72 CLINICAL REPORTS

Polyglandular autoimmune syndrome type III associatedwith coeliac disease and sarcoidosis

Konstantin I. Papadopoulos and Bengt Hallengren

Department ofEndocrinology, Lund University Clinics, General Hospital, S-21401 Malmi, Sweden

Summary: A female patient demonstrating a previously not reported constellation of polyglandularautoimmune syndrome type III (including autoimmune thyroiditis, Graves' ophthalmopathy, insulin-dependent diabetes mellitus and vitiligo), coeliac disease and sarcoidosis is described. This may be arandom association but might also indicate a common immunological and/or genetic disturbance.

Introduction

Autoimmune disorders and sarcoidosis may berelated' and the association between sarcoidosisand autoimmune thyroid disease has long beenrecognized.2'3 Polyglandular autoimmune (PGA)syndromes4 occurring together with sarcoidosishave only been described in a few cases.2517 How-ever, none of these was associated with coeliacdisease. We would like to report a female patientwith PGA syndrome type III (autoimmune thyroiddisease, insulin-dependent diabetes mellitus(IDDM), vitiligo), coeliac disease, transientlypositive adrenal antibodies and sarcoidosis.

Methods

Serum microsomal antibodies and thyroglobulinantibodies were measured by complement bindingreaction and passive haemagglutination, respec-tively. Serum adrenal, gluten (IgA/IgG), reticulin,parietal cell, smooth muscle, glomerular andmitochondrial antibodies as well as antinuclearfactors were measured by immunofluorescence.The HLA haplotype was analysed in Lund's trans-plantation laboratory according to the method ofVartdal et al.8

Case report

A female patient born in 1941, without knownheredity for autoimmune diseases, was admitted in1970 to our department due to polyuria, polydipsiaand weight loss and IDDM was diagnosed. In 1976a nodular goitre was noted, thyrotrophin was8 mIU/I (reference range <8), serum antibodies

against microsomal antigen (titre 1/640, referencevalue < 1/10) and thyroglobulin antibodies (titre1/10, reference value < 1/10) were present andL-thyroxine was instituted.

In October 1984 the patient complained of grittyforeign body sensation in the eyes associated withredness, tearing and photophobia. On examina-tion, lid retraction, periorbital oedema, conjunc-tival injection and slight chemosis were noted.Exophthalmometry ad modum Krahn demon-strated readings of 12 mm in the right and 14 mmin the left eye. Eye movements and a computerizedtomographic (CT) scan of the orbits were normal.The patient was euthyroid and thyroid-stimulatingimmunoglobulins were not demonstrated in theserum. Fine needle biopsy of the thyroid revealedautoimmune thyroiditis. The clinical diagnosis wasGraves' ophthalmopathy.

In April 1985 the patient complained of epigas-tric discomfort and frequent diarrhoea. Anaemia(erythrocyte sedimentation rate 35 mm/hour) withsideropenia and low blood folate 18 nmol/l(reference range 70-200) but a normal bone mar-row aspiration were noted. An electrophoresis ofthe plasma proteins showed a polyclonal rise ofIgA4.6 g/l (reference range 0.5-3.0) and a low serumalbumin 33 g/l (reference range 36-48). Serumantibodies against adrenal antigen (titre 1/20,reference value < 1/10), gluten (IgA/IgG: 9.0/5.3 U/ml, reference value: 2.5/3.0 U/ml) andreticulin (titre 1/100, reference value < 1/10) weredemonstrated. Hepatitis B surface antigen andserum antibodies against cytomegalovirus, parietalcell, smooth muscle, glomeruli and mitochondriaeas well as antinuclear factor were not detected. Isletcell antibodies were not analysed. A morningserum ACTH, a morning serum cortisol and ashort synthetic ACTH stimulation test were nor-mal. A computed tomographic (CT) scan of theabdomen including the adrenals was normal. A

Correspondence: Bengt Hallengren, M.D., Ph.D.Accepted: 10 July 1992

copyright. on 5 June 2018 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.69.807.72 on 1 January 1993. Dow

nloaded from

CLINICAL REPORTS 73

chest X-ray examination demonstrated bilateralhilar lymphadenopathy but no parenchymalinvolvement. A mediastinal lymph node biopsyshowed multiple non-caseating giant epitheloid cellgranulomas compatible with sarcoidosis (Figure 1)and without evidence of malignant disease. Stain-ing for mycobacteria and fungi was negative, aswas culture of the biopsy specimen. Culture anddirect microscopy of sputum and of specimensobtained by gastric lavage were negative formycobacteria. Pulmonary function tests andarterial blood gases were normal. A Mantoux testwas negative. A small bowel biopsy by Crosbycapsule revealed total villous atrophy withoutsarcoid granulomas and was compatible withcoeliac disease (Figure 2). The patient was dis-charged on a gluten-free diet and her conditionimproved markedly.

In July 1986 patchy vitiligo was observed. Nor-mal visual acuity but deteriorating ophthalmo-pathy with protrusion (17 mm on the right, 16 mmon the left eye) and diplopia with restricted eyemovements was noted. A CT scan disclosedenlargement of extraocular muscles. Oral cortico-steroids were administered (prednisolone 30 mg/day) but were ineffective and in November 1986 thepatient was given retrobulbar irradiation (30 Gy).The ophthalmopathy improved and cor-ticosteroids could be finally withdrawn in May

1988. In March 1988 a chest radiograph and a newsmall bowel biopsy were normal. In November1986 and in July 1990 no adrenal antibodies couldbe detected in the serum and a synthetic ACTHstimulation test was again normal. The HLAhaplotype was A1,3; B8,40; Cw3,w7; DR3,6;DQ1,2.

Discussion

This patient had PGA syndrome type III defined asautoimmune thyroid disease occurring togetherwith IDDM and/or pernicious anaemia and/orvitiligo/alopecia.4 In the present case, autoimmunethyroiditis, Graves' ophthalmopathy, IDDM andvitiligo were concurrent, and to the best of ourknowledge this is the first report of a patient withPGA syndrome type III, coeliac disease and sar-coidosis. In addition, transiently positive adrenalantibodies in serum were detected indicating thatour patient might develop Addison's disease andthus fulfil the criteria for PGA syndrome type IIdefined as Addison's disease and autoimmunethyroid disease and/or IDDM.4 Whether there wasa causal relationship between the treatment withcorticosteroids and the disappearance of theadrenal antibodies is open to speculation.Although the association between sarcoidosis

4t(*~~~~~~

f

-~~~~~~-

Figure 1 Mediastinal lymph node biopsy showing non-caseating giant epitheloid cell granulomas compatible withsarcoidosis (haematoxylin and eosin, x 125).

copyright. on 5 June 2018 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.69.807.72 on 1 January 1993. Dow

nloaded from

74 CLINICAL REPORTS

Figure 2 Small bowel biopsy showing total villous atrophy without sarcoid granulomas compatible with coeliacdisease (haematoxylin and eosin, x 125).

and autoimmune thyroid disease has long beenrecognized2'3 the association of sarcoidosis withPGA syndromes has been reported in only a fewcases almost exclusively with the PGA syndrometype II,'-' except in one report describing Graves'thyrotoxicosis, pernicious anaemia and vitiligo(PGA syndrome type III) in a patient with sar-coidosis.2 However, coeliac disease was not notedin any of the aforementioned cases. IDDM wasdiagnosed before thyroiditis in our patient, apattern previously observed in PGA syndromes.9"lo

Coeliac disease, also regarded as an autoimmunedisease," has been described in association with thePGA syndrome type III.' Coeliac disease andsarcoidosis occurring together in the same patienthas recently been described in five cases'2 and inaddition a high frequency of antibodies againstgliadin (41%) was found in a recent study ofpatients with sarcoidosis, where one of the patientswith gliadin antibodies showed total villousatrophy consistent with coeliac disease.'Although the pathogenesis of sarcoidosis is

unknown, it is probably a disease promoted byaberrations in immunological reactivity'4 and acombination of abnormalities of some aspects ofTcell function with enhanced or normal ability of Bcells to produce antibodies'4 has been documented.

The pathogenesis of autoimmune endocrinediseases involves a HLA-linked genetic suscepti-bility and a probable environment-induced ini-tiating event, leading to an abnormal immuneresponse in which both humoral and cellularmechanisms are involved.'5 The HLA haplotype ofour patient (A 1,3; B8,40; Cw3,w7; DR3,6; DQ1,2)was in good accordance with the findings of HLAAl, B8, DR3, Dw3, DR4 being more frequent inpatients with the PGA syndromes type II and III,4with adult coeliac disease4 or with sarcoidosis,'6 ascompared to the general population. This indicatesa common underlying genetic predisposition forthese conditions.4

In conclusion, the patient described demon-strates a previously unreported constellation ofPGA syndrome type III, coeliac disease and sar-coidosis, which may be a random association butmight also indicate a common immunologicaland/or genetic disturbance.

Acknowledgement

We wish to thank Associate Professor L. Bondesson forevaluating the histological tissue preparations and Dr J.Kurkus for the HLA analysis.

copyright. on 5 June 2018 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.69.807.72 on 1 January 1993. Dow

nloaded from

CLINICAL REPORTS 75

References

1. Wiesenbutter, C.W. & Sharma, O.P. Is sarcoidosis an auto-immune disorder? Report of four cases and review ofliterature. Semin Arthritis Rhewn 1979, 9 124-144.

2. Hanock, B.W. & Millard, L.G. Sarcoidosis and thyro-toxicosis. A study of five patients. Br J Dis Chest 1976, 70:129- 133.

3. Bell, N.H. Endocrine complications of sarcoidosis. Endo-crinol Metab Clin North Am 1991, 20: 645-654.

4. Neufeld, M., Maclaren, N.K. & Blizzard, R. Autoimmunepolyglandular syndromes. Pediatr Ann 1980, 9: 154-163.

5. Karlish, A.J. & MacGregor, G.A. Sarcoidosis, thyroiditisand Addison's disease. Lancet 1970, ii: 330-333.

6. Seinfield, E.D. & Sharma, O.P. TASS syndrome: unusualassociation of thyroiditis, Addison's disease, Sjogren syn-drome and sarcoidosis. J R Soc Med 1983, 76: 883-885.

7. Waltz, B. From GLA: Addison's disease and sarcoidosis:unusual frequency of coexisting hypothyroidism (Schmidt'ssyndrome) (letter). Am J Med 1990, 89: 692-693.

8. Vartdal, F., Gaudernack, G., Funderud, S. et al. HLA Class Iand II typing using cells positively selected from blood byimmunomagnetic isolation - a fast and reliable technique.Tissue Antigens 1986, 28: 301-312.

9. Gray, R.S., Herd, R. & Clarke, B.F. The clinical features ofdiabetes with coexisting autoimmune disease. Diabetol 1981,20: 602-606.

10. Papadopoulos, K.I. & Hallengren, B. Polyglandular auto-immune syndrome type II in patients with idiopathicAddison's disease. Acta Endocrinol (Copenh) 1990, 122:472-478.

11. Ferguson, A., Macdonald, T.T., McClure, J.P. & Holden,R.J. Cell-mediated immunity to gliadin within the smallintestinal mucosa in coeliac disease. Lancet 1975, i: 895-897.

12. Douglas, J.G., Gillon, J., Logan, R.F.A., Grant, I.W.B. &Cromton, G.K. Sarcoidosis and coeliac disease: an associa-tion? Lancet 1984, ui: 13-15.

13. McCormick, P.A., Feighery, C., Dolan, C. et al. Alteredgastrointestinal immune response in sarcoidosis. Gut 1988,29: 1628-1631.

14. Poulter, L.W. Immune aspects ofsarcoidosis. PostgradMedJ1988, 64: 536-543.

15. Holland, F.J., McConnon, J.K., Volpe, R. & Saunders, E.F.Concordant Graves' disease after bone marrow transplanta-tion: implications for pathogenesis. J Clin Endocrinol Metab1991, 72: 837-840.

16. Hedfors, E. & Linstrom, F. HLA - B8/DR3 in sarcoidosis.Tissue Antigens 1983, 22: 200-203.

Obstructive uropathy due to extramedullary haemato-poiesis in beta thalassaemia/haemoglobin E

Tanin Intragumtornchai, Kiat Arjhansiri', Makumkrong Posayachindal andVira Kasantikul2

Departments ofMedicine, 'Radiology and 2Pathology, Faculty ofMedicine, Chulalongkorn University,Bangkok 10330, Thailand

Summary: An 18 year old woman with beta thalassaemia/haemoglobin E developed a large pelvictumour resulting in bilateral obstructive uropathy. Technetium-99m sulphur colloid marrow image,computed tomographic scan of the abdomen and needle biopsy of the mass confirmed the diagnosis ofextramedullary haematopoiesis. Although radiation is the treatment of choice for decompression, themass in this patient did not respond satisfactorily due to its multiple area of tumour autoinfarction.Obstructive uropathy due to extramedullary erythropoiesis has not to our knowledge been previouslydescribed.

Introduction

Extramedullary haematopoiesis, a common mani-festation of severe thalassaemia, occurs as a conse-quence of uninhibited erythropoiesis.' Commonsites of involvement include the posterior medias-tinum, liver and spleen. Generally these extramed-ullary haematopoietic masses are asymptomatic,although spinal cord compression has been fre-

quently cited.2'3 A patient with beta thalassaemia/haemoglobin E in whom an unusually large pelvicextramedullary haematopoietic mass resulted insevere bilateral obstructive uropathy prompts thisreport.

Case report

An 18 year old woman with the diagnosis of betathalassaemia/haemoglobin E since the age of 10

Correspondence: Tanin Intragumtornchai, M.D.Accepted: 18 June 1992

copyright. on 5 June 2018 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.69.807.72 on 1 January 1993. Dow

nloaded from