Postparathyroidectomy calciphylaxis in a patient with primary hyperparathyroidism: a rare complication

Abstract

Calciphylaxis, a rare and life-threatening condition involving calcification of small to medium-sized arterioles in subcutaneous tissue, leads to ischemia and necrosis. While typically seen in chronic kidney disease (CKD), a small proportion of cases can present without CKD, referred to as nonuremic calciphylaxis (NUC). NUC associated with primary hyperparathyroidism is rare with limited evidence-based management. A 41-year-old woman with no prior medical history presented with cardiac arrest due to severe hypercalcemia of 17.87 mg/dL (4.46 mmol/L) (normal reference range, 8.6-10.3 mg/dL; 2.2-2.6 mmol/L) and markedly elevated parathyroid hormone (PTH) levels. She required intensive care and extracorporeal membrane oxygenation (ECMO). Following stabilization, she underwent emergency parathyroidectomy for a parathyroid adenoma. During her prolonged recovery over 100 days, she developed painful necrotic skin lesions. Histopathology confirmed calciphylaxis. Management was conservative, involving wound care and analgesia, without surgical debridement. Her skin lesions resolved, and she has remained free of recurrence with stable calcium and PTH levels for more than 10 years. NUC following parathyroidectomy for primary hyperparathyroidism is rare. Multifactorial causes could contribute to the pathogenesis of calciphylaxis in our case, involving acute kidney injury, ECMO, and prolonged immobility. Early recognition and multidisciplinary management are crucial given the high mortality rate in calciphylaxis.

Introduction

The etiology of hypercalcemia can be categorized into either parathyroid hormone (PTH)-mediated or non–PTH-mediated. Severe hypercalcemia, defined as serum calcium levels 14.03 mg/dL (3.5 mmol/L) (normal reference range, 8.6-10.3 mg/dL; 2.2-2.6 mmol/L), can have serious consequences requiring emergency management [1]. Patients with hypercalcemia may present with symptoms including polyuria, polydipsia, cognitive and neurobehavioral changes, constipation, nausea, and vomiting [2].

Calciphylaxis, a rare skin complication, is associated with poor prognosis in patients with hypercalcemia [3]. The pathophysiology of calciphylaxis includes calcification of the middle and small arterioles of the dermis, disrupting blood flow, and resulting in tissue ischemia and subcutaneous necrosis [3]. Calciphylaxis primarily affects patients with chronic renal failure on dialysis, as it is a complication linked to high calcium and phosphate product and the homeostatic failure to clear it [4, 5]. Although very rare, less than 20% of cases have been reported in patients without dialysis-dependent chronic kidney disease (CKD), a presentation known as nonuremic calciphylaxis (NUC) [6]. One of the underlying conditions associated with NUC is hyperparathyroidism, both primary and secondary [3]. NUC is associated with poorer prognosis, with a high mortality rate of 52%, with 50% of cases due to sepsis [7]. NUC in the context of primary hyperparathyroidism has rarely been documented, with only 53 reported cases globally [8].

Currently, evidence-based management options for NUC are limited due to the rarity of the condition. Treatment primarily involves wound care with or without surgical debridement [3].

Case presentation

A 41-year-old White woman presented to the emergency department (ED) following an out-of-hospital cardiac arrest, in ventricular fibrillation. She received cardiopulmonary resuscitation and advanced life support before arrival at the ED. There were no preceding symptoms, and her past medical history was unremarkable. There were no records of previous laboratory results, including calcium. Laboratory evaluation revealed severe hypercalcemia, with a serum calcium level of 17.87 mg/dL (4.46 mmol/L) (normal reference range, 8.6-10.3 mg/dL; 2.2-2.6 mmol/L), and markedly elevated PTH at 2463.116 pg/mL (261.2 pmol/L) (normal reference range, 12.26 −87.69 pg/mL; 1.3-9.3 pmol/L). Following initial stabilization, she was transferred to the intensive care unit (ICU). Due to acute lung injury and aspiration pneumonitis, oxygenation via conventional ventilation proved inadequate, and she was transferred to another center for extracorporeal membrane oxygenation (ECMO). Three weeks into her admission, she underwent emergency parathyroidectomy due to persistent hypercalcemia refractory to bisphosphonates and denosumab.

Postoperatively, she experienced a prolonged recovery period exceeding 100 days, which included ICU admission. During her ICU admission, she developed severely painful necrotic lesions over the axillae, thighs, and groin (Fig. 1). A timeline of the patient's clinical course is shown in Fig. 2. Histopathological analysis revealed foci of calcification with ulceration and vascular wall calcification, consistent with calciphylaxis (Fig. 3).

Figure 1.

Purplish red papular rash, which was nodular in some areas. There are areas of (n) necrosis and formation of a (c) golden crust; (b) shows the biopsy site.

Figure 2.

Timeline of patient's journey. The patient's hospital episode spanned 100 days and key events are summarized.

Abbreviation: AKI, acute kidney injury.

Figure 3.

The histology from the lesion in her groin shows calciphylaxis. A and C show calcification of the vessels, and B, D, and E show ulcerated and necrotic changes in the epidermal and dermal layers.

Diagnostic assessment

The baseline clinical investigations showed extremely high levels of adjusted calcium levels of 16.68 mg/dL (4.16 mmol/L) (normal reference range, 8.82-10.42 mg/dL; 2.20-2.60 mmol/L), as shown in Table 1. Her PTH was inappropriately elevated at 2463.116 pg/mL (261.2 pmol/L). The initial assessments revealed acute renal failure and abnormal liver function, indicating multiorgan failure due to cardiac arrest, as seen in Table 1.

Table 1.

Baseline clinical chemistry from the day of admission

Tests	Value	Reference ranges
Adjusted calcium	16.68 mg/dL (4.16 mmol/L)	8.82-10.42 mg/dL (2.2-2.6 mmol/L)
Phosphate	1.86 mg/dL (0.6 mmol/L)	2.48-4.65 mg/dL (0.8-1.5 mmol/L)
Bicarbonate	120.2 mg/dL (19.7 mmol/L)	(134.2-176.9 mg/dL) (22-29 mmol/L)
Urea	64.3 mg/dL (10.7 mmol/L)	15-46.8 mg/dL (2.5-7.8 mmol/L)
Creatinine	2.21 mg/dL (195 μmol/L)	0.62-1.19 mg/dL (55-105 μmol/L)
AST	94 U/L (1.566 μkat/L)	12-34 U/L (0.2-0.5667 μkat/L)
GGT	40 U/L (0.6667 μkat/L)	8-35 U/L (0.13- 0.58 μkat/L)
ALP	105 U/L (1.75 μkat/L)	30-130 U/L (0.5-2.17 μkat/L)
Total bilirubin	0.53 mg/dL (9 μmol/L)	<1.23 mg/dL (<21 μmol/L)
Total protein	6.1 g/dL (61 g/L)	6-8 g/dL (60-80 g/L)
Albumin	3 g/dL (30 g/L)	3.5-5 g/dL (35-50 g/L)
C-reactive protein	3.6 mg/dL (36 mg/L)	0-0.6 mg/dL (0-6 mg/L)

Abnormal values are bold. The values in parathesis are Système International (SI) units. Adjusted calcium (adjusted to albumin levels).

Abbreviations: ALP, alkaline phosphatase; AST, aspartate transaminase; GGT, γ-glutamyl transferase.

Treatment

After a period of ECMO, the patient had an urgent right parathyroidectomy with partial thyroidectomy on day 25, which resulted in a rapid normalization of her calcium levels, shown in Table 2 and Fig. 4. As her calcium and PTH levels were extremely high, parathyroid carcinoma was a possibility. Hence, a decision was made to perform a partial thyroidectomy. Her PTH rapidly normalized. Fig. 4 shows the correlation between PTH and adjusted calcium levels over time.

Table 2.

Routine clinical chemistry from the day of admission

Routine clinical chemistry
Date	Reference	During admission				Postparathyroidectomy
		D1	D2	D3	D4	D50	D78	D84
Calcium	8.6-10.3 mg/dL (2.15-2.70 mmol/L)	17.87 mg/dL (4.46 mmol/L)	15.99 mg/dL (3.99 mmol/L)	17.27 mg/dL (4.31 mmol/L)	18 mg/DL (4.49 mmol/L)	8.38 mg/dL (2.09 mmol/L)	10.02 mg/dL (2.5 mmol/L)	8.82 mg/dL (2.20 mmol/L)
Adjusted calcium	8.82-10.42 mg/dL (2.2-2.6 mmol/L)	18.84 mg/dL (4.70 mmol/L)	17.19 mg/dL (4.29 mmol/L)	18.4 mg/dL (4.59 mmol/L)	19.52 mg/dL (4.87 mmol/L)	9.74 mg/dL (2.43 mmol/L)	10.98 mg/dL (2.74 mmol/L)	10.01 mg/dL (2.52 mmol/L)
Phosphate	2.5-4.7 mg/dL (0.8-1.5 mmol/L)	0.62 mg/dL (0.2 mmol/L)	3.1 mg/dL (1 mmol/L)	8.05 mg/dL (2.6 mmol/L)	6.81 mg/dL (2.2 mmol/L)	___	3.72 mg/dL (1.2 mmol/L)	3.72 mg/dL (1.2 mmol/L)

Abnormal values are bold. The values in parathesis are SI units. Adjusted calcium (adjusted to albumin levels).

Abbreviations: D1, D2, etc, denote days of admission.

Figure 4.

Rapid decline in the patient’s parathyroid hormone and adjusted calcium level postoperatively. The calcium levels remain normal after the parathyroidectomy.

The histopathology of the parathyroid revealed a benign parathyroid adenoma, with no atypical features.

The management of the calciphylaxis included regular wound dressings and analgesia. Surgical debridement was not required.

Outcome and follow-up

Her lesions healed without complications. Following the resolution of her calciphylaxis and the restoration of her mobility, she experienced no recurrence of her calciphylaxis or the development of any similar skin lesions.

Discussion

Our patient had a rare presentation of parathyroid adenoma with extreme hypercalcemia of 16.68 mg/dL (4.16 mmol/L) that required an emergency parathyroidectomy. Following her surgery, she underwent a prolonged recovery period exceeding 100 days, which included ICU care due to cardiac complications that required ECMO support. During her ICU stay, she was bed bound, and her recovery was further complicated when she developed painful lesions on her axilla and groin, which was diagnosed as calciphylaxis following her histology reports.

Calciphylaxis associated with hypercalcemia is a recognized condition in patients with dialysis-dependent end-stage renal disease (ESRD) [5]. However, calciphylaxis without dialysis-dependent ESRD, NUC, is rare [3]. A systematic review from 2021 identified only 53 cases of documented NUC, with the most common presentation involving patients with multiple comorbidities (≥2 conditions), accounting for 18 cases [8]. In contrast, hyperparathyroidism was reported as the underlying cause in only one case [8]. Additionally, the review highlights that NUC is more common in women, accounting for 83.4% of the 53 cases [8]. At the time our patient developed calciphylaxis, she had already undergone parathyroidectomy and had well-controlled levels of PTH, calcium, and phosphate. This highlights the potential involvement of other contributing factors in the pathogenesis of developing calciphylaxis in her case. During our patient's initial presentation with hypercalcemia, she also developed acute kidney injury (AKI), which may have contributed to the subsequent development of NUC during her recovery. Five cases of NUC have been reported in the context of AKI [9]. While the pathophysiological link between AKI and NUC remains poorly understood, one proposed mechanism is that impaired renal clearance exacerbates disturbances in calcium and phosphate metabolism [9]. Restoration of renal function has been shown to improve calciphylaxis through the resolution of hyperphosphatemia and hyperparathyroidism [9]. This concept may explain how AKI, in the context of significantly elevated calcium and PTH levels, could have precipitated calciphylaxis in our patient.

Our patient experienced a complex recovery requiring ECMO support. It is important to consider the potential role of ECMO in the development of NUC, as it is known to cause considerable electrolyte disturbances, including imbalances in calcium and phosphate levels [10]. There has been one reported case of rapid development of calciphylaxis in a patient on venovenous ECMO [11]. In this case, the patient had a background of chronic renal failure and secondary hyperparathyroidism with a calcium level of 16.68 mg/dL (4.16 mmol/L). However, notably she developed calciphylaxis only after the initiation of ECMO [11]. This highlights that ECMO may be a potential risk factor for NUC. In our patient, the interval between the initial stabilization of her calcium levels and initiation of ECMO was notably brief, leaving no sustained period of electrolyte imbalance prior to ECMO therapy. This abrupt transition may have contributed to the pathogenesis of NUC in her case. Another factor we considered in the development of her NUC was the substantially prolonged period of immobility. A case report has previously highlighted an association between immobility and calciphylaxis, attributing this to immobility-induced hypercalcemia [12]. From this perspective, it is plausible that her immobility may have further exacerbated the risk and progression of NUC. In our patient's journey of severe hypercalcemia due to parathyroid adenoma, initial AKI and prolonged recovery following parathyroidectomy complicated by the need for ECMO and prolonged immobility may elucidate the multifactorial nature of how there may have been a permissive environment for the development of NUC. In a review of 7 cases over nearly 30 years, in which parathyroidectomies were performed for indications related to ESRD, calciphylaxis developed between 2 weeks and 2 years postoperatively, with most cases occurring within the first 3 months [13]. In another series of 30 patients with ESRD, the time of onset of calciphylaxis from commencement of renal replacement therapies ranged from 5 days to 18 years, with nearly half presenting within 2 years [14]. The pathogenesis of calciphylaxis involving calcification of small arterioles of the dermis and hypodermis resulting in thrombosis causes soft tissue and skin necrosis. These effects are hypothesized to be mediated by an imbalance between promoters and inhibitors of calcification [14]. The chief inhibitors of calcification include matrix G1a-protein, feutin-A, an albumin-like carrier protein, and inorganic phosphate [14]. Inflammatory states such as those experienced by our patient are known to upregulate procalcification factors, including cytokines and downregulate the protective factors such as feutin-A [14]. These processes evolve over a period of days or weeks, consistent with the development of the lesions in our patient.

Early recognition of painful necrotic skin lesions as calciphylaxis is essential in patients. Risk factors include female sex, severe hypercalcemia, AKI, and ECMO or renal replacement therapy. In such complex clinical scenarios, there should be a high index of suspicion for calciphylaxis, given its significantly high mortality rate of 52% [7]. While most available evidence focuses on uremic calciphylaxis, this case supports emerging studies that highlight recombinant PTH and other nonuremic factors as potential contributors to the development of calciphylaxis [15].

Learning points

• Development of new necrotic skin lesions in a patient with hyperparathyroidism receiving ECMO should raise a high index of suspicion for calciphylaxis.

• Calciphylaxis can occur as a complication in patients with AKI in the context of hypercalcemia.

• Factors such as high calcium × phosphate products may contribute, in conjunction with reduced mobility.

Contributors

All the authors made individual contributions to authorship. A.A. has been involved in the care of the patient during and after admission. A.K, L.A., and A.A. contributed to clinical data collection and literature review. J.H. was the intensivist responsible for the patient's care. S.M contributed to the histopathology section and provided histology slides. All authors reviewed and approved the final manuscript.

Abbreviations

AKI

acute kidney injury

CKD

chronic kidney disease

ECMO

extracorporeal membrane oxygenation

ED

emergency department

ESRD

end-stage renal disease

ICU

intensive care unit

NUC

nonuremic calciphylaxis

PTH

parathyroid hormone

Funding

No public funding or commercial funding.

Disclosures

No conflicts of interest, financial or otherwise, are declared by authors.

Informed patient consent for publication

Signed informed consent obtained directly from the patient.

Data Availability Statement

Original data generated and analyzed for this case report are included in this published article.