Alan Sacerdote – Autoimmunity

Autoimmunity, Insulin Resistance, and Non-Classic Adrenal Hyperplasia

Alan Sacerdote, MD, FACP, FABD, MABD
Department of Medicine, Woodhull Medical Center, Brooklyn, New York, United States |
+13476458255 |

We have previously reported that patients with the following autoimmune disorders generally have non-classic adrenal hyperplasia (NCAH): Type 1 diabetes mellitus, Graves’ disease, Hashimoto’s thyroiditis, vitiligo, psoriasis, and rheumatoid arthritis. In addition, it is almost universally encountered in Type 2 diabetes, with mellitus (T2DM)(with the exception of those patients who developed this disorder after HCV infection and lack a family history for Type 2 diabetes) [1-10].). Recently, it has been reported that about 2/3 of patients with T2DM have evidence of autoimmunity, when highly sensitive tests for cellular autoimmunity are employed (11). Very recently we diagnosed a patient with ulcerative colitis with both non-classic 21-hydroxylase deficiency and 11-hydroxylase deficiency.

It has also been reported that that both NCAH and classic CAH are associated with insulin resistance (IR) [12-15]. IR, in turn, has been associated with an increased risk of developing autoimmune disorders [16-20].

The inflammatory cytokine, tumor necrosis factor-α (TNF-α), as well as several other inflammatory cytokines, are involved in the pathogenesis of both IR and autoimmune disorders [21-35].

Serum vitamin D levels have been reported to be lower in patients with disorders typically associated with IR, including T2DM, polycystic ovarian syndrome (PCOS), and both classic congenital adrenal hyperplasia (CAH) and NCAH, pre-diabetes, Alzheimer’s disease, eclampsia and pre-eclampsia [36-50]. In other autoimmune disorders polymorphisms of the vitamin D receptor  (VDR) have been associated with susceptibility to the disorder or a more severe clinical course [51]

Supplementation with 1,25-(OH)2D3, the active form of vitamin D has been shown to lower the concentration of TNF-αin a rodent model of T2DM [51] and Vitamin D repletion has been associated with amelioration of PCOS, CAH, NCAH. [41, 43, 44, 46, 47 ]. Evidence for a beneficial role of Vitamin D repletion in prevention and treatment of autoimmune disorders other than psoriasis and vitiligo, where Vitamin D analogues or phototherapy are used routinely in treatment protocols is conflicting [52-58]

One study has shown a dose-effect of vitamin D supplementation from vitamin D treatment in infants >7 months old in the prevention of Type 1 diabetes [59]. Another randomized control study [60] showed a benefit from vitamin d supplementation in SLE patients on inflammatory and hemostatic markers and disease activity.

Overall there is good epidemiologic evidence that low serum 25-OH-Vitamin D levels and/or VDR polymorphisms are associated with increased risk for development of and increased severity of most, if not all, autoimmune disorders. Many more randomized, control, prospective studies are needed to assess the effects of Vitamin D repletion/supplementation on the prevention and treatment of autoimmune disorders.

We have reported that patients with both classic CAH and NCAH improve biochemically and clinically with interventions that reduce IR, including Vitamin D repletion in those with Vitamin D deficiency/insufficiency[61-67]. While some of the observed benefit of Vitamin D repletion in CAH and NCAH is likely due to a reduction in IR, the abundance of VDRs in the adrenal cortex suggests that Vitamin D may also have a direct regulatory effect on adrenal steroidogenesis [68].

In the case of 21-hydroxylase deficiency, approximately 9% of affected individuals have a contiguous gene deletion syndrome involving both 21-hydroxylase and tenascin XB, a collagen gene [69] on chromosome 6 opens up the possibility that numerous coexistent mutations of 21-hydroxylase and tenascin XB could arise with patients having both CAH or NCAH and a collagen disorder. The fact that these patient often have non-rheumatic cardiac valvular abnormalities related to the tenascin XB mutations is consistent with our earlier report of patients with such valvular abnormalities having NCAH, although such valvular abnormalities could also be related to disordered adrenal ouabain synthesis [70-71].

The location of the 21-hydroxylase gene within the HLA locus on chromosome 6, where a host of gene polymorphisms predisposing to autoimmune disorders reside, predicts that 21-hydroxylase deficiency will often coexist with autoimmune disorders.

Increase in serum Vitamin D levels in Type 2 diabetics was associated with decreases in serum amyloid A (SAA), a marker of inflammation [72].

Although we tend to think of adrenal insufficiency as an ‘all or none” type of disorder, it also may present as a partial disorder, wherein a patient may have an autoimmune response against one or moresteroidogenic enzymes in the adrenal cortex as often occurs in autoimmune polyglandular syndrome. Such partial forms of autoimmune adrenal insufficiency would be biochemically indistinguishable from classic CAH or NCAH and would respond clinically/biochemically to glucocorticoid/mineralocorticoid replacement.

In conclusion,


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