Best Practice & Research Clinical Endocrinology & Metabolism
Vol. 19, No. 1, pp. 67–84, 2005
available online at http://www.sciencedirect.com
Pituitary antibodies and lymphocytic
Annamaria De Bellis* MD
Chair of Endocrinology
Antonio Bizzarro PhD
Chair of Immunology and Allergology
Antonio Bellastella PhD
Chair of Endocrinology
Department of Clinical and Experimental Medicine and Surgery, ‘F. Magrassi, A. Lanzara’, Second University of Naples,
Via Pansini N. 5, Napoli 80131, Italy
Lymphocytic hypophysitis (LYH) is a pituitary disease which can cause headache, changes in
visual ﬁeld and pituitary dysfunction. The clinical, histopathological and morphological ﬁndings
and its association with other autoimmune disorders allow LYH to be included among the
autoimmune diseases. Pituitary trans-sphenoidal biopsy is thought to be the diagnostic gold
standard for LYH, even if some morphological ﬁndings on hypothalamic–pituitary magnetic
resonance imaging (MRI) can suggest the occurrence of this disease. Despite the fact that
organ-speciﬁc antibodies are good markers of many autoimmune endocrine diseases, the
pathogenetic and diagnostic roles of anti-pituitary antibodies (APAs) in LYH are still under
discussion. In fact, several methods have been used to detect APAs, but the conﬂicting
results from different methods have impaired the clinical relevance of these antibodies.
Recently, APAs have been detected by an immunoﬂuorescence method in patients with
selective idiopathic hypopituitarism (particularly in those with growth-hormone deﬁciency)
and in adults with autoimmune endocrine diseases. The results suggest that only when they
are present at high titres may they be considered a good marker of pituitary involvement,
and in particular of growth-hormone-producing cells.
Key words: lymphocytic hypophysitis; endocrine autoimmunity; anti-pituitary antibodies;
* Corresponding author. Tel.: C39 81 5666 634; Fax: C39 81 5666 628.
E-mail address: email@example.com (A. De Bellis).
1521-690X/$ - see front matter Q 2004 Published by Elsevier Ltd.
68 A. De Bellis et al
Lymphocytic hypophysitis (LYH) is thought to represent an autoimmune disease of the
pituitary gland1 which can impair pituitary hormonal secretion. Panhypopituitarism due
to lymphoplasmacytic pituitary inﬁltration was described by Rapp and Pashkis in 19532,
but they could not classify this disorder as autoimmune because the concept of
endocrine autoimmunity was introduced some years later for Hashimoto’s thyroiditis.3
An autoimmune pathogenesis for LYH was suggested for the ﬁrst time years later by
Gaudie and Pinkerton4, who described the occurrence of postpartum amenorrhoea
and hypothyroidism in a young woman who subsequently died from severe acute
secondary hyposurrenalism after appendicectomy. The autopsy revealed massive
lymphoplasmacytic inﬁltration of both the pituitary and thyroid glands and adrenal
atrophy. After this ﬁrst description several case reports appeared in the literature, but
these and the original series are generally of small size and have been accumulated over
a number of years.5,6 Over the last 13 years the number of diagnosed cases has
increased considerably, probably as a result of improved imaging criteria7,8, and over
200 cases have been described so far. Nevertheless, at the present time the LYH is still
considered uncommon, and its true incidence and prevalence are unknown.9
CRITERIA FOR ORGAN-SPECIFIC AUTOIMMUNITY IN LYMPHOCYTIC
For a long time, on the basis of the criteria for deﬁning a disease as autoimmune, some
endocrine diseases previously considered as idiopathic have been recognized as
autoimmune.10–17 LYH fulﬁls most of the criteria required to deﬁne a disease as organ-
speciﬁc autoimmune (Table 1).
Lymphocytic inﬁltration in the pituitary gland
In some endocrine diseases lymphocytic inﬁltration in the affected glands can be proven
relatively easily due to the simple approach to the gland. This is certainly true in the case
of autoimmune thyroid diseases but is much more difﬁcult in many other autoimmune
diseases, as in type 1 diabetes mellitus or Addison’s disease, whose autoimmune
Table 1. Criteria for organ-speciﬁc autoimmunity in lymphocytic hypophysitis (LYH).
Criterion Presence in LYH
Lymphocytic inﬁltration of the target organ Yes
Characteristic imaging suggestive of lymphocytic inﬁltration Yes
of the target organ
Presence of humoral or cellular autoimmune response in animals Yes
sensitized with autologous antigens
Organ-speciﬁc lesions in self-sensitized animals Yes
Circulating autoantibodies against the target organ Yes
Identiﬁcation of the speciﬁc antigens Discussed
Close association with other autoimmune diseases and Yes
or presence of other antibodies
Cycles of remission and relapses Yes
Good response to immunosuppressive therapy Yes
Pituitary antibodies and lymphocytic hypophysitis 69
diagnosis can be achieved by searching for the respective organ-speciﬁc autoanti-
bodies.18,19 As regards LYH, histopathological observations, initially derived from
autoptical20,21 or postsurgical pituitary examination, are more recently obtained by
trans-sphenoidal pituitary biopsy, which until now was thought to be the diagnostic gold
standard for LYH.10 The pathological ﬁndings are characterized by an inﬂammatory
process with diffuse pituitary inﬁltration of lymphocytes, plasma cells and macrophagic
cells. Lymphocyte aggregates, usually surrounding focal or diffuse areas of atrophic
pituitary cells, are sometimes arranged in lymphoid follicles with a germinal centre.22
Unlike studies in the other autoimmune endocrine diseases, the expression of major
histocompatibility complex (MHC) class II antigen on the pituitary cells from patients
with LYH has not been identiﬁed.21
Morphological ﬁndings on MRI
In some autoimmune endocrine diseases, such as chronic thyroiditis and central
diabetes insipidus, a thyroid diffuse lymphocyte inﬁltration and a lymphocytic-
infundibuloneurohypophysitis can be suggested by the presence of thyroid diffuse
hypoechogenic pattern on ultrasound and of pituitary stalk thickening on MRI,
As regards LYH, the presence of marked lymphocyte inﬁltration of the pituitary
gland could be suggested by some particular morphological ﬁndings on MRI. In patients
with LYH showing symptoms or signs related to pituitary enlargement, MRI evaluation
is particularly important to differentiate LYH from adenoma in the sellar region, even if
sometimes ﬁndings from imaging tend to overlap. On MRI, patients with LYH usually
show a pituitary enlargement with symmetrical sovrasellar extension which can
displace the optic chiasma, whereas patients with adenoma show asymmetrical
pituitary enlargement with deviation of the stalk, which is instead thickened but usually
not deviated in LYH. The pituitary enhancement after injection of gadolinium is
homogeneously intense in LYH and shows a strip of enhanced tissue along the dura
madre (also called ‘dural tail’). Patients with adenomas instead show delayed and poor
enhancement, usually without a dural tail after gadolinium (Table 2).22–25
Animal models of lymphocytic hypophysitis
Evidence of reproduction of the disease in experimental animals is considered another
of the major criteria for deﬁning a disease as autoimmune. Experimental subcutaneous
injection of human anterior pituitary gland homogenates in Freund’s adjuvant into rats
and rabbits produces a disease histopathologically similar to LYH.26,27 On the other
hand, although the induction of LYH in hamsters is associated with the development of
anti-pituitary antibodies, the passive transfer of these antibodies does not propagate
Table 2. Morphological ﬁndings suggestive of lymphocytic hypophysitis on MRI.
Pituitary enlargement with symmetrical sovrasellar expansion with possible
compression and displacement of chiasma
Stalk thickened but not deviated
Intense and homogeneous enhancement of pituitary mass (after gadolinium)
Appearance of ‘dural tail’ (after gadolinium)
70 A. De Bellis et al
the disease.28 Recently, it has been shown in transgenic mice that the pituitary gland is
susceptible to CD8 T-cell-mediated autoimmunity, triggered by viral infection (inﬂuenza
virus); subsequently pan-anterior hypophysitis and dwarﬁsm have been observed.29
Pituitary antigens and anti-pituitary antibodies
Considerable progress has been made in understanding the autoimmune diseases over
the last 20 years, particularly with regard to cloning of the antigens involved in the
disease and the evolution of the laboratory assays for detection of organ-speciﬁc
autoantibodies.30 Some autoantigens involved in LYH have been identiﬁed, and anti-
pituitary antibodies (APAs) have been detected in patients with LYH, suggesting an
autoimmune involvement in this disease (see below).
Association with other autoimmune diseases and presence of other
The frequent association with other autoimmune diseases and the possible presence of
other organ-speciﬁc autoantibodies in patients with LYH is a further argument
supporting an autoimmune involvement in this disease.9 This is also backed up by the
good response to immunosuppressive therapy and the occurrence of cycles of remission
and relapse frequently observed during the natural history of the disease, by analogy with
other autoimmune diseases.31–33 In fact, LYH is frequently associated with other
endocrine and non-endocrine autoimmune diseases (Table 3). The most common
association is with Hashimoto’s thyroiditis or Graves’ diseases.34 Moreover, an
association with central diabetes insipidus, type 1 diabetes mellitus, Addison’s disease,
hypoparathyroidism, chronic atrophic gastritis, and pernicious anaemia has been
described.35–37 Less frequently LYH can be associated with systemic lupus erythema-
tosus, autoimmune hepatitis and primary biliary cirrosis.38–40 Autoimmune diseases are
characterized not only by their frequent association with other autoimmune diseases,
but also by the presence of organ-/non-organ-speciﬁc autoantibodies with normal
functional state or subclinical impairment of the respective glands. In patients with LYH
Table 3. Autoimmune diseases associated with
Chronic autoimmune thyroiditis
Central diabetes insipidus
Type 1 diabetes mellitus
Chronic atrophic gastritis
Systemic lupus erythematosus
Primary biliary cirrhosis
Pituitary antibodies and lymphocytic hypophysitis 71
Table 4. Organ-speciﬁc antibodies in lymphocytic hypophysitis.
Thyroperoxidase antibodies (TPOAbs)
Thyroglobulin antibodies (TgAbs)
Vasopressin-cell antibodies (AVPcAbs)
Islet-cell antibodies (ICAs)
Glutamic acid decarboxylase antibodies (GADAbs)
Adrenocortical antibodies (ACAs)
21-Hydroxylase antibodies (21-OHAbs)
Parietal-cell antibodies (PCAs)
Tissue transglutaminase antibodies (TTGAs)
some organ-speciﬁc antibodies can also be detected (Table 4). The coexistence in
the same patient of two or more organ-speciﬁc and/or non-organ-speciﬁc
autoimmune diseases indicates an autoimmune polyendocrine syndrome (APS). Taking
into account this assumption, all patients with LYH associated with other autoimmune
diseases can be considered as having an APS. In particular, when LYH is associated with
hypoparathyroidism, mucocutaneous candidiasis and Addison’s disease, it could be
included among the minor autoimmune diseases of APS type 1.35 Few cases of LYH
could fall within the type 2 complete APS when it is associated with Addison’s disease,
autoimmune thyroid diseases and/or type 1 diabetes mellitus.15 Moreover, LYH may be
included in incomplete APS type 2, as in some of our cases with chronic autoimmune
thyroiditis and presence of ACA, 21-OHAb and ICA.41 Most cases of LYH show
characteristics of complete APS type 3 (autoimmune thyroid disease with or without
other autoimmune diseases, but not Addison’s disease and hypoparathyroidism).40,41
Instead, when LYH does not fall within the above-mentioned combination, it can be
included in type 4 APS (Figure 1). Concerning this, LYH may also be associated with
autoimmune central diabetes insipidus.41,42
Organ-speciﬁc antibodies are good markers of many autoimmune endocrine diseases.
Until now, APAs have not been considered good markers of LYH because of various
difﬁculties in methodology and clinical interpretation. In fact, conﬂicting results in
detecting APAs using different methods has impaired the clinical relevance of these
antibodies. Moreover, a longitudinal study demonstrated that these antibodies can
disappear over time43; for this reason the time of detection could inﬂuence their
The complement consumption test
This was the ﬁrst method used to detect APAs, testing plasma samples against human
pituitary homogenate. Some women, tested in the ﬁrst week after delivery, were
positive for APAs and proceeded towards pituitary insufﬁciency.44 This method has not
been used further by other researchers.
72 A. De Bellis et al
Incomplete/complete APS type 2
APS type 1
Hypoparathyroidism Addison’s disease and/or ACA, 21-OHAb
Mucocutaneous candidiasis Chronic autoimmune thyroiditis and/or TPOAb, TgAb
Addison’ s disease Grave’s disease
Type 1 diabetes mellitus and/or ICA, GADAb
Incomplete/complete APS type 3 Incomplete/complete APS type 4
Autoimmune thyroid diseases and/or TPOAb, TgAb Central diabetes insipidus and/or AVPcAb
Type 1 diabetes mellitus and/or ICA, GADAb Type 1 diabetes mellitus and/or ICA, GADAb
Central diabetes insipidus and/or AVPcAb Pernicious anemia
Chronic atrophic gastritis Primary biliary cirrosis
ASutoimmune hepatitis Systemic lupus erythematosus
Figure 1. Lymphocytic hypophysitis in autoimmune polyendocrine syndromes (APSs).
Pituitary antibodies and lymphocytic hypophysitis 73
The immunoﬂuorescence method
The immunoﬂuorescence method is one of the most widely used techniques for
detecting APAs.45 An important issue that may contribute to the clariﬁcation of
conﬂicting ﬁndings is the difference in the pituitary sections used in screening for
APAs. Some studies have been performed on tissues from a variety of species and
under a variety of conditions.46,47 A comparative study using porcine, rat, bovine,
sheep, adult baboon, foetal cynomolgus and foetal human pituitary tissues showed that
only human foetal pituitary should be used as substrate for APA evaluation in order to
produce speciﬁc and reliable results.48 Other organ-speciﬁc antibodies are, in the
majority of cases, only IgGs. Instead APAs include not only IgGs but also IgAs and
more rarely IgMs; moreover, half of the IgGs are complement-ﬁxing.47 Bottazzo et al
characterized for the ﬁrst time the hormone-secreting pituitary cells immunostained
by APAs using a four-layer double-ﬂuorochrome immunoﬂuorescence.49 By analogy
with other organ-speciﬁc autoantibodies (adrenocortical and steroid-cell antibodies,
vasopressin-cell antibodies), APAs also react with cytoplasmic antigens (still unknown
in this last case) distinct from pituitary hormones.49 These authors detected APAs at
low titres in sera of some patients with APS or with isolated autoimmune endocrine
diseases, providing evidence that APAs recognize exclusively PRL-secreting cells.50,51
Moreover, none of the patients positive for PRL-cell antibodies showed an impairment
of the pituitary function. Subsequently, APAs selectively staining growth hormone
(GH) pituitary cells were demonstrated in a girl with Turner’s syndrome and partial
GH deﬁciency (GHD)52 and in a patient with idiopathic GHD.46 APAs selectively
immunostaining TSH-, LH-, FSH- and ACTH-secreting cells were detected in isolated
cases of idiopathic TSH, LH, FSH and ACTH deﬁciency.46,53,54 A further problem with
immunoﬂuorescence was that APAs were demonstrated not only in some patients
with biopsy-proven LYH55,56 or in patients with suspected LYH (patients with
idiopathic hypopituitarism—isolated or associated with autoimmune endocrine
diseases, patients with Sheehan’s syndrome or with empty sella syndrome) but also
in patients with non-autoimmune pituitary diseases, such as ACTH-secreting adenoma
or other pituitary adenomas.57–59
The immunoblotting method
An alternative approach to APA detection was the immunoblotting method.60 This
method utilized a homogenate of human autopsy pituitary tissue as substrate. The
immunoblotting has been developed to identify the antigen target of APA. This method
is capable of detecting multiple autoantigens at once61; however, in spite of its quality, it
is very difﬁcult to standardize. Crock showed that serum antibodies against a 49 kDa
pituitary cytosolic protein were present in 70% of patients with biopsy-proven LYH and
in 55% of patients with suspected LYH, including patients with isolated ACTH
deﬁciency, patients with hypopituitarism associated to other autoimmune diseases or
females with Sheehan’s syndrome.62 However, APAs reactive to this protein were also
found in many patients with other autoimmune endocrine diseases without LYH and in
20% of patients with hypopituitarism secondary to pituitary adenomas. Recently, the
49 kDa pituitary cytoplasmatic protein has been identiﬁed as an a-enolase, an enzyme
ubiquitously expressed.63 Antibodies to a-enolase are not speciﬁc for LYH because
they are frequently present in other autoimmune diseases. However, the authors
74 A. De Bellis et al
suggested that these antibodies may be helpful in the diagnosis of patients with LYH
who would otherwise need pituitary biopsy.
The radioligand assay
Recently, APAs have been detected by radioligand assay.64 This method involves
producing 35S-labelled pituitary-speciﬁc proteins by in vitro transcription/translation
and then using these proteins in the immunoprecipitation assay. In particular Tanaka
et al64, using this method, demonstrated the presence of antibodies against GH and
against pituitary-speciﬁc proteins called PGSF1 and PGSF2, respectively, in some
patients with proven LYH and in some patients with idiopathic hypopituitarism, but
not in patients with pituitary adenomas. Also antibodies to a-enolase were found by
radioligand assay, conﬁrming the results by immunoblotting assay in 41.2% of
patients with LYH and in 23.5% of patients with idiopathic hypopituitarism.65
However, in contrast to the results obtained by immunoblotting, antibodies to
a-enolase were found in 46% of patients with non-functioning adenomas, showing a
similar frequency of these antibodies with respect to patients with LYH.65 Thus, the
authors suggested that detection of a-enolase antibodies is not suitable for the
speciﬁc diagnosis of LYH. The discrepancy between the results obtained by
radioligand and immunoblotting assays in patients with pituitary adenoma may be
explained by the different analytical methods. An important problem in these assays
is that neither method is capable of showing what hormone-secreting cells APAs
are immunostaining. Moreover, it seems impossible to show by immunoblotting
some hypothetical antigens present in vivo because of their disappearance during
Re-evaluation of APA detection by immunoﬂuorescence
On the basis of these discrepancies between immunoblotting and radioligand
methods, we recently performed a re-evaluation of APAs by indirect immuno-
ﬂuorescence using cryostat sections of young baboon pituitary glands (due to legal
difﬁculties in obtaining human foetal pituitary tissue).40 APAs were evaluated in
adults with idiopathic GHD, in adults with pituitary adenoma and in patients with
autoimmune endocrine diseases. APAs were found at high titres in 33% of patients
with idiopathic GHD but in no patients with acquired GHD. APAs were also
detected at low titres in six of 20 patients (30%) with pituitary adenomas and in 40
of 180 patients (22.2%) with autoimmune endocrine diseases, 35 of them at low
titres (87.5%) and ﬁve at high titres (12.5%). APA-positive patients at low titres had
normal pituitary function, whereas all APA-positive patients at high titres had a
severe isolated GHD. On the basis of these results, we suggested that a simple
immunoﬂuorescence method, using pituitary of young baboon as substrate, is a
good approach for the detection of APAs.40 In particular, only when present at high
titres may APAs be considered a good marker of pituitary involvement, not only in
patients with apparently isolated idiopathic GHD but also in adults with
autoimmune endocrine diseases with selective GHD. By subsequent retesting of
the APA-positive sera of the previously studied patients, using a four-layer double-
indirect immunoﬂuorescence technique, we were able to demonstrate that the
targets of APAs in patients with GHD are the somatrophs (De Bellis et al,
Pituitary antibodies and lymphocytic hypophysitis 75
Autoimmune mechanisms characterizing other organ-speciﬁc autoimmune diseases are
well known because of the ability to study animal models and the availability of target
organ tissues from patients in the subclinical stage or at the clinical onset of the disease.
At present, the mechanisms triggering the development and progression of LYH are not
known, although the presence of animal models of LYH may open the way to
understanding these events.26–28 The role of CD8 T cells in autoimmune disease is
gradually becoming better understood. In transgenic murine models it has been shown
that CD8 T cells can mediate autoimmune encephalomyelitis, diabetes mellitus and,
recently, LYH.66–68 Indeed, endocrine organs, having a specialized vasculature into
which large quantities of secreted proteins are released, may be particularly susceptible
to autoimmune aggression with consequent endocrine deﬁciency.29 In the pituitary of
patients with LYH, mast cells are randomly distributed and also localized in the vicinity
of capillaries. This could favour capillary permeability and angiogenesis, inﬂuencing the
inﬂammatory and immunological aggression to pituitary cells.69 As previously
reported29, de Jersey et al showed that transgenic murine pituitary gland is susceptible
to CD8 T-cell-mediated pathology after infection with an inﬂuenzavirus nucleoprotein,
A/NT/60/68 (NP). In particular, on day 7 after infection, NP-speciﬁc T cells were
detectable in the peripheral lymph nodes and spleen. However, 3–5 months after
immunization, viral NP is expressed on the pituitary somatotrophs followed by
migration to pituitary gland of NP-speciﬁc T cells. Despite the presence of activated
IFN-g-producing CD8 T cells in the pituitary gland, LYH is absent. When the frequency
of speciﬁc T cells was artiﬁcially raised, LYH—characterized by severe GH deﬁciency
and then multiple pituitary hormone deﬁciencies and dwarﬁsm—occurred.29,68 Major
obstacles in understanding autoimmune pituitary mechanisms are the difﬁculties in
obtaining pituitary tissue specimens with inﬁltrating lymphocytes and macrophagic cells
from patients with LYH and a normal hypothalamic–pituitary region on MRI. However,
histological studies of biopsy specimens of the pituitary glands from patients with LYH
and an enlarged pituitary mass on MRI reveal inﬂammatory inﬁltrates occurring in the
thyroid of patients with autoimmune chronic thyroiditis or Graves’ disease in active
phases. In fact, these inﬁltrates are characterized above all by T lymphocytes (CD8 and
CD4 cells) and B cells.70 Moreover, it is possible that in LYH the damage resulting from
inﬁltrating cytotoxic T cells could be the possible cause of the pituitary impairment,
even if inﬁltrating B lymphocytes are able to produce speciﬁc APAs. As a consequence
of lymphocytic inﬁltration, APAs become detectable in the sera and they could be
considered markers of T-cell-mediated aggression to the pituitary gland in patients with
silent LYH on MRI.
DIFFERENT EXPRESSIONS OF LYH DURING THE NATURAL HISTORY
OF THE DISEASE
Some patients may present with symptoms and signs related to pituitary enlargement
with possible extrasellar extension but without pituitary dysfunction, while others
with normal characteristics on MRI may present with varying degrees of pituitary
failure.25,65,71 Moreover, many patients with LYH can show high levels of PRL, while
others may have normal or even low levels of PRL (women with failure to lactate in the
postpartum period).1,6 The natural history of LYH is very variable, often showing during
76 A. De Bellis et al
its course an endless series of reversible changes in its morphological, clinical
and immunological characteristics that contribute to misdiagnosis of the disease; as a
result its prevalence is underestimated.9
During the natural course of the disease spontaneous partial or total pituitary
function recovery and/or mass resolution can occur.72 APAs, usually present at high
titre initially, can subsequently disappear.73 Transient hypopituitarism can be explained
by compression of pituitary cells by the inﬂammatory inﬁltrate and/or oedema.1,9
Instead, when cell destruction occurs, as observed in 10–15% of cases, an evolution
towards irreversible hypopituitarism can be observed.21 Finally, in some other cases the
natural course of LYH is characterized by cycles of remissions and relapses. In this
connection, since LYH most commonly occurs in women in late pregnancy or in the
postpartum period, many patients with a previous diagnosis of Sheehan’s syndrome
could actually be considered as having LYH.74
DIAGNOSIS OF LYH: ROLE OF ANTI-PITUITARY ANTIBODIES
LYH has to be suspected in patients presenting with hyperprolactinaemia, headache,
and impairment of visual ﬁeld—especially if they are pregnant women or women with
recent delivery and have symptoms of hypopituitarism of unclear aetiology. In these
patients a trans-sphenoidal pituitary biopsy is thought to be the diagnostic gold
standard for LYH.9 However, this procedure is invasive and not always feasible.
Moreover, despite the recent development of sophisticated techniques of imaging, the
diagnosis of LYH on MRI remains problematic because morphological ﬁndings of LYH
on MRI can frequently overlap with those of pituitary adenoma.75 For this reason
detection of APAs could be helpful for the diagnosis of LYH. In patients with pituitary
enlargement the presence of APAs at high levels is suggestive for LYH; the presence at
low titres or the absence of APAs can be suggestive of pituitary adenoma.41
These autoantibodies can be used in diagnostic ﬂow-charts in routine clinical
practice to disclose some forms of LYH which are usually misdiagnosed. In particular, in
patients with idiopathic selective hypopituitarism with normal hypothalamic–pituitary
characteristics on MRI, detection of APAs is very suggestive for the diagnosis of LYH. As
depicted in Figure 2, the presence of APAs at high titres in these patients allows
unambiguous diagnosis of active LYH, whereas the detection of APAs at low levels could
suggest the diagnosis of possible LYH of long duration. The absence of detectable APAs
cannot exclude the possibility of an autoimmune origin for the disease, because
autoantibodies could have been present in the past but may have disappeared by the
time of the analysis.
Frequently, in patients with an autoimmune disease the presence of other
autoantibodies but with normal function of the target gland could be possible.76–79
Betterle et al suggested that these patients could be considered as having a particular
incomplete potential APS.15 For this reason, in patients with LYH, serological screening
of other organ-speciﬁc or non-organ-speciﬁc antibodies could be performed (Figure 2).
Moreover, APA screening in patients with organ-speciﬁc and non-organ-speciﬁc
autoimmune diseases can be used for the discrimination of patients with an ongoing
pituitary autoimmune process (Figure 3). Interestingly, the correct diagnosis of LYH
depends in our experience on autoantibody titres. The presence of APAs at high titres
allows the revelation of an LYH characterized by selective hypopituitarism with or
Pituitary antibodies and lymphocytic hypophysitis 77
AUTOIMMUNE ENDOCRINE DISEASES
High Titres Low Titres
Absence of LYH
Pituitary function Pituitary function
Hypothalamic pituitary region on MRI
Findings suggestive of LYH Normal
Sicure LYH Sicure LYH
Figure 2. Diagnostic ﬂowchart of LYH in patients with autoimmune endocrine diseases.
without pituitary enlargement on MRI. When APAs are present at low levels and
pituitary function is normal, the presence of LYH could be excluded.
Before the start of therapeutic strategies of LYH, two important considerations may be
made: ﬁrst, the different expressions of this autoimmune disease require different
therapeutic strategies; and second, since a possible spontaneous remission during the
natural history of LYH can be observed, the improvement occurring after surgical or
medical treatment could be related to spontaneous resolution rather than to the
treatment itself. For this reason a careful follow-up is advisable in patients without
symptomatic extrasellar expansion or important hyposurrenalism.9 In fact, because
most deaths in patients with LYH have been attributed to untreated adrenal
insufﬁciency, glucocorticoid replacement using stress doses is essential in the acute
setting.21 Surgical trans-sphenoidal treatment, with intrasurgical cryostatic slide to
conﬁrm diagnosis and to save possible viable pituitary tissue, is required in patients with
symptoms and/or signs of severe compression.61 In some cases pituitary biopsy is both
diagnostic and therapeutic, because after this procedure a progressive recovery of
pituitary function can be observed.8
78 A. De Bellis et al
Idiopathic hypopituitarism with normal findings
High Titres Possibile LYH of
Idiopathic long duration
Sicure LYH Probable LYH of
Evaluation of others antibodies
Incomplete APS Isolated LYH
Figure 3. Diagnostic ﬂowchart of LYH in patients with idiopathic selective hypopytuitarism.
Glucocorticoids or other anti-inﬂammatory and immunosuppressive drugs
(methotrexate, cyclosporin-A and azathioprine) have been suggested as medical
treatment, but their long-term efﬁcacy still needs to be conﬁrmed.9 In some
patients—in whom morphological pituitary characteristics of LYH on MRI overlap
with ﬁndings of pituitary adenoma but APAs are present at high levels—high-dose
methylprednisolone pulse therapy seems to be useful for both diagnostic and
therapeutic procedures. In fact, in patients with LYH, but not in those with adenoma,
pituitary mass reduction and a decrease in APAs could be observed after two cycles
of this therapy.80
Therapy involves pituitary hormone replacement when LYH appears with
hypopituitarism; because some or all pituitary deﬁciency may resolve, patients initially
begun on treatment should be tested later to avoid unnecessary treatment.21 In fact,
this resolution of the pituitary impairment after short-term pituitary hormone
replacement can be attributed to a spontaneous resolution of the autoimmune process.
However, pituitary hormone replacement could also act as an ‘isohormonal therapy’ in
determining the restoration to the normal state of pituitary function in LYH. In
particular, as demonstrated in other autoimmune diseases76,78,79 as well as in LYH,
when the pituitary gland is not completely irreversibly destroyed, a feedback inhibition
of pituitary gland function may decrease the exposure of putative pituitary autoantigens
to further immune attack.
Pituitary antibodies and lymphocytic hypophysitis 79
† lymphocytic hypophysitis is thought a rare autoimmune disease but its true
prevalence is probably underestimated
† an endless series of reversible changes in morphological, clinical and
immunological characteristics shared with other diseases during the very
variable natural history of lymphocytic hypophysitis could contribute to
misdiagnosis of this disease
† a more accurate evaluation of the criteria required to deﬁne a disease as
autoimmune could determine an increase in the incidence and prevalence of
† in patients showing symptoms or signs related to pituitary enlargement,
histopathological characteristics are the gold standard for the diagnosis of
† lymphocytic hypophysitis is frequently associated with other autoimmune
endocrine and non-endocrine diseases; the most common association is with
Hashimoto’s thyroiditis or Graves’ disease
† many cases of lymphocytic hypophysitis could be included in complete type 3
autoimmune polyendocrine syndrome (autoimmune thyroid diseases without
† anti-pituitary antibodies have been detected in several patients with
lymphocytic hypophysitis, but their role as a diagnostic marker needs to be
† recently, a re-evaluation of APA detection has been performed in patients with
† APAs could be useful in clinical practice for diagnosis of particular forms of
lymphocytic hypophysitis in which morphological characteristics on MRI are
normal or inconclusive
† the pathogenesis of lymphocytic hypophysitis remains elusive at present, even
though transgenic animal models suggest that CD8 T cells could mediate this
† mouse pituitary gland is susceptible to CD8 T-cell-mediated pathology after
infection with an inﬂuenza virus nucleoprotein A-NT/60/68(NP)
† at the present time the role of anti-pituitary antibodies in lymphocytic
hypophysitis is not clear because of conﬂicting results between different assay
methods (immunoﬂuorescence, immunoblotting, radioligand) for detecting
† detection of anti-pituitary antibodies by immunoﬂuorescence is problematic
because studies have been performed on tissues from a variety of species and
under a variety of conditions
† individual pituitary antigens have not been demonstrated by
80 A. De Bellis et al
† some studies of immunoblotting assay have focused on identifying the antigen
targets of anti-pituitary antibodies
† immunoblotting assay demonstrated anti-pituitary antibodies to a 49-kDa
pituitary cytosolic protein in many patients with lymphocytic hypophysitis
compared to the same patients with pituitary adenoma or with autoimmune
† a 49-kDa autoantigen, subsequently identiﬁed as a-enolase, is not pituitary-
speciﬁc but has a ubiquitous tissue distribution
† radioligand assay seems to be able to detect antibodies against three pituitary-
speciﬁc proteins (GH and two novel pituitary-speciﬁc proteins, namely
pituitary gland speciﬁc factors 1a and 2a) in some patients with lymphocytic
hypophysitis but not in patients with pituitary adenoma; this method detected
antibodies against a-enolase in 41.2% of patients with lymphocytic hypophysitis
and in 46% of patients with pituitary non-functional adenoma
† recently, anti-pituitary antibodies have been retested by an immunoﬂuores-
cence method in patients with selective hypopituitarism (apparently idiopathic
GH deﬁciency) and in adults with autoimmune endocrine disease; their
prevalence suggests that only when they are present at high titres may they be
considered a good marker of pituitary involvement, not only in patients with
apparently isolated idiopathic GH deﬁciency but also in adults with
autoimmune endocrine diseases with selective GHD
LYH fulﬁls most of the criteria required to deﬁne a condition as an organ-speciﬁc
autoimmune disease. It has a special place among the spectrum of autoimmune
diseases, particularly because of the different forms it takes during its natural history.
The presence of clear morphological pituitary characteristics of LYH on MRI,
followed by trans-sphenoidal pituitary biopsy, is the diagnostic gold standard for LYH
in patients with hypopituitarism and symptoms and signs of an expanding pituitary
mass. Despite the recent development of sophisticated diagnostic imaging, the
diagnosis of LYH on MRI remains problematic. In particular, in these patients
morphological ﬁndings of LYH on MRI can frequently overlap with ﬁndings of
APAs have been detected in patients with LYH, suggesting an autoimmune
involvement in this disease. Currently, APAs are still not considered good markers of
LYH because of various difﬁculties in methodology and clinical interpretation. In fact,
conﬂicting result in detecting APAs using different methods (immunoﬂuorescence,
immunoblotting, radioligand) has impaired the clinical relevance of these antibodies.
Recently, detection of APAs by immunoﬂuorescence has been re-evaluated, leading
to the suggestion that they are legitimate organ-speciﬁc antibodies. In particular,
APAs at high titres are useful for the diagnosis of LYH of recent onset in patients
with apparently idiopathic selective hypopituitarism. Moreover, APAs screening has
also been performed in patients with organ-speciﬁc autoimmune diseases for the
discrimination of patients with an ongoing pituitary autoimmune process. It emerges
that the detection of APAs is very helpful for a clear diagnosis of different forms of
Pituitary antibodies and lymphocytic hypophysitis 81
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