we performed the pituitary gland biopsy and histochemical examination glucocorticoid therapy in a subject with igg4-related hypophysitis .
this case report provides the possibility that igg4 level is decreased spontaneously or with a physiological dose of glucocorticoid therapy .
we reported the clinical course of igg4-related hypophysitis without a high - dose glucocorticoid treatment , although there were a few reports about the retrospective examination .
although the patient had still higher igg4 level compared to normal range , his clinical symptom disappeared and his laboratory data were improved .
we should keep in mind the possibility of igg4-related hypophysitis when we examine one of the uncertain causes of a hypopituitarism including adrenal insufficiency , hypogonadism and hypothyroidism .
igg4-related disease is a multi- or single - organ disorder accompanied by the increase of serum igg4 level ( 1 ) .
recently , clinical characteristics of igg4-related hypophysitis have emerged as a part of systemic igg4-related disease ( 2 ) . to diagnose igg4-related disease
, histopathology is the key , and one of the major features of this disease is a dense lymphoplasmacytic infiltrate rich in igg4-positive plasma cells .
the recent reports showed that igg4-related hypophysitis might be detected in 30% of hypophysitis cases and 4% of all hypopituitarism and/or diabetes insipidus ( di ) cases ( 3 ) .
however , the pathogenesis of igg4-related hypophysitis remains unclear due to the limited number of case reports because of certain limitations in this technique .
generally , it has been thought that a high - dose glucocorticoid treatment is effective for igg4-related diseases , and thus , many clinicians have started the therapy with prednisolone in a dose of 0.61.0  mg / kg daily .
after 24 weeks , the dose is tapered by 5  mg every 12 weeks according to clinical responses ( 4 ) .
a 76-year - old man was hospitalized due to persistent general fatigue and appetite loss since approximately 2 months before . on admission ,
his vital signs were normal ( temperature : 36.6c ; blood pressure was 98/50  mmhg and heart rate was 62  beats / min ) .
he had eosinophilia ( 1098/l , 19.1% ) and hyponatremia ( na : 129  meq / l ( reference range : 137146  meq / l ) ) , and his fasting plasma glucose level was 69  mg / dl .
laboratory analyses showed this patient had a hypopituitarism including adrenal insufficiency ( acth : 13.2  pg / ml ( 7.263.3  pg / ml ) , cortisol : 1.2  g / dl ( 4.521.1  g / dl ) ) , hypogonadism ( lh < 0.10  iu / ml ( 0.795.72  iu / ml ) , fsh : 2.13  iu / ml ( 2.008.30  iu / ml ) , testosterone 0.03  ng / ml ( 1.318.71  ng / ml ) ) , hypothyroidism ( tsh : 0.036  iu / ml ( 0.4006.000  iu / ml ) , ft4 : 0.56  ng / ml ( 0.801.60  ng / dl ) ) and elevated prolactin level ( prl : 19.3  ng / ml ( 3.612.8  ng / ml ) ) .
the posterior pituitary hormone antidiuretic hormone ( adh ) level ( 1.0  pg / ml ( 0.04.2  pg / ml ) ) , the passage of volumes ( 1900  ml/24  h ) , the urine osmolality ( 264  mosmol / kg ) and the serum osmolality ( 291  mosmol / kg ) were within normal range , and he did not have diabetes insipidus .
cortisol response to crh was also not preserved in this subject although acth response to crh was observed ( fig .
in addition , in ghrp-2 test , gh response was also poor in this subject ( peak gh level : 4.55  ng / ml ) .
serum igg and igg4 levels were markedly elevated : 2800  mg / dl ( 10001800  mg / dl ) and 1030  mg / dl ( 4.8105.0  mg / dl ) respectively . furthermore , pituitary - enhanced magnetic resonance imaging ( mri ) showed swelling of the stalk and anterior lobe of his pituitary ( fig .
next , we performed a biopsy from the pituitary gland via the sphenoid sinus 2 weeks after admission .
immunohistochemical staining of the two part specimens of anterior gland revealed abundant igg4-positive plasma cell infiltration ( fig .
3a and b ) , although we failed to evaluate the specimens of dura mater due to tissue degradation during the process of sample collection . based on such findings
any other organ was not involved in igg4-related disease including autoimmune pancreatitis , mikulicz s disease and there was not any other autoimmune disease ( ana < 5.0 (  ) , rheumatoid factor < 15  iu / ml , anti - tpo antibodies 9.9  iu / ml , anti - thyroglobulin antibodies < 10.0  iu / ml , ss - a / ro antibodies < 1.0  u / ml , ss - b / la antibodies < 1.0  u / ml and serum pituitary cell antibody negative ) . 

( a ) swelling of the stalk and anterior lobe of patient pituitary on admission .
( a ) the hematoxylin and eosin staining of the pituitary gland ( magnification 20 ) .
there was about 30% of igg4-positive plasma cells , which were accounted for igg - positive cells . 
 
( a ) responses of trh to i.v . injection of trh ( 500  g ) .
injection of crh ( 100  g ) . enhanced magnetic resonance imaging ( mri ) with t1-weighted image .
( a ) swelling of the stalk and anterior lobe of patient pituitary on admission . ( b ) the improvement of such swelling of them 3 months later .
( a ) the hematoxylin and eosin staining of the pituitary gland ( magnification 20 ) .
there was about 30% of igg4-positive plasma cells , which were accounted for igg - positive cells . in general , clinical manifestations of igg4-related disease
therefore , glucocorticoid dose is usually tapered after a few days according to clinical response in each patient . to the best of our knowledge ,
however , no randomized treatment trials have been done yet , although there were a few reports about the retrospective examination .
therefore , we do not have enough information about the best therapy for igg4-related hypophysitis as well as the clinical course of pituitary function and image in igg4-related hypophysitis . in this case , his clinical symptoms ( general fatigue and appetite loss )
were markedly reduced , and some laboratory data were normalized as follows : fasting plasma glucose , 91  mg / dl and na , 138  meq / l .
therefore , although this subject showed hypopituitarism including adrenal insufficiency , it seemed that the symptoms were markedly reduced before starting steroid therapy .
these data suggest the possibility that the symptoms of igg4-related hypophysitis are spontaneously reduced without steroid therapy . in consideration of such improvement
, we started 10  mg / day of hydrocortisone as physiological replacement and 25  g / day of levothyroxine and continued the same dose for 3 months .
serum igg and igg4 levels were decreased as follows : igg : 2800  mg / dl ; igg4 : 1030  mg / dl ( at the beginning ) ; igg : 1778  mg / dl ; igg4 : 527  mg / dl ( 1 month later ) ; igg : 1924  mg / dl ; igg4 : 674  mg / dl 2 months later ) ; igg : 2013  mg / dl and igg4 : 580  mg / dl ( 3 months later ) .
consequently , as shown in table 1 , various endocrine hormone levels such as acth , cortisol , tsh , ft4 and prl levels were normalized , although lh , fsh and testosterone levels remained low . furthermore , as shown in fig . 1a , tsh response to trh
table 1endocrine hormone levels on admission and 3 months later.on admission3 months laternormal rangeacth , pg / ml13.221.07.263.2cortisol , g / dl1.212.04.521.1tsh , iu / ml0.0360.8320.4006.000ft4 , ng / dl0.560.920.801.60lh , iu / ml<0.10<0.100.795.72fsh , iu / ml2.130.632.008.30testosterone , ng / ml<0.03n.d.1.318.71gh , ng / ml0.830.27<0.13igf-1 , ng / ml406850181prl , ng / ml19.37.03.612.8adh , pg / ml1.01.00.04.2 
  endocrine hormone levels on admission and 3 months later .
herein we report a case of igg4-related hypophysitis that we diagnosed with the pituitary gland biopsy . in this case ,
the anterior pituitary response to trh was improved , and serum igg and igg4 levels were decreased .
the response of cortisol to crh also became better 3 months later , although the response was not completely normalized .
indeed , cortisol level at 90  min was increased to 18.0  g / dl , but cortisol level at 30 or 60  min was < 18.1  g / dl , suggesting that this subject still had mild adrenal insufficiency ( 5 ) .
first , we performed the pituitary gland biopsy and histochemical examination in a subject with igg4-related hypophysitis .
second , we reported the clinical course of igg4-related hypophysitis without a high - dose glucocorticoid treatment .
three month later , serum igg and igg4 levels were decreased , and pituitary size was normalized .
most of the cases with igg4-related hypophysitis are accompanied by complications of pituitary insufficiency . on the other hand , hattori et al .
reported a case of igg4-related hypophysitis without pituitary insufficiency ( 6 ) . in this case , he had a hypopituitarism including adrenal insufficiency , hypogonadism and hypothyroidism ; however , 3 months later , his igg4 level was decreased spontaneously or with a physiological dose of glucocorticoid therapy .
we think that our case shows the time course of igg4-related hypophysitis from the beginning to the improvement .
third , although the patient had still higher igg4 level compared with normal range , his clinical symptoms disappeared and his laboratory data were improved .
we think that after the disappearance of symptoms it is difficult to diagnose igg4-related hypophysitis .
in fact , the case reports of hattori and coworkers showed that he had higher igg4 levels without pituitary insufficiency ( 6 ) .
this case report provides the possibility that igg4 level is decreased spontaneously or with a physiological dose of glucocorticoid therapy .
therefore , when we examine subjects with central adrenal insufficiency and/or thyroid insufficiency after the normalization of serum igg4 level , it would be very difficult to diagnose igg4-related hypophysitis .
first , although we did not perform a high - dose glucocorticoid treatment , we used a physiological dose of glucocorticoid . therefore , we can not exclude the possibility that such treatment with a physiological dose of glucocorticoid facilitated the decrease in igg4 level .
we think it is possible that igg4 level was not spontaneously recovered in this subject .
second , although igg4 level was markedly decreased during the process , it was still higher compared to its normal range .
therefore , we can not conclude at this point that igg4-related disease in this subject was completely recovered .
further observation and/or evaluation for a longer period would be necessary to conclude our hypothesis . in conclusion
, we should keep in mind the possibility of igg4-related hypophysitis when we examine one of the uncertain causes of a hypopituitarism including adrenal insufficiency , hypogonadism and hypothyroidism .
h k has received honoraria for lectures and received scholarship grants from sanofi , novo nordisk , lilly , boehringer ingelheim , msd , takeda , ono pharma , daiichi sankyo , sumitomo dainippon pharma , mitsubishi tanabe pharma , pfizer , kissei pharma , astrazeneca , astellas , novartis , kowa , chugai and taisho pharma .
k k has been an advisor to , received honoraria for lectures from and received scholarship grants from novo nordisk pharma , sanwa kagaku kenkyusho , takeda , taisho pharmaceutical co. , ltd , msd , kowa , sumitomo dainippon pharma , novartis , mitsubishi tanabe pharma , astrazeneca , nippon boehringer ingelheim co. , ltd , chugai , daiichi sankyo and sanofi .
this research did not receive any specific grant from any funding agency in the public , commercial or not - for - profit sector .
f k , m t , r s and y k researched data and contributed to discussion .
h k , t m , k k and n o wrote and reviewed the manuscript .
 a 76-year - old man had a hypopituitarism including adrenal insufficiency , hypogonadism and hypothyroidism . based on various findings including the swelling of the pituitary gland , increase of serum igg4 level and abundant igg4-positive plasma cell infiltration in immunostaining of the pituitary gland 
 , we diagnosed this subject as igg4-related hypophysitis . in general , a high - dose glucocorticoid treatment is effective for igg4-related disease . 
 his clinical symptom , laboratory data and adrenal insufficiency were almost improved without any therapy . 
 the serum igg4 level was decreased and pituitary size was normalized with hydrocortisone as physiological replacement . 
 this case report provides the possibility that igg4 level is decreased spontaneously or with physiological dose of glucocorticoid therapy.learning points : we performed the pituitary gland biopsy and histochemical examination glucocorticoid therapy in a subject with igg4-related hypophysitis.this case report provides the possibility that igg4 level is decreased spontaneously or with a physiological dose of glucocorticoid therapy . 
 we reported the clinical course of igg4-related hypophysitis without a high - dose glucocorticoid treatment , although there were a few reports about the retrospective examination.although the patient had still higher igg4 level compared to normal range , his clinical symptom disappeared and his laboratory data were improved.we should keep in mind the possibility of igg4-related hypophysitis when we examine one of the uncertain causes of a hypopituitarism including adrenal insufficiency , hypogonadism and hypothyroidism . 
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