Case 2: Primary hypothyroidism in an infant with hepatomegaly

A one-month-old female infant presented with lethargy, prolonged jaundice and hepatomegaly. Pregnancy and delivery were uneventful, and the newborn screen was normal. On physical examination, the baby was lethargic but rousable. Length was 52.5 cm (third percentile), weight 4.5 kg (10th to 25th percentile) and head circumference 37 cm (third to 10th percentile). She was visibly jaundiced, the anterior fontanelle was of normal size, and she did not have a hoarse cry. No goiter was detected. Cardiac examination revealed tachycardia (heart rate 130 beats/min) and a 2/6 systolic ejection murmur. There was no respiratory distress. The abdomen was markedly distended, with a liver edge palpable just above the pelvic brim and no audible bruit heard over the liver. A reducible umbilical hernia was observed. Initial laboratory investigations revealed a hemoblogin level of 59 g/L (normal range 90 g/L to 140 g/L), thyroid-stimulating hormone level 352 mU/L (normal range 1 mU/L to 10 mU/L) total bilirubin level of 153 μmol/L (<20 μmol/L), conjugated bilirubin level 9 μmol/L (<10 μmol/L), alpha-fetoprotein level 5470 μg/L (<9 μg/L), aspartate aminotransferase level 50 U/L (<60 U/L), alanine aminotransferase level 12 U/L (<50 U/L), gamma-glutamyltransferase level 225 U/L (<55 U/L) and random blood glucose level 4.5 mmol/L. Further investigations revealed the underlying diagnosis. Magnetic resonance imaging of the abdomen revealed multiple well-circumscribed round lesions in the liver resulting in massive hepatomegaly, with the largest lesion measuring 7.5 cm × 6.6 cm × 5.5 cm (Figure 1). The lesions demonstrated peripheral nodular enhancement with centripetal progression, most consistent with a diagnosis of infantile hepatic hemangioendotheliomas. Further investigations showed profound primary hypothyroidism: thyroid-stimulating hormone (TSH) level 352 mU/L (normal range 1 mU/L to 10 mU/L), free tri-iodothyronine (FT3) 1.8 pmol/L (normal 2.4 pmol/L to 9.8 pmol/L), free thyroxine (FT4) 4.3 pmol/L (normal 9 pmol/L to 21 pmol/L), reverse tri-iodothyronine 511 ng/dL (normal 8.1 ng/dL to 52.8 ng/dL) Magnetic resonance imaging of the abdomen demonstrating multiple well-circumscribed round lesions with peripheral nodular enhancement and centripetal progression The patient was started on 50 μg L-thyroxine (10 μg/kg/day); however, the TSH level remained high, with an elevated FT4 level and low FT3 level. L-thyroxine was titrated up to a maximum of 125 μg (25 μg/kg/day) over an eight-week period before TSH and FT3 normalized. Prednisone was used to treat the hemangioendotheliomas in the first month of medical therapy. However, the patient continued to experience emesis, abdominal distension, discomfort while supine and a protruding umbilical hernia. Propranolol was added in addition to the prednisone, and by the second month of medical therapy, the abdominal distension improved greatly. With involution of the hepatomegaly, the patient developed symptoms of hyperthyroidism including irritability, increased stool frequency, tremulousness and a lid retraction, giving the infant a staring appearance. The L-thyroxine was discontinued and FT3 remained in the normal range. A repeat ultrasound at six months of age showed extensive shrinking in tumour size and number of lesions, with the largest measuring 2.6 cm × 2 cm × 2.7 cm. Infantile hepatic hemangioendotheliomas are the most common tumour of the liver in infants and may be complicated by hypothyroidism (1,2). The endothelium of these vascular tumours produces type 3 deiodinase, which converts thyroid hormones to inactive metabolites (2). Type 3 deiodinase rapidly converts thyroxine to reverse tri-iodothyronine and tri-iodothyronine to di-iodothyronine. The tumour can occupy most of the liver, which has been postulated to decrease the degradation of type 3 deiodinase by the liver (3). This process results in a state of consumptive hypothyroidism (2). Infants with hypothyroidism usually present with lethargy, poor feeding and prolonged jaundice, which can be confused for symptoms resulting from the hepatic hemangioendotheliomas. The liver mass can result in abdominal distension and respiratory distress (2–4). Some lesions form significant arteriovenous shunts, which result in high-output cardiac failure, anemia and consumptive coagulopathy (5). On the other hand, some patients are asymptomatic, and multiple or extensive cutaneous hemangiomas would be an indication to screen for liver hemangioendotheliomas and monitor for consumptive hypothyroidism (6,7). Consumptive hypothyroidism requires high replacement doses of L-thyroxine ranging from 15 μg/kg/day to 30 μg/kg/day, compared with congenital hypothyroidism, in which the dose is 10 μg/kg/day to 15 μg/kg/day (4). Hypothyroidism can be refractory to high doses of L-thyroxine because of the rapid deiodination of tri-iodothyronine to reverse tri-iodothyronine and may require replacement with triiodothyronine (liothyronine). However, tri-iodothyronine is expensive and may not be readily available. TSH, FT3 and FT4 levels should be monitored closely, and the dose of L-thyroxine should be titrated with the goal of normalizing FT3 and TSH levels. Diagnosing hypothyroidism is particularly important in infancy because it is a treatable and preventable cause for permanent intellectual disability, and tri-iodothyronine is necessary for neurodevelopment, gastrointestinal and cardiac function (8). Liver hemangiomas can cause consumptive hypothyroidism that may not be identified on newborn metabolic screen. All patients with liver hemangiomas should undergo an evaluation of their thyroid function including TSH, FT3 and FT4. The management of consumptive hypothyroidism may require high doses of thyroid hormone replacement, up to 30 μg/kg/day. Multiple cutaneous hemangioendotheliomas may be a clinical clue to evaluate the liver for hemangioendotheliomas and to screen for potential consumptive hypothyroidism.

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