A 56-Year-Old Woman With Subacute Onset of Severe Constitutional Symptoms, Part 2
Correct Answer: D. Administer immediate hydration and biphoshonates.
When comparing the case in part one1 to the present case, clear differences emerge. For the case in the part one, the onset of hypercalcemia was asymptomatic, minimal in nature, and involved a pathophysiology of autonomous synthesis of excessive PTH by a benign adenoma. The present case is more acute, with a violent onset, and symptoms related to malignant disease. The entire spectrum clinically, pathophysiologically, and therapeutically are very different, indeed.
Reviewing the question above, Answer C, surgery related to a primary hyperparathyroid causation, was clinically the wrong diagnosis here. Similarly, Answer B, administer high dose glucocorticoids, is a minimal approach to lower calcium levels, particularly when situations of excessive vitamin D levels are involved in the pathogenesis. This diagnosis is wrong, and the efficacy of the maneuver too light for the life-threatening disease presented here.
Answer A has somewhat subtle areas of accuracy in that immediate, aggressive hydration is always a good first step. However, the known malignancy renders a PTH level a mere detail, and the severity described renders waiting to use calcium lowering pamidronates incorrect for the presented case. Answer D, therefore, is most optimal here.
Discussion. Malignancy is responsible for roughly 35% of hypercalcemia cases.2, 3 Unlike primary cases, the onset is usually quicker (days to weeks) and more severe when considering manifested symptoms such as profound fatigue and muscle weakness, polyuria and polydipsia leading to significant dehydration, constipation, and neurological manifestations such as hyporeflexia, obtundation, and eventually stupor and coma. In almost all cases, the elephant in the room is usually a well-known background history that includes the presence of underlying malignancy.
It is still a "truism" of hypercalcemia that once basic chemistries reveal its presence, it remains a proper maneuver to send PTH levels. This time, unlike in primary PTH forms, the pathologic elevation of calcium will have driven endogenous PTH levels downward, in fact, almost uniformly to PTH levels below 20 pg/mL.4
As to the pathophysiology of malignancy-related hypercalcemia, there are three basic causations that are tumor specific to some degree. First, in plasma cell diseases, eg, multiple myeloma, tumor cells secrete an osteoclast stimulating factor, which dissolves bone and liberates calcium into the blood. Second, in certain carcinomas, especially lung, the malignant cells secrete a PTH-related protein which, although distinguishable and measurable from normal PTH, had similar PTH-like activity capable of mimicking a wildly abnormal degree of PTH-like effects. Finally, advanced malignancies that have spread to bone with osteolytic metastases causing focal increases in bone resorption throughout the skeleton. Any tumor can do this, although lung, prostate, and breast adenocarcinomas are over-represented.4 Clinically, the patient will be very ill as the current case presents.
In the emergent setting, clinicians should be mindful of calcium levels greater than 14 mg/dL and laboratory/clinical findings of profound dehydration. The underlying fact of pre-existing malignancy is known and rapid routine studies such as skeletal x-rays demonstrate the osseous metastases. PTH level is always a good study in any hypercalcemia, but with serious clinical scenarios, this is not required to initiate what may be life-saving therapeutics.
The strategies of therapeutics in this setting involve aggressive fluid resuscitation to reverse the vicious circle of hypercalcemia induced dehydration and to simply dilute the calcium level itself. This requires isotonic saline (and a lot of it). Liters of isotonic saline in the first days is common. Too cautious amounts of fluid are a frequent error in management. Previously published studies have generally called for 200-300 mL/hr.2,5
Proper therapeutic approaches should also include the administration of agents that inhibit bone resorption. These agents should be given early and will diminish the feed from bone of calcium caused by the tumor metastases. The most used agents in this class are the bisphosphonates pamidronate (60-90 mg IV over 2 hours) or zolendronic acid (4 mg IV over 15 minutes). One will find nuanced results when researching the preferable approach.2,5 The hormonal peptide calcitonin also inhibits bone resorption. The good news is that its onset of action is within hours compared to the bisphosphonates, which have onset of action requiring 1 day to 2 days The bad news is tachyphylaxis occurs with calcitonin after 48 hours. Therefore, a "one-two punch" of administering both types of agents early in the management of severs cases is warranted.
Finally, attempts to get at the root cause, the cancer itself, should be addressed. Unfortunately, this is not always possible. The improved therapeutics for multiple myeloma are a recent exception in this regard. Still, the above principles of therapy can often be lifesaving. Clinicians could potentially see reductions in dangerous levels within 48 hours. Within a week, clinicians could see "minimal hypercalcemia" or less than 13 mg/dL.2 However, a patient with cancer and hypercalcemia is an ominous prognostic event. Not surprisingly, since hypercalcemia is usually associated with advanced cancer, one study found a 17% in-hospital mortality.6 Larger trials found that most patients with malignancy-related hypercalcemia will reach mortality within 12 months of diagnosis.2
Patient follow-up. The patient was treated with IV hydration, isotonic saline at 250 cc per hour, and bisphosphonates and calcitonin were initiated as well. Additional diagnostics include serum PTH levels (both of which were less than 20 pg/dL). A skeletal survey showed diffuse osteolytic and osteoblastic disease in the axial skeleton and skull as well as several long bones. A positron emission tomography scan confirmed that the lesions were malignant deposits.
The patient manifested a good response with a decline in serum calcium to 11.5 mg/dL at 72 hours and near normocalcemia at 1 week. The biochemical improvements were accompanied by clinical improvement with clearing to normal mentation, euvolemia, and lowering of creatinine to 1.3 mg/dL. A medical oncology consultation was obtained, and an appropriate chemotherapeutic and hormonal therapy program is expected to be put into place. The patient understoof that severe hypercalcemia episodes are a poor prognostic event in advanced malignancy.
What’s the Take Home? Hypercalcemia, defined as total serum calcium above 10.5 mg/dL, is a common occurrence. The etiology and pathogenesis of hypercalcemia has an essentially bimodal distribution. Indeed, primary hypercalcemia is generally due to the presence of autonomous, excessive production of PTH due to an adenoma in a single PTH gland and hypercalcemia due to malignancy, which may involve tumor invasion/osteolysis of bone or tumor secretion of a PTH-related protein.
As discussed in part one,1 the primary causation of hyperparathyroidism is also common (55% of cases). Malignancy-related hypercalcemia has a more sudden and explosive onset pattern with higher calcium levels and severe life-threatening symptoms. Signs of malignancy-related hypercalcemia include polyuria, polydipsia, profound dehydration, and mental obtundation. A PTH level should be sent and is quite diagnostic. Normal range limits or elevated PTH means primary while lowered levels (<20 pg/dL) point to other causations, most commonly malignancy. Indeed, most patients will carry this pre-existing history. Rapid initiation of IV hydration (200-300 cc/hr) and immediate administration of bisphosphonates and calcitonin to inhibit bone resorption of calcium are indicated. Even with successful response acutely, the prognosis of malignancy-related hypercalcemia is poor, with 90% mortality within 1 year due to advanced cancer.2
AFFILIATIONS
1Lewis Katz School of Medicine at Temple University, Philadelphia, PA
2Department of Medicine, Temple University Hospital, Philadelphia, PACITATION
Rubin RN. A 56-year-old woman with subacute onset of severe constitutional symptoms, part 2. Consultant. 2023;63(11):e7. doi:10.25270/con.2023.11.000001.DISCLOSURES
The author reports no relevant financial relationships.CORRESPONDENCE:
Ronald N. Rubin, MD, Temple University Hospital, 3401 N Broad Street, Philadelphia, PA 19140 (blooddocrnr@yahoo.com)References
Rubin RN. A 57-year-old woman with an incidental laboratory finding, part 1. Consultant. 2023;63(10):e7. doi:10.25270/con.2023.09.000006.
Golzman O. Pathophysiology of hypercalcemia. Endocrinol Metab Clin North Am. 2021;50:591-607.
Mundy GR, Guise TA. Hypercalcemia of malignancy. Am J Med. 1997;103:1257-1272.
Donovan-Walker M, Shane E. Hypercalcemia: A review. JAMA. 2022;328:1624-1636.
Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcemia. BMJ. 2015;350:h2723.
Thillaindesan S, Twigg SM, Perera N. Prevalence, cause and associated mortality of hypercalcemia in modern hospital care. Int Med J. 2022;52:1596-1601.