Anemia, Iron Deficiency

Red Blood Cell Comparison. Courtesy medindia.com

What Is Iron Deficiency Anemia?

Iron deficiency anemia is a blood cell disorder that is characterized by formation of small, pale red blood cells, causing tissue hypoxia. Hypoxia is the inability to meet the demands of the body for oxygen.

Q: Why do small, pale red blood cells cause tissue hypoxia?

A: Small, pale red blood cells (erythrocytes) cause tissue hypoxia because they are not able, as do normal erythrocytes, to pick up adequate oxygen from the lungs and carry it to cells that use oxygen.

Red blood cell production and function are dependent on a sufficient level of iron in the body and also the ability to use available iron to make hemoglobin in red blood cells.

Hemoglobin is a protein that binds oxygen in red blood cells to be carried by the bloodstream to cells throughout the body. In iron deficiency anemia,  hemoglobin in females is below 12.5g/dl (normal range is 12.5 to 16g/dl) and in males it is below 13.5g/dl (normal range is 13.5 to 17.5g/dl).

Iron must be obtained from the diet, since the body cannot make it, but there are various factors that can interfere with absorption and use in the body, causing anemia. Iron absorption from the gut first requires ionization, or gaining a positive electrical charge, in the strongly acidic environment of stomach juice. Ionized iron, only, can be absorbed in the duodenum, which receives the acidic contents of the stomach before it is neutralized further along.

Dietary iron can be heme or non-heme depending on the food source. Heme iron obtained only from animal food sources is absorbed into the bloodstream by active transport across the brush border (microvilli) which cover the multitudinous villi of the small intestinal lining.

Non-heme iron obtained from plants must bind with apoprotein after entering the enterocyte (surface cell of small intestinal lining) to be ferried to the underlying basolateral membrane and exited by active transport into the bloodstream.

Frequently, chronic anemia due to iron deficiency is accompanied by increased platelets, and this thrombocytosis resolves with iron repletion (normal iron level). Conversely, in severe iron deficiency anemia, patients may have thrombocytopenia (low platelets), which also resolves with iron therapy.1

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

• Relationship between iron deficiency anemia and celiac disease. Iron deficiency anemia is a classic symptom of celiac disease. Of 338 celiac disease patients, only 14.8 % had normal hemoglobin levels at diagnosis.2
• Relationship between iron deficiency anemia and non-response to standard treatment in untreated celiac disease. In untreated celiac disease, iron deficiency anemia is refractory, or does not respond, to oral iron supplementation.3 That is, the body is not able to properly absorb and use iron for blood cell function largely because of inflammatory damage to the duodenal lining by gluten.
• Relationship between iron deficiency anemia and nutrient deficiencies. Adequate vitamin C, as well as intestinal acidity in the beginning region of the duodenum, is needed for absorption of iron. Other nutritional deficiencies that promote iron deficiency anemia are copper and riboflavin (vitamin B2), and these are commonly found in untreated celiac disease.4
• Relationship between iron deficiency anemia and screening in unexplained iron-deficiency anemia. Screening for celiac disease is recommended in patients with unexplained iron-deficiency anemia,5particularly because the presence of anemia in patients with celiac disease suggests more severe disease.
• Relationship between iron deficiency anemia and markers in celiac disease. A study by Singh et al. found celiac patients 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 than celiac patients without anemia. Thus, celiac 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.”6
• Relationship between iron deficiency anemia and screening for celiac disease. A national 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 and those who see a high volume of patients with IDA are more likely to screen for celiac disease.7
• Relationship between iron deficiency anemia and low cholesterol. Of interest is a study of 100 anemic patients that found all anemic patients with celiac disease had plasma cholesterol less than 156mg/100ml.8

• Relationship between iron deficiency anemia and H. pylori infection: H. pylori infection is an associated disorder in celiac disease with a 21% prevalence in untreated celiac disease patients of whom 71% had iron deficiency anemia.9 H. pylori infection is a factor responsible for iron deficiency in celiac disease patients who are predisposed to iron-deficiency anemia by means of these mechanisms:10

• Causes considerable decrease in the concentration of gastric juice ascorbic acid (vitamin C) that is the best promotor of non-heme iron absorption from food. Non-heme iron comes from plant sources. Heme iron comes from animal sources and is the type of iron in the body.
• May significantly increase iron demand from the body iron stores because iron is an essential bacteria growth factor for H. pylori.
• Bacteria contain a 19.6 kilodalton protein resembling ferritin (iron molecule in the body) with a binding activity for heme iron in erythrocytes (red blood cells). So in this way, H. pylori steals iron from the body.
• Probably increases lactoferrin uptake from neutrophils (white blood cells) and significantly increases iron demand.

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

• Iron deficiency anemia is a common and a classic presentation of celiac disease.11,12
• A study of 109 children with celiac disease  found an incidence rate of 81.6% having anemia at diagnosis.13
• A Dutch study in 80 newly diagnosed adult patients with celiac disease found 32% had anemia.14
• A study of 152 adult patients at the time of diagnosis of celiac disease showed 34% had anemia.15
• In the reverse, the prevalence of celiac disease in study patients with iron deficiency anemia was 2.8%.3

What Are The Symptoms Of Iron Deficiency Anemia?

Symptom of iron deficiency anemia include:

Circulatory Problems:

• Angina (pain over heart).
• Dyspnea (shortness of breath).
• Fatigue.
• Pallor or paleness of skin and mucous membranes.
• Lethargy and loss of vitality.
• Systolic heart murmur may develop.
• Tachycardia (rapid heartbeat).

Nervous System Problems:

• Anorexia (loss of appetite).
• Anxiety.
• Apathy.
• Inability to pay attention.
• Headache.
• Lightheadedness or faintness.
• Reduced memory/learning.
• Sensory motor incompetence.

Metabolic Problems:

• Alopecia (loss of hair).
• Dry and dull hair.
• Increased susceptibility to infection. Frequent illness. Sick all the time.
• Koilonychia (spooning of nails) that begins usually with the thumb nails.
• Visual impairment (blurry).
• In some cases, difficulty swallowing from web formation inside the esophagus (Plummer-Vinson Syndrome) may develop.

How Does Iron Deficiency Anemia in Celiac Disease Develop?

Iron deficiency anemia results from any or all of these mechanisms:

• Impaired absorption of iron from the gut (dietary or supplemental):

1. Failure to inonize iron in the stomach and upper duodenum due to low stomach acid so this mineral can be absorbed in the duodenum.
2. Failure to absorb iron into the bloodstream from the duodenum due to mucosal damage to intestinal absorptive cells from an immune reaction to gluten.
3. Inadequate vitamin C needed for iron absorption.
4. Inadequate copper needed to stimulate the absorption of iron through the copper transport protein ceruloplasmin.

• Interference with the usage of iron in the body for red blood cell production including deficiencies of these co-factors need for normal red blood cell health:

1. Copper, which is essential for the formation of hemoglobin and red blood cell production, and
2. Riboflavin (vitamin B2), which maintains the normal lifespan of red blood cells.

• Loss of iron from the body:

1. If present, infection of  the stomach with H. Pylori bacteria (an associated disorder of celiac disease) binds iron in stomach contents and depletes iron from the body for its own metabolism.
2. If present, gastrointestinal bleeding such as erosions and ulcers of the esophagus, stomach or intestine waste iron through the stool.
3. Other sources of bleeding, such as urinary or menstrual, can result from vitamin K, omega-6 fatty acid and/or vitamin C deficiency.
4. Cancer as a complication of celiac disease.

• Inflammation due to immune response to gluten:

1. Proinflammatory cytokines released in active celiac disease increase the production of hepcidin, a protein which inhibits iron release into circulation, and thereby, results in anemia.16

Does Iron Deficiency Anemia Respond To Gluten-Free Diet?

Yes. Celiac disease-related iron deficiency anemia responds to gluten free diet rich in iron and protein. Supplementation with iron is advised to restore iron levels and, if indicated, copper, riboflavin or vitamin C may be needed.

Suppression of intestinal inflammatory changes as a result of a gluten-free diet improves anemia by correcting iron and vitamin malabsorption as well as mechanisms contributing to anemia of chronic disease.17

6 Steps To Improve Iron Deficiency Anemia:

• 1Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

• 2 Reduce Inflammation. Foods to Eat and Foods Not to Eat:

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

• 3 Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

• 4 Manage Your Medications Safely: 

• 5Nutritional Supplements To Help Correct Deficiencies:

• 6Manage Natural Remedies:

What Do Medical Research Studies Tell About Iron Deficiency Anemia 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.7

“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.”2

“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 %).20

Vitamin and mineral deficiencies are highly prevalent in newly diagnosed celiac disease patients.” This study aiming to assess the nutritional and vitamin/mineral status of current “early diagnosed” untreated adult celiac disease (CD)-patients in the Netherlands found that vitamin/mineral deficiencies are still common in newly “early diagnosed” CD-patients. Specifically, 46% had decreased iron storage and 32% had anemia.

Eighty newly diagnosed adult CD-patients were included and a comparable sample of 24 healthy Dutch subjects was added to compare vitamin concentrations. Nutritional status and serum concentrations of folic acid, vitamin A, vitamin B6, vitamin B12, and (25-hydroxy) vitamin D, zinc, hemoglobin (Hb) and ferritin were determined before prescribing gluten free diet. Almost all CD-patients (87%) had at least one value below the lower limit of reference

Vitamin/mineral deficiencies were counter-intuitively not associated with a (higher) grade of histological intestinal damage or (impaired) nutritional status. Extensive nutritional assessments seem warranted to guide nutritional advices and follow-up in CD treatment.14

“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.21

“Anemia of chronic disease and defective erythropoietin production in patients with celiac disease.“ This study investigating the prevalence of anemia due to chronic disease found a significant role in some patients with celiac disease and that suppression of intestinal inflammatory changes as a result of a gluten-free diet improves anemia by correcting iron and vitamin malabsorption as well as mechanisms contributing to anemia of chronic disease.

One hundred and fifty-two patients with celiac disease at presentation were studied. Anemia was investigated by determining complete blood counts, body iron status, serum levels of the soluble transferrin receptor, erythropoietin, prohepcidin and interferon-gamma. Genotyping for HFE mutations associated with hereditary hemochromatosis was performed. Fifty-three anemic patients were re-evaluated for hematologic response after 1 year on a gluten-free diet.

At the time of diagnosis of celiac disease the prevalence of anemia was 34%. Fifty-three out of 65 anemic patients had either iron and/or vitamin deficiency (folate, vitamin B12). Hereditary hemochromatosis mutations did not affect the prevalence of anemia. In 11 cases iron status parameters were indicative of anemia of chronic disease, sometimes in association with iron deficiency (6 patients). Patients with anemia of chronic disease had low levels of erythropoietin for the degree of anemia and increased serum interferon-gamma. In most cases anemia improved following a gluten-free diet, response rates being similar in anemia of chronic disease and in anemia due to hematinic deficiencies.

Our study shows that, in addition to iron and vitamin deficiencies, anemia of chronic disease has a significant role in some patients with celiac disease. Suppression of intestinal inflammatory changes as a result of a gluten-free diet improves anemia by correcting iron and vitamin malabsorption as well as mechanisms contributing to anemia of chronic disease.15

“Prevalence of occult celiac disease in patients with iron deficiency anemia: a prospective study.” This study investigating the prevalence of celiac disease in patients with iron deficiency anemia supports a referral for endoscopy to exclude celiac disease.3

“Iron supplementation in children with celiac disease.” This study evaluating the effect of iron supplementation, in addition to the gluten free diet, on hematological 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 with iron supplementation.22

“Low plasma cholesterol: a correlate of nondiagnosed celiac disease in adults with hypochromic anemia.” This study defining the correlates of celiac disease in 100 anemic adults without overt malabsorption demonstrated that among patients with hypochromic anemia, plasma cholesterol in the high-to-normal range could be used to exclude the presence of celiac disease. Compared to anemic patients without Celiac Disease, anemic patients with Celiac Disease had significant or borderline significant differences for plasma cholesterol, albumin, and body mass index but not for blood hemoglobin, mean corpuscular volume, plasma iron, and ferritin. All anemic celiac disease patients had plasma cholesterol less than 156mg/100ml.23

CASE REPORT SUMMARIES

“Pericardial effusion in celiac disease.” This case report describes diagnosis of celiac disease in a 40-year-old woman with progressive fatigue and pitting edema in her lower extremities. Iron deficiency anemia and celiac disease were diagnosed on the basis of low serum ferritin, elevated serum level of IgA endomysial and tissue transglutaminase anti-bodies and histologic findings in small bowel biopsies. Pericardial effusion in her evaluation was detected incidentally. Asymptomatic pericardial effusion in this patient was only detectable with imaging.

After starting of gluten free diet and iron supplement fatigue, peripheral edema and pericardial effusion on echocardiography decreased. It should be noted that asymptomatic pericardial effusion may be seen in adults with celiac disease.24

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13. 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. [↩]
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15. Bergamaschi G, Markopoulos K, Albertini R, et al. Anemia of chronic disease and defective erythropoietin production in patients with celiac disease. Haematologica. 2008 Dec;93(12):1785-91. doi: 10.3324/haematol.13255. [↩] [↩]
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21. 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. [↩]
22. Kapur G, Patwari AK, Narayan S, Anand VK. Iron supplementation in children with celiac disease. Indian Journal of Pediatrics. Dec 2003; 70(12): 955-8. [↩]
23. Ciacci C., Cirillo M, Giorgetti G, et.al, Low plasma cholesterol: a correlate of nondiagnosed celiac disease in adults with hypochromic anemia. American Journal of Gastroenterology. Jul 1999; 4194(7):1888-91. [↩]
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