IgG4-Related Disease Manifesting as Interstitial Nephritis Accompanied by Hypophysitis.

BACKGROUND IgG4-related disease is a systemic disease with marked infiltration of IgG4-positive plasma cells into affected organs and elevated serum IgG4. On clinical examination, swelling, nodules, and hypertrophic lesions might appear simultaneously or metachronously in different organs. CASE REPORT An 85-year-old man with sudden-onset polydipsia and polyuria insipidus was transported to our hospital because of hypothermia and general malaise. Laboratory tests revealed renal failure and central diabetes insipidus. According to his serum IgG4 level, the patient was diagnosed with possible IgG4-related kidney disease accompanied by IgG4-related hypophysitis. Abdominal contrast-enhanced computed tomography, hypophysis magnetic resonance imaging, and histological examination of the kidney were performed. Glucocorticoid therapy was administered and his renal function improved gradually. However, his central diabetes insipidus did not improve. CONCLUSIONS Glucocorticoid therapy showed different therapeutic effects on the kidney and posterior lobe of the hypophysis. It is possible that glucocorticoid therapy needs to be supported by other immunomodulatory therapies to have an effect on all affected organs.

Cutting edge: neuronal recognition by CD8 T cells elicits central diabetes insipidus.

An increasing number of neurologic diseases is associated with autoimmunity. The immune effectors contributing to the pathogenesis of such diseases are often unclear. To explore whether self-reactive CD8 T cells could attack CNS neurons in vivo, we generated a mouse model in which the influenza virus hemagglutinin (HA) is expressed specifically in CNS neurons. Transfer of cytotoxic anti-HA CD8 T cells induced an acute but reversible encephalomyelitis in HA-expressing recipient mice. Unexpectedly, diabetes insipidus developed in surviving animals. This robust phenotype was associated with preferential accumulation of cytotoxic CD8 T cells in the hypothalamus, upregulation of MHC class I molecules, and destruction of vasopressin-expressing neurons. IFN-γ production by the pathogenic CD8 T cells was necessary for MHC class I upregulation by hypothalamic neurons and their destruction. This novel mouse model, in combination with related human data, supports the concept that autoreactive CD8 T cells can trigger central diabetes insipidus.

From idiopathic diabetes insipidus to neurodegenerative Langerhans cell histiocytosis--an unusual presentation and progression of disease.

Diabetes insipidus (DI) is rare in childhood and has a wide-ranging aetiology including the involvement of uncontrolled proliferation of dendritic cells in the hypothalamic-pituitary axis, characteristic of Langerhans cell histiocytosis (LCH). DI may manifest as a sequela of multisystem LCH disease involving skin, bone, liver, spleen and lymph nodes. In very rare cases patients diagnosed with LCH exhibit neurodegenerative changes, such as severe ataxia, tremor, dysarthria and intellectual impairment. We report a 2 1/2-year-old boy who presented initially with apparent idiopathic DI, developed anterior pituitary hormone deficiency and progressive neurological deterioration secondary to neurodegenerative LCH.

Coexistence of autoimmune polyglandular syndrome type 2 and diabetes insipidus in pregnancy.

Autoimmune polyglandular syndromes are rarely diagnosed conditions characterized by the association of at least 2 organ-specific autoimmune disorders. Very few cases of these syndromes have been described during pregnancy. The authors report a case of a patient diagnosed with autoimmune thyroiditis and a history of HELLP (hemolysis, elevated liver enzymes and low platelet) syndrome in a prior pregnancy. After increasing the levothyroxine dose, she developed Addisonian crisis. Normalization of adrenal cortex function resulted in the appearance of diabetes insipidus. This report shows that pregnancy may influence the course of preexisting endocrine disorders and lead to their unmasking. Although the risk of the development of autoimmune polyglandular syndromes during pregnancy is small, they may pose a serious health problem. The possible presence of these clinical entities should be considered in every woman with 1 or more endocrine disturbances.

A case of Langerhans cell histiocytosis with thyroid involvement.

Thyroid involvement with Langerhans cell histiocytosis (LCH) is very rare. We report here the case of a 15-year-old female patient with LCH affecting the thyroid gland. She was referred to the department of pediatric endocrinology for secondary amenorrhea. Prior to the diagnosis of LCH, the patient had symptoms of diabetes insipidus (DI) and amenorrhea. The mean time from symptom onset to diagnosis was 2 years. On physical examination the patient had grade 2 goiter, and ultrasound showed bilateral multiple hypoechoic nodules and thyroid heterogeneity. Biochemical analysis indicated central diabetes insipidus and panhypopituitarism. Magnetic resonance imaging (MRI) demonstrated a mass lesion involving the hypothalamus, which appeared iso- to hypo-intense on T2-weighted images and had an intense postcontrast enhancement on T1-weighted images. Nodular goiter coinciding with a hypothalamic mass suggested LCH, and an excisional biopsy was performed. Histological evaluation of the thyroid gland revealed extensive involvement by LCH, and this was confirmed by immunohistochemical analysis showing S-100 protein and CD1a positive Langerhans cells that were weakly positive for CD68. LCH should be considered in the differential diagnosis of a diffusely enlarged firm and irregular thyroid gland and posterior or anterior pituitary dysfunction.

Putative IgG4-related pituitary disease with hypopituitarism and/or diabetes insipidus accompanied with elevated serum levels of IgG4.

IgG4-positive plasma cell infiltration into multiple organs or tissues, such as the pancreas and salivary glands, associated with increased serum levels of IgG4 is a characteristic finding seen in IgG4-related disease. Affected organs may appear tumorous as a result of chronic inflammatory processes accompanied with progressive fibrosis. Recent cases of this disorder in which the pituitary gland was affected include cases of diffuse enlargement of the pituitary and/or its stalk associated with central diabetes insipidus and/or impaired anterior hormone production. Here we report two such cases, as well as two additional previously undiagnosed cases found in our database. In order to make a correct diagnosis of pituitary lesion involvement with IgG4-related disease, the clinical background and concomitant disorders should be carefully taken into consideration and the measurement of serum levels of IgG4 seems to be useful.

A case of relapsed autoimmune hypothalamitis successfully treated with methylprednisolone and azathioprine.

Autoimmune hypothalamitis is a rare autoimmune neuroendocirne disease. A case of a 70-year-old female with autoimmune hypothalamitis was reported. The chief clinical characteristics were diabetes insipidus and adenopituitary function deficiency. Cranial magnetic resonance imaging (MRI) scan indicated a mass in the hypothalamus. The diagnosis of autoimmune hypothalamitis was presumed. After treatment with prednisone, there was a marked reduction in the mass and the hypothalamus-adenopituitary function partially improved. However, after glucocorticoid therapy was withdrawn, the hypothalamic lesion relapsed progressively. High dose methylprednisolone pulse therapy (HDMPT) in combination with azathioprine was initiated thereafter. During follow-up, MRI scan indicated the lesion shrank strikingly, and the patient's clinical condition improved as well. In view of the good response of the hypothalamic lesion to glucocorticoid and immunodepressant, the putative diagnosis of autoimmune hypothalamitis was confirmed. This case report suggested that HDMPT in combination with azathioprine therapy might be an effective trial for autoimmune hypothalamitis treatment.

sirt1-null mice develop an autoimmune-like condition.

The sirt1 gene encodes a protein deacetylase with a broad spectrum of reported substrates. Mice carrying null alleles for sirt1 are viable on outbred genetic backgrounds so we have examined them in detail to identify the biological processes that are dependent on SIRT1. Sera from adult sirt1-null mice contain antibodies that react with nuclear antigens and immune complexes become deposited in the livers and kidneys of these animals. Some of the sirt1-null animals develop a disease resembling diabetes insipidus when they approach 2 years of age although the relationship to the autoimmunity remains unclear. We interpret these observations as consistent with a role for SIRT1 in sustaining normal immune function and in this way delaying the onset of autoimmune disease.

Post-transplant acute limbic encephalitis: clinical features and relationship to HHV6.

BACKGROUND: Acute limbic encephalitis has been reported in the setting of treatment-related immunosuppression and attributed to human herpesvirus-6 (HHV6) infection. Clinical and laboratory features of the syndrome, however, have not been well characterized. METHODS: We describe the clinical, EEG, MRI, and laboratory features of nine patients with acute limbic encephalitis after allogeneic hematopoietic stem cell transplantation (HSCT). To explore the relationship between HHV6 and this syndrome, we reviewed available CSF HHV6 PCR results from all HSCT patients seen at our center from March 17, 2003, through March 31, 2005. RESULTS: Patients displayed a consistent and distinctive clinical syndrome featuring anterograde amnesia, the syndrome of inappropriate antidiuretic hormone secretion, mild CSF pleocytosis, and temporal EEG abnormalities, often reflecting clinical or subclinical seizures. MRI showed hyperintensities within the uncus, amygdala, entorhinal area, and hippocampus on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI) sequences. CSF PCR assays for HHV6 were positive in six of nine patients on initial lumbar puncture. All patients were treated with foscarnet or ganciclovir. Cognitive recovery varied among long-term survivors. The one brain autopsy showed limbic gliosis and profound neuronal loss in amygdala and hippocampus. Among 27 HSCT patients with CSF tested for HHV6 over a 2-year period, positive results occurred only in patients with clinical limbic encephalitis. CONCLUSIONS: Patients undergoing allogeneic hematopoietic stem cell transplantation are at risk for post-transplant acute limbic encephalitis (PALE), a distinct neurologic syndrome. Treatment considerations should include aggressive seizure control and, possibly, antiviral therapy. PALE can be associated with the CSF presence of human herpesvirus-6, but the pathogenic role of the virus requires further exploration.

Lymphocytic infundibulo-neurohypophysitis associated with recurrent optic neuritis.

A 38-year-old woman presented with diabetes insipidus. The T1-weighted images showed a loss of the hyperintense signal of the posterior pituitary and thickening of the pituitary stalk. DDAVP was started with the diagnosis of lymphocytic infundibulo-neurohypophysitis (LINH). Three months later, she complained of right visual acuity loss. MRI revealed right optic nerve swelling, compatible with the diagnosis of the retrobulbar optic neuritis. She had two other such episodes in the next 3 months. She developed a transient oculomotor and abducens nerve palsies as well. Each time the symptoms disappeared with corticosteroid therapy. The pituitary stalk became normal in size 6 months later. LINH and recurrent optic neuritis occurred in a short duration. Accordingly, a common causative background is suspected. Since the auto-immune process has been hypothesized as a cause of optic neuritis, our case may present further clinical evidence to support the hypothesis of an auto-immune mechanism for LINH.

A longitudinal study of vasopressin cell antibodies, posterior pituitary function, and magnetic resonance imaging evaluations in subclinical autoimmune central diabetes insipidus.

Cytoplasmic autoantibodies to vasopressin-cells (AVPcAb) have been detected not only in patients with overt central diabetes insipidus (CDI), but also in patients with endocrine autoimmune diseases without CDI. This suggests that complete CDI can be preceded by a preclinical stage. Among 878 patients with endocrine autoimmune diseases without CDI, 9 patients found to be AVPcAb positive and 139 AVPcAb-negative controls were enrolled in this open prospective study. They were evaluated for AVPcAb and posterior pituitary function at least yearly for about 4 yr (range, 37-48 months); during this span, magnetic resonance imaging (MRI) of posterior pituitary and stalk was performed only in the AVPcAb-positive patients. Five of the 9 AVPcAb-positive patients had normal posterior pituitary function at study entry. They were AVPcAb positive throughout the follow-up period. At later stages of the study, 3 of them developed partial CDI, and 1 developed complete CDI. The remaining 4 patients showed impaired response to the water deprivation test at study entry and were diagnosed as having partial CDI. Two of them agreed to receive desmopressin replacement for 1 yr. After this treatment, the patients became negative for AVPcAb and displayed normal posterior pituitary function until the end of the follow-up. Conversely, the 2 untreated patients with partial CDI remained AVPcAb positive. One of them developed overt CDI. None of the controls became AVPcAb positive or developed CDI. The normal hyperintense MRI signal of the posterior pituitary, present at study entry, persisted subsequently in all 9 AVPcAb-positive patients, including those developing overt CDI, only disappearing in the late phase of complete CDI. In asymptomatic subjects, the monitoring of AVPcAb, but not MRI, seems to be useful to predict a progression toward partial/overt CDI. Early desmopressin therapy in patients with partial CDI could interrupt or delay the autoimmune damage and the progression toward clinically overt CDI.

Systemic sclerosis associated with diabetes insipidus.

A rare case of systemic sclerosis that preceded the development of diabetes insipidus is reported. This 25-year-old man presented with Raynaud's phenomenon and ulceration of the tip of the right thumb. The diagnosis of systemic sclerosis was based on findings of proximal scleroderma, sclerodactyly, serological abnormalities, and skin abnormalities verified histologically. Partial central diabetes insipidus was later diagnosed after the sudden appearance of polyuria and polydipsia. Coexistence of systemic sclerosis with diabetes insipidus suggests that diabetes insipidus in this patient might have occurred via an autoimmune mechanism.

Association of arginine vasopressin-secreting cell, steroid-secreting cell, adrenal and islet cell antibodies in a patient presenting with central diabetes insipidus, empty sella, subclinical adrenocortical failure and impaired glucose tolerance.

A 36-year-old woman with central diabetes insipidus (DI), diagnosed when she was 7, was referred to our Endocrine Unit in January 1993 for further hormonal investigations. Clinical and laboratory findings confirmed the diagnosis of central DI. Cranial computed tomography and magnetic resonance imaging showed only an empty sella. Moreover, we noted impaired glucose tolerance and unusual findings of subclinical adrenocortical failure, i.e. high plasma renin activity with normal aldosterone levels, high ACTH despite normal basal and ACTH-stimulated cortisol levels. Immunological study of the patient's serum showed the presence of arginine vasopressin (AVP)-secreting cell antibodies (Abs), steroid-producing cell Abs, adrenal and islet cell Abs. The following aspects of our case are stressed and discussed: (1) the presence of AVP-secreting cell Abs 29 years after the diagnosis of DI; (2) the association between DI, empty sella and subclinical autoimmune adrenocortical failure with unusual hormonal findings, and (3) impaired glucose tolerance with islet cell antibody positivity.

Lymphocytic hypophysitis presenting with diabetes insipidus: case report and literature review.

Lymphocytic adenohypophysitis is an autoimmune disorder of the anterior pituitary gland which usually occurs in a women in the postpartum period. It has been considered that lymphocytic hypophysitis is confined to the adenohypophysis sparing the neurohypophysis, and that diabetes insipidus is not a clinical feature of the disorder. Here we report the case of a 50-year-old woman with lymphocytic hypophysitis which presented with diabetes insipidus. MRI indicated homogeneous swelling of the whole pituitary gland, loss of the normal high intensity of the posterior pituitary, and thickening of the pituitary stalk. A biopsied specimen of the pituitary revealed diffuse lymphocytic infiltration. The diabetes insipidus was controlled by the administration of DDAVP. The anterior pituitary function was not greatly damaged, and no hormonal replacement therapy was necessary. We suggest that this case represents a variant of lymphocytic adenohypophysitis and/or lymphocytic infundibuloneurohypophysitis, in which the chronic inflammatory process involves the infundibulum, adenohypophysis and neurohypophysis.

[Diabetes insipidus and postpartum anterior hypophyseal insufficiency]. / Diabète insipide et insuffisance antéhypophysaire du post-partum.

There have only been thirty cases of total post-partum hypopituitarism published in the literature and these have nearly all been secondary to Sheehan's syndrome. The authors report a case of partial anterior hypopituitarism associated with diabetes insipidus which arose after an uneventful Caesarean operation and the origin of which seems to lie in auto-immune hypophysitis. The authors first describe the morphological and endocrine changes that the hypophysis undergoes during pregnancy and then point out that auto-immune hypophysitis seems to have been only recently recognised. This can be used to explain some cases of post-partum hypophyseal insufficiency occurring almost silently without any history of third haemorrhage. Research has been made systematically for anti-hypophyseal antibodies and for specific antibodies of the organ, but has not always been positive. So the diagnosis of auto-immune hypophysitis is often made only after eliminating other reasons for it. A brief review of the physiopathological mechanisms of diabetes insipidus makes it possible to suggest that vasopressinase coming from the placenta together with prostaglandins could play a role.

Cerebrospinal fluid placental alkaline phosphatase in the intracranial germinomas: results of enzyme antigen immunoassay.

The authors investigated the placental alkaline phosphatase (PALP) activity in cerebrospinal fluid (CSF) by enzyme-antigen immunoassay using polyclonal antibody as a marker for intracranial germinomas in 17 patients with germ cell tumors and 20 with other disorders. The detection limit of PALP activity was 0.072 optical density units equivalent to 5.9 ng/ml. Five of nine germinomas demonstrated high CSF PALP activities before treatment. These high PALP activities became undetectable following radiation therapy. The other tumors were small or had no CSF contact. CSF PALP activity is a useful tumor marker for pure germinomas.