Autoimmune Growth Hormone Deficiency: Whittling Away at Some of the Idiopathics

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Lymphocytic hypophysitis is a recognized cause of growth hormone deficiency (GHD) in adults, either isolated or associated with deficiency of other pituitary hormones. Histopathological diagnosis on pituitary biopsy is considered the gold-standard test, though antipituitary antibodies (APA) have been recently identified in adults with idiopathic GHD (IGHD) or GHD and other autoimmune endocrinopathies. The APA-positive adults with IGHD all had documented childhood-onset GHD; thus the authors aimed to investigate the presence of APA in prepubertal children.

De Bellis and colleagues studied APA in 3 groups of prepubertal patients: 26 with IGHD, 60 with idiopathic short stature (ISS), and 33 with organic GHD (destructive lesions or developmental malformations of the hypothalamus-pituitary). The definition of IGHD was a height z score below –2 SD, growth velocity <25th centile, delayed skeletal development, and blunted GH response (<10 µg/L) on both arginine and insulin stimulation tests; all patients had GH peaks <5 µg/L and abnormally low IGF-I levels for age and gender. The definition of ISS was the same except that GH peaked at >10 µg/L on at least one stimulation test. Ten of the 60 ISS patients had abnormally low IGF-I levels. MRI was normal, as were all other pituitary hormone functions, in both groups. Sera from 40 age- and sex-matched normal children were collected as controls. The APA were detected by indirect immunofluorescence on cryostat sections of young baboon pituitary, with fluorescein isothiocyanate (FITC)-conjugated goat anti-human immunoglobulins; positive samples were defined as titers >1:8. For sera that were APA positive, antibody specificity for the different anterior pituitary cell types was determined by a 4-layer double immunofluorescence technique, co-localizing the FITC-conjugated anti-human IgG antibody with rodhamine-conjugated antibodies directed against each of the pituitary hormones.

The APA antibodies were positive in 27% of the children with IGHD and 23% of those with ISS, but were negative in those with organic GHD and in normal controls. The APA titers ranged from 1:32 to 1:128 in the former and 1:16 to 1:64 in the latter group. Immunostaining confirmed selectivity for pituitary somatotrophs with minor staining of lactotrophs but no other cell type. Three of the 7 APA-positive GHD patients and 8 of the 14 ISS patients had parents or first degree relatives with autoimmune endocrinopathy or non-endocrine disease. Within the ISS group, all 10 patients with abnormally low IGF-I levels were APA positive.

Nineteen of the 60 patients with ISS were re-evaluated 2 years later; 11 had originally been APA negative and 8 APA positive. All 11 negative patients remained APA negative, retained normal GH response to provocative testing, and normal age-dependent increase in IGF-I levels. In contrast, all 8 APA-positive patients demonstrated an increase in their autoimmunity, with titers ranging from 1:32 to 1:128. IGF-I levels remained abnormally low in all 8 patients. Furthermore, 7 developed failure on provoked GH testing. MRI was normal.

The authors concluded that APA against somatotrophs are present in 27% of children with IGHD and 22% of children with ISS. The APA may therefore indicate autoimmune hypophysitis despite the absence of MRI abnormalities. Furthermore, children with APA-positive ISS may represent an earlier stage of autoimmune hypophysitis in which GH reserve is still normal on provocative testing, but with time may develop into full GHD.

De Bellis A, Salerno M, Conte M, et al. Antipituitary Antibodies Recognizing Growth Hormone (GH)-Producing Cells in Children with Idiopathic GH Deficiency and in Children with Idiopathic Short Stature. J Clin Endocrinol Metab. 2006; J Clin Endocrinol Metab. 2006;91:2484–2489.

Editor’s Comment

The authors pointed out the need for further testing in larger populations, as their study was not designed to establish predictive and/or pathogenic roles of APA. Nonetheless, this paper provides compelling data and a very plausible model that justifies pursuing this line of research. Endocrinologists certainly have precedent in using antibody titers to try to predict hormonal dysfunction and understand disease pathogenesis in disorders of the pancreas,^1,2 adrenals,³ and thyroid.⁴ From a practical perspective, measuring APA titers is a far more appealing diagnostic test than the inaccessible pituitary biopsy, for both clinicians and their patients in search of a diagnosis, with the default option of an “idiopathic” non-diagnosis. Hopefully, APA testing will be available to clinicians soon.

Adda Grimberg, MD

References - (linked to )

Last Updated: 04/30/2008