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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3047-3051
Copyright © 1999 by The Endocrine Society

Original Studies

A Longitudinal Study of Vasopressin Cell Antibodies, Posterior Pituitary Function, and Magnetic Resonance Imaging Evaluations in Subclinical Autoimmune Central Diabetes Insipidus

A. De Bellis, A. Colao, F. Di Salle, V. I. Muccitelli, S. Iorio, S. Perrino, R. Pivonello, C. Coronella, A. Bizzarro, G. Lombardi and A. Bellastella

Institute of Endocrinology (A.D.B., V.I.H., S.I., S.P., A.Be.) and Department of Clinical and Experimental Medicine (A.Bi.), Second University of Naples, and the Department of Molecular and Clinical Endocrinology and Oncology (A.C., R.P., G.L.) and the Institute of Radiological Sciences (F.D.S.), University Federico II, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria De Bellis, M.D., Istituto di Endocrinologia Seconda Universitá di Napoli, Via S. Pansini 5, 80131 Naples, Italy. E-mail: bellaste{at}unina.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Cytoplasmic autoantibodies to vasopressin-cells (AVPcAb) have been detected not only in patients with overt central diabetes insipidus (CDI), but also in patients with endocrine autoimmune diseases without CDI. This suggests that complete CDI can be preceded by a preclinical stage. Among 878 patients with endocrine autoimmune diseases without CDI, 9 patients found to be AVPcAb positive and 139 AVPcAb-negative controls were enrolled in this open prospective study. They were evaluated for AVPcAb and posterior pituitary function at least yearly for about 4 yr (range, 37–48 months); during this span, magnetic resonance imaging (MRI) of posterior pituitary and stalk was performed only in the AVPcAb-positive patients. Five of the 9 AVPcAb-positive patients had normal posterior pituitary function at study entry. They were AVPcAb positive throughout the follow-up period. At later stages of the study, 3 of them developed partial CDI, and 1 developed complete CDI. The remaining 4 patients showed impaired response to the water deprivation test at study entry and were diagnosed as having partial CDI. Two of them agreed to receive desmopressin replacement for 1 yr. After this treatment, the patients became negative for AVPcAb and displayed normal posterior pituitary function until the end of the follow-up. Conversely, the 2 untreated patients with partial CDI remained AVPcAb positive. One of them developed overt CDI. None of the controls became AVPcAb positive or developed CDI. The normal hyperintense MRI signal of the posterior pituitary, present at study entry, persisted subsequently in all 9 AVPcAb-positive patients, including those developing overt CDI, only disappearing in the late phase of complete CDI. In asymptomatic subjects, the monitoring of AVPcAb, but not MRI, seems to be useful to predict a progression toward partial/overt CDI. Early desmopressin therapy in patients with partial CDI could interrupt or delay the autoimmune damage and the progression toward clinically overt CDI.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE CLINICAL state of autoimmune endocrine diseases is considered to be preceded by a long subclinical stage, characterized only by the presence of the organ-specific autoantibodies with or without findings of altered function of the respective target gland (1, 2, 3, 4). The frequent association of idiopathic central diabetes insipidus (CDI) with endocrine autoimmune diseases and the detection of autoantibodies to AVP-secreting cells (AVPcAb) as well as other organ-specific autoantibodies in many patients with CDI suggested the existence of an autoimmune variant of this disease (5, 6, 7, 8, 9). AVPcAb were previously found in some patients with autoimmune endocrine diseases without overt CDI (10). In addition, magnetic resonance imaging study (MRI) of the posterior pituitary and stalk has been recently suggested to be a useful tool in the diagnosis of CDI, as it documents the disappearance of the physiological hyperintense signal characterizing the posterior pituitary (11, 12, 13, 14).

The aim of this open prospective study was 3-fold: first, to investigate whether the presence of AVPcAb might be considered to be a predictive marker of complete CDI in patients with autoimmune endocrine diseases without overt CDI; second, to evaluate possible relationships among changes in AVPcAb titer, posterior pituitary function, and MRI studies; and third, to investigate whether disappearance of AVPcAb and remission of subclinical CDI can occur spontaneously or can be induced by early desmopressin therapy.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients

On the basis of an autoantibody screening study of 878 autoimmune endocrine patients without central DI, 9 patients (1.2%) found to be positive for AVPcAb were enrolled in this open prospective study. Moreover, 139 of 869 AVPcAb-negative patients, matched for age and endocrine autoimmune diseases with normal postpituitary function, were also randomly chosen as controls. The diagnosis of autoimmune endocrine diseases in the 878 patients was made according to standard criteria and confirmed by appropriate laboratory testing. Data at study entry for the 9 AVPcAb-positive patients are summarized in Table 1Go.


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  		Table 1. Clinical and immunological findings of nine AVPcAb-positive patients with autoimmune endocrine diseases at the start of the study

 
None of them had received treatment in the 6 months preceding this study, except for two patients with insulin-dependent diabetes mellitus receiving insulin (no. 1 and 2, Table 1Go) and one patient with Graves’ disease (no. 3, Table 1Go) receiving methimazole. All subjects gave informed consent to participate in the study.

Protocol of the study

In all AVPcAb-positive patients, AVPcAb titers, MRI of posterior pituitary and stalk, and postpituitary function by the water deprivation test were evaluated at study entry and subsequently approximately every 12 months during the follow-up period (range, 37–48 months). In patients who developed overt CDI during the follow-up period, AVPcAb evaluations and MRI studies were also repeated after 12 months of intranasal desmopressin (DDAVP) therapy. All 139 AVPcAb-negative patients were periodically evaluated during a 4-yr follow-up period for AVPcAb, urine volume (24 h), and morning plasma and urinary osmolality after fluid deprivation from 1800 h on the preceding evening.

Postpituitary functional study

The prolonged water deprivation test was performed in agreement with the report by Miller et al. (15). In particular, the patients without polyuria and those with mild polyuria had had nothing to drink from the preceding evening (1800 h). Instead, in the patients showing severe polyuria during the follow-up period, fluid deprivation was started on the same morning of the test at 0700 h. Basal urine and plasma samples for the determination of urine and plasma osmolality were collected hourly during the test, starting at 0800 h. The procedure was continued until the occurrence of an increase in urine osmolality of less than 30 mosmol/kg over two succeeding samples; at these times, blood samples were also drawn for the measurement of plasma osmolality and plasma arginine vasopressin (AVP), as suggested by Zerbe and Robertson (16). Then, 2 µg DDAVP were injected im, and urinary osmolality was measured for 4 h. Moreover, patients with polyuria were weighed before, hourly during, and at the end of the water deprivation test. The diagnosis of partial CDI was performed on the basis of the following criteria: subnormal response of plasma AVP after prolonged water deprivation test, and increase in urinary osmolality ranging from 9–50% after DDAVP injection with respect to values observed after prolonged water deprivation test.

Plasma AVP was measured by RIA according to the method reported by Robertson (17) using commercial kits supplied by Medical System (Genova, Italy). In our laboratory the lower level of the normal response of plasma AVP during a prolonged water deprivation test was estimated as the mean - 2SD of the results obtained when a prolonged water deprivation test was performed in 40 healthy subjects (mean ± 2SD plasma AVP, 6.8 ± 3.4 pmol/L; range, 3.9–9.8) and was 3.4 pmol/L. The patients with AVP lower than 3.4 were considered to have a subnormal response of plasma AVP after prolonged water deprivation test. The diagnosis of complete CDI was performed on the basis of the following criteria: increase in urinary osmolality of more than 50% after DDAVP injection with respect to values observed after prolonged water deprivation test, and absent or lowest response of plasma AVP after prolonged water deprivation test.

Immunological study

AVPcAb were determined using an immunofluorescence method in cryostat sections of young baboon hypothalamus, as described previously (10). Two hundred healthy subjects (aged 18–46 yr; 160 women and 40 men) served as negative controls for AVPcAb.

MRI studies

MRI studies were performed using T1 weighted gradient recalled echo sequences (repetition time, 250 ms; echo time, 12 ms; flip angle, 90°; four signal averages) in the sagittal and coronal planes on a clinical 0.5 T Vectra scanner (General Electric, Milwaukee, WI). In each measurement we obtained seven slices centered on the posterior pituitary and stalk region. The slices were 3 mm thick, with an in-plane spatial resolution of 0.9375 mm (180 x 240 mm2 field of view, 192 x 256 matrix in the sagittal acquisitions, 150 x 180 mm2 field of view, 160 x 192 matrix in the coronal acquisitions). These acquisitions were repeated before and after the administration of 0.1 mmol/L·kg BW gadolinium diethylenetriamine pentacetate, analyzing the perfusion with a temporal resolution of 57 s.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The results of the water deprivation test in nine AVPcAb-positive patients at study entry are illustrated in Table 2Go. Five of them had normal posterior pituitary function (no. 1–5), and four had responses to the water deprivation test fulfilling the criteria for the diagnosis of partial CDI (no. 6–9). Two of them (no. 7, 9), after giving informed consent, were treated with intranasal DDAVP therapy, at doses ranging from 5–10 µg on the basis of periodical evaluation of 24-h urine volume, for 12 months.


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  		Table 2. Water deprivation test in nine AVPcAb-positive patients with autoimmune endocrine diseases at the beginning of the follow-up study

 
The longitudinal behavior of AVPcAb and the results of the water deprivation test during the follow-up in the five AVPcAb-positive patients with normal function of the posterior pituitary at study entry are summarized in Table 3Go. In all five patients, AVPcAb were present throughout the follow-up period. With regard to posterior pituitary function, three of them developed partial CDI (no. 1, 2, and 5), and one developed complete CDI (no. 3) during the follow-up period. Patient 4 still presented normal posterior pituitary function constantly during the follow-up period. With regard to MRI evaluation, none of five patients showed MRI abnormalities during the longitudinal study. In fact, a normal hyperintense signal on T1-weighted images was also present in the patient developing CDI at the presentation (no. 3), but disappeared subsequently, 12 months later. The longitudinal behavior of AVPcAb and the results of the water deprivation test during the follow-up in the four AVPcAb-positive patients with partial CDI at the beginning of the study are summarized in Table 4Go. Two patients, not receiving DDAVP therapy (no. 6 and 8), remained AVPcAb positive throughout the follow-up period, and one of them (no. 8) developed complete CDI after 3 yr, whereas the other showed a constant pattern of partial CDI. The MRI findings were normal in both patients; however, in the patient who developed clinically overt CDI (no. 8), the hyperintense signal, still evident at presentation, disappeared 12 months after the beginning of DDAVP therapy. By contrast, the two remaining AVPcAb-positive patients with partial CDI who agreed to undergo DDAVP therapy (no. 7 and 9) showed disappearance of AVPcAb and normal posterior pituitary function, not only 1 yr after DDAVP withdrawal, but also during all subsequent follow-up periods. MRI findings were normal in both patients throughout the study.


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  		Table 3. Evaluations of AVPcAb and results of the water deprivation test during the follow-up in five AVPcAb-positive patients with normal postpituitary function at the beginning of the study

 

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  		Table 4. Evaluations of AVPcAb and result of the water deprivation test during the follow-up in four AVPcAb-positive patients with partial CDI at the beginning of the study

 
None of the 139 AVPcAb-negative patients with autoimmune endocrine diseases showed AVPcAb or abnormalities of the posterior pituitary function during the 4-yr follow-up period.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We carried out the first longitudinal study of the time course of AVPcAb, posterior pituitary function, and MRI characteristics that was directed to investigate endocrine autoimmune patients without complete CDI.

Our results show that in autoimmune CDI, as in other autoimmune endocrine diseases, the overt clinical phase can be preceded by a long subclinical period. This preclinical stage is characterized by the presence of AVPcAb with or without findings of posterior pituitary function impairment. Our results also suggest that the presence of these antibodies could indicate a high risk for the development of overt CDI.

In our previous study we demonstrated a spontaneous disappearance of adrenocortical antibodies and remission of subclinical adrenocortical failure in patients at early functional stages of Addison’s disease (4). Instead, our present study demonstrates that AVPcAb persist over time in untreated patients with subclinical CDI and in most cases are associated with progressive worsening of posterior pituitary function. On the basis of our results, the natural history of autoimmune CDI in AVPcAb-positive patients with other autoimmune endocrine diseases seems to evolve through three functional stages in which AVPcAb are always present. Stage 1 is characterized by the presence of AVPcAb, but normal posterior pituitary function; stage 2 is characterized by the presence of AVPcAb and posterior pituitary functional findings suggestive of partial DI; stage 3 is characterized by the presence of AVPcAb and the development of complete CDI. The MRI studies carried out serially during the follow-up of these patients showed the persistence of hyperintense signal on T1-weighted images during the first two stages of the disease. The hyperintense MRI signal of the posterior pituitary can persist even in the early phase of stage 3, but disappear later. Thus, the persistence of the hyperintense signal, not only in preclinical but also in clinically overt states of CDI, suggests that MRI of posterior pituitary cannot be considered a useful tool for the prediction of the progression toward complete CDI in AVPcAb-positive patients. The apparent disagreement between our data and previous reports showing an absence of the MRI hyperintense signal of the posterior pituitary in a large cohort of patients with idiopathic CDI (14) can be ascribed to differences in the time of observation of the patients. In fact, the patients in these latter studies (14) were investigated several months after the diagnosis of CDI. At this time the disappearance of AVP granules can be complete; this could justify the lack of a MRI hyperintense signal. The presence of a posterior pituitary hyperintense signal at the onset of CDI in our patients can be ascribed to persistence of a residual amount of AVP granules (early stage 3). The subsequent disappearance might be due to the depletion of these granules (late stage 3).

The second crucial finding of this study regards the effect of preventive DDAVP replacement therapy. Among the four AVPcAb-positive patients with partial CDI at study entry, two were treated with DDAVP replacement for 1 yr; after therapy, both showed recovery of postpituitary function together with disappearance of AVPcAb. This suggests that in preclinical autoimmune CDI the early administration of DDAVP therapy could suppress the expression of AVPcAb, induce the remission of subclinical posterior pituitary function impairment, and thus prevent the progression toward the clinically overt CDI. These results are in line with the isohormonal therapy recently attempted in the preclinical stage of some endocrine autoimmune diseases, such as type 1 diabetes mellitus and Addison’s disease, to prevent or delay the onset of the clinical phase of these diseases (4). The isohormonal therapy has been supposed to act by causing a feedback inhibition of the target endocrine gland function. This feedback inhibition could decrease the exposure of autoantigens to the immune system or the susceptibility of the target tissue for the immune attack. In analogy, early intranasal desmopressin therapy can work as isohormonal therapy inducing AVPcAb disappearance and thereby restore the function of the posterior pituitary gland in patients with autoimmune partial CDI.

Received March 11, 1999.

Revised May 17, 1999.

Accepted May 21, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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