Supported by IBDWG GI Fellows Award 2011-12 (to C.H.).
Micronutrient deficiencies in inflammatory bowel disease: From A to zinc†
Article first published online: 5 APR 2012
Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 18, Issue 10, pages 1961–1981, October 2012
How to Cite
Hwang, C., Ross, V. and Mahadevan, U. (2012), Micronutrient deficiencies in inflammatory bowel disease: From A to zinc. Inflamm Bowel Dis, 18: 1961–1981. doi: 10.1002/ibd.22906
- Issue published online: 13 SEP 2012
- Article first published online: 5 APR 2012
- Manuscript Accepted: 11 JAN 2012
- Manuscript Received: 21 DEC 2011
- inflammatory bowel disease;
- micronutrient deficiencies
- Top of page
- MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- PATHOPHYSIOLOGY OF MALNUTRITION IN IBD
- SPECIFIC MICRONUTRIENT DEFICIENCIES
Inflammatory bowel disease (IBD) 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, 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)
Inflammatory bowel disease (IBD) is commonly associated with malnutrition. Large retrospective studies have demonstrated that as many as 70%–80% of IBD patients will exhibit weight loss during their disease course.1–4 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 developments, namely, immunomodulators and biologic therapy, have allowed a greater proportion of IBD patients to attain sustained clinical remission. There are a few studies demonstrating that patients in remission often have similar macronutrient 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 elements). 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 micronutrients are more common in patients with Crohn's disease (CD), especially those with fistulas, strictures, or prior surgical 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, thrombophilia, colorectal cancer, and poor wound healing.
MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- Top of page
- MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- PATHOPHYSIOLOGY OF MALNUTRITION IN IBD
- SPECIFIC MICRONUTRIENT DEFICIENCIES
Vitamins and minerals are naturally occurring compounds that are required for diverse functions in the body and must be obtained from the diet, as they are not sufficiently synthesized by humans. Vitamins are organic compounds 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), nicotinic acid/niacin (B3), pyridoxine (B6), cobalamin (B12), biotin, pantothenic acid, folic acid, and vitamin C (ascorbic acid). The fat-soluble vitamins (A, D, E, and K) are hydrophobic substances that are dissolved within fat droplets and must be broken down by lipases and combined with bile salts in the duodenum to form mixed micelles, which then facilitate diffusion across the enterocyte membrane.
Dietary minerals are inorganic elements that are important 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, potassium, 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. Macrominerals and trace elements are absorbed by passive or active transport through the intestinal mucosa, often using specialized transport proteins such as ferritin for Fe3+ or vitamin D-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 IBD
- Top of page
- MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- PATHOPHYSIOLOGY OF MALNUTRITION IN IBD
- SPECIFIC MICRONUTRIENT DEFICIENCIES
There 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 patient's disease course.
|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 vitamins|
|Hypermetabolic state||• Alterations of resting energy expenditure|
|Drug interactions||• Sulfasalazine and methotrexate inhibits folate absorption|
|• Glucocorticoids impair Ca2+, Zn2+, and phosphorus absorption, vitamin C losses and vitamin D resistance|
|• Cholestyramine impairs absorption of fat-soluble vitamins, vitamin B12 and iron|
|Long-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|
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 necrosis factor alpha [TNF-α]) as well as to minimize symptoms of abdominal pain and diarrhea, which are exacerbated 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 commonly occurs in CD, due to inflammation or resection of small bowel. Specifically, significant terminal ileal disease and/or resections >40–60 cm can lead to vitamin B12 deficiency as well as bile-salt wasting and resultant impaired fat-soluble vitamin absorption.13 In addition, patients with primary 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 interfere with normal micronutrient absorption. Glucocorticoids potently inhibit calcium, phosphorus, and zinc absorption and may also lead to impaired metabolism of vitamins C and D.4 Sulfasalazine is a folate antagonist,14 while cholestyramine can interfere with absorption of fat-soluble vitamins. Finally, the use of long-term parenteral nutrition can lead to deficiencies in any micronutrient not added in sufficient quantities, but most commonly include vitamins A, D, E, zinc, copper, and selenium.15
SPECIFIC MICRONUTRIENT DEFICIENCIES
- Top of page
- MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- PATHOPHYSIOLOGY OF MALNUTRITION IN IBD
- SPECIFIC MICRONUTRIENT DEFICIENCIES
A wide array of vitamin and mineral deficiencies occurs in IBD patients, with varying degrees of clinical significance. Of particular relevance to clinicians is the impact of micronutrient deficiencies on anemia, bone mineral density, thrombophilia, wound healing, and carcinogenesis. These are summarized in Table 2.
|Pathophysiology||Symptoms of Deficiency||Diagnosis||Prevalence|
|B Vitamins: Water-soluble||B1 (thiamine)||Unclear mechanism||Severe: peripheral neuropathy, cardiomyopathy (beri beri)||Mainly clinical; Can consider serum B1 if symptoms severe||32% of CD pts unknown prevalence in UC|
|B9 (folate)||Inadequate dietary intake Malabsorption (associated with ileitis/small bowel resection) Medications (MTX, sulfasalazine)||Megaloblastic anemia; Modestly increased risk of colonic dysplasia/CRC Hyperhomocysteinemia Glossitis, angular stomatitis, depression||Serum folate < 2.5ng/mL (can be falsely low, homocysteine > 16mmol/L confirms) RBC folate < 140||40-78% of IBD pts with inadequate folate intake[5,38]; 0-26% of Crohn's diseasepts with deficiency[34, 38]|
|B12||Active ileitis History of ileal/ileocolonic resection, ?ileoanal pouch||Megaloblastic anemia, pancytopenia Peripheral neuropathy, dementia||Serum B12 < 200pg/mL (may lack sensitivity) If B12 < 400, consider methylmalonic acid, homocysteine levels||11-22% of Crohn's pts[11,34]: 100% of pts with ileal resections >60cm 48% of resections 20-40cm|
|C||Inadequate dietary intake||Poor wound healing Gingivitis, scaly skin, arthralgias||Mainly clinical; Serum ascorbate <11.4μmol/L||>50% of Crohn's pts|
|Vitamins: Fat-soluble||A||Inadequate dietary intake Steatorrhea/fat malabsorption Bile salt deficiency (wasting, use of cholestyramine)||Poor wound healing Night blindness, xeropthalmia||Serum tests can be unreliable; Serum retinol, retinol-binding protein, β-carotene||35-90% of IBD pts with inadequate daily intake[5,11]; 0-44% with low serum levels[38,144,=145]|
|D||Same as above AND Decreased sunlight exposure/ inadequate dietary intake||Abnormal bone metabolism (likely contributes to osteopenia/osteoporosis) May increase inflammation/ CRC risk||Serum 25OHD <15 Deficiency <20 Insufficiency (>30 Optimal)||22-70% of CD pts and up to 45% of UC pts deficient[61-64]|
|E||Steatorrhea/bile salt deficiency||Neuropathies, retinopathy, anemia||Serum α-tocopherol < 5μg/mL||Unclear prevalence, but one study found to serum levels lower in CD (vs. controls)|
|K||Inadequate dietary intake Steatorrhea/fat malabsorption Bile salt deficiency (wasting, use of cholestyramine)||Likely contributes to abnormal bone metabolism (lesser degree than vit D) Bleeding, cartilage/arterial calcification||Bone levels: Uncarboxylated osteocalcin (% or total) Serum phylloquinone PT/INR||Unclear prevalence, but uncarboxylated osteocalcin levels lower in CD (vs. UC pts and controls) [86-88]|
|Minerals: Macro||Calcium||Inadequate dietary intake Vitamin D deficiency (decreased intestinal/renal absorption) Hypomagnesemia (from diarrhea)||Decreased bone density Hypoparathyroidism, hypertension, muscle spasm/twitching May increase sporadic polyp/CRC risk||Bone density scan; Serum calcium not reflective||80-86% of IBD pts with inadequate daily intake[5,38] 22-55% of CD and 32-67% of UC pts with osteopenia[50,51]|
|Magnesium||Inadequate dietary intake Losses from diarrhea||Minor contributor to bone health Hypocalcemia/hypoparathyroidism||24 urine magnesium most accurate||Unclear (likely very common)|
|Iron||Chronic blood loss Impaired iron metabolism (IL6, TNFαhepcidin upregulation Inadequate intake||Microcytic anemia Fatigue, glossitis, angular cheilitis, restless leg syndrome||Transferrin sat <16% Serum ferritin <30 (inactive disease, normal CRP) <100 (active, CRP)||36-90% of IBD pts with iron- deficiency anemia[23,24]|
|Minerals: Trace elements||Zinc||Chronic diarrhea Malabsorption (small bowel) Increased need in hypermetabolic states (sepsis, critical illness)||Poor wound healing Acrodermatitis, poor taste||Mainly clinical; No accurate measurement||Unclear (likely very common)|
|Selenium||Long-term TPN Unknown in non-TPN dependent pts||Cardiomyopathy, cartilage degeneration, hypothyroidism||Serum Se < 130ng/mL||Unclear prevalence, but mean levels lower in both CD/UC compared to controls[152-6]|
Anemia 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 studies of outpatient IBD patients, using population-based datasets in Switzerland and Scandinavia, found the prevalence of anemia 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-mercaptopurine, methotrexate, or sulfasalazine).
Iron 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 generally lower, 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 lipopolysaccharide, IL-6, and TNF-α, 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 macrophages often manifests with increased levels of ferritin, the body's 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 ineffective 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 guidelines suggest that in order to accurately interpret iron studies, patients' concurrent degree of inflammation needs to be considered. Therefore, in patients without clinical symptoms and normal C-reactive protein (CRP), a ferritin of <30 μg/L would be considered consistent with iron-deficiency anemia. However, in the presence of inflammation the lower limit of this parameter consistent with normal iron stores is 100 μg/L. In addition, low iron values as well as <16% transferrin saturation are supportive of iron deficiency.
Iron-deficiency anemia has been associated with impaired cardiac and renal function in the general population, as well as decreased physical activity, fatigue, and decreased quality of life in IBD patients.21, 23 It has also been associated more recently with restless leg syndrome, an entity more common in CD patients compared with the general population.29 When possible, the best long-term therapeutic approach to iron-deficiency anemia is effective control of the underlying disease. However, when this is not possible or is not expected to occur quickly, direct supplementation of iron is generally recommended in patients with overt anemia (hemoglobin <13 g/dL in males and < 12 g/dL in females).28 In cases of iron deficiency without anemia, use of iron supplements is more controversial. In patients at high risk of developing anemia, iron studies should be monitored closely and, in the short-term, nutritional interventions can be considered, including increase of dietary iron, concomitant intake of ascorbic acid, and discontinuation of proton-pump inhibitor or H2-antagonist therapy.
The preferred form of iron supplementation in anemic IBD patients has been the subject of multiple studies, including several recent randomized-controlled trials. While oral iron is much simpler and often the first supplement form tried in the outpatient setting, it is often poorly tolerated by patients, causing abdominal pain and diarrhea in up to 30%–56% of patients.30, 31 It has recently been associated with increased intestinal inflammation in animal models of colitis as well.32 According to expert guidelines for management of iron deficiency in IBD, intravenous iron is considered the preferred route of iron supplementation in IBD patients, especially for those with severe anemia (Hgb <10) or severe disease activity.28 Compared with oral iron, intravenous iron improves hemoglobin, iron stores, and quality-of-life more effectively; disadvantages include risk of infusion reactions, including anaphylaxis, and the need for multiple infusions since doses are limited to 200 mg/infusion. Recently, a novel form of intravenous (IV) iron, ferric carboxymaltose, has been developed, which can be administered in doses of up to 1000 mg. In a recent multicenter randomized controlled trial, ferric carboxymaltose appeared to be superior to traditional IV iron sucrose in both ability to increase hemoglobin as well as patient compliance.33
Following initiation of iron supplementation, serum ferritin and transferrin levels should be monitored within 4 weeks in asymptomatic patients and earlier in symptomatic patients, in order to evaluate and adjust treatment accordingly. Expert guidelines have suggested that the goal of treatment should be achievement of normal values of hemoglobin (12 g/dL in women, 13 g/dL in men), ferritin (>100 μg/L) and transferrin saturation (16%–50%).28
Deficiencies in folic acid (vitamin B9) can lead to a macrocytic megaloblastic anemia, owing to folate's important role as a cofactor in DNA synthesis and normal erythrocyte division. Unlike iron, all dietary folate is not stored in large quantities in the body, averaging only 500–20,000 μg in healthy individuals. Therefore, without ingestion of the DRI of 400–1000 μg of folic acid, stores can be depleted quite rapidly.34 Within the general population, rates of folic acid deficiency have decreased dramatically over the last two decades in countries such as the United States and Canada, where federal regulations have mandated folate supplementation in cereals and other enriched grain products to decrease neural tube birth defects.35
In spite of these folate fortification programs, IBD patients may be at increased risk of folic acid deficiency compared with the general population. While more recent studies demonstrate that folate deficiency is less prevalent than was previously reported in historical IBD cohort studies (51%–80%),14 folate deficiency still appears to be relatively common, particularly in CD. In a recent retrospective case-control study performed in 2010, abnormal serum folate levels (<3 ng/mL) were found in 28.8% of the CD patients, 8.8% of ulcerative colitis (UC) patients, and 3% of controls.34 Three studies performed in CD—one of which only included patients with disease in remission—reported similar rates (20%–26%) of subnormal whole-blood folate levels.36, 37 It should be noted that all of the above studies used serum folate levels, rather than red blood cell (RBC) folate levels, which may be a more accurate test as it reflects average folate levels over the preceding 3 months. There have been two studies utilizing RBC folate levels in IBD patients, with much lower rates of deficiency seen (0%–7%).38
Potential mechanisms of folate deficiency include inadequate dietary intake, malabsorption, and medication interactions. Inadequate intake is likely the most important cause, as supported by two studies in which prospective food records of outpatient IBD showed inadequate folate intake in 40%–78%.5, 38 Active Crohn's ileitis and history of small bowel resection have been demonstrated to be risk factors for folate deficiency, supporting malabsorptive mechanisms.11, 34 Finally, sulfasalazine and methotrexate both can cause folate deficiency, as both are inhibitors of dihydrofolate reductase and cellular uptake of folate.39
Folate deficiency is associated with multiple systemic side effects (Table 3), of which megaloblastic anemia is one of the latter manifestations but also the most responsive to oral folate therapy. The prevalence of folate-related anemia in IBD has not been well studied, but overall rates of macrocytic anemia was estimated to be ≈4% in one large longitudinal study of IBD patients performed in Hungary.40
|Micronutrient||Primary Site of Absorption||Dietary Sources||Dietary Reference Intakes (RDA)a1|
|Vitamins: Water-soluble||B1 (thiamine)||Jejunum/ileum||Pork, beef, ham, sunflower seeds||1.1mg (women) 1.2mg (men)|
|B2 (riboflavin)||Jejunum||Liver, milk, yogurt. pork||1.1mg (women) 1.3mg (men)|
|B3 (niacin)||Jejunum||Tuna, turkey, chicken, beef, peanuts, milk, cottage cheese||14mg (women) 16mg (men); 18mg (pregnancy)|
|B5 (pantothenic acid)||Jejunum||Mushrooms, corn, liver, broccoli||4mg AIb|
|B6 (pyridoxine)||Jejunum||Salmon, chicken, legumes, bananas, turnip greens||1.3-1.5mg (women) 1.3-1.7mg (men)|
|B7 (biotin)||Jejunum||Swiss chard, eggs, peanuts||30μg AIb|
|B9 (folate)||Jejunum/ileum||Asparagus, brusssel sprouts, cereals, spinach, cantaloupe||400μg 600μg (pregnancy)|
|B12 (cobolamin)||Terminal ileum||Trout, beef, shellfish, tuna, milk||2.4μg|
|C (absorbic acid)||Jejunum/ileum||Kiwi, orange, green peppers, cauliflower, broccoli||75mg (women) 90mg (men)|
|Vitamins: Fat-soluble||A||Ileum||Carrots, sweet potatoes, spinach, cantaloupe, liver||RAEc 700μg (women) 900μg (men)|
|D||Ileum||Salmon, tuna, milk||5-10μg (200-400IU) AIc|
|E||Ileum||Sunflower seeds, almonds, sweet potato, shellfish||15mg|
|K||Ileum||Kale, spinach, broccoli||90-120μg / 120μg|
|Minerals: Macroelements||Calcium||Duodenum/ Jejunum||Yogurt, milk, cheese, collard greens, tofu||1000mg (men aged 19-70, women aged 19-50 1200mg (men>70y, women >51yo|
|Magnesium||Duodenum/ jejunum||Peanuts, bran, legumes, bean sprouts, tofu||420mg (men) 320mg (women)|
|Minerals: Trace elements||Iron||Duodenum||Fortified cereal, liver, beef, baked beans, pork, prune juice, apricots||8mg (men, women >50y) 18mg (women <50y|
|Zinc||Unclear||Beef, crab, ham, pork, wheat germ, pecans||8-11mg|
|Chromium||Proximal small bowel||Beef, chicken, eggs, spinach, bananas, apples, wheat germ||20-35μg AIb|
|Copper||Duodenum||Oysters, beans, cashews||900μg (10,000μg ULd)|
|Manganese||Unclear||Pineapple, brown rice, beans||1.8-2.3mg|
|Selenium||Ileum||Lobster, tuna, shrimp, ham||55μg (400μg ULd)|
Currently, there are no clear guidelines on screening for folate deficiency in IBD patients, especially in patients with disease in remission and who report no major restrictions in their diet. However, measuring serum and RBC folate levels is definitely indicated in anemic IBD patients, particularly those with CD. If these tests are negative and suspicion for folate deficiency is high, homocysteine levels can also be assessed, as this is potentially more sensitive, although less specific, as hyperhomocystenemia also occurs with deficiencies of vitamin B6 and B12.11 Folate supplementation of 1 mg/day is usually sufficient to replenish deficient folate stores within 2–3 weeks.41 Folate is also generally recommended with most patients on methotrexate or sulfasalazine39 and can be considered for many pregnant IBD patients to prevent neural tube defects.35 Another potential indication for folate supplementation in IBD patients is prevention of colitis-associated colorectal cancer, although this is more controversial and addressed in a later section.
Also associated with a megaloblastic anemia, vitamin B12 (cobalamin) deficiency is less common than folate deficiency in the general population, but an especially important consideration in CD and elderly IBD patients.41 Unlike other water-soluble vitamins which are absorbed in the proximal small bowel, active vitamin B12 absorption is limited to the terminal ileum. Animal products are the principal food source of B12 for humans, and gastrointestinal absorption occurs by a fairly complex process. Dietary cobalamin is cleaved from R factor by pancreatic proteases and binds to intrinsic factor, which is produced in the stomach. The IF-cobalamin compound then travels to the ileum where it binds to a specific receptor, cobalamin, and then is absorbed through distal ileal mucosa. Any abnormality along the way can lead to B12 malabsorption.
CD frequently affects the ileum, with 30% of patients with isolated ileal inflammation and another 30% with ileocolonic involvement.2 Long-term inflammation can lead to impaired absorption, but also to fibrosis, strictures, and fistulas that necessitate surgical resection of the ileum. Therefore, patients with CD are thought to be at significant risk for developing vitamin B12 deficiency. There have been several recent studies evaluating vitamin B12 status in IBD cohorts, with deficiency seen in 11%–22% of CD patients.11, 34, 42 In the largest of these studies, Headstrom et al42 found from retrospective multivariate analysis of 201 CD patients that the greatest risk factors for B12 deficiency were prior ileal resection (odds ratio [OR] 7.22; 95% confidence interval [CI], 1.97–26.51) or ileocolonic resection (OR 5.81; 95% CI, 2.09–10.12). Neither disease location nor duration was independently associated with risk of B12 deficiency.
In contrast, UC is always confined to inflammation within the colon, and thus rates of B12 deficiency have generally been found to be comparable to that of the general population.11, 34 However, there have been several reports of B12 deficiency in UC patients who have undergone proctocolectomy with ileoanal pouch anastomosis, although it is unclear if this may be related to the small amount of ileum resected during this anastomotic reconstruction (≈20–40 cm) or small bowel overgrowth of the pouch.43
Diagnosis of vitamin B12 deficiency has traditionally been based on low serum vitamin B12 levels, usually less than 200 pg/mL (150 pmol/L), along with clinical evidence of disease. However, in many individuals, particularly elderly patients, irreversible neuropsychiatric manifestations can begin to occur, even in the absence of hematological manifestations of B12 deficiency.44 Therefore, it is advocated that if serum B12 levels are normal in at-risk populations, that methylmalonic acid and homocysteine levels—metabolites of vitamin B12—be assessed next, as these appear to be more sensitive than serum B12 level.45
Assessing for vitamin B12 status is definitively indicated in all patients with macrocytic anemia or anemia that is not responsive to iron or erythropoietin. In addition, periodic screening should be considered in all CD patients, especially those with active ileal CD or history of ileal resection, although the recommended intervals for screening have not been established. Previous studies have demonstrated that patients with terminal ileal resections of >60 cm will need lifelong B12 replacement,46, 47 while up to 48% of patients with shorter resection lengths of 20–40 cm are at risk of eventually developing B12 deficiency.13
The optimal method for vitamin B12 supplementation in patients who have had ileal resections is unclear. Traditionally, the preferred approach has been monthly parenteral injections, as this route is inexpensive and is effective in quickly correcting B12 deficiency associated with CD.13 A recent Cochrane meta-analysis suggested that high-dose oral cobalamin of 1000–2000 μg (initially daily, then weekly, then monthly) was as effective as intramuscular injections in patients with B12 deficiency, although the studies did not include patients with CD.48 However, it seems reasonable to assume that patients with IBD, especially active small bowel disease, may have impaired absorption of oral cobalamin. Therefore, at the current time further studies need to be performed before oral supplements can be widely recommended to IBD patients with B12 deficiency.
Bone disease is the one of the most common extraintestinal complications of IBD. Bone mass generally peaks in the second and third decade in life and then gradually declines. Bone mass is determined by the balance of activity by osteoblasts, which secrete bone, and osteoclasts, which resorb bone. This balance relies on complex signaling pathways, which include several hormones including parathyroid hormone (PTH), vitamin D, growth hormone, and calcitonin. It can also be directly affected by proinflammatory cytokines and the use of exogenous steroids, both relevant in the IBD population.49
It is well-established that osteopenia and osteoporosis occur more frequently in IBD patients and at an earlier age of onset than in the general population. The exact prevalence of decreased bone mass density (BMD), typically measured by dual-energy x-ray absorptiometry (DEXA), varies in the IBD literature, owing to heterogeneous cohorts and various definitions of bone disease. Osteopenia (BMD between −1 to −2.5 SDs below average for healthy individuals) and osteoporosis (greater than −2.5 SDs below) have been reported in 22%–55% and 3%–58% of CD patients, respectively, and 32%–67% and 4%–50% of UC patients.50, 51 Significantly, the rate of fracture has also been demonstrated in large epidemiological studies to be 40%–60% higher than among controls.52
Factors considered important in the pathogenesis of osteoporosis and fractures in IBD patients include age, gender, menopausal status, decreased body mass index, use of corticosteroids, and the presence of inflammation.50, 51 Specifically, the role of inflammation has gained increasing attention, with recent animal studies demonstrating that cytokines known to be elevated in IBD, including IL-1, IL-6, TNF-α, and a novel TNF subgroup called the RANK-RANKL-OPG family, potently activate osteoclastic activity.49 Finally, malnutrition and malabsorption are also important mechanisms, particularly in their impact on levels of vitamin D, a hormone essential for calcium absorption and homeostasis.53
Calcium is the most abundant mineral in the human body, with average body stores of ≈1–2 kg, 99% of which is in the skeleton. Extracellular calcium is normally regulated in a narrow range (2.2–2.6 mmol/L or 9–10.5 mg/dL) by the combined actions of calcitonin and parathyroid hormone, which in turn regulates the activity of the vitamin D system, the main inducer of active calcium absorption in the intestine. Intestinal absorption of calcium primarily occurs in the duodenum and proximal jejunum. Calcium absorption occurs by two mechanisms: 1) an unregulated paracellular route, which largely depends on dietary intake and luminal calcium concentration, and 2) an active intracellular route via calcium channels, the transcription of which is dependent on 1,25-vitamin D (1,25-OHD). In addition, calcium is secreted in the distal small bowel (distal jejunum and ileum) as well as in the colon by unclear mechanisms. Intestinal calcium losses are likely aggravated by diarrhea and malabsorption, although the extent has not been well studied.54
Surprisingly little is known about the extent to which active small bowel inflammation can directly affect calcium absorption. This is difficult to study, given that calcium absorption is interdependent on vitamin D, a micronutrient which is insufficient in a large proportion of IBD patients, as discussed below. Calcium malabsorption is known to be exacerbated by magnesium deficiency (from diarrhea) and glucocorticoids, which causes decreased absorption of calcium from both the intestine and kidney. In addition to malabsorption, several studies have demonstrated that as many as 80%–86% of IBD patients will have inadequate daily dietary calcium intake.5, 38 Avoidance of milk and other dairy products is quite common, due to high rates of concomitant lactose intolerance.
Calcium supplementation is recommended in most patients with IBD, at doses of 1000–1500 mg/day (1000 mg for women age 25 until menopause and men <65 years old; 1300 mg for women between 18–25 years; 1500 mg for postmenopausal women, and men >65 years old). There have been relatively few studies evaluating the efficacy of calcium alone or combined with vitamin D supplementation. However, from two observation cohorts it did appear that calcium at doses of 1000 mg with nontreatment doses of vitamin D may have resulted in a slight improvement in BMD after 1 year, although no change in the incidence of fractures was seen.55, 56 In general, however, calcium supplementation alone is probably not sufficient to prevent bone loss in IBD patients, especially those with significant glucocorticoid exposure.57, 58 The addition of higher doses of vitamin D to calcium should be considered in all IBD patients on steroids, as described below.
Vitamin D is a fat-soluble vitamin essential for normal bone mineralization, as it optimizes intestinal calcium absorption and increases osteoblastic differentiation. Low vitamin D levels can result in secondary hyperparathyroidism and bone resorption, as evidenced by elevated markers of bone turnover (alkaline phosphatase and undercarboxylated osteocalcin) in healthy and IBD patients with hypovitaminosis D compared with normal controls.59 However, while vitamin D levels have shown to have an inverse relationship with BMD in the general population, this has not been as consistently demonstrated in IBD cohorts, likely due to insufficient sample size and multiple mechanisms contributing to bone disease in IBD.53
In humans, vitamin D is mainly obtained from exposure to sunlight. UVB rays convert cutaneous sources of 7-dehydrocholesterol to cholecalciferol (D3). In addition, a few foods (mainly fortified dairy products and fish oils) contain either cholecalciferol or ergocalciferol (vitamin D2). Both skin and intestinal sources of vitamin D2/D3 are captured by binding to plasma vitamin D-binding protein (DBP), present in the capillary bed of the dermis and the intestinal epithelium. DBP bound to vitamin D precursors are delivered to the liver, where they undergo 25-hydroxylation, and then to the kidney, where they undergo 1-hydroxylation. 1,25-dihydroxy-vitamin D (1,25-OHD) is the hormonally active form of vitamin D and responsible for most of the biological effects of vitamin D. However, the most abundant metabolite in the human body is 25-OHD, which best reflects overall vitamin D status and is the measurement used most frequently in the clinical setting.53
Vitamin D status is generally not static and in the general population can vary with season, latitude, time of day, skin pigmentation, aging (due to waning levels of cutaneous 7-hydrocholesterol), smoking, and sunscreen use (SPF 30 blocks 95% of skin production).53 Vitamin D deficiency (defined as serum 25-OHD levels ≤15 ng/mL) and insufficiency (≤20 ng/mL) is extremely prevalent in healthy adults and children who live in the northern hemisphere, particularly during winter months.53, 60 Several reports have demonstrated that IBD patients are at higher risk for hypovitaminosis D, with rates between 22%–70% for CD patients and up to 45% in UC.61–64
Absorption of dietary vitamin D occurs mainly in the jejunum and it requires the presence of luminal bile acids for emulsification prior to binding to the DBP, which is a member of the albumin superfamily of binding proteins. Therefore, IBD patients at greatest risk for vitamin D deficiency appear to be CD patients with significant small bowel resection (>200–300 cm),65, 66 steatorrhea,67 and protein-losing enteropathy.53 In addition, lower mean 25-OHD levels have been associated with longer disease duration, higher Crohn's Disease Activity Index (CDAI), and higher CRP, suggesting that inflammation without overt malabsorption can also negatively affect vitamin D status.64, 68 Finally, multiple studies have demonstrated that vitamin D deficiency appears to be nearly as common in patients with UC and in quiescent IBD.38, 63 This suggests the importance of other risk factors that may be more common in IBD patients, including decreased exposure to sunlight, avoidance of vitamin-D fortified foods such as dairy products, and lifetime glucocorticoid exposure. In particular, glucocorticoid use appears to cause some degree of vitamin D resistance, as two trials have demonstrated that vitamin D supplementation at comparable doses that are effective in increasing BMD in general IBD cohorts were not sufficient to prevent bone loss in IBD patients on steroids.57, 69
Given the risk of bone disease in IBD patients, monitoring for regular intake of vitamin D is particularly important in this population. Several studies have demonstrated that inadequate dietary intake occurs in 36%–62% of IBD patients, even in patients with disease in remission.5 Because of the limited foods that contain vitamin D, oral supplements are often required. Practice guidelines from the Endocrine Society do not distinguish between oral D3 (cholecalciferol) and D2 (ergocalciferol), although several recent studies including one randomized controlled trial have demonstrated that cholecalciferol appears to be more effective than ergocalciferol in increasing 25-OHD levels.70 In IBD patients it has been suggested that at least 600 IU (adults 19–70 years) to 800 IU (70+ years) daily is required, irrespective of vitamin D status. These dosages have been associated with increased BMD at various skeletal sites in IBD patients after 6–12 months.50, 53 However, recent guidelines by a taskforce of the Endocrine Society have suggested that vitamin D dosages of between 1500–2000 IU/day may be preferred, in order to maintain serum 25-OHD levels of >30, which has been associated with optimal levels of parathyroid hormone and maximal efficiency of intestinal calcium absorption.71 For obese patients or those on glucocorticoids, it is recommended that vitamin D at two to three times greater than that recommended for their age group be given.53, 71
In addition, vitamin D deficiency should be routinely screened for in all patients with IBD, and levels monitored more closely in patients with significant small bowel disease or resection, on glucocorticoids, with known osteopenia/osteoporosis, and those who are postmenopausal, older (>70), or obese. If patients are found to have vitamin D deficiency (<15 ng/mol), various treatment regimens can be utilized. The most common are 50,000 IU once to twice per week for 8 weeks, or daily doses of 6000 IU until serum 25OH levels of >30 are achieved. Again, patients with 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 are achieved, maintenance dosages of vitamin D as discussed above should be continued indefinitely.
Magnesium is the fourth most abundant cation in the body and plays a fundamental role in most cellular reactions, mainly as a cofactor in enzymatic reactions involving ATP. In addition, 50%–60% of body magnesium is incorporated 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 deficiency on bone disease are not clear. In cell culture and animal models, magnesium has a mitogenic role on osteoblasts 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 intestinal 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 magnesium 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. Most oral magnesium formulations can exacerbate diarrhea, although magnesium heptogluconate (Magnesium-Rougier) or magnesium pyroglutamate (Mag 2) may be better tolerated, 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 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 multiple forms, but phylloquinone (vitamin K1), present in green leafy vegetables, is the principle dietary form. Vitamin K is a known cofactor for posttranslational γ-carboxylation of multiple proteins, including blood coagulation factors but also osteocalcin (OC), a regulator of bone mineral maturation. Osteocalcin is produced by osteoblasts and requires γ-carboxylation in order to bind calcium. Under conditions of 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 levels.78 The lack of a single reliable and direct method of vitamin K status is a principle limitation in interpretation of studies on this vitamin's importance in bone health.
There have been several large epidemiological studies, 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.79–81 However, studies correlating biochemical measures of vitamin K (uncarboxylated osteocalcin level or serum phylloquinone levels) with bone disease have been less consistent, with some studies showing an association while others do not.82–84 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-deficient.85 There have been two more recent studies that measured serum uncarboxylated osteocalcin levels in CD patients and found levels to be significantly lower compared 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 common in patients with active inflammation and more extensive small bowel involvement, suggesting malabsorption as a potential mechanism. There have been multiple studies showing that dietary intake of vitamin K is also significantly lower in IBD patients, even in patients with disease remission, compared with controls.9, 86
Currently, there does not appear to be sufficient evidence 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 phylloquinone supplementation in elderly women and healthy controls. None of these showed increased BMD in >1 skeletal site.89–91 There have been a few positive studies from Japan, in which menaquinone-4 (a different form of vitamin 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 further 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 restrictions, 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 insufficient 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 tolerate these foods, as a means for bone health.
Arterial and venous thromboembolism are increasingly recognized extraintestinal complications of IBD, with significant morbidity and mortality. From several large administrative database studies performed in North America and Europe, the risk of venous thrombosis (VTE) in IBD patients is ≈2–3.5-fold greater than that of the general population, with excess mortality 2.1-fold greater for IBD compared with non-IBD hospitalized patients.94, 95 In addition, higher rates of acute arterial thrombosis events, primarily acute mesenteric ischemia, but also cardiac and cerebral 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 3.5–4),94, 98 ambulatory patients (RR of 14.3),99 and peripartum women (RR of 6–8).100
An important risk factor for VTE appears to be disease 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 remission.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 hypercoagulability of IBD. While the mechanisms underlying inflammation and hypercoagulability have not been well delineated, several studies suggest that it may involve qualitative and quantitative impairment of platelets, procoagulant or fibrinolytic proteins, and decreased natural anticoagulant factors.96, 98
Besides inflammation, certain vitamin deficiencies may also contribute to a hypercoagulable and prothrombotic state in IBD. These include folate, vitamins B6 and B12—all 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 B12
Hyperhomocysteinemia is an established risk factor for arterial and potentially venous thromboembolism.101, 102 This pathological state can be due to genetic defects or secondary to renal dysfunction or certain vitamin deficiencies. Homocysteine is a sulfydril amino acid derived from catabolism of methionine; to convert this byproduct back to methionine requires folate and B12 as cofactors. Homocysteine 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 μmol/L), with reported frequency between 11%–52%, compared with 3.3%–5% in the control population.103–106 Several meta-analyses have established that hyperhomocystenemia seems to be associated with a greater risk of ischemic heart disease and venous thromboembolism in the general population,101, 102, 107 although this has not been as clearly demonstrated in the IBD population. Several case-control 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 theoretically 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 demonstrating 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 <10 nmol/L, and the classic manifestations include a seborrheic dermatitis-like rash, atrophic glossitis, and neurological symptoms including neuropathy. Vitamin B6 deficiency can be treated with 50–100 mg/day of pyridoxine daily.
In summary, because of the potential association between hyperhomocystenemia and thromboembolism, folate and vitamin B12 levels should be assessed in patients at risk of deficiencies (malabsorption, ileal resections) and aggressively repleted in the usual dosages to treat hematological complications. Vitamin B6 deficiency is comparatively rare and in patients with folate and/or vitamin B12 deficiency, one may consider checking serum PLP levels and/or empirically supplementing with low doses of pyridoxine, which is common in most standard multivitamin formulations.
Colonic Inflammation and Carcinogenesis
Chronic inflammation of the colonic mucosa has been associated with colorectal cancer (CRC), with cumulative risk of CRC estimated at 2% after 10 years of colitis, 8% after 20 years, and 18% after 30 years.112 Well-identified risk factors for colitis-associated CRC include longer duration (>8 years), extent of disease (pancolitis >left-sided), and coexisting primary sclerosing cholangitis. In addition, there is evidence to suggest that folate and potentially vitamin D deficiencies may be risk factors for colitis-associated carcinogenesis.
Folate has a central role in biological methylation and nucleotide synthesis, and deficiencies have been associated 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 epidemiological studies associating low dietary folate intake and sporadic CRC.114–117 Within the IBD population, there have been two case-control studies and a retrospective analysis that have shown decreased serum folate levels in patients with premalignant lesions or cancer in the colon, compared with colitis patients without neoplasms.118–120 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 potential 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 supplementation 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 supplementation 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.
The potential role of vitamin D and CRC has been suspected for over a quarter of century. The earliest epidemiological 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.123–126 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 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-α,129 known to be important in the pathogenesis of IBD. Treatment with vitamin D did appear to alleviate some of the chemical injury caused by dextran 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 preclinical data on vitamin D, there have been relatively few clinical 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 current availability 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 cancer, it seems reasonable to routinely screen for and aggressively treat vitamin D deficiency in patients with multiple years of colitis or other risk factors for CRC.
Calcium 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 significant 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% reduction in risk of CRC compared with those in the lowest quintile.140 Notably, most of the risk reduction was achieved from calcium intake of 700–800 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 pronounced for advanced adenoma, with a risk ratio of 0.65 (95% CI, 0.46–0.93) 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 Healing
Would healing is important in IBD patients, particularly in those with fistulizing CD and in all patients following abdominal or pelvic surgery. The process of wound healing consists of a coordinated cascade of sequential cellular and biochemical events, classically divided into three phases: inflammation, proliferation, and remodeling or maturation.142 There have been multiple studies in the surgical and geriatric literature that have demonstrated that malnutrition 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.
In 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, incorporated 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 enzymatic reactions that activate retinol.
There have been several small studies in which mean vitamin A and β-carotene levels were found to be significantly 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 stores are quite depleted. However, β-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 μg/d for females and 900 μg/d for males. Several studies have demonstrated 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 supplement 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, 10,000–15,000 IU/d is recommended to enhance wound healing.142, 143 Signs of vitamin A toxicity (headache, bone pain, liver toxicity, hemorrhage) should be closely monitored.
Vitamin 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 healing, 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 transport, 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
Zinc is an essential mineral, required for catalytic activity of ≈100 enzymes, including metalloproteinases, and is 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 relatively common in patients with chronic diarrhea, malabsorption, 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 symptoms of zinc deficiency (acrodermatitis, poor taste acuity) were not uncommon especially in CD,2 although more recent assessments of the incidence of subclinical zinc deficiency 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 suggested that for patients with significant diarrhea (>300 g of stool/day), zinc gluconate of 20–40 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 (25–50 mg elemental zinc) has been used as a standard adult oral replacement dose. Unless patients have severe ongoing diarrhea, such doses should not be given for longer than 2–3 weeks as excess zinc can interfere with iron and copper absorption and can lead to deficiency of these important minerals.142
Vitamin 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 peripheral neuropathy and cardiomyopathy (beri-beri). Thiamine is found in multiple dietary sources (eggs, meats, bread, nuts) and absorption mainly occurs in the jejunum by varying 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 thiamine intake was significantly lower than controls and low serum vitamin B1 was found in ≈32% of patients.5 The rate of thiamine deficiency in either active CD or in patients with UC is not known.
Vitamin 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 ocular (photophobia) symptoms. Riboflavin deficiency does not appear to be common in IBD, with only one study performed in 1983 documenting a modestly elevated incidence in CD patients compared with controls.110
Vitamin B3 (niacin or nicotinic acid) is another water-soluble member of the B complex family. It is a precursor to NAD+/NADH and NADP+/NADPH, and also is involved 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 (diarrhea, 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 prevalent 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 commonly found in standard multivitamin preparations should be encouraged.
Vitamin B7 (biotin) is a coenzyme in the metabolism of fatty acids and leucine, and it plays a role in gluconeogenesis. 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 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 γ-tocopherol is the most common in the North American diet, found in corn oil, soybean oil, margarine, and dressings. α-Tocopherol, the most 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 vitamin E status in IBD patients. The cohorts used were heterogeneous, 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 recommendations on monitoring and replacement of vitamin E. It may be considered in CD patients with significant fat malabsorption.
Selenium 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 significantly lower in both UC and CD patients, compared with controls.152–156 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 exception to this is in patients on long-term total parenteral nutrition (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 Parenteral or Enteral Nutrition (A.S.P.E.N.) recommend that 20-60 μg daily be supplemented in TPN.157
Copper 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 studies 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 ceruloplasmin 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 0.3–0.5 mg daily be supplemented in TPN.157 Copper is normally excreted in bile, so lower doses should be utilized in patients with cholestasis (i.e., PSC with elevated bilirubin).
Chromium is an element that exists in several valency states, with trivalent chromium being the only biologically 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 Currently, A.S.P.E.N. recommends 10–15 μg of chromium is added daily to TPN.157
Manganese is an essential trace element required as a catalytic cofactor for multiple enzymatic reactions. There have been virtually no cases of clinically significant manganese 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 especially 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.
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- MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- PATHOPHYSIOLOGY OF MALNUTRITION IN IBD
- SPECIFIC MICRONUTRIENT DEFICIENCIES
IBD 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, micronutrient deficiencies are still relatively common, particularly in CD patients with active small bowel disease and/or multiple 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 deficiencies, 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 status (25-OHD) should be monitored and treated with 8-week regimens, and then maintained on 600–800 IU of vitamin D and 1000–1500 mg of calcium indefinitely.
|Consider Empiric Supplementation:||Consider Screening for Deficiency:||Treatment Strategies for Deficiency|
|B Vitamins: Water-Soluble||B1 (thiamine)||Consider in pts with active ileitis or multiple jejunal/ileal resections (B-complex vitamin usually sufficient)||Usually no need to check levels Supplement if clinically suspicious||Thiamine 100mg/day (or vitamin B complex supplement often sufficient)|
|B3 (niacin)||Not sufficient evidence||Not sufficient evidence||–|
|B6 (pyridoxine)||Pts on isoniazid or corticosteroids (50-100mg pyrodoxine/day) Consider in pts with elevated homocysteine or history of thromboembolic disease (B-complex vitamin usually sufficient)||Usually no need to check levels, but can consider if clinically suspicious||Pyridoxine 50-100mg/day (or vitamin B complex supplement often sufficient)|
|B9 (folate)||Pts on methotrexate or sulfasalazine (folate 1mg/day usually sufficient) Can consider for CRC prevention, though not been validated in RCT||Definite: Pts with new anemia Probable: Regular screening in pts with active ileitis or small bowel resections Possible: Periodic screening in all Crohn's pts||Folate 1mg/day; 2 weeks sufficient if normaljejunal absorption Consider rechecking folate in 4-6 weeks if concernedabout absorption (active ileitis, multiple resections)|
|B12||All pts with ileal resections > 60cm will need lifelong IM B12||Definite: Pts with new anemia Probable: Regular screening in all patients with active ileitis or small bowel resection Probable: Periodic screening in all Crohn's pts||Intramuscular B12 1000mcg monthly preferred in pts with ileal disease/resections; monitor annually in high-risk pts Oral and intranasal B12 has been studied in non-IBD pts and likely equally efficacious in pts without ileal disease|
|C||Pts with fistulas or recent surgery (500mg/day x 10 days)||Usually no need to check levels Supplement if clinically suspicious||Vitamin C 100mg/day, can be indefinite as low risk of toxicity|
|Vitamins: Fat-Soluble||A||Pts with fistulas or recent surgery (10,000IU/day oral/IM x 10 days; 15,000IU/day for pts on steroids)||Significant steatorrhea/malabsorption, and/or multiple ileal resections||Vitamin A 10,000IU/day orally/IM x 10 days|
|D||Most IBD patients (600IU-2000IU/day indefinitely; 2-3x higher for pts on glucocorticoids or who are obese)||All IBD patients should be screened periodically Closer monitoring for pts with osteopenia/osteoporosis or risk factors (steroids, obesity, malabsorption)||Vitamin D2 50,000 IU 1-2 times/week for eight weeks until serum 25OH levels >30 achieved Alternatively, 6,000IU daily (choleciferol), 2-3x higher in pts with obesity, malabsorption or steroid use Consider checking vitamin D q8weeks in patients being treated and then q6mo – annually|
|E||No sufficient evidence||Significant steatorrhea/malabsorption, and/or multiple ileal resections||α-tocopherol 15 to 25 mg/kg po once/day; parental forms may need to be given in severe deficiency (rare)|
|K||Not sufficient evidence currently; May consider in pts with osteoporosis (small studies show increased bone density with menaquinone-4 (soybeans) monitor closely for toxicity||Significant steatorrhea/malabsorption, and/or multiple ileal resections||If bleeding complications, phytonadione 5 to 20 mg orally x 3 days; monitor PT/INR|
|Minerals: Macro||Calcium||Most IBD patients: 1000mg in women aged 18-25, men <65 1300mg in women 25-menopause 1500 mg in postmenopausal women, men>65||Serum calcium not reflective; Regular bone DEXA in pts with osteopenia/osteoporosis with h/o significant steroid exposure, postmenopausal, family history||1000-1500mg calcium (with vitamin D)|
|Magnesium||Pts with active diarrhea (>300g/day) or draining fistulae (elemental 5-20mmol/day)||Active diarrhea, fistulas||5-20mmol/day; consider checking serum/ urinary magnesium in cases of severe/persistent diarrhea or fistulas|
|Minerals: Traceelements||Iron||Not recommended||Definite: All patients with anemia Probable: Regular screening in pts with active inflammation, bleeding symptoms Possible: Periodic screening in all IBD pts||IV iron formulations preferred Ferric sucrose traditional IV form (200mg/infusion, given until anemia resoled); Ferric carboxymaltose recently developed and superior in 1 RCT (1000mg/infusion) Oral iron often poorly tolerated and may increase inflammation; Monitor iron/CBC every 4 weeks after treatment initiation asymptomatic pts (earlier in severe cases) Treatment goal is to restore Hgb >12 in women, >13 men|
|Zinc||Pts with fistulas or recent surgery, toimprove wound healing (220mg twice daily x 10 days Pts with severe diarrhea||No accurate screening test available||Can consider 220mg 1-2 times daily for pts with active, severe diarrhea, unclear length of supplementation acceptable|
|Selenium||All TPN formulations||Possible: Consider periodic screening in all pts with IBD||Selenium 100mcg/day x 2-3 weeks; unclear monitoring intervals|
|Chromium||Consider adding to TPN, though contaminants often present||Probable: Monitor in pts on TPN|
|Manganese||Consider adding to TPN, though contaminants often present; monitor for toxicities||Probable: Monitor in pts on TPN|
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 resection also have yearly vitamin B12 levels assessed. The exception is patients with >60 cm of ileum removed, in which 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: vitamins A, D, E, K, B12.
Long-term TPN: Iron, vitamin D, selenium, zinc, manganese (toxicity).
There are several novel indications for micronutrient supplementation, such as folate and vitamin D for CRC prevention 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 inadequate with respect to clear guidelines for micronutrient monitoring 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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- MAJOR MICRONUTRIENTS AND NORMAL ABSORPTION
- PATHOPHYSIOLOGY OF MALNUTRITION IN IBD
- SPECIFIC MICRONUTRIENT DEFICIENCIES
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