Endocrine Dysfunction

Endocrine dysfunction due to iron deposition and toxicity to the endocrine tissue is a common complication of iron overload, causing significant morbidity. Gonadal failure, sterility, and growth failure are common, as well as osteopenia and osteoporosis. Diabetes mellitus may also develop in patients with iron overload.

Routine endocrine screening

Height and weight should be measured accurately at each visit. Evaluate growth on CDC or WHO charts. Ethnic-specific charts are unnecessary. Sitting height should be measured semiannually.

Annual endocrinology consultation and screening should be started at five years of age, after three years of transfusions, or as otherwise clinically indicated. The following tests are recommended annually or semiannually.

1. TSH and free T4
2. Cosyntropin stimulation test (semiannually)
3. PTH
4. Serum calcium, ionized calcium, and vitamin D
5. Fasting glucose (semiannually)
6. Oral glucose tolerance testing as indicated by fasting glucose (see the following section)
7. IGF-1 and IGF BP-3 to screen for growth hormone deficiency
8. Bone density (DXA and CT)
9. Trace elements: zinc, copper, and selenium
10. Vitamins B1, B6, B12, C, E, and A; also pyridoxine, carnitine, methylmalonic acid, and homocysteine.

Specific endocrinopathies: testing and evaluation

Diabetes mellitus

A two-hour oral glucose tolerance test should be performed at 10, 12, 14, and 16 years of age. The oral glucose tolerance test should be performed annually thereafter. If fasting serum glucose is greater than 110 mg/dL, an oral glucose tolerance test is indicated.

• A fasting glucose greater than 126 mg/dL is diagnostic of diabetes mellitus.
• A serum glucose at two hours over 200 mg/dL is diagnostic of diabetes mellitus.
• A serum glucose at two hours between 140 and 200 mg/dL indicates glucose intolerance.
• A casual blood glucose greater than 200 mg/dL with associated symptoms such as polyuria, polydipsia, or unexplained weight loss is diagnostic of diabetes mellitus.

The patient should be referred to endocrinology for management of diabetes mellitus or glucose intolerance. Patients diagnosed with glucose intolerance should have their chelation therapy reviewed and intensified.

Low bone mass (osteoporosis)

Initial bone-density assessment by dual-energy X-ray absorptiometry (DXA) or quantitative computerized tomography (QCT) should be performed at eight years of age and annually thereafter, as necessary. As low bone mass has been observed in all thalassemia syndromes, it is suggested that all patients with thalassemia have an initial bone mineral density assessment. The same method of bone-density measurement should be used for each evaluation. There is significant inter-method variability in bone-density measures. Therefore, different manufacturers of instruments (e.g., Hologic versus Lunar) or methods of assay (DXA versus QCT) are not acceptable for monitoring of a single patient over time.

Bone-density measurements are influenced by the trabecular bone density and the cortical thickness of the bone. Patients with thalassemia have been noted to have thinner bone cortex. Therefore, integral density measures (DXA) may provide different results than a true volumetric density test (QCT).

The current accepted definition of low bone mass for all patients under 50 years is a bone mineral density Z-score by DXA greater than – 2.0. Low bone mass for chronological age may be observed in the spine, the hip, or whole body regions. (The hip region should not be used for diagnosis in patients less than ten years old.)

Patients should have an annual evaluation of calcium metabolism and parathyroid function: nutritional history, 25-hydroxy vitamin D, PTH, and serum calcium should be measured. If the patient has achieved puberty or is pubertal, FSH, LH, and testosterone or estrogen should be examined.

Follow nutritional status and keep up adequate vitamin levels. Supplement with up to 1,300 mg calcium per day starting at nine years of age. Patients with low levels (25-hydroxy vitamin D less than 30ng/mL) or those at high risk to develop vitamin D deficiency should be supplemented with vitamin D (1,000 units per day). Nutrition referral is recommended. (Also see Section 14, on nutrition.)

Endocrine referral is recommended for older patients with established osteoporosis (DXA T-score of greater than – 2.5) prior to treatment with bisphosphonates. Serious thought should be given to the safety of bisphosphonate use in women with childbearing potential.

Growth hormone deficiency

Endocrine evaluation is required if there is a 5 percent or more falloff on the growth curve or poor growth velocity for the age. The evaluation should include the following.

1. A dietary assessment by a registered dietitian
2. Laboratory tests: serum calcium, PO4, albumin, urinalysis, urine culture T4, TSH, IGF-1, and IGF BP-3
3. A bone age assessment

Low IGF-1 or IGF BP-3 should prompt referral to an endocrinologist for determination and treatment of growth hormone deficiency. Early diagnosis, for successful treatment before completion of puberty, is recommended.

Hypogonadism

Tanner staging should be determined every six months. Girls without evidence of an advancing pubertal stage by 12 years and boys by 14 years require screening with LH-ICMA, FSH, and estradiol levels. Bone age films should be obtained.

Elevated LH-ICMA and FSH suggest primary hypogonadism. If LH-ICMA and FSH levels are low for the patient’s age, suspect secondary or tertiary hypogonadism.

If LH-ICMA and/or FSH are abnormal, perform GnRH stimulation. Consider performing this treatment at age 12 in girls and age 14 in boys, then annually as clinically indicated. (This should to be done prior to a blood transfusion on a different day than the oral glucose tolerance test.)

Testosterone level should be checked annually in boys, starting in the early adolescent years (at approximately 12 years old). If a patient’s testosterone level is low, obtain an endocrine consultation and start monthly testosterone treatment. The starting dose is usually 50 to 100 mg, given monthly as an intramuscular shot. The dose will need to be adjusted periodically for the patient’s age and pubertal status, as well as for a sexually active man.

Estrogen replacement is recommended for amenorrheic adolescent girls and adult women: Premarin at a low dose (0.0375 µg per day for six months). The dose should be advanced after six months for an additional six to twelve months. Afterward, an oral contraceptive pill may replace Premarin. A gynecological consultation and fertility evaluation is recommended for women on estrogen therapy.

Hypothyroidism

TSH and free T4 should be measured at five years of age or after three years of transfusion. Elevated TSH and depressed T4 suggest primary hypothyroidism. Depressed TSH and depressed T4 suggest secondary or tertiary hypothyroidism. The patient should be referred for an endocrinology consultation and start replacement therapy as indicated.

Hypoparathyroidism

Parathyroid status should be evaluated annually with serum calcium. PTH, and 25-hydroxy vitamin D screening. A normal PTH with decreased calcium, or a decreased PTH with normal calcium, is diagnostic of hypoparathyroidism. The patient should be referred for an endocrinology consultation and start therapy with vitamin D (use an activated 1,25 OH vitamin D product) and calcium.

Adrenal insufficiency

Adrenal status should be checked biannually beginning at age five, using an ACTH stimulation test. The patient is given 1 µg of cosyntropin intravenously, and cortisol levels are then measured 30 and 60 minutes after dosing. A cortisol response of less than 17 mg/dL is diagnostic of adrenal insufficiency. The patient should be referred for an endocrinology consultation for further evaluation and replacement therapy. If a patient is acutely ill or at risk, the cortisol level is measured and a stress dose replacement is given.