Sarcoidosis and primary hyperparathyroidism

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Sarcoidosis

and Primary

Hyperparathyroidism* An Unusual Association PHILIP I). LIEF

M.D.,1 LEON J. BOGARTZ M.D.,$ SPENCER ABRAHAM S. BUCHBERC, M.D.

Bronx,

K.

KOERNER,

M.D. nnd

New York

Described here is a thirty-two year old man with proved sarcoidosis who was found to have concomitant primary hyperparathyroidism. The eight previous cases of this combination of diseases are reviewed, and the diagnostic tests and special features of this combination are discussed. It appears that hypercalcemia, although common in sarcoidosis, when accompanied hy hypophosphatemia and resistance to steroids, should suggest a second diagnosis of primary hyperparathyroidism.

HE

presence of hypercalcemia in a patient with proved sarcoidosis usually presents no diagnostic problem [I]. The possibility of a second disease producing an elevation of the serum calcium level always exists but the majority of these diseases can be ruled out. Difficulty most often arises when the second disease under consideration is primary hyperparathyroidism. Recently we studied a patient with these two entities, an association previously described [2-91.

The patient’s past medical history was unremarkable. He was born in Georgia and had lived there until 1953 when he moved to New York City. No family history of sarcoidosis or endocrine disease was obtained. Physical examination at the time of the first admission revealed a well developed, well nourished, young adult. male Negro who did not appear ill. Pertinent positive physical findings were limited to cervical, axillary and inguinal lymphadenopathy. Examination of the chest and abdomen was normal. The hematocrit was 42 per cent and the white blood cell count was 4,700 per cu. mm. with a nor-

CASE REPORT

mal differential distribution. The urine was clear with a specific gravity of 1.014 and a pH of 5.5. It contained no protein, sugar or acetone and the sediment contained no red cells. Fasting blood sugar was 84 mg. per cent, blood urea nitrogen 1fi mg. per cent and serum electrolytes were normal. Serum total proteins were 8.3 gm. per cent with 3.9 gm. albumin and 4.4 gm. globulin. Serum calcium was 11.0 mg. per cent, serum inorganic phosphorus J.0

T

A thirty-two year old Negro man (B.A., M.H.M.C. No. 102483) was referred for evaluation of an abnormal chest roentgenogram in December 1958. One year prior to this he had been treated for pneumonia. Six months later he had been rejected from the Armed Forces on medical grounds although he was unaware of the exact reason. For approximately one month before admission he had recurrent episodes of wheezing, a mild nonproductive cough and easy fat&ability. He also noted “lumps” under his left arm and behind his left ear. No history of fever, joint pain, swelling or hcmoptysis was elicited.

mg. per cent and alkaline phosphatase 3.0 ResneyLowry units. A twenty-four hour urine tollcction contained 1,150 mg. phosphorus in 1,440 ml. Sputum was negative for acid-fast bacilli on repealed smears and cultures. First and second strength purified protein derivative skin tests were negative, The

* From the Division of Pulmonary Medicine, Montefiore Hospital and Medical Center and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York. Requests for reprints should be addressed co Dr. Spencer K. Koerner, Montefiore Hospital and Medical Center, 111 East 210th Street, Bronx, New York 10467. Manuscript received December 12, 1968. ? Present address: The New England Medical Center, Boston, Massachusetts. 1 Present address: Kessler Air Force Base, Biloxi, Mississippi. VOL.

47,

NOVEMBER

1969

825

826

Sarcoidosis

and Primary

Hyperparathyroidism-Lief

et al.

In I\lay 1963 the patient presented with several skin nodules. Physical examination also revealed palpable splenomegaly. Biopsy of one of the nodules was positive for sarcoidosis. Treatment with chloroquine, 250 mg. twice daily, was begun at this time and continued until May 1965. The skin lesions cleared completely and the spleen decreased in size. At the time of the cessation of chloroquin therapy blood chemical studies included a calcium level of 10.9 mg. per cent, alkaline phosphatase 6.5 Bessey-Lowry units and serum protein 7.4 gm. per cent with 4.1 gm. albumin and 3.3 gm. globulin. In December 1965 the patient returned to the clinic with a history of renal colic followed by the passage of a small stone in the urine. His serum calcium was 12.0 mg. per cent and phosphorus 3.2 mg. per cent. Analysis of the stone revealed it to be 85 per cent calcium oxalate and 15 per cent calcium phosphate. An intravenous pyelogram demonstrated another opaque calculus in the lower calyx of the right kidney. For the next six months the patient was maintained on a low calcium diet, Mandelamine@ and urine acidification. During this time the serum calcium was 10.6 mg. per cent and serum phosphorus 2.9 mg. per cent.

Fig. 1. Chest roentgenogram

obtained

on July 31, 1959.

chest roentgenogram demonstrated bilateral hilar adenopathy and a fine nodular parenchymal infiltrate (Fig. 1). The electrocardiogram was within normal limits. After initial evaluation a right axillary lymph node biopsy was performed, revealing noncaseating granulomas compatible with sarcoidosis. The patient was discharged without therapy to be followed in the outpatient department. In February 1959 a Kveim test was positive for sarcoidosis. By December of that year the patient appeared to be clinically well, with x-ray evidence of a decrease in the hilar adenopathy and some resolution of the pulmonary parenchymal infiltrate. In July 1960 the patient complained of transient flank pain and stated that his urine was occasionally the color of dark tea. Urinalysis at that time included the finding of 5 to 8 red cells per high power field, occasional granular casts and many calcium oxalate crystals. Serum calcium was 9.6 mg. per cent, phosphorus 3.8 mg. per cent and alkaline phosphatase 2.1 Bessey-Lowry units. The chest roentgenogram was unchanged. The patient was treated with only a urinary tract antiseptic. In October 1961, when he was essentially asymptomatic, blood chemical determinations revealed a calcium of 10.8 mg. per cent, phosphorus 3.2 mg. per cent, alkaline phosphatase 2.2 Bessey-Lowry units and serum protein 7.5 gm. per cent of which 2.9 gm. was albumin and 3.6 gm. globulin.

In June 1966 the serum calcium was 10.3 mg. per cent and phosphorus 2.9 mg. per cent. Lung function studies revealed normal lung volumes and a diffusing capacity for carbon monoxide of 8.5 ml. per minute per mm. Hg. Because of the history of recurrent renal lithiasis, thought to be secondary to sarcoidosis, treatment was begun with prednisone, 30 mg. a day, which was gradually tapered to 10 mg. a day over the next five months. Despite this therapy the patient returned to the clinic in October 1966 stating that he had passed a small kidney stone one week before. Serum calcium was 10.8 mg. per cent, phosphorus 2.5 mg. per cent and serum protein 7.5 gm. per cent with 4.7 g-m. albumin and 2.8 gm. globulin. A repeat intravenous pyelogram demonstrated an opaque calculus in the upper third of the right ureter. From December 1966 through February 1967 the patient was treated with prednisone, 12.5 mg. a day, and ascorbic acid, 2 gm. a day. On two occasions his serum calcium was 11.2 and 10.6 mg. per cent and phosphorus 2.7 and 3.7 mg. per cent. Blood urea nitrogen was 18 mg. per cent and alkaline phosphatase 2.1 Bessey-Lowry units; a twenty-four hour urine collection with a volume of 1,150 ml. contained 270 mg. calcium and 910 mg. phosphorus. Chest roentgenogram revealed complete regression of the hilar adenopathy and almost complete clearing the previously described nodular infiltrate. In March 1967 the serum calcium was 11.7 mg. per cent and the phosphorus 2.4 mg. per cent; prednisone dosage was increased to 15 mg. a day. By June of that year the calcium was 10.9 mg. per AMERICAN

JOURNAL

OF

MEDICINE

Sarcx)idosis

and

Prinlary

Hyperparathyroidisrll-f,i~f

>i?7

~1 ~1.

(~111. ~)!;~,plloru~ 2.6 mg. per cent and alkaline ,‘lIo”]‘!“1l;l”’ 2.7 Resscy~Lowry units. A twenty-four IIO~I- uri11~ collrc I ioll contained 430 mg. calcium .111d W; III,~ pl~~sphorus in I.775 ml. Prednisone but the serum calcium level rher;tlq wci19contifluetl tr,nl,tirlvtl c~l(TdltYl ill Il.3 nlg. per tent with a 01 I .5 mg. per cent. reruln phospllorur III f ktolm I Wi7 the c.llcium level was 11.5 nig. 2.4 mg. per cent. :I 1)~r c(‘t~t ;ind tl~c phosphorus I hircl illtl ;I\ CIIOUS pvelogram was obtained which

1r~;~letl c~nplrtc obstr~iction of the right ureter was reatlII\ ;I c~llclllus. ;It this tilne the patient xnirt?tl to tllc, hospital. ‘1 11~. history on admission was unchanged and Lab l)hyhi( .~1 caarnination WI\ completely normal. 01-x101I tl;ir;~ included ;I liematocrit of 49 pel. cent, .I \vililC I ..I’15ml. contained’185 q.

ot phosphorus. 111 tl~c ltocpiral the pxtient underwent :I right I1relclolitllotomy. Following recovery from this prot cxlllrc. :I steroitl 5uppression test, with 200 rng. of I1vdrocortisonc administered daily for seven da>-s, \v;~s lnltlcrtakrn. Serum calcium levels remained c.1~1 ;~IuI ( 13.9. 13.9 and 13.0 mg. per cenr) and phosphorus le\ (.I$ remailled low (3.4, 3.4 and 2.0 rng. per celil). .\ twenty-four hour urine collection of L’.iii ml. obt;iined during the test contained 555 !II~. 01 calritlm and 945 mg. of phosphorus. \Vith rhe xrldit ion of oral phosphates at rhe conclusion of 11~: test the calcium level fell to 11.2 mg. per t ant. Surgic;ll exploration of the neck disclosrd a i by .i mm. grcyish tumor in the region of the right \uperiol parath~roitl gland which was totally exOYted. PtltkOIlen Ct ill. [14], in ;I disc-llssion of patients with sarcoitlosis. noted that it) eight of sixty (or I4 per cent) at least one cletcrniination of serum phosphorous was below 9.0 mg. per cent. Two of these (X.3 IXY cetlt) Il;ltl lxrsistenc‘e of this finding. He suggestetl tlu( hypephosphatemia might be more COI~~O~~ than had been appreciated previously. Ellman and Parfitt [15] described a patient \vith proved sarcoidosis associated with hypercalcemia and hypophosphatemia. After the patient was treated with bed rest and cortisone the values returned to normal levels. Longcopc and Freiman [Ic;l,

828

Sarcoidosis

and Primary

Hyperparathyroidism-Lie/ TABLE

SARCOIDOSIS

AND

PRIMARY

et al.

I

HYPERPARATHYROIDISM

COEXISTING

IN THE

SAME

PATIENT

Calcium

&SC

NO.

Source

Hcllstrom.

Clinical

Burr

6

Bernstein

7

Dent

et al.

[3]

et al.

and Warso”

[71

8

Ppah

9

Present

Diagnnstic

Criteria

mentioned

only,

(mg.

%)

Phosphorus (G.

Steroid

%)

Ivcmark

[41 Dent 151 Winnackcr et al. [9] Snapper et al. [Z]

5

Data

et al. [S]

cast

[6]

Case

“” details

given

. 35 year old ma”, twin had hypcrparathyroidism, sarcoidosis diagnosed first 57 year old woman, hypcrparathyroidism diagnosed fint 65 year old woman, 15 year history of high calcium, sarcoidosis diagnosed first, hypcmcphroma, marked azotcmia 44 year old ma”, sarcoidosis diagnosed first

21 year old man, renal lus, hyperparathyroidism diagnosed first

calcu-

32 year old man, multiple renal calculi, sarcoidosis diagnosed first

Sarcoid: typlcal course and roentgcnogr&. two skin biopsies. Hypcrporolhyroidrrm: cncision of clear cell adcnoma Sarcoid: removal of spleen with granulomas. Hyperpnrothyroidirm: excision of chief cell adcnoma So&d: Typical roentgcnqram, autopsy proof in lung. Hyperborathvroidism: incidental chief

Snrcoid: typical course and rocntgcnogram, node biopsy. Hypcrparalhyroidizm: cx&iion of chief cell adcnoma Sarcoid: incidental lymphoid tissue during neck exploration. Hypcrparothyroidirm: excision of chief ccl1 adcnoma Sax&d: w&al course and rocntge”ogr&“, positive Kvcim test, positive node biopsy. Hypcrpara. thvroidism: excision of chief cell

in a combined review from the Johns Hopkins Hospital and the Massachusetts General Hospital, mentioned several patients with low serum phosphorus levels in their series of 160 cases. They gave no statistical analysis, but commented that it was an unusual finding in sarcoidosis. There have been frequent reports of the successful use of adrenal cortical steroids in the treatment of hypercalcemic sarcoidosis [17-201. In the absence of complicating factors a return of the serum calcium to normal levels is the almost invariable response. Only three cases of sarcoidosis have been reported in which the serum calcium level did not return to normal with steroid therapy, and in each of these a partial response was obtained [7,21,22]. In addition to the infrequent negative response in sarcoidosis, a positive response has been noted in primary hyperparathyroidism. That is, patients proved to have this disease have had [5,23-281. steroid-responsive hypercalcemia However, when properly performed the value of a formal steroid suppression test is widely accepted. Dent [5] has emphasized that cortisone must be used for steroid suppression. It must be administered for adequate periods (ten days) and in adequate dosage (150 mg. a day).

1.9-2.3

Neg.

13.6-15.0

2.4-3.0

Neg.

13.0-13.6

3.7-6.1

POS.

15.0

16.4

2.1

Many

10.7-11.6

3.1-3.7

Not

9.6-13.9

1.5-4.0

Neg.

neg.

done

If a partial response is noted in this time, treatment should be continued for longer periods as these patients may go on to achieve normal levels of serum calcium. Carried out in this fashion, the Dent test is useful in the differential diagnosis of hypercalcemia. Pertinent data on recorded cases of coexistent sarcoidosis and primary hyperparathyroidism are summarized in Table I. Three cases were mentioned without description (Cases 1,2 and 3). The five remaining patients had elevated serum calcium levels (Cases 4 through 8). Three had hypophosphatemia (Cases 4, 5 and 7), one had a normal phosphorus level (Case 8) and one had azotemia with hyperphosphatemia (Case 6). Three of the described patients had a negative response to steroids (Cases 4, 5 and 7); a fourth, who had severe renal disease, responded to steroids by a lowering of the serum calcium level (Case 6). The test was not performed in the fifth patient (Case 8). The sarcoidosis had a typical clinical course and roentgenographic picture in three cases (Cases 4, 6 and 7). In one, the diagnosis of sarcoidosis was made on the histologic appearance of lymphoid tissue removed incidentally at the time of neck exploration (Case 8). In a fifth patient removal of an enlarged spleen involved with
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