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Primary hyperparathyroidism presenting as anticonvulsant-induced osteomalacia
Primary Hyperparathyroidism Presenting as Anticonvulsant-Induced Osteomalacia
ARTHUR E. BROADUS,
M.D., Ph.D.’
THOMAS A. S. HANSON, M.D. FREDERIC C. BARTTER, M.D. JOSEPH WALTON, M.D.+ Bethesda, Maryland
From the Hypertension-Endocrine Branch, National Heart and Lung Institute and the Laboratory of Pathology, National Cancer Institute. Bethesda, Maryland. Requests for reprints should be addressed to Dr. Frederic C. Bartter, Building 10, Room 8N214, National Institutes of Health, Bethesda, Maryland 20014. Manuscript accepted July 22, 1976. Present address: Division of Endocrinology, Department of Medicine, Yale University, 333 Cedar Street, New Haven, Connecticut 06510. + Present address: Division of Endocrinology, Department of Medicine University of North Carolina, Chapel Hill, North Carolina 27514. l
298
August 1977
A patient presented with the classic features of anticonvulsantinduced osteomalacia. Following discontinuance of diphenylhydantoin therapy and repletion with physiologic quantities of vitamin D, hypercalcemia and persistent biochemical hyperparathyroidism developed, and a parathyroid adenoma was removed. A history of nephrolithiasis and hypercalcemia preceding the institution of drug therapy allowed this patient’s underlying parathyroid disease to be defined as primary hyperparathyroidism, which had been obscured by anticonvulsant therapy. Anticonvulsant-induced osteomalacia has received much attention since the original clinical description of the syndrome in 1968 [ 11. In its fully developed form, this disorder consists of hypocalcemia, variable hypophosphatemia, increased serum alkaline phosphatase and decreased bone mass or frank osteomalacia [l-6]. A number of “risk factors” have been identified as contributing to the development and/or severity of the process, including duration of therapy, total anticonvulsant dosage, vitamin D intake, exposure to sunlight, race and, possibly, states of increased physiologic demand, such as growth, pregnancy and lactation [3-61. Features of anticonvulsant osteomalacia have been identified in 10 to 30 per cent of pediatric and adult patients taking the drugs [3-61. The pathogenesis of the disorder involves drug induction of hepatic microsomal oxidase systems, with increased conversion of vitamin D to polar, biologically inactive metabolites [6,7]. In addition, catabolism of 25hydroxyvitamin D (25 OHD) and 1,25dihydroxyvitamin D (1,25-(OH)* D), the biologically active metabolites of the vitamin, may be increased [6,7]. The net result is a decrease in the biologically active forms of vitamin D relative to vitamin D intake [ 5,6]. Primary hyperparathyroidism is recognized with increasing frequency, presumably because of physician awareness, the utilization of chemical screening and the improved biochemical methods for diagnosis [8-lo]. A large literature has evolved concerning patients with hyperparathyroidism whose serum calcium levels are persistently normal or only intermittently elevated [ 1 l-131. A number of patients with hyperparathyroidism have been described in whom hypercalcemia was “masked” by concomitant deficiency of vitamin D as a consequence of simple vitamin D deficiency [ 14- 161, malabsorption [ 17,181 and, in one case, use of anticonvulsant drugs [ 181. In these patients, hypercalcemia appeared following correction of the’vitamin D deficiency, and many of the cases have been reported as examples of “tertiary” hyperparathyroidism [ 14-181.
The American Journal of Medicine
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PRIMARY HYPERPARATHYROIOISM-BROADUS
ET AL.
12CALCIUM 10 -
(mg/dl)
8-
ALKALINE PHOSPHATASE W/liter
I
(pl eq/mf) iPTH
CLEARANCE RATIO (CAMP: treat.)
50
l::
\
J
2 :: DPH 1OOmgBID RestrictedUV, CalciumAnd Vitamin D
’
CONDITIONS
Physiologic
t III,III
3 6 9123 \ 1970 A
Replacement 3
III,,,,,1,,,,,,,,
6 9123 1971 A
6 9123 1972 A
6 9123 1973 //
6 9123 1974 A
6 912 1975 ,
Figure 1. Serum calcium, phosphorus and alkaline phosphatase levels, and parathyroid function before and after repletion with vitamin D in a 42 year old woman with hyperparathyroidism.
The patient described here presented with classic features of anticonvulsant-induced osteomalacia. Following discontinuance of diphenylhydantoin (DPH) therapy and supplementation with physiologic amounts of vitamin D, mild, intermittent hypercalcemia and persistent biochemical hyperparathyroidism developed leading to removal of a parathyroid adenoma. A history of nephrolithiasis and hypercalcemia anteceding the institution of DPH therapy allowed the patient’s underlying parathyroid disease to be defined as primary hyperparathyroidism, which had been obscured by anticonvulsant therapy. METHODS
the amino- and the carboxy-terminal [ 191; plasma iPTH is 7 90 /*leq/ml
phosphate
portions of the peptide in 95 per cent of normal
(AMP) were determined
[20], and nephrogenous cyclic AMP:creatinine greater
as described
previously
cyclic AMP was expressed as the
clearance
ratio, values progressively
than unity signifying increasing
renal contributions
of the nucleotide. The 95 per cent confidence limits for cyclic AMP excretion by normal subjects are 1.83 to 4.55 nmol/ min/lOO ml glomerular filtration rate and for the clearance ratio, 1.15 to 2.87 [20]. Serum 25OHD
was kindly measured
by Dr. T. J. Hahn according to methods previously described [21].
Other analyses
were by standard technics.
normal ranges are serum calcium
Pertinent
8.8 to 10.6 mg/dl, serum
phosphorus 2.4 to 5.0 mg/dl and alkaline phosphatase 78 Ill/liter. CASE
Plasma immunoreactive parathyroid hormone (IPTH) was measured with an antiserum (GP-101) which recognizes both
[ 191. Plasma and urinary cyclic: adenosine mono-
subjects
25 to
REPORT
A 42 year old Caucasian woman from Birmingham, Alabama was admitted to the Clinical Center on May 28, 1974, with a history of long-standing myotonic atrophy and a confusing history of calcium
August 1977
abnormalities.
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There was a striking family history of myotonic atrophy, with involvement of seven members in four generations, inherited as an autosomal dominant. The patient first noted grip myotonia at the age of 18 and subsequently experienced progressive weakness and loss of muscle bulk, leading to significant disability by the age of 30. She had used a cane and walker for seven years prior to admission, climbed stairs with extreme difficulty and had frequent falls because of quadriceps weakness. For four years she had noted myotonic facies, ptosis and nasal speech. She lived with her elderly mother and only rarely ventured out of doors. There was no history of cardiac arrythmia or of diabetes mellitus. In 1963 and 1969, the patient underwent, respectively, right and left ureterolithotomies for radiopaque calculi. She was instructed to force fluids and restrict her calcium intake, a program which she faithfully followed. Laboratory values from the 1960s are unavailable. In July 1970, the patient was referred to an internist, who noted a serum calcium of 11.7 mg/dl, phosphorus 1.8 mg/dl and a normal alkaline phosphatase of 75 Ill/liter (Figure 1). One month later, because of diffuse muscular aching and tenderness, the administration of DPH was begun, 100 mg twice daily. At about the same time she began to take multivitamins (containing 100 IU ergocalciferol in the daily dose). Serial follow-up over the next three and a half years revealed a high-normal serum calcium level, a low-normal serum phosphorus level and an alkaline phosphatase level which increased to 150 Ill/liter (Figure 1). In late 1973, the patient began to complain of vague, diffuse bone discomfort, most prominent over her lateral rib cage and costal margins. In March 1974, analyses performed in the laboratory of Dr. C. D. Arnaud revealed a serum calcium of 9.8 mg/dl and a serum iPTH of 77 /.deq/ml (normal 7 40 pleq/ml). Because of the somewhat confusing pattern of her laboratory values, the patient was referred to the NIH in May 1974. On admission, classic features of myotonic atrophy were noted. The patient had nasal speech and myotonic facies, with frontal alopecia, facial wasting, bilateral ptosis and cataracts. There was striking weakness of the neck flexors and rotators, and extensive muscle atrophy, most pronounced distally. Grip myotonia was easily elicited. There was moderate tenderness over the lateral ribs and both femurs. Band keratopathy was absent. A detailed dietary history revealed the patient’s calcium intake to be 300 to 400 mg/day and her vitamin D intake to be 150 U/day (including her multivitamin supplement). Normal routine laboratory analyses included complete blood count, electrolytes, serum glutamic oxaloacetic transaminase, creatine phosphokinase, 5’ nucleotidase, protein electrophoresis, immunoelectrophoresis, serum carotenes, urinary vanillylmandelic acid, and fasting and 2hour postprandial blood glucose. The serum folic acid level was low-normal at 7 ng/ml (normal 5 to 21 ng/ml); serum magnesium was 2.0 meq/liter (normal 1.40 to 2.0 meq/liter and fecal fat, collected on 100 g/day fat intake, was 4.3 g/day (normal < 7 g/day). Mean creatinine clearance was 54 ml/min (six determinations). Routine films showed no abnormalities except for a 6 mm calcific density in the left kidney and diffuse, moderate radiolucency of the axial skeleton. There was no roentgenologic evidence of osteitis fibrosa. The electrocardiogram was within normal limits.
300
August 1977
The patient was maintained on her dosage of DPH, 100 mg twice daily, and serum concentrations of the drug ranged between 10 and 14 pg/ml. Mean serum calcium (12 determinations) was 9.6 mg/dl (range 8.9 to 10.0 mgldl), serum phosphorus 2.3 mg/dl (range 1.3 to 2.8 mg/dl) and alkaline phosphatase 136 Ill/liter (range 118 to 147 Ill/liter). Under metabolic balance conditions (daily diet containing 675 mg calcium, 900 mg phosphorus and 69 meq sodium), the patient’s calcium balance was essentially zero, with an average urinary calcium of 110 mg/day and high fecal calcium indicating poor calcium absorption (Figure 2). The serum 25OHD level was low at 8.1 ng/ml. Biochemical hyperparathyroidism (Figure 1) was documented by an elevated iPTH level (mean 114 Nleq/ml) and striking increases in urinary cyclic AMP (mean 8.60 nmol/min/lOO ml glomerular filtration rate) and nephrogenous cyclic AMP (mean clearance ratio 5.07). A biopsy specimen of iliac crest bone (Figure 3) revealed moderate to severe osteomalacia: the bone core was sufficiently soft to be easily cut with a knife, and undecalcified sections showed wide osteoid borders on almost all the osseous trabeculae. Features of osteitis fibrosa were not present. Detailed neurologic investigations, including an electromyogram and muscle biopsy, were performed. All studies suggested a preponderance of myotonic features, such that the relative contribution of the neuromuscular syndrome of hyperparathyroidism [22,23] to the patient’s neurologic presentation could not be adequately assessed. Thus, in May 1974, the patient presented with classic clinical and chemical findings of anticonvulsant osteomalacia. However, her antecedent history suggested the possibility that pri,mary hyperparathyroidism might be obscured by her current presentation. It was elected to discontinue treatment with DPH, and the patient was instructed to drink 1 to 2 pints of milk daily (containing 500 to 1,000 mg calcium and 200 to 400 U ergocalciferol) and to be in direct sunlight for 1 hour daily. Serial follow-up revealed a progressive rise in the serum calcium level and fall in the alkaline phosphatase level with little change in serum phosphorus (Figure 1). The patient was readmitted in January 1975; she no longer experienced diffuse bone pain and stated that progressive improvement in muscle strength had allowed her to dispense with her cane and walker. However, clear-cut neuromuscular improvement could not be documented by objective testing. The mean serum calcium was 10.5 mg/dl (range 10.0 to 11 .O mg/dl), serum phosphorous 2.7 mg/dl (range 2.2 to 3.4 mg/dl) and alkaline phosphatase 81 Ill/liter (range 73 to 86 Ill/liter). Calcium balance had become positive, with an increase in urinary calcium (mean 231 mg/day) and decrease in fecal calcium (Figure 2). Similar changes in phosphorous balance were noted (Figure 2). The roentgenographic appearance of her bones was unchanged. Plasma iPTH and urinary and nephrogenous cyclic AMP levels remained elevated, although the cyclic AMP levels had fallen significantly as compared to those measured during her earlier admission (Figure 1). Thus, the patient had evidence of improvement in calcium balance and bone disease but continued to display biochemical hyperparathyroidism. Since secondary hyperparathyroidism remained a distinct possibility, several attempts were made to distinguish between primary and sec-
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MAY T
O
1974
FEBRUARY
ET AL
1975
Urine
250 -
CALCIUM (mg/day)
Feces
500
-
PHOSPHOROUS
FOUR-DAY
PERIODS
igure 2. Calcium and phosphorus balance in a 42 year old woman with hyperparathyroidism while taking diphenylhydantoin (May 1974) and seven months after withdrawal of the drug (February 7975).
ondary
hyperparathyroidism.
mg/kg/hour) normally,
failed indicating
parathyroid selective difficult
catheterization
of peripheral present graphically
underwent
small veins and atypical
However, from
over
an eightfold a vein
to be most suggestive
a component
It was elected
was also veno-
these findings
of primary
of secondary
not be excluded.
thyroid
appeared
hyperpara-
proximately
final
admission
14 months
she
chemically,
in August
1975,
had discontinued the
patient
was
ap-
and a calculus
90 IU/liter)
and urinary
phosphatase calcium
85 IWliter
275 mg/day
(range
clearance
of nephrogenous calcium
infusion
cyclic
no parathyroid
AMP in re-
[ 241. On September
neck exploration, adenoma
with removal
in the right upper
tissue could be identified
iliac crest
bone biopsy
of the osteomalacic
the appearance
of features
pattern
of osteitis
on the left.
revealed
fibrosa
and
cystica
(Figure
The perioperative
course
is depicted
in Figure
4. The
level fell rapidly postoperatively,
within the first 24 hours and remaining
reaching
7.7
in the range of
8 mg/dl for the next 10 days. The patient experienced
with a 600 mg
marked
noted previously,
3).
mg/dl
83 to
ab-
by failure
pole. The right lower pole gland was grossly and histologically
little
in the
151.
ratio
1). The patient’s
was again documented
2, 1975, the patient underwent
serum calcium
left kidney. The mean serum calcium was 10.4 mg/dl (range 9.9 to 10.6 mg/dl), serum phosphorous 2.8 mg/dl (range 2.4 alkaline
AMP (mean (Figure
of a 1.5 g chief cell parathyroid
DPH
from her second admission. Routine laboratory were within normal limits, and roentgenograms
cyclic
function
suppression
resolution
the patient
was normal at 17.5 ng/ml
increased
to a standard
to follow
changed analyses
to 3.3 mg/dl),
sponse
An intraoperative
Clinically
axial radiolucency
of normal
hyperparathyroidism
therapy.
again demonstrated
and
after
was
normal parathyroid
normal;
medically for an additional six months, while she continued to take physiologic supplements of calcium and vitamin D. The patient’s
intake. Serum 25OHD
3.36) were distinctly
15 times those
gradient
which
calcium
Plasma iPTH was high normal (mean 80 pleq/ml). but urinary cyclic AMP (mean 5.69 nmol/min/lOO ml glomerular filtration rate) and nephrogenous
from four small veins on the
to drain from the left side. Although
thought
thyroidism, could
blood.
(4
AMP
of autonomous
the patient
iPTH concentrations
in a sample
infusion cyclic
of neck veins, which was technically
Blood samples
right side showed
degree
In addition,
of extremely
venous anatomy.
were
[24].
calcium
nephrogenous
at least a relative
function
because
A standard
to suppress
only
minor symptoms of hypocalcemia. Serum magnesium did not change from preoperative values of 1.85 to 1.95 meq/ liter. Following a transient dip to normal, nephrogenous cyclic AMP increased to the preoperative range, thus defining biochemical hyperparathyroidism in a setting of postoperative hypocalcemia
August 1977
and confirming
the clinical
The American Journal of Medicine
diagnosis
of mild
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PRIMARY HYPERPARATHYROIDISM-BROADUS
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Figure 3. Undecalcified bone biopsy specimens (von Kossa stain) before and after vitamin D repletion in a 42 year old woman with hyperparathyroidism. Left, initial biopsy specimen (June 7974), polarized to demonstrate nonmineralized osteoid seams (represented by white bands) at surface of bone trabeculae. Righi, bioosv soecimen after vitamin D repletion (September 7979, demonstrating area of ;ysk bf bone trabecula (arrows):
“hungry bones syndrome.” These findings were corroborated by the prompt return of phosphaturia [25]. There were quantitative discrepancies between the nephrogenous cyclic AMP and plasma iPTH results throughout the perioperative course in this patient (Figure 4). Subjectively, the patient’s muscle strength improved postoperatively, but, again, objective testing failed to show significant change. The patient was discharged on the 12th postoperative day. Her convalescence was rapid, and her serum calcium returned to the normal range within three months.
COMMENTS In most of the reported cases, patients with hyperparathyroidism and associated vitamin D deficiency have had malabsorption [ 17,181. In addition, several patients with hyperparathyroidism and simple vitamin D deficiency [ 14-16,261 and one patient with complications due to the use of anticonvulsants [ 181 have been described. Correction of the deficiency led to the appearance of the characteristic chemical features of hyperparathyroidism; in most patients, the diagnosis was confirmed at operation. It is interesting that many of these cases have been reported as examples of “tertiary” hyperparathyroidism, and a review of these reports indicates that the evidence in support of such an interpretation is hardly compelling. It seems equally likely that most of these patients had coincident primary hyperparathyroidism, a view shared by others who have reviewed the literature [ 173. There is little doubt that the present patient had long-standing primary hyperparathyroidism, possibly for 15 years or more. Although the total anticonvulsant dose was not large (DPH, 200 mg daily), the patient had several “risk factors” for the development of clinical vitamin D deficiency, including a restricted intake of calcium and vitamin D, and her pseudoinstitutional life style. The net result was a serum 25OHD level of 8.1 ng/ml, considered to be in the rachitic range by Hahn
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et al. [ 51. In addition, antecedent hyperparathyroidism constituted a somewhat unique “risk factor” for the development of bone disease in this patient, which might have hastened or accentuated the development of the process. Although it is not clear how rapidly the osteomalacia developed, the disease was moderately severe at the time the patient was referred; if the condition had been left undiagnosed and the patient untreated, it might well have led to disasterous consequences in a patient with this degree of myotonic involvement. A number of factors were considered in the final clinical judgement to operate on this patient. Among these were our confidence in the preoperative diagnosis of primary hyperparathyroidism, the history and continued presence of nephrolithiasis, the clinical diagnosis of persistent, albeit mild, bone disease and the potential interrelationship between the neuromuscular syndrome of hyperparathyroidism [22,23] and myotonic atrophy in this patient. The latter point was the focus of considerable effort and speculation. Although the patient showed progressive subjective neuromuscular improvement following both vitamin D repletion and parathyroidectomy, objective measures could not distinguish between the features of myotonia and those of hyperparathyroidism, and the extreme variability of the neurologic picture in this patient (believed to result in part from underlying neurosis) precluded a clear assessment of improvement. Thus, moderate amelioration of the patient’s neuromuscular process, suspected clinically, could not be corroborated by objective testing. A number of the clinically useful features of the cyclic AMP analyses were typified by this patient. In our experience, the cyclic AMP results (nephrogenous cyclic AMP, or cyclic AMP excretion, expressed per milliliter of glomerular filtration rate) provide a sensitive measure of abnormal parathyroid function over a wide range of
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SERUM CALCIUM
-BROADUS
ET AL.
8
(mg/dl)
PLASMA
iPTH
+I eq/mll
3 CLEARANCE RATIO (CAMP : crest.) 2
1L 8-
URINARY CAMP (nmol/min/lOOml GFRl 4-
2
i
I
f
1
I
I
-2
-1
1
3
5
7
9
PERtOPERATIVE DAYS &we 4. Preoperative and postoperative values for serum calcium, plasma iPTH. nephrogenous cyclic AMP (clearance ratio) and urinary cyclic AMP. The shaded areas represent 95 per cent confidence limits for the cyclic AMP analyses [ 20) : iPTH is 7 90 pleq/ml in 95 per cent of normal subjects [ 191.
renal function, giving a “yield” of 90 per cent in a large series of patients with hyperparathyroidism 1201. During her last admission, the patient presented with highnormal serum calcium and iPTH values, but urinary cyclic AMP and nephrogenous cyclic AMP levels remained distinctly elevated, thus defining persistent biochemical hyperparathyroidism. In addition, the ability of the cyclic AMP determinations to reflect rapid changes in parathyroid function and to reliably estimate “zero” parathyroid activity (that is, a clearance ratio near unity) are features which make the analyses particularly useful in certain clinical and experimental settings. Examples in this patient were the demon-
stration of abnormal parathyroid suppressibility in response to calcium infusion I24 1 and the accurate biochemical definition of her postoperative course. The postoperative return of parathyroid function in this patient was more rapid than that customarily seen and presumably reflected, in addition to the “hungry bones syndrome,” only partial suppression of her normal parathyroid tissue by the borderline preoperative serum calcium. Finally. the cyclic AMP values in this patient demonstrated the inadequacy of expressing cyclic AMP excretion in relation to creatinine excretion, a widely used but nonparametric and physiologically irrational expression [ 20 1. That is, the loss of muscle mass and
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the low creatinine excretion (mean 575 mg/day) in this patient caused disproportionate “apparent” increases in cyclic AMP excretion expressed as a function of creatinine (i.e., nmol/mg creatinine). The potential hazard of this mode of expression has been previously documented [ 201, and its use is to be discouraged. The quantitative decrease in biochemical hyperparathyroidism in this patient after repletion with vitamin D was quite interesting. Although there were quantitative disparities between the cyclic AMP and iPTH results, both parameters showed decreases with time. We doubt that this decrease was fortuitous, for serial follow-up of a number of patients with “mild” hyperparathyroidism has demonstrated an impressively reproducible biochemical abnormality [20]. There may have been some degree of secondary hyperparathyroidism in this patient, but this is unlikely in view of the mid-normal range of serum calcium values (mean 9.6 mg/dl during the first admission). It is perhaps more likely that the patient’s adenoma was responding to a disproportionately low serum calcium, a response which has ample experimental support [27]. In addition, two hypercalcemic patients with simple vitamin D deficiency, osteomalacia and hyperparathyroidism have been described in whom dramatic reduction in iPTH accompanied repletion with vitamin D and healing of the bone disease [ 16,261. These patients remain hypercalcemic and probably have primary hyperparathyroidism, although surgical confirmation is lacking [ 16,261. Even though patients with hyperparathyroidism and
frank vitamin D deficiency are of considerable interest, such patients will remain clinical rarities. However, with the realization that many of the effects of parathyroid hormone are mediated by the active forms of vitamin D [28], it is possible that a reduced intake of vitamin D may contribute to the failure of serum calcium values to be more than borderlinehigh in some groups of patients with hyperparathyroidism. For example, patients with recurrent nephrolithiasis whose dietary intake of calcium and vitamin D has been restricted may have hyperparathyroidism with normal or borderline serum calcium values, and European studies suggest that hypercalcemia may appear in such patients after a short trial of 25-OHD therapy [29]. Similarly, elderly patients with borderline hypercalcemia frequently have poor diets and a pseudoinstitutional life style, suggesting that a degree of vitamin D deficiency may be present in some of these patients. Thus, in certain clinical settings there are clear limitations in the use of the serum calcium for chemical screening for hyperparathyroidism, and a more thoughtful and sophisticated diagnostic approach is required. accompanying
ACKNOWLEDGMENT We wish to thank Dr. Bayard Tynes for referring this patient to us, Drs. Richard Rosenbaum, Aubrey Hough, John Doppman and Murray Brennan for clinical and surgical assistance and Dr. T. J. Hahn for the measurements of 25-OHD. Mrs. Fredette West and Mrs. Belle Ruskin provided expert technical assistance.
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Philadelphia, W. B. Saunders Co., 1974. Strott CA, Nugent CA: Laboratory tests in the diagnosis of hyperparathyroidism in hypercalcemic patients. Ann Intern Med 68: 188, 1968. Wills MR: Normocalcemic primary hyperparathyroidism. Lancet 1: 849, 1971. Yendt ER, Gagne RJA: Detection of primary hyperparathyroidism, with special reference to its occurrence in hypercalciuric females with normal or borderline serum calcium. Can Med Assoc J 98: 33 1, 1968. Vaishnava H, Rizvi SNA: Primary hyperparathyroidism associated with nutritional osteomalacia. Am J Med 46: 640, 1969. Woodhouse NJY, Doyle FH, Jopkin GF: Vitamin D deficiency and primary hyperparathyroidism. Lancet 2: 283, 1971. Stanbury SW, Torkington P, Lumb GA, et al.: Asian tickets and osteomalacia: patterns of parathyroid response in vitamin D deficiency. Proc Nutr Sot 34: 111, 1975. Keynes WM. Caird FI: Hypocalcemic primary hyperparathyroidism. Br Med J 1: 208, 1970. Dent CE, Jones PE, Mullan DP: Masked primary (or tertiary) hyperparathyroidism. Lancet 1: 1161, 1975. Potts JT, Krutzik SR: Parathyroid hormone radioimmunoassay: clinical applications. Nichols Institute Radioimmunoassay Manual, 3rd ed, 1975, p 1. Broadus AE, et al.: Nephrogenous cyclic AMP as a parathyroid function test. J Clin Invest (in press).
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Haddad JG, Chyu KJ: Competitive protein-binding radioassay for 25hydroxycholecalciferol. J Clin Endocrinol Metab 33: 992,197l. Patten BM, Bilezikian JP, Mallette LE, et al.: Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 80: 182, 1974. Mallette LE, Patten BM, Engel WK: Neuromuscular disease in secondary hyperparathyroidism. Ann Intern Med 82: 474, 1975. Broadus AE, Bartter FC: A simple test for diagnosis of patients with hyperparathyroidism and episodic hypercalcemia. Clin Res 24: 637A. 1976. Goldsmith RE, Gall EA, Altemeier WA, et al.: Hyperparathy-
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roidism: therapy and response, with a test for assessment of response. Ann Intern Med 75: 395, 1971. Lumb GA, Stanbury SW: Parathyroid function in human vitamin D deficiency and vitamin D deficiency in primary hyperparathyroidism. Am J Med 56: 833, 1974. Murray TM, Peacock M. Powell D, et al.: Non-autonomy of hormone secretion in primary hyperparathyroidism. Clin Endocrinol 1: 235, 1972. Deluca HF: The kidney as an endocrine organ involved in the function of vitamin D. Am J Med 58: 39, 1975. Bordier P, Ryckewart A, Gueris J, et al.: On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med (in press).
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ARTHUR E. BROADUS,
M.D., Ph.D.’
THOMAS A. S. HANSON, M.D. FREDERIC C. BARTTER, M.D. JOSEPH WALTON, M.D.+ Bethesda, Maryland
From the Hypertension-Endocrine Branch, National Heart and Lung Institute and the Laboratory of Pathology, National Cancer Institute. Bethesda, Maryland. Requests for reprints should be addressed to Dr. Frederic C. Bartter, Building 10, Room 8N214, National Institutes of Health, Bethesda, Maryland 20014. Manuscript accepted July 22, 1976. Present address: Division of Endocrinology, Department of Medicine, Yale University, 333 Cedar Street, New Haven, Connecticut 06510. + Present address: Division of Endocrinology, Department of Medicine University of North Carolina, Chapel Hill, North Carolina 27514. l
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A patient presented with the classic features of anticonvulsantinduced osteomalacia. Following discontinuance of diphenylhydantoin therapy and repletion with physiologic quantities of vitamin D, hypercalcemia and persistent biochemical hyperparathyroidism developed, and a parathyroid adenoma was removed. A history of nephrolithiasis and hypercalcemia preceding the institution of drug therapy allowed this patient’s underlying parathyroid disease to be defined as primary hyperparathyroidism, which had been obscured by anticonvulsant therapy. Anticonvulsant-induced osteomalacia has received much attention since the original clinical description of the syndrome in 1968 [ 11. In its fully developed form, this disorder consists of hypocalcemia, variable hypophosphatemia, increased serum alkaline phosphatase and decreased bone mass or frank osteomalacia [l-6]. A number of “risk factors” have been identified as contributing to the development and/or severity of the process, including duration of therapy, total anticonvulsant dosage, vitamin D intake, exposure to sunlight, race and, possibly, states of increased physiologic demand, such as growth, pregnancy and lactation [3-61. Features of anticonvulsant osteomalacia have been identified in 10 to 30 per cent of pediatric and adult patients taking the drugs [3-61. The pathogenesis of the disorder involves drug induction of hepatic microsomal oxidase systems, with increased conversion of vitamin D to polar, biologically inactive metabolites [6,7]. In addition, catabolism of 25hydroxyvitamin D (25 OHD) and 1,25dihydroxyvitamin D (1,25-(OH)* D), the biologically active metabolites of the vitamin, may be increased [6,7]. The net result is a decrease in the biologically active forms of vitamin D relative to vitamin D intake [ 5,6]. Primary hyperparathyroidism is recognized with increasing frequency, presumably because of physician awareness, the utilization of chemical screening and the improved biochemical methods for diagnosis [8-lo]. A large literature has evolved concerning patients with hyperparathyroidism whose serum calcium levels are persistently normal or only intermittently elevated [ 1 l-131. A number of patients with hyperparathyroidism have been described in whom hypercalcemia was “masked” by concomitant deficiency of vitamin D as a consequence of simple vitamin D deficiency [ 14- 161, malabsorption [ 17,181 and, in one case, use of anticonvulsant drugs [ 181. In these patients, hypercalcemia appeared following correction of the’vitamin D deficiency, and many of the cases have been reported as examples of “tertiary” hyperparathyroidism [ 14-181.
The American Journal of Medicine
Volume 63
PRIMARY HYPERPARATHYROIOISM-BROADUS
ET AL.
12CALCIUM 10 -
(mg/dl)
8-
ALKALINE PHOSPHATASE W/liter
I
(pl eq/mf) iPTH
CLEARANCE RATIO (CAMP: treat.)
50
l::
\
J
2 :: DPH 1OOmgBID RestrictedUV, CalciumAnd Vitamin D
’
CONDITIONS
Physiologic
t III,III
3 6 9123 \ 1970 A
Replacement 3
III,,,,,1,,,,,,,,
6 9123 1971 A
6 9123 1972 A
6 9123 1973 //
6 9123 1974 A
6 912 1975 ,
Figure 1. Serum calcium, phosphorus and alkaline phosphatase levels, and parathyroid function before and after repletion with vitamin D in a 42 year old woman with hyperparathyroidism.
The patient described here presented with classic features of anticonvulsant-induced osteomalacia. Following discontinuance of diphenylhydantoin (DPH) therapy and supplementation with physiologic amounts of vitamin D, mild, intermittent hypercalcemia and persistent biochemical hyperparathyroidism developed leading to removal of a parathyroid adenoma. A history of nephrolithiasis and hypercalcemia anteceding the institution of DPH therapy allowed the patient’s underlying parathyroid disease to be defined as primary hyperparathyroidism, which had been obscured by anticonvulsant therapy. METHODS
the amino- and the carboxy-terminal [ 191; plasma iPTH is 7 90 /*leq/ml
phosphate
portions of the peptide in 95 per cent of normal
(AMP) were determined
[20], and nephrogenous cyclic AMP:creatinine greater
as described
previously
cyclic AMP was expressed as the
clearance
ratio, values progressively
than unity signifying increasing
renal contributions
of the nucleotide. The 95 per cent confidence limits for cyclic AMP excretion by normal subjects are 1.83 to 4.55 nmol/ min/lOO ml glomerular filtration rate and for the clearance ratio, 1.15 to 2.87 [20]. Serum 25OHD
was kindly measured
by Dr. T. J. Hahn according to methods previously described [21].
Other analyses
were by standard technics.
normal ranges are serum calcium
Pertinent
8.8 to 10.6 mg/dl, serum
phosphorus 2.4 to 5.0 mg/dl and alkaline phosphatase 78 Ill/liter. CASE
Plasma immunoreactive parathyroid hormone (IPTH) was measured with an antiserum (GP-101) which recognizes both
[ 191. Plasma and urinary cyclic: adenosine mono-
subjects
25 to
REPORT
A 42 year old Caucasian woman from Birmingham, Alabama was admitted to the Clinical Center on May 28, 1974, with a history of long-standing myotonic atrophy and a confusing history of calcium
August 1977
abnormalities.
The American Journal of Medicine
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299
PRIMARY HYPERPARATHYROIOISM-BROADUS
ET AL.
There was a striking family history of myotonic atrophy, with involvement of seven members in four generations, inherited as an autosomal dominant. The patient first noted grip myotonia at the age of 18 and subsequently experienced progressive weakness and loss of muscle bulk, leading to significant disability by the age of 30. She had used a cane and walker for seven years prior to admission, climbed stairs with extreme difficulty and had frequent falls because of quadriceps weakness. For four years she had noted myotonic facies, ptosis and nasal speech. She lived with her elderly mother and only rarely ventured out of doors. There was no history of cardiac arrythmia or of diabetes mellitus. In 1963 and 1969, the patient underwent, respectively, right and left ureterolithotomies for radiopaque calculi. She was instructed to force fluids and restrict her calcium intake, a program which she faithfully followed. Laboratory values from the 1960s are unavailable. In July 1970, the patient was referred to an internist, who noted a serum calcium of 11.7 mg/dl, phosphorus 1.8 mg/dl and a normal alkaline phosphatase of 75 Ill/liter (Figure 1). One month later, because of diffuse muscular aching and tenderness, the administration of DPH was begun, 100 mg twice daily. At about the same time she began to take multivitamins (containing 100 IU ergocalciferol in the daily dose). Serial follow-up over the next three and a half years revealed a high-normal serum calcium level, a low-normal serum phosphorus level and an alkaline phosphatase level which increased to 150 Ill/liter (Figure 1). In late 1973, the patient began to complain of vague, diffuse bone discomfort, most prominent over her lateral rib cage and costal margins. In March 1974, analyses performed in the laboratory of Dr. C. D. Arnaud revealed a serum calcium of 9.8 mg/dl and a serum iPTH of 77 /.deq/ml (normal 7 40 pleq/ml). Because of the somewhat confusing pattern of her laboratory values, the patient was referred to the NIH in May 1974. On admission, classic features of myotonic atrophy were noted. The patient had nasal speech and myotonic facies, with frontal alopecia, facial wasting, bilateral ptosis and cataracts. There was striking weakness of the neck flexors and rotators, and extensive muscle atrophy, most pronounced distally. Grip myotonia was easily elicited. There was moderate tenderness over the lateral ribs and both femurs. Band keratopathy was absent. A detailed dietary history revealed the patient’s calcium intake to be 300 to 400 mg/day and her vitamin D intake to be 150 U/day (including her multivitamin supplement). Normal routine laboratory analyses included complete blood count, electrolytes, serum glutamic oxaloacetic transaminase, creatine phosphokinase, 5’ nucleotidase, protein electrophoresis, immunoelectrophoresis, serum carotenes, urinary vanillylmandelic acid, and fasting and 2hour postprandial blood glucose. The serum folic acid level was low-normal at 7 ng/ml (normal 5 to 21 ng/ml); serum magnesium was 2.0 meq/liter (normal 1.40 to 2.0 meq/liter and fecal fat, collected on 100 g/day fat intake, was 4.3 g/day (normal < 7 g/day). Mean creatinine clearance was 54 ml/min (six determinations). Routine films showed no abnormalities except for a 6 mm calcific density in the left kidney and diffuse, moderate radiolucency of the axial skeleton. There was no roentgenologic evidence of osteitis fibrosa. The electrocardiogram was within normal limits.
300
August 1977
The patient was maintained on her dosage of DPH, 100 mg twice daily, and serum concentrations of the drug ranged between 10 and 14 pg/ml. Mean serum calcium (12 determinations) was 9.6 mg/dl (range 8.9 to 10.0 mgldl), serum phosphorus 2.3 mg/dl (range 1.3 to 2.8 mg/dl) and alkaline phosphatase 136 Ill/liter (range 118 to 147 Ill/liter). Under metabolic balance conditions (daily diet containing 675 mg calcium, 900 mg phosphorus and 69 meq sodium), the patient’s calcium balance was essentially zero, with an average urinary calcium of 110 mg/day and high fecal calcium indicating poor calcium absorption (Figure 2). The serum 25OHD level was low at 8.1 ng/ml. Biochemical hyperparathyroidism (Figure 1) was documented by an elevated iPTH level (mean 114 Nleq/ml) and striking increases in urinary cyclic AMP (mean 8.60 nmol/min/lOO ml glomerular filtration rate) and nephrogenous cyclic AMP (mean clearance ratio 5.07). A biopsy specimen of iliac crest bone (Figure 3) revealed moderate to severe osteomalacia: the bone core was sufficiently soft to be easily cut with a knife, and undecalcified sections showed wide osteoid borders on almost all the osseous trabeculae. Features of osteitis fibrosa were not present. Detailed neurologic investigations, including an electromyogram and muscle biopsy, were performed. All studies suggested a preponderance of myotonic features, such that the relative contribution of the neuromuscular syndrome of hyperparathyroidism [22,23] to the patient’s neurologic presentation could not be adequately assessed. Thus, in May 1974, the patient presented with classic clinical and chemical findings of anticonvulsant osteomalacia. However, her antecedent history suggested the possibility that pri,mary hyperparathyroidism might be obscured by her current presentation. It was elected to discontinue treatment with DPH, and the patient was instructed to drink 1 to 2 pints of milk daily (containing 500 to 1,000 mg calcium and 200 to 400 U ergocalciferol) and to be in direct sunlight for 1 hour daily. Serial follow-up revealed a progressive rise in the serum calcium level and fall in the alkaline phosphatase level with little change in serum phosphorus (Figure 1). The patient was readmitted in January 1975; she no longer experienced diffuse bone pain and stated that progressive improvement in muscle strength had allowed her to dispense with her cane and walker. However, clear-cut neuromuscular improvement could not be documented by objective testing. The mean serum calcium was 10.5 mg/dl (range 10.0 to 11 .O mg/dl), serum phosphorous 2.7 mg/dl (range 2.2 to 3.4 mg/dl) and alkaline phosphatase 81 Ill/liter (range 73 to 86 Ill/liter). Calcium balance had become positive, with an increase in urinary calcium (mean 231 mg/day) and decrease in fecal calcium (Figure 2). Similar changes in phosphorous balance were noted (Figure 2). The roentgenographic appearance of her bones was unchanged. Plasma iPTH and urinary and nephrogenous cyclic AMP levels remained elevated, although the cyclic AMP levels had fallen significantly as compared to those measured during her earlier admission (Figure 1). Thus, the patient had evidence of improvement in calcium balance and bone disease but continued to display biochemical hyperparathyroidism. Since secondary hyperparathyroidism remained a distinct possibility, several attempts were made to distinguish between primary and sec-
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PRIMARY HYPERPARATHYROIDISM-BROADUS
MAY T
O
1974
FEBRUARY
ET AL
1975
Urine
250 -
CALCIUM (mg/day)
Feces
500
-
PHOSPHOROUS
FOUR-DAY
PERIODS
igure 2. Calcium and phosphorus balance in a 42 year old woman with hyperparathyroidism while taking diphenylhydantoin (May 1974) and seven months after withdrawal of the drug (February 7975).
ondary
hyperparathyroidism.
mg/kg/hour) normally,
failed indicating
parathyroid selective difficult
catheterization
of peripheral present graphically
underwent
small veins and atypical
However, from
over
an eightfold a vein
to be most suggestive
a component
It was elected
was also veno-
these findings
of primary
of secondary
not be excluded.
thyroid
appeared
hyperpara-
proximately
final
admission
14 months
she
chemically,
in August
1975,
had discontinued the
patient
was
ap-
and a calculus
90 IU/liter)
and urinary
phosphatase calcium
85 IWliter
275 mg/day
(range
clearance
of nephrogenous calcium
infusion
cyclic
no parathyroid
AMP in re-
[ 241. On September
neck exploration, adenoma
with removal
in the right upper
tissue could be identified
iliac crest
bone biopsy
of the osteomalacic
the appearance
of features
pattern
of osteitis
on the left.
revealed
fibrosa
and
cystica
(Figure
The perioperative
course
is depicted
in Figure
4. The
level fell rapidly postoperatively,
within the first 24 hours and remaining
reaching
7.7
in the range of
8 mg/dl for the next 10 days. The patient experienced
with a 600 mg
marked
noted previously,
3).
mg/dl
83 to
ab-
by failure
pole. The right lower pole gland was grossly and histologically
little
in the
151.
ratio
1). The patient’s
was again documented
2, 1975, the patient underwent
serum calcium
left kidney. The mean serum calcium was 10.4 mg/dl (range 9.9 to 10.6 mg/dl), serum phosphorous 2.8 mg/dl (range 2.4 alkaline
AMP (mean (Figure
of a 1.5 g chief cell parathyroid
DPH
from her second admission. Routine laboratory were within normal limits, and roentgenograms
cyclic
function
suppression
resolution
the patient
was normal at 17.5 ng/ml
increased
to a standard
to follow
changed analyses
to 3.3 mg/dl),
sponse
An intraoperative
Clinically
axial radiolucency
of normal
hyperparathyroidism
therapy.
again demonstrated
and
after
was
normal parathyroid
normal;
medically for an additional six months, while she continued to take physiologic supplements of calcium and vitamin D. The patient’s
intake. Serum 25OHD
3.36) were distinctly
15 times those
gradient
which
calcium
Plasma iPTH was high normal (mean 80 pleq/ml). but urinary cyclic AMP (mean 5.69 nmol/min/lOO ml glomerular filtration rate) and nephrogenous
from four small veins on the
to drain from the left side. Although
thought
thyroidism, could
blood.
(4
AMP
of autonomous
the patient
iPTH concentrations
in a sample
infusion cyclic
of neck veins, which was technically
Blood samples
right side showed
degree
In addition,
of extremely
venous anatomy.
were
[24].
calcium
nephrogenous
at least a relative
function
because
A standard
to suppress
only
minor symptoms of hypocalcemia. Serum magnesium did not change from preoperative values of 1.85 to 1.95 meq/ liter. Following a transient dip to normal, nephrogenous cyclic AMP increased to the preoperative range, thus defining biochemical hyperparathyroidism in a setting of postoperative hypocalcemia
August 1977
and confirming
the clinical
The American Journal of Medicine
diagnosis
of mild
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301
PRIMARY HYPERPARATHYROIDISM-BROADUS
ET AL.
Figure 3. Undecalcified bone biopsy specimens (von Kossa stain) before and after vitamin D repletion in a 42 year old woman with hyperparathyroidism. Left, initial biopsy specimen (June 7974), polarized to demonstrate nonmineralized osteoid seams (represented by white bands) at surface of bone trabeculae. Righi, bioosv soecimen after vitamin D repletion (September 7979, demonstrating area of ;ysk bf bone trabecula (arrows):
“hungry bones syndrome.” These findings were corroborated by the prompt return of phosphaturia [25]. There were quantitative discrepancies between the nephrogenous cyclic AMP and plasma iPTH results throughout the perioperative course in this patient (Figure 4). Subjectively, the patient’s muscle strength improved postoperatively, but, again, objective testing failed to show significant change. The patient was discharged on the 12th postoperative day. Her convalescence was rapid, and her serum calcium returned to the normal range within three months.
COMMENTS In most of the reported cases, patients with hyperparathyroidism and associated vitamin D deficiency have had malabsorption [ 17,181. In addition, several patients with hyperparathyroidism and simple vitamin D deficiency [ 14-16,261 and one patient with complications due to the use of anticonvulsants [ 181 have been described. Correction of the deficiency led to the appearance of the characteristic chemical features of hyperparathyroidism; in most patients, the diagnosis was confirmed at operation. It is interesting that many of these cases have been reported as examples of “tertiary” hyperparathyroidism, and a review of these reports indicates that the evidence in support of such an interpretation is hardly compelling. It seems equally likely that most of these patients had coincident primary hyperparathyroidism, a view shared by others who have reviewed the literature [ 173. There is little doubt that the present patient had long-standing primary hyperparathyroidism, possibly for 15 years or more. Although the total anticonvulsant dose was not large (DPH, 200 mg daily), the patient had several “risk factors” for the development of clinical vitamin D deficiency, including a restricted intake of calcium and vitamin D, and her pseudoinstitutional life style. The net result was a serum 25OHD level of 8.1 ng/ml, considered to be in the rachitic range by Hahn
302
August 1977
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et al. [ 51. In addition, antecedent hyperparathyroidism constituted a somewhat unique “risk factor” for the development of bone disease in this patient, which might have hastened or accentuated the development of the process. Although it is not clear how rapidly the osteomalacia developed, the disease was moderately severe at the time the patient was referred; if the condition had been left undiagnosed and the patient untreated, it might well have led to disasterous consequences in a patient with this degree of myotonic involvement. A number of factors were considered in the final clinical judgement to operate on this patient. Among these were our confidence in the preoperative diagnosis of primary hyperparathyroidism, the history and continued presence of nephrolithiasis, the clinical diagnosis of persistent, albeit mild, bone disease and the potential interrelationship between the neuromuscular syndrome of hyperparathyroidism [22,23] and myotonic atrophy in this patient. The latter point was the focus of considerable effort and speculation. Although the patient showed progressive subjective neuromuscular improvement following both vitamin D repletion and parathyroidectomy, objective measures could not distinguish between the features of myotonia and those of hyperparathyroidism, and the extreme variability of the neurologic picture in this patient (believed to result in part from underlying neurosis) precluded a clear assessment of improvement. Thus, moderate amelioration of the patient’s neuromuscular process, suspected clinically, could not be corroborated by objective testing. A number of the clinically useful features of the cyclic AMP analyses were typified by this patient. In our experience, the cyclic AMP results (nephrogenous cyclic AMP, or cyclic AMP excretion, expressed per milliliter of glomerular filtration rate) provide a sensitive measure of abnormal parathyroid function over a wide range of
Volume 63
PRIMARY HYPERPARATHYROIDISM
SERUM CALCIUM
-BROADUS
ET AL.
8
(mg/dl)
PLASMA
iPTH
+I eq/mll
3 CLEARANCE RATIO (CAMP : crest.) 2
1L 8-
URINARY CAMP (nmol/min/lOOml GFRl 4-
2
i
I
f
1
I
I
-2
-1
1
3
5
7
9
PERtOPERATIVE DAYS &we 4. Preoperative and postoperative values for serum calcium, plasma iPTH. nephrogenous cyclic AMP (clearance ratio) and urinary cyclic AMP. The shaded areas represent 95 per cent confidence limits for the cyclic AMP analyses [ 20) : iPTH is 7 90 pleq/ml in 95 per cent of normal subjects [ 191.
renal function, giving a “yield” of 90 per cent in a large series of patients with hyperparathyroidism 1201. During her last admission, the patient presented with highnormal serum calcium and iPTH values, but urinary cyclic AMP and nephrogenous cyclic AMP levels remained distinctly elevated, thus defining persistent biochemical hyperparathyroidism. In addition, the ability of the cyclic AMP determinations to reflect rapid changes in parathyroid function and to reliably estimate “zero” parathyroid activity (that is, a clearance ratio near unity) are features which make the analyses particularly useful in certain clinical and experimental settings. Examples in this patient were the demon-
stration of abnormal parathyroid suppressibility in response to calcium infusion I24 1 and the accurate biochemical definition of her postoperative course. The postoperative return of parathyroid function in this patient was more rapid than that customarily seen and presumably reflected, in addition to the “hungry bones syndrome,” only partial suppression of her normal parathyroid tissue by the borderline preoperative serum calcium. Finally. the cyclic AMP values in this patient demonstrated the inadequacy of expressing cyclic AMP excretion in relation to creatinine excretion, a widely used but nonparametric and physiologically irrational expression [ 20 1. That is, the loss of muscle mass and
August 1977
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63
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PRIMARY HYPERPARATHYROIDISM-BROADUS ET AL
the low creatinine excretion (mean 575 mg/day) in this patient caused disproportionate “apparent” increases in cyclic AMP excretion expressed as a function of creatinine (i.e., nmol/mg creatinine). The potential hazard of this mode of expression has been previously documented [ 201, and its use is to be discouraged. The quantitative decrease in biochemical hyperparathyroidism in this patient after repletion with vitamin D was quite interesting. Although there were quantitative disparities between the cyclic AMP and iPTH results, both parameters showed decreases with time. We doubt that this decrease was fortuitous, for serial follow-up of a number of patients with “mild” hyperparathyroidism has demonstrated an impressively reproducible biochemical abnormality [20]. There may have been some degree of secondary hyperparathyroidism in this patient, but this is unlikely in view of the mid-normal range of serum calcium values (mean 9.6 mg/dl during the first admission). It is perhaps more likely that the patient’s adenoma was responding to a disproportionately low serum calcium, a response which has ample experimental support [27]. In addition, two hypercalcemic patients with simple vitamin D deficiency, osteomalacia and hyperparathyroidism have been described in whom dramatic reduction in iPTH accompanied repletion with vitamin D and healing of the bone disease [ 16,261. These patients remain hypercalcemic and probably have primary hyperparathyroidism, although surgical confirmation is lacking [ 16,261. Even though patients with hyperparathyroidism and
frank vitamin D deficiency are of considerable interest, such patients will remain clinical rarities. However, with the realization that many of the effects of parathyroid hormone are mediated by the active forms of vitamin D [28], it is possible that a reduced intake of vitamin D may contribute to the failure of serum calcium values to be more than borderlinehigh in some groups of patients with hyperparathyroidism. For example, patients with recurrent nephrolithiasis whose dietary intake of calcium and vitamin D has been restricted may have hyperparathyroidism with normal or borderline serum calcium values, and European studies suggest that hypercalcemia may appear in such patients after a short trial of 25-OHD therapy [29]. Similarly, elderly patients with borderline hypercalcemia frequently have poor diets and a pseudoinstitutional life style, suggesting that a degree of vitamin D deficiency may be present in some of these patients. Thus, in certain clinical settings there are clear limitations in the use of the serum calcium for chemical screening for hyperparathyroidism, and a more thoughtful and sophisticated diagnostic approach is required. accompanying
ACKNOWLEDGMENT We wish to thank Dr. Bayard Tynes for referring this patient to us, Drs. Richard Rosenbaum, Aubrey Hough, John Doppman and Murray Brennan for clinical and surgical assistance and Dr. T. J. Hahn for the measurements of 25-OHD. Mrs. Fredette West and Mrs. Belle Ruskin provided expert technical assistance.
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Philadelphia, W. B. Saunders Co., 1974. Strott CA, Nugent CA: Laboratory tests in the diagnosis of hyperparathyroidism in hypercalcemic patients. Ann Intern Med 68: 188, 1968. Wills MR: Normocalcemic primary hyperparathyroidism. Lancet 1: 849, 1971. Yendt ER, Gagne RJA: Detection of primary hyperparathyroidism, with special reference to its occurrence in hypercalciuric females with normal or borderline serum calcium. Can Med Assoc J 98: 33 1, 1968. Vaishnava H, Rizvi SNA: Primary hyperparathyroidism associated with nutritional osteomalacia. Am J Med 46: 640, 1969. Woodhouse NJY, Doyle FH, Jopkin GF: Vitamin D deficiency and primary hyperparathyroidism. Lancet 2: 283, 1971. Stanbury SW, Torkington P, Lumb GA, et al.: Asian tickets and osteomalacia: patterns of parathyroid response in vitamin D deficiency. Proc Nutr Sot 34: 111, 1975. Keynes WM. Caird FI: Hypocalcemic primary hyperparathyroidism. Br Med J 1: 208, 1970. Dent CE, Jones PE, Mullan DP: Masked primary (or tertiary) hyperparathyroidism. Lancet 1: 1161, 1975. Potts JT, Krutzik SR: Parathyroid hormone radioimmunoassay: clinical applications. Nichols Institute Radioimmunoassay Manual, 3rd ed, 1975, p 1. Broadus AE, et al.: Nephrogenous cyclic AMP as a parathyroid function test. J Clin Invest (in press).
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Haddad JG, Chyu KJ: Competitive protein-binding radioassay for 25hydroxycholecalciferol. J Clin Endocrinol Metab 33: 992,197l. Patten BM, Bilezikian JP, Mallette LE, et al.: Neuromuscular disease in primary hyperparathyroidism. Ann Intern Med 80: 182, 1974. Mallette LE, Patten BM, Engel WK: Neuromuscular disease in secondary hyperparathyroidism. Ann Intern Med 82: 474, 1975. Broadus AE, Bartter FC: A simple test for diagnosis of patients with hyperparathyroidism and episodic hypercalcemia. Clin Res 24: 637A. 1976. Goldsmith RE, Gall EA, Altemeier WA, et al.: Hyperparathy-
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roidism: therapy and response, with a test for assessment of response. Ann Intern Med 75: 395, 1971. Lumb GA, Stanbury SW: Parathyroid function in human vitamin D deficiency and vitamin D deficiency in primary hyperparathyroidism. Am J Med 56: 833, 1974. Murray TM, Peacock M. Powell D, et al.: Non-autonomy of hormone secretion in primary hyperparathyroidism. Clin Endocrinol 1: 235, 1972. Deluca HF: The kidney as an endocrine organ involved in the function of vitamin D. Am J Med 58: 39, 1975. Bordier P, Ryckewart A, Gueris J, et al.: On the pathogenesis of so-called idiopathic hypercalciuria. Am J Med (in press).
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