Nutritional deficiencies after bariatric surgery

REVIEWS Nutritional deficiencies after bariatric surgery Bikram S. Bal, Frederick C. Finelli, Timothy R. Shope and Timothy R. Koch Abstract | Lifestyle intervention programmes often produce insufficient weight loss and poor weight loss maintenance. As a result, an increasing number of patients with obesity and related comorbidities undergo bariatric surgery, which includes approaches such as the adjustable gastric band or the ‘divided’ Roux-en-Y gastric bypass (RYGB). This Review summarizes the current knowledge on nutrient deficiencies that can develop after bariatric surgery and highlights follow-up and treatment options for bariatric surgery patients who develop a micronutrient deficiency. The major macronutrient deficiency after bariatric surgery is protein malnutrition. Deficiencies in micronutrients, which include trace elements, essential minerals, and watersoluble and fat-soluble vitamins, are common before bariatric surgery and often persist postoperatively, despite universal recommendations on multivitamin and mineral supplements. Other disorders, including small intestinal bacterial overgrowth, can promote micronutrient deficiencies, especially in patients with diabetes mellitus. Recognition of the clinical presentations of micronutrient deficiencies is important, both to enable early intervention and to minimize long-term adverse effects. A major clinical concern is the relationship between vitamin D deficiency and the development of metabolic bone diseases, such as osteoporosis or osteomalacia; metabolic bone diseases may explain the increased risk of hip fracture in patients after RYGB. Further studies are required to determine the optimal levels of nutrient supplementation and whether postoperative laboratory monitoring effectively detects nutrient deficiencies. In the absence of such data, clinicians should inquire about and treat symptoms that suggest nutrient deficiencies. Bal, B. S. et al. Nat. Rev. Endocrinol. 8, 544–556 (2012); published online 24 April 2012; doi:10.1038/nrendo.2012.48 Introduction Department of Medicine (B. S. Bal, T. R. Koch), Department of Surgery (F. C. Finelli, T. R. Shope), Washington Hospital Center, POB North, Suite 3400, 106 Irving Street Northwest, Washington, DC 20010, USA. Correspondence to: T. R. Koch timothy.r.koch@ medstar.net Obesity is a major factor contributing to the global rise in the prevalence of diabetes mellitus.1 The prevalence of extreme obesity in US adults in 1999–2002 was 4.9%.2 Studies have demonstrated a continued increase in the age-adjusted prevalence of obesity in the USA from 22.9% in 1988–1994,3 to 30.5% in 1999–2000,3 to 35.8% of women and 35.5% of men in 2009–2010.4 Information on obesity trends in Europe is lacking, which has led to suggestions for improved collection of data on BMI and obesity trends.5 Weight loss by lifestyle modification (for example, by consumption of a low-calorie diet and increased physical activity) has been recommended by the WHO6 and the NIH7 for treatment of individuals with obesity. Unfortunately, lifestyle intervention programmes that include changes in diet and increased physical activity often result in insufficient weight loss, and maintenance of weight loss is usually inadequate in individuals with morbid obesity. Bariatric surgery remains a major treatment option for patients with a BMI ≥40 kg/m 2 (or those with a BMI ≥35 kg/m2 and comorbidities) in whom lifestyle intervention and pharmacotherapy result in inadequate weight loss.8 For patients with type 2 diabetes mellitus, Lebovitz has proposed that individuals with a BMI ≥35 kg/m2 should be considered as candidates for Competing interests The authors declare no competing interests. bariatric surgery, as well as those with a BMI <35 kg/m2 who are unresponsive to medical therapy.9 Bariatric surgery has medical as well as economic advantages.10 Large population-based studies from the USA and Europe have shown a significant reduction in long-term total mortality—particularly deaths from diabetes mellitus, cardiovascular-related events and cancer—with gastric bypass surgery.10,11 Patients who have undergone gastric bypass surgery have higher rates of resolution of diabetes mellitus, dyslipidaemia and hypertension than individuals with obesity who did not undergo surgery.12 When a patient considers undergoing a bariatric procedure, surgery on the stomach, on the small intestine or on both regions is contemplated. The type of surgery that is chosen is a major determinant of the risk of future nutritional deficiencies. Unfortunately, surgical options that are more effective for inducing weight loss are more likely to lead to nutritional deficiencies. This Review summarizes the nutrient deficiencies known to develop after bariatric surgery and provides follow-up and treatment options for bariatric surgery patients who develop these disorders. Types and effects of bariatric surgery In 2008, over 344,000 bariatric surgeries were performed worldwide.13 The laparoscopic adjustable gastric band and Roux-en-Y gastric bypass (RYGB) were the most common bariatric approaches in Europe and North America, respectively.13 544 | SEPTEMBER 2012 | VOLUME 8 www.nature.com/nrendo © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Placement of an adjustable gastric band does not bypass any part of the small intestine, and no reduction of or stapling of the stomach occurs (Figure 1). The mechanisms underlying weight loss after adjustable gastric banding are not well understood, but weight loss is often a slow gradual process. Appetite reduction appears to play an important part in this process. Some restriction of food intake, perhaps induced by dysphagia, occurs, but considerable malabsorption of ingested macronutrients is improbable. Other primarily restrictive bariatric procedures include the largely abandoned vertical-banded gastroplasty and the vertical sleeve gastrectomy, which is also known as gastric sleeve resection (Figure 1). Weight loss generally occurs within a 12–18 month period after these two restrictive surgeries. To achieve greater weight loss, vertical sleeve gastrectomy can be combined with a malabsorptive procedure, the duodenal switch (Figure 1). As an adjuvant therapy to restrictive surgical procedures, malabsorptive surgical procedures, including the duodenal switch and biliopancreatic diversion, induce malabsorption of foods from the small intestine by producing a short ‘common channel’, the length of small intestine between the enteroenteric anastomosis and the ileocecal valve. The shorter the common channel, the less of the small intestine available for mixture of bile and pancreatic secretions with small intestinal chyme before absorption of fatty acids, amino acids and small peptides. Bariatric surgical procedures designed to induce malabsorption result in three channels: the digestive tract in continuity (or Roux limb in the case of RYGB), a biliopancreatic limb, and a common channel (Figure 1). The risk of severe malabsorption is higher in those patients who have a common channel that is shorter than 120 cm, specifically, in whom the jejunoenteric anastomosis is formed <120 cm from the ileocecal valve. A clinician must, therefore, obtain a copy of the surgical report and examine the bariatric procedure performed to judge the potential postoperative nutritional risk for each patient. For example, the postoperative report may simply describe the preparation of an ‘extended’ gastric bypass in a patient who in fact has a short common channel because the enteroenteric anastomosis has been completed closer than usual to the ileocecal valve. Similar to the combination of sleeve gastrectomy with duodenal switch, RYGB can combine restriction of food intake with malabsorption in patients who have undergone an extended RYGB. The mechanisms for weight loss in the ‘divided’ RYGB approach are not fully understood. Malabsorption of both fat and nitrogen has been identified in a study of the Roux-en-Y reconstruction; this malabsorption was improved after providing oral, exogenous pancreatic enzymes.14 Multiple studies have examined micronutrient deficiencies after RYGB surgery. A major study of 318 patients, who had vitamin levels measured at 1 year of follow-up after a laparoscopic RYGB,15 revealed deficiencies of vitamin A (11% of patients), vitamin C (34.6%), vitamin D (7%), thiamine (18.3%), riboflavin (13.6%), vitamin B6 (17.6%) and vitamin B12 (3.6%). Key points ■ The rising prevalences of morbid obesity and type 2 diabetes mellitus have increased the number of patients undergoing bariatric surgery ■ Bariatric surgical approaches, including gastric bypass, the adjustable gastric band, vertical sleeve gastrectomy, the duodenal switch, and biliopancreatic diversion, can cause or exacerbate nutrient deficiencies ■ Standardized approaches to micronutrient supplementation and clinical and laboratory screening for micronutrient deficiencies after bariatric surgery are required ■ Vitamin D deficiency, a major clinical concern after bariatric procedures, must be aggressively treated with sufficient supplementation to prevent the development of metabolic bone diseases ■ Whether currently suggested laboratory blood tests that are intended to screen for micronutrient deficiencies identify all clinically relevant nutrient deficiencies is unclear These results must be considered in relation to both the patient’s preoperative nutritional status as well as the body’s reserves for specific vitamins (for example, up to 3 years for vitamin B12 but as little as 18 days for thiamine). In a head-to-head comparison of the duodenal switch with RYGB,16 the duodenal switch was associated with a greater risk of thiamine deficiency in the initial months after surgery and of vitamin A and vitamin D deficiencies in the first postoperative year. These results support the concern that bariatric procedures with a greater malabsorptive component, such as the duodenal switch, produce more long-term risks of complications induced by micronutrient deficiencies. Biliopancreatic diversion is a primarily malabsorptive surgical procedure that leads to substantial and sustained weight loss (Figure 1). However, a result of the massive induced weight loss is malnutrition, which can be lifethreatening.17,18 For these reasons, many major bariatric surgical centres do not perform this procedure. Multiple micronutrient deficiencies have been reported following formation of a short common channel.19,20 Low serum levels of zinc and copper are more common in individuals who undergo biliopancreatic diversion (prevalence of hypocupraemia 30.3%) than in patients who undergo RYGB (prevalence of hypocupraemia 3.8%),21 supporting the absorption of these micronutrients in the mid to distal jejunum. Moreover, severe malformations have been reported in neonates born to mothers who had biliopancreatic diversion for weight loss before pregnancy.22,23 Macronutrients After bariatric surgery, protein is the major macronutrient associated with malnutrition. The guidelines of the Endocrine Society suggest that bariatric patients should ingest 60–120 g of protein daily.24 However, many patients need to work closely together with a nutritionist after bariatric surgery in order to reach even a goal of 60 g of protein daily. Protein malnutrition is a potentially serious complication of bariatric surgery, especially in those individuals who postoperatively have a short common channel owing to the diminished length of small intestine available for mixture of pancreatic secretions with dietary protein.25 Studies of NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | SEPTEMBER 2012 | 545 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Procedure Anatomy Adjustable gastric banding Sleeve gastrectomy Roux-en-Y gastric bypass Biliopancreatic diversion hypoalbuminaemia after both biliopancreatic diversion and duodenal switch have shown that this biochemical abnormality is common in both procedures, occurring in 3.4–18.0% of patients.26–28 In many bariatric surgery patients, hair loss is the first suggestion that protein malnutrition is present. Other signs and symptoms of protein malnutrition, according to the WHO guidelines,29 include the clinical presence of oedema, emaciation and altered hair status, as well as biochemical findings of anaemia and hypoalbuminaemia. As serum albumin is an acute phase reactant,30 other considerations in patients with hypoalbuminaemia could include an acute inflammatory disorder, chronic liver disease or small intestinal bacterial overgrowth. Whether protein malnutrition can be prevented by increasing the dietary intake of protein is not clear. Adequately controlled studies examining the utility of liquid protein supplements for the treatment of protein malabsorption after bariatric surgery are not available. Owing to the risks of total parenteral nutrition, if protein supplementation is being considered, enteral feedings with liquid protein supplements should be attempted first. Patients with severe protein malnutrition, who often present with generalized oedema and evidence of severe muscle wasting, should be evaluated for potential surgical revision. Micronutrients Sleeve gastrectomy with duodenal switch Figure 1 | Comparison of bariatric surgical procedures. Adjustable gastric banding is usually performed laparoscopically. A rigid ring that incorporates a fluid-filled reservoir is positioned around the upper stomach, which restricts gastric volume and outflow. This procedure has replaced vertical-banded gastroplasty, in which a small gastric pouch is formed with staples and outflow restriction is achieved by a rigid, nonadjustable band, positioned at the base of a pouch. In sleeve gastrectomy, the gastric volume is reduced solely by excision of the fundus, which is the principal location of X/A-like cells. In Roux-en-Y gastric bypass, a small stomach pouch is divided from the remainder of the stomach, which remains in situ and in continuity with the duodenum. In biliopancreatic diversion, food moves from a gastric pouch, formed by horizontal partial gastrectomy, directly into the ileum. The duodenal switch is a development of biliopancreatic diversion. The procedures differ in that gastric volume is reduced by a sleeve gastrectomy and pyloric function is preserved by surgically connecting the ileum to the duodenum immediately distal to the pylorus. Adapted with permission from Macmillan Publishers © Field, B. C. et al. Nat. Rev. Endocrinol. 6, 444–453 (2010). Micronutrients are essential dietary factors that are required by humans in microgram or milligram quantities and function in various biochemical pathways and metabolic processes. Micronutrients include trace elements (chromium, copper, manganese, selenium and zinc), essential minerals (including calcium, iodine, iron and magnesium), water-soluble vitamins, such as thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3), folic acid, pyridoxine (vitamin B6), biotin, pantothenic acid, cobalamin (vitamin B12) and vitamin C, and fat-soluble vitamins (vitamins A, D, E and K). Minimal information exists about micronutrient requirements after bariatric surgery. Many bariatric programmes recommend taking one comprehensive tablet that contains multivitamins and minerals twice daily, as well as daily calcium supplementation (≥1.2 g per day of elemental calcium) after surgery.31 The Endocrine Society suggests that individuals who have undergone bariatric surgery should take one to two chewable multivitamin tablets with mineral supplements daily (including 1,200–2,000 mg per day of elemental calcium) and, after repletion of vitamin D deficiency, patients should chronically maintain intake of 1,200 mg per day of elemental calcium and of at least 1,000 IU per day of vitamin D3 (cholecalciferol).24 Whether these suggestions are sufficient for all patients who have undergone RYGB remains to be determined. However, these levels of supplementation are unlikely to be adequate in individuals with a short common channel (following extended gastric bypass surgery, duodenal switch or biliopancreatic diversion). 546 | SEPTEMBER 2012 | VOLUME 8 www.nature.com/nrendo © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Clinical symptoms and initial treatment of micronutrient deficiencies Vitamin Deficiency state Symptoms Dose* Thiamine (vitamin B1) Beriberi Neuropsychiatric: aggression, hallucinations, confusion, ataxia, nystagmus, paralysis of the motor nerves of the eye Neurologic or ‘dry’ beriberi: convulsions, numbness, muscle weakness and/or pain of lower and upper extremities, brisk tendon reflexes High-output cardiac or ‘wet’ beriberi: tachycardia or bradycardia, lactic acidosis, dyspnoea, leg oedema, right ventricular dilatation Gastroenterologic: slow gastric emptying, nausea, vomiting, jejunal dilatation or megacolon, constipation 100 mg twice daily In patients with Wernicke encephalopathy or acute psychosis: 250 mg for 3–5 days, intramuscularly or intravenously Riboflavin (vitamin B2) Ariboflavinosis Anaemia, dermatitis, stomatitis, glossitis 5–10 mg Water-soluble vitamins Niacin (vitamin B3) Pellagra Diarrhoea, confusion, dermatitis, ataxia 100–500 mg thrice daily Pantothenic acid (vitamin B5) Pantothenic acid deficiency Depression, infections, orthostatic hypotension, paraesthesias, foot drop, gait disorder 2–4 g Pyridoxine (vitamin B6) Pyridoxine deficiency Dermatitis, neuropathy, confusion 30 mg Folic acid (vitamin B9) Folate deficiency Weakness, weight loss, anorexia 1–5 mg Cobalamin (vitamin B12) Pernicious anaemia Depression, malaise, ataxia, paraesthesias 0.5–2.0 mg orally; 1,000 μg intramuscularly monthly or 500 μg sublingually daily Ascorbic acid (vitamin C) Scurvy Malaise, myalgias, gum disease, petechia 200 mg Biotin (vitamin B7) Biotin deficiency Loss of taste, seizures, hypotonia, ataxia, dermatitis, hair loss 20 mg Vitamin A Vitamin A deficiency Night blindness, itching, dry hair 10,000 IU Vitamin D Osteomalacia (in adults) Rickets (in children) Arthralgias, depression, fasciculations, myalgias Ergocalciferol 50,000 IU once weekly over 12 weeks, then switch to daily cholecalciferol 1,000–4,000 IU Vitamin E Vitamin E deficiency Anaemia, ataxia, motor speech disorder, muscle weakness 800–1,200 IU Vitamin K Vitamin K deficiency Bleeding disorder 2.5–25.0 mg Fat-soluble vitamins Minerals Calcium Osteoporosis Usually absent 1.2–2.0 g Iron Iron-deficiency anaemia Fatigue, shortness of breath, chest pain Ferrous sulfate 325 mg or ferrous fumarate 200 mg plus vitamin C 125 mg up to four times daily Zinc Hypozincaemia Skin lesions, nail dystrophy, alopecia, glossitis Zinc sulfate 220 mg or zinc gluconate 30–50 mg every other day Copper Hypocupraemia Usually absent Copper gluconate (2–4 mg) every other day Selenium Keshan disease Dyspnea, fatigue, leg swelling 100 μg sodium selenite Trace elements *Supplements are administered once daily and orally unless stated otherwise. Water-soluble vitamins The biochemical roles of water-soluble vitamins and their associated deficiency disorders are shown in Table 1. Only minor body stores exist of many water-soluble vitamins, for example thiamine (approximately 18 days), whereas vitamin B12 stores can be sufficient for 3–5 years. Thiamine Thiamine, or vitamin B1, is a coenzyme for the essential enzymes transketolase, pyruvate dehydrogenase and pyruvate carboxylase, in the early stages of the tricarboxylic acid cycle and in the pentose phosphate pathway in humans.32 Thiamine deficiency, which can lead to symptoms of beriberi, is a major nutritional complication. Thiamine deficiency after RYGB is quite common, with biochemical evidence for thiamine deficiency in up to 49% of patients.33 Hence, the European Federation of Neurological Societies recommends following up postoperative thiamine status for at least 6 months, as well as parenteral thiamine supplementation.34 Thiamine deficiency was originally described in individuals with neuropsychiatric, neurologic, cardiac or gastrointestinal symptoms that resolved after administration of ‘beriberi factor’, that is, thiamine (Table 1). By contrast, our group has described the presence of thiamine deficiency that does not resolve with oral thiamine supplementation after RYGB.33 This thiamine deficiency is associated with small intestinal bac terial NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | SEPTEMBER 2012 | 547 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS overgrowth, and antibiotic therapy may be required to correct thiamine deficiency in RYGB patients with so-called ‘bariatric beriberi’.33 As summarized in a WHO publication,35 the clinical diagnosis of thiamine deficiency in susceptible individuals is supported by two positive findings among three categories: bilateral lower limb oedema; laboured respiration (at rest or with exertion); or paraesthesias (that is, tingling, itching or burning sensation) of hands or feet, motor deficiency or loss of balance. In the laboratory diagnosis of thiamine deficiency, whole-blood thiamine levels, which include thiamine diphosphate levels, reflect only a small percentage of total-body thiamine concentration.36 Lower tissue levels of thiamine in humans compared with animal species may explain an increased risk of thiamine deficiency in humans.36 An alternative approach for the determination of thiamine stores is measurement of the catalytic activity of transketolase in erythrocytes, as this enzyme’s activity depends on its binding to thiamine pyrophosphate, the biologically active form of thiamine.37 Oral thiamine (100 mg twice daily) is a standard therapy for thiamine deficiency. The presence of small intestinal bacterial overgrowth should be considered if a patient has refractory thiamine deficiency. Patients presenting with symptoms of Wernicke encephalopathy or acute psychosis—the neuropsychiatric types of beriberi —should be considered medical emergencies; they require hospitalization with supportive care and they should receive a minimum of 250 mg of thiamine daily,38 given intramuscularly or intravenously for at least 3–5 days; intravenous infusions are given over 3–4 h to reduce the risk of an anaphylactic reaction. Within several days after initiation of parenteral thiamine administration, patients should report symptomatic improvement. Patients with Wernicke disease can also present with acute bilateral blindness.39 For the treatment of this serious disorder, intravenous thiamine can result in symptom resolution. Riboflavin Riboflavin, or vitamin B2, is present in the flavocoenzymes, flavin adenine dinucleotide and flavin mononucleotide. These enzymes are involved in a number of metabolic pathways and have important roles in the proper functioning of glutathione peroxidase (required for metabolism of hydroperoxides) and glutathione reductase (which generates reduced glutathione).40 After bariatric surgery, biochemical but not clinical riboflavin deficiency has been reported.15 In patients who have not undergone bariatric surgery, symptoms of riboflavin deficiency include sore throat, scaly dermatitis, stomatitis, and normochromic, normocytic anaemia. Treatment for riboflavin deficiency is 5–10 mg of riboflavin per day taken orally. Niacin Niacin, or vitamin B3, refers to both nicotinic acid and nicotinamide. Nicotinamide is generated from nicotinic acid and is a component of NAD in catabolic reactions and NADP in anabolic reactions. 41 Niacin deficiency, termed pellagra, after bariatric surgery has not been clinically reported. A diagnosis of niacin deficiency is supported by low plasma levels of niacin and symptomatic improvement after niacin supplementation. Patients exhibit neurologic, dermatologic or gastrointestinal symptoms, which can include delusions or hallucinations, headaches, ataxia or myoclonus, anxiety or depression, scaly dermatitis or a malabsorptive disorder or diarrhoeal illness. The treatment of pellagra is 100–500 mg of niacin, taken orally three times daily; however, the slow-release formulation of niacin should not be administered, as it can induce hepatitis.42 A common adverse effect of treatment with niacin is flushing. Folic acid Folate, a cofactor in the biosynthesis of methionine, thymidine nucleotides and purine nucleotides, is important for the synthesis of the coenzyme tetrahydrofolate.43 Folate deficiency has been associated with neural tube defects and cardiovascular disease, as well as macrocytic anaemia. In patients with folate deficiency, a normocytic, mixed anaemia with an increased red cell distribution width can be identified. Weakness, anorexia and weight loss are potential symptoms of folate deficiency. Serum folate levels in patients after bariatric surgery must be considered in the context of the risk of small intestinal bacterial overgrowth. Elevated serum levels of folic acid, also known as vitamin B9, have been validated as a marker of small intestinal bacterial overgrowth,44 an intestinal disorder that is common after bariatric surgery.33 Therefore, in patients who are folate-deficient after bariatric surgery, clinicians should consider the potential for another small intestinal malabsorptive disorder such as coeliac disease. Treatment of folate deficiency is 1–5 mg of folic acid daily, taken orally. The increasing incidence of obesity and advances in bariatric surgery techniques over the past 20 years have led to a dramatic rise in the number of pregnancies following bariatric or gastric bypass surgery. The American College of Obstetrics and Gynecology recommends that women who have undergone bariatric surgery receive counselling before conception and be provided with prenatal treatment of micronutrient deficiencies, including vitamin B12, calcium, iron and folate.45 The rapid phase of weight loss after bariatric surgery has been suggested to be a more risky time to become pregnant.46 Owing to the risk of neural tube defects, women who are trying to become pregnant after bariatric surgery should receive 1 mg of folic acid daily, as a routine supplement.31 Vitamin B6 Pyridoxal phosphate is the metabolically active form of vitamin B6 and serves as a coenzyme for many reactions. Vitamin B6 can help facilitate decarboxylation, transamination, racemization, elimination, replacement and β-group interconversion reactions.47 Patients with vitamin B6 deficiency can present with peripheral neuropathy, confusion and dermatitis.47 No clinical reports of vitamin B6 deficiency after bariatric surgery exist. This 548 | SEPTEMBER 2012 | VOLUME 8 www.nature.com/nrendo © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS deficiency is initially treated with 30 mg of vitamin B6 daily, taken orally. after RYGB.15 Treatment of vitamin C deficiency consists of 200 mg of ascorbic acid daily, taken orally. Vitamin B12 Vitamin B12, a cofactor in the biosynthesis of succinylcoenzyme A and methionine,48 is important for the functioning of neural cells. Lack of vitamin B12, also known as cobalamin, is a well-described nutritional deficiency after bariatric surgery. The reported prevalence of deficiency is 3.6% 12 months after RYGB,15 but rises to 61.8% ≥5 years after RYGB.49 The mechanisms underlying vitamin B12 deficiency are likely to be multifactorial in origin. Patients who have undergone antrectomy as part of a biliopancreatic diversion and exclusion of the antrum as part of RYGB lose the physiological function of parietal cells in the antrum. Parietal cells are the source of the gastric production of hydrochloric acid and the glycoprotein gastric intrinsic factor.48 Stomach acid improves the bioavailability of vitamin B12 in food,48 whereas gastric intrinsic factor forms a complex with vitamin B12 that is normally absorbed through a specific receptor in the distal ileum. Given that hepatic and kidney vitamin B12 stores last up to 3 years in humans, vitamin B12 deficiency can become clinically relevant only several years after surgery. Clinical manifestations include depression, pernicious anaemia and development of a potentially irreversible peripheral neuropathy, as well as neuropsychiatric symptoms or ataxia. A low normal blood level of vitamin B12 suggests the presence of vitamin B12 deficiency. The diagnosis of vitamin B12 deficiency is supported by an increased serum level of methylmalonic acid, because vitamin B12 is required for the metabolism of this compound.48 Effective treatments for vitamin B12 deficiency include oral vitamin B12 (500–2,000 μg of cyanocobalamin per day); intramuscular vitamin B12 (1,000 μg monthly to 3,000 μg every 6 months); nasal vitamin B12 (500 μg once weekly); or sublingual vitamin B12 (500 μg once daily) preparations. Large oral doses of vitamin B12 can be as effective as parenteral vitamin B12 for treatment of uncomplicated vitamin B12 deficiency.48 Biotin Biotin is a coenzyme of five mammalian carboxylases.52 Reported symptoms of biotin deficiency include seizures, hypotonia, ataxia, hair loss and dermatitis.52 A single case of a patient with loss of taste after sleeve gastrectomy has been reported.53 The patient’s taste was restored after several weeks of supplementation with 20 mg of oral biotin daily. Vitamin C Vitamin C or ascorbic acid is produced by biosynthesis using glucose as the substrate. Tissue concentrations of ascorbic acid in humans are regulated by gut absorption, tissue accumulation and renal reabsorption. 50 Ascorbic acid is a cofactor for copper-dependent monooxygenases and iron-dependent dioxygenases. The surgical literature studying wound healing and vitamin C supplementation based on the role of ascorbic acid in collagen synthesis is extensive.51 Vitamin C deficiency in humans is termed ‘scurvy’. Early symptoms of vitamin C deficiency include malaise, myalgias and petechiae (red spots on the skin). Scurvy can progress to gum disease and soft tissue disease, but no clinical reports of classic vitamin C deficiency after bariatric surgery exist to date. By contrast, biochemical evidence of vitamin C deficiency is common (34.6%) 12 months Pantothenic acid Pantothenic acid, which is also known as vitamin B5, is required for the function of coenzyme A. In humans, deficiency of pantothenic acid induces depression, infections, orthostatic hypotension, paresthesias and a gait disorder.54 Deficiency in humans has been treated with 2–4 g of oral pantothenic acid daily.54 A deficiency of pantothenic acid after bariatric surgery has not been reported. Fat-soluble vitamins Signs and symptoms of fat-soluble vitamin deficiency are summarized in Table 1. Vitamin A Multiple components are referred to as vitamin A, including β carotenes, carotenoids and retinols. When ingested in high doses, excessive doses of vitamin A can cause hepatitis or liver damage, headache, vomiting, diplopia, alopecia, dryness of the mucous membranes and abnormalities of the bone. After bariatric surgery, vitamin A deficiency has been identified in patients with a short common channel (biliopancreatic diversion, duodenal switch or extended RYGB).55,56 Bile and thus bile acids are present in the common channel. Given that fat and fat-soluble vitamin absorption require micelle formation with bile acids,57 potential origins of vitamin A deficiency include a relative deficiency of bile acids in the bypassed duodenojejunal segment, as well as deconjugation of bile acids by upper gut bacterial overgrowth. Vitamin A deficiency can result in decreased vision, poor night vision (nyctalopia), itching (pruritus) and dry hair. Initial treatment of vitamin A deficiency is oral vitamin A supplementation (10,000 IU daily). Signs of vitamin A toxicity have not been reported with β carotene, a pre-vitamin A analogue, which makes this compound a viable alternative therapy. Vitamin D Vitamin D, the primary regulator of calcium metabolism in humans, maintains adequate calcium and phosphate levels required for bone formation—thereby enabling proper functioning of parathyroid hormone—by promoting calcium absorption in the intestines.58 Vitamin D deficiency has been described as a common cause of disorders of calcium metabolism and metabolic bone disease after weight loss surgery that can result in clinically significant long-term morbidity, leading to bone NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | SEPTEMBER 2012 | 549 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS loss and possibly fractures.59 Clinicians must, therefore, prevent this linkage between vitamin D deficiency and calcium malabsorption after weight loss surgery. Lack of vitamin D due to malabsorption causes inadequate calcium absorption and utilization.60,61 As a result of this hypocalcaemic state, calcium stores are mobilized via positive feedback activation of the parathyroid glands. Under the control of increased parathyroid hor mone levels, calcium is reabsorbed from the bones and urinary calcium secretion is decreased.62 The prevalence of secondary hyperparathyroidism can reach 58% of patients after a gastric bypass.63 Subsequently, osteoporosis and osteomalacia develop.64 Despite being touted as a solely restrictive procedure, vertical sleeve gastrectomy can lead to postoperative vitamin D deficiency. In a 1-year study from the Netherlands, 39% of patients were vitamin D deficient despite daily multivitamin supplementation.65 Bone loss and bone remodelling also occur, as little as 1 year following vertical sleeve gastrectomy.66 Significant loss of bone mass and marked bone remodelling were reported by Nogués et al., who measured BMD and bone remodelling markers in 15 women with morbid obesity after vertical sleeve gastrectomy.66 Nevertheless, RYGB remains a higher risk procedure for nutrient deficiencies. 67 Standards similar to those suggested for patients undergoing RYGB should be considered for patients after sleeve gastrectomy. The goals are to increase early detection and appropriate treatment of vitamin D deficiency. Al-Shoha and co-workers have reported the development of osteomalacia and marrow fibrosis after RYGB, as determined by investigation of bone biopsy samples obtained from five patients.68 Symptoms were present for 2–5 years, but a combination of ergocalciferol (100,000 IU daily) with calcium carbonate (1.0–2.5 g daily) significantly improved the patients’ biochemical indices, functional status, clinical symptoms and BMD. An increased risk of hip fracture has been reported after RYGB;69 patients undergoing RYGB, therefore, need to be closely monitored postoperatively for abnormal bone metabolism. Studies have supported the concern that vitamin D deficiency is most severe after biliopancreatic diversion, which is associated with an increased risk of vitamin D deficiency in the first year after surgery.70 A retrospective study by Khandalavala et al. showed a 73% incidence of vitamin D deficiency following biliopancreatic diversion.71 A high rate of bone turnover associated with decreasing BMD has also been observed.72 Studies examining a link between adjustable gastric banding and vitamin D deficiency are preliminary. A study of 73 adolescents in whom an adjustable gastric band had been placed found vitamin D deficiency to be the second most common micronutrient deficiency, after iron-deficiency anaemia, within the first 2 years after surgery.73 As adjustable gastric banding continues to gain popularity, further studies are needed to gauge its effects on vitamin D utilization and BMD. Clearly, vitamin D deficiency following all bariatric procedures is an important issue that can seriously jeopardize the long-tem health of patients. Regular and close follow-up is required to prevent this disorder and its sequelae in this susceptible population. A dual energy X-ray absorptiometry scan should be considered if patients who have not been followed up regularly after bariatric surgery present with evidence of vitamin D deficiency. In patients diagnosed as having vitamin D deficiency through low serum levels of total 25-hydroxyvitamin D, treatment should be initiated with oral vitamin D (ergocalciferol 50,000 IU) once weekly. To confirm repletion, 25-hydroxyvitamin D levels should be measured 8–12 weeks after the start of supplementation. Some researchers have suggested switching patients to supplementation with 1,25-dihydroxyvitamin D3 (cholecalciferol 1,000–2,000 IU, taken with meals once or twice daily) after repletion has been confirmed. Individual patients may require large regular doses of vitamin D after bariatric surgery. The initial dose for the treatment of osteomalacia is 600,000 IU of ergocalciferol (vitamin D2) given as 50,000 IU doses once weekly. However, anecdotal reports of liver test abnormalities and hypercalcaemia resulting from high doses of oral vitamin D exist. Vitamin E The vitamin E family includes tocopherols and the less studied tocotrienols.74 A common form of vitamin E in the American diet is α-tocopherol.75 This vitamin can prevent lipid peroxidation owing to its location in cell membranes. Most individuals tolerate oral doses of vitamin E of 400–1,000 mg per day (0.67 mg of vitamin E equals 1 IU).76 Vitamin E deficiency after bariatric surgery has not been well studied. Complaints of ataxia, muscle weakness and visual symptoms or findings of anaemia or dysarthria are indicative of vitamin E deficiency. For initial treatment, oral vitamin E supplementation at 800–1,200 IU should be taken daily. Vitamin K Vitamin K is included in a group of compounds essential for the formation of prothrombin and other factors involved in blood clotting. Vitamin K can be moderately well absorbed (40–70%) from the ileum and jejunum.77 The turnover of vitamin K is rapid, so the whole-body pool of vitamin K is small. Biosynthesis of vitamin K by the intestinal flora provides humans with vitamin K.78 The absence of case reports of vitamin K deficiency after bariatric surgery suggests that this occurrence is likely to be rare. However, the observation of intracranial haemorrhage in five neonates after maternal bariatric surgery suggests that subclinical vitamin K deficiency might be present after RYGB.79 Vitamin K deficiency can be treated with either oral vitamin K (2.5–25.0 mg daily) or parenteral vitamin K (5–15 mg given intramuscularly or subcutaneously). Essential minerals Most of the studies of essential minerals after bariatric surgery involve iron and calcium. Long-term deficiencies of other minerals after bariatric surgery have not been fully evaluated. 550 | SEPTEMBER 2012 | VOLUME 8 www.nature.com/nrendo © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Iron Anaemia is common after bariatric surgery and is seen in 36% of patients ≥1 year after RYGB,80 5% of patients 1 year after sleeve gastrectomy81 and 1.5% of patients 5 years after gastric banding.82 Iron deficiency is an important postoperative cause of anaemia.83,84 Given that acid can improve absorption of non-haem iron, hypochlorhydria after RYGB can reduce iron absorption; in addition, bypass of the duodenum and proximal jejunum isolates segments in which improved absorption of iron occurs. After identification of iron deficiency in a bariatric surgery patient, other potential gastrointestinal causes of blood loss or anaemia, such as gastrointestinal cancer or a malabsorption disorder including coeliac disease, may need to be excluded, depending upon the patient’s clinical circumstances. Treatment of iron deficiency after bariatric surgery includes either 150–200 mg per day of oral elemental iron (ferrous gluconate, sulfate or fumarate) or a ferrous salt–vitamin C combination. Parenteral iron is occasionally needed in patients who have a poor response to oral iron therapy. Patients should be monitored while receiving iron supplements, as large doses of unnecessary iron supplements can result in an acquired iron overload disorder.85 Calcium Calcium is a mineral pivotal for normal cell physiology; the transfer of calcium ions across cell membranes acts as a signal for many cellular processes. The body’s main stores of calcium are bones and teeth. 86 Steatorrhoea caused by formation of a short common channel can underlie calcium malabsorption owing to the interaction of dietary calcium with intraluminal triglycerides.87 Long-term calcium deficiency leads to osteoporosis and increases the risk of fractures.88 Patients with calcium deficiency or vitamin D deficiency after bariatric surgery present with muscle cramps, back pain, bony pain or aching of the limbs. Calcium malabsorption and vitamin D deficiency must be simultaneously considered after bariatric surgery, because isolated serum calcium measurements are a poor marker of calcium metabolism. An ionized calcium level may be a better indicator of hypocalcaemia in patients with hypoalbuminaemia owing to the normal binding of albumin to calcium.89 Levels of serum alkaline phosphatase (a marker of bone formation) and 24 h urinary calcium are commonly determined every 6–12 months in patients after RYGB and in patients with a short common channel to exclude calcium malabsorption. Alkaline phosphatase should be fractionated if serum alkaline phosphatase levels are increased and/or urinary calcium excretion is low. However, the concomitant use of diuretics can also alter urine calcium secretion. If a patient has low 24 h urinary calcium excretion but no other biochemical abnormality, a total 25-hydroxyvitamin D level at least every 12 months should be ordered. Serum parathyroid hormone levels should be measured if elevated alkaline phosphatase originates from bone instead of the liver. Elevated parathyroid hormone levels support the need for aggressive supplementation with calcium and vitamin D and continued patient surveillance. Treatment of calcium deficiency requires correction of vitamin D deficiency, as well as administration of ≥1.2 g of calcium daily, taken orally. Iodine Iodine deficiency has not been reported after bariatric surgery. Resolution of subclinical hypothyroidism can occur with weight loss after bariatric surgery.90,91 Trace elements Trace elements are cofactors in antioxidant enzymes and proteins (Table 1). When giving oral trace element supplements, the safety range between the risks of deficiency compared with the toxicity of the trace element is narrow. Transition metals (including zinc, copper, manganese and chromium) have a potential role as acceptors or donors of electrons. Zinc Zinc is a major cofactor in cytosolic copper–zinc superoxide dismutase.92 The antagonism of iron and copper, redox-active transition metals, results in the production of the toxic hydroxyl radical (OH –); zinc can reduce this effect.93 Symptoms and findings of zinc deficiency include skin eruption (acrodermititis enteropathica), nail dystrophy, alopecia, hypoalbuminaemia (in patients with severe deficiency) and glossitis. Although clinical reports of zinc deficiency after bariatric surgery are lacking, hypozincaemia after bariatric surgery has been observed,94 with a higher prevalence of hypozincaemia at 1 year after duodenal switch than after RYGB or sleeve gastrectomy. Hypozincaemia can be initially treated with oral zinc sulfate (220 mg taken every other day) or zinc gluconate (30–50 mg elemental zinc taken every other day). Copper Copper is present in a diverse group of proteins,95 such as cytochrome oxidase and cytosolic copper–zinc superoxide dismutase.96 Animal studies support absorption of copper from the small intestine through the high-affinity copper transport protein 1 (CTR1).97 However, a study using a human cell line suggests that a different copper transport protein may be active in copper absorption in humans, because CTR1 in a human epithelial cell line has a basolateral rather than apical location—that is, CTR1 is not oriented toward the lumen of the gut.98 Low serum copper levels in susceptible individuals can lead to anaemia, neutropenia and pancytopenia.99,100 In the past decade, neurologists have reported the development of a new myeloneuropathy-like disorder with spastic gait and sensory ataxia in patients who had undergone RYGB; some of these patients were found to have low serum copper levels.101 The clinical and neuroimaging findings in these patients are similar to those of patients with vitamin B12 deficiency. Neurological symptoms can develop >10 years after RYGB,102 but the neurological NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | SEPTEMBER 2012 | 551 © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS Analysis of nutrient deficiencies adverse clinical outcomes. For example, a 15% prevalence of low preoperative thiamine levels was reported among 437 consecutive patients with obesity, 111 and Wernicke encephalopathy is a feared postoperative complication after bariatric surgery.34 Preoperative vitamin D deficiency has been reported in 25–96% of individuals with obesity,112–115 and, as described above, metabolic bone disease after bariatric surgery may increase the risk of fractures.69 Moreover, anaemia is quite common after bariatric surgery, and an Israeli study showed that 10.4% of adolescents with obesity were vitamin B12 deficient compared with 2.2% of normal-weight individuals in a prospective, descriptive study of individuals not seeking surgery.116 When considering trace elements, preoperative hypozincaemia (73.8%) and hypocupraemia (67.8%) were both identified in patients with obesity;117 by 4 years after biliopancreatic diversion, the prevalence of hypozincaemia and hypocupraemia had risen to 90.7%. These studies support the notion that preoperative assessment of candidates for bariatric surgery should include measurement of those micronutrients that frequently result in a postoperative deficiency. The potential origins of preoperative micronutrient deficiencies are multiple. A simple potential explanation is that the patients’ diets contain low concentrations of micronutrients.118 Individuals with morbid obesity tend to consume a diet high in calories and refined carbohydrates and utilize dietary supplements such as herbal teas and herbal preparations containing Hypericum perforatum that might induce micronutrient deficiencies.118–120 Small intestinal bacterial overgrowth is another potential explanation for the development of micronutrient defi ciencies in patients with obesity. A gut motility disorder has been suggested to be a risk factor for the development of small intestinal bacterial overgrowth in patients with diabetes mellitus.121 In support of this hypothesis, the prevalence of small intestinal bacterial overgrowth is higher in patients with diabetic autonomic neuropathy than in those without neuropathy.122 Thiamine deficiency is common in individuals who have evidence of small intestinal bacterial overgrowth, as demonstrated for patients after RYGB.33 Bacteria are known to secrete thiaminases, which can inactivate thiamine.123,124 Multiple studies have demonstrated that small intestinal bacterial overgrowth reduces vitamin B12 levels.125 A potentially clinically relevant finding is the obser vation that small intestinal bacterial overgrowth deconjugates bile acids that are required for micelle formation, which are important for the absorption of fat-soluble vitamins.125 Pharmacologic agents can also result in micronutrient depletion. The prototype drug for this proposed mechanism is the antibiotic metronidazole, which is converted to a structural thiamine analogue that acts as an inhibitor of thiamine pyrophosphokinase in vitro.126 Further studies will be important for delineating the origins of micronutrient deficiencies in individuals with obesity. Preoperative assessment Review of medical complications after bariatric surgery suggests that the presence of preoperative micronutrient deficiencies could underlie reported postoperative Postoperative assessment Which micronutrients should be measured after bariatric surgery and at what intervals has not been extensively symptoms are unfortunately not fully reversed with the use of oral copper therapy in patients with hypocupraemia.103 Treatment of copper deficiency can begin with copper gluconate (2–4 mg), taken orally every other day or daily. In one patient after RYGB, improvement was achieved after surgical revision to reduce the length of the bypassed jejunum, with resolution of ataxia 16 months after revisional surgery. 104 Further work is needed to understand better the origin and the treatment of this rare neurologic complication. Another serious concern is a report of sudden bilateral blindness in a patient with hypocupraemia after RYGB.105 The patient did not appear to benefit from treatment with copper. As mentioned previously, sudden blindness can be caused by thiamine deficiency; the appropriate treatment of blindness after bariatric surgery is, therefore, uncertain. Oral copper may not be well absorbed after bariatric surgery. The most aggressive approach for treatment of this sudden disabling symptom would be to immediately begin daily infusions of thiamine HCl (250 mg) with a commercially available combination of trace elements (zinc 5 mg, copper 1 mg, manganese 0.5 mg, selenium 60 μg and chromium 10 μg) mixed in 500 ml of 5% dextrose in water and given intravenously at 50 ml/h. Selenium Selenium is essential in the activity of glutathione peroxidase, which catalyzes the reaction of reduced glutathione with hydrogen peroxide. In regions of the world in which selenium levels in the soil are low, selenium deficiency induces cardiomyopathy, termed Keshan disease. 106 Indeed, a patient has been described who presented with severe cardiomyopathy 9 months after biliopancreatic diversion.107 For treatment of selenium deficiency, oral sodium selenite (100 μg) is taken daily. Chromium Whether chromium is a required cofactor in humans, or whether chromium deficiency occurs after bariatric surgery, is not known. A potential role of chromium in human nutrition was postulated on the basis of observations from patients receiving total parenteral nutrition. A case report has discussed, in a patient receiving total parenteral nutrition, the development of an abnormal intravenous glucose tolerance test, with peripheral neuropathy and weight loss associated with decreased blood chromium level.108 Manganese Deficiency in manganese, an important cofactor in inducible mitochondrial superoxide dismutase,109 has not been reported after bariatric surgery. In an animal model, lack of manganese caused skeletal deformation and inhibited collagen deposition during wound healing.110 552 | SEPTEMBER 2012 | VOLUME 8 www.nature.com/nrendo © 2012 Macmillan Publishers Limited. All rights reserved REVIEWS evaluated. The Endocrine Society supports a programme in which individuals who have undergone RYGB, duodenal switch or biliopancreatic diversion have laboratory measurements at 3 months and 6 months postoperatively, at 6-month intervals until 24 months after surgery, then once yearly (Box 1).24 According to these guidelines, similar intervals can also be recommended for patients who have undergone restrictive surgery (adjustable gastric banding or sleeve gastrectomy).24 However, no formal studies have investigated these screening intervals with respect to the development of micronutrient deficiencies after these bariatric surgical procedures. On the basis of clinical experience, frequent followup measurements are probably reasonable for patients who have extensive weight loss after adjustable gastric banding or sleeve gastrectomy. A weakness of these guidelines is the absence of routine measurements of whole-blood thiamine and serum copper levels, which should be determined at each postoperative follow-up. Symptomatic laboratory testing Strong scientific evidence from double-blinded clinical trials examining the appropriate postoperative care of bariatric surgery patients is lacking. Often, choices are based upon the types and timing of postoperative complications. Laboratory testing in patients after bariatric surgery can be based on the evaluation of symptoms associated with micronutrient deficiencies. In patients with visual symptoms, laboratory testing should include evaluation of serum vitamin A, vitamin E and copper levels, as well as whole-blood thiamine level. Patients with a bleeding disorder should be examined with a complete blood count (to include platelet count) and a measurement of prothrombin time. Testing of serum parathyroid hormone levels is suggested in those patients with refractory vitamin D deficiency. Patients with neurological symptoms warrant measurement of serum vitamin B12, vitamin E, vitamin B6, copper, whole-blood thiamine and plasma niacin levels. Evaluation of anaemia could include determination of serum ferritin, vitamin B12 and folate levels, followed by measurement of serum copper, zinc, vitamin A and vitamin E levels depending on the initial results. In patients with skin disorders or dermatitis, serum vitamin A, vitamin B2, vitamin B6, zinc and plasma niacin levels should be investigated. Evaluation of oedema should include determination of serum selenium, plasma niacin and whole-blood thiamine levels. The temporal development of clinical symptoms may not be useful or relevant, given that patients could have had a micronutrient deficiency before bariatric surgery, as discussed above. The initial treatment doses for repletion of micronutrient deficiencies are summarized in Table 1. These suggested doses may not be sufficient in patients with more severe nutritional deficiencies. In addition, patients with a short common channel (after biliopancreatic diversion, extended gastric bypass or duodenal switch) will require higher doses for the treatment of micronutrient deficiencies. Box 1 | Postoperative laboratory measurements* 3 months ■ Complete blood count ■ Liver tests ■ Glucose, electrolytes, creatinine 6, 12, 18 months Repeat laboratory tests performed at 3 months and additionally measure: ■ Iron and/or ferritin ■ Folate and vitamin B12 ■ Calcium and intact parathyroid hormone ■ Albumin and 25-hydroxyvitamin D 24 months and then once yearly Repeat laboratory tests performed at 3 months and 6 months and additionally measure: ■ Vitamin A ■ Zinc ■ BMD *Consider measuring whole-blood thiamine and serum copper levels at each examination. Conclusions Given the increasing prevalence of obesity and its comorbidities, a growing number of individuals with obesity will undergo bariatric surgery in the future. Moreover, bariatric surgery is gaining popularity for the treatment of type 2 diabetes mellitus, because most individuals show improved disease control after bariatric surgery. As a result, clinicians must increase their understanding of the presentation and treatment of macronutrient and micronutrient deficiencies that can arise after bariatric surgery. Recognition of these postoperative disorders will remain an ongoing educational process. Given its association with high rates of postoperative complications, diagnosis of vitamin D deficiency and appropriate preoperative and postoperative vitamin D supplementation are major areas requiring further clinical investigation. Clinicians who treat patients after bariatric surgery need to have standardized approaches to micronutrient supplementation and postoperative evaluation. Further studies are needed to examine the question of whether standardized measurements of micronutrient blood levels are adequate determinants of clinically relevant nutritional deficiencies. Review criteria A search for articles published between January 2009 and December 2011 in PubMed using the MeSH terms “malnutrition”, “nutritional deficiency”, “vitamin D”, “vitamin”, and “micronutrient” combined with “gastric bypass surgery”, “bariatric surgery”, “gastric band”, “sleeve gastrectomy” or “biliopancreatic diversion” was performed. Only articles describing studies in humans were considered. We selected articles for discussion that included information on definition, diagnosis, clinical signs and symptoms, pathophysiology and current treatment protocols. 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