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Crohn's Disease- Pathophysiology and Conventional and Alternative Treatment Options
Nutrient Deficiencies in Crohn’s Disease
A variety of nutrients have been found to be deficient in Crohn's Disease patients. Causes include malabsorption in the small intestine, increased nutrient need because of disease activity, low nutrient intake, nutrient loss due to chronic diarrhea or increased transit time, or effect of medications. Several studies have examined the specific nutrient deficiencies associated with Crohn's Disease.
Studies Examining Multiple Nutrient Deficiencies
A study measured serum, blood, and red blood cell levels of various nutrients in 24 Crohn's Disease patients and 24 healthy controls. Crohns Disease patients demonstrated significantly lower levels of vitamins A and E, thiamin, riboflavin, pyridoxine, and folic acid compared to controls. Blood levels of pantothenic acid were significantly higher in Crohn's Disease patients, and there were no statistically significant differences in levels of vitamins B12 and C, nicotinic acid, and biotin. No differences were noted on the basis of disease activity, duration, or location.163
Another study examining multiple nutrient deficiencies found 85 percent of 279 Crohn's Disease patients had deficiencies. Nutrients most frequently found deficient were iron and calcium, with zinc, protein, vitamin B12, and folate deficiencies noted less frequently.164
Nutrient status, body composition, and dietary intakes were analyzed in 32 Crohn's Disease patients with longstanding disease in remission and compared to 32 matched controls. Regarding body composition, bone mineral content was significantly lower in patients; percent body fat was significantly lower in male Crohns Disease patients. Patients had significantly lower dietary intakes of fiber and phosphorus, while no other nutrient intakes were significantly different. Serum levels of beta-carotene, vitamins C and E, selenium, magnesium, and zinc, and glutathione peroxidase activity were also significantly lower in patients than controls. As noted in a previous study, there was no correlation between nutrient status and duration of disease or extent of bowel resection.165
These same researchers conducted a study with the same design on newly diagnosed patients with IBD, 23 with Crohn's Disease. Even at diagnosis, bone mineral content was significantly lower in patients compared to controls. While all nutrients tested demonstrated slight decreases in patients, only Vitamin B12, serum albumin (a reflection of protein status), and glutathione peroxidase activity (a reflection of antioxidant status) were significantly decreased.166 These two studies seem to indicate that, although nutrient status is negatively impacted at the time of diagnosis, longstanding disease increases the extent of derangement.
A study published by the American Dietetic Association examined the effect of dietary counseling on nutrient status in Crohn's Disease. Subjects (n=137) were randomly assigned to one of two groups. The treatment group received dietary counseling monthly for six months, while the control group received no counseling. Iron, vitamin B12, and folate levels were found to be low in a significant portion of patients, with no significant differences between groups at study onset. Although dietary counseling was associated with normalization of serum folate and total iron binding capacity and moderate increases in intakes of vitamin B12, folic acid, and iron, the laboratory values as reflection of nutrient status did not change significantly.167
Vitamin D Status in Crohn’s Disease
A study of young Crohns Disease patients (ages 5-22) found low vitamin D (defined as serum concentrations of 25-hydroxyvitamin D < 38 nmol/L) in 16 percent of 112 subjects. Interestingly, the low levels did not significantly correspond to low bone mineral density (BMD) or dietary intakes. Factors associated with hypovitaminosis D included winter season, African-American ethnicity, extent of glucocorticoid medication, and disease confined to the upper gastrointestinal tract.168
Levels of serum vitamin D considered "low" have been inconsistent from study to study. Another study considered low plasma 25- hydroxyvitamin D to be less that 12 nmol/L. In this study, plasma vitamin D levels were examined in 37 Crohn's Disease patients and levels were found to be significantly lower in patients with active disease compared to those with inactive disease.169
Studies on vitamin D status have also examined active vitamin D levels. Recent research found circulating levels of 1,25-dihydroxyvitamin D were high in a large percentage of Crohn's Disease patients (42 percent of 138 subjects) compared to UC patients (seven percent of 20 Ulcerative Colitis patients) and were positively associated with disease activity. Low levels of 25-hydroxyvitamin D result in low serum calcium that in turn stimulates parathyroid hormone and a subsequent rise in 1,25- dihydroxyvitamin D levels to enhance calcium resorption from bone. High levels of active vitamin D were associated with significantly lower BMD in Crohn's Disease patients compared to Ulcerative Colitis patients, independent of glucocorticoid use. The researchers examined colonic biopsies of patients with Ulcerative Colitis and Crohn's Disease and found higher levels of 1alpha-hydroxylase in Crohn's Disease mucosa. This enzyme converts 25-hydroxy- to 1,25-dihydroxyvitamin D. Thus, it appears over-expression of this enzyme in the inflamed mucosa may be a cause of low BMD in Crohn's Disease.170
Vitamin K in Crohn’s Disease
Serum vitamin K status was assessed in 32 Crohn's Disease patients and compared to reference ranges from 384 healthy controls. Levels were significantly lower in Crohns Disease patients. Vitamin K is a cofactor for carboxylation of the protein osteocalcin, necessary for calcium binding to bone. Thus, deficiencies of vitamin K can contribute to osteoporosis and measurements of free osteocalcin (uncarboxylated) reflect bone-vitamin K status. Levels of free osteocalcin were higher in Crohn's Disease patients, while binding capacity of osteocalcin to hydroxyapatite was lower. High levels of free osteocalcin were associated with low BMD in the lumbar spine.171
Water-soluble Vitamin Deficiencies
As discussed previously, deficiencies of vitamins B6 and B12 and folate in Crohns Disease have been associated with increased homocysteine levels. Deficiencies may be associated with impaired absorption or decreased dietary intake. A study of folate absorption in patients with Crohn’s disease compared 100 patients with 20 healthy controls. Serum folate levels were assessed after a loading dose of folate and deemed normal in the 20 healthy subjects but in only 75 percent of the Crohn's Disease patients. Of the 25 patients with impaired folate absorption, nine demonstrated almost no increase after an oral dose, while 16 experienced an increase but still below normal.172 In addition to impaired absorption, Crohn's Disease patients frequently have diets devoid of fresh leafy green vegetables and fruits -- dietary sources of folate -- because of fear that these foods will exacerbate symptoms.
Several older studies focused on vitamin C status in Crohn's Disease. A 1986 study of 137 patients with Crohn's Disease found low serum ascorbate levels in 11 percent of males and 37 percent of females; leukocyte ascorbate levels were low in 26 percent of males and 49 percent of females. The deficiencies were not associated with disease activity. In this study the deficiencies were due in part to low intake and were remedied by diet counseling.173 Leukocyte ascorbate levels were found significantly lower than controls in two other studies. 174,175
Two studies examined ileal tissue levels of vitamin C. The 1974 study found depressed tissue levels of ascorbate in Crohn's Disease patients with fistulas compared to Crohn's Disease patients without fistulas or healthy controls.176 The 1987 study found tissue ascorbate levels higher in both fistulizing and nonfistulizing Crohn's Disease patients compared to controls. However, the levels in the patients with fistulas were significantly lower than Crohns Disease patients without fistulas. The authors speculate ascorbate is concentrated in the tissues because of vitamin C importance in collagen formation. Those subject to fistulas appear to be less efficient at mobilizing ascorbate.177 One of the researchers conducted a subsequent study and found absorption of vitamin C was not impaired in either fistulizing or nonfistulizing Crohn's Disease patients compared to controls.178
Fat-Soluble Antioxidants: Vitamin A, Vitamin E, and Carotenoids
As mentioned previously, oxidative stress plays a significant role in the pathogenesis of Crohn's Disease and several antioxidants, including vitamins A and E, have been found to be low in Crohn's Disease patients. Studies support the contention that vitamin E,179 vitamin A,180,181 and a combination of vitamins E and A,182 are low in Crohn's Disease patients. Low vitamin A appeared to be associated with low protein that contributes to a deficiency of retinol binding protein,181 and both A and E were normalized when active disease was brought under control.182
Carotenes, precursors to vitamin A, have been shown to be low in the Crohns Disease population. A 1987 study examining vitamin A/carotene levels over a six-month period in 137 Crohn's Disease patients (70 percent with inactive disease) found normal vitamin A status in all patients, while 20-25 percent of patients demonstrated low total serum carotenoids. 183 A more recent study confirms low serum vitamin A and carotenoid (zeaxanthin, alphaand beta-carotene, and lutein) levels in Crohn's Disease patients compared to controls.184
Several studies note zinc deficiencies are common in Crohn's Disease. A study of 54 Crohn's Disease patients found significant deficiencies in serum zinc, vitamin A, and retinol binding protein levels compared to healthy controls. Zinc levels decreased in accordance with disease activity, patients with active disease having significantly lower levels than those with inactive disease. Zinc deficiency is associated with impaired metabolism of retinol binding protein, resulting in a vitamin A deficiency.185
Other researchers have corroborated the tendency of zinc deficiency to parallel disease activity in Crohn's Disease. A small study compared five patients with active Crohn's Disease to five patients with inactive disease and found serum zinc levels significantly lower in those with active disease. Furthermore, low zinc levels seemed to be due to increased body clearance, rather than malabsorption. Reasons for the increased zinc clearance were not pursued.186
Another study found serum zinc levels deficient (defined as 75 mcg/dL) in 17 of 50 Crohn's Disease patients (34%). Low zinc levels were associated with an increased tendency toward fistula formation, with 65 percent (11/17) of Crohn's Disease patients with low zinc levels experiencing fistula formation. 187 Thus, both low zinc and vitamin C levels have been implicated in a tendency toward fistula formation in Crohn's Disease patients.
Colonic mucosal biopsies of tissue from Crohn's Disease patients found abnormally low levels of zinc from uninflamed but not from inflamed tissue.188 Increased levels in involved tissue may be due to the need for more zinc as a co-factor for superoxide dismutase.
Other Trace Mineral Deficiencies
Serum levels of copper, zinc, and selenium were examined in 47 Crohn's Disease patients and compared to 123 healthy controls. The patients had significantly lower selenium and higher copper levels than controls,189 supporting the premise of increased oxidative stress in the pathogenesis of Crohn's Disease. There were no differences in serum zinc concentrations between patients and controls. A similar study examined children with Crohn’s disease (n=36) and found significantly lower levels of selenium, copper, and zinc compared to controls.190
Iron Levels in Crohn's Disease: A Double-edged Sword
Iron Deficiency is common in Crohn's Disease and is thought to be due to decreased dietary intake or chronic gastrointestinal bleeding. Lomer et al investigated the seven-day diet diaries of 91 Crohn's Disease patients in remission compared to 91 controls. Only 32 percent of Crohns Disease patients compared to 42 percent of controls consumed the recommended daily intake of iron. Patients tended to eat less fiber and iron-fortified cereal than controls.191
Supplementation with iron, however, may not be a prudent recommendation in Crohn’s disease because it can exacerbate intestinal inflammation and contribute to oxidative stress. While circulating iron may be decreased in patients with IBD, mucosal levels may actually be increased.192 A small study examined the effect of 120 mg/day ferrous fumarate in 10 patients with Crohn's Disease (eight with active disease; nine with iron deficiency anemia) compared to controls. Assessment after one week found eight of 10 patients experienced gastrointestinal side effects of diarrhea; the opposite effect occurred in the control group - fewer stools. Seven of 10 patients experienced increased abdominal pain and six of 10 reported nausea, compared to none in the control group. After one week of ferrous fumarate supplementation, levels of reduced cysteine and glutathione (endogenous antioxidants) were significantly decreased in patients.193
Table 6 summarizes the nutrient deficiencies associated with Crohn's Disease.
Due to extensive side effects associated
with conventional medications and significant
nutrient deficiencies in Crohns Disease, the effort to maintain
remission with dietary changes, nutrients, and
botanicals should be considered.
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