Antipituitary Antibodies Research Articles

Hypothalamitis: a diagnostic and therapeutic challenge

To report an unusual case of biopsy-proven autoimmune hypophysitis with predominant hypothalamic involvement associated with empty sella, panhypopituitarism, visual disturbances and antipituitary antibodies positivity. We present the history, physical findings, hormonal assay results, imaging, surgical findings and pathology at presentation, together with a 2-year follow-up. A literature review on the hypothalamic involvement of autoimmune hypophysitis with empty sella was performed. A 48-year-old woman presented with polyuria, polydipsia, asthenia, diarrhea and vomiting. The magnetic resonance imaging (MRI) revealed a clear suprasellar (hypothalamic) mass, while the pituitary gland appeared atrophic. Hormonal testing showed panhypopituitarism and hyperprolactinemia; visual field examination was normal. Pituitary serum antibodies were positive. Two months later an MRI documented a mild increase of the lesion. The patient underwent biopsy of the lesion via a transsphenoidal approach. Histological diagnosis was lymphocytic "hypothalamitis". Despite 6months of corticosteroid therapy, the patient developed bitemporal hemianopia and blurred vision, without radiological evidence of chiasm compression, suggesting autoimmune optic neuritis with uveitis. Immunosuppressive treatment with azathioprine was then instituted. Two months later, an MRI documented a striking reduction of the hypothalamic lesion and visual field examination showed a significant improvement. The lesion is stable at the 2-year follow-up. For the first time we demonstrated that "hypothalamitis" might be the possible evolution of an autoimmune hypophysitis, resulting in pituitary atrophy, secondary empty sella and panhypopituitarism. Although steroid treatment is advisable as a first line therapy, immunosuppressive therapy with azathioprine might be necessary to achieve disease control.

The relationship between the antipituitary antibodies (APAs) and hypopituitarism after traumatic brain injury

Objective To investigate the relationship between antipituitary antibodies (APAs) and hypopituiarism following traumatic brain injury (TBI),as well as the severity of brain injury.Methods The study included 73 patients who suffered TBI 9 to 12 months ago and were diagnosed with hypopituitarism during the follow-up.Based on their Glasgow Coma Scale (GCS) on admission they were categorized into three groups:A (3-8),B (9-12) and C (13-15).Levels of plasma pituitary hormones (GH,TT,FT3 and FSH/LH) and APAs were measured in all patients with chemiluminescence assays and ELISA,respectively.Results Patients in group A had higher levels of APAs and lower levels of hormones compared with those in group B(P＜0.001) or group C(P＜0.001),while no significant difference was found between group B and group C for levels of either APAs (P＞0.05) or hormones (P＞0.05).Levels of APAs were negatively correlated with both GH (r=-0.64071,P＜0.001) and GCS (r=-0.50132,P＜0.001).Conclusion The present investigation provides preliminary evidence that APAs may be associated with the development of TBI-induced hypopituiarism.It suggests that the severity of hypopituiarism following TBI could be predicted by measuring the level of APAs. Key words: Antipituitary antibodies (APAs); Traumatic brain injury (TBI); Hypopituitarism

Involvement of Hypothalamus Autoimmunity in Patients with Autoimmune Hypopituitarism: Role of Antibodies to Hypothalamic Cells

Antipituitary antibodies (APA) but not antihypothalamus antibodies (AHA) are usually searched for in autoimmune hypopituitarism. Our objective was to search for AHA and characterize their hypothalamic target in patients with autoimmune hypopituitarism to clarify, on the basis of the cells stained by these antibodies, the occurrence of autoimmune subclinical/clinical central diabetes insipidus (CDI) and/or possible joint hypothalamic contribution to their hypopituitarism. We conducted a cross-sectional cohort study. Ninety-five APA-positive patients with autoimmune hypopituitarism, 60 without (group 1) and 35 with (group 2) lymphocytic hypophysitis, were studied in comparison with 20 patients with postsurgical hypopituitarism and 50 normal subjects. AHA by immunofluorescence and posterior pituitary function were evaluated; then AHA-positive sera were retested by double immunofluorescence to identify the hypothalamic cells targeted by AHA. AHA were detected at high titer in 12 patients in group 1 and in eight patients in group 2. They immunostained arginine vasopressin (AVP)-secreting cells in nine of 12 in group 1 and in four of eight in group 2. All AVP cell antibody-positive patients presented with subclinical/clinical CDI; in contrast, four patients with GH/ACTH deficiency but with APA staining only GH-secreting cells showed AHA targeting CRH- secreting cells. The occurrence of CDI in patients with lymphocytic hypophysitis seems due to an autoimmune hypothalamic involvement rather than an expansion of the pituitary inflammatory process. To search for AVP antibody in these patients may help to identify those of them prone to develop an autoimmune CDI. The detection of AHA targeting CRH-secreting cells in some patients with GH/ACTH deficiency but with APA targeting only GH-secreting cells indicates that an autoimmune aggression to hypothalamus is jointly responsible for their hypopituitarism.

Update on the diagnosis and management of hypophysitis

To discuss the multiple forms of hypophysitis, the various methods of classification, the recent findings in pituitary autoimmunity and novel methods of treating resistant or recurrent hypophysitis. (January 2010-December 2011). Multiple novel presentations of hypophysitis have been described including cytotoxic T-lymphocyte antigen-4 antibody-related hypophysitis, an adverse event associated with a novel treatment for cancer, Food and Drug Administration approved for use in the treatment of metastatic melanoma. A rare, but newly described entity of immunoglobulin G4 related plasmacytic hypophysitis has been described and reviewed. Multiple investigations addressing the role of autoimmunity in the diagnosis and pathogenesis of hypophysitis have been reported with positive antipituitary antibodies found in patients with autoimmune hypophysitis, other autoimmune diseases, and nonimmune-related pituitary diseases. Several case series and case reports present new associations with concomitant diseases and novel therapy for cases requiring treatment when standard therapy fails or is contraindicated. Hypophysitis is a rare disease with multiple subtypes. The description of hypophysitis related to cytotoxic T-lymphocyte antigen-4 antibody treatment is one of the first descriptions of hypophysitis triggered by medication. As the use of this novel treatment for cancer increases, so must our awareness of immune-related adverse effects and their treatment. Pituitary autoimmunity is a challenging field with multiple discoveries reported to help further our understanding of the disease and assist in diagnosis. Insufficient sensitivity and specificity of the currently reported methods prevents recommending measurement of antipituitary antibodies as standard of care in the diagnosis of hypophysitis. The treatment of hypophysitis remains controversial with recommendations ranging from hormonal replacement to newly described therapies such as azathioprine and radiation.

Bilateral Intracavernous Carotid Artery Occlusion Caused by Invasive Lymphocytic Hypophysitis

Lymphocytic hypophysitis is a rarely recognized disease that is characterized by inflammatory infiltration and destruction of the pituitary gland. The etiology of lymphocytic hypophysitis is still unclear, but an autoimmune pathogenesis has been advocated. In fact, histopathologic specimens reveal a diffuse infiltration of the hypophysis by CD3(+)CD4(+) T cells and CD20(+) plasma cells, and antipituitary antibodies are usually found in sera of affected patients. Although previous cases were found to be correlated only to pregnancy and the postpartum period, recent reports in men and women (without association with pregnancy) suggest a possibly higher prevalence of disease. We present the case of a 55-year-old woman affected by an unusually aggressive form of lymphocytic hypophysitis that infiltrated both cavernous sinuses causing bilateral internal carotid artery occlusion and acute ischemic stroke. Diagnosis was achieved with both a biopsy specimen of the pituitary gland and the detection of antipituitary antibodies. The prompt administration of steroid therapy was effective to obtain regression and stabilization of the disease, but both carotid arteries remained permanently occluded. The natural history of lymphocytic hypophysitis is unpredictable. It usually has a benign evolution, but in exceptional cases the inflammatory process may extend beyond the pituitary gland and infiltrate the surrounding structures. These extremely serious consequences highlight the importance of early diagnosis and treatment of this otherwise curable disease.

Pituitary autoimmune disease: nuances in clinical presentation

Pituitary autoimmune disease is considered an autoimmune organ-specific disorder, characterized by a pituitary infiltration of lymphocytes, macrophages, and plasma cells that could lead to loss of pituitary function. Hypophysitis may be secondary to systemic diseases or infections. Primary pituitary hypophysitis is classified into lymphocytic, granulomatous, xanthomatous, mixed forms (lymphogranulomatous, xanthogranulomatous), necrotizing and IgG4 plasmacytic, according to the histological findings. Concerning lymphocytic hypophysitis (LH), it is characterized by lymphocytic infiltration and can be subclassified according to the affected area on: lymphocytic adenohypophysitis, lymphocytic infundibulo-neurohypophysitis and lymphocytic panhypophysitis. LH had always been considered a rare disease. Nevertheless, with improved imaging techniques, especially magnetic resonance imaging (MRI), LH diagnosis has been increased. This disease usually affects young women during pregnancy or postpartum period with headache, visual impairment, ACTH deficiency and a homogenous sellar mass with thickening of pituitary stalk in MRI. Definitive diagnosis depends on histopathological evaluation; nevertheless, a presumptive diagnosis could be done in a typical case. As no specific autoantigen was identified in LH, there is no antipituitary antibody (APA) method available for helping diagnosis. However, APA used in some centers for research could support an autoimmune origin for some hypopituitarism previously named as idiopathic, confirming nuances in clinical presentation of pituitary autoimmune disease. Therapeutic approach should be based on the grade of suspicious and clinical manifestations of LH.

Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity?

Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean ± SD age 40.9 ± 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months. In addition, the occurrence of AHA and APA positivity due to acute infectious meningitis was demonstrated for the first time. Further longer-term prospective investigations need to be carried out on a larger cohort of patients to understand the role of autoimmunity in the pathogenesis of late hypopituitarism after acute infectious meningitis.

Prevalence of antipituitary antibodies in acromegaly

Acromegaly is a rare disorder due to an excessive production of growth hormone (GH), typically caused by a GH-secreting pituitary adenoma. Anti-pituitary antibodies (APAs) are often seen in patients with different kinds of pituitary pathologies. Because GH has been proposed as a possible antigen recognized by such antibodies, the prevalence of APAs may be higher in conditions characterized by excessive GH secretion. The primary aim of this study was to compare the prevalence of APAs in patients with acromegaly and in controls with other types of pituitary tumors and healthy subjects. Secondary aim was to characterize the pituitary cells targeted by the APAs. Thirty eight acromegaly patients and 215 controls, including 38 patients with prolactinomas, 64 with non-functioning pituitary adenomas (NFPA), and 113 healthy subjects were enrolled in the study. All subjects were tested for APAs using indirect immunofluorescence. Target cells recognized by APAs were identified by double staining immunofluorescence. APAs were significantly more prevalent in acromegaly cases than in healthy controls (10.5% vs. 1.8%, P < 0.05). This prevalence was similar to that found in patients with prolactinomas (7.9%) and NFPA (12.5%). Among APAs-positive subjects, antibodies recognizing somatotrope cells were more common in acromegaly cases than in healthy controls (3/4 vs. 0/113, P < 0.0001), but had similar frequencies in NFPA (2/8) and prolactinomas (1/3). APAs are more frequently found in patients with pituitary adenomas than healthy subjects, with no significant difference among the tumor types studied. GH-secreting cells could represent a target of the autoimmune response.

Detection of antipituitary and antihypothalamus antibodies to investigate the role of pituitary or hypothalamic autoimmunity in patients with selective idiopathic hypopituitarism

Antipituitary (APA) but not antihypothalamus antibodies (AHA) have been investigated in patients with idiopathic hypopituitarism. This study searched for APA and AHA in some of these patients to investigate whether pituitary or hypothalamic autoimmunity could play a role in their pituitary dysfunction. Sixty-six patients with selective idiopathic hypopituitarism were studied: 27 with ACTH deficiency, 20 with GH deficiency and 19 with hypogonadotropic hypogonadism. Twenty patients with hypopituitarism secondary to hypophysectomy and 50 healthy subjects were enrolled as controls. Antipituitary and AHA were evaluated by indirect immunofluorescence in sera of patients and controls. Positive sera were retested by a four-layer double immunofluorescence to identify the cells targeted by these antibodies. Antipituitary were present at high titre in 4 of 27 patients with ACTH deficiency (14·8%), 4 of 20 with GH deficiency (26%) and 5 of 19 with hypogonadotropic hypogonadism (21%) and targeted, respectively, corticotrophs, somatotrophs and gonadotrophs. AHA were found at high titre only in 5 patients with ACTH deficiency (18·5%), mostly targeting corticotrophin-releasing hormone-secreting cells; none of these 5 patients resulted positive for antipituitary antibodies. Among the controls, only 1 hypophysectomized patient resulted APA positive at low titre. Our results suggest that in patients with selective idiopathic hypopituitarism, detection of APA or AHA could better characterize an autoimmune process involving the pituitary or hypothalamus, respectively. In particular, detection of antibodies targeting selectively ACTH-secreting or corticotrophin-releasing hormone-secreting cells may differentiate, respectively secondary from tertiary variants of autoimmune hypoadrenalism.

Case of isolated adrenocorticotropic hormone deficiency mimicking major depressive disorder

ISOLATED ADRENOCORTICOTROPIC HORMONE (ACTH) deficiency is a rare pituitary disorder characterized by decreased secretion of ACTH, but not of the other hormones of the anterior pituitary and causes secondary adrenal insufficiency.1 Since isolated ACTH deficiency gradually and latently develops and shows non-specific symptoms, it is easily misdiagnosed. We report a case of middle-aged-onset isolated ACTH deficiency that showed a severe major depressive episode. A 62-year-old man was admitted to our hospital due to suicidal behavior. He did not have any previous history of neuropsychiatric or endocrine disorders. From 6 months before the admission, he complained of mild general fatigue, depressed mood, loss of pleasure, psychomotor retardation, insomnia, decrease in appetite, and weight loss. He was diagnosed as having major depressive disorder. A dose of 100 mg/day of sertraline did not relieve him of his depressive symptoms at all. At the time of admission, he was fully conscious and showed a severe major depressive episode with suicidal ideas. He did not show any symptoms suggestive of atypical depression or chronic fatigue syndrome, such as hypersomnia, lead paralysis, mood reactivity, rejection sensitivity, muscle pain, lymph node swelling, and fever. Magnetic resonance imaging of his brain did not show any structural abnormality, including an empty sella. Blood test revealed anemia (red blood cell count, 3.24 × 106/µL; hemoglobin, 10.0 mg/dL) and hyponatremia (117 mEq/L). Thyroid function studies were consistent with hypothyroidism: thyroid-stimulating hormone (TSH), 49.8 µIU/mL (normal range, 0.6–5.1); fT3, 2.45 pg/mL (2.47–4.34); and fT4, 0.71 ng/dL (0.97–1.79). Rheumatoid factor and antinuclear, antithyroglobulin, anti-thyroid peroxidase, TSH-receptor, and antipituitary antibodies were negative. Both serum ACTH (<2.0 pg/mL; normal range, 7.2–63.3) and cortisol (0.2 µg; 3.7–19.4) were extremely low, whereas aldosterone (61.6 pg/mL; 38.9–307.0) was within normal range. Neither ACTH nor cortisol responded to corticotrophin-releasing hormone stimulation test, showing that he suffered from secondary adrenocortical insufficiency. Thyrotropin-releasing hormone test, gonadotrophin-releasing hormone test, and growth hormone-releasing hormone test showed normal responses, revealing that his secondary adrenocortical insufficiency was caused by isolated ACTH insufficiency. We discontinued sertraline and started to administer him 5 mg/day of hydrocortisone. Three days later, his symptoms mimicking major depressive episode were dramatically resolved. As in our case, isolated ACTH deficiency may be comorbid with primary hypothyroidism although the mechanism of the coexistence is unknown.2 However, the comorbid hypothyroidism did not seem to induce his depressive state as hypothyroidism was recovered 4 months after rapid relief of his psychiatric state. Relationships between glucocorticoid function and symptoms mimicking major depressive episodes are complex but might reflect insufficient glucocorticoid signaling. Some major depressive episodes might be associated with the insufficient glucocorticoid signaling by decrease of glucocorticoid production or decrease of sensitivity of glucocorticoid receptors.3 Our case suggests that isolated ACTH deficiency should be added into a differential diagnostic list of major depressive disorder. The patient gave the authors informed consent to publish this letter.

Isolated secondary adrenal insufficiency - an underestimated consequence of asymptomatic autoimmune hypophysitis

We read with great interest the paper by Trevor A. Howlett et al. on autoimmune hypophysitis and we found it very important for management of this disorder. Autoimmune hypophysitis with clinical features of a pituitary mass is a rare event. We believe that a subclinical form of this disease is much more frequent in clinical practice. We have in our observation a group of 305 patients with idiopathic isolated secondary adrenal insufficiency. Interestingly, 203 (67%) of them had associated various autoimmune disorders. Apart from the well-known hypothalamic-pituitary-adrenal suppression because of exogenous corticosteroids, only an autoimmune mechanism is able to influence selectively the secretory function of the corticotrophs in adult patients. The most frequent finding in MRI of our patients was partially empty sella turcica, probably as a consequence of asymptomatic autoimmune hypophysitis. Thyroid autoimmune diseases, both hypothyroidism and thyrotoxicosis, as well as Hashimoto’s disease without apparent clinical manifestations, were the most frequent autoimmune disorders in this group of patients. Vitiligo, premature ovarian failure, type 1 diabetes mellitus and pernicious anaemia were also rather frequently observed. Coexistence of these autoimmune abnormalities and antipituitary antibodies detected in some of the tested cases 5 suggested adrenocorticotrophic hormone deficiency of autoimmune origin. By all means, in our patients, there was no indication to perform pituitary biopsy. In our experience, it is very important to diagnose correctly patients with idiopathic isolated secondary adrenal insufficiency because some of them are falsely treated as gastroenteritis in situation of an imminent adrenal crisis.

ACTH deficiency and PGI2 therapy in chronic thromboembolic pulmonary hypertension

Case 1 was a 26-year-old female. She developed chronic thromboembolic pulmonary hypertension (CTEPH) at 16 years of age, after the surgical removal of an ovarian tumour. She was given sildenafil at the age of 22, followed by prostaglandin I2 (PGI2) therapy for severe pulmonary hypertension (mean pulmonary arterial pressure [mPAP] 58 mm Hg, and pulmonary vascular resistance [PVR] 1121.2 dyn s/cm). She had never received steroid therapy. She developed appetite loss, diarrhea and systemic edema 4 years after the initiation of PGI2 therapy. Her systemic edemawas improved with diuretic administration plus a slight increase in the dose of PGI2 (from 10 to 10.5 ng/kg/min); however, anorexia, diarrhea, and general fatigue persisted. In addition, her serum Na level dropped to less than 130 mmol/L (normal range: 135–145). Both her cortisol and adrenocorticotropic hormone (ACTH) levels were low, at 3.4 μg/dL (normal range: 5.0–25.0) and 5 pg/mL (normal range: 5–46), respectively. An intravenous injection of ACTH (50 μg) yielded a lower (15.1 pg/mL) than normal peak serum cortisol (normal response: N20) at 60 min, which indicated adrenal insufficiency. In addition, her plasma ACTH response decreased after a challenge with 100 μg of corticotrophin-releasing hormone (CRH; Table 1). Intravenous injections of thyrotropin-releasing hormone (TRH, 500 μg), growth hormone-releasing hormone (GRH, 100 μg), and luteinising hormone-releasing hormone (LH-RH, 100 μg) showed normal responses for thyroid-stimulating hormone (TSH), growth hormone (GH), luteinising hormone (LH), follicle-stimulating hormone (FSH) and prolactin (PRL) secretion. Magnetic resonance imaging (MRI) did not reveal any pituitary or adjacent lesions. No autoantibodies were detected, including antipituitary antibody, antiphospholipid antibody (APA), lupus anticoagulant (LA), thyroid stimulating antibody (TsAb), thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb). These results indicated isolated ACTH deficiency (IAD). The patient's anorexia, diarrhea, and hyponatremia rapidly improved

Predictive Role of the Immunostaining Pattern of Immunofluorescence and the Titers of Antipituitary Antibodies at Presentation for the Occurrence of Autoimmune Hypopituitarism in Patients with Autoimmune Polyendocrine Syndromes over a Five-Year Follow-Up

Antipituitary antibodies (APA) are frequently present in patients with autoimmune polyendocrine syndrome (APS). The aim was to evaluate the predictive value of APA for the occurrence of hypopituitarism. A total of 149 APA-positive and 50 APA-negative patients with APS and normal pituitary function were longitudinally studied for 5 yr. APA, by indirect immunofluorescence, and anterior pituitary function were assessed yearly in all patients. The risk for developing autoimmune pituitary dysfunction was calculated using survival and multivariate analysis. Hypopituitarism occurred in 28 of 149 (18.8%) APA-positive patients but in none of the 50 APA-negative patients. The immunostaining pattern in APA-positive patients involved either isolated pituitary cells [type 1 pattern; n=99 (66.4%)] or all pituitary cells [type 2 pattern; n=50 (33.6%)]. All patients developing pituitary dysfunction throughout the study span had a type 1 pattern. Kaplan-Meier curves for cumulative survival showed a significantly higher rate for developing hypopituitarism in relation to positive APA tests (P<0.005), pattern of immunostaining (P<0.0001), and APA titers (P<0.000001). Cox regression analysis in APA-positive patients with a type 1 pattern demonstrated a significantly (P<0.0001) higher risk for the onset of hypopituitarism in relation to increasing titers of APA. APA measurement by immunofluorescence may help to predict the occurrence of hypopituitarism but only when considering the immunostaining pattern and their titers. Combined evaluation of these parameters allows identifying patients at higher risk for pituitary autoimmune dysfunction, thus requiring a strict pituitary surveillance to disclose a preclinical phase of hypopituitarism and possibly interrupt therapeutically the progression to clinically overt disease.

Anticuerpos antihipófisis en pacientes con sospecha de hipofisitis autoimmune

Introduction Definitive diagnosis of autoimmune hypophysitis (AH) is histological. However, a presumptive diagnosis can be made through clinical, biochemical and imaging data. Objective The objective of this study was to review the presence of antipituitary antibodies (APA) and antithyroid antibodies (ATA) in patients with suspected AH in order to determinate the utility of APA in the diagnosis of AH. Material and methods We studied 36 patients divided into seven groups according to the data suggesting AH (isolated corticotropin deficiency, other idiopathic pituitary deficiencies, idiopathic hyperprolactinemia, empty sella, sellar mass with thickened stalk, proven histological hypophysitis) or because of previous autoimmune endocrine diseases. Twenty-four controls without endocrinological disease were also included. In all subjects, APA were determined by immunofluorescence over primate pituitary gland and ATA by an agglutination technique. Results None of the controls and only 9 patients, all of them women, were APA-positive. Of the 9 APA-positive patients, 43% belonged to the group of patients with isolated ACTH deficiency. In 8 patients, APA were determined again during the follow-up; 6 remained APA-negative, but one patient became APA-positive and another became APA-negative. ATA were positive in 12 patients, 22.2% of whom were also APA-positive, and in one control. Conclusions The prevalence of APA positivity among the study patients was low. These antibodies were found only in women, mostly with isolated corticotropin deficiency. APA and ATA coexisted in only 22% of the patients studied.

Commentary on “Anti-Pituitary Antibodies in Children With Newly Diagnosed Celiac Disease: A Novel Finding Contributing to Linear Growth”

The pathogenesis of celiac disease (CD)-associated short stature is still unclear. The authors showed that newly diagnosed CD patients have a high prevalence of positive antipituitary antibodies that correlates with height impairment. Given the association of CD with other autoimmune disease, these authors' findings show one possible etiology for the poor growth seen in children with CD.

Investigation of antihypothalamus and antipituitary antibodies in amateur boxers: is chronic repetitive head trauma-induced pituitary dysfunction associated with autoimmunity?

Current data clearly demonstrate that sports-related chronic repetitive head trauma due to boxing might result in hypopituitarism. However, the mechanism of sports-related traumatic brain injury-induced pituitary dysfunction is still unclear. In order to understand whether autoimmune mechanisms could play a role in the pituitary dysfunction due to sports-related head trauma, we investigated the presence of antipituitary antibodies (APAs) and antihypothalamus antibodies (AHAs) in amateur boxers. Sixty-one actively competing (n=44) or retired (n=17) male boxers (mean age, 26 years; range, 17-53) who had been evaluated regarding pituitary functions previously were included in the study. In all boxers and in 60 age/sex-similar normal controls, AHAs and APAs were investigated by an indirect immunofluorescence method. AHAs were detected in 13 of 61 boxers (21.3%), and APAs were detected in 14 of 61 boxers (22.9%), but in none of the normal controls. Pituitary dysfunction was significantly higher in AHA-positive boxers (46.2%) than in AHA-negative boxers (10.4%) (P=0.003). There was a significant association between AHA positivity and hypopituitarism due to boxing (odds ratio: 7.37, 95% confidence interval 1.8-30.8). There was no significant association between APA positivity and hypopituitarism. This study demonstrates for the first time the presence of AHAs and APAs in boxers who were exposed to sports-related head trauma. Moreover, the present investigation provides preliminary evidence that AHAs are associated with the development of pituitary dysfunction in boxers, thus suggesting that autoimmunity may have a role in the pathogenesis.

Lymphocytic Hypophysitis: Differential Diagnosis and Effects of High-Dose Pulse Steroids, Followed by Azathioprine, on the Pituitary Mass and Endocrine Abnormalities — Report of a Case and Literature Review

We report on a man with a progressively increasing pituitary mass, as demonstrated by MRI. It produced neurological and ophthalmological symptoms, and, ultimately, hypopituitarism. MRI also showed enlargement of the pituitary stalk and a dural tail phenomenon. An increased titer of antipituitary antibodies (1:16) was detected in the serum. Pituitary biopsy showed autoimmune hypophysitis (AH). Neither methylprednisolone pulse therapy nor a subsequent treatment with azathioprine were successful in recovering pituitary function, or in inducing a significant reduction of the pituitary mass after an initial, transient clinical and neuroradiological improvement. Anterior pituitary function evaluation revealed persistent hypopituitarism. AH is a relatively rare condition, particularly in males, but it represents an emerging entity in the diagnostic management of pituitary masses. This case shows that response to appropriate therapy for hypophysitis may not be very favorable and confirms that diagnostic management of nonsecreting pituitary masses can be a challenge. Clinical, imaging, and laboratory findings are useful for suggesting the diagnosis, but pituitary biopsy may be necessary to confirm it.

The Growth Hormone-Insulin-like Growth Factor Axis in Glycogen Storage Disease Type 1: Evidence of Different Growth Patterns and Insulin-like Growth Factor Levels in Patients with Glycogen Storage Disease Type 1a and 1b

To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glycogen storage disease type 1 (GSD1). This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control subjects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary antibodies (APA). Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b (P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b (P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a (P = .008), 57.1% of patients with GSD1b (P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a (P = .02) and control subjects (P = .03). The GH response to the provocative test inversely correlated with the presence of APA (P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores (P = .003). Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The increased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment.

Anti-Pituitary Antibodies in Children With Newly Diagnosed Celiac Disease: A Novel Finding Contributing to Linear-Growth Impairment

The possible autoimmune involvement of the pituitary gland in patients with celiac disease (CD) has been suggested but demonstrated in only a few patients on gluten-free diet. We aimed to assess the prevalence and clinical meaning of anti-pituitary antibodies (APA) in children and adolescents with the newly diagnosed CD. A total of 119 patients with CD (0.9-15.8 years old) attending the inpatient clinic of University Hospital were recruited for the cross-sectional study. Their height, weight, and body mass index (BMI) were recorded, and insulin-like growth factor-1 (IGF-1) and APA were assayed. APA was also determined in 98 sex- and age-matched controls. APA were detected in 50 patients (42.0%), 15 of them with high titer (30%) and 35 with low titer (70%), and in 2 control subjects at low titer (2%) (P<0.001). IGF-1 was higher in patients with negative than with low titer (P=0.02) or high titer APA (P=0.03). Height was more reduced in high-titer APA patients than in the negative ones (P<0.01). Height was positively correlated with IGF-1 (P<0.01) and negatively with chronological age (P=0.001). IGF-1 was positively correlated with BMI (P<0.001). For height prediction the regression analysis showed the rank order 1 for chronological age and 2 for IGF-1. In this paper we have shown a remarkable prevalence of positive APA in newly diagnosed CD patients. High APA titers are associated with height impairment, likely mediated by a reduction of IGF-1, thus suggesting that autoimmune pituitary process could induce a linear-growth impairment.

Evaluation of GH-IGF-I Axis in Adult Patients with Coeliac Disease

The aim of this study was to evaluate GH/IGF-I axis and other pituitary functions in adult patients with coeliac disease. For this purpose, twenty-eight adult coeliac patients [20M, 8F:19-74 years; body mass index (BMI): 18.5-28 kg/m (2)] were recruited. Basal thyroid, adrenal and gonadal function, serum IGF-I and PRL, and routine parameters were evaluated. Dynamic GH secretion was carried out by GHRH plus arginine test. In 20 patients, antipituitary antibodies (APA) were also evaluated. Seven out of 28 patients, independently from disease onset and the gluten-free diet (GFD), showed an impaired GH secretion (25%). All were males, 2 with severe growth hormone deficiency (GHD) and 5 with partial GHD. In patients with GHD, as compared to coeliac patients with normal GH secretion, HOMA (2.1+/-1.2 vs. 0.9+/-0.4) and QUICKI (0.35+/-0.03 vs. 0.39+/-0.02) levels were significantly higher and lower, respectively, while IGF-I levels were slightly lower (17.7+/-3.7 vs. 24.7+/-6.3, p=NS). APA were negative in all 20 patients studied. In conclusion, a significant number of adult coeliac patients show an impaired GH secretion, this alteration being predominant in males and independent from disease onset and diet regimen. Given the absence of APAs, the cause of this pituitary dysfunction remains unclear even if a previous autoimmune involvement in some cases cannot be excluded.