INTESTINAL ADAPTATION AND HEPATIC DECOMPENSATION AFTER JEJUNOILEAL BYPASS FOR MORBID OBESITY Plasma amino acid patterns after jejunoileal bypass for the treatment of severe obesity are reminiscent of protein deficiency. The significance of this finding and other adaptations which occur after this operation are not understood. Key Words:jejunoileal bypass, amino acids, hepatic, malabsorption, obesity
The rationale for the jejunoileal bypass procedure is promotion of weight loss by creation of a new disease: intestinal malabsorption. AIthough its etiology is not defined, the massive steatorrhea which follows small intestinal bypass (usually with end to end anastomosis of 12 inches of jejunum to 8 inches of ileum and drainage of the bypassed intestinal limb into the colon) reflects the combination of interruption of the biliary enterohepatic circulation and exclusion of much of the lipid absorbing surface of the upper intestine.' Following operation, most patients lose one-third to one-half of their preoperative weight, the rate of loss proportional to original excess. Few patients attain ideal weight, however, most having reached a plateau at about 125 percent of ideal weight 12 to 18 months postoperatively.2 Possible reasons for this plateau in weight include improved appetite and increased absorptive function by the remaining small intestine. Previous evidence of intestinal adaptation following the bypass procedure includes the observation that D-XylOSe absorption, an index of jejunal function, is markedly decreased postoperatively but frequently returns to normal 24 months po~toperatively.~ On the other hand, a recent quantitative evaluation of jejunal biopsies obtained pre- and postoperatively (seven to 37 months) failed to show an adaptive increase in absorptive surface area or of activity of the surface disaccharidase enzyme^.^ In another study,S ileal function was assessed preoperatively and ten days and five months postoperatively using fecal and breath recoveries of isotope after oral administration of a labeled bile acid, "X-glycine-cholic acid. Marked immediate postoperative bile acid malabsorption was largely corrected by five months, indicating the occurrence of ileal adap-
tation (increased absorption per unit length) in the late postoperative period. After more than 20 years of experience with the bypass operation the major late postoperative complication remains hepatic dysfunction, resulting in death in about 1 percent of all bypass patients.2 Histologically, the liver damage is universally characterized by steatosis six to eight months after surgery and, in a minority of patients, inflammation similar to that seen in alcoholic hepatitis, with progression to cirrhosis.276 The etiology of progressive accumulation of fat in the liver is unknown. Hepatic steatosis is not the result of rapid weight reduction since the opposite finding, disappearance of fat in the liver, results from starvation dieting by obese individuals.' Moxley, Pozefsky and Lockwood observed that the accumulation of hepatic fat in 18 patients, studied four months postoperatively, was associated with marked depression of plasma essential amino acids and elevation of plasma glycine and serine.* With stabilization of body weight 12 to 36 months postoperatively, hepatic steatosis was much less marked and the plasma amino acid profile had become normal. Since the abnormal amino acid profile is similar to that found in kwashiorkor the authors suggested that postbypass hepatic steatosis results from proteincalorie malabsorption and malnutrition. They also showed by use of oral tolerance testing that the absorption of three amino acids (leucine, glycine and lysine) was depressed postoperatively, but returned towards normal at 12 to 26 months. Testing absorption by timed measurements of plasma levels after oral ingestion of a substance, however, does not account for effects on tissue disappearance. Recently, Fogel, Ravitch and Adibi studied intestinal function in the intact jejunal segment before and at intervals after the bypass procedure with the aims of measuring possible adaptation in the late postoperative period and of NUTRITION REVIEWS / VOL. 35, NO. 2 /FEBRUARY 1977
43
evaluating the etiology of the abnormal postoperative amino acid profile.9 Seven obese patients aged 30 to 45 years were studied by the techniques of jejunal perfusion and peroral jejunal biopsy preoperatively and two and seven months after the jejunoileal bypass. At the time of the postoperative studies conventional liver function tests were normal in five of the seven patients; liver biopsies were not performed. The isotonic jejunal perfusion solution contained 40 mM concentrations of either Lleucine (amino acid), glycyl-L-leucine (dipeptide) or maltose (disaccharide). At two and seven months postoperatively the “kwashiorkor pattern” of postabsorptive (fasting) plasma amino acids was obtained increased serine and glycine and decreased valine, isoleucine, leucine, tyrosine and phenylalanine. Sequential jejunal perfut;on studies showed a decrease in jejunal uptake of glucose or the dipeptide glycyl-leucine. Jejunal histology was qualitatively unchanged between the preoperative and seven month postoperative specimens. Thus, after the jejunoileal bypass in this small group of patients there was no compensatory increase in jejunal villous height, nor in dipeptide, disaccharide or glucose absorption from the jejunum. They ascribed the significant decrease in amino acid (leucine) absorption from the perfused segment to protein deprivation, shown previously to limit the absorption of amino acids but not dipeptides.1° The contribution of protein malabsorption to the observed abnormal postoperative amino acid pattern remains speculative. Since none of the patients had liver biopsies, and since the seven month weight loss appeared quite modest in five of the seven patients, these studies provide limited information on the changes in intestinal histology and function prevailing in one-third of the patient population that develops marked hepatic steatosis with rapid weight loss and is at risk for hepatic faiIure.ll Additional studies will have to be performed at later intervals to evaluate the phenomenon of intestinal adaptation. Although the method of jejunal perfusion provides precise information on one intestinal segment, intestinal protein absorption from the entire small intestine was not assessed. It is more likely 44
NUTRITION REVIEWS I VOL. 35, NO. 2 I FEBRUARY 1977
that ileal, and not jejunal compensation, is responsible for intestinal adaptation in these patients. The etiology of hepatic steatosis which follows the jejunoileal bypass procedure remains unclear. The analogy with the fatty liver of kwashiorkor is incomplete, since this lesion rarely progresses to inflammation and cirrhosis. Furthermore, the fat accumulation of kwashiorkor is thought to result from an imbalance of protein and total calories, i.e. selective protein deficiency.12 This situation has not been shown to pertain to the postoperative bypass patient with presumed total calorie malabsorption. Yet, if the problem were simply one of calorie deprivation, hepatic lipid should decrease, not accumulate.6 For these reasons, as discussed recently, many investigators have begun the search for a possible “loop factor”, i.e. a toxin elaborated by the bypassed loop, or for a specific alteration in biliary metabolism which could account for the potential of hepatic decompensation following the jejunoileal bypass.13 0
1. T.I.A. Sorenson and E. Krag: Fat Digestion after Jejunoileal Bypass Operation for Obesity. Scandinav. J. Gastro. 11: 491-496, 1976 2. G.A. Bray, R.E. Barry, J.R. Benfield, C. Castelnuovo-Tedesco, E.J. Drenick and E. Passaro: Intestinal Bypass Operation as a Treatment for Obesity. Ann. Int. Med. 85: 97-109, 1976 3. H.J. Shibata in Treating the Obese. W.L. Asher, Editor, pp. 197-216. Williams and Wilkins, Baltimore, 1974 4. P. Dano, O.V. Nielson, M. Petri and B. Jorgensen: Jejunal Morphology and Mucosal Enzyme Activity Following Intestinal Shunt Operation for Obesity. Scandinav. J. Gastro. 11: 129134, 1976 5. L. Wise, H. Margraf and T. Stein: Studies on Bile Salt Deconjugation Following Small Bowel Bypass Procedures. Ann. Surg. 181: 397-401, 1975 6. R.T. Holzbach, R.G. Wieland, C.S. Lieber, L. M. DeCarli, K.R. Koepke and S.G. Green: Hepatic Lipid in Morbid Obesity. Assessment at and Subsequent to Jejunoileal Bypass. New Engl. J. Med. 290: 296-299, 1974 7. E.J. Drenick, F. Simmons and J.F. Murphy: Effect on Hepatic Morphology of Treatment of
Obesity by Fasting, Reducing Diets and SmallBowel Bypass. New Engl. J . Med. 282: 829834, 1970 8. R.T. Moxley, 111, T. Pozefsky and D.H. Lockwood: Protein Nutrition and Liver Disease after Jejunoileal Bypass for Morbid Obesity. New Engl. J. Med. 290: 921-926, 1974 9. M.R. Fogel, M.M. Ravitch and S.A. Adibi: Absorptive and Digestive Function of the Jejunum after Jejunoileal Bypass for Treatment of Human Obesity. Gastroenterology 71 : 729-733, 1976 10. S.A. Adibi and E.R. Allen: Impaired Jejunal Absorption Rates of Essential Amino Acids
Induced by Either Dietary Caloric or Protein Deprivation in Man. Gastroenterology 59: 404-4 13, 1970 11. R.G. Brown, J.P. O'Leary and E.R. Woodward: Hepatic Effects of Jejunoileal Bypass for Morbid Obesity. Am. J. Surg. 127: 53-58, 1974 12. D.S. McLaren, J.G. Bitar and V.H. Nassar in Progress in Liver Diseases by H. Popper and F. Schaffner. Volume IV, pp. 527-536. Grune and Stratton, New York, 1972 13. Current Status of Jejunoileal Bypass for Obesity. Nutrition Reviews 32: 333-336, 1974
SERUM CAR NIT1NE IN SCHlSTOSOMIASIS Serum carnitine was reduced in malnourished subjects with active schistosomiasis and other parasitic infections. Key Words: carnitine, schistosomiasis
Carnitine is synthesized in the rat liver from lysine, which provides the carbon skeleton and the nitrogen atom, and methionine which contributes the N-methyl groups.' Although it has been estimated that less than 0.1 percent of the dietary lysine supply is converted directly into carnitine synthesis, it is possible to observe a decline of about 30 percent in the carnitine content of skeletal muscle and heart muscle when weanling rats are fed a diet low in carnitine (0.1 p g per gram diet) and lysine (0.37 percent).2 The metabolic impact of this amount of carnitine deficit and the possibility of a counterpart situation in man are questions of fundamental interest. Mikhail and Mansour3 sought information on the carnitine status of human subjects who were simultaneously malnourished and victims of either simple schistosomiasis or schistosomiasis complicated with colonic polyposis. The first group consisted of 16 male Egyptian farmers selected from the patients at NAMRU3 in Cairo. These subjects all had severe active schistosomal infection as well as signs of malnutrition and anemia. Other parasitic infections were also identified in this group, however, including Ancyclostoma duodenale, Ascaris lumbricoides, Hymenolepis nana and Giardia lamblia. Many also demonstrated he-
patosplenomegaly and kidney enlargement. The second group was composed of 12 additional farmers with a long history of heavy schistosomal infection which had resulted in the development of colonic polyposis. No comment was made as to the presence or absence of an additional parasite load in these individuals but that assumption seems likely. Ten healthy adult Egyptian males from a middle class background constituted a control group. Upon admission, hematological and biochemical analyses were performed on the two patient groups. After obtaining the baseline data, each patient in Group one was begun on a repletion regimen for an unstated interval of time. During this time he received the hospital diet as well as daily supplements of two glasses of milk, 200 g of meat, and a multivitamin-mineral mixture including folic acid and ferrous sulfate. The drug Ambilhar (nitrothiazole( 1-(5-nitro-2-thiazolyI)imidazolidine)) was then administered for a treatment period of six to ten days after the initial anemic condition had been corrected. Group two patients, because of their poor condition, were begun on drug therapy immediately following admission, simultaneously with the introduction of the nutritional support. Nutritional rehabilitation was effective in restoring the hemoglobin and hematocrit values of Group one to normal and a similar response NUTRITION REVIEWS I VOL. 35, NO. 2 I FEBRUARY 1977
45
The rationale for the jejunoileal bypass procedure is promotion of weight loss by creation of a new disease: intestinal malabsorption. AIthough its etiology is not defined, the massive steatorrhea which follows small intestinal bypass (usually with end to end anastomosis of 12 inches of jejunum to 8 inches of ileum and drainage of the bypassed intestinal limb into the colon) reflects the combination of interruption of the biliary enterohepatic circulation and exclusion of much of the lipid absorbing surface of the upper intestine.' Following operation, most patients lose one-third to one-half of their preoperative weight, the rate of loss proportional to original excess. Few patients attain ideal weight, however, most having reached a plateau at about 125 percent of ideal weight 12 to 18 months postoperatively.2 Possible reasons for this plateau in weight include improved appetite and increased absorptive function by the remaining small intestine. Previous evidence of intestinal adaptation following the bypass procedure includes the observation that D-XylOSe absorption, an index of jejunal function, is markedly decreased postoperatively but frequently returns to normal 24 months po~toperatively.~ On the other hand, a recent quantitative evaluation of jejunal biopsies obtained pre- and postoperatively (seven to 37 months) failed to show an adaptive increase in absorptive surface area or of activity of the surface disaccharidase enzyme^.^ In another study,S ileal function was assessed preoperatively and ten days and five months postoperatively using fecal and breath recoveries of isotope after oral administration of a labeled bile acid, "X-glycine-cholic acid. Marked immediate postoperative bile acid malabsorption was largely corrected by five months, indicating the occurrence of ileal adap-
tation (increased absorption per unit length) in the late postoperative period. After more than 20 years of experience with the bypass operation the major late postoperative complication remains hepatic dysfunction, resulting in death in about 1 percent of all bypass patients.2 Histologically, the liver damage is universally characterized by steatosis six to eight months after surgery and, in a minority of patients, inflammation similar to that seen in alcoholic hepatitis, with progression to cirrhosis.276 The etiology of progressive accumulation of fat in the liver is unknown. Hepatic steatosis is not the result of rapid weight reduction since the opposite finding, disappearance of fat in the liver, results from starvation dieting by obese individuals.' Moxley, Pozefsky and Lockwood observed that the accumulation of hepatic fat in 18 patients, studied four months postoperatively, was associated with marked depression of plasma essential amino acids and elevation of plasma glycine and serine.* With stabilization of body weight 12 to 36 months postoperatively, hepatic steatosis was much less marked and the plasma amino acid profile had become normal. Since the abnormal amino acid profile is similar to that found in kwashiorkor the authors suggested that postbypass hepatic steatosis results from proteincalorie malabsorption and malnutrition. They also showed by use of oral tolerance testing that the absorption of three amino acids (leucine, glycine and lysine) was depressed postoperatively, but returned towards normal at 12 to 26 months. Testing absorption by timed measurements of plasma levels after oral ingestion of a substance, however, does not account for effects on tissue disappearance. Recently, Fogel, Ravitch and Adibi studied intestinal function in the intact jejunal segment before and at intervals after the bypass procedure with the aims of measuring possible adaptation in the late postoperative period and of NUTRITION REVIEWS / VOL. 35, NO. 2 /FEBRUARY 1977
43
evaluating the etiology of the abnormal postoperative amino acid profile.9 Seven obese patients aged 30 to 45 years were studied by the techniques of jejunal perfusion and peroral jejunal biopsy preoperatively and two and seven months after the jejunoileal bypass. At the time of the postoperative studies conventional liver function tests were normal in five of the seven patients; liver biopsies were not performed. The isotonic jejunal perfusion solution contained 40 mM concentrations of either Lleucine (amino acid), glycyl-L-leucine (dipeptide) or maltose (disaccharide). At two and seven months postoperatively the “kwashiorkor pattern” of postabsorptive (fasting) plasma amino acids was obtained increased serine and glycine and decreased valine, isoleucine, leucine, tyrosine and phenylalanine. Sequential jejunal perfut;on studies showed a decrease in jejunal uptake of glucose or the dipeptide glycyl-leucine. Jejunal histology was qualitatively unchanged between the preoperative and seven month postoperative specimens. Thus, after the jejunoileal bypass in this small group of patients there was no compensatory increase in jejunal villous height, nor in dipeptide, disaccharide or glucose absorption from the jejunum. They ascribed the significant decrease in amino acid (leucine) absorption from the perfused segment to protein deprivation, shown previously to limit the absorption of amino acids but not dipeptides.1° The contribution of protein malabsorption to the observed abnormal postoperative amino acid pattern remains speculative. Since none of the patients had liver biopsies, and since the seven month weight loss appeared quite modest in five of the seven patients, these studies provide limited information on the changes in intestinal histology and function prevailing in one-third of the patient population that develops marked hepatic steatosis with rapid weight loss and is at risk for hepatic faiIure.ll Additional studies will have to be performed at later intervals to evaluate the phenomenon of intestinal adaptation. Although the method of jejunal perfusion provides precise information on one intestinal segment, intestinal protein absorption from the entire small intestine was not assessed. It is more likely 44
NUTRITION REVIEWS I VOL. 35, NO. 2 I FEBRUARY 1977
that ileal, and not jejunal compensation, is responsible for intestinal adaptation in these patients. The etiology of hepatic steatosis which follows the jejunoileal bypass procedure remains unclear. The analogy with the fatty liver of kwashiorkor is incomplete, since this lesion rarely progresses to inflammation and cirrhosis. Furthermore, the fat accumulation of kwashiorkor is thought to result from an imbalance of protein and total calories, i.e. selective protein deficiency.12 This situation has not been shown to pertain to the postoperative bypass patient with presumed total calorie malabsorption. Yet, if the problem were simply one of calorie deprivation, hepatic lipid should decrease, not accumulate.6 For these reasons, as discussed recently, many investigators have begun the search for a possible “loop factor”, i.e. a toxin elaborated by the bypassed loop, or for a specific alteration in biliary metabolism which could account for the potential of hepatic decompensation following the jejunoileal bypass.13 0
1. T.I.A. Sorenson and E. Krag: Fat Digestion after Jejunoileal Bypass Operation for Obesity. Scandinav. J. Gastro. 11: 491-496, 1976 2. G.A. Bray, R.E. Barry, J.R. Benfield, C. Castelnuovo-Tedesco, E.J. Drenick and E. Passaro: Intestinal Bypass Operation as a Treatment for Obesity. Ann. Int. Med. 85: 97-109, 1976 3. H.J. Shibata in Treating the Obese. W.L. Asher, Editor, pp. 197-216. Williams and Wilkins, Baltimore, 1974 4. P. Dano, O.V. Nielson, M. Petri and B. Jorgensen: Jejunal Morphology and Mucosal Enzyme Activity Following Intestinal Shunt Operation for Obesity. Scandinav. J. Gastro. 11: 129134, 1976 5. L. Wise, H. Margraf and T. Stein: Studies on Bile Salt Deconjugation Following Small Bowel Bypass Procedures. Ann. Surg. 181: 397-401, 1975 6. R.T. Holzbach, R.G. Wieland, C.S. Lieber, L. M. DeCarli, K.R. Koepke and S.G. Green: Hepatic Lipid in Morbid Obesity. Assessment at and Subsequent to Jejunoileal Bypass. New Engl. J. Med. 290: 296-299, 1974 7. E.J. Drenick, F. Simmons and J.F. Murphy: Effect on Hepatic Morphology of Treatment of
Obesity by Fasting, Reducing Diets and SmallBowel Bypass. New Engl. J . Med. 282: 829834, 1970 8. R.T. Moxley, 111, T. Pozefsky and D.H. Lockwood: Protein Nutrition and Liver Disease after Jejunoileal Bypass for Morbid Obesity. New Engl. J. Med. 290: 921-926, 1974 9. M.R. Fogel, M.M. Ravitch and S.A. Adibi: Absorptive and Digestive Function of the Jejunum after Jejunoileal Bypass for Treatment of Human Obesity. Gastroenterology 71 : 729-733, 1976 10. S.A. Adibi and E.R. Allen: Impaired Jejunal Absorption Rates of Essential Amino Acids
Induced by Either Dietary Caloric or Protein Deprivation in Man. Gastroenterology 59: 404-4 13, 1970 11. R.G. Brown, J.P. O'Leary and E.R. Woodward: Hepatic Effects of Jejunoileal Bypass for Morbid Obesity. Am. J. Surg. 127: 53-58, 1974 12. D.S. McLaren, J.G. Bitar and V.H. Nassar in Progress in Liver Diseases by H. Popper and F. Schaffner. Volume IV, pp. 527-536. Grune and Stratton, New York, 1972 13. Current Status of Jejunoileal Bypass for Obesity. Nutrition Reviews 32: 333-336, 1974
SERUM CAR NIT1NE IN SCHlSTOSOMIASIS Serum carnitine was reduced in malnourished subjects with active schistosomiasis and other parasitic infections. Key Words: carnitine, schistosomiasis
Carnitine is synthesized in the rat liver from lysine, which provides the carbon skeleton and the nitrogen atom, and methionine which contributes the N-methyl groups.' Although it has been estimated that less than 0.1 percent of the dietary lysine supply is converted directly into carnitine synthesis, it is possible to observe a decline of about 30 percent in the carnitine content of skeletal muscle and heart muscle when weanling rats are fed a diet low in carnitine (0.1 p g per gram diet) and lysine (0.37 percent).2 The metabolic impact of this amount of carnitine deficit and the possibility of a counterpart situation in man are questions of fundamental interest. Mikhail and Mansour3 sought information on the carnitine status of human subjects who were simultaneously malnourished and victims of either simple schistosomiasis or schistosomiasis complicated with colonic polyposis. The first group consisted of 16 male Egyptian farmers selected from the patients at NAMRU3 in Cairo. These subjects all had severe active schistosomal infection as well as signs of malnutrition and anemia. Other parasitic infections were also identified in this group, however, including Ancyclostoma duodenale, Ascaris lumbricoides, Hymenolepis nana and Giardia lamblia. Many also demonstrated he-
patosplenomegaly and kidney enlargement. The second group was composed of 12 additional farmers with a long history of heavy schistosomal infection which had resulted in the development of colonic polyposis. No comment was made as to the presence or absence of an additional parasite load in these individuals but that assumption seems likely. Ten healthy adult Egyptian males from a middle class background constituted a control group. Upon admission, hematological and biochemical analyses were performed on the two patient groups. After obtaining the baseline data, each patient in Group one was begun on a repletion regimen for an unstated interval of time. During this time he received the hospital diet as well as daily supplements of two glasses of milk, 200 g of meat, and a multivitamin-mineral mixture including folic acid and ferrous sulfate. The drug Ambilhar (nitrothiazole( 1-(5-nitro-2-thiazolyI)imidazolidine)) was then administered for a treatment period of six to ten days after the initial anemic condition had been corrected. Group two patients, because of their poor condition, were begun on drug therapy immediately following admission, simultaneously with the introduction of the nutritional support. Nutritional rehabilitation was effective in restoring the hemoglobin and hematocrit values of Group one to normal and a similar response NUTRITION REVIEWS I VOL. 35, NO. 2 I FEBRUARY 1977
45
