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Folate deficiency has often been described both in Crohn’s disease and ulcerative colitis

(Table 1). Decreased dietary intake, increased demands, malabsorption due to mucosal

impairment and sulfasalazine competitive inhibition of folate absorption, are associated with

folate deficiency. Folate deficiency may also be primary or secondary to vitamin B12

deficiency. Besides systemic deficiency, increased intestinal cell turnover due to epithelial

inflammation could also result in folate deficiency in patients with UC. Steger et al.

performed an oral folate absorption test in 100 CD patients and detected abnormal folate

absorption in 25 patients. The abnormal folate absorption test was correlated with disease

extent and activity. Furthermore, no increase of the serum folate levels was detected in 9 out

of 25 patients after oral folate supplementation [38]. Koutroubakis et al. reported that serum

folate levels were significantly lower in both CD and UC patients than in controls [21]. Zezos

et al. investigated the folate, vitamin B12 and homocysteine status in 40 UC patients and

identified 3 (7.5%) cases with low serum folate levels [39]. High prevalence (20-80%) of

folate deficiency in IBD patients is reported in data from 70’s and 80’s [11,40-43]. On the

contrary, in recent studies the prevalence of folate deficiency was low or even absent in IBD

patients, although serum folate levels were lower in IBD patients compared to healthy

controls [19,21,22]. One possible explanation for this discrepancy on data is the modification

of dietary folate intake in the recent years in the general population or the more frequent use

of vitamin supplements, including IBD patients. Furthermore, nowadays sulfasalazine has

been replaced by mesalazine, a drug that does not interfere with folate absorption, although a

correlation between intake of sulfasalazine and low folate levels has not been constantly

found in IBD patients [12,42]

64 Petros Zezos and Georgios Kouklakis

3. Clinical Consequences of Vitamin B Complex Deficiencies in IBD

Patients

The “vitamin B complex” deficiencies are implicated in a wide array of clinical

manifestations or complications in patients with IBD. Macrocytic anemia is associated with

folate and vitamin B12 deficiency. Deficiencies of folate, vitamin B12 and vitamin B6 can

cause hyperhomocysteinemia, an independent risk factor for both venous and arterial

thrombosis. Furthermore, low folate status has been associated with increased risk of

adenoma or colorectal cancer development in the general population and in individuals with

ulcerative colitis. Finally, there have been some rare cases reporting clinical syndromes

related to specific deficiencies of water-soluble B vitamins (pellagra, beriberi).

Megaloblastic Anemia in IBD Patients

Iron deficiency and anemia of chronic disease are the most common causes of anemia in

IBD patients [44]. Megaloblastic anemia due to folate or vitamin B12 deficiency is a less

frequent cause of anemia in IBD patients. The vitamin B12 is stored in the liver (~5 mg) and

has a low turnover rate with small daily requirements. In patients with inflammatory bowel

disease, ileal disease disrupting the enterohepatic circulation leads t greater losses of vitamin

B12 than that of a vegetarian not ingesting any vitamin B12. Thus, vitamin B12 deficiency

would occur in these patients in only a few years. Clinical evidence of vitamin B12 deficiency

occurs late as body stores have to be depleted to less than 10%. Vitamin B12 deficiency seems

to be common in patients with ileal CD or resection of the ileum, but its haematopoietic

consequence in CD is unclear. In general, folate deficiency seems to be more common than

vitamin B12 deficiency. Clinical manifestations of folate deficiency occur earlier as folate

stores last only 1-2 months.

In a recent study, Lakatos et al. [44] reported that the prevalence of macrocytic anemia

was 4.3% in CD patients and 4.9% in UC patients, but unfortunately without distinguishing

between folate and vitamin B12 deficiency. Overall, the percentages of macrocytic anemia

among anemic IBD patients were 7.3% in CD patients and 9.2% in UC patients.

Although folate and vitamin B12 deficiencies occur often in IBD patients the

manifestations of symptomatic deficiency (hematological and neurological consequences),

are not usually present. Several studies have observed a discrepancy between the measured

serum concentration of vitamin B12 and true deficiency as confirmed by Schilling test and

methylmalonic acid concentration. Methylmalonic acid accumulates in vitamin B12

deficiency and is specific for vitamin B12 deficiency state [45,46]. One possible explanation is

that in malnutrition states the carrier proteins in the serum are depleted before tissue levels

fall enough to produce symptoms of deficiency, and therefore serum levels of vitamin B12 do

not reflect true body stores. In general, red blood cell folate levels are considered as a better

indicator of tissue stores (intermediate-term stores) than serum folate levels (short-term

stores), and are less susceptible to rapid changes in diet [47,48]. Since most of the studies

have evaluated the serum folate status in IBD patients, it is possible that the folate deficiency

reported is not severe enough (depletion of tissue stores) to produce clinically evident

macrocytic anemia. On the other hand, some investigators suggest that serum folate

Nutritional Issues in Inflammatory Bowel Disease… 65

measurements provide equivalent information to red cell folate measurements about folate

status [49].

Hyperhomocysteinemia and Thromboembolic Disease in IBD Patients

The risk for thromboembolic complications is increased in patients with inflammatory

bowel disease. The incidence of arterial and venous thromboembolic disease in patients with

ulcerative colitis and Crohn’s disease has been reported between 1% and 8% [50,51], rising

to an incidence of 39% in some autopsy studies [52]. Several studies have shown that a

hypercoagulable state involving all components of clotting system exists in IBD [53-55]. This

hypercoagulable state may be related to an increased tendency for thromboembolic events

and may be linked to the disease pathogenesis through promoting microthrombi formation in

the intestinal microcirculation [56,57]. The aetiology and pathogenesis of the

hypercoagulable state in IBD have not been fully elucidated but may be induced through a

procoagulant effect of proinflammatory cytokines [58-62] in combination with acquired or

genetic defects of clotting factors (protein S, protein C, antithrombin, factor V Leiden,

prothrombin mutation 20210A, antiphospholipid antibodies) [63-65].

Homocysteine (Hcys) is a non-essential, sulfur-containing amino acid formed during the

metabolism of methionine (Figure 1). The first step in the synthesis of homocysteine is the

formation of S-adenosylmethionine (SAM, AdoMet), an important methyl donor, from

methionine. AdoMet is then converted to S-adenosylhomocysteine (AdoHcy), which is

further hydrolyzed to yield homocysteine and adenosine. Depending on whether there is a

relative excess or a deficiency of methionine, homocysteine may then enter either

transsulfuration or remethylation pathways. If methionine stores are adequate, homocysteine

enters the transsulfuration pathway, where it is converted to cysteine in a series of reactions

catalyzed by the vitamin B6 -dependent enzymes cystathionine beta-synthase (CBS) and

gamma-cystathionase. If methionine conservation is necessary, homocysteine enters a

remethylation pathway. Remethylation may occur by one of two reactions. In one,

homocysteine is reconverted to methionine by transfer of a methyl group from 5-

methyltetrahydrofolate in a reaction catalyzed by cobalamin (vitamin B12)-dependent

methionine synthase (MS). The formation of 5-methyltetrahydrofolate is catalyzed by

methylenetetrahydrofolate reductase (MTHFR), which requires vitamin B2 (riboflavin) as a

cofactor. The other remethylation pathway operates independently of vitamin B12 and folate

but uses betaine as a methyl donor and requires betaine-homocysteine methyltransferase

(BHMT). Abnormalities of these pathways, as a result of nutrient deficiencies or enzyme

inactivity, may result in the accumulation of homocysteine.

Mild hyperhomocysteinemia (hHcys), which occurs in approximately 5-7% of the

general population, has been proved to be thrombogenic and an independent risk factor for

coronary artery disease [66], arterial and venous thrombosis [67-72]. Elevated levels of Hcys

may result from abnormalities in metabolism pathways due to inherited abnormalities of the

enzymes involved or nutrient deficiencies such as insufficiency of folate and vitamins B2, B6

and B12 [73-74].

66 Petros Zezos and Georgios Kouklakis

Figure 1. Metabolic pathways of homocysteine.

The mechanism by which hyperhomocysteinemia promotes thrombosis is uncertain, but

it may be related to promoting a hypercoagulate state due to endothelial dysfunction [74-76].

Vitamin B12 and folate deficiency are relatively common conditions in IBD (especially in

active disease) through malnutrition, malabsorption or antifolate drugs such as methotrexate

and sulfasalazine. Deficiencies of key nutrients/cofactors in Hcys metabolism pathways (B2,

B6, B12, and folate) might lead to raised Hcys levels in IBD.

The association between IBD and hyperhomocysteinemia (hHcys) has been shown in

many recent studies, reporting an increased prevalence of hHcys in IBD (both UC and CD)

[17,19,21,22,39,77-81]. In most of these studies low serum folate level (and, to a lesser

extent, a low serum vitamin B12 level) was a strong independent risk factor for

hyperhomocysteinemia. Koutroubakis et al [21], Zezos et al. [39], Chowers et al. [19], and

Papa et al. [80] reported elevated homocysteine levels related to low serum folate status in

IBD patients. On the other hand, Romagnuolo et al. [79] reported an inverse correlation

between serum homocysteine levels and serum vitamin B12 levels. Furthermore, Saibeni et al.

[17] in their study underscored the relationship between low vitamin B6 plasma levels and

hyperhomocysteinemia in IBD patients. Moreover, Oldenburg et al. [78] found that

hyperhomocysteinemia correlated with serum folate, vitamin B12 and vitamin B6 status in

IBD patients. On the contrary, Drzewoski et al. [81] stated that elevated homocysteine levels

in UC patients correlated with disease activity and duration, and not with folate and vitamin

B12 deficiency.

Nutritional Issues in Inflammatory Bowel Disease… 67

Thromboembolic disease is a serious extraintestinal manifestation of inflammatory bowel

disease (IBD), causing significant morbidity and mortality in IBD patients. Thrombosis

occurs more often in the deep veins of the legs and the pulmonary circulation; however,

arterial thrombotic complications and numerous other less frequent sites of venous

thrombosis have also been described: cerebrovascular disease, internal carotid artery

occlusion, portal vein thrombosis, Budd-Chiari syndrome, cutaneous gangrene secondary to

microvascular thrombosis, retinal vein occlusion, ischaemic heart disease.

Hyperhomocysteinemia has been reported in the test results in cases of thromboembolic

complications in IBD patients. In our study [39], folate deficiency-related

hyperhomocysteinemia was found in one UC patient with severe cerebrovascular accident.

Gonera et al. reported cerebral venous thrombosis and deep vein thrombosis associated with

mild hyperhomocysteinemia in a 30-year-old woman with recently diagnosed ulcerative

colitis [82]. Slot et al. [83], described a case of folate deficiency-related

hyperhomocysteinemia in a 33-year-old woman with Crohn’s disease who presented with

ischemic spinal cord injury due to thrombosis of the distal aorta during a relapse of the

disease. Moreover, in another case [84] severe massive pulmonary embolism was described

in a young man with ulcerative colitis and laboratory investigation revealed

hyperhomocysteinemia due to folate and vitamin B12 deficiency. In addition, Younes-Mheni

et al. [85], reported a case of large-artery stroke in a 39-year-old woman with Crohn’s disease

due to vitamin B6 deficiency-induced hyperhomocysteinemia. Finally, Kao et al. [86]

described 4 pediatric patients with ulcerative colitis and cerebral sinovenous thrombosis.

Increased homocysteine levels were found in one patient.

Recently, Papa et al. [87] reported that elevated serum homocysteine was an important

factor associated with increased intima-media thickness of the wall of the common carotid

artery in IBD patients.

Increased homocysteine levels have also been observed in colonic mucosa of patients

with inflammatory bowel disease [88]. In a recent study, Danese et al. [89] observed

increased levels of homocysteine both in plasma and intestinal mucosa in IBD patients.

Increased levels of homocysteine contributed to mucosal microvascular inflammation through

activation of the endothelium.

Studies indicate that 20% of dietary methionine is metabolized in the gastrointestinal

tract. The gastrointestinal tract accounts for ~25% of whole body transmethylation and

transsulfuration and is a site of homocysteine release to the systemic circulation. It is possible

that a fraction of the increased circulating homocysteine levels in IBD patients may be due to

increased intestinal synthesis [90]. Further studies are needed to investigate the association

between the serum and mucosal homocysteine, the folate status and the inflammatory injury

in patients with inflammatory bowel disease.

Folate and Colorectal Carcinogenesis in IBD Patients

Research data from the past decade provided evidence that folate status may be involved

with the development and prevention of several malignancies, including cancer of the

colorectum, lungs, pancreas, esophagus, stomach, cervix, and breast, as well as

neuroblastoma and leukemia [91,92]. Overall, research data suggest an inverse association

68 Petros Zezos and Georgios Kouklakis

between folate status and the risk of these malignancies [91,92]. The role of folate in

carcinogenesis has been best studied for colorectal cancer [92-95].

Folate and Ulcerative Colitis-Associated Colorectal Carcinogenesis

Patients with chronic ulcerative colitis have a grater risk of developing colorectal cancer

than the general population [96]. In a recent meta-analysis of all published studies reporting

the colorectal cancer risk in ulcerative colitis patients, Eaden et al. reported that the risk for

any patient with ulcerative colitis is 2% at 10 years, 8% at 20 years, and 18% after 30 years

of disease [97]. Increased extent and longer duration of the disease are known risk factors for

the development of dysplasia and colorectal cancer in UC patients [98-100].

Epidemiological data have shown an inverse relationship between dietary folate intake

and sporadic colorectal cancer [101-103]. Although there is no direct evidence to link any

dietary factor and cancer risk, folate deficiency, which is common in UC patients, may be

implicated in the development of dysplasia and colorectal cancer in these patients. Lashner et

al. [104] first reported that individuals with long-standing ulcerative colitis and taking folate

supplementation had 62% lower incidence of colorectal dysplasia and cancer compared with

those not receiving folate supplementation. In another study by Lashner et al., the risk of

colorectal dysplasia and cancer was found to be significantly decreased by 18% for each 10

ng/ml increase in red blood cell folate concentrations in patients with ulcerative colitis [105].

Moreover, in a recent study, folic acid supplementation had an inverse dose-dependent

relationship with the risk of colorectal neoplasia in subjects with longstanding ulcerative

colitis [106]. These studies suggest an inverse relationship between folate status and the risk

of ulcerative colitis-associated colorectal cancer. There are currently no placebo-controlled

studies of folate supplementation in the prevention of ulcerative colitis-associated cancer.

Studies with animal models of colorectal dysplasia and cancer associated with ulcerative

colitis (interleukin-2 and β2- microglobulin deficient mouse) [107-110], have shown that

dietary folate supplementation at four times the basal dietary requirement significantly

suppresses colorectal carcinogenesis associated with ulcerative colitis in this model [107].

Carcinogenic Effects of Folate Deficiency

Folate is an essential cofactor for purine and pyrimidine metabolism and plays and

important role in DNA synthesis and cellular proliferation (Figure 2). Folate is also a critical

factor for DNA methylation (Figure 2), which is important epigenetic determinant in gene

expression, in the maintenance of DNA integrity and stability, in chromosomal modifications

and in the development of mutations. [91,92,111-115].

Accumulating evidence from in vitro, animal and human studies indicates that folate

deficiency is associated with DNA damage though many mechanisms (DNA strand breaks,

impaired DNA repair, altered DNA methylation and increased mutations) (Table 3), that

contribute to colorectal cancer development, and that folate supplementation can correct

some of these folate deficiency-induced defects [91,92,111-115].

Nutritional Issues in Inflammatory Bowel Disease… 69

Figure 2. Folate metabolic cycle involving DNA synthesis and methylation.

Table 3. Potential mechanisms of the folate deficiency-mediated colorectal cancer

development

1. Aberrant genomic and site specific DNA methylation

 Deactivation of tumor suppressor genes

2. Altered DNA methylation (hypomethylation) and cellular proliferation

 Increased gene expression

 DNA strand breaks, acquisition of mutations

 Proto-oncogene activation

3. DNA damage, nucleotide pool imbalance (uracil misincorporation)

4. Increased mutagenesis

5. Abnormal apoptosis

6. MTHFR polymorphisms ( thermolabile variant C677T) and related gene-nutrient

interactions

Impact of other Micronutrients in Colorectal Neoplasia

Some other members of the “vitamin B complex”, that participate in folate metabolism

play also role in DNA stability. The vitamin B12 is a cofactor for methionine synthase and

hence is a critical modulator of cellular methylation status. Riboflavin is also an important

cofactor for the MTHFR enzyme (Figure 2). Recently it has been demonstrated that

riboflavin binds with lower affinity to the MTHFR thermolabile variant (TT variant, C677T

mutation) and that riboflavin deficiency further impairs the functioning of this enzyme

[116,117]. Therefore, low riboflavin levels might accentuate the metabolic defect in MTHFR

thermolabile variant carriers, whereas high riboflavin levels might minimize the defect.

70 Petros Zezos and Georgios Kouklakis

The vitamin B12 and riboflavin levels were not measured in the majority of studies and

therefore their impact on the risk of developing colorectal cancer cannot be estimated. Future

studies in this area will have to address both the genetic and micronutrient factors (folate,

ideally colonic epithelial levels, vitamin B12, and methionine levels among others) involved

in folate metabolism to unravel the relative importance of each element.

A number of studies have suggested an increased risk of colorectal cancer in patients

with Crohn’s colitis [118,119,120], but few data exist about the factors that increase the risk

of dysplasia and colorectal cancer in Crohn’s colitis patients [121-125]. Although the risk of

colorectal neoplasia appears to be of the same magnitude in UC and Crohn’s colitis and the

“vitamin B complex” deficiencies are frequent in both diseases, we found no data about the

role of folate and the other members of the “vitamin B complex” in colorectal cancer

development in patients with Crohn’s disease affecting the colon. Future studies concerning

with the role of nutritional factors in colorectal neoplasia development should include

patients with Crohn’s colitis.

Clinical Syndromes Related to Deficiencies of the other Members of the

“Vitamin B Complex” (Except Folate and B12)

There are some rare cases in the literature reporting syndromes due to deficiencies of

water-soluble B vitamins in IBD patients, resembling beriberi (thiamine) [126], pellagra

(nicotinic acid) [127,128], or photophobia with dermatological changes (riboflavin) [129-

130].