Introduction
Autoimmune hypophysitisIt is an inflammatory disease of the pituitary caused by autoimmune reaction. The main clinical manifestations are pituitary enlargement and hypopituitarism. According to its etiology, it can be divided into primary pituitary inflammation and secondary pituitary inflammation (Table 1). This article next focuses on the diagnosis and treatment of lymphocytic pituitary inflammation and two new pituitary glands in recent years: cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) antibody-associated pituitaryitis and IgG4-related pituitary.
Epidemiological characteristics
Although autoimmune hypophysitis is a rare disease, in recent years, with the gradual recognition of the disease and the improvement of clinical diagnostic level, especially the technical progress of imaging MRI, more and more cases are diagnosed, but the specific incidence rate is still Not sure. Honegger et al analyzed 2362 clinical samples collected in Germany from 1982 to 1995 and found 7 (0.3%) autoimmune hypophysitis. Leung et al reported that 13 of the 2000 patients (0.65%) who underwent transsphenoidal pituitary resection in the United States between 1992 and 2003 showed autoimmune hypophysitis.
Lymphocytic pituitary inflammation is the most common subtype of autoimmune hypophysitis, so many scholars and clinicians often default to autoimmune hypophysitis as lymphocytic pituitary.
Pathogenesis
At present, it is basically recognized that autoimmune pituitary inflammation is caused by autoimmune reaction, but the specific autoimmune mechanism is still unclear. Some scholars believe that the possible mechanism is that the placenta and pituitary co-express an antigen or a highly homologous antigen. The maternal immune system attacks the placental antigen during pregnancy, and cross-injures the antigen expressed by the pituitary, causing pituitary-specific inflammation. It is currently known that placental chorionic growth prolactin is highly homologous to growth hormone secreted by the pituitary. Some scholars believe that the disease is caused by the direct attack of the pituitary antigen by the immune system, but it is unclear what causes this immune attack.
Clinical symptoms
The clinical symptoms of autoimmune hypophysitis can be summarized into five aspects.
1. Symptoms caused by intracranial masses:
This is the most common symptom, often sudden, manifested as headache, nausea, vomiting, lethargy and other symptoms of high blood pressure. The upward growth of the mass invades the optic chiasm, which can cause vision loss and hemianopia on both sides of the sac; the growth of the cranial nerves invading the cavernous sinus III, IV, and VI can cause ophthalmoplegia and eye movement disorders; Meninges, clinical manifestations of meningitis, such as dizziness, vomiting, and neck stiffness.
2. Lower anterior pituitary symptoms:
Lymphocytes attack the anterior pituitary hormone secreting cells, causing defects in the secretion of anterior pituitary hormones, often hidden. It can be expressed as a decrease in total pituitary function, or as a decrease in the secretion of a single hormone. The most common is the promotion of adrenocorticotropic hormone secretion, clinical manifestations of dizziness, nausea, vomiting, hypotension, pubic hair loss, etc., severe symptoms can be acute adrenocortical insufficiency, causing death; followed by thyroid axis Decreased function, manifested as apathy, unresponsiveness, slow heart rate, low heart bluntness, chills, weight loss, etc.; followed by hypogonadism, in women with amenorrhea, loss of libido, breast and genital atrophy, etc. For decreased sexual desire, impotence, etc.; prolactin deficiency is less common, mainly because women can not lactate after childbirth; growth hormone deficiency is even rarer.
3. Central diabetes insipidus performance:
This is a characteristic symptom of lymphocytic fungal neurohypophysitis, which may be caused by the direct destruction of the pituitary gland and funnel by the immune cells, or by the compression of the nerve pituitary and funnel. The clinical manifestations are polydipsia and polyuria. The urine specific gravity and urine osmotic pressure are lowered, and the blood osmotic pressure is increased.
Appears in about one-fourth of patients with autoimmune hypophysitis, manifested as amenorrhea and (or) galactorrhea.
5. Accompanied by other autoimmune disease symptoms:
Nearly 30% of patients with autoimmune pituititis are associated with other autoimmune diseases, the most common of which are Hashimoto's thyroiditis and Graves' disease. Relatively rare are Addison's disease, type 1 diabetes, hypoparathyroidism, Chronic atrophic gastritis, pernicious anemia, etc.
Imaging and pathology
The imaging diagnosis of lymphocytic pituitary inflammation mainly depends on MRI, and its MRI features are:
(1) The pituitary is diffusely enlarged, which can squeeze the optic chiasm and cavernous sinus.
(2) The pituitary stalk is thickened, but there is no offset.
(3) The increased pituitary T1 weighted image is a low signal or an equal signal, and the T2 weighted image is a high signal.
(4) Enhanced scanning lesions are significantly and evenly enhanced, and dural tail sign can occur. When the posterior pituitary is involved, its normal high signal on the T1-weighted image disappears.
(5) Late pituitary can also be expressed as a reduction in the size of the pituitary, and even empty saddle.
Pathologically, the early specimens of lymphocytic pituitary inflammation showed different degrees of pituitary enlargement, and the texture was tough. Microscopic examination showed that a large number of lymphocytes, plasma cells and scattered eosinophils, mast cells and other inflammatory cells infiltrated without granuloma. And the formation of multinucleated giant cells. Lymphocytes can be aggregated into the germinal center, and immunohistochemistry suggests that the infiltrating lymphocytes are mainly CD4+ T cells and B cells. As the disease progresses, pituitary tissue can also undergo varying degrees of necrosis, atrophy, and fibrosis.
Immunological examination
Antigen-antibody titer determination is an important auxiliary examination for many autoimmune diseases, which can assist in the diagnosis, response to disease progression or evaluation of treatment effects. In particular, the pathological biopsy of autoimmune pituititis is difficult to operate and invasive, and many scientists are committed to discovering immunological markers of autoimmune hypophysitis. High titers of anti-pituitary antibodies, especially high titers of anti-GH antibodies, have a greater impact on the diagnosis of pituitary inflammation.
Diagnosis and differential diagnosis
At present, the diagnosis of lymphocytic pituitary inflammation is often used. First, based on clinical symptoms and imaging findings, combined with endocrine laboratory test results to establish a diagnosis of suspected pituitary, if the above epidemiological characteristics are met, and anti-pituitary antibodies or other autoimmune antibodies are highly titer, it is highly suspected; Second, all possible secondary pituitary inflammations were excluded and carefully identified with the following differential diagnosis. Finally, according to the pathological results, it is feasible to pass the pituitary biopsy or to confirm the pathological examination. However, due to the invasive diagnosis method, the necessity of pathological diagnosis remains to be discussed. Some scholars believe that if it is highly suspected, it can be diagnosed with glucocorticoids first. After 2 weeks, the pituitary MRI should be reviewed. If the enlarged pituitary is narrowed and thickened. If the pituitary stalk becomes thinner or the clinical symptoms are significantly alleviated, the diagnosis is supported, and no pathological biopsy is necessary.
Diagnosis of lymphocytic pituitary inflammation requires careful identification of the following diseases.
1. Granulomatous pituitary and xanthomatous pituitary:
These two types of pituitary inflammation are also primary pituitary inflammation, but not effective for adrenocortical hormone therapy; lymphocytic pituitary and granulomatous pituititis can cause total pituitary inflammation, and xanthomatous pituitary inflammation is limited to pituitary The anterior lobe does not oppress the optic chiasm.
2. Pituitary tumor:
Pituitary inflammation is characterized by a decrease in the secretion of pituitary hormones, while functional pituitary tumors often show hypersecretion of pituitary hormones, other hormones are normal or decreased; for non-functional pituitary tumors, pituitary hormone secretion may also be reduced, often first It affects gonadotropins and growth hormones, while pituitary inflammation most often affects the adrenal axis, followed by the thyroid axis and the gonad axis, and growth hormone reduction is less common. Imaging is important for identifying pituitary and pituitary tumors.
3. Sheehan syndrome:
Sheen syndrome often occurs in postpartum, manifested as pituitary dysfunction, easy to misdiagnose pituitary inflammation as Sheen syndrome. However, Sheehan syndrome has a history of massive bleeding during childbirth, most often affecting the gonadal axis, clinical manifestations of long-term weakness, no milk secretion, amenorrhea, pubic hair loss, etc. MRI shows pituitary atrophy, density is significantly reduced, even in the sellar region A cavity echo occurs.
4. Germ cell tumor:
The germ cells in the saddle area showed hypopituitarism and diabetes insipidus. MRI showed thickening of the pituitary stalk and high signal of the posterior pituitary. These were similar to pituitary inflammation, but germ cell tumors mostly occurred in children, detecting cerebrospinal fluid and The level and proportion of serum chorionic gonadotropin in the serum can assist in the diagnosis and the disease is more sensitive to radiation therapy.
5. Craniopharyngioma:
Craniopharyngioma can also show symptoms such as intracranial space occupying, pituitary secretion loss, diabetes insipidus, etc., but it occurs in children and adolescents, and occurs in the saddle. CT can assist in diagnosis, mainly manifested as calcification. The pituitary lesions are located in the saddle area and calcification is rare.
In addition, when pituitary inflammation is characterized by pituitary stalk thickening, children should be differentiated from histiocytosis X and granulosa cell tumors. Adults need to be associated with diseases such as tuberculosis, sarcoidosis, plasmacytoma and lymphoma. Identification.
Treatment and prognosis
Like other autoimmune diseases, the course of autoimmune hypophysitis is characterized by repeated remission and recurrence. The main treatment goals are to reduce the size of the tumor, replace the lack of hormones and alleviate hyperprolactinemia.
1. Reduce the size of the mass:
(1) Medical immunotherapy: Immunotherapy is the first choice for autoimmune hypophysitis, which can relieve pituitary inflammation and reduce the size of the mass. Common glucocorticoids are used in large doses of shock therapy, but the specific use of hormones has not yet reached a consensus.
(2) Surgical treatment: surgical removal of pituitary mass is the most effective way to reduce the size of pituitary mass, and can provide pathological specimens to help to confirm the diagnosis, but because it can cause iatrogenic hypopituitarism and easy recurrence, clinically needed Use with caution. Surgical treatment is recommended only if the patient has a progressive progressive worsening of visual impairment or other severe intracranial mass symptoms, or if immunotherapy is ineffective. Modern pituitary surgery often uses endoscopic transsphenoidal pituitary resection, surgical removal of 1/3 to 1/2 of the pituitary can be done, no need to completely remove.
(3) Radiation therapy: Both stereotactic radiotherapy and gamma knife surgery can successfully treat patients with ineffective or recurrent immunotherapy and surgical treatment, but large-scale randomized controlled trials are needed to prove their safety and effectiveness.
2. Hormone replacement:
However, patients with a lack of pituitary hormone secretion need long-term hormone replacement therapy to supplement the different hormones that the patient lacks. During the treatment, hormone levels should be regularly measured and the drug dose adjusted. For patients with diabetes insipidus, vasopressin such as vasopressin (methane) can be treated.
3. Treatment of hyperprolactinemia:
Bromocriptine can improve hyperprolactinemia in patients and improve visual field defects, but has no significant effect on the size of the pituitary, and has little significance for the progression of the entire disease.
As for the prognosis, most of the (68%) patients with intracranial massaging can be improved by the above-mentioned treatment of reducing the pituitary mass, but long-term symptoms of hormone deficiency require hormone replacement therapy. 18% of patients are completely cured and no further treatment is needed. 6% of patients will relapse repeatedly, and the pituitary gland will gradually shrink with the course of the disease, showing an empty sella on MRI. 6% of patients died of adrenal insufficiency, infection, etc., and the remaining 2% were self-relieving patients.
CTLA-4 antibody-associated pituitary
CTLA-4, also known as CD152, is expressed on the surface of activated regulatory T cells, and when it binds to the corresponding receptor on the surface of antigen-presenting cells, it can negatively regulate the activation of T cells. If CTLA-4 is blocked, T cells are Continuous activation. This principle has been applied to the immunotherapy of tumors, and some anti-tumor drugs have been developed. Currently used in clinical applications, CTLA-4 blockers are Ipilimumab and Tremelimumab, which are commonly used in metastatic melanoma andRenal cell carcinoma,Lung cancer,Prostate cancerwithPancreatic cancerThe treatment of several advanced tumors, but anti-tumor will also cause some autoimmune dysfunction, that is, immune-related adverse reactions.
Therefore, pituitary inflammation is seen in the above-mentioned several tumor patients treated with CTLA-4 antibody, so the age of onset is relatively large (55±10 years old), which is more common in men. Its pathogenesis is still unclear.
Recognizing the severity of pituitary inflammation, clinicians need to be vigilant when treating patients with cancer with CTLA-4 antibody. Regularly check blood pressure, blood sugar, blood routine, blood osmotic pressure, electrolytes, adrenocortical hormones, thyroid hormones, gonads. Axon hormones, prolactin and brain MRI, in order to detect secondary pituitary inflammation in time.
IgG4-related pituitary
IgG4-related pituitary inflammation is one of the IgG4-related diseases, most of which are found in Japan, the specific cause is unclear, and may be related to human race. The main difference between IgG4-related hypophysitis and other types of pituitary inflammation is that the serum IgG4 concentration is increased. Pituitary tissue biopsy can detect IgG4-positive plasma cells, and the pathogenesis is still unclear, possibly with interleukin (IL)-4, IL- 5. IL-13 promotes the conversion of IgE to IgG4. In 2011, Leporati et al. proposed a diagnostic criteria for IgG4-related hypophysitis by literature review:
(1) Pituitary histopathology: mononuclear cell infiltration, lymphocyte and plasma cell enrichment, ≥4 IgG4 positive plasma cells per high-power field;
(2) pituitary MRI: lumps at the sella and/or thickening of the pituitary stalk;
(3) IgG4-positive plasma cells were found in biopsies of other affected organs;
(4) serum IgG4 concentration is greater than 140 mg / dl;
(5) After the hormone treatment, the pituitary mass rapidly shrinks and the symptoms are improved. When the criteria (1) or standards (2) and (3) are met or (2), (4), (5) are satisfied at the same time, the diagnosis can be made.
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