Background By treating obesity, one of the major epidemics of this past century, through bariatric surgery, we may cause complications due to malnourishment in a growing population. At present, vitamin D deficiency is of interest, especially in patients with inferior absorption of fat-soluble nutrients after biliopancreatic diversion with duodenal switch (BPD/DS). Methods Twenty BPD/DS patients, approximately 4 years postoperatively, were randomized to either intramuscular supplemen- tation of vitamin D with a single dose of 600,000 IU cholecalciferol, or a control group. Patients were instructed to limit their supplementation to 1400 IU of vitamin D and to avoid the influence of UV-B radiation; the study was conducted when sunlight is limited (December to May). Results Despite oral supplementation, a pronounced deficiency in vitamin D was seen (injection 19.3; control 23.2 nmol/l) in both groups. The cholecalciferol injection resulted in elevated 25[OH]D levels at 1 month (65.4 nmol/l), which was maintained at 6 months (67.4 nmol/l). This resulted in normalization of intact parathyroid hormone (PTH) levels. No changes in vitamin D or PTH occurred in the control group. Conclusions In BPD/DS patients, having hypovitaminosis D despite full oral supplementation, a single injection of 600,000 IU of cholecalciferol was effective in elevating vitamin D levels and normalizing levels of intact PTH. The treatment is simple and highly effective and thus recommended, especially in cases of reduced UV-B radiation. . . . Keywords Hypovitaminosis D Cholecalciferol Biliopancreatic diversion Duodenal switch Background common limb). However, in addition to massive weight loss, the procedure is associated with a significantly higher preva- The global trends of obesity predict that the number of patients lence of nutrient deficiencies, including but not limited to treated with bariatric surgery will continue to grow, and pos- vitamin D [3, 4]. Despite recommended multivitamin supple- sibly begin to include patients as young as teenagers [1, 2]. Of mentation, including 2000 IU vitamin D3 daily, two thirds of the bariatric procedures performed in Sweden and elsewhere, BPD/DS patients were found to have vitamin D deficiency biliopancreatic diversion with duodenal switch (BPD/DS) re- . sults in the most significant weight loss, and is therefore often Normal physiological functioning is highly dependent up- reserved for patients with severe morbid obesity (BMI > on calcium, which relies upon a complex feedback system that 50 kg/m ). BPD/DS obtains weight loss through its dual regulates the levels in blood and extracellular fluids. The para- mechanisms of restriction and malabsorption. The restrictive thyroid gland releases parathyroid hormone (PTH) in response mechanism arises from the gastric sleeve, and the to a decrease in serum calcium concentration which in turn malabsorptive mechanism by leaving only 100 cm of the dis- signals for increased uptake of calcium in the intestine. This tal ileum for absorption of fat-soluble nutrients (the so-called uptake is strictly dependent upon an adequate level of vitamin D. Vitamin D is a fat-soluble prohormone, present in var- ious forms and not active until hydroxylation by 1-alpha-hy- * Magnus Sundbom droxylase. The inactive storage form of vitamin D is 25- firstname.lastname@example.org hydroxycholecalciferol (25[OH]D), which is widely accepted when measuring levels of vitamin D in the clinical setting . Department of Surgical Sciences, Uppsala University, Entrance 70, A deficiency in vitamin D is a causative agent of rickets, SE-751 85 Uppsala, Sweden OBES SURG secondary hyperparathyroidism, and osteoporosis. Other As demonstrated in Table 1, there were no differences be- health concerns associated with vitamin D deficiency include tween the injection group and controls concerning gender, neuropsychiatric disorders, cardiovascular disease, diabetes, age, pre- and post-operative BMI, or time after surgery. and cancer. Major comorbidities, including sleep apnea (n = 1), diabetes Hypovitaminosis D is often described in the obese popula- mellitus (n = 0), hypertension (n = 0), dyslipidemia (n = 0), tion, where plausible causes include limited sun exposure, and depression (n = 2), were rare at the time of the study. poor nutrition, and sequestration of vitamin D in adipose tis- Vitamin D levels are subjected to considerable seasonal sue [7–9]. Massive weight loss through bariatric surgery has variation, where in northern Europe the lowest levels in a been shown to restore levels initially; however, post-operative geographically stationary population measure in April and hypovitaminosis D is equally commonly described in the long the highest in October . This study was conducted from term, despite various types of oral supplementation [10–13]. December to May when sunlight is limited in Sweden to avoid A previous study conducted by our group demonstrated that the influence of UV-B radiation, as it is a major source in the gastric bypass patients could be effectively treated for vitamin process of vitamin D synthesis. The injection group received a D deficiency with UV-B treatment three times a week . single dose of 600,000 IU cholecalciferol vitamin D3 Streuli® However, as the treatment was considered tiresome, compli- (Streuli Pharma AG, Uznach); the dosage was chosen accord- ance as well as vitamin D levels decreased during the course. ing to earlier studies [14, 17]. Patients in both groups were As BPD/DS patients often have more severe vitamin D defi- instructed to limit their total diet supplementation to 1400 IU ciencies, and the altered anatomy undermines oral vitamin D of vitamin D. Diet was not otherwise regulated in either group. absorption , alternative treatments, especially in patients with deficiencies in spite of full oral supplementation, is Laboratory Tests warranted. The aim of this study was to evaluate intramuscular admin- Both groups left blood samples at the start and at 1, 3, and istration of cholecalciferol in patients with hypovitaminosis D 6 months. Blood samples were analyzed for 25[OH]D, intact after BPD/DS, despite standardized oral supplementation with PTH, and serum calcium. Albumin and creatinine levels were 1400 IU cholecalciferol. analyzed at baseline only. The analysis of 25[OH]D was per- formed at Vitas Labs, Oslo, using a HPLC method (Agilent Technologies, Palo Alto, CA, USA). The remaining analyses Materials and Method were performed by the clinical chemistry laboratory at the University Hospital in Uppsala. Intact plasma PTH (normal Patients range 1.1–6.9 pmol/L) was measured with a chemilumines- cent solid-phase two-site immunoassay using an IMMULITE Seventy-three patients having undergone BPD/DS at Uppsala 2500 (Diagnostics Product Corporation, Los Angeles, USA). University Hospital between 2008 and 2010 were invited to Serum calcium was measured spectrophotometrically with a participate in the study by mail. By the order of acceptance, complexometric method using orthocresolphtalein (normal participants were randomly assigned 1:1 to either intramuscu- range 2.15–2.50 mmol/L). Serum albumin was determined lar supplementation of vitamin D or to a control group. Both by spectrophotometry using Bromine Bresol Breen (normal groups left blood samples at baseline, and at 1, 3, and range 37–48 g/L). Serum creatinine was measured by spectro- 6months. photometry using Jaffe’s reaction (normal range 60– Participants were excluded from the study if they had re- 106 μmol/L). cently or planned upcoming travels to sunny climates or were concomitantly using potentially interacting drugs, such as thi- Statistics azides, corticosteroids, phenytoin, cholestyramine, phenobar- bital, and/or cardiac glycosides. Patients treated for hypercal- Unless stated, values are presented as median and interquartile cemia, osteoporosis, primary hyperparathyroidism, and/or re- range (IQR). Significance was established using the Mann- nal failure were also excluded as well as pregnant and Whitney non-parametric U test. A p value < 0.05 was consid- breastfeeding patients. ered significant. A sample size calculation was based on the None of the patients had undergone bariatric surgery prior increase to 80 mmol/L (SD 18) in 25[OH]D, this in response to their BPD/DS procedure. Our BPD/DS procedure entails a to an identical dose of intramuscular cholecalciferol as used in linear stapled gastric sleeve resection and the creation of a the study by Einarsdóttir  and the assumption that the 250-cm alimentary limb, of which the last 100 cm constitutes present BPD/DS patients had a baseline value no greater than the common limb (distal ileum). The duodeno-ileal anastomo- 50 (as found in our previous work in gastric bypass patients sis is hand sewn end-to-side, using the total width of the du- . In order to demonstrate an increase from 50 to 80 with an odenal bulb . SD of 18 and a power index of 95% at p < 0.05, the required OBES SURG Table 1 Demographics of the patient population at time of entry into the study, i.e., baseline. Data is presented as a percentage of the total and median values (interquartile range) Injection group (n = 11) Control group (n =9) p value % female 61.5% 72.7% 0.88 Age (years) 42.0 (7.0) 38.0 (8.0) 0.71 Years postop 4.2 (1.7) 4.9 (1.8) 0.15 Preop BMI (kg/m ) 54.5 (4.6) 54.9 (2.4) 0.60 BMI at study (kg/m ) 33.1 (5.2) 35.0 (8.6) 0.66 Albumin (g/L) 36.0 (5.5) 37.0 (3.0) 0.88 Creatinine (μmol/L) 58.0 (13.5) 56.0 (12.0) 0.82 The p value is calculated using the Mann-Whitney non-parametric U test sample size was nine patients in each group. The study was Both groups maintained a normal serum calcium level; approved by the local ethics committee at the University of however, the elevated PTH levels suggest that compensation Uppsala (Reference 2012/201) and the Medical Products through PTH-mediated mechanisms had been necessary. All Agency, responsible for surveillance of the development, patients in the treatment group obtained normalized PTH manufacturing, and marketing of drugs nationally (EudraCT levels up to 6 months post-injection. The changes in 2012-002217-19). 25[OH]D and PTH levels for all patients in the two groups are demonstrated in Fig. 1. No complications, e.g., hypercalcemia with severe thirst and polyuria, or impaired renal function due to vitamin D Results intoxication occurred. Despite oral supplementation post-surgery, both groups had 25[OH]D levels below 50 nmol/l (injection 19.3; control Discussion 23.2 nmol/l) after more than 4 years postoperatively. As dem- onstrated in Table 2 the cholecalciferol injection resulted in A single injection of 600,000 IU of cholecalciferol was effec- elevated 25[OH]D levels at 1 month (65.4 vs. 29.2 nmol/l in tive in restoring and maintaining normal levels of vitamin D controls, p < 0.01) and maintained at that level until the con- and PTH for 6 months in BPD/DS patients with clusion of the study, 6 months post-administration (67.4 vs. hypovitaminosis D, despite full oral supplementation. No 29.2 nmol/l, p =0.04). complications occurred during the study period. This simple Table 2 Effect of a single cholecalciferol injection on 25[OH] vitamin D, PTH, and calcium from baseline to 6 months Baseline (n = 11 and 9, resp.) 1 month (n = 11/8) 3 months (n = 7/6) 6 months (n =9/5) 25[OH]D (nmol/l) Injection group 19.3(9.3) 65.4 (6.3) 66.6 (11.0) 67.4 (16.1) Controls 23.2 (22.5) 29.2 (13.4) 24.0 (23.0) 29.2 (31.4) p value 0.30 < 0.01 0.03 0.04 Intact PTH (pmol/l) Injection group 12.3 (9.9) 6.4 (2.1) 7.3 (4.0) 9.6 (6.2) Controls 9.5 (6.8) 8.5 (4.3) 8.4 (2.4) 9.1 (1.8) p value 0.20 0.15 0.23 0.90 Calcium (mmol/l) Injection group 2.2(0.14) 2.18 (0.13) 2.22 (0.13) 2.19 (0.06) Controls 2.2 (0.10) 2.20 (0.20) 2.20 (0.20) 2.20 (0.10) p value 0.33 0.40 0.84 1.0 Data is presented as median value (interquartile range) and was compared to the Mann-Whitney non-parametric U test OBES SURG of 25[OH]D below 75 nmol/l is associated with muscle weakness, increased risk of fall, and type 2 diabetes mellitus, and levels below 25 nmol/l is further associated with diabetes mellitus type 1, cardiovascular disease, neo- plasms, fibromyalgia, chronic fatigue, neuropsychiatric disorders, and secondary hyperparathyroidism followed by osteoporosis [19–21]. Bone Health Few retrospective studies have been published concerning incidence of fractures and prevalence of osteoporosis among bariatric patients; however, of these few, a study conducted in Quebec, Canada, of 12,676 postoperative bariatric patients versus obese and non-obese patients showed that bariatric patients have a significantly increased relative risk of fracture. The biliopancreatic diversion procedure was associated with the most significant relative risk of fracture when compared to other bariatric procedures . A study conducted in Minnesota analyzed retrospectively 258 post-bariatric surgery patients for incidence of fracture and found a twofold in- creased risk of fracture of the hip/spine/wrist, where most fractures occurred at least 5 years postoperatively . BPD/DS Fig. 1 The changes in 25[OH]D and PTH levels for all patients in the two The BPD/DS surgery is an effective weight loss procedure groups because of its two working mechanisms: reduced intake and reduced absorption of ingested nutrients. The uptake of fat- soluble substances can only occur in the most distal 100 cm of and effective treatment is therefore a recommended substitute the distal ileum (common limb), after mixing with bile, mak- to oral vitamin D supplements, especially in patients receiving ing BPD/DS the most malabsorptive bariatric procedure . limited UV radiation. Moreover, the bypass of the duodenum, which has the highest density of vitamin D receptors, results in reduced effect of oral Vitamin D vitamin D supplements . A study of 43 BPD/DS patients demonstrated deficiencies of micronutrients 5 years postoper- Calcium homeostasis is obtained through the interplay be- atively where the most significant deficiency was vitamin D tween multiple factors and organs. To maintain the narrow (76.7%) despite recommended multivitamin supplementation range of acceptable serum concentration, the body relies upon including 2000 IU vitamin D3 daily . At the time of the the skeleton as the ultimate calcium storage source to com- study, the recommended vitamin supplementation for patients pensate for deficient amounts obtained via the skin and the having undergone BPD/DS at Uppsala University Hospital alimentary tract. The parathyroid glands release PTH in re- included 1400 IU cholecalciferol daily. Awaiting national con- sponse to low serum calcium concentrations which in turn sensus regarding supplementation post bariatric surgery, dos- signals for increased vitamin D activation in the kidney, age recommendations have varied between centers. Thus, pa- increased uptake of vitamin D in the intestine, and metab- tients having had BPD/DS require life/long monitoring of olism of bone to release stored calcium. Vitamin D pro- micronutrients at a specialized bariatric center and possibly motes the uptake of calcium from the diet at the duodenal better micronutrient supplementation. mucosa by increasing the number of calcium channels. Vitamin D is therefore essential to maintain calcium Limitations homeostasis. The definition of vitamin D sufficiency remains a topic of The strengths of this study include the same geographic loca- discussion; however, commonly used cutoffs are 75 nmol/l tion and thereby controlled UV-B radiation, all Caucasian par- for insufficiency and 25 nmol/l for deficiency . Levels ticipants, identical length of the common limb (100 cm) in all OBES SURG 4. Homan J, Betzel B, Aarts EO, et al. Vitamin and mineral deficien- patients,and a modernmodeofvitamin D laboratory analysis. cies after biliopancreatic diversion and biliopancreatic diversion Moreover, patients were not allowed to travel to sunny cli- with duodenal switch—the rule rather than the exception. 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Published: Jun 4, 2018