Br. J. Surg. Vol. 63 (1976) 30-32
Symptomatic hypoglycaemia, liver glycogen depletion and cirrhosis following jejuno-ileal bypass for gross obesity R. G . W I L C O X * SUMMARY
A new complication following jejuno-ileal bypass for gross obesity is described. The patient suflered from hypoglycnemic attacks which were associated with total depletion of liver glycogen together with a progressive micronodular cirrhosis. Increased dietary protein and calorie content relieved her symptoms, restored liver glycogen but had no effect on the development of the cirrhosis over the next I2 months.
SURGICAL bypass of the small bowel has been used for the treatment of gross obesity since experimental work in animals (Kremen et al., 1954) was extended to man (Payne et al., 1963; Payne and DeWind, 1969). Some of the complications of small bowel bypass include electrolyte imbalance and diarrhoea (Weismann, 1973), megacolon and calcium oxalate renal stones (Fikri and Cassella, 1974) and a nonspecific polyarthritis (Shagrin et al., 1971). This report describes a patient who suffered hypoglycaemic attacks following jejuno-ileal bypass and in whom liver biopsies showed glycogen depletion and progressive micronodular cirrhosis. Case report In October 1972 a 32-year-old housewife, weighing 157 kg, had a jejuno-ileal bypass and cholecystectomy (Professor J. D. Hardcastle). The proximal 35 cm of the jejunum were anastomosed end to side to the ileum at a point 10 cm from the ileocaecal valve. The liver was macroscopically normal but was not biopsied. She denied any significant intake of alcohol and her preoperative liver function tests were all within the normal range. Following operation she had an unrestricted diet estimated at 2000 calories, and lost 50 kg in the first year. She had frequent bowel actions, numbering 2-6 per day. Twentyseven months after operation, when she weighed 79 kg, she began to suffer frequent periods of faintness, dizziness, sweating and transient slurring of speech. These episodes occurred particularly upon waking and were relieved by food or sweet drinks. Physical examination at that time was unremarkable. The following investigations were within normal limits: full blood count, ESR, blood urea, serum electrolytes, serum calcium and phosphorus, diurnal serum cortisols, serum thyroxine, whole blood folate and serum vitamin BIZ. Blood glucose estimations during two 24-hour fasts ranged between 25 and 50 mg/100 ml with serum insulin levels from 20 to 25 pu./ml. During these fasts she complained of faintness and dizziness and was observed to be pale, sweaty and to have a tachycardia. These symptoms were rapidly relieved at the end of the fast periods by sweet drinks. A 50-g glucose tolerance test showed a flat response, with levels of 75, 75, 70, 75 and 70 mg/100 ml at 0, 30, 60, 90 and 120 minutes respectively. Serum insulin during the 50-g glucose tolerance test increased from a basal 21 yu./ml to a maximum at 30 minutes of 31 pu./ml. The intravenous glucagon test, shown in Fig. 1, produced a minimal increase in blood glucose from 45 mg/ 100 ml fasting t o 55 mg/100 ml at 15 minutes. Serum insulin
30
increased from 12 yu./ml fasting to a maximum a t 15 minutes of 40 yu./ml. The o-xylose test showed a 1.5-g excretion in a 5-hour urine collection following a 25-g oral dose. The liver function tests showed: total serum protein 5.9 g/ 100 ml (albumin 3.1 g/lOO ml), alkaline phosphatase 106 i.u., alanine aminotransferase 48 i.u. and a total serum bilirubin 0.8 mg/100 ml. The liver biopsy showed virtual absence of glycogen; in addition, there was severe fatty change involving over 80 per cent of the liver cells with reticulin strands extending into the parenchyma from the portal tracts (Fig. 2). She was placed on a 3000-calorie diet containing 100 g of protein and her attacks rapidly subsided. During a 24-hour fast 1 week later the blood glucose levels were between 75 and 90 mg/100 ml. After 6 months on this diet, during which she remained entirely well and with no appreciable weight gain, she was admitted for reassessment. A 24-hour fast showed blood glucose levels between 60 and 90 mg/100 ml, during which she remained asymptomatic. A repeat 50-g glucose tolerance test showed no improvement in glucose absorption. I n order to assess the absorptive capacity of the remaining small bowel for glucose the glucose tolerance test was repeated using 100 g and then 200 g of glucose. There was no significant increase in blood glucose during either test (Fig. 3). The intravenous glucagon test now produced an increase of blood glucose from 60 mg/100ml fasting to a maximum at 15 minutes of 100 mg/100 ml (Fig. l), representing a significant increase from the previous glucagon response. The basal serum insulin had not increased at 20 pu./ml, but now reached a maximum at 15 minutes of 84 pu./ml in response to intravenous glucagon. She continued to have steatorrhoea with a faecal fat excretion of approximately 50 g/24 hours. This represents about 50 per cent of her daily fat intake. A Crosby capsule biopsy of the small bowel was normal both macroscopically and histologically. Conventional tests of liver function had not altered. A repeat liver biopsy showed an abundance of liver glycogen together with a great reduction in the degree of fatty change. The degree of fibrosis, however, had increased and 6 months later showed the characteristic features of an established micronodular cirrhosis (Fig. 4).
Discussion There is no doubt that this patient’s attacks were caused by hypoglycaemia. The fasting blood glucose levels, however, varied from day to day. The investigations showed a significant degree of carbohydrate malabsorption and depletion of liver glycogen. The former is well documented after ileal shunting (Weismann, 1973) but not to the degree shown in this patient. This may be explained by a reduced area and thus saturation of the available absorptive sites for glucose as a consequence of the shortening operation, or by an increased transit time. If a high carbohydrate load is presented to the remaining small bowel, however, there is no appreciable improvement in absorption. One might have expected an acute high
* General
Hospital, Nottingham.
Hypoglycaemia following jejuno-ileal bypass
carbohydrate load to have compensated, in part, for an increase in transit time if present. The absorptive capacity for glucose is, presumably, operating maximally. Neither symptomatic hypoglycaemia nor depletion of glycogen has previously been described as a complication of bypass surgery. Indeed Moxley et al. (1970) have found normal levels of blood glucose and liver glycogen in their postoperative patients. By increasing the caloric and protein content of
this patient's diet it was possible to prevent her attacks, to restore blood glucose levels to normal and to replete the liver stores of glycogen. Presumably, the increased protein content is making a significant contribution to gluconeogenesis for there has been no identifiable improvement in glucose absorption. There has been no change in the levels of serum insulin. It is known that patients with gross obesity develop a state of relative insulin resistance and hyperinsulinaemia. The serum insulin in this patient was
loo
r
-2 sotM
Aug 1974 Jan 1974
I mg
I.V.
glucagon
I
I
I
30
60
90
1 I20
Minutes
30
60
90
I20
Minutes
Fig. 1. Blood glucose response to intravenous glucagon before (0 . . . . . 0 ) and after (0-0) modified diet.
Fig. 3. Glucose tolerance tests using 50, 100 and 200 g of glucose.
Fig. 2. Histological section of the liver showing severe fatty infiltration. HE. ( x 63.)
Fig. 4. Histological section of liver showing micronodular cirrhosis. Reticulin stain. ( x 6 3 . )
31
R. G . Wilcox excessively elevated although it may have been inappropriately high for the level of blood glucose, thereby contributing to the hypoglycaemia (Marks, 1974). The other serious change in this patient is the progression towards hepatic cirrhosis unaffected by the increased protein in the dict. Approximately 70 per cent of non-alcoholic patients with gross obesity submitted for ileal shunting show varying degrees of fatty infiltration of the liver preoperatively (Buchwald et al., 1974). Following small bowel bypass there is commonly an increase in the degree of fatty infiltration in the first 6 months but this regresses within 2 years. Transient disturbances of liver function with jaundice and elevated levels of liver enzymes may also occur following operation (Weismann, 1973; Fikri and Cassella, 1974). If these disturbances persist, take-down of the shunt usually restores liver function and morphology to normal (Brown et al., 1974). Compared with the earlier jejunocolic shunts death from fulminant hepatic failure is rare following jejunoileal bypass. Single cases have been reported amongst large series of patients and the cause of liver failure attributed to serum hepatitis (Fikri and Cassella, 1974), intractable vomiting of psychic origin (Weismann, 1973), hepatic necrosis (Drenick et al., 1972) and ‘hepatic coma’ (Brown et al., 1974). Occasionally periportal fibrosis is seen in follow-up liver biopsies, but to date only 1 case of definite cirrhosis following a jejuno-ileal shunt has been reported (McGill et al., 1972). Their patient had a normal liver biopsy preoperatively but died 11 months later in liver failure due to micronodular cirrhosis. A second patient, described by Jagdish et al. (1974), also developed cirrhosis and died 2 years postoperatively; however, she had a history of heavy alcohol intake and continued to drink after operation. The liver was not biopsied preoperatively. Two patients described by Wills (1969) had preoperative histological changes of cirrhosis. One died from uncontrollable bleeding from oesophageal varices but the other was reported to be well 14 months after operation. There is no doubt about the efficacy of small bowel bypass surgery in the treatment of gross obesity as compared with conservative forms of management. The average loss following surgery amounts to approximately 40 per cent of the preoperative weight and is usually achieved by 18 months. Whether surgery will affect the long term prognosis of severely obese patients will be answered only by a randomized prospective study comparing surgery with more conventional treatment (Quaade, 1974).
32
Acknowledgements I would like to thank Dr M. V. Wells and Professor J. D. Hardcastle for permission to report details of this patient, Dr P. J. Toghill for helpful criticism and the Photographic Department, General Hospital, Nottingham, for the illustrations. References and WOODWARD E. R. (1974) Hepatic effects of jejunoileal bypass for morbid obesity. Am. J. Surg. 127, 53-58. BUCHWALD H., LOBER P. H. and VARCO R. L. (1974) Liver biopsy findings in seventy-seven consecutive patients undergoing jejunoileal bypass for morbid obesity. Am. J . Surg. 127, 48-52. DRENICK E. J., SIMMONS F. and MURPHY J. F. (1972) Effect on hepatic morphology of treatment of obesity by fasting, reduced diets and small bowel bypass. New Engl. J . Med. 282, 829-834. FIKRI E. and CASSELLA R. R. (1974) Jejunoileal bypass for massive obesity: results and complications in fifty-two patients. Ann. Surg. 179, 460-464. JAGDISH c. M., HOY w., YOUNGMAN K. and CHOPEK M. (1974) Cirrhosis and death after jejunoileal shunt for obesity. Digestive Dis.19, 759-765. KREMEN A. J., LINNER J. H. and NELSON c. H. (1954) Experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann. Siirg. 140, 439448. MCGILL D. B., HUMPHREYS s. R., BAGENSTOSS A. H. and DICKSON E. R. (1972) Cirrhosis and death after jejunoileal shunt. Gastroenterology 63, 872-877. MARKS v. (1974) The investigation of hypoglycaemia. Br. J . Hosp. Med. 2, 731-743. MOXLEY R. T., POZEFSKY T. and LOCKWOOD D. H. (1974) Protein nutrition and liver disease after jejunoileal bypass for morbid obesity. New Engl. J. Med. 290, 921-926. PAYNE J. H. and DEWIND L. T. (1969) Surgical treatment of obesity Am, J. Surg. 118, 141-147. PAYNE J . H., DEWIND L. T. and COMMONS R. R. (1963) Metabolic observations in patients with jejunocolic shunts. Am. J. Surg. 106, 273-289. QUAADE F. (1974) Untraditional treatment of obesity. In: BURLAND w. L., SAMUEL P. D. and YUDKIN J. (ed.) Obesity Symposium. Edinburgh, Churchill Livingstone, pp. 338-352. SHAGRIN J. w., FRAME B. and DUNCAN H. (1971) Polyarthritis in obese patients with intestinal bypass. Ann. Intern. Med. 75, 377-380. WEISMANN R. E. (1973) Surgical palliation of massive and severe obesity. Am. J. Surg. 125, 437446. WILLS C. E. (1969) Jejunoileostomy for obesity. J. Med. Assoc. Ga. 58, 456-461. BROWN R. G., O’LEARY J. P.
Symptomatic hypoglycaemia, liver glycogen depletion and cirrhosis following jejuno-ileal bypass for gross obesity R. G . W I L C O X * SUMMARY
A new complication following jejuno-ileal bypass for gross obesity is described. The patient suflered from hypoglycnemic attacks which were associated with total depletion of liver glycogen together with a progressive micronodular cirrhosis. Increased dietary protein and calorie content relieved her symptoms, restored liver glycogen but had no effect on the development of the cirrhosis over the next I2 months.
SURGICAL bypass of the small bowel has been used for the treatment of gross obesity since experimental work in animals (Kremen et al., 1954) was extended to man (Payne et al., 1963; Payne and DeWind, 1969). Some of the complications of small bowel bypass include electrolyte imbalance and diarrhoea (Weismann, 1973), megacolon and calcium oxalate renal stones (Fikri and Cassella, 1974) and a nonspecific polyarthritis (Shagrin et al., 1971). This report describes a patient who suffered hypoglycaemic attacks following jejuno-ileal bypass and in whom liver biopsies showed glycogen depletion and progressive micronodular cirrhosis. Case report In October 1972 a 32-year-old housewife, weighing 157 kg, had a jejuno-ileal bypass and cholecystectomy (Professor J. D. Hardcastle). The proximal 35 cm of the jejunum were anastomosed end to side to the ileum at a point 10 cm from the ileocaecal valve. The liver was macroscopically normal but was not biopsied. She denied any significant intake of alcohol and her preoperative liver function tests were all within the normal range. Following operation she had an unrestricted diet estimated at 2000 calories, and lost 50 kg in the first year. She had frequent bowel actions, numbering 2-6 per day. Twentyseven months after operation, when she weighed 79 kg, she began to suffer frequent periods of faintness, dizziness, sweating and transient slurring of speech. These episodes occurred particularly upon waking and were relieved by food or sweet drinks. Physical examination at that time was unremarkable. The following investigations were within normal limits: full blood count, ESR, blood urea, serum electrolytes, serum calcium and phosphorus, diurnal serum cortisols, serum thyroxine, whole blood folate and serum vitamin BIZ. Blood glucose estimations during two 24-hour fasts ranged between 25 and 50 mg/100 ml with serum insulin levels from 20 to 25 pu./ml. During these fasts she complained of faintness and dizziness and was observed to be pale, sweaty and to have a tachycardia. These symptoms were rapidly relieved at the end of the fast periods by sweet drinks. A 50-g glucose tolerance test showed a flat response, with levels of 75, 75, 70, 75 and 70 mg/100 ml at 0, 30, 60, 90 and 120 minutes respectively. Serum insulin during the 50-g glucose tolerance test increased from a basal 21 yu./ml to a maximum at 30 minutes of 31 pu./ml. The intravenous glucagon test, shown in Fig. 1, produced a minimal increase in blood glucose from 45 mg/ 100 ml fasting t o 55 mg/100 ml at 15 minutes. Serum insulin
30
increased from 12 yu./ml fasting to a maximum a t 15 minutes of 40 yu./ml. The o-xylose test showed a 1.5-g excretion in a 5-hour urine collection following a 25-g oral dose. The liver function tests showed: total serum protein 5.9 g/ 100 ml (albumin 3.1 g/lOO ml), alkaline phosphatase 106 i.u., alanine aminotransferase 48 i.u. and a total serum bilirubin 0.8 mg/100 ml. The liver biopsy showed virtual absence of glycogen; in addition, there was severe fatty change involving over 80 per cent of the liver cells with reticulin strands extending into the parenchyma from the portal tracts (Fig. 2). She was placed on a 3000-calorie diet containing 100 g of protein and her attacks rapidly subsided. During a 24-hour fast 1 week later the blood glucose levels were between 75 and 90 mg/100 ml. After 6 months on this diet, during which she remained entirely well and with no appreciable weight gain, she was admitted for reassessment. A 24-hour fast showed blood glucose levels between 60 and 90 mg/100 ml, during which she remained asymptomatic. A repeat 50-g glucose tolerance test showed no improvement in glucose absorption. I n order to assess the absorptive capacity of the remaining small bowel for glucose the glucose tolerance test was repeated using 100 g and then 200 g of glucose. There was no significant increase in blood glucose during either test (Fig. 3). The intravenous glucagon test now produced an increase of blood glucose from 60 mg/100ml fasting to a maximum at 15 minutes of 100 mg/100 ml (Fig. l), representing a significant increase from the previous glucagon response. The basal serum insulin had not increased at 20 pu./ml, but now reached a maximum at 15 minutes of 84 pu./ml in response to intravenous glucagon. She continued to have steatorrhoea with a faecal fat excretion of approximately 50 g/24 hours. This represents about 50 per cent of her daily fat intake. A Crosby capsule biopsy of the small bowel was normal both macroscopically and histologically. Conventional tests of liver function had not altered. A repeat liver biopsy showed an abundance of liver glycogen together with a great reduction in the degree of fatty change. The degree of fibrosis, however, had increased and 6 months later showed the characteristic features of an established micronodular cirrhosis (Fig. 4).
Discussion There is no doubt that this patient’s attacks were caused by hypoglycaemia. The fasting blood glucose levels, however, varied from day to day. The investigations showed a significant degree of carbohydrate malabsorption and depletion of liver glycogen. The former is well documented after ileal shunting (Weismann, 1973) but not to the degree shown in this patient. This may be explained by a reduced area and thus saturation of the available absorptive sites for glucose as a consequence of the shortening operation, or by an increased transit time. If a high carbohydrate load is presented to the remaining small bowel, however, there is no appreciable improvement in absorption. One might have expected an acute high
* General
Hospital, Nottingham.
Hypoglycaemia following jejuno-ileal bypass
carbohydrate load to have compensated, in part, for an increase in transit time if present. The absorptive capacity for glucose is, presumably, operating maximally. Neither symptomatic hypoglycaemia nor depletion of glycogen has previously been described as a complication of bypass surgery. Indeed Moxley et al. (1970) have found normal levels of blood glucose and liver glycogen in their postoperative patients. By increasing the caloric and protein content of
this patient's diet it was possible to prevent her attacks, to restore blood glucose levels to normal and to replete the liver stores of glycogen. Presumably, the increased protein content is making a significant contribution to gluconeogenesis for there has been no identifiable improvement in glucose absorption. There has been no change in the levels of serum insulin. It is known that patients with gross obesity develop a state of relative insulin resistance and hyperinsulinaemia. The serum insulin in this patient was
loo
r
-2 sotM
Aug 1974 Jan 1974
I mg
I.V.
glucagon
I
I
I
30
60
90
1 I20
Minutes
30
60
90
I20
Minutes
Fig. 1. Blood glucose response to intravenous glucagon before (0 . . . . . 0 ) and after (0-0) modified diet.
Fig. 3. Glucose tolerance tests using 50, 100 and 200 g of glucose.
Fig. 2. Histological section of the liver showing severe fatty infiltration. HE. ( x 63.)
Fig. 4. Histological section of liver showing micronodular cirrhosis. Reticulin stain. ( x 6 3 . )
31
R. G . Wilcox excessively elevated although it may have been inappropriately high for the level of blood glucose, thereby contributing to the hypoglycaemia (Marks, 1974). The other serious change in this patient is the progression towards hepatic cirrhosis unaffected by the increased protein in the dict. Approximately 70 per cent of non-alcoholic patients with gross obesity submitted for ileal shunting show varying degrees of fatty infiltration of the liver preoperatively (Buchwald et al., 1974). Following small bowel bypass there is commonly an increase in the degree of fatty infiltration in the first 6 months but this regresses within 2 years. Transient disturbances of liver function with jaundice and elevated levels of liver enzymes may also occur following operation (Weismann, 1973; Fikri and Cassella, 1974). If these disturbances persist, take-down of the shunt usually restores liver function and morphology to normal (Brown et al., 1974). Compared with the earlier jejunocolic shunts death from fulminant hepatic failure is rare following jejunoileal bypass. Single cases have been reported amongst large series of patients and the cause of liver failure attributed to serum hepatitis (Fikri and Cassella, 1974), intractable vomiting of psychic origin (Weismann, 1973), hepatic necrosis (Drenick et al., 1972) and ‘hepatic coma’ (Brown et al., 1974). Occasionally periportal fibrosis is seen in follow-up liver biopsies, but to date only 1 case of definite cirrhosis following a jejuno-ileal shunt has been reported (McGill et al., 1972). Their patient had a normal liver biopsy preoperatively but died 11 months later in liver failure due to micronodular cirrhosis. A second patient, described by Jagdish et al. (1974), also developed cirrhosis and died 2 years postoperatively; however, she had a history of heavy alcohol intake and continued to drink after operation. The liver was not biopsied preoperatively. Two patients described by Wills (1969) had preoperative histological changes of cirrhosis. One died from uncontrollable bleeding from oesophageal varices but the other was reported to be well 14 months after operation. There is no doubt about the efficacy of small bowel bypass surgery in the treatment of gross obesity as compared with conservative forms of management. The average loss following surgery amounts to approximately 40 per cent of the preoperative weight and is usually achieved by 18 months. Whether surgery will affect the long term prognosis of severely obese patients will be answered only by a randomized prospective study comparing surgery with more conventional treatment (Quaade, 1974).
32
Acknowledgements I would like to thank Dr M. V. Wells and Professor J. D. Hardcastle for permission to report details of this patient, Dr P. J. Toghill for helpful criticism and the Photographic Department, General Hospital, Nottingham, for the illustrations. References and WOODWARD E. R. (1974) Hepatic effects of jejunoileal bypass for morbid obesity. Am. J. Surg. 127, 53-58. BUCHWALD H., LOBER P. H. and VARCO R. L. (1974) Liver biopsy findings in seventy-seven consecutive patients undergoing jejunoileal bypass for morbid obesity. Am. J . Surg. 127, 48-52. DRENICK E. J., SIMMONS F. and MURPHY J. F. (1972) Effect on hepatic morphology of treatment of obesity by fasting, reduced diets and small bowel bypass. New Engl. J . Med. 282, 829-834. FIKRI E. and CASSELLA R. R. (1974) Jejunoileal bypass for massive obesity: results and complications in fifty-two patients. Ann. Surg. 179, 460-464. JAGDISH c. M., HOY w., YOUNGMAN K. and CHOPEK M. (1974) Cirrhosis and death after jejunoileal shunt for obesity. Digestive Dis.19, 759-765. KREMEN A. J., LINNER J. H. and NELSON c. H. (1954) Experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann. Siirg. 140, 439448. MCGILL D. B., HUMPHREYS s. R., BAGENSTOSS A. H. and DICKSON E. R. (1972) Cirrhosis and death after jejunoileal shunt. Gastroenterology 63, 872-877. MARKS v. (1974) The investigation of hypoglycaemia. Br. J . Hosp. Med. 2, 731-743. MOXLEY R. T., POZEFSKY T. and LOCKWOOD D. H. (1974) Protein nutrition and liver disease after jejunoileal bypass for morbid obesity. New Engl. J. Med. 290, 921-926. PAYNE J. H. and DEWIND L. T. (1969) Surgical treatment of obesity Am, J. Surg. 118, 141-147. PAYNE J . H., DEWIND L. T. and COMMONS R. R. (1963) Metabolic observations in patients with jejunocolic shunts. Am. J. Surg. 106, 273-289. QUAADE F. (1974) Untraditional treatment of obesity. In: BURLAND w. L., SAMUEL P. D. and YUDKIN J. (ed.) Obesity Symposium. Edinburgh, Churchill Livingstone, pp. 338-352. SHAGRIN J. w., FRAME B. and DUNCAN H. (1971) Polyarthritis in obese patients with intestinal bypass. Ann. Intern. Med. 75, 377-380. WEISMANN R. E. (1973) Surgical palliation of massive and severe obesity. Am. J. Surg. 125, 437446. WILLS C. E. (1969) Jejunoileostomy for obesity. J. Med. Assoc. Ga. 58, 456-461. BROWN R. G., O’LEARY J. P.
