Consumptive Hypothyroidism Research Articles

Thyroid Hormone Inactivation in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib.1 The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism.2 Multiple mechanisms of this effect have been proposed, including decreased iodine organification3 and glandular capillary regression.4 Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone–inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.

Studies of Molecular Mechanisms Associated With Increased Deiodinase 3 Expression in a Case of Consumptive Hypothyroidism

Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to increased catabolic activity of type 3 iodothyronine deiodinase (DIO3) that can occur in large tumors. PATIENTs with CH typically present with markedly increased requirements for exogenous thyroid hormone and resolution after removal of the source of ectopic DIO3. DIO3 is encoded by DIO3, an imprinted gene expressed on the paternal allele that is located in a DIO3/delta-like 1 homolog (DLK1) gene locus regulated by a common control region, intergenic differentially methylated region (IGDMR). Because DIO3 is an imprinted gene, loss of imprinting at the IGDMR is thought to play a role in its increased expression; however, the molecular mechanism for DIO3 in CH currently is not known. The aim of the study was to determine the molecular mechanism for CH in an adult patient. The study was conducted in the Department of Endocrinology of a tertiary care center in Singapore. We report the case of an adult Asian female patient with a large intrathoracic fibrous tumor and severe hypothyroidism that resolved after tumor resection. The patient's tumor expressed increased levels of DIO3 and DLK1 mRNA and protein levels. Methylation-specific PCR of the IGDMR showed similar hypomethylation in placenta, thyroid, leukocytes, and tumor. Western blotting showed activation of sonic hedgehog (SHH) and MAPK signaling pathways that can increase DIO3 and DLK1 expression. Loss of imprinting did not account for overexpression of DIO3 in the patient's tumor. Instead SHH and MAPK/ERK pathway activation was associated with systemic thyroid hormone catabolism and growth of the tumor. These findings raise the possibility that other tumors that have increased SHH and MAPK/ERK signaling also may have intratumor or systemic effects on thyroid hormone function.

Propranolol as a First‐line Treatment for Diffuse Infantile Hepatic Hemangioendothelioma

Propranolol as a First‐line Treatment for Diffuse Infantile Hepatic Hemangioendothelioma

Consumptive hypothyroidism in an Egyptian baby with benign neonatal hemangiomatosis: a case report

IntroductionBenign neonatal hemangiomatosis is a condition in which multiple cutaneous hemangiomas appear at birth or shortly thereafter; visceral complications are absent. Here, we report a case of a consumption hypothyroidism in an Egyptian baby with benign neonatal hemangiomatosis.Case presentationAn 8-month-old Egyptian boy with benign neonatal hemangiomatosis was referred to our institution for evaluation of developmental delay. Initial examination revealed a quiet baby who was able to sit only with support. He had hypotonia, a large anterior fontanelle, puffy eyes, cold extremities, hypothermia, bradycardia, and abdominal distension. An examination of his skin revealed more than 100 dome-shaped red-purple cutaneous hemangiomas that varied in size from 5 to 10mm on the back, the abdomen and the extremities without mucus membrane involvement. He had low serum free thyroxine concentration and triiodothyronine levels and high thyroid-stimulating hormone and reverse-triiodothyronine levels. A work-up that involved appropriate imaging ruled out visceral involvement. Based on the above mentioned data, a diagnosis of consumptive hypothyroidism due to benign neonatal hemangiomatosis was made. He was started on oral thyroid medication which was gradually increased to 90μg L-thyroxine daily (15μg/kg/day). After three months of treatment, he was able to sit alone without support and he had normal levels of thyroid-stimulating hormone and serum free thyroxine.ConclusionThyroid function should be assessed periodically in babies with benign neonatal hemangiomatosis, especially if symptoms of hypothyroidism appear or the size and number of hemangiomatosis increase rapidly. Moreover, high doses of L-thyroxine may be needed to achieve euthyroidism during the infancy.

Type 3 Deiodinase and Consumptive Hypothyroidism: A Common Mechanism for a Rare Disease

The major product secreted by the thyroid is thyroxine (T4), whereas most of the biologically active triiodothyronine (T3) derives from the peripheral conversion of T4 into T3. The deiodinase enzymes are involved in activation and inactivation of thyroid hormones (THs). Type 1 and type 2 deiodinase (D1 and D2) convert T4 into T3 whereas D3 degrades T4 and T3 into inactive metabolites and is thus the major physiological TH inactivator. The hypothalamic-pituitary-thyroid axis maintains circulating TH levels constant, while the deiodinases tissue-specifically regulate intracellular thyroid status by controlling TH action in a precise spatio-temporal fashion. Here we review the data related to the recent identification of a paraneoplastic syndrome called “consumptive hypothyroidism,” which exemplifies how deiodinases alter substantially the concentration of TH in blood. This syndrome results from the aberrant uncontrolled expression of D3 that can induce a severe form of hypothyroidism by inactivating T4 and T3 in defined tumor tissue. This rare TH insufficiency generally affects patients in the first years of life, and has distinct features in terms of diagnosis, treatment, and prognosis with respect to other forms of hypothyroidism.

Unusual Case of Hypothyroidism in an Infant With Hepatic Hemangioma

Unusual Case of Hypothyroidism in an Infant With Hepatic Hemangioma

Difficult treatment of consumptive hypothyroidism in a child with massive parotid hemangioma

Consumptive hypothyroidism is a rare condition related to massive infantile hemangiomas producing an excess of the thyroid-hormone-inactivating enzyme type 3 iodothyronine deiodinase. We report the first case of consumptive hypothyroidism secondary to a large parotid hemangioma, highlighting the difficulties in selecting an adequate therapeutic strategy. The affected child was initially referred to our center for congenital hypothyroidism with a hypoplastic thyroid gland. L-Thyroxine (L-T4) replacement therapy was started at seven days of life. In the following weeks, the hemangioma rapidly increased in volume and the child developed severe hypothyroidism refractory to high doses of L-T4 therapy. The concentration of reverse triiodothyronine was elevated, suggesting that the underlying cause was an excessive conversion of thyroid hormones by high type 3 iodothyronine deiodinase levels in the tumor. Corticosteroid treatment showed only partial benefit. Introduction of propranolol instead led to normalization of thyroid hormones along with a dramatic involution of the hemangioma.

Consumptive Hypothyroidism Resulting from Hepatic Vascular Tumors in an Athyreotic Adult

Consumptive hypothyroidism is a rare syndrome resulting from increased catabolism of T(4) and T(3) by increased type 3 iodothyronine deiodinase (D3) activity. Consumptive hypothyroidism has primarily been described as a paraneoplastic syndrome in infants as well as in two adults with D3-expressing tumors. The aim of the study was to report the third case of consumptive hypothyroidism in an adult and the first in an athyreotic patient. We present a 38-yr-old athyreotic female who was euthyroid on a stable therapeutic dose of thyroid hormone for many years and then developed marked hyperthyrotropinemia, coincident with the discovery of large D3-expressing hepatic vascular tumors. The patient also had low serum T(3) and elevated serum rT(3). Hyperthyrotropinemia transiently worsened after surgical resection of the vascular tumors and then persisted for 3 wk after the operation, despite further increases in levothyroxine therapy. The patient's vascular tumor and adjacent normal liver parenchyma were probed with a polyclonal antibody directed against D3. D3 immunostaining of the patient's vascular tumor was positive, with no significant immunoreactivity in the adjacent normal hepatic tissue. This is the third case report of consumptive hypothyroidism in an adult and the first in an athyreotic individual. This case demonstrates that hyperthyrotropinemia may persist after partial liver resection, possibly from the hepatic resection itself.

Consumptive hypothyroidism: a case report and review of the literature

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.

Thyroid hormone metabolism in heart failure: iodothyronine deiodinases in focus

Heart disease is the leading cause of death worldwide and no efficient treatment against this threatening condition exists. Based on their recognized regulatory action on cardiovascular system, thyroid hormones emerged as a good alternative for patients with heart disease. Although many studies have shown beneficial effects of thyroid hormone replacement in patients with heart failure, many questions are still unsolved. Thus, the purpose of this review was to discuss changes in thyroid hormone economy with special emphasis on thyroid hormone metabolism in models of heart failure. Severe illness, such as heart failure, is characterized by changes in thyroid hormone economy, characterized by decreased serum T3 and increased serum rT3, a condition called the 'low T3-syndrome'. Unlike other animal models of thyroid status derangement during systemic illness, some clinical and experimental studies have observed compensatory stimulation of the hypothalamus-pituitary-thyroid axis in patients and models of heart failure. In this context, induction of type 3 deiodinase is the main cause of decreased T3. This is uniquely reminiscent of the pathophysiology of the 'consumptive hypothyroidism', which has previously been described in patients with large D3-expressing tumors. Tight regulation of cardiac T3 levels occurs in heart failure and understanding the pathophysiology of this phenomenon might support future researches to find new efficient strategies to treat heart failure.

Increased type 3 iodothyronine deiodinase activity in a regrown hepatic hemangioma with consumptive hypothyroidism

Infantile hepatic hemangioma with consumptive hypothyroidism is a rare condition. A 4-month-old girl presented with diffuse hepatic hemangiomas during treatment of congenital hypothyroidism. Serum reverse triiodothyronine was elevated, and her hypothyroidism improved concomitant with involution of the hemangioma following prednisolone and interferon-alpha administration. At 20 months of age, 7 months after discontinuing prednisolone and interferon-alpha, a focal hemangioma regrew from one of the previous lesions and was surgically resected. The expression and activity of type 3 iodothyronine deiodinase (D3) were elevated in the resected tumor tissue compared with placenta. Here, we describe a patient with consumptive hypothyroidism and diffuse infantile hepatic hemangiomas, one of which regrew after involution following pharmacotherapy. The etiology of elevated D3 activity is also discussed. It is important to identify infantile hepatic hemangioma in patients with hypothyroidism refractory to hormone replacement therapy, who have low free triiodothyronine despite high thyrotropin and normal free thyroxine levels, and long-term follow-up will be needed for these patients.

Case report: consumptive hypothyroidism consequent to multiple infantile hepatic haemangiomas

A 10-month-old infant with multiple infantile hepatic hemangiomas and developmental delay is reported. He was found to be profoundly hypothyroid. Evaluation and management issues are discussed. This case emphasizes the importance of screening for hypothyroidism in patients with hemangiomas and the potential therapeutic benefit of prednisolone therapy in this condition.

Massive Hepatic Hemangioendothelioma and Consumptive Hypothyroidism

Hypothyroidism was diagnosed in an infant with massive hepatic hemangioendothelioma. Markedly elevated serum reverse-triiodothyronine levels confirmed consumptive hypothyroidism. Large doses of thyroxine were initially required to normalise TSH. Thyroxine was tapered as the tumor regressed and was discontinued at 16 months old. Thyroid function remains normal without treatment.

Thyroid Function Disturbance and Type 3 Iodothyronine Deiodinase Induction after Myocardial Infarction in Rats—A Time Course Study

In humans, there is a significant decrease in serum T(3) and increase in rT(3) at different time points after myocardial infarction, whereas serum TSH and T(4) remain unaltered. We report here a time course study of pituitary-thyroid function and thyroid hormone metabolism in rats subjected to myocardial infarction by left coronary ligation (INF). INF- and sham-operated animals were followed by serial deiodination assays and thyroid function tests, just before, and 1, 4, 8, and 12 wk after surgery. At 4 and 12 wk after INF, liver type 1 deiodinase activity was significantly lower, confirming tissue hypothyroidism. Type 3 deiodinase (D3) activity was robustly induced 1 wk after INF only in the infarcted myocardium. Reminiscent of the consumptive hypothyroidism observed in patients with large D3-expressing tumors, this induction of cardiac D3 activity was associated with a decrease in both serum T(4) ( approximately 50% decrease) and T(3) (37% decrease), despite compensatory stimulation of the thyroid. Thyroid stimulation was documented by both hyperthyrotropinemia and radioiodine uptake. Serum TSH increased by 4.3-fold in the first and 3.1-fold in the fourth weeks (P < 0.01), returning to the basal levels thereafter. Thyroid sodium/iodide-symporter function increased 1 wk after INF, accompanying the increased serum TSH. We conclude that the acute decrease in serum T(4) and T(3) after INF is due to increased thyroid hormone catabolism from ectopic D3 expression in the heart.

Consumptive Hypothyroidism Caused by Paraneoplastic Production of Type 3 Iodothyronine Deiodinase

Consumptive hypothyroidism is characterized by excessive inactivation of thyroid hormone by type 3 iodothyronine deiodinase (D3). Previously this rare syndrome was described in association with massive hemangiomas in children and in a single case of a hemangioendothelioma in an adult. Here we report the first case of consumptive hypothyroidism from a nonvascular tumor in a patient who required supraphysiologic doses of levothyroxine prior to the resection of a large malignant solitary fibrous tumor. The tumor expressed D3 message, protein and exhibited functional D3 enzymatic activity. The clinical presentation of this patient expands the differential diagnosis of hypothyroidism, adds to the growing list of paraneoplastic syndromes that impact the endocrine system, and extends the spectrum of tumor types associated with consumptive hypothyroidism.

Physiology and Pathophysiology of Type 3 Deiodinase in Humans

Type 3 iodothyronine deiodinase (D3) is the physiologic inactivator of thyroid hormones, catalyzing the inner ring deiodination of thyroxine (T(4)) to reverse triiodothyronine (rT(3)) and (T(3)) to 3, 3'-diiodothyronine (T(2)), both of which are biologically inactive. Its physiologic role and pathophysiologic effects in humans can be understood in this context. D3 activity in the normal uteroplacental unit regulates the transfer of maternal thyroid hormone to the fetus and, in patients with consumptive hypothyroidism, the rapid destruction of circulating thyroid hormone by tumoral D3 can produce severe hypothyroxinemia. D3 is expressed in multiple fetal structures, but the uterine endometrium and the placenta are the only normal tissues known to express high levels of D3 activity in the mature human. D3 has also been found in vascular anomalies, in human brain tumors, and in some malignant cell lines. These data have led to the categorization of D3 as an oncofetal protein, but recent data indicate that postnatal expression can be reactivated in normal tissues during critical illness and other pathologic conditions.

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases.

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T(3) production. We discuss the pathological role of D3 overexpression causing "consumptive hypothyroidism" as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.

Biochemistry, Cellular and Molecular Biology, and Physiological Roles of the Iodothyronine Selenodeiodinases

The goal of this review is to place the exciting advances that have occurred in our understanding of the molecular biology of the types 1, 2, and 3 (D1, D2, and D3, respectively) iodothyronine deiodinases into a biochemical and physiological context. We review new data regarding the mechanism of selenoprotein synthesis, the molecular and cellular biological properties of the individual deiodinases, including gene structure, mRNA and protein characteristics, tissue distribution, subcellular localization and topology, enzymatic properties, structure-activity relationships, and regulation of synthesis, inactivation, and degradation. These provide the background for a discussion of their role in thyroid physiology in humans and other vertebrates, including evidence that D2 plays a significant role in human plasma T3 production. We discuss the pathological role of D3 overexpression causing “consumptive hypothyroidism” as well as our current understanding of the pathophysiology of iodothyronine deiodination during illness and amiodarone therapy. Finally, we review the new insights from analysis of mice with targeted disruption of the Dio2 gene and overexpression of D2 in the myocardium.