Autoimmune hepatitis (AIH) is a rare cause of chronic liver disease. The backbone of treatment is immunosuppressive medication, typically prednisolone as induction therapy and azathioprine as a maintenance therapy. Side effects of the long-term use of systemic corticosteroids are well known and have led to the use of alternative induction regimens. An attractive alternative is budesonide, a nonhalogenated glucocorticosteroid characterized by a high first-pass effect in the liver (90%), resulting in a high topical anti-inflammatory activity and a low systemic activity. It should be stressed that budesonide is contraindicated in patients with established cirrhosis with portal hypertension and portocaval shunting. In this case report, we present the first case of adrenal insufficiency following treatment with budesonide for AIH.

Autoimmune-poly-endocrinopathy-candidiasis-ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison's disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto's thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G>C (p.Arg132Ser; p.R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin α molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to α importins, we show that p.R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings.

Kidney transplant patients (KTPs), and particularly those with advanced chronic kidney rejection, may be affected by opportunistic infections, metabolic alterations and vascular and oncologic diseases that promote clinical conditions that require a variety of treatments, the combinations of which may predispose them to hyponatremia. Salt and water imbalance can induce abnormalities in volemia and/or serum sodium depending on the nature of this alteration (increase or decrease), its absolute magnitude (mild or severe) and its relative magnitude (body sodium:water ratio). Hyponatremia appears when the body sodium:water ratio is reduced due to an increase in body water or a reduction in body sodium. Additionally, hyponatremia is classified as normotonic, hypertonic and hypotonic and while hypotonic hyponatremia is classified in hyponatremia with normal, high or low extracellular fluid. The main causes of hyponatremia in KTPs are hypotonic hyponatremia secondary to water and salt contraction with oral hydration (gastroenteritis, sepsis), free water retention (severe renal failure, syndrome of inappropriate antidiuretic hormone release, hypothyroidism), chronic hypokalemia (rapamycin, malnutrition), sodium loss (tubular dysfunction secondary to nephrocalcinosis, acute tubular necrosis, tubulitis/rejection, interstitial nephritis, adrenal insufficiency, aldosterone resistance, pancreatic drainage, kidney-pancreas transplant) and hyponatremia induced by medication (opioids, cyclophosphamide, psychoactive, potent diuretics and calcineurinic inhibitors). In conclusion, KTPs are predisposed to develop hyponatremia since they are exposed to immunologic, infectious, pharmacologic and oncologic disorders, the combinations of which alter their salt and water homeostatic capacity.

The prognostic significance of clinical characteristics and neuroimaging features, especially cranial magnetic resonance imaging (MRI)-based neuroimaging features, in patients with human immunodeficiency virus (HIV)-negative cryptococcal meningitis (CM) has rarely been examined in the literature. We analyzed the clinical characteristics and MRI findings of 65 HIV-negative patients (43 men, 22 women, age 19-86 years) collected during a study period of 15 years (January 2001-December 2015). Their underlying conditions included diabetes mellitus, liver cirrhosis, hematologic disorders, autoimmune disorders, malignancy, chronic obstructive pulmonary disease, adrenal insufficiency and organ transplantation, and their clinical presentations included headache, altered consciousness, fever, seizure, visual disturbance and hearing impairment. The main cranial MRI findings were basal meningeal enhancement (44.6%, 29/65), dilated Virchow-Robin space/pseudocyst (43.1%, 28/65), "dirty" cerebrospinal fluid sign (38.5%, 25/65), hydrocephalus (36.9%, 21/65), acute/subacute cerebral infarct (ASCI, 21.5%, 14/65), cryptococcoma (9.2%, 6/65), and hazy brain base (1.5%, 1/65). The therapeutic results of the 65 patients were evaluated using the Glasgow Outcome Scale (GOS). A comparison of the good outcome group (GOS score = 4-5, n = 37) and poor outcome group (GOS score = 1-3, n = 28) revealed that both the presence of seizures and ASCI were significantly associated with the prognosis. A comparison of the groups with ASCI (n = 14) and without ASCI (n = 51) revealed that the presence of basal meningeal enhancement was a significant factor for the development of ASCI, and that this correlation may be associated with intense basal meningeal inflammation in adjacent small vessels.

The discovery of "oestrus-producing" hormones was a major research breakthrough in biochemistry and pharmacology during the early part of the 20th century. The elucidation of the molecular weight and chemical structure of major oxidative metabolites of dehydroepiandrosterone (DHEA) led to the award of the Nobel Prize in 1939 to Adolf Frederick Johann Butenandt and Leopold Ruzicka. Considered a bulk androgen in the circulation, DHEA and its sulfated metabolite DHEA-S can be taken up by most tissues where the sterols are metabolized to active androgenic and estrogenic compounds needed for growth and development. Butenandt's interactions with the German pharmaceutical company Schering led to production of gram quantities of these steroids and other chemically modified compounds of this class. Sharing chemical expertise allowed Butenandt's laboratory at the Kaiser Wilhelm Institute to isolate and synthesize many steroid compounds in the elucidation of the pathway leading from cholesterol to testosterone and estrogen derivatives. As a major pharmaceutical company worldwide, Schering AG sought these new biological sterols as pharmacological agents for endocrine-related diseases, and the European medical community tested these compounds in women for conditions such as postmenopausal depression, and in men for increasing muscle mass. Since it was noted that circulating DHEA-S levels decline as a function of age, experimental pathology experiments in animals were performed to determine how DHEA may protect against cancer, diabetes, aging, obesity, immune function, bone density, depression, adrenal insufficiency, inflammatory bowel disease, diminished sexual function/libido, AIDS/HIV, chronic obstructive pulmonary disease, coronary artery disease, chronic fatigue syndrome, and metabolic syndrome. While the mechanisms by which DHEA ameliorates these conditions in animal models have been elusive to define, even less is known about its role in human disease, other than as a precursor to other sterols, e.g., testosterone and estradiol. Our groups have shown that DHEA and many of its oxidative metabolites serve as a low-affinity ligands for hepatic nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and estrogen receptors α/β (ERα/ERβ) as well as G protein-coupled ER (GPER1). This chapter highlights the founding research on DHEA from a historical perspective, provides an overview of DHEA biosynthesis and metabolism, briefly summarizes the early work on the beneficial effects attributed to DHEA in animals, and summarizes the human trials addressing the action of DHEA as a therapeutic agent. In general, most human studies involve weak correlations of circulating levels of DHEA and disease outcomes. Some support for DHEA as a therapeutic compound has been demonstrated for postmenopausal women, in vitro fertilization, and several autoimmune disorders, and adverse health effects, such as, acne, embryo virilization during pregnancy, and possible endocrine-dependent cancers.

One in 10 Americans experience chronic pain. Although opioids do play a role in the management of pain, long-term opioid use may lead to adverse effects. Endocrine-related adverse effects have been described but remain poorly recognized. Opioid-induced adrenal insufficiency occurs because of suppression of hypothalamic-pituitary-adrenal communication and may be challenging to diagnose but has been reported in 9% to 29% of patients receiving long-term opiate therapy. Little data exist to guide case detection and patient management. Treatment includes cessation of opiates (the inciting factor) if possible and glucocorticoid replacement.