Annals of Clinical & Laboratory Science 37:280-284 (2007)
© 2007 Association of Clinical Scientists
Rapid Resolution of Consumptive Hypothyroidism in a Child with Hepatic Hemangioendothelioma Following Liver Transplantation
Andrea E. Balazs1,
Ioanna Athanassaki1,
Sheila K. Gunn1,
Nina Tatevian1,
Stephen A. Huang2,
Morey W. Haymond1 and
Lefkothea P. Karaviti1
1 Division of Pediatric Endocrinology and Metaboolism, and Department of Pediatric Pathology of Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas; 2 Division of Endocrinology, Children’s Hospital Boston, Harvard Medical School, Boston, Massachusetts
Address correspondence to Morey W. Haymond, M.D., Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, 1100 Bates Street, Houston, TX 77030, USA; tel 713 798 6776; fax 713 798 7119, e-mail mhaymond{at}bcm.tmc.edu.
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Abstract
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We report a unique case of a 3-mo-old female with consumptive hypothyroidism and liver hemangioendothelioma who required pharmacological doses of thyroid hormones and was cured following liver transplantation. Liver hemangioendotheliomas are capable of producing an excess of the thyroid hormone inactivating enzyme, type-3 iodothyronine deiodinase. The increased tumoral enzyme activity leads to rapid degradation of thyroid hormones, resulting in consumptive hypothyroidism. Review of similar cases indicated variable outcomes. We focus on our patient’s clinical course and describe in detail the thyroid hormone replacement therapy and a unique outcome of this rare type of hypothyroidism. This first example of a prompt and complete resolution of consumptive hypothyroidism in an infant after liver transplantation confirms the concept and the reversibility of consumptive hypothyroidism and provides novel insights into the rapidity of response of the infant’s hypothalamic-pituitary-thyroid axis to thyroid hormone replacement.
Keywords: liver hemangioendothelioma, consumptive hypothyroidism, liver transplantation
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Introduction
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The association between consumptive hypothyroidism and liver hemangioendothelioma was first reported in 2000 [1]. Liver hemangioendotheliomas contain increased type-3 deiodinase mRNA and elevated type-3 deiodinase enzyme activity [1,2]. Type-3 deiodinase is the enzyme that is primarily responsible for the inactivation of thyroxine (T4) and triiodothyronine (T3). When the rate of inactivation exceeds the maximum synthesis rate of T4 and T3, hypothyroidism results [1,2]. In some cases, children with this condition require pharmacological doses of T4 and T3 (22 to 70 µg/kg/day, whereas the normal replacement dose is 5–10 µg/kg/day) to maintain euthyroid status (normal plasma thyrotropin (TSH) concentration) [1,3,4].
We describe the pre-surgical management and the prompt and permanent resolution of the consumptive hypothyroidism following liver transplantation in a 3-mo-old infant. The surgical aspect of the case has been briefly reported, but not the endocrine aspect [5]. Based on this experience, we believe that the ultimate replacement dose, which normalized the serum TSH concentration, reflects the tumor growth and the rate of whole body type-3 deiodinase activity. Following liver transplantation, the patient’s thyroid function returned to normal, indicating intact thyroid gland function and regulation. We recommend rapid and aggressive thyroid replacement therapy in children with this disorder.
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Case Report
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The patient was a 2.8 kg product of a normal pregnancy, labor, and delivery. Her newborn thyroid screening studies were reported to be normal. At 6 wk of age she was brought to our emergency room with an acute febrile illness and abdominal distension. On physical examination she had a normal thyroid gland, abdominal distension, and hepatomegaly. Abdominal ultrasound, CT, and Doppler studies were consistent with multinodular hepatic hemangioendothelioma. She was treated initially with prednisone, 15 mg/day, and was discharged at 8 wk of age.
At 3 mo of age the patient was hospitalized for respiratory distress and further abdominal distension. Upon admission her weight was 6 kg. Laboratory studies revealed a serum TSH of 182 µIU/ml (normal 0.3 – 5.0 µIU/ml), serum free T4 of 0.8 ng/dl (normal 1.0–2.5 ng/dl), and a serum T3 of 144 ng/dl (normal 85–250 ng/dl) that decreased to 60 ng/dl on the 5th hospital day. No serum anti-peroxidase or anti-thyroglobulin antibodies were detected. She was started on oral thyroid medication with 88 µg L-thyroxine daily (14 µg/kg/day) (Fig. 1
). The usual replacement dose at this age is 7 µg/kg/day [1].
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Fig. 1. The upper part of the graph depicts the serum TSH concentrations, the second panel shows the serum T3 concentrations, the third panel shows the serum free T4 concentration, and the fourth panel shows the serum T4 concentrations. The dashed lines show the normal range for each hormone. The bottom panel shows the L-thyroxine and triiodothyronine treatments. The arrow indicates the time of the orthotopic liver transplant. The number 1952 in the rectangle shows the extremely high serum T3 concentration post surgery, after one thyroid hormone dose. To convert values for thyroxine to nmol/L, multiply by 12.87; to convert values for triiodothyronine to nmol/L, multiply by 0.0154; to convert free thyroxine values to pmol/L multiply by 12.87.
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The patient was begun on 
-interferon (9 x 106 units; 1.5 x 106 units/kg) and continued at a dose of 134.000 units/kg/day for 5 wk. In addition, she was switched from prednisone to dexamethasone (2.5 mg/day). An echocardiogram revealed a small persistent foramen ovale and patent ductus arteriosus with bilateral atrial dilatation but good bilateral ventricular function. Abdominal distension secondary to hepatomegaly progressed due to tumor growth and resulted in deterioration of her respiratory status, necessitating mechanical ventilation. At 14 wk of age (hospital day 13), she developed transient bradycardia and temperature instability. Her serum free T4 level was 1.1 ng/dl, her serum TSH was 68 µIU/ml, and her weight was 6.7 kg. She was subsequently diagnosed with Moraxella pneumonia, for which she was treated. Because she could no longer receive fluids or medications orally, the oral thyroid hormone replacement was discontinued and all subsequent thyroid hormone was administered intravenously. Following the initiation of iv L-thyroxine (44 µg L-thyroxine daily, 6.5 µg/kg/day, on hospital day 14), her free T4 decreased to 0.7 ng/dl and TSH decreased to 39 µIU/ml. Three days later her L-thyroxine dose was increased to 90 µg per day (13 µg/kg/day) but, despite this increase, her serum TSH increased from 39 µIU/ml to 65 µIU/ml and her serum free T4 decreased to 0.6 ng/dl (Fig. 1
). Thyroid hormone doses were progressively increased on the basis of the serial thyroid function tests every 5 to 7 days. We added iv triiodothyronine in an attempt to normalize the TSH. On the 29th day of hospitalization, the serum reverse-T3 level was 900 ng/dl (normal 10–50 ng/dl). By the 50th hospital day, her weight increased to 7.5 kg and serum TSH level (3.4 µIU/ml) decreased progressively to within the normal range and remained normal, whereas her serum T3 (60 ng/dl) remained below the lower limit of normal for her age at a total daily dose of 625 µg (75 µg/kg/day of T4 and 19 µg/kg/day of T3, a total of 94 µg/kg/day).
Because of the normalization of her serum TSH level, the thyroid hormone dose was decreased by 40%, which resulted in a dramatic increase in her serum TSH (from 3 to 32 µIU/ml) within 48 hr (Fig. 1). At the same time her serum T3 level was 51 ng/dl and her T4 level was 9.7 µg/dl (normal 7 to 15 µg/dl). Because of further progression of respiratory distress, the patient was ultimately listed for and underwent orthotopic liver transplantation on hospital day 65. No extra-hepatic tumor was observed at the time of transplantation. On the day of surgery in the morning (0900 hr) she received 500 µg of L-thyroxine iv (75 µg/kg/day). On the next day (day 66), (post-operative day #1) at 0100 hr, she received 125 µg of triiodothyronine iv (19 µg/kg/day), which resulted in serum T3 increasing to 1952 ng/dl, when serum T4 was 3.6 µg/dl, free T4 was 1.7 ng/dl, and TSH was 3.7 µIU/ml. On the same day at 0900 hr, before the serum T3 level was known, she received 500 µg of L-thyroxine iv (75 µg/kg/day), resulting in a total dose of 625 µg (94 µg/kg/day) of thyroid hormone. Her serum T3 level decreased to 721 ng/dl by 1700 hr. Subsequently all thyroid hormone replacement therapy was discontinued on day 67 of hospitalization and she remained euthyroid. On the 2nd post-operative day (day 67), the seum T3 was 125 ng/dl; on the 3rd post-operative day, serum TSH was 0.14 µIU/ml; on the 6th post-operative day, serum TSH was 0.6 µIU/ml and free T4 was 1.7 ng/dl; on the 9th postoperative day, serum TSH was 2.4 µIU/ml and T3 was 123 ng/dl; on the 17th post-operative day, serum TSH was 1.96 µIU/ml, T4 was 8.6 µg/dl, free T4 was 1.3 ng/dl, and T3 was 215 ng/dl.
Following liver transplantation, she had transient thrombocytopenia and hypoalbuminemia for which she was treated. Since the transplantation she has been hospitalized twice for viral pneumonia. Otherwise she has been well and is developing normally. At 13 mo of age her thyroid function studies were normal (T4 10.2 µg/dl, T3 222 ng/dl, TSH 4.4 µIU/ml) without thyroid medication; her weight (9.7 kg) was at the 42nd percentile and height (74 cm) at the 34th percentile.
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Methods
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Thyroid function tests.
Serum concentrations of T4, T3, TSH, and free T4 were measured in the Texas Children’s Hospital chemistry laboratory using ADVIA Centaur hormone assays and direct chemiluminescent technology. Tests for serum anti-thyroglobulin antibody and anti-thyroid peroxidase antibody were performed by the ADVIA Centaur anti-Tg assay and anti-TPO assay, respectively. Serum reverse-T3 concentration was measured in a commercial laboratory (Esoterix, Inc., Calabasas Hills, CA).
Tissue homogenization and type-3 deiodinase assay.
Cellular sonicates of liver hemangioendothelioma and placental tissue were prepared for enzyme analysis using a buffer (pH 6.9) that contained 0.1 M phosphate, 1 mM EDTA, 10 mM dithiothreitol, and 0.25 M sucrose as previously described [6]. Type-3 iodothyronine deiodinase (D3) activity was assayed by high performance liquid chromatography as previously described [7] using 1 to 10 µg of cellular protein, 200,000 cpm of 3,5[125I] 3'-triiodothyronine (New England Nuclear Corp, Boston, MA), 1 mM 6N-propylthiouracil, 10 mM dithiothreitol, and 0 to 10 nM unlabeled T3 in each reaction. Reactions were stopped by addition of methanol and the products of deiodination were quantified by HPLC as described by Richard et al [6]. Tissue D3 maximum velocity (Vmax) was expressed as fmol of T3 inner-ring deiodinated per mg of sonicate protein per min.
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Results
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The explanted liver weighed 1199 g, approximately 7 times the normal size. The multinodular hem-angioendothelioma almost replaced the entire liver, without disrupting Glisson’s capsule. The liver was sectioned and stained with hematoxylineosin and immunohistochemical stains. Microscopic examination revealed a type II hemangioendothelioma composed of intercommunicating vascular channels, lined by a single layer of endothelial cells, and occasionally demonstrating atypia and increased mitotic activity. Upon immunohistochemical staining for CD34, the tumor cells were positive, indicating an endothelial tissue (Fig. 2). Increased proliferative activity was confirmed by KI-67 (MIB-1) immunohistochemical staining. Cytogenetic analysis of the tumor revealed a normal 46,XX karyotype; no deletion of chromosome 6 was found.
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Fig. 2. The macroscopic photograph shows the cut section of the explanted liver. The multinodular hemangioendothelioma almost replaced the entire liver. Under high magnification x100, on the photomicrographic insert, active proliferation of the vascular channels can be observed. The immunohistochemical stain for CD34 (QBEnd-10, Signet Labs, Emeryville, CA) highlights the endothelial lining of the vessels.
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The patient’s hemangioendothelioma expressed high D3 enzymatic activity. The maximal velocity (Vmax) of this tumor (62 fmol of T3 deiodinated/min/mg protein) was similar to that of a human term placenta (60 fmol/min/mg protein) used in the same assay as a positive control, since normal liver has little D3 activity [6]. Inner-ring deiodinase activity was confirmed to be authentic D3 by its resistance to 1 mM propylthiouracil (PTU) and a nanomolar Km for T3 (0.4 nM T3).
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Discussion
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This case report documents the cure of a child with liver hemangioendothelioma and consumptive hypothyroidism. A total dose of thyroid hormone of 94 µg/kg/day using a combination of iv L-thyroxine (75 µg/kg/day) and iv triiodothyronine (19 µg/kg/day) normalized the elevated serum TSH concentrations. This dose is the largest supplemental dose reported in a child with consumptive hypothyroidism. We believe that the reverse-T3 concentration and the total thyroid replacement dose that normalized the serum TSH both reflect the type-3 deiodinase activity of the tumor. We estimate that her whole body deiodination rate was approximately 17 times normal. Type-3 deiodinase enzyme activity of our patient’s tumor was significantly elevated, compared to normal liver, and was equivalent to the D3 activity of mature human placental tissue. In this patient, tumor growth and the presumed increase in whole body D3 activity paralleled the dramatic increase in thyroid hormone requirement, which necessitated a near doubling of the thyroid hormone supplement every 5–7 days. In addition, the patient was treated with high dose dexamethasone (equivalent to 200 mg/m2/day hydrocortisone) during the first wk of hospitalization, which could contribute to the decrease of T3 by hospital day 5, since large doses of glucocorticoids may cause up to a 30% decrease in serum T3 level [8]. Glucocorticosteroids can increase the thyroid hormone requirement by inducing type-3 deiodinase activity [9] and can maintain persistently low T3 concentrations by impairing the type-1 deiodinase function, leading to decreased conversion of T4 to T3 [10,11]. The patient’s non-thyroid illness probably influenced the serum thyroid hormone concentrations, as well, although it is impossible to estimate the magnitude of its effects, if any, in this complex physiology.
The clinical outcomes of children with consumptive hypothyroidism associated with liver hemangioendothelioma are variable (Table 1) [1–4,12–13]. In the cases reported to date (8 infants and 1 adult) there has been spontaneous regression of the tumor in 2 cases and incomplete resolution after a variety of treatment approaches in the other cases. All of the surviving children and the one adult required thyroid hormone supplementation for months or years, despite liver transplantation or spontaneous regression, hepatic artery ligation, or radiotherapy of the tumor. Two children failed all treatment and died.
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Table 1. Thyroid hormone replacement doses and outcome data in patients with consumptive hypothyroidism caused by liver hemangioendothelioma.
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Our patient’s outcome differs from the reported cases in that: (a) her consumptive hypothyroidism immediately resolved after liver transplantation, presumably because all of her tumor was removed with the hepatectomy; and (b) her thyroid gland function rapidly returned to normal. Her unique outcome illustrates not only the dependence of consumptive hypothyroidism on tumoral type-3 deiodinase activity but the complete reversibility of this type of hypothyroidism and the rapid recovery of the infant’s hypothalamopituitary-thyroid gland axis.
In conclusion, in children with hepatic hemangioendothelioma and consumptive hypothyroidism, normalization of serum TSH concentration can be achieved by aggressive thyroid hormone replacement. A progressive increase in thyroid hormone replacement requirements may indicate continued tumor growth and reflects the whole body type-3 deiodinase activity. In a patient in whom complete removal of the hemangioendothelioma is not possible, the thyroid hormone replacement dose necessary to normalize serum TSH is an indicator of ongoing tumor activity. We recommend rapid and aggressive thyroid hormone replacement in children with this disorder.
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References
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Abstract
Introduction
