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Therapy Insight: Metabolic and Endocrine Disorders in Sickle-cell Disease

Authors: Dawn Smiley, MD ; Samuel Dagogo-Jack, MD, FRCP ; Guillermo Umpierrez, MDFaculty and Disclosures


Summary and Introduction


Sickle cell disease (SCD) is an autosomal, recessive hemoglobinopathy characterized by hemolytic anemia, intermittent occlusion of small vessels leading to acute and chronic tissue ischemia, and organ dysfunction. Red blood cell transfusions are a therapeutic mainstay in SCD and repeated transfusions can result in iron overload. Endocrine dysfunction is the most common and earliest organ toxicity seen in subjects with chronic iron-induced cellular oxidative damage and can be seen in those without clinical evidence of iron overload. The predicted risks of iron overload and endocrine organ failure increase with both the duration of disease requiring transfusion therapy and the number of transfusions. Assessing the state of iron-overload in patients with SCD constitutes a diagnostic challenge because of the unreliability of serum ferritin levels and the risks associated with liver biopsy. In turn, MRI is the preferred noninvasive screening tool for iron overload. This article describes the endocrine and metabolic disorders reported in patients with SCD, discusses their management, and identifies gaps in current knowledge and opportunities for future research.


Sickle cell disease (SCD) is a hereditary hemoglobino pathy characterized by abnormal hemoglobin production, hemolytic anemia, and intermittent occlusion of small vessels, leading to acute and chronic tissue ischemia, chronic organ damage, and organ dysfunction.[1] Hemoglobin A is a tetrameric protein that is composed of two α-globin chains and two β-globin chains. In sickle cell anemia, a point mutation on the β-globin gene results in glutamic acid substituting for valine at position 6 of the amino acid sequence. This single amino acid substitution results in the formation of sickle cell hemoglobin.[2] In the United States, 1 in 12 African Americans carries the sickle cell gene and 1 in 375 has sickle cell anemia.[3] It is estimated that approximately 72,000 Americans are homozygous for the sickle cell gene (i.e. the SS genotype) and have SCD,[4] and 2 million are heterozygous carriers (i.e. the AS genotype) and therefore have sickle cell trait.[3,4]

Anemia is usually severe in SCD but varies among patients. One of the most frequently used therapies in sickle cell anemia is red blood cell transfusion (see Box 1). Repeated transfusions are associated with iron overload and possible iron-induced organ damage.[5] Iron overload results primarily in an increase in storage iron held in ferritin and hemosiderin. Progressive iron accumulation eventually overwhelms the body's capacity for safe sequestration of the excess. Symptomatic patients might have any of the characteristic manifestations of systemic iron overload: liver disease with the eventual development of cirrhosis and hepatocellular carcinoma, arthropathy, increased skin pigmentation, cardiomyopathy, diabetes mellitus, gonadal insufficiency and other endocrine disorders.[6] The mechanism of iron overload has not been completely defined. Normally, the body has a limited capacity to control iron absorption and no intrinsic ability to regulate excretion. Chronic transfusion therapy overrides this limited control, thereby leading to whole-body iron overload. Subsequent tissue iron uptake can lead to organ injury via iron-mediated cellular oxidative damage.[7]

Endocrine dysfunction has been reported as the most common and earliest toxic effect seen in iron-overloaded subjects.[8-10] The majority of cases of hemoglobinopathy-associated endocrine dysfunction have been reported in persons with thalassemia rather than SCD; nonetheless, the causal relationship with iron overload and the fact that about 10% of people with SCD also have thalassemia make it feasible that common pathophysiology pathways probably underlie endocrine dysfunction in the two diseases. Increased duration of disease requiring transfusion therapy and number of blood trans fusions (more than eight per year) are predictors of iron overload and have been associated with greater risk of endocrine organ failure.[11,12] The overall magnitude of iron storage and accumulation seems to be the principal determinant of clinical outcome in patients with iron overload.[13]

Measurement of serum ferritin provides an indirect estimate of body iron stores, but the usefulness of this measure is limited by the many conditions in which serum ferritin is not a dependable indicator of body iron storage. Serum ferritin may be an unreliable marker of iron overload in the setting of inflammatory and hepatocellular disease processes (necrosis or neoplasms). In addition, a prospective study by Harmatz et al.[14] evaluated iron overload in children with SCD and found that serum ferritin levels correlated poorly with qualitative iron levels on liver biopsy. Liver biopsy with chemical analysis of tissue iron content provides the most accurate measurement of iron status, but the discomfort and risks associated with the procedure limit its use. In clinical practice, MRI is the most useful noninvasive screening technique for the detection and distribution of iron stores.[13-16]

In addition to MRI, the superconducting quantum interference device (SQUID) has been used in European countries as a noninvasive tool to evaluate iron overload. This technique, however, is expensive, complex and limited to four clinical centers in the world.[16]

It is important to note that endocrine dysfunction can also be seen in lieu of iron overload. Zinc deficiency due to urinary losses is common in subjects with SCD and studies by Prasad and Cossack[17] suggested that zinc deficiency in adolescent patients with SCD was associated with growth retardation and hypogonadism in males. Although zinc supplementation in this population improved testosterone levels and longitudinal growth, the underlying mechanism has not been fully elucidated. Defects in zinc-dependent enzymes such as alkaline phosphatase and lactate dehydrogenase have been considered as potential factors in SCD; however, alkaline phosphatase levels remained low despite moderate-dose zinc supplementation in the studies by Prasad and Cossack.[17]

In this article, we describe the endocrine and metabolic disorders reported in patients with SCD, discuss their management, and identify gaps in current knowledge and opportunities for future research. The specific disorders reviewed include growth failure and delayed pubertal development, hypogonadism, diabetes and carbo hydrate intolerance, and primary hypothyroidism.

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