Severe hypocalcaemia episodes in a patient of primary hypoparathyroidism precipitated by underlying stress due to haemophagocytic lymphohistiocytosis (HLH) secondary to pulmonary tuberculosis

  1. Tushar Ashok Vidhale 1,
  2. Rucha Prafulla Bhalde 2,
  3. Minal Pande 1 and
  4. Shital Pradeep Mahure 3
  1. 1 General Medicine, Grant Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
  2. 2 Radiology, Grant Government Medical College and Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
  3. 3 Pathology, Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, Maharashtra, India
  1. Correspondence to Dr Tushar Ashok Vidhale; tusharvidhale@hotmail.com

Publication history

Accepted:15 Feb 2023
First published:02 Mar 2023
Online issue publication:02 Mar 2023

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

A man in his 20s who had previously experienced multiple episodes of transient loss of consciousness, majorly attributable to the seizures, presented with a 1-month history of increased seizure frequency, high-grade fever and weight loss. Clinically, he had postural instability, bradykinesia and symmetrical cogwheel rigidity. His investigations revealed hypocalcaemia, hyperphosphataemia, inappropriately normal intact parathyroid hormone, metabolic alkalosis, normomagnesemic magnesium depletion, and increased plasma renin activity and serum aldosterone concentration. CT scan of the brain revealed symmetrical calcification of the basal ganglia. The patient had primary hypoparathyroidism (HP). A similar presentation of his brother indicated a genetic cause, most likely autosomal dominant hypocalcaemia with Bartter’s syndrome type 5. The patient’s fever was caused by underlying haemophagocytic lymphohistiocytosis secondary to pulmonary tuberculosis, which triggered acute episodes of hypocalcaemia. This case represents a complex interplay of a multifaceted relationship between primary HP, vitamin D deficiency and an acute stressor.

Background

A calcium-sensing receptor (CaSR) activating (gain of function) mutation causes autosomal dominant hypocalcaemia (ADH), a subtype of primary hypoparathyroidism (HP).1–4 These individuals exhibit abnormal biochemical profiles, including hypocalcaemia, hypomagnesaemia, hyperphosphataemia, inappropriately normal serum intact parathormone (iPTH) concentrations and high or high normal urine calcium excretion.1–3 ADH was long considered to induce mild, asymptomatic hypocalcaemia that required no therapy; however, it is now evident that it can cause refractory hypocalcaemia and severe symptoms, such as convulsions, depending on the mutation and its impact on parathyroid cells.4 5 People with ADH often appear in their adult years since most patients initially receive a preliminary diagnosis of idiopathic HP or hypocalcaemia.4 They have prolonged hypocalcaemia and hyperphosphataemia with an elevated calcium phosphate product, leading to the development of intracranial calcification. However, extrapyramidal neurological manifestations owing to basal ganglia calcification are rare.6 Adult patients may occasionally experience recurring nephrolithiasis and nephrocalcinosis, especially after treatment with calcium and vitamin D supplements.1 2 5 A phenotype resembling Bartter’s syndrome (BS) might result from a severe gain of function mutation of CaSR, which could cause potassium deficiency, hypomagnesaemia and metabolic alkalosis.2 Patients with BS type 5 vary in terms of their clinical presentation and symptom onset age depending on their specific mutation.7 Few patients of primary HP might have inappropriately normal iPTH secretions despite hypocalcaemia, suggesting that these individuals still have some secretory capability but not nearly enough to fulfil physiologic demands.5 Under stressful conditions, because of hyperventilation, catecholamine release, physical activity and glucocorticoid secretion are all thought to contribute to severe hypocalcaemia among these individuals, potentially revealing concealed mild phenotypes of primary HP.8 We report a patient with severe hypocalcaemia caused by primary HP, with a multifaceted interaction between vitamin D deficiency and an acute stressor, that is, unexplained fever, which finally proved to be because of haemophagocytic lymphohistiocytosis (HLH) secondary to pulmonary tuberculosis in this case.

Case presentation

A man in his 20s, presented to the healthcare facility with a 1-month history of recurring seizures and high-grade intermittent fever. He had impaired sensorium for the preceding 2 hours due to recurring episodes of seizures. His fever was high grade, intermittent in nature and was associated with chills for a month; his maximum temperature was 101°F; the fever used to resolve with paracetamol; and was accompanied by weight loss of around 3–4 kg. His parents mentioned that he had been experiencing behavioural issues (irritability, aggression) for around 15 days and had been vomiting for about 4–5 days. As per the records, clinically, he had Glasgow Coma Scale (GCS) scores of E3V4M5 and exhibited no meningeal irritation signs. His initial evaluation at the hospital revealed hypocalcaemia, hyperphosphataemia, inappropriately normal intact parathyroid hormone (iPTH) and symmetrical calcification of the basal ganglia on CT of the brain. His seizures were treated with continuous calcium gluconate infusion and intravenous antiepileptic drugs (AEDs), that is, carbamazepine, sodium valproate and phenobarbitone. His seizures, however, were not under control even with three AEDs. Levetiracetam and lacosamide caused a hypersensitive response in him. In view of the patient’s financial limitations and the refractory nature of the seizures, he was referred to our facility. On presentation to us, the patient was in an active generalised convulsive state with tonic posturing, GCS of E2V3M5 and pupils were normal in size and reacting to light and bilateral flexor plantar response. He also had a fever (axillary temperature 102°F), tachycardia (heart rate 134 beats/min), tachypnoea (respiratory rate 28 breaths/min), hypotension (blood pressure 80/50 mm Hg), hypoxaemia (SpO2 88% by digital pulse oximeter), zero central venous pressure and random blood sugar 94 mg/dL by finger prick. After securing the airway by positioning manure and airway devices, the patient received 100% oxygen, intravenous hydration (0.9% normal saline) and lorazepam 4 mg intravenous over 2 min. He also received a valproic acid loading dosage of 20 mg/kg and calcium gluconate 1 g infusion over 20 min, followed by maintenance infusion at the rate of 2 mg/kg/hour. His blood pressure responded to fluid resuscitation. Although valproic acid reduced the frequency of his seizures, they ceased completely after a loading dosage of phenytoin sodium. On day 2 of admission, the patient was seizure free, and his ionised serum calcium levels improved to 0.9 mmol/L. He was alert and able to communicate, but he was restless and had difficulty paying attention. On detailed history, it was revealed that the patient had been experiencing seizures since he was an infant. The patient had generalised tonic–clonic convulsive activity, which lasted for 2 min during the first episode, which was treated by the general practitioner as febrile seizures. The patient had not had another seizure in almost 5 years after the initial event. In his early childhood, the patient began experiencing recurrent seizures of similar semiology, which were generalised tonic–clonic in character and were accompanied by a loss of consciousness and tongue biting, each one of which was followed by postictal confusion. The absence of fever during these episodes is noteworthy. He was hospitalised 12–14 times in 7 years for these episodes of loss of consciousness, all of which were treated by private paediatricians in his neighbourhood. Due to their inability to pay for the treatment, parents typically chose early discharge against medical advice. The patient was not started on maintenance AEDs after being discharged, and neither the patient nor his parents were provided any knowledge or advice about the child’s condition. The patient was not initiated on maintenance AED until his early adolescence, at which point he was continued on sodium valproate for 3 years with gradual tapering as he was seizure free. In addition, periodically, the patient exhibited bradykinesia and gait instability with repeated en bloc backward falls producing blunt injuries to the back that began insidiously 2 years prior to the present hospitalisation. Moreover, during the past 2 years, he has shown a progressive decline in his academic performance. The patient was seizure free in the past 4 years until a month prior to present admission when he started having recurrent convulsive episodes along with high-grade fever. His parental marriage was consanguineous. He was delivered at full term by vaginal delivery, and there were no perinatal complications during his birth. He cried shortly after delivery, and his immunisation was complete. The birth weight and developmental milestones of the patient remained normal till late adolescence. The history of delayed fall of temporary teeth and superadded dentition is noteworthy (figure 1). He was the eldest of the two siblings. Similar history of seizure disorder is present in his first-degree relative. Clinical examination of his sibling was unremarkable. The patient’s social background was low, and he was accustomed to living in overcrowded conditions. He used to live in a slum having high endemicity for tuberculosis. There was no history of neck surgery, congenital defects or recurrent infections in the past. There had been no history of brain trauma, cerebral infection or myoclonus. Physical examination on day 3 of admission revealed a mini–mental state examination score of 24/30 (missed 3 points in calculation, 2 points in recall and 1 point in copying a figure); bradykinesia, symmetrical cogwheel rigidity in upper limbs. His eye movement was characterised by slow saccades and broken pursuit movements. His other extrapyramidal, motor, sensory, cerebellar and cranial nerve examinations were unremarkable. He had a wide-based ataxic gait with a problem with tandem walking. On approximation of both feet with eyes closed, he tends to sway backwards. No meningeal irritation signs were noted. Fundus examination was within normal limits. There was no lymphadenopathy, oral candidiasis or vitiligo, nor were there any signs of development failure, congenital defects, hearing loss, dysmorphic facial features or mental retardation. Another system review was unremarkable.

Figure 1

Axial CT of the head—bone window image at the level of mandibular alveolar processes shows abnormal dentition with unerupted tooth. Abnormal dentition is also seen in maxillary alveolar processes.

During his hospital stay, the patient was seizure free by the 2nd day when calcium and magnesium depletion were corrected. His bradykinesia and postural instability improved with the correction of hypocalcaemia. He was afebrile for 7 days, but he had a resurgence of high-grade fever on day 8, which escalated to continuous fever (the highest temperature was 101°F–102°F) on day 10 of hospitalisation. There were no clinical clues to the location of the fever. Given the overcrowded living circumstances, high tuberculosis incidence in the region, persistent fever with no localisation-related symptoms, associated weight loss and pulmonary infiltrates on CT of the chest prompted us to consider empirical therapy with antitubercular drugs on day 10 of admission. His high-grade fever was persistent from day 10 to day 14. From day 14, he started having hyperpyrexia (max temperature 105oF–106oF); the patient also has periodically complained of paraesthesia in his fingers and toes as well as muscle cramps. Clinically, these episodes were distinguished by increased bradykinesia, increased cogwheel rigidity and evident Chvostek’s and Trousseau’s signs. His serum calcium at that time was low. Intravenous calcium gluconate supplementation was used to alleviate these intermittent episodes of neuromuscular irritability and extrapyramidal symptoms. On day 18 of admission, the patient had clinically apparent cervical lymphadenopathy. Lymph nodes were approximately 1×1 cm, non-tender, mobile, non-matted and were palpable in the bilateral jugulodigastric region. A detailed timeline of the presentation is given in tables 1 and 2.

Table 1

Timeline of clinical presentation till present admission

Table 1

Timeline of clinical presentation till present admission

Table 2

Timeline of clinical presentation after admission

On day 1 of admission

  • On admission, the patient had status epilepticus.

  • Seizures were under control after patients received intravenous calcium, magnesium and antiepileptic drugs.
Days 3–6 of admission

  • The patient’s seizures were under control, and he had no fever.

  • The patient becomes ambulant independently on day 3.

  • Aetiology for hypocalcaemia was attributed to primary hypoparathyroidism after initial evaluation.
Day 8 of admission

  • The resurgence of high-grade fever (max temperature 101°F).

  • No localisation-related symptoms or signs of fever.
Day 10 of admission

  • Continuous high-grade fever (max temperature 101°F–102°F).

  • Initiation of antitubercular treatment.
Days 10–14 of admission

  • Continues to have high-grade fever (max temperature 101°F–102°F).
Days 14–18 of admission

  • Continuous high-grade fever with hyperpyrexia (range of temperature 100°F–106°F).

  • Blood (three different sites at hourly intervals) and urine cultures were repeated. Antibiotics were upgraded to intravenous meropenem, linezolid and gentamicin.
Day 18 of admission

  • The appearance of cervical lymphadenopathy.

  • Bone marrow aspirate and biopsy were performed.

  • Initiation of steroids—tablet dexamethasone 10 mg/m2/day in divided doses.
Day 20 of admission

  • A positron emission tomography CT scan was done.

  • It revealed mildly enlarged bilateral level I–V cervical lymph nodes, which show low-grade fluorodeoxyglucose (FDG) uptake with the representative right level II lymph node measuring 1.7×1.3 cm (SUVMax 4.9). Splenomegaly (13.9 cm) with low-grade increased FDG uptake. Low-grade reactive diffuse FDG uptake in the bone marrow. The final impression was likely an inflammatory bilateral cervical lymphadenopathy with a reactive increase in the marrow and splenic activity.
Day 21 of admission

  • Lymph node excision biopsy done.
Day 23 of admission

  • Remission of fever with subjective improvement.

  • Bone marrow aspirate report received which revealed hypocellular marrow with an increase in histiocytes along with few erythrophagocytosis.
Day 26 of admission

  • The lymph node biopsy report was suggestive of expansion of the paracortical zone. Secondary lymphoid follicles with germinal centres are seen in the paracortical zone. All findings were suggestive of the reactive lymph node.
Final diagnosis

  • Chronic primary hypoparathyroidism with underlying genetic aetiology (possibly autosomal dominant hypocalcaemia type 1 and Bartter’s syndrome type 5).

  • Pulmonary tuberculosis with haemophagocytic lymphohistiocytosis.

Investigations

His routine complete blood count trend and biochemical investigations have been mentioned below (tables 3–6). His serum creatinine phosphokinase (CPK) was 1642 U/L (24–195 U/L); plasma renin activity was 18.28 µg/L/hour (0.5–3.3 µg/L/hour); serum aldosterone concentration in supine position was 35.6 ng/dL (2–22 ng/dL). His creatinine, renal function test, routine urine microscopy, glycated haemoglobin (5.5%), blood sugar profile (fasting and postprandial), thyroid function test (3.18 µIU/mL, (0.3–5.5 µIU/mL)) and liver function test (except slightly raised serum aspartate aminotransferase) were within normal limits. Morning serum cortisol measured at 6:00 (16.36 µg/dL (6.2–19.4 µg/dL)) and Acton Prolongatum (Ferring pharmaceutical) stimulation test (APST) were within normal limits. During APST, his serum cortisol 120 min after 0.5 mL intramuscular injection of Acton Prolongatum, that is, porcine ACTH (Adrenocorticotropic hormone) 1–39 was 28.8 µg/dL (reference range more than 19.5 µg/dL).9 Antinuclear antibody, antineutrophil cytoplasmic antibody profile, antithyroid peroxidase antibody, antiparietal cell antibody and intrinsic factor antibody were negative. Serology for HIV, hepatitis B virus and hepatitis C virus were non-reactive. His workup for common infective aetiology of fever, that is, antigen and peripheral smear examination for malaria; IgM and IgG for dengue, leptospira and brucella; IgM scrub typhus; COVID-19, H1N1 reverse transcription PCR, was unremarkable. Blood and urine culture sensitivity revealed no growth. Repeated induced sputum (with 3% normal saline) was negative for mycobacterium tuberculosis on Gene Xpert(Mycobacterium tuberculosis) MTB/RIF(Rifampicin). Induced sputum culture and sensitivity showed no growth of bacteria or fungal elements. His tuberculin skin test was equivocal (8 mm). Repeated transthoracic echocardiography was unremarkable. His 24 hours urine protein was 305 mg/24 hours (normal range less than 150 mg/24 hours). His cerebrospinal fluid (CSF) was suggestive of lymphocytic pleocytosis (total leucocyte count 15 cells/mm3 (0–5 cells/mm3)), neutrophils 33%, lymphocytes 67%, sugar 56 mg/dL (blood sugar 96 mg/dL), proteins 50 mg/dL (5–60 mg/dL). CSF culture was negative for bacterial, fungal or mycobacterial growth. There were no malignant cells on CSF cytospin. CSF Gene Xpert (Mycobacterium tuberculosis) MTB/RIF(Rifampicin) Ultra (performed on large volume repeated samples), Herpes simplex virus (HSV) PCR and venereal disease research laboratory were negative. Repeated arterial blood gas (ABG) analysis suggested metabolic alkalosis.

Table 3

Complete blood count

Table 3

Complete blood count

Table 4

Inflammatory phase reactants and workup for haemophagocytic lymphohistiocytosis

Table 4

Inflammatory phase reactants and workup for haemophagocytic lymphohistiocytosis

Table 5

Investigations for hypocalcaemia

Table 5

Investigations for hypocalcaemia

Table 6

Investigations for hypocalcaemia

1 day prior to admission At admission 36 hours after admission 48 hours after admission 72 hours after admission Reference range
ECLIA, electrochemiluminescence immune assay; iPTH, intact parathyroid hormone.
iPTH by ECLIA (pg/mL) 12.96 19.0 15–65
25-OH Vitamin D (ng/ mL) 16.01       30–100
Magnesium (mg/dL) 2.52 1.50 1.8 2.02 2.60 1.6–2.6
Alkaline phosphatase (U/L) 200 179       75–275
24 hours urinary calcium level per day (mg/24 hours)     40 mg/24 hours; urine volume 5000 mL 100–300 mg/24 hours
Spot urinary chloride
(mEq/L)		 45   50

Differential diagnosis

Our patient was suffering from a chronic progressive illness that is responsible for seizures, bradykinesia, postural instability and a gradual decline in academic performance. He has been having subacute worsening seizures, abnormal behaviour and fever for the last month. Clinically he had symmetrical cogwheel rigidity, bradykinesia and postural instability, indicating a hypokinetic movement disorder characterised by bilateral basal ganglia involvement. As a result, we looked at the differentials of early-onset subacute to chronic hypokinetic movement disorder. The most common causes of early-onset subacute to chronic parkinsonism include drugs (dopamine receptor blockers); encephalitides such as Japanese encephalitis and West Nile encephalitis; toxins (methanol poisoning, 1-methyl-4-phenyl-1,2,3,6-terahydropyridine, ethylene oxide or organophosphates); major alcohol withdrawal; pontine and extra pontine myelinolysis; metabolic disorders (Wilson disease, haemochromatosis, endocrinopathies such as HP); neurodegenerative disorders such as neurodegeneration with brain iron accumulation, mitochondrial disorders and Huntington chorea. Also, neuroleptic malignant syndrome and catatonia can have rigidity.10 Our patient had no history of exposure to harmful toxins or drugs, and he has chronic psychiatric issues requiring dopamine receptor blockers. He had never experienced hyponatraemia, was not an alcoholic and his slit lamp test revealed no evidence of the Kayser-Fleischer ring. Nevertheless, severe hypocalcaemia, hyperphosphataemia, an inappropriately normal iPTH and bilateral basal ganglia calcification were seen during our patient’s initial workup, pointing to the diagnosis of HP.1 2 11 12 There was no prior history of thyroid or parathyroid surgery. He tested negative for antinuclear, antithyroid peroxidase, antiparietal cell and antiintrinsic factor antibodies. Through the patient’s medical history, a clinical examination and serological tests, we attempted to rule out possible autoimmune causes of the HP in our patient, including autoimmune polyendocrinopathy,candidiasis ectodermal dystrophy and other autoimmune disorders. The affected first-degree relative was examined extensively, and we found that clinically he too had cogwheel rigidity and biochemically hypocalcaemia, hypomagnesaemia, hyperphosphataemia, an abnormally normal iPTH, hypokalaemia and increased spot urine chloride. This hinted towards the possibility of the genetic cause of HP with solitary parathyroid endocrinopathy without other syndromic manifestations, mostly favouring a diagnosis of primary HP owing to activating (gain of function) mutation of the CaSR gene as the most likely cause of his ailment. The most common genetic aetiology for isolated HP is ADH.1 2 12 13 Our patient also had hypocalcaemia refractory to calcium correction, which got corrected with magnesium replacement pointing to the possibility of normomagnesemic magnesium depletion. Because of PTH’s involvement in magnesium homeostasis in the kidney, a few patients with HP (especially those with ADH) may have hypomagnesaemia and benefit from magnesium supplements.12 Blood magnesium levels can be normal even when intracellular magnesium levels are low; hence ruling out hypomagnesaemia as a cause or contributor to hypocalcaemia can be challenging.1 2 12 In most cases, serum calcium levels are only mildly reduced if magnesium depletion is the predominant problem.1 Due to the severity of the hypocalcaemia that our patient was experiencing, we have reason to assume that hypomagnesaemia may be a contributing factor rather than a cause for his hypocalcaemia. Our patient also had vitamin D deficiency as well, but in classic vitamin D deficiency, iPTH levels are elevated, and serum phosphorus levels are low or at the lower end of the normal range.13 This is in stark contrast to the high levels seen in our patient, where serum phosphorus levels are typically high.1 12 13 He also showed features of possible associated BS, including hypokalaemia, elevated spot urine chloride with normal blood pressure and persistent metabolic alkalosis, and elevated renin and aldosterone levels. Therefore, a combination of ADH type 1 (ADH 1) with BS type 5 was regarded as the most likely diagnosis.2 He did not have hypokalaemia, and his BS manifestations, in our case, were minor, and it is known that phenotypic heterogeneity exists due to various activating mutations of CaSR.7 Though hypocalcaemia with increased urinary calcium excretion is a characteristic of ADH, vitamin D deficiency may conceal hypercalciuria in this condition.14 Unfortunately, his genetic analysis was never conducted due to a lack of resources and no genetic testing facilities at our institution.

He had chronic fever, which was persistent even after admission, with no localisation-related features on history or physical examination. His fever of unknown origin (FUO) may have served as a stressor, aggravating his hypocalcaemia. His CT scan showed ascites and hepatosplenomegaly in the abdomen, as well as pulmonary infiltration, pleural thickening and subcentimetric lymphadenopathy in the thorax. His inflammatory markers were increased, and the tuberculin skin test was equivocal (8 mm). His evaluation for other usual infectious and autoimmune aetiologies of fever revealed nothing unusual. Broncho alveolar lavage was not performed in view of the non-availability of facilities in the hospital. Given the squalid living circumstances, high TB incidence in the region, persistent fever, weight loss and pulmonary infiltrates on the CT of the thorax, the probability of disseminated tuberculosis was taken into account. However, his high-grade fever and induced sputum (with 3% normal saline) negativity for mycobacterium tuberculosis on Gene Xpert MTB/RIF was not corroborating with tubercular aetiology. Still, antitubercular treatment (ATT) was initiated on day 10 of admission in accordance with national guidelines for situations with clinically suspected TB, but his fever did not subside even after 7 days of ATT. Chronic fungal infections, such as histoplasmosis, aspergillosis and candidiasis, can also result in pulmonary infiltration. Histoplasmosis became less plausible in our case due to negative blood culture and the disease’s low prevalence in India, yet, it was extremely difficult to entirely rule it out. Aspergillosis and candidiasis occurred less often in people who did not have underlying cancer, granulocytopaenia, diabetes or HIV infection.

On day 14 of the admission, the patient started having hyperpyrexia with a recurrence of symptoms of neuromuscular irritability due to hypocalcaemia. He required intravenous calcium infusion multiple times for hypocalcaemia correction from day 14 to day 20 of admission. On day 18, he had an appearance of lymphadenopathy. Since the patient had lymphadenopathy, hepatosplenomegaly and persistent fever despite 7 days of ATT, we maintained the additional differentials of lymphoma, multidrug-resistant TB and HLH related to tuberculosis. He was initiated on oral dexamethasone at doses of 10 mg/m2/day on day 18 of admission with a plan to tap it over 8 weeks. A lymph node histological examination ruled out the likelihood of lymphoma. His PET CT scan revealed bilateral cervical lymphadenopathy (SUVMax 4.9), indicating inflammatory lymphadenopathy with reactive marrow and splenic activity. Hyperpyrexia, hepatosplenomegaly, elevated serum ferritin and triglyceride levels, and enhanced histiocytosis and erythrophagocytosis on bone marrow aspiration, with reactive lymph node on histopathology, were all indicative of HLH. His fever subsided, and he showed signs of recovery 4 days after beginning the steroids. We believe that his HLH was secondary to pulmonary TB. Despite the fact that we were unable to confirm TB microbiologically, the patient gained 1 kg and his CT of the chest demonstrated a reduction in pulmonary infiltrates after 2 months of follow-up.

Although myopathy caused by HP is well-documented, our patient showed no evidence of myopathy on EMG. Elevated CPK in our patient may have been caused by hypocalcaemia-related seizures and increased muscular activity, which was alleviated by normocalcaemia. Few case reports have noted comparable clinical situations in which individuals with idiopathic HP presented with neuromuscular irritability and increased CPK, which resolved on treatment of hypocalcaemia.10 15

This index case illustrates the complex interplay between numerous overlapping processes, such as HP, BS, vitamin D deficiency and FUO. The patient’s acute illnesses were most likely the triggering events that prompted the identification of underlying primary HP. It is clear from this situation that the Occam razor is not always applicable when attempting to explain complex clinical situations like this.

Treatment

On hospitalisation at our facility, the patient had severe dehydration, status epilepticus, lymphocytic meningitis and lower respiratory tract infection. Initially, the airway was secured with positioning manures and an airway device. For dehydration, fluid resuscitation was initiated, after which his blood pressure normalised. His status was managed with benzodiazepine, the loading dose of AED and calcium replacement. He received 1 g of calcium gluconate slowly over 20 min, followed by 2 mg/kg/hour continuous infusion, but despite that, his ionised calcium was <1 mmol/L after 6 hours; hence his infusion rate increased by 3 mg/kg/hour. Though the patient had near normal magnesium, considering the refractory nature of his hypocalcaemia possibility of normomagnesemic magnesium depletion was considered, and an intravenous magnesium sulphate 2 g solution with continuous infusion over 12 hours was given for 3 days, followed by a maintenance dose of tablet magnesium oxide 500 mg once a day. He received capsule calcitriol 0.25 μg/day followed by up-titration to 0.5 μg/day the subsequent week. On day 2 of admission, the patient was seizure free, and his ionised serum calcium levels improved to 0.9 mmol/L. On day 2, he was initiated on the tablet of calcium carbonate 1 g (500 mg elemental calcium) three times a day along with continuous calcium gluconate infusion, which was gradually tapered and stopped on day 3. The patient was ambulant independently from day 4, but his fever was persistent. For CSF pleocytosis, he received an empirical course of intravenous antibiotics (ceftriaxone and vancomycin) and antiviral (acyclovir) for 14 days. In view of prolonged fever, chest infiltrates and raised inflammatory markers, the patient was started on ATT (rifampicin, isoniazid, pyrazinamide and ethambutol) along with pyridoxine as per the national guidelines. In view of hyperpyrexia (even after 7 days of ATT), lymphadenopathy and hepatosplenomegaly, with biochemical evidence of raised ferritin and triglyceride, the possibility of HLH was considered. He was initiated on oral dexamethasone at doses of 10 mg/m2/day on day 18 of admission with a plan to taper it over 8 weeks. With ATT and steroids for HLH, his fever got settled on day 23 of admission. The opinions of endocrinology, neurology and nephrology were sought for his primary HP.

Outcome and follow-up

The patient was discharged on day 35. He followed up after 1 month; he did not have any episode of seizures. Clinically, he was unremarkable. His repeat albumin-corrected calcium was 8 mg/dL, phosphorus was 6 mg/dL and 24-hour urinary calcium was 160 mg/24 hours. Follow-up after 2 months, the patient gained 1 kg weight and his CT of the chest demonstrated a reduction in pulmonary infiltrates.

Discussion

HP, which primarily causes hypocalcaemia due to a lack of PTH, is a relatively rare disorder with an estimated incidence of 23–37 cases per 100 000 person-years. PTH synthesis is inadequate to mobilise calcium from bone, reabsorb calcium from the distal nephron and promote renal 1∝-hydroxylase activity, resulting in hypocalcaemia among the patients of HP.1 2 12

The clinical manifestation of hypocalcaemia is determined by its duration, severity and speed of progression. It frequently ranges from asymptomatic hypocalcaemia on one end of the spectrum to neuromuscular irritation on the other end. Muscle cramps, twitching and spasms; circumoral and acral numbness and paresthesias; laryngospasm, bronchospasm and even seizures are all symptoms of neuromuscular irritability. Inappropriate or absent PTH secretion, in addition to hypocalcaemia, can also cause hyperphosphataemia and an increase in the fractional excretion of calcium in the urine.1 2 12

In routine clinical practice, acute stress (due to physical exertion, inflammation or infection) is a frequent precipitant of hypocalcaemia episodes in an individual with primary HP. The mechanism behind this brief disturbance in calcium homeostasis is unknown.8 16–18 Despite taking calcium and vitamin D supplements on a regular basis during his hospital stay, our patient experienced episodes of hypocalcaemia that required intravenous correction; we believe that the majority of these hypocalcaemia-related episodes were caused by underlying stress. According to Bhadada et al, the rationale for these irregularities might simply be that sickness reduces the consumption and absorption of dietary calcium, as well as the frequent administration of AEDs for seizures. They also advocated a sick day protocol to prevent severe hypocalcaemia in individuals with HP, which makes sense.16

Patients with HP often develop brain calcifications after receiving prolonged treatment with calcium salts and activated vitamin D metabolites, both of which have a tendency to increase the calcium and phosphate product. However, it has been shown that brain calcifications can be noticed at the time of diagnosis, even before the medication are commenced. This is especially true for individuals who might have underlying activating mutations in the CaSR.5

There is also a lack of clear understanding of the mechanism of parkinsonism in HP. Intracranial calcifications, hypocalcaemia and ischaemia to the basal ganglia (speculated to be a result of vascular calcification) are all potential causes of parkinsonism in HP.10 15 19 Walter reported a case similar to ours in which the patient had chronic HP with basal ganglia calcification and presented with neuromuscular irritability and parkinsonism. His exercise-induced extrapyramidal motor symptoms improved when he corrected his hypocalcaemia.15 In addition, parkinsonism due to striatal calcification is rare and is linked to a poor response to levodopa treatment.10 15 19

In adults, complications from anterior neck surgery account for nearly 75% of all cases of HP.1 2 12 Other probable aetiologies include genetic and autoimmune causes. These may cause isolated non-syndromic parathyroid endocrinopathy or contribute to syndromic disorders in which HP might be just one of the features. It is estimated that only around 10% of HP cases may be traced back to a genetic aetiology.1 3 12 Clinically, a genetic cause may be suggested for HP when symptoms manifest at a young age. Congenital abnormalities (such as cleft lip and congenital heart disease), deafness, renal dysplasias, chronic mucocutaneous candidiasis and strokes can all indicate to a genetic or autoimmune aetiology.3

The CaSR, a G-protein-coupled receptor, plays a key role in controlling the release of PTH in an inhibitory manner. Along with the parathyroid, other tissues, including the kidney, also expresses CaSR. Genetic studies have linked gain-of-function mutations in CaSR, and G11α protein to ADH types 1 and 2, respectively.2 4 ADH is the most prevalent inherited cause of isolated HP.13 ADH type 1 is characterised by hypocalcaemia, low or inappropriately normal PTH levels and high fractional calcium excretion, resulting in blatant hypercalciuria even when blood calcium levels are low.4

The activating mutation of CaSR shifts the set point for PTH secretion to the left, resulting in inappropriately normal PTH levels despite hypocalcaemia. The set point is defined as the extracellular calcium level necessary for half-maximal inhibition of secretion.5 CaSR is highly expressed in the renal cortex on the basolateral side of the thick ascending limb of the loop of Henle (TALH). Whereas the renal outer medullary potassium channel (ROMK) is expressed in the apical membrane of TALH. The activated CaSR, in turn, suppresses ROMK activity in rats.20 21 ROMK-mediated potassium secretion is required for positive luminal potential in the TAHL, which drives the paracellular reabsorption of calcium and magnesium. In individuals with CaSR activating mutations, a leftward shift in set point induces inhibition of ROMK at lower extracellular calcium levels, which is expected to increase urine excretion of calcium.20 22 As a result, one differentiating feature of ADH type 1 from postsurgical HP is the occurrence of more substantial hypercalciuria, particularly after the initiation of calcium and vitamin D replacement.2 4

In a comprehensive study of 338 ADH type 1 patient, Roszko K et al found that the clinical presentations of the condition were variable. Even though somewhat 27% of the patients were asymptomatic, more than one-third (41%) experienced at least one serious symptom due to neuromuscular irritability. It is remarkable that seizures were the most frequent presentation. The median age at the time of a complete diagnosis of ADH type 1 was 24 years. Several patients (around 99%) had hypocalcaemia at the time of their initial assessment, but it’s worth noting that about 34% of them had obvious hypercalciuria, and the other individuals had inappropriately normal urine calcium levels despite hypocalcaemia.4

Some individuals with ADH type 1 who have significant gain-of-function CaSR mutations may also have a Bartter’s-like syndrome (BS type 5), which includes hypokalaemic alkalosis, renal salt wasting and hyper-reninaemia along with hyperaldosteronism in addition to hypocalcaemia and HP.2 7 Depending on the precise mutation, clinical presentation and age of onset of BS may differ.7 Our patient showed only minor evidence of BS syndrome. He exhibited subnormal serum magnesium values, a mild metabolic alkalosis, increased plasma renin activity and serum aldosterone concentration. His serum potassium values were normal, and Choi et al have provided a similar case description.7

In contrast to the majority of hormone deficiencies, where hormone replacement is the basis of therapy, HP has traditionally been treated with vitamin D and calcium supplements.1 2 4 12 There are several calcium salts available for oral administration, including calcium carbonate, calcium citrate and calcium glubionate. One of these, calcium carbonate, is widely available, inexpensive and contains 40% elemental calcium by weight. Moreover, it requires an acidic environment for proper absorption. Thus, people on proton pump inhibitors or H2 blockers should be switched to a different form of calcium salt, such as calcium citrate.1 2 12 Calcium supplements should be taken with meals since it acts as a phosphate binder. Furthermore, food improves calcium absorption. Vitamin D analogues that have already undergone 1α-hydroxylation (calcitriol and alfacalcidol) are generally preferred because they reduce the risk of prolonged hypercalcaemia in the event of vitamin D intoxication.1 2 12

In the absence of PTH replacement, renal calcium reabsorption or phosphate excretion is not addressed by standard medical therapy. Hence, even with thorough supervision, individuals may develop hyperphosphataemia and hypercalciuria. As a result, the objective of conventional therapy is to raise blood calcium to the low-normal or slightly below the normal range, where symptoms related to hypocalcaemia can be avoided while hypercalciuria and its long-term complications (nephrocalcinosis, nephrolithiasis and decreased renal function) are minimised. Hypercalciuria brought on by calcium and vitamin D medication can be treated with thiazide diuretics. As 24-hour urine calcium levels approach 250 mg, the addition of a thiazide diuretic and low-sodium diet may be necessary.1 2 4 12

The aims of therapy include symptomatic relief, a serum albumin-adjusted total calcium level at the lower end of the normal range (about 8.0–8.5 mg/dL or 2.00–2.12 mmol/L), a 24-hour urine calcium level well below 300 mg and a calcium phosphate product below 55.1

Learning points

  • A calcium-sensing receptor (CaSR) activating (gain of function) mutation causes autosomal dominant hypocalcaemia (ADH), which is characterised by hypocalcaemia, hyperphosphataemia, inappropriately normal serum intact parathormone values and hypercalciuria.

  • Some ADH type 1 patients with severe gain-of-function CaSR mutations may also be associated with Bartter’s syndrome (BS) type 5. Depending on the precise mutation, clinical presentation and age of onset of BS may differ.

  • Although ADH type 1 is typically linked with normal or increased urine calcium excretion, it can exist in a small percentage of individuals with hypocalciuria if they also have concomitant vitamin D insufficiency.

  • In clinical practice, acute stress is considered a common trigger for hypocalcaemia episodes in people with primary hypoparathyroidism (HP).

  • Although basal ganglia calcification is frequent in chronic primary HP, it rarely causes parkinsonism. Extrapyramidal motor symptoms may have a multifactorial aetiology, and they may improve in a few individuals once hypocalcaemia is corrected.

Ethics statements

Patient consent for publication

Acknowledgments

We would like to express our gratitude towards Dr Ketan Ingle (Department of Pathology,Prince Aly Khan hopsital) for his immense contribution in diagnosis and collection of evidence in favor of HLH.We would like to thank Dr Mohammad Arfat Ganiyani, Grant Grant Government Medical College for his help in writing this manuscript.

Footnotes

  • Contributors TAV, RPB, MP and SPM were involved in drafting the report and analyse and interpret the data required for the work. TAV designed the concept. All authors critically reviewed the manuscript. All authors have given approval for the publication of the final version of manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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