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Nutritional support in alcoholic liver disease—Losing control(s)?
2186
CORRESPONDENCE
GASTROENTEROLOGY
tion of a first variceal hemorrhage. Gastroenterology 1990; 99:1401-1407. 6. Bosch J. Effect of pharmacological agents on portal hypertension. A hemodynamic appraisal. Clin Gastroenterol 1985;14: 169-184.
Nutritional Support in Alcoholic Disease-Losing Control(s)?
Liver
Dear Sir: In a recent paper,’ Kearns et al. assess the value of enteral nutrition in patients admitted for alcoholic liver disease. The patients receiving supplements of a standard, commercially available liquid feeding preparation showed improvements in a variety of “laboratory” parameters (antipyrine half-lives, serum bilirubin concentration, body weight, and nitrogen balance] compared with those who had been randomized to the control (no supplemental nutritional therapy) group. The treated group also showed an early improvement in “encephalopathy scores.” However, the mean such scores at the beginning and end of the first week were 1.1 and 0.4; scores of 0 and 1 both represented normal performances in psychometric testing, the difference being that a score of 1 represented a “subjective disturbance in the day-night schedule.” The comparable scores in the control group were 0.7 and 0.9. It would appear that most of the patients did not have clinically apparent encephalopathy. Several other outcome parameters were assessed. No statistically significant differences were found in the duration of acute hospitalization, diarrhea, renal insufficiency, gastrointestinal bleeding, anthropometric measurements, ascites, lactulose requirements, or other serum liver test results. An early arithmetical trend suggesting a nutritional support-associated improved survival rate disappeared over the next 1 or 2 months. In their discussion, the authors cite the results of other randomized trials,2.3 a review,4 and a meta-analysis,5 in addition to their findings, to advance the proposal that “semistarvation” (presumably untreated controls) should no longer be permitted in future trials. (Of note, one reference’ evaluated nonalcoholic as well as alcoholic patients and the other threeZm5 discussed the role of branched-chain amino acids, not standard nutritional formula-
Table
Vol. 102, No. 6
tions.) The authors appear convinced that nutritional support has established efficacy. The results of the randomized trials comparing standard nutritional support and no supplemental nutritional support in patients with alcoholic liver disease are summarized in Table 1. Other than an effect of this support in lowering serum bilirubin levels, it is difficult to see how the treated patients fared any better than the controls. Many of these trials do suffer from a variety of problems, particularly the involvement of small numbers of patients and the possibility of a type II error. Nonetheless, there is a lack of compelling evidence that standard nutritional support, such as tested by Kearns et al. improves clinical outcome. Even the possible benefit of specialized parenteral nutrition, using branched-chain amino acids,’ may represent nothing more than a pharmacological effect of the amino acids themselves.14 The authors, in commenting on a possible early survival advantage from enteral feeding, calculated that 120 patients would need to be studied. Rather than calling for a halt to trials using untreated controls, it would seem more appropriate to undertake these large studies to establish or disprove the role of enteral and parenteral nutrition in alcoholic liver disease. Such trials would, by necessity, have to compare a treated group with an untreated one. RONALD L. KORETZ, M.D.
Department of Medicine Olive View Medical Center 14445 Olive View Drive Sylmar, California 91342 Kearns PJ, Young H, Garcia G, Blaschke T, O’Hanlon G, Rinki M, Sucher K, Gregory P. Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, Esteve M, Acero D, Fernandez-Baares F, Xion X. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: a randomized controlled trial. Gastroenterology 1990;98:715-720.
2. Nutritional Support in Alcoholic Liver Disease Improvement in
Reference (route support) 6 (P) 7 (PI 8 (PI 9 (PI 10 (PI 11 (PI 12 (PI 13 (El 2 (EId 1 (El
Mortality
+a No No No No No No No
diff diff diff diff diff diff diff + No diff
Ascites
Encepalopathy
No diff No diff No diffb
No No No No No No
No diff +b No diff
No diff +b +e
No diff No diff b _
Bleeding
Bilirubin
+
diff diffb diff diff diff diffb
+
No diff No diff
No diff +c No diffb + +b +
P, parenteral nutrition; E, enteral nutrition; +, statistically significant difference favoring recipients of nutritional support; -, statistically significant difference favoring controls (no supplemental nutrition); No diff, no statistically significant difference between the two groups: blank space, no data provided. “The authors initially reported the differences as significant, but in a subsequent publication they noted that this was a “trend” that could not be reproduced in a similarly designed trial.” %linical score used encompassing these (and other) elements. “P value reported as “<0.07.” dOnly 23 of 35 patients had alcoholic liver disease. or lactulose requirements. eDifferences in “day-night schedule disturbances”: no differences in overt encephalopathy
CORRESPONDENCE
June 1992
3. Christie ML, Sack DM, Pomposelli J, Horst D. Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis. JPEN 1985;9:671678. 4. Eriksson LS, Conn HO. Branched-chain amino acids in the management of hepatic encephalopathy: an analysis of variants. Hepatology 1989;10:228-246. 5. Naylor CD, O’Rourke K, Detsky AS, Baker JP. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. Gastroenterology 1989;97:1033-1042. 6. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1278. 7. Diehl AM, Boitnott JK, Herlong HF, Potter JJ, Van Duyn MA, Chandler E, Mezey E. Effect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5:57-63. 8. Naveau S, Pelletier G, Poynard T, Attali P, Poitrine A, Buffet C, Etienne J-P, Chaput J-C. A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6:270-274. 9. Alchord J. A prospective randomized clinical trial of peripheral amino acid-glucose supplementation in acute alcoholic hepatitis. Am J Gastroenterol 1987;82:871-875. 10. Simon D, Galambos JT. A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis. J Hepatol 1988;7:200-207. 11. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200-1208. 12. Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcome in severe alcoholic hepatitis: a randomized controlled trial. Hepatology 1991;14:10901096. 13. Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 14.Koretz RL. Branched-chain amino acids in hepatic encephalopathy (letter). Gastroenterology 1990;99:287-288. Reply. Dr. Koretz notes differences between control and treated patients in our study’ but challenges the conclusions. A critical feature to emphasize is the acceleration in improvement of encephalopathy and biochemical outcomes. Analyzing the means leads Dr. Koretz to conclude that even though improved, most patients did not have clinically apparent encephalopathy. This would make the therapy of questionable value. We found the disturbance in day-night cycle distressing to patients and clinically apparent. In addition, analyzing means hides the fact that 6 of 15 controls had a deterioration in mental status during the first 2 weeks, whereas no treated patient increased the degree of encephalopathy. One control increased to grade 4 and three others increased to grade 2. Dr. Koretz bases his challenge on parenteral and/or enteral nutrition studies. We hesitate to compare studies of fundamentally different therapies. Restricting oneself to enteral studies listed, one study showed improved survival, encephalopathy and biochemical markers in treated patients.’ Our study showed accelerated improvement in encephalopathy and biochemical indices.’ The third enteral study cited includes parenteral as well as enteral supplement? and failed to achieve different nitrogen intakes in control and treated arms. Failure to observe differences in outcome when nitrogen intake was similar lends credibility to our conclusion. Even the studies of Diehl et al,* Naveau,’ and Bonkovsky’ show at least one outcome improved at a faster rate in
2187
supplemented patients. Nasrallah7 and Mezey’ found an overall improvement in biochemical, nutritional, and metabolic or survival outcomes. A majority of studies listed show benefit with nutritional supplements. We remain convinced that aggressive nutritional supplementation should serve as control therapy for future studies. PATRICK J. KEARNS, M.D. Nutritional Support Services Santa Clara Valley Medical Center Fourth Floor 751 South Bascom Avenue San Jose, California 95128 Kearns PJ, Young H, Garcia G, et al. Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. 2. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, et al. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: a randomized controlled trial. Gastroenterology 1990;98:715-720. 3. Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 4. Diehl AM, Boitnott JK, Herlong HF, et al. Effect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5:57-63. 5. Naveau S, Pelletier G, Poynard T, et al. A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6:270-274. 6. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. ,4 randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrilion and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200-1208. 7. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1278. 8. Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcome in severe alcoholic hepatitis: an randomized controlled trial. Hepatology 1991;14:10901096. 1.
Prophylactic Sclerotherapy: Versus ‘Aggregate’ Analysis
Meta-analysis
Dear Sir: Van Ruiswyk and Byrd’s meta-analysis’ of prophylactic sclerotherapy (PS) for primary prevention of variceal hemorrhage dealt with an important clinical question. While we commend the authors for attempting a much-needed synthesis of the randomized trials, we agree with Blei’ that for this topic “the significant heterogeneity amongst studies does not allow the satisfactory use of meta-analysis.” Clinical heterogeneity [dissimilarity] is present among the individual trials in the populations randomized (for etiology and severity of both varices and liver disease); in the method of sclerotherapy (sclerosant, injection site, number of injections, volume used, and interval between treatments); in the accompanying therapies (frequency of follow-up visits); and for outcomes, with varying lengths of follow-up for the combined tabular data. Using meta-analysis to “pool” such clinically heterogeneous data may “drown out” any effect of PS in clinically distinct patient subgroups. In addition, though only eight trials were pooled, the authors’ statistical test of homogeneity showed significant heterogeneity for the outcomes of first variceal bleed and death due to variceal bleed. Such heterogeneity would indicate that the studies are not combinable from a statistical standpoint.
CORRESPONDENCE
GASTROENTEROLOGY
tion of a first variceal hemorrhage. Gastroenterology 1990; 99:1401-1407. 6. Bosch J. Effect of pharmacological agents on portal hypertension. A hemodynamic appraisal. Clin Gastroenterol 1985;14: 169-184.
Nutritional Support in Alcoholic Disease-Losing Control(s)?
Liver
Dear Sir: In a recent paper,’ Kearns et al. assess the value of enteral nutrition in patients admitted for alcoholic liver disease. The patients receiving supplements of a standard, commercially available liquid feeding preparation showed improvements in a variety of “laboratory” parameters (antipyrine half-lives, serum bilirubin concentration, body weight, and nitrogen balance] compared with those who had been randomized to the control (no supplemental nutritional therapy) group. The treated group also showed an early improvement in “encephalopathy scores.” However, the mean such scores at the beginning and end of the first week were 1.1 and 0.4; scores of 0 and 1 both represented normal performances in psychometric testing, the difference being that a score of 1 represented a “subjective disturbance in the day-night schedule.” The comparable scores in the control group were 0.7 and 0.9. It would appear that most of the patients did not have clinically apparent encephalopathy. Several other outcome parameters were assessed. No statistically significant differences were found in the duration of acute hospitalization, diarrhea, renal insufficiency, gastrointestinal bleeding, anthropometric measurements, ascites, lactulose requirements, or other serum liver test results. An early arithmetical trend suggesting a nutritional support-associated improved survival rate disappeared over the next 1 or 2 months. In their discussion, the authors cite the results of other randomized trials,2.3 a review,4 and a meta-analysis,5 in addition to their findings, to advance the proposal that “semistarvation” (presumably untreated controls) should no longer be permitted in future trials. (Of note, one reference’ evaluated nonalcoholic as well as alcoholic patients and the other threeZm5 discussed the role of branched-chain amino acids, not standard nutritional formula-
Table
Vol. 102, No. 6
tions.) The authors appear convinced that nutritional support has established efficacy. The results of the randomized trials comparing standard nutritional support and no supplemental nutritional support in patients with alcoholic liver disease are summarized in Table 1. Other than an effect of this support in lowering serum bilirubin levels, it is difficult to see how the treated patients fared any better than the controls. Many of these trials do suffer from a variety of problems, particularly the involvement of small numbers of patients and the possibility of a type II error. Nonetheless, there is a lack of compelling evidence that standard nutritional support, such as tested by Kearns et al. improves clinical outcome. Even the possible benefit of specialized parenteral nutrition, using branched-chain amino acids,’ may represent nothing more than a pharmacological effect of the amino acids themselves.14 The authors, in commenting on a possible early survival advantage from enteral feeding, calculated that 120 patients would need to be studied. Rather than calling for a halt to trials using untreated controls, it would seem more appropriate to undertake these large studies to establish or disprove the role of enteral and parenteral nutrition in alcoholic liver disease. Such trials would, by necessity, have to compare a treated group with an untreated one. RONALD L. KORETZ, M.D.
Department of Medicine Olive View Medical Center 14445 Olive View Drive Sylmar, California 91342 Kearns PJ, Young H, Garcia G, Blaschke T, O’Hanlon G, Rinki M, Sucher K, Gregory P. Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, Esteve M, Acero D, Fernandez-Baares F, Xion X. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: a randomized controlled trial. Gastroenterology 1990;98:715-720.
2. Nutritional Support in Alcoholic Liver Disease Improvement in
Reference (route support) 6 (P) 7 (PI 8 (PI 9 (PI 10 (PI 11 (PI 12 (PI 13 (El 2 (EId 1 (El
Mortality
+a No No No No No No No
diff diff diff diff diff diff diff + No diff
Ascites
Encepalopathy
No diff No diff No diffb
No No No No No No
No diff +b No diff
No diff +b +e
No diff No diff b _
Bleeding
Bilirubin
+
diff diffb diff diff diff diffb
+
No diff No diff
No diff +c No diffb + +b +
P, parenteral nutrition; E, enteral nutrition; +, statistically significant difference favoring recipients of nutritional support; -, statistically significant difference favoring controls (no supplemental nutrition); No diff, no statistically significant difference between the two groups: blank space, no data provided. “The authors initially reported the differences as significant, but in a subsequent publication they noted that this was a “trend” that could not be reproduced in a similarly designed trial.” %linical score used encompassing these (and other) elements. “P value reported as “<0.07.” dOnly 23 of 35 patients had alcoholic liver disease. or lactulose requirements. eDifferences in “day-night schedule disturbances”: no differences in overt encephalopathy
CORRESPONDENCE
June 1992
3. Christie ML, Sack DM, Pomposelli J, Horst D. Enriched branched-chain amino acid formula versus a casein-based supplement in the treatment of cirrhosis. JPEN 1985;9:671678. 4. Eriksson LS, Conn HO. Branched-chain amino acids in the management of hepatic encephalopathy: an analysis of variants. Hepatology 1989;10:228-246. 5. Naylor CD, O’Rourke K, Detsky AS, Baker JP. Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. Gastroenterology 1989;97:1033-1042. 6. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1278. 7. Diehl AM, Boitnott JK, Herlong HF, Potter JJ, Van Duyn MA, Chandler E, Mezey E. Effect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5:57-63. 8. Naveau S, Pelletier G, Poynard T, Attali P, Poitrine A, Buffet C, Etienne J-P, Chaput J-C. A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6:270-274. 9. Alchord J. A prospective randomized clinical trial of peripheral amino acid-glucose supplementation in acute alcoholic hepatitis. Am J Gastroenterol 1987;82:871-875. 10. Simon D, Galambos JT. A randomized controlled study of peripheral parenteral nutrition in moderate and severe alcoholic hepatitis. J Hepatol 1988;7:200-207. 11. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200-1208. 12. Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcome in severe alcoholic hepatitis: a randomized controlled trial. Hepatology 1991;14:10901096. 13. Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 14.Koretz RL. Branched-chain amino acids in hepatic encephalopathy (letter). Gastroenterology 1990;99:287-288. Reply. Dr. Koretz notes differences between control and treated patients in our study’ but challenges the conclusions. A critical feature to emphasize is the acceleration in improvement of encephalopathy and biochemical outcomes. Analyzing the means leads Dr. Koretz to conclude that even though improved, most patients did not have clinically apparent encephalopathy. This would make the therapy of questionable value. We found the disturbance in day-night cycle distressing to patients and clinically apparent. In addition, analyzing means hides the fact that 6 of 15 controls had a deterioration in mental status during the first 2 weeks, whereas no treated patient increased the degree of encephalopathy. One control increased to grade 4 and three others increased to grade 2. Dr. Koretz bases his challenge on parenteral and/or enteral nutrition studies. We hesitate to compare studies of fundamentally different therapies. Restricting oneself to enteral studies listed, one study showed improved survival, encephalopathy and biochemical markers in treated patients.’ Our study showed accelerated improvement in encephalopathy and biochemical indices.’ The third enteral study cited includes parenteral as well as enteral supplement? and failed to achieve different nitrogen intakes in control and treated arms. Failure to observe differences in outcome when nitrogen intake was similar lends credibility to our conclusion. Even the studies of Diehl et al,* Naveau,’ and Bonkovsky’ show at least one outcome improved at a faster rate in
2187
supplemented patients. Nasrallah7 and Mezey’ found an overall improvement in biochemical, nutritional, and metabolic or survival outcomes. A majority of studies listed show benefit with nutritional supplements. We remain convinced that aggressive nutritional supplementation should serve as control therapy for future studies. PATRICK J. KEARNS, M.D. Nutritional Support Services Santa Clara Valley Medical Center Fourth Floor 751 South Bascom Avenue San Jose, California 95128 Kearns PJ, Young H, Garcia G, et al. Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992;102:200-205. 2. Cabre E, Gonzalez-Huix F, Abad-Lacruz A, et al. Effect of total enteral nutrition on the short-term outcome of severely malnourished cirrhotics: a randomized controlled trial. Gastroenterology 1990;98:715-720. 3. Calvey H, Davis M, Williams R. Controlled trial of nutritional supplementation, with and without branched chain amino acid enrichment, in treatment of acute alcoholic hepatitis. J Hepatol 1985;1:141-151. 4. Diehl AM, Boitnott JK, Herlong HF, et al. Effect of parenteral amino acid supplementation in alcoholic hepatitis. Hepatology 1985;5:57-63. 5. Naveau S, Pelletier G, Poynard T, et al. A randomized clinical trial of supplementary parenteral nutrition in jaundiced alcoholic cirrhotic patients. Hepatology 1986;6:270-274. 6. Bonkovsky HL, Fiellin DA, Smith GS, Slaker DP, Simon D, Galambos JT. ,4 randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrilion and oxandrolone. I. Short-term effects on liver function. Am J Gastroenterol 1991;86:1200-1208. 7. Nasrallah SM, Galambos JT. Aminoacid therapy of alcoholic hepatitis. Lancet 1980;2:1276-1278. 8. Mezey E, Caballeria J, Mitchell MC, Pares A, Herlong HF, Rodes J. Effect of parenteral amino acid supplementation on short-term and long-term outcome in severe alcoholic hepatitis: an randomized controlled trial. Hepatology 1991;14:10901096. 1.
Prophylactic Sclerotherapy: Versus ‘Aggregate’ Analysis
Meta-analysis
Dear Sir: Van Ruiswyk and Byrd’s meta-analysis’ of prophylactic sclerotherapy (PS) for primary prevention of variceal hemorrhage dealt with an important clinical question. While we commend the authors for attempting a much-needed synthesis of the randomized trials, we agree with Blei’ that for this topic “the significant heterogeneity amongst studies does not allow the satisfactory use of meta-analysis.” Clinical heterogeneity [dissimilarity] is present among the individual trials in the populations randomized (for etiology and severity of both varices and liver disease); in the method of sclerotherapy (sclerosant, injection site, number of injections, volume used, and interval between treatments); in the accompanying therapies (frequency of follow-up visits); and for outcomes, with varying lengths of follow-up for the combined tabular data. Using meta-analysis to “pool” such clinically heterogeneous data may “drown out” any effect of PS in clinically distinct patient subgroups. In addition, though only eight trials were pooled, the authors’ statistical test of homogeneity showed significant heterogeneity for the outcomes of first variceal bleed and death due to variceal bleed. Such heterogeneity would indicate that the studies are not combinable from a statistical standpoint.