Prevalence of clinical remission in patients with sporadic idiopathic hypoparathyroidism.

Abstract

Remission of disease activity is a characteristic feature of autoimmune endocrine disorders such as Graves' disease, Addison's disease and occasionally in patients with premature ovarian failure. Autoimmunity is also implicated in sporadic idiopathic hypoparathyroidism (SIH) with clinical remission of disease reported in three cases.
To assess the rate of remission in patients with sporadic idiopathic hypoparathyroidism and review the cases reported so far.
Subjects included 53 patients (M:F, 24:29) with SIH who had been symptomatic for at least 1 year (range 1-31 years). They were treated with calcium and 1-alpha-(OH)D(3)/cholecalciferol therapy and had a mean duration of follow up of 5.0 +/- 3.2 years. Treatment was withdrawn in two stages in the patients who maintained normal levels of serum total calcium during the preceding year of treatment. In stage-1, the dose of therapy was reduced to half and subsequently all treatment was stopped (stage 2) in those patients who maintained normal serum total calcium levels on the reduced dose. Remission of SIH was defined as maintenance of normal serum total (>or=2.12 mmol/l) and ionized calcium, inorganic phosphorus and serum intact parathyroid hormone (iPTH) for at least 3 months after withdrawal of calcium and 1-alpha-(OH)D(3)/cholecalciferol therapy. Calcium sensing receptor autoantibodies (CaSRAb) were determined by Western blot.
Two of the 53 patients (3.8%) with SIH stayed in remission for 1 year after complete withdrawal of therapy. CaSRAb was absent in both the cases. The clinical features, age at onset and duration of hypocalcaemic symptoms in cases with remission were comparable to those who did no show remission.
Sporadic idiopathic hypoparathyroidism is not irreversible as is widely believed and spontaneous remission of disease may occur in 3.8% of patients.

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O R I G I N A L A R T I C L E
Prevalence of clinical remission in patients with sporadic idiopathic
hypoparathyroidism
Ravinder Goswami*, Siya Goel*, Neeraj Tomar*, Nandita Gupta*, Vanshika Lumb† and Yagya Dutta Sharma†
*Department of Endocrinology and Metabolism and †Department of Biotechnology, All India Institute of Medical Sciences, New Delhi,
India
Summary
Background Remission of disease activity is a characteristic
feature of autoimmune endocrine disorders such as Graves’
disease, Addison’s disease and occasionally in patients with prema-
ture ovarian failure. Autoimmunity is also implicated in sporadic
idiopathic hypoparathyroidism (SIH) with clinical remission of
disease reported in three cases.
Objective To assess the rate of remission in patients with
sporadic idiopathic hypoparathyroidism and review the cases
reported so far.
Subjects and methods Subjects included 53 patients (M:F,
24:29) with SIH who had been symptomatic for at least 1 year
(range 1–31 years). They were treated with calcium and
1-a-(OH)D3/cholecalciferol therapy and had a mean duration of
follow up of 5Æ0 ± 3Æ2 years. Treatment was withdrawn in two
stages in the patients who maintained normal levels of serum total
calcium during the preceding year of treatment. In stage-1, the dose
of therapy was reduced to half and subsequently all treatment was
stopped (stage 2) in those patients who maintained normal serum
total calcium levels on the reduced dose. Remission of SIH was
defined as maintenance of normal serum total (‡2Æ12 mmol/l) and
ionized calcium, inorganic phosphorus and serum intact para-
thyroid hormone (iPTH) for at least 3 months after withdrawal of
calcium and 1-a-(OH)D3/cholecalciferol therapy. Calcium sensing
receptor autoantibodies (CaSRAb) were determined by Western
blot.
Results Two of the 53 patients (3Æ8%) with SIH stayed in remis-
sion for 1 year after complete withdrawal of therapy. CaSRAb was
absent in both the cases. The clinical features, age at onset and
duration of hypocalcaemic symptoms in cases with remission were
comparable to those who did no show remission.
Conclusion Sporadic idiopathic hypoparathyroidism is not irre-
versible as is widely believed and spontaneous remission of disease
may occur in 3Æ8% of patients.
(Received 5 November 2008; returned for revision 24 November
2008; finally revised 1 May 2009; accepted 25 May 2009)
Introduction
Remission is a characteristic feature of autoimmune endocrine and
nonendocrine disorders such as Graves’ disease,1,2adrenal insuffi-
ciency,3premature ovarian failure,4,5vitiligo6and rheumatoid
arthritis.7Blizzard et al. first identified autoantibodies to para-
thyroid tissue in sporadic idiopathic hypoparathyroidism (SIH) in
1966 and suggested that this disease may have an autoimmune
origin.8Subsequently, four other studies have reported the
presence of calcium sensing receptor autoantibodies (CaSRAb) in
patients with SIH.9–12
Interestingly, there are three case reports of spontaneous remis-
sion in SIH.11,13,14We have a large cohort of patients with SIH on
follow up.9,15–18One of them stopped her replacement therapy of
calcium and cholecalciferol without medical consultation and
returned for follow up after 3 years. She had no symptoms of hypo-
calcaemia and her serum total calcium, inorganic phosphorus and
parathyroid hormone levels were normal. This observation
prompted us to systematically assess for the possibility of remission
in SIH.
Subjects and methods
Subjects
The study was conducted in the Department of Endocrinology and
Metabolism at the All India Institute of Medical Sciences, New
Delhi during 2007–2008. The 53 subjects included were part of a
larger cohort of 110 patients with SIH who have been treated by us
since 1998.15–18The criteria used to diagnose SIH included pres-
ence of hypocalcaemia and hyperphosphataemia in association
with subnormal or an inappropriately normal level of serum intact
PTH (iPTH), normal serum total magnesium and renal function.19
None of the patients had clinical or biochemical features of haemo-
chromatosis. Patients with postsurgical hypoparathyroidism were
excluded. None of them had a family history of hypoparathyroidism
Correspondence: Dr Ravinder Goswami, Departmentof Endocrinology
and Metabolism, All India Institute of Medical Sciences, New Delhi 110029,
India. Tel: +91 11 26594272;Fax: +91 11 26588663 (or) +91 11 26588641;
E-mail: gosravinder@hotmail.com
Clinical Endocrinology (2010) 72, 328–333doi: 10.1111/j.1365-2265.2009.03653.x
328
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or features of autoimmune polyendocrinopathy with candidiasis
and ectodermal dystrophy syndrome.20Autoimmune adrenal dis-
orders were excluded by demonstrating absence of adrenal cortical
autoantibodies by indirect immunofluoresence21and normal
plasma ACTH and cortisol (08:00 hours) levels. Six of the 53
(11Æ3%) subjects had thyroid peroxidase autoantibodies (TPOAb)
and one had thyroid dysfunction at presentation. These findings
were similar to those reported by us in our larger cohort of patients
with SIH.16
All the subjects were enrolled after ethical clearance of the Insti-
tutional ethics committee and written informed consent. They
were put on oral calcium carbonate (elemental calcium, 2 g/day,
Elder Pharmaceutical, India) and 1-a-(OH) D3(0Æ25–2Æ0 lg/day,
Cipla Pharmaceutical, India or Panacea Biotech, India) or cholecal-
ciferol (60,000 IU/alternate days, Cadila Pharmaceutical, India) to
maintain serum total calcium between 1Æ99–2Æ12 mmol/l.19
Patients were called for follow up at intervals of 3 months.
Assessment of remission of disease
To date, there are no criteria to define remission of disease in SIH.
In this study a two-stage protocol involving stepwise withdrawal of
therapy was devised to assess remission (Fig. 1).
Patient selection for assessment for remission. After the diagnosis
of SIH, a minimum period of 1 year of follow up was con-
sidered essential before assessing them for remission. Patients
who could not be followed were excluded from the study. In
other patients a minimum of three values of serum total cal-
cium, measured at least 1 month apart, while they were on
calciumand1-a-(OH)D3/cholecalciferol
assessed. Patients with any value <2Æ12 mmol/l were consid-
ered to have persistent disease. Only patients with at least
three values of serum total calcium ‡2Æ12 mmol/l over 1 year
were assessed further.
therapy were
Stage I: Reduction in the dose of calcium and 1-a-(OH) D3/cholecal-
ciferol. The dose of oral calcium and 1-a-(OH)D3/cholecalci-
ferol was reduced to half in patients who maintained serum
total calcium values ‡2Æ12 mmol/l over 1 year as discussed
above. They were followed up every month for the next
3 months. In case of occurrence of symptoms of hypocalcaemia
they were asked to contact any of the two authors (RG or SG)
by telephone. On follow up visits, the patients were examined
clinically for signs and symptoms of hypocalcaemia and blood
samples were taken for estimation of serum total calcium, in-
organic phosphorus, iPTH and 25(OH)D. Patients with serum
total calcium less than 2Æ12 mmol/l were classified as having
persistent disease.
Stage II: Withdrawal of calcium and 1-a-(OH) D3/cholecalciferol
therapy. Patients who maintained serum total calcium levels
‡2Æ12 mmol/l on the halved dose of calcium and 1-a-(OH)
D3/cholecalciferol during Stage I were evaluated further. Therapy
was stopped completely and they were examined clinically and
biochemically every month for the next 3 months. Patients in
whom serum total calcium fell below 2Æ12 mmol/l were classified as
having persistent disease.
Patients who did not show any signs and symptoms of hypo-
calcaemia and maintained normal serum total calcium, inorganic
phosphorus and iPTH values on all the three follow up visits
after withdrawal of the treatment were categorized as having
undergone clinical remission. Normalization of serum calcium
was also confirmed by measurement of ionized calcium on their
last visit.
Biochemical assays
Serum total calcium, inorganic phosphorus and alkaline phospha-
tase were measured using an automated analyser (Hitachi
917, Roche, Mannheim, Germany; normal range (NR); 2Æ12–2Æ59,
Serum total Ca > 2·12 mmol/l Serum total Ca < 2·12 mmol/l Incidentally observed in remission
(n = 5) (n = 47) (n = 1, case 2)
St ag e I
No further assessmen t
(therapy reduced to half &
assessed for three m onths)
Seru m total Ca
< 2·12 mmol/l
(n = 4)
> 2·12 mmol/l
(n = 1, case 1)
St ag e II
(therapy stopped &
assessed for three months)
Assessment of remission
(n = 53)
No further assessment
Maintained norm al serum Ca & iPTH
Remission
(Total n = 2)
Off therapy
for 3·6 years
Fig. 1 Summary of the protocol for the assessment
of remission in patients with sporadic idiopathic
hypoparathyroidism (SIH).
Remission in hypoparathyroidism
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0Æ81–1Æ45 mmol/l and 98–279 IU/l respectively). Serum magne-
sium was measured using Cobas Integra 400 (Roche, NR: 0Æ70–
1Æ05 mmol/l). Intra-assay and interassay coefficients of variation
for these assays ranged from 3Æ5 to 5Æ0%. Serum 25(OH)D was
measuredbyradio-immunoassay(Diasorin;NR:22Æ5–93Æ8 nmol/l).
Serum iPTH, TPOAb and ferritin were measured by electrochemi-
luminescence immunoassay (Elecsys-2010, Roche diagnostics,
MannheimGermany;NR,iPTH = 1Æ6–6Æ8 pmol/l,ferritin,males =
67–898andfemales = 34–337 pmol/l.TPOAb<34Æ0 IU/ml).
Calcium sensing receptor autoantibodies
Western blot assay was used to detect CaSRAb in the serum of
patients showing remission. The assay was performed as described
in our earlier study,9except that the antigen used was the recombi-
nant extracellular domain of the calcium sensing receptor. The
positive control used consisted of polyclonal antibodies against the
N terminal of the extracellular domain of the calcium sensing
receptor (CasR-H-100, Santa Cruz Biotechnology, CA, USA)
(Fig. 2).
Assessment of GNAS1 gene
Genomic DNA was obtained from peripheral leucocytes for
sequencing GNAS1 in one of the patients (case 1) to exclude
pseudohypoparathyroidism. Sequencing of all the 13 coding exons
was performed using a set of 10 pairs of primers as described by
Ahrens et al.22and Big Dye?v3Æ1 Cycle Sequencing Chemistry on
the ABI PRISM?310 Genetic Analyzer (Applied Biosystems, CA,
USA).21The nucleotide sequences were compared with the pub-
lished sequence of human GNAS1 gene (GenBank accession no.
NT_011362Æ9).
Statistical analysis
The data is given as mean ± SD and percentages. Statistical analysis
was performed using SPSS statistical software (version 10Æ0; SPSS
Inc, Chicago, IL, USA).
Results
The male female ratio (M 23, F 28), body mass index (20Æ9 ± 3Æ8
kg/m2), mean age at presentation to the hospital (27Æ4 ± 3Æ8 years),
total duration of symptoms (9Æ3 ± 6Æ7 years), mean duration of
follow up (5Æ0 ± 3Æ2 years), serum total calcium (1Æ35 ± 0Æ24
mmol/l), inorganic phosphorus (2Æ23 ± 0Æ48), iPTH (1Æ21 ± 0Æ88)
values, frequency of basal ganglia calcification (72Æ2%) and cataract
(55Æ6%) among the 53 study subjects at presentation were com-
parable to that reported by us in the larger cohort of patients with
SIH.15–18
Patient selection for assessment of remission
In the present study the 53 patients with SIH had mean serum total
calcium level of 1Æ85 ± 0Æ29 mmol/l during 1 year of follow up on
therapy. Only six of them (11Æ3%) had normal serum total calcium
on three or more occasions while on therapy with calcium and
1-a-(OH) D3(mean value: 2Æ29 ± 0Æ13 mmol/l) and were assessed
further.
Stage I: Reduction in dose of calcium and 1-a-(OH) D3/
cholecalciferol
Five of the 53 patients fulfilled the criteria for inclusion in stage I.
The dose of calcium and 1-a-(OH) D3was reduced to half in all of
them. Within a month, serum total calcium fell to below
<2Æ12 mmol/l in four of them. Their individual serum total cal-
cium values were 1Æ79, 1Æ64, 2Æ04 and 2Æ07 mmol/l and correspond-
ing iPTH values were 0Æ34, 0Æ70, 4Æ71 and 0Æ13 pmol/l respectively.
These four patients were put back on the full therapeutic regimen
and classified as having persistent disease.
Stage II: Withdrawal of therapy
The patient who had normal serum total calcium on reduction of
therapy in stage I maintained normal serum total calcium and ion-
ized calcium levels for three months following complete with-
drawal of therapy. This case and the one which was incidentally
observed to be in remission were therefore considered to have
achieved remission of SIH. They did not have clinical features of
sarcoidosis (potential mechanism of reversible hypoparathyroid-
ism) and their X-ray chest, Mantoux test and serum angiotensin
converting enzyme levels were normal. The details of these two
patients at presentation, during stage 1 and II are described below
and summarized in Table 1.
Case 1, presented to us at the age of 17 years in 2000 with short
stature (145 cm, <5th percentile) and absence seizures for 4 years.
Slit lamp examination revealed posterior subcapsular cataract and
computerized tomography showed bilateral basal ganglia calcifica-
tion. His serum total calcium and inorganic phosphorus were 1Æ72
and 2Æ22 mmol/l respectively and iPTH values were 5Æ58 and
2Æ63 pmol/l on two different days. His 24 h urine calcium excretion
was 77 mg. Renal and thyroid function tests and serum TPOAb
titers were normal and CaSRAb was absent. He was put on oral
elemental calcium (2Æ0 g/day) and cholecalciferol (60,000 IU/
95 KDa M.W.
Blank Case-1 Case-2 MW
1% Blotto (at baseline) Control (at remission)
+ve Case-1 Case-2
73 KDa CaSR band
1 2 3 4 5 6 7
Fig. 2 Western blot for analysis of CaSRAb positivity in two patientswith
SIH showing clinical remission. A 7% SDS–PAGE performed using minigel
electrophoresis apparatus (Hoeffer, San Francisco, CA, USA). Lane 4
contains molecular weight marker. All other lanes contain20 lg of extracel-
lular domain of recombinant CaSR protein expressed in Escherichia coli C43
(DE3) using pProExHtb vetctor. Lane 5 is the positive control antibody
(1:200 dilution) showingimmunoreactivity against CaSR at 73 kDa
(CasR-H-100, Santa Cruz Biotechnology, CA, USA). Lane 1 is blank and
contained with no primary antibody but only 1% blotto. Lane 2 & 3 and 6 &
7 contained sera of two patients each in dilution of 1:50 at presentation and
again at the time of remission respectively, showing absence of CaSRAb.
Secondary antibody usedwas antihumanalkaline phosphates conjugated
antibody used in 1:2000 dilution (Dako, Glostrup, Denmark).
330
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alternate days) along with carbamazepine (200 mg/day) following
which his serum calcium normalized (‡2Æ12 mmol/l). In view of
his short stature and normal PTH values, the DNA sequence of
coding exons of GNAS1 gene was also performed to rule out
pseudohypoparathyroidism. Coding sequence of all the 13 exons
was normal.
His serum total calcium had decreased to 1Æ99 mmol/l on two
occasions in 2001 attributable to poor compliance with therapy.
However, since 2006, all of his serum calcium values were
‡2Æ12 mmol/l and serum inorganic phosphorus values were nor-
mal. He attained a height of 167 cm (between 50th–90th percentile
for Delhi males, http://icmr.nic.in/final/lg_48.html). His treatment
was reduced to half the dose in 2007 andwas completely withdrawn
in 2008. The patient has maintained normal serum calcium, phos-
phorus and iPTH values for the past 1 year (Table 1). His serum
25(OH)D, assessed at 1 year of complete withdrawal of therapy
was, 24Æ2 nmol/l.
Case 2 (mentioned in the introduction) presented to us at the
age of 18 years in 2002 with complaint of cramps for 4 years.
Examination revealed positive Chvostek’s and Trousseau’s signs.
Her serum total calcium, inorganic phosphorus and iPTH values
were 1Æ59, 1Æ99 and 0Æ86 pmol/l respectively. Baseline renal func-
tion and thyroid function tests were normal. There was no cataract
or basal ganglia calcification. She was put on oral elemental calcium
(2Æ0 g/day) and cholecalciferol (60,000 IU/alternate days). Her
serum total calcium values were in the normal range (‡2Æ12 mmol/
l) after 6 months of therapy. While on treatment, her 24 h urine
calcium excretion was 120 mg. Her serum total calcium decreased
to 1Æ77 mmol/l in 2004 attributable to poor compliance with ther-
apy. Subsequently she did not report for follow up until we con-
tacted her again in 2008 for assessment of remission. History
revealed that she had stopped all the medicines for the past 3 years.
Reassessment of her serum total calcium, phosphorus and iPTH
revealed normal values (Table 1). However, her repeat thyroid
function test showed primary hypothyroidism with serum total T4
of 65Æ5 nmol/l and TSH of 42Æ5 mU/l for which she was put on
thyroxine therapy. Serum TPOAb titres were normal and CaSRAb
could not be detected at presentation and at remission (Fig. 2).
Now she is in regular follow up and continues to be in remission
withnormalserum calcium,phosphorusandiPTHvalues(Table1)
and serum 25(OH)D value of 48Æ7 nmol/l.
Discussion
Sporadic idiopathic hypoparathyroidism is considered to be an
irreversible disorder. The results of this study reveal that remission
of disease may be possible in patients with SIH. We adopted a care-
ful approach to define remission and observed a remission rate of
3Æ8% in patients with SIH. Their mean duration of symptoms was
9 years and the mean follow up was of 5 years. Most of our patients
with SIH suffered from recurrent attacks of hypocalcaemia during
treatment because of noncompliance with the expensive treatment.
In fact, 88Æ7% could not maintain their serum calcium levels
‡2Æ12 mmol/l. The two patients who went into remission had also
experienced episodes of hypocalcaemia during the first few years of
treatment.
The rate of remission observed in this study can at best be
described as modest. However if we had used less strict criteria, it is
possible that more patients would have been classified as being in
remission. For instance, we graded all patients with serum total cal-
cium levels below 2Æ12 mmol/l as having active disease. According
to the statistical normal distribution serum calcium is below the
lower limit of normal in 2Æ5% of the population. Thus, a minimum
of four out of the 53 patients included could realistically be
expected to have one value below 2Æ12 mmol/l even when their
disease was in remission.
Spontaneous remission of disease in hypoparathyroidism has
been reported only in three cases to date.11,13,14Posillico et al.
reported a 70-year-old male with history of intermittent hypo-
calcaemia of a few year duration who showed fall of serum calcium
to 1Æ72 mmol/l following an episode of haemorrhagic cerebro-
vascular accident.13The patient had normal serum magnesium and
C terminal PTH values. After 1 month serum total calcium was
1Æ99 mmol/l and PTH was low normal. The rise in serum total
calcium levels correlated with a decline in levels of PTH secretion
inhibiting autoantibodies against the parathyroid cell surface.
In2004,Kiforetal.reporteda25-year-oldmalewithhypothyroid-
ism and primary adrenal insufficiency who had subnormal serum
Table 1. Serum biochemical parameters in two cases with sporadic idiopathic hypoparathyroidism who showed remission, at the time of presentation, stage I
and II of the study
Patients At presentation
Stage I
(Reductionof Ca
and vitamin D3
therapy)
Stage II (3 monthsafter complete
withdrawal of Ca and vitamin D3
therapy)
After 1 year of complete
withdrawal of therapy
Patients
(case identity) Total CaPO4
iPTH Total Ca PO4
Total Ca iCaPO4
iPTH Total CaiCa PO4
iPTH
SD (1)
NI** (2)
1Æ72
1Æ59
2Æ22
1Æ99
*2Æ63/5Æ58
0Æ86
2Æ50
NA
1Æ51
NA
2Æ45
2Æ17
1Æ10
1Æ19
1Æ32
1Æ48
2Æ63
2Æ84
2Æ39
2Æ14
1Æ15
1Æ28
1Æ51
1Æ45
3Æ72
2Æ35
Normal range for serum calcium (Ca) = 2Æ12–2Æ59 mmol/l; inorganic phosphorus (PO4) = 0Æ81–1Æ45 mmol/l; intact parathyroid hormone (iPTH) = 1Æ6–
6Æ8 pmol/l; ionized calcium (iCa) = 1Æ10–1Æ38 mmol/l.
*PTH sample repeated on two different occasions before the start of treatment to confirm PTH values.
**Data not available (NA) for stage I, as the patient came to us after 3 years of withdrawal of therapy.
Remission in hypoparathyroidism
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total and ionized calcium levels (2Æ0 and 1Æ0 mmol/l respectively)
andactivating CaSRAb.11Thoughserum totalmagnesium level was
mildly decreased (0Æ62–0Æ7 mmol/l, NR = 0Æ74–1Æ04 mmol/l),
serum intact PTH values were normal on two occasions (3Æ8 and
2Æ3 pmol/l,NR = 1Æ05–6Æ84 pmol/l).Whenre-evaluatedafter3and
13months,hehadnormalserumtotalcalciumlevels.
Furuto-Kato et al.14described a 67-year-old female with numb-
ness of the fingers and low serum total calcium (1Æ62 mmol/l),
inappropriately normal serum intact PTH of 1Æ4 pmol/l and nor-
mal serum magnesium levels. Her serum calcium normalized fol-
lowing treatment with 1,25(OH)2D3(1Æ5–2Æ0 lg/day). Treatment
was then tapered off over the next 9 months. After 1 year of follow
up, her serum calcium and intact PTH levels had risen above the
normal range and she underwent parathyroidectomy. The left
upper parathyroid gland removed was larger than the other glands
and showed lymphocytic infiltration. However, parathyroid
specific autoantibodies were not assessed.
In this study we could not identify specific clinical features which
correlate with the phenomenon of remission. Interestingly, two of
the three previously reported cases11,14and case 1 of this study had
normal serum PTH values. While normal serum iPTH values in the
presence of hypocalcaemia reflect partial hypoparathyroidism, it
can also be regarded as evidence of a sufficient number of viable
PTH secreting parathyroid cells. Thus, the presence of normal
serum iPTH values at baseline or during therapy could suggest
potential for recovery. In these patients and in those who maintain
normal serum calcium continuously for at least a year, the physi-
cian may attempt reduction of ongoing therapy with monitoring of
serum calcium values. The presence of normal serum total calcium
and PTH levels on complete withdrawal of therapy indicates remis-
sion of the disease. However, more data on SIH and remission
would be required to substantiate these guidelines.
Hypomagnesaemia and sarcoidosis (due to expression of
1-alpha-hydroxylase) are possible causes of ‘reversible’ hypopara-
thyroidism.23,24Recently, Ebstein et al. reported hypomagnesaemia
and reversible hypoparathyroidism following use of proton pump
inhibitors.23In fact, one of our patients (not included in the study)
had also used rabeprazole 20 mg/day for 2 months followed by
occurrence of hypomagnesaemia and hypocalcaemia, both of
which reversed following withdrawal of rabeprazole. Hypo-
magnesaemia and sarcoidosis were excluded as possible causes of
remission in both the patients who showed remission in this study.
The molecular mechanisms involved in the pathogenesis of
SIH are under investigation. The hypothesis of an auto-
immune origin is favoured because of demonstration of (a)
CaSRAb in these patients,9–12
observed at autopsy in a few patients with hypoparathyroid-
ism25and (c) generalized activation of T cells.26Theoretically,
patients with SIH may achieve remission by switching anti
CaSRAb production from the ‘activating’ to the ‘inactivating’
type, akin to that observed in autoimmune thyroid disor-
ders.27,28De Bellis et al, have described reversibility of sub-
clinical adrenocortical insufficiency following the disappearance
of low titres of antiadrenal autoantibodies.4Similarly Rebar et
al have documented spontaneous ovulation and pregnancy in
20% of women with premature ovarian failure.5
(b) lymphocyte infiltration
One of two patients with clinical remission had primary hypo-
thyroidism which can be considered as indirect evidence for the
involvement of an autoimmune mechanism. Though CASRAb was
absent in both patients with remission, they might have other sero-
logical markers for parathyroid autoimmunity such as autoanti-
bodies against the new parathyroid auto antigen Human NACHT,
leucine-rich-repeat and pyrin domain containing protein 5
(NALP5).29
Thus, this report shows that it is possible for patients with spo-
radic idiopathic hypoparathyroidism to achieve spontaneous
remission following treatment with calcium and vitamin D. Such
remissions are rare and observed in only 3Æ8% of cases. Neverthe-
less, the observation has clinical relevance when explaining the
prognosis of the disease to patients. Besides, it supports the theory
of an autoimmune basis for this disease and provides scope for
exploring novel immunomodulatory/immunosuppressive thera-
pies to induce remission in these patients.
Acknowledgements
The authors are thankful to Dr V. Sreenivas for statistical help in
the study. The SG and NT acknowledge financial support from the
Indian Council of Medical Research for the Research fellowship.
Competing interests/financial disclosure
There is no conflict of interest that could be perceived as prejudic-
ing the impartiality of the research reported. This research did not
receive any specific grant from any funding agency in the public,
commercial or not for profit sector.
References
1 Takasu, N., Yamashiro, K., Komiya, I. et al. (2000) Remission of
Graves’ hyperthyroidism predicted by smooth decreases of thy-
roid-stimulating antibody and thyrotropin-binding inhibitor
immunoglobulin during antithyroid drug treatment. Thyroid,
10, 891–896.
2 Benker, G., Reinwein, D., Kahaly, G. et al. (1998) Is there a methi-
mazole dose effect on remission rate in Graves’ disease? Results
from a long-term prospective study. The European Multicentre
Trial Group ofthe Treatment ofHyperthyroidism with Antithyroid
Drugs. Clinical Endocrinology (Oxf), 49, 451–457.
3 De Bellis, A., Bizzarro, A., Rossi, R. et al. (1993) Remission of
subclinical adrenocortical failure in subjects with adrenal autoanti-
bodies. Journal of Clinical Endocrinology and Metabolism, 76, 1002–
1007.
4 Rebar, R.W. & Connolly, H.V. (1990) Clinical features of young
women with hypergonadotropic amenorrhea. Fertility Sterility, 53,
804–810.
5 Patel, B., Haddad, R., Saxena, I. et al. (2003) Spontaneous long-
term remission in a patient with premature ovarian failure. Endo-
crine Practice, 9, 380–383.
6 Dogra, S. & Kumar, B. (2005) Repigmentation in vitiligo univer-
salis: role of melanocyte density, disease duration, and melanocytic
reservoir. Dermatology Online Journal, 11, 30.
7 Mierau, M., Schoels, M., Gonda, G. et al. (2007) Assessing remis-
sion in clinical practice. Rheumatology (Oxford), 46, 975–979.
332
R. Goswami et al.
? 2010 Blackwell Publishing Ltd, Clinical Endocrinology, 72, 328–333

Page 6

8 Blizzard, R.M., Chee, D. & Davis, W. (1966) The incidence of para-
thyroid and other antibodies in the sera of patients with idiopathic
hypoparathyroidism.Clinical
119–128.
9 Goswami, R., Brown, E.M., Kochupillai, N. et al. (2004) Prevalence
of calcium sensing receptor autoantibodies in patients with
sporadic idiopathic hypoparathyroidism. European Journal of
Endocrinology, 154, 9–18.
10 Mayer, A., Ploix, C., Orgiazzi, J. et al. (2004) Calcium-sensing
receptor autoantibodies are relevant markers of acquired hypo-
parathyroidism. Journal of Clinical Endocrinology and Metabolism,
89, 4484–4488.
11 Kifor, O., McElduff, A., LeBoff, M.S. et al. (2004) Activating anti-
bodies to the calcium-sensing receptor in two patients with auto-
immune hypoparathyroidism. Journal of Clinical Endocrinology
and Metabolism, 89, 548–556.
12 Gavalas, N.G., Kemp, E.H., Krohn, K.J. et al. (2007) The
calcium-sensing receptor is a target of autoantibodies in patients
with autoimmune polyendocrine syndrome type 1. Journal of
Clinical Endocrinology and Metabolism, 92, 2107–2114.
13 Posillico, J.T., Wortsman, J., Srikanta, S. et al. (1986) Parathyroid
cell surface autoantibodies that inhibit parathyroid hormone secre-
tion from dispersed human parathyroid cells. Journal of Bone and
Mineral Research 1, 475–483.
14 Furuto-Kato, S., Matsukura, S., Ogata, M. et al. (2005) Primary
hyperparathyroidism presumably caused by chronic parathyroid-
itis manifesting from hypocalcemia to severe hypercalcemia. Inter-
nal Medicine, 44, 60–64.
15 Goswami, R., Mohapatra, T., Gupta, N. et al. (2004) Parathyroid
hormone gene polymorphism and sporadic idiopathic hypopara-
thyroidism. Journal of Clinical Endocrinology and Metabolism, 89,
4840–4845.
16 Goswami, R., Marwaha, R.K., Goswami, D. et al. (2006) Prevalence
of thyroid autoimmunity in sporadic idiopathic hypoparathyroid-
ism in comparison to type 1 diabetes and premature ovarian
failure. Journal of Clinical Endocrinology and Metabolism, 91,
4256–4259.
17 Sarin, R., Tomar, N., Debarti, R. et al. (2006) Absence of patho-
genic calcium sensing receptor gene mutations in sporadic
Experimental Immunology,1,
idiopathic hypoparathyroidism. Clinical Endocrinology (Oxf), 65,
359–363.
18 Laway, B.A., Goswami, R., Singh, N. et al. (2006) Pattern of bone
mineral density in patients with sporadic idiopathic hypoparathy-
roidism. Clinical Endocrinology (Oxf), 64, 405–409.
19 Downs, R.W. (2001) The hypoparathyroid states. In: J.P. Bileziki-
an, R. Marcus, M.A. Levine eds. The Parathyroid: Basics and Clini-
cal Aspect, 2nd edn. Academic Press, Boston, MA, 755–762.
20 Perheentupa, J. (2002) APS-I/APECED: the clinical disease and
therapy. Endocrinology and Metababolism Clinics of North America,
31, 295–320.
21 Goswami, R., Srikanta, S.S. & Kochupillai, N. (1995) Prevalence,
significance of pancreatic islet cell and adrenal antibodies in
patients with Graves’ disease. Indian Journal of Medical Research,
101, 201–206.
22 Ahrens, W., Hiort, O., Staedt, P. et al. (2001) Analysis of the
GNAS1 gene in Albright’s hereditary osteodystrophy. Journal of
Clinical Endocrinology and Metabolism, 86, 630–4634.
23 Epstein, M., McGrath, S. & Law, F. (2006) Proton-pump inhibitors
and hypomagnesemic hypoparathyroidism. New England Journal
of Medicine, 355, 1834–1836.
24 Mitchell, T.H., Stamp, T.C., Jenkins, M.V. et al. (1983) Hypercal-
caemic sarcoidosis in hypoparathyroidism. British Medical Journal,
286, 764–765.
25 Boyce, B.F., Doherty, V.R. & Mortimer, G. (1982) Hyperplastic
parathyroiditis – a new autoimmune disease? Journal of Clinical
Pathololgy, 35, 812–814.
26 Wortsman, J., McConnachie, P., Baker, J.R. Jr et al. (1992)
T-lymphocyte activation in adult-onset idiopathic hypoparathy-
roidism. American Journal of Medicine, 92, 352–356.
27 Ohye, H., Nishihara, E., Sasaki, I. et al. (2006) Four cases of Graves’
disease which developed after painful Hashimoto’s thyroiditis.
Internal Medicine, 45, 385–389.
28 Takasu, N., Yamada, T., Sato, A. et al. (1990) Graves’ disease fol-
lowing hypothyroidism due to Hashimoto’s disease: studies of
eight cases. Clincal Endocrinology (Oxf), 33, 687–698.
29 Alimohammadi, M., Bjo ¨rklund, P., Hallgren, A. et al. (2008) Auto-
immunepolyendocrine syndrometype1andNALP5,aparathyroid
autoantigen. NewEngland Journal of Medicine,358,1018–1028.
Remission in hypoparathyroidism
333
? 2010 Blackwell Publishing Ltd, Clinical Endocrinology, 72, 328–333