This case highlights the rare presentation of parathyroid cystic adenoma extending into the mediastinum presenting with parathyroid crisis and with very high serum calcium and Intact PTH levels. In addition, the size of the cystic adenoma was huge. The clinical and biochemical presentation mimicked that of parathyroid carcinoma. This case also illustrates the unmasking of primary hyperparathyroidism after Vitamin D replacement in Vitamin D deficient patients. The consistent hypokalemia seen in this patient together with hypercalcemia needs further research.
Parathyroid crisis is a life-threatening emergency. It is also known in literature as acute hyperparathyroidism, parathyroid storm, parathyrotoxicosis, acute parathyroid intoxication, parathormone intoxication, hypercalcemic crisis and calcium intoxication. It was first described in 1923 by Dawson and Struthers [13
]. It is characterized by severe hypercalcemia (>14
mg/dL or >3.5
mmol/L) associated with signs and symptoms of multi-organ failure [12
]. Although most cases of severe hypercalcemia are seen in malignancy [14
], it is important to emphasize that severe hypercalcemia with raised PTH is pathognomonic of primary hyperparathyroidism [16
]. Patients with parathyroid crisis demonstrate gastrointestinal and neurological symptoms, renal failure and cardiac rhythm abnormalities. Our patient had very high corrected serum calcium level of 23.0
mg/dL. She exhibited gastrointestinal features like nausea, vomiting and constipation. She was severely dehydrated and had acute kidney injury as confirmed by her laboratory indices. She didn’t have any neurological or cardiac rhythm abnormalities.
The biochemical profile, size of the cystic adenoma, and the fact that it was palpable, all mimicked parathyroid carcinoma. Corrected serum calcium level of 23.0
mg/dL is rarely seen with parathyroid adenoma [17
]. Today, primary hyperparathyroidism usually presents with mild hypercalcemia (within 1
mg/dL above the upper limit of normal), is usually asymptomatic, and diagnosed incidentally on routine investigations for minor non-specific complains. Parathyroid carcinoma, on the other hand, presents with severe hypercalcemia (>14
]. High serum calcium seen in our patient was associated with a high Intact PTH level (1182
pg/mL). E. Shane suggested that benign disease have PTH level <2 times the upper limit of normal, whereas carcinoma may have PTH level up to 10 times the upper limit of normal [18
]. Robert et all suggested that PTH level <4 times the upper limit of normal excludes malignancy [19
]. Case series studying solitary parathyroid adenomas with asymptomatic disease derived mean preoperative PTH levels of 186
] and 165
], while research studying parathyroid carcinoma yielded higher PTH levels of 714
] and 1220
]. The huge size of the cystic adenoma (11 x 7 x 6
cm) in our case is extremely rare [3
], though giant parathyroid cysts of up to 15
cm in diameter have also been reported [24
]. It may be interesting to note that a palpable neck mass is highly unusual in primary hyperparathyroidism [25
]. Hence, parathyroid carcinoma should be borne in mind while dealing with huge, palpable parathyroid masses, with very high serum calcium and PTH levels.
Histopathological report of the excised parathyroid lesion may become extremely important in cases that mimic parathyroid carcinoma. According to Shantz and Castleman, the histological features of parathyroid carcinoma are; 1) uniform sheets of (usually chief) cells arranged in a lobular pattern separated by dense fibrous trabeculae, 2) capsular or vascular invasion, and 3) mitotic figures within tumor parenchymal cells that must be distinguished from endothelial cell mitoses [26
]. However, these features have also been reported in parathyroid adenomas [25
]. Studies suggest that the overall histological appearance should be taken into consideration, and the presence of more than one in a lesion should raise suspicion of parathyroid carcinoma [27
]. The histopathology in our case did not show any of these features. Our patient had thrombosed left internal jugular vein, which has also been reported previously with large cystic parathyroid lesions compressing internal jugular vein [3
Data suggest that most patients presenting with parathyroid crisis have underlying chronic hyperparathyroidism [17
]. In our case, the diagnosis of hyperparathyroidism was not made prior to the presentation. But there were clues suggesting chronic hyperparathyroidism in our case. The patient had history of depression and acid peptic disease for last eight years. Both these clinical entities could well have been the manifestations of longstanding hypercalcemia. Moreover, serum calcium checked eight months before presentation was elevated at 11.4
mg/dL (8.6-10.2), but no workup was done at that time. The fact that our patient did not experience any neurological symptoms at a corrected serum calcium level of >20
mg/dL somewhat supports the presence of chronic hyperparathyroidism. However, our patient did not have any features to suggest nephrolithiasis, which could have been present in chronic hyperparathyroidism.
It is important to note that our patient developed parathyroid crisis after receiving vitamin D replacement for documented deficiency (<4.0
ng/mL). Although vitamin D was replaced too quickly in our patient, the repeat vitamin D level (119
ng/mL) was not in toxic range, and as such, the hypercalcemia cannot be solely attributed to vitamin D intoxication. But it shows that vitamin D replacement may unmask subclinical primary hyperparathyroidism. PTH helps in converting vitamin D to its active form (1,25-dihydroxy vitamin D), which in turn increases calcium absorption from the intestines. Hence, primary hyperparathyroidism may have been present in our patient chronically (as we discussed earlier), but vitamin D deficiency did not allow the serum calcium levels to rise very high. As soon as vitamin D was replaced, the patient tipped into parathyroid crisis. But in most cases, Vitamin D replacement does not result in life threatening hypercalcemia.
Patients with parathyroid crisis are initially managed medically with fluid hydration followed by loop diuresis and intravenous bisphosphonates [29
]. Medical optimization is followed by early excision [30
]. Mortality for patients with parathyroid crisis, who are appropriately managed, is reported to be 2.8% [29
]. This is an improvement from 14% mortality reported when emergency surgery used to be done instead of bridging it with medical optimization [30
]. In our patient, we medically optimized before surgically excising the tumour.
We also observed consistent hypokalemia in our patient together with hypercalcemia, until surgery was performed. Urinary excretion of potassium was also low along with hypokalemia. After surgery, both calcium and potassium levels normalized. In horses, hypercalcemia has been associated with hypokalemia with increased urinary potassium excretion [32
]. We could not ascertain the cause of this unexplained hypokalemia in our patient. Further research is warranted to look into possible association of hypercalcemia with hypokalemia.