Diagnosis and differential diagnosis of hypercalcemia

Diagnosis of primary, secondary, and tertiary hyperparathyroidism

Diagnosis of hypoparathyroidism

Monitoring end-stage renal failure patients for possible

renal osteodystrophy

Parathyroid hormone (PTH) is produced and secreted by the

parathyroid glands, which are located along the posterior aspect of

the thyroid gland. The hormone is synthesized as a 115-amino acid

precursor (pre-pro-PTH), cleaved to pro-PTH and then to the 84-amino

acid molecule, PTH (numbering, by universal convention, starting at

the amino-terminus). The precursor forms generally remain within the

parathyroid cells.

Secreted PTH undergoes cleavage and metabolism to form

carboxyl-terminal fragments (PTH-C), amino-terminal fragments

(PTH-N), and mid-molecule fragments (PTH-M). Only those

portions of the molecule that carry the amino terminus (ie, the

whole molecule and PTH-N) are biologically active. The active

forms have half-lives of approximately 5 minutes. The inactive

PTH-C fragments, with half-lives of 24 to 36 hours, make up >90% of

the total circulating PTH and are primarily cleared by the kidneys.

In patients with renal failure, they can accumulate to high levels.

PTH 1-84 is also elevated in these patients, with mild elevations being

considered a beneficial compensatory response to end organ PTH

resistance, which is observed in renal failure.

The serum calcium level regulates PTH secretion via negative

feedback through the parathyroid calcium sensing receptor (CASR).

Decreased calcium levels stimulate PTH release. Secreted PTH

interacts with its specific type II G-protein receptor, causing rapid

increases in renal tubular reabsorption of calcium and decreased

phosphorus reabsorption. It also participates in long-term

calciostatic functions by enhancing mobilization of calcium from

bone and increasing renal synthesis of 1,25-dihydroxy vitamin D,

which, in turn, increases intestinal calcium absorption. In rare inherited

syndromes of parathyroid hormone resistance or unresponsiveness

and in renal failure, PTH release may not increase serum calcium

levels.

Hyperparathyroidism causes hypercalcemia, hypophosphatemia,

hypercalcuria, and hyperphosphaturia. Long-term consequences

are dehydration, renal stones, hypertension, gastrointestinal

disturbances, osteoporosis and sometimes neuropsychiatric

and neuromuscular problems. Hyperparathyroidism is most

commonly primary and caused by parathyroid adenomas. It can

also be secondary in response to hypocalcemia or hyperphos-

phatemia. This is most commonly observed in renal failure.

Long-standing secondary hyperparathyroidism can result in

tertiary hyperparathyroidism, which represents the secondary

development of autonomous parathyroid hypersecretion. Rare

cases of mild, benign hyperparathyroidism can be caused by

inactivating CASR mutations.

Hypoparathyroidism is most commonly secondary to thyroid

surgery, but can also occur on an autoimmune basis, or due to

activating CASR mutations. The symptoms of hypoparathyroidism

are primarily those of hypocalcemia, with weakness, tetany, and

possible optic nerve atrophy.

PTH

      15-50 pg/mL

      Reference values apply to all ages.

CALCIUM

      Males

             0-11 months: not established*

             1-14 years: 9.6-10.6 mg/dL

             15-16 years: 9.5-10.5 mg/dL

             17-18 years: 9.5-10.4 mg/dL

             19-21 years: 9.3-10.3 mg/dL

             > or =22 years: 8.9-10.1 mg/dL

      Females

             0-11 months: not established*

             1-11 years: 9.6-10.6 mg/dL

             12-14 years: 9.5-10.4 mg/dL

             15-18 years: 9.1-10.3 mg/dL

             > or =19 years: 8.9-10.1 mg/dL

PHOSPHORUS

      Males

             0-11 months: not established**

             1-4 years: 4.3-5.4 mg/dL

             5-13 years: 3.7-5.4 mg/dL

             14-15 years: 3.5-5.3 mg/dL

             16-17 years: 3.1-4.7 mg/dL

             > or =18 years: 2.5-4.5 mg/dL

      Females

             0-11 months: not established**

             1-7 years: 4.3-5.4 mg/dL

             8-13 years: 4.0-5.2 mg/dL

             14-15 years: 3.5-4.9 mg/dL

             16-17 years: 3.1-4.7 mg/dL

             > or =18 years: 2.5-4.5 mg/dL

CREATININE

      Males

             0-11 months: not established

             1-2 years: 0.1-0.4 mg/dL

             3-4 years: 0.1-0.5 mg/dL

             5-9 years: 0.2-0.6 mg/dL

             10-11 years: 0.3-0.7 mg/dL

              12-13 years: 0.4-0.8 mg/dL

             14-15 years: 0.5-0.9 mg/dL

             > or = 16 years: 0.8-1.3 mg/dL

      Females

              0-11 months: not established

              1-3 years: 0.1-0.4 mg/dL

             4-5 years: 0.2-0.5 mg/dL

             6-8 years: 0.3-0.6 mg/dL

             9-15 years: 0.4-0.7 mg/dL

             > or = 16 years: 0.6-1.1 mg/dL

*The serum concentration of calcium varies significantly during the

immediate neonatal period. In general, the serum calcium

concentration decreases over the first days of life, followed by a

gradual increase to adult concentrations by the second or third

week of life.

**The plasma concentrations of inorganic phosphate in the

neonatal period can be greater than those of the adult.

About 90% of the patients with primary hyperparathyroidism have

elevated PTH levels. The remaining patients have normal

(inappropriate for the elevated calcium level) PTH levels. About

40% of the patients with primary hyperparathyroidism have serum

phosphorus levels <2.5 mg/dL and about 80% have serum

phosphorus <3.0 mg/dL.

An (appropriately) low PTH level and high phosphorus level in a

hypercalcemic patient suggests that the hypercalcemia is not

caused by PTH or PTH-like substances.

An (appropriately) low PTH level with a low phosphorus level in a

hypercalcemic patient suggests the diagnosis of paraneoplastic

hypercalcemia caused by parathyroid related peptide (PTHRP).

PTHRP shares N-terminal homology with PTH and can

transactivate the PTH receptor. It can be produced by many

different tumor types.

A low or normal PTH in a patient with hypocalcemia suggests

hypoparathyroidism, provided the serum magnesium level is

normal. Low magnesium levels inhibit PTH release and action

and can mimic hypoparathyroidism.

Low serum calcium and high PTH levels in a patient with normal

renal function suggest resistance to PTH action

(pseudohypoparathyroidism type 1a, 1b, 1c, or 2) or, very rarely,

bio-ineffective PTH.

A limited number of the PTH-C fragments, which accumulate in

renal failure, chiefly PTH 7-84, cross-react in this and other intact

PTH assays. PTH 1-84 is also elevated in renal failure, with mild

elevations being considered beneficial. Consequently, when

measured with an intact PTH assay, concentrations of 1.5 to 3 times

the upper limit of the healthy reference range appear to represent

the optimal range for end-stage renal failure patients. Lower

concentrations may be associated with adynamic renal bone

disease, while higher levels suggest possible secondary or tertiary

hyperparathyroidism, which can result in high-turnover renal

osteodystrophy.

Some patients with moderate hypercalcemia and equivocal

phosphate levels, who have either mild elevations in PTH or

(inappropriately) normal PTH levels, may be suffering from

familial hypocalciuric hypercalcemia, which is due to inactivating

CASR mutations. The molar renal calcium to creatinine clearance

is typically <0.01 in these individuals. The condition can be

confirmed by CASR gene mutation screening (#83703 "Calcium

Sensing Receptor [CASR] Gene, Mutation Screen" or #83817

"Calcium Sensing Receptor [CASR] Gene Mutation Screening,

Biochemical and Genetic," which includes the molar renal calcium/

creatinine calculation).

For diagnostic purposes, PTH values should be interpreted

with other test results and the overall clinical presentation and

history of the patient.

Normal reference ranges may vary based on geographical

locations of the populations studied.

The PTH-C fragment 7-84, which accumulates in renal failure,

shows substantial cross-reactivity in this assay. Healthy population

reference ranges, therefore, do not apply in renal failure.

As with all tests containing monoclonal mouse antibodies, erroneous

findings may be obtained from samples taken from patients who have

been treated with monoclonal mouse antibodies or have received

them for diagnostic purposes.

In rare cases, interference due to extremely high titers of antibodies

to ruthenium or streptavidin can occur.

1.   Souberbielle JC, Fayol V, Sault C, et al: Assay-specific decision

      limits for two new automated parathyroid hormone and

      25-hydroxyvitamin D assays. Clin Chem 2005;51(2):395-400

2.   Boudou P, Ibrahim F, Cormier C, et al: Third- or second-

      generation parathyroid hormone assays: a remaining debate in

      the diagnosis of primary hyperparathyroidism. J Clin Endocrinol

      Metab 2005;90(12):6370-6372

3.   Silverberg SJ, Bilezikian JP: The diagnosis and management

      of asymptomatic primary hyperparathyroidism. Nat Clin Pract

      Endocrinol Metab 2006;2(9):494-503

4.   Brossard JH, Cloutier M, Roy L, et al: Accumulation of a non-

(1-84) molecular form of parathyroid hormone (PTH) detected

by intact PTH assay in renal failure: importance in the

interpretation of PTH values. J Clin Endocrinol Metab

1996;81:3923-3929

5.   Garfield N, Karaplis AC: Genetics and animal models of hypo-

      parathyroidism. Trends Endocrinol Metab 2001;12:288-294

6.   Sakhaee K: Is there an optimal parathyroid hormone level in

      end-stage renal failure: the lower the better? Curr Opin Nephrol

      Hypertens 2001;10:421-427

7.   Vetter T, Lohse MJ: Magnesium and the parathyroid. Curr Opin

      Nephrol Hypertens 2002;11:403-410

8.   Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, et al: Summary

      statement from a workshop on asymptomatic primary

      hyperparathyroidism: a perspective for the 21st century. J Clin

      Endocrinol Metab 2002;87:5353-5361