What's The Take Home?

A 57-Year-Old Woman With an Incidental Laboratory Finding, Part 1

Ronald N. Rubin, MD1,2 —Series Editor

Volume 63 - Issue 10 - October 2023

  • Correct Answer: B. The patient can be safely managed either with medical management/observation or elective parathyroid surgery at this time

    Discussion. The presented case serves as a gateway to discuss one of the classic metabolic disorders encountered in clinical medicine: hypercalcemia. Most US laboratories define hypercalcemia as serum calcium that is greater than 10.5 mg/dL. A review of normal calcium homeostasis is needed to understand the abnormal pathophysiologies that cause hypercalcemia. The key organ systems involved are the bones—the great reservoir of calcium in the body—as well as the kidney, due to its excretion or no of calcium from the body, and the gastrointestinal (GI) tract, due to its rate of absorption of calcium. All these systems work to maintain a tight level of 8.5-10.5 mg/dL. The parathyroid glands are the controlling thermostat to these systems. They sense serum calcium levels and secrete varying levels of parathyroid hormone (PTH) in response. A low serum calcium level induces increases in PTH, which stimulate bone osteoclasts to resorb bone calcium into the blood. This also leads to an increase in the calcium absorption in the renal tubules, as well as metabolic activation of vitamin D into its more active calcitriol form, which increases calcium absorption in the small intestine. These all serve to increase the serum calcium level and restore normal blood levels.1

    Conversely, derangements along this continuum will result in overactivity of the calcium, raising mechanisms with resultant hypercalcemia. Thus, autonomously excessive PTH will cause increased bone reabsorption, enhanced kidney calcium reabsorption, and conversion of calcidiol to calcitriol with enhanced gut calcium absorption. Tumors metastatic to bones will cause markedly increased bone resorption and calcium release into the serum. Thiazide diuretics can cause increased renal tubular calcium reabsorption. Excessive vitamin D ingestion (hypervitaminosis D) will result in excessive GI calcium absorption. These comprise the core of etiologies of hypercalcemia. However, in the clinic, there are but two major pathophysiologies: autonomous PTH production (almost always from an adenoma in one parathyroid gland) and malignancy (almost always advanced and involving bone) which comprise 90% of causation of hypercalcemia.2 (NOTE: Part 1 of this article focuses on the former, while Part 2 will address the latter, namely because their presentations, findings, and management are very different.)

    When a gland is producing PTH autonomously rather than in response to low serum calcium, the patient has primary hyperparathyroidism (PHPT). The thermostat is broken so to speak. The heater is on (and stays on) despite the temperature (in this case, the calcium level) having risen to an abnormal range.

    Currently, the ubiquity of laboratory testing has resulted in almost all cases presenting like the index case—an abnormal incidental laboratory finding. And as with any presentation of hypercalcemia, the key initial test to probe etiology is a PTH level. The couplet of elevated serum calcium and an elevated (or even normal) PTH level indicates the presence of autonomous PTH production and is essentially diagnostic for primary hyperparathyroidism. A vast majority of cases will be asymptomatic, although some patients may on reflection (and our repeated questioning) manifest fatigue and constipation. Since we meet the process early, today, in my view, there are far less instances of metabolic bone disease (osteitis fibrosa cystica), renal calcium sone formation, and dangerously high calcium levels with their attendant dehydration and mental obtundation/coma than what was previously found in older literature.3 When we consider hypercalcemia as less than 12 mg/dL, moderate hypercalcemia as 12-14 mg/dL, and severe hypercalcemia greater than 14 mg/dL,3 most patients will be in the mild categories and not require urgent or aggressive in-hospital methods to lower calcium levels.

    A helpful initial maneuver is to reverse any aggravating factors such as concomitant thiazide use or ingestion of vitamin D supplements. But for most patients with hyperparathyroid, the crux of our treatment decision-making is determining whether to proceed with parathyroid surgery and when to do so. Two conflicting variables come into play when making judgements on surgery. First, is it clear that we are seeing and diagnosing PHPT sooner? The symptomatic and very high calcium levels of the past have been replaced by an asymptomatic demographic most often with mild or moderate hypercalcemia discovered incidentally.3,4 These patients have a good prognosis without surgery going out 10 to 15 years in observational studies.3 However, parathyroid surgery is curative and far safer (in the hands of an experienced neck surgeon) than decades ago. Still, surgery is surgery. To try to balance these conflicting issues, specialist societies have formulated a rather complex series of guidelines that consider the target organs at risk in PHPT. Thus, patients with asymptomatic hypercalcemia and minimally elevated calcium levels can be safely followed by observation until any one of the following occurs:

    1. Serum calcium rises to more than 1.0 mg/dl above normal.
    2. Bone densitometry scores are less than -2.5.
    3. Occurrence of vertebral fracture
    4. Creatinine clearance less than 60 mL/min
    5. Specifically high levels of urine calcium (renal calculus risk)
    6. Actual presence of nephrolithiasis on imaging
    7. Younger than 50 years of age5

    Studies indicate that 40% of patients under observation will manifest one of the surgical criteria listed within 10 to 15 years.3,6 But a randomized, controlled trial did not demonstrate a mortality benefit with surgical parathyroidectomy at 10-year follow up,7 which makes Answer D an overstatement and not correct.

    Answers A and C are treatments for more severely elevated calcium levels, which are not needed or indicated for the minimally elevated calcium levels present in our case. The best answer is B. The patient does not yet manifest any of the criteria for recommending surgery. Her calcium level is minimally elevated, so she can safely be monitored and followed or choose elective parathyroid surgery now with either choice offering a very good long-term prognosis.

    Patient follow-up. Several serial calcium levels were in the 10.5 to 11.4 mg/dL range with ionized calcium levels of 6.0 mg/dL range, confirming the presence of true hypercalcemia. PTH levels were obtained and were 52 pgm/dL and 56 pgm/dL (normal range: 20-65 pgm/dL). The presence of hypercalcemia with concomitant high-normal PTH levels confirmed PHPT. Careful review of the patient's history confirmed that she was asymptomatic with no constitutional symptoms such as fatigue or constipation. An experienced neck surgeon was consulted with a detailed discussion of therapeutic alternatives. There was no suspicion of the presence of metabolic bone disease and a bone mineral density T score was well within normal range. A detailed follow-up plan with calcium and creatinine levels and clinical observation was initiated. The patient elected to defer parathyroid surgery for now. She knows that data indicate that nearly half of patients in her demographic will require surgery in 10-15 years and is ready for that if such surgical indications arise.

    What’s The Take Home? Hypercalcemia, defined as total serum calcium (the usual value measured and reported on most US biochemical testing) above 10.5.mg/dL. It is more common than is thought with epidemiological studies reporting a 1% incidence.4 The etiology and demographics of patients with hypercalcemia has an essentially bimodal distribution clinically, namely, primary hypercalcemia due to the presence of autonomous, excessive production of parathyroid hormone due to the presence of adenoma in a single parathyroid glans; and hypercalcemia due to malignancy, which may involve tumor invasion/osteolysis of bone or tumor secretion of a parathyroid hormone related protein. The latter will not be measured as PTH in assays. Primary hyperparathyroidism is a bit more common—55% of cases, most frequently in asymptomatic cases, found on routine blood testing or minimally so with fatigue and constipation. Malignancy-related hypercalcemia (35%) has a more sudden, explosive onset pattern with higher calcium levels and severe, or even life-threatening, signs and symptoms including polyuria, polydipsia, profound dehydration, and mental obtundation.3 In any case of hypercalcemia, the initial and most important study is measurement of PTH.

    A normal or elevated level in the presence of a high serum calcium is essentially diagnostic of PHPT, which is almost always due to parathyroid adenoma. A depressed PTH level has a broader differential diagnosis the unfortunate highlight of which is malignancy along with a scattering of more esoteric causations (familial, excess vitamin D).

    For PHPT, a catalog of criteria for indication of parathyroid surgery have been developed. Unless these criteria are present, many patients can be treated with non-surgical observation and reversing any aggravating factors (thiazides, excessive calcium intake). In stable cases, surgery is not associated with increased long-term mortality. In long-term (10 to 15-year studies) about 40% of nonsurgically managed cases will develop risk criteria and require surgery. Overall, the prognosis is excellent for patients with PHPT.3

    AFFILIATIONS
    1Lewis Katz School of Medicine at Temple University, Philadelphia, PA
    2Department of Medicine, Temple University Hospital, Philadelphia, PA

    CITATION
    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

    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

    1. Goltzman D. Pathophysiology of hypercalcemia. Endocrine Metab Clin North Am. 2021;50: 591-607.
    2. Mundy GR, Guise TA. Hypercalcemia of Malignancy. Am J Med. 1997;103:1257-1272.
    3. Donovan-Walker M. Shane E. Hypercalcemia: A review. JAMA. 2022;328:1624-1632.
    4. Minisola S, Pepe J , Piamonte S, Cipriani C. The diagnosis and management of hypercalcemia. BMJ. 2015:350:2723-2732.
    5. Bilesikian JP, Silverberg SJ, Bandeira F, et al. Task Force #8: management of primary hyperparathyroidism. J Bone Miner Res. 2022;10:2391-2403.
    6. Silverberg SS, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10 year prospective study of primary hyperparathyroidism with or without parathyroid surgery. N Eng J Med. 1999;341:1249-1255.
    7. Pretorius M, Lundstadt K, Heck A, et al. Mortality and morbidity in mild hyperparathyroidism: results from a 10 year prospective randomized controlled trial of parathyroidectomy versus observation. Ann Int Med. 2022;175: 812-819.