When Oral Iron Is Not Effective

Top Papers of the Month 

What may underlie a lack of response to oral iron therapy?

Physicians have options when choosing iron supplements for their patients. Oral iron has been the gold standard, but now safer parenteral iron supplements are available. There has been a habit (I am guilty as well) of ascribing oral iron failure to non-adherence. I would find oral iron difficult to take consistently because of side effects. The next step is parenteral iron. However, there are other reasons oral iron fails to correct the deficiency. Remember that stomach acid is crucial for the absorption of non-heme iron. Therefore, gastritis (Helicobacter pylori), gastric bypass procedures, and possibly proton pump inhibitors may be responsible. Celiac disease, especially with duodenal involvement, can be another reason. A recent “Top Paper” forced me to “dig deeper” into the topic and taught me once again that simple is better.1

MULTIPLE MECHANISMS OF HYPOTHYROID ANEMIAS

Let’s begin with some basics. Patients with hypothyroidism experience anemia. But hypothyroid anemias are not always the result of a single, pathological mechanism. Hypothyroid anemias may be accompanied by other comorbidities and can be micro-, normo-, or macrocytic. Interestingly enough, there seems to be a higher incidence of iron-deficiency anemia in persons with hypothroidism.² Additionally, thyroid hormone deficiency can also be associated with pernicious anemia (macrocytic), celiac disease, and bacterial overgrowth syndromes. Even without an associated disorder such as celiac disease, thyroid hormone plays a critical role in erythropoiesis.³ Hypo-proliferation of red cell precursors with sufficient erythropoietin has been implicated in the anemia of dialysis patients who are simultaneously hypothyroid.⁴

ROLE OF SUBCLINICAL HYPOTHYROIDISM

That was about frank hypothyroidism, but what about the subclinical variety? It has downsides as well. These can include heart disease (arteriosclerosis), low-density lipoprotein cholesterol elevations, neuropsychiatric symptoms, fatigue, slowness, and progression to clinical hypothyroidism.² Would it surprise you to learn that persons with subclinical hypothyroidism also do not absorb iron without the help of thyroid hormone supplementation? Data more than a decade old suggest that they do not.⁵ Let’s look first at why this combination, that is, thyroid replacement plus iron, is important in primary care.

The “Top Paper”¹ demonstrated (n = 40 with subclinical hypothyroidism; 20 received levothyroxine plus iron; 20 iron alone) a superior rise with thyroid replacement plus iron. Subclinical hypothyroidism should be diagnosed and treated in persons with iron deficiency, especially those who do not have an alternative reason for unresponsiveness to oral iron. The results substantiated an earlier study demonstrating the same exact pattern.² A jump to parenteral iron would not be appropriate in this clinical situation (in fact, in many more clinical situations).⁶ Those who use parenteral iron would be guilty of 2 mistakes: missing the diagnosis of thyroid disease and wasting a more expensive therapy. The fundamental problem, that is, a lack of response to erythropoietin, would persist.

IMPLICATIONS FOR CLINICAL PRACTICE

I am going to change my practice as a result of the “Top Paper.” A thyroid-stimulating hormone test will now inform me prior to oral iron replacement. Further reading rewarded me. A number of specific cohorts will benefit from my change in practice. It was demonstrated 20 years ago that menorrhagic women (with and without intrauterine devices) have a greater incidence of occult hypothyroidism.⁷ They may be the tip of a hypothyroid iceberg. Be on the lookout for the combination of subclinical hypothyroidism and failure to respond to oral iron! ■

REFERENCES:

1.Ravanbod M, Asadipooya K, Kalantarhormozi M, et al. Treatment of iron-deficiency anemia in patients with subclinical hypothyroidism. Am J Med. 2013;126:420-424.

2.Cinemre H, Bilir C, Gokosmanoglu F, et al. Hematologic effects of levothyroxine in iron-deficient subclinical hypothyroid patients: a randomized, double-blind, controlled study. J Clin Endocrinol Metab. 2009;94:151-156.

3.Das KC, Mukherjee M, Sarkar TK, et al. Erythropoiesis and erythropoietin in hypo- and hyperthyroidism. J Clin Endocrinol Metab. 1975;45:211-220.

4.Ng YY, Lin HD, Wu SC, et al. Impact of thyroid dysfunction on erythropoietin dosage in hemodialysis patients. Thyroid. 2013;23:552-561.

5.Duntas LH, Papanastssiou L, Mantzou E, et al. Incidence of sideropenia and effects of iron repletion with subclinical hypothyroidism. Exp Clin Endocrinol Diabetes. 1999;107:356-360.

6.Rizvi S, Schoen RE. Supplementation with oral vs. intravenous iron for anemia with IBD or gastrointestinal bleeding: is oral iron getting a bad rap? Am J Gastroenterol. 2011;106:1872-1879.

7.Blum M, Blum G. The possible relationship between menorrhagia and occult hypothyroidism in IUD-wearing women. Adv Contracept. 1992;8:313-317.