para>HHM, humoral hypercalcemia of malignancy; PTH, parathyroid hormone. *PTH may be normal or increased in hypocalcemic patients due to renal failure, acute pancreatitis, vitamin D deficiency. " PTH may be normal or increased in hypercalcemic patients due to acromegaly, vitamin A intoxication, MEN type IIA, RTA, chronic renal failure.
TABLE 16 " 62Laboratory Findings in Various Diseases of Calcium and Phosphorus MetabolismView LargeTABLE 16 " 62Laboratory Findings in Various Diseases of Calcium and Phosphorus Metabolism Disease Serum Calcium* Serum Phosphorus Serum ALP Urine Calcium " Urine Phosphorus Serum PTH Serum 1,25-Dihydroxyvitamin D Primary hyperparathyroidism I D (<3 mg/dL in 50%) I slightly in 50% (N if no bone disease) I in two thirds I I I Humoral hypercalcemia of malignancy I; frequently marked D in 50% Frequently I I I D D Familial hypocalciuric hypercalcemia Mild I N or slightly D N D or low N I or inappropriately N Proportional to PTH Hypoparathyroidism D I N D D " ¡ D D Pseudohypoparathyroidism D I N; occasionally D D D " ¡ N or I D Pseudohypoparathyroidism N N N N N N Secondary hyperparathyroidism (renal rickets) D or N I I or N D or I D I D Vitamin D excess I N D I I D I Rickets and osteomalacia D or N D or N I D D D Osteoporosis N N N N or I N Polyostotic fibrous dysplasia N N N or I N N Paget disease N N or I I N or I I Metastatic neoplasm to bone N or I V N or I V I Multiple myeloma N or I V N or I N or I N or I I Sarcoidosis N or I N or I N or I I N Fanconi syndrome or renal loss of fixed base D or N D N or I I I Histiocytosis X (Letterer-Siwe disease, Hand-Sch ¼ller-Christian disease, eosinophilic granuloma) N N N or I N or I N Hypercalcemia and excess intake of alkali (Burnett syndrome) I I or N N N N Solitary bone cyst N N N N N N
D, decreased; I, increased; N, normal; V, variable.
*Serum calcium. Repeated determinations may be required to demonstrate abnormalities. Serum total protein level should always be known. See also response to cortisone. " Urine calcium. The patient should be on a low-calcium diet (e.g., Bauer-Aub). " ¡See Ellsworth-Howard test.
TABLE 16 " 63Comparison of Primary Hyperparathyroidism (HPT) and Humoral Hypercalcemia of Malignancy (HHM)View LargeTABLE 16 " 63Comparison of Primary Hyperparathyroidism (HPT) and Humoral Hypercalcemia of Malignancy (HHM) HHM HPT Etiology Squamous or large cell carcinoma of the bronchus, hypernephroma of the kidney, cancer of the ovary, colon, others Primary hyperplasia, adenoma, carcinoma of the parathyroids Serum calcium Very high: >14 mg/dL in 75% of patients Moderately high: >14 mg/dL in 25% of patients Suppressed by cortisone in 25 " 50% of patients Suppressed by cortisone in 50% of cases with and 23% of cases without osteitis fibrosa Serum PTH Decreased Increased Serum PTHRP Increased Not increased Serum chloride Low: <99 mEq/L High: >102 mEq/L Serum chloride phosphorus ratio <30 >33 Serum bicarbonate Increased or normal Normal or low pH Alkalosis Acidosis Serum ALP Increased in 50% of patients, even without bone disease Seldom increased unless bone disease is present Serum phosphorus Increased, normal, or low Normal or low Urine calcium Often >400 mg/24 h Usually <400 mg/24 h Serum 1,25-dihydroxyvitamin D Decreased Increased Urine cAMP Increased in HHM but not due to bone metastases only Increased in 90% of cases ESR Usually increased Normal Anemia May be present Absent Serum albumin Often decreased Usually normal Renal stones Absent Common Pancreatitis Rare Occurs Radiographic changes in hand bones Absent May be present
Figure 16 " 2Algorithm for diagnosis of hypercalcemia.
(ESR, erythrocyte sedimentation rate; PTH, parathyroid hormone.)
(Data from Wong ET, Freier EF. The differential diagnosis of hypercalcemia: an algorithm for more effective use of laboratory tests. JAMA. 1982;247:75 and Johnson KR, Howarth AT. Differential laboratory diagnosis of hypercalcemia. CRC Crit Rev Clin La Sci. 1984;21:51.)
View OriginalFigure 16 " 2Algorithm for diagnosis of hypercalcemia.
(ESR, erythrocyte sedimentation rate; PTH, parathyroid hormone.)
(Data from Wong ET, Freier EF. The differential diagnosis of hypercalcemia: an algorithm for more effective use of laboratory tests. JAMA. 1982;247:75 and Johnson KR, Howarth AT. Differential laboratory diagnosis of hypercalcemia. CRC Crit Rev Clin La Sci. 1984;21:51.)
View Original
Figure 16 " 3Diagrammatic illustration of distribution of patients according to serum calcium and serum PTH.
The values of some patients may lie outside the exact boundaries indicated, and some conditions may overlap. The exact cutoff will vary somewhat with the assays used, the patient mix, and the locally established normal reference ranges.
(From Mayo Laboratories Test Catalog. Rochester, MN: Mayo Medical Laboratories; 1995. By permission of Mayo Foundation for Medical Education and Research. All rights reserved.)
View OriginalFigure 16 " 3Diagrammatic illustration of distribution of patients according to serum calcium and serum PTH.
The values of some patients may lie outside the exact boundaries indicated, and some conditions may overlap. The exact cutoff will vary somewhat with the assays used, the patient mix, and the locally established normal reference ranges.
(From Mayo Laboratories Test Catalog. Rochester, MN: Mayo Medical Laboratories; 1995. By permission of Mayo Foundation for Medical Education and Research. All rights reserved.)
View Original
Use
- PTHrP is useful clinically in differentiating primary hyperthyroidism from HHM. Also useful as a marker in the management of patients with tumor-associated hypercalcemia.
- The usual pattern of HHM is elevated total and ionized calcium, low PTH in the absence of other causes of hypercalcemia (e.g., excessive vitamin D, sarcoid, TB). If the presence of a malignancy is uncertain, or there are several possible causes for hypercalcemia, measurement of PTHrP can be of assistance.
- HHM occurs in patients with cancer (typically squamous, transitional cell, renal, ovarian), 5 " 20% who have no bone metastases compared to patients with widespread bone metastases (myeloma, lymphoma, breast cancer).
- HHM occurs in approximately 20 " 35% of patients with breast cancer, approximately 10 " 15% of cases with lung cancer, approximately 70% of cases with multiple myeloma, and rare in lymphoma and leukemia.
- Rarely hypercalcemia may occur in association with benign tumors (e.g., pheochromocytoma, dermoid cyst of the ovary) ( "humoral hypercalcemia of benignancy " ).
- Very high serum calcium (e.g., >14.5 mg/dL) is much more suggestive of HHM than primary HPT; less marked increase with renal tumors. Less than or equal to 5% of hypercalcemia patients have simultaneous HPT and HHM.
Interpretation
Increased In
- Increased serum PTHrP (>2.6 pmol/L) can make a positive diagnosis in most cases of HHM, but approximately 20% of cancer patients with hypercalcemia have only local osteolytic changes with no increased PTHrP.
- PTHrP is also increased in (>2.6 pmol/L)
- Greater than 80% of hypercalcemic patients with solid tumors with or without bone metastasis.
- Some patients with hypercalcemia and hematologic cancers.
- Approximately 10% of cancers without hypercalcemia; PTHrP becomes normal when hypercalcemia is corrected by treatment of cancer.
- May be increased in nonmalignant pheochromocytoma.
Normal In
- Healthy persons: values <1.0 pmol/L.
- Other causes of hypercalcemia (e.g., sarcoidosis, vitamin D intoxication).
- Low-normal or suppressed intact PTH (<20 pg/mL) excludes hyperparathyroidism.
- Serum 1,25-dihydroxyvitamin D is usually decreased or low-normal in HHM but is increased in HPT.
Limitations
- Production of PTHrP by the fetoplacental unit can cause transient increase during pregnancy, especially in the third semester.
- Primary hyperparathyroidism occurs in ≤10% of patients with HHM as well as in those receiving thiazides or with other causes of hypercalcemia.