review article: the nutritional and pharmacological ... · review article: the nutritional and...

Review article: the nutritional and pharmacologicalconsequences of obesity surgeryJ. Stein*,†, C. Stier†,‡, H. Raab†,‡ & R. Weiner†,‡

*Department of Gastroenterology andClinical Nutrition, SachsenhausenHospital, Frankfurt/Main, Germany.†German Obesity Center (GOC),Frankfurt-Sachsenhausen, Frankfurt/Main, Germany.‡Department of Surgery,Sachsenhausen Hospital,Frankfurt/Main, Germany.

Correspondence to:Dr J. Stein, Gastroenterology/ClinicalNutrition, KrankenhausSachsenhausen, Teaching Hospital ofthe J. W. Goethe University, Frankfurt,Schulstrasse 31, 60594 Frankfurt/Main, Germany.E-mail: [email protected]

Publication dataSubmitted 17 September 2013First decision 22 November 2013Resubmitted 20 May 2014Resubmitted 20 June 2014Accepted 21 June 2014EV Pub Online 30 July 2014

This uncommissioned review article wassubject to full peer-review.

SUMMARY

BackgroundObesity surgery is acknowledged as a highly effective therapy for morbidly obesepatients. Beneficial short-term effects on common comorbidities are practicallyundisputed, but a growing data pool from long-term follow-up reveals increasingevidence of potentially severe nutritional and pharmacological consequences.

AimsTo assess the prevalence, causes and symptoms of complications after obesity sur-gery, to elucidate and compare therapy recommendations for macro- and micronu-trient deficiencies, and to explore surgically-induced effects on drug absorption andbioavailability, discussing ramifications for long-term therapy and prophylaxis.

MethodsPubMed, Embase and MEDLINE were searched using terms including, but notlimited to, bariatric surgery, gastric bypass, obesity surgery and Roux-en-Y, coupledwith secondary search terms, e.g. anaemia, micronutrients, vitamin deficiency, bac-terial overgrowth, drug absorption, pharmacokinetics, undernutrition. All studies inEnglish, French or German published January 1980 through March 2014 wereincluded.

ResultsMacro- and micronutrient deficiencies are common after obesity surgery. Themost critical, depending on surgical technique, are hypoalbuminemia (3–18%) anddeficiencies of vitamins B1 (≤49%), B12 (19–35%) and D (25–73%), iron (17–45%)and zinc (12–91%). Many drugs commonly administered to obese patients (e.g.anti-depressants, anti-microbials, metformin) are subject to post-operative and/orPPI-associated changes affecting bioavailability and absorption.

ConclusionsComplications are associated with pre-operative and/or post-operative malnutritionor procedure-related changes in intake, absorption and drug bioavailability. The highprevalence of nutrient deficiencies after obesity surgery makes life-long nutritionalmonitoring and supplementation essential. Post-operative changes to drug absorp-tion and bioavailability in bariatric patients cast doubt on the validity of standarddrug dosage and administration recommendations.

Aliment Pharmacol Ther 2014; 40: 582–609

ª 2014 John Wiley & Sons Ltd

doi:10.1111/apt.12872

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Alimentary Pharmacology and Therapeutics

INTRODUCTIONEvidence confirming the effectiveness of obesity surgery,not only as a means of weight reduction but also interms of lowering rates of morbidity and mortality inseverely obese patients, has been reported in many publi-cations.1–7 Today, obesity surgery is accepted as a safeand effective treatment for morbid obesity, with a meanmortality rate of 0.3% for all procedures, comparable tothose for hip replacement (0.3%) or laparoscopic chole-cystectomy (0.35–0.6%).8–11 Indeed, high-volume obesitycenters are now achieving even lower mortality rates ofonly 0.04–0.13%.12, 13 However, in a small proportion ofcases, depending on the surgical technique employed, awide spectrum of early and late complications can occur,causing serious detriment to patients’ everyday lives. Insome instances, severe and even life-threatening nutri-tional deficiencies may result. In addition, surgery-specific alterations to drug absorption and bioavailabilitycan have wide-reaching implications in terms of drugdosage and administration.

This review focuses on nutritional and pharmacologicalcomplications after obesity surgery, aiming not only to elu-cidate their causes but also to explore the appropriate diag-nostic, therapeutic and preventive management options.

METHODSWe performed a literature search in PubMed, Embaseand MEDLINE, using the terms bariatric surgery, gastricbypass, obesity surgery, Roux-en-Y, gastric band, lapband, laparoscopic adjustable gastric band (LAGB), ga-stroplasty and biliopancreatic diversion. These termswere then coupled with secondary search terms: compli-cations, malnutrition, undernutrition, anaemia, micronu-trients, calcium, magnesium, trace elements, vitamindeficiency, bacterial overgrowth, diarrhoea, vomiting,food intolerance, drug absorption, pharmacokinetics andpharmacoepidemiology. We included all studies in Eng-lish, French or German published between January 1980and March 2014.

Types of procedures in obesity surgeryWhile the scope of this review does not allow for anexhaustive description of all obesity surgery procedures(for extensive review see14), these can broadly be categor-ised into the following groups (Figure 1):

(i) purely restrictive procedures designed to causeweight loss by induction of early satiety through limita-tion of gastric capacity, e.g. laparoscopic adjustablegastric banding (LAGB);

(ii) mainly restrictive approaches, such as proximalRoux-en-Y gastric bypass (RYGB), in which weightreduction is, however, assumed to be mainly due torestriction rather than malabsorption, and laparoscopicsleeve gastrectomy (LSG), an ostensibly restrictive proce-dure in which malabsorption resulting from the surgicalresection of hormone-secreting stomach parts is nowalso thought to play a role15;(iii) primarily malabsorptive procedures [e.g. biliopan-

creatic diversion (BPD) with or without duodenal switch(DS)] which reduce nutrient absorption by dividing thesmall intestine into an alimentary and a biliopancreaticlimb flowing into a short common channel (50–100 cm),resulting in impaired fat absorption.

The most frequently used techniques in obesity surgeryworldwide are RYGB, LAGB and LSG.

Nutritional consequences of obesity surgeryCauses and mechanisms of nutrient deficiencies followingobesity surgery are multifaceted. The magnitude andseverity of such deficiencies depend primarily on proce-dure-specific alterations to digestion and absorption.Other impacting factors include persisting pre-operativedeficiencies, sustained post-operative nausea and vomiting,food intolerance, modified eating behaviour and mealpatterns, and non-adherence to dietary and supplementrecommendations.

Persistence of pre-operative deficienciesMorbid obesity has been shown to be associated with ahigh prevalence of micronutrient deficiency, most consis-tently observed for vitamin D, iron, vitamin B12 and thi-amine (see below). Underlying mechanisms may includeimpaired expression of transporter proteins (e.g. iron)due to chronic inflammation, small intestinal overgrowthsyndrome (e.g. thiamine, vitamin B12 and fat-solublevitamins) and, last but not least, inappropriate eatingbehaviour, favouring foods with high energy density andpoor micronutrient content. A recent retrospectiveBrazilian study of 80 patients awaiting obesity surgeryconfirmed high pre-operative rates of a range of nutrientdeficiencies, especially magnesium, vitamin A, vitamin Cand iron, despite reported macronutrient intake being inaccordance with current recommendations.16 However,obese patients frequently misreport actual intake (whichhas been found to be generally high in protein andlipids, and low in carbohydrates) presumably as a resultof perceived and learned ideals of a more appropriatediet. Routine pre-operative screening and early supple-

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Review: nutritional consequences of obesity surgery

mentation are therefore advisable in order to preemptthe occurrence of serious conditions due to a predictablepost-operative exacerbation of already evident deficien-cies (Table 1).17, 18

Altered digestion and absorptionNutrient absorption is influenced in both purely malab-sorptive and combined restrictive-malabsorptive proce-dures by surgically induced alteration of biliary andpancreatic functions, intestinal transit time and gastricsecretion, the bypassing of primary sites of absorption(e.g. duodenum) and small intestinal bacterial over-growth (SIBO), which occurs particularly in the redun-dant part of the gut.

Patients with SIBO may be asymptomatic or show arange of symptoms including abdominal pain, waterydiarrhoea and dyspepsia or weight loss. The presence of‘faecal microorganisms’ (usually anaerobic species and/orcoliforms) in the small intestine at a density of>105 microbes/mL is regarded as biological criterion forbacterial overgrowth.

Depending on surgical technique, the prevalence ofbacterial overgrowth following obesity bypass surgery isreported at 25–40%.19, 20 SIBO results in malabsorptionof thiamine (due to bacterial secretion of thiaminases),19

vitamin B12 (due, for example, to bacterial production ofcobamides, biologically inactive vitamin B12 analogues),

21

and fat-soluble vitamins (due to impaired micelle forma-tion as a result of bacterial deconjugation of conjugatedbile acids).

Diagnostic testing for SIBO includes non-invasivebreath tests (H2, or marked 13CO2 or 14CO2) and/ordetermination of bacteria concentrations in duodenal/jejunal aspirate. However, these tests lack clear cut-offsto define a positive result, and in the case of the latterare too costly and time-consuming for clinical use. As amore practical approach, the so-called ‘therapeutic trial’has been recommended: initiation of treatment whenclinical symptoms and/or non-invasive surrogate markerssuggest the presence of SIBO.22, 23

The majority of patients require antibiotic therapy,which should be chosen to be effective against both aer-

Biliopancreatic diversionwith duodenal switch

Alimentarylimb

limb

Common channel

Biliopancreatic

(a) (b)

(c) (d)

Figure 1 | Schematicillustration of commonprocedures of obesity surgery:(a) gastric banding; (b) sleevegastrectomy; (c) Roux-en-Ybypass (RYGB); (d)biliopancreatic diversion withduodenal switch (BPD-DS).(Illustrations reprinted withpermission from Atlas ofMetabolic and Weight LossSurgery, Jones et al. Cine-Med, 2010.)

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Table 1 | Prevalence, risk factors, symptoms, supplementation and treatment of common nutritional deficienciesfollowing obesity surgery

Macro-/micronutrient

Pre-OPdeficiency

Post-OPdeficiency Risk factors

Signs andsymptoms

Suggestedsupplementation

Prevention Treatment

AGB RYGBBPD/

BPD-DS CommentsMultivitamin-/mineral supplementation (*a high-potency vitamin

supplement containing 100% of recommended daily dose for at leasttwo-thirds of nutrients)

100%of dailydose*

200%of dailydose*

200%of dailydose*

Begin on day 1after hospitaldischarge

Protein 5% 3–18% Low protein (andenergy) intakes,intercurrentillness, extremeweight loss (i.e.low food intake)short commonchannel

Weakness,decreased musclemass, brittle hair,generalisedoedema

Recommended intake:60–120 g/day (dairy,fish, eggs, meat) ororal proteinsupplements

Enteral orparenteralnutrition;reversal ofsurgicalprocedure

Calcium 8.5–10.5% Approx.10%

Pre-existing/deficiency,vitamin Ddeficiency, RYGB,BPD-DS, LSG,insufficientsupplementationwith calciumand/orvitamin D

Low bone density,osteoporosis,musclecontractions, pain,spasms,paresthesia

Oral calcium citrate,1200–2000 mg/day

(bisphosphonatesto be consideredif T-score <2.5)

Magnesium 35% 32% Pre-existingdeficiency,vitamin Ddeficiency, RYGB,BPD-DS,insufficientsupplementationwith magnesiumand/or vitamin D

Musclecontractions, pain,spasms,osteoporosis

Oral magnesiumcitrate, 300 mg/day

Vitamin B1(thiamine)

15–29% Up to49%

Recurrent vomiting(AGB, LSG),intravenousglucose infusionwith novitamin B1supplementation

‘Dry’ beriberi:convulsions,muscle weaknessand/or pain oflower and upperextremities, brisktendon reflexes‘Wet’ beriberi:tachycardia orbradycardia, lacticacidosis, dyspnoea,leg oedema, rightventriculardilatationNeuropsychiatric:confusion, ataxia,nystagmus,paralysis of themotor nervesof the eye

Standard multivitaminpreparation duringweight-loss phase; ifvomiting, aggressivethiamine oralsupplementationwith thiamine 100mg/dayfor 7–14 days

Wernickeencephalopathytreatment:500 mg i.v.3 9 /day for 2–3 days 250 mg/day i.v. for 5 days30 mg twice aday orally




Table 1 | (Continued)


Pre-OPdeficiency


Signs andsymptoms



Vitamin B12(cobalamin)

18% Post-BPD/RYBG4–62%after2 years,19–35%after5 years

Decreased meatand dairy intakes,malabsorptiveprocedure (GBP),extreme weightloss (i.e. low foodintake)

Pernicious anaemia,tingling in fingersand toes,depression,dementia, ataxia,

Oral supplementation(RYGB/BPD-DS):1000 lg/week(1 ampoule) orallyor 250–350lg/day orally or1000 lg/monthintramuscularly or3000 lg every6 monthsintramuscularly

1000 or2000 lg/day(1–2 ampoules)orally or1000 lg/weekintramuscularly

Folic acid 2–10% 9–38% Low intake, lowadherence withsupplements

Macrocyticanaemia,palpitations,fatigue, neuraltube defects

Routine multivitaminpreparation duringweight-loss phase,800–1000 lg/dayorally for all womenof child-bearing age(included inmultivitamin)

1 mg/day orallyfor about1–3 months

Vitamin A Up to 17% RYGB8–11%BPD61–69%

Malabsorptiveprocedure (BPD-DS > RYGB),extreme weightloss (i.e. low foodintake)

Loss of nocturnalvision, itching, dryhair,xerophthalmia,decreasedimmunity

No recommendations No cornealchanges: 10 000–25 000 IU/dayorally for1–2 weeks.If corneal lesionspresent: 50 000–100 000 IUi.m. followed by50 000 IU/dayi.m. for 2 weeks

Vitamin D 25–68% 25–80% Malabsorption afterSG, RYGB, BPD-DS

Osteomalacia (inadults), rickets (inchildren),arthralgia,depression,fasciculation,myalgia

Oral Vitamin D (400–800 U/day)[ergocalciferol(vitamin D2) orcholecalciferol(vitamin D3)] or100 000 U/3–6months orally

Severe vitamin Ddeficiency:50 000–150 000 IU/day;if necessary:calcitriol [1,25(OH)2D] orally

Iron 8–18% LSG 17%RYGB/BPD30%(45%after2 years)

Pre-existingdeficiency,menstruation (ifexcessive), BPD-DS, RYGB, SG,GI-bleeding,insufficientsupplementationwith iron,avoidance ofmeat, copperdeficiency

Fatigue, impairedwork performanceand productivity,anaemia, inabilityto regulate bodytemperature, whitefingernail beds

Oral ferroussulphate 300mg 2–3 times/day

Parenteral ironAdministrationaccording toTable 3



J. Stein et al.

obes and anaerobes. Although many different antibioticregimens have been successfully used in SIBO, includingciprofloxacin, metronidazole, clindamycin, norfloxacinand doxycycline,24 no clear consensus has been reachedon the most efficacious dose or optimum treatmentduration,22, 24 even in the bariatric population.25, 26

Food intoleranceFood intolerance, caused by nausea, vomiting and regur-gitation, has a reported prevalence of 35–65% and occursmainly during the first months of adaptation to a smallgastric pouch or LGB.27–29 Resulting changes of eatingbehaviour and meal pattern have been shown to triggerprotein and micronutrient deficiencies.30, 31 In this con-text, thiamine deficiency associated with prolongednausea and vomiting has been reported as the mostcritical micronutrient deficiency.32, 33

Non-adherence to dietary and supplementrecommendationsNon-adherence to recommendations for nutritional sup-plementation is widely recognised to be a critical causalfactor for nutritional deficiency after obesity surgery.While data analysing adherence to nutritional supple-mentation recommendations are inexplicably scarce, the

few reports published highlight a dangerous lack ofpatient awareness for the vital necessity of rigorous life-long supplementation. Modi et al. determined meanadherence to vitamin supplementation of 29.8% after6 months (data derived from electronic monitoring) in acohort of 41 adolescents after obesity surgery.34 In linewith this, Brolin et al.35 reported that over a 10-yearperiod only 33% of patients post-operatively adhered tomultivitamin supplementation regimens, while 8%reported never taking vitamin supplementation. Andreuet al. examined 101 consecutive patients undergoing lap-aroscopic RYGB (LRYGB) or LGB. Based on 3-day foodrecords, the authors demonstrated that, despite their rec-ommendation of protein supplementation, adherencedecreased from 63.4% at 4 months to 33.7% at12 months post-surgery.36 Despite the paucity of relevantdata, these few studies suffice to demonstrate the essen-tial importance of regular patient education in thecontext of long-term post-operative management, em-phasising the necessity for strict adherence to nutritionalsupplementation recommendations.

MacronutrientsWhile changes in protein ingestion and metabolism, lead-ing to protein malnutrition, are well-documented conse-



Pre-OPdeficiency


Signs andsymptoms



Zinc Up to30%

LSG 12%RYGB21–33%BPD-DS74–91%

Pre-existingdeficiency, BPD-DS, RYGB, SG,avoidance ofmeat, high use ofantacids

Skin lesions, poorwound healing;dermatitis,blunting of tastesense, hair loss,altered immunefunction, alopecia,glossitis

No recommendations Oral zincgluconate,sulphate, oracetate toprovide 8–15 mgelemental zinc,1 mg coppershould be givenfor each 8–15mg of zincreceived

Copper Unknown RYGB 2%BPD-DS10–24%

BPD-DS, RYGB, SG,high use ofantacids, high useof zincsupplementationor zinc lozenges

Anaemia,leukopenia,unsteady gait,numbness andtingling in handsand feet, painfulparesthesia, poorwound healing,paralysis

Oral copper gluconate,oxide or sulphate toprovide 2 mg elementalcopper; 1 mg of copperfor each 8–15 mg zinc

In severe deficiency:copper sulfate at adose of 2.4mg(elementalcopper) mixed in100ml normalsaline. Infusionover 4 hours dailyfor 5 days,followed by oralsubstitution.

Calcium and magnesium doses are per day.




quences of malabsorptive procedures, studies focusing oncarbohydrate intolerance are scarce. In 50% of bypasspatients (secondary) lactase deficiency may develop, or anexisting minor deficiency may manifest post-opera-tively.37 In a most recently presented pilot study, Opekunand colleagues38 reported for the first time impairedeffectivity of intestinal sucrase, a trypsin-activatedenzyme, in patients who had undergone RYGB surgery,evidenced by a13C-sucrose/glucose breath test.

Weight management strategies optimally aim toreduce body fat mass (FM) while minimising the reduc-tion in lean tissue mass (LTM). However, review of theavailable data shows that, compared to nonsurgicalweight-loss intervention, obesity surgery may be associ-ated with a greater loss of LTM. Furthermore, it isfrequently accompanied by nutritional protein defi-ciency39, 40 (serum albumin level <3.5 mg/dL), whichoccurs in up to 13% of morbidly obese patients 2 yearsafter distal RYGB (<150 cm small intestine remaining),in 5% after proximal RYGB, and in 3–18% after BPD.Muscle mass may considerably diminish over time andin extreme cases severe protein malnutrition (PM) mayoccur.41 PM is usually observed 3–6 months post-surgeryand has been demonstrated to increase both morbidityand annual hospitalisation rates.27

Both the severity of PM and the amount of LTM lostare evidentially influenced not only by average daily pro-tein intake (PI) and exercise but also to a considerabledegree by the surgical procedure.39, 42, 43 PM is mostcommonly seen after distal RYGB where the Roux limbexceeds 150 cm, with a post-procedural incidence of13% after 2 years and up to 27.9% after 10 years.44 Inaddition, PM is attributable to the development ofintolerance to protein rich foods containing lactose (seeabove).

While early clinical symptoms of PM often includehair loss, the presence of oedema is an indicator ofsevere PM. Diagnostic options include the determinationof serum albumin which, however, as a negative acute-phase reactant, has limited diagnostic value and shouldonly be assessed in the context of inflammatorystatus.36, 43, 45, 46 Although dual X-ray absorptiometry(DEXA) has been widely considered the ‘gold standard’for the measurement of FM and free fat mass (FFM) insevere obesity, it may overestimate pre-surgical FFMcompared to total body water.47 The use of body imped-ance assessment (BIA) has been shown to be a simple,inexpensive, non-invasive tool for repeated measure-ments of body composition, but its accuracy in the

severely obese and bariatric population appears limiteddue to a tendency to overestimate FM.36, 39, 48, 49

Although conclusive evidence is still lacking, currentconsensus guidelines recommend average daily PI of 60–120 g after RYGB, and 60–80 g or 1.1 g/kg of ideal bodyweight (IBW) following LSG to maximise post-surgicalLTM.27, 50, 51 In line with these recommendations, amore recently published prospective trial by Moize et al.provides supportive evidence that an average daily PI of60–120 g or 1.1 g/kg of IBW following obesity surgery isassociated with significantly better preservation ofLTM.46, 52 According to recently updated Europeanguidelines, daily PI should be increased by 30% followingBPD-DS, aiming for a daily PI of about 90 g.53, 54 Inaddition, credible evidence from three randomisedcontrolled trials has demonstrated that regular resistancetraining and aerobic exercise significantly improve thepreservation of LTM, and especially muscle mass, duringsubstantial weight loss.55–57

Several studies have demonstrated that, during cata-bolic periods, branched-chain amino acids (BCAA), par-ticularly leucine, stimulate muscle protein synthesis.58 Ofthese BCAAs, only leucine has been shown to beinvolved in the anabolic action of insulin, interactingwith the insulin-AKT pathway by stimulating the mam-malian target of rapamycin (mTOR), thus triggeringincreased muscle protein synthesis.59–61 The Food andAgriculture Organization of the UN/WHO thereforerecommends 1–3 g/day of leucine to maintain nitrogenbalance, whereas Layman’s review of 2004 advocateddaily intake of 7–12 g.62

Patients with manifest PM should be managed withoral protein supplements first, resorting if necessary toenteral feeding. Ideally, protein supplements should berich in BCAAs, especially leucine, rapidly digestibleand lactose-free. In severe cases of PM where enteralnutrition is not sufficient, the initiation of parenteralnutrition support may be required. Prolonged paren-teral feeding, however, is cause to consider whethersurgical revision in the form of elongation of the com-mon channel may be warranted in order to reducePM.27, 53

Essential mineralsWhile most studies dealing with long-term deficienciesof essential minerals after obesity surgery focus oncalcium or, less commonly, magnesium, other mineraldeficiencies, e.g. iodine, fluoride, are described only in afew case reports.



J. Stein et al.

Calcium. Calcium not only plays a vital role in the for-mation of bone mineral and regulation of enzymeactivities but also performs a secondary messengerfunction within the cell. In humans, daily dietary cal-cium intake is approximately 1000 mg, of which400 mg is absorbed. Absorption takes place primarilyin the ileum and jejunum via a passive paracellularroute, while active transcellular calcium transportoccurs chiefly in the duodenum. This pathway is satu-rable and is regulated by 1,25OH vitamin D.63, 64 Since99% of body calcium is stored in the skeleton, changesin calcium homoeostasis reflect changes in bone mass,and vice versa.

The reported incidence of calcium deficiency afterobesity surgery (e.g. distal RYGB) is approximately10%.65, 66 Malabsorption of calcium (and vitamin D) fol-lowing RYGB and BPD is caused by anatomical changes,in particular exclusion of the duodenum and the shortcommon channel.67 Steatorrhea, instigated by the inter-action of dietary calcium with fatty acids, also hinderscalcium (and magnesium) availability.68 A further riskfactor for calcium deficiency is secondary lactose malab-sorption, since those affected often follow low-lactosediets rigorously excluding milk products, and subse-quently have considerably reduced calcium intake.Regular and consistent avoidance of milk and milkproducts results in an average calcium intake ofapproximately 250–300 mg, whereas 1000–1200 mg arein fact required.

Patients with acute hypocalcemia present with oral,perioral and acral paresthesia as well as carpopedal and/or generalised tetany. Life-threatening complicationssuch as laryngospasm and cardiac arrhythmias mayoccur. Long-term calcium (and vitamin D) deficiencyresults in decreased bone mineral density (BMD),increasing the risk for osteoporosis and fractures.69–71

Since serum calcium concentrations do not reflect cal-cium status, isolated determination of serum calcium isof limited diagnostic value. Slight decreases in calciumlevels are compensated and normalised by a parathyroidhormone (PTH)-vitamin D-controlled increase in intesti-nal absorption, reduction in renal elimination, and inten-sified osteolysis. In addition, due to the affinity ofalbumin to calcium, low serum calcium levels may bemimicked in the presence of hypoalbuminemia, which iscommon in patients who have undergone obesity sur-gery. Measurement of calcium excretion in 24 h urine isrecommended, and alkaline phosphatase in serum shouldbe assessed at 6–12 month intervals. Serum PTH hasbeen reported to indicate increased bone turnover and

decreased bone mineral density. Therefore, serum PTHdetermination is recommended by several authors72

(Table 2). Since more than 90% of human body calciumis stored in the bone, measurement of bone density byDEXA is considered a more reliable marker.27 AxialDEXA measurements (spine and hip) are recommendedfor osteoporosis monitoring in patients who have under-gone RYGB or BPD (with or without DS) at baselineand at 2 years.73 However, since extreme obesity andexcess fat have been shown to reduce the accuracy ofDEXA, these measurements should be interpreted withcaution.74–76 Serum N-telopeptide, C-telopeptide andosteocalcin have been demonstrated to be promisingbone markers after RYGB (for review see77).

Different guidelines, respectively, specify daily cal-cium supplementation of 1200–1500 mg or up to2000 mg for effective treatment and prophylaxis ofcalcium deficiency following obesity surgery.27, 51

However, it must be borne in mind that oral calciummay impede intestinal absorption of cationic trace ele-ments such as iron, zinc and copper. In case ofincreased serum PTH, supplementation of calcium (andvitamin D) should be intensified. Since, not only ingeneral but also specifically in RYGB patients, thebioavailability of calcium citrate has proved superior tothat of calcium carbonate, the former is preferable forcalcium supplementation.78, 79 Bisphosphonates shouldbe considered in patients in whom osteoporosis persistsdespite appropriate calcium and vitamin D supplemen-tation (e.g. in case of persisting increased intact PTH(iPTH) and/or 24-h urine levels). As there are concernsregarding the adequacy of oral absorption and thepotential for ulcers, intravenous application should befavoured (e.g. 5 mg zoledronic acid once a year, or3 mg ibandronate every 3 months).73

Magnesium. Magnesium is the fourth commonest cationand the second most common intracellular cation in thehuman body. It plays a pivotal role as cofactor in morethan 300 enzymatic reactions (e.g. energy metabolism,muscle contraction, neuronal activity and cardiac excit-ability).80–82 Magnesium deficiency not only directlyinfluences bone crystal formation but also impacts thesecretion and activity of parathyroid hormone, thuscontributing to osteoporosis.83

The real post-operative prevalence of hypomagnese-mia, which may cause symptoms such as tetany seizures,cardiac arrhythmia and concomitant secondary electro-lyte disturbances such as hypocalcemia, is still a matterof debate.84 Dalcanale et al. showed in a recent study




that 32% of patients treated with RYGB are magnesiumdeficient. However, the data suggest that in somepatients, magnesium deficiency was already manifestpre-operatively.84, 85 In line with this, Lefebvre et al.most recently reported inadequate magnesium concen-trations in 35.4% of patients prior to obesity surgery.86

Furthermore, the data of Dalcanale and colleagues con-tradict those of Johansson et al. which demonstrateincreased circulating magnesium concentrations afterRYGB.87 These discrepancies may be explained at leastin part by the fact that that serum magnesium is a poor

indicator of total body magnesium stores, since it in factunderdetects magnesium deficits. Further well-designedstudies on magnesium status after obesity surgery aretherefore warranted. Nevertheless, since long-term intakeof proton pump inhibitors (PPIs), routinely given afterobesity surgery, has been shown to induce severe magne-sium depletion, clinical awareness of hypomagnesemia inthese patients is essential.88, 89

There is still no ‘gold standard’ for the determination ofmagnesium status in humans. However, serum magne-sium <0.75 mmol/L is a useful marker for severe defi-

Table 2 | Suggested biochemical tools for monitoring nutrient status in patients following obesity surgery

Macro-/micronutrient Screening marker Normal range Additional laboratory markers Pathological cut-off

Protein Serum albuminSerum protein

4–6 g/dL6–8 g/dL

↓ Pre-albumin↓ DEXA (fat free mass)

<20 mg/dL

Calcium Ionised calcium 4.48–4.92 mg/dL ↑ Alkaline phosphatase↑ intact PTH↓ DEXA (bone density)

> 65 U/mL> 51 pg/mlT-score <2.5

Magnesium Serum magnesium 1.5–2.0 mg/dL ↓Urinary magnesium <9.7 mg/24 hVitamin B1(thiamine)

Serum thiamine 10–64 lg/L ↓ Thiamine pyrophosphate(TPP)

↓ Erythrocyte transketolaseactivity (ETK)

<60 nmol/L<0.60 lmol/min/g Hb

Vitamin B12(cobalamin)

Serum B12 156–672 pmol/L ↓ HoloTC↓ MMA↑ Homocysteine

<37 pmol/L<271 nmol/L<12 lmol/mL

Folic acid Serum folate, RBC folate 4–20 nmol341–1.022 nmol/L

↑ Homocysteine <12 lmol/mL

Vitamin A Serum vitamin A 1.05–2.80 lmol/L ↓ Plasma retinol↓ Retinal binding protein

<10 mg/L<12 lg/mL

Vitamin D 25(OH) vitamin D <20 ng/mL: deficiency20–30 ng/mL:insufficiency>30: sufficiency

↑ Alkaline phosphatase↑ intact PTH↓ DEXA (bone density)

>65 U/mL>51 pg/mLT-score <2.5

Vitamin K IncreasedProthrombintime (INR)

<1.2 ↓ Plasma Vitamin K↑ des-c-carboxyprothrombin(also known as ProteinsInduced by Vitamin KAbsence; PIVKA-II)

<0.30 nmol/L<10 U/mL

Iron Ferritin <30 lg/L, CRP <5 lg/L<100 lg/L, CRP ≥5

↓ % Transferrin saturation(TSAT)

↑ Transferrin solublereceptor (sTfR)

↑ Zinc protoporphyrin(ZPP)

<20%>28 nmol/L>40 lmol/mol Hb

Zinc Plasma zinc 11–23 lmol/L ↓ RBC or WBC zinc↓ Urinary zinc

Not yet standardised

Copper Serum copper 11–22 lmol/L Copper chaperone forcopper/zinc superoxidedismutase

Not yet standardised

DEXA, dual-energy X-ray absorptiometry; PTH, parathyroid hormone; BPD-DS, biliopancreatic diversion with duodenal switch;RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy.



J. Stein et al.

ciency, while for values between 0.75 and 0.85 mmol/L,post-intake urinary magnesium monitoring can identifydeficient subjects90, 91 (Table 2). Analogous to calcium,the bioavailability of magnesium citrate has been found tobe superior to that of other magnesium preparations.92

MicronutrientsMicronutrients, including trace elements and water- andfat-soluble vitamins, are essential dietary factors whichcommonly act as enzymatic cofactors in various biochem-ical pathways and metabolic processes. While in 20% ofpatients, vitamin and mineral deficiencies are clearly evi-dent prior to surgery,18 severe – and occasionally poten-tial fatal – deficiencies may develop post-operatively inthe longer term, despite appropriate supplementationwith multivitamin and mineral preparations. Deficienciesvary in frequency according to the micronutrients con-cerned and the type of obesity surgery performed.93, 94

Clinical symptoms, diagnosis and treatment recommen-dations for micronutrient deficiencies following bariatricsurgery are summarised in Tables 1 and 2.

Water soluble vitaminsThiamine (Vitamin B1). Following absorption in theduodenum and proximal jejunum by an active,carrier-mediated process,95 thiamine (vitamin B1) isinitially phosphorylated to its active form, thiaminediphosphate (TDP). As TDP, thiamine plays a key rolein the metabolism of carbohydrates (i.e. glycolysis andoxidative decarboxylation), lipids and BCAAs.96–98

Pre-operative asymptomatic low thiamine concentra-tions have been reported in up to 29% of obese patients.99–102 Symptomatic thiamine deficiency occurs in up to 49%of patients post-surgery, depending on operative tech-nique.103 Persistent post-operative vomiting, identified asone of the main risk factors, occurs primarily in associa-tion with restrictive procedures, and less commonly inpatients who have undergone other forms of bypass sur-gery.104 Eating avoidance and noncompliance with oralsupplementation have also been identified as major causalfactors for thiamine deficiency.61, 62, 102, 103 A furthercritical factor is the short half-life of the vitamin (body thi-amine stores are usually sufficient only for 18–20 days).105

The most common early symptoms of thiamine defi-ciency are nausea, vomiting and constipation.97 Clinicalmanifestations of thiamine deficiency are highly variableand may involve the central and peripheral nervous sys-tem (e.g. ‘dry beriberi’), the cardiovascular system (e.g.‘wet beriberi’), and the metabolic system (e.g. metabolicacidosis).

‘Dry’ beriberi is a polyneuritic form of thiamine defi-ciency, manifesting as Wernicke’s encephalopathy (a dis-order affecting the eye movements, caused by lamenessof the eye muscles and double vision) and Korsakoff’spsychosis (antero- and retrograde amnesia, loss of long-term memory and retentiveness, and cerebellar trunk,stance and gait ataxia caused by atrophy of the cerebel-lum). These two disorders commonly occur together, ina combination known as the Wernicke–KorsakoffSyndrome: horizontal nystagmus, reflex disorders,impaired consciousness, disorientation, apathy andsomnolence, impairment of fine motor skills withdysdiadochokinesia, and vegetative disorders such ashypotension, hypothermia and hyperhidrosis (organicpsychosis). Polyneuritis usually manifests as symmetrical,bilateral, peripheral neural inflammation, beginning inthe lower extremities, with axonal degeneration anddemyelination.106, 107

‘Wet’ beriberi, on the other hand, is characterised bycardiovascular disorders; in particular, cardiomyopathy,with typical right ventricle enlargement (beriberi heartdisease), and cardiac insufficiency with subsequentoedema. In severe cases, lactic acidosis (‘Shoshin disease’)may occur, a potentially lethal complication.

Some symptoms are common to both beriberiforms; for example, pain and paresthesia. Besides theWernicke-Korsakoff syndrome, thiamine deficiency mayalso cause a painful acute peripheral neuropathy clini-cally reminiscent of Guillain-Barr�e syndrome.103, 108 Incases where appropriate oral thiamine substitution failsto effect clinical improvement, the term ‘bariatric’ beri-beri is used, the underlying cause of which is bacterialovergrowth.109

Thiamine levels should be monitored post-operativelyat 6-month intervals during the first 3 years aftersurgery.109, 110 For laboratory testing, the EuropeanFederation of Neurological Societies’ (EFNS) guidelinesrecommend the measurement of TDP in erythrocytes(red blood cells) by means of high-performance liquidchromatography, on account of its superior sensitivityand specificity.111 According to the WHO, clinical diag-nosis requires the presence of two out of the followingthree categories of diagnostic findings: (i) bilateral lowerlimb oedema; (ii) laboured respiration at rest or withexertion and (iii) paresthesia of the hands or feet, motordeficiency or loss of balance.112

Although in less severe (subclinical) cases, regularoral thiamine supplementation of 100 mg daily may besufficient, patients with suspected deficiency who alsoshow clinical symptoms should receive daily thiamine




supplementation of 100–200 mg (i.m/i.v.). Acute psy-choses and Wernicke’s encephalopathy call for inpatienttherapy with i.v. administration of 200–300 mg 3 9 /day for 3–5 days followed by 250 mg i.v. daily untilclinical improvement is seen.105, 107, 113, 114 Typicalinitial oculomotoric symptoms such as nystagmus,bilateral abducens paresis, conjugate gaze palsy andpupil disturbances resolve in response to adequate andtimely supplementation. Due to morphological changes,however, anamnestic disorders and chronic atactic gaitdisorder remain irreversible in approximately 50% ofpatients.115 Once clinical improvement has beenachieved, an oral maintenance dose of 50–100 mg dailyis recommended.97, 105

Cobalamin (vitamin B12). Despite existing recommenda-tions for nutrient supplementation, vitamin B12 defi-ciency is – after iron deficiency – one of the mostcommon causes of anaemia following biliopancreaticdiversion or Roux-en-Y stomach bypass (but not LAGBor LSG), with a prevalence of 4–62% after 2 years and19–35% after 5 years.116–119 Pre-operative low bloodvitamin B12 concentrations have been reported in upto 18%.18, 93, 94, 101, 102, 116, 120–123 Significant risk fac-tors for the development of pre-operative vitamin B12deficiency include not only SIBO (see above), but alsothe intake of metformin and proton pump inhibitors(PPIs), medications commonly taken by obesepatients.124, 125

Typical early (nonhaematological) neurological andpsychiatric symptoms of vitamin B12 deficiency precede‘pernicious’ anaemia often by months or even years.Neurological symptoms include paresthesia of the armsand legs, numbness of the skin (tingling, ‘furry’ feeling,pins and needles), numbness of the hands and feet,disturbances affecting coordination and sense of position,and in severe cases unsteady gait and paralysis. Thisdisorder, known as ‘myelosis funicularis’, is the mostfrequent secondary complication of vitamin B12 defi-ciency. In addition, lack of vitamin B12 can lead not onlyto concentration difficulties, memory disturbances andlack of retentiveness, but even, in some instances, todementia.126

Baseline and post-operative screening for vitamin B12deficiency is recommended in all bariatric patients. Inaddition, joint guidelines published by the AmericanAssociation of Clinical Endocrinologists (AACE), TheObesity Society (TOS) and the American Society forMetabolic and Bariatric Surgery (ASMBS) recommendannual screening in patients who have undergone surgi-

cal procedures excluding the lower part of the stom-ach.51, 73 However, measurement of vitamin B12 inserum has only limited sensitivity and specificity as adefining parameter, missing up to 30% of deficiencies.Thus, many patients exhibit clinical symptoms of defi-ciency despite vitamin B12 status being well within thespecified reference range.127

Vitamin B12 deficiency progresses through variousstages defined by specific clinical and subclinical symp-toms.128 On suspicion of anaemia induced by folic acid orvitamin B12 deficiency, serum homocystein or holotran-scobalamin (HoloTC, the first marker to show earlydepletion of vitamin B12) are the parameters of choice,due to their superior sensitivity.129, 130 Normal homocy-stein status (10–12 lmol/L) rules out folic acid andvitamin B12 deficiency with almost complete certainty.131

Measurement of methylmalonic acid (MMA) has beenshown to be a highly specific and sensitive (>98%) screen-ing marker for vitamin B12 deficiency, allowing earlydetection when used in combination with HoloTC.132

Following malabsorptive procedures (e.g. RYGB,BPD), oral supplementation at a dosage of 1000 lg ormore is recommended to maintain normal vitamin B12levels.73 On the other hand, there is no evidence to sup-port the use of high-dose vitamin B12 supplementationafter restrictive bariatric surgery (e.g. LAGB, LSG). Oraldosing according to the recommended daily allowance(RDA) seems adequate to prevent nutritional deficienciesin these patients.133 In the case of existing vitamin B12deficiency, parenteral (intramuscular or subcutaneous)administration remains the preferred route, especially inthe immediate post-operative period until stable serumlevels are achieved.73, 133 Unfortunately, therapy recom-mendations regarding dosage and timing of vitamin B12supplementation are largely inconsistent. However, thegiven dose must be calculated to take account of the factthat clinical symptoms usually only begin to manifestwhen body vitamin B12 stores (3–5 mg) are depleted toas little as 5–10%.134 The aim of therapy must thereforebe to fully compensate the deficit, and the dosage chosenaccordingly. To achieve the quickest possible repletion ofbody stores, administration of 1000 lg vitamin B12 i.m/s.c. daily for 5–7 days, followed by four or five furtherweekly injections of 1000 lg, is recommended.128, 131

Intranasal and sublingual applications of vitamin B12bypass the need for intrinsic factor (IF) and an ade-quately functioning ileum and have thus been proven tobe effective parenteral options.135, 136 However, studiesto prove their efficacy in the bariatric population areneeded.133



J. Stein et al.

Folate. Folate (folic acid, vitamin B9) is absorbedthroughout the intestinal tract by a specific pH-depen-dent, Na+-independent carrier-mediated mechanism.137

Acting as coenzyme for cellular one-carbon metabolism,folate plays a crucial role in the synthesis of thymidineand purine as well as in the metabolism of severalamino acids, e.g. homocysteine. Folate deficiency leadsto clinical abnormalities ranging from megaloblasticanaemia to growth retardation and congenital (neuraltube) defects.

The prevalence of folate deficiency after both restric-tive and malabsorptive procedures has been reportedto be 9–39%, and is especially common in womenwho become pregnant after bariatric surgery.138–141

Since body stores of folate (analogous to thiamine andzinc) are minimal, folate deficiency may occur at anearly post-operative stage. Since with adequate foodintake, folate is well absorbed throughout the smallintestine (and colon),137 folate deficiency is thought tobe predominantly due to decreased intake rather thanmalabsorption, and can easily be corrected by oralvitamin supplementation. Therefore, decreased serumfolate levels may reflect poor adherence to vitaminsupplementation.139 Consistent with this, Boylan et al.reported that, while gastric bypass patients taking 800–1000 lg folic acid per day maintained normal serumfolate levels, patients non-adherent to folate supple-mentation showed marginal or deficient status.35 Itshould also be kept in mind that folate deficiency mayarise as a consequence of vitamin B12 deficiency, sincethe latter plays an important role in the conversionof inactive methyltetrahydrofolic acid to activetetrahydrofolic acid.142

Since folate is essential for prevention of neural tubedefects in infants, women considering pregnancy follow-ing obesity surgery should receive counselling beforeconception and prophylactic supplementation of folateand vitamin B12.

143, 144

Vitamin C. Vitamin C (ascorbate, ascorbic acid), byaccelerating hydroxylation and amidation reactions,plays a crucial role in a variety of biochemical path-ways. In collagen biosynthetics, vitamin C is requiredas a cofactor for prolyl and lysyl hydroxylases, whichare essential for the hydroxylation of proline and lysinein collagen. Hydroxyproline and hydroxylysine areresponsible for the stabilisation of collagen, cross-linking the collagen peptides. Given orally, lower dosesof vitamin C (30–200 mg) are effectively absorbed (to70–85%) in the proximal jejunum, but absorption

decreases as the dose increases. Thus, doses greaterthan 500 mg daily contribute little to plasma or tissuestores. Unbound to protein, ascorbic acid is glomerular-ly filtered and effectively reabsorbed by the renaltubule.145

Vitamin C deficiency results in scurvy, characterisedby the degeneration of capillaries, bone and connectivetissue, leading to poor wound healing, perifollicularpetechiae, bleeding gums and corkscrew hair. Earlysymptoms of vitamin C deficiency, occurring within oneto 3 months, include fatigue and myalgia.146 While onlytwo cases of manifest scurvy have been reported in thebariatric population,147, 148 biochemical evidence of vita-min C deficiency is common, with a reported prevalenceof 10–50%.117, 149, 150

The RDA for vitamin C in healthy subjects, aiming tomaintain near maximal tissue concentrations, was set at75 mg/day (smokers 110 mg/day). However, there areno data concerning the prevention or treatment of vita-min C deficiency in patients following obesity surgery.Vitamin C deficiency in nonbariatric patients withscurvy was successfully treated with either 100 mg 3 9 /day or 500 mg once daily, reaching complete remissionafter 1 month.

Fat-soluble vitaminsVitamin D. Vitamin D is known to be the key regula-tor of calcium and bone metabolism, (i) by modulat-ing intestinal absorption and renal excretion ofcalcium and phosphate, thereby enabling proper PTHfunction, and (ii) by stimulating osteoblast and inhibit-ing osteoclast activity in order to optimise bone for-mation.151

Secondary hyperparathyroidism (SHPT), vitamin Ddeficiency and bone loss occur frequently after obesitysurgery.152–156 Increased post-surgical serum PTH levelshave been reported in up to 53% of patients.157–160

Depending on the operational technique, the duration offollow-up, and its defining parameters (e.g. for25-OH-vitamin D, <20 ng or <30 ng/mL), vitamin Ddeficiency with subsequent bone metabolism disordershas been reported to arise in 25–73% of cases, being sub-stantially higher after malabsorptive surgery. Malhayet al. retrospectively analysed vitamin D levels in 78patients with RYGB: 80% of these patients showed avitamin deficiency, and in 45%, this deficiency persisteddespite supplementation.161 It should be kept in mindthat sleeve gastrectomy, originally touted as a purelyrestrictive procedure, can also invoke clinically relevantvitamin D deficiency.162, 163




Notably, significant hypovitaminosis D is already pres-ent in a high proportion of patients prior to surgery,with reports ranging from 25% to 80%.102, 163–172

Reasons discussed for these low pre-operative levelsare inadequate intake, reduced sun exposure, anddecreased bioavailability of vitamin D due to its beingdeposited in adipose tissue.173 The latter is confirmed byrecent investigations showing that 25-OH-vitamin Dserum levels increase during the initial 6 months aftersurgery, only to decrease over the following months andyears.170, 174, 175 Therefore, to minimise post-operativerisk for the development of osteoporosis and osteomala-cia, all patients should undergo screening for vitaminD deficiency in advance of obesity surgery. In the caseof diagnosed vitamin D deficiency (25-OH-vitamin D <50 nmol/L), treatment should be commenced with20 000 IU two or three times a week (or 50 000 IU onceweekly). There are currently no evidence-based recom-mendations for effective vitamin D substitution followingobesity surgery. Two recently published prospective trialsconcluded that, following RYGB, at least 5000 IU/day arerequired to maintain and achieve adequate vitamin Dlevels.176, 177 In BPD patients, doses of up to 50 000 IU2–3 9 /day are recommended as prophylaxis.27, 51

Since individual patients may require larger (or smal-ler) doses, 25-OH-vitamin D levels should be measured2–4 weeks after initiation of supplementation andrepeated every 3 months in the first post-operative year.Most studies in non-obese patients have shown serumlevels of 50 nmol/L to suffice for prevention of osteopo-rosis.178 However, in a recent meta-analysis, Bisc-hoff-Ferrari et al. suggest that a 25-OH-vitamin D levelof over 60 nmol/L may be optimal in terms of fracturerisk reduction.179 Two reports demonstrated that follow-ing obesity surgery, 25-OH-vitamin D levels of at least75 nmol/L are more beneficial,154, 155 while in a morerecently published paper, Hewitt et al. suggest that inpatients with either gastric bypass or BPD-DS, levels ofaround 100 nmol/L or higher might be more effectivefor prevention of SHPT.72

Vitamin A. The term vitamin A includes provitamin car-otenoids such as beta-carotene, found in vegetables andfruits, and the more bioavailable retinols, found in ani-mal products. Vitamin A requires micelle formation withconjugated bile acids, and is mainly absorbed in theproximal jejunum.180, 181 Thus, vitamin A deficiency(VAD) after obesity surgery is observed both in the con-text of relative bile acid deficiency in patients with ashort common channel (after BPD, with or without duo-

denal switch, or extended RYGB),182–184 and in associa-tion with bile acid deconjugation due to upper intestinalbacterial overgrowth (see above). Reported prevalencesare 61–69% after BPD and 8–11% after RYGB.117, 184

Clinical manifestations of VAD are nyctalopia (nightblindness), pruritus, xerophthalmia and dry hair,185, 186

night blindness being one of the first clinical signs ofthe deficiency. In severe VAD, complete blindness canoccur, since vitamin A plays a vital role in phototrans-duction. VAD has also been shown to contribute tomaternal mortality and poor outcomes in pregnancyand lactation, leading to an increased risk for low birthweight, restricted intrauterine growth and mortalityduring the first 6 months of life.187 In addition, vitaminA is involved in maintaining immunocompetence (e.g.acting as key regulator of TGF-b-dependent immuneresponses).188, 189

Measurement of serum retinol concentrations and/orassessment of the carrier protein retinol-binding pro-tein (RBP) are the most common biomarkers used toidentify patients at risk of vitamin A deficiency,186 withserum retinol levels <0.35 lmol/L and/or RBP<4.8 lmol/L usually taken to define severe VAD. How-ever, clinical interpretation of serum retinol concentra-tions is subject to a number of limitations, namely: (i)analogous to vitamin B12, serum retinol concentrationsdo not begin to decline until liver vitamin A stores aredangerously low; (ii) iron deficiency may negativelyaffect serum retinol concentration and decrease mobili-sation of vitamin A from the liver,190 and (iii) sinceRBP is a negative acute-phase protein, retinol levels aredecreased even in the case of subclinical inflamma-tion.190, 191 Therefore, both of these markers should beevaluated only in the context of CRP status.192 Severalstudies carried out recently have demonstrated that theratio of serum retinol-binding protein to transthyretin(TTR) (RBP/TTR ratio) can diagnose VAD even in thepresence of inflammation. A cut-off value of <0.37 isproposed to have the highest sensitivity, specificity andpositive predictive value for VAD.192 More recently, thedetection of XN (night blindness) via standardisedinterview as a functional non-invasive, easy-to-performand inexpensive evaluation of VAD has been provensuccessful in class III obesity before and after bariatricsurgery.193, 194

Current guidelines do not recommend post-surgicalprophylactic vitamin A supplementation. However, sev-eral authors have clearly shown that daily supplementa-tion using over-the-counter multivitamins containing5000 IU of retinol acetate (RA) fails to prevent vitamin



J. Stein et al.

A deficiency.35, 183, 195 Comparing different vitamin Asupplementation protocols after RYGB, Pereira et al.most recently demonstrated a daily oral dose of10 000 IU of RA to be optimal.193 However, data are asyet insufficient for general recommendations regardingoptimal daily supplementation, and further studies areneeded. Nevertheless, in the light of the considerableimpact of VAD on health, especially during pregnancy,pre- and post-operative vitamin A status should be regu-larly monitored in individuals at risk.187

The ASMBS recommends 10 000–25 000 IU/day vita-min A orally for 1–2 weeks for the treatment of manifestvitamin A deficiency in the absence of corneal changes,and in the presence of corneal lesions 50 000–100 000 IUi.m. followed by 50 000 IU i.m. daily for 2 weeks.53 Vita-min A toxicity, leading to liver damage, headache, vomit-ing, diplopia, alopecia and bone abnormalities, may occurif daily intake exceeds 100 000 IU over more than6 months, but there is wide interindividual variability forthe threshold which may elicit toxicity.196

Vitamin E and K. There are few conclusive data regard-ing vitamin E and K deficiencies, and those which existare largely based on case descriptions. Reduced serumlevels of vitamin E have been found to occur in up to22% of RYGB patients after surgery. Neurological symp-toms (ataxia, muscle weakness, peripheral neuropathy)or unexplained anaemia may indicate vitamin E defi-ciency.197 While the optimal dose to prevent and/or treatvitamin E deficiency after RYGB or BPD is not known,recommendations range from 300–600 mg53 to 800–1200 IU198 per day.

Vitamin K acts as key cofactor for the carboxylationof glutamic acid residues in several proteins includingprothrombin and other factors involved in blood clot-ting, as well as proteins involved in bone homoeostasis(e.g. osteocalcin).199 Main sites of absorption are thedistal jejunum and ileum. Like other fat-soluble vita-mins requiring incorporation into micelles, vitamin Khas a rapid turnover and minimal body reservoirs,resulting, as in the case of thiamine, in a short half-life.200 While vitamin K is largely supplied by dietaryphylloquinones, biosynthesis by colonic bacteria mayserve as a further important source in humans.199

Symptoms of vitamin K deficiency include bleedingarteriosclerosis and osteoporosis.201, 202

Apart from case reports, there is only one prospectivetrial demonstrating vitamin K deficiency after malab-sorptive procedures (long limb LRYGB, BPD andBPD-DS).203, 204

Traditionally, vitamin K status is assessed by func-tional assays such as prothrombin time, which has, how-ever, been shown to underdetect vitamin K deficiency.205

Better strategies for assessment are the measurementof undercarboxylated proteins (also known as proteinsinduced by vitamin K absence; PIVKA-II) using highlysensitive enzyme-linked immunosorbent assays (ELISAs),or direct quantification of plasma vitamin K by means ofhigh-performance liquid chromatography (HPLC).206

Normal vitamin K plasma concentration usually rangesbetween 150 and 1150 ng/mL.206

Vitamin K deficiency should be treated initially with10 mg intramuscularly or subcutaneously for repletion,followed by 1–2 mg/week parenterally or orally afterRYGB or BPD.53

Trace elementsIron deficiency. Anaemia is one of the most frequentlong-term complications of all bariatric procedures, withan average prevalence of 17% (LSG) to 30% (verticalbanded gastroplasty, BPD, RYGB) after 2 years, and 45%after 5 years (BPD, RYGB).18, 119, 207, 208 Iron deficiencyanaemia (IDA) is seen in many morbidly obese patientseven prior to surgery18, 100, 209 and is significantly morecommon in men than in menstruating or pregnantwomen (35.5% vs. 14%).100, 209 Iron deficiency, alongwith vitamin B12 deficiency, is regarded as by far themost common cause of anaemia, occurring on average in15% of patients after 2 years and 31% after 5 years(LSG, BPD, RYGB).18, 207, 209 Interestingly, a veryrecently published study by Alexandrou et al. found ratesof IDA following RYGB and SG to be similar after4 years.210

Crucial causative factors in IDA are reduced ironabsorption due to the operatively induced dissociationof the resorptive area (duodenum) from the chyme,hindrance of iron resorption due to inflammation andthe release of stored iron (anaemia of chronic disease,ACD).211 The latter may explain the notably higherprevalence of IDA in males (android type): The con-siderably higher leptin and cytokine levels in menresult in increased hepcidin synthesis leading in turnto reduced intestinal iron absorption.212–214 Inaddition, intolerance of red meat and diminished gas-tric acid secretion may be causal factors in thedevelopment of iron deficiency and iron deficiencyanaemia.

Diagnosis of IDA and the criteria for efficient (andsufficient) supplementation of iron mirror those of otherforms of chronic inflammatory disease207, 211 assessment




of Hb and ferritin levels in relation to CRP and, in addi-tion, determination of zinc protoporphyrin to detectlatent iron deficiency independent of inflammatory sta-tus.204, 209 Due to the deactivation of the main site ofiron resorption, the duodenum (see above), it is hardlysurprising that oral iron substitution (haem or nonhaem)has been shown to be relatively ineffective.215–217

Furthermore, oral iron is associated with significantgastrointestinal side effects (e.g. nausea, abdominal pain,diarrhoea), resulting in poor adherence. European guide-lines recommend the use of oral iron supplementationfollowing obesity surgery only in the context of a pre-ventive regimen, a recommendation also applicable toother micronutrients.54 For the correction of ID or IDA,intravenous iron supplementation should bepreferred.54, 218–220 High-molecular intravenous ironpreparations of the new generation (e.g. ferric carboxy-maltose), which allow doses of up to 1000 mg to beadministered in a single session and over a short periodof time, have been shown to be highly effective in thetreatment of ID or IDA following bariatricsurgery.221, 222

For the correct calculation of individual iron require-ments, total body iron deficit in mg is usually deter-mined by means of the traditional Ganzoni formula223

(body weight in kg 9 (target Hb-actual Hb in g/dL) 9 0.24 + 500). However, although still generallyrecommended, the formula is not only inconvenientand error prone but also tends to underestimate ironrequirements. Furthermore, it is inconsistently used inclinical practice. In a recent study in patients withinflammatory bowel disease, Evstatiev et al. demon-strated that a novel and simple dosing strategy basedon body weight and baseline Hb was at least as safeand effective as Ganzoni-calculated dosing. A tableusing body weight in kg and Hb levels was used to cal-culate iron dosage in this study and can be used as apractical guide for everyday use224 (Table 3).

Zinc. As a major cofactor of over 300 enzymatic reac-tions, zinc plays a key role in cell division, cell growth,wound healing and immunity.225 Analogous to iron (andcopper), zinc is absorbed via the cation transporterDMT-1 in the duodenum and (to some degree) in theproximal jejunum. A growing number of recent studieshave examined the prevalence of zinc deficiency afterobesity surgery.226 While zinc deficiency is reportedlypresent in up to 30% of patients even before opera-tion,118, 138, 227, 228 its post-surgical prevalence is report-edly higher after BPD (74–91%) than after RYGB(21–33%) or LSG (12–13%).43, 94, 101, 138, 229

Due to decreased intestinal absorption and the lack offunctional body reserves, zinc deficiency may develop inthe early stages after obesity surgery.102, 230, 231 Clini-cally, the main symptoms of deficiency are alopecia,glossitis, nail dystrophy and in some severe cases,acrodermatitis enteropathica232.140

There are no standardised recommendations for zincsupplementation. However, since most of the standardmultivitamin formulations contain only small amountsof zinc, it seems questionable whether instructingpatients to take those containing zinc would be sufficientto prevent zinc deficiency.164, 230 In particular duringpregnancy, when daily requirements are higher due tofoetal and maternal development, a more aggressive sup-plementation regimen must be considered.44 Dependingon the bioavailability of the preparation given,233 zincdeficiency can initially be treated with 220 mg zincsulphate (50 mg elemental zinc), 50 mg zinc gluconateor 30 mg zinc histidine, daily or every other day. TheASMBS recommends 60 mg elemental zinc twice aday.53

Since, as already mentioned, zinc may interfere withabsorption of iron and copper, it is important to bear inmind that oral zinc substitution (e.g. 15 mg zinc histi-dine, to be taken approximately 45 min before breakfast)may, if carried out over a longer period of time, lead toreduced intestinal absorption of copper and iron.234, 235

Copper. Copper is a key component of many enzymesinvolved in the synthesis of neurotransmitters (i.e.norepinephrine) as well as intestinal iron absorption.Until recently, only a few case studies existed describ-ing hypocupremia following gastrointestinal bypasssurgery.109, 236–238 A contemporary study229 analysingpatients after RYGB or BPD with a 5-year follow-upshowed that, as has previously been shown for hypoz-incaemia, hypocupremia is much more frequent afterBPD (10.1–23.6%) than RYGB (1.9%).

Table 3 | Novel iron dosing strategy based on bodyweight and Hb levels modified from Evstatiev et al.224

Haemoglobin g/L Body weight <70 kg Body weight ≥70 kg

≥100 1000 mg 1500 mg70–100 1500 mg 2000 mg<70 2000 mg 2500 mg

First infusion 1000mg, then weekly infusions of 500mg up tocalculated dose.



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Even if none of the typical haematological (normo-chromic anaemia), cardiac (e.g. ICG anomalies, mitralvalve prolapse) or neurological (ataxia, myeloneuropathy)symptoms are initially observed, it is important to con-sider that neurological and/or haematological disordersrelated to copper deficiency may not occur until manyyears (mean onset 11.4 years) after obesity sur-gery.239, 240 Furthermore, anaemia induced by copperdeficiency is often misinterpreted as iron or vitamin B12deficiency anaemia.241 While there is no general recom-mendation for routine copper screening following obesitysurgery, copper levels should be evaluated in patientswith unexplained anaemia, neutropenia, myeloneuropa-thy and/or impaired wound healing.73

Current methods for assessing copper deficiency arebased on blood copper and ceruloplasmin which can,however, give false high results in the presence of obes-ity-induced inflammation. Data from animal and humanstudies suggest that copper chaperone for copper/zincsuperoxide dismutase is a more sensitive biomarker ofmild copper deficiency.242, 243 However, reference valuesare not yet available.

Copper levels should be closely monitored in patientsroutinely taking zinc supplementation, as this can causeimpairment to intestinal copper absorption. In fact, zincoverload has been described as the second commonestaetiology of copper myelopathy, accounting for up to16% of reported cases.240 Patients receiving zinc supple-mentation on a longer term basis should thereforereceive 1 mg of copper for each 8–15 mg of zinc.73

While there are no controlled trials or even specificguidelines for the repletion of copper in patients withneurological (or haematological) signs of copper defi-ciency, 2(1.5–3) mg i.v. copper for 5–6 days has beensuggested.73, 105, 237, 238, 244 Kazemi et al. successfullytreated copper deficiency in two gastric bypass patientswith 2 mg intravenous copper chloride infused over onehour.245 O’Donnell used 2 mg oral copper gluconatedaily combined with a multivitamin preparation andtube feeding, providing a total of 4.4 mg copper,236

while Koch et al. suggest 2 mg oral copper gluconateevery other day.198 Overall, it is recommended to pro-gress to i.v. administration only if oral supplementationfails. While the adult RDA for copper is 0.9 mg inhealthy subjects, the optimal dose of copper supplemen-tation for prevention of copper deficiency in the bariat-ric population is not known, but recent guidelinesrecommend that copper supplementation (2 mg/day)should be included as part of routine multivitamin andmineral supplementation.73

Selenium deficiency. Selenium is a part of the enzymeglutathione peroxidase, which protects cells from freeradical damage. Selenium deficiency following obesitysurgery has been described at a prevalence of up to20%.140 Clinical manifestations include peripheral andcardiac myositis and, in severe cases, cardiomyopathy(Morbus Keshan) with subsequent heart failure.246, 247

However, except for one case report describing cardio-myopathy probably due to selenium deficiency ninemonths after BPD,247 no other symptomatic cases ofselenium deficiency following obesity surgery have beenreported. There is currently insufficient evidence to sup-port routine selenium screening or supplementation afterobesity surgery. However, selenium levels should bechecked in patients who have undergone malabsorptivesurgical procedures and develop anaemia or fatigue, per-sistent diarrhoea, signs of cardiomyopathy or metabolicbone disease.73

Pharmacological consequences of obesity surgeryAlthough many comorbidities have been shown toimprove post-operatively, most patients still requiredrug therapy. Comparing pre- to post-surgery medica-tion, Darwich et al. recently showed that, while pre-scriptions of anti-diabetic and cardiovascular agents aresignificantly reduced following surgery, the number ofpatients prescribed anti-depressants remains constant.Furthermore, these and other authors have observed asignificant post-surgical increase in the prescription ofparacetamol, opioids, anti-microbials, and in particular,proton pump inhibitors/histamine H2-receptor antago-nists.248 It is therefore surprising that few data havebeen published analysing the effect of obesity surgeryon drug absorption and bioavailability, and thatthose available are based only on case reports or smallstudies.

However, for several reasons, changes in drugabsorption and/or bioavailability are serious potentialconcerns in obese patients who have undergone sur-gery249: First, nearly all oral drugs are absorbed in theproximal small intestine, which is bypassed after diver-sionary procedures. Second, gastric emptying disorders,diminished mucosal exposure, and changes in drug dis-solution and solubility resulting from alterations tointestinal pH are additional factors which may poten-tially impair drug absorption. Third, metabolism ofdrugs (e.g. statins) and xenobiotics by the intestinalcytochrome P450 enzymes (e.g. CYP3A4, CYP2C19)has been shown to be an important determinant oforal drug bioavailability.248, 250–252 Fourth, intestinal




efflux transporters such as P-glycoprotein (P-gp) mayalso influence the absorption of orally administereddrugs (e.g. immunosuppressants) through active sub-strate efflux253–255 (Table 4).

In the light of the reported post-surgical increase inPPI prescription, clinicians should also be aware thatseveral studies (including a systematic review of 16 stud-ies) have shown that by increasing gastric pH, coadmin-istration of PPIs may diminish bioavailability of weakbasic drugs (e.g. the anti-fungal agents, ketoconazole anditraconazole and the antibiotics,256, 257 cefpodoxime andenoxacin).258 In contrast, an increase in the bioavailabil-ity of several cardiovascular drugs (e.g. digoxin,nifedipine) has been reported. Metabolic interaction ofPPIs with the hepatic cytochrome P450 isoformCYP2C19 may additionally result in altered pharmacody-namic and pharmacokinetic drug properties.258, 259 Lastbut not least, coadministration of PPIs has been demon-strated to hinder the absorption of a variety of micronu-trients such as cobalamin, iron and zinc.256, 257, 259

As mentioned above, only a few studies have yetinvestigated the influence of obesity surgery on pharma-cokinetics and/or drug bioavailability, and those pub-lished largely pertain to RYGB or JIB (for review,see248, 260–262). Overall, most of the studies exhibit clearlimitations not only in terms of their small subject popu-lations but also in their use of only a single dose analysisperformed at different (mostly single) post-surgery timepoints. Depending on drug lipophilicity, the metabolicpathway involved (e.g. cytochrome P450 enzymes orefflux transporters) and the bypassed absorption area,bioavailability (assessed by area under the curve, AUC)

has been shown to be decreased, unchanged or evenincreased.

Reduced bioavailability has been found for anti-microbial drugs (azithromycin, moxifloxacin, nitrofuran-toin, amoxicillin, penicillin),263–266 immunosuppressiveagents (ciclosporin, tacrolimus, sirolimus, mycophenolicacid),267 the thyroid hormone levothyroxine,268, 269

anti-convulsants (phenytoin, phenobarbital)270 and thehighly lipophilic tricyclic anti-depressants (TCAs) andselective serotonin reuptake inhibitors (SSRIs).271–273 How-ever, in a study comparing the bioavailability of differentSSRIs six and twelve months after obesity surgery, Hamadet al. found that decreased AUC levels returned to base-line after 12 months in approximately 50% of cases.

In contrast, increased absorption and bioavailabilitywere demonstrated for metformin, first line drug ofchoice for the treatment of type II diabetes.274 A signifi-cant increase in systemic exposure after both RYGB andBPD-DS was also demonstrated for atorvastatin, albeitwith large inter- and intraindividual variations.275–277

Therefore, and bearing in mind the above-mentionedfindings of Hamad et al., close monitoring is essential inpatients treated with these drugs or others with similarpharmacokinetic properties. Table 5 summarises currentpublished data concerning alterations in absorption and/or bioavailability of the most common drugs used afterobesity surgery.

Conclusion and future aspectsSince the introduction of laparoscopic techniques, obesitysurgery has become not only a safe and effective meansof achieving sustainable weight loss but also – more

Table 4 | Summary of physiological parameter alterations following obesity surgery affecting drug bioavailability(mod. from Darwich et al. 2012)248

Physiological parameters RYGB BPD-DS JIB SG

StomachGastric emptying time (min) 7 (CV 45%) Unaltered Unaltered 13.6 (CV 53%)Initial fluid volume (mL) 9.9 (CV 30%) Unaltered Unaltered 24.2 (CV 30%)Gastric pH 6.4 (CV 38%) 1.5 (CV 38%) 1.5 (CV 38%) 1.5 (CV 38%)Small intestineBypass (segments) Duo, jejunum I Jejunum I, II Jejunum II UnalteredBile delay (segments)* Duo-jejunum II Duo-ileum II Jejunum II UnalteredSmall intestinal metabolismCyp3A bypass (segments) Duo, jejunum I Jejunum I, II Jejunum II-ileum III UnalteredCyp3A4 bypass (nmol/total gut) 50.2 (CV 60%) 30.0 (CV 60%) 32.3 (CV 60%) 66.2 (CV 60%)Cyp3A5 bypass (nmol/total gut) 18.7 (CV 60%) 11.2 (CV 60%) 12.1 (CV 60%) 24.2 (CV 60%)

BPD-DS, biliopancreatic diversion with duodenal switch; CV, coefficient of variation; duo, duodenum; IL, ileum; jej, jejunum; JIB, je-junoileal bypass; RYGB, Roux-en-Y gastric bypass; SG, sleeve gastrectomy.

* Following RYGB and BPD-DS surgery, the inlet of bile and pancreatic fluids is delayed to the common channel.



J. Stein et al.

Table 5 | Controlled trials on drug bioavailability following obesity surgery

Author Drug DosagePatients(n)

Surgicalprocedure

AUCratio* P-value

Practicalimplicationsfor doseadjustment§

AnalgesicsTerry et al. 1982265 Paracetamol 1500 mg 8 JIB 1.0 >0.05 NoneAndreasen et al. 1977279 Phenazone 15 mg/kg bw 28 JIB 1.0 >0.05 None

Anti-microbialsKampmann et al. 1984280 Ampicillin 750 mg 6 JIB 0.37 <0.05 IncreasePadwal et al. 2012263 Azithromycin 500 mg 28 RYGB 0.68 <0.05 IncreasePrince et al. 1984281 Erythromycin 250 mg 7 RYGB 0.61 >0.05 IncreaseDe Smet et al. 2012266 Mofloxacin 400 mg 12 RYGB <0.05 IncreaseTerry et al. 1982265 Phenoxymethylpenicillin 1000 mg 3 JIB 10.4 <0.05 ReduceGarrett et al. 1981282 Sulfisoxazole 1000 mg 3 JIB 0.84 <0.05 Increase

Anti-convulsantsPournaras et al.2011270 Phenytoin 200 mg 16 JIB 0.32 <0.05

Anti-depressants/Anti-psychotics

Hamad et al. 2012273

Roerig et al. 2012272

Roerig et al. 2013271

SSRIs†SNRIs†sertralineDuloxetine

100 mg60 mg

661012

RYGBRYGBRYGBRYGB

0.5410.400.58

n.c.n.c.< 0.05< 0.05

IncreaseIncreaseIncreaseIncrease

Anti-diabeticsPadwal et al. 2011274 Metformin 1000 mg 32 RYGB 1.20 <0.05 Reduce

Anti-ulcerativesCossu et al. 1999283 Ranitidine 300 mg 21 BPD 1.43 <0.05 ReduceAdami et al. 1991284 Ranitidine 150/300 mg 7 BPD ‘unaltered’

Cardiovascular drugsGerson et al. 1980285 Digoxin 0.5 mg 25 JIB 0.76 <0.05 IncreaseMarcus et al. 1977286 Digoxin 0.5 mg 11 JIB 0.89 >0.05 IncreaseBackman et al. 1979287 Hydrochlorothiazide 75 mg 11 JIB 0.46 <0.05 Increase

ImmunosuppressantsRogers et al. 2008267 Mycophenolic acid

SirolimusTacrolimus

2000 mg6 mg2.4 mg

766

RYGBRYGBRYGB

0.660.54“reduced”

n.c.n.c.n.c.

IncreaseIncrease

StatinsSkottheim et al. 2009276

Skottheim et al. 2010277

Jakobsen et al. 2013275

AtorvastatinAtorvastatinAtorvastatin

20–80 mg20–80 mg

10121210

BPD-DSRYGBRYGBBPD-DS

1.851.83‡1.2 (0.8)‡2.0 (0.7)

<0.05<0.05<0.05<0.05

ReduceReduceReduceReduce

Thyroid blockersKampmann et al. 1984280 Propylthiouracil 400 mg 9 JIB 1.09 >0.05 None

Thyroid hormonesRubio et al. 2012269 Levothyroxine* 600 lg 30 RYGB 1.0 > 0.05 None

AUC, area under curve; GBP, gastric bypass (gastroplasty and Roux-en-Y gastric bypass); JIB, jejunoileal bypass; BPD, biliopancre-atic diversion; BPD-DS, Biliopancreatic Diversion with duodenal switch; RYGB, Roux-en-Y gastric bypass; n.c., not calculated.

* AUC post-surgery/AUC pre-surgery, values <1 indicates decreased, >1 increased bioavailability.

† SSRIs, selective serotonin reuptake inhibitors (citalopram, n = 2, sertraline, n = 2, escitalopram, n = 2); SNRIs, serotonin-norepi-nephrine reuptake inhibitors (venlafaxine, n = 25, duloxetine, n = 1).

‡ Short-ratio 3–8 weeks post-surgery (long-term-ratio >21 months post-surgery).

§ In the light of the mostly inadequate data, dose modification should be performed with due caution and in the context of closeclinical and laboratory monitoring.




Table 6 | Pre- and post-operative laboratory monitoring in patients following obesity surgery (for biochemical toolssee Table 2)*

Macro-/Micronutrient Pre-operative 1 month 3 months 6 months 12 months 18 months 24 months Annually

Chemistrypanel†

AGB AGB AGB AGB AGB AGB AGB AGB

SG SG SG SG SG SG SG SGRYGB RYGB RYGB RYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Thiamine(vitamin B1)

AGB AGB AGB AGB AGB AGB

SG SG SG SG SG SGRYGB RYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Cobalamin(vitamin B12)

AGB AGB AGB AGB AGB

SG SG SG SG SGRYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Vitamin A AGBSGRYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Vitamin D AGB AGB AGB AGBSG SG SG SGRYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Vitamin K AGBSGRYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS

Iron AGB AGB AGB AGBSG SG SG SGRYGB RYGB RYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Zinc AGB AGB AGB AGBSG SG SG SGRYGB RYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS BPD-DS

Copper AGBSGRYGB RYGB RYGB RYGBBPD-DS BPD-DS BPD-DS BPD-DS

Calcium AGB AGB AGB AGB AGBSG SG SG SG SGRYGB RYGB RYGB RYGB RYGBBPD/BPD-DS BPD/BPD-DS BPD/BPD-DS BPD/BPD-DS BPD/BPD-DS

iPTH AGB AGB AGB AGBSG SG SG SGRYGB RYGB RYGB RYGBBPD/BPD-DS BPD/BPD-DS BPD/BPD-DS BPD/BPD-DS

DEXA, bonedensity

AGB AGB AGB every 2–5years

SG SG SGRYGB RYGB RYGBBPD/BPD-DS BPD/BPD-DS BPD/BPD-DS



J. Stein et al.

importantly – a successful treatment approach for obes-ity-associated comorbidities such as metabolic andcardiovascular diseases (e.g. diabetes, hypertension, non-alcoholic fatty liver disease).

However, since all of the procedures currentlyperformed involve radical modifications of the gastroin-testinal anatomy and physiology, they have the potentialto cause not only nutritional deficiencies but alsosubstantial relevant changes in the bioavailability of awide range (probably the majority) of drugs. Althoughthe crucial significance of these pharmacological effectsis becoming clearly evident, very few clinical dataare currently available on drug absorption followingobesity surgery. Thus, clinical studies designed toestablish guidelines for commonly prescribed drugs inbariatric patients, and for the monitoring of drugs exhib-iting a narrow therapeutic window, are urgentlywarranted.

Like organ transplant patients, individuals who haveundergone any form of obesity surgery require closemonitoring with respect to nutrient levels and pharmaco-logically significant parameters on a lifelong basis,and especially meticulously during the first post-operativeyear. Furthermore, patient education stressing the needfor rigorous lifelong adherence to nutritional supplemen-tation therapy is of utmost importance. Regular andmeticulous long-term monitoring of nutrient status(Table 6) is therefore essential for two reasons; first, toassess patient adherence to supplementation regimens,

and second, to facilitate the timely detection of a varietyof macro- and micronutrient deficiencies which may occa-sionally develop even in spite of consistent and adequatesupplementation. Moreover, in the light of the evidentiallyhigh prevalence of nutrient deficiencies in obese patientseven prior to surgery, appropriate screening and earlysupplementation therapy should be considered fundamen-tal elements of routine pre-surgical procedure.278

AUTHORSHIPGuarantor of the article: J. Stein.Author contributions: CS, HR: acquisition of data; analy-sis and interpretation of data; critical revision of themanuscript for important intellectual content. RW:analysis and interpretation of data; critical revision ofthe manuscript for important intellectual content. JS:design and concept of review article; acquisition of data;analysis and interpretation of data; drafting of themanuscript; critical revision of the manuscript forimportant intellectualcontent. All authors approved thefinal version of the manuscript. The authors thank JanetCollins for language support and proof-reading of themanuscript.

ACKNOWLEDGEMENTSDeclaration of personal interests: The authors have noconflicts of interests.Declaration of funding interests: No funding was receivedin connection with this article.


Macro-/Micronutrient Pre-operative 1 month 3 months 6 months 12 months 18 months 24 months Annually

Albumin(pre-albumin)

AGB AGB AGB AGB

SG SG SG SGRYGB RYGB RYGB RYGB RYGB RYGBBPD/BPD-DS BPD/BPD-DS BPD/BPD-DS BPD/BPD-DS BPD/BPD-DS BPD/

BPD-DS

AGB, adjustable gastric banding; BPD, biliopancreatic diversion; BPD-DS, biliopancreatic diversion with duodenal switch; CBC,complete blood cell count; DEXA, dual-energy X-ray absorptiometry; iPTH, intact parathyroid hormone.

* Data adapted from references.54, 278

† Includes liver function tests, glucose, electrolytes, creatinine.




REFERENCES1. Weiner RA, El-Sayes I, Manger T,

et al. Antidiabetic efficacy of obesitysurgery in Germany: A qualityassurance nationwide survey. SurgObes Relat Dis 2014; 10: 322–7.

2. Sjostrom L, Gummesson A., Sj€ostr€omCD, et al. Effects of bariatric surgeryon cancer incidence in obese patientsin Sweden (Swedish Obese SubjectsStudy): a prospective, controlledintervention trial. Lancet Oncol 2009;10: 653–62.

3. Sjostrom L, Sj€ostr€om CD, Sullivan M,Wedel H; Swedish Obese SubjectsStudy Scientific Group. Lifestyle,diabetes, and cardiovascular riskfactors 10 years after bariatricsurgery. N Engl J Med 2004; 351:2683–93.

4. Sjostrom L, Narbro K, Sj€ostr€om CD,et al. Effects of bariatric surgery onmortality in Swedish obese subjects. NEngl J Med 2007; 357: 741–52.

5. Sjostrom L, Peltonen M, Jacobson P,et al. Bariatric surgery and long-termcardiovascular events. JAMA 2012;307: 56–65.

6. Bradley D, Magkos F, Klein S.Effects of bariatric surgery on glucosehomeostasis and type 2 diabetes.Gastroenterology 2012; 143: 897–912.

7. Sj€ostr€om L, Peltonen M, Jacobson P,et al. Association of bariatric surgerywith long-term remission of type 2diabetes and with microvascular andmacrovascular complications. JAMA2014; 311: 2297–304.

8. Lancaster RT, Hutter MM. Bands andbypasses: 30-day morbidity andmortality of bariatric surgicalprocedures as assessed by prospective,multi-center, risk-adjusted ACS-NSQIP data. Surg Endosc 2008; 22:2554–63.

9. Morino M, Toppino M, Forestieri P,Angrisani L, Allaix ME, Scopinaro N.Mortality after bariatric surgery:analysis of 13,871 morbidly obesepatients from a national registry. AnnSurg 2007; 246: 1002–7; discussion1007–1009.

10. Buchwald H, Estok R, Fahrbach K,Banel D, Sledge I. Trends in mortalityin bariatric surgery: a systematicreview and meta-analysis. Surgery2007; 142: 621–32; discussion 632–625.

11. Longitudinal Assessment of BariatricSurgery (LABS) Consortium, FlumDR, Belle SH, et al. Perioperativesafety in the longitudinal assessmentof bariatric surgery. N Engl J Med2009; 361: 445–54.

12. Ballantyne GH, Belsley S, Stephens D,et al. Bariatric surgery: low mortalityat a high-volume center. Obes Surg2008; 18: 660–7.

13. Birkmeyer NJ, Dimick JB, Share D,et al. Hospital complication rateswith bariatric surgery in Michigan.JAMA 2010; 304: 435–42.

14. Elder KA, Wolfe BM. Bariatricsurgery: a review of procedures andoutcomes. Gastroenterology 2007; 132:2253–71.

15. Melissas J, Koukouraki S, AskoxylakisJ, et al. Sleeve gastrectomy: arestrictive procedure? Obes Surg 2007;17: 57–62.

16. Nicoletti CF, Lima TP, Donadelli SP,Salgado W Jr, Marchini JS, NoninoCB. New look at nutritional care forobese patient candidates for bariatricsurgery. Surg Obes Relat Dis 2013; 9:520–5.

17. Moize V, Deulofeu R, Torres F, deOsaba JM, Vidal J. Nutritional intakeand prevalence of nutritionaldeficiencies prior to surgery in aSpanish morbidly obese population.Obes Surg 2011; 21: 1382–8.

18. Schweiger C, Weiss R, Berry E,Keidar A. Nutritional deficiencies inbariatric surgery candidates. ObesSurg 2010; 20: 193–7.

19. Lakhani SV, Shah HN, Alexander K,Finelli FC, Kirkpatrick JR, Koch TR.Small intestinal bacterial overgrowthand thiamine deficiency after Roux-en-Y gastric bypass surgery inobese patients. Nutr Res 2008; 28:293–8.

20. Machado JD, Campos CS, Lopes DahSilva C, et al. Intestinal bacterialovergrowth after Roux-en-Y gastricbypass. Obes Surg 2008; 18: 139–43.

21. Murphy MF, Sourial NA, Burman JF,et al. Megaloblastic anaemia due tovitamin B12 deficiency caused bysmall intestinal bacterial overgrowth:possible role of vitamin B12analogues. Br J Haematol 1986; 62:7–12.

22. Grace E, Shaw C, Whelan K,Andreyev HJ. Review article: smallintestinal bacterial overgrowth–prevalence, clinical features, currentand developing diagnostic tests, andtreatment. Aliment Pharmacol Ther2013; 38: 674–88.

23. Bohm M, Siwiec RM, Wo JM.Diagnosis and management of smallintestinal bacterial overgrowth. NutrClin Pract 2013; 28: 289–99.

24. Shah SC, Day LW, Somsouk M,Sewell JL. Meta-analysis: antibiotictherapy for small intestinal bacterial

overgrowth. Aliment Pharmacol Ther2013; 38: 925–34.

25. Stein JM, Schneider AR. Bacterialovergrowth syndrome. ZGastroenterol 2007; 45: 620–8.

26. Di Stefano M, Miceli E, Missanelli A,Mazzocchi S, Corazza GR. Absorbablevs. non-absorbable antibiotics in thetreatment of small intestine bacterialovergrowth in patients with blind-loop syndrome. Aliment PharmacolTher 2005; 21: 985–92.

27. Heber D, Greenway FL, Kaplan LM,Livingston E, Salvador J, Still C.Endocrine and nutritionalmanagement of the post-bariatricsurgery patient: an Endocrine SocietyClinical Practice Guideline. J ClinEndocrinol Metab 2010; 95:4823–43.

28. Hsu LK, Mulliken B, McDonagh B,et al. Binge eating disorder inextreme obesity. Int J Obes RelatMetab Disord 2002; 26: 1398–403.

29. Monteforte MJ, Turkelson CM.Bariatric surgery for morbidobesity. Obes Surg 2000; 10: 391–401.

30. Laurenius A, Larsson I, Bueter M,et al. Changes in eating behaviourand meal pattern following Roux-en-Y gastric bypass. Int J Obes (Lond)2012; 36: 348–55.

31. Powers PS, Perez A, Boyd F,Rosemurgy A. Eating pathologybefore and after bariatric surgery: aprospective study. Int J Eat Disord1999; 25: 293–300.

32. Singh S, Kumar A. Wernickeencephalopathy after obesity surgery:a systematic review. Neurology 2007;68: 807–11.

33. Jeong HJ, Park JW, Kim YJ, Lee YG,Jang YW, Seo JW. Wernicke’sencephalopathy after sleevegastrectomy for morbid obesity - Acase report. Ann Rehabil Med 2011;35: 583–6.

34. Modi AC, Zeller MH, Xanthakos SA,Jenkins TM, Inge TH. Adherence tovitamin supplementation followingadolescent bariatric surgery. Obesity(Silver Spring) 2013; 21: E190–5.

35. Brolin RE, Leung M. Survey ofvitamin and mineral supplementationafter gastric bypass andbiliopancreatic diversion for morbidobesity. Obes Surg 1999; 9: 150–4.

36. Andreu A, Moize V, Rodriguez L,Flores L, Vidal J. Protein intake, bodycomposition, and protein statusfollowing bariatric surgery. Obes Surg2010; 20: 1509–15.

37. Song A, Fernstrom MH. Nutritionaland psychological considerations after



J. Stein et al.

bariatric surgery. Aesthet Surg J 2008;28: 195–9.

38. Opekun RA, Fracolli K, Brandt ML,Sherman V, Hernandez K,Chumpitazi BP. Mucosal SucraseActivity Is Diminished FollowingBariatric Roux-en-Y Surgery.Gastroenterology 2014; 146: S493.

39. Chaston TB, Dixon JB, O’Brien PE.Changes in fat-free mass duringsignificant weight loss: a systematicreview. Int J Obes (Lond) 2007; 31:743–50.

40. Moize V, Andreu A, Rodriguez L,et al. Protein intake and lean tissuemass retention following bariatricsurgery. Clin Nutr 2013; 32: 550–5.

41. Faintuch J, Matsuda M, Cruz ME,et al. Severe protein-caloriemalnutrition after bariatricprocedures. Obes Surg 2004; 14: 175–81.

42. Friedrich AE, Damms-Machado A,Meile T, et al. Laparoscopic sleevegastrectomy compared to amultidisciplinary weight loss programfor obesity–effects on bodycomposition and protein status. ObesSurg 2013; 23: 1957–65.

43. Moize V, Andreu A, Flores L, et al.Long-term dietary intake andnutritional deficiencies followingsleeve gastrectomy or Roux-En-Ygastric bypass in a mediterraneanpopulation. J Acad Nutr Diet 2013;113: 400–10.

44. Levinson R, Silverman JB, Catella JG,Rybak I, Jolin H, Isom K.Pharmacotherapy prevention andmanagement of nutritionaldeficiencies post Roux-en-Y gastricbypass. Obes Surg 2013; 23: 992–1000.

45. Gehring N, Imoberdorf R. WegmannM, Ruhlin M, Ballmer PE.Serumalbumin–a qualified parameterto determine the nutritional status?Swiss Med Wkly 2006; 136: 664–9.

46. Moize V, Andreu A, Rodriguez L,et al. Protein intake and lean tissuemass retention following bariatricsurgery. Clin Nutr 2012; 32: 550–5.

47. Levitt DG, Beckman LM, Mager JR,et al. Comparison of DXA and watermeasurements of body fat followinggastric bypass surgery and aphysiological model of body water,fat, and muscle composition. J ApplPhysiol 2010; 1985: 786–95.

48. Savastano S, Belfiore A, Di Somma C,et al. Validity of bioelectricalimpedance analysis to estimate bodycomposition changes after bariatricsurgery in premenopausal morbidlywomen. Obes Surg 2010; 20: 332–9.

49. Alvarez VP, Dixon JB, Strauss BJ,Laurie CP, Chaston TB, O’Brien PE.

Single frequency bioelectricalimpedance is a poor method fordetermining fat mass in moderatelyobese women. Obes Surg 2007; 17:211–21.

50. Snyder-Marlow G, Taylor D, LenhardMJ. Nutrition care for patientsundergoing laparoscopic sleevegastrectomy for weight loss. J AmDiet Assoc 2010; 110: 600–7.

51. Mechanick JI, Kushner RF,Sugerman HJ, et al. AmericanAssociation of ClinicalEndocrinologists, The Obesity Society,and American Society for Metabolic &Bariatric Surgery medical guidelines forclinical practice for the perioperativenutritional, metabolic, and nonsurgicalsupport of the bariatric surgery patient.Obesity (Silver Spring) 2009; 17(Suppl.1): S1–70.

52. Faria SL, Faria OP, Buffington C,deAlmeida Cardeal M, Ito MK.Dietary protein intake and bariatricsurgery patients: a review. Obes Surg2011; 21: 1798–805.

53. Aills L, Blankenship J, Buffington C,Furtado M, Parrott J. ASMBS AlliedHealth Nutritional Guidelines for theSurgical Weight Loss Patient. SurgObes Relat Dis 2008; 4: S73–108.

54. Fried M, Hainer V, Basdevant A,et al. Inter-disciplinary Europeanguidelines on surgery of severeobesity. Int J Obes (Lond) 2007; 31:569–77.

55. Rice B, Janssen I, Hudson R, Ross R.Effects of aerobic or resistanceexercise and/or diet on glucosetolerance and plasma insulin levels inobese men. Diabetes Care 1999; 22:684–91.

56. Janssen I, Ross R. Effects of sex on thechange in visceral, subcutaneousadipose tissue and skeletal muscle inresponse to weight loss. Int J Obes RelatMetab Disord 1999; 23: 1035–46.

57. Janssen I, Fortier A, Hudson R, RossR. Effects of an energy-restrictive dietwith or without exercise onabdominal fat, intermuscular fat, andmetabolic risk factors in obesewomen. Diabetes Care 2002; 25: 431–8.

58. Rennie MJ, Bohe J, Smith K,Wackerhage H, Greenhaff P.Branched-chain amino acids as fuelsand anabolic signals in humanmuscle. J Nutr 2006; 136: 264S–8S.

59. Jitomir J, Willoughby DS. Leucine forretention of lean mass on ahypocaloric diet. J Med Food 2008;11: 606–9.

60. Devkota S, Layman DK. Proteinmetabolic roles in treatment ofobesity. Curr Opin Clin Nutr MetabCare 2010; 13: 403–7.

61. Dodd KM, Tee AR. Leucine andmTORC1: a complex relationship.Am J Physiol Endocrinol Metab 2012;302: E1329–42.

62. Layman DK. Protein quantity andquality at levels above the RDAimproves adult weight loss. J Am CollNutr 2004; 23: 631S–6S.

63. Dimke H, Hoenderop JG, Bindels RJ.Molecular basis of epithelial Ca2+and Mg2+ transport: insights fromthe TRP channel family. J Physiol2011; 589: 1535–42.

64. Christakos S, Dhawan P, Porta A,Mady LJ, Seth T. Vitamin D andintestinal calcium absorption. MolCell Endocrinol 2011; 347: 25–9.

65. Bloomberg RD, Fleishman A, NalleJE, Herron DM, Kini S. Nutritionaldeficiencies following bariatricsurgery: what have we learned? ObesSurg 2005; 15: 145–54.

66. Brethauer SA, Chand B, Schauer PR.Risks and benefits of bariatricsurgery: current evidence. Clevel ClinJ Med 2006; 73: 993–1007.

67. Riedt CS, Brolin RE, Sherrell RM,Field MP, Shapses SA. True fractionalcalcium absorption is decreased afterRoux-en-Y gastric bypass surgery.Obesity (Silver Spring) 2006; 14:1940–8.

68. Haderslev KV, Jeppesen PB,Mortensen PB, Staun M. Absorptionof calcium and magnesium inpatients with intestinal resectionstreated with medium chain fattyacids. Gut 2000; 46: 819–23.

69. Brzozowska MM, Sainsbury A,Eisman JA, Baldock PA, Center JR.Bariatric surgery, bone loss, obesityand possible mechanisms. Obes Rev2013; 14: 52–67.

70. Fleischer J, Stein EM, Bessler M,et al. The decline in hip bone densityafter gastric bypass surgery isassociated with extent of weight loss.J Clin Endocrinol Metab 2008; 93:3735–40.

71. Williams SE. Metabolic bone diseasein the bariatric surgery patient. J Obes2011; 2011: 634614.

72. Hewitt S, Sovik TT, Aasheim ET,et al. Secondary hyperparathyroidism,vitamin D sufficiency, and serumcalcium 5 years after gastric bypassand duodenal switch. Obes Surg 2013;23: 384–90.

73. Mechanick JI, Youdim A, Jones DB,et al. Clinical practice guidelines forthe perioperative nutritional,metabolic, and nonsurgical support ofthe bariatric surgery patient–2013update: cosponsored by AmericanAssociation of ClinicalEndocrinologists, The Obesity Society,and American Society for Metabolic




& Bariatric Surgery. Obesity (SilverSpring) 2013; 21(Suppl. 1): S1–27.

74. Tothill P, Laskey MA, OrphanidouCI, van Wijk M. Anomalies in dualenergy X-ray absorptiometrymeasurements of total-body bonemineral during weight change usingLunar, Hologic and Norlandinstruments. Br J Radiol 1999; 72:661–9.

75. Hangartner TN, Johnston CC.Influence of fat on bonemeasurements with dual-energyabsorptiometry. Bone Miner 1990; 9:71–81.

76. Yu EW, Thomas BJ, Brown JK,Finkelstein JS. Simulated increases inbody fat and errors in bone mineraldensity measurements by DXA andQCT. J Bone Miner Res 2012; 27:119–24.

77. Hage MP. El-Hajj Fuleihan G. Boneand mineral metabolism in patientsundergoing Roux-en-Y gastric bypass.Osteoporos Int 2014; 25: 423–39.

78. Sakhaee K, Bhuket T, Adams-Huet B,Rao DS. Meta-analysis of calciumbioavailability: a comparison ofcalcium citrate with calciumcarbonate. Am J Ther 1999; 6: 313–21.

79. Tondapu P, Provost D, Adams-HuetB, Sims T, Chang C, Sakhaee K.Comparison of the absorption ofcalcium carbonate and calcium citrateafter Roux-en-Y gastric bypass. ObesSurg 2009; 19: 1256–61.

80. Kupetsky-Rincon EA, Li Q, Uitto J.Magnesium reduces carotid intima-media thickness in a mouse model ofpseudoxanthoma elasticum: a noveltreatment biomarker. Clin Transl Sci2012; 5: 259–64.

81. Weisinger JR, Bellorin-Font E.Magnesium and phosphorus. Lancet1998; 352: 391–6.

82. Fawcett WJ, Haxby EJ, Male DA.Magnesium: physiology andpharmacology. Br J Anaesth 1999; 83:302–20.

83. Castiglioni S, Cazzaniga A, AlbisettiW, Maier JA. Magnesium andosteoporosis: current state ofknowledge and future researchdirections. Nutrients 2013; 5: 3022–33.

84. Haenni A. Magnesium status aftergastric bypass surgery. Obes Surg2011; 21: 951; author reply 952.

85. Corica F, Allegra A, Ientile R, BuemiM. Magnesium concentrations inplasma, erythrocytes, and platelets inhypertensive and normotensive obesepatients. Am J Hypertens 1997; 10:1311–3.

86. Lefebvre P, Letois F, Sultan A, NoccaD, Mura T, Galtie RF. Nutrient

deficiencies in patients with obesityconsidering bariatric surgery: a cross-sectional study. Surg Obes Relat Dis2013; 10: 540–6.

87. Johansson HE, Zethelius B, OhrvallM, Sundbom M, Haenni A. Serummagnesium status after gastric bypasssurgery in obesity. Obes Surg 2009;19: 1250–5.

88. Luk CP, Parsons R, Lee YP, HughesJD. Proton pump inhibitor-associatedhypomagnesemia: what do FDA datatell us? Ann Pharmacother 2013; 47:773–80.

89. Hess MW, Hoenderop JG, Bindels RJ,Drenth JP. Systematic review:hypomagnesaemia induced by protonpump inhibition. Aliment PharmacolTher 2012; 36: 405–13.

90. Fleming CR, George L, Stoner GL,Tarrosa VB, Moyer TP. Theimportance of urinary magnesiumvalues in patients with gut failure.Mayo Clin Proc 1996; 71: 21–4.

91. Arnaud MJ. Update on theassessment of magnesium status. Br JNutr 2008; 99(Suppl. 3): S24–36.

92. Walker AF, Marakis G, Christie S,Byng M. Mg citrate found morebioavailable than other Mgpreparations in a randomised,double-blind study. Magnes Res 2003;16: 183–91.

93. Donadelli SP, Junqueira-Franco MV,de Mattos Donadelli CA, et al. Dailyvitamin supplementation andhypovitaminosis after obesity surgery.Nutrition 2012; 28: 391–6.

94. Gehrer S, Kern B, Peters T,Christoffel-Courtin C, Peterli R.Fewer nutrient deficiencies afterlaparoscopic sleeve gastrectomy (LSG)than after laparoscopic Roux-Y-gastric bypass (LRYGB) - aprospective study. Obes Surg 2010;20: 447–53.

95. Laforenza U, Patrini C, Alvisi C,Faelli A, Licandro A, Rindi G.Thiamine uptake in human intestinalbiopsy specimens, includingobservations from a patient withacute thiamine deficiency. Am J ClinNutr 1997; 66: 320–6.

96. Lonsdale D. Review of thebiochemistry, metabolism and clinicalbenefits of thiamin(e) and itsderivatives. Evid-Based ComplementAlternat Med 2006; 3: 49–59.

97. Sriram K, Manzanares W, Joseph K.Thiamine in nutrition therapy. NutrClin Pract 2012; 27: 41–50.

98. Manzetti S, Zhang J, van der Spoel D.Thiamin function, metabolism,uptake, and transport. Biochemistry2014; 53: 821–35.

99. Carrodeguas L, Kaidar-Person O,Szomstein S, Antozzi P, Rosenthal R.

Preoperative thiamine deficiency inobese population undergoinglaparoscopic bariatric surgery. SurgObes Relat Dis 2005; 1: 517–22;discussion 522.

100. Flancbaum L, Belsley S, Drake V,Colarusso T, Tayler E. Preoperativenutritional status of patientsundergoing Roux-en-Y gastric bypassfor morbid obesity. J GastrointestSurg 2006; 10: 1033–7.

101. Ernst B, Thurnheer M, Schmid SM,Schultes B. Evidence for the necessityto systematically assess micronutrientstatus prior to bariatric surgery. ObesSurg 2009; 19: 66–73.

102. Saif T, Strain GW, Dakin G, GagnerM, Costa R, Pomp A. Evaluation ofnutrient status after laparoscopicsleeve gastrectomy 1, 3, and 5 yearsafter surgery. Surg Obes Relat Dis2012; 8: 542–7.

103. Aasheim ET. Wernickeencephalopathy after bariatricsurgery: a systematic review. AnnSurg 2008; 248: 714–20.

104. Angstadt JD, Bodziner RA. Peripheralpolyneuropathy from thiaminedeficiency following laparoscopicRoux-en-Y gastric bypass. Obes Surg2005; 15: 890–2.

105. Rudnicki SA. Prevention andtreatment of peripheral neuropathyafter bariatric surgery. Curr TreatOptions Neurol 2010; 12: 29–36.

106. Thomson AD, Cook CC, Guerrini I,Sheedy D, Harper C, Marshall EJ.Wernicke’s encephalopathy revisited.Translation of the case history sectionof the original manuscript by CarlWernicke ‘Lehrbuch derGehirnkrankheiten fur Aerzte andStudirende’ (1881) with acommentary. Alcohol Alcohol 2008;43: 174–9.

107. Thomson AD, Marshall EJ. Thenatural history and pathophysiologyof Wernicke’s Encephalopathy andKorsakoff’s Psychosis. Alcohol Alcohol2006; 41: 151–8.

108. Juhasz-Pocsine K, Rudnicki SA,Archer RL, Harik SI. Neurologiccomplications of gastric bypasssurgery for morbid obesity. Neurology2007; 68: 1843–50.

109. Bal B, Koch TR, Finelli FC, Sarr MG.Managing medical and surgicaldisorders after divided Roux-en-Ygastric bypass surgery. Nat RevGastroenterol Hepatol 2010; 7: 320–34.

110. Galvin R, Brathen G, Ivashynka A,Hillbom M, Tanasescu R, Leone MA.EFNS guidelines for diagnosis,therapy and prevention of Wernickeencephalopathy. Eur J Neurol 2010;17: 1408–18.



J. Stein et al.

111. Mancinelli R, Brathen G, IvashynkaA, et al. Simultaneous liquidchromatographic assessment ofthiamine, thiamine monophosphateand thiamine diphosphate in humanerythrocytes: a study on alcoholics. JChromatogr B Analyt Technol BiomedLife Sci 2003; 789: 355–63.

112. WHO. Thiamine deficiency and itsprevention and control in majoremergencies [online]. http://whqlibdoc.who.int/hq/1999/WHO_NHD_99.13.pdf, 1999.

113. Thomson AD, Marshall EJ. Thetreatment of patients at risk ofdeveloping Wernicke’sencephalopathy in the community.Alcohol Alcohol 2006; 41: 159–67.

114. Sechi G, Serra A. Wernicke’sencephalopathy: new clinical settingsand recent advances in diagnosis andmanagement. Lancet Neurol 2007; 6:442–55.

115. Kopelman MD, Thomson AD,Guerrini I, Marshall EJ. TheKorsakoff syndrome: clinical aspects,psychology and treatment. AlcoholAlcohol 2009; 44: 148–54.

116. Blume CA, Boni CC, Casagrande DS,Rizzolli J, Padoin AV, Mottin CC.Nutritional profile of patients beforeand after Roux-en-Y gastric bypass:3-year follow-up. Obes Surg 2012; 22:1676–85.

117. Clements RH, Yellumahanthi K,Wesley M, Ballem N, Bland KI.Incidence of vitamin deficiency afterlaparoscopic Roux-en-Y gastricbypass in a university hospital setting.Am Surg 2006; 72: 1196–202;discussion 1203-1194.

118. Dalcanale L, Oliveira CP, Faintuch J,et al. Long-term nutritional outcomeafter gastric bypass. Obes Surg 2010;20: 181–7.

119. Skroubis G, Sakellaropoulos G,Pouggouras K, Mead N, NikiforidisG, Kalfarentzos F. Comparison ofnutritional deficiencies after Roux-en-Y gastric bypass and afterbiliopancreatic diversion with Roux-en-Y gastric bypass. Obes Surg 2002;12: 551–8.

120. Aasheim ET, Johnson LK, Hofso D,Bohmer T, Hjelmesaeth J. Vitaminstatus after gastric bypass and lifestyleintervention: a comparativeprospective study. Surg Obes RelatDis 2012; 8: 169–75.

121. Damms-Machado A, Friedrich A,Kramer KM, et al. Pre- andpostoperative nutritional deficienciesin obese patients undergoinglaparoscopic sleeve gastrectomy. ObesSurg 2012; 22: 881–9.

122. Ramaswamy A, Gonzalez R, SmithCD. Extensive preoperative testing is

not necessary in morbidly obesepatients undergoing gastric bypass. JGastrointest Surg 2004; 8: 159–64;discussion 164-155.

123. Toh SY, Zarshenas N, Jorgensen J.Prevalence of nutrient deficiencies inbariatric patients. Nutrition 2009; 25:1150–6.

124. Long AN, Atwell CL, Yoo W,Solomon SS. Vitamin B(12) deficiencyassociated with concomitantmetformin and proton pumpinhibitor use. Diabetes Care 2012; 35:e84.

125. de Jager J, Kooy A, Lehert P, et al.Long term treatment with metforminin patients with type 2 diabetes andrisk of vitamin B-12 deficiency:randomised placebo controlled trial.BMJ 2010; 340: c2181.

126. Lachner C, Steinle NI, Regenold WT.The neuropsychiatry of vitamin B12deficiency in elderly patients. JNeuropsychiatry Clin Neurosci 2012;24: 5–15.

127. Carmel R. Subclinical cobalamindeficiency. Curr Opin Gastroenterol2012; 28: 151–8.

128. Herrmann W, Obeid R. Causes andearly diagnosis of vitamin B12deficiency. Dtsch Arztebl Int 2008;105: 680–5.

129. Herrmann W, Obeid R. Utility andlimitations of biochemical markers ofvitamin B12 deficiency. Eur J ClinInvest 2013; 43: 231–7.

130. Nexo E, Hoffmann-Lucke E.Holotranscobalamin, a marker ofvitamin B-12 status: analytical aspectsand clinical utility. Am J Clin Nutr2011; 94: 359S–65S.

131. Hvas AM, Nexo E. Diagnosis andtreatment of vitamin B12 deficiency–an update. Haematologica 2006; 91:1506–12.

132. Snow CF. Laboratory diagnosis ofvitamin B12 and folate deficiency: aguide for the primary care physician.Arch Intern Med 1999; 159: 1289–98.

133. Majumder S, Soriano J, Louie CruzA, Dasanu CA. Vitamin B12deficiency in patients undergoingbariatric surgery: Preventive strategiesand key recommendations. Surg ObesRelat Dis 2013; 9: 1013–9.

134. Dali-Youcef N, Andres E. An updateon cobalamin deficiency in adults.QJM 2009; 102: 17–28.

135. Slot WB, Merkus FW, Van DeventerSJ, Tytgat GN. Normalization ofplasma vitamin B12 concentration byintranasal hydroxocobalamin invitamin B12-deficient patients.Gastroenterology 1997; 113: 430–3.

136. Sharabi A, Cohen E, Sulkes J, GartyM. Replacement therapy for vitaminB12 deficiency: comparison between

the sublingual and oral route. Br JClin Pharmacol 2003; 56: 635–8.

137. Said HM. Intestinal absorption ofwater-soluble vitamins in health anddisease. Biochem J 2011; 437: 357–72.

138. Madan AK, Orth WS, Tichansky DS,Ternovits CA. Vitamin and tracemineral levels after laparoscopicgastric bypass. Obes Surg 2006; 16:603–6.

139. Mallory GN, Macgregor AM. Folatestatus following gastric bypass surgery(the great folate mystery). Obes Surg1991; 1: 69–72.

140. Shankar P, Boylan M, Sriram K.Micronutrient deficiencies afterbariatric surgery. Nutrition 2010; 26:1031–7.

141. von Drygalski A, Andris DA. Anemiaafter bariatric surgery: more than justiron deficiency. Nutr Clin Pract 2009;24: 217–26.

142. Shane B, Stokstad EL. Vitamin B12-folate interrelationships. Annu RevNutr 1985; 5: 115–41.

143. American College of Obstetriciansand Gynecologists. ACOG Committeeopinion no. 549: obesity inpregnancy. Obstet Gynecol 2013; 121:213–7.

144. Obeid R, Koletzko B, Pietrzik K.Critical evaluation of lowering therecommended dietary intake of folate.Clin Nutr 2014; 33: 252–9.

145. Padayatty SJ, Levine M. New insightsinto the physiology andpharmacology of vitamin C. CMAJ2001; 164: 353–5.

146. Sauberlich HE. Pharmacology ofvitamin C. Annu Rev Nutr 1994; 14:371–91.

147. Hansen EP, Metzsche C, HenningsenE, Toft P. Severe scurvy after gastricbypass surgery and a poorpostoperative diet. J Clin Med Res2012; 4: 135–7.

148. Simmons M. Modern-day scurvy: acase following gastric bypass. BariatNurs Surg Patient Care 2009; 4: 139–44.

149. Strohmayer E, Via MA, YanagisawaR. Metabolic management followingbariatric surgery. Mt Sinai J Med2010; 77: 431–45.

150. Riess KP, Farnen JP, Lambert PJ,Mathiason MA, Kothari SN. Ascorbicacid deficiency in bariatric surgicalpopulation. Surg Obes Relat Dis 2009;5: 81–6.

151. Anderson PH, Atkins GJ, Turner AG,Kogawa M, Findlay DM, Morris HA.Vitamin D metabolism within bonecells: effects on bone structure andstrength. Mol Cell Endocrinol 2011;347: 42–7.

152. DiGiorgi M, Daud A, Inabnet WB,et al. Markers of bone and calcium




metabolism following gastric bypassand laparoscopic adjustable gastricbanding. Obes Surg 2008; 18:1144–8.

153. Clements RH, Yellumahanthi K,Wesley M, Ballem N, Bland KI.Hyperparathyroidism and vitamin Ddeficiency after laparoscopic gastricbypass. Am Surg 2008; 74: 469–74;discussion 474-465.

154. Grethen E, McClintock R, Gupta CE,et al. Vitamin D andhyperparathyroidism in obesity. J ClinEndocrinol Metab 2011; 96: 1320–6.

155. Balsa JA, Botella-Carretero JI,Peromingo R, et al. Role of calciummalabsorption in the development ofsecondary hyperparathyroidism afterbiliopancreatic diversion. J EndocrinolInvest 2008; 31: 845–50.

156. Signori C, Zalesin KC, Franklin B,Miller WL, McCullough PA. Effect ofgastric bypass on vitamin D andsecondary hyperparathyroidism. ObesSurg 2010; 20: 949–52.

157. Youssef Y, RichardsWO, SekharN,et al.Risk of secondaryhyperparathyroidism after laparoscopicgastric bypass surgery in obesewomen.Surg Endosc 2007; 21: 1393–6.

158. Diniz Mde F, Diniz MT, Sanches SR,et al. Elevated serum parathormoneafter Roux-en-Y gastric bypass. ObesSurg 2004; 14: 1222–6.

159. Johnson JM, Maher JW, Samuel I,Heitshusen D, Doherty C, DownsRW. Effects of gastric bypassprocedures on bone mineral density,calcium, parathyroid hormone, andvitamin D. J Gastrointest Surg 2005;9: 1106–10; discussion 1110-1101.

160. Johnson JM, Maher JW, DeMaria EJ,Downs RW, Wolfe LG, Kellum JM.The long-term effects of gastricbypass on vitamin D metabolism.Ann Surg 2006; 243: 701–4;discussion 704-705.

161. Mahlay NF, Verka LG, Thomsen K,Merugu S, Salomone M. Vitamin Dstatus before Roux-en-Y and efficacyof prophylactic and therapeutic dosesof vitamin D in patients after Roux-en-Y gastric bypass surgery. ObesSurg 2009; 19: 590–4.

162. Aarts EO, Janssen IM, Berends FJ.The gastric sleeve: losing weight asfast as micronutrients? Obes Surg2011; 21: 207–11.

163. Gudzune KA, Huizinga MM, ChangHY, Asamoah V, Gadgil M, ClarkJM. Screening and Diagnosis ofMicronutrient Deficiencies Before andAfter Bariatric Surgery. Obes Surg2013; 23: 1581–9.

164. Gasteyger C, Suter M, Gaillard RC,Giusti V. Nutritional deficiencies afterRoux-en-Y gastric bypass for morbid

obesity often cannot be prevented bystandard multivitaminsupplementation. Am J Clin Nutr2008; 87: 1128–33.

165. Ybarra J, S�anchez-Hern�andez J, GichI, et al. Unchanged hypovitaminosisD and secondaryhyperparathyroidism in morbidobesity after bariatric surgery. ObesSurg 2005; 15: 330–5.

166. Gemmel K, Santry HP, Prachand VN,Alverdy JC. Vitamin D deficiency inpreoperative bariatric surgerypatients. Surg Obes Relat Dis 2009; 5:54–9.

167. Stein EM, Strain G, Sinha N, et al.Vitamin D insufficiency prior tobariatric surgery: risk factors and apilot treatment study. Clin Endocrinol2009; 71: 176–83.

168. Carlin AM, Rao DS, Meslemani AM,et al. Prevalence of vitamin Ddepletion among morbidly obesepatients seeking gastric bypasssurgery. Surg Obes Relat Dis 2006; 2:98–103; discussion 104 .

169. Nelson ML, Bolduc LM, Toder ME,Clough DM, Sullivan SS. Correctionof preoperative vitamin D deficiencyafter Roux-en-Y gastric bypasssurgery. Surg Obes Relat Dis 2007; 3:434–7.

170. Lin E, Armstrong-Moore D, Liang Z,et al. Contribution of adipose tissueto plasma 25-hydroxyvitamin Dconcentrations during weight lossfollowing gastric bypass surgery.Obesity (Silver Spring) 2011; 19: 588–94.

171. Ducloux R, et al. Vitamin Ddeficiency before bariatric surgery:should supplement intake beroutinely prescribed? Obes Surg 2011;21: 556–60.

172. Censani M, Stein EM, Shane E, et al.Vitamin D deficiency is prevalent inmorbidly obese adolescents prior tobariatric surgery. ISRN Obes 2013;2013: pii: 284516.

173. Wortsman J, Matsuoka LY, Chen TC,Lu Z, Holick MF. Decreasedbioavailability of vitamin D inobesity. Am J Clin Nutr 2000; 72:690–3.

174. Sinha N, Shieh A, Stein EM, et al.Increased PTH and 1.25(OH)(2)Dlevels associated with increasedmarkers of bone turnover followingbariatric surgery. Obesity (SilverSpring) 2011; 19: 2388–93.

175. Pramyothin P, Biancuzzo RM, Lu Z,Hess DT, Apovian CM, Holick MF.Vitamin D in adipose tissue andserum 25-hydroxyvitamin D afterroux-en-Y gastric bypass. Obesity(Silver Spring) 2011; 19: 2228–34.

176. Goldner WS, Stoner JA, Lyden E,et al. Finding the optimal dose ofvitamin D following Roux-en-Ygastric bypass: a prospective,randomized pilot clinical trial. ObesSurg 2009; 19: 173–9.

177. Flores L, Osaba MJ, Andreu A, Moiz�eV, Rodr�ıguez L, Vidal J. Calcium andvitamin D supplementation aftergastric bypass should beindividualized to improve or avoidhyperparathyroidism. Obes Surg 2010;20: 738–43.

178. Ross AC, Manson JE, Abrams SA,et al. The 2011 report on dietaryreference intakes for calcium andvitamin D from the Institute ofMedicine: what clinicians need toknow. J Clin Endocrinol Metab 2011;96: 53–8.

179. Bischoff-Ferrari HA, Willett WC,Orav EJ, et al. A pooled analysis ofvitamin D dose requirements forfracture prevention. N Engl J Med2012; 367: 40–9.

180. Parker RS. Absorption, metabolism,and transport of carotenoids. FASEB J1996; 10: 542–51.

181. D’Ambrosio DN, Clugston RD,Blaner WS. Vitamin A metabolism:an update. Nutrients 2011; 3: 63–103.

182. Hatizifotis M, Dolan K, Newbury L,Fielding G. Symptomatic vitamin Adeficiency following biliopancreaticdiversion. Obes Surg 2003; 13: 655–7.

183. Eckert MJ, Perry JT, Sohn VY, et al.Incidence of low vitamin A levels andocular symptoms after Roux-en-Ygastric bypass. Surg Obes Relat Dis2010; 6: 653–7.

184. Zalesin KC, Miller WM, Franklin B,et al. Vitamin A deficiency aftergastric bypass surgery: anunderreported postoperativecomplication. J Obes 2011; 2011: pii:760695.

185. Sommer A. Vitamin A deficiency andclinical disease: an historicaloverview. J Nutr 2008; 138: 1835–9.

186. Tanumihardjo SA. Vitamin A:biomarkers of nutrition fordevelopment. Am J Clin Nutr 2011;94: 658S–65S.

187. Chagas CB, Saunders C, Pereira S,et al. Vitamin A deficiency inpregnancy: perspectives after bariatricsurgery. Obes Surg 2013; 23: 249–54.

188. Stephensen CB. Vitamin A, infection,and immune function. Annu RevNutr 2001; 21: 167–92.

189. McLaren DS, Kraemer K. Vitamin Ain health. World Rev Nutr Diet 2012;103: 33–51.

190. Tanumihardjo SA. Assessing vitaminA status: past, present and future. JNutr 2004; 134: 290S–3S.



J. Stein et al.

191. Thurnham DI, McCabe GP,Northrop-Clewes CA, Nestel P.Effects of subclinical infection onplasma retinol concentrations andassessment of prevalence of vitaminA deficiency: meta-analysis. Lancet2003; 362: 2052–8.

192. McLaren DS, Kraemer K. Assessmentof vitamin A status. World Rev NutrDiet 2012; 103: 52–64.

193. Pereira S, Saboya C, Ramalho A.Impact of different protocols ofnutritional supplements on the statusof vitamin A in class III obesepatients after Roux-en-Y gastricbypass. Obes Surg 2013; 23: 1244–51.

194. Pereira SE, Saboya CJ, Saunders C,Ramalho A. Serum levels and liverstore of retinol and their associationwith night blindness in individualswith class III obesity. Obes Surg 2012;22: 602–8.

195. Pereira S, Saboya C, Chaves G,Ramalho A. Class III obesity and itsrelationship with the nutritionalstatus of vitamin A in pre- andpostoperative gastric bypass. ObesSurg 2009; 19: 738–44.

196. Penniston KL, Tanumihardjo SA. Theacute and chronic toxic effects ofvitamin A. Am J Clin Nutr 2006; 83:191–201.

197. Ueda N, Suzuki Y, Rino Y, et al.Correlation between neurologicaldysfunction with vitamin E deficiencyand gastrectomy. J Neurol Sci 2009;287: 216–20.

198. Koch TR, Finelli FC. Postoperativemetabolic and nutritionalcomplications of bariatric surgery.Gastroenterol Clin North Am 2010;39: 109–24.

199. Shearer MJ, Vitamin K. Lancet 1995;345: 229–34.

200. Olson RE. The function andmetabolism of vitamin K. Annu RevNutr 1984; 4: 281–337.

201. Booth SL. Roles for vitamin Kbeyond coagulation. Annu Rev Nutr2009; 29: 89–110.

202. Rishavy MA, Berkner KL. Vitamin Koxygenation, glutamate carboxylation,and processivity: defining the threecritical facets of catalysis by thevitamin K-dependent carboxylase.Adv Nutr 2012; 3: 135–48.

203. Slater GH, Ren CJ, Siegel N, et al.Serum fat-soluble vitamin deficiencyand abnormal calcium metabolismafter malabsorptive bariatric surgery.J Gastrointest Surg 2004; 8: 48–55;discussion 54-45.

204. Bersani I, De Carolis MP, Salvi S,Zecca E, Romagnoli C, De Carolis S.Maternal-neonatal vitamin Kdeficiency secondary to maternal

biliopancreatic diversion. BloodCoagul Fibrinolysis 2011; 22: 334–6.

205. Strople J, Lovell G, Heubi J.Prevalence of subclinical vitamin Kdeficiency in cholestatic liver disease.J Pediatr Gastroenterol Nutr 2009; 49:78–84.

206. Ducros V, Pollicand M, Laporte F,Favier A. Quantitative determinationof plasma vitamin K1 by high-performance liquid chromatographycoupled to isotope dilution tandemmass spectrometry. Anal Biochem2010; 401: 7–14.

207. Munoz M, Botella-Romero F, Gomez-Ramirez S, Campos A, Garcia-ErceJA. Iron deficiency and anaemia inbariatric surgical patients: causes,diagnosis and proper management.Nutr Hosp 2009; 24: 640–54.

208. Obinwanne KM, Fredrickson KA,Mathiason MA, Kallies KJ, Farnen JP,Kothari SN. Incidence, treatment, andoutcomes of iron deficiency afterlaparoscopic Roux-en-Y gastricbypass: a 10-year analysis. J Am CollSurg 2014; 218: 246–52.

209. Skroubis G, Karamanakos S,Sakellaropoulos G, Panagopoulos K,Kalfarentzos F. Comparison of earlyand late complications after variousbariatric procedures: incidence andtreatment during 15 years at a singleinstitution. World J Surg 2011; 35:93–101.

210. Alexandrou A, Armeni E, KouskouniE, Tsoka E, Diamantis T,Lambrinoudaki I. Cross-sectionallong-term micronutrient deficienciesafter sleeve gastrectomy versus Roux-en-Y gastric bypass: a pilot study.Surg Obes Relat Dis 2014; 10: 262–8.

211. Stein J, Hartmann F, Dignass AU.Diagnosis and management of irondeficiency anemia in patients withIBD. Nat Rev Gastroenterol Hepatol2010; 7: 599–610.

212. del Giudice EM, Santoro N, AmatoA, et al. Hepcidin in obese childrenas a potential mediator of theassociation between obesity and irondeficiency. J Clin Endocrinol Metab2009; 94: 5102–7.

213. Chung B, Matak P, McKie AT, SharpP. Leptin increases the expression ofthe iron regulatory hormone hepcidinin HuH7 human hepatoma cells. JNutr 2007; 137: 2366–70.

214. McClung JP, Karl JP. Iron deficiencyand obesity: the contribution ofinflammation and diminished ironabsorption. Nutr Rev 2009; 67: 100–4.

215. Ruz M, Carrasco F, Rojas P, et al. Ironabsorption and iron status are reducedafter Roux-en-Y gastric bypass. Am JClin Nutr 2009; 90: 527–32.

216. Ruz M, Carrasco F, Rojas P, et al.Heme- and nonheme-iron absorptionand iron status 12 mo after sleevegastrectomy and Roux-en-Y gastricbypass in morbidly obese women. AmJ Clin Nutr 2012; 96: 810–7.

217. Gesquiere I, Lannoo M, Augustijns P,Matthys C, Van der Schueren B,Foulon V. Iron deficiency after Roux-en-Y gastric bypass: insufficient ironabsorption from oral iron supplements.Obes Surg 2014; 24: 56–61.

218. Varma S, Baz W, Badine E, et al.Need for parenteral iron therapy afterbariatric surgery. Surg Obes Relat Dis2008; 4: 715–9.

219. Vargas-Ruiz AG, Hernandez-RiveraG, Herrera MF. Prevalence of iron,folate, and vitamin B12 deficiencyanemia after laparoscopic Roux-en-Ygastric bypass. Obes Surg 2008; 18:288–93.

220. Love AL, Billett HH. Obesity,bariatric surgery, and iron deficiency:true, true, true and related. Am JHematol 2008; 83: 403–9.

221. DeFilipp Z, Lister J, Gagn�e D,Shadduck RK, Prendergast L,Kennedy M. Intravenous ironreplacement for persistent irondeficiency anemia after Roux-en-Ygastric bypass. Surg Obes Relat Dis2013; 9: 129–32.

222. Malone M, Alger-Mayer S, LindstromJ, Bailie GR. Management of irondeficiency and anemia after Roux-en-Y gastric bypass surgery: anobservational study. Surg Obes RelatDis 2013; 9: 969–74.

223. Ganzoni AM. Intravenous iron-dextran: therapeutic and experimentalpossibilities. Schweiz Med Wochenschr1970; 100: 301–3.

224. Evstatiev R, Marteau P, Iqbal T, et al.FERGIcor, a randomized controlledtrial on ferric carboxymaltose for irondeficiency anemia in inflammatorybowel disease. Gastroenterology 2011;141: 846–53; e841–842.

225. King JC. Zinc: an essential but elusivenutrient. Am J Clin Nutr 2011; 94:679S–84S.

226. Pires LV, Martins LM, Geloneze B,et al. The effect of Roux-en-Y gastricbypass on zinc nutritional status.Obes Surg 2007; 17: 617–21.

227. de Luis DA, Pacheco D, Izaola O,Terroba MC, Cuellar L, Martin T.Zinc and copper serum levels ofmorbidly obese patients before andafter biliopancreatic diversion: 4 yearsof follow-up. J Gastrointest Surg 2011;15: 2178–81.

228. de Luis DA, Pacheco D, Izaola O,Terroba MC, Cuellar L, Cabezas G.Micronutrient status in morbidly




obese women before bariatric surgery.Surg Obes Relat Dis 2013; 9: 323–7.

229. Balsa JA, Botella-Carretero JI,G�omez-Mart�ın JM, et al. Copper andzinc serum levels after derivativebariatric surgery: differences betweenRoux-en-Y Gastric bypass andbiliopancreatic diversion. Obes Surg2011; 21: 744–50.

230. Ruz M, Carrasco F, Rojas P, et al.Zinc absorption and zinc status arereduced after Roux-en-Y gastricbypass: a randomized study using 2supplements. Am J Clin Nutr 2011;94: 1004–11.

231. Salle A, Demarsy D, Poirier AL, et al.Zinc deficiency: a frequent andunderestimated complication afterbariatric surgery. Obes Surg 2010; 20:1660–70.

232. Tuerk MJ, Fazel N. Zinc deficiency.Curr Opin Gastroenterol 2009; 25:136–43.

233. Hambidge KM, Miller LV, WestcottJE, Sheng X, Krebs NF. Zincbioavailability and homeostasis. Am JClin Nutr 2010; 91: 1478S–83S.

234. Troost FJ, Brummer RJ, Dainty JR,Hoogewerff JA, Bull VJ, Saris WH.Iron supplements inhibit zinc but notcopper absorption in vivo inileostomy subjects. Am J Clin Nutr2003; 78: 1018–23.

235. Olivares M, Pizarro F, Ruz M, deRomana DL. Acute inhibition ofiron bioavailability by zinc: studiesin humans. Biometals 2012; 25:657–64.

236. O’Donnell KB, Simmons M. Early-onset copper deficiency followingRoux-en-Y gastric bypass. Nutr ClinPract 2011; 26: 66–9.

237. Kumar N, Butz JA, Burritt MF.Clinical significance of the laboratorydetermination of low serum copper inadults. Clin Chem Lab Med 2007; 45:1402–10.

238. Shahidzadeh R, Sridhar S. Profoundcopper deficiency in a patient withgastric bypass. Am J Gastroenterol2008; 103: 2660–2.

239. Lazarchick J. Update on anemia andneutropenia in copper deficiency.Curr Opin Hematol 2012; 19: 58–60.

240. Jaiser SR, Winston GP. Copperdeficiency myelopathy. J Neurol 2010;257: 869–81.

241. Griffith DP, Liff DA, Ziegler TR, EsperGJ, Winton EF. Acquired copperdeficiency: a potentially serious andpreventable complication followinggastric bypass surgery. Obesity (SilverSpring) 2009; 17: 827–31.

242. Iskandar M, Swist E, Trick KD,Wang B, L’Abb�e MR, Bertinato J.Copper chaperone for Cu/Znsuperoxide dismutase is a sensitive

biomarker of mild copper deficiencyinduced by moderately high intakesof zinc. Nutr J 2005; 4: 35.

243. Arredondo M, Weisstaub G, MedinaM, Suazo M, Guzm�an M, Araya M.Assessing chaperone for Zn, Cu-superoxide dismutase as an indicatorof copper deficiency in malnourishedchildren. J Trace Elem Med Biol 2014;28: 23–7.

244. Goldberg ME, Laczek J, NapierkowskiJJ. Copper deficiency: a rare cause ofataxia following gastric bypasssurgery. Am J Gastroenterol 2008;103: 1318–9.

245. Kazemi A, Frazier T, Cave M.Micronutrient-related neurologiccomplications following bariatricsurgery. Curr Gastroenterol Rep 2010;12: 288–95.

246. Harris S, Naina HV, Beckman TJ.Heartbreaking weight loss.Am J Gastroenterol 2009; 104:1322–3.

247. Boldery R, Fielding G, Rafter T,Pascoe AL, Scalia GM. Nutritionaldeficiency of selenium secondary toweight loss (bariatric) surgeryassociated with life-threateningcardiomyopathy. Heart Lung Circ2007; 16: 123–6.

248. Darwich AS, et al. Trends in oraldrug bioavailability following bariatricsurgery: examining the variable extentof impact on exposure of differentdrug classes. Br J Clin Pharmacol2012; 74: 774–87.

249. Padwal R, Brocks D, Sharma AM. Asystematic review of drug absorptionfollowing bariatric surgery and itstheoretical implications. Obes Rev2010; 11: 41–50.

250. Paine MF, Hart HL, Ludington SS,Haining RL, Rettie AE, Zeldin DC.The human intestinal cytochromeP450 “pie”. Drug Metab Dispos 2006;34: 880–6.

251. Paine MF, Khalighi M, Fisher JM,et al. Characterization ofinterintestinal and intraintestinalvariations in human CYP3A-dependent metabolism. J PharmacolExp Ther 1997; 283: 1552–62.

252. Kolars JC, Lown KS, Schmiedlin-RenP, et al. CYP3A gene expression inhuman gut epithelium.Pharmacogenetics 1994; 4: 247–59.

253. Mouly S, Paine MF. P-glycoproteinincreases from proximal to distalregions of human small intestine.Pharm Res 2003; 20: 1595–9.

254. Darwich AS, Neuhoff S, Jamei M,Rostami-Hodjegan A. Interplay ofmetabolism and transport indetermining oral drug absorption andgut wall metabolism: a simulationassessment using the “Advanced

Dissolution, Absorption, Metabolism(ADAM)” model. Curr Drug Metab2010; 11: 716–29.

255. Benet LZ, Cummins CL. The drugefflux-metabolism alliance:biochemical aspects. Adv Drug DelivRev 2001; 50(Suppl. 1): S3–11.

256. Ruscin JM, Page RL 2nd, Valuck RJ.Vitamin B(12) deficiency associatedwith histamine(2)-receptorantagonists and a proton-pumpinhibitor. Ann Pharmacother 2002;36: 812–6.

257. Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls oflong-term effects of proton pumpinhibitors. Expert Rev Clin Pharmacol2013; 6: 443–51.

258. Annibale B, Lahner E, Fave GD.Diagnosis and management ofpernicious anemia. Curr GastroenterolRep 2011; 13: 518–24.

259. Moayyedi P, Leontiadis GI. The risksof PPI therapy. Nat Rev GastroenterolHepatol 2012; 9: 132–9.

260. Brocks DR, Ben-Eltriki M, Gabr RQ,Padwal RS. The effects of gastricbypass surgery on drug absorptionand pharmacokinetics. Expert OpinDrug Metab Toxicol 2012; 8: 1505–19.

261. Edwards A, Ensom MH.Pharmacokinetic effects of bariatricsurgery. Ann Pharmacother 2012; 46:130–6.

262. Yska JP, van der Linde S, Tapper VV,et al. Influence of bariatric surgery onthe use and pharmacokinetics ofsome major drug classes. Obes Surg2013; 23: 819–25.

263. Padwal RS, Ben-Eltriki M, Wang X,et al. Effect of gastric bypass surgeryon azithromycin oral bioavailability. JAntimicrob Chemother 2012; 67:2203–6.

264. Magee SR, Shih G, Hume A.Malabsorption of oral antibiotics inpregnancy after gastric bypasssurgery. J Am Board Fam Med 2007;20: 310–3.

265. Terry SI, Gould JC, McManus JP,Prescott LF. Absorption of penicillinand paracetamol after small intestinalbypass surgery. Eur J Clin Pharmacol1982; 23: 245–8.

266. De Smet J, Colin P, De Paepe P,et al. Oral bioavailability ofmoxifloxacin after Roux-en-Y gastricbypass surgery. J AntimicrobChemother 2012; 67: 226–9.

267. Rogers CC, Alloway RR, AlexanderJW, Cardi M, Trofe J, Vinks AA.Pharmacokinetics of mycophenolicacid, tacrolimus and sirolimus aftergastric bypass surgery in end-stagerenal disease and transplant patients:a pilot study. Clin Transplant 2008;22: 281–91.



J. Stein et al.

268. Pirola I, Formenti AM, Gandossi E,et al. Oral liquid L-thyroxine (L-t4)may be better absorbed compared toL-T4 tablets following bariatricsurgery. Obes Surg 2013; 23: 1493–6.

269. Rubio IG, Galrao AL, Santo MA,Zanini AC, Medeiros-Neto G.Levothyroxine absorption in morbidlyobese patients before and after Roux-En-Y gastric bypass (RYGB) surgery.Obes Surg 2012; 22: 253–8.

270. Pournaras DJ, Footitt D, Mahon D,Welbourn R. Reduced phenytoinlevels in an epileptic patient followingRoux-En-Y gastric bypass for obesity.Obes Surg 2011; 21: 684–5.

271. Roerig JL, Steffen KJ, Zimmerman C,Mitchell JE, Crosby RD, Cao L. Acomparison of duloxetine plasmalevels in postbariatric surgery patientsversus matched nonsurgical controlsubjects. J Clin Psychopharmacol2013; 33: 479–84.

272. Roerig JL, Steffen K, Zimmerman C,Mitchell JE, Crosby RD, Cao L.Preliminary comparison of sertralinelevels in postbariatric surgery patientsversus matched nonsurgical cohort.Surg Obes Relat Dis 2012; 8: 62–6.

273. Hamad GG, Helsel JC, Perel JM,et al. The effect of gastric bypass onthe pharmacokinetics of serotoninreuptake inhibitors. Am J Psychiatry2012; 169: 256–63.

274. Padwal RS, Gabr RQ, Sharma AM,et al. Effect of gastric bypass surgeryon the absorption and bioavailabilityof metformin. Diabetes Care 2011; 34:1295–300.

275. Jakobsen GS, Skottheim IB, SandbuR, et al. Long-term effects of gastricbypass and duodenal switch onsystemic exposure of atorvastatin. SurgEndosc 2013; 27: 2094–101.

276. Skottheim IB, Jakobsen GS, StormarkK, et al. Significant increase insystemic exposure of atorvastatinafter biliopancreatic diversion withduodenal switch. Clin PharmacolTher 2010; 87: 699–705.

277. Skottheim IB, Stormark K,Christensen H, et al. Significantlyaltered systemic exposure toatorvastatin acid following gastricbypass surgery in morbidly obesepatients. Clin Pharmacol Ther 2009;86: 311–8.

278. Ziegler O, Sirveaux MA, Brunaud L,Reibel N, Quilliot D. Medical followup after bariatric surgery: nutritionaland drug issues. Generalrecommendations for the preventionand treatment of nutritionaldeficiencies. Diabetes Metab 2009; 35:544–57.

279. Andreasen PB, Dano P, Kirk H,Greisen G. Drug absorption andhepatic drug metabolism in patientswith different types of intestinalshunt operation for obesity. A studywith phenazone. Scand JGastroenterol 1977; 12: 531–5.

280. Kampmann JP, Klein H, Lumholtz B.Molholm Hansen JE. Ampicillin andpropylthiouracil pharmacokinetics inintestinal bypass patients followed upto a year after operation. ClinPharmacokinet 1984; 9: 168–76.

281. Prince RA, Pincheira JC, Mason EE,Printen KJ. Influence of bariatricsurgery on erythromycinabsorption. J Clin Pharmacol 1984;24: 523–7.

282. Garrett ER, Suverkrup RS, Eberst K,Yost RL, O’Leary JP. Surgicallyaffected sulfisoxazolepharmacokinetics in the morbidlyobese. Biopharm Drug Dispos 1981; 2:329–65.

283. Cossu ML, Caccia S, Coppola M,et al. Orally administered ranitidineplasma concentrations before andafter biliopancreatic diversion inmorbidly obese patients. Obes Surg1999; 9: 36–9.

284. Adami GF, Gandolfo P, Esposito M,Scopinaro N. Orally-administeredSerum Ranitidine Concentrationafter Biliopancreatic Diversionfor Obesity. Obes Surg 1991; 1:293–4.

285. Gerson CD, Lowe EH, Lindenbaum J.Bioavailability of digoxin tablets inpatients with gastrointestinaldysfunction. Am J Med 1980; 69:43–9.

286. Marcus FI, Quinn EJ, Horton H,et al. The effect of jejunoileal bypasson the pharmacokinetics of digoxinin man. Circulation 1977; 55: 537–41.

287. Backman L, Beerman B, Groschinsky-Grind M, Hallberg D. Malabsorptionof hydrochlorothiazide followingintestinal shunt surgery. ClinPharmacokinet 1979; 4: 63–8.




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