Key words
paraesthesia - misdiagnosis - carpopedal spasm
Introduction
Hypoparathyroidism leads to abnormal calcium metabolism characterised by
hypocalcaemia and hyperphosphatemia due to deficient synthesis or secretion of
parathyroid hormone [1]. It is a relatively
uncommon disorder with prevalence estimated in a large epidemiological population
based study to be around 37 per 100 000 person-years [2]. The data on prevalence and incidence of
hypoparathyroidism is still lacking in most countries. The aetiology of
hypoparathyroidism can be divided into primary hypoparathyroidism, which occurs due
to intrinsic defect within the parathyroid gland and the acquired or secondary
hypoparathyroidism due to conditions that impair parathyroid gland function.
Acquired hypoparathyroidism is more common than primary hypoparathyroidism, with
hypoparathyroidism after neck surgery being the most common overall cause of
hypoparathyroidism [3]. The aetiology is
labelled as idiopathic if no cause is found after exclusion of all possible
aetiologies. Idiopathic hypoparathyroidism usually has a genetic aetiology [4].
The clinical signs and symptoms of hypoparathyroidism are broadly related to
neuromuscular dysfunction (due to hypocalcaemia) and ectopic mineralisation in
various soft tissues (due to hyperphosphatemia) [5]. The quality of life (QOL) is altered in patients leading to a
decreased sense of well-being. But still no conclusive evidence of increased
mortality has been shown in patients of hypoparathyroidism [6]. The highly variable signs and symptoms
often leads to a misdiagnosis in the initial stages of the disease. There is often
a
latent period of many years from the onset of symptoms to the correct diagnosis of
hypoparathyroidism [7]. Only a few case series
of hypoparathyroidism have been reported. We describe here the clinical and
biochemical profile of patients of hypoparathyroidism admitted over a period of five
years.
Patients and Methods
We analysed the case records of 32 consecutive patients of idiopathic
hypoparathyroidism admitted between January 2014 to December 2018 at our institute.
Demonstration of hypocalcaemia and hyperphosphatemia with low levels of parathyroid
hormone (iPTH) were consistent with the diagnosis of hypoparathyroidism. Only cases
of idiopathic hypoparathyroidism were included in the study and cases of
postoperative hypoparathyroidism, autoimmune hypoparathyroidism (as part of
Autoimmune Polyglandular Syndrome), hypoparathyroidism post-radiation exposure, and
hypoparathyroidism due to infiltration (likely to metastasis, hemochromatosis,
Wilson’s disease, etc.) were excluded from analysis.
Detailed clinical history and examination were noted. Age at onset of symptoms,
duration of symptoms, presenting complaint, various symptoms and signs related to
hypocalcaemia and hyperphosphatemia were recorded for each patient. Treatment
history pertaining to the symptoms was also taken. Ophthalmic assessment especially
to look for posterior subcapsular cataract was done.
Blood samples for total serum calcium (reference range:
8.6–10.2 mg/dl), inorganic phosphorus (reference range:
2.5–4.5 mg/dl), serum alkaline phosphatase (reference range:
40–130 King IU/l), albumin (reference range:
3.5–5.5 g/dl), and creatinine (reference range:
0.6–1.2 mg/dl) were collected and estimated by automated
analyser (model: BS-800; make: Mindray). Ionised calcium values (reference range:
1.1–1.35 mmol/l) were also estimated from a venous blood gas
sample. Total serum calcium levels were corrected for respective serum albumin
levels. Twenty-four-hour urinary calcium values (with simultaneous detection of 24-h
urinary creatinine to assess adequacy of sample collection) were noted. iPTH levels
(reference range: 11–67 pg/ml) were measured by
immunochemiluminiscence assay (model: Unicel DxI 600; make: Beckman Coulter). Serum
25 hydroxyvitamin D levels were estimated by immunochemiluminiscence (reference
range 9–37 ng/ml, model: Unicel DxI 600; make: Beckman
Coulter). All patients had ultrasound abdomen to look for nephrolithiasis and
nephrocalcinosis. Non-contrast computed tomography of the head was also performed
in
each patient to look for intracranial calcification.
Categorical variables were presented in number and percentage (%) and
continuous variables were presented as mean±SD and median. Qualitative
variables were corelated using Fisher’s exact test. A p-value of
<0.05 was considered statistically significant. The data were entered in MS
Excel spreadsheet and analysis were done using Statistical Package for Social
Sciences (SPSS) version 21.0.
Results
A total of 32 consecutive patients admitted with idiopathic hypoparathyroidism were
studied. Twenty (62%) patients were males with the mean age at presentation
being 27.1±8.52 years (8–45 years). The mean age at the onset of
symptoms was 21.2±9.2 years (1–42 years) and there was a lag period
of 5.94±4.07 years (3 months to 15 years) from the first reported symptom to
the diagnosis ([Table 1]).
Table 1 Demographic and biochemical profile of the patients
(n=32).
|
Characteristic
|
Mean±SD
|
Median
|
Min–Max
|
Inter quartile Range
|
|
Age (years)
|
27.19±8.52
|
27.5
|
10–45
|
21.500–32.500
|
|
Age at onset of symptoms (years)
|
21.25±9.2
|
21
|
1–42
|
16–25
|
|
Duration of symptoms (years)
|
5.94±4.07
|
5
|
0.25–15
|
3–8
|
|
Serum calcium (mg/dl)
|
5.82±0.77
|
5.85
|
2.9–6.9
|
5.400–6.350
|
|
Serum phosphorus (mg/dl)
|
6.94±0.59
|
7.05
|
4.8–7.56
|
6.800–7.400
|
|
Ionized calcium (mmol/l)
|
0.57±0.08
|
0.57
|
0.41–0.69
|
0.506–0.621
|
|
Ca Po4 product
|
40.23±7.05
|
41.36
|
19.14–49.5
|
36.570–44.970
|
|
Serum PTH (pg/ml)
|
5.75±1.2
|
5.85
|
2.5–7.8
|
5.050–6.700
|
|
Serum albumin (g/l)
|
3.96±0.33
|
3.9
|
3.2–4.6
|
3.800–4.200
|
|
Serum ALP (IU/l)
|
183.25±110.9
|
135
|
26–486
|
112–194
|
|
BMI (kg/m2)
|
21.56±2.53
|
21.35
|
16.6–27.2
|
19.850–23.100
|
Carpopedal spasm was the most common reason for admission to hospital, present in
25
(59.5%) patients followed by seizures (40.5% of patients). Overall
fatigue was the most common reported symptom (84%) followed by paraesthesia
(62.5%) followed by carpopedal spasm and seizures each seen in 59.3%
of the patients. Twenty patients (62.5%) had presence of cataract on
ophthalmologic examination. Dental abnormalities were present in 8 (25%)
patients. Only 2 patients had nephrocalcinosis on renal imaging. As many as 15
(46.5%) patients gave history of treatment with antiepileptic drugs ([Table 2]). One of the patients had brittle
nails with transverse grooves and ridging ([Fig.
1]).
Fig. 1 Characteristic nail changes in a patient of idiopathic
hypoparathyoidism.
Table 2 Clinical profile of the patients (n=32).
|
Clinical features
|
Frequency (n=32)
|
Percentage
|
|
Fatigue
|
27
|
84.37%
|
|
Paraesthesia
|
20
|
62.50%
|
|
Seizures
|
19
|
59.38%
|
|
Carpopedal spasm
|
19
|
59.38%
|
|
Irritability
|
17
|
53.13%
|
|
Treatment with Antiepileptic drugs
|
15
|
46.88%
|
|
Cataract
|
20
|
62.50%
|
|
Dental abnormalities
|
8
|
25.00%
|
|
Family history
|
7
|
21.88%
|
|
Chovstek sign
|
11
|
34.38%
|
|
Trousseau’s sign
|
19
|
59.38%
|
|
Basal ganglia calcification
|
22
|
68.75%
|
Mean serum total calcium and phosphorus levels at presentation were
5.82±0.77 mg% (2.9–6.9 mg%) and
6.94±0.59 mg% (4.8–7.56) respectively. The mean
calcium phosphorus product was 40.23±7.05 (19.14–49.5). Ionised
calcium levels ranged between 0.41 to 0.69 with a mean of 0.57±0.08. Basal
ganglia calcification was present on imaging in 22 (68.75%) of the patients
([Fig. 2]). Presence of basal ganglia
calcification was corelated with the presence of seizure (89.5% of patients,
p=0.005).
Fig. 2 Diffuse cerebral calcification on brain imaging.
Discussion
Hypoparathyroidism is a relatively uncommon metabolic disorder, which results from
inadequate secretion or synthesis of PTH [1].
Overall postsurgical hypoparathyroidism is the most common aetiology of
hypoparathyroidism in clinical practice, accounting for about 75% of the
cases. Idiopathic hypoparathyroidism is generally due to several genetic
aetiologies, which result in loss of parathyroid action or function [8].
PTH is the major hormone regulating calcium and phosphate homeostasis in the body
via
its direct actions on bone and kidney and indirect action on gastrointestinal tract
through 1,25-dihydroxyvitamin D production [9]. Thus, the main biochemical hallmarks of hypoparathyroidism are
hypocalcaemia and hyperphosphatemia. Hypocalcaemia causes neuromuscular signs and
symptoms of hypoparathyroidism while hyperphosphatemia causes mainly ectopic
mineralisation in soft tissues (brain, kidney, vasculature, and other tissues).
Hypoparathyroidism can involve nearly every organ system of the body over the course
of the disease [9].
The mean age of presentation in our study was 27.1±8.52 years, which is quite
similar to the 28.7±14.1 years reported in a study done in India by Bhadada
et al. [10]. In contrast, in a study done in
USA, which included all aetiologies of hypoparathyroidism, the mean age of
presentation was 58±20 years [2]. The
difference could be due to inclusion of cases of post-surgical hypoparathyroidism
as
well. Our study showed a time lag of 5.94±4.07 years from the first reported
symptom to the diagnosis. As the early manifestations of hypoparathyroidism are
highly variable and nonspecific, it is prudent to keep a high index of suspicion for
the diagnosis. The delay in diagnosis may lead to poor quality of life.
Fatigue (84%) and paraesthesia (62.5%) were the most common reported
symptoms in our study, which again highlights the fact that hypoparathyroidism can
have nonspecific symptoms in the early stage of the disease. History of previous
episode of seizure and carpopedal spasm was present in 60% of the patients
each. Most common indication of admission to hospital was carpopedal spasm.
Carpopedal spasm followed by paraesthesia were the most common reported symptoms in
a study done by Bhadada et al. [10]. The
typical cataract described in patients of hypoparathyroidism is a subcapsular
cortical region opacity having a radial spoke like appearance [11]. Since the cataract associated with
idiopathic hypoparathyroidism develops slowly and typically do not affect the vision
until past middle age, it goes often unrecognised [12]. In our study also, 62.5% of patients had cataract on
presentation. Basal ganglia calcification is also commonly seen in patients of
hypoparathyroidism. It is due to hyperphosphatemia leading to high calcium-phosphate
product leading to ectopic calcification. Goswami et al. [13] also hypothesised that inorganic phosphate
transporter pit 1 (SLC20A1) may be activated by hyperphosphatemia resulting in the
expression of osteogenic molecules in the caudate nucleus and gray matter.
Almost half of the patients were misdiagnosed as seizure disorder and were on
antiepileptic drugs. A literature review done by Li et al. [14] reviewing 1020 cases of hypoparathyroidism
showed a misdiagnosis rate of 29.51%. Frequently these patients are
misdiagnosed as epilepsy, neurosis, and mental disorders [15]. Patients of idiopathic hypoparathyroidism
are also frequently misdiagnosed as Fahr disease based on intracranial calcification
if the clinical and biochemical profile of the patients are ignored [15].
Conclusion
The symptoms of presentation of idiopathic hypoparathyroidism were related to the
severity of hypocalcaemia. Carpopedal spasm and seizure were the most common
presentation for hospital admission. The highly nonspecific and variable
presentation of idiopathic hypoparathyroidism often leads to a long lag period of
diagnosis as well as high probability of misdiagnosis. A serum calcium profile done
in patients with complaint as trivial as that of paraesthesia may avoid the long
delay as well as misdiagnosis of patients of idiopathic hypoparathyroidism.
Data Availability Statement information
Data Availability Statement information
We state that findings of this study can be taken up from the corresponding author
upon reasonable request.
