*Department of Pediatrics
†Department of Radiology, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Baltimore, MD
‡Pediatric Interventional Radiology, Texas Children's Hospital, Houston, TX
§Division of Endocrinology and Diabetes, the Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA.
Address correspondence and reprint requests to Wikrom Karnsakul, MD, Assistant Professor, Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins University School of Medicine, Brady 320, 600 N Wolfe St, Baltimore, MD 21287 (e-mail: firstname.lastname@example.org).
Received 16 March, 2011
Accepted 17 June, 2011
The authors report no conflicts of interest.
Infantile hepatic hemangiomas (IHHs) are the most common tumors of infancy and occur in approximately 5% of children younger than age 1 year (1–4). Hemangiomas are postulated to arise from dysregulated angiogenesis (3,5), and vascular endothelial growth factor (VEGF) may play a role in the development of these tumors; thus, serum levels of VEGF can be used for diagnostic and therapeutic guidance (2). VEGF levels could be different in the proliferative versus involuting hemangiomas (6). A recently published study has shown that corticosteroids can suppress VEGF-A production by hemangioma-derived stem cells, thereby inhibiting vasculogenesis (7). Hepatic hemangioma can occur at all ages, diagnosed most commonly in individuals ages 30 to 50 years. Infants develop a type of hepatic hemangioma called benign hepatic hemangioendothelioma; these IHHs have also been detected prenatally in a growing fetus (8,9). IHHs are the most common benign neoplasm of hepatic vascular neoplasms of infancy; most are small and clinically silent. Symptomatic patients present in the first few months of age with a history of abdominal enlargement with or without other symptoms or signs related to their unique physiology. Extensive multifocal or diffuse hemangiomas may manifest as cardiac failure secondary to high-volume shunting, hypothyroidism, jaundice, and abdominal compartment syndrome. Hepatic failure is uncommon except after poorly performed embolization.
Treatment of symptomatic IHH is aimed toward tumor suppression by the administration of corticosteroids, β-blockers, vincristine, and, in some instances, endovascular or surgical intervention. (10,11) Currently, first-line treatment consists of β-blocker (propranolol) therapy. Embolization may be required for severe high-output cardiac overload, only if pharmacotherapy is unsuccessful. Several groups have reported the development of an unusual form of consumptive hypothyroidism in infants with IHH (12–15). The hemangiomas in these infants express excessive amounts of type 3 iodothyronine 5-deiodinase (D3). This enzyme is considered an inactivating enzyme because it converts T4 and T3 to inactive metabolites reverse T3 and 3,3-di-iodothyronine, respectively, by 5-deiodination. Varying degrees of hypothyroidism have been reported in affected patients, from clinically silent increases in serum thyroid-stimulating hormone (TSH) to severe hypothyroidism associated with cardiac failure and profound mental retardation (1). The treatment of these patients usually requires administration of large amounts of thyroid hormone. Excessive expression of D3 is noted in hemangioma tissues from several patients, including an infant with IHH and severe hypothyroidism who required extremely high doses of liothyronine in addition to levothyroxine supplementation (12). Here we report on an infant with IHH who developed hypothyroidism caused by apparent inhibition of the conversion of T4 to T3, which was responsive to treatment with a small amount of liothyronine.
A 4-month-old African American girl was noted to have abdominal distension by her parents. The pediatrician noted massive hepatomegaly and referred her to the Johns Hopkins Hospital for consultation. At the time of her initial evaluation height and weight were at the 69th and 76th percentile, respectively, and weight for height was at the 68th percentile. The physical examination was significant for an enlarged liver with a sharp edge that was 12 cm below the right costal margin, splenomegaly with a spleen tip that was 4 cm below the left costal margin, and an abdominal girth of 49 cm. No vascular skin lesions were noted.
The patient was delivered at 41 weeks of gestation from her 19-year-old G1P0A0 mother by cesarean section because of the failure of labor to progress. The pregnancy was uneventful except for a weight gain of 50 lb and the development of premature contractions at 33 weeks of gestation that responded to administration of tocolytics. Birth weight was 3630 g; the physical examination was remarkable for jaundice for which she was treated with phototherapy for 2 days. She had been discharged home with her mother at age 4 days without any complications.
Laboratory investigation demonstrated a serum albumin concentration of 3.7 g/dL and an abnormal liver panel (aspartate aminotransferase 84 U/L, alanine aminotransferase 37 U/L, lactic dehydrogenase 607 U/L, and γ-glutamyl transpeptidase 556 U/L). Total and direct bilirubin were normal (0.4 and 0.1 mg/dL, respectively). Other biochemical analyses were normal, including serum uric acid (4.2 mg/dL), phosphorus (7.7 mg/dL), α-fetoprotein (64 ng/mL, normal range 0–74 for this age group), prothrombin time 12 seconds, and partial thromboplastin time 37.5 seconds. Hemoglobin was 10 g/dL, hematocrit 31%, white blood cell count 6220/mm3, and platelets 452,000/mm3 with a normal differential count. Duplex sonogram of the liver demonstrated multiple nodular lesions of varying size throughout that were mildly vascular without exaggerated hepatic arterial and venous flow (Figs. 1 and 2). A contrast-enhanced computed tomography (CT) scan of the abdomen showed peripheral rim enhancement of these hepatic nodules and decreased caliber of the aorta below the celiac axis. An echocardiogram and magnetic resonance angiogram of the brain were normal.
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.
1. Christison-Lagay ER, Burrows PE, Alomari A, et al. Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg
2. Takahashi K, Mulliken JB, Kozakewich HP, et al. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest
3. Boscolo E, Bischoff J. Vasculogenesis in infantile hemangioma. Angiogenesis
4. Sevinir B, Ozkan TB. Infantile hepatic hemangioendothelioma: clinical presentation and treatment. Turk J Gastroenterol
5. Moon SB, Kwon HJ, Park KW, et al. Clinical experience with infantile hepatic hemangioendothelioma. World J Surg
6. Przewratil P, Sitkiewicz A, Andrzejewska E. Local serum levels of vascular endothelial growth factor in infantile hemangioma: intriguing mechanism of endothelial growth. Cytokine
7. Greenberger S, Boscolo E, Adini I, et al. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med
8. Dreyfus M, Baldauf JJ, Dadoun K, et al. Prenatal diagnosis of hepatic hemangioma. Fetal Diagn Ther
9. Dong KR, Zheng S, Xiao X. Conservative management of neonatal hepatic hemangioma: a report from one institute. Pediatr Surg Int
10. Zheng JW, Ye WM, Wang YA, et al. Current treatment of infantile hemangiomas: an overview of the literature. Shanghai Kou Qiang Yi Xue
11. Mazereeuw-Hautier J, Hoeger PH, Benlahrech S, et al. Efficacy of propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. J Pediatr
12. Huang SA, Tu HM, Harney JW, et al. Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med
13. Kalpatthi R, Germak J, Mizelle K, et al. Thyroid abnormalities in infantile hepatic hemangioendothelioma. Pediatr Blood Cancer
14. Bessho K, Etani Y, Ichimori H, et al. Increased type 3 iodothyronine deiodinase activity in a regrown hepatic hemangioma with consumptive hypothyroidism. Eur J Pediatr
15. Balazs AE, Athanassaki I, Gunn SK, et al. Rapid resolution of consumptive hypothyroidism in a child with hepatic hemangioendothelioma following liver transplantation. Ann Clin Lab Sci
16. Christoffolete MA, Arrojo e Drigo R, Gazoni F, et al. Mice with impaired extrathyroidal thyroxine to 3,5,3′-triiodothyronine conversion maintain normal serum 3,5,3′-triiodothyronine concentrations. Endocrinology
17. Schneider MJ, Fiering SN, Pallud SE, et al. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol