Hypophysitis Research Center

What is Autoimmune Hypophysitis?

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Definition +

Autoimmune hypophysitis is a chronic inflammation of the pituitary gland caused by autoimmunity. This disease is most commonly known in the literature as lymphocytic hypophysitis, although the term "lymphocytic" is imprecise. After the original description (see below), the disease was called, more precisely, "lymphocytic adenohypophysitis" because the lymphocytic infiltration was limited to the anterior hypophysis. It was then realized that the autoimmune attack could also and exclusively involve the infundibular stem and the posterior lobe, and so the term "lymphocytic infundibulo-neurohypophysitis" was created. Finally it was realized that the lymphocytic infiltration can affect both the adenoyhypophysis and the infunbibulo-neurohypophysis and so the term "lymphocytic infundibulo-hypophysitis" arose. We prefer the simpler term autoimmune hypophysitis, followed by the specific anatomic location when known (anterior, posterior or both).

Historical Notes
Autoimmune hypophysitis was first described in 1962 by Goudie and Pinkerton (from Glasgow, UK). They reported a 22 year old woman who died of adrenal insufficiency 14 months after the birth of her second child. Symptoms had begun approximately 3 months post-partum, with lassitude, goiter and amenorrhea. At autopsy the anterior pituitary was diffusely infiltrated by lymphocytes (the posterior lobe was normal), the thyroid showed Hashimoto's thyroiditis and the adrenal glands could not be found and thus presumed severely atrophic. We found, however, in the autopsy archives of the Johns Hopkins hospital, an earlier patient (1932) with the features of autoimmune hypophysitis.

Symptoms
The clinical presentation of Autoimmune Hypophysitis includes 4 categories of symptoms.

  1. The most common are symptoms derived from mass effect, such as headaches (47% of patients) and visual disturbances (33%).
  2. Then there are symptoms derived from the hypofunction of one or more of the adenohypophyseal hormones: the most frequent endocrine cells affected are the corticotropes (33%) and the thyreotropes (13%), followed by lactotropes (31%) and gondadotropes (26%).
  3. The third category includes the symptoms indicating an involvement of the neurohypophysis (polyuria and polydipsia), which were present in 27% of the patients.
  4. Last are the symptoms due to hyperprolactinemia (mainly amenorrhea/oligomenorrhea and galactorrhea), which were present in 23% of the patients.

These symptoms of AH are indistinguishable from those of any expanding mass located the sella turcica. It is true that some characteristics are unique to AH, such as the observation that the degree of hypopituitarism (partial or complete) is frequently disproportionate to the size of the accompanying pituitary mass, and that the loss of hormonal function in AH (ACTH first with or without TSH, gonadotropins frequently spared and GH almost always spared) is different that the loss observed in pituitary adenomas (GH function is lost first, then gonadotropins, and then ACTH and TSH). These characteristics, however, do not permit differentiation between autoimmune hypophysitis and other sellar lesions.


Epidemiology +

Autoimmune hypophysitis is rare, but part of the rarity is due to the fact that many physicians do not know about it and therefore do not diagnose it. Introduction of magnetic resonance imaging (MRI) in the mid 1980s has made physicians more aware of autoimmune hypophysitis, and now this disease should enter in the differential diagnosis of any mass occupying the sella turcica (see Figure 1).

There are at the moment no good epidemiologic data that can be used to derive the prevalence of autoimmune hypophysitis in the general population. We reviewed all the articles we could find on autoimmune hypophysitis, and identified a total of 332 patients, up to January 1 2003. Most of the patients are women (268 of 332 = 81%), as in many other autoimmune diseases (Figure 2).

Unique, however, to autoimmune hypophysitis is the striking association with pregnancy: in 43% of the women (115 of 268), the disease appears late in pregnancy or in the post-period. As shown in Figure 3 most commonly symptoms appear around the time of delivery.


Histopathology +

The defining histological feature of Autoimmune Hypophysitis is the infiltration of the pituitary with lymphocytes. As indicated in Figure 1, this infiltration can involve only the anterior lobe, only the infundibulum/posterior lobe, or both. The end result is a loss and/or partial loss of function of the endocrine cells forming the anterior pituitary. Lymphocytes aggregate to form true lymphoid follicles in 18% of the cases, often with germinal centers. This feature can be clearly seen in the cross cut of the pituitary from one of the first patients reported in the literature (by Egloff in 1969), see Figure 1. In addition to lymphocytes, however, other cells are present in the infiltrate, especially plasma cells and eosinophils (Table).

Focal areas of necrosis can be seen, albeit rare (3% of the cases). In even more rare instances, the necrosis is massive and involves the entire pituitary (1%). This necrotizing form, described thus far only in 3 patients, is considered by some authors separate from lymphocytic hypophysitis and by others as part of the pathological spectrum, depending on whether one is a "lumper" or a "splitter". Granulomas hypophysitis is distinct from lymphocytic hypophysitis. In some cases however, (3%) the two pathological features (lymphocytic and granulomatous) can occur together in a mix lymphocytic/granulomatous form. The histological spectrum of the disease would then go from a pure lymphocytic form at one end, to the lymphocytic/granulomatous form and finally to the lymphocytic/necrotizing form at the other end.

Other Cell Types seen in AHPatients
(% of total)
Plasma cells126 (54)
Lymphoid Follicles36 (15)
Eosinophils28 (12)
Neutrophils15 (6)
Macrophages16 (7)
HIstiocytes10 (4)
Edema8 (3)
Necrosis8 (3)
Granulomas8 (3)
Extensive necrosis (necrotizing form) 3 (1)

Typical Clinical Scenario +
  1. Autoimmune Hypophysitis affects young females most frequently
    In 81% of cases, Autoimmune Hypophysitis affects women. Several autoimmune processes prefer females as their favorite "target". This high prevalence probably correlates with genetic and environmental factors. Because autoimmune processes are more prevalent after puberty or near menopause, researchers think that estrogens may represent one of the multifactorial triggers in developing autoimmune disorders. This theory can also explain why, sometimes, estrogen treatment may worsen some autoimmune diseases (Systemic Lupus Erythematosus, SLE, for example). (learn more about autoimmunity)
  2. Females are affected especially in the early postpartum period
    Autoimmune Hypophysitis usually becomes clinically evident after a delivery, in the early postpartum period. The reason for this, is not completely known, but has been observed in other autoimmune diseases, such as in autoimmune thyroid diseases. The most accepted theory is based on immunological and hormonal bases. During pregnancy, the autoimmune system turns off some of the physiologic ways to discovering the exogenous enemies, because a tolerance of the fetus (half belongs to the mother, but half to the father) is needed. After delivery, the immune system turns its defenses back on. This can also produce an attack against the self, as an autoimmune reaction occurs. The role of the hormones in triggering autoimmune disease has been studied for a long time. The hormonal changes that happen during pregnancy and after delivery, may influence the autoimmune overreaction, but these putative sex differences need to be well established.
  3. Early symptoms are visual impairment and headache
    The autoimmune process produces the enlargement of the pituitary, because a lot of autoimmune cells, such as lymphocytes and others hematopoietic cells, migrate into the pituitary tissue. The gland situated just behind the optic chiasm, starts to press the optical structures. The result of this anatomical injury is a visual impairment: the patients reports that they cannot see things as well. Specifically, the peripheral part of the field of vision decreases, determining the clinical condition also named Bitemporal Hemianopsia. Hemianopsia derives from the old Greek: "hemi" means a half and "anopsy" means without vision; "bitemporally" refers to the fact that both halves near the temporal bones of the skull are deficient. For this reason ophthalmologists are sometimes the physicians which diagnose the disease first, because the patient reports impaired peripheral vision.

    Another frequent symptom is headache. This is probably caused by the compression that the inflamed and enlarged gland produces on the dura mater, the membrane covering the brain.
  4. Clinical history: Maria's case
    Maria is a 28 year old female. She married Paul two years ago, and became pregnant in September. During the pregnancy she had no problems. She delivered a beautiful son, Mike, in June. Some weeks after the delivery, she started not feeling well. She noted that sometimes she cannot watch TV well, and sometimes she bumps into doors. She also has a persistent headache, and does not sleep well at night; she thought she was so tired during the day because of this. She went to her physician and he suggested having blood tests done and referred her to an optician. The blood tests were normal, so Maria decided to go to her optician. She didn't find anything wrong inside the patient's eyes, but there was a severe visual impairment on the field of vision examination. The optician thought that Maria needs radiological study of the brain.
  5. Hypophysis examination by radiological assessment represents the most useful cost/benefit study for pituitary enlargement
    During the last 20 years Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) have been used to study both vascular and organic diseases of the brain. They are also routinely utilized in studying the pituitary; especially MRI which has a very high sensitivity and resolution factor. These radiological machines unlikely have a lower specificity. Sometimes pituitary tumors and inflammation (enlargement), as well as occurs in Autoimmune Hypophysitis, are not differentiable. In fact, both can appear as hyperdense images, after a contrast medium is injected. But they are useful in testing if a disease has involved the pituitary, or when visual impairment occurs.
  6. Usually tends to recover spontaneously, but sometimes a persistent, partial or total, pituitary defect can remain
    Autoimmune Hypophysitis differs from other autoimmune diseases. The visual impairment can represent the proof of the gland enlargement, without any sign of hormonal defect. But, especially when the field of vision contraction is the first symptom, a wrong diagnosis can be made, because of the radiological misunderstanding. Clinical history (recent pregnancy, sex, and a family history for autoimmune disease) can help in the correct handling of the patient.

    Sometimes the autoimmune process is so aggressive that most of the gland is injured. In this case a hormonal defect is present, because pituitary is no longer able to produce those hormones necessary to regulate the function of the peripheral endocrine gland. The most important and dangerous hormone deficiency is that which affects the adrenal glands. In fact, a rapid and severe develop in cortisol production, can cause cardiovascular failure (hypovolemic shock) and subsequently death. But also thyroid and gonadal functions could be affected, and respectively hypothyroidism or a precocious menopause (with infertility) can develop. When the clinic history suggests that one or more hormones are defective, a functional study of the gland is needed. The hormone defect can be transient or, unlikely, persistent. In the last case, a hormone replacement therapy is needed for the rest of the patient's life.