Clinical case 1

A 59-year-old man who was admitted due to asthenia, poor general condition, generalized myalgia, hyporexia, decreased diuretic rate, nausea, and vomiting of bilious content for three days. He reported constipation and goat feces associated with a loss of 8 kg of body weight of ap proximately one year of evolution.

During the physical exam the patient was found to have decreased skin turgor, blood pressure of 140/90 mmHg, heart rate of 110 beat per minute, respiratory rate of 20 breath per minute, and an axillary temperature of 36.3°C. The patient was alert and oriented in time, place and person, generalized hyperreflexia, and distal fine tremor were confirmed.

The biochemical reports showed a calcium level of 24.7 mg/dl, a PTH level of 2416 pg/ml, and a serum creatinine level of 2.84 mg/dl. Table 1 (case 1) summarizes the bio chemical findings. Biochemical reports suggested PHPT. Ul trasonography (USG) did not reveal any parathyroid lesions, while parathyroid scan coupled with SPECT using 99mTc-sestamibi tracer showed a 30 mm mass in superior medias tinum, to the right of the esophagus and in contact with the posterior edge of the trachea. Hydration was started with crystalloids and, later, loop diuretics. Due to the persistence of severe hypercalcemia, emergency hemodialysis was per formed. Finally, minimally invasive parathyroidectomy was performed with normalization of calcium levels. Pathology revealed a lesion with a maximum diameter of 25 mm, 4 grams, without signs of malignancy, compatible with a gi ant parathyroid adenoma (GPA).

Tabla 1 Biochemical characteristics of patients before surgery and at discharge 

At the follow-up three year later, a recurrence of hy perparathyroidism was confirmed due to a hyperplasia of two parathyroid glands.

Clinical case 2

A 67-year-old man with a history of arterial hyperten sion, bipolar disorder, and benign prostatic hyperplasia, who was admitted with a two-week history characterized by alteration in his behavior over the past two weeks, in the form of apathy, irritability, and decreased alertness. In treatment with valproic acid, lamotrigine, quetiapine, tera zosin, tamsulosin, and amlodipine. Physical examination: dry mucosa, decreased skin turgor. Blood pressure 100/70 mmHg, heart rate 100 /min, respiratory rate 16 /min. Brad ypsychia, irrelevant talk, without neck stiffness. A 30-mm elastic, a palpable nodule was detected in projection of the right thyroid lobe. Biochemical reports showed a serum calcium level of 14.1 mg/dl, serum phosphate of 2.47 mg/ dl, PTH of 1143 pg/ml, and serum creatinine of 1.73 mg/ dl (Table 1). USG revealed a 25-mm nodular mass behind the upper pole of the left thyroid lobe. Parathyroid scan coupled with SPECT using 99mTc-sestamibi tracer showed a nodular image of approximately 20 mm, suggesting the presence of a left upper parathyroid adenoma. Hydration with crystalloids was started and 48 hours after admis sion parathyroidectomy was performed. Pathology study revealed a parathyroid adenoma of 8 grams, 40 mm by 20 mm, without signs of malignancy, compatible as GPA. Af ter surgery, a normalization of calcium and PTH levels was found. These findings suggested HC due PHPT.

After one year of follow-up, the patient is in remission, with normal levels of serum calcium, serum phosphate, and PTH.

Clinical case 3

A 58-year-old man with a history of hepatic transplant for non-alcoholic steatohepatitis complicated with post-surgical stricture of the bile duct, undergoing hospital ization for acute cholangitis, with percutaneous drain age placement and antimicrobial treatment. The patient evolved with acute confusional state. The biochemical report showed a serum calcium adjusted for albumin of 23.46 mg/dl, PTH of 764 pg/ml, and serum creatinine of 1.94 mg/dl (Table 1, case 3). USG revealed an 18-mm hy poechoic nodular lesion adjacent to the right thyroid lobe. Magnetic resonance imaging (MRI) of the cervical region showed a mass measuring 50 by 18 mm, hypointense on T1 and hyperintense on T2, in low right laterocervical to pography. Hydration was started to reduce pre-surgical serum calcium levels and parathyroidectomy was per formed. Pathology showed a parathyroid adenoma of 7 grams, 40 mm by 30 mm, with extensive hemorrhage, and solid/trabecular growth patterns compatible with an atypical giant adenoma. After surgery, calcium and PTH levels returned to normal range (Table 1).

The publication was approved by the Ethics Commit tee of the Grupo Gamma, and written informed consent was obtained from each participant.

Discussion

HIHC is an unusual state of progressive and marked of PHPT. Patients with HIHC have pro found hypercalcemia (serum calcium ≥14 mg/dl) resulting in anorexia, vomiting, dehydration, de creased renal function, impaired mental status, confusion, coma, and if untreated, death^1,2,5. In this report, we present three cases of PHPT that presented with severe hypercalcemia with satis factory evolution after parathyroidectomy.

Patients with HIHC may have severe symp toms such as renal failure, acute pancreatitis, and mental changes⁵. In our report, the most frequent symptoms were dehydration with renal failure and altered mental status. These symptoms im proved markedly after parenteral hydration and as expected, after parathyroidectomy.

HIHC demands an accelerated approach and requires immediate improvement within hours. Conservative management strategy for HIHC in cludes rapid intravascular volume expansion with isotonic saline solution, and loop diuretics as furo semide to induce calciuresis^1-3. Most patients pre senting with severe hypercalcemia have intravas cular volume depletion. This situation exacerbates hypercalcemia by altering renal calcium clearance. Isotonic saline solution for 24 to 48 hours corrects possible volume depletion and consequently low ers calcium levels. In some cases, hemodialysis may be considered⁶, as in one of our patients. On the other hand, the use of bisphosphonates is controversial and may be associated with an in creased risk of hypocalcemia in the postoperative period⁷. However, although medical treatment can rapidly reduce serum calcium levels, the definitive approach is urgent parathyroidectomy due to the life-threatening risk to patients.

Ultrasonography (USG) and (99mTc)-sestami bi scintigraphy (with SPECT) are recommended as first-line imaging methods, with the goal of obtaining preoperative localization. If two stu-dies are concordant, the positive predictive val ue for the correct localization of the parathyroid tumor is close to 97%⁸, and one can go for mini mally invasive or focused parathyroidectomy. This technique has modified the management of hypercalcemic crisis, due to a shorter operat ing time, smaller incision, and less perioperative pain². Our patients underwent a focused para thyroidectomy, achieving biochemical remission of the disease in the short term and without complications associated with the surgical procedure, such as hematoma/bleeding in the sur gical bed or neuronal damage.

PHPT is due to the presence of an adenoma/ single-gland disease in 80-85%. Although para thyroid carcinoma is a rare cause of PHPT, it can be seen in about 5% cases of HIHC^1,4,9. However, the most common pathological finding in HIHC is a solitary parathyroid adenoma. Other types of tumors, such as GPA and atypical parathyroid tumors, are less frequent. Interestingly, our pa tients had GPAs adenomas and one of them had a GPA with characteristics of an atypical para thyroid tumors. None of our patients present ed histopathological findings compatible with parathyroid carcinoma.

GPA is a rare type of parathyroid adenoma defined as weighing >3.5 g, and consequently, only a few cases of GPA have been reported. A systematic review by Wong et al. identified 65 GPAs¹⁰. Subsequently, four more cases were pub lished^11,12. They manifest as PHPT but exhibit el evated laboratory parameters and severe clinical manifestations^5,13, bearing a closer resemblance to parathyroid carcinoma rather than a typical benign adenoma. This should draw attention to the potential malignant nature of the tumor¹⁴.

Furthermore, histopathological analysis of parathyroid tumors of HIHC may display some unique features which include necrosis, fibrosis, extensive hemorrhage, microcystic pattern, and presence of intracytoplasmic vacuoles⁹. Some reports have suggested that hemorrhage with in an intact parathyroid gland may precipitate HIHC. Only one of our patients (case 3) showed evidence of intratumoral hemorrhage in the pa thology.

In 2022, the WHO reclassified atypical para thyroid adenomas now as atypical parathyroid tumors due to their potential for malignant be havior¹⁵. These tumors display some histologic features that can often be seen in parathyroid car cinoma, such as cytologic atypia, sheet-like or tra becular growth, adherence to adjacent structures, fibrosis (which may be band-like, tumor cells ex tend towards the tumor capsule but not through it) and mitotic activity, but do not present other signs such as full-thickness capsular invasion, vascular invasion, perineural invasion or invasion of adjacent structures¹⁵. One of our patients (case 3) presented a GPA with a solid trabecular growth pattern. In these situations, parafibromin immunohistochemistry is recommended to appreciate the risk of recurrence and to estimate de possibil ity of an underlying CDC73 mutation¹⁵. However, we do not have this immunohistochemistry panel to estimate these issues. To date, the patient has not presented signs of recurrence.

Hungry bone syndrome is a rapid, severe, and prolonged hypocalcemia following parathyroid ectomy, caused by an abrupt drop in PTH levels and osteoclastic resorption. Risk factors include a PTH level >1000 pg/ml, and alkaline phospha tase levels three times higher than the normal upper limit¹³. Although our patients had low calcium levels during follow-up, they did not present this syndrome, possibly due to routine administration of calcitriol and calcium after surgery.