Severe Hypocalcemia in Hungry Bone Syndrome After Parathyroid Surgery: A Case Study and Review

Introduction

Hungry bone syndrome (HBS) is a severe, rapid, profound, prolonged, and sometimes fatal condition characterized by hypocalcemia, exacerbated by suppressed parathyroid hormone levels following parathyroidectomy in severe primary hyperparathyroidism (PHPT) associated with high preoperative bone turnover [1,2].

There are few reported cases of HBS in the literature, but data regarding its incidence are sparse and inconsistent. PHPT is reported to affect 1% of the general population and its prevalence is increasing with age, reaching 2% among people over age 55 years [3]. More than 80% of all cases of primary hyperparathyroidism are asymptomatic for most of the disease duration [4–6]. Usually, the first sign of the disease is an abnormal calcium level in routine laboratory tests. More advanced stages of PHPT manifest with bone pains, osteitis fibrosa cystica, pathological fractures, proximal muscle weakness, nephrocalcinosis, psychosis, pancreatitis, peptic ulcer disease, and arterial hypertension.

Parathyroidectomy is the only available treatment of hyperparathyroidism that can restore normal calcium and PTH levels [7]. A common complication of parathyroidectomy is hypocalcemia, transient in 35% of patients and persistent in 0% to 3.8% of patients [8]. The essential condition for correction of hypocalcemia is achievement of normal magnesium levels. The incidence of HBS in patients with primary hyperthyroidism is 9.8% (range, 4–13%) [9,10]. Other less common causes of HBS include parathyroid carcinoma, multiple endocrine neoplasia, some medications, and metastases from prostatic gland cancer [11,12]. HBS refers to the severe, hypocalcemia with total calcium level <2.095 mmol/L, ionized calcium level <1.117 mmol/L, that is persistent (lasting from 9 months up to 4 years) [13,14]. The process of bone resorption takes about 2 weeks and is preceded by osteogenesis lasting about 2 to 3 weeks and bone formation lasting about 3 months. The bone remodeling space refers to the total volume of reabsorbed bone that has not yet ossified because of the temporal gap between resorption and osteogenesis. This space is larger in hyperparathyroidism and can lead to calcium depletion in bones and hypercalcemia over time [15,16]. Successful parathyroidectomy in patients with high bone turnover markers can effectively inhibit bone resorption, decrease the bone remodeling space, and reduce remodeling volume, thereby increasing the overall bone mass. Consequently, an abrupt and sustained decrease in serum levels of calcium, phosphorus, and magnesium is observed [1]. The longer the duration of elevated PTH levels preoperatively, the more severe the postoperative hypocalcemia. Continuous stimulation of bone turnover by PTH is abruptly halted by parathyroidectomy, resulting in a sudden interruption of osteoclastic activity while the process of persistent bone formation continues, leading to increased uptake of calcium, magnesium, and phosphorus in the bone [1]. It is also important to note the coexisting problem of hypomagnesemia, without which proper PTH secretion and function cannot be restored, even with supplementation.

Clinical manifestations of hypocalcemia in HBS range from minor signs and symptoms such as positive Chwostek and Trousseau signs, headaches, weakness, and paraesthesia, to life-threatening conditions including tetany, convulsions, laryngospasm, cardiac arrhythmia, and severe heart failure [17,18].

Here, we present a case of HBS with the one of lowest calcium levels ever reported. This case study meets the Surgical Care Report Guidelines (SCARE) criteria.

Case Report

A 67-year-old woman was admitted to the Department of Endocrinology, Diabetology, and Internal Diseases on July 1, 2022 due to severe weakness, walking difficulties, memory problems, and confusion. Obtaining a medical history from the patient was challenging because she had difficulties recalling facts, changed her answers frequently, and was disoriented to time, place, and person. According to the medical documentation provided by the patient’s family, she was hospitalized from May 27 to June 2, 2022 in the Department of Internal Diseases (in another hospital), where she was diagnosed with anemia and suspected malignancy (because of numerous metastatic lesions described in the bones). Upon the current admission, she was diagnosed with primary hyperparathyroidism, thyroid nodular goiter, and disseminated brown tumors of the bones. Laboratory tests showed: hypercalcemia 3.368 mmol/L, corrected calcium 3.493mmol/L (albumin: 3.4 g/dl), PTH 1225 pg/ml (N 14.9–56.9), ALP 1000 U/l (N25–104), phosphorus: 4.1 mg/dl (2.5–4.5), and creatinine: 1.1 mg/dl (N<0.9 mg/dl). Preoperative imaging studies included SestaMIBI (Tc 99m) and FNAB of the parathyroid adenoma with PTH determination from the biopsy washings. Agreement was obtained between MIBI and high-frequency neck ultrasonography in the anatomical location of the lesion. A preoperative ultrasound examination revealed a nodular goiter with a volume of approximately 30 ml, and the patient reported compressive symptoms. The largest focal lesion measured 15×9×12 mm and was hypoechoic EU-TIRADS 4. On June 6, 2022 she underwent parathyroidectomy with total thyroidectomy. Intraoperatively, it was decided to perform an extended parathyroidectomy. The diagnosis of multinodular disease was made after bilateral neck exploration. The parathyroid glands were located in an ectopic location, and intraoperative retrograde laryngeal nerve stimulation (neuromonitoring) was utilized. She was discharged from the Department of Surgery with directions to take L-thyroxine 100 μg daily, but no directions regarding calcium and vitamin D supplementation or calcium level monitoring were provided. On June 25, 2022 she was admitted to the Emergency Department (ED) of a community hospital, where she was diagnosed with hypocalcemia (ionized calcium: 0.54 mmol/L) and directed to take oral calcium carbonate 4 g daily and vitamin D (cholecalciferol) 30 000 IU/2 weeks. Physical examination upon admission to the Department of Endocrinology, Diabetology, and Internal Diseases showed a moderately severe state, cachexia, pale skin, scars following parathyroidectomy and total thyroidectomy, tumors of the jaw (Figure 1), crackles at the bases of both lungs, blood pressure 132/82 mmHg, heart rate 87 bpm, regular heart rhythm, systolic heart murmur over the mitral valve area, a soft abdomen with no peritoneal signs, hypoactive bowel sounds, no swelling of the lower limbs, tumors of the right tibia and right clavicle, facial bone deformity, and positive Chvostek and Trousseau signs.

Laboratory tests on the day of the admission showed hypocalcemia: total calcium: 3.7 mg/dL (corrected 3.9 mg/dL); hypomagnesemia: 1.2 mg/dL; hyperphosphatasemia: 5.5 mg/dL; high ALP: 1046 U/L; PTH: 34 pg/mL; vitamin 25(OH)D: 35 ng/mL (N 30–50); elevated creatinine: 1.4 mg/dL, eGFR: 44.8 mL/min (N >60); Nt-proBNP: 3797 pg/mL (N <125); TSH: 5.43 uIU/mL(N 0.27–4.2); fT4: 17.1 pmol/L (N 12–22); fT3: 1.7 pmol/L (3.1–6.8); decreased total protein: 5.22 g/dL (N 6.6–8.7); normocytic anemia: Hb: 8.7 g/dL (N 12–16); MCV: 86.6 fL (N 82–96); increased CRP: 2.16 mg/dl (N <0.5); and signs of urinary tract infection on urinalysis: cloudy urine, erythrocyturia, leukocyturia, bacteriuria, nitrites. Urine culture was positive for Escherichia coli, count >105 CFU/mL (Figures 2–7). The electrographic QTc interval was 490 ms. Low calcium excretion, as measured by 24-hour urine collection, persisted during the whole hospital stay: 29–65 mg/daily (normal range: 100–300 mg).

Bone window head CT scans performed at the ER showed sclerotic remodeling of the skull bone system with numerous osteolytic lesions, the largest of them observed in the head of the condylar process of the mandible left ramus along with 2 additional ones in the left side of the frontal bone. X-ray imaging of the ribs demonstrated thickening of the outline of the right 6th rib in the lateral arch. Areas of bone thinning were noted in the shaft of the left scapula. X-ray imaging of the clavicles revealed a balloon-like areas of bone thinning in the body of the right clavicle, accompanied by thickening of the outline of the clavicle body. Atrophy or destruction of the sternal end of the right clavicle and widening of the acromioclavicular joint gap up to 11 mm were also noted. Macular thinning of the bone structure was observed in the head of the right humerus. X-rays of the lower legs showed balloon-like areas of bone thinning with intact periosteum, and the largest such area was in the shaft of the right tibia, with widening of its outline up to 10.5×3.5 cm. A similar area, measuring 10×5 cm, was observed in the proximal epiphysis and shaft of the left tibia. In the shaft of the left fibula, there was a 5×3 cm lesion, with thickening and slightly uneven outline of the periosteum on the medial side – all these lesions correspond to brown tumors (Figure 8) Cardiac ultrasonography showed borderline thickening of the cardiac walls, normal contractility, fibrosis of the valve cusps with no significant limitations of their mobility, and no significant increases in pressure gradients across the valves. There were low-to-moderate mitral and tricuspid regurgitations. Small atrial dilation was observed. There was no fluid in the pericardial cavity. The inferior vena cava was not dilated and showed normal respiro-phasic movements.

Abdominal ultrasound revealed kidneys of normal size and shape with normal parenchymal thickness and increased parenchymal echogenicity. Numerous small calcifications were observed in the renal parenchyma and in the projection of the pelvicalyceal system, without signs of the pelvicalyceal system dilation. During the hospital stay, she received unprecedented amounts of calcium in her postoperative treatment. On the day of the hospital admission (July 1, 2022) she was administered 2 ampoules of calcium gluconate in 150 mL of 5% glucose, and from July 1, 2022 to July 27, 2022, she received continuous infusion of calcium gluconate into the central line, maintained using 6 to 8 ampoules diluted in 500 mL of 5% glucose with the flow rate of 25 mL/h (0.669–0.892 mmol/L/h) corresponding to the daily dose of elemental calcium 558 to 744 mg (13.38–17.84 mmol/L). From July 1 to July 14, 2022, she was administered 8 ampoules of calcium gluconate daily, and from July 15 to July 27, 2022 she received 6 ampoules of calcium gluconate daily. The cumulative dose of intravenous calcium was 17 112 mg of elemental calcium. Additionally, oral calcium carbonate was administered in the following doses: 1 g at breakfast, 1 g an hour after breakfast, 1 g at lunch, 1 g an hour after lunch, 1 g at dinner, and 1 g at bedtime; as well as oral cholecalciferol 1000 IU/daily, intravenous magnesium sulphonate 2 g daily, and oral hydrochlorothiazide 25 mg daily. A low-phosphate diet was provided.

As a result of this treatment, on the day of the hospital discharge, she had achieved an increase in total serum calcium level up to 2.071 mmol/L, an increase in ionized calcium level up to 1.03 mmol/L, an increase in magnesium calcium level up to 2.6 mg/dL, a decrease in ALP down to 806 U/L, an increase in Hb up to 10.1 g/dL (with no blood product transfusion), a decrease in Nt-proBNP down to 382 pg/mL, an increase in total protein up to 5.5 g/dL, and an increase in albumin up to 39.5 g/L (Table 1). The results of the study are depicted in Figures 3–7).

The patient was discharged from hospital in good performance status, oriented and verbally responsive, and able to walk on her own. The QTc interval on ECG was 0.4 s. The medical team decided to continue the ongoing treatment plan, which involved providing the necessary amount of calcium, with close monitoring of serum calcium levels. The discharge medications included: L-thyroxin 125 μg daily, oral calcium carbonate 6 g daily in divided doses (3 g at mealtimes and 3 g between the meals), alfacalcidol 2 mcg at breakfast and 2 mcg at dinner, cholecalciferol 1000 IU/daily, and magnesium stearate 100 mg daily. A low-phosphate diet was recommended. A follow-up examination on October 20, 2022 showed normocalcemia with considerable reduction in alkaline phosphatase level to 499 U/L (Table 1).

After discharge from the hospital, she did not use the services of the hospital endocrinology outpatients clinic due to the long distance from her place of residence. When preparing this case report, we contacted her family doctor. We received the results of her periodic check-ups, which show normal calcium and phosphate metabolism (Table 2). She did not develop permanent hypoparathyroidism and is currently taking calcium and vitamin D supplements.

Discussion

In a study of 162 patients undergoing parathyroidectomy, 52% developed postoperative hypocalcemia. Among those with HPT, 42% experienced hypocalcemia, but only 2% required intravenous calcium administration [19]. HBS risk factors include older age, as confirmed in a study by Brasier and Nussbaum, higher preoperative calcium, PTH, and ALP levels [15,20], and lower preoperative magnesium, albumin, and vitamin D levels [15,20,21]. ALP serves as a marker of bone mineralization, with elevated preoperative ALP levels indicating high bone turnover with osteoclastic activity and bone resorption [1,22]. Therefore, its level is a predictor of HBS [23]. HBS is more prevalent in patients with bone lesions typical of hyperparathyroidism, including osteosis fibrosa cystica, subperiostal erosion, lytic lesions, brown tumors, and multiple fractures, ranging from 25% to 90%, as compared to 0% to 6% of patients without radiologic lesions [1]. Another predictive factor is parathyroid adenoma size; Zamboni et al found that 11 out of 16 patients with adenomas larger than 2 g developed postoperative hypocalcemia, whereas only 3 out of 21 patients with adenomas smaller than 1 g experienced this condition [23]. HBS is also more likely to develop in patients who undergo parathyroidectomy with total thyroidectomy, as postoperative hypothyroxinemia can aggravate hypocalcemia. Our patient had several preoperative risk factors: older age, combined thyroidectomy and parathyroidectomy, high levels of serum alkaline phosphatase (1000), elevated levels of PTH (1225), bone lesions, brown tumors, advanced osteoporosis, and osteitis fibrosa cystica. Severe bone lesions in HPT are now extremely rare. In a recent study by Silverberg, no patients with brown tumors were reported, whereas in the late 1970s brown tumors were observed in more than 15% of patients with HPT [25,26]. Osteitis fibrosa cystica is a term used to denote advanced bone changes in HPT characterized by softened and deformed bones. Cysts that develop in these conditions are known as brown tumors, which are highly vascular osteolytic lesions reflecting a reparative cellular process and appearing most frequently as solitary lesions in the ribs, clavicles, pelvis, and mandibles [27,28]. These solid lesions have well-defined margins and are heterogeneous, hypo- and isointense to skeletal muscles on T1-weighted areas [29]. They often present a diagnostic dilemma as they may be difficult to differentiate from metastatic lesions [30], as was the case in our patient. Areas of the bone affected by osteitis fibrosa cystica (OFC, also known as von Recklinghausen disease of the bone) start to recover as early as 1 week after successful parathyroidectomy. The extent of the mineralization varies between patients, but it usually takes from 3 months to several years before the radiological lesions resolve [31].

HBS requires massive amounts of calcium to prevent symptoms of tetany and neuromuscular irritability. In the early stages of HBS, intravenous calcium must be administered due to the poor tolerance and limited absorption of oral calcium [32]. Calcium gluconate is preferred over calcium chloride due to its lower risk of local irritation. Calcium should be administered into large veins or via central venous catheter, to minimize the risk of local irritation and tissue necrosis by accidental extravasation in tissues. Continuous ECG is essential to prevent arrhythmias that can arise from rapid correction of calcium levels [33]. In cases of severe hypocalcemia, an intravenous bolus injection of 1 to 2 ampoules of calcium gluconate diluted in 150 mL of 5% glucose should be administered over 10 minutes and followed by a continuous infusion [19]. At the beginning of the treatment, calcium levels should be monitored every 6 hours [12]. According to Rathi et al, the calcium gluconate dosing regimen in HBS in a patient with body weight of 65 kg is 10 ampoules of calcium gluconate in 500 mL glucose 5% administered at a flow rate of 30 mL/h to maintain calcium level of 2 to 2.25 mmol/L or to prevent symptoms [12]. Excessive doses of calcium gluconate (eg, 16 ampoules daily) pose a risk of pulmonary calcification due to higher calcium levels in the pulmonary versus systemic circulation and the alkaline environment facilitates its precipitation. Intravenous calcium administration may be discontinued, and calcium administered orally only when calcemia is >7.5 mg/dL and the QT interval is within the normal range [34,35]. It is important to note that calcium carbonate administered with meals has a different effect; it can reduce the absorption of phosphorus from the gastrointestinal tract, subsequently enhancing the absorption of calcium administered between meals. In HBS, the preferred form of vitamin D is calcitriol because of the impaired conversion of 25-hydroxyvitamin D to 1.25-dihydroxyvitamin D, as this process requires the activity of 1-alpha hydroxylase in the kidneys. The sudden decrease in PTH levels minimizes the activity of 1-alpha hydroxylase. Calcitriol administration improves the gastrointestinal and renal absorption of calcium. The recommended dose of calcitriol in HBS is 3 to 5 mcg/daily [36].

Hypocalcemia remains irreversible until magnesium levels are corrected [37]. Hypomagnesemia exacerbates hypocalcemia by impairing the release of PTH and its action at the tissue level. It also interferes with the synthesis of 1,25-dihydroxycalciferol [12]. The recommended doses of magnesium are 1 to 2 g of intravenous magnesium sulphate 3 to 4 times daily for several days [12]. It is worth emphasizing the role of magnesium in regulating calcium and phosphate metabolism, the concentration of which depends on supply, elimination by the kidneys, mobilization from bones and muscles, and medications used. PTH affects the absorption of both magnesium and calcium. Hypomagnesemia, on the other hand, can disrupt PTH synthesis and secretion, leading to hypocalcemia. The primary hyperparathyroidism described in our case, which generates hypercalcemia, can cause magnesium loss through the kidneys. The second mechanism is the HBS described after surgical treatment of hyperparathyroidism, which causes Mg deposition in tissues. As in the management of our patient, proper Mg supplementation is necessary to help balance PTH and Ca concentrations [38]. The need to normalize magnesium concentrations is crucial for maintaining proper calcium-phosphate metabolism. This is also confirmed by cases of secondary hypocalcemia observed in congenital hypomagnesemia caused by mutations in the TRPM6 ion channel (transient receptor potential melastin type 6) and impaired further transport in the presence of CNNM4 (cyclin and CBS domain divalent metal cation transport mediator 4), resulting in poorer absorption in the large intestine and loss of Mg through the gastrointestinal tract. These patients require intravenous MgSO4 treatment for severe symptoms, followed by individual therapy with oral potassium and magnesium aspartate (PMA), and normalization of Mg and Ca (without the need for calcium preparations) was observed [39].

Hypophosphatemia treatment is usually not required until the phosphorus level is <0.31 mmol/L [36]. Premature phosphorus supplementation can lead to a further decrease in calcium level due to calcium precipitation. In our patient, hyperphosphatasemia was observed, most likely the consequence of the previous kidney damage caused by chronic hypercalcemia in the preoperative period.

During the therapy, careful monitoring for nephrocalcinosis and acute kidney injury (AKI) is necessary as these complications are associated with excessive calcium and vitamin D supplementation, potentially resulting in hypercalciuria. In our patient, kidney lesions were observed prior to the surgery; however, hypercalciuria was not observed. Pre- and postoperative hypercalcemia can cause vasoconstriction and induce hypovolemia, with subsequent prerenal renal failure [40]. Therefore, the therapy should aim at restoring and maintaining calcium at the lower normal range (2–2.1 mmol/l) to prevent hypercalciuria and nephrocalcinosis [41]. If hypercalciuria >300 mg/24 h occurs, vitamin D and calcium doses should be reduced. Calciuria must be monitored every 7 to 14 days at the beginning of the therapy and every 3 to 6 months thereafter [42].

In our patient, reversible cardiac dysfunction was observed with elevated Nt-proBNP levels, which gradually decreased with calcium supplementation. The literature also documents a case report of a 42-year-old woman with HBS and reversible left ventricle dysfunction [43].

The duration of HBS is defined as the time necessary to achieve remineralization of the skeleton [1], healing of the radiological features of osteitis fibrosa cystica and brown tumors, as well as a significant gain in bone mass. The duration of HBS and cumulative doses of elemental calcium varied in published case studies. For instance, an 18-year-old female patient after surgical resection of a parathyroid adenoma required intravenous administration of calcium products in doses up to 1289 mg of elemental calcium daily in intravenous infusions for 3 months. Her bone density returned to normal after 42 months [44]. Another case involved a pregnant woman who experienced a decrease in calcium level down to 4.5 mg/dL within 2 days of parathyroidectomy and required a continuous infusion of calcium for 40 days to restore her calcium level to 8 mg/dL [45]. In a Japanese case report, a 39-year-old woman with calcium level of 5.7 mg/dL received intravenous calcium gluconate for 14 days at a dose of 628 mg of elemental calcium every 24 hours, while oral calcium and alfacalcidol were administered for 4 months [46]. Another patient was administered intravenous calcium 2 to 2.5 g daily for 4 weeks, followed by oral calcium 6 to 8 g along with 2 to 4 mcg of alfacalcidol [12]. The importance of monitoring calcium therapy is highlighted by the case of recurrent torsade de point in a previously healthy 49-year-old woman who developed HBS after parathyroidectomy with thyroidectomy despite continuous intravenous calcium supplementation [47]. The recovery of bone mass in patients with HBS is often incomplete [48,49]. The bone mass gain is usually greatest within 1 year after the surgery but continues for about 4 to 5 years [50]. In a case report of a 29-year-old woman with HBS following parathyroidectomy for HPT, mineral bone density returned to normal 147 days after the surgery [51]. However, due to the residual bone mass reduction, the risk of bone fractures in these patients usually remains elevated for the rest of their lives [21].

As bisphosphonates block osteoclastic bone resorption [21], their preoperative administration prevents HBS; for example, preoperative administration of pamidronate 30 mg for 2 days reduced the postoperative calcium requirement [52]. In a study by Lee, no HBS cases were observed in 6 patients treated preoperatively with bisphosphonates, whereas sustained hypocalcemia in the postoperative period was seen in 6 out 17 patients in the control group. The risk of HBS was low in a group of 46 HPT patients treated preoperatively with zoledronate [53,54]. Additionally, in a study describing patients with osteitis fibrosa cystica, none of the 6 patients treated preoperatively with alendronate or pamidronate developed HBS [55]. Although these reports seem promising, it is noteworthy that the administration of bisphosphonates in the preoperative period can suppress bone resorption with no accompanying suppression of bone formation, potentially exacerbating hypocalcemia. Consequently, the conclusions from the available case reports are inconsistent [21,56] and if bisphosphonates are administered, their use should be continued until the ALP level is normalized [1].

Preventing vitamin D deficiency in the preoperative period is crucial, as the restoration of normal vitamin D concentration is associated with a decrease in ALP and PTH levels [57]. A balanced preoperative intake of vitamin D can reduce the risk of severe and persistent HBS [58]. Another approach to prevent HBS involves the administration of calcitriol 2 mcg/24 h for 5 days prior to surgery and calcium 2 to 3 g/24 h for 2 days prior to surgery, even in patients with hypercalcemia. This approach enhances intestinal calcium absorption, resulting in its peak at the time of parathyroidectomy. Some authors have proposed that alfacalcidol 1 mcg/24 h should be administered preoperatively for 1 to 10 weeks [12]. Additionally, it is crucial to administer active vitamin D metabolites as soon as possible after surgery, as this can shorten the hospital stay.

Careful monitoring of calcium and phosphorus levels after parathyroidectomy has been shown to reduce the risk of HBS [9]. Unfortunately, our patient was not provided with appropriate preventive care and monitoring for HBS during her hospital stays in community hospitals, and active forms of vitamin D were not administered before or after surgery. Upon discharge from the Surgery Department, she was instructed to visit her GP in 4 weeks for calcium monitoring, which was insufficient. During her stay in the ED of the community hospital on June 25, 2022, she should have received an intravenous calcium infusion; the recommendation to take cholecalciferol and calcium carbonate was inadequate.

When evaluating a patient with disturbances in calcium-phosphate homeostasis, maintaining a high index of oncological suspicion is essential. Both parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) can be secreted by malignancies, including those originating from the gastrointestinal tract or lungs. Notably, as described by Quinn [59], neuroendocrine tumors (NETs) can also be ectopic sources of PTH. A 76-year-old woman with a history of surgical resection of a small intestinal carcinoid tumor in 2009 was found in 2019 to have hypercalcemia (serum calcium 10.8 mg/dL). A 1.5-cm mass suspected to be a parathyroid adenoma was excised from the mediastinum. Two days after parathyroidectomy, her PTH level remained elevated at 221 pg/mL, and serum calcium was 10.9 mg/dL. Subsequent imaging with dotatate PET/CT revealed multiple sites of metastatic neuroendocrine tumors producing native PTH. Treatment with intramuscular octreotide (30 mg every 4 weeks) was initiated, resulting in a gradual normalization of both serum PTH and calcium levels.

Popov et al demonstrated that a subset of patients with hyperparathyroidism (HPT) and skeletal abnormalities – particularly jaw-localized brown tumors – may have an underlying genetic predisposition. Mutations in the CDC73 gene were associated with decreased parafibromin expression in these individuals. Specifically, a CDC73 mutation was identified in approximately 60% of patients with negative parafibromin immunostaining and the presence of brown tumors. Conversely, a MEN1 mutation was detected in a patient presenting with a brown tumor and positive parafibromin staining. Given these findings, similar genetic testing should have been considered in our patient [60].

Conclusions

We described a rare case of primary hyperparathyroidism with brown tumors complicated by severe HBS after combined parathyroid and thyroid surgery. To the best of our knowledge, this is the one of the first case reports ever published that presents such low levels of calcium. Currently, no specific guidelines are available on the management of HBS, but the general treatment approach involves correction of calcium deficiency and normalization of bone turnover, which often requires large doses of calcium. When HBS develops, hospitalization and aggressive intravenous calcium infusion should be continued until hypocalcemia resolves to prevent neuromuscular and cardiac complications. HBS can be prevented through early diagnosis and control of risk factors, as well as the use of calcitriol and bisphosphonates. It is also essential to achieve normal magnesium levels.