OUP user menu

Journal of Crohn's and Colitis: 11 (1)


Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium


Published on behalf of

Autoimmune polyglandular syndrome type 2, alopecia universalis and Crohn's disease

Marijana Protic, Vladimir Gligorijevic, Daniela Bojic, Bojana Popovic, Svetozar Damjanovic, Njegica Jojic
DOI: http://dx.doi.org/10.1016/j.crohns.2012.05.009 318-321 First published online: 1 May 2013


Autoimmune polyglandular syndromes are defined as a spectrum of association between 2 or more organ specific endocrinopaties and non-endocrine autoimmune diseases. Autoimmune polyglandular syndromes type 2 is characterized by the coexistence of adrenal failure with autoimmune thyroid disease and diabetes mellitus type 1. Inflammatory bowel diseases are rarely associated with these autoimmune disorders.

Here, we report about a case of 33 years old male with known history of Crohn's colitis diagnosed in childhood. In 2003 the patient experienced sudden loss of hair, eyebrows, eyelashes, beard and body hair – alopecia universalis was diagnosed. At the age of 28, the patient was hospitalized with severe dehydration and clinical signs of ketoacidosis. Increased blood glucose (40 mmol/L), ketonuria and metabolic acidosis indicated diabetes mellitus type 1. In 2005, he had severe relapse of Crohn's disease and was treated with systemic corticosteroid. Although patient responded well to the induction therapy, fatigue, hypotension, bradycardia called for further investigations: free thyroxine – 6.99 pmol/L, thyroid-stimulating hormone > 75 U/ml, anti-thyroid peroxidase antibodies > 1000 U/mL, so diagnosis of Haschimoto thyroiditis was confirmed. Persistent hypotension and fatigue, recurrent hypoglycemic crises indicated a possible presence of hypo-function of adrenal glands. After complete withdrawal of corticosteroid therapy, low cortisol levels (69.4 nmol/L) and positive tetracosactide stimulation test proved adrenal cortex failure.

Regardless of the intensive treatment for diabetes, hypothyroidism, adrenal insufficiency and Crohn's disease, it was extremely difficult to achieve and maintain control of all four diseases.

  • Crohn's disease
  • Inflammatory bowel disease
  • Autoimmune polyglandular syndromes
  • Alopecia universalis

1 Introduction

Autoimmune polyglandular syndromes (APS) are defined as a spectrum of association between 2 or more organ specific endocrinopaties and non-endocrine autoimmune diseases. Generally, two major types of APS are recognized1 according to the age of presentation, characteristic patterns of disease combination and different mode of inheritance2 : APS 1—very rare, juvenile type inherited in an autosomal recessive manner and APS 2—relatively common, adult type, known as a Schmidt's or Carpenter's syndrome. APS 2 is characterized by the coexistence of adrenal failure with autoimmune thyroid disease and diabetes mellitus type 1. A third type of APS (APS 3), described in adults, contrary to APS1 and APS2 does not involve adrenal cortex. Inflammatory bowel diseases are rarely associated with APS. To our knowledge, only two cases have been reported so far.3,4 We present a case of APS 2, Crohn's disease (CD) and alopecia universalis.

2 Case report

Here, we report about a case of 33 year old male with history of Crohn's colitis diagnosed in childhood. The disease had mild course with last relapse in 1998. CD was in a long-term remission without maintenance therapy. The lack of the therapy was the patient's decision. In 2003 the patient experienced loss of hair, eyebrows, eyelashes, beard and body hair—general alopecia was diagnosed. In 2005, he was admitted to the hospital with severe dehydration and clinical signs of ketoacidosis. Laboratory studies showed increased blood glucose (40 mmol/L), ketonuria and metabolic acidosis (pH 7.12). An intensive insulin regimen was started after ketonuria had been resolved. Anti-glutamic acid decarboxylase (anti GAD) antibodies were highly elevated 182.4 U/mL (normal < 10 U/mL). Diagnosis of diabetes mellitus type 1 was established. The course of diabetes was unpredictable and severe, with frequent hypo and hyperglycemic crises.

In 2007, the patient was admitted to hospital again, with severe abdominal pain, more than 10 bloody diarrhea, nausea and weight loss. At the admission he was pale, febrile, dehydrated, tachycardic, with mild, diffuse abdominal tenderness and audible peristaltic. The blood count indicated hypochromic anemia (erythrocytes 3.45 × 1012/L, hemoglobin 95 g/L, serum ferritin 10.7 μg/L) and thrombocytosis (thrombocytes 710 × 109/L). Elevated inflammatory parameters (C-reactive protein (CRP)—36.5 mg/L; erythrocyte sedimentation rate (ESR)—75 mm/h), hypoalbuminemia—26 g/L (36–52 g/L) and decreased serum calcium—1.88 mmol/L (2.20–2.70 mmol/L) were registered. Stool culture (including stool tests for Campylobacter jejuni and Yersinia enterocolitica) and fecal parasite and ova examination were negative. Colonoscopy established relapse of CD with segmental inflammation and deep ulceration in transversum and colon descedens, as well as punctiform erosions and aphthous lesions in terminal ileum, coecum and rectum. A simple perianal fistula was detected by inspection of perianal region. Histology of multiple biopsies of the colon showed reduced number of crypts, focal crypt architectural irregularity with crypt distortion, crypt abscesses, chronic patchy inflammation (moderate infiltration of lamina propria with lymphocytes and plasma cells) and rare granulomas. Erosions of epithelial surface, villous and crypt irregularity were observed by histological analysis of the specimen of terminal ileum. Small bowel follow-through indicated slow passage, edematous, cobblestoned mucosa of ileum with narrowed and rigid terminal segment. Small bowel biopsy and negative antiendomysial antibodies (EMA) excluded coeliac disease.

Treatment with systemic corticosteroids was introduced and response was very good. Standard maintenance therapy with azathioprine in two divided doses (50 mg in the morning, 100 mg in the evening—73 kg body weight) was soon administrated. During the following weeks, a dose of azathioprine had to be increased to 200 mg daily (2.5 mg/kg) due to the worsening of the symptoms in the period of corticosteroid tapering.

Although the patient responded well to the induction therapy for CD, frequent hypoglycemic crises, hypotension, bradycardia called for further investigations: free thyroxine (FT4)—6.99 pmol/L (10.3–23 pmol/L), thyroid-stimulating hormone (TSH) > 75 U/mL (0.4–4.0 U/mL), anti-thyroid peroxidase (anti-TPO) antibodies > 1000 U/mL (normal < 35 U/mL). Diagnosis of Hashimoto thyroiditis was established based on laboratory characteristics, clinical symptoms and ultrasound findings. Subsequently l-thyroxine treatment (75 μg/day) was applied.

At that point, diabetes and autoimmune thyroiditis were verified and treated, but hypotension, recurrent hypoglycemic crises, fatigue and nausea indicated a possible presence of hypo-function of adrenal glands. Approximately 3 months later, 20 days after complete withdrawal of corticosteroid therapy, patient was hospitalized once more (Endocrinology Department) with clinical symptoms and signs of Addison's crisis. Serum cortisol level was low—69.4 nmol/L (131–642 nmol/L) as well as plasma adrenocorticotropic hormone (ACTH)—3.7 ng/L (10.0–90.0 ng/L). Due to previous, 3 months long corticosteroid therapy for CD, secondary hypocortisolism could have been expected. In order to test adrenal function, ACTH stimulation test with tetracosactide was performed. Cortisol response was subnormal during the test (120.7…192.5…208.9 nmol/L, after 0, 20 and 60 minutes, expected normal response > 550 nmol/L). These results suggested adrenal cortex failure. The replacement therapy with hydrocortisone was introduced immediately. The finding that the patient was seropositive for 21-hydroxilase antibodies confirmed the autoimmune nature of adrenal insufficiency.

Normal basal testosterone level (18.0 nmol/L, reference range 8.2–34.8 nmol/L) and normal testosterone response during human chorionic gonadotropin (hCG) stimulation test (28.2 nmol/L and 37.0 nmol/L at 0 and 72 hours respectively) excluded primary hypogonadism.

Low level of plasma calcium—1.88 mmol/L (2.20–2.70 mmol/L), vitamin D—9.02 mmol/L (> 30 mmol/L) and elevated level of parathyroid hormone (PTH)—175 pg/mol (10–69 pg/mol) observed in previous hospitalization were interpreted as indicator of malabsorption due to small bowel involvement of CD. Repeated measurements during the phase of CD remission demonstrated normal calcium (2.25 mmol/L) and PTH (30.2 pg/mol) levels.

After all investigation, the patient was diagnosed with CD, APS2 and alopecia universalis. His therapy included intensive insulin regimen, replacement therapy with l-thyroxine (75 μg/day), hydrocortisone (20 mg—at 8 h and 5 mg—at 16 h), and azathioprine (200 mg) for maintaining CD remission.

3 Discussion

Inflammatory bowel diseases (IBD) are rarely a part of APS. To our knowledge this is the third case describing association of IBD and APS, and the first one showing relation between ASP2, alopecia universalis and CD in particular.

APS 2 mostly occurs in third and fourth decade. The prevalence of APS 2 is 1:20,000.5 Women are more frequently affected (male: female ratio 1:3).1

Compared to APS1, caused by mutation in autoimmune regulatory gene (AIRE) on chromosome 21, inheritance of APS2 is more complex. Susceptibility genes in APS2 increase the risk for developing autoimmune disorders, but must not be causative. There are 3 major factors: HLA genes (alleles B8 and DR3) on chromosome 6,6 the cytotoxic T lymphocyte antigen gene (CTLA-4) on chromosome 2,7 and the protein tyrosine phosphatase non receptor type 22 gene (PTPN22) on chromosome 1.8 On the contrary, the major signal in HLA region (alleles DR) is associated with ulcerative colitis (UC) and not with CD. Recent studies showed that PTPN22 gene might contribute to susceptibility of APS2, yet it also has a role in genetic trait of CD.9 This gene encodes a lymphocyte-specific protein tyrosine phosphatase that down-regulates lymphocyte signaling; the variant Arg620Trp increases risk of several autoimmune diseases (type 1 diabetes, autoimmune thyroiditis, systemic lupus erythematosus, rheumatoid arthritis).10 Exchange of arginine (Arg) at codon 620 to tryptophan increases the phosphatase activity of PTPN22, compared to Arg620, to inhibit B- and T-cell activation. Surprisingly, this type of polymorphism decreases the risk of CD.11 Although, the genetic heterogeneity and incomplete phenotypic penetrance are common characteristics of both, APS2 and CD, it seems that association between these diseases should not be sought in genetic overlap. Our patient was heterozygous carrier for CARD15 (L1007fs) polymorphism.

Alopecia universalis, diagnosed at young age of our patient, may occur in APS. This type of alopecia is characterized by rapid and total loss of scalp and body hair. Alopecia universalis is the rarest (estimated 1 per 100,000) and most severe form of alopecia areata. It is defined as organ specific autoimmune disease and often associated with Hashimoto's thyroiditis and vitiligo.12 Experimental data support a causative role of both cytotoxic T cells and humoral factors. Putative auto-antigens expressed by growing hair follicles include hair-specific keratin and trichohyalin.13 Alopecia universalis is rarely associated with Crohn's disease.14,15 Although some authors described successful treatment of alopecia with immunomodulators,15 our patient showed no improvement under the treatment of corticosteroids and azathioprine given due to CD.

The patient was subsequently diagnosed with severe form of Type 1 diabetes and hypothyroidism. Hypoglycemic crises were the earliest signs of the adrenal failure. The thyroid hormones increase glucocorticoid metabolism, so hypothyroidism may mask Addison's disease by prolongation of cortisol half-life. Substitution by l-thyroxine induces normalization of cortisol half-life, decreases plasma level of this hormone and therefore may contribute to adrenal cortex insufficiency.16 Due to flair of CD, our patient was treated with corticosteroids simultaneously with l-thyroxine. However, corticosteroid therapy had to be withdrawn in order to confirm the diagnosis of adrenal insufficiency despite suspicions of existence of Addison's disease.

Regardless of the intensive treatment for diabetes, hypothyroidism, adrenal insufficiency and CD, it proved difficult to achieve and maintain control of all four diseases. Due to poor quality of life, disabilities and frequent hospitalizations, the patient became increasingly depressive. This resulted in poor therapeutic compliance and refusal of further investigation and therapy optimization. During the following 2 years, he was in stable clinical (no abdominal pains, 1–2 stool/day) and laboratory remission (CRP < 5 mg/L, fecal calprotectin < 350 μg/g feces) of CD. Nevertheless, he continued to suffer from severe headaches, hypoglycemic crises with poorly controlled diabetes (HbA1C—14.5%) and development of diabetic polyneuropathy and nephropathy. Despite endocrinologists' suggestions, he rejected insulin pump application.

Finally, we believe that this single case of multiple disease associations may be helpful for giving insight into common pathogenetic mechanisms, even though this combination of diseases may have occurred by chance. This report also may encourage other physicians to recognize patients so affected and then collect several of them from across different countries that might characterize the phenotype and genotype of the association.


Marijana Protic participated in the design and coordination of the study, data collection, data analysis, manuscript drafting, and revision.

Vladimir Gligorijevic contributed in data collection, data analysis, design of the study and manuscript drafting.

Daniela Bojic and Bojana Popovic participated in the data collection, data analysis and manuscript drafting.

Svetozar Damjanovic and Njegica Jojic participated in the design of the study, manuscript drafting, and provided significant scientific advice.

All authors read and approved the final manuscript. All authors have no interests to declare.

We would like to thank Dr. Biljana Jojic (Department of Endocrinology, University Hospital Zvezdara) for valuable contribution in diagnosing and treating the patient.


  • 1 Tel.: + 381 11 3086340.

  • 2 Tel.: + 381 11 361 6317.


View Abstract