Addison,pernicious anemia and adrenal insufficiency

In 1849 Thomas Addison described the clinical entity now known as pernicious anemia. In 1855 he reported several cases of adrenal insufficiency, or Addison''s disease. Considering the importance of these works, there remains a great deal of confusion about them. Contrary to what many historians have written, a review of Addison''s original publications demonstrates a firm appreciation of the distinction between pernicious anemia and adrenal insufficiency, based particularly on the discoloration of the skin in these conditions. Three major sources of possible confusion for historians who are attempting to understand Addison''s views include Addison''s early attempts to link pernicious anemia with disease of the supra-renal capsules, Addison''s redefinition of pernicious anemia in his monograph on adrenal disease, and several confusing statements made by Wilks and Daldy in the first reprint of Addison''s monograph.     

Antibody that blocks stimulation of cortisol secretion by adrenocorticotrophic hormone in Addison's disease

To investigate whether Addison''s disease may in some cases be due to the blocking of adrenocorticotrophic hormone''s action at the adrenal cortex by antibodies IgG isolated from a woman with Addison''s disease associated with the autoimmune polyglandular syndrome type I was studied. Its effects on guinea pig adrenal cells in vitro were investigated and compared with those of IgG from three normal subjects and IgG obtained commercially. IgG from the patient inhibited the stimulation of cortisol secretion by adrenocorticotrophic hormone by 77 (SD 2)% and 57 (12)% at concentrations of 0·5 and 0·05 g/l, respectively; IgG prepared five months after she had started treatment with replacement steroids inhibited cortisol secretion by 74 (1)% (0·5 g/l) and 51 (15)% (0·05 g/l). The other IgGs had no inhibitory effects. The IgG from the patient and that obtained commercially did not inhibit the stimulation of cortisol secretion by dibutyryl cyclic adenosine monophosphate or precursors of cortisol. None of the IgGs bound to adrenocorticotrophic hormone.These results suggest that the IgG from the patient acted against the receptor for adrenocorticotrophic hormone, and its presence may explain the patient''s raised concentrations of adrenocorticotrophic hormone, failure to respond to exogenous adrenocorticotrophic hormone, and normal basal cortisol concentrations. Addison''s disease may thus in some instances be a receptor antibody disease.     

Immunoreactive Corticotrophin Levels in Adrenocortical Insufficiency

Plasma concentrations of immunoreactive corticotrophin (ACTH) have been determined in 14 patients with untreated Addison''s disease and in 42 patients with secondary adrenocortical insufficiency. Basal morning plasma ACTH levels were markedly raised in those with Addison''s disease but were either in the normal range or undetectable in the group with secondary adrenocortical insufficiency. In the group with Addison''s disease circulating ACTH values showed a definite nyctohemeral rhythm, a pronounced rise in response to insulin-induced hypoglycaemia, and an immediate fall following the intravenous injection of corticosteroids, with a half-life of between 13·5 and 44·2 minutes. When assays were performed with antisera directed against the portion of the ACTH molecule responsible for corticosteroidogenesis (the N-terminal portion) the apparent ACTH concentrations were lower than with antisera directed against the non-steroidogenic (C-terminal) portion of the molecule. This emphasizes that different antisera may give different apparent hormone concentrations, and that the ranges of values obtained in normal and abnormal states must be established for each antiserum.     

A novel heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED)

Background

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) is an autosomal recessive disease due to mutations of the autoimmune regulator (AIRE) gene. Typical manifestations include candidiasis, Addison's disease, and hypoparathyroidism. Type 1 diabetes, alopecia, vitiligo, ectodermal dystrophy, celiac disease and other intestinal dysfunctions, chronic atrophic gastritis, chronic active hepatitis, autoimmune thyroid disorders, pernicious anemia and premature ovarian failure are other rare associated diseases although other conditions have been associated with APECED.

Case presentation

What follows is the clinical, endocrinological and molecular data of a female APECED patient coming from Lithuania. The patient was affected by chronic mucocutaneous candidiasis, hypoparathyroidism and pre-clinical Addison's disease. Using direct sequencing of all the 14 exons of the AIRE gene in the patient's DNA, we identified in exon 6 the known mutation c.769 C>T (p.Arg257X) in compound heterozygosity with the newly discovered mutation c.1214delC (p.Pro405fs) in exon 10. The novel mutation results in a frameshift that is predicted to alter the sequence of the protein starting from amino acid 405 as well as to cause its premature truncation, therefore a non-functional Aire protein.

Conclusions

A novel mutation has been described in a patient with APECED with classical clinical components, found in compound heterozygosity with the c.769 C>T variation. Expanded epidemiological investigations based on AIRE gene sequencing are necessary to verify the relevancy of the novel mutation to APECED etiopathogenesis in the Lithuanian population and to prove its diagnostic efficacy in association with clinical and immunological findings.     

Visceral and skin granuloma annulare,diabetes, and polyendocrine disease.

A middle aged man suffered with insulin dependent diabetes, autoimmune Addison''s disease, myxoedema, and severe ulcerative colitis, for which he had undergone subtotal colectomy with formation of an ileostomy. Granuloma annulare confined to the anterior abdominal wall was diagnosed in 1981. In 1983 an episode of severe colicky pain and excessive working of the ileostomy occurred associated with severe hyperglycaemia and increased irritation of the granuloma annulare. Laparotomy disclosed adhesions and numerous white nodules over bowel, mesentery, and peritoneum histologically identical with the skin lesions. Two further episodes of subacute small bowel obstruction occurred, and a repeat laparotomy showed widespread intra-abdominal granuloma annulare. Visceral granuloma annulare appears not to have been reported before, and in this patient exacerbation of the skin lesion was associated with poor diabetic control.     

Thyroid Function in Addison's Disease

Clinical evidence of a thyroid disorder was present in 10 out of 40 patients with Addison''s disease. Though the remaining 30 patients had no clinical evidence of thyroid disease, six (out of 15 tested) had thyroid microsomal antibodies and a considerably impaired response to thyrotrophin. These changes are interpreted as very early indications of developing thyroid failure. When circulating microsomal antibodies are found this seems to indicate the presence of established thyroid disease.     

A successful transplant of embryonic adrenal tissue in a patient with Addison's disease.

Well documented reports of the successful transplantation of human adrenal cortical tissue cannot be found in the literature. In 1951 we achieved the successful transplantation of human embryonic adrenal gland (cortical tissue) in a patient with symptomatic adrenal insufficiency (Addison''s disease), apparently the first instance of histologically documented successful homografting of human adrenal cortex. Because of its historical pertinence, the authors, many years later, herein report on this case, which appeared in the senior author''s medical thesis. The report must be viewed in the context of the existing clinical knowledge and technology available 40 years ago.     

THE CLINICAL SIGNIFICANCE OF URINARY 17-KETOSTEROID ASSAYS

The urinary 17-ketosteroids are a group of compounds derived from complex steroids produced by the adrenal cortex, testis, or ovary. The method of determining the amount excreted has been simplified so that it is available for routine diagnostic purposes. Usually the amount is increased in diseases in which there is hyperfunction of the adrenal cortex due to tumor or hyperplasia, and decreased in lesions that impair the function of the adrenal cortex.Other conditions such as myxedema, eunuchism, gout, and arthritis may alter the excretion of the 17-ketosteroids. Low levels are also found in the young and in the aged. Case histories are presented to illustrate the findings in the following diseases: Tumors of the adrenal cortex with (a) masculinization, (b) Cushing''s syndrome with virilism and, (c) hirsutism; as well as in gigantism with acromegaly, in gout, eunuchism, Addison''s disease, myxedema, and severe panhypopituitarism.     

A Chronobiological Approach to Circulating Levels of Renin,Angiotensin-Converting Enzyme,Aldosterone, ACTH,and Cortisol in Addison's Disease

This study deals with a chronobiological approach to the circadian rhythm of the renin-angiotensin-aldosterone system (RAAS) and the ACTH-cor-tisol axis (ACA) in patients with Addison's disease (PAD). The aim is to explore the mechanism(s) for which the circadian rhythmicity of the RAAS and ACA takes place. The study has shown that both the RAAS and ACA are devoid of a circadian rhythm in PAD. The lack of rhythmicity for renin and ACTH provides indirect evidence that their rhythmic secretion is in some way related to the circadian oscillation of aldosterone and cortisol. This implies a new concept: a positive feedback may be included among the mechanisms which chronoregulate the RAAS and ACA.     

口腔微生态与干燥综合征相关性研究进展

干燥综合征是一种炎性细胞侵犯外分泌腺体的慢性自身免疫疾病,口干是其最常见的症状。伴随着干燥综合征患者口腔内微环境的改变,口腔各种微生物之间及微生物与宿主之间的平衡被打破,进而出现口腔微生态失调。口腔微生态失调与自身免疫疾病关系密切,其不仅是疾病所导致的结果,也可能是疾病进一步发展的原因。目前研究认为干燥综合征患者口腔微生态失调与唾液微环境的改变及口腔黏膜免疫受损存在密切的关系,本文对口腔微生态与干燥综合征关系的新近研究进展进行综述。     

Adult cerebral adrenoleukodystrophy and Addison's disease in a female carrier

We described a 38-year-old woman of rapidly progressive dementia with white matter encephalopathy and death. She had Addison's disease but the adrenal glands were hyperplastic. Brain magnetic resonance imaging revealed diffuse white matter lesion predominantly in the frontal lobe with band-like contrast enhancement. l-Methyl-11C-methionine positron emission tomography revealed accumulation of tracer in bilateral frontal lobes. Stereotactic biopsy demonstrated demyelination changes. A number of urinary organic acids were elevated. Adrenoleukodystrophy was diagnosed by elevated plasma very long chain fatty acid and ABCD1 gene mutation (C1544C/T). Adrenoleukodystrophy should be considered as a differential diagnosis in women with rapidly progressive white matter encephalopathy.     

Genetic control of disease in an experimental model for Sjögren's syndrome

Sjögren's syndrome is an autoimmune disease with a complex etiology depending on hereditary and environmental factors. The disease is characterized by lymphocytic infiltration and inflammation in the salivary and lacrimal glands, leading to oral and ocular dryness. To understand the genetic susceptibility in Sjögren's syndrome, studies of disease phenotypes have been performed in the non-obese diabetic (NOD) mouse. By the identification of genetic regions controlling development of autoimmune exocrinopathy in the NOD mouse and by reducing one of these regions considerably, Nguyen et al. in a recent issue of Arthritis Research and Therapy propose candidate genes for development of Sjögren's syndrome.     

Autoimmunity as a Candidate for the Etiopathogenesis of Meniere's Disease: Detection of Autoimmune Reactions and Diagnostic Biomarker Candidate

Meniere''s disease is an inner ear disorder that can manifest as fluctuating vertigo, sensorineural hearing loss, tinnitus, and aural fullness. However, the pathologic mechanism of Meniere''s disease is still unclear. In this study, we evaluated autoimmunity as a potential cause of Meniere''s disease. In addition we tried to find useful biomarker candidates for diagnosis. We investigated the protein composition of human inner ear fluid using liquid column mass spectrometry, the autoimmune reaction between circulating autoantibodies in patient serum and multiple antigens using the Protoarray system, the immune reaction between patient serum and mouse inner ear tissues using western blot analysis. Nine proteins, including immunoglobulin and its variants and interferon regulatory factor 7, were found only in the inner ear fluid of patients with Meniere''s disease. Enhanced immune reactions with 18 candidate antigens were detected in patients with Meniere''s disease in Protoarray analysis; levels of 8 of these antigens were more than 10-fold higher in patients than in controls. Antigen-antibody reactions between mouse inner ear proteins with molecular weights of 23–48 kDa and 63–75 kDa and patient sera were detected in 8 patients. These findings suggest that autoimmunity could be one of the pathologic mechanisms behind Meniere''s disease. Multiple autoantibodies and antigens may be involved in the autoimmune reaction. Specific antigens that caused immune reactions with patient''s serum in Protoarray analysis can be candidates for the diagnostic biomarkers of Meniere''s disease.     

Hypothyroidism after Thyroidectomy for Graves's Disease: A Search for an Explanation

Out of 38 patients who had undergone subtotal thyroidectomy for Graves''s disease seven to 20 years previously 15 developed hypothyroidism. In these 15 patients autoantibodies against thyroid cytoplasm were significantly more frequent than in the 23 euthyroid patients, though there was no difference in the prevalence of autoantibodies against thyroglobulin. Histological examination of the thyroid tissue removed at operation showed that significantly more plasma cells and lymphoid follicles with germinal centres were present in patients who subsequently developed hypothyroidism than in those who remained euthyroid. No differences in the amount of lymphocytic infiltration were seen in hypothyroid and euthyroid patients.The results suggest that B lymphocytes play a part in the development of postoperative hypothyroidism in Graves''s disease. It is proposed that Graves''s disease and Hashimoto''s disease are different aspects of the same basic autoimmune process.     

Population based study of 12 autoimmune diseases in Sardinia, Italy: prevalence and comorbidity

Background

The limited availability of prevalence data based on a representative sample of the general population, and the limited number of diseases considered in studies about co-morbidity are the critical factors in study of autoimmune diseases. This paper describes the prevalence of 12 autoimmune diseases in a representative sample of the general population in the South of Sardinia, Italy, and tests the hypothesis of an overall association among these diseases.

Methods

Data were obtained from 21 GPs. The sample included 25,885 people. Prevalence data were expressed with 95% Poisson C.I. The hypothesis of an overall association between autoimmune diseases was tested by evaluating the co-occurrence within individuals.

Results

Prevalence per 100,000 are: 552 rheumatoid arthritis, 124 ulcerative colitis, 15 Crohn''s disease, 464 type 1 diabetes, 81 systemic lupus erythematosus, 124 celiac disease, 35 myasthenia gravis, 939 psoriasis/psoriatic arthritis, 35 systemic sclerosis, 224 multiple sclerosis, 31 Sjogren''s syndrome, and 2,619 autoimmune thyroiditis . An overall association between autoimmune disorders was highlighted.

Conclusions

The comparisons with prevalence reported in current literature do not show outlier values, except possibly for a few diseases like celiac disease and myasthenia gravis. People already affected by a first autoimmune disease have a higher probability of being affected by a second autoimmune disorder. In the present study, the sample size, together with the low overall prevalence of autoimmune diseases in the population, did not allow us to examine which diseases are most frequently associated with other autoimmune diseases. However, this paper makes available an adequate control population for future clinical studies aimed at exploring the co-morbidity of specific pairs of autoimmune diseases.     

Maladie de Basedow et maladie de Crohn : étiopathogénie croisée ou association fortuite ? (À propos de deux cas)

An increased prevalence of the association between autoimmune thyroid diseases and ulcerative colitis has been suggested, while the association with Crohn's disease has only been reported in about ten cases. We describe two patients, one with Crohn's disease complicated with Graves’ disease and the other one with the reverse sequence. The treatment of hyperthyroidism in such cases must be early and efficient in order to avoid an intensification of the systemic manifestations of Crohn's disease. Genetic, environmental and immunologic aetiologies have been suggested for the pathogenesis of this association, although the exact mechanism remains unclear.     

Enhanced chemiluminescent immunoassay for aldosterone

A solid phase immunoassay for aldosterone using enhanced chemiluminescent detection has been developed. Monoclonal antibodies against aldosterone were used for the immune reaction and compared with polyclonal antibodies. Uniform Protein A coated polystyrene tubes were used as solid phase for the monoclonal antibody and second (anti-rabbit) antibody coated tubes for the polyclonal antibody. Horseradish peroxidase was covalently linked to aldosterone as enzyme label. Optimum conditions were established for the generation and measurement of the luminescent reactions using luminol, p-iodophenol as enhancer and hydrogen peroxide. The advantages of this assay are the high sensitivity with a detection limit of 100fg/tube, the prolonged luminescence signal with a simplification of the measurement (simpler detectors, external start pipetting) and the short measure time with the possibility of repeated measurement. The coefficients of variation were 4.2%–7.3% in the concentration range 140–1180 pmol/l. The assay showed a significant correlation (r = 0.91) with the ELISA. The aldosterone concentrations in plasma and saliva of patients with Conn's syndrome were significantly increased, and in patients with Addison's disease were found near the detection limit.     

Shared molecular and functional frameworks among five complex human disorders: a comparative study on interactomes linked to susceptibility genes

Background

Genome-wide association studies (gwas) are invaluable in revealing the common variants predisposing to complex human diseases. Yet, until now, the large volumes of data generated from such analyses have not been explored extensively enough to identify the molecular and functional framework hosting the susceptibility genes.

Methodology/Principal Findings

We investigated the relationships among five neurodegenerative and/or autoimmune complex human diseases (Parkinson''s disease-Park, Alzheimer''s disease-Alz, multiple sclerosis-MS, rheumatoid arthritis-RA and Type 1 diabetes-T1D) by characterising the interactomes linked to their gwas-genes. An initial study on the MS interactome indicated that several genes predisposing to the other autoimmune or neurodegenerative disorders may come into contact with it, suggesting that susceptibility to distinct diseases may converge towards common molecular and biological networks. In order to test this hypothesis, we performed pathway enrichment analyses on each disease interactome independently. Several issues related to immune function and growth factor signalling pathways appeared in all autoimmune diseases, and, surprisingly, in Alzheimer''s disease. Furthermore, the paired analyses of disease interactomes revealed significant molecular and functional relatedness among autoimmune diseases, and, unexpectedly, between T1D and Alz.

Conclusions/Significance

The systems biology approach highlighted several known pathogenic processes, indicating that changes in these functions might be driven or sustained by the framework linked to genetic susceptibility. Moreover, the comparative analyses among the five genetic interactomes revealed unexpected genetic relationships, which await further biological validation. Overall, this study outlines the potential of systems biology to uncover links between genetics and pathogenesis of complex human disorders.     

Lack of an association of PD-1 and its ligand genes with Behcet's disease in a Chinese Han population

Background

Behcet''s disease is a chronic, multi-systemic autoimmune disease. Programmed cell death 1 (PD-1) gene is one of non-human leucocyte antigen genes. It has been demonstrated to be associated with several autoimmune diseases. However, only a few studies have addressed the association of ligand genes of PD-1, PD-L1 and PD-L2 with autoimmune disease. The purpose of this study was to analyze the potential association of the PD-1 and its ligand genes with Behcet''s disease in a Chinese Han population.

Methodology/Principal Findings

Four single-nucleotide polymorphism (SNPs) rs2227981 and rs10204525 of PD-1, rs1970000 of PD-L1 and rs7854303 of PD-L2 were genotyped in 405 Behcet''s patients and 414 age-, sex-, ethnic-matched healthy controls using polymerase chain reaction-restriction fragment length polymorphism assay. The results revealed that there were no significant differences in the genotype and allele frequencies of PD-1 rs2227981 and rs10204525 between the Behcet''s patients and controls. A similar result was found for PD-L1 rs1970000 versus healthy controls. Only the C allele and the CC genotype of PD-L2 rs7854303 were identified in patients and controls. Stratification analysis based on gender and clinical findings did not show any associations between PD-1 or its ligand polymorphisms and Behcet''s disease.

Conclusions/Significance

None of the currently studied SNPs, PD-1 rs2227981 and rs10204525, PD-L1 rs1970000 and PD-L2 rs7854303, are associated with the susceptibility to Behcet''s disease in a Chinese Han population. More studies are needed to confirm these findings in Behcet''s patients with other ethnic backgrounds.     

药物作用靶点研究最新进展

通过对我国学者近2年在国内外发表的相关论文进行检索和整理,分类综述针对神经退行性疾病（如阿尔茨海默病、帕金森病等）、心血管疾病（如高血压、心律失常、心衰、冠心病、心肌梗死、动脉粥样硬化等）、脑血管疾病、代谢类疾病（如肥胖症、血脂异常、脂肪肝、糖尿病等）、感染性疾病（如艾滋病、流感、结核病等）、恶性肿瘤、自身免疫性疾病等多种疾病的药物作用靶点研究最新进展。