Primary Hyperparathyroidism: A Rare Form of Presentation Open Access

Primary hyperparathyroidism (PHPT) is characterized by parathyroid hormone (PTH) overproduction which, in the majority of cases, is caused by a parathyroid adenoma. Other less common causes are parathyroid hyperplasia and parathyroid carcinoma. In PHPT, elevated levels of PTH typically lead to hypercalcemia, which is responsible for most clinical manifestations of this disease. In developed countries, PHPT most frequently presents as asymptomatic hypercalcemia or with nonspecific symptoms and is usually detected in routine blood tests. Less frequently, the classical manifestations of bone disease and/or nephrolithiasis are present at diagnosis. In much rarer cases, hypercalcemia-induced acute pancreatitis (AP) has been reported as the initial manifestation of PHPT [1‒5].

Although hypercalcemia is well established as a possible cause of both acute and chronic pancreatitis, the underlying pathophysiological mechanisms are not fully understood. One of the suggested mechanisms is that high serum calcium contributes to the formation of pancreatic calculi which leads to ductal obstruction, promoting pancreatic inflammation [6]. Additionally, studies show that hypercalcemia can lead to the activation of trypsinogen to trypsin, causing pancreatic autodigestion and subsequent pancreatitis [7].

A 37-year-old man presented to the Emergency Department (ED) due to a 3-day history of worsening epigastric pain which irradiated to the back, nausea and vomiting. Initial tests revealed elevated amylase {164 U/L (normal range [NR] 13–53 U/L)} and lipase levels (106 U/L [NR 13–60 U/L]), hypercalcemia (14.9 mg/dL [NR 8.6–10.2 mg/dL]), hypophosphatemia (1.9 mg/dL [NR 2.5–4.5 mg/dL]), and acute kidney injury (creatinine: 1.52 mg/dL [NR 0.70–1.20 mg/dL]). The diagnosis of AP was made and the patient was therefore admitted.

Due to the severe hypercalcemia detected on admission, further investigation was conducted during hospitalization, which showed mild vitamin D deficiency (19.7 ng/mL [NR 30–50 ng/mL]) and elevated serum PTH levels (1,241 pg/mL [NR 14–72 pg/mL]), suggesting PHPT. Alternative causes of AP such as vesicular lithiasis were excluded.

In what concerns the hypercalcemia, the patient was treated with intravenous fluids and pamidronate 90 mg. On discharge, the symptoms that motivated admission had resolved, calcium levels had decreased to 10.3 mg/dL, amylase and lipase levels had normalized (amylase: 34 U/L, lipase: 56 U/L) and renal function had returned to normal (creatinine: 1.13 mg/dL) (shown in Table 1).

The patient was then referred to the Endocrinology Clinic. He denied any previous history of bone disease, nephrolithiasis, or other symptoms or complications of hypercalcemia. Renal ultrasound and bone densitometry (lumbar spine Z-score: −0.9, femoral neck Z-score: −0.7, distal radius Z-score: −0.8) were performed, excluding kidney stones and osteoporosis, respectively.

Considering the patient’s age and the severity of both the hypercalcemia and the elevation of serum PTH, he underwent further tests to evaluate for the presence of multiple endocrine neoplasias (MEN) syndrome types 1 and 2 – complete pituitary function, calcitonin, and plasma metanephrines were measured, which were all normal (results are shown in Table 2).

To identify the abnormal parathyroid gland, a neck CT was performed, which showed a hypodense nodule measuring 23 mm posterior to the right thyroid lobe (Fig. 1). 99mTc-Sestamibi scintigraphy confirmed that this nodule was compatible with a hyperfunctioning right inferior parathyroid nodule, by revealing an area of nodular hyperfixation adjacent to the inferior pole of the right thyroid lobe.

Therefore, the patient underwent right inferior parathyroidectomy, with an intraoperative PTH level decrease to 7 pg/mL. Histology then revealed a parathyroid adenoma as the etiology of PHPT in this patient.

To prevent hungry bone syndrome as a postoperative complication, cholecalciferol supplementation had been started prior to surgery and, after surgery, the patient was discharged under calcium carbonate and cholecalciferol treatment (6,000 mg and 1,600 IU per day, respectively). In the first postoperative appointment, laboratory tests showed normal PTH (71 pg/mL), calcium (9.7 mg/dL), and phosphorus levels (3.2 mg/dL). Calcium carbonate and cholecalciferol treatment were then progressively tapered and stopped after 21 months, with PTH, calcium, and phosphorus levels remaining normal months later (59 pg/mL, 9.6 mg/dL, and 2.7 mg/dL, respectively). There has been no recurrence of pancreatitis.

The majority of AP cases are caused either by gallstones or alcohol use. Less frequent causes include hypertriglyceridemia, certain drugs, neoplastic obstruction of the bile tract, ischemia, infection, and autoimmune disorders [8]. Rarely, in around 1% of cases, AP is caused by hypercalcemia [9].

Hypercalcemia-induced AP is an uncommon complication of PHPT, with an estimated prevalence of 1.5%–13% [4], and it is even more uncommon as the initial manifestation of this disease [10, 11]. However, this case report shows that PHPT can be diagnosed as a consequence of a hypercalcemia-induced AP episode.

Therefore, we propose that calcium levels should be measured in all patients with AP, particularly when no other likely cause of pancreatitis, such as vesicular lithiasis, has been identified. In patients whose calcemia is elevated during an AP episode, investigation of endocrine causes such as PHPT should be prompted. Although infrequent, this could lead to the diagnosis of previously unidentified PHPT cases, as was the case with our patient, as well as in a few similar cases reported in the literature [1‒5]. After the diagnosis of PHPT was made in this patient, his young age of onset raised concern for the possibility that a MEN syndrome could be present.

MEN syndromes are rare autosomal-dominant disorders associated with endocrine tumors of the pancreas, pituitary, thyroid, adrenal gland, and parathyroid. PHPT can be a manifestation of both MEN-1 and MEN-2 syndromes, with an estimated incidence of 90–100% in MEN-1 [12, 13] and 20–30% in MEN-2 [14]. In both these syndromes, PHPT typically appears at a young age, with a mean age of onset between 20 and 25 years for MEN-1 [13] and between 30 and 35 years for MEN-2 [15, 16], while sporadic PHPT’s typical onset is at 50–60 years of age [17]. Additionally, in MEN-1, PHPT is the most frequent first clinical expression of the syndrome [12, 13]; although in MEN-2 it is rare as a first manifestation [16].

Therefore, our patient’s age at diagnosis of PHPT prompted us to screen for MEN-1 by ordering complete pituitary function tests, and for MEN-2 by measuring plasma metanephrines and calcitonin levels. We found that all of these were within NR. Additionally, no other factors that would favor MEN-associated PHPT were present, namely multiglandular disease or a positive family history. Therefore, though exclusion would only be definitive if genetic tests were to be ordered, we concluded that the probability that our patient had either of the MEN syndromes was very low.

Other causes of heritable PHPT should be considered as well in patients with a PHPT diagnosis at a young age, namely hyperparathyroidism-jaw tumor syndrome [18]. However, considering the rarity of this syndrome, the patient’s age (over 35 years old) and the absence of a family history, the need for genetic testing for this syndrome was not deemed necessary either.

It is also important to note that, although histology in this clinical case suggested a parathyroid adenoma, this patient presented with certain clinical characteristics that suggested a possible diagnosis of parathyroid carcinoma.

Parathyroid carcinomas are much less common than adenomas (accounting for less than 1% of all PHPT cases versus 80–85% of cases, respectively) [19], and this patient’s young age would make a parathyroid carcinoma diagnosis even less likely. However, this patient presented with both severe hypercalcemia and very high serum PTH, which have been described in the literature as predictive factors of parathyroid carcinoma [19, 20]. Both calcemia greater than 14 mg/dL and serum PTH levels greater than three times the upper limit of normal are considered suspicious for malignancy, while PTH levels 10 times the upper limit of normal (as was the case with our patient) have a positive predictive value of 84% for parathyroid carcinoma [21].

Taking this into account, as well as the fact that the histopathological distinction between benign and malignant parathyroid tumors is difficult due to the lack of pathognomonic features for malignant parathyroid disease [22], the patient remains under close clinical and biochemical surveillance for any signs of recurrence or disease progression.

The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000546900).

This study has been granted an exemption from requiring ethics approval by the Ethics Committee of our institution – Comissão de Ética do Centro Académico de Medicina de Lisboa. The reason for this exemption was that it is a case report which the patient consented to be published. Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Maria João Bugalho was a member of the Journal’s Editorial Board at the time of submission. The authors have no other conflicts of interest to declare.

This study was not supported by any sponsor or funder.

Marta Vaz Lopes: manuscript writing and organizing and literature review. José Vicente Rocha, Carolina Peixe, Mariana de Griné Severino, and Maria Inês Alexandre: manuscript review. Ana Coelho Gomes: clinical approach to the patient, manuscript review. Maria João Bugalho: manuscript review and scientific consultant.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.