Autoimmune hypophysitis is defined as inflammation of the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The ...

due to

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

Signs and symptoms

Autoimmune hypophysitis can lead to deficiencies in one or more pituitary hormones, causing central diabetes insipidus if the posterior pituitary gland is affected as well as central adrenal insufficiency and central hypothyroidism if the anterior pituitary gland is affected. The symptoms depend on what part of the pituitary is affected. Lymphocytic adenohypophysitis (LAH) occurs when the anterior pituitary cells are affected by

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

resulting in either no symptoms, adrenal insufficiency (if the

ACTH Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important c ...

producing cells are affected), hypothyroidism (if the TSH producing cells are damaged), or

hypogonadism Hypogonadism means diminished functional activity of the gonads—the testes or the ovaries—that may result in diminished production of sex hormones. Low androgen (e.g., testosterone) levels are referred to as hypoandrogenism and low estroge ...

(if the LH and/or FSH producing cells are involved). In some cases, the presence of inflammation within the pituitary gland leads to interruption of dopamine flow from the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

into the pituitary causing high levels of the hormone

prolactin Prolactin (PRL), also known as lactotropin, is a protein best known for its role in enabling mammals to produce milk. It is influential in over 300 separate processes in various vertebrates, including humans. Prolactin is secreted from the pit ...

and, often as a consequence, milk production from the breasts (in older girls and women). Lymphocytic Infundibuloneurohypophysitis (LINH) occurs when the

posterior pituitary The posterior pituitary (or neurohypophysis) is the posterior lobe of the pituitary gland which is part of the endocrine system. The posterior pituitary is not glandular as is the anterior pituitary. Instead, it is largely a collection of axonal ...

is affected resulting in

diabetes insipidus Diabetes insipidus (DI), recently renamed to Arginine Vasopressin Deficiency (AVP-D) and Arginine Vasopressin Resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced ...

. Both LAH and LINH may also lead to symptoms of an intracranial mass such as headache or disturbance of vision, i.e. bitemporal hemianopia. The

pituitary In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The hypoph ...

produces multiple hormones relating to various metabolic functions. Sufficiently low production of certain pituitary hormones can be fatal resulting in the failure of the

thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...

adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...

. Common symptoms include nausea, vomiting, fatigue, loss of libido, amenorrhea, and dizziness. It is estimated that, typically, it takes from 12 to 40 years for autoimmune destruction to present symptoms. However, there have been cases of isolated attacks as a result of drug reactions (i.e., use of

blocking antibody A blocking antibody is an antibody that does not have a reaction when combined with an antigen, but prevents other antibodies from combining with that antigen. This function of blocking antibodies has had a variety of clinical and experimental uses. ...

ipilimumab Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. Cytotoxic T lymphocytes (CTLs) can recogniz ...

) or idiopathic events that have presented symptoms which may disappear after relatively short term treatment (i.e., 1 year on corticoids or other immune suppressants). However, more rapid development of the disorder is the rule when it occurs during, or shortly after, pregnancy (even after miscarriage or abortion). Indeed, autoimmune hypophysitis occurs more commonly during and shortly after pregnancy than at any other time.

Antibodies

80% of patients with pituitary antibodies also have antibodies to thyroid gland or its hormones. Likewise, 20% of autoimmune thyroid patients also have pituitary antibodies. It follows that a subset of thyroid patients may have a disease related to autoimmune hypophysitis. Recent research has focused on a defect at the

CTLA-4 CTLA-4 or CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 ( cluster of differentiation 152), is a protein receptor that functions as an immune checkpoint and downregulates immune responses. CTLA-4 is constitutively exp ...

gene which, coupled with other factors, may result in autoimmunity primarily focusing on certain

endocrine gland Endocrine glands are ductless glands of the endocrine system that secrete their products, hormones, directly into the blood. The major glands of the endocrine system include the pineal gland, pituitary gland, pancreas, ovaries, testes, ...

s including the pituitary and thyroid.

Cause

Diagnosis

Lymphocytic hypophysitis continues to be a diagnosis of exclusion, and histopathology with tissue biopsy is needed for a definitive diagnosis. However, clinical, laboratory data, and imaging can all help with the diagnosis. First and foremost, patients present with symptoms of hypopituitarism and must undergo pituitary hormone function evaluation. Biopsy is the only means of accurate

diagnosis Diagnosis is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in many different disciplines, with variations in the use of logic, analytics, and experience, to determine " cause and effect". In systems engin ...

as no

autoantigen In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease". ...

has been discovered. Biopsy of the pituitary gland is not easily performed with safety as it sits under the brain, however, a

test Test(s), testing, or TEST may refer to: * Test (assessment), an educational assessment intended to measure the respondents' knowledge or other abilities Arts and entertainment * ''Test'' (2013 film), an American film * ''Test'' (2014 film), ...

does exist to detect antibodies to the pituitary without biopsy: autoantibodies to M(r) 49,000 pituitary cytosolic protein may represent markers for an immunological process affecting the pituitary gland. Tests for normal pituitary gland hormone production tend to be expensive and in some cases difficult to administer. In addition, certain hormone levels vary largely throughout the day and in response to metabolic factors, making abnormal levels difficult to calibrate—further hampering diagnosis. Assessment for other autoimmune and inflammatory diseases should also be performed by obtaining complete blood count, complete metabolic panel, c-reactive protein, erythrocyte sedimentation rate, antinuclear antibody, and lupus antibodies at the very least. Gadolinium-enhanced MRI of the pituitary is the imaging of choice as well, and it is important to distinguish lymphocytic hypophysitis from a pituitary adenoma.

Treatment

Inflammation resolves usually after several months of glucocorticoid treatment For those that show no improvement with corticosteroids or have relapsed after treatment with corticosteroids, immunosuppressive medications such as methotrexate, azathioprine, and cyclosporine can be used as well. There have also been some cases where dopamine agonists such as cabergoline/bromocriptine have also been successfully used in those with hyperprolactinemia due to pituitary inflammation. Surgery is only an option for those suffering from visual problems/

ophthalmoplegia Ophthalmoparesis refers to weakness (-paresis) or paralysis (-plegia) of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic, ophthalmologic, and endocrine disease. Internal ...

, have a mass like an effect from compression of nearby structures, or for those that require histology for diagnosis.

Epidemiology

A large scale study on

cadavers A cadaver or corpse is a dead human body that is used by medical students, physicians and other scientists to study anatomy, identify disease sites, determine causes of death, and provide tissue to repair a defect in a living human being. Stud ...

done in Sweden, performed biopsies on hundreds of pituitary glands. The study indicated that perhaps as much as 5% of the population experiences some amount of autoimmune pituitary destruction. It is further hypothesized that perhaps half that many show, or may experience, clinical manifestations. The prevalence of all the types of hypophysitis is low, with an incidence of approximately 1 in 9 million. However, it is thought that this may be an underestimate, especially due to the recent use of immune checkpoint inhibitors for cancer treatments, which have endocrine side effects affecting the pituitary gland. Although cases have been reported in children and the elderly, the mean age of diagnosis for men is 44.7 years, and the mean age of diagnosis for women is 34 years.

History

Autoimmune attack of the pituitary gland resulting in reduced hormone production was first discovered as a result of an autopsy in 1962. The autopsy described destruction of the pituitary and thyroid consistent with autoimmune attack and included atrophy of the adrenal glands.Caturegli, Patrizio, and Tzou, Shey-Cherng, ''Hypophysitis'', in Rose, Noel R., and Mack, Ian R., The Autoimmune diseases, chap. 40, at pg. 548. As magnetic resonance imaging became more available diagnosis increased dramatically. At this time it is believed that the disease is far more prevalent than is diagnosed. Nevertheless, autoimmune hypophysitis is frequently referred to as a

rare disease A rare disease is any disease that affects a small percentage of the population. In some parts of the world, an orphan disease is a rare disease whose rarity means there is a lack of a market large enough to gain support and resources for discov ...

and the most recent estimates as to its

prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...

give it a value of around 5 per million.

References

External links

{{Hypersensitivity and autoimmune diseases Pituitary disorders Autoimmune diseases IgG4-related disease