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ASMBS Nutrition Guidelines Micronutrient Evidence And Recommendations

ASMBS INTEGRATED HEALTH NUTRITIONAL GUIDELINES FOR THE

SURGICAL WEIGHT LOSS PATIENT — 2016 UPDATE: MICRONUTRIENTS

MICRONUTRIENTS: EVIDENCE AND RECOMMENDATIONS

The report below is organized into sections for each of the studied micronutrients, and

evidence pertaining to each of the four domains is further organized into subsections

within micronutrients. Each subsection begins with a brief literature review and concludes

with recommendations.

“Routine preoperative and postoperative screening” refers to acquiring a baseline

before WLS and a nutrient assessment after WLS every 3-6 months in the first year and

annually thereafter; unless otherwise specified in the recommendations.

If a nutrient deficiency is identified pre-WLS, nutrient repletion should be implemented

following the Recommended Dietary Allowance (RDA), plus an additional, individualized

amount to facilitate optimal absorption for repletion.

Definitions[2]

Dietary Reference Intake (DRI) is the general term for a set of reference values

used to plan and assess nutrient intakes of healthy people. These values, which

vary by age and gender, include:

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o Recommended Dietary Allowance (RDA): average daily level of intake

sufficient to meet the nutrient requirements of nearly all (97%-98%)

healthy people.

o Adequate Intake (AI): established when evidence is insufficient to

develop an RDA and is set at a level assumed to ensure nutritional

adequacy. Tolerable Upper Intake Level (UL): maximum daily intake

unlikely to cause adverse health effects.

Vitamin B1 (Thiamin)

Thiamin is a water-soluble vitamin absorbed primarily in the duodenum and upper

jejunum.[3-7] Thiamin plays both coenzyme and non-coenzyme roles within the body and

is found in several food sources, including whole grains, pork, and fish.[3-8] Absorption of

thiamin from food is thought to be high; however, thiamin is rapidly destroyed in an

alkaline environment with a pH >8 or with high temperatures.[4] Therefore, medications

such as antacids, H2 antagonists and proton pump inhibitors (PPIs) may inhibit thiamin

digestion; however, no studies have examined this relationship directly. Several foods and

beverages contain anti-thiamin factors, which also impair digestion and/or absorption;

these include alcohol, tea, coffee, raw fish, and shellfish.[4, 8]

Thiamin absorption is dependent upon the amount of thiamin present in the proximal

intestine.[3, 4, 7, 8] The average total thiamin storage in a healthy adult is approximately

0.11mmol (30 mg), with 40% stored in muscle.[9] The half-life of thiamin in humans has

been estimated to be 9.5 to 18.5 days.[4] Free thiamin in excess of tissue needs is excreted

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intact or catabolized for urinary excretion.[4, 8] Long-term diuretic therapy is associated

with increased urinary loss of thiamin.[10-12] Moreover, several studies have reported

thiamin deficiency (TD) among patients with cardiac failure who have been treated with

furosemide.[11-13] The limited total pool of thiamin, coupled with its short half -life and

constant requirement for use in metabolic processes, results in the need for consistent

thiamin intake.[14]

Thiamin deficiency (TD) results in impaired oxidative and energy metabolism, often

affecting various organ systems, including the heart, gastrointestinal (GI) tract, and

peripheral and central nervous systems.[4-6, 8] Patients with TD can develop high-output

cardiovascular disease (wet beriberi) and have been reported to exhibit tachycardia,

respiratory distress, or lower extremity edema, with right-to-left ventricular dilation and

lactic acidosis.[15, 16] Patients with neurologic (dry beriberi) may have numbness or

muscle weakness (neuropathy), pain of lower to upper extremities, convulsions, or

exaggerated tendon reflexes.[6, 15-18] GI symptoms associated with beriberi can include

delayed gastric emptying, nausea and emesis in patients with mega-jejunum, and

constipation in patients with megacolon.[19] In addition, patients with small bowel

bacterial overgrowth (SBBO) after WLS are at risk for TD.[19, 20] Patients with severe TD

often present with Wernicke encephalopathy (WE), with associated symptoms such as

confusion, nystagmus, ataxia and ophthalmoplegia.[6, 20-25] Patients with

neuropsychiatric beriberi may have auditory and visual hallucinations, aggressive

behavior, and selective memory disorders, which is often referred to as Wernicke’s

Korsakoff syndrome (WKS). [6, 24-28] Signs and symptoms of TD are summarized in Table

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5.

Assessment of thiamin status should be made by a whole blood (erythrocyte)

concentration of the active form of thiamin, TDP, or TDP activity/stimulation or

concentrations of the thiamin-dependent enzyme transketolase (Table 5).[4, 7, 29] This is

because 80-90% of body's thiamin is found in cells and only about 10% is found in plasma

or serum.[46] In the serum, thiamin is mostly carried by albumin; thus albumin status

would influence laboratory results, and plasma levels of thiamin more accurately reflect

recent intake.[22] An alternative approach to support a diagnosis of TD is measurement of

erythrocyte transketolase activity (Table 5). However, low concentrations of the vitamin do

not always result in clinical manifestations and there is not a specific threshold of serum or

red blood cell thiamin below which an individual will develop symptoms of TD. Therefore,

clinicians should be skilled at detecting physical signs and symptoms of TD.[6]

Identification of TD should include a thorough nutrition assessment, nutrition-focused

physical assessment, and if available, biochemical evaluation.[6, 30] In the acute-care

setting, reliable laboratory tests may not be available, may be too costly, or may be

impractical due to a long turnaround time. Since serious and potentially irreversible

neurological damage can occur with untreated TD, when the diagnosis of TD is suspected,

the patient should be treated before, or in the absence of, laboratory confirmation of

deficiency, and then monitored and evaluated for resolution of signs and symptoms.[6, 31]

According to the 1998 IOM report, there is no determined tolerable upper intake level

(UL) for thiamin.[5] In one study, oral doses of large amounts (500 mg daily) for >1 month

failed to elicit any adverse effects.[32] Large doses of thiamin given intravenously (IV) or

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intramuscularly (IM), however, have resulted in headaches, convulsions, cardiac

arrhythmias, anaphylactic shock, and other signs and symptoms.[26]

Preoperative Thiamin Screening

Prevalence of low preoperative levels of thiamin have been reported to range from

16% to 29%, and may be higher in African Americans and Hispanics.[33] Previously

published CPGs have not recommended routine preoperative screening of thiamin.[1, 31,

34, 35] However, patients with obesity have been shown to have lower plasma thiamin

concentrations, possibly due to increased intracellular thiamin storage.[36] In addition,

the risk of developing symptomatic TD after WLS is greater for those patients with low

thiamin status prior to surgery, [34] highlighting the importance of screening for and

repletion of low thiamin prior to surgery.

Postoperative Thiamin Screening

Prevalence of post-WLS TD has been reported to range from <1 to 49% [18, 20],

with variation based on the type of procedure, postoperative time frame, and risk factors.

Very few of the studies published since the 2008 nutrition guidelines, regarding

postoperative TD in RYGB, BPD/DS or SG[19, 33, 37-41] have been prospective studies;

most are retrospective or case studies. Some [37, 40, 41] but not all [19, 34, 36, 38, 40]of

these studies show decline in thiamin status despite patients receiving thiamin as part of a

multivitamin supplement. Reports of thiamin status post-WLS have been mixed. In a

cohort of 60 patients at 12 months post- SG; both hypervitaminosis B1 and

hypovitaminosis B1 were reported.[40] In a long-term examination of 5-year surveillance

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data of SG patients, 31% had low thiamin.[41] A randomized clinical trial comparing the

nutrition outcomes among RYGB and BPD patients over one year also showed thiamin

concentrations changed at different rates in the 2 groups; B1 concentrations declined

steeply and transiently after duodenal switch, but declined gradually after RYGB.[37] These

differences in outcomes underscore the methodological limitations of existing studies, such

as small sample sizes and heterogeneity of study design and outcomes, with most of these

studies relying upon self-report to assess multivitamin intake. Furthermore, different

studies assess thiamin status at different time points after surgery and by different

methodology. In accordance with the EFNS guidelines, monitoring of thiamin status for at

least 6 months post-WLS is recommended, however, more studies are needed to evaluate

the long-term impact of thiamin status after various surgical procedures.[42]

Risk factors associated with neurological complications following surgery include

the absolute amount of weight loss, malnutrition, prolonged GI symptoms, poor

postoperative nutritional follow up and reduced serum albumin and transferrin.[43] A

recent systematic review suggests that bariatric beriberi generally occurs 1-3 months after

surgery. [43] However, TD can occur at any time if risk factors are present.[6, 21, 23, 39]

Symptomatic TD occurs in up to 49% of patients post-surgery, varying by procedure.[6, 21,

23, 39] Several systematic reviews on the risk of WE after all types of WLS have been

published.[6, 21, 23, 39] All of these reports suggest, that a primary determinant and

predictor of this major neurological complication is persistent vomiting.

Routine screening is recommended after surgery for patients who present with the

following risk factors: rapid weight loss, protracted vomiting, parenteral nutrition,

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excessive alcohol use, neuropathy or encephalopathy and/or heart failure.[1, 31, 44] Based

on additional evidence, routine screening is also recommended in the following at-risk

groups: patients with alcoholism,[24-26, 31] malnourished patients,[6, 31, 45] female

patients[43, 46], African American or Hispanic patients[34, 35] and patients with GI

symptoms such as slow gastric emptying, nausea, vomiting, jejunal dilation, megacolon,

constipation and/or SBBO. [19, 20] [19, 20]

Preventative Supplementation of Thiamin

A multivitamin supplement containing 100% of the RDA of thiamin has been previously

recommended in order to prevent TD.[1] More recent guidelines suggest a minimal daily

nutritional supplementation of 1 adult multivitamin plus minerals for LAGB patients and 2

adult multivitamins plus minerals (each containing iron, folic acid, and thiamin) and a B-

complex preparation (amount not specified) for RYGB and SG patients.[31]

Practitioners should understand, however, that multivitamins, which generally provide

the RDA of thiamin (1.1 -1.2 mg/day), may not be adequate to prevent TD.[19, 37, 40, 41,

46] On the other hand, overuse should be avoided. For instance, data from Aarts et al.,[40]

also reported some hypervitaminosis B1 in 31% of their sample, despite, multivitamin use

up to three times daily. Supplementation of a bariatric B-vitamin preparation containing 12

mg of thiamin, along with 350 µg vitamin B12 and 800 µg folic acid, for three months did

not change mean blood thiamin levels.[47] Although these investigations had several

limitations, including a small, female-only sample, short duration and low blood thiamin

levels with no symptomatic TD, few dose-response studies exist on which to base

recommendations, and thus based on the studies cited above, it is recommended that 7

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patients receive a 50 mg oral dose of thiamin from a B-complex supplement once or twice

daily.[48]

Repletion of Postoperative Thiamin Deficiency

The AACE/TOS/ASMBS 2013 CPG[31] recommends that empiric thiamin

supplementation be considered in WLS patients with specific risk factors (rapid weight

loss, protracted vomiting, need for parenteral nutrition, excessive alcohol use, neuropathy

or encephalopathy, or heart failure). Patients with suspected or confirmed TD who are

seen on an outpatient basis or who do not have IV access may be treated with oral thiamin

supplementation. Previous CPGs suggested that early symptoms of neuropathy can often be

resolved by providing the patient with oral thiamin doses of 20–30 mg/day until symptoms

disappear.[1] Others recommend 100 mg oral thiamin two[16] to three[26] times daily

until symptoms resolve. However, oral therapy may be inadequate to treat symptomatic

patients, and data is lacking in WLS patients, in whom thiamin absorption may be impaired

due to altered GI structure and function. For patients with SBBO, 100 mg oral thiamin twice

daily for 2 months and antibiotic therapy with metronidazole, amoxicillin, or rifaximin for

7-10 days each month for 2 months on average has been suggested.[20]

For patients presenting with mild deficiency symptoms and who have access to IV

therapy, the AACE/TOS/ASMBS 2013 CPG recommends patients receive 100 mg IV thiamin

for 7-14 days.[31] These guidelines are similar to previous nutrition practice guidelines

recommending parenteral treatment for patients with hyperemesis with 100 mg/day for

the first 7 days followed by daily oral doses of 50 mg/day until complete recovery.[1]

Thiamin deficiency syndromes are typically initially treated with IV thiamin between 8

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100 mg once a day and 500 mg three times a day.[7, 26, 32] For WLS patients with

suspected or established severe TD (e.g. WE or WKS), there is a discrepancy between

existing CPGs. Aills et al., suggested that patients with WKS generally require ≥ 100 mg

thiamin administered IV for several days or longer, followed by IM thiamin or high oral

doses until symptoms have resolved or significantly improved.[1] In contrast, the

AACE/TOS/ASMBS 2013 CPG recommends 500 mg/day of parenteral thiamin for 3-5 days

followed by 250 mg/day for 3-5 days or until resolutions of symptoms, then to consider

treatment with 100 mg/day orally, usually indefinitely or until risk factors have been

resolved.[31] The European Federation of Neurological Societies (EFNS) recommends

monitoring thiamin status after WLS for up to 6 months , to provide parenteral thiamin

supplementation if indicated, and to provide 200 mg IV thiamin, three times daily for the

postoperative patient with WE.[42]

Other investigators recommend IM repletion of thiamin; however, recommendations

for IM protocols have been inconsistent. Some investigators have recommended 100-200

mg IM monthly or every other month with or without 200 mg oral thiamin,[19], while

others recommend a minimum of 250 IM mg daily for at least 3-5 days.[16, 24] Results of a

randomized, double-blind, multi-dose study showed a greater clinical benefit from giving ≥

200 mg IM thiamin compared to

≤ 100 mg IM thiamin, in alcoholic patients with WE or WKS.[27] However, according to the

European Federation of Neurological Societies (EFNS), use of the IM route for thiamin

repletion should be limited to patients without IV access in emergent situations.[42]

Furthermore, it may be impractical to treat patients IM, as many hospitals do not use the

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IM route for repletion but replete only through oral or parenteral routes. In summary,

although recommendations for the treatment of mild-to-severe TD for the WLS patient

appear to be discordant, there is agreement across studies that high, frequent doses of

thiamin via the IV or IM routes are more effective than oral supplementation.

The recommendations published by AACE/TOS/ASMBS 2013 CPG[31] are similar to the

practice guidelines for non-WLS patients with alcoholism published by the Royal College of

Physicians.[24-26, 49] The recommended dose of thiamin required to prevent or treat WE

in these patients has been >500 mg once or twice daily, provided parenterally for 3-5 days.

[49, 50] This estimate is based on data from uncontrolled trials and empirical clinical

practice. These authors conclude that oral thiamin is poorly absorbed and ineffective for

both prophylaxis and treatment of WE in patients with alcoholism.[26, 49] However,

further studies are needed to understand the applicability of these guidelines to the WLS

patient.

Administration of IV thiamin therapy should be provided slowly over 30 minutes to

minimize risk of anaphylaxis.[26, 32] Thomson[26] and Wrenn[32] prospectively

evaluated the safety of thiamine hydrochloride given as a 100 mg IV bolus in 989

consecutive patients (1,070 doses) and reported a total of 12 adverse reactions (1.1%), all

but one of which were minor, such as transient local irritation. The one major reaction

consisted of generalized pruritus.[26, 32] Treatment should be individualized, based on

severity of TD and availability of repletion options.

Caution needs to be taken when treating patients for dehydration with an IV dextrose

or an oral carbohydrate solution, because the oxidation of glucose is a thiamin-dependent

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process.[4, 8] To avoid prolonged or severe TD, thiamin should be given before any

carbohydrate [42] or at least simultaneously along with magnesium, potassium, and

phosphorus, among patients at risk for refeeding syndrome;[51] include the chronically

under-nourished, patients with dysphagia and/ or those with little intake for greater than

10 days.[52] Thiamin, vitamin B complex and multi-vitamin supplements should be started

with refeeding. Simultaneous therapeutic doses of other B vitamins including vitamin B6

and vitamin B12 at doses of 100 mg and 1000 mcg, respectively, may also be of benefit to

the WLS patient with TD.[28] The Royal College of Physicians’ guideline for the

management of WE, non-WLS patients, recommends that per 250 mg thiamin dose (e.g. 1

ampule), there should be the addition of 4 mg riboflavin (vitamin B2), 50 mg pyridoxine

(vitamin B6), 160 mg nicotinamide (vitamin B3), 500 mg vitamin C, 10-30 mEq magnesium,

60-180 mEq potassium, and 10-40 mmol/l phosphate daily.[26, 49] Although more high-

quality research is needed to develop standardized clinical practice guidelines for the WLS

patient with TD, it is agreed that therapy should be initiated urgently, as late interventions

may put the patient at risk for irreversible sequelae.[53]

Thiamin – Summary

Recommendations for preoperative screening of thiamin

Routine preoperative screening of thiamin is recommended for all patients.

(Grade C, BEL 3)

Recommendations for postoperative screening of thiamin

Routine postoperative screening of thiamin is recommended for high-risk groups:

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o Patients with risk factors for TD (Grade B, BEL 2)

o Patients with concomitant medical conditions such as cardiac failure

(especially those receiving furosemide) (Grade B, BEL 2)

o Females (Grade B, BEL 2)

o African Americans (Grade B, BEL 2)

o Patients not attending a nutritional clinic after surgery (Grade B, BEL 2)

o Patients with GI symptoms (intractable nausea and vomiting, jejunal dilation,

mega-colon, or constipation) (Grade B, BEL 2)

o Patients with SBBO (Grade C, BEL 3)

If signs and symptoms or risk factors are present in post WLS patients, thiamin

status should be assessed at least during the first 6 months, then every 3-6

months until symptoms resolve. (Grade B, BEL 2)

Recommendations for supplementation of thiamin for preventing deficiency

Thiamin Supplementation above the RDA is suggested to prevent TD:

o Post-WLS patients should take at least 12 mg thiamin daily (Grade C, BEL

3) and

o preferably a 50 mg dose of thiamin from a B-complex supplement or

multivitamin once or twice daily (Grade D, BEL 4) to maintain blood levels of

thiamin and prevent TD.

Recommendations for postoperative thiamin repletion12

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Practitioners should treat post-WLS patients with a suspected thiamin deficiency

before or in the absence of laboratory confirmation of deficiency AND monitor and

evaluate resolution of signs and symptoms. (Grade C, BEL 3)

Repletion dose for TD varies based on route of administration:

o Oral therapy: 100 mg orally two -to -three times daily until symptoms

resolve. (Grade D, BEL 4).

o IV therapy: 200 mg three times daily to 500 mg once or twice daily for 3-5

days followed by 250 mg/day for 3-5 days or until resolutions of symptoms,

then consider treatment with 100 mg/day orally, usually indefinitely or until

risk factors have been resolved. (Grade D, BEL 4)

o IM thiamin repletion: 250 mg once daily for 3-5 days or 100-250 mg monthly.

(Grade C, BEL 3)

Simultaneous administration of magnesium, potassium and phosphorus should

occur in patients at risk for refeeding syndrome. (Grade C, BEL 3)

Vitamin B12 (Cobalamin)

Cobalamin (B12) is a water-soluble vitamin that plays key roles in the normal

functioning of the brain and nervous system, in the maturation of red blood cells, in neural

functioning, and in DNA synthesis.[54] B12 is also believed to be a factor in the prevention

of osteoporosis and age-related macular degeneration.[54] Both vitamin B12, cobalamin,

and folate are often mentioned together in the literature because of the synergistic effect

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the two vitamins have on the synthesis and maturation of red blood cells. In addition, B12

and folate function in DNA synthesis, cellular metabolism, and the conversion of

homocysteine to methionine.[54] B12 and folate play a role in the prevention of

cardiovascular disease and cognitive decline.[18, 54, 55] B12 deficiency may also cause

folate deficiency. Deficiencies in either or both B12 and folate can manifest as

megaloblastic macrocytic anemia.

B12 metabolism involves a complex pathway.[56] B12 in food is bound to, protein, and

released from proteins by the action of a high concentration of hydrochloric acid (HCl)

present in the stomach. This process results in the free form of the vitamin, which is

immediately bound to a mixture of glycoproteins secreted by the stomach and salivary

glands. These glycoproteins, called R-binders, protect B12 from chemical denaturation in

the stomach. The stomach’s parietal cells, which secrete HCl, also secrete a glycoprotein

called intrinsic factor (IF). IF binds B12 and enables its active absorption. When the

contents of the stomach enter the duodenum, the R-binders become partly digested by

pancreatic proteases, which causes them to release their bound B12. The pH in the

duodenum is more neutral than that in the stomach, increasing the binding affinity of IF for

B12. Therefore, IF quickly binds B12 as it is released from R-binders in the duodenum, the

B12-IF complex then proceeds to the distal small intestine, where it is absorbed through

phagocytosis by specific ileal receptors.

Since B12 absorption and transport is dependent upon this complex mechanism, any

pre-existing medical or surgical condition that disrupts the normal mechanism of B12

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metabolism may be considered a preoperative risk for deficiency in patients seeking WLS.

[1]

Preoperative Vitamin B12 Screening

Obesity is a risk factor for B12 deficiency, [56] reported in 2%-18% of patients

seeking WLS.[34, 38, 57-64] Commonly used medications have also been noted to affect

preoperative B12 absorption and stores, most notably metformin and omeprazole.[65-70]

Approximately 6% to 30% of patients taking metformin present with B12 deficiency.[65-

69] The mechanism for this has not been fully elucidated but metformin is suspected to

either compete for absorption sites, alter IF, or change gut flora or motility.[71] In patients

with obesity and concomitant gastroesophageal reflux disease (GERD) requiring proton-

pump inhibitors (PPIs), long-term omeprazole use has been shown to decrease B12 levels

by up to 30%.[70, 72]

While long-term evidence is lacking, there is suspicion that Helicobacter pylori (H.

pylori) may have a causal role in B12 malabsorption and subsequent deficiency. Kaptan et

al., [73] reported that 56% of patients in their cohort who tested positive for H. pylori had a

concomitant B12 deficiency and megaloblastic anemia. Preliminary results support the

importance of screening WLS patients for both H. pylori infection, and B12 deficiency in the

preoperative period.

As noted above, the functions of B12 and folate are intertwined biochemically; thus, the

final common pathway that impairs DNA synthesis in hematopoietic cells is the same when

either vitamin is deficient. Neuropathy can occur in the setting of B12 deficiency, but not

with folate deficiency.. Due to the synergistic effect of both B12 and folate in 15

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hematopoiesis, the absence of anemia with adequate folate can mask a B12 deficiency.[1,

18] This can lead to irreversible neurologic damage.

A methylmalonic acid (MMA) assay is the preferred test for B12 status because

metabolic changes often precede low B12 levels in the progression to deficiency. An

elevated MMA result may be an early indicator of a B12 deficiency even when serum B12

levels are still within normal lab limits. Conversely, serum B12 assays may miss as many as

25-30% of cases of B12 deficiency.[59] Thus, MMA is the preferred assay when screening

for B12 deficiency.

Postoperative Vitamin B12 Screening

Risk for B12 deficiency after WLS is dependent upon a number of factors, including

type of surgical procedure (procedures that involve bypass or removal of all or part of the

stomach, such as the SG, RYGB and BPD/DS, put patients at higher risk for deficiency);

preoperative B12 deficiency; post-surgical timeframe and frequency of follow-up;

adequacy of dietary intake; concomitant use of medications that interfere with B12

bioavailability; and adherence to B12 supplementation.[1, 37, 39, 40, 66, 71, 74-76]

Disruption of B12 absorption may occur when a WLS procedure leads to a significantly

decreased intake of dietary protein and/or impairs hydrolysis of free cobalamin by

reducing pepsin and HCl production.[1] In purely restrictive procedures such as the LAGB,

B12 deficiency is less likely as there is no effect on gastric acid or IF production. However,

due to food intolerances, restriction of dietary protein intake, and chronic use of PPIs seen

in some LAGB patients, B12 deficiency can be seen in this population as well.

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Early research from the late 1990s to early 2000s indicated that the prevalence of B12

deficiency in RYGB typically ranged from 8% to >30%, but could be as high as 70% with a

length of follow-up between one and seven years.[77-81] It appears that the risk for

deficiency increases with duration of follow-up. One explanation for delayed manifestation

of B12 deficiency is that long-term hepatic storage of B12 is approximately 2000 mcg and

low values typically emerge two to three years after surgery. [68] Even though

recommendations for B12 supplementation have been widely published and accepted, B12

deficiency is still being seen in post RYGB patients.[1, 31, 82] Current research is

encouraging, however, with observed prevalence of B12 now under 20%, and

postoperative levels returning back to preoperative levels with routinely recommended

B12 supplementation.[39, 46, 64, 83, 84]

Current research suggests that patients taking B12 supplementation may initially show

elevated levels, but this stabilizes over time in RYGB patients;[84] whereas B12 levels were

reported stable in DS patients.[39] This may be due to better tolerance of animal proteins

in a larger sleeve rather than a pouch, greater pepsin and gastric acid production to release

protein-bound B12, and increased availability and interaction of IF with the sleeve

contents.[1, 85, 86] [87] SG has been shown to pose a risk for, B12 deficiency, with

reported prevalence ranging from 4%-20% at 2 to 5 years after surgery.[88-91] In this

procedure, the removal of 70%-85% of the stomach physically eliminates a majority of

parietal cells needed to secrete pepsinogen, HCl, and IF, potentially leading to B12

deficiency via the reduced formation of both free cobalamin and cobalamin-IF complex. It

is not clear whether there is a higher risk for B12 deficiency in SG compared to other

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bariatric surgical procedures, or if the risk for deficiency increases with post-surgical

duration. Some studies show B12 deficiency occurs in SG in the early post-operative period

and at one-year, but not in patients who had undergone SG three to five years earlier.[40,

41, 88] In some studies comparing the risk for B12 deficiency between SG and RYGB, no

significant difference was observed in the risk for B12 deficiency over the duration of five

years[74] while other studies have found that risk for B12 deficiency is higher in RYGB.[92]

Mechanisms underlying risk for B12 deficiency may differ between the two procedures: the

malabsorptive component of RYGB may have a greater deleterious effect on B12

absorption; whereas SG disrupts the cobalamin-IF complex.[92]Because research

regarding risk and frequency of vitamin B12 deficiency in SG patients is sparse and findings

are variable, it is recommended to screen all patients for B12 deficiency after SG.

Some authors have questioned the need to screen and treat asymptomatic patients for

B12 deficiency. However, given the possibility of irreversible neurological damage in the

setting of prolonged untreated B12 deficiency, routine screening is recommended. B12

status is typically assessed via serum or plasma levels. Values below approximately 170–

250 pg/mL (120–180 picomol/L) for adults indicate a B12 deficiency.[93] However,

evidence suggests that serum B12 concentrations may not accurately reflect intracellular

concentrations.[57] An elevated serum homocysteine level (values >13 micromol/L)might

also suggest a vitamin B12 deficiency.[94] However, this indicator has poor specificity

because it is influenced by other factors, such as low vitamin B6 or folate levels. [94]

Elevated MMA levels (values >0.4 micromol/L) might be a more reliable indicator of B12

status because they indicate a metabolic change that is highly specific to B12 deficiency.[38,

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57, 93] In addition, some literature on RYGB patients shows that symptoms of deficiency

may be present even in the setting of normal serum B12 levels. Thus, serum MMA and

homocysteine assays are the preferred method to assess B12 status,[69, 95-97] although

MMA has more specificity in detecting B12 deficiency than Hcy.

Preventative Supplementation of Vitamin B12

Cobalamin stores are known to persist for long periods of time (3 to 5 years) but levels

are dependent upon dietary repletion and daily depletion. Post-WLS patients have

decreased intake of dietary protein, decreased contact of stomach acid with food, and

decreased availability of IF and concomitant malabsorption; therefore, without appropriate

supplementation, B12 deficiency may develop. Since the typical absorption pathway cannot

be relied upon in SG, RYGB and BPD/DS, patients who have undergone these procedures

should consider supplementation that allows for passive absorption of B12, independent of

the cobalamin-IF complex pathway,[54, 79] Research supports additional supplementation

of B12 recommended beyond standard MVI that provide 100% DRI ([1, 57, 85, 98-100]

For SG patients, evidence supporting supplementation with B12 in order to maintain

normal levels up to three years post surgery is mixed. Meta-analyses show great variability

in findings, leading to recommendations for vitamin B12 in SG, that range from no

supplementation, supplementation contributed solely from a multivitamin (about 20 mcg),

to varying dosages (350 mcg, 500 mcg and 1000mcg per day) and varying frequencies of

B12 supplementation (daily to monthly).[41, 64, 91, 99, 101-103] It is difficult to gauge,

from the current body of research, what the optimal level of B12 supplementation should

be for SG patients. For instance, one study found elevated serum B12 at 3 months in 19

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patients who have SG when taking one of the lowest doses 350 mcg daily.[47] Taken

together, the body of literature on this topic suggests that SG patients do need B12

supplementation, though specifics regarding dosage and frequency cannot yet be derived

from existing data.

The most recent guidelines by AACE/TOS/ASMBS 2013 CPG are not specific and

detailed in regard to the supplement regimen for vitamin B12 for LAGB, RYGB, SG, and

BPD/DS , recommending only that supplementation is provided as needed to maintain

levels in the normal range.[31] Based on early research [37, 104, 105] the 2008 ASMBS

Nutrition CPG recommended 350-500 mcg oral crystalline B12 daily.[1] Until more

rigorous and long-term studies can be identified, the historical and current studies support

maintaining the current recommendation for B12 outlined by Aills et al.,[1]

B12 may be given in various forms including oral liquid or disintegrating tablet,

sublingual, parenteral (subcutaneous (SQ) or IM), or nasal spray. The choice of form and

frequency of supplementation should be guided by considerations of factors related to

postoperative anatomy and patient adherence. Poor adherence with vitamin regimens has

resulted in B12 deficiencies with serious consequences of B12 deficiency, including

pernicious anemia and neurological dysfunction. [75, 95, 106] Practitioners should assess

the patient’s preferences and potential barriers to adherence when considering a daily,

weekly, or monthly regimen of B12 supplementation.

Repletion of Postoperative Vitamin B12 Deficiency

Deficiency of B12 is typically defined at levels less than 200 pg/ml, although this

reference range has been questioned, as clinical manifestation does not always accompany 20

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abnormally low laboratory values;[1] conversely, about 50% of patients with obvious signs

and symptoms of deficiency (Table 5) also have normal B12 levels.[1, 107, 108]

The recommended treatment for B12 deficiency in the non-bariatric population in the

United States is 1000 mcg daily for 8 weeks and then once a month.[108] A monthly

dosage of 650 to 1000 mcg was found to adequately reduce MMA in an estimated 80%-

90% of an non-bariatric, elderly sample.[97] In early WLS research, B12 deficiency was

usually found to resolve after several weeks of treatment with 700 to 2000 mcg per week

(daily, twice daily, or weekly),[109] or with B12 1000 mcg IM once a month until the

deficiency is corrected.[110] Current research, however, indicates a dosage of 1000 mcg

daily to treat B12 deficiency in SG and 1000-3000 mcg B12 every 6-12 months if sufficiency

not maintained.[76] Because recent research on repletion of B12 in WLS patients is

limited, recommendations published in Aills et al., and the more recent AACE/TOS/ASMBS

2013 CPG have not been revised.[1, 31]

B12 – Summary

Recommendations for preoperative screening of vitamin B12

Routine pre-WLS screening of B12 is recommended for all patients.

(Grade B, BEL 2)

Serum B12 may not be adequate to identify B12 deficiency. It is recommended to

include serum MMA to identify metabolic deficiency of B12 in symptomatic or

asymptomatic patients, and in those with history of B12 deficiency or pre-

existing neuropathy (Grade B, BEL 2)

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Recommendations for postoperative screening of vitamin B12

Routine postoperative screening of vitamin B12 is recommended in patients

who have undergone RYGB, SG, or BPD/DS. (Grade B, BEL 2)

More frequent screening in the first post-operative year, every 3 months and

then at least annually or as clinically indicated is recommended for post-WLS

patients who are chronically using medications that exacerbate risk of B12

deficiency: nitrous oxide, neomycin, metformin, colchicine, PPIs, or seizure

medications (Grade B, BEL 2)

Serum B12 may not be adequate to identify B12 deficiency. It is recommended to

include serum MMA with or without homocysteine to identify metabolic

deficiency of B12 in symptomatic or asymptomatic patients, and in those

patients with history of B12 deficiency or pre-existing neuropathy(Grade B, BEL

2)

Recommendations for supplementation of vitamin B12 for preventing deficiency

All post-WLS patients should take vitamin B12 supplementation. (Grade B, BEL

2)

The recommended supplement dose for vitamin B12 varies based on route of

administration. (Grade B, BEL 2):

o Orally by disintegrating tablet, sublingual, or liquid: 350-500 mcg daily

o Nasal spray: as directed by manufacturer

o Parenteral (IM or SQ): 1000 mcg monthly

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Recommendations for postoperative vitamin B12 repletion

Post-WLS patients with a B12 deficiency should take 1000 mcg per day to

achieve normal levels and then resume dosages recommended in Table 5 to

maintain normal levels. (Grade B, BEL 2)

Folate (Folic Acid)

Folate (naturally food-derived) and folic acid (synthetic) are forms of the water-soluble

vitamin B9. Folate is essential for cell division, hematopoiesis, nucleic acid synthesis,

amino acid metabolism, and methionine regeneration from homocysteine.[111] Folate is

needed for single-carbon transfers for the production of the methylating agent, S-

adenosylmethionine, and the transfer of a methyl group that can yield products of energy

metabolism such as creatine, convert homocysteine to methionine, and produce certain

neurotransmitters and phospholipids.[112] The biochemically active form of folate, called

5-methyltetrahydrofolate, is believed to reduce cardiovascular disease by improving

endothelial function.[113] Folate is also essential for prevention of fetal neural tube

defects, megaloblastic pernicious anemia, stroke, osteoporosis, depression, elevated

homocysteine, some forms of cancer, Alzheimer’s disease and other forms of cognitive

decline.[55, 112]

Folate absorption from dietary sources occurs mainly in the jejunum, but passive

diffusion is seen at higher doses. Only a small amount of folate is stored. The total amount

of body folate is estimated to be approximately 10 to 30 mg, with the liver containing

approximately half of the total folate pool.[55] An estimated 0.3% to 0.8% of the total

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folate pool is excreted daily, which does not vary with levels of dietary or supplemental

folate intake.[55]

While the primary symptom of folate deficiency is megaloblastic anemia, this rarely

occurs independent of B12 deficiency since the two vitamins work synergistically in

hematopoiesis.[24] Folate deficiency can manifest in clinical signs such as oral mucosal

ulcerations, changes in skin and nail pigmentation, and elevated homocysteine serum levels

(See Table 5).[114]

Preoperative Folate Screening

Because folate works synergistically with B12, pre-WLS patients may be at risk for

concomitant folate deficiency as well.[112] The prevalence of folate deficiency has been

reported to be as low as 0% and as high as 54% in patients seeking WLS. More recent

research reports preoperative SG patients with 24% folate deficiency.[115] Risk of

deficiency is exacerbated by insufficient intake of folate-containing foods, alcoholism, and

aging.[38, 57, 58, 61, 64, 85, 116] It is recommended that all patients seeking WLS be

screened preoperatively for suboptimal or deficient folate. A folate deficiency can be

identified by decreased RBC folate, elevated serum homocysteine and normal MMA levels.

[112]

Patients who take medications that either decrease folate absorption or act as folate

antagonists are at particular risk for folate deficiency. In addition, surgical patients seeking

WLS who have pre-existing medical or surgical conditions that decrease gastric acid

secretion or interrupt absorption of folate in the jejunum are at increased risk for

deficiency. Particular attention should be paid to prospective WLS patients who plan future 24

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pregnancy, due to the profound effect of folate on prevention of neural tube disorders.

[117]

Postoperative Folate Screening

Post-WLS patients with rapid weight loss and/or malnutrition may be at an especially

high risk for micronutrient deficiencies. Risk for folate deficiency is reported in all

currently performed WLS procedures and may be secondary to low intake of folate-rich

foods, poor adherence to supplement regimens, taking vitamin regimens that contain less

than 400 mcg of folate, chronic use of medications that interfere with the bioavailability of

folate, alcoholism, pre-existing medical or surgical conditions that interfere with folate

absorption, and/or an existing preoperative folate deficiency.[54, 55, 76, 114, 118-121] In

earlier research studies, low serum folate levels have been observed in up to 65 % of post-

RYGB patients and more recent studies of post-SG report a prevalence of 18%.[58, 85, 116,

122] An increased risk of deficiency has also been noted even among LAGB patients,

possibly due to decreased folate intake. [121]

Similar to the case with B12, most post-WLS patients who are folate deficient are

asymptomatic or suffer from sub-clinical symptoms, so these deficient states may not be

easily identified.[54, 55]

Preventative Supplementation of Folate

While it is important to note that postoperative folate deficiencies may occur less

frequently than deficiencies of other vitamins after surgery, folate deficiency can occur

even in the context of routine supplementation, especially if multivitamins do not contain

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the proper dosage of folic acid and the dietary intake of folate is inadequate.

AACE/TOS/ASMBS 2013 CPG recommend taking two multivitamins that contain folic acid

for patients who have had WLS.[1] A multivitamin containing 100% or less of the RDA for

folic acid may be insufficient to maintain normal levels in a post- WLS patient. Two earlier

studies found that 47% and 41% of RYGB patients had low folate levels at 6 months and 1

year, respectively, despite patient adherence to a multivitamin supplement; however this

supplement contained less than the RDA for folate.[118] Folate deficiencies in RYGB and

SG has been linked to, and most likely exacerbated by, a sharp decrease in dietary intake

coupled with insufficient supplementation.[38, 40, 74, 88, 101] Despite recommendation

of a multivitamin containing 150% of the RDA for folate, 22% of patients in one study had

confirmed folate deficiency.[40]However, current research contradicts this finding. A

gradual increase in folate levels has been noted in RYGB patients over the course of 5 years

after surgery, even though during the same time period, folate intake was gradually

decreased.[84]

Recommended intake of folate for non-bariatric adult men and women is 400 mcg per

day.[123] However, the United States Preventative Services Task Force recommends that

women capable of or planning pregnancy take a daily supplement of 400 to 800 mcg per

day.[124] Research conducted in the WLS population has shown that taking up to 1000

mcg may be appropriate. Studies of RYGB and SG have produced evidence that folate

deficiency can be avoided and/or treated with supplemental dosages that range from 200

mcg to 1000 mcg per day.[41, 47, 74, 85, 86, 91, 99, 101, 125] Folate supplementation

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above 1 mg per day is not recommended due to the potential masking of vitamin B12

deficiency.[54]

Folic acid supplementation may be given as part of a multivitamin, B-complex, or as a

singular nutrient if necessary. The form of folic acid supplementation (i.e., liquid, chewable,

oral tablet) should be chosen with regard to enhancing patient adherence.

Repletion of Postoperative Folate Deficiency

As previously noted, WLS patients who have folate deficiency may be asymptomatic, so

these deficient states may not be easily identified, underscoring the need for routine

screening. Since rigorous research for repletion of folic acid is sparse, the current

recommendation concurs with Aills et al., and is not to exceed 1000 mcg per day due to the

potential masking of vitamin B12 deficiency.[1, 54]

Folate – Summary

Recommendations for preoperative screening of folate

Routine pre-WLS screening of folate status is recommended for all patients.

(Grade B, BEL 2)

Recommendations for postoperative screening of folate

Routine post-WLS screening of folate status is recommended in all patients. (Grade B,

BEL 2)

Particular attention should be paid to female patients of childbearing age. (Grade B, BEL

2)27

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Recommendations for supplementation of folate for preventing deficiency

Post-WLS patients who are not female and childbearing age should take 400-800 mcg

oral folate daily from their multivitamin. (Grade B, BEL 2)

Women of childbearing age should take 800-1000 mcg oral folate daily. (Grade B, BEL

2)

Recommendations for postoperative folate repletion

All post-WLS patients who have folate deficiency should take an oral dose of 1000 mcg

daily of folate to achieve normal levels and then resume the dosage recommended to

maintain normal levels. (Grade B, BEL 2).

Folate supplementation above 1 mg per day is not recommended in post-WLS patients,

due to the potential masking of vitamin B12 deficiency. (Grade B, BEL 2)

Iron

Iron is a component of hemoglobin and myoglobin and is critical for growth,

development, normal cellular functioning, and synthesis of some hormones and connective

tissue. Dietary iron has two main forms, heme (found in meat, seafood and poultry) and

non-heme (found in plants and iron-fortified foods). Most iron in the body is found in

hemoglobin, with the rest stored as ferritin or hemosiderin in the liver, spleen, and bone

marrow, or as, myoglobin in the muscle. Iron losses are greater in menstruating women

due to blood loss.[126, 127]

Absorption of iron occurs mainly in the duodenum and proximal jejunum.[126, 128]

Storage levels of iron have the greatest influence on iron absorption; however, the type of

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dietary iron consumed also affects absorption, with heme being more bioavailable.[127]

Non-heme iron absorption is affected by other foods consumed; foods high in vitamin C

improve absorption, while those high in tannins can decrease absorption. Ferrous and

ferric iron salts are the most commonly used forms of iron supplement. Ferrous iron is

more bioavailable than ferric iron, due to its higher solubility. Decreased exposure of

consumed foods or supplements to gastric acid can impair the conversion of ferric iron to

absorbable ferrous iron. However, high doses of ferrous and ferric iron supplements may

cause GI side effects, whereas other forms such as heme iron polypeptides, carbonyl iron,

iron amino-acid chelates, and polysaccharide-iron complexes may have fewer side effects.

[126-129]

Preoperative Iron Screening

The reported prevalence of iron deficiency in preoperative bariatric patients ranges

from 0-58%.[38, 41, 60, 88, 99, 116, 127, 130-134] In adults with obesity, multiple factors

may contribute to preoperative iron deficiency. These include poor diet; obesity-related

inflammation causing alterations in iron homeostasis; menstruation; menorrhagia (often

present in with polycystic ovarian syndrome); GERD with esophagitis; and/or other

factors.[130, 135, 136]

The highest rate of iron deficiency is typically seen in menstruating females. In the

presence of inflammation, diagnosing iron deficiency can be challenging. Although

screening for iron status may include the use of serum ferritin levels, these should not be

used to diagnose deficiency as ferritin is an acute phase reactant (APR) and may fluctuate

with age, inflammation, and infection.[1] It is useful to evaluate soluble transferrin 29

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receptor levels in addition to routine iron studies, as soluble transferrin is not an APR.[135]

Soluble transferrin receptor levels reflect the cellular need for iron, and are less impacted

by inflammation than are ferritin levels.[126] Hemoglobin and hematocrit changes reflect

late iron-deficient anemia, and are less valuable in identifying early anemia.[1] Iron

deficiency has been defined in different ways in the literature, which must be taken into

account when interpreting research results.[38, 41, 60, 88, 99, 116] Some researchers have

used a single laboratory value (serum iron, serum transferrin saturation, or serum ferritin);

[38, 60, 99, 116, 131, 133, 134] while others have used a combination of indices, including

serum iron and serum transferrin saturation; serum ferritin or soluble transferrin

receptor; serum iron with serum transferrin saturation; or serum iron, serum transferrin

saturation and total iron-binding capacity.[41, 88, 132] A combination of laboratory values

(serum iron with serum transferrin saturation and total iron-binding capacity) is

recommended for diagnosing iron deficiency.

Postoperative Iron Screening

The reported prevalence of iron deficiency in post-WLS patients is variable, differing by

procedure type and duration of time since surgery; ranging from 20-58% (RYGB), 0-18%

(SG), 13-62% (BPD), 8-50% (DS) and 14% (LAGB) from 3 months to 20 years follow-up.

[38, 41, 60, 88, 99, 116, 125, 129, 131-134, 137, 138] Post-WLS iron deficiency may occur

due to the bypassing of absorption sites in the GI tract; decreased intake of iron rich foods

due to intolerance or preference; age; gender; inadequate supplement adherence; and/or

altered absorption due to interaction of iron with calcium supplements or certain food

components.[80, 131-133, 135, 139]30

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Recent research indicates that patients who undergo SG or LAGB are at risk for iron

deficiency, but to a lesser extent than seen in RYGB or BPD/DS.[38, 41, 88, 116, 128, 132]

Clinicians should assess iron status in all patients post-WLS, using both physiological signs

and symptoms (Table 5) and laboratory results.[126] Laboratory values, including serum

iron, serum ferritin, transferrin saturation, and elevated total iron-binding capacity may be

affected by extraneous factors, such as inflammation and infection, and the clinician should

consider testing soluble transferrin receptor as well.[124]

Preventative Supplementation of Iron

Patients considered to be at high risk for iron deficiency include: menstruating females

and patients with history of anemia who have had RYGB, SG, or BPD/DS. These at-risk

patients should take a total of 45-60 mg of elemental iron daily, from all supplements

combined. Additional iron supplementation above the DRI (18 mg) may not be indicated in

LAGB patients.[31] However, if an LAGB patient is a female of childbearing age, the

multivitamin should contain at least the DRI. Iron supplements may be taken in the form of

a ferrous iron salt, heme iron polypeptide, carbonyl iron, iron amino-acid chelate, or

polysaccharide-iron complex, with the latter four having potentially fewer GI side effects. A

history of anemia or change in laboratory values may indicate the need for additional

supplementation, taking into account, age, gender, and reproductive considerations.[31]

Studies have shown a dose dependent effect of calcium on iron absorption, more so in

single meal studies than multiple meal studies.[140] Calcium doses > 300-1000 mg exhibit

an inhibitory effect on absorption of 5mg non-heme iron; calcium doses >300-800 mg also

inhibit the absorption of 5mg heme-iron; when taken together, either at a meal or on an 31

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empty stomach.[141, 142] More than one mechanism may be involved: 1) through

inhibition of the iron transfer process from the enterocyte to the plasma; and/or 2) high

calcium levels may affect the function of divalent metal ion transporter-1 (DMT-1), the

brush border transporter for elemental iron in duodenal enterocytes. [140, 143, 144] It

may also be possible that high levels of calcium alter the rheological properties of the

upper small intestine mucous layer. [140] However, the absorption of iron from a

multivitamin also containing calcium may not be inhibited due to the lower dosages

ingested.[140, 142-144]

Repletion of Postoperative Iron Deficiency

The development of iron deficiency develops over time, in the following stages:

Stage 1: Serum ferritin decreases to 20 ng/mLStage 2: Serum iron decreases to < 50 ug/dL; transferrin saturation <15% Stage 3: Anemia with normal-appearing RBCs and indexes is observed Stage 4: Microcytosis and then hypochromia developsStage 5: Iron deficiency affects tissues, resulting in clinical signs and symptoms

Similarly, repletion of iron stores takes time. Duration of treatment should be at least

three months, if not longer, since red blood cell turnover takes 120 days.[126] Oral

supplementation should be tried first and, if unsuccessful in correcting iron deficiency, IV

iron should be considered.[38, 102, 131, 138, 145] The recommended amount of iron

should be based on the needs of the patient, bearing in mind that different products contain

varying amounts of elemental iron. Ferrous calcium citrate and ferrous gluconate contain

9.5% and 12%, respectively, of elemental iron; carbonyl iron, heme iron polysaccharide

complex, and heme iron polypeptide contain 98-100% elemental iron.[126] Side effects of

iron therapy may include GI upset, nausea, vomiting, and constipation. Such side effects 32

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may hinder adherence. Dividing iron into smaller doses taken more frequently, and/or

taking iron supplements with food may decrease these side effects.[126] However,

consuming iron supplements simultaneously with foods rich in phytates (beans, peas,

lentils, nuts, seeds, grains) or polyphenols (herbal teas) can reduce ferrous iron absorption

by up to 50%.[126] Acid-reducing medications, calcium, and zinc may also affect

absorption rates Chan.[126, 145]

For correction of iron deficiency, the AACE/TOS/ASMBS 2013 CPG recommend taking

up to 150-200 mg of elemental iron daily, along with Vitamin C to increase absorption.[31]

However, taking ascorbic acid with iron better enhances absorption of iron from foods than

from iron supplements.[126] For severe intolerance to oral iron or refractory deficiency,

IV iron infusion (preferably with ferric gluconate or sucrose) may be used.[31, 102, 131,

145] The 2010 Endocrine Society published guidelines[82] recommended two phases of

treatment; of iron deficiency; the first phase consists of administration of ferrous sulfate

300 mg 2-3 times daily, taken with vitamin C, followed if needed by a second phase of

parenteral iron administration using iron dextran, ferric gluconate or ferric sucrose.

Iron – Summary

Recommendations for preoperative screening of iron deficiency

Routine pre-WLS screening of iron status is recommended for all patients. (Grade B,

BEL 2)

Screening patients for iron status, but not for the purpose of diagnosing iron

deficiency, may include the use of ferritin levels. (Grade B, BEL 2)

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A combination of tests (serum iron with serum transferrin saturation and total iron-

binding capacity) is recommended for diagnosing iron deficiency. (Grade B, BEL 2)

Pre-WLS screening for iron status should include assessment of clinical signs and

symptoms common to this condition (see Table 5). (Grade B, BEL 2)

Recommendations for postoperative screening of iron deficiency

Routine post-WLS screening of iron status is recommended for all patients within

three months after surgery, and then every 3- 6 months until the 12-month visit,

and annually thereafter. (Grade B, BEL 2)

Iron status in post-WLS patients should be monitored at regular intervals using an

iron panel, complete blood count, total iron-binding capacity, ferritin and soluble

transferrin receptor if available, along with clinical signs or symptoms. (Grade C,

BEL 3)

Additional iron screening in post-WLS patients who should be conducted as

warranted by clinical signs or symptoms and or laboratory findings, or in other

instances in which a deficiency is suspected. (Grade B, BEL 2)

Recommendations for supplementation of iron for preventing deficiency

Patients at low risk of postoperative iron deficiency should receive at least 18 mg of

iron from their multivitamin. (Grade C, BEL 3)

Menstruating females who have had RYGB, SG or BPD/DS should take 45-60mg of

elemental iron daily (cumulative from all vitamin and mineral supplements). (Grade

C, BEL 3)

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Oral supplementation should be taken in divided doses separately from calcium

supplements, acid-reducing medications, and foods high in phytates or polyphenols.

(Grade D, BEL 3)

Recommendations for postoperative iron repletion

In post-WLS patients with iron deficiency, oral supplementation should be increased

to provide from 150-200mg of elemental iron daily to amounts as high as 300 mg 2-

3 times daily. (Grade C, BEL 3)

Oral supplementation should be taken in divided doses separately from calcium

supplements, acid-reducing medications, and foods high in phytates or polyphenols.

(Grade D, BEL 3)Recommendation is downgraded to D, since majority of evidence

is from non-WLS patients.

If post-WLS iron deficiency does not respond to oral therapy, intravenous iron

infusion should be administered. (Grade C, BEL 3)

Vitamin D and Calcium

Vitamin D is important in calcium and phosphorus absorption and resorption, as well as

mineralization, and maturation of bone. It also modulates cell growth, neuromuscular and

immune function, and reduction of inflammation. Vitamin D exists in two forms: vitamin D2

(which is minimally obtained from the diet) and vitamin D3 (almost 80% obtained from

sun exposure).[8] As commonly used, the term "vitamin D” typically denotes D2, or D3, or

both. In the general population, daily intakes of vitamin D from foods average less than

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400 IU/d, but mean 25-hydroxy vitamin D [25(OH)D] levels are typically above 20 ng/ml

(50 nmol/liter).[146]

Once vitamin D is ingested, it is incorporated into chylomicrons, which are absorbed by

the lymphatic system and enter the venous blood. Without vitamin D, only 10–15% of

dietary calcium and about 60% of phosphorus are absorbed. Sufficient 25(OH)D levels

(greater than 30 ng/ml) enhance absorption of calcium by 30-40% and phosphorus

absorption by 80%.[147] Behavioral factors and genetics can have a profound effect on

vitamin D bioavailability.[148] Wearing a sunscreen with a sun protection factor of 30

reduces vitamin D synthesis in the skin by more than 95%. Additionally, people with a

naturally darker skin have extra sun protection and require at least three to five times

more sun exposure to convert the same amount of vitamin D as would people with lighter

skin.[149]

Calcium is integral to bone and tooth formation, as well as blood coagulation, muscle

contraction, myocardial conduction, nerve transmission, intracellular signaling and

hormonal secretion. There are several factors that impact the absorption of calcium

regardless of preoperative or postoperative status. These include dietary fat consumption

to facilitate vitamin D absorption, physiological levels of vitamin D, needed to facilitate

calcium absorption, and nutrient-nutrient interactions such as the creation of insoluble

salts from green leafy vegetables and foods containing high amounts of oxalates (spinach

and other greens, rhubarb, dry cocoa), and phytates (beans, peas, lentils, nuts, seeds,

grains), which inhibit the absorption of calcium and other minerals. [150, 151]

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25(OH)D is the primary circulating form of vitamin D, with a half-life of about 15 days;

it is the preferred biochemical assay for assessing vitamin D status. Serum 1,25(OH)2D has

a half-life of about 15 hours and is typically normal or even elevated in vitamin D

deficiency, due to secondary hyperparathyroidism. Thus, serum 1,25(OH)2D is neither

useful nor recommended as an indicator of vitamin D reserves or status.

Mildly reduced calcium and phosphate levels are commonly seen in vitamin D

deficiency (VDD), but levels may also be normal (Table 5). Often, alkaline phosphatase is

elevated due to increased bone turnover. VDD causes a decrease in the absorption of

dietary calcium and phosphorus, resulting in an increase in parathyroid hormone (PTH)

levels. The PTH-mediated increase in osteoclastic activity creates bone weakness and a

generalized decrease in bone mineral density, resulting in osteopenia and osteoporosis, as

well as skeletal deformities and muscle weakness.[147]

Preoperative Vitamin D and Calcium Screening

Studies have found that up to 90% of patients seeking WLS are deficient in 25(OH)D

levels.[35, 74, 76, 152-156] Obesity may promote VDD through several mechanisms,

including increased uptake of the circulating vitamin into adipose tissue, resulting in

sequestration and poor bioavailability, inadequate sun exposure, or 1,25(OH)2D

enhancement and concomitant negative feedback control on hepatic synthesis of 25(OH)D.

[1, 147, 149, 157] Numerous studies have reported an inverse relationship between

vitamin D levels and body mass index.[157-159] In fact, Stein et al.,[159] reported that

each body mass index increase of 1 kg/m2 was associated with a mean decrease of 1.3

nmol/l 25(OH)D.37

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There is strong evidence to recommend preoperative screening for vitamin D

insufficiency (VDI) or deficiency in all patients, which, if found, should be repleted with

appropriate supplementation before surgery.[31, 35, 101, 115, 158] Index levels for VDD,

insufficiency, and sufficiency have been defined as <20 ng/mL, 21-29 ng/mL, and 30-

100ng/mL, respectively.[147] With these newer, more conservative indices have come

increased reports of vitamin D deficiency in the general population and in patients with

obesity, [146, 160] and the reported prevalence of VDD in patients seeking WLS has

increased 20-30% since the 2008 Aills et al. guidelines were published.[1, 152, 153]

Most Americans, including pre-WLS patients do not consume adequate dietary calcium,

according to current recommendations.[146] Poor calcium intake in early childhood tends

to continue into the adult years.[161] Vitamin D is critical for calcium absorption and is

known to be a compounding factor, which makes it important to evaluate along with an

individual’s dietary calcium intake. Currently, there is no single commonly-recommended

labaratory assay used to determine calcium deficiency. There is, however, emerging

research on parathyroid hormone levels and bone density as they relate to calcium status.

[162-165] Due to the difficulty of screening for physiological adequacy of calcium intake, it

is critical to screen for vitamin D and to recommend preoperative supplementation of both

calcium and vitamin D.[158, 165]

Calcium requirements are known to increase with menopause due to decreasing

estrogen levels, which lead to an increase in bone resorption and a decrease in the

efficiency of both intestinal absorption and renal conservation of calcium.[166, 167]

Though screening for calcium sufficiency is difficult, WLS patients are at risk for calcium

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deficiency and can be screened with a combination of laboratory tests (vitamin D, 25-OH,

serum alkaline phosphatase, PTH, and 24 hour urinary calcium in relationship to dietary

intake).[168] Both pre-and post-menopausal women may be screened for increased bone

resorption by using urinary and/or serum type I collagen N-telopeptide (NTX) levels,

which are higher in patients with decreasing estrogen production.[167] In patients under

50 years of age, elevated values of carboxy- terminal telopeptide (CTX) have also been

reported in 67% of patients.[169]

Postoperative Vitamin D and Calcium Screening

Postoperative prevalence of VDD is high, approaching 100% in some samples.[35, 74, 76,

153, 169-172] Vitamin D insufficiency and deficiency rates are more pronounced in RYGB

and BPD/DS than in LAGB and SG due to procedure-specific factors, such as shortening or

bypassing portions of the small intestine, length of the common limb channel, bile

production and availability to mix with nutrients.[164, 173] A review of 30 clinical studies

identified VDD in 90% of both pre- and post- RYGB patients and VDI in up to 98% of post-

RYGB patients. A transient postoperative increase in vitamin D levels occurred by 6

months and a subsequent decrease in vitamin D levels with VDD persisted up to 18 months.

Prevalence of VDD in patients who had undergone SG was less than in RYGB patients and

decreased significantly from 84% to less than 50% at 12 months.[35] However, high rates

of VDI and VDD may persist for years after surgery.[74] In a Mediterranean population,

VDI and or VDD was the most common nutrient deficiency reported throughout 5 years for

both SG and RYGB (60% at all study time points). Correspondingly, a high proportion of

patients had elevated PTH throughout the study after both types of surgery. Dietary intake 39

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of calcium, phosphorus and magnesium were lower than current recommendations.[74]

More recent data, (5 year follow up data comparing BPD/DS and RYGB) demonstrated

10-20% greater weight loss with BPD/DS, but also more long-term deficiency of vitamin D

and other fat-soluble vitamins.[174] Other data for BPD/DS demonstrated that 45% of

patients continued to have VDD at 10-year follow-up, even though 65% patients were

taking both calcium and vitamin D supplements.[175]

Some methods of assessing insufficiency or deficiency of vitamin D and calcium may not

be completely accurate. There is a physiological compensatory mechanism between

calcium availability and actual absorption, as well as within bone mineral density (BMD)

preservation.[146, 176, 177] Due to the significant impact of WLS on bone health, it is

crucial to ensure robust screening, utilizing a variety of available screening tools in

addition to laboratory assays, in order to detect later-developing deficiencies. Particular

attention should be paid to BMD;[31, 163] as time elapses after WLS, dual-energy x-ray

absorptiometry (DXA) and PTH become more important in the interpretation of calcium

and vitamin D levels, and may be conducted at two years postoperatively or as indicated

after WLS.[31] It should be noted that recent research suggests that typically-used

methods for assessing VDI or VDD may not be accurate in some genetic subpopulations of

African Americans; [166, 167] and that PTH alone may not be sensitive enough to identify

BMD loss in post-WLS patients.

Pre- and post-menopausal patients, and patients who have had RYGB (with greater lean

mass loss), are at particular risk for BMD loss at the femoral neck and lumbar spine.[178]

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These patients should be followed closely, with periodic densitometries, as it is difficult to

determine BMD from biochemical markers alone.

Preventative Supplementation of Vitamin D and Calcium

Since post-WLS care begins preoperatively, it is important to begin a supplement

regimen pre-WLS. In patients preparing for WLS who are not vitamin D deficient, the RDAs

for vitamin D have been set at 600 IU/d for ages 1–70 years and increases to 800 IU/d for

71 years and older, corresponding to a serum 25(OH)D level of at least 20 ng/ml (50

nmol/liter). These RDAs were derived based on conditions of minimal sun exposure, due to

wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. In

vitamin D-sufficient patients, higher supplementation values have not consistently been

found to be associated with greater benefit.[146]

The RDA for calcium in the generally healthy population should be used for making

recommendations in patients who are pre-WLS and in patients without any identified

nutrient deficiencies.[147] The Institute of Medicine Committee concluded in 2011 that

available scientific evidence supported a key role of calcium and vitamin D in skeletal

health, consistent with a cause-and-effect relationship, and provided a sound basis for

determination of daily intake recommendations.[146] For optimal bone health, the RDAs

for calcium, which apply to >97.5% of the population aged > 1 year old, range from 700 to

1300 mg/d. For extraskeletal health, including cancer, cardiovascular disease, diabetes, and

autoimmune disorders, the evidence was inconsistent, and insufficient to inform

recommendations.[82][147]

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There are a number of recommendations currently in the lay media, suggesting how to

increase calcium and vitamin D absorption while inhibiting the formation of calcium

oxalate kidney stones. One particular suggestion, sauteéing green leafy vegetables to

increase calcium bioavailability seems intuitive, yet the research reports no beneficial

effects for either of the desirable outcomes.[150] There is emerging and promising

research in post-WLS patients, with regard to using calcium or potassium citrate

preferentially over other forms of calcium, and using probiotics to help inhibit formation of

oxalic salts via increased enteric oxalate absorption. Thus, educational strategies for

achieving adequate calcium and Vitamin D should take into account the individual patient’s

knowledge base and whether erroneous beliefs are contributing to a patient’s personal

dietary regimen.

In perimenopausal and postmenopausal women, the recommendations for optimal

bone health are higher. The North American Menopause Society[179] recommends

adequate calcium (<1000 mg calcium/day and UL <2500 mg/day for women < 50 yrs, and

< 1200 mg calcium/day and UL < 2000 mg/day for women >50 yrs) in the presence of

adequate vitamin D (serum 25(OH)D > 30 ng/mL).

Recommendations for vitamin D and calcium in post-WLS patients exceed the IOM

supplement recommendations for the general population.[146] Recommended levels of

supplementation are different for different types of surgery. For instance, distal RYGB and

BPD/DS alter digestion and nutrient absorption, thus creating a need for greater intake of

calcium and vitamin D.[31, 174] In one study of Mediterranean SG and RYGB patients, even

though participants were prescribed a multivitamin and mineral regimen which provided a

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total of 1,120 mg of calcium citrate plus 1040 IU of vitamin D, VDI or VDD was the most

common (>60% at all timepoints) nutrient deficiency reported for both procedures

throughout the 5 year follow up.[74] It is not clear if these patients were assessed

preoperatively, thus VDI or VDD may be exacerbated by lack of appropriate preoperative

diagnosis and repletion.[31, 101, 158]

Bone mineral loss is strongly associated with weight loss.[163] Research indicates that

even with vitamin D and calcium repletion, bone loss among WLS patients is still a concern.

[163, 164, 180] For instance, in one study, even though calcium, vitamin D and PTH levels

were reported to be within the norm, BMD continued to decrease an additional 9% by 2

years after RYGB as compared with a control group.[181] In WLS patients, who are at high

risk for pre- and postoperative calcium and VDD, it is imperative to supplement these

micronutrients to prevent acute problems. Bone loss may occur due to impaired calcium

absorption caused by decreased activation of vitamin D-dependent calcium absorption

mechanisms.[182] However, the clinician should be aware that, with calcium

supplementation, “more is not always better”. In fact, long-term intake of higher than

recommended calcium doses may be associated with health risks, though findings have

been inconsistent and it is difficult to infer causality in hypovitaminosis D or hypocalcemia

and non-skeletal diseases.[183] Thus, the current recommendations are for slightly lower

levels of calcium supplementation than detailed in the previous ASMBS guidelines, [1]

consistent with the AACE/TOS/ASMBS 2013 CPG.[31] Additionally, ranges that include

dietary sources and supplements rather than exact supplementation amounts are provided

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to allow for supplementation (or repletion, see below) to vary based on patient dietary

intake of vitamin D and calcium.

Although ergocalciferol (vitamin D2) may be used for supplementation, research

indicates that cholecalciferol (vitamin D3) is a more effective form,[184, 185] especially

when given in bolus dose, due to a potentially increased affinity of cholecalciferol to

vitamin D binding protein and receptors.[186] A dose of 2000 g (50 000 IU) vitamin D2 μ

should be considered equivalent to ≤375 g (15000 IU) vitamin D3, and likely closer to μ

125 g (5000 IU) vitamin D3.μ [184] When the varying modes of dosage administration was

compared in one study [184] there was a significant response for vitamin D3 when given as

a bolus dose (P = 0.0002) compared with administration of vitamin D2, but the difference

was not statistically significant when comparing daily doses of D2 and D3. More research is

needed to establish efficacious doses of each of the forms of vitamin D.

The most commonly available forms of calcium supplementation in the United States

are calcium carbonate and calcium citrate. Calcium lactate, gluconate, bone meal and

hydroxyapatite are also available, but the elemental calcium content in these supplements

varies. The type of nutrient delivery (capsules tablets, chews, wafers, powders, liquids)

impacts the bioavailability of the calcium in the supplement. Calcium carbonate provides

approximately 40% absorption of elemental calcium when taken in doses no greater than

500 mg and ingested with meals, which increases the acid production needed for

absorption. [187] Possible adverse reactions to calcium carbonate supplementation are

constipation, nausea and bloating. Calcium citrate provides approximately 21% elemental

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calcium, which can be absorbed in either an acidic or non-acidic environment. Other forms

of calcium salts provide less than 20% absorption.[187, 188]

Repletion of Postoperative Vitamin D and Calcium Deficiency

Vitamin D and calcium deficiency are very common in both pre- and post-WLS patients.

[153, 170, 171] Recommendations by Mechanick for treatment of vitamin D and calcium

deficiency or insufficiency after WLS concur with other research findings.[31, 147, 185,

188], Even with prescribed treatment for VDD, deficiencies may persist and multiple

treatment courses may be necessary. Lack of treatment effectiveness may be due, in part, to

inadequate patient adherence to the repletion regimen.[188, 189] However, more frequent

monitoring with adjustment of calcium and VDD may be needed in more malabsorptive

procedures; ie., a 200 cm BP limb may require more frequent monitoring than a 60 cm BP

limb or a 150cm RYGB limb.[132] As with supplementation, vitamin D3 is more potent

than vitamin D2 for repletion of vitamin D deficiencies.[186]

Vitamin D and Calcium – Summary

Recommendations for preoperative screening of Vitamin D insufficiency or deficiency

Routine pre-WLS screening of Vitamin D status is recommended for all patients.

(Grade A, BEL 1)

Routine pre-WLS screening of calcium status and vitamin D deficiency and

insufficiency is particularly important for peri-menopausal women. (Grade D, BEL

4)

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Recommendations for postoperative screening of Vitamin D and calcium

Routine post-WLS screening of vitamin D status is recommended for all patients.

(Grade B, BEL 2)

More research is needed before a recommendation can be made regarding the use

of vitamin D binding protein assays as an additional tool for determining vitamin D

status in post-WLS patients. (Grade C, BEL 3)

Recommendations for supplementation of vitamin D and calcium for preventing deficiency

All post-WLS patients should take calcium supplementation. (Grade C, BEL 3)

The appropriate dose of calcium varies by surgical procedure:

o BPD/DS: 1800-2400 mg/day

o LAGB, SG, RYGB: 1200-1500 mg/day

The recommended preventative dose of vitamin D in post-WLS patients should be

based on serum vitamin D levels:

o Recommended vitamin D3 dose is 3000 IU daily, until blood levels of 25(OH)D

are greater than sufficient (30 ng/mL) (Grade D, BEL 4)

o As compared to recommended vitamin D2 doses, a 70-90% smaller vitamin D3

bolus dose, is needed to achieve the same effects in healthy non-bariatric

surgical patients (Grade A, BEL 1)

In order to enhance calcium absorption in post-WLS patients, the following dosing

considerations apply (Grade C, BEL 3):

o Calcium should be given in divided doses

o Calcium carbonate should be taken with meals46

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o Calcium citrate may be taken with or without meals

Recommendations for repletion of postoperative vitamin D and calcium deficiency

Vitamin D levels must be repleted if deficient or insufficient, in order to normalize

calcium. (Grade C, BEL 3)

All post-WLS patients with vitamin D deficiency or insufficiency should be repleted with

the following doses:

Vitamin D3 dosages of at least 3000 IU/day and as high as 6000 IU/day or 50,000 IU

vitamin D2 once to three times weekly. (Grade A, BEL 1)

Vitamin D3 is recommended as a more potent treatment than vitamin D2 for

repletion of vitamin D. However, both forms can be efficacious, depending on the

dosing regimen. (Grade A, BEL 1)

The recommendations for repletion of calcium deficiency varies by surgical

procedure. (Grade C, BEL 3):

o BPD/DS: 1800-2400 mg/day calcium

o LAGB, SG, RYGB: 1200-1500 mg/day calcium

Vitamins A, E, K

Vitamin A is critical for normal vision; it supports cell growth and differentiation, and

plays a major role in the normal formation and maintenance of the heart, lungs, kidneys,

and other organs. It is important in maintaining healthy skin, teeth, skeletal and soft tissue,

and mucus membranes.[190, 191]

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Vitamin A exists in two forms: preformed vitamin A (found in animal products e.g., eggs,

meat, fortified milk, etc.) and pro-vitamin A, (found in plant-based foods (e.g., bright yellow

and orange fruits and vegetables)). The most common form of pro-vitamin A is beta-

carotene, a carotenoid. Alternative names for vitamin A include retinol, retinal, retinoic

acid, and carotenoid.

Vitamin E (alpha-tocopherol and gamma-tocopherol) is an antioxidant that protects the

body from the damages of free radicals, helps to strengthen the immune system; plays a

role in the formation of red blood cells; and helps the body use vitamin K by dilating blood

vessels and preventing thrombosis. Adequate vitamin E levels are best maintained by

obtaining this vitamin through food; sources of vitamin E include vegetable oils, nuts and

seeds. Though vitamin E levels may be increased through supplementation, high doses of

vitamin E in supplement form may increase the risk for bleeding.[191-194]

Vitamin K is integral to blood clotting, thus patients with a vitamin K deficiency may

present with bruising or bleeding; considered rare in the general population; but may

occur if the GI tract is not absorbing nutrients properly, such as after WLS or as a result of

long-term antibiotic treatment.[191, 193, 194]Patients taking blood-thinning drugs should

be cautioned about risks of excessive intake of vitamin K both from food and supplemental

sources.[191, 193, 194]

Lipid digestion is delayed in post-WLS patients, especially in patients who undergo

RYGB, and BPD/DS. In these procedures, the fats do not pass through the duodenum

impairing the release of bile and pancreatic lipase. Limited production of these enzymes

lead to the malabsorption of fat; thus, fat soluble vitamin deficiency may result. Water

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soluble vitamin deficiencies tend to occur early in the postoperative period, but fat soluble

deficiencies develop more slowly, based on the rate of the progression of fat

malabsorption.[195]

Preoperative Vitamin A, E and K Screening

Reported prevalences of vitamin A and E deficiencies in pre-WLS patients is low

(vitamin A (14%), vitamin E (2.2%); there are no data regarding the prevalence of vitamin

K deficiencies in this population.[35, 115, 156, 196, 197] However, AACE/TOS/ASMBS

2013 CPG recommended that all WLS patients undergo micronutrient assessment,

including screening for deficiencies of fat-soluble vitamins (A, E, D, K), before any WLS

procedure.[31]

The Aills guidelines do not include specific recommendations for preoperative

screening of fat-soluble vitamin deficiencies, as most research on these deficiencies has

focused on the postoperative period.[1] However, it is known that obesity increases the

need for vitamin A and contributes to the depletion of liver stores, enhancing the risk for

developing metabolic disorders.[192, 197, 198] High BMI, poor quality food choices and

inflammation are factors that may predispose some pre-WLS patients to be at risk for

vitamin A deficiency.[193, 197, 199]

Postoperative Vitamin A, E and K Screening

Vitamin A deficiency has been found to be relatively common (up to 70%) in LAGB,

RYGB, and BPD/DS patients within 4 years after surgery.[1, 199, 200] Additionally, vitamin

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A deficiency has been found to be associated with low serum concentration of pre-albumin.

[197]

In RYGB and to a more pronounced extent after BPD, there is a consistent and

continuous decline in all carotenoids to almost undetectable levels after surgery. In fact,

patients who had BPD/DS have been found to have serum vitamin A levels that were about

one-half to one-third the amount of vitamin A levels found in patients who had RYGB.[201]

Based on current data, vitamin A should be measured in patients who have undergone

BPD/DS or RYGB, and deficiency should be suspected in those with evidence of protein-

calorie malnutrition.[201]

As noted in the AACE/TOS/ASMBS 2013 CPG,[31] there is insufficient evidence to

support routine postoperative screening for vitamin E or vitamin K deficiencies, given that

the prevalence of these conditions is typically observed to be fairly low[31], and vitamin E

levels may actually increase after both RYGB and BPD/DS.[37] On the other hand, serum

concentrations of the vitamin E derivative alpha-tocopherol has been found to be

decreased after one year in both RYGB and BPD/DS.[201]The significance of alpha-

tocopherol levels is unclear, however, since normal vitamin E levels have been observed in

RYGB patients with subthreshold levels of alpha tocopherol.[202]

Data published both before and since the Aills guidelines suggest that it is unusual and

rare to observe complications related to vitamin K deficiency post-WLS; however, any

malabsorptive procedure (BPD/DS or RYGB) does confer an elevated risk for vitamin K

deficiency (Table 5).[1, 203] Low prothrombin time has been used as an indicator of

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vitamin K deficiency, and mean prothrombin time was found to be lower in the RYGB group

than either LAGB or conventional weight loss treatment groups.[203]

Preventative Supplementation of Vitamin A, E and K

Current research continues to suggest that the risk of fat-soluble vitamin deficiency is

greater in patients who have RYGB and BPD/DS.[37] Compared with RYGB, DS may be

associated with a greater risk of vitamin A deficiency in the first year after surgery,

indicating that long term vigilant monitoring of postoperative BPD/DS patients may be

warranted.[37]

There have been recent data showing that post-WLS patients who are inadequately

supplemented during pregnancy may expose the fetus or newborn to problems such as

cerebral hemorrhage or other bleeding disorders related to vitamin K deficiency, and

microcephaly, hypotonia, microphthamia, and permanent retinal damage due to vitamin A

deficiency.[204] Special attention should be given to prenatal supplementation of vitamin K

in early pregnancy in women who have undergone BPD/DS.

Repletion of Postoperative Vitamin A, E, and K Deficiency

Although recent literature does not suggest that any changes to the Aills guidelines[1]

are needed; there have been a number of case studies describing the sequelae of vitamin A,

E, or K deficiencies, underscoring the importance of addressing such deficiencies when

they are identified.[194, 205]

Vitamins A,E,K – Summary

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Recommendations for preoperative screening of vitamins A, E, K deficiency

Routine pre-WLS screening of vitamins A, E, K status is recommended for all

patients. (Grade C, BEL 3)

Recommendations for postoperative screening of vitamins A, E, K deficiency

Post-WLS patients should be screened for vitamin A deficiency within the first year

after surgery, particularly those who have had BPD/DS, whether symptoms are

present or not. (Grade B, BEL 2)

Vitamin A should be measured in patients who have had RYGB or BPD/DS,

particularly in those patients with evidence of protein-calorie malnutrition. (Grade

B, BEL 2)

While Vitamin E and K deficiencies are uncommon after WLS, patients who are

symptomatic should be screened. (Grade B, BEL 2)

Recommendations for supplementation of Vitamins A, E, K for preventing deficiency

Post-WLS patients should take vitamins A, E, and K, with the dosage based upon type of

procedure:

o LAGB: Vitamin A (5000 IU/d) and Vitamin K (90-120 ug/day)(Grade C, BEL 3)

o RYGB, and SG: Vitamin A (5000-10,000 IU/d) and Vitamin K (90-120 ug/day)(Grade

D, BEL 4)

o LAGB, SG, RYGB, BPD/DS: Vitamin E (15 mg/d) (Grade D, BEL 4)

o DS: Vitamin A (10,000 IU/d) and Vitamin K (300 µg/d) (Grade B, BEL 2)

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Higher maintenance doses of fat-soluble vitamins may be required for post-WLS

patients who have a previous history of vitamin A, E, or K deficiency. (Grade D, BEL 4)

Water-miscible forms of fat soluble vitamins are also available to improve absorption

(Grade D, BEL 4)

Special attention should be given to prenatal supplementation of vitamin A and K in

pregnant women who have had WLS. (Grade D, BEL 4)

Recommendations for postoperative Vitamin A, E, and K repletion

Vitamin A

In post-WLS patients with vitamin A deficiency and without corneal changes:

10,000-25,000 IU/d vitamin A should be administered orally until clinical

improvement is evident (1-2 weeks). (Grade D, BEL 4)

In post-WLS patients with vitamin A deficiency and with corneal changes: 50,000 –

100,000 IU vitamin A should be administered IM for 3 days followed by 50,000 IU/d

IM for 2 weeks. (Grade D, BEL 4)

Post-WLS patients with vitamin A deficiency should also be evaluated for

concurrent iron and/or copper deficiencies as these can impair resolution of

vitamin A deficiency. (Grade D, BEL 4)

Vitamin E

The optimal therapeutic dose of vitamin E in post-WLS patients has not been clearly

defined. There is potential for antioxidant benefits of vitamin E to be achieved with

supplements of 100-400 IU/d. This is higher than the amount typically found in a

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multivitamin; thus additional vitamin E supplementation may be required for

repletion. (Grade D, BEL 4)

Vitamin K

For post-WLS patients with acute malabsorption, a parenteral dose of 10 mg vitamin

K is recommended. (Grade D, BEL 4)

For post-WLS patients with chronic malabsorption, the recommended dosage of

vitamin K is either 1-2 mg/d orally or 1-2 mg/week parenterally. (Grade D, BEL 4)

Zinc

Zinc is a trace mineral that plays important roles in nucleic acid metabolism, gene

regulation, immune function, hormone activity, lipid and protein metabolism, cell growth,

cell replication, and cell death (apoptosis), as well as taste acuity, vision, wound healing,

growth and reproduction, and over 300 enzymatic reactions.[206, 207] Unlike other

nutrients, there are no body reserves of zinc beyond levels present in body tissues,

between 1.5 to 3.0 grams of zinc.[206, 207]

Zinc is absorbed in the proximal jejunum. Absorption efficiency is inversely

correlated with zinc intake.[208] Once zinc is absorbed in the intestinal mucosal cells, the

metal-binding protein metallothionein binds zinc and impedes its movement into the

bloodstream. More metallothionein is produced when zinc intake is high. When zinc intake

is low, zinc is absorbed into intestinal mucosal cells and circulates in the bloodstream to

tissues bound to albumin and alpha2- macroglobulin. Zinc contained in intestinal cells and

unabsorbed dietary zinc is excreted in the feces when not needed in the body.[206]

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Preoperative Zinc Screening

Research reports of estimated prevalence of zinc deficiency vary widely, ranging from

9% to 74% of patients seeking BPD/DS.[208-210] Copper, zinc, and iron compete for the

same trans-membrane transport molecule, which can lead to an imbalance of these

minerals. Zinc also causes up-regulation of the production of metallothionein, which can

bind and trap copper in small intestinal cells, leading to copper depletion with sloughing of

these cells.[211] High intake of dietary zinc increases the synthesis of metallothionein, and

because metallothionein has a higher affinity for copper than zinc, a decrease in copper

absorption can occur with high intake of dietary zinc or oral zinc supplementation, as

copper will displace zinc and remain in the enterocyte. On the other hand, it has been

questioned whether zinc competes with iron absorption.[212-215] However, use of a

modest zinc supplement (22 mg/day zinc gluconate) has been shown to induce a cellular

iron deficiency and, possibly, further reduce iron status.[216]

More recent studies in pre-WLS patients have found that patients with obesity have

lower serum zinc levels (and lower concentrations of zinc in plasma and erythrocytes than

leaner patients).[58, 208-210, 217] It is suggested that the accumulation of adipose tissue,

increases the production of adipocytokines, resulting in a chronic inflammatory state.[38]

The inflammation then induces the expression of metallothionein and zinc-copper

transporters in hepatocytes, proteins that promote metal accumulation in the liver and in

adipocytes, thus contributing to low zinc concentrations.[38]

Although Aills et al.,[1] suggest that there is no reliable way to determine zinc status,

plasma, urinary, and hair zinc have been established as reliable biomarkers of zinc status in

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healthy patients, and these are commonly used to assess zinc in WLS patients (Table 5).

[218] Zinc stable isotope techniques can be used to determine zinc absorption;[218]

however, serum zinc levels may be decreased in the pro-inflammatory state of obesity,

[209, 219, 220] rendering plasma zinc an unreliable marker in the presence of systemic

inflammation.[31, 93, 221] Plasma zinc corresponds to 0.1% of total body zinc, and small

alterations in the tissues will affect this value, which is why some authors advocate

evaluating zinc erythrocyte concentration.[153, 220, 222] On the other hand, plasma zinc

concentration is still the preferred biomarker, because the erythrocyte may contaminate

the zinc. In addition, plasma concentrations are maintained even in the setting of decreased

or increased intake of zinc unless such changes are prolonged.[198]

Despite evidence suggesting that patients with obesity are at higher risk for zinc

deficiency, routine screening of zinc has not been recommended by recent CPGs.[31, 93,

209] Because of the unreliability of measures of zinc status in patients with obesity, and

limited data regarding zinc status pre-WLS, there is limited evidence to recommend routine

screening for zinc deficiency prior to WLS. However, patients undergoing certain WLS

procedures are at higher risk for developing zinc deficiency after surgery, indicating the

need for a baseline assessment of zinc status prior to surgery.

Postoperative Zinc Screening

The risk for postoperative zinc deficiency varies by the type of surgical procedure.

Postoperative zinc deficiency has been reported in 34% of patients post LAGB, 19% post-

SG, 40% post RYGB, and 70% post-BPD/DS.[223-226] Factors that increase risk of zinc

deficiency include the bypassing of the duodenum and proximal jejunum, which is the 56

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primary site of zinc absorption; reduction in the digestive enzymes containing zinc that are

secreted by the pancreas into the small intestine; reduction in gastric production of

hydrochloric acid, which is needed to improve bioavailability of zinc and absorption;

intolerance to food rich in zinc; and decreased dietary intake of zinc.[225, 227, 228]

As is the case with most micronutrients, zinc deficiency is more common after BPD/DS

than after other WLS procedures.[37] The AACE/TOS/ASMBS CPG advised monitoring of

zinc status in patients who have undergone malabsorptive (RYGB or BPD/DS) procedures

and who have not had routine supplementation, due to the risk of iatrogenic copper

deficiency.[31] Reported rates of zinc deficiency in BPD/DS patients are variable. Studies

have found prevalence rates ranging from 33% to 74% anywhere from one to ten years

postoperatively.[175, 229, 230] Because zinc is excreted in the feces, patients who

experience chronic diarrhea (which occurs in a subset of BPD or BPD/DS patients) are at

increased risk for zinc deficiency.[31, 93, 221] Therefore, the updated AACE/TOS/ASMBS

guidelines recommend routine zinc screening and supplementation for BPD/DS patients.

[31]

Reported rates of zinc deficiency in RYGB patients range from 40% to 60% at 6 months

postoperatively, despite standard supplementation.[38, 98, 223, 225] In one study, for

instance, 40% of patients taking 15 mg daily zinc as part of their daily multivitamin/

mineral regimen and a separate group taking 25 mg daily as additional zinc experienced

zinc deficiency.[98, 208, 231] Despite patients taking a multivitamin and mineral

supplement containing 8 mg zinc daily, 3% and 12% of patients had zinc deficiency at 6

and 24 months postoperatively, respectively.[98] Overall, reports of increased frequency

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of zinc deficiency post-RYGB, despite standard zinc supplementation, justifying a

recommendation of postoperative monitoring of zinc status. It is recommended that

screening be conducted using the same biomarkers as employed in preoperative screening,

as described above.[31]

Recent studies have examining zinc deficiency in SG patients, have yielded mixed

results.[232] In post-SG patients, 19% prevalence of zinc deficiency has been reported at

one year.[208] In another study, 14% of patients who had SG and were not initially

supplemented with zinc had to be supplemented with 15 mg/day zinc when they presented

with zinc deficiency post-surgery.[90] On the other hand, several studies did not detect

postoperative zinc deficiencies in patients who had SG and who were provided with

standard multivitamin and mineral supplementation containing zinc.[41, 233] However, in

another study, 34% of SG patients provided with a multivitamin containing 10 mg zinc

presented with zinc deficiency within the first year after surgery.[38] Low serum zinc

levels and hair loss related to zinc deficiency was detected at 24 months postoperatively in

a different sample of SG patients.[234] These studies all suggest that the zinc content of

standard multivitamin and mineral supplementation may not be sufficient to prevent zinc

deficiency in SG patients.

Decreased intake of foods containing zinc after surgery is associated with lower zinc

concentrations.[235] One preliminary report found a larger change in erythrocyte and

urinary zinc concentrations versus plasma zinc in unsupplemented patients 2 months post-

RYGB.[235] The authors concluded that zinc supplementation was not necessary for the

first 2 months after RYGB surgery if nutritional status was adequate before surgery.

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However, food logs indicate that patients may have had a lower dietary zinc intake in the

postoperative period, putting them at risk for long-term deficiency and supporting the

need for supplementation. For example, low serum levels of zinc were found in a small

study (n=30) at 3 months post-LAGB, and this was attributed to decreased dietary intake of

zinc.[236] Further studies are needed to correlate dietary intake of zinc to the response of

different zinc biomarkers for zinc at various time periods following WLS. It was suggested

by the authors of one study that preoperative and early postoperative deficiency could be

related to protein status, as evidenced by differences in serum pre-albumin concentration.

[208] This was not correlated with reported protein intake, however, but rather only with

indirect markers of protein nutritional status[208].

Since zinc absorption efficiency is inversely correlated with zinc intake, adaptation to

zinc absorption is not possible after malabsorptive procedures, such as the BPD/DS and

RYGB, as greater intestinal absorption and reduced excretion are unlikely when the

duodenum and part of the proximal jejunum are bypassed.[208] Overall, zinc deficiency is

less common after purely restrictive procedures, such as the LAGB, but decreased intake of

zinc-containing foods after the LAGB, as well as other WLS procedures, increases the

likelihood of postoperative deficiency.[38]

The AACE/TOS/ASMBS 2013 CPG recommend regular zinc screening in RYGB and

BPD/DS patients, without specifying a frequency.[31] Review of new evidence, however,

suggests that it is appropriate to screen at least annually in RYGB and BPD/DS patients.

Screening for zinc status in post-LAGB and SG patients is not recommended in the

AACE/TOS/ASMBS 2013 CPG[31]; however, the current evidence suggests it is important

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to conduct zinc screening in patients presenting with clinical symptoms of deficiency,

particularly in patients who have undergone surgeries that affect nutrient absorption,

particularly after BPD/DS, RYGB, and (to a lesser extent) SG, using the same biomarkers

used preoperatively.

Preventative Supplementation of Zinc

The risk for zinc deficiency remains even in patients taking a standard multivitamin

and mineral supplement.[38, 206, 210, 220, 222, 224, 226, 230, 237] In the studies

reviewed, the researchers used various supplemental zinc dosages, ranging from 8-30

mg/day of elemental zinc. [38, 41, 98, 206, 208, 210, 222, 224, 226, 230] In these studies,

higher doses of zinc (15 mg/day to 30 mg/day) were reserved for BPD patients and lower

doses (8 to 10 mg/day) were provided to RYGB and SG patients.[90, 98, 223] Some of the

vitamin and mineral supplements used in these studies contained 100% of the RDA for

zinc, but even when 200% of the RDA was provided, deficiencies were observed. [38, 90,

98, 223]

Zinc deficiency appears to be more pronounced among BPD patients who do not

receive, or who do not adhere to, standard multivitamin and mineral supplementation after

surgery.[90] However, relatively small doses of zinc (0.8 mg zinc) used daily in a

multivitamin have been found insufficient to maintain zinc status within normal levels two

years after BPD, with 34% of one sample developing a zinc deficiency. In order to achieve

zinc levels within normal limits, elemental zinc was increased in 81% of these patients, to a

much larger dose, (60 mg/day).[238] This led the researchers to recommend a dose of 30

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mg/day elemental zinc, in addition to the zinc found in a multivitamin, following BPD in

order to prevent post-operative zinc deficiency following BPD.[238]

There are only two recent RCT’s that have assessed zinc status in RYGB patients given

various dosages of zinc. One study (n=67) found impaired zinc absorption among

participants 6 months and 18 months post-surgery, despite supplementation of 7.5 or 15

mg/day.[220] Based on these findings, the authors recommended daily supplementation

of 40-50 mg of zinc per day. This study was expanded by the same group of authors, who

gave a third group 24 mg/day zinc and examined inflammatory parameters.[237]

Increased plasma and hair zinc levels were found in all three treatment groups. The

authors attributed this to a decreased inflammatory state post-surgery.

Even though patients who had SG were provided daily standard multivitamin and

mineral supplementation containing zinc, patients still developed zinc deficiencies[41, 233]

In fact, in one study, 34% of patients supplemented with 10 mg zinc in a daily multivitamin

also presented with zinc deficiency within the first year after surgery.[38] Additionally,

zinc deficiency was detected at 24 months postoperatively in SG patients.[234] Thus, the

zinc content of standard multivitamin and mineral supplementation may not be sufficient

to prevent zinc deficiency in SG patients.

The AACE/ASMBS/TOS 2013[31] guidelines recommend routine zinc supplementation

post-WLS, and note that the dose must be carefully considered. Review of the recent

literature suggests that 100-200% of the RDA may not be adequate; yet seems to be most

appropriate to prevent zinc deficiency, especially in BPD/DS and RYGB patients.

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Supplementation with a standard multivitamin containing at least 100% of the RDA for

zinc (8-11 mg/day) is recommended for patients who have SG.

Multivitamin formulations vary in concentrations of elemental zinc and the salt form

of zinc. Zinc gluconate contains 14.3% elemental zinc, zinc oxide contains 80% elemental

zinc, zinc acetate contains 30% elemental zinc, and zinc sulfate contains 23% elemental

zinc.[1, 239]

Care must be taken to ensure that the appropriate ratio of zinc to copper

supplementation is achieved. Copper depletion can occur when large doses of zinc (e.g.,

>60 – 600 mg/day) are given for long periods of time. Nausea, vomiting, and cramping

have been reported with zinc intakes of 50-150 mg/day.[198] When daily doses of >60

mg/day of zinc are consumed for longer than 10 weeks, reduced copper biomarkers have

been observed.[198] At doses of 150 mg/day of elemental zinc, copper deficiencies can

arise.[207] At doses of 600 mg/day of elemental zinc, there have been case reports of

myeloneuropathies, thought to be a consequence of copper deficiency [240, 241] Typically,

multivitamin and mineral supplements contain a ratio of 15 mg of zinc for each 1-2 mg of

copper. Griffith et al. report that a zinc to copper ratio of 15 mg of zinc for each 1-2 mg of

copper [240] may be too high for patients post-RYGB, as over-supplementation with zinc

can lead to a copper deficiency-related anemia. Accordingly, AACE/TOS/ASMBS 2013

CPG[31] recommend that appropriate supplements contain 8-15 mg of elemental zinc for

every 1 mg of copper. Any supplementation with high doses of zinc greater than 50 mg/day

should be implemented with caution and closely monitored. In addition, despite the

uncertainty regarding whether zinc inhibits iron absorption, high dosages of supplemental

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iron (i.e., beyond the DRI of 18 mg), should be taken at different times than zinc

administration, in order to avoid competition for intestinal absorption.

Repletion of Postoperative Zinc Deficiency

There are very few studies examining repletion doses for zinc deficiency in WLS

patients. The Merck Manual of Diagnosis and Therapy recommends treatment with 15 to

120 mg/day elemental zinc in the non-bariatric patient.[242] Although no optimal dose for

zinc deficiency in WLS patients has been firmly established, the 2008 ASMBS Nutritional

Guidelines [1] recommend repletion with 60 mg elemental zinc orally twice a day.

However, as new research on this topic has emerged, this recommendation requires

further elaboration. Although studies with a high level of evidence are still needed, case

studies can provide a basis for recommendations regarding repletion of zinc. In one study

in which 90% of patients who had RYGB and SG were zinc deficient, 30 mg/day of oral zinc

gluconate (4.29 elemental) was needed for repletion.[38] However, repletion of zinc

deficient patients who were not given multivitamin and mineral supplementation, was

effectively achieved with 15 mg/day of oral elemental zinc.[90] The discussion by

Jeejeehboy et al.[232] of a pivotal paper by Kay et al., [243] describes repletion of zinc

deficiency in the non-bariatric patient with 220 mg oral or 80 mg IV zinc sulfate over 10

days to a few weeks in a series of three nonbariatric cases. A single case report described a

patient with acquired zinc deficiency 3 years post-RYGB who was effectively treated with

220 mg zinc sulfate (50 mg of elemental zinc), though the route of administration was not

specified. Based on this case report, the authors suggested that treatment for zinc

deficiency should be initiated at 3 mg/kg/day of elemental zinc.[244] In general, while 63

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some patients may require more than 30 mg of zinc for repletion therapy, it may be

beneficial to split doses to < 30 mg per dose period to reduce the risk of GI distress and side

effects. [198]

As noted above, while zinc toxicity is rare, high oral intake of zinc can lead to copper

deficiency. The risks of copper deficiency caused by zinc intake is decreased with IV

repletion, as the gut, which is the site of competition between zinc and copper absorption,

is bypassed. Although standard dosing for zinc repletion has not yet been established for

WLS patients, it is important to provide a repletion level that will not disrupt the

homeostasis of other micronutrients.

Zinc – Summary

Recommendations for preoperative zinc screening

Routine screening of zinc status is recommended for patients prior to RYGB or

BPD/DS. (Grade D, BEL 3)

Zinc assays in pre-WLS patients should be interpreted in light of the fact that

patients with obesity have lower serum zinc levels and lower concentrations of zinc

in plasma and erythrocytes than leaner patients. (Grade C, BEL 3)

Recommendations for postoperative screening

While evidence does not suggest that all post-WLS patients should be screened for

zinc deficiency, patients who have RYGB or BPD/DS should be screened at least

annually for zinc deficiency. (Grade C, BEL 3)

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Serum or plasma zinc are the most appropriate biomarkers for zinc screening in

post-WLS patients. The same biomarkers should be used in preoperative and post-

operative patients. (Grade C, BEL 3)

Zinc should be evaluated in all post-WLS patients when the screening results for

iron deficiency anemia are negative. (Grade C, BEL 3)

Post-WLS patients who have chronic diarrhea should be evaluated for zinc

deficiency. (Grade D, BEL 4)

Recommendations for supplementation of zinc for preventing deficiency

All post-WLS patients should take zinc, with the dosage based upon type of

procedure (Grade C, BEL 3):

o BPD/DS: Supplement with16-22 mg/day of zinc.

o RYGB: Supplement with 8-22 mg/day of zinc.

o SG/LAGB: Supplement with 8-11 mg/day of zinc.

To minimize the risk of copper deficiency in post-WLS patients, it is recommended

that the supplementation protocol contain a zinc-to-copper ratio of 8-15 mg of

supplemental zinc per 1 mg of copper. (Grade C, BEL 3)

Formulation and composition of zinc supplements must be taken into account for

accurate calculation of elemental zinc levels. (Grade D, BEL 4)

Recommendations for postoperative zinc repletion

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There is insufficient evidence to make a dose-related recommendation for repletion. The

previous recommendation of 60 mg elemental zinc, orally twice a day, needs to be re-evaluated

in light of emerging research that this dose may be inappropriate.

Repletion doses of zinc in post-WLS patients should be chosen carefully to avoid inducing a

copper deficiency. (Grade D, BEL 3)

Zinc status should be routinely monitored using consistent parameters throughout the course

of treatment. (Grade C, BEL 3)

Copper

Copper is an essential trace mineral that acts as an antioxidant and is involved in the

synthesis of the pigment melanin and the connective tissue proteins collagen and elastin.

[207] Copper is a component of ceruloplasmin, the enzyme that oxidizes ferrous iron to

ferric iron for incorporation into transferrin before it is transported in the plasma.

Ceruloplasmin is also involved in the erythrocyte-forming cells of bone marrow.[207]

Copper plays a role in myelinization of nerves, immune function, and cardiovascular

function.[206] Copper concentrations are highest in the liver, brain, heart, and kidney.

Copper is secreted from the liver as a component of bile.[207] The adult body stores about

100 mg of copper at any time, and excess copper is excreted in feces from unabsorbed

dietary copper; released in bile; and sloughed within cells from the intestinal wall.[206]

Copper is absorbed in the stomach and duodenum. Copper absorbed in the small

intestine is bound to metallothionein, a metal binding protein that has greater affinity for

copper than for zinc or other metal ions. Because of this affinity, copper may be trapped in

the enterocyte and sloughed off into the intestinal tract and eliminated, thus decreasing

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copper absorption.[245] Copper is bound to albumin and transported via the blood to the

liver. In the liver, copper binds to metallothionein, and is incorporated into ceruloplasmin,

enzymes, and bile. It is eventually secreted into the plasma and transported to the cells of

other tissues, while excess copper is excreted in bile.[206, 207]

Preoperative Copper Screening

There is a relative dearth of data regarding the prevalence of preoperative copper

deficiencies in WLS patients, as assessment of copper levels is not typically part of the

preoperative micronutrient evaluation. Recent data regarding copper status and/or

copper deficiencies in patients with obesity and/or seeking WLS are somewhat mixed, with

some studies finding rather high rates of copper deficiency or low copper levels (e.g., in

68% of women undergoing BPD)[85] or no differences in copper levels between patients

with and without obesity.[239, 240, 246] In two studies conducted in 2009 by Ernst et al.,

no copper deficiencies (as assessed with serum copper levels) were seen in two different

samples of pre-WLS patients.[58] More research is needed to determine the prevalence of

copper deficiency pre-WLS.

As has been the case with zinc, the inflammatory processes common in obesity have led

researchers to question the reliability of copper measures and status in pre-WLS patients.

Copper deficiency has historically been diagnosed by the observation of a decrease in

serum copper and ceruloplasmin levels, with superoxide dismutase levels also providing

supporting evidence of copper deficiency.[198, 207, 247] While ceruloplasmin is a marker

of copper status, its rate of synthesis is not affected by dietary copper intake, while serum

copper is low when copper is deficient.[198, 248, 249] Serum copper does not correlate 67

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with dietary intake of copper except in instances when serum copper is below a certain

level.[198] Another drawback of serum ceruloplasmin as a marker for copper deficiency is

that it is an acute phase reactant protein and increases with pregnancy, age, anemia, and

medications such as oral contraceptives, thus complicating the interpretation of this assay.

[198, 250] Erythrocyte superoxide dismutase may be a more valid biomarker of copper

status, as it does not vary with the conditions that increase serum copper and

ceruloplasmin, such as pregnancy and oral contraceptive use.[198, 250] It may also be

more sensitive to long-term copper status. However, this assay is not typically readily

available and is also costly.[198, 251]

Postoperative Copper Screening

Copper deficiency is more common following RYGB (10-20%) and BPD/DS (up to 90%),

as the stomach and duodenum, the primary sites of absorption, are bypassed.[37, 58, 219,

222, 223, 252, 253]

Patients with BPD/DS may also experience loss of copper due to chronic diarrhea. Gastric

pH, which is altered by certain WLS procedures, such as the BPD/DS and RYGB, plays a role

in freeing copper from food. The extent to which decreased dietary copper intake

increases the risk for copper deficiency post-WLS is unknown, but impaired ability to

absorb copper is likely a factor.[254]

Few large-scale studies have measured copper status after WLS using serum copper or

ceruloplasmin levels.[58, 219, 222, 223, 255, 256] In some studies, decreased biomarkers

for copper status have been observed as early as one year post-WLS, and in many of the

studies reviewed, copper deficiency was observed many years after surgery. These findings 68

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were mostly in BPD/DS and RYGB patients. In general, the prevalence of copper deficiency

post-RYGB has been found to be lower than that seen in BPD/DS, but case study data[223,

254] and larger studies suggest that RYGB patients are still at risk for this deficiency.[219,

223, 240, 255, 257-269]

Even though we would not expect to see copper deficiency in patients with LAGB, one

study found a decrease in serum copper and ceruloplasmin levels 3 months after LAGB

surgery compared to preoperative levels, though these levels were not in the deficiency

range.[236] Data are lacking regarding copper deficiency in SG patients, with only one case

report, which described peripheral and central neurological complications related to

copper deficiency after SG.[261] However, there is a somewhat larger body of literature

documenting copper deficiencies in patients who have undergone gastrectomy or partial

gastrectomy for non-bariatric indications, suggesting that the stomach, and not solely the

proximal jejunum, may play a role in copper absorption after RYGB and SG.[267]

AACE/TOS/ASMBS 2013 CPG’s recommend copper screening be undertaken only in

RYGB and BPD/DS patients, and only in those presenting with signs and symptoms of

deficiency of neuropathy, myeloneuropathy, impaired wound healing, or anemias not

related to iron deficiency anemia [31](see Table 5). While previous guidelines did not

recommend routine postoperative laboratory screening of copper in the absence of

symptoms [1, 31] recent case reports and surveillance studies suggest the appropriateness

of a recommendation for annual copper screening in BPD/DS and RYGB patients, even in

the absence of clinical signs/symptoms of copper deficiency.

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Serum ceruloplasmin is a better indicator of copper status than serum copper, and

serum biomarkers coincide with the physical presentation of copper deficiency.

Deficiencies in copper may not only cause anemia but also myelopathy and gait disturbance

similar to that found with deficiencies in vitamin B12.[219, 240, 247, 257, 258, 267, 269]

Preventative Supplementation of Copper

Existing reports regarding copper levels and deficiencies among post-WLS patients are

not always clear as to whether the participants were taking supplemental copper after

surgery. Of those studies that did describe the supplement regimen of their participants,

three observed copper deficiencies in patients whose multivitamin supplement did contain

copper.[222, 223, 253, 255]

These studies, along with reports of RYGB and BPD/DS patients presenting with long-term

copper-related complications, warrant recommending copper supplementation after WLS.

While AACE/TOS/ASMBS 2013 CPG recommends routine supplementation of copper to

prevent deficiencies, it is important to avoid over-supplementation, as this may result in

decreased oral bioavailability of copper from supplements or food, or even liver damage

when intake exceeds the recommended upper limits.[31, 38, 198, 263, 268] Care should be

taken in choosing the form of copper supplementation; for instance, copper oxide is poorly

absorbed, while copper gluconate may be a safer alternative, as it has not been reported to

cause liver failure or GI effects.[198, 263] At least 2 mg/day of copper supplementation is

recommended, in the form of copper gluconate or sulfate, as part of routine multivitamin

and mineral supplementation. As noted above regarding zinc, a ratio of 1 mg copper

supplementation has been recommended for every 8-15 mg of elemental zinc, to prevent 70

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copper deficiency.[31] Based on the literature reviewed above, RYGB and BPD/DS patients

are at a greater risk for copper deficiency than LAGB and SG patients; BPD/DS and RYGB

patients require 200% of the RDA for copper (2mg); SG and LAGB patients require only

100% of the RDA (1 mg).

Repletion of Postoperative Copper Deficiency

Treatment of copper deficiency typically involves intravenous repletion, followed by

oral supplementation to normalize serum levels. Although there is currently no standard

dosage recommended for repletion of copper deficiency, examination of the existing

surveillance studies and case reports provides the best available evidence on which to base

recommendations for clinical practice.[223, 247, 258, 260] One series described patients

who had been treated successfully with 2 mg copper sulfate intravenously for 5 days over

an 8 week period.[247] Two additional individual case studies describe patients with

copper deficiency and ataxia who were repleted with 2.4 mg elemental copper sulfate

infused (IV) daily for 5 to 6 days, in addition to an oral elemental copper (as copper

gluconate) at a dose of 2mg every 6 hours.[240, 258, 269] The 8 mg/day of oral elemental

copper was continued for months after the patients’ symptoms improved.[269]

Serum copper levels have also been restored to normal levels with an oral regimen of

copper. Studies describe the treatment of patients with hematological abnormalities were

treated with oral copper doses ranging from 2 to 8 mg/day, and while other patients with

pancytopenia, treated with 4 mg oral copper gluconate three times a day.[258, 260] Other

types of copper regimens have also been used for repletion; such as oral copper gluconate

provided with a multivitamin and a tube feeding (4.42 mg/day total copper).[260] In 71

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another study, a cohort of RYGB patients were treated with 1.6-7.5 mg/day of oral

elemental copper in the form of copper sulfate.[223] Though most reports in the literature

describe symptom improvement or resolution upon successful copper repletion, there may

be cases in which repletion does not lead to improvement of symptoms.[259, 262]

Treatment of copper deficiency will vary based on the severity of the deficiency.[1, 31]

Mild to moderate deficiency, as in patients with low hematological indices, may be treated

with 3 to 8 mg/day oral copper gluconate or sulfate until markers return to normal. In

severe deficiency, as in patients exhibiting hematological and neurological symptoms, 2 to

4 mg/day of intravenous copper can be administered for five to six days or until serum

levels return to normal and neurological symptoms resolve. Once copper deficiency is

treated, copper status should be monitored every 3 months.[31] The duration of repletion

required to bring serum levels to normal and resolve neurological symptoms has varied

across published studies, depending on the doses provided (1mg to 8mg, daily); frequency

(multiple times daily, daily and weekly,) and route of administration (oral and IV).[256,

260, 262]

Copper – Summary

Recommendations for preoperative screening of copper deficiency

Routine screening of copper status by using serum copper and ceruloplasmin is

recommended for patients prior to RYGB or BPD/DS, but results must be

interpreted with caution. (Grade D, BEL 4)

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Erythrocyte superoxide dismutase is the preferred assay for determining copper

status in patients who have WLS. It is a more precise biomarker for screening of

copper deficiency; when it is available and affordable. (Grade D, BEL 4)

Recommendations for postoperative screening of copper deficiency

Routine screening of copper status in post-WLS patients is recommended at least

annually after BPD/DS and RYGB, even in the absence of clinical signs or symptoms

of deficiency. (Grade C, BEL 4)

In post-WLS patients, serum copper and ceruloplasmin are the recommended

biomarkers for determining copper status, as they are closely correlated with

physical symptoms of copper deficiency. (Grade C, BEL 4)

Recommendations for supplementation of copper for preventing deficiency

All post-WLS patients should take copper as part of routine multivitamin and

mineral supplementation, with dosage based upon type of procedure (Grade C, BEL

3):

o BPD/DS or RYGB patients should supplement with 200% of the RDA for

copper (2 mg/day)

o SG or LAGB patients should supplement with 100% of the RDA for copper (1

mg/day)

In post-WLS patients, supplementation with 1 mg copper is recommended for every

8-15 mg of elemental zinc to prevent copper deficiency. (Grade C, BEL 3)

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In post-WLS patients, copper gluconate or sulfate is the recommended source of

copper for supplementation. (Grade C, BEL 3)

Recommendations for postoperative copper repletion

In post-WLS patients with a copper deficiency, the recommended regimen for repletion

of copper will vary with the severity of the deficiency (Grade C, BEL 3):

o Mild to moderate deficiency (e.g., in cases with low hematological indices): 3 to 8

mg/day oral copper gluconate or sulfate until indices return to normal

o Severe deficiency: 2 to 4 mg/day of intravenous copper, should be initiated for

six days or until serum levels return to normal and neurological symptoms

resolve.

o Once copper levels are normal: monitor copper levels every 3 months. (Grade C,

BEL 3)

SUMMARY

This paper is an update for the American Society for Metabolic and Bariatric Surgery

(ASMBS) Nutrition Committee’s Allied Health Nutritional Guidelines for the Surgical

Weight Loss Patient (2008)[1] and serves as an educational tool for not only dietitians,

but other providers working with pre-WLS patients. The focus of this paper has been to

up-date the guideline with findings from current literature regarding key micronutrient

deficiencies and WLS. As evidence-based guidelines continue to be updated and

recommendations become more established into the daily practice of perioperative

nutrition care, it will be important to investigate differences in responders to treatment

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and new potential mechanisms explaining changes in nutrient status. Additionally,

controlling for confounding factors (such as dietary intake of nutrients from both food

and supplements, food-medication interactions, food-nutrient interactions, and if, how,

and by whom nutrition assessment and counseling is conducted) in nutrient-related

studies will increase the rigor of data collection and consistency in the quality of

research reported.

The Nutrition Committee of the Integrated Health Clinical Issues and Guidelines

Committee of the ASMBS sincerely hopes that this document will serve to enhance the

general nutrition knowledge necessary for the care of the pre- and postoperative

patient, with consideration for the individual patient’s unique medical needs, as well as

the variable protocols established among surgical centers and individual practices.

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AUTHORS’ DISCLOSURES — POTENTIAL CONFLICTS OF INTEREST

Speaker’s bureaus, consultant fees, or research grants:

Anonymous

Acknowledgments:

We would like to thank Dr. Stephanie Sogg, Chair of the ASMBS Integrated Health Clinical Issues and Guidelines committee for her oversight and editing, advice and support. We thank our peer reviewers: Sue Cummings and Dr. Ann Rogers, and the encouraging guidance provided by Research Methodologist, Dr. James S. Parrott. We also thank the American Society for Metabolic and Bariatric Surgery Executive Council and the Integrated Health Executive Council.

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Appendices A-D

Appendix A. Literature Search and Review Process by Nutrient

77

Search History Articles identified Articles

Reviewed

Articles

Included

Vitamin B1 or

thiamin or thiamine

45 + hand searches 65 61

Vitamin B12

Folate or

folic acid

57

45

107 total 66

31

Iron 92 63 58

Calcium

Vitamin D

127

84

45

71

14

56

Vitamins A,E, K 50 40 36

Zinc

Copper

30 + hand searches

24 + hand searches

48

32

48

32

Total 554 471 402

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Appendix B. Grading Scheme for Sources Reviewed, per the 2010 AACE Protocol for

Production of Clinical Practice Guidelines–Step I: Evidence Ratinga

The evidence level and strength of evidence scheme follows that of Mechanick et al.10 A

brief summary of the evidence level and strength of evidence scheme is below.

Numerical descriptor (evidence level)

Semantic descriptor (reference methodology)

Strong1 Meta-analysis of randomized controlled trials (MRCT)1 Randomized controlled trial (RCT)

Intermediate2 Meta-analysis of nonrandomized prospective or case-

controlled trials (MNRCT)2 Nonrandomized controlled trial (NRCT)2 Prospective cohort study (PCS)2 Retrospective case-control study (RCCS)

Weak333

Nonrandomized noncontrolled trial (NRNCT)Retrospective Observational (RO)Cross-sectional study (CSS)

3 Surveillance study (registries, surveys, epidemiologic study) (SS)

3 Consecutive case series (CCS)3 Single case reports (SCR)

No Evidence4 No evidence (theory, opinion, consensus, or review)

(NE)a 1 = strong evidence; 2 = intermediate evidence; 3 = weak evidence; 4 = no evidence.

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Appendix C. 2010 American Association of Clinical Endocrinologists Protocol for

Production of Clinical Practice Guidelines—Step II: Evidence Analysis and Subjective Factors

Study Design Data AnalysisInterpretation of

ResultsPremise correctness Intent-to-treat GeneralizabilityAllocation concealment

(randomization) Selection bias Appropriate statistics LogicalAppropriate blinding IncompletenessUsing surrogate end points

(especially in “first-in-its-class” intervention) Validity

Sample size (beta error)Null hypothesis versus

Bayesian statistics

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Appendix D. Grading Scheme for Recommendations, per the AACE Protocol for Production

of Clinical Practice Guidelines–Step III: Grading of Recommendations; How Different Evidence

Levels can be Mapped to the Same Recommendation Grade10

Best Evidence Level

Subjective Factor Impact

Consensus

Mapping Recommendation Grade

Strong

1 None Yes Direct A

2 Positive Yes Adjust up A

Intermediate

2 None Yes Direct B

1 Negative Yes Adjust down B

3 Positive Yes Adjust up B

Weak

3 None Yes Direct C

2 Negative Yes Adjust down C

4 Positive Yes Adjust up C

No Evidence

4 None Yes Direct D

3 Negative Yes Adjust down D

1,2,3,4 N/A No Adjust down D

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ASMBS Nutrition CPG List of Abbreviations

Academy Of Nutrition And Dietetics (AND)Acute Phase Reactant (APR)Acute Post-Gastric Reduction Surgery (APGARS)Adequate Intake (AI)Adjustable Gastric Band (Agb)American Association Of Clinical Endocrinologists (AACE)American Society For Metabolic And Bariatric Surgery (ASMBS)American Society For Parenteral And Enteral Nutrition (ASPEN)Biliopancreatic Diversion With Duodenal Switch BPD/DSCarboxy-Terminal Telopeptide (CTX)Case Reports (CS)Clinical Practice Guideline (CPG)Consecutive Case Series (CCS)Cross-Sectional Studies (CSS)Deciliter (DL)Daily Value (DV)Dual-energy x-ray absorptiometry (DXA)Des-Gamma-Carboxy Prothrombin (DCP)Dietary Reference Intake (DRI)Duodenal Switch (Ds)European Federation Of Neurological Societies (EFNS)Gastrointestinal (GI)Gram (Gm)Homocysteine (Hcy)Institute Of Medicine (IOM)Intact Parathyroid Hormone (Ipth)International Unit (IU)Intramuscular (IM)Intravenous (IV)Iron (Fe)Liter (L)Medical Nutrition Therapy (Mnt)Meta-Analysis Non-Randomized Controlled Trial (MNRCT)Meta-Analysis Randomized Controlled Trials (MRCT)Methyl Malonic Acid (MMA)

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Microgram (Mcg)Milligram (Mg)Milliliter (Ml)No Evidence (Theory, Opinion, Consensus, Or Review) (NE)Nutrition Care Process (NCP)Nutrition-Focused Physical Assessment (NFPA)Office Of Dietary Supplements (ODS)Parathyroid Hormone (PTH)Picogram (Pg)Prospective Cohort Studies (PCS)Proton Pump Inhibitors (Ppis)Randomized Controlled Trials (RCT)Recommended Dietary Allowance (RDA)Red Blood Cell (RBC)Registered Dietitian (RD)Retrospective Cohort Studies (RCS/RCCS)Roux-En-Y Gastric Bypass (RYGB),Sleeve Gastrectomy (SG)Small Bowel Bacterial Overgrowth (SBBO)Surveillance Study (Registries, Surveys, Epidemiologic Study) (SS)The Obesity Society (TOS)Thiamin Deficiency (TD)Thiamin, whole blood (TDP)Thiamin Pyrophosphate (TPP)Tolerable Upper Intake Level (UL)Total Iron Binding Capacity (TIBC)Transferrin Saturation (Tsat)Type 1 Collagen N-Telopeptide (NTX)Upper Intake Level (UL)Vitamin D Deficiency (VDD)Vitamin D Insufficiency (VDI)Weight Loss Surgery (WLS)Wernicke-Korsakoff Syndrome (Wks)Wernicke's Encephalopathy (WE)

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bypass. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2011;7:309-14. EL 2, PCS[226] Pires LV, Martins LM, Geloneze B, Tambascia MA, Hadad do Monte SJ, do Nascimento Nogueira N, et al. The effect of Roux-en-Y gastric bypass on zinc nutritional status. Obesity surgery. 2007;17:617-21. EL 3, SS[227] de Torres Rossi RG, Dos Santos MT, de Souza FI, de Cassia de Aquino R, Sarni RO. Nutrient intake of women 3 years after Roux-en-Y Gastric bypass surgery. Obesity surgery. 2012;22:1548-53. EL 3, CSS; Controlled [228] Sturniolo GC, Montino MC, Rossetto L, Martin A, D'Inca R, D'Odorico A, et al. Inhibition of gastric acid secretion reduces zinc absorption in man. Journal of the American College of Nutrition. 1991;10:372-5. EL 3, SS; small sample sz (n=11)[229] Slater GH, Ren CJ, Siegel N, Williams T, Barr D, Wolfe B, et al. Serum fat-soluble vitamin deficiency and abnormal calcium metabolism after malabsorptive bariatric surgery. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2004;8:48-55; discussion 4-5. EL 3, SS[230] Larrad-Jimenez A, Diaz-Guerra CS, de Cuadros Borrajo P, Lesmes IB, Esteban BM. Short-, mid- and long-term results of Larrad biliopancreatic diversion. Obesity surgery. 2007;17:202-10. EL 2, PCS[231] Dalcanale L, Oliveira CP, Faintuch J, Nogueira MA, Rondo P, Lima VM, et al. Long-term nutritional outcome after gastric bypass. Obesity surgery. 2010;20:181-7. [232] Jeejeebhoy KN. Human zinc deficiency. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2007;22:65-7. EL 4, NE[233] Ruiz-Tovar J, Oller I, Llavero C, Zubiaga L, Diez M, Arroyo A, et al. Hair loss in females after sleeve gastrectomy: predictive value of serum zinc and iron levels. The American surgeon. 2014;80:466-71. EL 2, PCS[234] Pirolla EH, Jureidini R, Barbosa ML, Ishikawa LC, Camargo PR. A modified laparoscopic sleeve gastrectomy for the treatment of diabetes mellitus type 2 and metabolic syndrome in obesity. American journal of surgery. 2012;203:785-92. EL 1, RCT[235] Cominetti C, Garrido AB, Jr., Cozzolino SM. Zinc nutritional status of morbidly obese patients before and after Roux-en-Y gastric bypass: a preliminary report. Obesity surgery. 2006;16:448-53. EL 3, NRNCT[236] Boyuk A, Banli O, Gumus M, Evliyaoglu O, Demirelli S. Plasma levels of zinc, copper, and ceruloplasmin in patients after undergoing laparoscopic adjustable gastric banding. Biological trace element research. 2011;143:1282-8. EL 3, SS[237] Rojas P, Carrasco F, Codoceo J, Inostroza J, Basfi-fer K, Papapietro K, et al. Trace element status and inflammation parameters after 6 months of Roux-en-Y gastric bypass. Obesity surgery. 2011;21:561-8. EL 2, PCS[238] Topart P, Becouarn G, Salle A, Ritz P. Biliopancreatic diversion requires multiple vitamin and micronutrient adjustments within 2 years of surgery. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2014;10:936-41. EL 3, Retrospective Observational weaker than EL 2, NRCT

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[239] Saper RB, Rash R. Zinc: an essential micronutrient. Am Fam Physician. 2009;79:768-72. EL 4, NE[240] Griffith DP, Liff DA, Ziegler TR, Esper GJ, Winton EF. Acquired copper deficiency: a potentially serious and preventable complication following gastric bypass surgery. Obesity. 2009;17:827-31. EL 3, CSS[241] Willis MS, Monaghan SA, Miller ML, McKenna RW, Perkins WD, Levinson BS, et al. Zinc-induced copper deficiency: a report of three cases initially recognized on bone marrow examination. Am J Clin Pathol. 2005;123:125-31. EL 3, CCS[242] Beers M. Ther Merck Manual of Diagnosis and Therapy. White Station, NJ: Merck Research Laboratories; 2006. EL 4, NE[243] Kay RG, Tasman-Jones C, Pybus J, Whiting R, Black H. A syndrome of acute zinc deficiency during total parenteral alimentation in man. Annals of surgery. 1976;183:331-40. EL 2, PCS[244] Bae-Harboe YS, Solky A, Masterpol KS. A case of acquired Zinc deficiency. Dermatology online journal. 2012;18:1. EL 3, SCR[245] Fiske DN, McCoy HE, 3rd, Kitchens CS. Zinc-induced sideroblastic anemia: report of a case, review of the literature, and description of the hematologic syndrome. American journal of hematology. 1994;46:147-50. EL 3, SCR[246] Alasfar F, Ben-Nakhi M, Khoursheed M, Kehinde EO, Alsaleh M. Selenium is significantly depleted among morbidly obese female patients seeking bariatric surgery. Obesity surgery. 2011;21:1710-3. EL 3, SS[247] Kumar N, McEvoy KM, Ahlskog JE. Myelopathy due to copper deficiency following gastrointestinal surgery. Archives of neurology. 2003;60:1782-5. EL 3, CCS[248] Hellman NE, Gitlin JD. Ceruloplasmin metabolism and function. Annual review of nutrition. 2002;22:439-58. EL 4, NE[249] Jaiser SR, Winston GP. Copper deficiency myelopathy. Journal of neurology. 2010;257:869-81. EL 3, CCS[250] Goldberg ME, Laczek J, Napierkowski JJ. Copper deficiency: a rare cause of ataxia following gastric bypass surgery. The American journal of gastroenterology. 2008;103:1318-9. EL 3, SCR[251] Iskandar M, Swist E, Trick KD, Wang B, L'Abbe MR, Bertinato J. Copper chaperone for Cu/Zn superoxide dismutase is a sensitive biomarker of mild copper deficiency induced by moderately high intakes of zinc. Nutrition journal. 2005;4:35. EL 2, NRCT[252] Gobato RC, Seixas Chaves DF, Chaim EA. Micronutrient and physiologic parameters before and 6 months after RYGB. Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery. 2014;10:944-51. EL2, PCS[253] Papamargaritis D, Aasheim ET, Sampson B, le Roux CW. Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation. J Trace Elem Med Biol. 2015;31:167-72. EL 2, PCS[254] Btaiche IF, Yeh AY, Wu IJ, Khalidi N. Neurologic dysfunction and pancytopenia secondary to acquired copper deficiency following duodenal switch: case report and review of the literature. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2011;26:583-92. EL 3, SCR

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[255] Ernst B, Thurnheer M, Schultes B. Copper deficiency after gastric bypass surgery. Obesity. 2009;17:1980-1. EL 3, SS[256] Shahidzadeh R, Sridhar S. Profound copper deficiency in a patient with gastric bypass. The American journal of gastroenterology. 2008;103:2660-2. EL 3, SCR[257] Juhasz-Pocsine K, Rudnicki SA, Archer RL, Harik SI. Neurologic complications of gastric bypass surgery for morbid obesity. Neurology. 2007;68:1843-50. EL 3, CCS[258] Kumar N, Ahlskog JE, Gross JB, Jr. Acquired hypocupremia after gastric surgery. Clin Gastroenterol Hepatol. 2004;2:1074-9. EL 3, CCS[259] Naismith RT, Shepherd JB, Weihl CC, Tutlam NT, Cross AH. Acute and bilateral blindness due to optic neuropathy associated with copper deficiency. Archives of neurology. 2009;66:1025-7. EL 3, SCR[260] O'Donnell KB, Simmons M. Early-onset copper deficiency following Roux-en-Y gastric bypass. Nutrition in clinical practice : official publication of the American Society for Parenteral and Enteral Nutrition. 2011;26:66-9. EL 3, SCR[261] Oliveira YS, Iba Ba J, Mba Angoue JM, Emery Itoudi Bignoumba P, Nzenze JR. [Copper deficiency and peripheral neuropathy as an outcome of gastrectomy]. Rev Med Interne. 2013;34:234-6. EL 3, SCR[262] Pineles SL, Wilson CA, Balcer LJ, Slater R, Galetta SL. Combined optic neuropathy and myelopathy secondary to copper deficiency. Survey of ophthalmology. 2010;55:386-92. EL 3, CCS[263] Pratt WB, Omdahl JL, Sorenson JR. Lack of effects of copper gluconate supplementation. The American journal of clinical nutrition. 1985;42:681-2. EL 1, RCT 2; small sample size (n=14)[264] Prodan CI, Bottomley SS, Vincent AS, Cowan LD, Greenwood-Van Meerveld B, Holland NR, et al. Copper deficiency after gastric surgery: a reason for caution. The American journal of the medical sciences. 2009;337:256-8. EL 2, RCCS; Small sample size[265] Rapoport Y, Lavin PJ. Nutritional Optic Neuropathy Caused by Copper Deficiency After Bariatric Surgery. J Neuroophthalmol. 2016;36:178-81. EL 3, SCR[266] Robinson SD, Cooper B, Leday TV. Copper deficiency (hypocupremia) and pancytopenia late after gastric bypass surgery. Proc (Bayl Univ Med Cent). 2013;26:382-6. EL 3, CCS[267] Tan JC, Burns DL, Jones HR. Severe ataxia, myelopathy, and peripheral neuropathy due to acquired copper deficiency in a patient with history of gastrectomy. JPEN Journal of parenteral and enteral nutrition. 2006;30:446-50. EL 3, SCR[268] Wapnir RA. Copper absorption and bioavailability. The American journal of clinical nutrition. 1998;67:1054S-60S. EL 4, NE[269] Yarandi SS, Griffith DP, Sharma R, Mohan A, Zhao VM, Ziegler TR. Optic neuropathy, myelopathy, anemia, and neutropenia caused by acquired copper deficiency after gastric bypass surgery. J Clin Gastroenterol. 2014;48:862-5. EL 3, SCR

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