Therapy Insight: metabolic and endocrine disorders in sickle cell disease
Dawn Smiley, Samuel Dagogo-Jack and Guillermo Umpierrez* About the authors
Correspondence *General Clinical Research Center, Emory University School of Medicine, 49 Jesse Hill Jr Drive, Atlanta, GA 30303, USA
Email geumpie@emory.edu
Medscape Continuing Medical Education online
Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please complete the post-test.
Learning objectives
Upon completion of this activity, participants should be able to:
- Describe the prevalence of sickle cell disease and its carrier state among US African Americans.
- Identify the clinical features and treatment of sickle cell disease.
- Describe the most accurate test for the assessment of iron overload in sickle cell disease.
- List predictors of iron overload and diabetes mellitus in patients with sickle cell disease.
- Describe the most common types of endocrine and metabolic disorders seen in sickle cell disease.
Competing interests
The authors declared no competing interests. Désirée Lie, the CME questions author, declared no relevant financial relationships.
To complete the questions online and earn continuing education credits, you must be a registered user on Medscape.com. If you are not registered on Medscape.com please click on the New Users: Free Registration link on the top left-hand side of the website to register. Registration is free. For questions regarding the content of this activity, contact the accredited provider for this CME activity: CME@medscape.net. For technical assistance, contact CME@webmd.net.
Summary
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.
Review criteria
We searched for original articles focusing on sickle cell disease and metabolic disorders or endocrine disorders in Ovid and PubMed published between 1977 and 2007. The search terms we used were "sickle cell anemia", "hemolytic anemia", "growth failure", "metabolic disorders" and "endocrine disorders". All papers identified were English-language, full-text papers. We also searched the reference lists of identified articles for further papers.
Keywords:
endocrine disorders, metabolic disorders, sickle cell anemia
Introduction
Sickle cell disease (SCD) is a hereditary hemoglobinopathy 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 
-globin chains and two 
-globin chains. In sickle cell anemia, a point mutation on the -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
Box 1 Characteristic features of sickle cell disease.
Presentation of symptoms by age63
By 6 months of age, 6% have presented
By 12 months of age, 32% have presented
By 2 years of age, 61% have presented
By 6 years of age, 92% have presented
Life expectancy64
Median age of death 42 years for males and 48 years for females
Nonendocrine clinical features65
Hematologic crises
- Moderate to severe anemia
- Aplastic crises
Vaso-occlusive crises
- Acute chest syndrome
- Cerebrovascular ischemia or infarction
- Retinopathy
- Joint discomfort
Recurrent infection
Gallstones
Renal insufficiency
Priapism
Diagnostic tests (as necessary)
Complete blood count and smear, hemoglobin electrophoresis
Chest radiography to test for pneumonia or infiltrate
Bone radiography
Ultrasonography to evaluate hepatomegaly and splenomegaly
Head CT or MRI for suspected neurologic crisis
Bone scans
Potential crisis precipitants
Infection
Dehydration
Cold weather (causes vasospasms)
Hypoxia or low oxygen tension
Alcohol intoxication
Stress
Pregnancy
Mainstays of treatment
Intravenous and oral hydration
Analgesics for pain control
Antibiotic therapy if needed
Transient oxygen therapy
Transfusion therapy
Endocrine dysfunction has been reported as the most common and earliest toxic effect seen in iron-overloaded subjects.8, 9, 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 transfusions (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, 14, 15, 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 Cossack17 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 carbohydrate intolerance, and primary hypothyroidism.
Endocrine disorders in patients with sickle cell disease
Delayed growth and pubertal development
Growth failure is the most frequent endocrine abnormality observed in patients with SCD.6, 18 Children with SCD have significantly decreased height, weight, and BMI when compared with healthy, control subjects of comparable age, sex, and ethnicity.19 Puberty is delayed an average of approximately 2 years in both boys and girls with sickle cell anemia, resulting in an exacerbation of growth delay in the early and mid-teen years of adolescents with SCD.20 Reasons for decreased growth are multifactorial with contributions from abnormal endocrine function,10 suboptimal nutrition,21 an increase in metabolism because of hyperactivity of the bone marrow and chronic inflammation,22, 23 and hypogonadism.24
Recent evidence suggests abnormalities in the GH–IGF-I–IGFBP3 (growth hormone–insulin-like growth factor I–IGF-binding protein 3) axis as an important etiologic factor of impaired growth in SCD.25, 26 Short children with SCD have significantly decreased serum IGF-I concentrations compared with children with constitutional short stature.18 Decreased synthesis of IGF-I might be secondary to a disturbed GH–IGF-I axis and/or undernutrition, probably due to the hypermetabolic status of these children.18, 25, 26 Several studies have linked excessive caloric loss to elevated resting energy expenditure in children with SCD; this raised expenditure might result from elevated cardiac effort and more-rapid erythropoiesis and protein turnover.23, 27
Delayed onset of puberty is a frequent finding in girls and boys with SCD. Menarche is delayed by a mean interval of 2–3 years.28, 29 A case-control study performed by Soliman et al. found that two-thirds of girls with SCD have delayed breast development (mean age of thelarche at 13.5 years), and the mean age of spontaneous menarche is 15.6 years.18 Similarly, 25% of boys who have SCD and are above the age of 14 years have absent testicular development. Males with SCD and delayed pubertal development have significantly smaller testicular volume and lower testosterone concentrations.18, 30
Gonadal failure
Hypogonadism is one of the most prevalent endocrinopathies in subjects with SCD. Male patients with SCD frequently present with eunuchoid body habitus, absent or diminished secondary sexual characteristics, and small testicular size.31 Biochemical studies have demonstrated low levels of testosterone and dihydrotestosterone and variable levels of follicle-stimulating hormone and luteinizing hormone.10, 12, 30
The etiology for hypogonadism in SCD is unclear; however, several causes have been proposed, including primary testicular failure, hypothalamic and/or pituitary dysfunction, zinc deficiency, and constitutional delay of puberty.18, 21, 32 Primary testicular failure due to structural abnormalities has also been suspected as an important cause of gonadal failure and infertility. Episodes of intravascular sickling, vaso-occlusion, and infarction, as well as tissue hypoxia associated with chronic anemia, are responsible for the testicular failure in SCD.33 Semen analyses in patients with SCD have revealed decreased total sperm counts, reduced sperm density, reduced mobility, and reduced indices of semen quality compared with healthy, fertile control subjects.34, 35 Infertility seems to be a greater problem among males than females with SCD, because such men have rarely fathered children, whereas many women with SCD have had successful pregnancies.36
Adrenal dysfunction
The human adrenal glands are vulnerable to vascular insults from hemorrhage or thromboembolism in patients with SCD. In addition, iron deposition might contribute to pituitary–adrenal axis dysfunction. Osifo et al.37 compared basal plasma cortisol levels among 108 children with various hemoglobin genotypes (AA, AS and SS) and found lower levels in children with the SS genotype compared with those harboring other genotypes. Persons with subcritical hypoadrenalism might remain asymptomatic under unstressed conditions, but the stress of illness (e.g. a sickle cell crisis) can uncover adrenal insufficiency and might even precipitate an Addisonian crisis. Rosenbloom et al.38 assessed the pituitary–adrenal axis (using the insulin hypoglycemia test) in patients with SCD during crisis and non-crisis periods. Plasma cortisol concentrations were diminished during painful crises. The researchers also found impaired 11-deoxycortisol responses to metyrapone in patients with SCD.38
To clarify the underlying mechanisms, Saad and Saad39 measured serum cortisol levels during infusion of synthetic adrenocorticotropic hormone in 14 patients with SCD under crisis-free conditions, and compared their responses with those of 16 controls. They found no significant differences in cortisol responses between the two groups, suggesting a central origin for the hypoadrenalism. More-rigorous studies of the hypothalamic–pituitary–adrenal axis are required, however, to fully understand the definitive lesions along that axis in patients with SCD. As a practical matter, a reasonable index of suspicion for adrenal insufficiency should be entertained when managing patients with sickle cell crisis, especially if there is hemodynamic compromise.
Carbohydrate intolerance and diabetes
Clinical experience in tropical countries with a high incidence of SCD indicates that the concurrence of SCD with either type 1 or type 2 diabetes is a rare finding.40, 41 Although there are no population-based data to determine the relative prevalence of diabetes among patients with SCD in the tropics, it seems that the SCD population enjoys relative 'protection' from diabetes. Theoretical mechanisms for such protection would include the low BMI, hypermetabolism, and possibly other genetic factors.
The situation in the tropics might be quite different from that in affluent countries, where blood transfusions are more widely used to palliate the anemia of SCD.42 Endogenous or exogenous iron overload due to multiple transfusions can result in -cell damage and decreased insulin production. The result can range from glucose intolerance to frank diabetes that requires insulin for control.
There is also evidence of insulin resistance in SCD, implying damage to insulin-responsive mechanisms. A recent report from the Multi-Centre Study of Iron Overload, a 5 year prospective study in Canada, the USA and the UK, reported that diabetes mellitus affects 2% of patients with SCD.12 In logistic regression analysis, the strongest predictor of diabetes was the length of time since patients had started receiving transfusions. After adjusting for diagnosis (e.g. SCD and thalassemia) and serum ferritin levels in the model, both duration and age at which the subject began chronic transfusion remained significant. The analysis revealed that, for every 10 years of transfusion use, transfused subjects with SCD had 2.5-times greater odds of diabetes. The analysis showed, moreover, that transfused patients with thalassemia had 5.2-fold greater odds of diabetes compared with transfused patients with SCD.
HbA1c might not be a reliable measurement of hyperglycemia in some patients with certain types of hematologic disorders, such as SCD.43, 44 Limited data have been published on the effect of such hemoglobinopathies on glycemic monitoring. Schnedl et al.44 reported that several hemoglobinopathies cause false HbA1c results. SCD causes the lifespan of the red blood cell to be shortened to approximately 10–14 days (the normal lifespan is 
120 days). The HbA1c measurement in a person with SCD would, therefore, not accurately reflect glycemic control over a 3 month period as normally expected, because the red blood cells do not have time to become glycosylated before being removed from circulation. Consequently, the measured HbA1c might be spuriously low. Serum fructosamine levels have been proposed as an appropriate laboratory measurement when monitoring long-term glycemic control in patients with diabetes mellitus and SCD.45, 46, 47 Moderately raised serum bilirubin concentrations do not cause any significant interference in the assay of fructosamine in such patients.46
The fructosamine test, a colorimetric assay, is now one of the most widely used tests used to assess glycemic control and corresponds well with the concentrations of glucose and HbA1c.47 A single measurement with this assay provides an assessment of glycemic control over the preceding 2–3 weeks.45, 46, 47, 48 Some limitations with the use of the fructosamine assay have been noted, including the short half-life of fructosamine, which might result in fructosamine being more susceptible to rapid changes in blood glucose, difficulty with standardization of the assay because albumin can be highly affected by disease states and drugs, and limited practical use for outpatient evaluations in which patients are seen at lengthy intervals of 3–6 months. Despite these limitations, it seems that fructosamine might be useful in monitoring glycemic control in patients with SCD, in whom there would be an overabundance of young erythrocytes.
Hypothyroidism
The reports of thyroid assessment in patients with SCD have been inconsistent. Abnormal thyroid function studies have been reported in patients with SCD9, 10, 12 or hemochromatosis.48 Male patients with the SS genotype had significantly lower endogenous T3 and higher TSH levels than a comparison group.49 Stimulation with TSH-releasing hormone showed increases in TSH that were significantly greater in SCD compared with controls and thus were suggestive of primary thyroidal failure.49
The etiology of thyroid dysfunction in SCD is not clear; however, most affected patients have received multiple transfusions consistent with severe iron overload. Autopsy reports in some patients have shown significant iron deposition in the thyroid gland, suggesting that the etiology of the primary thyroid failure might well be transfusional hemosiderosis and subsequent cellular damage to the thyroid gland.50
More-recent studies, however, have failed to show significant clinical abnormalities of the pituitary–thyroid axis. In a study of 90 children with homozygous SCD, 45 children with heterozygous sickle cell trait and 162 control (healthy) children, serum levels of endogenous T4, the in vitro T3 resin uptake (T3RU) and the calculated 'free thyroxine index' (T4 
T3RU) were not significantly different between the three groups.11 The T3RU indirectly measures the number of unoccupied protein binding sites for T4 and T3 in the serum. Low T3RU levels therefore correlate with states of elevated thyroid-binding globulin levels and high T3RU levels correlate with decreased thyroid-binding globulin levels. In situations where a free-T4 assay is not available, the free thyroxine index can be used to correct for variation in thyroid-binding globulin and the calculated result correlates well with the level of free T4 in the circulation.
Body composition and energy expenditure
SCD is associated with a consistent pattern of anthropomorphic findings characterized by low lean body mass and fat mass.18, 19, 32 The combination of increased resting energy expenditure and nutritional factors accounts for many of the reported changes in body composition in children and adolescents with SCD. The effects of chronic illness, anemia, increased cardiac workload, hyperactive erythropoiesis, increased protein turnover, and inflammatory and oxidative stress all contribute to the hypermetabolic state in SCD.23, 27 In one study comparing measures of metabolism derived from indirect calorimetry and the doubly labeled water technique in children with SCD and matched healthy control subjects, the children with SCD had elevated resting energy expenditure but decreased activity-related energy expenditure.51 Elevated resting energy expenditure and lower activity-related energy expenditure, coupled with growth failure, strongly implicate chronic energy deficiency in children with SCD.
Barden et al. studied growth dynamics, nutritional status and body composition in 36 African American children with SCD and 30 healthy control children of similar age and ethnicity.19 Compared with control subjects, children with SCD had impaired growth, delayed skeletal maturation and significantly lower z-scores for weight, height, arm circumference, and upper arm fat and muscle areas. Low z-scores for upper arm fat area indicate subnormal fat stores and the low fat-free mass indicates muscle wasting and low protein stores. Contributory factors for these deficits include decreased appetite and food intake and increased energy expenditure due to hyperactive bone marrow and hypermetabolism.
Better management of nutritional needs and timely correction of endocrine deficiencies have been advocated as a means of improving adult height in children with SCD.18, 51, 52 In contrast to the findings in children and adolescents, a study of adult women with SCD indicated a disproportionately high amount of body fat for their BMI.53 It is thus possible that antecedent nutritional deficiency in childhood might predispose to excessive adiposity later in life.
In addition to macronutrient deficits, deficiencies of zinc and other vitamins have been reported in SCD.54 Children with SCD have, furthermore, been shown to have partial fat and vitamin E malabsorption caused by decreased bile salt secretion.55 Low serum vitamin D status is prevalent in African American children with SCD.52, 56
Risk factors for hypovitaminosis D include inadequate sun exposure, impaired intestinal absorption of vitamin D, hepatic and renal abnormalities, and reduced intake of milk and dairy products because of lactose intolerance, among others. Because diffuse musculoskeletal aches and pains associated with vitamin D deficiency can be confused with or superimposed upon the classical bone pain crisis of SCD, it is imperative that physicians routinely evaluate and correct any vitamin D deficiency. Lastly, socioeconomic status should also be taken into account in addition to clinical factors when assessing nutritional status of patients with SCD and, in turn, the health care provider should tailor an adequate nutrition plan that is appropriate for the patient's financial limitations.
Bone mineral density
Low BMD has been reported in male and female children and adults with SCD.57, 58 In a study of 32 adults with SCD (mean age of 34 years), 72% had low BMD at one or more anatomic sites and 40% were classified as osteoporotic.58 The lumbar spine seems to be particularly susceptible to osteoporotic changes in patients with SCD, and there were significant correlations between low BMD and low BMI, male gender, and low serum zinc concentrations.58 Markers of bone formation are elevated whereas bone resorption is decreased in children with SCD compared with healthy children.58 Additional mechanisms and risk factors for osteopenia in SCD include delayed puberty and low accrual of peak bone mass, bone microinfarcts resulting from repeated sickling crises, chronic illness with immobilization, and calcium, vitamin D and other nutritional deficiencies.56, 59 Despite reports of pervasive osteopenia in SCD, data on fracture risk and effects of therapeutic interventions are lacking.
Management of endocrine dysfunction in sickle cell disease
Treatment of endocrine dysfunction includes replacement of particular hormone deficiencies according to recommended guidelines and improvement of nutritional status (see Box 2). The goals of hormone replacement therapy are to achieve normal levels of circulating hormones, to restore normal physiology as closely as possible, and to avoid symptoms of deficiency with minimal side effects. In patients with documented hormonal deficiencies, the replacement dosage of thyroid, gonadal, adrenal, and growth hormones is similar to that recommended for other causes of endocrine deficiencies.
Box 2 Management of endocrine disorders in sickle cell disease.
- Screen for endocrine disorders and nutritional deficiencies on the basis of clinical suspicion, particularly during growth spurts in childhood and adolescence
- Replace hormone deficiencies according to recommended guidelines and improve nutritional status via counseling, repletion, and continued supplementation as needed
- Replacement dosage of thyroid, gonadal, adrenal, and growth hormones is similar to that recommended for other causes of endocrine deficiencies
- The goals of hormone replacement therapy are to achieve normal levels of circulating hormones, to restore normal physiology, and to avoid symptoms of hormonal deficiency or excess
- In addition to assessing age-appropriate weight goals and daily nutritional requirements, routine evaluation and correction of vitamin D deficiency should be performed
- Although there are no definitive guidelines for dual-energy X-ray absorptiometry (DXA) assessments in patients with sickle cell disease, assessment of BMD and bone area should be considered, since many patients have multifactorial risk factors for bone fracture
Assessment of nutritional needs and correction of caloric, macronutrient, and micronutrient deficits is critical to the holistic management of patients with SCD, particularly during childhood and adolescence growth periods. It is now clear that undiagnosed vitamin D deficiency is rife among African American patients with SCD. Musculoskeletal complaints of hypovitaminosis D can be superimposed on pain crises caused by SCD. Routine evaluation and correction of vitamin D deficiency could, therefore, reduce morbidity associated with SCD. Additional research is needed to determine the screening guidelines and optimal intervention and fracture-prevention strategies for patients with SCD.
The glycemic goal and type of antidiabetic agent used are similar to those of patients with type 2 diabetes. In our experience, most patients require insulin therapy or a combination of oral agents and insulin therapy to achieve glycemic targets. Educating the patients about their disease, including its influence on daily life and the need to modify or change the treatment during intercurrent illness, is an important aspect of their management. Although low BMI and hemorrheological factors might improve insulin sensitivity in children and adolescents with SCD,57 subsequent weight gain in adult years actually poses a risk for diabetes. Such risk is compounded by potential deleterious effects of pancreatic iron overload from multiple transfusions and vasodilation. Dietary interventions to optimize weight should therefore be targeted at adult subjects with SCD who show evidence of overweight.
Chronic iron overload due to red cell transfusion can increase the risk of endocrine disorders in patients with SCD. Despite various efforts to decrease the amount of iron accumulated by the transfusion of red cells, transfusion-induced iron overload continues to be a problem in patients with chronic hemolysis and SCD. Chelation therapy with deferoxamine is the standard of care for patients who have transfusional iron overload, but the necessity to administer this drug parenterally limits compliance. New orally administered chelator agents are safe and effective in reducing iron deposition in patients with SCD.60, 61 Although chelation therapy might prevent the development of end-organ dysfunction, it is unlikely that it will reverse established endocrine deficiencies associated with chronic iron overload.62
The endocrine and metabolic perturbations in SCD range from obvious deficiencies (e.g. growth failure or delayed puberty) to subtle or subclinical deficiencies (e.g. hypoadrenalism or vitamin D deficiency). Timely diagnosis and treatment of these disorders is often delayed as a result of concentration of clinical attention on the primary hematological problems and pain syndromes associated with SCD. A high index of suspicion is thus required to detect endocrine and metabolic disorders in patients with SCD, the proper treatment of which would improve their overall quality of life.
Conclusions
Manifestations of endocrine and nutritional abnormalities are more common than once perceived in patients with SCD with and without evidence of iron overload. The current gaps in medical knowledge afford opportunities for future research investigating optimal approaches to the diagnosis, intervention, and prevention of these hormonal and nutritional dyscrasias.
Key points
- Sickle cell disease is an autosomal, recessive hemoglobinopathy that can be complicated by endocrine dysfunction that is most commonly caused by iron overload in these patients
- MRI, rather than the serum ferritin assay, is the most useful noninvasive screening technique for the detection of the distribution of iron stores
- Increased disease duration and number of blood transfusions (>8 per year) are predictors of iron overload and have been associated with greater risk of endocrine organ failure
- The most common types of endocrine and metabolic disorders seen in patients with sickle cell disease include growth failure, osteopenia, hypogonadism, carbohydrate intolerance, and primary hypothyroidism
- Treatment of endocrine dysfunction includes replacement of particular hormone deficiency and improvement of nutritional status; the goals of hormone replacement therapy for patients with sickle cell disease are to achieve normal levels of circulating hormones, restore normal physiology, and to avoid symptoms of deficiency with minimal side effects
Acknowledgments
D Smiley is supported by a research grant from the NIH (K12 RR-017643). S Dagogo-Jack is supported by research grants from the NIH (R01 DK-067269) and the General Clinical Research Center (M01 RR-00211). G Umpierrez is supported by research grants from the American Heart Association (0555306B), the NIH (R03 DK 073190-01) and the General Clinical Research Center (M01 RR-00039). Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.
References
- Ballas SK (2002) Sickle cell anaemia: progress in pathogenesis and treatment. Drugs 62: 1143–1172 | Article | PubMed | ChemPort |
- Wilson RE et al. (2003) Management of sickle cell disease in primary care. Clin Pediatr (Phila) 42: 753–761 | PubMed |
- Sickle Cell Disease Guideline Panel (1993) Sickle Cell Disease: Screening, Diagnosis, Management, and Counseling in Newborns and Infants. Clinical Practice Guideline No. 6. AHCPR Pub. No. 93–0562. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, US Department of Health and Human Services
- Genes and Disease NCBI [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&&rid=
gnd.section.98] (accessed 26 October 2007) - Olivieri NF (2001) Progression of iron overload in sickle cell disease. Semin Hematol 38 (Suppl 1): 57–62 | Article |
- Batts KP (2007) Iron overload syndromes and the liver. Modern Pathology 20 (Suppl 1): S31–S39 | Article |
- Walter PB et al. (2006) Oxidative stress and inflammation in iron-overloaded patients with -thalassaemia or sickle cell disease. Br J Haematol 135: 254–263 | Article | PubMed | ChemPort |
- Chatterjee R and Katz M (2000) Reversible hypogonadotrophic hypogonadism in sexually infantile male thalassaemic patients with transfusional iron overload. Clin Endocrinol (Oxf) 53: 33–42 | Article | PubMed | ChemPort |
- Phillips G Jr et al. (1992) Hypothyroidism in adults with sickle cell anemia. Am J Med 92: 567–570 | Article | PubMed |
- el-Hazmi MA et al. (1991) Endocrine functions in sickle cell anaemia patients. J Trop Pediatr 38: 307–313 | PubMed | ChemPort |
- Lukanmbi FA et al. (1986) Endocrine function and haemoglobinopathies: biochemical assessment of thyroid function in children with sickle cell disease. Afr J Med Med Sci 15: 25–28 | PubMed | ChemPort |
- Fung EB et al. (2006) Increased prevalence of iron-overload associated endocrinopathy in thalassaemia versus sickle cell disease. Br J Haematol 135: 574–582 | Article | PubMed |
- Alustiza JM et al. (2007) Iron overload in the liver diagnostic and quantification. Eur J Radiol 61: 499–506 | Article | PubMed |
- Harmatz P et al. (2000) Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 96: 76–79 | PubMed | ISI | ChemPort |
- Martin DR and Semelka RC (2005) Magnetic resonance imaging of the liver: review of techniques and approach to common diseases. Semin Ultrasound CT MR 26: 116–131 | Article | PubMed |
- Brittenham GM and Badman DG (2003) Noninvasive measurement of iron: report of an NIDDK workshop. Blood 101: 15–19 | Article | PubMed | ChemPort |
- Prasad AS and Cossack ZT (1984) Zinc supplementation and growth in sickle cell disease. Ann Intern Med 100: 367–371 | PubMed | ChemPort |
- Soliman AT et al. (1999) Growth and pubertal development in transfusion-dependent children and adolescents with thalassaemia major and sickle cell disease: a comparative study. J Trop Pediatr 45: 23–30 | Article | PubMed | ChemPort |
- Barden EM et al. (2002) Body composition in children with sickle cell disease. Am J Clin Nutr 76: 218–225 | PubMed | ChemPort |
- Thomas PW et al. (2000) . Height and weight reference curves for homozygous sickle cell disease. Arch Dis Child 82: 204–208 | Article | PubMed | ChemPort |
- Prasad AS (1997) Malnutrition in sickle cell disease patients. Am J Clin Nutr 66: 423–424 | PubMed | ChemPort |
- Hibbert JM et al. (2006) Erythropoiesis and myocardial energy requirements contribute to the hypermetabolism of childhood sickle cell anemia. J Pediatr Gastroenterol Nutr 43: 680–687 | PubMed |
- Akohoue SA et al. (2007) Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia. Pediatr Res 61: 233–238 | Article | PubMed | ChemPort |
- Barden EM et al. (2002) Body composition in children with sickle cell disease. Am J Clin Nutr 76: 218–225 | PubMed | ChemPort |
- Soliman AT et al. (1997) Growth hormone secretion and circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 concentrations in children with sickle cell disease. Metabolism 46: 1241–1245 | Article | PubMed | ChemPort |
- Collett-Solberg PF et al. (2007) Short stature in children with sickle cell anemia correlates with alterations in the IGF-I axis. J Pediatr Endocrinol Metab 20: 211–218 | PubMed |
- Singhal A et al. (1997) Is there an energy deficiency in homozygous sickle cell disease? Am J Clin Nutr 66: 386–390 | PubMed | ChemPort |
- Balgir RS (1994) Age at menarche and first conception in sickle cell hemoglobinopathy. Indian Pediatr 31: 827–832 | PubMed | ChemPort |
- Abbiyesuku FM and Osotimehin BO (1999) Anterior pituitary gland assessment in sickle cell anaemia patients with delayed menarche. Afr J Med Med Sci 28: 65–69 | PubMed | ChemPort |
- Modebe O and Ezeh UO (1995) Effect of age on testicular function in adult males with sickle cell anemia. Fertil Steril 63: 907–912 | PubMed | ChemPort |
- Abbasi AA et al. (1976) Gonadal function abnormalities in sickle cell anemia. Studies in adult male patients. Ann Intern Med 85: 601–605 | PubMed | ChemPort |
- Reed JD et al. (1987) Nutrition and sickle cell disease. Am J Hematol 24: 441–455 | Article | PubMed | ChemPort |
- Li M et al. (2003) Repeated testicular infarction in a patient with sickle cell disease: a possible mechanism for testicular failure. Urology 62: 551 | Article | PubMed |
- Nahoum CR et al. (1980) Semen analysis in sickle cell disease. Andrologia 12: 542–545 | PubMed | ChemPort |
- Osegbe DN and Akinyanju OO (1987) Testicular dysfunction in men with sickle cell disease. Postgrad Med J 63: 95–98 | PubMed | ChemPort |
- Osegbe DN et al. (1981) Fertility in males with sickle cell disease. Lancet 2: 275–276 | Article | PubMed | ChemPort |
- Osifo BO et al. (1988) Plasma cortisol in sickle cell disease. Acta Haematol 79: 44–45 | PubMed | ChemPort |
- Rosenbloom BE et al. (1980) Pituitary–adrenal axis function in sickle cell anemia and its relationship to leukocyte alkaline phosphatase. Am J Hematol 9: 373–379 | PubMed | ChemPort |
- Saad ST and Saad MJ (1992) Normal cortisol secretion in sickle cell anemia. Trop Geogr Med 44: 86–88 | PubMed | ChemPort |
- Reid HL et al. (1990) Insulin-dependent diabetes mellitus in homozygous sickle cell anaemia. Trop Geogr Med 42: 172–173 | PubMed | ChemPort |
- Mohapatra MK (2005) Type 1 diabetes mellitus in homozygous sickle cell anaemia. J Assoc Physicians India 53: 895–896 | PubMed | ChemPort |
- Alayash AI and al-Quorain A (1989) Prevalence of diabetes mellitus in individuals heterozygous and homozygous for sickle cell anemia. Clin Physiol Biochem 7: 87–92 | PubMed | ChemPort |
- Reid HL et al. (1992) Glycosylated haemoglobin HbA1c and HbS1c in non-diabetic Nigerians. Trop Geogr Med 44: 126–130 | PubMed | ChemPort |
- Schnedl WJ et al. (1999) HbA1c determination in patients with hemoglobinopathies. Diabetes Care 22: 368–369 | Article | PubMed | ChemPort |
- Kosecki SM et al. (2005) Glycemic monitoring in diabetics with sickle cell plus -thalassemia hemoglobinopathy. Ann Pharmacother 39: 1557–1560 | Article | PubMed |
- Yahaya IA et al. (2006) Serum fructosamine in the assessment of glycaemic status in patients with sickle cell anaemia. Niger Postgrad Med J 13: 95–98 | PubMed | ChemPort |
- Panzer S et al. (1982) Glycosylated hemoglobins (GHb): an index of red cell survival. Blood 59: 1348–1350 | PubMed | ChemPort |
- Oerter KE et al. (1993) Multiple hormone deficiencies in children with hemochromatosis. J Clin Endocrinol Metab 76: 357–361 | Article | PubMed | ChemPort |
- Parshad O et al. (1989) Abnormal thyroid hormone and thyrotropin levels in homozygous sickle cell disease. Clin Lab Haematol 11: 309–315 | PubMed | ChemPort |
- Ohene-Frempong K and Steinberg MH (2001) Clinical aspects of sickle cell anemia in adults and children. In Disorders of Hemoglobin: Genetics, Pathophysiology and Clinical Management, 641–670 (Eds Steinberg MH et al.) Cambridge, UK: Cambridge University Press
- Barden EM et al. (2000) Total and resting energy expenditure in children with sickle cell disease. J Pediatr 136: 73–79 | Article | PubMed | ChemPort |
- Buison AM et al. (2004) Low vitamin D status in children with sickle cell disease. J Pediatr 145: 622–627 | Article | PubMed | ChemPort |
- Woods KF et al. (2001) Body composition in women with sickle cell disease. Ethn Dis 11: 30–35 | PubMed | ChemPort |
- Finan AC et al. (1988) Nutritional factors and growth in children with sickle cell disease. Am J Dis Child 142: 237–240 | PubMed | ChemPort |
- Chiu D et al. (1982) Peroxidation, vitamin E, and sickle cell anemia. Ann N Y Acad Sci 393: 323–335 | Article | PubMed | ChemPort |
- Lal A et al. (2006) Bone mineral density in children with sickle cell anemia. Pediatr Blood Cancer 47: 901–906 | Article | PubMed |
- Miller RG et al. (2006) High prevalence and correlates of low bone mineral density in young adults with sickle cell disease. Am J Hematol 81: 236–241 | Article | PubMed |
- Fung EB et al. (2007) Markers of bone turnover are associated with growth and development in young subjects with sickle cell anemia. Pediatr Blood Cancer 135: 574–582
- Almeida A and Roberts I (2005) Bone involvement in sickle cell disease. Br J Haematol 129: 482–490 | Article | PubMed |
- Voskaridou E et al. (2005) Deferiprone as an oral iron chelator in sickle cell disease. Ann Hematol 84: 434–440 | Article | PubMed | ChemPort |
- Kwiatkowski JL and Cohen AR (2004) Iron chelation therapy in sickle cell disease and other transfusion-dependent anemias. Hematol Oncol Clin North Am 18: 1355–1377, ix | Article | PubMed |
- Sklar CA et al. (1987) Adrenal function in thalassemia major following long-term treatment with multiple transfusions and chelation therapy. Evidence for dissociation of cortisol and adrenal androgen secretion. Am J Dis Child 141: 327–330 | PubMed | ChemPort |
- Bainbridge R et al. (1985) Clinical presentation of homozygous sickle cell disease. J Pediatr 106: 881–885 | Article | PubMed | ChemPort |
- Platt OS et al. (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330: 1639–1644 | Article | PubMed | ISI | ChemPort |
- Buchanan GR et al. (2004) Sickle cell disease. Hematology Am Soc Hematol Educ Program 35–47
Competing interests
The authors declared no competing interests.
Contact the journal about this article
Subject areas under which this article appears: Multihormonal system disorders | Metabolism
