JOURNAL OF BONE AND MINERAL RESEARCH

Volume 6. Supplement 2. 1991

Mary Ann Liebert, Inc.. Publishers

Differential Diagnosis of Hypercalcemia

FREDERIC W. LAFFERTY

ABSTRACT

The differential diagnosis of hypercalcemia has expanded to over 25 separate disease states, with primary hy-
perparathyroidism and malignancy accounting for 8O-9O% of all hypercalcemic patients. Primary hyper-
parathyroidism comprises the majority of hypercalcemic patients among the ambulatory population, but
malignancy accounts for up to 65% of such patients in the hospital. Factors favoring primary hyperparathy-
roidism include a family history of hyperparathyroidism or multiple endocrine neoplasia, a history of child-
hood radiation to the head and neck, the postmenopausal state, a history of renal calculi or peptic ulcer, hy-
pertension, the induction of hypercalcemia by thiazides, or an asymptomatic patient with a prolonged, stable
mild hypercalcemia. The usefulness of the serum calcium, parathyroid hormone, chloride, phosphorus,
serum 25-OHD, and 1,25-(OH),D, and urinary calcium in the differential diagnosis of hypercalcemia is dis-
cussed. The pitfalls of an excessive reliance on the serum PTH in diagnosing hyperparathyroidism are
stressed. The discriminant values of the serum calcium, chloride, phosphorus, and parathyroid hormone are
explored, with the serum parathyroid hormone, chloride, and calcium proving most useful in separating pri-
mary hyperparathyroidism from other forms of hypercalcemia. Multivariate discriminant analysis using the
serum calcium, phosphorus, and chloride and the hematocrit achieves an accuracy of 95-98% and is the
most economical method of identifying hyperparathyroidism. The addition of the amino-terminal or intact
PTH assay increases the accuracy to 99% and is essential in the presence of renal insufficiency.

INTRODUCTION With good renal function and suppressed parathyroid hor-

of inexpensive, routine serum multi-
W ITH THE A D V E N T
ple chemical analysis during the past four decades,
the problem of the differential diagnosis of hypercalcemia
more often confronts the physician in ambulatory office
practice than in the hospital. The purpose of this presenta-
tion is to facilitate the differential diagnosis of hypercal-
cemia in an uncomplicated and economical manner with
particular emphasis on identifying the patient with primary
hyperparat hyroidism.
Hypercalcemia results when the sum of the calcium com-
ing from bone resorption (BR), the net intestinal absorp-
tion, and from soft tissue deposits exceeds the quantity of
calcium being deposited in bone (BF) and soft tissue and
excreted in urine."l
BR + net intestinal Ca absorption + soft tissue Ca
release > BF + soft tissue deposition + urinary Ca
- tserum Ca
mone secretion, one may excrete in excess of lo00 nig cal-
cium per day in the urine, but with a creatininc clearance
of less than 40 ml/minute the excretion may be limited to
less than 200 rng/day.'l)
DIFFERENTIAL DIAGNOSIS AND
CLINICAL PRESENTATION
The diagnostic spectrum of hypercalcemia has steadily
expanded over the past 30 years to a current list in excess
of 25 different entities, as shown in Table I . The mecha-
nism of hypercalcemia in these disease states has become
more clearly understood with the development of assays
for parathyroid hormone, parathyroid-related protein, 25-
hydroxyvitamin D (25-OHD), and 1,25-dihydroxyvitamin
D [ 1,25-(OH),D] but is still incompletely understood for
many malignancies, myxedema, familial hypocalciuric hy-
percalcemia, thiazides, lithium, milk alkali syndrome, Wil-

Department of Medicine, University Hospitals of Cleveland, and Case Western Reserve School of Mcdicinc. C'lcvcland, Ohio.

S5 1
 LAFFERTY

TABLE
1. HYPERCALCEMIA:
DIFFERENTIAL
DIAGNOSIS ham's syndrome, rhabdomyolysis, and advanced liver dis-
ease. The importance of the local production in bone of
Endocrine prostaglandins, interleukins, tumor necrosis factors, and
Hyperparathyroidism transforming growth factor remains to be determined.I3)
Primary Primary hyperparathyroidism and malignancy account
Secondary (postrenal shutdown or transplant, post- for 8O-9OVo of hypercalcemia states seen today. In the am-
pancreatitis) bulatory setting hyperparathyroidism accounts for 50-60%
Tertiary (uremia, malabsorption) ~ ~ hospital for 27% or less.'6.')
of h y p e r c a l ~ e m i a , ~in' ~ the
Familial hypocalciuric hypocalcemia (FHH) By contrast, malignancy accounts for 31% or less of am-
Hyper- and hypothyroidism bulatory hypercalcemia but for up to 65% of that seen in
Adrenal insufficiency the hospital (Table 2).
Pheochromocytoma Carcinomas of the bronchus, breast, head and neck,,
Vipoma urogenital tracts, and multiple myeloma account for 75%
Malignancy of the hypercalcemia in malignancy.") A humoral mecha-
Humoral hypercalcemia of malignancy [PTHrP, 1,25- nism with an elevated nephrogenous cyclic AMP and
(OH),D, PTHI serum parathyroid-related protein (PTHrP) or an elevated
Metastatic bone disease (local osteolytic factors) serum 1,25-(OH),D may be found in up to 80% of malig-
Exogenous agents nancies with hypercalcemia.'") Local osteolytic factors pre-
Thiazides dominate in the remaining 20070, including multiple mye-
Vitamin D loma and carcinoma of the breast.I3) One must also be
Vitamin A cognizant of the concurrence of primary hyperparathy-
Milk alkali roidism and malignancy, especially with carcinomas of the
Lithium breast, thyroid, gastrointestinal tract, and genitourinary
Aluminum tract. 1
Beryllium A careful history is the basis for evaluating all patients
Theophylline with hypercalcemia even though a cause seems readily ap-
Granulomatous disease parent. The use of thiazides, large doses of vitamins A or
Sarcoidosis D, lithium, or large amounts of calcium carbonate or the-
Tuberculosis ophylline must be eliminated before proceding with more
Leprosy complex tests. Immobilization, recent renal failure associ-
Fungal ated with muscle injury, and a history of tuberculosis or
Immobilization fungal infection may be quickly determined. A family his-
Miscellaneous tory of hypercalcemia suggestive of familial hypocalciuric
Post-acute renal failure with rhabdomyolysis hypercalcernia or multiple endocrine neoplasia are impor-
Infantile hypercalcemia (William's syndrome) tant clues. Finally, a long-term history of stable, mild hy-
Advanced chronic liver disease percalcemia without symptoms or weight loss is most con-
Disseminated cytomegalovirus in AIDS sistent with a diagnosis of primary hyperparathyroidism,

TABLE2. FREQUENCY
OF HYPERCALCEMIC
STATESIN AMBULATORY
AND HOSPITAL
POPULATIONS~
Ambulatory Hospital
Ref. 4: Ref. 5: Ref. 6: Ref. 7:
Cause N = 61/26,000 (%)b N = 95/15,903 (%)C N = 57(%) N = 469 (%)

Hyperparathyroidism 27
Malignancy 54
Hypervitaminosis D 2.3
Milk alkali syndrome -
Hyperthyroidism 1
Hypothyroidism -
Addison's disease -
Sarcoidosis 0.2
Thiazides -
Renal transplant or dialysis 14.5
Unknown 1
~~

=Frequency is indicated by N = number per population screened.

bPrevalence of hypercalcemia was 0.23% in the ambulatory population.
CPrevalence of hypercalcemia was 0.60% in the ambulatory population.
 TABLE3. USEFUL TESTSIN THE DIFFERENTIAL
DIAGNOSIS
OF HYPERCALCEMIA~
~ ~~~ ~~ ~ ~ ~~~~~~
Intact
Serum serum Serum Urinary Serum Serum
Diagnosis CI PTH P CU 2.5-OHD, I,2S-(OH),D3 NcAMP Comments
Primary hyper- I I 1N tN N t f Radiographic evidence of osteitis
parat hyroidism fibrosa cystica seen in only 5%
Familial hypocal- Nt N( 1) N( 1) 1N N N(1) t Ratio of renal calcium clearance
ciuric hypercal- to creatinine clearance less than
cemial I I. I 1I
0.01
Thyrotoxicosis' I J 1 1(N) 1 Nt It N N1 N Hypercalcemia may mask symp-
toms of thyrotoxicosis
Humoral hyper- 1(1) 1 1N It N 1 I Confirmed by a high serum
calcemia of ma- PTHrP and a low-normal or
lignancy low PTH
(PTHrP)"']
Lymphoma and 1 1 Nt tt N f 1 Ectopic production of 1,25-
Hodgkins"" (OH),D similar to granuloma-
tous diseases
Metastatic bone 1 1 Nt It N 1 1 Elevated NcAMP suggests
disease' 7 , 1 6 ) humoral mechanism
Thiazides'I7] 1 1 N 1 N Hypercalcemia resolves within 2
weeks of stopping thiazides
Vitamin D intoxi- 1 1 Nt tt tt Nt1 1 Excess 1,25-(OH),D ingestion
cation'18) causes 1 25-OHD and t 1,25-
(OHLD
Milk alkali syn- 1 1 f 1 Elevated serum creatinine and
dr~me"~~ bicarbonate
Lithium'20' I t NJ 1 N Nt Seen in 10% of patients on
long-term lithium
Aluminum intoxi- N (N) N 1 Dialysis, TPN, biliary tract dis-
cation(1" ease
Sarcoidosis and 1 1 Nf tf N It 1 Unmasked or aggravated by
granulomatous small doses of vitamin D
diseases(z2'
Imm~bilization'~~' 1 1 Nt tt N 1 1 Develops within 1-3 months in
high bone turnover states
Idiopathic hyper- I I N I N1 N Elfin facies and growth retarda-
calcemia of in- tion, hypersensitive to vitamin
fancy' 2 4 ) D
Advanced chronic Nl Nf Nt I IN Seen in 2% of advanced cases
liver disease[15' considered for transplantation
Postacute renal 1 NI IN f 1 I I 1 Muscle uptake of m T c medro-
failure with nate on bone scan
rhabdomyoly-
sisl161
at, high; I , low; N. normal; parentheses indicate occasionally. The first symbol represents the more common finding.
s54
familial hypocalciuric hypercalcemia, and occasionally sar-
coidosis. A short-term picture of a rising serum calcium,
weight loss, or fever point toward malignancy, tuberculo-
sis, fungal infection, cytomegalovirus in acquired immune
deficiency disease, and adrenal insufficiency.
The physical examination is usually normal in primary
hyperparathyroidism and most other forms of hypercal-
cemia. Notable exceptions are the presence of tumor
masses or nodes in malignancy, hepatosplenomegaly in
malignancy, granulomatous disease or chronic vitamin A
intoxication, hyperpigmentation in Addison's disease, and
a goiter in thyrotoxicosis. Hypertension increases the likeli-
hood of primary hyperparathyroidism, but a pheochromo-
cytoma must be ruled out.'1o)Of course, severe hypercal-
cemia may lead to dehydration, cachexia, weakness, and
metastatic hypercalcemia in all forms of hypercalcemia.
Factors favoring the diagnosis of primary hyperparathy-
roidism include a positive family history of hyperparathy-
roidism or multiple endocrine neoplasia, a history of child-
hood radiation of the head and neck, a postmenopausal
woman, a history of renal calculi or peptic ulcer disease,
hypertension, the induction of hypercalcemia by thiazides,
or an asymptomatic patient with a prolonged, stable mild
hypercalcemia and a normal physical examination.
TABLE
4. PRIMARY
HYPERPARATHYROIDISM:
PITFALLS
LABORATORY
A low-Ca and high-P diet may obscure mild hypercalcemia
The serum intact PTH may be high-normal in 10-15% pri-
mary hyperparathyroidism
A high Ca and PTH seen in 20% of FHH
A high Ca and P T H seen with lithium hypercalcemia
A high intact P T H is rarely seen in malignancy (true ectopic
PTH syndrome)
A high Ca and CI may be seen in thyrotoxicosis
Renal failure may destroy value of serum chloride, phos-
phorus, 1,25-(OH),D, urinary calcium, hematocrit,
NcAMP, and multivariate analysis but not the value of
serum intact or N-terminal PTH
5 . RADIOIMMUNOASSAYS
TABLE
P T H r P fragment
Detectable in normals, N (To)
Elevated P T H r P
All malignant hypercalcemias, N (To)
H H M syndrome, N (To)
Primary hyperparathyroidism, N ('7'0)
aSolid tumors exclusive of breast and prostate.
bSolid tumors without skeletal metastases.
CDefined by an elevated urinary cyclic AMP.
LAFFERTY
X-RAY AND LABORATORY TESTING
All patients with hypercalcemia should have a complete
blood count, routine serum chemical profile, and chest
x-ray. One can also make a case for routinely determining
the serum free thyroxine index and high-sensitivity thyroid-
stimulating hormone (TSH) since the signs and symptoms
of thyrotoxicosis may be obscured by hypercalcemia, espe-
cially among older patients. Routine skeletal x-ray surveys
and nuclear bone scans are unnecessary unless there is a
suspicion of malignancy or the serum alkaline phosphatase
is elevated in the presence of a normal serum gamma-glu-
tamyltransferase.
Useful laboratory tests in the differential diagnosis of
hypercalcemia have expanded from the serum calcium,
phosphorus, and alkaline phosphatase and the 24 h urinary
calcium in 1948 to currently include the serum ionized cal-
cium, immunoradiometric intact PTH, chloride, 25-OHD,
1,25-(OH),D, osteocalcin, and the urinary cyclic AMP.
Table 3 is a composite of the prevailing results of many of
these tests from the literature as well as the author's per-
sonal experience. The blanks represent a lack of sufficient
data.
Additional laboratory tests are needed according to the
patient's presentation. The hypercalcemic patient with hy-
pertension should have a measurement of the urinary cate-
cholamines to rule out a pheochromocytoma, and the pa-
tient with intractable diarrhea and a dilated gallbladder
needs measurement of the serum vasoactive intestinal poly-
peptide (VIP) to determine if a vipoma of the pancreas is
present. The presence of acute renal failure following mas-
sive muscle injury requires measurement of the serum crea-
tine kinase, and the patient with weakness, hypotension,
or a low serum sodium needs determination of the morn-
ing serum cortisol.
Following the completion of the history just outlined,
physical examination, and basic radiologic and laboratory
tests, the clinician may still be faced with a differential di-
agnosis of primary hyperparathyroidism, familial hypocal-
cemic hypercalcuria, occult granulomatous disease, and
occult malignancy. The task is made easier by an elevated
serum intact PTH, but elevated levels may be seen in 20%
of patients with familial hypocalcemic hypocalcuria and
most lithium-induced hypercalcemia.(11,12.zo' A 24 h uri-
OF P T H R P
Ref. 30 Ref. 31 Ref. 32 Ref. 8
1-37 1-34 1-34 1-74
5/17 (32) 2/39 ( 5 ) 43/48 (90) 28/60 (47)
36/65 ( 5 5 ) 19/38 (50) 17/36 (47) 30/38 (79)
30/42 (71)a - 10/19 (53)b 25/30 (83)c
1/16 (6) 4/20 (20) 0/8 (0) 0/13 (0)
DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA

SERUM C H L O R I D E
SERUM CALCIUM MG% MEQ/L
r20
I
I
: .. I

I
I
I
0

0.
b18
I A
..*..
...........
0.
I
-1 1 0 -
I
I
0 AX
A
.............
........... - I
A 0

....................
A A
I-1 6 I
......
0

8
.X
AA
XAXXX
105 A
0.. 0
0.0
0.. I xxxx
A A.
XAAXX
B~.K~~-
0.. 0 -1 03-
d
xxx
A.
000.00
x ox
xxxx
X
0 I XAXX
XXAOA
AA
0.0 -100- X A.AX
OX AX
.X
00
0 1I - x
AX.
-
X.

.
.XXX
XAOXX AAXAX
0 I X0A.X

110 -95- AAXAX

I X

I X.A. X

I X.AX
I
-90- xx
I I A

I I
I
1I 6 0 I
X
X

PRIMARY OTHER
HYPER- HYPER-
PRIMARY OTHER
PARATHY ROlD CALCEMIAS
HYPERPARATHYROlD HYPERCALCEMIAS ~~ ~

FIG. 1. Serum calcium levels in hyperparathyroidism ver-
sus other hypercalcemic states. The mean of each group is
shown by dashes. The best discriminant level is 12.5 mg/dl
(3.12 mmol/liter). (X) Metastatic bone disease; (A)humoral
hypercalcemia of malignancy; (0)thyrotoxicosis. (From
Lafferty FW 1988 Disorders of calcium metabolism and
parathyroid function. In: Mendelsohn G (ed.) Diagnosis
and Pathology of Endocrine Diseases. Copyright 1988,
J.B. Lippincott Co.)
FIG. 2. Serum chloride levels in hyperparathyroidism
versus other forms of hypercalcemia. The mean of each
group is shown by the dashes. The best discriminant level
was 103 mEq/liter (103 mmol/liter): (0)diuretics or vom-
iting; (X) metastatic bone disease; (A)humoral hypercal-
cemia of malignancy; (0)thyrotoxicosis. (From Lafferty
FW 1981 Primary hyperparathyroidism. Arch Intern Med
141:1761. Copyright 1981, American Medical Associa-
tion.)

nary calcium of less than 100 mg, or more specifically a
ratio of the renal clearance of calcium to the clearance of
creatinine of less the 0.01, indicates familial hypocalciuria
hypercalcemia. Finally, in the author’s experience 10-15%
of patients with primary hyperparathyroidism may have an
intact serum PTH in the upper normal range so that the
lack of a high value may not rule out the diagnosis.
The importance of the intake of calcium and phos-
phorus to the serum calcium and parathyroid hormone
levels deserves emphasis. A low daily phosphorus intake of
430 mg may increase the serum calcium by 0.3-0.7 mg/dl
in hyperparathyroidism, whereas no such rise occurs
among subjects.(z71Conversely, a high daily phosphorus
intake of 3000 mg may reduce the serum calcium in hyper-
parathyroidism and other forms of hypercalcemia. Re-
cently it has been reported that an oral calcium load of
I500 mg causes a mean rise in the serum calcium of 0.5
mg/dl within 2 h in hyperparathyroidism, with only a 0.3
mg/dl rise in normal subjects. The serum amino-terminal
P T H fell by 73% in normal subjects, whereas i t fell by
S56 LAFFERTY

TABLE6. COSTEFFECTIVENESS
OF LABORATORY
TESTING
HYPERPARATHYROIDISM
VERSUS
OTHERHYPERCALCEMIC
STATES

Retrospective Cost to patient

Tests Discriminant levels accuracy (To) (CI.S.) dollarsa
Single
Serum calcium 5 12.5 mg/dl or 84 8
5 3.12 mmol/liter
Intact PTHb >65 pg/ml 85-90 68
Serum chloride 2 103 mEq/liter 91 8
Serum phosphorus 5 2 . 9 mg/dl or 72 8
I0.94 mmol/liter
Hematocrit 2 39% 72 4
Multiple
Ca, CI, P, Hct 98 30
Ca, CI, P , Hct, PTH 99 98
C o s t s represent 1990 charges in Cleveland, Ohio.
bBased on experience with Nichols Laboratory two-site immunoradiometric assay of intact para-
thyroid hormone. Essential test in renal insufficiency (serum creatinine > 2.5 mg/dl).

only 21 070 in hyperparathyroidism.'z81Table 4 outlines
some of the laboratory pitfalls in the diagnosis of primary
hyperparathyroidism.
When the serum immunoradiometric intact PTH is low
normal or subnormal in the hypercalcemia patient, one is
often faced with a differential diagnosis between occult
granulomatous disease and malignancy. A high serum
1,25-(OH),D, suggests granulomatous disease, but patients
with lymphoma and Hodgkin's disease may also have ele-
vated levels. Both conditions may present with hepato-
splenomegaly and adenopathy on abdominal computed to-
mography (CT), and both may respond to suppressive
doses of prednisone. Without the typical changes of gran-
ulomatous disease on chest x-ray, only a biopsy can distin-
guish between these diseases.
The laboratory distinction between primary hyperpara-
thyroidism and the humoral hypercalcemia of malignancy
(HHM) has been facilitated by the serum immunoradio-
metric intact PTH in which patients with hypercalcemia of
malignancy consistently have low or low normal levels and
patients with primary hyperparathyroidism have high or
high normal levels of PTH."') The presence of a high
serum chloride and 1,25-(OH),D also favors hyperparathy-
roidism over malignancy, but these tests are not always re-
liable discriminators. The new assay of the serum parathy-
roid hormone related protein (PTHrP) facilitates the dif-
ferentiation of the humoral hypercalcemia of malignancy
from not only primary hyperparathyroidism but, more im-
portantly, from other forms of hypercalcemia in which the
serum PTH is suppressed. T o date four assays for serum
PTHrP have been d e ~ c r i b e d , ( ~ ,but
' ~ -problems
~~~ still exist
(Table 5). In two of the a ~ s a y s ' ~ OP.T~H~ r)P has been de-
tected in primary hyperparathyroidism (6-20%). Only the
two-site assay of the 1-74 amino-terminal fragment de-
scribed by Burtis et a1.(8)found elevated PTHrP levels in a
high percentage (83%) of cases of HHM and no elevated
level among 13 patients with primary hyperparathyroid-
ism. A commercially available PTHrP two-site immunora-
diometric assay using the Burtis antibodies is now
available, but its sensitivity and specificity in widespread
clinical use have yet to be determined.
The rare true ectopic P T H syndrome in which a malig-
nant tumor secretes PTH rather than PTHrP has long
been suspected but only recently documented. This was
strongly suggested by the finding of elevated serum PTH
levels plus mRNA coding for PTH in small cell lung can-
cers from two patients with h y p e r c a l ~ e m i a . ( ~Nuss-
~.~~)
baum et al.'.35)recently reported secretion of PTH by an
ovarian carcinoma in which the serum P T H rapidly fell
following resection of the tumor.
MULTIVARIATE DISCRIMINANT ANALYSIS
The most cost efficient use of laboratory tests in sepa-
rating primary hyperparathyroidism from other forms of
hypercalcemia can be addressed by the use of multivariate
discriminant analysis using the serum calcium, chloride,
and phosphorus and the hematocrit. This was originally
described by the author in 1981(361by comparing the labo-
ratory values among I 0 0 consecutive cases of surgically
proven primary hyperparathyroidism with 64 cases of
 DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA S51

of accuracy for each test are shown in Table 6. In the ab-

sence of vomiting and diuretic use, the serum chloride
D I SC R I MI N A N T S C ORE proved to be the most reliable discriminator, with only 9%
misclassifications. Thus, some have referred to the serum
chloride as “the poor man’s PTH assay.” Thyrotoxicosis
I
I and 20% of HHM cases may also show serum chloride
I levels of 103 mEq/liter or higher. Serum calcium levels
I above 13.5 mg/dl are unusual in hyperparathyroidism but
10 are almost the rule in untreated malignancies with hyper-
I calcemia.
I A discriminant function using the serum chloride, cal-
I
cium, and phosphorus and the hematocrit was derived so
4 A that a positive score indicates primary hyperparathyroid-
ism and a negative score another type of hypercalcemia
I 0
I with an overall accuracy of 95%, and an accuracy of 98%
I in the absence of vomiting, renal failure, or the use of
-- 1
0- ------
A
X
diuretics.
ox
I
0 I
.X
XXXA
0.22Hct + 0.76CI - 1.5Ca,, - 1.9P - 77.4
0
. XA.
I xxxxx
.XX
-5 Calcium excess Caex is the difference between the total
XX.
serum calcium expressed in milligrams per deciliter in a
I given patient and the upper limit of normal for a given lab-
I oratory. The hematocrit is expressed as a percentage, the
I A h
A chloride in millequivalents per liter, and the phosphorus in

0
-10
I
:i milligrams per deciliter.
The discriminant scores of 100 cases of primary hyper-
I i:
AA
parathyroidism and 64 cases of other hypercakemias are
I X contrasted in Fig. 3. All 5 patients with primary hyperpara-
-15 xx thyroidism who were misclassified with a negative score
X were taking diuretics. The validity of this discriminant
I X
function using the serum calcium, chloride, and phospho-
I
I A rus and the hematocrit was tested prospectively by Keller
-20
I
1
.
X
and Keller”’) among 37 patients with verified primary hy-
perparathyroidism and found to be correct in 35 for a 95%
overall accuracy. This formula is not applicable to sepa-
PRIMARY OTHER rating primary hyperparathyroidism from either normal
HYPERPARATHY ROIDS HYPERCACCEMIAS subjects or patients with secondary hyperparathyroidism.
The addition of the serum PTH increases the accuracy
FIG. 3. Discriminant scores using the serum calcium, of multivariate analysis to 99%. Since renal insufficiency
phosphorus, chloride, and hematocrit in hyperparathy- alters the serum phosphorus and chloride and lowers the
roidism versus other hypercalcemias. (0) Diuretics or hematocrit, multivariate analysis using these factors is un-
vomiting; (X) metastatic bone disease; (A)humoral hyper- reliable with serum creatinine values above 2.5 mg/dl. One
calcemia of malignancy; (0)thyrotoxicosis. (From Laf- must rely on the combination of an elevated amino-termi-
ferty FW 1981 Primary hyperparathyroidism. Arch Intern nal or immunoradiometric intact serum PTH and hyper-
Med 141:1761. Copyright 1981, American Medical Associ- calcemia to make the diagnosis of primary (or tertiary) hy-
ation.) perparathyroidism in renal failure.
The use of multivariate discrimination analysis of labo-
ratory tests in the differential diagnoses of hypercalcemia
was first described by Fraser et a1.(”8’in 1971 and has sub-
sequently been explored by seven other groups (Table
other forms of hypercalcemia including 31 cases of meta- 7).(39-45)The final proof of the validity of these multivari-
static bone disease, 20 cases of HHM or pseudohyperpara- ate discriminant formulas rests with their prospective accu-
thyroidism, 4 cases of vitamin D intoxication, 3 cases of racy, which has been reported in half of these studies.
thyrotoxicosis, 2 cases of thiazide-induced hypercalcemia, Only Benson reported discriminant analysis between pri-
and I case each of milk alkali syndrome, sarcoidosis, Ad- mary hyperparathyroidism and normal subjects with a
dison’s disease, and marked hyperglycemia. The best dis- 92% accuracy using the albumin-corrected serum total cal-
criminant levels of serum calcium (Fig. l), phosphorus, cium, the serum ionized calcium, and an assay to the mid-
and chloride (Fig. 2), the hematocrit, and the percentages portion (44-68) of human PTH.‘45’
S58 LAFFERTY

TABLE
7. MULTIVARIATE
DISCRIMINANT
ANALYSES
Other Retrospective Prospective
Hyperparathyroid hypercalcemia accuracy accuracy
Reference N N Discriminant factorsa (YO) N (%)
38 68 19 P, BUN, AP, C1, HCO; 90 123/140 (88)(”’
39 I58 32 P, BUN, AP, CI, HCO;, ESR 93 -
40 78 23 Ca, P, Ccr, UCa 94 23/26 (88)
41 36 48 P, TRP, CI, HCO;, AP, Ca, Cr 96 34/34 (100)
36 100 64 CI, Ca, P, Hct 95 35/37 (95)(37’
100 64 C1, Ca, P, Hctb 98
76 20 PTH, CI, Ca, P, Hctb 99
42 40 64c Alb, Ca, AST, CI, HCO; 90
43 16 14 PTH, AP, CI, Ca 97
44 106 74c Alb, PTH, C1 94
45 88 46 Cam, Ca*+,PTH 81
91 88 Normals Cam, Ca2+,PTH 92
~ ~

aListed in order of decreasing discriminatory value. Symbols include AP, serum alkaline phosphatase; ESR, erythrocyte sedimentation
rate, C,,, creatinine clearance; U,,, 24 h urinary calcium; AST, serum aspartate transaminase; Alb, serum albumin; Ca,,, total serum Ca
corrected for albumin; and Ca”, serum ionized calcium.
bPatients with vomiting or diuretics excluded.
CMalignancy cases only.

nign hypercalcemia. J Clin Endocrinol Metab 72541 -546.

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I . Lafferty FW 1988 Disorders of calcium metabolism and
parathyroid function: Lboratory evaluation. In: Mendelsohn
G (ed.) Diagnosis and Pathology of Endocrine Disease. J.B.
Lippincott, Philadelphia, pp. 119-137.
2. Lemann J Jr, Adams ND. Gray RW 1979 Urinary calcium
excretion in human beings. N Engl J Med 301535-541.
3. Mundy GR 1989 Calcium Homeostasis: Hypercalcemia and
Hypocalcemia. Martin Dunitz, London, pp. 37-181.
4. Boonstra CE, Jackson CE 1965 Hyperparathyroidism de-
tected by routine serum calcium analysis: Prevalence in a
clinic population. Ann lntern Med 63:468-474.
5. Christensson T , Hellstrom K, Wengle B, Alveryd A, Wik-
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