Micronutrient Deficiencies in Inflammatory Bowel Disease_ From a to Zinc - Hwang - 2012 -...

CLINICAL REVIEW

Micronutrient Deficiencies in Inflammatory Bowel Disease:From A to ZincCaroline Hwang, MD,* Viveca Ross, RD CNSC, and Uma Mahadevan, MD*

Abstract: Inflammatory bowel disease (IBD) has classically been associated with malnutrition and weight loss, although this has become lesscommon with advances in treatment and greater proportions of patients attaining clinical remission. However, micronutrient deficiencies are still

relatively common, particularly in CD patients with active small bowel disease and/or multiple resections. This is an updated literature review of

the prevalence of major micronutrient deficiencies in IBD patients, focusing on those associated with important extraintestinal complications,

including anemia (iron, folate, vitamin B12) bone disease (calcium, vitamin D, and possibly vitamin K), hypercoagulability (folate, vitamins B6,

and B12), wound healing (zinc, vitamins A and C), and colorectal cancer risk (folate and possibly vitamin D and calcium).

(Inflamm Bowel Dis 2012;18:19611981)

Key Words: inflammatory bowel disease, micronutrient deficiencies

I nflammatory bowel disease (IBD) is commonly associ-ated with malnutrition. Large retrospective studies havedemonstrated that as many as 70%80% of IBD patients

will exhibit weight loss during their disease course.14

However, most of the previous studies reporting a high

prevalence of malnutrition were performed from the 1960 to

1980s and focused mainly on hospitalized patients with

severe active disease, often on chronic steroid therapy. Over

the last two decades, several important therapeutic develop-

ments, namely, immunomodulators and biologic therapy,

have allowed a greater proportion of IBD patients to attain

sustained clinical remission. There are a few studies demon-

strating that patients in remission often have similar macro-

nutrient intake5,6 and similar body mass indices7,8 as healthy

controls. In fact, there are several studies now reporting on a

growing proportion of obese IBD patients.7,9,10

Nutritional issues in IBD patients can be divided into

those involving macronutrients (energy and protein intake)

and those of micronutrients (vitamins, minerals, trace ele-

ments). Protein-energy malnutrition most often occurs with

active, severe IBD. However, micronutrient deficiencies

can occur even with disease that is relatively mild or in

remission. Multiple simultaneous deficiencies in micronu-

trients are more common in patients with Crohns disease

(CD), especially those with fistulas, strictures, or prior sur-

gical resections of the small bowel.2

Numerous vitamin and mineral deficiencies have been

reported in IBD patients, with varying degrees of clinical

significance. In this article we will provide a comprehensive

review of the micronutrient deficiencies that can occur

with IBD and their clinical significance in this population.

Specifically, we will discuss the impact of micronutrient

deficiencies in the development of common complications

associated with IBD, including anemia, osteoporosis, throm-

bophilia, colorectal cancer, and poor wound healing.

MAJOR MICRONUTRIENTS AND NORMALABSORPTION

Vitamins and minerals are naturally occurring com-

pounds that are required for diverse functions in the body

and must be obtained from the diet, as they are not suffi-

ciently synthesized by humans. Vitamins are organic com-

pounds that can be classified as either water- or fat-soluble.

Water-soluble vitamins are readily absorbed in the intestinal

lumen across enterocyte membranes by either diffusion (for

noncharged, low-molecular vitamins such as vitamin B3, B6,

and C) or by carrier-dependent active transport. The water-

soluble vitamins include thiamine (B1), riboflavin (B2), nico-

tinic acid/niacin (B3), pyridoxine (B6), cobalamin (B12), bio-

tin, pantothenic acid, folic acid, and vitamin C (ascorbic

acid). The fat-soluble vitamins (A, D, E, and K) are hydro-

phobic substances that are dissolved within fat droplets and

must be broken down by lipases and combined with bile

Received for publication December 21, 2011; Accepted January 11, 2012.

From the *Division of Gastroenterology, and Department of Nutrition,

University of California, San Francisco, California.

Supported by IBDWG GI Fellows Award 2011-12 (to C.H.).

Reprints: Uma Mahadevan, MD, Associate Professor of Clinical Medicine,

Co-Medical Director, UCSF Center for Colitis and Crohns Disease, 2330 Post

St., #610, San Francisco, CA 94115 (e-mail: [email protected]).

Copyright VC 2012 Crohns & Colitis Foundation of America, Inc.

DOI 10.1002/ibd.22906

Published online 5 April 2012 in Wiley Online Library (wileyonlinelibrary.

com).

Inflamm Bowel Dis Volume 18, Number 10, October 2012 1961

salts in the duodenum to form mixed micelles, which then

facilitate diffusion across the enterocyte membrane.

Dietary minerals are inorganic elements that are im-

portant in the makeup of cellular structure and as cofactors

and catalysts in enzymatic processes. The so-called macro

minerals are those present in larger quantities in the body

(i.e., kilo- or milligrams), including calcium, phosphate, po-

tassium, magnesium, and iron. Trace elements are present in

very small amounts in the body (i.e., nanograms or parts per

million), and include zinc, copper, and selenium. Macromin-

erals and trace elements are absorbed by passive or active

transport through the intestinal mucosa, often using special-

ized transport proteins such as ferritin for Fe3 or vitaminD-induced channels for calcium.

Normally, over 95% of vitamins and minerals within

food are absorbed in the proximal small bowel, usually by

mid-jejunum. The exception to this is vitamin B12, which,

bound to intrinsic factor, is absorbed in the terminal ileum.

In addition, the distal ileum also absorbs bile acids, which

are critical for the absorption of fat and fat-soluble vitamins.

PATHOPHYSIOLOGY OF MALNUTRITION IN IBDThere are multiple mechanisms that can contribute to

micronutrient deficiencies in IBD, and these are summarized

in Table 1. These can occur in combination and to varying

degrees during an individual patients disease course.

One of the most important and underrecognized

mechanisms is reduced food intake. Globally reduced

intake and specific avoidance of foods is common among

IBD patients. This may be particularly significant with

active disease, due to anorexia (secondary to inflammatory

cytokines, including interleukin [IL]-1, IL-6, and tumor ne-

crosis factor alpha [TNF-a]) as well as to minimize symp-toms of abdominal pain and diarrhea, which are exacer-

bated by large fatty meals and high-residue diets. However,

a recent study of patients with disease in remission found

that avoidance of major food groups remained common,

with 1/3 avoiding grains, 1/3 avoiding dairy, and 18%avoiding vegetables entirely.9 Multiple nutritional studies

performed in a variety of IBD cohorts report that intake of

calcium and vitamin C are most frequently inadequate

according to USDA Daily Recommended Intake (DRI),

although folate, vitamin B1 and B6, beta-carotene, vitamin

K, and vitamin E have also been reported to be low.5,11

Two other important causes of malnutrition are

enteric loss of nutrients and malabsorption (Table 1).

Chronic diarrhea and fistula output can lead to wasting of

zinc, calcium, and potassium,3 while iron deficiency is the

most common nutritional deficiency in colitis due to

chronic gastrointestinal bleeding.12 Malabsorption most com-

monly occurs in CD, due to inflammation or resection of

small bowel. Specifically, significant terminal ileal disease

and/or resections >4060 cm can lead to vitamin B12 defi-ciency as well as bile-salt wasting and resultant impaired fat-

soluble vitamin absorption.13 In addition, patients with pri-

mary sclerosing cholangitis are also at risk for malabsorption,

as biliary strictures especially within the main branches of the

biliary tract can lead to bile-salt insufficiency and steatorrhea.

Finally, multiple medications used for IBD can inter-

fere with normal micronutrient absorption. Glucocorticoids

potently inhibit calcium, phosphorus, and zinc absorption

and may also lead to impaired metabolism of vitamins C

TABLE 1. Pathogenesis of Micronutrient Deficiency in IBD

Decreased food intake Anorexia (TNF-mediated) Mechanical (fistulas, post-operative) Avoidance of high-residue food (can worsen abdominal pain/diarrhea) Avoidance of lactose-containing foods (high rates of concomitant lactose intolerance

Increased intestinal loss Diarrhea (increased loss of Zn2, K, Mg2) Occult/overt blood loss (iron deficiency) Exudative enteropathy (protein loss, and decrease in albumin-binding proteins,eg vitamin D-binding protein)

Steatorrhea (fat and fat-soluble vitamins)Malabsorption Loss of intestinal surface area from active inflammation, resection, bypass or fistula

Terminal ileal disease associated with deficiencies in B12 and fat-soluble vitaminsHypermetabolic state Alterations of resting energy expenditureDrug interactions Sulfasalazine and methotrexate inhibits folate absorption

Glucocorticoids impair Ca2, Zn2, and phosphorus absorption, vitamin C lossesand vitamin D resistance

Cholestyramine impairs absorption of fat-soluble vitamins, vitamin B12 and ironLong-term total parenteral nutrition Can occur with any micronutrient not added to TPN;

Reported deficiencies include thiamine, vitamin, and trace elements Zn2,Cu2, selenium, chromium

Inflamm Bowel Dis Volume 18, Number 10, October 2012Hwang et al

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and D.4 Sulfasalazine is a folate antagonist,14 while choles-

tyramine can interfere with absorption of fat-soluble vita-

mins. Finally, the use of long-term parenteral nutrition can

lead to deficiencies in any micronutrient not added in suffi-

cient quantities, but most commonly include vitamins A,

D, E, zinc, copper, and selenium.15

SPECIFIC MICRONUTRIENT DEFICIENCIESA wide array of vitamin and mineral deficiencies

occurs in IBD patients, with varying degrees of clinical sig-

nificance. Of particular relevance to clinicians is the impact

of micronutrient deficiencies on anemia, bone mineral den-

sity, thrombophilia, wound healing, and carcinogenesis.

These are summarized in Table 2.

AnemiaAnemia is the most common systemic complication

of IBD, with reported rates of 40%70% in historical

cohorts of hospitalized IBD patients.16,17 More recent stud-

ies of outpatient IBD patients, using population-based datasets

in Switzerland and Scandinavia, found the prevalence of ane-

mia to be 19%25%.18,19 Despite the fact that anemia has

been shown to affect patients quality of life and the ability

to work,20,21 it is often overlooked by gastroenterologists.22

Anemia can be the result of deficiencies of iron, folic acid, or

vitamin B12, or may be due to chronic inflammation (anemia

of chronic disease) and/or medications (azathioprine, 6-mer-

captopurine, methotrexate, or sulfasalazine).

IronIron deficiency is the leading cause of anemia in the

IBD population, present in 36%90% of patients.23,24 Iron

deficiency can be due to inadequate dietary intake (avoidance

of green leafy vegetables and/or vegetarian diets), chronic

blood loss from the gastrointestinal tract, and most important,

impaired absorption and utilization. Normal absorption of

iron occurs primarily in the duodenum and proximal jejunum,

and the amount absorbed from the dietary sources varies

between 5%35%, depending on the type of iron ingested

and status of iron stores of the patient.25 In general, iron in

the form of heme from animal products is more efficiently

absorbed, while iron in the salt form (Fe2, Fe3) is generallylower, is dependent on the presence of an acidic environment,

and can therefore be inhibited by concomitant treatment with

proton pump inhibitors or antacids.26

Impaired iron metabolism can occur in patients with

active IBD, irrespective of sufficient dietary intake and/or

supplementation. Proinflammatory stimuli, such as lipopoly-

saccharide, IL-6, and TNF-a, cause upregulation of hepcidin,a key mediator in iron homeostasis that blocks iron from

being exported from enterocytes into the bloodstream and

causes iron retention in macrophages and monocytes.27 The

latter mechanism is especially important as 90% of daily

iron stores come from recycling of iron from senescent red

blood cells by macrophages. Iron retention within macro-

phages often manifests with increased levels of ferritin, the

bodys main circulating iron storage protein.

Classically, the most accurate measurement of iron

status is serum ferritin levels, although serum transferrin

saturation is often helpful. However, as ferritin is an acute-

phase reactant and can also be elevated in cases of ineffec-

tive iron metabolism, the diagnosis of iron deficiency in

IBD patients can be challenging. Recently, an international

working party published guidelines on the diagnosis and

treatment of iron deficiency anemia in IBD.28 These guide-

lines suggest that in order to accurately interpret iron studies,

patients concurrent degree of inflammation needs to be con-

sidered. Therefore, in patients without clinical symptoms and

normal C-reactive protein (CRP), a ferritin of

TABLE

2.Micronutrients

withReportedDeficiency

inIBD

Pathophysiology

SymptomsofDeficiency

Diagnosis

Prevalence

BVitam

ins:

Water-soluble

B1(thiamine)

Unclearmechanism

Severe:

peripheral

neuropathy,

cardiomyopathy(beriberi)

Mainly

clinical;Can

consider

serum

B1ifsymptomssevere

32%

ofCD

pts[5]unknownprevalence

inUC

B9(folate)

Inadequatedietary

intake

Malabsorption(associated

with

ileitis/sm

allbowel

resection)

Medications(M

TX,sulfasalazine)

Megaloblastic

anem

ia;

Modestlyincreasedrisk

of

colonic

dysplasia/CRC

Hyperhomocysteinem

iaGlossitis,angularstomatitis,

depression

Serum

folate16mmol/Lconfirm

s)RBCfolate70), or obese. If patients are found to have vitamin Ddeficiency (30 are achieved. Again, patientswith malabsorption, on glucocorticoids, or who are obese

should receive 2-3 times higher treatment dosages (12,000

18,000 IU/day).71 Once serum 25-OHD levels of >30 areachieved, maintenance dosages of vitamin D as discussed

above should be continued indefinitely.

MagnesiumMagnesium is the fourth most abundant cation in the

body and plays a fundamental role in most cellular reac-

tions, mainly as a cofactor in enzymatic reactions involving

ATP. In addition, 50%60% of body magnesium is incor-

porated in the hydroxypatite crystal of bone and may be

important in bone cell activity. There have been several

epidemiological studies suggesting that dietary magnesium

and hypomagnesemia may be weakly associated with

osteoporosis.72,73 The mechanisms for magnesium defi-

ciency on bone disease are not clear. In cell culture and

animal models, magnesium has a mitogenic role on osteo-

blasts and deficiency of this cation leads to a decrease in

osteoblastic activity. Likely more important, however, is

the influence that magnesium balance has on calcium

homeostasis. Magnesium deficiency is known to induce

hypocalcemia, via impaired parathyroid gland function and

inappropriately low PTH levels, which leads to lower intes-

tinal calcium absorption.73

Magnesium deficiency is a growing problem in the

Western world, with 32% of Americans failing to meet US

recommended daily intake (RDI).74 IBD patients appear to be

at increased risk of magnesium deficiency, with rates reported

in 13%88% of patients.75,76 Deficiency is likely due to a

combination of decreased dietary intake,9 losses from chronic

diarrhea and fistula output,75 and malabsorption.

Magnesium status is generally assessed by random

serum magnesium levels, although 24-hour urinary magne-

sium is technically more accurate in determining total body

stores. Magnesium screening and supplementation should

be considered in all patients with significant diarrhea

(>300 g/day), while diarrheal symptoms are active. Mostoral magnesium formulations can exacerbate diarrhea,

although magnesium heptogluconate (Magnesium-Rougier)

or magnesium pyroglutamate (Mag 2) may be better toler-

ated, especially if mixed with oral rehydration solution and

sipped throughout the day. The total dose of elemental

magnesium required to ensure normal serum magnesium

varies between 5 and 20 mmol/day.77

Vitamin KVitamin K has been implicated in bone health,

although its significance is less clear than that of vitamin

D. Vitamin K is a fat-soluble vitamin that exists in multi-

ple forms, but phylloquinone (vitamin K1), present in green

leafy vegetables, is the principle dietary form. Vitamin K

is a known cofactor for posttranslational c-carboxylation ofmultiple proteins, including blood coagulation factors but

also osteocalcin (OC), a regulator of bone mineral matura-

tion. Osteocalcin is produced by osteoblasts and requires

c-carboxylation in order to bind calcium. Under conditionsof vitamin K deficiency, OC remains uncarboxylated and is

transferred into the circulation. Serum uncarboxylated

osteocalcin (percent or total) reflects vitamin K status in

the bone and is often used as an indirect measure of total

vitamin K stores. The other method of measuring vitamin

K status is serum phylloquinone levels, although levels can

be influenced by recent dietary intake and triglyceride lev-

els.78 The lack of a single reliable and direct method of

vitamin K status is a principle limitation in interpretation

of studies on this vitamins importance in bone health.

There have been several large epidemiological stud-

ies, including two that used the Nurses Health Study cohort

and the Framingham cohort, which demonstrate that low

dietary intake of vitamin K appears to be associated with

osteoporotic fracture risk and low BMD.7981 However,

studies correlating biochemical measures of vitamin K

(uncarboxylated osteocalcin level or serum phylloquinone

Inflamm Bowel Dis Volume 18, Number 10, October 2012 Micronutrient Deficiencies in IBD

1969

levels) with bone disease have been less consistent, with

some studies showing an association while others do

not.8284 This likely reflects either limitations of current

tests of vitamin K status, or a weak association between

vitamin K status and bone disease.

Within the IBD literature, there have been relatively

few studies addressing vitamin K status. The earliest study

utilized abnormal prothrombin antigen assay as a surrogate

measure of vitamin K status, and found that 31% of IBD

patients (17/18 CD and one UC) were vitamin K-defi-

cient.85 There have been two more recent studies that

measured serum uncarboxylated osteocalcin levels in CD

patients and found levels to be significantly lower com-

pared with controls86 and UC patients.87,88 Although these

studies were too small to perform subgroup analysis, there

was a suggestion that vitamin K deficiency was more com-

mon in patients with active inflammation and more exten-

sive small bowel involvement, suggesting malabsorption as

a potential mechanism. There have been multiple studies

showing that dietary intake of vitamin K is also signifi-

cantly lower in IBD patients, even in patients with disease

remission, compared with controls.9,86

Currently, there does not appear to be sufficient evi-

dence to support the use of vitamin K supplements in IBD

patients as a means to prevent or treat bone disease. While

there have been no trials performed in the IBD population,

there have been four randomized controlled trials of phyl-

loquinone supplementation in elderly women and healthy

controls. None of these showed increased BMD in >1 skel-etal site.8991 There have been a few positive studies from

Japan, in which menaquinone-4 (a different form of vita-

min K, naturally present in natto, a fermented soybean

product common in Japan) at doses of 45 mg/day appeared

to be more effective at improving BMD and decreased

fracture risk.92,93 However, these studies lacked sufficient

sample size and many were not placebo-controlled, so fur-

ther prospective studies need to be performed.

In summary, there is evidence that inadequate dietary

vitamin K may increase risk of bone disease, although this

may not be adequately reflected in current measurements

of vitamin K. Because of malabsorption and dietary restric-

tions, IBD patients may be at risk for vitamin K deficiency.

There is limited evidence suggesting vitamin K deficiency

may contribute to bone disease, especially in those with

normal vitamin D status, although currently there is insuffi-

cient evidence to recommend oral vitamin K supplements.

Rather, at the current time increased dietary vegetables and

legumes should be encouraged in all patients who can tol-

erate these foods, as a means for bone health.

CoagulationArterial and venous thromboembolism are increas-

ingly recognized extraintestinal complications of IBD, with

significant morbidity and mortality. From several large

administrative database studies performed in North Amer-

ica and Europe, the risk of venous thrombosis (VTE) in

IBD patients is 23.5-fold greater than that of the generalpopulation, with excess mortality 2.1-fold greater for IBD

compared with non-IBD hospitalized patients.94,95 In addi-

tion, higher rates of acute arterial thrombosis events, pri-

marily acute mesenteric ischemia, but also cardiac and cer-

ebral thromboembolic events have been demonstrated.96,97

While the absolute risks of venous thromboembolism occur

in the elderly and hospitalized, there is a greater relative

risk (RR) of thromboembolism in younger IBD patients (at

age 40, RR of 3.54),94,98 ambulatory patients (RR of

14.3),99 and peripartum women (RR of 68).100

An important risk factor for VTE appears to be dis-

ease activity. In one large population-based study of IBD

patients in the UK, ambulatory patients with active disease

had a 14-fold higher rate of VTE than patients in remis-

sion.99 Other groups have reported that between 50%80%

of patients with VTE have active IBD symptoms at the

time of their thrombosis diagnosis.94,95 This highlights the

important role that inflammation plays in the hypercoagul-

ability of IBD. While the mechanisms underlying inflam-

mation and hypercoagulability have not been well

delineated, several studies suggest that it may involve qual-

itative and quantitative impairment of platelets, procoagu-

lant or fibrinolytic proteins, and decreased natural anticoa-

gulant factors.96,98

Besides inflammation, certain vitamin deficiencies

may also contribute to a hypercoagulable and prothrom-

botic state in IBD. These include folate, vitamins B6 and

B12all of which increase serum homocysteine. The exact

contribution that such micronutrient deficiencies have on

thromboembolic risk is not well studied, although is likely

to be small but also easily reversible.

Folate, Vitamin B6, and B12Hyperhomocysteinemia is an established risk factor

for arterial and potentially venous thromboembolism.101,102

This pathological state can be due to genetic defects or sec-

ondary to renal dysfunction or certain vitamin deficiencies.

Homocysteine is a sulfydril amino acid derived from catab-

olism of methionine; to convert this byproduct back to

methionine requires folate and B12 as cofactors. Homocys-

teine can also be converted to cysteine by a vitamin B6-

dependent trans-sulfuration process.

In patients with IBD there is an increased prevalence

of hyperhomocystenemia (defined as fasting plasma level

>15 lmol/L), with reported frequency between 11%52%,compared with 3.3%5% in the control population.103106

Several meta-analyses have established that hyperhomocys-

tenemia seems to be associated with a greater risk of ische-

mic heart disease and venous thromboembolism in the


1970

general population,101,102,107 although this has not been as

clearly demonstrated in the IBD population. Several case-con-

trol and retrospective studies have been performed and have

failed to show higher serum homocysteine in IBD patients

with VTE compared with those without VTE, although it

may be limited by insufficient sample sizes.103,105,106,108

Although elevated homocysteine levels has not been

established as a major risk factor for thromboembolism,

prevention of acquired hyperhomocystenemia could theo-

retically be protective and is fully reversible with vitamin

supplementation. Folate appears to be the most common

and strongest determinant of homocysteine levels, while

deficiencies in vitamins B6 and B12 alone appear to have

much more modest effects.109 Risk factors and treatment

strategies for folate and vitamin B12 deficiencies have

been discussed in previous sections (see Anemia).

Vitamin B6 (pyridoxine) is a water-soluble vitamin

that comes in several forms, but pyridoxal phosphate (PLP)

is the active form. Vitamin B6 is widely distributed in

foods (meats, whole grains, bananas, nuts) and is absorbed

by passive diffusion in the jejunum and ileum. Therefore,

deficiencies in vitamin B6 are less common than other B

vitamins and rarely occurs in isolation. Only two studies to

date have looked at vitamin B6 status in IBD patients.

From these small studies, it appears that rates of vitamin

B6 deficiency were 10%13%, with one study demonstrat-

ing a greater risk in patients with active disease compared

with those with quiescent disease.110,111 Certain drugs,

including corticosteroids and isoniazid, may interfere with

B6 metabolism. Vitamin B6 deficiency is defined by serum

PLP levels 8 years), extent of disease (pancolitis >left-sided), and coexisting primary sclerosing cholangitis. In

addition, there is evidence to suggest that folate and poten-

tially vitamin D deficiencies may be risk factors for colitis-

associated carcinogenesis.

FolateFolate has a central role in biological methylation

and nucleotide synthesis, and deficiencies have been associ-

ated with reduced levels of p53 mRNA, increased DNA

strand breaks, and DNA hypomethylation in the colon in

animal models.14,113 In humans, there have been several epi-

demiological studies associating low dietary folate intake

and sporadic CRC.114117 Within the IBD population, there

have been two case-control studies and a retrospective anal-

ysis that have shown decreased serum folate levels in

patients with premalignant lesions or cancer in the colon,

compared with colitis patients without neoplasms.118120

This has potentially widespread implications, given that IBD

patients are at increased risk of folate deficiency, for reasons

discussed in previous sections (see Anemia).

There have been a few studies demonstrating a poten-

tial benefit of folate supplementation against both sporadic

and colitis-associated CRC, at least at the molecular level. In

a prospective, placebo-controlled study of folate supplementa-

tion in 20 patients with sporadic adenoma, 5 mg of daily

folate was associated with an increase in the extent of

genomic DNA methylation and a decrease in the extent of

p53 strand breaks, at 6 and 12 months of the study.113 In UC

patients, supplementation with folate at 15 mg/day resulted in

reduced cell proliferation/kinetics in the rectal mucosa.121

While the above studies are suggestive, there have

been no studies to date demonstrating that folate supple-

mentation can significantly reduce cancer risk. Certainly,

however, it is warranted to evaluate for and correct folate

deficiency in all colitis patients. Adequate folate intake

should be encouraged, particularly in patients with multiple

years of pancolitis or other risk factors for CRC.

Vitamin DThe potential role of vitamin D and CRC has been

suspected for over a quarter of century. The earliest epide-

miological evidence supporting a possible link was the

observation that there was an inverse relationship between

mean solar radiation and age-adjusted cancer death rates,

of which CRC was the strongest linked.122 Since that time,

there have been multiple observational studies performed

in several populations that have suggested a link between

low vitamin 25-OHD serum levels and an increased risk of

colorectal adenomas and cancer.123126 An association

between vitamin D deficiency and cancer risk within IBD

cohorts has not been studied to date.

Vitamin D could decrease CRC risk through various

mechanisms. In multiple animal and in vitro studies, vitamin


1971

D supplementation and activation of the vitamin D receptor

pathway (VDR) inhibits colonic epithelial cell proliferation,

induces differentiation and apoptosis, and can decrease

angiogenesis and metastasis of CRC cells.127,128 In addition,

there is increasing evidence for antiinflammatory properties

of vitamin D, particularly within IBD. Activated vitamin D is

known to be important in regulating macrophage and T-cell

function, including prevention of excessive TH1-mediated

cytokines such as IL-2 and TNF-a,129 known to be importantin the pathogenesis of IBD. Treatment with vitamin D did

appear to alleviate some of the chemical injury caused by dex-

tran sodium sulfate (DSS) in murine models.130,131 In humans,

there have been multiple studies demonstrating an association

between VDR gene polymorphisms and IBD.132,133

Despite these encouraging observational and preclini-

cal data on vitamin D, there have been relatively few clini-

cal trials of vitamin D supplementation for extraskeletal

health. To date, there have been two randomized trials of

vitamin D supplementation that have shown no significant

decrease in CRC or adenoma incidence.134,135 Similarly,

there has only been one clinical trial to date on vitamin D

and inflammation in CD, in which 108 patients were

randomized to either high-dose vitamin D3 (1200 IU daily)

with calcium (1200 mg) or to calcium alone. After 1 year

of follow-up, vitamin D supplementation was associated

with a decreased but not statistically significant risk of

relapse (29% vs. 13%, P 0.06).136 Based on the currentavailability of current vitamin D trial data, there does not

currently appear to be sufficient data to recommend routine

vitamin D supplementation for the purpose of preventing

inflammation or CRC risk. However, given the strength of

epidemiological data linking vitamin D deficiency and can-

cer, it seems reasonable to routinely screen for and aggres-

sively treat vitamin D deficiency in patients with multiple

years of colitis or other risk factors for CRC.

CalciumCalcium has been proposed to reduce the risk of

CRC by binding to toxic secondary bile acids and ionized

fatty acids, and potentially reducing oxidative stress and

inflammation in the colon.137 There have been several large

observational studies that have shown a modest but signifi-

cant inverse association between calcium intake and CRC

risk.138,139 In a recent meta-analysis of these studies, those

in the highest quintile of calcium intake had a 22% reduc-

tion in risk of CRC compared with those in the lowest

quintile.140 Notably, most of the risk reduction was

achieved from calcium intake of 700800 mg/day, which

suggests a threshold level above which further calcium

would not be beneficial. The findings from observational

studies have been confirmed in one randomized controlled

trial performed in patients with history of adenoma, in

which 1200 mg of calcium was associated with a small but

significant (38% vs. 31%) risk of recurrent adenoma at 4

years. In subsequent analyses, the benefit was most pro-

nounced for advanced adenoma, with a risk ratio of 0.65

(95% CI, 0.460.93) compared with placebo.141

There have been no studies of the effect of calcium

in colitis-associated carcinogenesis. However, based on the

above data it seems reasonable for patients with increased

risk of CRC to take at least 1200 mg of calcium daily

(similar dose recommended for bone health in IBD).

Micronutrients Important to Wound HealingWould healing is important in IBD patients, particu-

larly in those with fistulizing CD and in all patients follow-

ing abdominal or pelvic surgery. The process of wound

healing consists of a coordinated cascade of sequential cel-

lular and biochemical events, classically divided into three

phases: inflammation, proliferation, and remodeling or mat-

uration.142 There have been multiple studies in the surgical

and geriatric literature that have demonstrated that malnu-

trition negatively affects wound healing by decreasing

fibroblast proliferation and collagen production, reducing

angiogenesis, and also increasing risk of infection due to

decreased T-cell function and phagocytic activity. The

micronutrients that appear to be most important for wound

healing include vitamins A and C, as well as zinc.

Vitamin AIn addition to its role in light absorption and color

vision in the eye, vitamin A (retinol), known as retinoic

acid in its oxidized form, is an important hormone-like

growth factor for epithelial cells. Specifically, retinoic acid

plays an important role in wound healing, by increasing the

macrophage and monocyte presence at the wound site and

stimulating fibroblasts production of collagen.143

Vitamin A is a fat-soluble vitamin that can be found

in two principle dietary foods: retinol in animal sources

and carotenes (alpha, beta, and gamma) which are found in

plants such as carrots, sweet potatoes, and broccoli leaves.

Following solubilization by bile salts, vitamin A is

absorbed by enterocytes throughout the small bowel, incor-

porated in chylomicrons, and shuttled between the liver

(main storage site, 50%80% of stores) and to tissues such

as the retina and skin. Normal vitamin A metabolism is

also dependent on zinc, as this mineral is necessary for the

synthesis of retinol binding protein (RBP), which transports

retinol through the circulation and also is required for en-

zymatic reactions that activate retinol.

There have been several small studies in which mean

vitamin A and b-carotene levels were found to be signifi-cantly lower in IBD patients.38,144,145 These studies need to

be interpreted carefully, as assessing vitamin A status can

be quite complicated. Serum vitamin A (retinol) levels can

be kept quite constant by release of liver stores, until body


1972

stores are quite depleted. However, b-carotene levels,which were used in most of the studies on vitamin A status

in IBD, can vary dramatically depending on recent vitamin

A intake.

The DRI for daily vitamin A consumption is 700 lg/dfor females and 900 lg/d for males. Several studies havedemonstrated that this DRI is not met in 36%90% of IBD

patients.5,11 Vitamin A supplementation in IBD patients

has not been well studied and doses significantly higher

than RDI for long periods should be used with caution,

given the risk of vitamin A toxicity. However, in certain

situations, such as in patients with significant fistulas or in

the perioperative period, it may be reasonable to supple-

ment with oral retinol. To enhance wound healing in the

acute setting, various expert groups have recommended

10,000 IU/day orally or intramuscularly for 10 days. For

individuals on corticosteroids, 10,00015,000 IU/d is rec-

ommended to enhance wound healing.142,143 Signs of vita-

min A toxicity (headache, bone pain, liver toxicity, hemor-

rhage) should be closely monitored.

Vitamin CVitamin C, also known as ascorbic acid or L-ascorbic

acid, is an important antioxidant in multiple tissues and

also serves as a cofactor in multiple enzymatic reactions,

including collagen synthesis. With respect to wound heal-

ing, vitamin C is also important, as it supports angiogenesis

and regulates neutrophil activity.142 Severe deficiency can

result in clinical scurvy, which is characterized by bleeding

gums, hemarthroses, and poor wound healing. Less severe

deficiencies, as measured by subnormal serum vitamin C

levels, are relatively common in IBD.5,145 Vitamin C is

absorbed in the jejunum by both active and passive trans-

port, but deficiency appears to be equally common in

patients with UC or CD and are not dependent on disease

activity.36,38 More likely, low vitamin C intake is a major

mechanism underlying vitamin C deficiency, as this has

been demonstrated in multiple IBD cohorts, including those

in remission.5,38

Vitamin C supplementation at 100 to 200 mg/d is

recommended for patients who have vitamin C deficiency

and/or with acute wound healing needs, including fistulas

or recent surgery.142

ZincZinc is an essential mineral, required for catalytic ac-

tivity of 100 enzymes, including metalloproteinases, andis also important in immune function, protein and collagen

synthesis, and wound healing. Zinc is absorbed along the

length of the small intestine by a poorly characterized

transport mechanism, but is also excreted in intestinal and

pancreatic secretions. Zinc deficiency is thought to be rela-

tively common in patients with chronic diarrhea, malab-

sorption, and hypermetabolic states (sepsis, burns).

A number of studies have reported low plasma zinc

levels in IBD patients.5,38 These results are difficult to

interpret, given that very little zinc is present in the serum,

so this is likely a poor measure of zinc status. There have

been several historical studies reporting that clinical symp-

toms of zinc deficiency (acrodermatitis, poor taste acuity)

were not uncommon especially in CD,2 although more

recent assessments of the incidence of subclinical zinc defi-

ciency among IBD cohorts are not well characterized.

The current USDA recommendation for zinc intake is

11 mg/d for men and 8 mg/d for women. It has been sug-

gested that for patients with significant diarrhea (>300 g ofstool/day), zinc gluconate of 2040 mg/day can be used.146

To enhance wound healing, zinc supplementation of 40 mg

of elemental zinc (176 mg zinc sulfate) for 10 days has been

suggested. Zinc sulfate 220 mg twice daily (2550 mg ele-

mental zinc) has been used as a standard adult oral replace-

ment dose. Unless patients have severe ongoing diarrhea,

such doses should not be given for longer than 23 weeks as

excess zinc can interfere with iron and copper absorption

and can lead to deficiency of these important minerals.142

Other Micronutrients

Vitamin B1Vitamin B1 (thiamine) is a water-soluble vitamin that

is important in the catabolism of sugars and amino acids,

and in which severe deficiencies are associated with periph-

eral neuropathy and cardiomyopathy (beri-beri). Thiamine

is found in multiple dietary sources (eggs, meats, bread,

nuts) and absorption mainly occurs in the jejunum by vary-

ing degrees of active and passive transport, depending on

body stores and luminal concentrations of thiamine. There

have been two small studies demonstrating that thiamine

deficiency may be more common in CD patients compared

with controls.5,110 The more recent of these studies was

performed within the last decade on 54 CD patients whose

disease was in remission. Even in this group, dietary thia-

mine intake was significantly lower than controls and low

serum vitamin B1 was found in 32% of patients.5 Therate of thiamine deficiency in either active CD or in

patients with UC is not known.

Vitamin B2Vitamin B2 (riboflavin) is a water-soluble vitamin

that acts as an oxidant in several important reactions,

including fatty acid oxidation, reduction of glutathione, and

pyruvate decarboxylation. Absorption occurs in the jejunum

by sodium-dependent active transport, and deficiency can

manifest with oral (angular cheilitis, cracked lips) and ocu-

lar (photophobia) symptoms. Riboflavin deficiency does not

appear to be common in IBD, with only one study per-

formed in 1983 documenting a modestly elevated incidence

in CD patients compared with controls.110


1973

Vitamin B3Vitamin B3 (niacin or nicotinic acid) is another

water-soluble member of the B complex family. It is a pre-

cursor to NAD/NADH and NADP/NADPH, and also isinvolved in both DNA repair and production of adrenal steroid

hormones. Absorption of niacin occurs mainly in the jejunum,

and dietary sources include chicken, beef, fish, cereal, nuts,

dairy, and eggs. Severe deficiency can cause pellagra (diar-

rhea, dermatitis, and dementia), although dermatological and

psychiatric symptoms are common in mild deficiency.

A recent study found plasma vitamin B3 levels to be

low in 77% of CD patients with disease in remission.5

These results need to be carefully interpreted, given that

niacin status should be assessed via urinary biomarkers, as

these are more reliable than plasma levels.147 However, this

study does suggest that niacin deficiency may be fairly prev-

alent in the CD population (prevalence in UC patients is not

known). The recommended daily allowance of niacin is

14 mg/day for women, 16 mg/day for men, and 18 mg/day

for pregnant or breast-feeding women. If patients cannot

meet these requirements, oral vitamin B3 at doses com-

monly found in standard multivitamin preparations should

be encouraged.

Vitamin B7Vitamin B7 (biotin) is a coenzyme in the metabolism

of fatty acids and leucine, and it plays a role in gluconeo-

genesis. Like the other B vitamins, its absorption occurs

primarily n the jejunum. Deficiency in biotin is rare and

tends to present with mild symptoms. There has only been

one study of biotin status in IBD patients, in which serum

levels did not differ from that of healthy controls.110

Vitamin EVitamin E is used to refer to a group of fat-soluble

vitamins, with important antioxidant function. There are

many different forms of vitamin E, of which c-tocopherol isthe most common in the North American diet, found in corn

oil, soybean oil, margarine, and dressings. a-Tocopherol, themost biologically active form of vitamin E, is the second

most common form of vitamin E and found in sunflower

and safflower oils. Vitamin E is absorbed similarly to other

fat-soluble vitamins, so theoretically could be impacted by

fat malabsorption and/or cholestyramine treatment.

There have been three studies to date looking at vita-

min E status in IBD patients. The cohorts used were heter-

ogeneous, with one only including CD patients,110 one

with only UC148 and one study which combined UC and

CD patients.145 Of these three studies, only the study of

CD patients found a significantly lower serum vitamin E

level, compared with controls, and this difference appeared

irrespective of disease activity. Given these very scant data

on vitamin E deficiency in IBD, there are no current rec-

ommendations on monitoring and replacement of vitamin

E. It may be considered in CD patients with significant fat

malabsorption.

Minerals

SeleniumSelenium is a necessary component of vital enzymes

with antioxidant function, including glutathione peroxidase

and thioredoxin reductase. In animal models, selenium has

been associated with reduced risk of cancer, including

colorectal,149,150 although human epidemiological data are

mixed.151

Absorption of selenium is poorly understood, but is

believed to occur most avidly in the ileum, followed by the

jejunum and large intestine. There have been five studies to

date, in which selenium levels were found to be signifi-

cantly lower in both UC and CD patients, compared with

controls.152156 This observation was seen irrespective of

disease activity and/or location. The exact prevalence of

true selenium deficiency was not obtainable from these

studies, as most only reported mean selenium levels. Thus,

currently there is no evidence to support checking for or

repleting selenium deficiency in IBD patients. The excep-

tion to this is in patients on long-term total parenteral nutri-

tion (TPN). Selenium is now routinely added to TPN, often

in premixed commercial trace element concentrates (often

also including zinc, copper, manganese, and chromium).

Updated guidelines from the American Society of Paren-

teral or Enteral Nutrition (A.S.P.E.N.) recommend that

20-60 lg daily be supplemented in TPN.157

CopperCopper is a trace element that has diverse roles in

biological electron transport and oxygen transportation.

Because of large stores of copper in the liver, muscle, and

bone, deficiency is relatively rare. There have been several

small studies that have addressed copper status in IBD

patients, with equivocal results. While a recent study of

CD patients in remission reported that serum copper was

found to be low in up to 84% of patients,5 two other stud-

ies have failed to show this.155,156 In several studies of UC

patients, serum copper was found to be similar to controls

in one, and elevated in UC patients in two studies.154,155

This highlights the limitation of serum copper and cerulo-

plasmin in determining body copper stores, as both may be

acute phase reactants. Serum copper may also be falsely

decreased with certain renal diseases, with prolonged

inflammation, and due to increased iron or zinc intake.

Currently, there are no recommended screening or

supplementation guidelines for copper, other than in TPN.

Guidelines from A.S.P.E.N. recommend that 0.30.5 mg

daily be supplemented in TPN.157 Copper is normally


1974

TABLE

4.Screeningan

dTreatmentStrategiesforMicronutrientDeficiencies

Consider

Empiric

Supplementation:

Consider

ScreeningforDeficiency:

TreatmentStrategiesforDeficiency

BVitam

ins:

Water-Soluble

B1(thiamine)

Consider

inptswithactiveileitisor

multiple

jejunal/ileal

resections

(B-complexvitam

inusually

sufficient)

Usually

noneedto

checklevels

Supplementifclinically

suspicious

Thiamine100mg/day

(orvitam

inB

complexsupplementoften

sufficient)

B3(niacin)

Notsufficientevidence

Notsufficientevidence

B6(pyridoxine)

Ptsonisoniazidorcorticosteroids

(50-100mgpyrodoxine/day)

Consider

inptswithelevated

homocysteineorhistory

of

thromboem

bolicdisease

(B-complex

vitam

inusually

sufficient)

Usually

noneedto

checklevels,

butcanconsider

ifclinically

suspicious

Pyridoxine50-100mg/day

(orvitam

inB

complexsupplementoften

sufficient)

B9(folate)

Ptsonmethotrexateorsulfasalazine

(folate

1mg/day

usually

sufficient)

Can

consider

forCRCprevention,

thoughnotbeenvalidated

inRCT

Definite:

Ptswithnew

anem

iaProbable:Regularscreening

inptswithactiveileitisor

smallbowel

resections

Possible:Periodic

screeningin

allCrohns

pts

Folate

1mg/day;2weekssufficientif

norm

aljejunal

absorption

Consider

recheckingfolate

in4-6

weeksifconcernedaboutabsorption

(activeileitis,multiple

resections)

B12

Allptswithilealresections>

60cm

willneedlifelongIM

B12

Definite:

Ptswithnew

anem

iaProbable:Regularscreeningin

allpatientswithactiveileitisor

smallbowel

resection

Probable:Periodic

screeningin

allCrohns

pts

Intram

uscularB121000mcg

monthly

preferred

inptswithileal

disease/resections;monitorannually

inhigh-riskpts

Oralandintranasal

B12has

been

studiedin

non-IBD

ptsandlikelyequally

efficaciousin

ptswithoutilealdisease

CPtswithfistulasorrecentsurgery

(500mg/day

x10days)

Usually

noneedto

checklevels

Supplementifclinically

suspicious

Vitam

inC100mg/day,canbeindefinite

aslow

risk

oftoxicity

Vitam

ins:

Fat-Soluble

APtswithfistulasorrecentsurgery

(10,000IU

/day

oral/IM

x10days;

15,000IU

/day

forptsonsteroids)

Significantsteatorrhea/m

alabsorption,

and/ormultiple

ilealresections

Vitam

inA

10,000IU

/day

orally/IM

x10days

DMostIBD

patients(600IU

-2000IU

/day

indefinitely;2-3xhigher

forptson

glucocorticoidsorwhoareobese)

AllIBD

patientsshould

be

screened

periodically

Closermonitoringforptswith

osteopenia/osteoporosisorrisk

factors

(steroids,obesity,malabsorption)

Vitam

inD250,000IU

1-2

times/week

foreightweeksuntilserum

25OH

levels>30achieved

Alternatively,6,000IU

daily

(choleciferol),2-3xhigher

inptswith

obesity,malabsorptionorsteroid

use

Consider

checkingvitam

inD

q8weeks

inpatientsbeingtreatedandthen

q6moannually

ENosufficientevidence


alabsorption,

and/ormultiple

ilealresections

a-tocopherol15to

25mg/kgpo

once/day;parentalform

smay

needto

begiven

inseveredeficiency

(rare)

(Continued)


1975

TABLE

4.(Continued

)

Consider

Empiric

Supplementation:

Consider

ScreeningforDeficiency:

TreatmentStrategiesforDeficiency

KNotsufficientevidence

currently;

May

consider

inptswithosteoporosis

(smallstudiesshow

increasedbone

density

withmenaquinone-4(soybeans)

monitorclosely

fortoxicity


alabsorption,

and/ormultiple

ilealresections

Ifbleedingcomplications,phytonadione

5to

20mgorallyx3days;

monitorPT/INR

Minerals:

Macro

Calcium

MostIBD

patients:

1000mgin

women

aged

18-25,

men65

Serum

calcium

notreflective;

RegularboneDEXA

inptswith

osteopenia/osteoporosiswithh/o

significantsteroid

exposure,

postmenopausal,familyhistory

1000-1500mgcalcium

(withvitam

inD)

Magnesium

Ptswithactivediarrhea

(>300g/day)or

drainingfistulae(elemental

5-20mmol/day)

Activediarrhea,fistulas

5-20mmol/day;consider

checkingserum/

urinarymagnesium

incasesof

severe/persistentdiarrhea

orfistulas

Minerals:

Traceelem

ents

Iron

Notrecommended

Definite:

Allpatientswithanem

iaProbable:Regularscreening

inptswithactiveinflam

mation,

bleedingsymptoms

Possible:Periodic

screening

inallIBD

pts

IVironform

ulationspreferred

Ferricsucrose

traditional

IVform

(200mg/infusion,given

until

anem

iaresoled);

Ferriccarboxymaltose

recently

developed

andsuperiorin

1RCT

(1000mg/infusion)

Oralironoften

poorlytoleratedand

may

increase

inflam

mation;

Monitoriron/CBCevery4weeks

aftertreatm

entinitiationasymptomatic

pts(earlier

inseverecases)

Treatmentgoal

isto

restore

Hgb>12

inwomen,>13men

Zinc

Ptswithfistulasorrecentsurgery,

toim

provewoundhealing

(220mgtwicedaily

x10days

Ptswithseverediarrhea

Noaccurate

screeningtestavailable

Can

consider

220mg1-2

times

daily

forptswithactive,

severe

diarrhea,unclearlength

of

supplementationacceptable

Selenium

AllTPN

form

ulations

Possible:Consider

periodic

screening

inallptswithIBD

Selenium

100mcg/day

x2-3

weeks;

unclearmonitoringintervals

Chromium

Consider

addingto

TPN,though

contaminantsoften

present

Probable:Monitorin

ptsonTPN

Manganese

Consider

addingto

TPN,though

contaminantsoften

present;

monitorfortoxicities

Probable:Monitorin

ptsonTPN


1976

excreted in bile, so lower doses should be utilized in

patients with cholestasis (i.e., PSC with elevated bilirubin).

ChromiumChromium is an element that exists in several

valency states, with trivalent chromium being the only bio-

logically active form and an important regulator of insulin

action. Chromium deficiency is rare and has been reported

mainly in patients on long-term TNP and presented with

glucose intolerance and neuropathy, both of which were

reversed with addition of chromium to TPN.158,159 Cur-

rently, A.S.P.E.N. recommends 1015 lg of chromium isadded daily to TPN.157

ManganeseManganese is an essential trace element required as a

catalytic cofactor for multiple enzymatic reactions. There

have been virtually no cases of clinically significant man-

ganese deficiency reported, so assessing manganese status

is not necessary for IBD patients. The only exception to

this is in patients on long-term TPN, in which manganese

toxicity is an increasingly important problem. This is espe-

cially problematic in patients with chronic liver disease

and/or cholestasis, as manganese is primarily excreted in

bile. Manganese toxicity is associated with liver injury as

well as neurotoxicity.160 The 2004 guidelines put forth by

A.S.P.E.N. recommended lower doses of manganese (0.04

0.1 mg) than previous guidelines.161 However, there have

been several studies demonstrating that even at these lower

doses, whole-blood manganese levels was elevated in

82%93% of long-term TPN patients.162 This may be due

to the fact that most TPN formulas contain high levels of

manganese contaminants and commercial trace element

mixtures contain excessive manganese.

CONCLUSIONSIBD has classically been associated with malnutrition

and weight loss, although this has become less common

with advances in treatment and greater proportions of

patients attaining clinical remission. However, micronu-

trient deficiencies are still relatively common, particularly

in CD patients with active small bowel disease and/or mul-

tiple resections.

Micronutrient deficiencies are associated with several

important extraintestinal complications of IBD. Anemia is

the most common of these, and can be due to iron, vitamin

B12, and folate deficiencies. Abnormal bone metabolism,

manifesting as osteopenia or osteoporosis, is affected

largely by calcium, vitamin D, magnesium, and possibly

vitamin K. Risk of venous thromboembolism may be

increased by folate, vitamin B12, and pyrodoxine deficien-

cies, by inducing hyperhomocysteinemic states. Folate and

vitamin D deficiencies appear, mainly in preclinical studies,

to predispose to colonic inflammation and cancer.

There are no current guidelines for assessment of

micronutrient deficiencies in IBD patients. Clearly, in the

presence of clinical symptoms of deficiency, evaluating

micronutrient status and treating deficiencies is indicated

(Table 4). In anemic patients, iron (ferritin, transferrin %

saturation), folate (serum, RBC folate, homocysteine), and

B12 (B12, methylmalonic acid) should be checked. Iron

deficiency is the most common etiology and treating with

intravenous iron is recommended until normal hemoglobin

is restored. For osteopenia and osteoporosis, vitamin D sta-

tus (25-OHD) should be monitored and treated with 8-

week regimens, and then maintained on 600800 IU of

vitamin D and 10001500 mg of calcium indefinitely.

In our practice, even without clinical symptoms of

deficiency and irrespective of disease activity, we assess

folate, iron, and vitamin D status in all patients annually.

CD patients with a history of ileal disease or bowel resec-

tion also have yearly vitamin B12 levels assessed. The

exception is patients with >60 cm of ileum removed, inwhich intramuscular cobalamin will definitely need to be

replaced for life. In patients with a significant flare, these

vitamins will be assessed more frequently, especially if the

patient requires surgery or glucocorticoids.

There are specific situations which may call for

empiric supplementation and/or more careful monitoring,

in conjunction with a nutritionist. These include:

Sulfasalazine or methotrexate treatment: folate 1 mg/day. Significant diarrhea (>300 g/day): magnesium, zinc. Fistulas or nonhealing wounds: zinc, vitamin C. Steatorrhea, multiple ileal resections, severe ileitis: vita-mins A, D, E, K, B12.

Long-term TPN: Iron, vitamin D, selenium, zinc, manga-nese (toxicity).

There are several novel indications for micronutrient

supplementation, such as folate and vitamin D for CRC pre-

vention and vitamin K (menaquinone-4) for bone health in

which there is some preliminary data, but randomized clinical

trials are lacking. While nutrition is one of the most common

concerns of patients with IBD, the literature remains inad-

equate with respect to clear guidelines for micronutrient mon-

itoring and supplementation. The above recommendations are

based on currently available data. These will likely change

over time based on ongoing studies, but currently can serve

as a useful tool for clinicians to apply in their practice.

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