 kcal as Hepatic Aid (American McGaw, Irvine, CA). Patients in the nutritional therapy group took in significantly greater calories and protein than the control group (3236 us 2313 kcal). It is important to note that even the patient in the control group, which received the hospital diet, had a relatively good dietary intake in the hospital considering the severity of their disease. This points out the value of the close attention to care that is delivered in a clinical study, with vigorous -encouragement of oral intake. Careful nursing and dietary care can often improve the anorexia and poor nutrition intake observed in most hospitalized patients with alcoholic hepatitis. Overall mortality was similar in both groups. Nutritional status improved in both groups, but there was a significantly greater improvement in creatinine/height index in the branched-chain therapy group. Thus, abstaining from alcohol and eating a &dquo;nutritious&dquo; diet caused improvement in nutritional status in controls, and an added benefit was observed with specialized
showed enhanced
disappearance
of
Mallory bodies
in
patients who receive peripheral hyperalimentation. A randomized trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients by Naveau et al57 showed a significant improvement in bilirubin in the
supplemented group, but no difference in liver enzymes or mortality. Other studies have been performed showing little or no improvement in liver function and no improvement in mortality. While most studies show improvement in nutritional status and liver function with nutritional support, no study has been large enough to detect anything but dramatic improvement in mortality. For that reason, these studies could easily have missed small or moderate benefits in mortality that were not
statistically significant (type II statistical error). Furthermore, these studies tend not to address morbidity such as infection or changes in functional activities (e.g., strength). None of these studies addresses duration of hospitalization. Recently, Cabre et al have published the
first randomized controlled study of total enteral nutrition (TEN) in severely malnourished cirrhotics via tube feeding with a BCAA-enriched balanced tube formula us encouraged ingestion of an equicaloric, equinitrogenous hospital diet.14 In this study, the control group caloric intake was significantly lower (1320 us 2115 kcal/d) than the treatment group intake. Both groups were similar in the etiology of cirrhosis, frequency of alcoholic hepatitis, Child’s score, and nutritional parameters at admission. Both groups had the same incidence of major complications but albumin concentration significantly increased and in-hospital mortality decreased in the TEN group. supplementation. 54 While nutritional support seems to improve nutri- From this study, it is impossible to separate the beneficial tional status, a major question is whether it improves effects of the increased calorie and nitrogen intake from liver function or mortality in patients without overt those of the BCAA-enriched formula. A large VA CoopStudy on Alcoholic Hepatitis is evaluating the hepatic encephalopathy. Early studies such as those by erative Patek et ap3 in 1948 stimulated interest in the role of effects of oral nutritional support on nutritional status, nutritional support on outcome in alcoholic liver disease. liver function, mental status, hospitalization, and morHowever, the nutritional supplement being used Indeed, at that time it was generally believed that alco- tality. holic cirrhosis was largely caused by malnutrition. Patek is a specialized liver formulation high in BCAA and low in methionine and AAA. Whether a much cheaper standet a1,13 studying 124 patients with alcoholic liver disease, showed improved survival in those patients fed a nutri- ard enteral nutritional support product would be equally tious diet compared to historical control subjects who efficacious will still not be answered by this project even if positive results are obtained. received no care. Much more
specific dietary
recently,
Nasrallah and Galambos55 studied 35 patients with alcoholic hepatitis who were randomly allocated to control Acute Hepatic Encephalopathy or study groups. The study group received 70 to 85 g of Portal-systemic encephalopathy (PSE or hepatic enintravenous standard amino acids, and both the control cephalopathy) is a disorder of mentation neuromuscular group and treatment group were offered diets composed function, and consciousness due to metabolic abnormalof 3000 kcal and 100 g of protein. The study group had ities in patients with liver disease. a significant improvement in bilirubin and albumin comThere have been a large number of studies evaluating pared to the control group, and there was a trend toward the effects of nutritional support, and specifically BCAA improvement in mortality at 4 weeks. All patients in the supplementation, in acute hepatic encephalopathy54,58-65 nutritional support group tolerated the protein well with- (many reviewed by Hiyama and Fischer&dquo; and Eriksson out development of encephalopathy, and those study and Conn66). O’Keefe et aF7 clearly demonstrated that patients receiving peripheral intravenous amino acids patients with fulminant hepatic failure are severely catactually had fewer problems with ascites. Thus, this very abolic with marked muscle breakdown. Thus, nutritional positive study showed improvement in liver function and support in these patients makes good sense. W’e have a marginally significant improvement in mortality. outlined the rationale for BCAA supplementation in Adhord 51 followed a format similar to that of Nasrallah hepatic encephalopathy. Several studies evaluating the and Galambos and confirmed the findings of improved effect of BCAA in patients with acute PSE are summaliver function with nutritional support. Their study also rized in Table II. Unfortunately, most cases of acute Downloaded from pen.sagepub.com at DARTMOUTH COLLEGE on January 2, 2015
I
342
hepatic encephalopathy have features that make them and certainly had no deleterious effects. Recently Naylor and co-workers’° performed an exstudy candidates. Most patients have some precipitating factor for their encephalopathy such as gastroin- haustive meta-analysis of the controlled, randomized testinal bleeding, infection, or medication. When this studies, published in the English language, of parenteral precipitating factor is corrected, the patient will &dquo;spon- BCAA in patients with cirrhosis and acute PSE. This taneously&dquo; improve from the acute PSE unrelated to meta-analysis reported that BCAA-enriched formulas nutritional therapy or support with drugs such as lactu- were able to improve acute PSE, but the beneficial effects lose or neomycin. Thus, evaluating the efficacy of nutri- were less clear when improvement in mortality was anational support in addition to correcting precipitating lyzed. Furthermore, design flaws in these studies have factors and using standard forms of therapy such as been suggested, due in part to the previously mentioned lactulose makes for very &dquo;muddy&dquo; studies with a large &dquo;noise&dquo; factors that make acute PSE studies very difficult &dquo;noise&dquo; factor. For example, in a study by Cerra et al,67 to design, carry out, and interpret. 71 From this information, we conclude that the use of positive beneficial effects were reported with a BCAAenriched solution compared to the control group receiv- BCAA-enriched solutions can be nutritionally beneficial ing 25% dextrose plus 4 g of neomycin. While this study to patients with alcoholic cirrhosis and symptomatic reports beneficial effects of BCAA, it must be realized acute PSE (especially in grades III and IV), but only in that the control group received all of their calories from addition to conventional therapy for PSE including cordextrose and received no protein calories for the initial rection of precipitating factors. If a BCAA-enriched for4 days. Thereafter, their mean protein intake was only mula is used, it also makes sense to change the patient 4.4 g/d. The BCAA group on the other hand received to a standard amino acid formula after the PSE has protein in increasing amounts from day 1 with the mean resolved and to use the enteral route of feeding as soon protein intake being >80 g/d. Furthermore, the portal- as possible. systemic (hepatic) encephalopathy (PSE) data in this study only report results on 18 of 59 patients with the Latent or Chronic Encephalopathy mortality during therapy being similar for both groups Patients with either latent PSE (subclinical PSE that (the difference in mortality occurred after completion of can be detected only with the use of psychometric testtherapy). or chronic stable PSE (PSE that remains present or There also are multiple studies showing no beneficial ing) recurs during a follow-up of more than 6 months while effects of branched-chain-enriched solutions over standon a 40-g/d protein diet or that recurs every time the ard medical therapy. Michel and co-workers68 performed patient ingests more than 40 g of protein a day while on a randomized study of TPN with either standard or no anti-PSE therapy) represent the best patients for branched-chain-enriched solutions in 47 patients. This the effects of therapy. A variety of intervenis one of the better experimental designs. Results of their evaluating tions have been shown to improve chronic encephalopstudy demonstrated significant correction of amino acid athy and latent encephalopathy including nonnutritional profile in the branched-chain-enriched group. There was measures such as liver transplant and lactulose therapy. no difference between the two groups in improvement of Specialized forms of nutritional therapy such as vegetamental status. It is important to observe that in this diets or ornithine salts of branched-chain ble-protein negative study and also in the negative study of Wahren keto acids have been effective in treating chronic enand co-workers,60 both the control and the BCAA-treated cephalopathy.’2°’3 The role of BCAA in chronic encephgroup received 50 to 62% of nonprotein calories as lipids, alopathy is debated. Several studies evaluating the effect whereas subjects in all the other analyzed studies re- of special diets or supplements on chronic stable PSE ceived all nonprotein calories as dextrose. This raises the are summarized in Table III. Some studies, such as that question of a positive effect of lipids on PSE or the by Millikan et al, demonstrated no benefit whereas othpossibility of a negative interaction of lipids with BCAA. ers, such as that by Horst and co-workers, showed benThese last questions concerning lipids have been par- eficial effects. 11,49,74-79 One of the most interesting and tially evaluated in the recent work of Glynn and co- most persuasive studies concerning the positive effects workers69 who studied cirrhotics with alcoholic hepatitis of BCAA is by Caballeria and co-workers.78 Because this and established PSE. They showed that when 4 g of article is written in Spanish, it has been overlooked in nitrogen as a standard amino acid solution were given the American literature. In this study, 11 patients with with a nonprotein calorie source (1400 kcal-64% as chronic hepatic encephalopathy served as their own conlipid and 36% as dextrose), the clinical grade of PSE trol, and they were followed for over 1 year. The patients improved and the concentration of plasma BCAA in were diagnosed as having PSE by both clinical and these patients did not decrease. On the other hand, when electroencephalographic criteria, and all had biopsy-docall nonprotein calories where given as dextrose, the umented cirrhosis. These patients also had chronic PSE plasma concentration of BCAA declined but the clinical for over 1 year. The patients were placed on a 40-g grade of PSE did not change. All these patients had protein diet because they were unable to tolerate more severe liver disease as demonstrated by their high death than this without developing encephalopathy. All parate during the hospitalization (however, none of the tients had the equivalent of 30 g of protein as Hepatic patients died within 10 days of the end of the study). Aid added to their diet, and all patients had an improveThis study suggests that the inclusion of lipids in the ment in mental status. At a mean of 21 days all patients TPN of these patients may have had beneficial effects were at grade 0 hepatic encephalopathy (PSE). One year
poor
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343
before treatment, each patient had a mean of 1.5 episodes of decompensation in mental status per year. During the year on Hepatic Aid, this decreased to 0.1 ± 0.3. Thus, this study clearly demonstrated positive effects of the BCAA supplement Hepatic Aid in patients with chronic PSE. It is important, however, to be aware that there are only a limited number of patients with chronic encephalopathy who will benefit from this form of therapy.
12. Soberon
S, Pauley MP, Duplantier R, et al: Metabolic effects of feeding in alcoholic hepatitis. Hepatology 7:1204-
enteral formula
1209, 1987 13. Patek AJ, Post J. Ratnoff OD, et al: Dietary treatment of cirrhosis of the liver: Results in one hundred and twenty-four patients observed during a ten year period. JAMA 138:543-549, 1948 14. Cabre E, Gonzales-Huix F, Abad-La Cruz A, et al: Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: A randomized controlled trial. Gastroenterology
98:715-720, 1990 DR, McClain CJ: Nutrition and alcoholism. IN Alcohol and the Brain, Tarter RE, Thiel DH (eds). Plenum Publishing Corporation, New York, 1985, pp 81-120
15. Antonow
SUMMARY
In summary, there is a high rate of malnutrition in patients with alcoholic hepatitis and cirrhosis (approaching 100%). The reasons for this are multiple, and nutritional status often worsens during hospitalization because of testing procedures and unpalatable diets. Patients with severe liver disease seem to be hypermetabolic/hypercatabolic, but it is less clear about patients with stable cirrhosis. Balance studies suggest that these patients should get at least 60 g of protein a day to remain in positive nitrogen balance. Data in the literature are fairly consistent in showing that nutritional support improves nutritional status in patients with alcoholic liver disease. Thus, it makes sense to provide nutritional support to malnourished patients. However, whether or not nutritional support improves outcome or encephalopathy is more debatable. Our current practice is to provide nutritional support for all these patients. In patients who do not have encephalopathy, we provide standard hospital diets or inexpensive enteral nutritional support products. If a patient develops clinical hepatic encephalopathy, we then use a specialized high branchedchain solution because of theoretical benefits that have been demonstrated in some clinical situations. We categorically do not treat all patients hospitalized with alcoholic liver disease with specialized liver formulations because of the increased cost of these products. REFERENCES 1. Roe DA: Nutritional
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a
controlled
study in cirrhotics with porto-caval anastamosis. IN Hepatic Encephalopathy in Chronic Liver Failure, Capocaccia L, Fischer JE, Rossi-Fanelli F (eds). Plenum Press, New York, 1984, pp 183-192 Caballeria C, Lopez A, Vicente J, et al: Tratamiento de la encefalopatia hepatica con aminoacidos de cadena ramificada (BCAA) por via oral: II. Encefalopatia hepatica cronica. Rev Esp Enf Ap Digest 72:201-205, 1987
79. Schafer VK, Winthe MB, Ukida M, et al: Influence of an orally administered protein mixture enriched in branched chain amino acids on the chronic hepatic encephalopathy (CHE) of patients with liver cirrhosis. Z Gastroenterol 19:356-362, 1981 80. Jeppsson B, Kjallman A, Aslund U, et al: Effect of vegan and meat protein diets in mild chronic portal-systemic encephalopathy. IN Hepatic Encephalopathy in Chronic Liver Disease, Capocaccia L, Fischer JE, Rossi-Fanelli F (eds). Plenum Press, New York, 1984, pp 359-367
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AND
CRAIG J.
MCCLAIN, M.D.
and Nutrition, University of Kentucky Medical Center and Administration Medical Center, Lexington, Kentucky
Department of Medicine, Division of Digestive Diseases
Lexington Veterans
ABSTRACT. While the rate of malnutrition is relatively modest in alcoholic patients without alcoholic liver disease, the rate of malnutrition is virtually 100% in patients with alcoholic hepatitis and/or alcoholic cirrhosis. The reasons for malnutrition in the alcoholic hepatitis patient include various factors such as anorexia, poor diet, malabsorption, and altered metabolic state. When the patient is hospitalized, the malnutrition frequently worsens because of fasting for tests, continued anorexia, and complications such as gastrointestinal bleeding. Patients with severe acute hepatitis appear to be both hypermetabolic and hypercatabolic, whereas data are much more conflicting concerning patients with more stable liver disease.
Most studies suggest that patients with alcoholic liver disease require at least 60 g of protein per day to maintain positive nitrogen balance. Consistent alterations in plasma amino acid profiles occur in alcoholic liver disease, and specialized nutritional formulations have been devised to correct this amino acid profile with the intent of improving overall nutritional status, hepatic encephalopathy, and mortality. The effects of nutritional support (including use of specialized products) on outcome, on acute hepatic encephalopathy, and on chronic or latent portal systemic encephalopathy are reviewed. ( Journal of Parenteral and Enteral Nutrition 15 :337-344, 1991)
PREVALENCE OF MALNUTRITION
Many physicians and other alcohol-treatment personnel erroneously applied information obtained from these studies to the chronic alcoholic population in general. However, in six separate studies evaluating alcoholics without liver disease, nutritional status (as determined by visceral proteins, anthropometric measurements, immune function, and dietary history) was relatively well
Alcoholism Without Liver Disease
Nutritionists traditionally have been interested in alcohol for its high level of calories while being a source of &dquo;empty&dquo; calories.1-3 Regular alcohol intake can be a major source of calories, with beer having approximately 150 maintained.5-1O calories per 12-ounce can and bourbon or scotch with a mixer having approximately 130 calories per drink. Thus, a social drinker can easily consume 500 calories per day Alcoholic Hepatitis in alcohol. Chronic alcoholics without liver disease usually take In opposition to the above-noted alcoholics without in 1/3 or more of their total calories as ethanol.4 Although liver disease are the patients with alcoholic hepatitis, ethanol generally lacks nutritional value, it is important who regularly suffer malnutrition. Indeed, every patient to note that most of the better studies suggest that the entered into the recent Veterans Administration (VA) majority of alcoholics without major liver disease are not Cooperative Study on Alcoholic Hepatitis had some deseverely malnourished.5-lo Thus, it is a misconception gree of malnutrition. In this study, 363 patients with held by many health care providers that just because a alcoholic hepatitis were evaluated at six VA Medical patient is an alcoholic, he/she also is severely malnour- Centers, and 284 of these subjects had complete nutritional assessments.4 Patients were categorized as having ished. In the context of this manuscript, we have used the mild, moderate, or severe alcoholic hepatitis. The mean term, malnutrition, to indicate a pathologic state in alcohol consumption for these patients was 228 g of which an individual fails to ingest adequate calories and/ ethanol per day. Patients with mild disease took in a or protein to meet his needs, causing a series of functional mean of 45% of their calories as alcohol, whereas patients changes which result in changes in body composition with severe disease consumed 50% of calories as alcohol. and eventually in clinical and biochemical abnormalities. Anorexia was present in 46% of patients with mild disThe original studies dealing with nutritional deficiencies ease and 66% of patients with severe disease. Creatinine/ in chronic alcoholics evaluated only hospitalized patients height index was 76% in mild disease and 64% in severe with liver disease who were often indigent and who had disease. Triceps skin fold, arm-muscle circumference, severely decompensated liver disease with cirrhosis. and responsiveness to skin testing were abnormal in these patients, and the severity of liver disease generally correlated with malnutrition. This is by far the most detailed study of nutritional status in alcoholic hepatitis. Luis of Marsano, MD, Department Reprint requests: Medicine, Other studies also have reported a high rate of malnutriDivision of Digestive Diseases and Nutrition, MN654, University of tion in alcoholic hepatitis, although many studies did not Kentucky Medical Center, Lexington, KY 40536-0084. 337 Downloaded from pen.sagepub.com at DARTMOUTH COLLEGE on January 2, 2015
338 evaluate
a
relationship between severity of disease and
malnutrition.ll-1~
nutritional status often does not improve with ization. METABOLIC
Stable Cirrhosis with Ascites A limited number of studies have evaluated stable alcoholic cirrhotics without superimposed alcoholic hepatitis. We investigated 25 alcoholic cirrhotics who were not actively drinking, who had no clinical evidence of alcoholic hepatitis, who had serum bilirubin levels 1 year before study and were tested postprotocol 14.5 ± 8 months. =
=
=
=
=
=
=
=
=
progression of cirrhosis,51 and methylprednisolone (for the subgroup of patients with severe alcoholic hepatitis by either markedly elevated discriminant function or spontaneous hepatic encephalopathy).5’ Thus, the hepatologist regularly is faced with patients for whom there is no universally accepted form of therapy. Therefore, it is clear why the concept of specialized nutritional support as a form of therapy for alcoholic hepatitis might be attractive to both the physician and the patient. Major questions need
to be addressed
=
=
concerning nutritional
=
=
=
=
=
=
=
support in alcoholic liver disease. Specifically, does nutritional support affect outcome including nutritional status, liver function, mental status, morbidity/compli-
cations, hospital stay,
or
mortality?
.
Several studies indicate that aggressive nutritional support of varying types improves nutritional status. Various studies have used high caloric density enteral feedings, oral BCAA supplementation, standard total parenteral nutrition (TPN) solutions, TPN solutions high in BCAA, and a &dquo;nutritious diet. &dquo;16,17,53-59 Thus,
Downloaded from pen.sagepub.com at DARTMOUTH COLLEGE on January 2, 2015
341
data from many different groups using different products support the concept that nutritional support improves nutritional status in patients with alcoholic liver disease. One of the more recent studies is a VA Cooperative Study on Alcoholic Hepatitis. Thirty-four patients with alcoholic hepatitis served as &dquo;controls&dquo; and 23 were &dquo;treatment&dquo; patients. The control patients were given a routine hospital diet consisting of 2500 kcal with protein content individualized for hepatic encephalopathy. Food consumption was determined. In the treatment group, 1000 kcal or greater as a hospital diet was provided as well as 2240 kcal as Hepatic Aid (American McGaw, Irvine, CA). Patients in the nutritional therapy group took in significantly greater calories and protein than the control group (3236 us 2313 kcal). It is important to note that even the patient in the control group, which received the hospital diet, had a relatively good dietary intake in the hospital considering the severity of their disease. This points out the value of the close attention to care that is delivered in a clinical study, with vigorous -encouragement of oral intake. Careful nursing and dietary care can often improve the anorexia and poor nutrition intake observed in most hospitalized patients with alcoholic hepatitis. Overall mortality was similar in both groups. Nutritional status improved in both groups, but there was a significantly greater improvement in creatinine/height index in the branched-chain therapy group. Thus, abstaining from alcohol and eating a &dquo;nutritious&dquo; diet caused improvement in nutritional status in controls, and an added benefit was observed with specialized
showed enhanced
disappearance
of
Mallory bodies
in
patients who receive peripheral hyperalimentation. A randomized trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients by Naveau et al57 showed a significant improvement in bilirubin in the
supplemented group, but no difference in liver enzymes or mortality. Other studies have been performed showing little or no improvement in liver function and no improvement in mortality. While most studies show improvement in nutritional status and liver function with nutritional support, no study has been large enough to detect anything but dramatic improvement in mortality. For that reason, these studies could easily have missed small or moderate benefits in mortality that were not
statistically significant (type II statistical error). Furthermore, these studies tend not to address morbidity such as infection or changes in functional activities (e.g., strength). None of these studies addresses duration of hospitalization. Recently, Cabre et al have published the
first randomized controlled study of total enteral nutrition (TEN) in severely malnourished cirrhotics via tube feeding with a BCAA-enriched balanced tube formula us encouraged ingestion of an equicaloric, equinitrogenous hospital diet.14 In this study, the control group caloric intake was significantly lower (1320 us 2115 kcal/d) than the treatment group intake. Both groups were similar in the etiology of cirrhosis, frequency of alcoholic hepatitis, Child’s score, and nutritional parameters at admission. Both groups had the same incidence of major complications but albumin concentration significantly increased and in-hospital mortality decreased in the TEN group. supplementation. 54 While nutritional support seems to improve nutri- From this study, it is impossible to separate the beneficial tional status, a major question is whether it improves effects of the increased calorie and nitrogen intake from liver function or mortality in patients without overt those of the BCAA-enriched formula. A large VA CoopStudy on Alcoholic Hepatitis is evaluating the hepatic encephalopathy. Early studies such as those by erative Patek et ap3 in 1948 stimulated interest in the role of effects of oral nutritional support on nutritional status, nutritional support on outcome in alcoholic liver disease. liver function, mental status, hospitalization, and morHowever, the nutritional supplement being used Indeed, at that time it was generally believed that alco- tality. holic cirrhosis was largely caused by malnutrition. Patek is a specialized liver formulation high in BCAA and low in methionine and AAA. Whether a much cheaper standet a1,13 studying 124 patients with alcoholic liver disease, showed improved survival in those patients fed a nutri- ard enteral nutritional support product would be equally tious diet compared to historical control subjects who efficacious will still not be answered by this project even if positive results are obtained. received no care. Much more
specific dietary
recently,
Nasrallah and Galambos55 studied 35 patients with alcoholic hepatitis who were randomly allocated to control Acute Hepatic Encephalopathy or study groups. The study group received 70 to 85 g of Portal-systemic encephalopathy (PSE or hepatic enintravenous standard amino acids, and both the control cephalopathy) is a disorder of mentation neuromuscular group and treatment group were offered diets composed function, and consciousness due to metabolic abnormalof 3000 kcal and 100 g of protein. The study group had ities in patients with liver disease. a significant improvement in bilirubin and albumin comThere have been a large number of studies evaluating pared to the control group, and there was a trend toward the effects of nutritional support, and specifically BCAA improvement in mortality at 4 weeks. All patients in the supplementation, in acute hepatic encephalopathy54,58-65 nutritional support group tolerated the protein well with- (many reviewed by Hiyama and Fischer&dquo; and Eriksson out development of encephalopathy, and those study and Conn66). O’Keefe et aF7 clearly demonstrated that patients receiving peripheral intravenous amino acids patients with fulminant hepatic failure are severely catactually had fewer problems with ascites. Thus, this very abolic with marked muscle breakdown. Thus, nutritional positive study showed improvement in liver function and support in these patients makes good sense. W’e have a marginally significant improvement in mortality. outlined the rationale for BCAA supplementation in Adhord 51 followed a format similar to that of Nasrallah hepatic encephalopathy. Several studies evaluating the and Galambos and confirmed the findings of improved effect of BCAA in patients with acute PSE are summaliver function with nutritional support. Their study also rized in Table II. Unfortunately, most cases of acute Downloaded from pen.sagepub.com at DARTMOUTH COLLEGE on January 2, 2015
I
342
hepatic encephalopathy have features that make them and certainly had no deleterious effects. Recently Naylor and co-workers’° performed an exstudy candidates. Most patients have some precipitating factor for their encephalopathy such as gastroin- haustive meta-analysis of the controlled, randomized testinal bleeding, infection, or medication. When this studies, published in the English language, of parenteral precipitating factor is corrected, the patient will &dquo;spon- BCAA in patients with cirrhosis and acute PSE. This taneously&dquo; improve from the acute PSE unrelated to meta-analysis reported that BCAA-enriched formulas nutritional therapy or support with drugs such as lactu- were able to improve acute PSE, but the beneficial effects lose or neomycin. Thus, evaluating the efficacy of nutri- were less clear when improvement in mortality was anational support in addition to correcting precipitating lyzed. Furthermore, design flaws in these studies have factors and using standard forms of therapy such as been suggested, due in part to the previously mentioned lactulose makes for very &dquo;muddy&dquo; studies with a large &dquo;noise&dquo; factors that make acute PSE studies very difficult &dquo;noise&dquo; factor. For example, in a study by Cerra et al,67 to design, carry out, and interpret. 71 From this information, we conclude that the use of positive beneficial effects were reported with a BCAAenriched solution compared to the control group receiv- BCAA-enriched solutions can be nutritionally beneficial ing 25% dextrose plus 4 g of neomycin. While this study to patients with alcoholic cirrhosis and symptomatic reports beneficial effects of BCAA, it must be realized acute PSE (especially in grades III and IV), but only in that the control group received all of their calories from addition to conventional therapy for PSE including cordextrose and received no protein calories for the initial rection of precipitating factors. If a BCAA-enriched for4 days. Thereafter, their mean protein intake was only mula is used, it also makes sense to change the patient 4.4 g/d. The BCAA group on the other hand received to a standard amino acid formula after the PSE has protein in increasing amounts from day 1 with the mean resolved and to use the enteral route of feeding as soon protein intake being >80 g/d. Furthermore, the portal- as possible. systemic (hepatic) encephalopathy (PSE) data in this study only report results on 18 of 59 patients with the Latent or Chronic Encephalopathy mortality during therapy being similar for both groups Patients with either latent PSE (subclinical PSE that (the difference in mortality occurred after completion of can be detected only with the use of psychometric testtherapy). or chronic stable PSE (PSE that remains present or There also are multiple studies showing no beneficial ing) recurs during a follow-up of more than 6 months while effects of branched-chain-enriched solutions over standon a 40-g/d protein diet or that recurs every time the ard medical therapy. Michel and co-workers68 performed patient ingests more than 40 g of protein a day while on a randomized study of TPN with either standard or no anti-PSE therapy) represent the best patients for branched-chain-enriched solutions in 47 patients. This the effects of therapy. A variety of intervenis one of the better experimental designs. Results of their evaluating tions have been shown to improve chronic encephalopstudy demonstrated significant correction of amino acid athy and latent encephalopathy including nonnutritional profile in the branched-chain-enriched group. There was measures such as liver transplant and lactulose therapy. no difference between the two groups in improvement of Specialized forms of nutritional therapy such as vegetamental status. It is important to observe that in this diets or ornithine salts of branched-chain ble-protein negative study and also in the negative study of Wahren keto acids have been effective in treating chronic enand co-workers,60 both the control and the BCAA-treated cephalopathy.’2°’3 The role of BCAA in chronic encephgroup received 50 to 62% of nonprotein calories as lipids, alopathy is debated. Several studies evaluating the effect whereas subjects in all the other analyzed studies re- of special diets or supplements on chronic stable PSE ceived all nonprotein calories as dextrose. This raises the are summarized in Table III. Some studies, such as that question of a positive effect of lipids on PSE or the by Millikan et al, demonstrated no benefit whereas othpossibility of a negative interaction of lipids with BCAA. ers, such as that by Horst and co-workers, showed benThese last questions concerning lipids have been par- eficial effects. 11,49,74-79 One of the most interesting and tially evaluated in the recent work of Glynn and co- most persuasive studies concerning the positive effects workers69 who studied cirrhotics with alcoholic hepatitis of BCAA is by Caballeria and co-workers.78 Because this and established PSE. They showed that when 4 g of article is written in Spanish, it has been overlooked in nitrogen as a standard amino acid solution were given the American literature. In this study, 11 patients with with a nonprotein calorie source (1400 kcal-64% as chronic hepatic encephalopathy served as their own conlipid and 36% as dextrose), the clinical grade of PSE trol, and they were followed for over 1 year. The patients improved and the concentration of plasma BCAA in were diagnosed as having PSE by both clinical and these patients did not decrease. On the other hand, when electroencephalographic criteria, and all had biopsy-docall nonprotein calories where given as dextrose, the umented cirrhosis. These patients also had chronic PSE plasma concentration of BCAA declined but the clinical for over 1 year. The patients were placed on a 40-g grade of PSE did not change. All these patients had protein diet because they were unable to tolerate more severe liver disease as demonstrated by their high death than this without developing encephalopathy. All parate during the hospitalization (however, none of the tients had the equivalent of 30 g of protein as Hepatic patients died within 10 days of the end of the study). Aid added to their diet, and all patients had an improveThis study suggests that the inclusion of lipids in the ment in mental status. At a mean of 21 days all patients TPN of these patients may have had beneficial effects were at grade 0 hepatic encephalopathy (PSE). One year
poor
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343
before treatment, each patient had a mean of 1.5 episodes of decompensation in mental status per year. During the year on Hepatic Aid, this decreased to 0.1 ± 0.3. Thus, this study clearly demonstrated positive effects of the BCAA supplement Hepatic Aid in patients with chronic PSE. It is important, however, to be aware that there are only a limited number of patients with chronic encephalopathy who will benefit from this form of therapy.
12. Soberon
S, Pauley MP, Duplantier R, et al: Metabolic effects of feeding in alcoholic hepatitis. Hepatology 7:1204-
enteral formula
1209, 1987 13. Patek AJ, Post J. Ratnoff OD, et al: Dietary treatment of cirrhosis of the liver: Results in one hundred and twenty-four patients observed during a ten year period. JAMA 138:543-549, 1948 14. Cabre E, Gonzales-Huix F, Abad-La Cruz A, et al: Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: A randomized controlled trial. Gastroenterology
98:715-720, 1990 DR, McClain CJ: Nutrition and alcoholism. IN Alcohol and the Brain, Tarter RE, Thiel DH (eds). Plenum Publishing Corporation, New York, 1985, pp 81-120
15. Antonow
SUMMARY
In summary, there is a high rate of malnutrition in patients with alcoholic hepatitis and cirrhosis (approaching 100%). The reasons for this are multiple, and nutritional status often worsens during hospitalization because of testing procedures and unpalatable diets. Patients with severe liver disease seem to be hypermetabolic/hypercatabolic, but it is less clear about patients with stable cirrhosis. Balance studies suggest that these patients should get at least 60 g of protein a day to remain in positive nitrogen balance. Data in the literature are fairly consistent in showing that nutritional support improves nutritional status in patients with alcoholic liver disease. Thus, it makes sense to provide nutritional support to malnourished patients. However, whether or not nutritional support improves outcome or encephalopathy is more debatable. Our current practice is to provide nutritional support for all these patients. In patients who do not have encephalopathy, we provide standard hospital diets or inexpensive enteral nutritional support products. If a patient develops clinical hepatic encephalopathy, we then use a specialized high branchedchain solution because of theoretical benefits that have been demonstrated in some clinical situations. We categorically do not treat all patients hospitalized with alcoholic liver disease with specialized liver formulations because of the increased cost of these products. REFERENCES 1. Roe DA: Nutritional
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mycin in hepatic encephalopathy (abstr). Hepatology 3:862, 1983 64. Gluud C, Dejgaard A, Hardt F, et al: Preliminary treatment results with balanced amino acid infusion to patients with hepatic encephalopathy (abstr). Scand J Gastroenterol 18(suppl 86):19, 1983 65. Caballeria E, Arago JV, Masso RM, et al: Tratamiento de la
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