Nutritional concerns in pediatric inflammatory bowel disease

1. Cytokines

Retardation of growth and delayed pubertal development are one of the major nutritional issues in the children and adolescents with IBD, especially with CD. The main factors inducing these problems are poor nutritional conditions, the severity of the disease itself, genotype and the most important things; various cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β2). The presence of pro-inflammatory cytokines, secreted from the inflammation sites, interferes linear growth of the patients. Among the numerous cytokines, TNF-α has a core role in the cytokine-associated growth retardation 345). The effect upon growth is more aggressive as the severity of the disease itself is more fulminant and aggravated. It is documented when we see treatment with anti-TNFα improves patient's growth as well as clinical problems6).

This problem is more noticeable in the patients of CD. The patients with CD already show decreased growth velocity far before the diagnosis of CD, and become large burden to their parents and their doctors.

2. Nutritional deficit

The symptoms of IBD between children and adults are all the same but the distinctive delayed growth. In the adults the growth is already completed and does not matter of linear growth, even though sometimes severe status accelerates weight loss. Contracting IBD before full growth let the patient have poor appetite due to gastrointestinal (GI) symptoms, avoid well-eating and suffer from nutritional loss through the GI mucosa despite enough nutrient intake. So pediatric IBD patients show delayed growth. Furthermore, their developmental velocities are also retarded, and make them look younger than their peers. During active stage of CD, protein-losing enteropathy, mucosal hemorrhage, fistula, and hepatopathy result in hypoproteinemia. Chronic mucosal hemorrhage causes iron deficiency, and severe diarrhea induces electrolyte (potassium, magnesium) loss, and zinc deficiency, which in a cascade incur another GI problems of aggravated diarrhea, decreased immunity, and decreased tissue integrity7).

Patients with IBD showed increased energy requirements and decreased energy expenditure, especially in the active status. With these reasons, 85% of CD patients, and 65% of ulcerative colitis (UC) already have weight loss at the time of initial diagnosis8).

Those nutrient-associating problems in CD children may result in growth hormone (GH) resistance. They show decreased lean body mass with circulating IGF-I decrease9). Poor oral intake and malnutrition are related with acquired GH resistance at the site of GH receptor, and deficient serum nutrients conduct a GH-independent stimulatory effect on the height growth10).

3. Severity of disease

Even though their nutritional intake is enough, growth may be threatened by the disease severity, the loci of the active disease, pharmacologic agents. The usual activity index such as C-reactive protein (CRP) which reflects a short-term phenomenon does not give enough information concerning the severity itself in the chronic complicating diseases11).

The severity of disease was documented to be the impactful indicator to predict retarded growth. The patients with higher pediatric CD's disease activity index (PCDAI) score12) grow more slowly than those with lower score.

4. Pharmacologic agents

Corticosteroid therapy may be the direct cause of poor growth when it is used for long term. Glucocorticocoids directly inhibit the chondrocytes of bony growth plate. But short-term therapy is not directly related with growth retardation. The height of the patient is already low at the time of first diagnosis. And disease complications such as fistula also cannot be a reason of poor growth13).

In the large study of Griffiths et al14), the effect of corticosteroids on linear growth was weaker than the effect by disease severity, and they emphasized that major risk factor for growth retardation is disease severity.

These complicated problems of growth and development bother the patients even more than the clinical difficulties.

1. Protein in IBD

The indirect index of protein-energy efficiency is kidney function, increase of body weight, biochemistry laboratory data, and acute phase reactant. Weight-for height explains the acute condition, while height-for-age suggests chronic status. Weight velocity and height velocity are very efficient indices for body growth. The indices which explain the quantitative status of protein are total protein, albumin, prealbumin, transferrin, retinol-binding protein. The qualitative examinations to evaluate the disease activities of IBD are acute phase reactant proteins such as α1-, α2-macroglobulin, transferrin, CRP, complements, and erythrocyte sedimentation rate.

Physicians need to measure weight, height, and monitor the above mentioned laboratory tests to assess the current disease activity and nutritional status.

2. Fat intake in IBD

The patient who suffers from IBD in the ileum or has undergone operation ileectomy requires low fat diet. Medium-chain triglyceride is helpful for the patient with steatorrhea. Fish oil is also effective for the prevention of relapse. A research performed in high risk patients of CD showed that supplementation of enteric-coated fish oil for one year prevented relapses in 59%, compared with 26% in the placebo group (P=0.003)21). The effect of fish oil on UC is still controversial22).

It is an important concern to know what oil is more helpful. High-fat meals rich in n-6 polyunsaturated fatty acids (PUFA) reportedly accelerate bacterial overgrowth but deplete microbes from Bacteroidetes and Firmicutes phyla. Fish oil supplementation (n-3 PUFA) recovered microbiota and inflammatory cell infiltration and accentuated regulatory T-cell recruitment. These findings suggest that n-6 PUFA-rich diet may induce dysbiosis and gut inflammation in aged mice, while fish oil supplementation together with an n-6 PUFA diet can down-regulate dysbiosis2324).

Trans fatty acids (TFA), known as major causes of metabolic syndrome, negatively affect IBD development and aggravation. Cytokine expression from the lesion sites is higher in lipopolysaccharide-stimulated cells exposed to TFA. It exacerbates colonic inflammation by inducing Th₁₇ polarization and by up-regulating the pro-inflammatory cytokines from the affected mucosa2526). Accordingly, patients with IBD should avoid TFA-containing foods such as fried and instant foods.

3. Micronutrients and minerals in IBD

IBD patients are prone to be deficient in water-soluble vitamins as well as lipid-soluble vitamins. They are on low-fiber, low-residue diet during active stage. In that case water-soluble vitamins are deficient. If the lesion is within the ileum, a vitamin B₁₂ deficiency follows. After small intestine surgery or if a small intestinal lesion is severe, vitamin D, calcium, magnesium, phosphorus, and iron are more likely to become deficient.

Micronutrient deficiency are caused by insufficient intake due to the disease itself, acute or chronic GI mucosal loss, and as a side effect of some drugs. Sulfasalazine (SSZ) inhibits the absorption of folate, corticosteroids suppress the absorption of calcium, and cholestyramine interrupt the absorption of lipids and lipid-soluble vitamins.

As such, physicians recommend the use of elemental formula rather than a general diet to patients with severe disease or acute-onset status.

Folate is absorbed in the small intestine and stored in the liver. The storage period is several months, so folate-rich food intake is recommended. Patients with small intestine diseases are prone to folate deficiency, which may also be induced by drugs as SSZ and methotrexate (MTX). SSZ is a potent inhibitor of reduced folate carrier, the dominant cell membrane transporter for natural folate27). MTX is predominantly in its polyglutamated form with scarce of hepatic folate storage 28). Folate is important in human body because it synthesizes DNA, repairs DNA, methylates DNA, and acts as a cofactor in certain biological reactions; accordingly, it prevents the development of colon cancer in patients with UC29). Daily requirement of folate in normal adult is 50 µg per day, while patients with IBD require 6-8 times that amount.

Vitamin B₁₂ is synthesized in the ileum. Deficiencies occur in approximately 20% of patients with CD30). If the lesion is in the ileum or the patient underwent ileectomy, deficiency is more likely to occur. Periodic intramuscular injections are required if the patient is too severely affected to acquire sufficient nutrition via oral intake31).

Vitamin B₆ may become deficient in patients with CD, followed by deficiencies of vitamin B₁, vitamin B₂, and pantothenic acid.

Vitamin C deficiency is common in IBD. Vitamin C is a strong antioxidant. During the initial severe clinical stage, patients are recommended to follow low-residue diet and eat fewer vegetables and fruits, making them prone to vitamin C deficiency. Vitamin C protects intestinal mucosa from inflammation. Vitamin C deficiency is suspicious in patients with ano-enteral fistula32).

Vitamin A deficiency is uncommon, but may occur if the lesion site is within the small intestine. Vitamin A deficiency leads to impairment of night vision. Beta carotene, precursor of vitamin A is a representative antioxidant.

Vitamin D deficiency is common in patients with CD. Poor absorption of lipids, deficiency of bile juice, and ileal surgery in patients with CD even more cause the deficiency. In this case, growth retardation and osteoporosis are noticed especially in CD rather than UC. Bone fractures sometimes occur in pediatric patients with CD treated with corticosteroid therapy33).

Vitamin E also may be deficient in patients with IBD, which delays healing of the mucosal lesions.

Vitamin K, which is produced in the small intestine, is commonly deficient in patients with CD as well as those with UC. The major causes of this deficiency are impaired absorption and antibiotic therapy34).

Zinc deficiency, caused by poor absorption or hypoalbuminemia is sometimes recognized in patients with CD. This deficiency is responsible for some disease manifestations such as malaise, poor wound healing and rashes inducing anorexia, decreased GI absorption or increased GI loss35). A research report showed that there is a correlation between zinc and vitamin A and the disease activity score (PCDAI), and a weaker correlation with serum proteins to this score. No correlation was found with vitamin B₁₂ absorption, disease localization, or previous ileal resection36).

Calcium supplementation is required as well. Deficiency is caused by not only decreased dietary intake but also hypoalbuminemia induced by the disease itself or medication like MTX. Calcium deficiency is not apparent at the early stage of diagnosis, but as the disease progress, the deficiency can develop. Vitamin D enhances calcium absorption in the intestine, so the intake of these two nutrients is helpful. The daily requirements for patients with IBD are 1,200 mg of calcium, and 1,000 IU of vitamin D, which are beyond the daily requirements of average normal adults37).

Magnesium may also be deficient, symptoms of which include muscle spasm and bone pain. In IBD, magnesium deficiency is caused by small intestine surgery, malabsorption, and mucosal loss.

4. Micronutrient to be alert

Iron deficiency, the most common micronutrient deficiency in patients with IBD, caused by mucosal hemorrhage, anorexia, and malabsorption. A recent study showed that the oral supplementation of iron increases oxidative stress and aggravates the mucosal inflammation38). Iron deficiency prevents CD-like ileitis by altering the gut microbiota39). As such, supplementation via intravenous route with decreased oral dose amount is desirable in the very acute stage.

Choline and carnitine, which are sufficient in red meat and eggs, comprise major components of cell membrane and have a pivotal role in synthesizing very low density cholesterol in the liver. If their levels become depleted in an obese person, fatty liver disease can easily develop40). In a patient of acute ulcerative colitis the intraepithelial choline level is lower than that of remission state patients41). However, it is still to be determined whether choline deficiency plays a role in the development of experimental colitis and human IBD. It is believed that red meat can alter or aggravate ulcerative colitis. Until now there is no evidence to resist this opinion. Intestinal microbial choline metabolism may be linked with IBD. Germ-free mice do not produce increased timethylamine-N-oxide (TMA) when on a high-choline diet. Interestingly, IBD patients are tend to be at increased risk of cardiovascular disease. Recent study showed that IBD is associated with increased levels of urinary TMA, which is indicative of enhanced choline metabolism and decreased choline bio-availability42). So these patients are recommended to be monitor their intake of this nutrient.