Consumptive hypothyroidism: a case report and review of the literature

Abstract

Hepatic haemangioendothelioma is a rare vascular tumour in infants and may be associated with a unique form of thyroid function abnormalities. Hepatic haemangioendotheliomata is capable of producing an excess of the thyroid hormone inactivating enzyme, type 3 iodothyronine deiodinase. The increased enzyme activity leads to rapid degradation of thyroid hormones, resulting in frank hypothyroidism. We report a case of a three-month-old neonate with multiple hepatic haemangioendotheliomata and associated hypothyroidism. The patient required increasing doses of thyroid hormone.

Introduction

Haemangioendothelioma (HHE) is a vascular lesion which occurs in approximately 5–10% of one-year-old children. The term HHE has been applied to a spectrum of vascular lesions ranging from benign and self-limiting to aggressive and life-threatening. The hepatic form of HHE is a rare tumour typically presenting in infancy. ¹ The natural course of HHE is characterized by a proliferation phase followed by plateau and involution phases. Rapidly growing HHE is associated with life-threatening complications such as cardiac failure, respiratory distress and consumptive coagulopathy. More recently, it has been documented that HHE may be associated with hypothyroidism. ^2,3 Hypothyroidism in this group of patients is attributed to the expression of type 3 iodothyronine deiodinase (D3) by the tumour tissue. D3 is a selenoenzyme with particularly high expression in human placenta and brain. While the D2 deiodinase is the enzyme responsible for conversion of thyroxine (T4) to triiodothyronine (T3), D3 is the physiological inactivator of the thyroid hormones. D3 catalyses the inner-ring deiodination of T4 to reverse T3 (rT3), and of T3 to 3,3′-diiodothyronine (T2); both rT3 and T2 are biologically inactive. High D3 activity in HHE is thought to be responsible for increased degradation of T4 to rT3. ^3,4 Hypothyroidism develops when thyroid hormone inactivation by D3 exceeds the synthetic capacity of the thyroid gland. This form of hypothyroidism is therefore known as consumptive hypothyroidism. Although the biochemical pattern seen is similar to that of primary hypothyroidism, the thyroid gland in this group of patients is functional. In this report we present a case of a three-month-old infant who developed hypothyroidism secondary to HHE, and review previously published cases.

Case report

A male twin born at 35 weeks gestation was admitted at the age of eight weeks with episodes of apnoea and respiratory syncytial virus-positive bronchiolitis. On routine examination, he had a distended abdomen with 7–8 cm of hepatomegaly. Following the resolution of his bronchiolitis, he was transferred to the Children's Liver & GI unit where magnetic resonance imaging scan of the abdomen showed an enlarged liver containing multiple lesions consistent with haemangioendotheliomata. Full blood count, clotting profile, alphafetoprotein, human chorionic gonadotrophin and liver enzymes were all normal with the exception of gamma-glutamyl transpeptidase (GGT) of 428 IU/L (adult reference interval 0–45). Cardiology review, including echocardiography, showed no evidence of heart failure. He was started on prednisolone 2 mg/kg/d but three days later started having recurrent severe apnoeic episodes usually associated with defecation. Bronchoscopy revealed significant tracheobronchomalacia possibly secondary to a dilated pulmonary artery demonstrated on computed tomography scan and cardiac angiography. Therefore, at 15 weeks age, he underwent surgical ligation of the hepatic artery which was well tolerated and the patient's apnoeic episodes resolved. He was discharged after two weeks.

The neonatal thyroid-stimulating hormone (TSH) (Guthrie) screening test was normal. On the second day of admission to the hepatology unit, however, TSH was 138 mU/L (age-related reference interval 0.3–5.88), free T4 (fT4) 16.6 pmol/L (age-related reference interval 11.4–20.9), total T4 (TT4) 140 nmol/L (age-related reference interval 73.6–174.4), total T3 (TT3) 0.96 nmol/L (age-related reference interval 1.18–4.18) and rT3 5.52 nmol/L (adult reference interval 0.14–0.34) (Siemens Centaur, Siemens Healthcare Diagnostics, Surrey, UK). rT3 and T2 were measured using an in-house radioimmunoassay. Heterophilic antibody interference was screened for by repeating the thyroid function test (TFT) measurements on a different analyser (Abbott Architect System, Berkshire, UK) before and after using heterophilic blocking tubes (Scantibodies Laboratories, Inc, Dorset, UK). The patient had no evidence of any exposure to iodide. The patient remained clinically euthyroid until the date of discharge.

Three days postdischarge the patient suffered a recurrence of apnoeic episodes that resulted in re-admission to the intensive care unit. Ultrasound scan showed an increase in the size of the largest HHE and the development of collateral feeding vessels that were treated by embolization and he was started on alpha interferon 2b, 1.1million units/m². He also required insertion of stents in the distal trachea and left main bronchus. During this period, there was a massive increase in TSH and rapid lowering of fT4 concentration, while TT3 remained below the lower limit of the age-related reference interval during the period of hospitalization. The fall in fT4 and TT3 was associated with an increase in rT3 and T2 concentrations (see Figure 1). Despite the initiation of l-thyroxine replacement therapy (25 μg/d) TSH continued to rise to 650 mU/L and fT4 remained at 6.3 pmol/L. The dose of l-thyroxine was doubled to 50 μg/d two weeks later. Although TFTs remained consistent with severe hypothyroidism, the patient remained free of clinical features of hypothyroidism such as hypothermia and bradycardia. Although the size of the hepatic haemangiomata and pulmonary artery stabilized, and the TSH started to fall, the tracheobronchomalacia resulted in the patient becoming ventilator-dependent and he died from respiratory complications at six months of age.

Figure 1

Thyroid function course over the period of hospitalization. The upper part of the graph shows the serum TSH concentration. The second panel shows serum fT4 concentration, the third panel shows rT3 concentration. The gap in the third graph was due to lack of specimen availability. The dashed line for fT4 shows the reference interval for this hormone. Reference intervals for the other hormones are given next to each figure. TSH, thyroid-stimulating hormone; fT4, free thyroxine; T2, 3,3′-diidothyronine; TT3, total triiodothyronine; rT3, reverse triiodothyronine

Discussion

The association between consumptive hypothyroidism and HHE was first described in 2000. ³ To date, consumptive hypothyroidism secondary to HHE has been reported in 15 infants and one adult. ⁵

The pathophysiology of this condition is explained by the high expression of the D3 isoenzyme by the vascular tumour. Huang et al. ³ analysed redundant surgical specimens collected from 11 infants under the age of 12 months who underwent a surgical removal for HHE. Tumoral expression of D3 activity was found in all but one HHE tissue sample. The D3 enzyme inactivates T4 and T3 by converting them to biologically inactive rT3 and T2, respectively. In a recent case report, the expression of D3 activity in the resected tumour was found to be significantly higher than the mean of placental tissues of four subjects. ⁴ The tumoral D3 expression in these vascular lesions together with the disappearance of hypothyroidism after liver transplantation or HHE involution support the concept that this endocrinopathy is due to excessive degradation of thyroid hormones. ^3,4 The rate of T4 degradation is a product of the enzyme activity and the mass of the HHE; hence the large variations in values of TSH and fT4 reported in the previous cases. It has been reported that the most rapid rate of T4 degradation is associated with the proliferative phase of HHE. ³ Recent reports from Huang et al., who also analysed patients with hepatic and cutaneous HHE for thyroid abnormalities, indicated increased D3 activity in two patients with massive cutaneous HHE as well as in one patient with HHE. This suggests that HHE in sites other than the liver may also lead to hypothyroidism. ³ In another two reports, inactive TSH secreted by HHE was thought to be contributing to the biochemical hypothyroidism picture. Ayling et al. ⁶ demonstrated histological expression of TSH-like factor in HHE tissue but not in normal liver tissue in one of eight patients presented with HHE and hypothyroidism. Three of the patients in that report showed a rapid increase in TSH associated with a decrease in fT4 concentration (a biochemical picture similar to that seen in patients with consumptive hypothyroidism). However, as rT3 or T2 has not been reported, the presence of D3 cannot be excluded in this group of patients. Possible secretion of TSH-like factor in patients with HHE may explain why in some cases a high dose of thyroid replacement therapy may treat the clinical hypothyroidism and restore fT4 to reference level, with TSH remaining markedly elevated. ^2,4

There are various medical modalities of treatment for HHE. It is usually treated successfully with steroids and/or α-interferon. ⁷ Failure of conservative treatment options in a rapidly growing HHE may warrant an aggressive surgical intervention such as ligation of the feeding hepatic artery, tumour resections or liver transplantation. ^8,9 Treatment of the consumptive hypothyroidism can be complex, because the exogenous hormones are also converted to inactive forms. This has implications both for the support during management of the haemangiomas and the long-term brain development outcome of the infant patients. ^3,8,10

Our patient presented with subclinical hypothyroidism manifested by a massive increase in TSH concentration with normal free and total T4 and slightly low TT3 for age. He remained asymptomatic throughout his hospital stay. The differential diagnosis of this pattern includes production of a TSH-like factor by the tumour tissue, ² TSH-secreting pituitary adenoma or a hormone-resistant state. However, none of these possibilities explains the progressive decrease in fT4 seen here. In addition, the concomitant increase in TSH, rT3 and T2 paralleled the deterioration in the patient condition as a result of the rapidly growing hepatic lesion. This finding is consistent with previous case reports which all reported that the high D3 expression accompanied the proliferative phase of HHE growth. ^3,11

In some of the previous cases, children required extremely high doses of T4, T3 or combined thyroid replacement therapy. ^4,12,13 Doses ranging between 5 and 94 μg/kg/d have been reported. ⁸ (For comparison, in conventional hypothyroidism the thyroid replacement therapy dose that maintains euthyroid status in infants ranges from 5 to 10 μg/kg/d.) A requirement for rapid intravenous administration of T3 replacement was reported by Mason et al. ¹⁰ However, unlike previous cases, our patient's requirement for thyroxine (25 to 50 μg/d) remained within the normal weight-adjusted dose.

The diagnostic test to identify consumptive hypothyroidism is the demonstration of D3 activity in the tumour tissue in the presence of biochemical indices of hypothyroidism. However, HHE is not routinely biopsied due to the increased risk of bleeding of these vascular tumours. As hypothyroidism in this case was not the life-threatening issue, the risk of a biopsy was not clinically justified. Hence, the suspicion of consumptive hypothyroidism should be raised from certain clinical and laboratory features which are commonly seen in patients with this condition; for example, a rapid change in the thyroid profile values is seen especially during the proliferative phase of HHE. Usually the hypothyroidism appears during the period of a rapid lesion growth and resolves (or biochemical indices improve) after medical or surgical treatment.

Finally, recently consumptive hypothyroidism has also been described in two infants with clinically asymptomatic HHE. ^11,12 This suggests that a search for HHE should be undertaken in infants with severe unexplained hypothyroidism.

In conclusion, a high index of suspicion for consumptive hypothyroidism should be maintained by the clinicians and the laboratory, and TFTs should be measured in patients with HHE. In consumptive hypothyroidism, T3 values lower than the reference range, with a rapidly changing thyroid profile, are indicative of this condition. In addition, unexplained hypothyroidism should be an indicator to search for a vascular tumour in infants or adults. Once the condition is identified, an aggressive thyroid replacement treatment may be required to maintain the euthyroid status. Furthermore, due to the rapidity with which thyroid hormone concentrations change, patients with this condition require an increased frequency of monitoring. Therefore, the minimum six-week period recommended by national guidelines is not appropriate for a condition like consumptive hypothyroidism, and more frequent monitoring (e.g. weekly as here) to titrate the thyroxine dose is suggested ^14–16 (Table 1).

Table 1

TFT on admission and thyroid replacement therapy dose in published cases of consumptive hypothyroidism caused by hepatic HHE

Patient/age of presentation	Gender	TFT on admission	Thyroid hormone dose	References
11 weeks	F	TSH → 90 mU/L (0.2–6.0)	62 μg/d of T4	2
		fT4 → 21.5 pmol/L (8.0–22)
6 weeks	M	TSH → 156 mU/L (0.3–6.2)	50 μg/d of T4	3
		TT4 → 95 nmol/L (58–161)	96 μg/d of T3
7 weeks	F	TSH → 45.2 mU/L (0.4–3.8)	7.5 μg/kg/d of T4	4
		TT4 → 23 pmol/L (NA)
21 years	F	TSH → 26.6 mU/L (0.4–4.0)	88 μg/d of T4	5
		TT4 → 95 nmol/l (58–161)
8 weeks	F	TSH → 103 mU/L (0.3–5.0)	25 μg/d of T4	6
		fT4 → 17 pmol/L (10–26)
At birth	M	TSH → 24 mU/L (0.3–5.0)	T4 dose unknown	6
		fT4 → 26 pmol/L (10–26)
4 months	F	TSH → 475 mU/L (0.3–5.0)	25 μg/d of T4	6
		fT4 → 16 pmol/L (10–26)
3 months	F	TSH → 182 mU/L (0.3–5.0)	Total of 625 μg/d	8
		fT4 → 10.3 (12.9–32)	of T4 and T3
6 weeks	F	TSH → 182 mU/L (0.32–5.0)	15 μg/kg/d of T4	9
		fT4 → 10.3 pmol/L (9.0–19)
3 weeks	F	TSH → 17 pmU/L (0.4–4.0)	25 μg/kg/d of T4	10
		fT4 → 21.3 pmol/L (11–32)
10 months	M	TSH → 18.98 mU/L (0.4–5.0)	120 μg/d of T4	11
		fT4 → 21 pmol/L (10–21)
7 weeks	M	TSH → 156 mU/L (0.3–5.0)	37.5 μg/d of T4	12
		fT4 → 5.9 pmol/L (11.5–23.2)	plus iv T3
9 weeks	M	TSH → 100 mU/L (0.5–5.0)	28 μg/d of T4	13
		fT4 → 5 pmol/L (10–23)
4 weeks	M	TSH → 66.2 mU/L (<6.0)	25 μg/d of T4	14
		fT4 → 16.9 pmol/L (19–39)
At birth	F	Not available	20 μg/kg/d of T4	15
			5 μg/kg/d of T3
4 weeks	M	TSH → 53.3 mU/L (0.5–5.8)	112 μg/d of T4	16
		fT4 → 19.1 pmol/L (5.9–16.3)
11 weeks	M	TSH → 138 mU/L (0.2–6.0)	50 μg/d of T4	This case
		fT4 → 16.6 pmol/L (10–25)

TFT, Thyroid function test; HHE, Haemangioendothelioma; TSH, thyroid-stimulating hormone; fT4, free thyroxine; TT4, total thyroxine

The data have been converted to SI units using conversion factors (fT4 ng/dl × 2.9 = pmol/L and TSH U/mL ×1 = mU/L). Data in parenthesis are reference ranges as listed in publications

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Patient's parent gave a verbal consent to present this case.

Guarantor: JHB.

Contributorship: All authors contributed to the content and the approach to the paper. NJ did the literature review and drafted the paper. TJV analysed the patient samples for rT3 and T2. All authors have read and agreed to the manuscript as written.