An unrecognized cause of recurrent hypercalcemia: immobilization.

Abstract: We report a 66-year-old Chinese man with chronic renal insufficiency (creatinine 1.7 mg/dL) and gout suffering from slurred speech and right hemiplegia for 3 days. Acute cerebral infarction was confirmed by computed tomography. Conscious disturbance occurred on the tenth hospital day without significant changes on imaging study when compared with a previous scan. Hypercalcemia (total calcium 14.1 mg/dL) and acute exacerbation of chronic renal failure (serum creatinine 2.5 mg/dL) were noticed. Hypercalciuria (F[E.sub.Ca] 3.2%), and low serum levels of intact parathyroid hormone and 1,25(OH)[.sub.2][D.sub.3] suggested nonparathyroidal hypercalcemia. An extensive workup failed to identify any etiology of hypercalcemia. Hypercalcemia and renal failure were temporarily ameliorated after aggressive volume expansion and loop diuretic treatment but recurred 2 weeks later. Immobilization hypercalcemia was considered after the exclusion of other discernible causes and was successfully treated with rehabilitative exercises and bisphosphonates without further recurrence during a 2-year follow-up. Clinical alertness to immobilization as a possible cause of hypercalcemia may avoid unnecessary and invasive examinations, life-threatening complications and annoying recurrences.

Key Words: Hypercalcemia, immobilization, renal failure, stroke.

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Hypercalcemia, a common electrolyte imbalance, can induce multiple organ dysfunction and diverse manifestations, such as renal symptoms (polyuria, polydipsia), intestinal symptoms (nausea, vomiting, constipation), neurologic symptoms (weakness, headache, depression), and cardiac symptoms (tachycardia, hypertension). Hypercalcemic crisis (especially total calcium [Ca] > 16 mg/dL) endangers the patient with encephalopathy, acute renal failure and even death. (1)

The commonly encountered causes of hypercalcemia are malignancy (70%), primary hyperparathyroidism (20%) and chronic granulomatous disorders. Immobilization, a well-established cause of hypercalcemia since 1941, is still under appreciated due to vague clinical features. (2) In most previous reports, immobilization hypercalcemia occurred in adolescents with normal renal function and a median onset time of 4 weeks. (3) There is a paucity of literature describing immobilization hypercalcemia in impaired renal function and in the elderly. (4,5) Herein we describe an elderly patient with chronic renal insufficiency who developed recurrent hypercalcemia and acute exacerbation of chronic renal failure following stroke-related immobilization.

Case Report

A 66-year-old Chinese male presented to our emergency department with slurred speech and right hemiplegia x 3 days in October 2003. No head injury or use of sedatives was noted. His pertinent medical history included hypertension, gout, and chronic renal insufficiency for 10 years. His family history was noncontributory.

On physical examination, the patient was alert with a supine blood pressure of 112/72 mm Hg, heart rate 96 beats/min, respiratory rate 18 breaths/min, and body temperature 37.0[degrees]. Neurologic examination showed dysarthria, right facial palsy, deviated tongue to the right, right hemiplegia (0/5 strength in the right upper and lower extremities), and right-sided positive Babinski sign. The remainder of the physical examination was unremarkable.

Laboratory values at admission showed a white blood cell count of 10,700/[micro]L, platelets 393,000/[micro]L, alkaline phosphatase 85 U/L, glucose 168 mg/dL, creatinine 1.7 mg/dL, uric acid 9.7 mg/dL, and albumin 3.2 g/dL. The remainder of the values are listed in the Table. The urinalysis revealed only trace proteinuria without hematuria or cast. The estimated glomerular filtration rate through creatinine clearance rate was around 20 mL/min. Computed tomography (CT) scan of the brain showed acute cerebral infarction in the left middle cerebral artery territory. Aspirin 100 mg and piracetam 800 mg t.i.d. were prescribed. On the 10th hospital day, conscious disturbance and an elevated serum creatinine (2.5 mg/dL) were noticed. Repeat CT of the brain did not show new infarction or intracranial hemorrhage. Cerebrospinal fluid studies ruled out the possibility of encephalomeningitis. Renal ultrasound revealed relatively small-sized kidneys (right 8.7 cm, left 8.5 cm). The subsequent electrolyte survey revealed hypercalcemia (total/ionized Ca: 14.1/8.2 mg/dL), high urinary Ca excretion (fraction excretion of Ca (FECa): 3.2%, normal < 2%), and low intact parathyroid hormone (iPTH: 0.1 pg/mL). A 1,25(OH)[.sub.2][D.sub.3] of 7.7 pg/mL indicated nonparathyroidal hypercalcemia (Table). The patient was on no medication that could lead to hypercalcemia.

A series of examinations, including CT scan of the whole abdomen, panendoscopy of the upper gastrointestinal tract, whole body bone scan, tumor markers and Gallium-67 scan were nonrevealing for malignancy. Bence-Jones protein, skull film, serum and urine protein electrophoresis and bone marrow biopsy were also not suggestive of multiple myeloma. Chest film lacked features of sarcoidosis. The serum cortisol level was also within normal range, at 11.7 [micro]g/dL at 8:00 AM.

Saline hydration with 2000 mL per day and IV infusion of furosemide 40 mg every 4 hours for 7 days had corrected the serum Ca, renal function and consciousness. Unfortunately, gouty arthritis over the knees occurred, followed by recurrent hypercalcemia. Renal function deteriorated on the 24th hospital day (Table). Immobilization hypercalcemia was considered due to the presence of right hemiplegia and lack of other identifiable causes of hypercalcemia. IV infusion of pamidronate disodium 90 mg and saline hydration with 2000 mL per day, together with a rehabilitative program, began on the 25th hospital day. The patient's consciousness, serum calcium and renal function recovered within 1 week. The serial change of serum Ca and creatinine is shown in Figure 1. During a 2-year follow-up period, the patient maintained steady renal function (creatinine 1.7-1.9 mg/dL) without recurrent hypercalcemic episode.

Discussion

The homeostasis of calcium is complex because the bone, gastrointestinal tract, and kidney all affect the balance of calcium. Alteration of calcium homeostasis from any of these organ systems can lead to serum calcium changes. Therefore, hypercalcemia can be divided into three categories: accelerated bone calcium resorption (resorptive hypercalcemia), increased gastrointestinal calcium absorption (absorptive hypercalcemia), and enhanced renal calcium reabsorption (reabsorptive hypercalcemia) (Fig. 2). (6,7) In addition to the comprehensive medical history and physical examinations, measurement of urinary calcium excretion, serum iPTH and 1,25-(OH)[.sub.2][D.sub.3] is very helpful in the rapid differentiation of these three categories. Urinary calcium excretion (F[E.sub.Ca]) is lower in reabsorptive hypercalcemia, whereas it is higher in resorptive and absorptive hypercalcemia. 1,25-(OH)[.sub.2][D.sub.3] is usually high in absorptive hypercalcemia. The serum iPTH level can further subdivide resorptive hypercalcemia, the most common cause of hypercalcemia, into parathyroidal and non-parathyroidal hypercalcemia.

Our patient had recurrent hypercalcemia and acute exacerbation of chronic renal failure during hospitalization. His high urine F[E.sub.Ca] excluded reabsorptive hypercalcemia; while his low serum iPTH and 1,25-(OH)[.sub.2][D.sub.3] excluded parathyroidal hypercalcemia and endogenous or exogenous vitamin D-related hypercalcemia. A detailed review of his medications ruled out the possibility of milk-alkali syndrome and vitamin D analogue overdose. Further studies, including serum cortisol, ACTH, Gallium scan, CT scan of whole abdomen, and whole body bone scan failed to conclude either adrenal insufficiency or occult malignancy. Because of cautious exclusion of other causes and an excellent response to passive mobility on paralyzed limbs, immobilization was confirmed as the final cause of hypercalcemia.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Immobilization hypercalcemia mainly results from rapid bone turnover and may be seen after spinal cord injury or long bone fracture in children and adolescents. (8) In the elderly population, immobilization hypercalcemia is usually a sequela of cerebrovascular accident and is easily misdiagnosed due to several pitfalls related to poor nutritional and inflammatory status with low serum albumin and 25(OH)[D.sub.3] levels. Disturbed consciousness in a recent stroke patient may be easily attributed to intracranial events, such as a new infarction, hemorrhage, or infection.

The exact mechanisms of immobilization hypercalcemia remain elusive. Loss of mechanical stress (mechanostat theory) has proven critical for bone loss. (9) Another proposed mechanism is the acidic environment created by low blood flow that may impair mineralization of bone and increase PTH activity. (10,11) Overall, increased osteoclastic bone resorption and decreased osteoblastic bone formation are hallmarks in bone biopsy.

The serum calcium level in immobilization hypercalcemia depends on the rate of bone resorption and the capacity of renal calcium excretion. In the bone resorptive aspect, the speed of bone mineral density (BMD) loss in first-year stroke patients is determined by age of onset, severity and duration of paralysis, baseline serum Ca and 25(OH)[D.sub.3] concentration. (12) Resumption of walking within 2 months after the stroke may reduce the BMD loss rate. (13) In renal calcium handling aspects, the median interval between initiation of immobilization and onset of hypercalcemia had been reported as 4 weeks, but may extended to 16 weeks in patients with normal renal function. (3) When the capacity of calcium excretion decreases in patients with chronic renal insufficiency or uremia, the interval is shortened, with a reported range from 3 to 16 days. (4,5) Similarly, our patient developed hypercalcemia 10 days following a stroke.

Hypercalcemia itself can induce acute impairment of renal function via afferent glomerular arteriolar vasoconstriction, volume depletion, and nephrocalcinosis and then in turn, compromise calcium clearance and accentuate the degree of hypercalcemia. (14) Irreversible renal failure can supervene if the diagnosis is delayed. Hypercalcemia-induced acute exacerbation of chronic renal insufficiency was diagnosed in our patient due to lack of rhabdomyolysis, nephrotoxic agents, or other identifiable causes, and when correction of the hypercalcemia stabilized his renal function.

The therapeutic goals of immobilization hypercalcemia are retardation of bone resorption and enhancement of renal calcium excretion. Preliminary management includes discontinuation of medications that directly or indirectly lead to hypercalcemia (eg, calcium tablets, calcitriol, vitamin D, lithium and thiazides), volume repletion and loop diuretic treatment, followed by antiosteoclastic agents. Bisphosphonate has been proven to effectively reduce serum ionized calcium and BMD loss in hemiplegic stroke patients. (15) A passive mobility or weight-bearing rehabilitative program is undoubtedly the curative treatment and should be instituted early. Control of the underlying illness generating immobilization is crucial to foster recovery or alleviation of immobilization.

Conclusion

Immobilization hypercalcemia should be kept in mind as a differential diagnosis for stroke patients with unexplained altered mentality and deterioration of renal function. Patients with pre-existent renal function impairment carry a potentially higher risk and a shorter time to develop hypercalcemia. Early diagnosis and prompt correction of immobilization hypercalcemia results in avoidance of unnecessary investigations, unwanted recurrences and potentially life-threatening complications.

References

1. Ziegler R. Hypercalcemic crisis. J Am Soc Nephrol 2001;12:S3-9.

2. Albright F, Burnett CH, Cope O, et al. Acute atrophy of bone (osteoporosis) simulating hyperparathyroidism. J Clin Endocrinol 1941;1:711-716.

3. Stewart AF, Adler M, Byers CM, et al. Calcium homeostasis in immobilization: an example of resorptive hypercalciuria. N Engl J Med 1982;306:1136-1140.

4. Drivas G, Ward M, Kerr D. Immobilization hypercalcaemia in patients on regular haemodialysis. Br Med J 1975;3:468.

5. Gopal H, Sklar AH, Sherrard DJ. Symptomatic hypercalcemia of immobilization in a patient with end-stage renal disease. Am J Kidney Dis 2000;35:969-972.

6. Lin SH, Lin YF, Cheema-Dhadli S, et al. Hypercalcaemia and metabolic alkalosis with betel nut chewing: emphasis on its integrative pathophysiology. Nephrol Dial Transplant 2002;17:708-714.

7. Henriquez-Kries D, Sommerer C, Dikow R, et al. Hypercalcaemia-induced renal failure--a mystery. Nephrol Dial Transplant 2002;17:677-678.

8. Tori JA, Hill LL. Hypercalcemia in children with spinal cord injury. Arch Phys Med Rehabil 1978;59:443-446.

9. Bikle DD, Halloran BP. The response of bone to unloading. J Bone Miner Metab 1999;17:233-244.

10. Krieger NS, Sessler NE, Bushinsky DA. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol 1992;262:F442-F448.

11. Raisz LG. Bone resorption in tissue culture: Factors influencing the response to parathyroid hormone. J Clin Invest 1965;44:103-116.

12. Sato Y. Abnormal bone and calcium metabolism in patients after stroke. Arch Phys Med Rehabil 2000;81:117-121.

13. Jorgensen L, Jacobsen BK, Wilsgaard T, et al. Walking after stroke: does it matter? Changes in bone mineral density within the first 12 months after stroke. A longitudinal study. Osteoporos Int 2000;11:381-387.

14. Wang W, Li C, Kwon TH, et al. Reduced expression of renal [Na.sup.+] transporters in rats with PTH-induced hypercalcemia. Am J Physiol 2004;286:F534-F545.

15. Sato Y, Asoh T, Kaji M, et al. Beneficial effect of intermittent cyclical etidronate therapy in hemiplegic patients following an acute stroke. J Bone Miner Res 2000;15:2487-2494.

Chih-Jen Cheng, MD, Chung-Hsing Chou, MD, and Shih-Hua Lin, MD

From the Division of Nephrology, Department of Medicine, and the Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Reprint requests to Shih-Hua Lin, MD, Division of Nephrology, Department of Medicine Tri-Service General Hospital No. 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan, R.O.C. Email: [e-mail]

Accepted January 13, 2006.

RELATED ARTICLE: Key Points

* Immobilization is a well-established but under appreciated etiology of hypercalcemia.

* A high index of suspicion for immobilization-induced hypercalcemia can obviate the need to order unnecessary examinations.

* Due to the reduced ability to excrete calcium, patients with pre-existing renal function impairment are prone to develop immobilization hypercalcemia in a shorter time frame.

* In addition to enhancing renal calcium excretion, the standard treatments for immobilization hypercalcemia include the use of antiosteoclastic agents, early rehabilitative exercises and control of the underlying illness.

Table 1. Serial serum biochemical values during hospitalization

Hospital Day                        1     10     17    24     28    40

Total calcium (NR 8.4-10.2 mg/dL)    8.7   14.1  10.3   15.3  10.1   8.6
Ionized calcium (NR 4.5-5.3 mg/dL)   -      8.2   5.6    6.8   4.8   3.4
Phosphate (NR 2.7-4.5 mg/dL)         -      4.2   -      4.0   -     -
Alkaline phosphatase (NR 35-104     85    125     -    146     -     -
  U/L)
Albumin (NR 3.4-4.8 g/dL)            3.2    3.3   -      3.5   -     -
Urea nitrogen (NR 7-20 mg/dL)       16     32    27     20    22    17
Creatinine (NR 0.5-1.0 mg/dL)        1.7    2.5   1.4    2.1   1.8   1.5
Intact PTH (NR 12.6-57.5 pg/dL)      -      0.1   -      -     1.8  97
1,25-(OH)[.sub.2][D.sub.3] (NR       -      7.7   -      -    12.8  25.9
  16-42 pg/mL)
25-(OH)[D.sub.3] (NR 9.7-41.7        -      9.1   -      -    12.9  11.4
  ng/mL)
F[E.sub.Ca] (%) (NR < 2%)            -      3.2   -      2.5   -     1.5

NR, normal range; F[E.sub.Ca], urinary fraction excretion of calcium;
PTH, parathyroid hormone.