Saturday 1 July 1978 BONE DISEASE AFTER JEJUNO-ILEAL BYPASS FOR OBESITY
JULIET E. COMPSTON M. F. LAKER J. S. WOODHEAD J.-C. GAZET
L. W. L. HORTON A. B. AYERS H. J. BULL T. R. E. PILKINGTON
Gastrointestinal Research Unit, Department of Surgical
Pathology, Department of Radiology, and Department of Chemical Pathology and Metabolic Disorders, St. Thomas’ Hospital, London SE1; St. George’s Hospital, London SW17; and Department of Medical Biochemistry, Welsh National School of Medicine, Cardiff
Bone tissue was examined in 21 patients who had undergone jejuno-ileal bypass for obesity between 1971 and 1974. 10 patients had osteomalacia with evidence of secondary hyperparathyroidism. Clinical symptoms and biochemical and radiological investigations were often unreliable in diagnosing bone disease, although plasma-25-hydroxyvitamin-D and plasma-phosphate concentrations were significantly lower and plasma-parathyroid-hormone concentrationswere significantly higher in the patients with bone disease. The presence of osteomalacia was unrelated to age, length of time since bypass, or post-bypass weight-loss, and plasma-25-hydroxyvitamin-D levels did not correlate closely with bone histological changes. It is concluded that osteomalacia is common after jejuno-ileal bypass and that factors other than simple vitamin-D deficiency may contribute to its development.
Summary
Introduction
SURGICAL treatment of gross obesity by small-intestinal bypass has been widely practised in the U.S.A.,’ and two series have been reported from Great Britain.2.3 Most patients achieve satisfactory weight-loss, largely as a result of reduced food intake,4 but many late complications of intestinal bypass have been described. Hypocalcaemia5.6 and hypomagnesaemia7 are both well recognised, and in one study low levels of plasma-25-hydroxyvitamin-D (25-[OH]D), the major circulating metabolite of vitamin D, were found in many patients during the first 1-2 years after bypass.8 However, although bone biopsy is the most sensitive method of diagnosing osteomalacia,9 there have been no studies of bone histology in an unselected group of patients, and the incidence of osteomalacia occurring after bypass is unknown. BX’e have studied the prevalence of histological osteomalacia in 21 patients 3-6 year" after jejuno-ileal bypass, and we have examined the relationship between bone-histology findings and clinical, biochemical, and radiological findings in these patients.
Patients and Methods Patients Patients with the
longest follow-up since bypass were by those operated on over successive years. Of 30 patients operated on between 1971 and 1974 who were asked to take part in the study, 21 accepted (3 men and 18 women, aged 25-59 years [mean 43.6]). End-toside anastomosis was performed in all cases: the length of jejunum and ileum left in continuity were 4 in and 10 in respectively in 15 patients, and 14 in and 4 in, 2 in and 14 in, approached initially,
followed
5 in and 9 in, 8 in and 6 in, 10 in and 4 in, and 6 in and 10 in in each of the remaining six patients. The mean weight-loss after operation was 43-8 kg (range 16-83 kg). 2 patients (7 and 8) were taking three ’Multivite’ tablets daily (containing 250 units of vitamin Dz per tablet). Patient 18, an epileptic, was taking sulthiame (’Ospolot’) 200 mg twice daily, and 2 other patients (8 and 10) regularly consumed large amounts of alcohol. All patients had normal renal function, as judged by the plasma-creatinine. The study was carried out between October, 1977, and March, 1978.
Biochemistry Blood and urine for all measurements apart from 24 h urinary calcium excretion were taken from fasting patients. Plasma-levels of calcium, phosphate, alkaline phosphatase, albumin, bilirubin, and aspartate aminotransferase were measured on a Vickers M.300 analyser. Plasma-calcium was corrected for the plasma-albumin.10 Serum-magnesium was measured by atomic-absorption spectroscopy. Liver and bone isoenzymes of alkaline phosphatase were measured after heat inactivation at 560C by the p-nitrophenyl-phosphate method." Plasma-25-(OH)D concentrations were measured by a competitive-protein-binding assay,12 in which normal human serum was used as binding protein. Plasma-parathyroid-hormone (P.T.H.) was measured by an immunoradiometric assay’3 using an antiserum provided by the Medical Research Council
(code BW 211/41). Serum and urinary creatinine were measured by the alkaline-picrate method on a mark-1 ’AutoAnalyzer’. Urinary phosphate was measured with acid molybdate and aminonaphtholsulphonic acid as reducing agent on a mark-1 autoanalyser. The maximum tubular reabsorption capacity for phosphate relative to glomerular-filtration rate (TmpojG.F.R.) was
calculated from the phosphate/creatinine clearance ratio. 14 Urinary calcium was measured in 24 h collections with a Corning calcium analyser 940 (E.G.T.A. titration).
Radiology All patients had standard metabolic bone surveys consisting of films of the lateral skull, lateral dorsal and lumbar spine, pelvis, tibia, forearm, chest, and hands. These were qualitatively assessed by one observer who did not know the results of bone histology.
Bone
Histology
8 tim undecalcified sections of full-thickness iliac-crest 8079 ©
2 TABLE
I---QUANTITATIVE BONE HISTOLOGY JEJUNO-ILEAL BYPASS*
IN PATIENTS WITH
(49.7 kg versus 38.4 kg) this difference was not statistically significant. The presence of osteomalacia was unrelated to age (mean 46 years in patients with bone disease and 41 years in those without), length of time since bypass (mean 60 mo versus 62 mo), stool frequency (3-2/24 h versus 2-7/24 h), or estimated sunlight without
exposure, which was within normal limits in all the patients studied. Bone pain was present in 6 patients with bone disease and 5 without.
Radiology No patient had pseudofractures or pathological fractures. A definite radiological diagnosis of osteomalacia, based on loss of corticomedullary differentiation and alteration of the trabecular pattern was made in patients 1 and 4; in both cases there was also subperiosteal resorption suggesting secondary hyperparathyroidism.
*The 10 patients with bone disease are shown in order of decreasing severity, as judged by osteoid volume. were stained with the von Kossa technique and thionin or 1% toluidine-blue, and were quantitated with a Zeiss 25-point eye-piece graticule. Quantitation of the calcification fronts was performed using sections stained with thionin or 1% toluidine-blue. These sections were qualitatively compared with fluorescence-microscopy examination of 10 pjn unstained sections after oral administration of 900 mg of demethylchlortetracycline 48 h before the biopsy. Histological osteomalacia was diagnosed when an increased volume and surface area of osteoid were associated with reduced calcification fronts; hyperparathyroidism was qualitively assessed from the amount of inactive and active bone resorption. Control values for osteoid volume and surface area were obtained at necropsy from 7 women and 19 men aged 29-75 years (mean 53) who had died suddenly with no history of immobilisation or metabolic bone disease.
biopsy specimens"
Results Bone Histology (Table I) 10 patients (2 men, 8 women) had osteomalacia with evidence of secondary hyperparathyroidism. Osteomalacia was severe in patients 1-5, and secondary hyperparathyroidism was most striking in patients 3, 4, 5, and 7. Calcification fronts demonstrated by metachromatic staining generally correlated well with tetracycline fluorescence on unstained sections, although in patient 8 more calcification fronts were seen in sections stained with toluidine-blue (45.6%) than in tetracycline-fluorescent sections (18%). Although patients with osteomalacia had lost more weight postoperatively than those
Possible osteomalacia was diagnosed radiologically in 2 patients (2 and 3), and osteopenia, a generalised nonspecific bone demineralisation was seen in 4 (6, 11, 12, and 18). 5 patients with histological osteomalacia had
radiological abnormality.
no
Biochemistry (Table II) Plasma-calcium.-The
plasma-calcium,
corrected for
2-22 ±0-13 mmol/1 plasma-albumin concentration, (meanis.D.) in osteomalacic patients and 2-29 ±0-08 mmol/1 in the non-osteomalacic group. 6 patients with osteomalacia and 4 without were hypocalcsemic. Plasma-phosphate.- The mean plasma-phosphate concentration was significantly lower in patients with osteomalacia (0-83±0-14 mmol/1) than in those without (106±017 mmol/1) (P
JULIET E. COMPSTON M. F. LAKER J. S. WOODHEAD J.-C. GAZET
L. W. L. HORTON A. B. AYERS H. J. BULL T. R. E. PILKINGTON
Gastrointestinal Research Unit, Department of Surgical
Pathology, Department of Radiology, and Department of Chemical Pathology and Metabolic Disorders, St. Thomas’ Hospital, London SE1; St. George’s Hospital, London SW17; and Department of Medical Biochemistry, Welsh National School of Medicine, Cardiff
Bone tissue was examined in 21 patients who had undergone jejuno-ileal bypass for obesity between 1971 and 1974. 10 patients had osteomalacia with evidence of secondary hyperparathyroidism. Clinical symptoms and biochemical and radiological investigations were often unreliable in diagnosing bone disease, although plasma-25-hydroxyvitamin-D and plasma-phosphate concentrations were significantly lower and plasma-parathyroid-hormone concentrationswere significantly higher in the patients with bone disease. The presence of osteomalacia was unrelated to age, length of time since bypass, or post-bypass weight-loss, and plasma-25-hydroxyvitamin-D levels did not correlate closely with bone histological changes. It is concluded that osteomalacia is common after jejuno-ileal bypass and that factors other than simple vitamin-D deficiency may contribute to its development.
Summary
Introduction
SURGICAL treatment of gross obesity by small-intestinal bypass has been widely practised in the U.S.A.,’ and two series have been reported from Great Britain.2.3 Most patients achieve satisfactory weight-loss, largely as a result of reduced food intake,4 but many late complications of intestinal bypass have been described. Hypocalcaemia5.6 and hypomagnesaemia7 are both well recognised, and in one study low levels of plasma-25-hydroxyvitamin-D (25-[OH]D), the major circulating metabolite of vitamin D, were found in many patients during the first 1-2 years after bypass.8 However, although bone biopsy is the most sensitive method of diagnosing osteomalacia,9 there have been no studies of bone histology in an unselected group of patients, and the incidence of osteomalacia occurring after bypass is unknown. BX’e have studied the prevalence of histological osteomalacia in 21 patients 3-6 year" after jejuno-ileal bypass, and we have examined the relationship between bone-histology findings and clinical, biochemical, and radiological findings in these patients.
Patients and Methods Patients Patients with the
longest follow-up since bypass were by those operated on over successive years. Of 30 patients operated on between 1971 and 1974 who were asked to take part in the study, 21 accepted (3 men and 18 women, aged 25-59 years [mean 43.6]). End-toside anastomosis was performed in all cases: the length of jejunum and ileum left in continuity were 4 in and 10 in respectively in 15 patients, and 14 in and 4 in, 2 in and 14 in, approached initially,
followed
5 in and 9 in, 8 in and 6 in, 10 in and 4 in, and 6 in and 10 in in each of the remaining six patients. The mean weight-loss after operation was 43-8 kg (range 16-83 kg). 2 patients (7 and 8) were taking three ’Multivite’ tablets daily (containing 250 units of vitamin Dz per tablet). Patient 18, an epileptic, was taking sulthiame (’Ospolot’) 200 mg twice daily, and 2 other patients (8 and 10) regularly consumed large amounts of alcohol. All patients had normal renal function, as judged by the plasma-creatinine. The study was carried out between October, 1977, and March, 1978.
Biochemistry Blood and urine for all measurements apart from 24 h urinary calcium excretion were taken from fasting patients. Plasma-levels of calcium, phosphate, alkaline phosphatase, albumin, bilirubin, and aspartate aminotransferase were measured on a Vickers M.300 analyser. Plasma-calcium was corrected for the plasma-albumin.10 Serum-magnesium was measured by atomic-absorption spectroscopy. Liver and bone isoenzymes of alkaline phosphatase were measured after heat inactivation at 560C by the p-nitrophenyl-phosphate method." Plasma-25-(OH)D concentrations were measured by a competitive-protein-binding assay,12 in which normal human serum was used as binding protein. Plasma-parathyroid-hormone (P.T.H.) was measured by an immunoradiometric assay’3 using an antiserum provided by the Medical Research Council
(code BW 211/41). Serum and urinary creatinine were measured by the alkaline-picrate method on a mark-1 ’AutoAnalyzer’. Urinary phosphate was measured with acid molybdate and aminonaphtholsulphonic acid as reducing agent on a mark-1 autoanalyser. The maximum tubular reabsorption capacity for phosphate relative to glomerular-filtration rate (TmpojG.F.R.) was
calculated from the phosphate/creatinine clearance ratio. 14 Urinary calcium was measured in 24 h collections with a Corning calcium analyser 940 (E.G.T.A. titration).
Radiology All patients had standard metabolic bone surveys consisting of films of the lateral skull, lateral dorsal and lumbar spine, pelvis, tibia, forearm, chest, and hands. These were qualitatively assessed by one observer who did not know the results of bone histology.
Bone
Histology
8 tim undecalcified sections of full-thickness iliac-crest 8079 ©
2 TABLE
I---QUANTITATIVE BONE HISTOLOGY JEJUNO-ILEAL BYPASS*
IN PATIENTS WITH
(49.7 kg versus 38.4 kg) this difference was not statistically significant. The presence of osteomalacia was unrelated to age (mean 46 years in patients with bone disease and 41 years in those without), length of time since bypass (mean 60 mo versus 62 mo), stool frequency (3-2/24 h versus 2-7/24 h), or estimated sunlight without
exposure, which was within normal limits in all the patients studied. Bone pain was present in 6 patients with bone disease and 5 without.
Radiology No patient had pseudofractures or pathological fractures. A definite radiological diagnosis of osteomalacia, based on loss of corticomedullary differentiation and alteration of the trabecular pattern was made in patients 1 and 4; in both cases there was also subperiosteal resorption suggesting secondary hyperparathyroidism.
*The 10 patients with bone disease are shown in order of decreasing severity, as judged by osteoid volume. were stained with the von Kossa technique and thionin or 1% toluidine-blue, and were quantitated with a Zeiss 25-point eye-piece graticule. Quantitation of the calcification fronts was performed using sections stained with thionin or 1% toluidine-blue. These sections were qualitatively compared with fluorescence-microscopy examination of 10 pjn unstained sections after oral administration of 900 mg of demethylchlortetracycline 48 h before the biopsy. Histological osteomalacia was diagnosed when an increased volume and surface area of osteoid were associated with reduced calcification fronts; hyperparathyroidism was qualitively assessed from the amount of inactive and active bone resorption. Control values for osteoid volume and surface area were obtained at necropsy from 7 women and 19 men aged 29-75 years (mean 53) who had died suddenly with no history of immobilisation or metabolic bone disease.
biopsy specimens"
Results Bone Histology (Table I) 10 patients (2 men, 8 women) had osteomalacia with evidence of secondary hyperparathyroidism. Osteomalacia was severe in patients 1-5, and secondary hyperparathyroidism was most striking in patients 3, 4, 5, and 7. Calcification fronts demonstrated by metachromatic staining generally correlated well with tetracycline fluorescence on unstained sections, although in patient 8 more calcification fronts were seen in sections stained with toluidine-blue (45.6%) than in tetracycline-fluorescent sections (18%). Although patients with osteomalacia had lost more weight postoperatively than those
Possible osteomalacia was diagnosed radiologically in 2 patients (2 and 3), and osteopenia, a generalised nonspecific bone demineralisation was seen in 4 (6, 11, 12, and 18). 5 patients with histological osteomalacia had
radiological abnormality.
no
Biochemistry (Table II) Plasma-calcium.-The
plasma-calcium,
corrected for
2-22 ±0-13 mmol/1 plasma-albumin concentration, (meanis.D.) in osteomalacic patients and 2-29 ±0-08 mmol/1 in the non-osteomalacic group. 6 patients with osteomalacia and 4 without were hypocalcsemic. Plasma-phosphate.- The mean plasma-phosphate concentration was significantly lower in patients with osteomalacia (0-83±0-14 mmol/1) than in those without (106±017 mmol/1) (P
