ABSTRACT
BACKGROUND: Angiotensinogen is the sole precursor of angiotensin peptides and has a key role in the pathogenesis of hypertension. Zilebesiran, an investigational RNA interference therapeutic agent with a prolonged duration of action, inhibits hepatic angiotensinogen synthesis. METHODS: In this phase 1 study, patients with hypertension were randomly assigned in a 2:1 ratio to receive either a single ascending subcutaneous dose of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg) or placebo and were followed for 24 weeks (Part A). Part B assessed the effect of the 800-mg dose of zilebesiran on blood pressure under low- or high-salt diet conditions, and Part E the effect of that dose when coadministered with irbesartan. End points included safety, pharmacokinetic and pharmacodynamic characteristics, and the change from baseline in systolic and diastolic blood pressure, as measured by 24-hour ambulatory blood-pressure monitoring. RESULTS: Of 107 patients enrolled, 5 had mild, transient injection-site reactions. There were no reports of hypotension, hyperkalemia, or worsening of renal function resulting in medical intervention. In Part A, patients receiving zilebesiran had decreases in serum angiotensinogen levels that were correlated with the administered dose (r = -0.56 at week 8; 95% confidence interval, -0.69 to -0.39). Single doses of zilebesiran (≥200 mg) were associated with decreases in systolic blood pressure (>10 mm Hg) and diastolic blood pressure (>5 mm Hg) by week 8; these changes were consistent throughout the diurnal cycle and were sustained at 24 weeks. Results from Parts B and E were consistent with attenuation of the effect on blood pressure by a high-salt diet and with an augmented effect through coadministration with irbesartan, respectively. CONCLUSIONS: Dose-dependent decreases in serum angiotensinogen levels and 24-hour ambulatory blood pressure were sustained for up to 24 weeks after a single subcutaneous dose of zilebesiran of 200 mg or more; mild injection-site reactions were observed. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT03934307; EudraCT number, 2019-000129-39.).
Subject(s)
Angiotensinogen , Antihypertensive Agents , Hypertension , Humans , Angiotensinogen/blood , Angiotensinogen/metabolism , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Antihypertensive Agents/pharmacokinetics , Antihypertensive Agents/therapeutic use , Blood Pressure/drug effects , Blood Pressure/physiology , Blood Pressure Monitoring, Ambulatory , Double-Blind Method , Hypertension/blood , Hypertension/drug therapy , Hypertension/etiology , Hypertension/metabolism , Irbesartan/administration & dosage , Irbesartan/adverse effects , Irbesartan/pharmacokinetics , Irbesartan/therapeutic use , RNA Interference , Tetrazoles , Diet , Injections, SubcutaneousABSTRACT
BACKGROUND & AIMS: Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that target all major HBV transcripts. METHODS: We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n = 24 and n = 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200 mg of VIR-2218 (total n = 24) vs. placebo (n = 8), given 4 weeks apart, in participants with cHBV infection. RESULTS: In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200 mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion. CONCLUSIONS: VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188. IMPACT AND IMPLICATIONS: A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.
Subject(s)
Hepatitis B, Chronic , Hepatitis B , Humans , Animals , Mice , Hepatitis B, Chronic/drug therapy , Hepatitis B virus , Hepatitis B Surface Antigens , RNAi Therapeutics , Randomized Controlled Trials as Topic , Antiviral Agents , DNA, Viral , Hepatitis B e Antigens , Hepatitis B/drug therapyABSTRACT
Purpose To determine the relationship between demographic and sonographic characteristics of thyroid nodules and malignancy in a pediatric population. Materials and Methods All thyroid nodules in patients younger than 19 years that underwent ultrasound (US)-guided fine-needle aspiration biopsy between January 2004 and July 2017 were retrospectively identified. Age, sex, and background appearance of the thyroid gland were recorded for each patient, and sonographic characteristics and pathologic diagnosis were recorded for each nodule. Demographic and sonographic characteristics were assessed to determine which were associated with malignancy. Categorical and continuous variables and interobserver variability were assessed. Results A total of 404 nodules in 314 patients (82.8% female) (age range, 2-18 years; mean age, 14.9 years) were analyzed. A total of 77 nodules (19.1%) were malignant, the majority of which were papillary thyroid carcinoma (n = 68 [88.3%]). The likelihood of malignancy did not differ between boys and girls (27.8% vs 22.7%, P = .64), nor did it differ between prepubertal and pubertal patients (18.8% vs 19.1%, P > .99). The cancer rate in patients with a solitary nodule was higher than that in patients with multiple nodules (29.4% vs 14.2%, P = .003). Sonographic characteristics associated with malignant nodules included larger size, solid parenchyma, taller-than-wide shape, presence of speckled calcifications, lack of a smooth margin, and presence of abnormal lymph nodes. Interobserver variability for assessment of sonographic characteristics ranged from moderate to very strong. Conclusion In children with thyroid nodules, solitary nodules, larger nodule size, solid parenchyma, taller-than-wide shape, speckled calcifications, irregular margins, and abnormal lymph nodes raise concern for malignancy.
Subject(s)
Carcinoma, Papillary/diagnostic imaging , Carcinoma, Papillary/pathology , Thyroid Neoplasms/diagnostic imaging , Thyroid Neoplasms/pathology , Thyroid Nodule/diagnostic imaging , Thyroid Nodule/pathology , Ultrasonography, Interventional/methods , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Image-Guided Biopsy/methods , Male , Observer Variation , Retrospective Studies , Sensitivity and Specificity , Thyroid Cancer, Papillary , Thyroid Gland/diagnostic imaging , Thyroid Gland/pathologyABSTRACT
Ectopic intrathyroidal thymic tissue is a benign lesion of nonthyroid origin occasionally found in the pediatric thyroid gland. Accurate diagnosis of such lesions is critical to avoid unnecessary biopsy or surgery. Twelve children referred to our center for the concern of thyroid nodules were found to have intrathyroidal thymic tissue. Most of the lesions had a classic sonographic appearance of a hypoechoic mass with sharp margins and multiple focal internal nonshadowing echogenicities identical to thymic tissue. Sonography and, in select cases, fine-needle aspiration can be used to diagnose benign thymic tissue within the thyroid and avoid unnecessary surgery.
Subject(s)
Thyroid Gland/abnormalities , Thyroid Gland/diagnostic imaging , Thyroid Nodule , Ultrasonography/methods , Adolescent , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Infant , Male , Retrospective StudiesABSTRACT
Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. 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.
Subject(s)
Gastrointestinal Neoplasms/enzymology , Gastrointestinal Stromal Tumors/enzymology , Hypothyroidism/enzymology , Hypothyroidism/etiology , Iodide Peroxidase/metabolism , Thyroid Hormones/deficiency , Gastrointestinal Neoplasms/complications , Gastrointestinal Neoplasms/diagnostic imaging , Gastrointestinal Stromal Tumors/complications , Gastrointestinal Stromal Tumors/diagnostic imaging , Humans , Iodide Peroxidase/genetics , Male , Middle Aged , Radiography, AbdominalABSTRACT
In a retrospective analysis of childhood thyroid nodules, 18% were radiographic incidentalomas and 41% were discovered by a clinician's palpation; 40% were discovered by patients' families. The latter group had the largest nodules and highest rates of thyroid cancer metastasis, suggesting opportunities for earlier detection through annual well-child visits.
Subject(s)
Thyroid Nodule/diagnosis , Adolescent , Child , Child, Preschool , Early Diagnosis , Female , Humans , Incidental Findings , Male , Neoplasm Metastasis , Physical Examination/statistics & numerical data , Radiography , Retrospective Studies , Self-Examination/statistics & numerical data , Sex Distribution , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/epidemiology , Thyroid Nodule/diagnostic imagingABSTRACT
The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on their role in preserving serum levels of the biologically active molecule T(3) during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-kappaB, growth factors, bile acids, hypoxia-inducible factor-1alpha, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.
Subject(s)
Iodide Peroxidase/metabolism , Thyroid Gland/metabolism , Thyroxine/metabolism , Triiodothyronine/metabolism , Animals , Humans , Signal Transduction , Thyroid Diseases/metabolism , Thyroid Gland/enzymologyABSTRACT
Thyroid hormone is a critical determinant of cellular metabolism and differentiation. Precise tissue-specific regulation of the active ligand 3,5,3'-triiodothyronine (T3) is achieved by the sequential removal of iodine groups from the thyroid hormone molecule, with type 3 deiodinase (D3) comprising the major inactivating pathway that terminates the action of T3 and prevents activation of the prohormone thyroxine. Using cells endogenously expressing D3, we found that hypoxia induced expression of the D3 gene DIO3 by a hypoxia-inducible factor-dependent (HIF-dependent) pathway. D3 activity and mRNA were increased both by hypoxia and by hypoxia mimetics that increase HIF-1. Using ChIP, we found that HIF-1alpha interacted specifically with the DIO3 promoter, indicating that DIO3 may be a direct transcriptional target of HIF-1. Endogenous D3 activity decreased T3-dependent oxygen consumption in both neuronal and hepatocyte cell lines, suggesting that hypoxia-induced D3 may reduce metabolic rate in hypoxic tissues. Using a rat model of cardiac failure due to RV hypertrophy, we found that HIF-1alpha and D3 proteins were induced specifically in the hypertrophic myocardium of the RV, creating an anatomically specific reduction in local T3 content and action. These results suggest a mechanism of metabolic regulation during hypoxic-ischemic injury in which HIF-1 reduces local thyroid hormone signaling through induction of D3.
Subject(s)
Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Hypoxia/metabolism , Iodide Peroxidase/physiology , Ischemia/metabolism , Thyroid Hormones/metabolism , Animals , Enzyme Induction , Hypertrophy, Right Ventricular/metabolism , Male , Rats , Rats, Wistar , Signal Transduction , Triiodothyronine/physiologyABSTRACT
The type 3 deiodinase (D3) inactivates thyroid hormone action by catalyzing tissue-specific inner ring deiodination, predominantly during embryonic development. D3 has gained much attention as a player in the euthyroid sick syndrome, given its robust reactivation during injury and/or illness. Whereas much of the structure biology of the deiodinases is derived from studies with D2, a dimeric endoplasmic reticulum obligatory activating deiodinase, little is known about the holostructure of the plasma membrane resident D3, the deiodinase capable of thyroid hormone inactivation. Here we used fluorescence resonance energy transfer in live cells to demonstrate that D3 exists as homodimer. While D3 homodimerized in its native state, minor heterodimerization was also observed between D3:D1 and D3:D2 in intact cells, the significance of which remains elusive. Incubation with 0.5-1.2 m urea resulted in loss of D3 homodimerization as assessed by bioluminescence resonance energy transfer and a proportional loss of enzyme activity, to a maximum of approximately 50%. Protein modeling using a D2-based scaffold identified potential dimerization surfaces in the transmembrane and globular domains. Truncation of the transmembrane domain (DeltaD3) abrogated dimerization and deiodinase activity except when coexpressed with full-length catalytically inactive deiodinase, thus assembled as DeltaD3:D3 dimer; thus the D3 globular domain also exhibits dimerization surfaces. In conclusion, the inactivating deiodinase D3 exists as homo- or heterodimer in living intact cells, a feature that is critical for their catalytic activities.
Subject(s)
Iodide Peroxidase/metabolism , Iodide Peroxidase/physiology , Thyroid Hormones/metabolism , Amino Acid Sequence , Catalysis , Cells, Cultured , Dimerization , Fluorescence Resonance Energy Transfer , Humans , Iodide Peroxidase/chemistry , Iodide Peroxidase/genetics , Luminescent Proteins/analysis , Membrane Proteins/metabolism , Models, Molecular , Molecular Sequence Data , Protein Binding , Protein Structure, Tertiary/physiology , Sequence Homology, Amino Acid , Surface Properties , TransfectionABSTRACT
Disturbances in energy homeostasis can result in obesity and other metabolic diseases. Here we report a metabolic pathway present in normal human skeletal muscle myoblasts that is activated by the small polyphenolic molecule kaempferol (KPF). Treatment with KPF leads to an approximately 30% increase in skeletal myocyte oxygen consumption. The mechanism involves a several-fold increase in cyclic AMP (cAMP) generation and protein kinase A activation, and the effect of KPF can be mimicked via treatment with dibutyryl cAMP. Microarray and real-time PCR studies identified a set of metabolically relevant genes influenced by KPF including peroxisome proliferator-activated receptor gamma coactivator-1alpha, carnitine palmitoyl transferase-1, mitochondrial transcription factor 1, citrate synthase, and uncoupling protein-3, although KPF itself is not a direct mitochondrial uncoupler. The cAMP-responsive gene for type 2 iodothyronine deiodinase (D2), an intracellular enzyme that activates thyroid hormone (T3) for the nucleus, is approximately threefold upregulated by KPF; furthermore, the activity half-life for D2 is dramatically and selectively increased as well. The net effect is an approximately 10-fold stimulation of D2 activity as measured in cell sonicates, with a concurrent increase of approximately 2.6-fold in the rate of T3 production, which persists even 24 h after KPF has been removed from the system. The effects of KPF on D2 are independent of sirtuin activation and only weakly reproduced by other small polyphenolic molecules such as quercetin and fisetin. These data document a novel mechanism by which a xenobiotic-activated pathway can regulate metabolically important genes as well as thyroid hormone activation and thus may influence metabolic control in humans.
Subject(s)
Energy Metabolism/drug effects , Kaempferols/pharmacology , Triiodothyronine/metabolism , Animals , Cell Line , Chalcones/pharmacology , Cyclic AMP/metabolism , Cyclic AMP-Dependent Protein Kinase Type II , Cyclic AMP-Dependent Protein Kinases/metabolism , Dose-Response Relationship, Drug , Gene Expression Profiling , Gene Expression Regulation/drug effects , Humans , Iodide Peroxidase/genetics , Iodide Peroxidase/metabolism , Myoblasts/drug effects , Oxygen Consumption/drug effects , RNA Interference , Rats , Resveratrol , Stilbenes/pharmacology , Iodothyronine Deiodinase Type IIABSTRACT
The relative roles of the types 1 and 2 iodothyronine deiodinases (D1 and D2) in extrathyroidal 3,5,3'-triiodothyronine (T3) production in humans are unknown. We calculated the rate of thyroxine (T4) to T3 conversion by intact cells transiently expressing D1 or D2 at low (2 pM), normal (20 pM), and high (200 pM) free T4 concentrations. Deiodinase activities were then assayed in cell sonicates. The ratio of T3 production in cell sonicates (catalytic efficiency) was multiplied by the tissue activities reported in human liver (D1) and skeletal muscle (D2). From these calculations, we predict that in euthyroid humans, D2-generated T3 is 29 nmol/d, while that of D1-generated T3 is 15 nmol/d, from these major deiodinase-expressing tissues. The total estimated extrathyroidal T3 production, 44 nmol/d, is in close agreement with the 40 nmol T3/d based on previous kinetic studies. D2-generated T3 production accounts for approximately 71% of the peripheral T3 production in hypothyroidism, but D1 for approximately 67% in thyrotoxic patients. We also show that the intracellular D2-generated T3 has a greater effect on T3-dependent gene transcription than that from D1, which indicates that generation of nuclear T3 is an intrinsic property of the D2 protein. We suggest that impairment of D2-generated T3 is the major cause of the reduced T3 production in the euthyroid sick syndrome.
Subject(s)
Iodide Peroxidase/metabolism , Thyroid Gland/metabolism , Triiodothyronine/blood , Cell Line , Humans , Iodide Peroxidase/genetics , Iodine Radioisotopes/metabolism , Liver/metabolism , Molecular Structure , Muscle, Skeletal/metabolism , Thyroxine/chemistry , Thyroxine/metabolism , Triiodothyronine/chemistry , Iodothyronine Deiodinase Type IIABSTRACT
Thyroid hormone (TH) plays a key role on post-natal bone development and metabolism, while its relevance during fetal bone development is uncertain. To study this, pregnant mice were made hypothyroid and fetuses harvested at embryonic days (E) 12.5, 14.5, 16.5 and 18.5. Despite a marked reduction in fetal tissue concentration of both T4 and T3, bone development, as assessed at the distal epiphyseal growth plate of the femur and vertebra, was largely preserved up to E16.5. Only at E18.5, the hypothyroid fetuses exhibited a reduction in femoral type I and type X collagen and osteocalcin mRNA levels, in the length and area of the proliferative and hypertrophic zones, in the number of chondrocytes per proliferative column, and in the number of hypertrophic chondrocytes, in addition to a slight delay in endochondral and intramembranous ossification. This suggests that up to E16.5, thyroid hormone signaling in bone is kept to a minimum. In fact, measuring the expression level of the activating and inactivating iodothyronine deiodinases (D2 and D3) helped understand how this is achieved. D3 mRNA was readily detected as early as E14.5 and its expression decreased markedly ( approximately 10-fold) at E18.5, and even more at 14 days after birth (P14). In contrast, D2 mRNA expression increased significantly by E18.5 and markedly ( approximately 2.5-fold) by P14. The reciprocal expression levels of D2 and D3 genes during early bone development along with the absence of a hypothyroidism-induced bone phenotype at this time suggest that coordinated reciprocal deiodinase expression keeps thyroid hormone signaling in bone to very low levels at this early stage of bone development.
Subject(s)
Bone and Bones , Fetus , Iodide Peroxidase/metabolism , Signal Transduction/physiology , Thyroid Hormones/metabolism , Animals , Bone and Bones/anatomy & histology , Bone and Bones/physiology , Collagen Type X/genetics , Collagen Type X/metabolism , Female , Fetus/anatomy & histology , Fetus/physiology , Gestational Age , Iodide Peroxidase/genetics , Isoenzymes/genetics , Isoenzymes/metabolism , Mice , Osteocalcin/genetics , Osteocalcin/metabolism , Pregnancy , Thyroid Hormone Receptors alpha/genetics , Thyroid Hormone Receptors alpha/metabolism , Thyroid Hormone Receptors beta/genetics , Thyroid Hormone Receptors beta/metabolism , Thyroxine/blood , Triiodothyronine/blood , Iodothyronine Deiodinase Type IIABSTRACT
Thyroid hormones influence gene expression in virtually all vertebrate tissues. Precise regulation of the active endogenous ligand, 3,5,3'-triiodothyronine (T(3)), is achieved by the sequential removal of iodine moieties from the thyroid hormone molecule. Type III iodothyronine deiodinase (D3) is the major inactivating enzyme terminating the action of T(3) and preventing activation of the prohormone, thyroxine (T(4)). Recent studies have revealed the induction of high D3 activity in diverse animal models of tissue injury including starvation, cryolesion, cardiac hypertrophy, infarction, and chronic inflammation. By analyzing serum and tissues taken from hospitalized patients at the time of death, investigators have also documented the robust induction of D3 activity in several human tissues that normally have none, including the liver and skeletal muscle, and shown clinically relevant consequences to systemic thyroid status. These studies reveal a novel role of D3 in the tissue response to injury and in the derangement of thyroid hormone homeostasis commonly observed during critical illness.
Subject(s)
Critical Illness , Iodide Peroxidase/metabolism , Thyroid Hormones/metabolism , Wounds and Injuries/enzymology , Animals , Euthyroid Sick Syndromes/blood , Euthyroid Sick Syndromes/metabolism , Euthyroid Sick Syndromes/pathology , Humans , Iodide Peroxidase/blood , Thyroid Hormones/bloodABSTRACT
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.
Subject(s)
Iodide Peroxidase/biosynthesis , Myocardial Infarction/physiopathology , Thyroid Gland/physiopathology , Animals , Heart/physiopathology , Iodide Peroxidase/metabolism , Iodine Radioisotopes/pharmacokinetics , Male , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Myocardium/pathology , Radioimmunoassay , Rats , Rats, Wistar , Symporters/metabolism , Thyroid Gland/metabolism , Thyrotropin/blood , Thyrotropin-Releasing Hormone/pharmacology , Thyroxine/blood , Time Factors , Triiodothyronine/bloodABSTRACT
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.
Subject(s)
Hemangioendothelioma/surgery , Hypothyroidism/physiopathology , Liver Neoplasms/surgery , Liver Transplantation , Female , Hemangioendothelioma/complications , Hemangioendothelioma/pathology , Humans , Infant , Liver Neoplasms/complications , Liver Neoplasms/pathology , Thyrotropin/blood , Thyroxine/blood , Thyroxine/therapeutic use , Treatment Outcome , Triiodothyronine/blood , Triiodothyronine/therapeutic useABSTRACT
Context: Circulating thyroglobulin antibodies (TgAb) can confound measurement of serum thyroglobulin and impair thyroid cancer surveillance. Few data exist on the significance of TgAb in pediatric thyroid cancer. Objective: To describe the prevalence, natural history, and clinical significance of TgAb in children with thyroid cancer. Design: Retrospective cohort study. Setting: Single academic pediatric center. Patients: Seventy-three consecutive children (≤18 years) with nonmedullary thyroid cancer who had serum TgAb measured within 6 months after diagnosis. Main Outcome Measures: Prevalence and natural history of TgAb; association of TgAb status and resolution with patient and disease characteristics. Results: TgAb were detected in 41% of subjects (30 of 73) and were associated with lymph node metastasis (83% vs 53%, P = 0.01) but not distant metastasis. In patients with TgAb, resolution occurred in 44% (11 of 25) over a median follow-up of 3.8 years. Median time to clear TgAb was 10.7 months, and 10 of 11 patients who cleared (91%) did so within 2 years. Resolution of TgAb was associated with lower initial TgAb level (median 4.5 vs 76 normalized units, P = 0.003). TgAb positivity at diagnosis was not independently associated with persistent or recurrent disease (odds ratio 3.20, 95% confidence interval 0.95 to 10.80, P = 0.06). Conclusions: TgAb are common at diagnosis in children with thyroid cancer but resolve in nearly half of patients within 1 to 2 years. TgAb are associated with the presence of lymph node metastasis at diagnosis, but the long-term prognostic significance remains to be determined.
Subject(s)
Biomarkers, Tumor/blood , Carcinoma/immunology , Immunoglobulins, Thyroid-Stimulating/blood , Thyroglobulin/blood , Thyroid Neoplasms/immunology , Academic Medical Centers , Adolescent , Age Factors , Carcinoma/epidemiology , Carcinoma/pathology , Carcinoma/surgery , Carcinoma, Papillary , Child , Cohort Studies , Female , Humans , Male , Pediatrics , Prevalence , Prognosis , Retrospective Studies , Risk Assessment , Sex Factors , Thyroid Cancer, Papillary , Thyroid Neoplasms/epidemiology , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Thyroidectomy/methodsABSTRACT
BACKGROUND: The thyroid hormone-inactivating enzyme type 3 deiodinase (D3) is induced during hypertrophic and ischemic cardiomyopathy, leading to a state of local cardiac hypothyroidism. Whether D3 induction occurs in dilated cardiomyopathy is unknown. METHODS: This study characterized changes in cardiac D3 and thyroid hormone signaling in a transgenic model of progressive dilated cardiomyopathy (TG9 mice). RESULTS: Cardiac D3 was dramatically induced 15-fold during the progression of dilated cardiomyopathy in TG9 mice. This D3 induction localized to cardiomyocytes and was associated with a decrease in myocardial thyroid hormone signaling. CONCLUSIONS: Cardiac D3 is induced in a mouse model of dilated cardiomyopathy, indicating that D3 induction may be a general response to diverse forms of cardiomyopathy.
Subject(s)
Cardiomyopathy, Dilated/metabolism , Iodide Peroxidase/metabolism , Myocardium/metabolism , Thyroxine/blood , Triiodothyronine/blood , Animals , Cardiomyopathy, Dilated/pathology , Disease Models, Animal , Disease Progression , Mice , Mice, Transgenic , Myocardium/pathologyABSTRACT
T(4), the main product of thyroid secretion, is a critical signal in plasma that mediates the TSH-negative feedback mechanism. As a prohormone, T(4) must be converted to T(3) to acquire biological activity; thus, type 2 iodothyronine deiodinase (D2) is expected to play a critical role in this feedback mechanism. However, the mechanistic details of this pathway are still missing because, counterintuitively, D2 activity is rapidly lost in the presence of T(4) by a ubiquitin-proteasomal mechanism. In the present study, we demonstrate that D2 and TSH are coexpressed in rat pituitary thyrotrophs and that hypothyroidism increases D2 expression in these cells. Studies using two murine-derived thyrotroph cells, TtT-97 and TalphaT1, demonstrate high expression of D2 in thyrotrophs and confirm its sensitivity to negative regulation by T(4)-induced proteasomal degradation of this enzyme. Despite this, expression of the Dio2 gene in TalphaT1 cells is higher than their T(4)-induced D2 ubiquitinating capacity. As a result, D2 activity and net T(3) production in these cells are sustained, even at free T(4) concentrations that are severalfold above the physiological range. In this system, free T(4) concentrations and net D2-mediated T(3) production correlated negatively with TSHbeta gene expression. These results resolve the apparent paradox between the homeostatic regulation of D2 and its role in mediating the critical mechanism by which T(4) triggers the TSH-negative feedback.