Abstract
Context
Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).
Evidence acquisition
Guidelines, pertinent original articles, ...systemic reviews, and meta-analyses.
Evidence synthesis
Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection–related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.
Conclusions
A clear trend towards serological diagnosis and medical treatment of GD has emerged.
Abstract
Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. ...This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.
Graves’ disease (GD) is a systemic autoimmune disorder characterized by the infiltration of thyroid antigen-specific T cells into thyroid-stimulating hormone receptor (TSH-R)-expressing tissues. ...Stimulatory autoantibodies (Ab) in GD activate the TSH-R leading to thyroid hyperplasia and unregulated thyroid hormone production and secretion. Diagnosis of GD is straightforward in a patient with biochemically confirmed thyrotoxicosis, positive TSH-R-Ab, a hypervascular and hypoechoic thyroid gland (ultrasound), and associated orbitopathy. In GD, measurement of TSH-R-Ab is recommended for an accurate diagnosis/differential diagnosis, prior to stopping antithyroid drug (ATD) treatment and during pregnancy. Graves’ hyperthyroidism is treated by decreasing thyroid hormone synthesis with the use of ATD, or by reducing the amount of thyroid tissue with radioactive iodine (RAI) treatment or total thyroidectomy. Patients with newly diagnosed Graves’ hyperthyroidism are usually medically treated for 12–18 months with methimazole (MMI) as the preferred drug. In children with GD, a 24- to 36-month course of MMI is recommended. Patients with persistently high TSH-R-Ab at 12–18 months can continue MMI treatment, repeating the TSH-R-Ab measurement after an additional 12 months, or opt for therapy with RAI or thyroidectomy. Women treated with MMI should be switched to propylthiouracil when planning pregnancy and during the first trimester of pregnancy. If a patient relapses after completing a course of ATD, definitive treatment is recommended; however, continued long-term low-dose MMI can be considered. Thyroidectomy should be performed by an experienced high-volume thyroid surgeon. RAI is contraindicated in Graves’ patients with active/severe orbitopathy, and steroid prophylaxis is warranted in Graves’ patients with mild/active orbitopathy receiving RAI.
Autoimmune Polyendocrinopathy Frommer, Lara; Kahaly, George J
The journal of clinical endocrinology and metabolism,
10/2019, Letnik:
104, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Abstract
Context
This mini-review offers an update on the rare autoimmune polyendocrinopathy (AP) syndrome with a synopsis of recent developments.
Design and Results
Systematic search for studies ...related to pathogenesis, immunogenetics, screening, diagnosis, clinical spectrum, and epidemiology of AP. AP (orphan code ORPHA 282196) is defined as the autoimmune-induced failure of at least two glands. AP is divided into the rare juvenile type I and the adult types II to IV. The prevalence is 1:100,000 and 1:20,000 for types I and types II to IV, respectively. Whereas type I (ORPHA 3453) is a monogenetic syndrome with an autosomal recessive transmission related to mutations in the autoimmune regulator (AIRE) gene, types II to IV are genetically complex multifactorial syndromes that are strongly associated with certain alleles of HLA genes within the major histocompatibility complex located on chromosome 6, as well as the cytotoxic T lymphocyte antigen 4 and the protein tyrosine phosphatase nonreceptor type 22 genes. Addison disease is the major endocrine component of type II (ORPHA 3143), whereas the coexistence of type 1 diabetes and autoimmune thyroid disease is characteristic for type III (ORPHA 227982). Genetic screening for the AIRE gene is useful in patients with suspected type I, whereas serological screening (i.e., diabetes/adrenal antibodies) is required in patients with monoglandular autoimmunity and suspected AP. If positive, functional endocrine testing of the antibody-positive patients as well as serological screening of their first-degree relatives is recommended.
Conclusion
Timely diagnosis, genetic counseling, and optimal long-term management of AP is best offered in specialized centers.
This mini-review offers a comprehensive description of the current pathophysiology, immunology, and clinical spectrum of the complex autoimmune polyendocrinopathy syndrome, as well as a synopsis of recent and novel reports.
Type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) are the most frequent chronic autoimmune diseases worldwide. Several autoimmune endocrine and non-endocrine disorders tend to occur ...together. T1D and AITD often cluster in individuals and families, seen in the formation of autoimmune polyendocrinopathy (AP). The close relationship between these two diseases is largely explained by sharing a common genetic background. The HLA antigens DQ2 (
) and DQ8 (
), tightly linked with DR3 and DR4, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms (or rare variants) of various genes, such as the
, the
, the
, the
, and the
that are involved in immune regulation have been identified to confer susceptibility to both T1D and AITD. Other genes including cluster of differentiation
, the
, the
Class I
,
, the
, the
gene, the
, and various cytokine genes are also under suspicion to increase susceptibility to T1D and AITD. Further,
(
,
(
,
(
, and
(
are found to be associated with T1D and AITD by various independent genome wide association studies and overlap in our list, indicating a strong common genetic link for T1D and AITD. As several susceptibility genes and environmental factors contribute to the disease aetiology of both T1D and AITD and/or AP subtype III variant (T1D+AITD) simultaneously, all patients with T1D should be screened for AITD, and vice versa.
Polyglandular autoimmune syndromes Kahaly, George J
European journal of endocrinology,
07/2009, Letnik:
161, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The polyglandular autoimmune syndromes (PAS) comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (PAS type I) and a relatively common adult type with (PAS II) ...or without adrenal failure (PAS III). First clinical manifestation of PAS I usually occurs in childhood, whereas PAS II mostly occurs during the third and fourth decades. PAS I is caused by mutations in the autoimmune regulatory (AIRE) gene on chromosome 21 and is inherited in an autosomal recessive manner. Mutations in the AIRE gene result in defect proteins which cause autoimmune destruction of target organs by disturbing the immunological tolerance of the patients. Genetic testing may identify patients with PAS I, but not those with PAS II/III. For PAS II/III, susceptibility genes are known which increase the risk for developing autoimmune disorders, but must not be causative. These are certain HLA genes, the cytotoxic T lymphocyte antigen gene, and the protein tyrosine phosphatase non-receptor type 22 gene on chromosomes 6, 2 and 1 respectively. Actual diagnosis of PAS involves serological measurement of organ-specific autoantibodies and subsequent functional testing. Management of patients with PAS including their family relatives is best performed in centres with special expertise in autoimmune endocrine disorders.
Thyrotropin Receptor Blocking Antibodies Diana, Tanja; Olivo, Paul D; Kahaly, George J
Hormone and metabolic research,
12/2018, Letnik:
50, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Autoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the ...action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were used to study the pathophysiology of Graves' disease and Hashimoto's thyroiditis. In the past, bioassays for anti-TSHR-Abs were laborious and time-consuming and varied widely in performance from laboratory to laboratory. Recent advances in the development of cell-based assays, including the application of molecular engineering, have led to significant improvements that have enabled bioassays to be employed routinely in clinical laboratories. The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab. There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD. In the present review, we summarize the different methods used to measure TBAb, and discuss their prevalence and clinical relevance.
Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley and rye. The ...prevalence of celiac disease is increased in patients with monoglandular and/or polyglandular autoimmunity and their relatives. Between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5 to 7% of patients with autoimmune thyroid disease and/or type 1 diabetes are IgA anti-tissue transglutaminase antibody positive. The close relationship between celiac disease and endocrine autoimmunity is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and/or DQ8 (DQA1*0301-DQB1*0302), that are tightly linked to DR3 and DR4, respectively, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms of various genes that are involved in immune regulation have been identified as “overlap” susceptibility genes for both celiac disease and monoglandular or polyglandular autoimmunity. While plausible, it remains to be established how far a gluten free diet may prevent or ameliorate glandular autoimmunity. In conclusion, all patients with celiac disease should be screened for type 1 diabetes and/or autoimmune thyroid disease. Conversely, patients with the above autoimmune endocrine disorders should be also screened for celiac disease.
Pathophysiology of thyroid-associated orbitopathy Lee, Alan Chun Hong; Kahaly, George J.
Baillière's best practice & research. Clinical endocrinology & metabolism,
March 2023, 2023-03-00, Letnik:
37, Številka:
2
Journal Article
Recenzirano
Thyroid-associated orbitopathy, the most common extrathyroidal manifestation of Graves' disease, is characterized by orbital inflammatory infiltration and activation of orbital fibroblasts, which ...mediates de novo adipogenesis, excessive production of hyaluronan, myofibroblast differentiation and ultimately tissue fibrosis. Interactions among T cells, B cells, and orbital fibroblasts result in their activation and perpetuation of orbital inflammation as well as tissue remodelling. T helper 17 cells belong to a newly identified pathogenic CD4+ T cell subset which possesses prominent pro-inflammatory and profibrotic capabilities. Thyroid stimulating hormone receptor/insulin-like growth factor-1 receptor crosstalk and the downstream signalling pathways of both receptors represent the major mechanisms leading to activation of orbital fibroblasts. Thyroid stimulating hormone receptor autoantibody is the disease specific biomarker of great clinical relevance and utility. There is growing evidence that oxidative stress, gut microbiome and epigenetics also play a role in the pathogenesis and their manipulation may represent novel therapeutic strategies.
PDF
