BRIEF CLINICAL
ERYTHROPOIETININ AN ANEPHRICPATIENT WITH ADRENAL MEDULLARYHYPERPLASIA
1
OBSERVATIONS
Serum Erythropoietin (EPO) Levels Drawn Before Dialysis
There are few known causes for an increase in the hematocrit level in anephric patients undergoing dialysis. These include blood transfusions, active hepatitis, and therapy with erythropoietin (EPO). We observed an increase in hematocrit and serum EPO levels in an anephric patient who had clinical and biochemical characteristics of pheochromocytoma. After removal of the hypersecreting left adrenal gland, his hematocrit decreased and the patient required exogenous EPO. Evidence for EPO was found in the hyperplastic adrenal medulla by immunohistochemistry. This is the first evidence of EPO secretion by a hyperplastic adrenal medulla. Methods. The levels of EPO were determined with a sensitive radioimmunoassay (RIA). The details of the RIA procedure used in our laboratory have been published previously [l]. Immunoperoxidase staining of the adrenal medulla for EPO was done by using a previously published technique [2]. Case Report. The patient was a 27-year-old man who developed end-stage renal disease in 1984 after 10 years of hypertension. From 1984 through 1986 while he was receiving hemodialysis, his hypertension continued to be a problem. Gradually, he became unresponsive to fluid removal and simultaneous therapy with four antihypertensive agents. After bilateral nephrectomy, his blood pressure was controlled with the use of two antihypertensive agents for 2 years. Again he became severely hypertensive and was reevaluated. After he had been screened for cocaine and amphetamine use, a work-up for pheochromocytoma was done. Supine and resting serum norepinephrine and epinephrine levels were measured by SmithKline Bio-Science Laboratories and were 2,260 pg/mL (reference range 110 to 410 pg/mL) and 82 pg/mL (reference range less than 50 pg/mL), respectively. There was no change after clonidine suppression. The patient required phenoxybenzamine at a dose of 60 to 80 mg three times a day to maintain a diastolic blood pressure of less than 100 mm Hg. Abdominal computed tomography, nuclear magnetic imaging, and the meta-iodobenzylguanidine-131 (MIBG131) whole body scan were unhelpful in localizing the tumor. Venous sampling demonstrated a marked increase in both norepinephrine and epinephrine levels in the region of the left adrenal gland. After surgical removal of the left adrenal gland, antihypertensive medication was no longer needed. Fortuitously, during this period, blood samples were drawn and measured in retrospect for EPO levels (Table I).
Before nephrectomy on dialysis 9/4/85
I
I
2% years after nephrectomy
814189 a/9/89 a/la/a9 a/21/89 a/25/89 %98g 9/b/89 l/24/90
Day of surgery for adrenalectomy
2/22/90
10.04 1.23 39.34
4.75 15.59 57.37 75.96 37.37 60.18 16.00 22.60 8.71 6.09
The chronology of the patient’s hematocrit is striking. It shows his need for blood transfusions during his first 5 years on dialysis and then the unexpected increase in his hematocrit as his hypertension became so severe. This is shown in Figure 1. During the first 2 years of dialysis, his hematocrit ranged between 20% and 25% and he required 2 to 4 units of packed red blood cells (PRBC) per year. After his bilateral nephrectomy, he received 12 units of PRBC per year for 2 years. In 1989, he suddenly no longer required transfusions. Six months later, the patient’s hematocrit began increasing and reached a peak level of 35% over 3 months. It remained above 30% until 2 months after his left adrenal gland was removed. This rise in hematocrit was preceded by an increase in EPO. Once the hematocrit reached 30%, the level of EPO decreased. Pathologic examination of the 16-g adrenal gland revealed medullary hyperplasia. This tissue was further evaluated for EPO production. Weak, focal reactivity of anti-EPO antibody 194-2 was present in the hyperplastic adrenal medullary cells. Less than 10% of the cells were reactive. The reactive cells showed weak, fine, granular cytoplasmic staining. Serum levels of EPO at the time of adrenalectomy were low at 6.09 mU/mL. Comments. This patient’s clinical course and the measurement of EPO in both the blood and tissue suggest that the patient’s increase in hematocrit was stimulated by the secretion of EPO by the hyperplastic adrenal medulla. Because the patient was anephric, the liver is his only other known potential source of EPO. There are reports in the literature of an increase in hematocrit in both nephric and anephric dialysis patients during the recovery phase of acute hepatitis [3-51. However, our patient
August 1992 The American Journal of Medicine
Volume 93
235
BRIEF CLINICAL
OBSERVATIONS
1 -..-.--
Hematocntl
-
EPO8/8!3-2/90 100
40 35
NephreaMY
Figure
1. The
before picted
and from
1989.
range
after July
Starting
in
monthly hematocrit by a solld circle (e) age
6184
II67
1189
6189
9189
12169
3190
was hepatitis B antigen- and antibody-negative, and results of monthly liver function tests were normal. An increase in the hematocrit has not been reported in patients with adrenal medullary hyperplasia [6-3] and only rarely in patients with pheochromocytoma [9]. In two patients with pheochromocytoma, EPO was considered the reason for the elevated hematocrit. The evidence was indirect. One patient with malignant pheochromocytoma had a hematocrit of 73% and inappropriately high EPO levels [9]. With chemotherapy, the hematocrit decreased as his blood pressure improved. In 1961, Waldmann and Bradley [lo] reported a lo-year-old boy with a pheochromocytoma and hemoglobin level of 21 g/dL. The patient’s serum and extracts of the tumor were injected into rats to assay for erythropoietic stimulating factor. The increases in red cell iron uptake and the reticulocyte count suggested erythropoietic stimulation by the pheochromocytoma. In summary, the EPO in the serum of this patient was not secreted by renal tissue, nor is it likely to have been secreted by the liver. Some control of its secretion is evident by the decrease in EPO levels once the patient’s hematocrit exceeded 30%. After removal of the hyperplastic and hypersecreting left adrenal gland, the patient required exogenous EPO. This strongly suggests that EPO can be pro-
236
August
1992
The American
Journal
of Medicine
Volume
6190
of
three
of
hematocrit
transfusions 1984 until
is deJanuary
1989,
each
is represented and is an aver-
determinations.
rum
levels
of
EPO
1989 solid
1990 are square (w). and
Se-
measured depicted
in by
a
duced by the adrenal medulla and may be responsive to tissue hypoxemia. SUZANNEM. BERGMAN,M.D. CHANDRA CHOUDHURY, M.D. BARBARA S. BECKMAN, Ph.D. G.J. KOCHEVAR, M.D.
Tulane School of Medicine New Orleans, Louisiana and Texas A&M University College Station, Texas
1. Mason-Garcia M, Beckman BS, eta/. Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin. Kidney Int 1990; 38: 969-75. 2. Hsu S. Raine L. Fanger H. Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques. J Histochem Cytochem 1981; 29: 577-80. 3. Meyrier A, Simon P. Boffa G, Brissot P. Uremia and the liver: the liver and erythropoiesis in chronic renal failure. Nephron 1981; 29: 3-6. 4. Brunois JP, Lavaud S, eta/. Acute hepatitis and erythropoiesis in chronically haemodialyzed patients. Nephron 1981; 28: 1523. 5. Brown S, Caro J, Erslev AJ. Murray TG. Spontaneous increase in erythropoietin and hematocrit value associated with transient liver enzyme abnormalities in an anephric patient undergoing hemodialysis. Am J bled 1980; 68: 280-4. 6. Montalbano FP. Baronofsky IO, Ball Ii. Hyperplasia of the adrenal medulla. JAMA 1962; 182: 264-7. 7. DuPont AG, Vanderniepen P, Gerlo E. A case of unilateral adrenal epinephrine excess: adrenal medullary hyperplasia? Acta Clin Etelg 1985; 40: 230-5. 6. Maki Y, lrie S. Ohashi T, Ohmori H. A case of unilateral adrenal medullary hyperplasia. Acta Med Okayama 1989; 43: 311-5. 9. Shulkin BL, Shapiro B, Sisson JC. Pheochromocytoma, polycythemia, and venous thrombosis. Am J Med 1987; 83: 773-6. 10. Waldmann TA, Bradley JE. Polycythemia secondary to a pheochromocytoma with production of an etythropoiesis stimulating factor by the tumor. Proc Sot Exp Biol Med 1961; 108: 425-7. Submitted
93
February
19, 1992, andaccepted
March
18. 1992
ERYTHROPOIETININ AN ANEPHRICPATIENT WITH ADRENAL MEDULLARYHYPERPLASIA
1
OBSERVATIONS
Serum Erythropoietin (EPO) Levels Drawn Before Dialysis
There are few known causes for an increase in the hematocrit level in anephric patients undergoing dialysis. These include blood transfusions, active hepatitis, and therapy with erythropoietin (EPO). We observed an increase in hematocrit and serum EPO levels in an anephric patient who had clinical and biochemical characteristics of pheochromocytoma. After removal of the hypersecreting left adrenal gland, his hematocrit decreased and the patient required exogenous EPO. Evidence for EPO was found in the hyperplastic adrenal medulla by immunohistochemistry. This is the first evidence of EPO secretion by a hyperplastic adrenal medulla. Methods. The levels of EPO were determined with a sensitive radioimmunoassay (RIA). The details of the RIA procedure used in our laboratory have been published previously [l]. Immunoperoxidase staining of the adrenal medulla for EPO was done by using a previously published technique [2]. Case Report. The patient was a 27-year-old man who developed end-stage renal disease in 1984 after 10 years of hypertension. From 1984 through 1986 while he was receiving hemodialysis, his hypertension continued to be a problem. Gradually, he became unresponsive to fluid removal and simultaneous therapy with four antihypertensive agents. After bilateral nephrectomy, his blood pressure was controlled with the use of two antihypertensive agents for 2 years. Again he became severely hypertensive and was reevaluated. After he had been screened for cocaine and amphetamine use, a work-up for pheochromocytoma was done. Supine and resting serum norepinephrine and epinephrine levels were measured by SmithKline Bio-Science Laboratories and were 2,260 pg/mL (reference range 110 to 410 pg/mL) and 82 pg/mL (reference range less than 50 pg/mL), respectively. There was no change after clonidine suppression. The patient required phenoxybenzamine at a dose of 60 to 80 mg three times a day to maintain a diastolic blood pressure of less than 100 mm Hg. Abdominal computed tomography, nuclear magnetic imaging, and the meta-iodobenzylguanidine-131 (MIBG131) whole body scan were unhelpful in localizing the tumor. Venous sampling demonstrated a marked increase in both norepinephrine and epinephrine levels in the region of the left adrenal gland. After surgical removal of the left adrenal gland, antihypertensive medication was no longer needed. Fortuitously, during this period, blood samples were drawn and measured in retrospect for EPO levels (Table I).
Before nephrectomy on dialysis 9/4/85
I
I
2% years after nephrectomy
814189 a/9/89 a/la/a9 a/21/89 a/25/89 %98g 9/b/89 l/24/90
Day of surgery for adrenalectomy
2/22/90
10.04 1.23 39.34
4.75 15.59 57.37 75.96 37.37 60.18 16.00 22.60 8.71 6.09
The chronology of the patient’s hematocrit is striking. It shows his need for blood transfusions during his first 5 years on dialysis and then the unexpected increase in his hematocrit as his hypertension became so severe. This is shown in Figure 1. During the first 2 years of dialysis, his hematocrit ranged between 20% and 25% and he required 2 to 4 units of packed red blood cells (PRBC) per year. After his bilateral nephrectomy, he received 12 units of PRBC per year for 2 years. In 1989, he suddenly no longer required transfusions. Six months later, the patient’s hematocrit began increasing and reached a peak level of 35% over 3 months. It remained above 30% until 2 months after his left adrenal gland was removed. This rise in hematocrit was preceded by an increase in EPO. Once the hematocrit reached 30%, the level of EPO decreased. Pathologic examination of the 16-g adrenal gland revealed medullary hyperplasia. This tissue was further evaluated for EPO production. Weak, focal reactivity of anti-EPO antibody 194-2 was present in the hyperplastic adrenal medullary cells. Less than 10% of the cells were reactive. The reactive cells showed weak, fine, granular cytoplasmic staining. Serum levels of EPO at the time of adrenalectomy were low at 6.09 mU/mL. Comments. This patient’s clinical course and the measurement of EPO in both the blood and tissue suggest that the patient’s increase in hematocrit was stimulated by the secretion of EPO by the hyperplastic adrenal medulla. Because the patient was anephric, the liver is his only other known potential source of EPO. There are reports in the literature of an increase in hematocrit in both nephric and anephric dialysis patients during the recovery phase of acute hepatitis [3-51. However, our patient
August 1992 The American Journal of Medicine
Volume 93
235
BRIEF CLINICAL
OBSERVATIONS
1 -..-.--
Hematocntl
-
EPO8/8!3-2/90 100
40 35
NephreaMY
Figure
1. The
before picted
and from
1989.
range
after July
Starting
in
monthly hematocrit by a solld circle (e) age
6184
II67
1189
6189
9189
12169
3190
was hepatitis B antigen- and antibody-negative, and results of monthly liver function tests were normal. An increase in the hematocrit has not been reported in patients with adrenal medullary hyperplasia [6-3] and only rarely in patients with pheochromocytoma [9]. In two patients with pheochromocytoma, EPO was considered the reason for the elevated hematocrit. The evidence was indirect. One patient with malignant pheochromocytoma had a hematocrit of 73% and inappropriately high EPO levels [9]. With chemotherapy, the hematocrit decreased as his blood pressure improved. In 1961, Waldmann and Bradley [lo] reported a lo-year-old boy with a pheochromocytoma and hemoglobin level of 21 g/dL. The patient’s serum and extracts of the tumor were injected into rats to assay for erythropoietic stimulating factor. The increases in red cell iron uptake and the reticulocyte count suggested erythropoietic stimulation by the pheochromocytoma. In summary, the EPO in the serum of this patient was not secreted by renal tissue, nor is it likely to have been secreted by the liver. Some control of its secretion is evident by the decrease in EPO levels once the patient’s hematocrit exceeded 30%. After removal of the hyperplastic and hypersecreting left adrenal gland, the patient required exogenous EPO. This strongly suggests that EPO can be pro-
236
August
1992
The American
Journal
of Medicine
Volume
6190
of
three
of
hematocrit
transfusions 1984 until
is deJanuary
1989,
each
is represented and is an aver-
determinations.
rum
levels
of
EPO
1989 solid
1990 are square (w). and
Se-
measured depicted
in by
a
duced by the adrenal medulla and may be responsive to tissue hypoxemia. SUZANNEM. BERGMAN,M.D. CHANDRA CHOUDHURY, M.D. BARBARA S. BECKMAN, Ph.D. G.J. KOCHEVAR, M.D.
Tulane School of Medicine New Orleans, Louisiana and Texas A&M University College Station, Texas
1. Mason-Garcia M, Beckman BS, eta/. Development of a new radioimmunoassay for erythropoietin using recombinant erythropoietin. Kidney Int 1990; 38: 969-75. 2. Hsu S. Raine L. Fanger H. Use of avidin-biotin peroxidase complex (ABC) in immunoperoxidase techniques. J Histochem Cytochem 1981; 29: 577-80. 3. Meyrier A, Simon P. Boffa G, Brissot P. Uremia and the liver: the liver and erythropoiesis in chronic renal failure. Nephron 1981; 29: 3-6. 4. Brunois JP, Lavaud S, eta/. Acute hepatitis and erythropoiesis in chronically haemodialyzed patients. Nephron 1981; 28: 1523. 5. Brown S, Caro J, Erslev AJ. Murray TG. Spontaneous increase in erythropoietin and hematocrit value associated with transient liver enzyme abnormalities in an anephric patient undergoing hemodialysis. Am J bled 1980; 68: 280-4. 6. Montalbano FP. Baronofsky IO, Ball Ii. Hyperplasia of the adrenal medulla. JAMA 1962; 182: 264-7. 7. DuPont AG, Vanderniepen P, Gerlo E. A case of unilateral adrenal epinephrine excess: adrenal medullary hyperplasia? Acta Clin Etelg 1985; 40: 230-5. 6. Maki Y, lrie S. Ohashi T, Ohmori H. A case of unilateral adrenal medullary hyperplasia. Acta Med Okayama 1989; 43: 311-5. 9. Shulkin BL, Shapiro B, Sisson JC. Pheochromocytoma, polycythemia, and venous thrombosis. Am J Med 1987; 83: 773-6. 10. Waldmann TA, Bradley JE. Polycythemia secondary to a pheochromocytoma with production of an etythropoiesis stimulating factor by the tumor. Proc Sot Exp Biol Med 1961; 108: 425-7. Submitted
93
February
19, 1992, andaccepted
March
18. 1992
