EXPERIENCE AND REASON |
Spontaneous Regression of Severe Acquired Infantile Hypothyroidism Associated With Multiple Liver Hemangiomas
* Division of Endocrinology
Department of Biochemistry, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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ABSTRACT |
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 TOP ABSTRACT CASE REPORTSDISCUSSIONREFERENCES |
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A 9-week-old infant presented with severe postnatal hypothyroidism. His hypothyroidism corrected only after his L-thyroxine dose was progressively increased to 28 µg/kg/d. At 6 months of age, multiple clinically asymptomatic hepatic hemangiomas were detected and support a diagnosis of consumptive hypothyroidism as a result of increased type 3 iodothyronine deiodinase activity in the hemangiomas. Coincident with the involution of the hemangiomas, the child’s hypothyroidism improved and L-thyroxin replacement could be stopped at the age of 3 years. Despite some degree of hypothyroidism for several weeks during infancy, his growth and development have been normal.
Key Words: type 3 iodothyronine deiodinase • L-thyroxine • reverse T3 • free T4
Abbreviations: D3, type 3 iodothyronine deiodinase • rT3, reverse T3 • TSH, thyroid-stimulating hormone • fT4, free T4
In 2000, Huang et al1 described an infant with fatal liver hemangiomas and severe infantile hypothyroidism. Supranormal doses of intravenous liothyronine and L-thyroxine were required to normalize the serum thyrotropin concentration. Despite the vigorous replacement therapy, the serum thyroxine concentration remained low. At postmortem analysis, the hemangioma tissue showed high activity of the type 3 deiodinase enzyme (D3), and there was high in situ hybridization of a D3 complementary RNA to hemangioma cells. High D3 activity was thought to be responsible for the increased degradation of T4 to reverse (rT3). We present a similar case with severe hypothyroidism and multiple hepatic hemangiomas. In contrast to all previously reported cases of consumptive hypothyroidism that were associated with massive and clinically symptomatic hemangiomas,2 our patient had no obvious symptoms regarding the hemangioma. We were able to document the course of spontaneous regression of the initial severe hypothyroidism and subsequent normal growth and development.
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CASE REPORTS |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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A male infant was born at 29 weeks of gestation after spontaneous rupture of the membranes. A thyroid-stimulating hormone (TSH) screening test done in the first week of life was normal (<15 mU/L). After an uneventful neonatal course, he presented at 9 weeks of age with mild but increasing jaundice and decreased feeding. His liver edge was barely palpable, and his indirect bilirubin concentration was 211 µmol/L with no measurable direct bilirubin. No liver enzyme activities were measured. His TSH was >100 mU/L, and his free T4 (fT4) was low (5.0 pmol/L). (fT4, TSH, and later T3 were analyzed on a Ciba-Corning/Chiron Diagnostics (Medfield, MA) ACS 180 analyzer and later on a Miles/Bayer Diagnostics Immuno (Tarrytown, NY) 1 analyzer. Initial results were confirmed on an Abbott (Mississauga, Ontario, Canada) AxSym analyzer.) There was no history of any exposure to iodide. A thyroid scan showed intense homogeneous uptake. L-thyroxine replacement was initiated at 13 µg/kg/d. Surprisingly, the child remained lethargic and constipated despite increasing L-thyroxine doses (Table 1). At 16 weeks of age, the concentration of TSH (428.7 mU/L) and rT3 (6.53 nmol/L) remained elevated, whereas fT4 (8.9 pmol/L) and T3 (0.8 nmol/L) were low. (rT3 was measured using a radioimmunoassay kit from Adaltis, Rome, Italy). At that time, he was mildly jaundiced, and his liver was palpable 1 cm below the right costal margin. To exclude any compliance problem, the child was brought daily as an outpatient to the Endocrine Clinic, and an Endocrine Nurse Specialist administered the L-thyroxine. On 2 occasions, blood was drawn before and 3 hours after L-thyroxine administration. fT4 increased from 12.9 to 18.6 pmol/L and from 12.3 to 20.5 pmol/L, confirming that the dose was absorbed.
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At 19 weeks of age, at a peak L-thyroxine dose of 28 µg/kg/d, the child was clinically euthyroid but the TSH concentration was still elevated (97.8 mU/L). Therefore, the thyroxine dose was increased from 125 to 150 µg/d, although the serum fT4 (17.3 pmol/L) was in the normal range. The jaundice had resolved, but the liver was now palpable 2 cm below the costal margin. Bilirubin and other liver function tests were normal. At 6 months of age, the liver was 3 cm below the costal margin, and an ultrasound revealed multiple hepatic hemangiomas (Fig 1). Magnetic resonance imaging of the abdomen revealed no other lesions, and no cutaneous hemangiomas were observed. There was no evidence of congestive heart failure, and no treatment for the hemangiomas was initiated because of a lack of any other cardiovascular, hematologic, or metabolic symptoms.3
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By 26 weeks of age, the TSH concentration finally decreased into the normal range, but the fT4 was elevated at 28.6 pmol/L. The L-thyroxine dose was then gradually reduced and was discontinued at the age of 3 years. A repeat thyroid scan demonstrated normal uptake. At the age of 5.5 years, TSH was slightly elevated (7.6 mU/L) but the rT3 concentration (0.33 nmol/L) was normal. Hearing (tested by speech and impedance audiometry, latest test done at 27 months) and clinical neurodevelopmental assessments have demonstrated no abnormality. After correction for prematurity, his length has followed the 50th percentile, consistent with his parental height centiles. His length and weight at 5.5 years of age are 110.7 cm (50th percentile) and 23.3 kg (90–97th percentile), respectively. The size of the liver hemangiomas decreased over time, but they are still detectable (Fig 1).
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DISCUSSION |
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TOPABSTRACTCASE REPORTSDISCUSSIONREFERENCES |
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Our patient with severe hypothyroidism and multiple hepatic hemangioma resembles the patient described by Huang et al.1 Both their patient and ours required unusually high doses of L-thyroxine to normalize thyroid function. However, unlike their patient, our patient survived, and after the age of 6 months, the thyroxine replacement therapy was gradually reduced and was stopped at 3 years.
Functionally active T4 and T3 are inactivated by inner ring deiodination to rT3 and 3,3'-diiodothyronine, respectively. This inactivation step is catalyzed by D3.4 D3 is highly expressed in fetal liver and placenta. Hence, fetal serum T3 is low whereas fetal serum rT3 is high because of increased degradation of T4 to rT3. After 30 weeks of gestation, there is an increase in serum T3 levels5 associated with an increase in liver type 1 iodothyronine deiodinase and a decrease in D3 activity.4
We hypothesize that in our patient as well, the severe hypothyroidism observed during the first 6 months was attributable to increased thyroxine degradation to rT3 in the liver hemangiomas as a consequence of increased D3 activity.1 The increased serum rT3 levels support this hypothesis. As our patient was clinically well, the risk of liver biopsy was too high to justify obtaining a tissue sample to verify increased enzyme activity. The spontaneous remission of the hypothyroidism probably reflects the involution and gradual regression of the hemangiomas as has been previously reported for liver hemangiomas.6,7 This is supported by the normal rT3 concentration at 5.5 years of age. We speculate that a functional maturation of the hemangioma tissue with a decrease in D3 activity may also occur. It is interesting that during fetal development, hepatic D3 activity decreases after 30 weeks of gestation.4
Recently, Ayling et al8 described a series of 7 patients with hepatic hemangiomas and altered thyroid function. Seven patients had raised TSH concentrations. Thyroxine concentrations were low in 4 of them, increased in 2, and not measured in 1. At least in the 4 patients with low thyroxine levels, increased D3 activity in the hemangioma might explain the decreased serum thyroxine concentrations despite apparently increased TSH concentrations as we would suggest occurred in the patient presented here. All 4 patients showed a remission of hypothyroidism after treatment of the hemangiomas either by hepatic artery ligation or by liver transplantation. In contrast, in our patient, there was a spontaneous regression of hypothyroidism without any intervention regarding the hemangiomas. Surprising is that in 2 of the patients described by Ayling, including 1 with a TSH of 220 mU/L and a thyroid deplete of colloid at autopsy, TSH bioactivity could not be demonstrated. Immunohistochemistry showed positive staining of tumor tissue for thyrotropin. It therefore was proposed that a thyrotropin-like factor was secreted by the tumor. However, in our patient, the thyroid scan was consistent with intense TSH bioactivity. In contrast to all previously reported patients with consumptive hypothyroidism who experienced clinically obvious massive hemangiomas,2 our patient presented with a clinically asymptomatic hemangioma.
When Huang et al1 retrospectively analyzed other patients with hemangiomas, they found increased thyrotropin concentrations in 2 other patients with massive hepatic hemangiomas. In addition, they found D3 activity in 1 hepatic and 2 cutaneous hemangiomas that were analyzed retrospectively. These findings suggest that hemangiomas at sites other than the liver might also lead to acquired hypothyroidism, especially when they are massive. Treatment of the hemangioma may result in improvement of the thyroid function as was recently presented in an adult patient with a vascular tumor expressing D3.9
Of particular interest in our patient is the normal neurodevelopment despite a prolonged period of hypothyroidism in early infancy. In infants with congenital hypothyroidism, persistent hyperthyrotropinemia (>97 mU/L at 19 weeks of age) might be a poor prognostic sign for normal neurodevelopment.10 However, our patient did not have congenital hypothyroidism and was spared the effects of decreased intrauterine thyroid hormone. The hyperthyrotropinemia was acquired, not persistent, as evidenced by the normal neonatal thyroid screen. Although the accurate assessment of neurodevelopment in the first 6 months of life was complicated by the inherent complexities of such assessments in a child who was born prematurely, at 2 years of age, there was no evidence of any neurologic sequelae. It is possible that our patient still may have some subtle learning difficulties that did not declare themselves by 5.5 years of age.
Because the patient presented here was otherwise asymptomatic, we concluded that a search for (liver) hemangiomas should be undertaken in infants with unexplained severe acquired hypothyroidism with a normal eutopic thyroid gland and apparent unresponsiveness to thyroxine treatment. In these patients, L-thyroxine doses should be increased gradually until normalization of thyroid function occurs. This may require supranormal doses of thyroid hormone and frequent titration of the dose of thyroid hormone replacement to normalize biochemical parameters. Combined therapy with liothyronine may be considered. In more severe cases of hepatic hemangiomas, parenteral thyroxine administration, with or without liothyronine, may be used to bypass the liver and hemangioma. Fortunately, such hemangiomas may demonstrate variable amounts of spontaneous regression, leading to an increase in the amount of mature hepatic tissue compared with immature hemangioma tissue. With aggressive treatment of the transient severe hypothyroidism, normal growth and development may occur. We support the recent recommendation of monthly thyroid function testing in infants with large hemangiomas through the first year of life.9
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ACKNOWLEDGMENTS |
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Dr Konrad was supported by grants from the Swiss National Science Foundation, the Research Institute of The Hospital for Sick Children (Clinician Scientist Award), and the Zürcher Diabetes Gesellschaft. We thank Dr R.W. Moore of Sunnybrook Medical Centre, Toronto, for the rT3 assays and Dr R. Ng for referring the patient.
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FOOTNOTES |
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Received for publication Aug 14, 2002; Accepted Mar 11, 2003.
Reprint requests to (K.P.) Division of Endocrinology, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8, Canada. E-mail: kusiel.perlman{at}sickkids.ca
Dr Ellis’s current affiliation is Department of Clinical Biochemistry, St. John’s Hospital, Livingston, West Lothian, Scotland.
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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