Metabolic Bone Disease After Intestinal Bypass for Treatment of Obesity A. MICHAEL PARFITT, M.B., B.CHIR., F.R.C.P., F.R.A.C.P., F.A.C.P.; MICHAEL J. MILLER, M.D.; BOY FRAME, M.D., F.A.C.P.; ANTHONY R. VILLANUEVA, B.A.; D. S. RAO, M.D.; I. OLIVER, M.D.; and DAVID L THOMSON, M.D.; Detroit, Michigan
We studied the bone status in 5 2 patients 1 to 14 years after intestinal shunt surgery. Before operation, bone mass measured by photon absorptiometry and radiographic morphometry was normal by two criteria and slightly reduced by a third. After jejunocolostomy both cross-sectional and longitudinal data showed accelerated loss of bone due to increased net endosteal resorption. Similar but less significant changes occurred after jejunoileostomy. The severity of bone loss correlated better with hypoproteinemia than with any other biochemical measurement. Bone biopsy after tetracycline labeling in 10 patients with bone pain showed osteomalacia in two and significant impairment of osteoblast function in seven. Plasma 25hydroxycholecalciferol levels were normal or low despite prescription of 1.25 mg of vitamin D2 daily. Plasma parathyroid hormone levels were raised in only three of the patients with abnormal bone histology. We conclude that intestinal shunt surgery has an adverse effect on the bones. There is persistent intestinal malabsorption of vitamin D and calcium, doses of which ordinarily given to these patients may be too small, but it is likely that other nutritional deficiencies are also important.
INTESTINAL BYPASS surgery has been done for the treat-
ment of intractable, morbid obesity since the early 1960s. Complications have included nephrolithiasis and nephrocalcinosis associated with hyperoxaluria (1, 2), polyarthritis and polyarthralgia resembling rheumatoid arthritis (3), fatty metamorphosis and decompensation of the liver (4), and electrolyte imbalance (4); the subject has been extensively reviewed (5, 6). Malabsorption and steatorrhea are inevitable results of intestinal bypass so that metabolic bone disease similar to that occurring in patients with other forms of steatorrhea would be expected. We observed 52 patients subsequent to bypass surgery. Despite supplements of calcium and vitamin D significant losses of bone have occurred, and nine patients have developed either frank osteomalacia or lesser degrees of osteoblastic dysfunction shown by bone biopsy after tetracycline labeling. • From the Fifth Medical Division and Bone and Mineral Research Laboratory, Henry Ford Hospital; Detroit, Michigan.
Materials and Methods
Forty-seven obese subjects who had undergone intestinal bypass surgery between 1963 and 1976 at the Henry Ford Hospital were studied. At present this operation is offered if patients are more than 45 kg over ideal weight, have been unable to lose weight by other means, are fully informed of potential complications, and are judged to be psychiatrically stable. These criteria were less stringently applied before 1970. From 1963 to 1966 and from 1968 to 1971 the operation performed was either a jejuno-transverse-colostomy or jejunocecostomy. There were 17 patients in this group with complete exclusion of the ileum, henceforth referred to as jejunocolostomy. In four, revision to a jejunoileostomy was carried out after 1 to 8 years. In 1967 and from 1972 to 1976 the standard operation was an end-to-end jejunoileostomy (leaving 0.4 m of proximal jejunum and 0.1 m of terminal ileum in continuity (7). Five patients operated on elsewhere were also studied. Three were referred specifically for assessment of metabolic bone disease and are analyzed separately. The other two were combined with the Henry Ford Hospital series to form two groups without complete exclusion of the ileum—early jejunoileostomy (seven patients) and recent jejunoileostomy (25 patients). Nutritional supplementation was begun in all patients after the early postoperative period. This consisted of calcium, 1 g/ day (usually as four oyster-shell calcium carbonate [Os-Cal®] tablets); magnesium, 0.75 g/day (usually as three magnesium oxide tablets); and vitamin D2, 1.25 mg (50 000 U)/day (usually as four Cornell Hi-D® drops). Potassium, folic acid, vitamin B12, iron, and other B complex vitamins were given in usual replacement doses. Standard biochemical and radiographic monitoring was done, and more recently, plasma levels of parathyroid hormone (8) and of 25-hydroxycholecalciferol (9) have been obtained. The latter method was modified by substitution of Sephadex LH-20® (Pharmacia Fine Chemicals, Piscataway, New Jersey) for silicic acid in the chromatography step (10); the normal range is 8 to 40 ng/ml (mean, 21.8) in whites and 7 to 22 ng /ml (mean, 11.7) in blacks. Beginning in 1973 bone mineral content was measured where possible by photon absorptiometry (11,12) using the Norland-Cameron Bone Mineral Analyzer® with an l25 I source (Norland Instruments, Fort Atkinson, Wisconsin). The mean was taken of four scans, each at two sites: one third of the distance from the radial styloid to the olecranon process (proximal) and 1.5 cm above the ulnar styloid (distal). The proximal site consists almost entirely of cortical bone, whereas the distal site contains a higher proportion of trabecular bone (13); results were expressed as the ratio of bone mineral content to bone width in grams per square centimeter. Each observed value for bone mineral content/bone width was compared with the value expected for age, sex, and race (11-13), and the difference was divided by the standard deviation to obtain a z score (12, 14), the + 2 to — 2 z score range including approximately 95% of the normal values. With each bone mineral measurement a radiograph of the hands was taken on industrial film.
Annals of Internal Medicine 89:193-199, 1978
Downloaded From: http://annals.org/ by a University of Manitoba User on 06/12/2015
©1978 American College of Physicians
193
Table 1. Incidence of Some Complications of Jejunocolostomy or Jejunoileostomy
Jejunocolostomy
Jejunoileostomy
17 134
30 47
3
5
Nephrolithiasis
6
8
Nephrocalcinosis
2
0
Joint pain
2
7
Bone pain
12
7
Patients at risk, no. Mean duration, months* Complications, no. Tetany
P
— Not significant Not significant Not significant Not significant < 0.0005
the interface between osteoid tissue and bone averaged over the entire osteoid seam surface (18). Normal values for iliac cortex are still uncertain, but iliac and rib cortices agree closely enough (19) to use rib normal values (18) for both sites. For iliac trabecular bone, normal values of Schenk, Olah, and Merz (20) were used. Results
The mean maximum weight loss was significantly greater after jejunocolostomy (54.9 kg) than after jejunoileostomy (43.5 kg). The incidence of some complications after the two types of operation is shown in Table 1. Only bone pain was significantly more common after complete ileal exclusion ( X 2 = 13.39, P< 0.0005). Liver biopsy was not carried out systematically. LABORATORY S T U D I E S
* Until March 1977.
Measurements were made by Helios calipers of the outer diameter (D), inner diameter (d), and length (L) of the second metacarpal of the nondominant hand. From these values were calculated cortical thickness from the formula D—d, and the ratio of cortical areas to total area from the formula D 2 —d 2 /D 2 (15). These were compared with normal values for age, sex, and race in 10 midwestern states (16). Patients whose postoperative proximal bone mineral content/ bone width z score was less than —2 were advised to have a bone biopsy. Seven patients consented to this procedure, which was done 3 to 5 days after completion of two tetracycline bone labels given for periods of 4 and 6 days, separated by a 10-day interval. Bone biopsy was also done in the three patients referred with suspected metabolic bone disease. An eleventh rib biopsy was done in two cases, a transileal biopsy in seven cases, and both procedures in one case. The specimens were placed in 70% ethanol. Sections of rib containing cortical bone only were prepared by abrasion without embedding (17). Sections of ileum containing both cortical and trabecular bone were cut with a Jung microtome after embedding in polymethacrylate (17). Histomorphometric measurements and analysis of data were done as previously described (17, 18). The mineral appositional rate (the width of new bone mineralized per day) was estimated by dividing the mean distance between fluorescent hands by 15, the number of days between the midpoints of the labels. This quantity multiplied by the proportion of the osteoid seam surface showing a tetracycline label gives the corrected mineral appositional rate, or radial closure rate, which is the rate of advance of
There was no significant difference between the two operations, so the three groups were combined for this purpose. Before operation mean values for serum bilirubin, serum glutamic-oxalacetic transaminase (SGOT), sulfobromophthalein (Bromsulphalein®, BSP) retention, total protein, serum calcium, serum magnesium, serum inorganic phosphate, serum carotene, and D-xylose excretion were within normal limits (Table 2). During the immediate postoperative period (0 to 6 months) there were significant falls in serum calcium, serum magnesium, serum carotene, and total serum protein levels and significant increases in alkaline phosphatase, SGOT, and BSP retention values. The serum inorganic phosphate value did not change. Several individuals had a substantial increase in serum bilirubin, but the mean value did not change significantly. The abnormalities in the values of serum calcium, magnesium, total protein, and alkaline phosphatase persisted unchanged in the early postoperative period (6 months to 5 years) and late postoperative period (beyond 5 years). Although the alkaline phosphatase value remained elevated, the SGOT value and BSP retention returned to normal, and the bilirubin value remained unchanged. The serum carotene value continued to fall
Table 2. Mean Values for Laboratory Data Before and at Various Times After Operation
Laboratory Test*
Normal
Patient Valuest Preoperative
Bilirubin, mg/dl SGOT, W/litre BSP, %/45min Calcium, mg/dl Phosphate, mg/dl Total protein, g/dl Magnesium, meq/litre Alkaline phosphatase, W/litre Carotene, ng/dl D-xylose, g/5 h Fecal fat, g/72 h
0.2 to 1.0 5 to 21 0 to 4 8.7 to 10.7 2.5 to 4.0 6.8 to 8.5 1.5 to 1.9 1.8 to 62 70 to 200 >5.0
We studied the bone status in 5 2 patients 1 to 14 years after intestinal shunt surgery. Before operation, bone mass measured by photon absorptiometry and radiographic morphometry was normal by two criteria and slightly reduced by a third. After jejunocolostomy both cross-sectional and longitudinal data showed accelerated loss of bone due to increased net endosteal resorption. Similar but less significant changes occurred after jejunoileostomy. The severity of bone loss correlated better with hypoproteinemia than with any other biochemical measurement. Bone biopsy after tetracycline labeling in 10 patients with bone pain showed osteomalacia in two and significant impairment of osteoblast function in seven. Plasma 25hydroxycholecalciferol levels were normal or low despite prescription of 1.25 mg of vitamin D2 daily. Plasma parathyroid hormone levels were raised in only three of the patients with abnormal bone histology. We conclude that intestinal shunt surgery has an adverse effect on the bones. There is persistent intestinal malabsorption of vitamin D and calcium, doses of which ordinarily given to these patients may be too small, but it is likely that other nutritional deficiencies are also important.
INTESTINAL BYPASS surgery has been done for the treat-
ment of intractable, morbid obesity since the early 1960s. Complications have included nephrolithiasis and nephrocalcinosis associated with hyperoxaluria (1, 2), polyarthritis and polyarthralgia resembling rheumatoid arthritis (3), fatty metamorphosis and decompensation of the liver (4), and electrolyte imbalance (4); the subject has been extensively reviewed (5, 6). Malabsorption and steatorrhea are inevitable results of intestinal bypass so that metabolic bone disease similar to that occurring in patients with other forms of steatorrhea would be expected. We observed 52 patients subsequent to bypass surgery. Despite supplements of calcium and vitamin D significant losses of bone have occurred, and nine patients have developed either frank osteomalacia or lesser degrees of osteoblastic dysfunction shown by bone biopsy after tetracycline labeling. • From the Fifth Medical Division and Bone and Mineral Research Laboratory, Henry Ford Hospital; Detroit, Michigan.
Materials and Methods
Forty-seven obese subjects who had undergone intestinal bypass surgery between 1963 and 1976 at the Henry Ford Hospital were studied. At present this operation is offered if patients are more than 45 kg over ideal weight, have been unable to lose weight by other means, are fully informed of potential complications, and are judged to be psychiatrically stable. These criteria were less stringently applied before 1970. From 1963 to 1966 and from 1968 to 1971 the operation performed was either a jejuno-transverse-colostomy or jejunocecostomy. There were 17 patients in this group with complete exclusion of the ileum, henceforth referred to as jejunocolostomy. In four, revision to a jejunoileostomy was carried out after 1 to 8 years. In 1967 and from 1972 to 1976 the standard operation was an end-to-end jejunoileostomy (leaving 0.4 m of proximal jejunum and 0.1 m of terminal ileum in continuity (7). Five patients operated on elsewhere were also studied. Three were referred specifically for assessment of metabolic bone disease and are analyzed separately. The other two were combined with the Henry Ford Hospital series to form two groups without complete exclusion of the ileum—early jejunoileostomy (seven patients) and recent jejunoileostomy (25 patients). Nutritional supplementation was begun in all patients after the early postoperative period. This consisted of calcium, 1 g/ day (usually as four oyster-shell calcium carbonate [Os-Cal®] tablets); magnesium, 0.75 g/day (usually as three magnesium oxide tablets); and vitamin D2, 1.25 mg (50 000 U)/day (usually as four Cornell Hi-D® drops). Potassium, folic acid, vitamin B12, iron, and other B complex vitamins were given in usual replacement doses. Standard biochemical and radiographic monitoring was done, and more recently, plasma levels of parathyroid hormone (8) and of 25-hydroxycholecalciferol (9) have been obtained. The latter method was modified by substitution of Sephadex LH-20® (Pharmacia Fine Chemicals, Piscataway, New Jersey) for silicic acid in the chromatography step (10); the normal range is 8 to 40 ng/ml (mean, 21.8) in whites and 7 to 22 ng /ml (mean, 11.7) in blacks. Beginning in 1973 bone mineral content was measured where possible by photon absorptiometry (11,12) using the Norland-Cameron Bone Mineral Analyzer® with an l25 I source (Norland Instruments, Fort Atkinson, Wisconsin). The mean was taken of four scans, each at two sites: one third of the distance from the radial styloid to the olecranon process (proximal) and 1.5 cm above the ulnar styloid (distal). The proximal site consists almost entirely of cortical bone, whereas the distal site contains a higher proportion of trabecular bone (13); results were expressed as the ratio of bone mineral content to bone width in grams per square centimeter. Each observed value for bone mineral content/bone width was compared with the value expected for age, sex, and race (11-13), and the difference was divided by the standard deviation to obtain a z score (12, 14), the + 2 to — 2 z score range including approximately 95% of the normal values. With each bone mineral measurement a radiograph of the hands was taken on industrial film.
Annals of Internal Medicine 89:193-199, 1978
Downloaded From: http://annals.org/ by a University of Manitoba User on 06/12/2015
©1978 American College of Physicians
193
Table 1. Incidence of Some Complications of Jejunocolostomy or Jejunoileostomy
Jejunocolostomy
Jejunoileostomy
17 134
30 47
3
5
Nephrolithiasis
6
8
Nephrocalcinosis
2
0
Joint pain
2
7
Bone pain
12
7
Patients at risk, no. Mean duration, months* Complications, no. Tetany
P
— Not significant Not significant Not significant Not significant < 0.0005
the interface between osteoid tissue and bone averaged over the entire osteoid seam surface (18). Normal values for iliac cortex are still uncertain, but iliac and rib cortices agree closely enough (19) to use rib normal values (18) for both sites. For iliac trabecular bone, normal values of Schenk, Olah, and Merz (20) were used. Results
The mean maximum weight loss was significantly greater after jejunocolostomy (54.9 kg) than after jejunoileostomy (43.5 kg). The incidence of some complications after the two types of operation is shown in Table 1. Only bone pain was significantly more common after complete ileal exclusion ( X 2 = 13.39, P< 0.0005). Liver biopsy was not carried out systematically. LABORATORY S T U D I E S
* Until March 1977.
Measurements were made by Helios calipers of the outer diameter (D), inner diameter (d), and length (L) of the second metacarpal of the nondominant hand. From these values were calculated cortical thickness from the formula D—d, and the ratio of cortical areas to total area from the formula D 2 —d 2 /D 2 (15). These were compared with normal values for age, sex, and race in 10 midwestern states (16). Patients whose postoperative proximal bone mineral content/ bone width z score was less than —2 were advised to have a bone biopsy. Seven patients consented to this procedure, which was done 3 to 5 days after completion of two tetracycline bone labels given for periods of 4 and 6 days, separated by a 10-day interval. Bone biopsy was also done in the three patients referred with suspected metabolic bone disease. An eleventh rib biopsy was done in two cases, a transileal biopsy in seven cases, and both procedures in one case. The specimens were placed in 70% ethanol. Sections of rib containing cortical bone only were prepared by abrasion without embedding (17). Sections of ileum containing both cortical and trabecular bone were cut with a Jung microtome after embedding in polymethacrylate (17). Histomorphometric measurements and analysis of data were done as previously described (17, 18). The mineral appositional rate (the width of new bone mineralized per day) was estimated by dividing the mean distance between fluorescent hands by 15, the number of days between the midpoints of the labels. This quantity multiplied by the proportion of the osteoid seam surface showing a tetracycline label gives the corrected mineral appositional rate, or radial closure rate, which is the rate of advance of
There was no significant difference between the two operations, so the three groups were combined for this purpose. Before operation mean values for serum bilirubin, serum glutamic-oxalacetic transaminase (SGOT), sulfobromophthalein (Bromsulphalein®, BSP) retention, total protein, serum calcium, serum magnesium, serum inorganic phosphate, serum carotene, and D-xylose excretion were within normal limits (Table 2). During the immediate postoperative period (0 to 6 months) there were significant falls in serum calcium, serum magnesium, serum carotene, and total serum protein levels and significant increases in alkaline phosphatase, SGOT, and BSP retention values. The serum inorganic phosphate value did not change. Several individuals had a substantial increase in serum bilirubin, but the mean value did not change significantly. The abnormalities in the values of serum calcium, magnesium, total protein, and alkaline phosphatase persisted unchanged in the early postoperative period (6 months to 5 years) and late postoperative period (beyond 5 years). Although the alkaline phosphatase value remained elevated, the SGOT value and BSP retention returned to normal, and the bilirubin value remained unchanged. The serum carotene value continued to fall
Table 2. Mean Values for Laboratory Data Before and at Various Times After Operation
Laboratory Test*
Normal
Patient Valuest Preoperative
Bilirubin, mg/dl SGOT, W/litre BSP, %/45min Calcium, mg/dl Phosphate, mg/dl Total protein, g/dl Magnesium, meq/litre Alkaline phosphatase, W/litre Carotene, ng/dl D-xylose, g/5 h Fecal fat, g/72 h
0.2 to 1.0 5 to 21 0 to 4 8.7 to 10.7 2.5 to 4.0 6.8 to 8.5 1.5 to 1.9 1.8 to 62 70 to 200 >5.0
