Anemia, Refractory Iron Deficiency In Childhood (Unresponsive To Iron)

What Is Refractory Iron Deficiency Anemia In Childhood?

[dropcap]R[/dropcap]efractory iron deficiency anemia (IDA) is a microcytic (small cell) type anemia.

It is characterized by formation of abnormally small, pale red blood cells and iron depletion, or inadequate iron content in the body, that does not respond to prescribed treatment with oral iron supplementation as expected.

Q: How is iron content in the body determined?

A: Iron content in the body is determined by measuring the ferritin level in blood. Ferritin is a protein within cells that stores iron and releases it as needed.

According to the World Health Organization (WHO) mild anemia corresponds to a hemoglobin (Hb) of  9.5 g/dL, moderate anemia to a Hb of  8 g/dL but less than 9.5 g/dL, and severe anemia to a Hb of less than 8.0 g/dL.

What Is Refractory Iron Deficiency Anemia In Childhood In Celiac Disease and/or Gluten Sensitivity?

• Refractory iron deficiency anemia in childhood is a classic symptom of celiac disease and is a common presenting feature of untreated celiac disease.
• A pediatric study evaluating the effect of iron supplementation, in addition to a gluten free diet, on the blood profile of children with celiac disease demonstrated that iron deficiency anemia is commonly associated with celiac disease and the iron deficiency state continues a long time even after excluding gluten from the diet and iron supplementation.¹
• Researchers found that an abnormal level of ferritin (iron) present in blood indicating iron deficiency does not correspond to the degree of damage present in the small intestinal lining (villous atrophy) caused by celiac disease. That is, low iron stores can develop in children with any degree of villous atrophy, from minimal to extensive.
• Furthermore, in follow-up evaluation of iron deficient children on a gluten free diet, the average hemoglobin levels were comparable with healthy children (controls), but they (subjects) continued to have abnormally small blood cells, lower blood iron levels and higher than normal total iron binding capacity (TIBC) results. TIBC is a blood test to see if there is too much or too little iron in the blood. Iron moves through the blood attached to a protein called transferrin. This test indicates how well that protein can carry iron in the blood.²
• Celiac disease patients with anemia had more severe disease than those without anemia. When compared with celiac disease patients without anemia, those with anemia had significantly longer duration of symptoms, lower albumin levels, and higher anti-tissue transglutaminase fold rise, and a higher proportion had abnormal d-xylose tests and severe villous abnormalities.³
• A questionnaire study investigating screening practices for celiac disease in patients with iron-deficiency anemia (IDA) because no screening guidelines exist in the literature found that practicing hematologists infrequently screen for celiac disease in IDA. Only 8.6% believed all patients with IDA should be screened for celiac disease. Physicians who have recently finished their fellowship, those who see a high volume of patients with IDA, and those who saw predominately pediatric patients with IDA are more likely to screen for celiac disease.⁴

How Prevalent Is Refractory Iron Deficiency Anemia In Childhood In Celiac Disease and/or Gluten Sensitivity?

• The prevalence of iron deficient anemia was 81.6% of 109 pediatric patients at diagnosis of celiac disease.⁵
• Refractory anemia may be the sole presentation in children with subclinical celiac disease, meaning before the appearance of intestinal symptoms.⁶
• A retrospective study of children diagnosed with non-diarrheal celiac disease observed a prevalence of 43.2% with persistent anemia.⁷

What Are The Symptoms Of Iron Deficiency Anemia In Childhood?

Refractory iron deficiency anemia in childhood is marked by these features:

• Pallor or  paleness of skin and mucous membranes.
• Fatigue.
• Drowsiness.
• Weakness.
• Irritability.
• Loss of appetite.
• Anxiety.
• Dyspnea (shortness of breath) on exertion, such as running.
• Mental sluggishness or apathy.
• Reduced memory/learning.
• Negativity.
• Inability to pay attention.
• Headache.
• Visual impairment (blurry).
• Alopecia (loss of hair).
• Dry and dull hair.
• Increased susceptibility to infection.
• Systolic heart murmur may develop.

How Does Refractory Iron Deficiency Anemia Develop In Celiac Disease and/or Gluten Sensitivity?

• Refractory iron deficiency anemia in childhood results from malabsorption of iron from the small intestine in celiac disease.
• Study of ferrokinetics has shown that an anemia was caused by deficiency in many elements with preponderence of iron-deficiency erythropoiesis (blood cell production).
• The most sensitive and reliable indicators of early detection of latent anemia without decrease in hemoglobin level were ferritin content, the coefficient of saturation of transferrin and transferrin’s receptors.⁸

Does Refractory Iron Deficiency Anemia Respond To Gluten-Free Diet?

Yes. Iron deficiency anemia in celiac disease responds slowly to gluten free diet containing iron and folic acid supplementation.⁹

• [dropcap]1[/dropcap]Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

[box type=”shadow” ]Treatment. This condition responds to the complete elimination of gluten, which is the required treatment that improves both anemia and gut health.

• Gut health is the foundation to restore ALL health.
• A strict gluten free diet means removing 100% of wheat, barley, rye and oats from the diet.
• Cutting out bread and other obvious sources of gluten is not good enough for recovery. Even 1/8th teaspoon of flour or bread crumb is enough to sustain the inflammation that is damaging the small intestine, causing increased permeability (leaky gut) and allowing undigested gluten to enter the body where it can damage structures and function, and instigate immune inflammatory responses.

Correct Individual Nutritional Needs.

• Serve foods that can replenish missing nutrients. Find them under NUTRIENT DEFICIENCIES.
• Take nutritional supplements as needed. Find them under NUTRIENT DEFICIENCIES.

Recovery. The child should begin to feel better within a week and notice more energy as inflammation subsides and the  absorbing cells that make up the surface lining of  the small intestine are better able to function.

• Intestinal lining cells are replaced every 5 days. The healing process is like sunburn where the damaged surface layer of skin sloughs off and is replaced with new normal cells.
• Leaky gut normally resolves in two month after starting a gluten free diet and brings about a big improvement in health. Improvement in intestinal permeability precedes morphometric recovery (cell appearance and structure) of the small intestine in celiac disease.¹⁰
• The intestinal lining may take up to a year to heal.[/box]

• [dropcap]2[/dropcap] Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from the child’s diet to reduce an additive effect to gluten. At the same time, try to serve foods that reduce inflammation (anti-inflammatory).

[box type=”shadow” ]Here Are Major Inflammatory Food Types:

• Damaging Foods. In susceptible persons, includes corn, dairy (cow), and soy. Lactose, the sugar in any animal milk disrupts intestinal permeability causing leaky gut.¹¹
• Allergenic Foods. Includes foods that trigger the immune sytem to produce IgE antibodies. Allergy testing is the usual way to discover these offending foods.
• Shelf Stable Processed Foods. Includes any that contain additives and preservatives. Look for them on the nutrition label of the box or package. Additives and preservatives also disrupt intestinal permeability causing leaky gut.¹¹
• Bad Fats. Includes deep fried foods, trans-fats, saturated fats (animal fat/butter), and EXCESSIVE omega-6 fatty acid oils like corn oil. Rancid fats, sodium caprate (a medium chain fat), and sucrose monester fatty acid (a food grade surfactant) induce significant disruption of the intestinal barrier that causes leaky gut.¹¹.
• Excessive Refined White Flours (bran layer removed). Includes products made from them such as cookies, bread, cakes, pies. Bran contains the vitamins and minerals that metabolize grains and slows the otherwise rapid entry of sugar from their digestion into the bloodstream. Also disrupt intestinal permeability causing leaky gut.¹¹
• Refined Sugars.  Includes white sugar, corn fructose and high fructose corn syrup.
• Certain Spices. Includes paprika and cayenne pepper which disrupt intestinal permeability causing leaky gut.¹¹[/box]

[box type=”shadow” ]Here Are Important Anti-Inflammatory Food Types to Promote Health:

• Fruits. Contain ample amounts of vitamins, minerals and phytochemicals which are naturally occuring components in plants that detoxify toxins, carcinogens (reducing the risk by 50%) and mutagens.
• Non-Starchy Vegetables. Support intestinal integrity and provide ample amounts of vitamins, minerals and phytochemicals. Includes lettuce, kale, onion, broccoli, garlic, and others.
• High Quality Complex Carbohydrates. Provide vitamins, minerals, phytochemicals, and fiber while boosting serotonin levels to help you relax and feel calm. Includes whole grains, legumes, and root vegetables such as carrots, parsnips, sweet potatoes, turnips, red beets, and others.
• Antioxidants. Protect the body from inflammatory oxidant molecules that continually occur and help us handle stress and reduce irritability. Includes vitamin C-containing foods such as lemon, grapefruit, apricot, Brussels sprouts and strawberries, and others. Also, includes vitamin E-containing foods such as nuts, seeds, avocado, olive oil, and others. Cocoa is good, too.
• Omega-3 Fatty Acids. Balance opposing omega-6 fatty acids and bad fats. Fish sources include tuna, salmon, cod, and others. Plant sources include flax, chia seeds, canola oil, and others.
• Probiotics. Supply normal microbes needed for colon health and health of the body such as these fermented foods: yogurt, kefir, and unpasteurized apple cider vinegar.
• Prebiotics/ High Fiber Foods.  Food with fiber keeps our population of colonic microbes healthy.
• Protective Herbs and Spices.  See below #6 for examples such as ginger.[/box]

• [dropcap]3[/dropcap] Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• [dropcap]4[/dropcap] Manage Your Medications Safely: 

[box type=”shadow” ]Certain  medications can cause nutritional deficiencies. Ask the doctor or pharmacist about this possible adverse effect of these drugs below if using. For example, children with headaches could be given aspirin which would make anemia worse. Do not stop prescribed medications without supervision.

This is not a complete listing.

ANTI-INFLAMMATORIES  disrupt intestinal permeability.

•  Aspirin and Salicylates deplete Iron.

ANTACIDS / ULCER MEDICATIONS

• Pepcid®, Tagamet®, Zantac® deplete Iron.
• Magnesium and Aluminum Antacid preparations (Gaviscon®, Maalox®, Mylanta®) deplete Iron.[/box]

• [dropcap]5[/dropcap]Nutritional Supplements To Help Correct Deficiencies:

[box type=”shadow” ]

• Multivitamins.
• Ferrous fumarate or gluconate as prescribed to supply iron. Do not take with other supplements because of interactions.  Always check with your doctor when taking supplements to avoid interactions with medications.

Storage Note for Supplements: Store container tightly sealed, away from heat, moisture and direct light to avoid loss of potency. That is, in a safe kitchen cabinet  – not in the bathroom or on the kitchen table.[/box]

• [dropcap]6[/dropcap]Manage Natural Remedies:

[box type=”shadow” ]Hydration:

• Four to eight glasses of water depending on age of patient are recommended per day unless there is a contraindication such as kidney or heart disease.
• If thirsty, drink water. Add fresh, squeezed lemon to water. Lemon is anti-inflammatory, alkalizing and provides vitamin C.
• Hydration Test: Urine should be pale yellow. Fingertips should be plump, without pruning but this may not be reliable when fingers are swollen with edema. Lips should be plump, without puckering. The feeling of thirst can be unreliable.
• What is wrong with soda? These drinks are dehydrating, increase acid, and deplete nutrients.[/box]

[box type=”shadow” ]Carminatives are plant sources that tone muscle and improve peristalsis, and thus aid in the expulsion of gas from the stomach and intestine to relieve digestive colic and gastric discomfort.

Carminative Food Remedies:

• Raspberry.
• Carrot is also a cleansing digestive tonic.
• Grape is also bile stimulating and a cleansing remedy for sluggish digestion and laxative.
• Redbeets stimulate and improve digestion and are easily digested.
• Cabbage stimulates and improves digestion and is also a liver decongestant.
• Lettuce stimulates and improves digestion and is also an alterative, meaning it improves the function of organs involved with the digestion and excretion of waste products to bring about a gradual change.
• Potatoes are antispasmodic (due to atropine like properties) and a liver remedy.

Carminative Herb Remedies:

• Chamomile (as a tea) also promotes healing and help relieve nervous tension. Drink as a tea.
• Parsley relieves colic, gas and indigestion.
• Rosemary as a tea and in cooking also is a nervous system tonic for stress and fatigue, bile stimulant, and can relieve headaches and indigestion.

Carminative Spice Remedies:

• Cloves are also antispasmodic. and can be used in baking cookies and cakes.
• Ginger also supresses inflammation.[/box]

[box type=”shadow” ]Exercise Helps:

Exercise improves circulation and rids the body of toxins. Any type of play activity is helpful for the child that can be tolerated.

• Walking is aerobic exercise that reconditions the whole body to improve stamina. Read more about Exercise and Fitness.

Note: Exercise is important, but the amount and type of exercise undertaken depends on the child’s health. The first priority is to heal. [/box]

What Do Medical Research Studies Tell About Refractory Iron Deficiency Anemia In Childhood In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“How often do hematologists consider celiac disease in iron-deficiency anemia? Results of a national survey.” This study investigating screening practices for celiac disease in patients with iron-deficiency anemia (IDA), which is a common presentation of celiac disease, because no screening guidelines exist in the literature found that practicing hematologists infrequently screen for celiac disease in IDA. Physicians who have recently finished their fellowship and those who see a high volume of patients with IDA are more likely to screen for celiac disease.

A survey was e-mailed to members of the American Society of Hematology to survey hematologists to determine rates of celiac disease screening.
There were 385 complete responses from 4551 e-mails. Most respondents were practicing clinicians (74%), clinical researchers (10%), or laboratory researchers (6%). Specialists in benign hematology accounted for 45% of respondents, oncologists accounted for 33%, and specialists in malignant hematology accounted for 22%. The most common practice types were university-affiliated hospital (43%), private clinic (29%), community hospital (12%), and Veterans Affairs or military hospital (9%).

Only 8.6% believed all patients with IDA should be screened for celiac disease. Respondents who had completed their fellowship within 5 years were more likely than more experienced clinicians to believe that all patients with IDA should receive celiac disease screening. Having a higher volume of IDA patients per month also increased the likelihood of testing. In multivariate analysis, specialists in malignant hematology and oncologists were more likely than specialists in benign hematology to screen all patients for celiac disease, as were those who saw predominately pediatric patients with IDA vs adult patients.¹²

“Presence of anemia in patients with celiac disease suggests more severe disease.” This database study investigating what proportion of celiac disease patients had normal hemoglobin levels and if there were any differences in characteristics of those with and without anemia found that celiac disease patients with anemia had more severe disease than those without anemia.

Of 338 celiac disease patients, 14.8 % had normal hemoglobin levels at diagnosis. When compared with celiac disease patients without anemia, those with anemia had significantly longer duration of symptoms, lower albumin levels, and higher anti-tissue transglutaminase fold rise, and a higher proportion had abnormal d-xylose tests and severe villous abnormalities. Thus, celiac disease patients with anemia had more severe disease than those without anemia. “It is therefore important to diagnose these patients at an earlier stage of the disease even when the classical feature such as anemia is not clinically evident.”³

“Celiac disease presentation in a tertiary referral centre in India: current scenario.” This facility-based retrospective observational study compared the clinical spectrum of nondiarrheal celiac disease  (NDCD) with that of diarrheal/classical celiac disease (CCD) included consecutive patients diagnosed with celiac disease as per modified ESPGHAN criteria from October 2009 to August 2011 found persistent anemia in 43.2%.

A total of 381 patients were diagnosed with celiac disease during the study period. NDCD was present in 192 (51.8 %). NDCD had higher mean age at presentation (5.8 ± 2.8 years vs. 6.9 ± 2.9 years respectively) and longer duration of symptoms prior to diagnosis (2.9 ± 1.7 years vs. 3.6 ± 2.2 years) as compared to CCD.

In the NDCD group, the most frequent gastrointestinal symptoms were recurrent abdominal pain in 122 patients (63.5 %) and abdominal distension in 102 patients (53.1 %) followed by constipation in 48 patients (25 %), vomiting in 76 (39.6 %) and recurrent oral ulcers in 89 (46.4 %). Vomiting and constipation were more frequently seen in NDCD as compared to CCD. Common extraintestinal manifestations in NDCD included failure to thrive in 109 (56.8 %), isolated short stature in 36 (18.8 %), persistent anemia in 83 (43.2 %) and hepatomegaly/splenomegaly or both in 56 (29.2 %).

Associated comorbidities included autoimmune thyroiditis in 11 (5.7 %), type 1 diabetes mellitus in 8 (4.2 %), bronchial asthma in 23 (11.9 %), idiopathic pulmonary hemosiderosis in 4 (2.1 %), Down’s syndrome in 3 (1.6 %), alopecia areata in 6 (3.1 %), polyarthritis in 2 (1.0 %), dermatitis herpetiformis in 6 (3.1 %) and chronic liver disease in 6 (3.1 %).¹³

“Celiac Disease: Presentation of 109 Children.” In this study, retrospective evaluation of clinical and laboratory features of 109 patients with celiac disease to determine presentation and manifestations found a prevalence of iron deficiency anemia in 81.6% of patients. Sixty-six (60.6%) were classical type, 41 (37.6%) were atypical type and 2 (1.8%) were silent type. The mean age was 8.81 ± 4.63 years and the most common symptom was diarrhea (53.2%) followed by failure to thrive, short stature, and abdominal pain. Paleness (40.4%), underweight (34.8%), and short stature (31.2%) were the most common findings.

Iron deficiency anemia (81.6%), zinc deficiency (64.1%), prolonged prothrombin time (35.8%), and elevated transaminase levels (24.7%) were the most common laboratory findings. Eight percent of patients had at least 1 autoantibody, and 28 of 52 patients had low BMD. Four of 38 patients had abnormality in electroencephalograms. The prevalance of selective immunoglobulin (Ig) A deficiency was 9.1%. Abdominal distention, iron deficiency, prolonged prothrombine time, hypoalbuminemia, and elevated transaminase levels were more significantly frequent in the classical type than atypical type.⁵

“Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study.” This study evaluating the effect of iron supplementation, in addition to a gluten free diet, on hematological (blood) profile of children with celiac disease demonstrated that iron deficiency anemia is commonly associated with celiac disease and iron deficiency state continues a long time even after excluding gluten from the diet and iron supplementation.

In the follow-up evaluation of these cases on a gluten free diet, mean hemoglobin levels were comparable with controls but the cases continued to have lower mean MCV (size of blood cells), MCV serum ferritin levels and higher mean TIBC. Seven children had mild anemia. Serum ferritin levels showed a negative correlation with the grade of villous atrophy and lamina propria infiltrate. Apart from offering children a gluten free diet rich in iron, early detection and treatment of IDA (iron deficiency anemia) and prophylactic iron folic acid supplementation will go a long way to optimize mental and psychomotor functions.¹

“Specificity of ferrokinetics in children with enzymopathy of small intestine.” This study investigating 154 children with intestinal enzymopathies, which included 57 with celiac disease, 52 with intestinal enzymopathies and disaccharide deficiency, and 45 with disaccharide deficiency syndrome, demonstrated that the typical changes in blood of children with intestinal enzymopathies were presented in decreasing of MCV, MCH, MCHC and increasing of RDW. Study of ferrokinetics has shown that an anemia was caused by deficiency in many elements with preponderence of iron-deficiency erythropoiesis. The most sensitive and reliable indicators of early detection of latent anemia without decrease in hemoglobin level were ferritin content, the coefficient of saturation of transferrin and transferrin’s receptors.¹⁴

Sources:

1. Karnam US, Felder LR, Raskin JB. Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study. Southern Medical Journal. Jan 2004;97(1):30-4. [↩] [↩]
2. http://www.nlm.nih.gov/medlineplus/ency/article/003489.htm [↩]
3. Singh P, Arora S, Makharia GK. Presence of anemia in patients with celiac disease suggests more severe disease. Indian J Gastroenterol. 2013 Nov 19. [↩] [↩]
4. Smukalla S, Lebwohl B, Mears JG, Leslie LA, Green PH. How often do hematologists consider celiac disease in iron-deficiency anemia? Results of a national survey. Clin Adv Hematol Oncol. 2014 Feb;12(2):100-5. [↩]
5. Kuloğlu Z, Kirsaçlioğlu CT, Kansu A, Ensari A, Girgin N. Celiac Disease: Presentation of 109 Children. Yonsei Med J. 2009 October 31; 50(5): 617–623. [↩] [↩]
6. Economou M, Karyda S, Gombakis, Tsatra J, Athanassiou-Metaxa M. Subclinical celiac disease in children: refractory iron deficiency as the sole presentation. Journal of Pediatric Hematology/Oncology. Mar 2004;26(3):153-4 [↩]
7. Bhattacharya M, Kapoor S, Dubey AP. Celiac disease presentation in a tertiary referral centre in India: current scenario. Indian J Gastroenterol. 2013 Mar;32(2):98-102. doi: 10.1007/s12664-012-0240-y. Epub 2012 Aug 19. [↩]
8. Umarnazarova ZE. Specificity of ferrokinetics in children with enzymopathy of small intestine. Likars’ka Sprava. Oct-Nov 2003;(7):63-7. [↩]
9. Karnam US, Felder LR, Raskin JB. Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study. Southern Medical Journal. Jan 2004;97(1):30-4. [↩]
10. Cummins AG, Thompson FM, Butler RN, et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clinical Science. Apr 2001;100(4):379-86. [↩]
11. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Journal of Gastroenterology and Hepatology. 2003;18:479-91. [↩] [↩] [↩] [↩] [↩]
12. Smukalla S, Lebwohl B, Mears JG, Leslie LA, Green PH. How often do hematologists consider celiac disease in iron-deficiency anemia? Results of a national survey. Clin Adv Hematol Oncol. 2014 Feb;12(2):100-5. [↩]
13. Bhattacharya M, Kapoor S, Dubey AP. Celiac disease presentation in a tertiary referral centre in India: current scenario. Indian J Gastroenterol. 2013 Mar;32(2):98-102. doi: 10.1007/s12664-012-0240-y. [↩]
14. Umarnazarova ZE. Specificity of ferrokinetics in children with enzymopathy of small intestine. Likars’ka Sprava. Oct-Nov 2003;(7):63-7. [↩]