Thyrotoxicosis

Thyroid hormones are essential for skeletal development and are important regulators of bone maintenance in adults. Childhood hypothyroidism causes delayed skeletal development, retarded linear growth and impaired bone mineral accrual. Epiphyseal dysgenesis is evidenced by classic features of stippled epiphyses on X-ray. In severe cases, post-natal growth arrest results in a complex skeletal dysplasia. Thyroid hormone replacement stimulates catch-up growth and bone maturation, but recovery may be incomplete dependent on the duration and severity of hypothyroidism prior to treatment. A severe phenotype characteristic of hypothyroidism occurs in children with resistance to thyroid hormone due to mutations affecting THRA encoding thyroid hormone receptor α (TRα). Discovery of this rare condition recapitulated animal studies demonstrating that TRα mediates thyroid hormone action in the skeleton. In adults, thyrotoxicosis is well known to cause severe osteoporosis and fracture, but cases are rare because of prompt diagnosis and treatment. Recent data, however, indicate that subclinical hyperthyroidism is associated with low bone mineral density (BMD) and an increased risk of fracture. Population studies have also shown that variation in thyroid status within the reference range in post-menopausal women is associated with altered BMD and fracture risk. Thus, thyroid status at the upper end of the euthyroid reference range is associated with low BMD and increased risk of osteoporotic fragility fracture. Overall, extensive data demonstrate that euthyroid status is required for normal post-natal growth and bone mineral accrual, and is fundamental for maintenance of adult bone structure and strength.

BackgroundThyroid storm (TS) is life threatening. In the mid-2000s, its incidence was poorly defined, peer-reviewed diagnostic criteria were not available, and management and treatment did not seem to be verified based upon evidence and latest advances in medicine.MethodsFirst, diagnostic criteria were developed based on 99 patients in the literature and seven patients in this study. Then, initial and follow-up surveys were conducted from 2004 through 2008, targeting all hospitals in Japan to obtain and verify information on patients who met diagnostic criteria for TS. Based on these data, the diagnostic criteria were revised, and management and treatment guidelines were created.ResultsThe incidence of TS in hospitalized patients in Japan was estimated to be 0.20 per 100,000 per year and 0.22% of all thyrotoxic patients. The mortality rate was 10.7%. Multiple organ failure was the most common cause of death, followed by congestive heart failure, respiratory failure, and arrhythmia. In the final diagnostic criteria for TS, the definition of jaundice as serum bilirubin concentration >3 mg/dL was added. Based upon nationwide surveys and the latest information, guidelines for the management and treatment for TS were extensively revised and algorithms were developed.ConclusionsTS remains a life-threatening disorder, with >10% mortality in Japan. New peer-reviewed diagnostic criteria for TS are presented and its clinical features, prognosis, and incidence are clarified based on nationwide surveys. Furthermore, this information helped to establish detailed guidelines for the management and treatment of TS. A prospective prognostic study to validate the guidelines is eagerly anticipated.

Immune checkpoints are small molecules present on the cell surface of T-lymphocytes. They maintain self-tolerance and regulate the amplitude and duration of T-cell responses. Antagonism of immune checkpoints with monoclonal antibodies (immune checkpoint inhibitors) is a rapidly evolving field of anti-cancer immunotherapy and has become standard of care in management of many cancer subtypes. Immune checkpoint inhibition is an effective cancer treatment but can precipitate immune related adverse events (irAEs). Thyroid dysfunction is the most common endocrine irAE and can occur in up to 40% of treated patients. Both thyrotoxicosis and hypothyroidism occur. The clinical presentation and demographic associations of thyrotoxicosis compared to hypothyroidism suggest unique entities with different etiologies. Thyroid irAEs, particularly overt thyrotoxicosis, are associated with increased immune toxicity in other organ systems, but also with longer progression-free and overall survival. Polygenic risk scores using susceptibility loci associated with autoimmune thyroiditis predict development of checkpoint inhibitor associated irAEs, suggesting potentially shared mechanisms underpinning their development. Our review will provide an up-to-date summary of knowledge in the field of thyroid irAEs. Major focus will be directed toward pathogenesis (including genetic factors shared with autoimmune thyroid disease), demographic associations, clinical presentation and course, treatment, and the relationship with cancer outcomes.

Thyroid storm, or thyrotoxic crisis, is a rare but life-threatening hypermetabolic state arising from severe thyrotoxicosis with a high risk of multiorgan failure. It typically occurs in individuals with untreated or poorly controlled hyperthyroidism, most often Graves' disease, though various other disorders may also precipitate it. Common triggers include infection, surgery, trauma, abrupt discontinuation of antithyroid medication, severe emotional or physical stress, and iodine exposure. Clinical manifestations involve hyperthermia, tachyarrhythmia, cardiac and respiratory failure, and hepatic dysfunction. Neurological and gastrointestinal symptoms, such as agitation, confusion, delirium, vomiting, diarrhea, and profuse sweating, are frequent. Diagnosis is clinical rather than biochemical, and scoring systems are used to support the diagnosis. Thyroid storm is more common in females, with an incidence of approximately 0.2 to 1.1 per 100 000 in the general population and 4.8 to 6.3 per 100 000 among hospitalized patients. Without rapid intervention, mortality remains high (5 to 25%), primarily due to cardiovascular collapse or multiorgan dysfunction. Management requires immediate supportive therapy, including cardiovascular stabilization, respiratory support, and temperature control, along with identification and treatment of precipitating factors. Pharmacologic therapy involves antithyroid agents to block thyroid hormone synthesis, beta blockers to counteract adrenergic effects, corticosteroids to reduce peripheral conversion and support adrenal function, and, when appropriate, iodine administration after thionamides. Early recognition and intensive management are crucial to prevent fatal outcomes, highlighting the need for vigilance in patients with severe thyrotoxicosis or decompensated hyperthyroidism.