Recalcitrant Hypocalcaemia in AutoimmuneEnteropathy

abstractAutoimmune polyendocrinopathy candidiasis ectodermal dystrophy syn-drome is a monogenic disorder associated with autoimmune destruc-tion of both endocrine and nonendocrine tissues. The classic triadincludes candidiasis, hypoparathyroidism, and Addison disease. Up to25% of patients with autoimmune polyendocrinopathy candidiasis ec-todermal dystrophy syndrome also have gastrointestinal manifestations,which can have an impact on the management of other aspects of thedisease. The management of the case discussed was challenging be-cause of the complex interplay between the manifestations and treat-ment of his hypoparathyroidism, Addison disease, and autoimmuneenteropathy. Attempts at management of hypocalcemia were largelyunsuccessful until the introduction of immunosuppressive therapy forautoimmune enteropathy. This case supports early consideration of im-munosuppression in this condition. Pediatrics 2014;134:e1720–e1726

AUTHORS: Myfanwy Geyer, MBBS,a Jan Fairchild, MBBS,FRACP,a David Moore, MBBS, FRACP,b,c Lynette Moore,MBBS, FRCPA, MBA,d Paul Henning, MBBS, FRACP,e andElaine Tham, MBBS, FRACP, M Med Scia

Departments of aEndocrinology and Diabetes, bGastroenterology,dSurgical Pathology, and eNephrology, Women’s and Children’sHospital, Adelaide, South Australia; and cUniversity of Adelaide,Adelaide, South Australia

KEY WORDSautoimmune polyendocrinopathy candidiasis ectodermaldystrophy syndrome, APECED, autoimmune polyendocrinopathysyndrome 1, APS-1, autoimmune enteropathy, enteroendocrinecells, hypocalcaemia

ABBREVIATIONS17OH—17 hydroxylaseAPECED—autoimmune polyendocrinopathy candidiasis ectoder-mal dystrophyGAD—glutamic acid decarboxylaseGH—growth hormoneICA—islet cell antibodyIF—intrinsic factorNR—normal rangeSCC—cholesterol side chain cleavageTPH—tryptophan hydroxylase

Dr Geyer drafted the initial manuscript; Dr Fairchild assistedwith drafting sections related to early management ofhypoparathyroidism and Addison disease, and reviewed andrevised the manuscript; Dr D. Moore assisted with draftingsections relating to autoimmune enteropathy and reviewed andrevised the manuscript; Dr L. Moore assisted with staining ofbiopsies, drafting sections related to histopathology ofcondition, and reviewed and revised the manuscript; Dr Henningassisted with drafting sections relating to hypocalcemia andhyperphosphatemia, and reviewed and revised the manuscript;Dr Tham assisted with drafting sections relating to managementof complex interplay between enteropathy andendocrinopathies, and reviewed and revised the manuscript;and all authors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-3308

doi:10.1542/peds.2013-3308

Accepted for publication Jul 10, 2014

Address correspondence to Myfanwy Geyer, MBBS, Department ofEndocrinology and Diabetes, Women’s and Children’s Hospital, 72King William Rd, North Adelaide, South Australia 5006. E-mail:myfanwy.geyer@health.sa.gov.au

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2014 by the American Academy of Pediatrics

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Autoimmune polyendocrinopathy candi-diasis ectodermal dystrophy syndrome(APECED; also known as autoimmunepolyglandular syndrome type1) is a rareautosomal recessive condition resultingin autoimmune destruction of a rangeof tissues.1–4 Mutations in the autoim-mune regulator gene on chromosome21q22.3 are responsible andmore than60 mutations have been identified.1,3,4

These mutations affect negative selec-tion of T cells by the thymus and pe-ripheral immune tissues, resulting inloss of self-tolerance, predisposing toautoimmunity.2,4–6 Prevalence varies from1:9000 (Iranian Jewish population) to1:500 000 (North-western France).2

The large spectrum of endocrine andnonendocrine system involvement, withassociated antibodies, is listed in Table 1.Candidiasis is the most common initialfinding, usually presenting in infancy.Hypoparathyroidism follows in child-hood, then adrenal failure in the sec-ond decade of life.2,4 More than half thepatients in a case series had all 3 man-ifestations by 15 years of age.1 Gastro-intestinal manifestations of APECED arepresent in ∼25% of patients and can

have severe consequences for patientsymptomatology and management.8,14,15

The case presented had chronic diarrheaand recalcitrant hypocalcemia despitehigh supplemental doses of calciumand calcitriol (1,25-dihydroxyvitamin D).Multiple measures were taken tooptimize calcium absorption withoutsuccess until commencement of im-munosuppressive therapy to treat au-toimmune enteropathy.

CASE REPORT

A 5-year-old boy presented with a hy-pocalcemic seizure caused by primaryhypoparathyroidism.Hewascommencedon calcitriol and calcium supplementsappropriate for his age and weight. Nopast history of oral candidiasis wasreported; however, groin candidiasiswas noted. He was the oldest child ofnonconsanguineous parents of Austrianand Australian background. A familyhistory of autoimmune diseases includ-ing systemic lupus erythematosus,Sjogrensyndrome,ulcerativecolitis,andthyroid diseasewas present in first- andsecond-degree relatives.

Addisondiseasewasdiagnosed6monthslater after an acute salt wasting adrenalcrisis. Glucocorticoids (hydrocortisone)and mineralocorticoids (fludrocortisoneacetate) were commenced. APECED wasdiagnosed clinically and confirmed withgenetic studies. DNA sequencing re-vealed heterozygosity for 2 separatemutations in the autoimmune regula-tor gene: c.769C.T(p.Arg2573), oneof the most common mutations as-sociated with APECED and c.789delC(p.Ala264LeufsX114) a frameshift mu-tation reported once previously, in anAustralian family.16 Both parents carried1 gene. Investigations revealed positiveinterferon-omega (w) antibodies in ad-dition to antibodies directed to theadrenal cortex (21 hydroxylase, 17 hy-droxylase [17OH], cholesterol side chaincleavage [SCC]), pancreas (glutamicacid decarboxylase [GAD], islet cellantibody [ICA]), skin and liver (aromaticL-amino acid decarboxylase), intrinsicfactor (IF), gonads (SCC, 17OH), and in-testine (tryptophan hydroxylase [TPH],GAD). Parathyroid antibodies (NACHTleucine rich repeat protein 5) werenegative.

He subsequently developed dental enamelhypoplasia, alopecia, mucocutaneous can-didiasis, and significant gastrointestinalmanifestations including autoimmunegastritis, pernicious anemia, cholelithi-asis, and intermittently elevated liverenzymes.

Recurrent diarrhea, morning nausea,and intermittentabdominalpainoccurredfrom age 9, and he became Cushingoidbecause of frequent stress doses of hy-drocortisone. Stool microscopy was ini-tially positive for Cryptosporidium, butno pathogens were found in subsequentstool samples, despite ongoing diar-rhea. Pernicious anemia was diag-nosed with a vitamin B12 of 80 pmol/L(normal range [NR], 100–700), positiveIF antibodies, and elevated serum gas-trin (510 pg/mL, NR ,100 pg/mL). Hecommenced vitamin B12 injections. A

TABLE 1 Clinical Components of APECED With Associated Antibodies

Clinical Presentation Frequency, % Age at Presentation, y Antibody Target

APECEDa IFN omega, IFN a

Candidiasis 18–100 ,5 IL-17F, IL-22EndocrineHypoparathyroidism 76–100 ,10 NALP5, CaSRAddison disease 22–100 5–15 SCC, 21OH, 17OHHypogonadism 0–71 15–35 17OH, SCCType 1 diabetes 0–12 4–37 IA2, GAD, ICAHypothyroidism 4–36 5–45 TPO, TGHypophysitis-GH,

GnT, ACTH deficiency,5 5–15 TDRD6

GastrointestinalPernicious anemia 0–30 6–48 PC, IF, TPHEnteropathy 6–22 6–30 TPH, HDC, GADHepatitis 5–31 0.7–16 AADC, LKM-A

EctodermalAlopecia 13–72 2.5–30 TH, hair follicleVitiligo 0–31 0.7–45 Melanocyte, SOX9, SOX10Keratitis 0–35 1.3–16 Corneal epithelium

21OH, 21 hydroxylase; AADC, aromatic L-amino acid decarboxylase; ACTH, adrenocorticotropic hormone; CaSR, calciumsensing receptor; GnT, gonadotropin; HDC, histidine decarboxylase; IA2, insulinoma antigen 2; LKM-A, liver kidney microsomalantibodies; NALP5, NACHT leucine rich repeat protein 5; PC, parietal cell; SOX9 and SOX10, transcription factors; TDRD6, Tudordomain containing protein 6; TG, thyroglobulin; TH, tyrosine hydroxylase; TPO, thyroid peroxidase.1–5,7–13a Interferon antibodies positive in 98% of patients with APECED and thought to be diagnostic markers.

CASE REPORT

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trial of esomeprazole gave some im-provement to nausea.

Episodes of diarrhea increased in fre-quency and severity and were associ-ated with symptomatic hypocalcemia,hyperphosphatemia, and hypokalemia.Stool microscopy was positive for fatglobules and fatty acid crystals. Fecalelastase was borderline, 210 mg/g(NR .200 mg/g). Celiac screen wasnegative, and a lactulose hydrogen breathtest excluded the possibility of bacterialovergrowth. Pancreatic enzyme replace-ment was trialed for borderline exocrinefunction with initial but not ongoing im-provement.

Upper gastrointestinal endoscopy andbiopsy revealed no evidence of candidi-asis or Helicobacter pylori. Gastric bi-opsies revealed chronic inflammatorychange, some atrophy, and an absenceof parietal cells. Hematoxylin and eosinstaining of duodenal biopsy was nor-mal with no excess inflammatory cells(Fig 1A). Chromogranin A staining re-vealed absent enteroendocrine cellsin duodenal mucosa (,1 per 20 crypts;Fig 1B). This, along with positive TPHantibodies, confirmed the diagnosisof autoimmune enteropathy. Normalstaining of enteroendocrine cells withchromogranin A is shown as brownstained cells in Fig 1C.

By age 12, he had persistent hypocalce-mia,with continueddiarrheaandgrowthfailure (Fig 2). Thyroid function andgrowth hormone (GH) stimulation test-ing were normal (thyrotropin 0.71mU/L,Free thyroxine 14 pmol/L, peak GH32.8 mIU/L). Gonadotropins were pre-pubertal (luteinizing hormone,1.0 IU/L,follicle stimulating hormone ,1 IU/L,testosterone , 0.7 nmol/L), and boneage was 4 years delayed. Growth failurewas attributed to chronic illness andiatrogenic Cushing’s syndrome. Puber-tal induction with oral testosterone wascommenced at 13 years and 4months andchanged to3monthlydepot intramuscularinjections at 14 years and 5 months.

FIGURE 1Duodenal biopsies. A, Normal appearance of duodenal mucosa of the case with hematoxylin and eosinstain. B, ChromograninAstainof sameduodenalbiopsyrevealingsignificantly reducedenteroendocrinecells (brown color;,1:20 crypts), compared with (C) normal control duodenal chromogranin A stainwith 29:20 crypts enteroendocrine cells.

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FIGURE 2Growth charts.26

CASE REPORT

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At 14 years of age, it became difficult tomaintain his ionized calcium above 0.9mmol/L despite calcitriol of 0.06 mg/kgper day (3 mg/day) and calcium sup-plements between 4000mg and 7000mgelemental calcium (carbonate) ti-trated to symptoms. Timing of calciumcarbonate administration was changedand esomeprazole ceased to improvegastric acidity and thereby calciumabsorption. When this failed to havean effect, calcium supplements werechanged to calcium citrate as absorp-tion is less dependent on gastric acid-ity. Increased doses of hydrocortisonewere avoidedwhere possible, to optimizecalcium absorption. Ongoing diarrheaand lower hydrocortisone contributedto weight loss. Hypomagnesaemiawas managed with magnesium sup-plements to further support calciumabsorption.

With increased calcitriol doses and on-going hypocalcemia, phosphate levelsincreased to 3.63 mmol/L. Urinary cal-ciumwas lowand 1,25-dihydroxyvitaminD elevated at 175 pmol/L. Renal functionwas normal. This was managed withlowphosphatediet, phosphatebinders(aluminumbased followedbysevelamer),and reducing calcitriol to 0.04 mg/kg perday (2 mg/day).

Despite the above measures, calciumlevels were unable to be maintained(4000 mg/day calcium citrate), and hebecame symptomatic with difficultybreathing with exercise, muscle cramp-ing, and prolonged QTc on electrocardio-graph. Parathyroid hormone injectionswere not considered an option becauseof the possible risk of osteosarcoma.17

A decision to trial immunosuppressivetherapy for autoimmune enteropathywas made.

Cyclosporinwascommencedatadoseof3.5 mg/kg per day (divided) and titratedto a serum trough level of 100 ng/mLat 15 years and 4 months. Within3 months, his diarrhea, hypocalcemia,and alopecia improved, enabling ces-

sation of calcium supplements and re-duction of calcitriol dose to 0.02 mg/kgper day.

Hypertension developed 3months aftercommencing cyclosporin. Investigationsrevealed normal renin and electrolytesindicating appropriate fludrocortisonedose. Two years after commencement oftherapy, screening renal biopsy revealedsignificant scarring attributed to cyclo-sporin. This was weaned over 3 months,and he commenced azathioprine, onwhich he has remained for 3 yearswithout relapse of hypocalcemia ormalabsorption.

Subsequently, a younger sibling de-veloped symptomatic hypocalcemia andwasdiagnosedwithhypoparathyroidism.He was found to have the same mu-tations and adrenal cortex antibodies.He went on to develop Addison disease,enamel hypoplasia, and oral candi-diasis, without other gastrointestinalmanifestations of APECED. Thyroid per-oxidase, thyroglobulin, GAD, ICA, andinsulinoma antigen 2 antibodies werenegative. Other antibodies were nottested given absence of clinical in-dication.

DISCUSSION

Hypocalcemia in the setting of primaryhypoparathyroidism is usually easilytreated with oral calcitriol.4,5 We havedescribed a case of recalcitrant hypo-calcemia, attributed to autoimmuneenteropathy. Other contributors to hy-pocalcemia, both pathologic and iat-rogenic are discussed.

Chronic diarrhea and malabsorptionseen in APECED have been attributed toa number of causes including bacterialovergrowth, celiac disease, intestinalinfections, and pancreatic exocrine in-sufficiency.1,2,8,18 Hypocalcemia can alsolead to malabsorption through reduc-tion of cholecystokinin, decreased gallbladder emptying, and pancreatic in-sufficiency.2,5,14

More recently, autoimmune enteropa-thy has been described as a significantcontributor with destruction of enter-oendocrine cells by TPH antibodies.12,19

TPH is an enzyme involved in the syn-thesis of serotonin by enteroendocrinecells. These cells assist gut growth,circulation, motility, and secretion ofpancreatic enzymes and bile.2,14,18 Lackof enteroendocrine cells in small bowelbiopsies confirms autoimmune en-teropathy and is demonstrated withchromogranin A and serotonin stain-ing. Hematoxylin and eosin stains areoften normal, as shown in this case.There are multiple other gastrointesti-nal manifestations of APECED includingconstipation, gastrointestinal candidi-asis, and autoimmune hepatitis withwhich there is significant morbidityand mortality.8,12,14

The small intestine is primarily re-sponsible for calcium absorption, pre-dominantly the duodenum throughactive transport stimulated by 1,25-dihydroxyvitaminD.When this system issaturated (high calcium intake), pas-sive absorption occurs in the jejunumand ileum.19,20

Widely available calcium carbonate isbest absorbed in a highly acidic en-vironment. When administered withmeals or other factors that increasestomach pH (proton pump inhibitors,pernicious anemia) absorption is re-duced. Calcium citrate absorption isnot affected by acidity and thereforeis preferable in autoimmune enterop-athy.20,21

Glucocorticoids reduce intestinal cal-cium absorption, renal calcium resorp-tion, and bone remodelling4; therefore,the need for stress dosing must becarefully assessed. In this case, re-current diarrhea necessitated stressdoses of hydrocortisone to preventadrenal crisis and at times resultedin short-term improvement of diar-rhea, suggesting immunosuppressivebenefits.

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There is currently no consensus on thetreatment of autoimmune enteropathy.The largest case series published byPerheentupa1 recommends the use ofimmunosuppressive agents to treat au-toimmune hepatitis, autoimmune enter-opathy, and keratoconjunctivitis. Despitethe efficacy of cyclosporin, the risk of ne-phropathy is well described and requiresscreening.22 A possible adverse effect ofimmunosuppressives is generalized can-didiasis, which has been reported in1 patient.18 This requires ongoing investiga-tion. Other immunosuppressive agentshave been used successfully such aspulse methylprednisolone, cyclophos-phamide, and azathioprine, with smallerstudies involving mycophenolate,6-mercaptopurine, tacrolimus, sirolimus,infliximab, and rituximab.23–25

CONCLUSIONS

Primaryhypoparathyroidism in childrenisararepresentation,andconsiderationof APECEDshouldbemade, particularlyif associated with family history of au-toimmunity.1,4,5 This instructive casehighlights multiple factors involved incalcium absorption including calciumformulation, gastric acidity, enter-oendocrine cells, and glucocorticoids.Chromogranin A staining to demon-strate reduced enteroendocrine cellsand TPH antibody testing have enabledmore accurate diagnosis of autoim-mune enteropathy in children withAPECED.8 Small case series have shownimprovement with immunosuppres-sion.2,22,25 The swift and persistentimprovement in enteropathy in this case

highlights the need for consideration ofearly commencement of immunosup-pression and further studies balancingtheir risks with regression of the as-pects of the disease.

ACKNOWLEDGMENTSThe authors thank Elizabeth Thompsonfor assistance with genetic investiga-tions, Hamish Scott for assistance withantibody and genetic investigations,and Jaakko Perheentupa for adviceregarding initiationof immunosuppres-sion. Antibody testing was performedby Eystein Husebuye’s research group,Bergen, Norway. Genetic studies wereperformed by Institute of Medicaland Veterinary Science, Adelaide,Australia.

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FINANCIAL DISCLOSURE: Dr David Moore is principal investigator in a trial with pegylated interferon sponsored by Roche, of no relevance to this case report; theother authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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DOI: 10.1542/peds.2013-3308 originally published online November 17, 2014; 2014;134;e1720Pediatrics 

Elaine ThamMyfanwy Geyer, Jan Fairchild, David Moore, Lynette Moore, Paul Henning and

Recalcitrant Hypocalcaemia in Autoimmune Enteropathy

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Recalcitrant Hypocalcaemia in Autoimmune Enteropathy

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