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Human Molecular Genetics Aug 2022Autoimmune thyroid disease (AITD) and pernicious anemia (PA) often coexist, but the directionality is unknown. In a two-sample Mendelian randomization (MR) analysis,...
Autoimmune thyroid disease (AITD) and pernicious anemia (PA) often coexist, but the directionality is unknown. In a two-sample Mendelian randomization (MR) analysis, using summary statistics from large genome-wide association studies (GWASs) in Europeans (N = 49 269-755 406), we examined the genetic associations between thyroid function, PA and markers of erythropoiesis. We performed inverse variance weighted random-effects MR, several sensitivity MR analyses, and bidirectional MR and MR Steiger for directionality. AITD and PA were associated bidirectionally (P ≤ 8 × 10-6). Neither euthyroid thyroid stimulating hormone (TSH) nor free thyroxine (FT4) were causally associated with PA. One standard deviation (SD) increase in euthyroid FT4 regulated by genetic variants in deiodinases 1 and 2 genes (DIO1/DIO2), corresponding to low-normal free triiodothyronine (FT3) levels, was causally associated with a pernicious/macrocytic anemia pattern, i.e. decreased erythrocyte counts (rank-based inverse normal transformed β = -0,064 [95% confidence interval: -0,085, -0,044], P = 8 × 10-10) and hemoglobin (-0.028 [-0.051, -0.005], P = 0.02) and increased mean corpuscular hemoglobin (0.058 [0.025, 0.091], P = 5 × 10-4) and mean corpuscular volume levels (0.075 [0.052, 0.098], P = 1 × 10-8). Meanwhile, subclinical hyperthyroidism mirrored that pattern. AITD was causally associated with increased erythrocyte distribution width (P = 0.007) and decreased reticulocyte counts (P ≤ 0.02), whereas high-normal FT4 regulated by DIO1/DIO2 variants was causally associated with decreased bilirubin (-0.039 (-0.064, -0.013), P = 0.003). In conclusion, the bidirectional association between AITD and PA suggests a shared heritability for these two autoimmune diseases. AITD was causally associated with impaired erythropoiesis and not autoimmune hemolysis. Additionally, in euthyroid individuals, local regulation of thyroid hormones by deiodinases likely plays a role in erythropoiesis.
Topics: Anemia, Pernicious; Erythropoiesis; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Thyroid Gland; Thyrotropin; Thyroxine
PubMed: 35225327
DOI: 10.1093/hmg/ddac052 -
Cardiovascular & Hematological Agents... Nov 2017Pernicious Anemia (PA), the most common cause of cobalamin deficiency anemia worldwide, is an autoimmune disease of multifactorial etiologies involving complex... (Review)
Review
BACKGROUND
Pernicious Anemia (PA), the most common cause of cobalamin deficiency anemia worldwide, is an autoimmune disease of multifactorial etiologies involving complex environmental and immunological factors. Although it was first reported by Addison in 1849 with subsequent advances in understanding of pathogenesis and molecular biology, diagnosis of PA is still challenging for clinicians because of its complexity and diverse clinical presentations.
CONCLUSION
Herein, we provide an overview of PA, mainly focusing on its scientific and practical aspects in diagnosis. We also discuss the limitations of currently available diagnostic tools for the evaluation of cobalamin deficiency and PA.
Topics: Anemia, Pernicious; Autoantibodies; Gastritis, Atrophic; Humans; Vitamin B 12; Vitamin B 12 Deficiency
PubMed: 28164751
DOI: 10.2174/1871525715666170203114632 -
Immunologic Research Feb 2017Pernicious anemia is the hematologic manifestation of chronic atrophic gastritis affecting the corpus of the stomach that denudes the gastric mucosa of gastric parietal... (Review)
Review
Pernicious anemia is the hematologic manifestation of chronic atrophic gastritis affecting the corpus of the stomach that denudes the gastric mucosa of gastric parietal cells. Asymptomatic autoimmune gastritis, a chronic inflammatory disease of the gastric mucosa, precedes the onset of corpus atrophy by 10-20 years. The gastritis arises from activation of pathologic Th1 CD4 T cells to gastric H/K ATPase that is normally resident on gastric mucosal secretory membranes. The onset of autoimmune gastritis is marked by circulating parietal cell antibody to gastric H/K ATPase. Gastric parietal cells produce two essential biologics: intrinsic factor and HCl acid. Pernicious anemia is a consequence of intrinsic factor loss and neutralizing intrinsic factor antibody that impairs cobalamin absorption. Acid loss leads to iron deficiency anemia that precedes cobalamin-deficient pernicious anemia by 20 years. Laboratory diagnosis rests on parietal cell antibody with or without intrinsic factor antibody, cobalamin-deficient megaloblastic anemia and elevated serum gastrin from loss of acid secretion. Autoimmune gastritis is associated with autoimmune thyroiditis and type 1 diabetes mellitus.
Topics: Anemia, Pernicious; Animals; Autoimmune Diseases; Gastritis, Atrophic; Humans
PubMed: 27538411
DOI: 10.1007/s12026-016-8841-7 -
Current Opinion in Immunology Dec 2016The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator... (Review)
Review
The gene causing the severe organ-specific autoimmune disease autoimmune polyendocrine syndrome type-1 (APS-1) was identified in 1997 and named autoimmune regulator (AIRE). AIRE plays a key role in shaping central immunological tolerance by facilitating negative selection of T cells in the thymus, building the thymic microarchitecture, and inducing a specific subset of regulatory T cells. So far, about 100 mutations have been identified. Recent advances suggest that certain mutations located in the SAND and PHD1 domains exert a dominant negative effect on wild type AIRE resulting in milder seemingly common forms of autoimmune diseases, including pernicious anemia, vitiligo and autoimmune thyroid disease. These findings indicate that AIRE also contribute to autoimmunity in more common organ-specific autoimmune disorders.
Topics: Anemia, Pernicious; Animals; Autoimmunity; Cell Differentiation; Clonal Selection, Antigen-Mediated; Humans; Immune Tolerance; Mutation; Polyendocrinopathies, Autoimmune; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thymus Gland; Thyroiditis, Autoimmune; Transcription Factors; Vitiligo; AIRE Protein
PubMed: 27504588
DOI: 10.1016/j.coi.2016.07.003 -
Clinical Toxicology (Philadelphia, Pa.) Feb 2020The clinical consequences of excess vitamin B induced by multiple oral doses of cyanocobalamin are not well-known. A young woman was treated with multiple daily doses...
The clinical consequences of excess vitamin B induced by multiple oral doses of cyanocobalamin are not well-known. A young woman was treated with multiple daily doses of 1 mg of cyanocobalamin for severe pernicious anemia. After a total dose of 12 mg, she developed acne, palpitations, anxiety, akathisia, facial ruddiness, headache, and insomnia. She improved two weeks after stopping the drug. There were no sequelae nor complications. Although these symptoms of cobalamin toxicity were unexpected and unusual, the case reminds us that the administration of any drug is not entirely safe.
Topics: Acne Vulgaris; Adult; Anemia, Pernicious; Anxiety; Dose-Response Relationship, Drug; Female; Humans; Injections, Intramuscular; Treatment Outcome; Vitamin B 12
PubMed: 31018715
DOI: 10.1080/15563650.2019.1606432 -
BMJ (Clinical Research Ed.) Apr 2020
Topics: Anemia, Pernicious; Attention; Erythrocyte Indices; Fatigue; Humans; Hydroxocobalamin; Injections, Intramuscular; Missed Diagnosis; Peripheral Nervous System Diseases; Vitamin B 12 Deficiency; Vitamin B Complex
PubMed: 32332011
DOI: 10.1136/bmj.m1319