Mild fatigue follows progressively heavy monthly periods

Figure 1. Hypochromic blood cells have decreased hemoglobin.
Figure 1. Hypochromic blood cells have decreased hemoglobin.

Ms. D, a white woman aged 36 years, was told she was anemic after attempting to donate blood at a local blood drive. Her hemoglobin was 9.9 g/dL, hematocrit 24.9%, and mean corpuscular volume (MCV) 76 fL. Platelets, WBC, and differential were all within normal limits. Ms. D reported that she had noticed some mild fatigue and shortness of breath upon exertion over the past few months, which she attributed to being busy, not sleeping well, and being out of shape. She also complained of an occasional burning sensation with ingestion of hot or spicy foods.

1. History

A record review showed that Ms. D had hemoglobin of 11.4 g/dL at her annual physical examination six months earlier. All four components of the iron panel (serum ferritin, serum iron, total iron binding capacity [TIBC], and transferrin) were within normal limits at that time. Stools for occult blood were negative. The patient complained of some reflux symptoms at night and had been prescribed omeprazole (Prilosec). Ms. D's family practitioner felt that she was mildly anemic secondary to menstrual blood loss. Her periods had become progressively heavy, with clotting and cramping. She averaged a period every 20 days, each lasting seven to nine days. She had to change tampons every two to three hours and at night she used pads and tampons simultaneously because of heavy bleeding. A multivitamin with iron was recommended, which Ms. D elected not to take.

In addition to the nighttime reflux, Ms. D had a history of migraine headache and hypothyroidism; her current medication regimen included calcium with vitamin D and levothyroxine (Levoxyl, Synthroid). At the time of presentation, the patient's physical examination was unremarkable except for mild conjunctival pallor and papillary atrophy of the tongue. Additional laboratory tests done at this visit included thyroid-stimulating hormone (6.8 mU/L) and iron (33 ug/dl).

2. Treatment

Ms. D was clearly iron-deficient. A pelvic ultrasound performed to assess the nature of her heavy bleeding demonstrated no uterine pathology. A gynecologic consult was initiated, and the patient was placed on hormonal therapy to control the excessive bleeding. The menorrhagia improved over the next few months. Oral iron supplementation was initiated, but this led to constipation, which resulted in inconsistent adherence at first. Ms. D worked closely with the nurse practitioner to find a supplement regimen that agreed with her and was able to take the iron on a consistent basis after a couple of visits.

The patient was noted to be hypothyroid in spite of treatment for the condition. It was felt that this might have contributed to her heavy bleeding, and her thyroid medication was increased. Ms. D's anemia improved somewhat once the bleeding was better controlled, but her iron deficiency persisted, and she continued to complain of fatigue. In general, the hemoglobin/hematocrit should return to normal after two months of supplemental iron. Ms. D's ferritin level remained low, however, and her TSH was still elevated. A full GI consult was obtained, but no significant pathology was found.

At a subsequent follow-up visit, the NP reviewed Ms. D's medication regimen in detail, including the timing of administration. It was discovered that she was taking her levothyroxine with her calcium in the morning. Once she was told not to do this, her thyroid tests corrected. The connection between Ms. D's persistent iron deficiency and omeprazole was also discovered. She was advised to discontinue the omeprazole and try calcium carbonate at bedtime, since her reflux symptoms struck primarily at night. The patient did well with this medication change, and once the omeprazole was discontinued, her iron deficiency and anemia resolved as well.

3. Discussion

Iron-deficiency anemia affects an estimated two billion people worldwide, making it the most common nutritional deficiency on a global scale.1 In the United States, it affects up to 12% of all adult women and 20% of Hispanic and black women.2 When assessing the etiology of anemia, it is important to first look at the MCV, which measures the average size of the patient's RBCs (Table 1).

The MCV is elevated when RBCs are larger than normal (macrocytic), as seen in anemia caused by B12 or folate deficiency. A low MCV indicates smaller than normal RBCs (microcytic). In addition to iron deficiency, the differential diagnosis for microcytic anemia includes the thalassemias, some types of anemia of chronic disease, and lead poisoning. Iron deficiency occurs when there are increased iron requirements resulting from blood loss, pregnancy and lactation, or inadequate iron supply. This can occur with insufficient dietary iron or impaired iron absorption, most commonly occurring after gastric surgery or with intestinal malabsorption. In Ms. D's case, the hypochlorhydria induced by the omeprazole impaired absorption of orally administered iron,3 which is why her symptoms did not improve.

Subjective complaints in patients with iron deficiency may include fatigue, pica, paresthesias, brittle nails, cold intolerance, burning of the tongue, or angina. Objective findings may include spoon nails (koilonychia), conjuctival pallor, papillary atrophy, glossitis, angular cheilitis, and tachycardia.

A serum ferritin is the preferred initial test for evaluating whether a microcytic anemia is secondary to iron deficiency.4 Most of the body's stored iron is bound to ferritin. When the rate of iron loss exceeds the amount absorbed by the body, iron stores are slowly depleted. In the early stages of this process, ferritin will decrease, but serum iron and TIBC will remain normal. There may be no evidence of anemia at this point. Over time, the serum iron will drop, TIBC and transferrin levels will rise, and anemia will develop.

The ability to evaluate a peripheral smear is also useful. With iron deficiency, the RBCs will typically show an area of central pallor; this is an indication that they are hypochromic. RBCs are also usually decreased in number, and there is variation in the size (anisocytosis) and shape (poikilocytosis) of these cells (Figure 1).

A reticulocyte count can help monitor the effectiveness of iron supplementation. Reticulocytosis will peak at seven to 10 days after the initiation of iron in patients with moderate-to-severe cases of anemia.5

In a woman of reproductive age, a trial of iron would be an acceptable approach if other significant pathology has been ruled out. Tolerance and absorption can be issues in oral iron supplementation. Per evidence-based recommendations, ferrous sulfate remains the recommended first-line treatment of iron-deficiency anemia. Randomized controlled studies have found that ferrous salt preparations (ferrous sulfate, ferrous gluconate, and ferrous fumarate) are equally tolerable. For some patients, controlled-release iron preparations may be better tolerated than conventional ferrous sulfate; although the discontinuation rates between the two iron formulations were similar, they are much more costly and are generally not as well absorbed.6

Vitamin C helps the body absorb iron, and it is recommended that patients increase their dietary intake of fruits and vegetables—especially guava, sweet red pepper, kiwi, oranges and orange juice, and green pepper. Alternatively, taking iron with a 250-mg vitamin C tablet can improve absorption.

Ms. D's case illustrates the importance of careful medication review and assessment at each office visit. Certain foods and medicines can reduce the effectiveness of iron tablets. Patients should not take iron at the same time they ingest tea, coffee, calcium supplements, or milk, but rather one hour before or two hours after these beverages and two hours before or four hours after antacids. When initiating iron therapy, always start the patient on a stool softener and back off if the patient develops diarrhea at any point. Although potentially better tolerated, enteric-coated iron tablets may not deliver optimal results because iron is best absorbed from the duodenum and jejunum, and enteric-coated tablets release iron further down in the intestinal tract, where it is not as easily absorbed.7

Finally, it is important to evaluate thyroid function in women with menorrhagia. Both hypothyroidism and hyperthyroidism can result in heavy uterine bleeding. Even subclinical cases of hypothyroidism produce menorrhagia in 20% of patients. Correction of the disorder improves symptoms.8

Ms. D's iron-deficiency anemia was clearly a result of multifactorial causation. It is important to consider that therapeutic nonresponse may be interconnected with the timing and quality of the patient's medication self-administration.

Dr. Cairo is a nurse practitioner specializing in medical oncology and hematology at Aurora Advanced Health Oncology in Kenosha, Wisc.

References

1. Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet. 2007;370:511-520.

2. Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Phyician. 2007;75:671-678. 

3. Sharma VR, Brannon MA, Carloss EA. Effect of omeprazole on oral iron replacement in patients with iron deficiency anemia. South Med J. 2004;97:887-889.

4. Tefferi A, Hanson CA, Inwards DJ. How to interpret and pursue an abnormal blood cell count in adults. Mayo Clin Proc. 2005; 80:923-936.

5. Castro RS, Irwin C, Moriarity-Suggs C. Diagnosis and management of iron deficiency anemia. Ca J Health Sys Pharm. 2010;2:5-14.

6. McDiarmid T, Johnson ED. Clinical inquiries. Are any oral iron formulations better tolerated than ferrous sulfate? J Fam Pract. 2002;51:576.

7. UpToDate. Patient information: anemia caused by low iron.

8. eMedicine. Menorrhagia. 

All electronic documents accessed March 15, 2011.

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