Consumptive Hypothyroidism due to Hepatic Hemangiomas: A Case Series and Review of the Literature

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TL;DR

This case series and systematic review describes consumptive hypothyroidism (CH) caused by hepatic hemangiomas in three infants, two with multifocal and one with diffuse infantile hepatic hemangiomas (IHH). CH results from overexpression of thyroid hormone-inactivating enzyme type 3 deiodinase by vascular tumor endothelium, leading to severe hypothyroidism that requires high-dose levothyroxine and often propranolol therapy. Clinicians should screen for CH in all children with IHH and consider unexplained infantile hypothyroidism as a potential red flag for underlying hepatic hemangioma.

Full summary

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**Background:** Hepatic hemangiomas (infantile and congenital) are benign vascular tumors affecting 4% to 5% of Caucasian infants. Consumptive hypothyroidism (CH) is a rare form of hypothyroidism resulting from overexpression of thyroid hormone inactivating enzyme type 3 (deiodinase) by vascular endothelium, converting thyroxine (T4) to reverse triiodothyronine (rT3) and T3 to diiodothyronine. CH was first described in 2000 by Huang et al. in a 6-week-old infant with multiple hepatic hemangiomas. The expression of D3 in hemangioma is induced by basic fibroblast growth factor and vascular endothelial growth factor, with activity increasing parallel to tumor size.

**Methods:** The authors report three cases of CH associated with infantile hepatic hemangiomas (IHH) from their institution. They also conducted a systematic review of PubMed using search terms for 'Consumptive hypothyroidism' and 'Hemangioma AND Hypothyroidism' with no language or date restrictions. Studies describing CH associated with hemangioma in children were included. Two authors independently extracted data in a stepwise approach.

**Key Results:** - Patient 1: Full-term female, presented at 3 months with abdominal distension and poor feeding. TSH was 58.7 mIU/L. Treated with levothyroxine (10 µg/kg/day) until 13 months and propranolol (1-3 mg/kg/day) until 22 months. At 4 years, normal development; MRI showed absent hemangiomas after 19 months of propranolol and 10 months of levothyroxine. - Patient 2: Preterm male (26 weeks), diagnosed with hypothyroidism at 1 month (TSH: 36,700 mIU/ml — likely a typo for 36.7 mIU/L). Treated with levothyroxine (12 µg/kg/day) until 1 year 9 months and propranolol (1-2 mg/kg/day) for 7 months. Currently off medications since age 3 with normal neurological development. - Patient 3: Full-term, presented at 6 months with pallor, abdominal distension, thrombocytopenia, and coagulopathy (Kasabach-Merritt syndrome). TSH was 60.7 mIU/L. Treated with levothyroxine (15 µg/kg/day), steroids, vincristine, then propranolol (3 mg/kg/day) at 9 months. Hypothyroidism recurred at 32 months with enlarging liver nodules. Underwent liver transplantation at age 3; histology confirmed IHH with foci of Kaposiform hemangioendothelioma. After transplant, levothyroxine was stopped. Mild developmental delay possibly related to autism spectrum disorder.

Systematic review identified 42 studies including 48 patients. CH was found in infants with multifocal/diffuse hepatic hemangiomas (24 cases) and hepatic plus cutaneous hemangiomas (19 cases). Mean age at detection was 1 month. Mean TSH at diagnosis ranged from 15-475 mIU/L. Neonatal screening showed CH in 7 cases, normal in 13, not reported in remaining. Among 43 patients, 8 received propranolol alone, 13 propranolol with other medications, 21 no propranolol; 35 were treated with T4 and 10 with T3. Two patients underwent liver transplantation. CH was also associated with nonhepatic hemangiomas: parotid (2 cases), benign neonatal hemangiomatosis (1), internal acoustic meatus plus cutaneous (1), and large cutaneous hemangioma (1).

**Clinical Implications:** CH should be investigated in all patients with IHH and possibly in those with large cutaneous or extrahepatic visceral hemangiomas. Thyroid function should be periodically assessed, especially when hemangiomas increase rapidly. Early hormone replacement may prevent neurocognitive impairment. Current guidelines recommend abdominal ultrasound when 5 or more cutaneous hemangiomas are present, but IHH can occur with one or no cutaneous lesions, as seen in patients 1 and 3. Feeding difficulties and abdominal distension are red flags. Unexplained infantile hypothyroidism with normal neonatal screening may indicate underlying IHH. The level of rT3 could be useful in nonresponders to T4 but is not always clinically feasible. The authors did not measure rT3 or tissue D3 activity due to bleeding risk from biopsy; diagnosis was inferred from high TSH, poor response to usual levothyroxine doses, and gradual normalization of thyroid profile with hemangioma regression.