Correspondence

Clinical Problem-Solving: Stopping Short of Certainty

N Engl J Med 1994; 331:1456-1458November 24, 1994

Article

To the Editor:

In the Clinical Problem-Solving exercise on hypercalcemia (July 7 issue),1 I disagree with Dr. Kreisberg's comment, made more than once, that the diagnosis of primary hyperparathyroidism can be ruled out at an early stage. I submit that this is not the case at all. It is important in any differential diagnosis to bear in mind at the outset that common disorders occur commonly, and the initial diagnostic approach should be based on this principle. The clinical history recounted in the first paragraph is extremely suggestive of primary hyperparathyroidism; in contrast, steroid-responsive vitamin D-mediated hypercalcemia is extremely uncommon.

My second point relates to the interpretation of the C-terminal parathyroid hormone assay. Assays of this kind are notoriously difficult both to carry out and to interpret. A parathyroid hormone level at the low end of the normal range in such an assay is certainly compatible with a diagnosis of primary hyperparathyroidism, and it is not at all surprising that a neck exploration was carried out at that stage. It is only with the results of the intact-hormone assay that the diagnosis of hyperparathyroidism can clearly be ruled out.

With the increasing availability of intact-hormone assays, problems such as this should become rarer in the future. I still believe, however, that more harm is done by chasing obscure diagnoses at an early stage than by being easily persuaded to accept a diagnosis of a common condition.

Roger A. Fisken, M.D.
Northallerton Health Services, North Yorkshire DL6 1JG, United Kingdom

1 References

1
Kreisberg RA. Stopping short of certainty. N Engl J Med 1994;331:42-45
Full Text | Web of Science | Medline

To the Editor:

Dr. Kreisberg comments on a 68-year-old man with recurrent nephrolithiasis, chronic renal insufficiency, and persistent hypercalcemia. A presumptive diagnosis of hyperparathyroidism was incorrectly made, and a neck exploration resulted in the diagnosis of parathyroid adenoma. Persistent hypercalcemia with mildly elevated 1,25-dihydroxyvitamin D levels and decreased intact parathyroid hormone levels was subsequently noted. Determining the cause of hypercalcemia is a diagnostic challenge appropriate for the Clinical Problem-Solving section. However, we believe that measurement of angiotensin-converting enzyme activity should be part of the initial evaluation for a patient with hypercalcemia and that with the information provided by an early determination of such activity, this case might have been managed differently.

A diagnosis of sarcoidosis is not unreasonable in this patient with hypercalcemia, decreased parathyroid hormone levels, increased 1,25-dihydroxyvitamin D levels, a parathyroid adenoma, and increased angiotensin-converting enzyme activity. In the literature, as well as in our own experience, there have been cases of coexisting hyperparathyroidism and sarcoidosis.1-3 This known association should have placed sarcoidosis higher on the differential-diagnosis list, despite the incorrect diagnosis of primary hyperparathyroidism. Also, contrary to the commentary, a normal chest radiograph does not exclude sarcoidosis from the differential diagnosis, since there have been reported cases of sarcoidosis with hypercalcemia initially presenting with normal plain-film radiographs of the chest.2,4

Second, if the elevated angiotensin-converting enzyme activity had been detected during the initial evaluation for hypercalcemia, then several studies might have provided clues to the correct diagnosis. For example, pulmonary-function tests, including a measurement of the diffusion capacity of carbon monoxide, if abnormal, would have prompted a diagnostic bronchoscopy with a transbronchial biopsy that might have yielded the noncaseating granulomata characteristic of sarcoidosis. The less invasive approach of ophthalmologic examination with a conjunctival biopsy5 could also have been considered without “stopping short of certainty.” Would either of these biopsies have been more expensive than the extended workup that the patient received? A serum angiotensin-converting enzyme assay costs only $35 at our institution, and if it had been performed earlier in the course of this patient's illness, it would have led to the correct diagnosis and could have prevented the considerable delay in the diagnosis with the concomitant additional morbidity, the expensive laboratory workup, and even the surgical neck exploration.

We believe that prednisone should not be used in patients with a presumptive diagnosis of sarcoidosis. Instead, we confirm our clinical impression with an appropriate biopsy and then adjust the dose of prednisone by serial evaluation of the multisystem involvement and the patient's well-being.

Jamie S. Lieberman, M.D.
James J. O'Connor, M.D.
Herbert Patrick, M.D.
Jefferson Medical College, Philadelphia, PA 19107

5 References

1
Burr JM, Farrell JJ, Hills AG. Sarcoidosis and hyperparathyroidism with hypercalcemia: special usefulness of the cortisone test. N Engl J Med 1959;261:1271-1275
Full Text | Web of Science | Medline

2
Dent CE, Watson L. Hyperparathyroidism and sarcoidosis. BMJ 1966;1:646-649
CrossRef | Web of Science | Medline

3
Winnacker JL, Becker KL, Friedlander M, Higgins GA Jr, Moore CF. Sarcoidosis and hyperparathyroidism. Am J Med 1969;46:305-312
CrossRef | Web of Science | Medline

4
Nabriski D, Bendahan J, Shapiro MS, Feund U, Lidor C. Sarcoidosis masquerading as a parathyroid adenoma. Head Neck 1992;14:384-386
CrossRef | Web of Science | Medline

5
Nichols CW, Eagle RC Jr, Yanoff M, Menocal NG. Conjunctival biopsy as an aid in the evaluation of the patient with suspected sarcoidosis. Ophthalmology 1980;87:287-291
Web of Science | Medline

To the Editor:

In the case of the man with hypercalcemia ascribed to sarcoidosis, the normal chest film and computed tomographic (CT) scan left the discussant puzzled, because a normal chest x-ray film is used to rule out sarcoidosis as a cause of hypercalcemia.1 We recently investigated a similar case in which we used gallium-67 lung scanning, which has been shown to be more sensitive than chest radiography in the detection of hilar-node involvement or alveolitis.2,3

The patient was a 73-year-old woman who was known to have had hypercalcemia one year before weakness and loss of appetite developed. She had a history of nephrolithiasis. She was taking no medications regularly. Her vital signs were normal, and except for a systolic murmur compatible with mild aortic stenosis, the remainder of the physical examination was negative.

A complete blood count was normal. The serum calcium level was 14.0 mg per deciliter, the inorganic phosphate level 4.9 mg per deciliter, the alkaline phosphatase level 74 U per liter, the creatinine level 3.4 mg per deciliter, the blood urea nitrogen level 45 mg per deciliter, the albumin level 4.4 g per deciliter, and the globulin level 3.7 g per deciliter. The results of electrophoretic studies of plasma proteins were normal. The serum level of parathyroid hormone was less than 6 pg per milliliter (normal range, 10 to 55), and the serum level of angiotensin-converting enzyme was 133 U per liter (normal range, 45 to 125). The plasma level of 1,25-dihydroxyvitamin D was 155 pg per milliliter (normal range, 36 to 96), and the level of 25-hydroxyvitamin D was 21.9 ng per milliliter (normal range, 14 to 36).

Both a plain radiograph and a CT scan of the chest were normal. Ultrasound and CT scans of the abdomen were normal except for the presence of small calculi in both kidneys. Gallium-67 scintigraphic scanning revealed an increased uptake by the right pulmonary hilus. Bronchoalveolar washings consisted of 36 percent lymphocytes, of which 88 percent were CD4+. A transbronchial biopsy at the right lung hilus yielded noncaseating granulomas; the lung tissue was infiltrated with epithelioid cells and multinucleated giant cells. Ziehl-Neelsen and periodic acid-Schiff stains were negative.

The patient began taking 20 mg of prednisone daily; two weeks later her serum calcium level had dropped to 9.8 mg per deciliter and her serum creatinine level had dropped to 1.9 mg per deciliter. The dose of prednisone was tapered during the next two months to 10 mg per day without a recurrent increase in these values.

The combination of low serum values for parathyroid hormone and parathyroid hormone-related protein and an increased level of 1,25-dihydroxyvitamin D suggests vitamin D-mediated hypercalcemia. After ruling out an increased intake of vitamin D or its metabolites and other granulomatous diseases, we made a diagnosis of sarcoidosis. We propose that gallium-67 scintigraphy can be a guide in deciding whether to carry out a needle biopsy of the lung in such cases.

Abid Assali, M.D.
Yitzhak Beigel, M.D.
Menahem Fainaru, M.D.
Beilinson Medical Center, Petah-Tiqva, 49100 Israel

3 References

1
Thrasher DR, Briggs DD Jr. Pulmonary sarcoidosis. Clin Chest Med 1982;3:537-563
Web of Science | Medline

2
Fajman WA, Greenwald LV, Staton G, et al. Assessing the activity of sarcoidosis: quantitative 67Ga-citrate imaging. AJR Am J Roentgenol 1984;142:683-688
Web of Science | Medline

3
Line BR, Hunninghake GW, Keogh BA, Jones AE, Johnston GS, Crystal RG. Gallium-67 scanning to stage the alveolitis of sarcoidosis: correlation with clinical studies, pulmonary function studies, and bronchoalveolar lavage. Am Rev Respir Dis 1981;123:440-446
Web of Science | Medline

To the Editor:

I recently evaluated a 54-year-old woman with impaired renal function (creatinine level, 1.7 mg per deciliter), proteinuria (3.2 g of protein per day), microscopic hematuria, and an elevated blood pressure. Physical examination was completely normal. There were no signs or symptoms of systemic disease, and antineutrophil cytoplasmic antibodies, antibodies against double-stranded DNA, and anti-glomerular-basement-membrane antibodies were not found. The chest film was unremarkable, but sonography revealed enlarged kidneys with echolucent parenchyma. The urinary sediment contained numerous coarsely granulated and cellular casts, with no definitely dysmorphic erythrocytes. Chemical analysis showed hypercalcemia (3.12 mmol per liter of calcium) with a low level of intact parathyroid hormone (1.2 pmol per liter) and a borderline-elevated 1,25-dihydroxyvitamin D level (95 pmol per liter; normal range, 35 to 90). The angiotensin-converting enzyme level was 82 U per liter (normal range, 18 to 55).

A renal biopsy showed marked chronic interstitial nephritis with fibrosis and multinucleated giant cells containing Schaumann's bodies and interstitial calcifications. No glomerular immune deposits were seen. The diagnosis was renal sarcoidosis without pulmonary manifestations but with 1,25-dihydroxyvitamin D-dependent hypercalcemia causing renal interstitial calcifications. Treatment with corticosteroids resulted in a return of the serum creatinine, serum calcium, blood pressure, and urinary sediment to normal values. This patient was remarkably similar to the patient described in the Clinical Problem-Solving article. Nephritic characteristics of the urinary sediment in combination with the other findings, not the least of which was impaired renal function, would make the diagnosis of sarcoidosis with renal involvement very likely. In the case that was presented, however, the urinary sediment was not described.

Michael Siebels, M.D.
University of Heidelberg, 69120 Heidelberg, Germany

Author/Editor Response

Dr. Kreisberg replies:

To the Editor: I agree with the first point that Fisken makes in his letter. I thought it was clear that we used a probabilistic approach first and considered common disorders in this patient with hypercalcemia. We were not “chasing obscure diagnoses at an early stage.” I disagree with his statement that a low C-terminal parathyroid hormone value is compatible with the diagnosis of primary hyperparathyroidism. The important issue is what is meant by “low.” When parathyroid hormone measurements are used for the diagnosis of primary hyperparathyroidism or hypercalcemia associated with cancer, C-terminal parathyroid hormone values can be in the normal range (the percentage of values that are normal varies with the assay), but virtually all the values are abnormal when they are plotted against the simultaneously measured calcium concentration.1 No value for C-terminal parathyroid hormone in this survey was at or near the lower limit of normal for the assay being evaluated. Furthermore, in the presence of renal disease, C-terminal parathyroid hormone values would be expected to be increased; hence, the low value in the patient I described is doubly remarkable.

I appreciate learning about the two patients described by Assali and colleagues and by Siebels. Gallium lung scanning is a good idea, and it might have been helpful in our patient. If the scan had been abnormal, it would have been reasonable to perform bronchoalveolar lavage or a lung biopsy (or both) to establish the diagnosis. If the scan had been normal, neither of these invasive procedures would have been indicated. With regard to Siebels's letter, it never occurred to me to consider sarcoidosis that was confined to the kidney. The urinalysis in our patient was unremarkable, except for mild proteinuria and hematuria; casts were not present. I will certainly keep the patient Siebels describes in mind if I see another patient with these features.

I also thank Lieberman and colleagues for their letter, their references to coexistent primary hyperparathyroidism and sarcoidosis, of which I was aware, and the reports on patients with sarcoidosis and hypercalcemia who had normal chest radiographs, which I did not find. Whether these patients, like the patient described in the Clinical Problem-Solving article, would also have had normal CT or magnetic resonance imaging chest scans is unknown. I disagree with the statement that measurement of angiotensin-converting enzyme should be part of the initial evaluation of a patient with hypercalcemia. Sarcoidosis is a relatively uncommon cause of hypercalcemia. When sarcoidosis is present, the diagnosis is usually more straightforward, and measurement of angiotensin-converting enzyme would be unnecessary. Furthermore, angiotensin-converting enzyme is not specific for sarcoidosis. Occult sarcoidosis as a cause of hypercalcemia has been seen by many physicians, but there are no reports on series of such cases. If sarcoidosis occurs in less than 5 percent of patients with hypercalcemia and if occult sarcoidosis occurs in 2 percent of patients with sarcoidosis and hypercalcemia (1 in 1000 patients with hypercalcemia), it would cost approximately $35,000 in angiotensin-converting enzyme measurements to make the diagnosis in 1 patient. Perhaps limiting the measurement of angiotensin-converting enzyme to patients who do not have primary hyperparathyroidism, cancer-associated hypercalcemia, or multiple myeloma would be more cost effective. I agree that a definitive diagnosis would have been preferable to empirical steroid therapy, but the magnitude of the patient's hypercalcemia, the continuing recurrence of nephrolithiasis, his mild chronic renal failure, and his general lack of well-being justified therapy, in my opinion and that of the expert clinician who discussed the case. We agree that the lowest dose of glucocorticoids that controls the hypercalcemia should be used. The dose of prednisone was rapidly tapered to 5 mg per day in this patient.

Robert A. Kreisberg, M.D.
University of Alabama, Birmingham, AL 35294

1 References

1
Raisz LG, Yajnik CH, Bockman RS, Bower BF. Comparison of commercially available parathyroid hormone immunoassays in the differential diagnosis of hypercalcemia due to primary hyperparathyroidism or malignancy. Ann Intern Med 1979;91:739-740
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