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Recurrence of autonomous hyperparathyroidism in calcium nephrolithiasis
Recurrence of Autonomous Calcium Nephrqlithiasis
GIUSEPPE MASCHIO, M.D. ROBERTO VECCHIONI, M.D. NICOLA TESSITORE, M.D. Verona, Italy
Hyperparathyroidism
in
In a woman with bilateral recurrent calcium nephrolithiasis and hypercalciuria, hypercalcemia developed and she underwent parathyroid surgery, which led to excision of a histologically-confirmed adenoma. The patient became normocalcemic but remained hypercalciuric despite reduction of dietary calcium intake. Several calculi recurred in both kidneys. Four to six years after parathyroidectomy, hypercalcemia recurred and the patient underwent a new surgical exploration; a parathyroid gland with diffuse adenomatous aspects and another gland with pure hyperplasia were excised. Once again, after surgery the patient became normocalcemic but remained hypercalciuric. Evidence for a “renal calcium leak” hypercalciuria was obtained, and thiazide administration led to normalization of urinary calcium excretion. In calcium nephrolithiasis, persistent hypercalciuria may lead to recurrence of autonomous hyperparathyroidism. Hypercalciuria and recurrent urinary stone formation have been described after successful surgery for primary hyperparathyroidism [1,4. Persistent hypercalciuria may result either from decreased tubular reabsorption of calcium [I] or from excessive gastrointestinal calcium absorption [z] . We describe the first patient in whom decreased renal calcium reabsorption after surgery for “primary” hyperparathyroidism eventually led to recurrence of autonomous hyperparathyroidism.
CASE REPORT
From the Division of Nephrology, and the Institute of Surgical Pathology, University Hospital of Verona, Verona, Italy. Requests for reprints should be addressed to Dr. Giuseppe Maschio, Divisione Nefrologia-Istituti Ospitalieri. 37100 Verona. Italy. Manuscript accepted October 15, 1979.
A 35 year old housewife presented in 1979 with bilateral renal calculi. Between 1968 and 1973 she had passed 5 calculi [calcium phosphate and calcium oxalate) and ureterolithotomy and nephrolithotomy had been performed twice. Urinary calcium excretion was occasionally measured and was found to be increased (290 to 380 mg/24 hours). Plasma calcium was normal (9.4 mg/dl). In 1973, sustained hypercalcemia (mean values 12 mg/dl), and hypercalciuria (305 to 340 mg/24 hours) were found. The patient underwent parathyroid surgery on December 18,1973. The glands on the right side of the neck and the upper left gland were apparently normal, and no biopsy was performed. The lower left gland, which appeared grossly enlarged, was removed; its weight was 650 mg. The histologic examination showed a large adenomatous nodule composed primarily of chief cells with large, multiple, deep-staining nuclei, and surrounded by rims of tissue containing both normal and hyperplastic chief cells and oxyphil cells. After surgery, the patient became normocalcemic but remained hypercalciuric [Figure 1). Serum calcium determinations were made twice a month until March 1974 and gave values between 8.8 and 9.2 mg/dl.
October
1980
The American
Journal
of Medicine
Volume
69
607
AUTONOMOUS
HYPERPARATHYROIDISM
IN
CALCIUM
NEPHROLITHIASIS-MASCHIO
ET AL.
I? PTX
P?PTX
1
I THIAZIDE 4
12.00 SERUM CALCIUM
. i
11.00
.
8
.
10.00 1
W/d1
.
.
9.0 0
0.0
. .
480 24 HOUR URINARY CALCIUM
360 240
(ms) 120 0 1968
69
70
71
72
73
74
75
76
77
78
79
Figure 1. Persisting hypercalciuria, despite normocalcemia, after the first remove of parathyroid adenoma (lo PTX) in 1973. After the second parathyroid surgery (2’ PTX) in 1979, the patient once again became normocalcemic but remained hypercalciuric. Note normal urinary calcium excretion after long-term administration of hydrochlorothiazide. (Serum and urinary calcium values are g/ven as mean of several determinations).
Dietary calcium intake was lowered to about 400 mg/24 hours. No thiazide was administered. Eventually, serial roentgenograms showed the recurrence of several calculi in both kidneys. Significant bacteriuria was observed occasionally. In 1977, serum calcium was 10.2 to 10.5 mg/dl, urinary calcium excretion 300 to 400 mg/24 hours and serum immunoreactive parathyroid hormone (iPTH) 2.9 pg/liter (normal range 0.2 to 0.8 pg/liter). In 1979, serum calcium concentration was 10.8 to 11.0 mg/dl, urinary calcium excretion 260 to 350 mg/24 hours and serum iPTH 6.2 pg/liter. The calcium to creatinine excretion ratio, according to Pak et al. [3], was found to be 0.35’5 fasting and 0.484 after calcium loading. Renal function (creatinine clearance), serum alkaline phosphatase and a roentgenologic skeletal survey were within normal limits. No evidence of renal cystic disease, sarcoidosis, thyroid disease or malignancy was found. Glycosuria, proteinuria and aminoaciduria were absent. On February 27,1979, the patient underwent a new surgical exploration [Prof. R. Vecchioni) and the upper right gland, which was enlarged and had some architectural nodular@, was excised. The lower right gland was also slightly enlarged and was also excised, whereas the upper left gland appeared once again apparently normal. The weight of the upper right gland was 350 mg. The histologic examination showed an adenomatous nodule, subdivided into three smaller nodules and composed mainly of chief cells, often with multiple nuclei. The surrounding tissue had some degree of hyperplasia of chief cells. The weight of the lower right gland was 90 mg. The histologic examination showed diffuse hyperplasia of chief cells.
606
October
1960
The American
Journal of Medicine
Once again, after surgery, the patient became normocalcemic but remained slightly hypercalciuric (Figure 1). The calcium to creatinine excretion ratio was 0.165 fasting and 0.280 after calcium loading. Serum iPTH values were 0.3 pg/liter. Hydrochlorothiazide (50 mg/24 hours] was then prescribed.
METHODS Serum and urine calcium was measured with atomic absorption spectrophotometry (Perkin-Elmer]. Serum iPTH was determined following the method of Fischer et al. [4] (normal range, 0.2 to 0.8 pg/liter] on serum samples collected without venous stasis and with the patient fasting. Serum and urine creatinine was measured with a Technicon@ Autoanalyzer. The calcium to creatinine (mg:mg) ratio was measured following the protocol of Pak et al. [3] on a 2 hour urine sample fasting and on a 4 hour urine sample after an oral calcium load (1 g) [normal range 0.030 to 0.084 fasting and 0.096 to 0.166 after calcium loading].
COMMENT Persisting hypercalciuria after successful surgery for primary hyperparathyroidism has been recently observed as a result of excessive gastrointestinal calcium absorption [z]. In our opinion, the patient described probably had a chance association between parathyroid adenoma and idiopathic “absorptive” hypercalciuria. A completely different situation has been described in some patients who apparently present with normocalcemic primary hyperparathyroidism. In these cases, persisting hypercalciuria after surgery for parathyroid adenoma resulted from a primary renal calcium leak
Volume
69
AUTONOMOUS
HYPERPARATHYROIDISM
IN
CALCIUM
NEPHROLITHIASIS-MASCHIO
ET AL.
hypercalciuria may result in recurrent autonomous hyperparathyroidism. In view of the well known effectiveness of thiazide diuretics in patients with “renal” hypercalciuria [l], it might well be that if our patient were treated after the first parathyroidectomy with long-term hydrochlorothiazide, the recurrence of autonomous hyperparathyroidism would be avoided. Yet, after the second surgery, thiazide administration proved to be effective in normalizing urinary calcium excretion. We agree with Muir and Baker [z] that careful metabolic studies are necessary not only before but also after surgery for “primary” hyperparathyroidism.
that led initially to a state of secondary hyperparathyroidism and eventually to tertiary or autonomous hyperparathyroidism [l]. This metabolic and morphologic sequence probably took place also in our patient, who clearly had primary “renal” hypercalciuria. Yet, hypercalciuria persisted after parathyroidectomy; it was not abolished by calcium restriction, and there was no evidencb of malformative kidney disease or kidney damage resulting from previous hypercalcemia. Moreover, the results of the Pak’s test after parathyraidectomy were typical for a “renal” form of hypercalciuria. This case report provides evidence that continued
REFERENCES 1. BordierP,RyckewartA, et al.:On the pathogenesisof so-called idiopathic hypercalciuria. Am JMed 1977; 63: 398. 2. Muir JW,Baker LRI: Hypercalciuria and recurrent urinary stone formation despite successfulsurgeryfor primary hyperparathyroidism. Br Med J1978; 2: 738. 3. Pak CYC, Kaplan RA. Bone H, Townsend J, Waters 0: A simple test for the diagnosisof absorptive.resorptive, and
October
renal hypercalciurias.N Engl JMed 1975; 292: 497. 4. FischerJA,BinswangerLJ,Dietrick FM: Human parathyroid hormone: immunological characterization of antibodies againsta glandular extractand the syntheticamino-terminal fragmentsl-12 and 1-34 and their usein the determination of immunoreactive hormone in human sera. J Clin Invest 1974;
1980
54: 1382.
The American
Journal of Medicine
Volume
69
609
GIUSEPPE MASCHIO, M.D. ROBERTO VECCHIONI, M.D. NICOLA TESSITORE, M.D. Verona, Italy
Hyperparathyroidism
in
In a woman with bilateral recurrent calcium nephrolithiasis and hypercalciuria, hypercalcemia developed and she underwent parathyroid surgery, which led to excision of a histologically-confirmed adenoma. The patient became normocalcemic but remained hypercalciuric despite reduction of dietary calcium intake. Several calculi recurred in both kidneys. Four to six years after parathyroidectomy, hypercalcemia recurred and the patient underwent a new surgical exploration; a parathyroid gland with diffuse adenomatous aspects and another gland with pure hyperplasia were excised. Once again, after surgery the patient became normocalcemic but remained hypercalciuric. Evidence for a “renal calcium leak” hypercalciuria was obtained, and thiazide administration led to normalization of urinary calcium excretion. In calcium nephrolithiasis, persistent hypercalciuria may lead to recurrence of autonomous hyperparathyroidism. Hypercalciuria and recurrent urinary stone formation have been described after successful surgery for primary hyperparathyroidism [1,4. Persistent hypercalciuria may result either from decreased tubular reabsorption of calcium [I] or from excessive gastrointestinal calcium absorption [z] . We describe the first patient in whom decreased renal calcium reabsorption after surgery for “primary” hyperparathyroidism eventually led to recurrence of autonomous hyperparathyroidism.
CASE REPORT
From the Division of Nephrology, and the Institute of Surgical Pathology, University Hospital of Verona, Verona, Italy. Requests for reprints should be addressed to Dr. Giuseppe Maschio, Divisione Nefrologia-Istituti Ospitalieri. 37100 Verona. Italy. Manuscript accepted October 15, 1979.
A 35 year old housewife presented in 1979 with bilateral renal calculi. Between 1968 and 1973 she had passed 5 calculi [calcium phosphate and calcium oxalate) and ureterolithotomy and nephrolithotomy had been performed twice. Urinary calcium excretion was occasionally measured and was found to be increased (290 to 380 mg/24 hours). Plasma calcium was normal (9.4 mg/dl). In 1973, sustained hypercalcemia (mean values 12 mg/dl), and hypercalciuria (305 to 340 mg/24 hours) were found. The patient underwent parathyroid surgery on December 18,1973. The glands on the right side of the neck and the upper left gland were apparently normal, and no biopsy was performed. The lower left gland, which appeared grossly enlarged, was removed; its weight was 650 mg. The histologic examination showed a large adenomatous nodule composed primarily of chief cells with large, multiple, deep-staining nuclei, and surrounded by rims of tissue containing both normal and hyperplastic chief cells and oxyphil cells. After surgery, the patient became normocalcemic but remained hypercalciuric [Figure 1). Serum calcium determinations were made twice a month until March 1974 and gave values between 8.8 and 9.2 mg/dl.
October
1980
The American
Journal
of Medicine
Volume
69
607
AUTONOMOUS
HYPERPARATHYROIDISM
IN
CALCIUM
NEPHROLITHIASIS-MASCHIO
ET AL.
I? PTX
P?PTX
1
I THIAZIDE 4
12.00 SERUM CALCIUM
. i
11.00
.
8
.
10.00 1
W/d1
.
.
9.0 0
0.0
. .
480 24 HOUR URINARY CALCIUM
360 240
(ms) 120 0 1968
69
70
71
72
73
74
75
76
77
78
79
Figure 1. Persisting hypercalciuria, despite normocalcemia, after the first remove of parathyroid adenoma (lo PTX) in 1973. After the second parathyroid surgery (2’ PTX) in 1979, the patient once again became normocalcemic but remained hypercalciuric. Note normal urinary calcium excretion after long-term administration of hydrochlorothiazide. (Serum and urinary calcium values are g/ven as mean of several determinations).
Dietary calcium intake was lowered to about 400 mg/24 hours. No thiazide was administered. Eventually, serial roentgenograms showed the recurrence of several calculi in both kidneys. Significant bacteriuria was observed occasionally. In 1977, serum calcium was 10.2 to 10.5 mg/dl, urinary calcium excretion 300 to 400 mg/24 hours and serum immunoreactive parathyroid hormone (iPTH) 2.9 pg/liter (normal range 0.2 to 0.8 pg/liter). In 1979, serum calcium concentration was 10.8 to 11.0 mg/dl, urinary calcium excretion 260 to 350 mg/24 hours and serum iPTH 6.2 pg/liter. The calcium to creatinine excretion ratio, according to Pak et al. [3], was found to be 0.35’5 fasting and 0.484 after calcium loading. Renal function (creatinine clearance), serum alkaline phosphatase and a roentgenologic skeletal survey were within normal limits. No evidence of renal cystic disease, sarcoidosis, thyroid disease or malignancy was found. Glycosuria, proteinuria and aminoaciduria were absent. On February 27,1979, the patient underwent a new surgical exploration [Prof. R. Vecchioni) and the upper right gland, which was enlarged and had some architectural nodular@, was excised. The lower right gland was also slightly enlarged and was also excised, whereas the upper left gland appeared once again apparently normal. The weight of the upper right gland was 350 mg. The histologic examination showed an adenomatous nodule, subdivided into three smaller nodules and composed mainly of chief cells, often with multiple nuclei. The surrounding tissue had some degree of hyperplasia of chief cells. The weight of the lower right gland was 90 mg. The histologic examination showed diffuse hyperplasia of chief cells.
606
October
1960
The American
Journal of Medicine
Once again, after surgery, the patient became normocalcemic but remained slightly hypercalciuric (Figure 1). The calcium to creatinine excretion ratio was 0.165 fasting and 0.280 after calcium loading. Serum iPTH values were 0.3 pg/liter. Hydrochlorothiazide (50 mg/24 hours] was then prescribed.
METHODS Serum and urine calcium was measured with atomic absorption spectrophotometry (Perkin-Elmer]. Serum iPTH was determined following the method of Fischer et al. [4] (normal range, 0.2 to 0.8 pg/liter] on serum samples collected without venous stasis and with the patient fasting. Serum and urine creatinine was measured with a Technicon@ Autoanalyzer. The calcium to creatinine (mg:mg) ratio was measured following the protocol of Pak et al. [3] on a 2 hour urine sample fasting and on a 4 hour urine sample after an oral calcium load (1 g) [normal range 0.030 to 0.084 fasting and 0.096 to 0.166 after calcium loading].
COMMENT Persisting hypercalciuria after successful surgery for primary hyperparathyroidism has been recently observed as a result of excessive gastrointestinal calcium absorption [z]. In our opinion, the patient described probably had a chance association between parathyroid adenoma and idiopathic “absorptive” hypercalciuria. A completely different situation has been described in some patients who apparently present with normocalcemic primary hyperparathyroidism. In these cases, persisting hypercalciuria after surgery for parathyroid adenoma resulted from a primary renal calcium leak
Volume
69
AUTONOMOUS
HYPERPARATHYROIDISM
IN
CALCIUM
NEPHROLITHIASIS-MASCHIO
ET AL.
hypercalciuria may result in recurrent autonomous hyperparathyroidism. In view of the well known effectiveness of thiazide diuretics in patients with “renal” hypercalciuria [l], it might well be that if our patient were treated after the first parathyroidectomy with long-term hydrochlorothiazide, the recurrence of autonomous hyperparathyroidism would be avoided. Yet, after the second surgery, thiazide administration proved to be effective in normalizing urinary calcium excretion. We agree with Muir and Baker [z] that careful metabolic studies are necessary not only before but also after surgery for “primary” hyperparathyroidism.
that led initially to a state of secondary hyperparathyroidism and eventually to tertiary or autonomous hyperparathyroidism [l]. This metabolic and morphologic sequence probably took place also in our patient, who clearly had primary “renal” hypercalciuria. Yet, hypercalciuria persisted after parathyroidectomy; it was not abolished by calcium restriction, and there was no evidencb of malformative kidney disease or kidney damage resulting from previous hypercalcemia. Moreover, the results of the Pak’s test after parathyraidectomy were typical for a “renal” form of hypercalciuria. This case report provides evidence that continued
REFERENCES 1. BordierP,RyckewartA, et al.:On the pathogenesisof so-called idiopathic hypercalciuria. Am JMed 1977; 63: 398. 2. Muir JW,Baker LRI: Hypercalciuria and recurrent urinary stone formation despite successfulsurgeryfor primary hyperparathyroidism. Br Med J1978; 2: 738. 3. Pak CYC, Kaplan RA. Bone H, Townsend J, Waters 0: A simple test for the diagnosisof absorptive.resorptive, and
October
renal hypercalciurias.N Engl JMed 1975; 292: 497. 4. FischerJA,BinswangerLJ,Dietrick FM: Human parathyroid hormone: immunological characterization of antibodies againsta glandular extractand the syntheticamino-terminal fragmentsl-12 and 1-34 and their usein the determination of immunoreactive hormone in human sera. J Clin Invest 1974;
1980
54: 1382.
The American
Journal of Medicine
Volume
69
609