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 | Alan.Sacerdote@woodhullhc.nychhc.org
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 
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  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 . Another randomized control study  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 .
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  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 .
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.
- Sacerdote, A., Vergara, R., and Carnegie B.: Do All Patients with NIDDM Have Late-Onset Congenital Adrenal Hyperplasia? Program and Abstracts, 76th Annual Meeting of The Endocrine Society: 350, 1994 (poster presentation).
- Sacerdote, A.: Adrenal Hyperandrogenemia in NIDDM. Diabetes Care 18(2):278-279, 1995.
- Sacerdote, A.: Adrenal Hyperandrogenemia in IDDM. Program and Abstracts, 77th Annual Meeting of The Endocrine Society:545, 1995 (poster presentation).
- Sacerdote, A.: Adrenal Hyperandrogenemia in Graves’ Disease. Program and Abstracts, Tenth International Congress of Endocrinology II:1000, 1996 (poster presentation).
- Sacerdote, A.: Adrenal Hyperandrogenemia in Hashimoto’s Thyroiditis. Program and Abstracts, Tenth International Congress of Endocrinology II: 1000, 1996 (poster presentation).
- Sacerdote, A. and Li, Y.: Adrenal Hyperandrogenemia in Psoriasis. Program and Abstracts, 79th Annual Meeting of The Endocrine Society: 310, 1997 (poster presentation).
- Sacerdote, A.: Vitiligo Is Associated with Adrenal Hyperandrogenemia. Program and Abstracts, 80th Annual Meeting of The Endocrine Society: 199, 1998 (poster presentation).
- Sacerdote AS, Bahtiyar G, Mejía J. Rheumatoid arthritis is associated with non-classical adrenal hyperplasia. Program and Abstracts, Endo 2007, 89th Annual Meeting of The Endocrine Society 672, 2007 (poster presentation).
- Sacerdote, Alan. The expanding universe of androgenic disorders: plasticity of gene expression. Endocrine Today Feb 2005; : 4-7.
- Bahtiyar G, Sacerdote A.Latest Therapeutic Advances in the Treatment of Congenital Adrenal Hyperplasia in Adolescents and Adults. In “Amenorrhea; publisher-Intech,Amar Chatterjee Ed. ISBN 978-953-307-988-2, 148 pages Published on line 11-2011; published in print 12-2011.
- Itariu BK, Stulnig TM. Autoimmune aspects of type 2 diabetes mellitus – a mini-review. Gerontology. 2014;60(3):189-96.
- Speiser PW, Serrat J, New MI, Gertner JM Insulin insensitivity in adrenal hyperplasia due to nonclassical steroid 21-hydroxylase deficiency. J ClinEndocrinolMetab. 1992 Dec;75(6):1421-4.
- Saygili F, Oge A, Yilmaz C. Hyperinsulinemia and insulin insensitivity in women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the relationship between serum leptin levels and chronic hyperinsulinemia. Horm Res. 2005;63(6):270-4.
- Atabek ME, Kurtoğlu S, Keskin M. Female pseudohermaphroditism due to classical 21-hydroxylase deficiency and insulin resistance in a girl with Turner syndrome. Turk J Pediatr. 2005 Apr-Jun;47(2):176-9.
- Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos GP, Merke DP. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications.J ClinEndocrinolMetab. 2002;87(5):2114-20.
- 16.Nokoff NJ, Rewers M, Cree Green M.The interplay of autoimmunity and insulin resistance in type 1 diabetes.Discov Med. 2012;13(69):115-22.
- 17.Pozzilli P1, Guglielmi C, Caprio S, Buzzetti R.Obesity, autoimmunity, and double diabetes in youth. Diabetes Care. 2011;34Suppl 2:S166-70.
- Arora S, Sinha K, Kolte S1, Mandal A. Endocrinal and autoimmune linkage: Evidences from a controlled study of subjects with polycystic ovarian syndrome.J Hum Reprod Sci. 2016 Jan-Mar;9(1):18-22.
- Gyldenløve M, Storgaard H2, Holst JJ3, Vilsbøll T2, Knop FK4, Skov L. Patients with psoriasis are insulin resistant.J Am AcadDermatol. 2015;72(4):599-605.
- Siemińska L, Foltyn W, Głogowska-Szeląg J, Kajdaniuk D, Marek B, Nowak M, Walczak K, Kos-Kudła B.Relationships between adiponectin, sex hormone binding globulin and insulin resistance in hyperthyroid Graves’ disease women.Endokrynol Pol. 2013;64(1):26-9.
- Borst SE. The role of TNF-alpha in insulin resistance. Endocrine. 2004;23(2-3):177-82.
- Feldmann M, Maini RN.Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?Annu Rev Immunol. 2001;19:163-96.
- Santos FM, Telles RW, Lanna CC, Teixeira AL Jr4, Miranda AS, Rocha NP, Ribeiro AL. Adipokines, tumor necrosis factor and its receptors in female patients with systemic lupus erythematosus.Lupus. 2016 Jun 30. pii: 0961203316646463. [Epub ahead of print].
- Campanati A1, Orciani M2, Lazzarini R2, Ganzetti G1, Consales V1, Sorgentoni G2, Di Primio R, Offidani A. TNF-α inhibitors reduce the pathological Th1 -Th17 /Th2 imbalance in Cutaneous Mesenchymal Stem Cells of psoriasis patients.ExpDermatol. 2016 Jul 4. doi: 10.1111/exd.13139. [Epub ahead of print].
- Heilig B, Fiehn C, Brockhaus M, Gallati H, Pezzutto A, Hunstein W.Evaluation of soluble tumor necrosis factor (TNF) receptors and TNF receptor antibodies in patients with systemic lupus erythematodes, progressive systemic sclerosis, and mixed connective tissue disease.J ClinImmunol. 1993;13(5):321-8.
- Lamprecht P. TNF-alpha inhibitors in systemic vasculitides and connective tissue diseases.Autoimmun Rev. 2005 Jan;4(1):28-34.
- 27.Durães C, Moreira CS, Alvelos I1, Mendes A, Santos LR, Machado JC, Melo M, Esteves C, Neves C, Sobrinho-Simões M, Soares P. Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease.PLoS One. 2014 Aug 15;9(8):e105492.
- Díez JJ, Hernanz A, Medina S, Bayón C, Iglesias P.Serum concentrations of tumour necrosis factor-alpha (TNF-alpha) and soluble TNF-alpha receptor p55 in patients with hypothyroidism and hyperthyroidism before and after normalization of thyroid function.ClinEndocrinol (Oxf). 2002;57(4):515-21.
- Sharma CK, Sharma M, Aggarwal B, Sharma V. Different Advanced Therapeutic Approaches to Treat Vitiligo.J Environ PatholToxicolOncol. 2015;34(4):321-34.
- Kasumagic-Halilovic E, Prohic A, Cavaljuga S.Tumor necrosis factor-alpha in patients with alopecia areata. Indian J Dermatol. 2011;56(5):494-6.
- 31.Lee LF, Xu B, Michie SA, Beilhack GF, Warganich T, Turley S, McDevitt HO.The role of TNF-alpha in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation.Proc Natl AcadSci U S A. 2005;102(44):15995-6000.
- Daniele G, Guardado Mendoza R, Winnier D, Fiorentino TV, Pengou Z, Cornell J, Andreozzi F, Jenkinson C, Cersosimo E, Federici M, Tripathy D, Folli F.The inflammatory status score including IL-6, TNF-α, osteopontin, fractalkine, MCP-1 and adiponectin underlies whole-body insulin resistance and hyperglycemia in type 2 diabetes mellitus.ActaDiabetol. 2014 Feb;51(1):123-31.
- Schäkel K, Schön MP2, Ghoreschi K. Pathogenesis of psoriasis.Hautarzt. 2016 ;67(6):422-31.
- Türkcü FM, Şahin A, Cingü AK, Kaya S, Yüksel H, Cinar Y, Batmaz İ. Serum omentin, resistin and tumour necrosis factor-α levels in Behcet patients with and without ocular involvement.Graefes Arch ClinExpOphthalmol. 2015 Sep;253(9):1565-8.
- Caminero A, Comabella M, Montalban X.Tumor necrosis factor alpha (TNF-α), anti-TNF-α and demyelination revisited: an ongoing story.J Neuroimmunol. 2011 May;234(1-2):1-6. 36.Scragg R. Vitamin D and Type 2 Diabetes. Are We Ready for a Prevention Trial?Diabetes. 2008 Oct; 57(10): 2565–2566.
- Thys-Jacobs S, Donovan D, Papadopoulos A, Sarrel P, Bilezikian JP. Vitamin and calcium dysregulation in the polycystic ovarian syndrome. Steroids. 1999;64:430–435.
- 38.Panidis D, Balaris C, Farmakiotis D, Rousso D, Kourtis A, Balaris V, Katsikis I, Zournatzi V, Diamanti-Kandarakis E. Serum parathyroid hormone concentrations are increased in women with polycystic ovary syndrome. Clin Chem. 2005;51:1691–7.
- Hahn S, Haselhorst U, Tan S, Quadbeck B, Schmidt M, Roesler S, Kimmig R, Mann K, Janssen OE. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. ExpClinEndocrinol Diabetes. 2006;114:577–83.
- 40.Kotsa K, Yavropoulou MP, Anastasiou O, Yovos JG. Role of vitamin D treatment in glucose metabolism in polycystic ovary syndrome. FertilSteril. 2009;92:1053–8.
- 41,Rashidi B, Haghollahi F, Shariat M, Zayerii F. The effects of calcium-vitamin D and metformin on polycystic ovary syndrome: a pilot study. Taiwan J Obstet Gynecol. 2009;48:142–7.
- Finkielstain GP1, Kim MS, Sinaii N, Nishitani M, Van Ryzin C, Hill SC, Reynolds JC, Hanna RM, Merke DP.Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia.J ClinEndocrinolMetab. 2012;97(12):4429-38.
- 43.Vitiello M, Bahtiyar G, Sacerdote AVitamin D Deficiency/Insufficency in Patients with Non-Classic Adrenal Hyperplasia and Response of the Latter to vitamin D Replacement.Endoc Rev 110: Sun-470; presented at the 94thAnnual Meeting of The Endocrine Society 6-24-2012.
- Thomas N, Kalani A, Vincent R, Luis Lam M, Gul Bahtiyara, Borensztein A, Quinto E, Sacerdote A. Effect of Vitamin D in a Patient With Classical Adrenal Hyperplasia due to 11-Hydroxylase Deficiency.J Med Cases 2013;4, (8), 2013: 569-575.
- Bahtiyar G, Sacerdote A. Management Approaches to Congenital Adrenal.
- Hyperplasia in Adolescents and Adults; Latest Therapeutic Developments. In “Amenorrhea; publisher-Intech, Rijeka, Croatia Published on line 11-2011; published in print 12-2011.
- Sacerdote A Bahtiyar G. Treatment of Congenital Adrenal Hyperplasia byReducing Insulin Resistance and Cysticercosis Induced Polycystic Ovarian Syndrome. In Contemporary Gynecologic Practice, Prof. AtefDarwish (Ed.), ISBN: 978-953-51-1736-0, 2015InTech, Rijeka, Croatia.
- Sacerdote AS, Inoue T, Luis Lam M, Bahtiyar G. Vitamin D in the Treatment of Non-Classic 21-Hydroxylase Deficiency with Central Hypogonadism. Program: Abstracts – Orals, Poster Previews, and Posters.
- Session: FRI 409-475-Case Reports: Adrenal Insufficiency, CAH, Cushing Syndrome and Paraganglioma (posters)Clinical.
- Poster Board FRI 464 presented 4/1/2016 at Endo 2016, Boston, MA
- 48.Endocrine Society. “Raising low vitamin D levels lowers risk of prediabetes progressing to diabetes.” ScienceDaily. ScienceDaily, 23 June 2014. <www.sciencedaily.com/releases/2014/06/140623092052.htm>.
- Gezen-Ak D, Yılmazer S, Dursun E. Why vitamin D in Alzheimer’s disease? The hypothesis.J Alzheimers Dis. 2014;40(2):257-69.
- Bakacak M, Serin S, Ercan O, Köstü B, Avci F, Kılınç M, Kıran H, Kiran G.Comparison of Vitamin D levels in cases with preeclampsia, eclampsia and healthy pregnant women.Int J ClinExp Med. 2015;8(9):16280-6.
- Ma R, Deng XL, Du GL, Li C, Xiao S, Aibibai Y, Zhu J. Active vitamin D3, 1,25-(OH)2D3, protects against macrovasculopathy in a rat model of type 2 diabetes mellitus.Genet Mol Res. 2016 Jun 3;15(2). doi: 10.4238/gmr.15028113.
- Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin D in systemic and organ-specific autoimmune diseases. Clin Rev Allergy Immunol. 2013 Oct;45(2):256-66.
- 53..Schwalfenberg GK. Solar Radiation and Vitamin D: Mitigating Environmental Factors in Autoimmune Disease. Journal of Environmental and Public Health.
- Volume 2012 (2012), Article ID 619381, 9 pageshttp://dx.doi.org/10.1155/2012/619381.
- Smolders J, Thewissen M, Peelen E, Menheere P, Tervaert JW, Damoiseaux J, Hupperts R.Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis.Vitamin D status is positively correlated with regulatory T cell function in patients with multiple sclerosis.PLoS One. 2009 Aug 13;4(8):e6635. doi: 10.1371/journal.pone.0006635.
- Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016 Mar.
- CADTH Rapid Response Reports.Vitamin D for the Treatment or Prevention of Multiple Sclerosis: A Review of the Clinical Effectiveness [Internet].
- Brola W, Sobolewski P, Szczuchniak W, Góral A, Fudala M, Przybylski W, Opara J. Association of seasonal serum 25-hydroxyvitamin D levels with disability and relapses in relapsing-remitting multiple sclerosis.Eur J ClinNutr. 2016 Mar 30. doi: 10.1038/ejcn.2016.51. [Epub ahead of print].
- Muscogiuri G, Mitri J2, Mathieu C, Badenhoop K, Tamer G, Orio F, Mezza T, Vieth R, Colao A, Pittas A. Mechanisms in endocrinology: vitamin D as a potential contributor in endocrine health and disease. Eur J Endocrinol. 2014 Sep;171(3):R101-10. doi: 10.1530/EJE-14-0158. Epub 2014 May 28.
- Kamen DL Vitamin D in lupus – new kid on the block?Bull NYU HospJt Dis. 2010;68(3):218-22.
- Antico A, Tampoia M, Tozzoli R, Bizzaro N.Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature.Autoimmun Rev. 2012 Dec;12(2):127-36.
- Abou-Raya A, Abou-Raya S, Helmii M.The effect of vitamin D supplementation on inflammatory and hemostatic markers and disease activity in patients with systemic lupus erythematosus: a randomized placebo-controlled trial.J Rheumatol. 2013 Mar;40(3):265-61. Bahtiyar G, Sacerdote A. Latest Therapeutic Advances in the Treatment of Congenital Adrenal Hyperplasia in Adolescents and Adults. In Amenorrhea, ed. A. Chatterjee, 2011; 65-90, publ. Intech, Rijeka, Croatia.
- Sacerdote A, Bahtiyar G. Treatment of Congenital Adrenal Hyperplasia by Reducing Insulin Resistance and Cysticercosis Induced Polycystic Ovarian Syndrome. In Contemporary Gynecologic Practice, ed. 2015, AtefDarwish, publ. Intech, Rijeka, Croatia ISBN: 978-953-51-1736-0.
- Kalani A, Thomas N, Sacerdote A, Bahtiyar G.Roux-en-Y gastric bypass in the treatment of non-classic congenital adrenal hyperplasia due to 11-hydroxylase deficiency.BMJ Case Rep. 2013 Mar 18;2013. pii: bcr2012008416. doi: 10.1136/bcr-2012-008416.
- Kalani A, Bahtiyar G, Sacerdote A.Ashwagandha root in the treatment of non-classical adrenal hyperplasia.BMJ Case Rep. 2012 Sep 17;2012. pii: bcr2012006989. doi: 10.1136/bcr-2012-006989.
- Mapas-Dimaya AC, Agdere L, Bahtiyar G, Mejia JO, Sacerdote AS.Metformin-responsive classic salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a case report.EndocrPract. 2008 Oct;14(7):889-91.
- Bahtiyar G, Weiss K, Sacerdote AS.Novel endocrine disrupter effects of classic and atypical antipsychotic agents and divalproex: induction of adrenal hyperandrogenism, reversible with metformin or rosiglitazone.EndocrPract. 2007 Oct;13(6):601-8.
- Thomas N, Kalani A Vincent R, Luis Lam M, Gul Bahtiyar, Borensztein A, Quinto E, Alan Sacerdote A.Effect of Vitamin D in a Patient With Classical Adrenal Hyperplasia due to 11-Hydroxylase Deficiency. J of med Cases 2013;4(8);569-575.
- Lundqvist J, Wikvall K, Norlin M. Vitamin D-mediated regulation of CYP21A2 transcription – a novel mechanism for vitamin D action. BiochimBiophysActa. 2012; 1820(10):1553-1559.
- Chen W, Kim MS, Shanbhag S, Arai A, VanRyzin C, McDonnell NB, Merke DP.The phenotypic spectrum of contiguous deletion of CYP21A2 and tenascin XB: quadricuspid aortic valve and other midline defects.Am J Med Genet A. 2009 Dec;149A(12):2803-8.
- 70.Sacerdote, A. and Li, Y.: AdrenalHyperandrogenemia is Associated with Non-Rheumatic Cardiac Abnormalities. Program and Abstracts, 79th Annual Meeting of The Endocrine Society:310, 1997 (poster presentation).
- el-Masri MA, Clark BJ, Qazzaz HM, Valdes R Jr.Human adrenal cells in culture produce both ouabain-like and dihydroouabain-like factors.Clin Chem. 2002 Oct;48(10):1720-30.
- Shab-Bidar S, Neyestani TR, Djazayery A, Eshraghian MR, Houshiarrad A, Kalayi A, Shariatzadeh N, Khalaji N, Gharavi A.Improvement of vitamin D status resulted in amelioration of biomarkers of systemic inflammation in the subjects with type 2 diabetes.Diabetes Metab Res Rev. 2012 Jul;28(5):424-30.