Polyendocrine syndromes

Polyendocrine syndromes encompass a cluster of disorders in which multiple endocrine organs are involved. Immune mediated processes either blocking or mimicking hormones are the most common pathophysiological basis. Since immune system disorders are involved the type of diabetes frequently encountered is type 1 diabetes mellitus.

Historical Aspects:

The first documentation of a polyglandular association was in 1853 when a case of adrenocortical failure with pernicious anaemia was reported [1]. The discovery of individual autoantibodies date back to the 1950s and 1960s. Roitt and Doniach in the year 1956 demonstrated the presence of circulating thyroid autoantibodies[2].

Adams and Purves discovered TSH-receptor antibodies during the same time. Anderson demonstrated a circulatory antibody to adrenal cortex extracts taken forward by Witebsky is formulating a definition based on adrenal autoantibodies [2]. However it wasnot until the 1970s when Bottazzo recognized type 1 diabetes as a part of APS II[2].

In 1980 Neufeld and Blizzard first classified APS as type I & II[1].

Pathophysiology:

The HLA system:

The major function of HLA proteins especially HLA class II is to present antigens to CD4+ T-cells. The T-cells in turn are of two varieties – T-helper (Th2) & pathogenic helper T-cells (Th1). The exact mechanism of autoimmunity is still poorly understood. In Type 1 diabetes mellitus the defect in HLA is the lack of aspartate residue at position 57 of the HLA DQ β chain[3]. These abnormalities in the HLA alleles can result in abnormal antigen recognition resulting in auto destruction. The same process can be identified in Addison’s disease, autoimmune thyroid disease, Myasthenia gravis, Coeliac disease etc.

The Th1 & Th2 balance:

The defective antigen presentation as well as induction of release of pro-inflammatory cytokines tilts the balance in favor of the pathogenic T- helper cells (Th1>Th2). In type 1 diabetes this is observed during the transition from the pre-insulinitis (Th2>Th1) to the phase of β-cell destruction[3]. Why is there involvement of multiple endocrine organs is not fully understood. We have not yet identified a common auto-antigen responsible for multiorgan involvement.

Genetic Basis:

At present the most plausible explanation for the multiple endocrine organ involvement is a genetic predisposition. This can be understood while analyzing the picture of autoimmune polyendocrine syndrome type II (APS II). For example genetic susceptibility to Addison’s disease, autoimmune thyroid disease and type 1 diabetes can be traced to a genetic susceptibility traceable to HLA DR3 (DQ A1* 0501, DQ B1* 0201) gene located on the short arm of chromosome 6[3]. In the Japanese population a variant of APS III (APS 3v) was characterized by the co-existence of type 1 diabetes and autoimmune thyroid disease. While comparing those with pure type 1 diabetes and APS3v it was observed that they were different both genetically as well as in their clinical presentations. There were distinct differences in the HLA DRB1-DQB1 haplotypes and CTLA4 gene polymorphisms between the two groups indicating a genetic difference between those with type 1 diabetes and APS3v[4].

Different types of Poyendocrine Syndromes[5]:

APS I, APS II, APS III & IV, Schmidt syndrome, Carpenter syndrome, Acanthosis nigricans, POEMS syndrome

Clinical Picture (with special reference to diabetes):

APS I:

Diagnosis requires the presence of 2 out of the 3 components: autoimmune Addison’s disease, primary hypoparathyroidism with severe hypocalcaemia and chronic, recurrent mucocutaneous candidiasis. Type 1 diabetes mellitus features in the list of minor components including autoimmune thyroid disease, GI manifestations, pernicious anaemia, chronic atrophic gastritis, chronic active hepatitis, vilitigo, alopecia, vasculitis & dental and enamel changes. Type 1 diabetes is found in 2-12% cases of APS I[3]. This figure climbs up to 50% in those above 50 years of age[3].

APS II:

Peak age: 30 years. Major components include Addison’s disease, autoimmune thyroid disease (primary hypothyroidism) and/or type 1 diabetes mellitus[5]. Other components include pernicious anemia, vitiligo, alopecia, myasthenia gravis, diabetes insipidus, coeliac disease and stiff-man syndrome. Type 1 diabetes mellitus is found in approximately 52% patients with APS II[3].

APS III:

Thyroid involvement without Addison’s disease.

APS IV:

Adrenal disease without the involvement of thyroid gland.

Schmidt syndrome:

Addison’s disease & autoimmune hypothyroidism

Carpenter syndrome:

Addison’s disease & autoimmune hypothyroidism and/or type 1 diabetes mellitus.

Acanthosis Nigricans (AN):

The predominant defect is insulin resistance. Those without very high anti-insulin antibodies are categorized as type A and those with AN with anti-insulin antibodies are categorized as type B. While treating this entity insulin requirements are very high but patients are protected from ketoacidosis[3]. Other associated endocrinopathies include: Hashimoto’s thyroiditis, Grave’s disease, and hypogonadism.

POEMS Syndrome:

Endocrinopathies include hypogonadotropic hypogonadism, and diabetes mellitus. In contrast to all the disorders discussed above diabetes here is immune mediated and hence hyperglycaemia is managed with low doses of insulin[3].

Screening protocols:

A German data looking into the different autoantibodies directed at other endocrinopathies in patients with type 1 diabetes could not find a correlation between the clinical picture and the positive antibody titer. The only endocrinopathy of significance was thyropathy with the highest prevalence, which increased by 3.5% within 12 months[6].

It has been documented that individuals with a single endocrine organ involvement progresses to APS II in 2.4% cases[5].

Hence the screening protocol recommends testing for other organ involvement at an interval of 3 years until 75 years of age[5]. Parameters to be tested includes: Serum electrolytes & full blood count. FT4 & TSH FSH, LH, testosterone or oestradiol. Fasting cortisol. Fasting plasma glucose. ACTH stimulation test (optional). If however the patient is diagnosed with two endocrinopathies we need to perform autoantibody testing in both the patient as well first-degree relatives [5]. The parameters include: Islet cell antibodies, GAD, IA-2. TPO, TSH-R antibody. Cytochrome P450 enzymes. H+-K+-ATPase of the parietal cells, intrinsic factor (IF). Transglutaminase, gliadin.

Screening with special reference to type 1 diabetes:

Figure 1. [Ref. 7]
Figure 1. [Ref. 7]
Screening for thyropathy: This is done on an annual basis with FT4, TSH & TPO antibodies. It TPO antibodies are positive but thyroid function test (TFT) is normal a bi-annual TFT is performed [7]. Screening for Coeliac disease: Done at presentation and then annually with tTGA & Ema antibodies for the first 3 years. If normal testing is performed once in 5 years[7]. Screening for pernicious anaemia: Performed in those with GAD & TPO antibodies positive on an annual basis for 3 years and once in 5 years from thereon[7]. Screening for Addison’s disease: Performed at similar intervals as in Coeliac disease with 21-OHAA.

Role of Imaging in diagnosing Polyglandular Endocrinopathies:

There is no role of imaging as far as type 1 diabetes is concerned. The major utility of imaging (CT/MRI) is in imaging the adrenal glands. Individuals with adrenal insufficiency were found to have a low gland volume with features of atrophy[2]. Ultrasound of the thyroid demonstrating hypoechoeic pattern either multifocal in nature or diffuse in indicative of autoimmune gland involvement[2].

Management:

As of now treatment of the individual endocrine organ dysfunction is done in accordance to the prevailing recommendations. Prior glucocorticoid support is required in those with Addison’s disease and primary hypothyroidism to prevent sudden increase of metabolic activity and precipitation of an acute adrenal crisis[3]. As the pathophysiological basis of the APS is immune mediated use of immunosuppressant’s to either prevent or treat the disease progression theoretically looks attractive. Primary prevention trial: Several trials looking into the measures to prevent multiple autoimmune endocrinopathies in high-risk children are being done. Some of the strategies include elimination of cow’s milk from the diet, delayed childhood exposure to gluten (BABY DIET study), vaccination strategies using oral or intra-nasal insulin (POINT study) etc[3]. Secondary prevention strategies: Several strategies like nicotinamide supplementation (DENIS & ENDIT trials) and parenteral or nasal insulin supplementation in those at high-risk of type 1 diabetes (DPT-1 trial)[3]. As of now all the secondary prevention strategies has been a failure. Tertiary prevention: From the point of view of type 1 diabetes the objective was to preserve beta cells. It was hypothesized that the C-peptide molecule is responsible for lesser hypoglycaemic episodes as well as better glycaemic control while on insulin therapy. Strategies employed to achieve this aim included starting insulin therapy at near normal plasma glucose values, immunosuppressive agents (azathioprine & cyclosporine), and vaccination with rGAD65, DiaPep 277 etc[3]. At present ongoing data points at use of anti-CD3 antibody as the most promising agent[3].

References

  1. ^ Jain J, Banait S, Jajoo U.N. et al. Polyglandular autoimmune syndrome: We should entertain this possibility more than often. Thyroid Research and Practice 2012; 9(3): 93-95

  2. ^ Betterle C. , Lazzarotto F. and Presotto F. Autoimmune polyglandular syndrome Type 2: the tip of an iceberg? Clin Exp Immunol 2004;137:225–233.

  3. ^ John A.H.Wass and Paul M.Stewart. Oxford Textbook of Endocrinology and Diabetes. 2011. Second Edition. Oxford: Oxford University Press.

  4. ^ Horie I, Kawasaki E, Ando T, et al. Clinical and Genetic Characteristics of Autoimmune Polyglandular Syndrome Type 3 Variant in the Japanese Population. Journal of Clinical Endocrinology & Metabolism 2012; 97(6):E1043-50.

  5. ^ Boris Draznin, Sol Epstein, Helen E. Turner & John A.H. Wass.Oxford American Handbook of Endocrinology and Diabetes. 2012. Oxford New York: Oxford University Press.

  6. ^ Hunger-Battefeld W, Fath K, Mandecka A, et al. Prevalence of polyglandular autoimmune syndrome in patients with diabetes mellitus type 1. Med Klin (Munich). 2009; 104(3):183-91.

  7. ^ Driessche A.V, Eenkhoorn V, Van Gaal F, et al. Type 1 diabetes and autoimmune polyglandular syndrome: a clinical review. The Netherlands Journal of Medicine 2009; 67(11): 376-387.

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