Juniper Publishers- Open Access Journal of Case Studies
Autoimmune Polyglandular Syndrome Type 3 with Multiple Genetic Alterations in a Young Male Patient with Type 1 Diabetes Mellitus
Authored by Abel Decmann
Abstract
Introduction: Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases among young and adolescent patients. A genetically predisposed person develops autoantibodies against beta-cells after certain environmental stimuli. Patients with T1DM can develop other organ-specific autoantibodies, most often causing autoimmune thyroiditis, coeliac disease or pernicious anaemia. Patients with multiple autoimmune diseases might be diagnosed with one of the autoimmune polyglandular syndromes. Case presentation: We present a 32-year-old male patient with type 1 diabetes mellitus and Hashimoto-thyroiditis. The habitus and laboratory tests taken at admission lead us to further investigations. The patient could be diagnosed with pernicious anaemia and hyperhomocysteinemia, as well. The latter disease raises the already higher cardiovascular risk of the diabetic patient. Conclusion: Patients with autoimmune type 1 diabetes mellitus should undergo screening for other autoimmune diseases, most importantly, autoimmune thyroid disease, pernicious anaemia and primary adrenal insufficiency.
Keywords:Diabetes mellitus type 1; Pernicious anaemia; Hashimoto-thyroiditis; Homocysteine; Autoimmune polyglandular syndrome
Abbreviations: APS: Autoimmune Polyendocrine/Polyglandular Syndrome; APECED: Autoimmune Polyendocrinopathy, Candidiasis, Ectodermal Dystrophy/Dysplasia; T1DM: Diabetes Mellitus Type 1
Introduction
Type 1 diabetes mellitus (T1DM) is one of the most common chronic diseases in young and adolescent patients which. After certain environmental stimuli a genetically predisposed persons develop autoantibodies which lead to the immune-mediated destruction of pancreatic beta-cells. People with HLA (human leukocyte antigen) genotypes of HLA-DR4-DQ8 or DR3-DQ2 have the highest genetic risk for developing T1DM [1]. The incidence of the disease varies between geographical regions, from 1-3 per 100.000/year in China and Asia to 30-60 per 100.000/year in Scandinavia [2,3]. No environmental factor has been found that is clearly associated with the development of T1DM, so far [4]. Patients with T1DM are usually not obese and develop diabetes in early childhood or in relatively young age compared to type 2 diabetes mellitus (T2DM). Characteristic circulating, islet-specific pancreatic autoantibodies may be present [against insulin, glutamic acid decarboxylase 65 (GAD65), zinc transporter 8 (ZnT8), 40k fragment of tyrosine phosphatase (IA2)] – however their absence does not necessarily rule out T2DM [5] – and lead to insulin deficiency. Patients with T1DM can develop other organ-specific autoantibodies, most often causing autoimmune thyroiditis, coeliac disease or pernicious anaemia. At least two organ-specific autoimmune diseases can be part of autoimmune polyendocrine/polyglandular syndromes (APS). APS type 1 [formerly called Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy/Dysplasia (APECED)] is due to a mutation in the autoimmune regulator (AIRE) gene, it has an autosomal recessive inheritance pattern. Usually it affects children and has a prevalence of 1:9.000-14.400 [6]. A patient must have two from the three characteristic manifestations (chronic mucocutaneous candidiasis, hypoparathyroidism, autoimmune adrenal insufficiency) [7]. Other diseases can be part of this syndrome: T1DM, pernicious anaemia, hypothyroidism, ectodermal dysplasia, autoimmune hepatitis, primary hypogonadism, alopecia, malabsorption and vitiligo [8]. APS type 2 is relatively rare, affects young adults and its prevalence is 1-5:100.000 population [9,10]. Obligatory features of the syndrome are autoimmune primary adrenal insufficiency (Addison’s disease) and autoimmune thyroid disease and/or T1DM. Additional autoimmune disease, such as vitiligo, autoimmune hepatitis, alopecia, pernicious anaemia, primary hypogonadism may also accompany it [10,11]. No clear inheritance pattern has been described so far. APS type 3 is characterised by autoimmune thyroid disease and at least one other autoimmune organ-specific disorder (T1DM, primary hypogonadism, pernicious anaemia, coeliac disease, vitiligo, alopecia, psoriasis etc.) that is not Addison’s disease or hypoparathyroidism [12]. The inheritance pattern of APS3 is yet to be determined.
Case Presentation
A 32-year-old male patient with diabetes mellitus presented to ambulatory care because of suboptimal blood sugar levels, alleged weight loss, vague low-back pain and supposed malabsorption. The patient history contained 3 years’ history of T1DM, 2 years’ history of thyroid disease and mitral and aortic valve prolapse. The patient’s mother had Hashimoto-thyroiditis and myasthenia gravis. On physical examination, the patient was underweight (height 180cm, weight 52kg, BMI: 16kg/m2). His posture, his long limbs and fingers suggested marfanoid habitus. HbA1c level of the patient was 8.2% (normal range: 4-6), with a fasting glucose level of 11mmol/l (4.1-5.9). Antibodies against glutamic acid decarboxylase [1745IU/ml (<10)] and against ZnT8 [17IU/ml (<15)] tested positive and antibodies against tyrosine phosphatase-A2 [2IU/ml (<20)] and insulin [6IU/ml (<12)] tested negative, result of islet-cell antibody was uncertain. Based on low BMI, relatively young age and islet-specific antibody positivity we could confirm the diagnosis of T1DM.
We evaluated the thyroid function of the patient. TSH (thyroid stimulating hormone) [3.9mU/l (0.35-4.9)], fT4 [12.97pmol/l (9-23.2)] and fT3 [5.11pmol/l (2.63-5.7)] were in normal range without therapy. Anti-thyroid peroxidase antibody level was highly elevated [1196U/ml (<5.6)]. Subsequent thyroid sonography showed inhomogeneous, hypervascularized lobes of thyroid gland. These findings were consistent with a euthyroid Hashimoto-thyroiditis (Figure 1).
The laboratory tests performed at admission showed mild, macrocytic anaemia (Table 1). Vitamin B12 level was below reference range with 72pmol/l (138-652). Gastroscopy showed type A atrophic gastritis and histologic evaluation revealed severe chronic gastritis with intestinal metaplasia without H. pylori infection. Immunological tests were also performed. Anti-parietal cell antibodies tested positive, while antibodies against intrinsic factor were negative. According to the abovementioned results, the diagnosis of pernicious anaemia could be established.
Clearly, the patient had vitamin B12 malabsorption. However, iron-, lipid-, protein- and calcium/vitamin D3-metabolism were without marked alterations. Coeliac disease could also be excluded because of the negativity of antibodies against tissue transglutaminase and deamidated gliadin peptides. The gastroscopy showed no typical signs of coeliac disease in the small intestine. There were no ionic disturbances [serum sodium 142mmol/l (135-146), potassium 4.4mmol/l (3.5-5.1)], fasting serum cortisol level was within the normal range [cortisol 465.3nmol/l (220-690)] and no clinical signs of hypoadrenalism were detected, therefore we could rule out clinically manifested Addison’s disease.
Concurrent Hashimoto-thyroiditis, T1DM and pernicious anaemia, and the absence of Addison’s disease and hypoparathyroidism suggested the diagnosis of autoimmune polyendocrine syndrome type 3. Maternal anamnesis of Hashimoto-thyroiditis and myasthenia gravis that could be diagnosed also as APS3, strengthens the diagnosis.
We performed further tests because of the marfanoid habitus and valvular prolapses of the patient. Because of the vague lowback pain and the characteristic phenotype of the patient, we performed tests to evaluate ankylosing spondylitis. There was no clear sign of sacroiliitis on plain pelvic x-ray (Figure 2). From the 11 characteristic ankylosing spondylitis symptoms, the patient showed only 1, namely HLA-B27 positivity. According to the relevant guideline, sacroiliitis on MRI would further strengthen the diagnosis, but it is itself not diagnostic [13]. Because of vitamin B12 deficiency homocysteine level was measured and was found to be extremely elevated [homocysteine 100.2μmol/l (5.4- 16)]. Homocysteine is produced by complex enzymatic activity from dietary methionine. B12 and folate-dependent enzymatic conversions are responsible for keeping homocysteine levels relatively low by conversion to methionine or cysteine [14]. We, therefore, performed genetic analysis of the two most frequent mutations of the methylenetetrahydrofolate reductase (MTHFR) gene. We have found the A1298C mutation in homozygous variant [MTHFR (methylenetetrahydrofolate reductase) C677T normal variant, MTHFR A1298C homozygous variant)]. Therefore, we have concluded that elevated homocysteine level may be explained by vitamin B12 deficiency and the patient’s genetic predisposition.
Discussion
The young patient has multiple autoimmune conditions (T1DM, pernicious anaemia, Hashimoto-thyroiditis), that can together be classified as autoimmune polyendocrine syndrome type 3. At the time of hospitalization, the patient did not need any thyroid hormone replacement therapy but needed insulin therapy and replacement of vitamin B12. However, the cardiovascular risk of the patient is higher because of the T1DM. We measured homocysteine levels and performed genetic testing for hyperhomocysteinaemia. Elevated homocysteine levels are associated with higher cardiovascular risk and more frequent thromboembolic events, moreover, homocysteine is an independent risk factor of cardiovascular diseases [15,16]. Approximately, 10% of the US population are homozygous for the thermolabile variant of MTHFR (C677T), and 30% are heterozygous for another polymorphism of MTHFR gene, A1298C is found in approximately 10% of Caucasian population [17]. There is no clear consensus on whether reducing homocysteine level through vitamin B12 replacement lowers the cardiovascular risk [18]. However, there are articles that discuss the role of vitamin D3 replacement in patients with hyperhomocysteinaemia to lower homocysteine levels [19]. We observed genetic alteration independent from the comorbidities of type 1 diabetes mellitus.
Conclusion
In conclusion, in patients with type 1 diabetes mellitus and with autoimmune polyglandular syndrome who have higher cardiovascular risk the presence of other genetically known risk factors, such as hyperhomocysteinaemia or spondylarthritis should be considered, in order to initiate, if possible, preventive measures.
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