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[Pages:3]CASE REPORT

Autoimmune Hypopituitarism in Patients with Coeliac Disease: Symptoms Confusingly Similar

P. Collin, M. Hakanen, J. Salmi, M. Ma?ki & K. Kaukinen Depts. of Medicine and Paediatrics, Tampere University Hospital, Tampere; Institute of Medical Technology and Medical School, University of Tampere, Tampere, Finland

Collin P, Hakanen M, Salmi J, Ma?ki M, Kaukinen K. Autoimmune hypopituitarism in patients with coeliac disease: symptoms confusingly similar. Scand J Gastroenterol 2001;36:558? 560. Coeliac disease does not always respond properly to a gluten-free diet, and treatment may be complicated by an underlying autoimmune endocrine disorder. We report three cases of hypopituitarism in patients with coeliac disease who seemed to have incomplete dietary response. The rst patient had diabetes and suffered from hypoglygaemic events; the second had muscular atrophy of unknown origin while the third had growth failure. None had a pituitary mass, suggesting that hypopituitarism was of autoimmune origin. Overall condition improved only after replacement therapy for the underlying hormone de ciency; this association should thus be recognized. Key words: Autoimmune hypopituitarism; coeliac disease; gluten-free diet Pekka Collin, Medical School, University of Tampere, FIN-33014 University of Tampere, Finland (fax. 358 3 215 7746, e-mail. pekka.collin@uta. )

Coeliac disease is a genetically determined disorder in which the ingestion of gluten results in small-bowel mucosal damage characterized by in ammation, villous atrophy and crypt hyperplasia. Diarrhoea, malabsorption and, in children, growth retardation and failure to thrive are typical features. Both mucosal lesions and symptoms recover after adoption of a gluten-free diet (1). Occasionally, however, the response to the diet is unsatisfactory or even lacking. The most common reason will undoubtedly prove to be poor dietary compliance. Coeliac disease can also sometimes be unresponsive to proper dietary treatment (refractory sprue) (2). In addition, certain severe conditions should also be borne in mind. Lymphoma must be considered especially in cases where coeliac disease has recently been detected in elderly individuals (3). Ulcerative jejunoileitis can complicate coeliac disease; it does not usually respond to a gluten-free diet and distinction from lymphoma can be dif cult (2).

Patients with coeliac disease run an increased risk of autoimmune conditions, which may again hamper the response to a gluten-free diet. An underlying autoimmune thyroid disease, Addison's disease, or even multiple autoimmune endocrine disorder may complicate the treatment of coeliac patients (4, 5). To our knowledge, hypopituitarism has not previously been described as occurring concomitantly with coeliac disease.

We describe here three coeliac disease patients suffering from hypopituitarism. Some symptoms of this latter disorder were initially considered symptoms of poorly controlled coeliac disease. This inevitably involved some diagnostic

delay, which might conceivably be deleterious for the patient. This association should thus be recognized as early as possible.

Case Reports

Case 1 A 41-year-old Finnish woman has suffered from type 1

diabetes since the age of 14 years. She had also developed neuropathy, retinopathy and nephrotic syndrome. She was admitted to hospital because of acute ketoacidosis. Serum sodium was low, 127 mmol/l (reference values 135?146 mmol/l), and potassium high, 5.8 mmol/l (reference values 3.5?5.0 mmol/l). The serum cortisol level was 436 nmol/l (reference values 180?680 nmol/l). Her haemoglobin was 9.8 g/dl and serum endomysial antibodies positive. Subtotal small-bowel mucosal villous atrophy was subsequently found and she started on a gluten-free diet. She refused a control biopsy, but endomysial antibodies became negative during the follow-up. She had been complaining for 2?3 years of chronic diarrhoea, which disappeared after 1 year on the gluten-free diet. The patient had HLA DQ2 haplotype.

One and a half years later she was again hospitalized, complaining of malaise, tiredness and loss of appetite. She also had problems with both high and low blood glucose levels. Compliance with the gluten-free diet was good. At this juncture, serum cortisol was very low, 35 nmol/l (Table I). Plasma adrenocorticotrophic hormone (ACTH) was also decreased, con rming the pituitary origin of the hypocorti-

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Table I. Anterior pituitary and peripheral hormone secretion de cits in three patients with coeliac disease

Patient 1 Patient 2 Patient 3 (female) (male) (male)

Age at diagnosis of coeliac

41

49

6

disease (years)

Growth hormone

*

Adrenocorticotrophic hormone

N

Serum cortisol

N**

Gonadotropins (FSH, LH)

N

*

Thyroid-stimulating hormone

N = normal; = abnormal; = abnormal requiring hormone replacement; * = abnormal in exercise test; ** = subnormal in ACTH test; FSH = follicle-stimulating hormone; LH = luteinizing

hormone.

normal during treatment with a gluten-free diet. However, his height remained low during the follow-up. Somatomedin C and growth hormone levels were low, and serum cortisol increased subnormal in the ACTH test (Table I). The pituitary gland was seen in CT to be small. On follow-up, serum-free thyroxin decreased (7.2 pmol/l; reference values 9.0? 19.0 pmol/l), but TSH remained at a relatively low level, 2.4 mU/l (reference values 0.4?6.0 mU/l), excluding peripheral hypothyroidism. Growth hormone replacement therapy was started at the age of 11, and thyroxin at the age of 13. At 15 years of age the boy's height was comparable to the average of Finnish boys of that age.

Discussion

solism. In further studies, the thyroid-stimulating hormone (TSH) level was found to be low, later also serum-free thyroxin, requiring hormone replacement. Her menstrual cycle was regular, but serum gonadotropin levels remained low during hormone challenge. Pituitary imaging was normal. Corticosteroid treatment alleviated her general condition but she continued to have periodic hyperglycaemic events.

Case 2 A 49-year-old Finnish man was remitted for examination

after a weight loss of 10 kg within 4 years; he was also found to have anaemia (blood haemoglobin 11.0 g/dl). Despite negative endomysial antibodies, further examination revealed subtotal small-bowel mucosal villous atrophy. HLA DQ2 haplotype was found. The response to the gluten-free diet was good, he gained weight and a follow-up biopsy showed normal villous structure. Haemoglobin values became normal, albeit only over a period of 5 years. However, he also suffered from slowly progressive muscle weakness and muscular atrophy. There were no signs of sarcoidosis, muscle biopsy showed no speci c abnormalities and despite thorough neurological investigations a diagnosis of myopathy of unknown origin was made.

At the age of 59 he received thyroxin medication; the hypothyroidism diagnosis had been made in a local health centre on the basis of low serum-free thyroxin; the TSH level was not known. One year subsequently he underwent an operation for gallstones. During the operation he suffered from low blood pressure, and later at home from fever and tiredness. He was again admitted to hospital, and now the serum cortisol level was under 30 nmol/l, and serum ACTH was low (Table I). He continued with thyroxin, and corticosteroid treatment was started. As a result, his overall condition improved and muscle strength returned. Computed tomography (CT) examinations showed an empty sella.

Case 3 A 6-year-old boy was examined because of growth failure.

Endomysial antibodies were positive, and biopsy showed subtotal mucosal villous atrophy. The antibody levels became

The feature common to all three coeliac disease cases was that treatment with a gluten-free diet seemed unsatisfactory. Diet history revealed no signi cant transgressions. The alleviation of gastrointestinal symptoms along with prolonged observation excluded lymphoma or ulcerative jejunoileitis. Even though associated conditions emerged as plausible keys to the problems, the ultimate diagnosis was not easy. In dermatitis herpetiformis, one similar treatment failure has been described in a 53-year-old male. However, this patient differed from ours in that he had a giant pituitary adenoma; the skin disorder disappeared only after successful removal of the tumour (6).

There are numerous publications on the association of type 1 diabetes with coeliac disease (7). According to some reports, untreated coeliac disease may increase the risk of hypoglycaemic events in patients with diabetes (8). In our case 1, hypoglycaemic events also occurred after seemingly adequate dietary treatment. The nal diagnosis of hypopituitarism was especially dif cult to establish, as the serum corticosteroid concentration was normal when the serum sample was taken under stressful conditions.

Neurological disorders are well-known complications of coeliac disease and may even precede intestinal symptoms. In the series of Hadjivassiliou et al. (9), as many as 35% of patients with neurological symptoms were seen to be suffering from coeliac disease--ataxia and myopathy being the most common manifestations. Case 2 in the present series appeared to t well in this category. However, a treatable disease, de ciency of adrenocorticotrophic hormone and cortisol, was detected only after many years' surveillance. Untreated hypocortisolism is a potentially hazardous state in stressful conditions. This emphasizes the need for a complete diagnostic work-up in cases of coeliac disease not responding properly to a gluten-free diet.

In patient 3, inadequate growth response resulted in the nal diagnosis. It is noteworthy that in this case, as in case 1, hypothyroidism appeared later. To avoid diagnostic delay it is therefore important to keep patients evincing a de ciency of pituitary hormones under surveillance. Coeliac disease is much more common than previously

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P. Collin et al.

assumed, and many associated diseases are therefore probably coincidental. Today, we have altogether 800 patients with coeliac disease in our area. This gives a 0.4% prevalence of detected hypopituitarism in coeliac disease. Hypopituitarism is not genetically uniform (10), a variety of congenital causes have been described, and its prevalence in the population is not known. However, it seems that autoimmune endocrinological conditions are truly associated with coeliac disease; both are associated with the HLA DQ2 haplotype, which may explain the increased risk of developing multiple autoimmune diseases (5). The pituitary gland might therefore well be a target for an autoimmune process in coeliac disease. Lymphocytic hypophysitis is a rare condition where autoimmune pathogenesis is suggested (10, 11). However, this disorder affects predominantly young women during pregnancy, and in contrast to the patients here pituitary mass is found in the majority of cases.

Pituitary autoantibodies have been detected in sera from patients with hypopituitarism. The diagnostic validity of this is limited, however: in a series studied by Stro?mberg et al. (12), these were present in 28% of patients with hypopituitarism compared to 6.8% in control subjects. On the other hand, in their series of 21 patients, there were equally male and female, and in contrast to the case of lymphocytic hypophysitis, none showed pituitary mass; two patients had type-1 diabetes and some patients other autoimmune conditions. This type of autoimmune hypophysitis might be the cause of hormone de ciency in our series as well.

Ventura et al. (4) suggested that in coeliac disease gluten in itself is harmful to many target organs, and early dietary treatment might protect from the development of autoimmune disorders. This intriguing hypothesis, however, must be tested in a large series.

To summarize, we describe for the rst time an association between coeliac disease and hypopituitarism. An important observation is that a seemingly poor clinical response to a

gluten-free diet is due to an uncommon associated condition which may be treatable and therefore should be recognized.

Acknowledgements

The Coeliac Disease Study Group is supported by the Emil Aaltonen Foundation and the Medical Research Fund of Tampere University Hospital.

References

1. Ma?ki M, Collin P. Coeliac disease. Lancet 1997;349:1755? 9. 2. O'Mahony S, Howdle PD, Losowsky MS. Review article:

management of patients with non-responsive coeliac disease. Aliment Pharmacol Ther 1996;10:671? 80. 3. Hankey GL, Holmes GKT. Coeliac disease in the elderly. Gut 1994;35:65? 7. 4. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. Gastroenterology 1999;117:297? 303. 5. Kaukinen K, Collin P, Mykka?nen A-H, Partanen J, Ma?ki M, Salmi J. Celiac disease and autoimmune endocrinologic disorders. Dig Dis Sci 1999;44:1428? 33. 6. Spitzweg C, Hofbauer LC, Heufelder AE. Dermatitis herpetiformis cured by hormone replacement for panhypopituitarism. Endocr J 1997;44:437? 40. 7. Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet 1997;349:1096? 7. 8. Iafrusco D, Rea F, Prisco F. Hypoglycemia and reduction of the insulin requirement as a sign of celiac disease in children with IDDM. Diabetes Care 1998;21:1379? 80. 9. Hadjivassiliou M, Gibson A, Davies-Jones GAB, Lobo AJ, Stephenson TJ, Milford-Wars A. Does cryptic gluten sensitivity play a part in neurological illness? Lancet 1996;347:369? 71. 10. Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S. Clinical case seminar: lymphocytic hypophysitis: clinicopathological ndings. J Clin Endocrinol Metab 1995; 80:2302? 11. 11. Pestell RG, Best JD, Alford FP. Lymphocytic hypophysitis. The clinical spectrum of disorder and evidence for an autoimmune pathogenesis. Clin Endocrinol 1990;33:457? 66. 12. Stro?mberg S, Crock P, Lernmark A? , Hulting A-L. Pituitary autoantibodies in patients with hypopituitarism and their relatives. J Endocrinol 1998;157:475? 80.

Received 9 August 2000 Accepted 27 September 2000

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