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25-Year-Old Woman With Anemia

Ranjini R. Roy, MD,* and Matthew R. Thomas, MD
25-year-old female graduate student presented to her primary care physician after she was rejected as a blood donor because she was anemic. She was told her hemoglobin was 9 g/dL. She had donated blood 6 years before this attempt without difficulty. The patient was otherwise healthy and had no major symptoms. She noted some generalized fatigue but had been attributing this to her stressful life. She had been prescribed the oral contraceptive ethinyl estradiol/levonorgestrel (Seasonale) 9 months earlier and had her menses once every 3 months. She denied any abdominal pain, nausea, vomiting, melena, hematochezia, or changes in weight or appetite. She was a nonsmoker, drank occasional alcohol on the weekends, and denied any illicit drug use. There was no family history of anemia or other hematologic problems. Physical examination revealed a healthy-appearing young woman in no acute distress. Conjunctivae were not pale. Findings on cardiac examination were normal (no evidence of murmurs, rubs, or gallops), as were findings on lung examination. Abdominal examination revealed normal active bowel sounds. The abdomen was soft, nontender, nondistended, with no obvious masses. Gynecologic examination was also unremarkable. Laboratory testing yielded the following results: hemoglobin, 10.2 g/ dL; hematocrit, 29.7%; mean corpuscular volume, 77.8 fL; red cell distribution width, 19.6%; white blood cell count, 5.3 109/L; and platelets, 439 109/L. 1. Which one of the following would be the best test to perform next? a. Serum ferritin assay b. Endoscopy c. Colonoscopy d. Stool analysis for occult blood e. Serum vitamin B12 assay The patient's low mean corpuscular volume and elevated red cell distribution width suggest a microcytic anemia. Common causes of microcytic anemia include iron deficiency, anemia of chronic disease, thalassemias, and lead poisoning. Although all of the tests listed may be appropriate at some point in the work-up, the next best test to evaluate for iron deficiency would be a serum ferritin assay. A low serum ferritin level would be expected in iron deficiency anemia. Endoscopy and colonoscopy may be necessary if blood loss from the gastrointestinal tract is suspected and iron deficiency is confirmed. Stool analysis for occult blood in this situation would lack sensitivity and specificMayo Clin Proc. March 2010;85(3):e9-e12

ity to adequately guide subsequent management decisions. Vitamin B12 deficiency typically presents with a macrocytic anemia, and neurologic symptoms may also be present. Iron studies revealed a serum ferritin level of 2 g/L, and peripheral smear confirmed microcytosis and hypochromia. These findings were most consistent with iron deficiency anemia. 2. On the basis of the patient's history, which one of the following is the most likely diagnosis? a. Menorrhagia b. Repeated blood donations c. Gastrointestinal malignancy d. Peptic ulcer disease e. Celiac disease Iron deficiency anemia is most commonly caused by blood loss. Other causes include pregnancy and malabsorption. Menorrhagia is a frequent cause of iron deficiency anemia (secondary to blood loss) in young women. However, this patient was taking oral contraceptives, with menses occurring only once every 3 months, making menorrhagia less likely. Frequent blood donation can also cause iron deficiency anemia, but this patients history did not suggest this as an etiology. Gastrointestinal malignancy could cause occult blood loss, resulting in iron deficiency anemia; however, the patients young age and otherwise healthy status suggest that other more common etiologies should be explored. Serious peptic ulcer disease could cause bleeding, but a history of melenic stools, abdominal discomfort, or other gastrointestinal symptoms would be expected. This patients history did not suggest any obvious sources of blood loss, thus celiac disease is the most likely etiology on the basis of her presentation. The prevalence of celiac disease in patients with iron deficiency anemia ranges from 2% to 9%.1,2 Celiac disease can present with gastrointestinal symptoms, such as abdominal discomfort, diarrhea, vomiting, weight loss, and anorexia, but may also be clinically silent.

*Resident in Internal Medicine, Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN. Adviser to resident and Consultant in Primary Care Internal Medicine, Mayo Clinic, Rochester, MN. Individual reprints of this article are not available. Address correspondence to Matthew R. Thomas, MD, Division of Primary Care Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (thomas.matthew@mayo. edu). 2010 Mayo Foundation for Medical Education and Research

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On further questioning, the patient reported that she would occasionally note a dull stomachache after meals. 3. Which one of the following laboratory tests would be most helpful in establishing the suspected diagnosis? a. Serum antigliadin antibody assay b. Serum antimitochondrial antibody assay c. Serum antitissue transglutaminase (anti-tTG) antibody assay d. Serum antismooth muscle antibody assay e. Serum antinuclear antibody assay Serum antigliadin antibody levels were previously used for diagnosis of celiac disease but are currently considered not to be sensitive or specific enough for the diagnosis unless the patient is younger than 18 months. Serum antimitochondrial antibody levels are used for the diagnosis of primary biliary cirrhosis, which would not typically present with iron deficiency anemia. A serum anti-tTG antibody assay, with a sensitivity approaching 90%, is the best choice for diagnosing celiac disease.3,4 In patients who are not IgA deficient, IgA tTG levels are a sensitive marker for the diagnosis of celiac disease. However, up to 3% of the population may be IgA deficient; under these circumstances, the use of IgG tTG levels may be helpful. The use of IgG tTG levels in patients who are IgA sufficient is of limited value. Serum endomysial antibody levels are also still widely used for the diagnosis of celiac disease and are highly specific (approaching 98%); however, sensitivity may be variable. A serum endoymsial antibody assay would have been a reasonable option had it been given as an answer choice.4 Serum antismooth muscle antibody levels are used to help establish the diagnosis of autoimmune hepatitis. Serum antinuclear antibody levels are nonspecific and can be seen in a wide variety of autoimmune and rheumatologic disorders. Serum IgG and IgA tTG levels were noted to be elevated at 24.3 U and greater than 250.0 U, respectively (reference range for both, <20.0 U). The patient's iron deficiency anemia and substantially elevated serum anti-tTG antibody levels strongly suggested an underlying diagnosis of celiac disease. The patient underwent an upper endoscopy with small bowel biopsy to officially confirm the diagnosis. 4. Which one of the following histologic findings would be most likely on this patients biopsy specimen? a. Noncaseating granulomas with lymphocytic infiltrate b. Villous atrophy and blunting of the villi in the small intestine with increased intraepithelial lymphocytosis c. Generalized dilation of small intestine lymphatics d. Periodic acid-Schiffpositive macrophages in the small bowel mucosa e. Extensive lymphocytic infiltration with loss of normal mucosa
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Noncaseating granulomas with lymphocytic infiltrate suggest an inflammatory condition and are commonly seen in Crohn disease. Villous atrophy and blunting of the villi in the small intestine, commonly seen in malabsorptive processes such as celiac disease, would be expected on this patients biopsy specimen. Other common histologic features seen in celiac disease include intraepithelial lymphocytes and crypt hyperplasia. Generalized dilation of small intestine lymphatics would suggest intestinal lymphangiectasia. Whipple disease, a rare disease caused by the organism Tropheryma whippelii, can cause diarrhea and steatorrhea and is associated with periodic acid-Schiff positive macrophages in the small bowel mucosa. Extensive lymphocytic infiltration with loss of normal mucosa would be suggestive of a lymphoma and would not be an expected finding in this patient. Small bowel biopsy revealed villous blunting and total villous atrophy of the small bowel, consistent with celiac disease. After being told of her diagnosis, the patient revealed that her maternal aunt also had the disease and inquired whether celiac disease had a genetic component. Her sister wondered if she should also be tested. 5. On the basis of the clinical diagnosis, which one of the following would be the most appropriate recommendation for the patients sister? a. Serologic testing (serum anti-tTG antibody assay) b. Upper endoscopy with small bowel biopsy c. Genetic testing for serum human leukocyte antigen (HLA) DQ2 or DQ8 d. Genetic counseling e. Complete blood cell count and serum ferritin assay Celiac disease appears to have a genetic component, and relatives of patients with celiac disease are at higher risk of developing the disease. The prevalence of celiac disease in relatives approaches 10%, compared with 1% in the general population. However, despite this increased risk, no set guidelines exist for screening asymptomatic relatives of patients with celiac disease.1 Although a highly specific test, serologic testing for anti-tTG antibodies would not be recommended. An upper endoscopy with small bowel biopsy is an invasive procedure and, in an asymptomatic patient, could result in unnecessary complications. Patients must have either HLA-DQ2 or HLA-DQ8 to develop celiac disease, but the simple presence of these alleles does not ensure its development.1,5 Roughly 40% of the population may carry these alleles but do not necessarily develop celiac disease.6 Thus, environmental and other factors are likely to play a role in its development.3 Up to two-thirds of family members could carry the HLA-DQ2 or -DQ8 gene pair, a finding that can be misleading in an otherwise asymptomatic person.7 Other implications of genetic test www.mayoclinicproceedings.com

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ing should be discussed with the patients family members, and genetic counseling would be appropriate in this setting. Screening an asymptomatic family member with a complete blood cell count and ferritin assay to monitor for iron deficiency anemia is not recommended. The patient was prescribed oral iron supplementation and was screened for osteoporosis with a bone scan. She met with a dietician and successfully initiated a gluten-free diet, with resolution of all symptoms. At a follow-up visit 6 months later, she was feeling well, and her hemoglobin and ferritin levels had normalized. DISCUSSION Celiac disease is an autoimmune gluten-sensitive enteropathy that occurs as a result of a combination of genetic and environmental factors when gluten is ingested.8 Gluten, the protein component of wheat that is also found in barley and rye, is not well absorbed in the upper gastrointestinal tract. Gliadin, the alcohol-soluble portion of gluten, contains the toxic components and remains in the intestinal lumen after ingestion of gluten because it is not degraded by intestinal enzymes. Patients with celiac disease produce an immune response to gliadin, causing inflammation in the small intestine with an increase in proinflammatory cytokines. This inflammatory reaction leads to villous injury, atrophy, and subsequent malabsorption.8 A familial predisposition exists for the development of celiac disease and has been associated with the major histocompatibility alleles HLA-DQ2 and HLA-DQ8. Environmental factors, such as early introduction of gluten in children younger than 4 months, have been associated with an increased risk of celiac disease.1 The prevalence of celiac disease approaches 1%.6,9 Adults presenting with iron deficiency anemia have occult celiac disease up to 9% of the time.1,2,10 In addition, iron deficiency anemia can be found in up to 46% of patients with subclinical celiac disease.11 Patients are considered to be at higher risk if they have first- or second-degree relatives with celiac disease, unexplained iron deficiency anemia, underlying osteoporosis, type 1 diabetes mellitus, liver disease, thyroid disease, Down syndrome, or other autoimmune diseases. These high-risk patients should be considered for celiac disease testing.1 Dermatitis herpetiformis is a frequently associated finding and presents as a pruritic, blistering rash, most commonly on the extensor surfaces. Granular IgA depositions are present along the basement membrane. The diagnosis is supported by serologic findings, including positive findings on IgA endomysial antibody or IgA tTG antibody assays. Although both tests have sensitivities greater than 90%, recent studies have suggested that the IgA tTG assay may have a higher
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sensitivity than the IgA endomysial antibody assay.4,6 In addition, the IgA tTG assay has excellent specificity (95%) and is less time-consuming than the antiendomysial antibody assay. In patients in whom IgA deficiency is suspected, it may be appropriate to also obtain an IgG tTG level.1 Even with the high predictive value of serologic tests, the mainstay for diagnosis remains findings on small bowel biopsy of villous atrophy, intraepithelial lymphocytosis, and crypt hyperplasia.4 Improvements in these findings can be seen in response to a strict gluten-free diet. In patients in whom serologic testing and small bowel biopsy are not suggestive of celiac disease but in whom the diagnosis is still suspected because of clinical findings, HLA testing may play a role in excluding celiac disease. Because approximately 95% of patients with celiac disease test positive for either the HLA-DQ2 or HLA-DQ8 allele, the absence of these alleles would make the diagnosis of celiac disease very unlikely.1 Treatment is directed at avoiding the offending agent, gluten. Gluten is mainly found in such foods as wheat, pastas, cereals, and breads. However, it can also be found in many other foods, including seasonings and sauces, and thus close attention to food labels is essential. Diagnostic studies should be performed before initiating a gluten-free diet. Patients must commit to a lifelong gluten-free diet. Clinical improvement usually occurs within days to weeks of initiation; however, histologic recovery may require more than 24 months.4,9 Adherence to a gluten-free diet is also essential for maintaining adequate nutrition because micronutrient malabsorption can occur with nonadherence. In addition, patients with celiac disease are at higher risk of developing malignancies, such as enteropathy-associated T-cell lymphoma, and adherence to a gluten-free diet has been shown to partially protect against this complication.12 Follow-up serologic testing after initiation of a strictly gluten-free diet has not been shown to correlate appropriately with histologic recovery, and therefore its value is controversial.3,4 However, if nonadherence to a gluten-free diet is suspected or if monitoring for inadvertent ingestion of gluten is desired, a follow-up anti-tTG antibody assay would be reasonable. Also recommended is an annual clinical evaluation, including weight, complete blood cell count, and folate, calcium, and alkaline phosphatase levels.1
REFERENCES 1. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease. Gastroenterology. 2006;131(6):1981-2002. 2. Grisolano SW, Oxentenko AS, Murray JA, Burgart LJ, Dierkhising RA, Alexander JA. The usefulness of routine small bowel biopsies in evaluation of iron deficiency anemia. J Clin Gastroenterol. 2004;38(9):756-760. 3. Tursi A, Brandimarte G, Giorgetti G. Lack of usefulness of anti-transglutaminase antibodies in assessing histologic recovery after gluten-free diet in celiac disease. J Clin Gastroenterol. 2003;37:387-391.

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4. Hopper AD, Hadjivassiliou M, Hurlstone DP, et al. What is the role of serologic testing in celiac disease? A prospective, biopsy-confirmed study with economic analysis. Clin Gastroenterol Hepatol. 2008;6(3):314-320. 5. Kaukinen K, Partanen J, Maki M, et al. HLA-DQ typing in the diagnosis of celiac disease. Am J Gastroenterol. 2002;97:695-699. 6. Kaukinen K, Sulkanen S, Maki M, et al. IgA-class transglutaminase antibodies in evaluating the efficacy of gluten-free diet in celiac disease. Eur J Gastroenterol Hepatol. 2002;14:311-315. 7. Rashtak S, Murray JA. Tailored testing for celiac disease [editorial]. Ann Intern Med. 2007;147(5):339-341. 8. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007;357(17):17311743. 9. Niewinski MM. Advances in celiac disease and gluten-free diet. J Am Diet Assoc. 2008;108(4):661-672.

10. Karnam US, Felder LR, Raskin JB. Prevalence of occult celiac disease in patients with iron-deficiency anemia: a prospective study. South Med J. 2004;97(1):30-34. 11. Halfdanarson TR, Litzow MR, Murray JA. Hematologic manifestations of celiac disease. Blood. 2007;109(2):412-421. 12. Silano M, Volta U, De Vincenzi A, et al. Effect of a gluten-free diet on the risk of enteropathy-associated T-cell lymphoma in celiac disease. Dig Dis Sci. 2008;53:972-976.

Correct answers: 1. a, 2. e, 3. c, 4. b, 5. d

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For personal use. Mass reproduce only with permission from Mayo a Clinic Proceedings.