Clinical Chemistry

Case 4: Hypercalcemia from suspected primary hyperparathyroidism

(Some details of this case have been changed for the purpose of patient anonymity)

Clinical History:

The patient was a 32 year old, African-American woman, in the first trimester of pregnancy, with no significant medical history.  She had been experiencing nausea and vomiting and progressive weakness and lethargy for several weeks and was unable to keep fluids down.  As a consequence, she had suffered significant weight loss (22 lbs in two weeks, 10% of her body weight).  The patient was admitted to a local emergency room with complaints of nausea, vomiting and weakness to the extent that she had trouble holding her head erect.  A diagnosis of hyperemesis gravidarum  was made (a disorder of excessive nausea and vomiting with weight loss during the first trimester of pregnancy).  The patient was administered 3 liters of intravenous hydration and discharged to home following improvement in symptoms.  

The following day, she was found collapsed at home and was brought back to the emergency room. She was lethargic, responsive only to pain stimuli, and disoriented. Physical examination showed that she had dry mucous membranes, miosis (pin-point pupil size), mild tachycardia (fast heart rate), and tachypnea (fast breathing).  Laboratory tests at this facility confirmed that the patient had renal insufficiency, dehydration, and severe metabolic alkalosis, all likely due to her constant vomiting. Transabdominal ultrasound revealed intrauterine fetal demise. The patient was therefore intubated, and dilatation and curettage performed to rule-out septic abortion from infected products of conception or necrotic fetal material. Samples were sent to Anatomic Pathology for examination. Specimens revealed an immature placenta and blood clots. No fetal parts were identified, leading the pathologist to suspect that fetal demise had occurred much earlier and that the fetus had been re-adsorbed. No radiography was performed to confirm this theory.

The patient was transferred to University Hospital due to the complexity of her situation.  Upon arrival, she was unresponsive. Her breathing was assisted by mechanical ventilation. After ensuring her condition was stable, a more thorough evaluation was undertaken.

Clinical/Laboratory Findings:

Non-specific ST and T wave changes were noted on her electrocardiogram.  Computerized tomography of the head /spine showed no abnormalities. Clinical Laboratory test results were as follows:

Tests Results Ref. Range Tests Results Ref. Range
WBC count 22.3 x103/:L 4.7-10.3 x103/L Arterial Gases:

 

 
Hemoglobin 15.0 g/dL 12.0-16.0 g/dL pH 7.66

 
Platelets 233 x103/:L 140-440 x103/:L pCO2 23

 
Sodium, serum 154 mEq/L 136-146 mEq/L pO2 298

 
Potassium 2.2 mEq/L 3.5-5.1 mEq/L FDP 10 :g/mL <10:g/mL
Chloride 121 mEq/L 96-108 mEq/L Fibrinogen 538 mg/dL 186-596 mg/dL
Bicarbonate 29 mEq/L 22-30 mEq/L PT 16.1 secs 10.7-12.2 secs
BUN 67 mg/dL 7-18 mg/dL INR 2.04

 
Creatinine 2.9 mg/dL 0.7-1.2 mg/dL Lactic acid 4.4 mmol/L 0.5-2.2 mmol/L
Glucose 113 mg/dL 65-110 mg/dL Ammonia 20 :mol/L 11-35 :mol/L
Total protein 7.3 gm/dL 6.4-8.4 gm/dL TSH 0.17:U/mL 0.49-4.67 :U/mL
Albumin 3.3 mg/dL 3.7-5.6 mg/dL T-uptake 23.1% 25–35 %
Total calcium 40.1 mg/dL 8.6-10 mg/dL< Total T4 12.3 :g/dL 4.5-12.0 :g/dL
Phosphorus 1.6 mg/dL 2.5-4.5 mg/dL FTI 2.84

 
Total bilirubin 2.1 mg/dL 0.2-1.3 mg/dL Myoglobin, urine positive

 
Alkaline phosphatase

141 U/L

38-126 U/L

 Urine: (60mL)    

Aspartate transaminase

129 U/L

7-40 U/L

 Potassium

16.3 mEq/L

 
Magnesium 0.7 mg/dL 1.6-2.6 mg/dL Sodium 79 mEq/L

 
Amylase 39 U/L 0-88 U/L Creatinine 20.1 mg/dL

 
Lipase 153 U/L 114-286 U/L Calcium 30.5 mg/dL

 
Creatine phosphokinase 4910 U/L (100% MM) 37-289 U/L Phosphorus 4.3 mg/dL  

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The first round of Clinical Pathology Laboratory tests were problematic due to the rapid clotting of the patient's blood in collection tubes containing anti-cogulants: blood drawn in EDTA tubes clotted immediately and small clots were noted in citrated blood. This resulted in premature cancellation of some tests. Initial and repeat coagulation studies suggested disseminated intravascular coagulation (DIC). An unbelievably high serum calcium level of 38 mg/dL (normal range approx. 8-11mg/dL) was obtained by making 1:1 dilutions of serum with deionized water. The test was repeated using a fresh sample and gave a higher value of 40.1 mg/dL. A fresh sample was drawn and split for analysis at the Clinical Pathology Labs at the University Hospital and the nearby VA Hospital using differing methodologies, but similar high values were obtained.  Ionized calcium was determined using a point-of-care blood gas instrument but a reading of  >5.00 mmol/L (>20 mg/dL) was obtained indicating a value outside of the linear range of the instrument. An earlier drawn blood sample was tested by atomic absorption spectrophotometry and produced a serum calcium value of 36 mg/dL. All the evidence indicated that the patient's hypercalcemia was not an artifact produced by error or interfering substances.

Treatment and Outcome:

Day1

The patient was put on mechanical ventilation and intense intravenous fluid. Intravenous pamidronate and calcitonin were administered to reduce the patients high serum calcium, and esmolol used to counteract symptoms attributable to hyperthyroidism.  Pamidronate was later discontinued and calcitonin and calcium-free hemodialysis initiated in an aggressive attempt to normalize the extraordinarily high calcium levels (although there are no reports in the literature detailing the management of a hypercalcemia of this magnitude). Temporal changes in the patient's calcium and phosphate levels are tabulated below:

Day/time Total Ca2+ (mg/dL) Ionized Ca2+ (mmol/L,mg/dL) PO4(mg/dL) Product
Ca2+x PO4
Day 1
2230 38 >5.00, >20.0 >0.53

 

 
0000 40.1 >5.00, >20.0 >0.50 1.6 64
0145 35.2 4.87, 19.5 0.55 2.3 81
0300

35.6

 >5.00, >20.0 >0.56 2.6 93
0400 31.5 4.99, 20.0 0.63 2.9 91
1000

13.1

 1.74, 6.9 0.53 2.8 37
1400 17.6 2.48, 9.9 0.56 3.7 65
1800 19.2

 

 

 5.4 104
2143 18.1 2.53, 10.1 0.56 5.5 100
Day 2
0000 17.7 2.40, 9.6 0.54 5.9 104
0600 16.4

 

 

 5.5 90
0816

 

 1.75, 7.0

 

 

 
1000 15.1

 

 

 6.4 97
1208 13.1 1.14, 4.6 0.35

 

 
1234

 

 1.61, 6.4

 

 

 

Day 2

The patient initially appeared comfortable and somewhat more responsive following hemodialysis; however, overnight, the patient's urine output decreased from 400 to 60 mL/hour, her blood pressure declined from 140/80 to110/60 mmHg, and pulse rate increased from 105 to 125 beats/min. Over the next four hours, these parameters precipitously worsened: urine output dropped to 10 cc/hour and then stopped (anuria); blood pressure declined to 70/40mm/Hg; pulse increased to 180 beats/minute; and respiratory rate increased to 40/min with increasing inspiratory resistance. Since the hypotension was unresponsive to the aggressive intravenous fluid challenge, esmolol was discontinued, and dobutamine was initiated for vasopressive support. Unfortunately,  the patient subsequently experienced ventricular fibrillation and expired in spite of intense resusitative measures. No autopsy was performed following the wishes of family members. Serum PTH and PTH-rP levels and retrospective analysis of residual serum and urine for markers of malignancy and bone metabolism were determined after death. These results are tabulated below:

Test Result Reference Range
1,25-D3 11.3 pg/mL*test problem 15.9-55.6 pg/mL
25-D3 11.2 ng/mL 8.9-46.7 ng/mL
Calcium (Dade Dimension RxL) 35.6 mg/dL 8.6-10 mg/dL
Calcium (Atomic absorption spectrophotometry) 36 mg/dL 9-11 mg/dL
PTH, intact 1722 pg/mL 10-65 pg/mL
PTH, intact (prior to UH admit) 2908 pg/mL 12-72 pg/mL
PTH-rP 0.4 pmol/L <1.3 pmol/L
CEA 1.31 ng/mL 0-5.00 ng/mL
CA-125 71.18 U/mL 0-35 U/mL
DPD/creatinine ratio 19.5 2.3-7.4
N-Tx/creatinine ratio 1174 5-65
SPEP normal (no M-spikes)

 

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Discussion:

To the best of our knowledge, the severity of this patient's hypercalcemia is unparalleled in the English medical literature. No definitive cause of the patient's hypercalcemia was established; the patient did not consume antacids or calcium supplementation. However, laboratory data are highly suggestive of malignancy-induced hypercalcemia, and strongly support a diagnosis of primary hyperparathyroidism. If an autopsy had been permitted and performed, there is a high probability that a parathyroid tumor would have been discovered in this case.

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