The hepatic lesions were most likely to be IHHs or multinodular hepatic hemangiomatosis that involved the entire liver. We analyzed the patient's urine for angiogenesis markers, which showed normal levels of basic fibroblast growth factor (bFGF) (<1000 pg/L, normal < 4000 pg/L) and VEGF (86 pg/mL, normal < 300 pg/mL) (Table 1). Percutaneous liver biopsy was initially contemplated, but it was deferred after consultation with pediatric oncologists and surgeons who emphasized the high risk of hemorrhage after biopsy.
We elected to initiate therapy with corticosteroids to reduce the size of the tumors, and at age 4.5 months treatment was begun with oral prednisone (3 mg · kg−1 · day−1). Ranitidine was administered to prevent glucocorticoid-associated peptic ulcer disease. Because of the strong association of IHH with consumptive hypothyroidism (1), we analyzed serum levels of thyroid hormone. Initial thyroid function tests revealed an elevated serum level of thyroxine (T4) and a low serum level of 3,5,3-triiodothyronine (T3); the serum thyrotropin (TSH) concentration was elevated (Table 1). Treatment with prednisone was associated with worsening of hypothyroidism: TSH increased despite persistently elevated serum levels of T4 and reverse T3 (Table 1). This unusual pattern of thyroid function studies is consistent with decreased conversion of T4 to T3, the active form of thyroid hormone. Based on these abnormal thyroid function studies, we initiated therapy with liothyronine (T3) when the patient was 5 months old, with rapid normalization of the serum TSH concentration (Table 1). Despite reduced serum levels of TSH, serum T4 levels remained elevated (15.5–17.0 μg/dL).
At 9.5 months of age the infant was noted to have growth failure, with weight at the 33rd percentile and height at the 3rd percentile, with weight for height at the 92nd percentile. She showed features of glucocorticoid excess on examination; at that time, she had already completed more than 4 months of corticosteroid therapy. The decrease in linear growth was thought to be related to her glucocorticoid therapy.
At 10 months of age the liver size had normalized and IHH had regressed. Thus, prednisone was slowly tapered and discontinued. Liothyronine was discontinued at 14 months of age, and subsequent thyroid function tests showed normal serum levels of TSH, T4, and T3, indicating resolution of the previously abnormal thyroid function status. Sequence analysis of the Dio2 gene, which encodes the type II iodothyronine 5′-deiodinase (D2), revealed that the patient was heterozygous for a known common allelic variant, Thr92Ala. Her father was homozygous for this variant and her mother was homozygous for the wild-type allele. Thyroid function tests in both parents were normal. The infant was heterozygous for a known benign polymorphism in the Dio2 gene, and her father was homozygous for this allele. No other sequence abnormalities in Dio2 were identified in the infant; thus, it is unlikely that a genetic defect in Dio2 could account for the apparent transient loss of D2 activity in our patient.
At 18 months of age, her IHH had completely resolved and the patient continued to do well developmentally, with weight at the 36th percentile, height at the 58th percentile, and weight for height at the 40th percentile. Repeat duplex sonogram of the liver revealed a homogenous liver with a normal span of 9.5 cm compared with 14 cm earlier. Four months after discontinuation of therapy with liothyronine the patient continued to maintain normal serum thyroid function tests and had returned to a euthyroid state (Table 1 and Fig. 3)
We describe an infant with IHH and abnormal thyroid function tests. In contrast to the typical biochemical profile of consumptive hypothyroidism that occurs in some patients with IHH (12), the pattern of thyroid function tests and the response to physiological doses of liothyronine in our patient were consistent with resistance of the pituitary to feedback by T4. Specifically, the elevated serum concentrations of TSH, T4, and reverse T3 and low or low normal circulating levels of T3 (Fig. 3) are most consistent with the biochemical features that are present in mice with targeted disruption of Dio2(16,17). In contrast to the genetic disruption of D2 activity, the coincidental resolution of the hypothyroidism with regression of the IHH suggests that this condition was likely the result of secretion of a putative factor by the tumor that inhibits D2 activity. The identification of this factor remains unknown, however. Theoretically a high dose of glucorticoids can suppress conversion of T4 to T3, with a resulting increase in rT3 and would suppress TSH and cause a decreased level of T4. In our patient the dose of prednisone was modest and the TSH increased. The increase in TSH is inconsistent with a steroid effect as the primary defect of hypothyroidism.
Thyroid hormones are crucial for neurodevelopment and maintenance of the basal metabolic rate and adaptive responses to stress. Infantile hypothyroidism can lead to severe cognitive and developmental problems. Thyroid hormones are produced in the thyroid gland as the active hormone T3 and the prohormone T4, under the regulation of pituitary TSH. Approximately 15% of circulating T3 is secreted from the thyroid gland, but the majority (∼85%) of T3 is produced by the metabolism of T4 in extrathyroidal tissues. T4 is converted to T3 by outer ring deiodination by 2 related iodothyronine selenodeiodinases, D2 and D1 (Fig. 4). D1 is expressed predominately in liver, kidney, thyroid, and pituitary, and contributes significantly to the circulating concentration of T3. D2 is highly expressed in the anterior pituitary, brown adipose tissue, placenta, thyroid gland, pituitary thyrotroph cells, aortic smooth, and skeletal muscle, where it activates intracellular T4 via conversion to T3 (Fig. 4). Thus, D2 action is required for maintenance of physiological levels of cytoplasmic T3, and thereby D2 modulates nuclear T3 concentration and thyroid hormone action. D3 removes iodine from the inner ring and generates reverse T3, an inactive metabolite.
To our knowledge, the case we report represents a unique form of hypothyroidism and suggests that inhibition of the D2 iodothyronine deiodinanse in humans can cause clinically relevant disease. The absence of a loss of function mutation in Dio2, which encodes D2, and the resolution of hypothyroidism coincident with the tumor regression suggest that IHH secreted a factor that can inhibit the D2 iodothyronine deiodinase or the transport of T4 into T3-producing cells.
We suggest a full set of thyroid function tests including TSH, T3, T4, free T4, and rT3 in patients with IHH. This case suggests that hypothyroidism can arise by at least 2 mechanisms in patients with IHH: consumptive hypothyroidism caused by the overexpression of D3 and impaired generation of intracellular T3 and pituitary resistance to T4 that likely arises as a result of tumor secretion of a putative inhibitor of D2 activity. Further studies will be necessary to determine the prevalence of this inhibitor and its identity by using a serum from a suspected case to perform an in vitro assay to suppress D2 activity, compared with a control serum.
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