Pheochromocytoma with nephrotic syndrome

Case Reports Pheochromocytoma with Nephrotic Syndrome* VINCENT J . RIZZUTO, M .D ., JAMES T . MAZZARA, M .D .

and WILLIAM J .

GRACE, M .D ., F .A .C .C .

New York, New York

T

nE nephrotic syndrome has been defined as

Physical examination revealed a well nourished, well developed Caucasian girl in no acute distress . The temperature was 99 0 , pulse 120/min ., and respiration 16 ; the blood pressure was 200/140 mm . Hg . Funduscopic examination revealed bilateral arteriovenous nicking, papilledema of a mild degree, and macular stars but no hemorrhages . Examination of the heart revealed no murmurs, gallops, thrills nor enlargement . Physical findings of the neck, lungs, abdomen and extremities were unremarkable . The admission laboratory data revealed I + proteinuria and a urine sediment containing white cell and hyaline casts, oval fat bodies, 6 to 12 white cells, and 0 to 2 red cells per high power field . The white cell count was 12,600 ; the differential count was normal . The hematocrit was 400/,, hemoglobin 14 gm.%, and erythrocyte sedimentation rate 18 mm ./hr. A Kahn test was nonreactive . The blood urea nitrogen was 15 mg . and the fasting blood sugar 84 mg . per 100 ml. The serum sodium was 142, potassium 3 .9, chloride 93, and carbon dioxide content 28 mEq . per liter. The serum calcium was 11 .6, phosphorus 4 .5, creatinine 1, and uric acid 6 .2 mg . per 100 ml . A posteroanterior roentgenogram of the chest revealed no abnormalities . An electrocardiogram showed regular sinus rhythm and left ventricular hypertrophy . Repeated urinalyses (clean-catch, mid-stream specimens) showed persistent proteinuria ranging from 11- to 4+ and doubly retractile fat bodies . Urine for quantitative protein determination revealed 9 .9 gm . of protein per 24 hours . Total serum cholesterol was 323 mg . and serum phospholipids 9 .3 mg . per 100 ml . Three urine cultures were sterile. The serum complement was 40 units (normal 31 .47 units) . Antistreptolysin-O titer was 50 Todd units . A throat culture demonstrated normal bacterial flora . The total serum protein determination was 8 .1 gm/100 ml . ; the albumin-globulin ratio was 4.4/3 .7 gm . Serum protein electrophoresis revealed the following : albumin 60 .2, alpha-I globu-

a disease state characterized by "increased

glomerular membrane permeability that is manifested in massive proteinuria (i .e., greater than 3 .5 gm ./24 hr .) and the excretion of fat bodies" with a "variable tendency toward edema, hypoproteinemia, and hyperlipemia ."I The purpose of this report is to document for the first time a patient who had a pheochromocytotna and the aforementioned nephrotic syndrome . There was spontaneous remission of the nephrosis following the surgical removal of the tumor . The study of this patient led to a general review of pertinent literature with respect to the renal disturbances in patients with pheochromocytoma . CASE REPORT

A 13 year old girl was admitted to St. Vincent's Hospital on Feb . 18, 1964, for evaluation of hypertension . She had been apparently well until December 1963 when intermittent frontal and suboccipital headaches and transient scotomata developed . The headaches occurred daily and persisted for approximately three hours ; the scotomata developed soon after and persisted for only a few minutes at a time . On Dec . 26, 1963, she was examined by an ophthalmologist for evaluation of her visual symptoms and was advised to consult her private physician . After being found to have hypertension, she was treated with hvdrochlorothiazide for two weeks, then with a rauwolfia derivative until the time of admission . The patient had been treated for a genitourinary tract infection in October 1963 but had never had genitourinary complaints prior to that time . The scotoniata and headaches subsided two weeks before hospital admission . The remainder of the past history, system review and family history were not contributory .

* From the Department of Medicine, St . Vincent's Hospital and Medical Center of New York, New York, N .Y. 432

THE AMERICAN JOURNAL OF CARDIOLOGY



433

Pheochromocytoma

Fin. 1 . Renal biopsy specimen (P.A .S . preparation) showing glomerulus with thickened basement membrane (X 430, reduced by 60%) .

Fin . 2 . Renal biopsy specimen (hematoxylin and eosin stain) showing hypertrophy of the media of the arteries (X 200, reduced by 62%) .

lin 6 .9, alpha-2 globulin 10 .5, beta globulin 13 .3, and gamma globulin 9 .1 per cent . Three lupus erythematosus preparations were negative . Urea clearance was 69 .1 cc ./min . An intravenous pyelogram and oral glucose tolerance test were normal . The basal metabolic rate was +13 per cent . A 24 hour urine for catecholamines revealed 1,675 pg,/24 hr . (normal up to 103 µg.) (The patient had received no medication for two weeks .) In a 24 hour

specimen of urine the 3-methoxy-4-hydroxymandelic acid (VMA) was 9 .9 mg . (normal up to 6 .8 mg) . Twenty-four hour urine specimens contained 9 .1 mg . of 17-hydroxysteroids and 7 .7 mg . of 17-ketosteroids . With 1 mg . of phentolaminc (one-fifth the recommended adult dose) given intravenously, a decrease of 30 mm . Hg in the systolic pressure and 20 men . Hg in the diastolic was obtained in one minute . A percutaneous biopsy of the right kidney (Fig . I and 2)

B

Fm . 3 . Aortogram from earlier (A) to later (B) phases, respectively, revealing a soft tissue mass with contrast medium stain (arrows) located above the superior pole of the right kidney . VOLUME

16,

SEPTEMBER

1965



434

Rizzuto, Mazzara and Grace

PIG . 4 .

Phcochromocytoma with surrounding capsule and normal adrenal cortical tissue in neighboring areas ( X 100, reduced by 43% ) .

showed glomerulonephritis with associated hypertrophy of the media of the arteries . A retrograde femoral aortogram (Fig . 3) showed a soft tissue mass with a stain of contrast medium located above the superior pole of the right kidney . Course and Operative Findings : All medications were discontinued . The patient's hypertension persisted throughout the initial hospital course and ranged from 210/160 to 180/110 mm . Hg . On March 11, 1964, surgical exploration through a right subcostal incision revealed a pheochromocytoma of the right adrenal gland (Fig . 4) . Following excision of the tumor, the blood pressure fell to 110/70 diastolic and remained in this range throughout the patient's hospital stay . With 0 .02 mg . of histamine phosphate given intravenously on the twelfth postoperative day, no significant rise of blood pressure was observed . Funduscopic examination just prior to discharge revealed a hemorrhage of the right fundus . 'There was some reduction in the degree of arteriovenous nicking ; the optic disc margins appeared more distinct . The patient was discharged on March 25, to be followed up in our outpatient department . A repeat renal biopsy is planned for a later date . Postoperative Studies : The tumor was 3 by 3 .8 cm, in size and weighed 28 gm . It was analyzed for catecholamines and found to contain 7 ug . of epinephrine and 3,700 ug, of norepinephrine per gram of tumor tissue . A 24 hour urine specimen for quantitative protein on the second postoperative day was 2 .6 gm . Urinalysis revealed trace proteinuria, 2 red cells and many white cells per high power field ; no casts nor doubly

refractile or oval fat bodies were noted . Total serum cholesterol was 177 mg . and total serum protein was 6 .5 gm . per 100 ml . with an albumin-globulin ratio of 2 .6/3 .9 gm . Repeated 24 hour urine specimens for quantitative protein taken on the sixth and eighth postoperative days showed 180 and 165 mg . of protein, respectively . Urinary catecholamines taken on the seventh postoperative day revealed 37 .g ./24 hr . DISCUSSION

In 1951 Berkheiser and Rappoport2 reported the case of an 11 year old white girl with hypertension . Her urinalysis revealed 3+ albumin . She was discharged with a clinical diagnosis of "chronic glomerulonephritis ." The patient died five years later ; postmortem examination disclosed a pheochromocytoma of the left adrenal gland . Included in this same report were several other patients with hypertension and proteinuria who died of "unsuspected pheochromoeytoma of the adrenal ." Fertig et at.' presented the case of a 29 year old white man with hypertension, proteinuria, retinal arteriolar sclerosis, maximal urine concentrating ability of 1 .021, slightly decreased glomerular filtration rate, and a decreased maximal tubular excretion of para-aminohippuric acid . The clinical diagnosis was "early chronic glomerulonephritis ." When this patient died shortly afterward of intracerebra] hemorrhage, autopsy revealed a pheochroniocytoma of the right adrenal gland . THE AMERICAN JOURNAL OF CARDIOLOGY



Pheochromocytonia Kremer' in 1936 described an interesting case of a 14 year old girl whose urine varied in specific gravity from 1 .010 to 1 .025, and albumin from 0 to 2+ . There was an occasional hyaline cast . Blood pressure was normal . One year later, blood urea nitrogen was 15 mg .% ; phenolsulfonphthalein, 50% excreted in one hour and 25% in the second hour, a total of 75% . She was discharged with a diagnosis of "parenchymatous nephritis ." Three years later, hypertension, facial and peripheral edema, and "nephritic retinitis (with) bilateral atrophy of the optic nerve" developed . A diagnosis of "chronic diffuse nephritis with hypertension" was made . One year later the blood pressure was 206/152 mm . Hg ; urine specific gravity 1 .016 to 1 .029 ; albumin I to 2 + ; there was an occasional granular cast but no red cells ; phenolsulfonphthalcin excretion at this time was 10% in the first hour and 20% in the second hour, a total of 30%, ; blood urea nitrogen was 9 rng ./100 ml, The patient died suddenly with pulmonary edema . At autopsy, the kidneys showed "recent anemic infarcts, arteriolar and intraglomerular hyaline thrombosis, severe tubular hyalinization, and mild eccentric thickening of the intima of the renal arteries ." A pheochromocytoma was found in each adrenal gland . Perret et al ." reported the case of a 22 year old man who was hospitalized for epigastric pain and vomiting . Laboratory findings revealed hemoglobin 115%, blood urea nitrogen 41 mg ./100 ml ., normal blood electrolytes, and proteinuria (14 gm ./L .) . Blood pressure was unstable, changing suddenly from 120/110 to 230/160 mm . Hg . Urinary catecholamine studies were performed ; the urinary excretion of epinephrine was 560 and of norepinephrine 290 pg ., in 24 hours . The patient died later in acute pulmonary edema . Autopsy revealed a right adrenal tumor with the histologic structure of a pheochromocytoma . In view of case reports such as these, it becomes readily apparent that adrenal medullary tumors can oftentimes masquerade as renal disease . Various forms of renal functional or anatomic abnormalities, or both, with adrenal medullary tumors have been reported . In 1957 Watkinss reviewed all reported cases of pheochromocytoma and found that lesions characteristic of arteriolonephrosclerosis occurred with long-standing hypertension . Green' noted nephrosclerotic changes in patients with chronic hypertension and pheochromocytoma . VOLUME 16, SEPTEMBER 1965

435

Silva and Sonuners' published renal biopsy data of 9 patients with pheochromocytoma (renal biopsies were obtained during operative removal of the tumors) . They found hypertrophic and degenerative changes within the large arteries, a lesser degree of narrowing of the arterioles by muscle spasm, and hypertrophy and hyperemia of the glomeruli (the reverse of of the findings with typical essential hypertension) . Laboratory studies in this same series of patients revealed 2 patients with slightly elevated blood urea or nonprotein nitrogen, 1 with an abnormal phenolsulphonphthalein excretion test, 3 with evidence of pyelitis by intravenous pyelography, and 3 patients with 1+ to 2+ albuminuria and casts in the urine sediment . Green found altered renal function in the form of albuminuria (intermittent or constant), subnormal phenolsulfonphthalcin excretion, abnormal urine sediments, azotemia and decreased concentrating ability in 24 of 37 chronically hypertensive patients with pheochromocytoma ; on the other hand, in the interval between paroxysms, kidney dysfunction of any type was recorded in only 5 of 14 cases of the intermittently hypertensive group . In general, therefore, one may postulate that the marked renal vasoconstriction in paroxysmal hypertensive cases may result in anoxia of the capillary tufts and tubular epithelium. The reversibly damaged vascular walls then permit such conditions as proteinuria and lipiduria . With the development of chronic hypertension more permanent renal damage occurs, and the functional efficiency of the kidney markedly decreases . Among the 18 cases reviewed by Howard and Barker' the blood urea nitrogen between attacks of hypertension was normal in 9 ; there was intermittent proteinuria regardless of attacks in 3, and persistent proteinuria in 6, 5 of whom had persistent hypertension . Blood nonprotein nitrogen or urea was elevated in 4 of 12 at sometime during the course of their disease . MacKeith'o states that "during the attack there may be anuria or oliguria with albumin and casts in the urine, and azotemia, which may exceed 150 mg . urea per 100 cc . . . .' In an analysis of 207 cases of pheochromocytoma, Graham" found that altered kidney function is frequently observed, as albuminuria was present in 90 of 132 cases, either constantly or immediately following an attack . He states that serum cholesterol, recorded in only 22 cases, was above 250 tng .%o in 9 of those cases and below that level in 13 . Quantitative urine



436

Rizzuto, Mazzara and Grace

protein and lipid excretion data are not available on these patients ; the possibility exists that they too may have represented cases of pheochromocytoma with the nephrotic syndrome . Wilkins et al . 12 have described a case of pheochromocytoma with extensive renal function studies . Besides intermittent albuminuria, they found that in the presence of a normal glomerular filtration rate the renal plasma flow was reduced and the filtration fraction increased in a manner characteristic of essential hypertensive vascular disease . However, there was no evidence of shunting of blood past functioning parenchymal tissue (since the renal extraction of para-aminohippuric acid was virtually complete) . The renal biopsy obtained from this same patient revealed benign nephrosclerosis . The glomeruli were described as possessing "focal hyperplastic clustering of deeply staining nuclei of endothelial cell type and the basement membrane in the immediate vicinity of these nuclear aggregates presents a 'smudgyappear-ing' thickening ." The aortogram in our patient revealed a soft tissue mass with a contrast-medium stain located above the superior pole of the right kidney . This marked the second instance during this year wherein an adrenal medullary tumor was accurately diagnosed (and located) using aortography at our hospital . In our hands, we have found the aortogram to be a safe procedure . Its unique value, moreover, lies in the fact that it can be used as a diagnostic tool to rule out two of the prime causes of "curable hypertension" (i .e ., pheochromocytoma and obstructive renal arterial disease) . Aortography offers the added advantage of not being altered by the patient's diet or medications (both of which have time and again been incriminated as contributing toward "false positive" or "false negative" phentolamine or histamine tests or sympathetic amine values) .I 3,14 It is to be noted also that retroperitoneal gas studies, although generally considered safe and worthwhile, involve a significant degree of difficulty in the interpretation of retroperitoneal masses even by those with considerable experience in this field 1 L

be modified as follows : "Hypertension occurring even in the presence of the usual indications of renal disease does not exclude the possibility of an adrenal medullary tumor" as a basis for the patient's hypertension . 'Foo often in the past has the mistaken diagnosis of chronic glomerulonephritis led to the assumption of secondary hypertension . It is our contention that all hypertensive patients be fully evaluated to rule out the possibility of a curable disease . More specifically, with reference to pheochromocytoma, we feel that aortography, besides the conventional modalities of diagnosis, offers an important device for the diagnosis and localization of adrenal medullary tumors . SUMMARY

The case of a 13 year old girl with hypertension, pheochromocytoma, and the nephrotic syndrome is presented . The spontaneous remission of the hypertension and nephrotic syndrome following surgical removal of the tumor raises the probability of a causal relationship . The fact that nephropathy may be an outstanding manifestation of adrenal medullary tumors emphasizes the necessity for a complete study in all patients with hypertension . The usefulness of aortography as a safe, accurate and reliable procedure in the diagnosis and localization of pheochromocytoma is mentioned . A brief review of pertinent material from the literature regarding renal manifestations of adrenal medullary tumors has been included . ACKNOWLEDGMENTS

We are indebted to Dr . Raymond Gettinger of the Department of Pathology of St. Vincent's Hospital for his aid in preparing and interpreting the biopsy specimens, to Dr. F . F . Ruzicka, Jr . of the Department of Radiology for his role in aortography, to Dr . David Befeler of the Department of Surgery for his cooperation in the surgical management of this patient, and to Dr . A . A . Sjoerdsma of the National Institutes of Health, Bethesda, Maryland, for his kind assistance in obtaining hormonal assays of the tumor . We are especially grateful to Dr . Thomas Mulcahy, who referred this patient to us for study . REFERENCES

CONCLUSION

In view of the body of evidence we have presented, it is our feeling that the classic teaching that "hypertension occurring in the absence of obvious renal disease should make one consider the possibility of a pheochromocytoma" should

G . E . The nephrotic syndrome . In : Diseases of the Kidney, p. 335 . Edited by STRAUSS, M . B . and WELT, L. G. Boston, 1963 . Little, Brown & Co . BERRHEISER, S . W_ and RAPPOPORT, A . F . Unsuspected pheochromocytoma of the adrenal. Report of five cases . Am. J . Chn . Path ., 21 : 657,

1 . SCHREINER,

2.

1951 . 3 . FERTIG, H .

H. :

TAYLOR, R .

D .,

CORCOR .AN, A . C .

THE AMERICAN JOURNAL

OF

CARDIOLOGY

Pheochromocvtolna and PAGE, I . H . The renal manifestations of pheochromocytoma . Report of a ease . .Ann . lot . Med., 35 : 1358, 1951 . 4 . KREMER . D. N . Medullary tumor of the adrenal glands with hypertension and juvenile arteriosclerosis . Arch . Int . Med ., 57 : 999, 1936 . 5 . PERRET . C .,DUPASQUIER, E . and PACHE, D . Deceptive symptomatology ofpheochromocytnma . In : Yearbook of Medicine, 1963-64 series, p . 748 . Edited by BEESON . P . B . et al . Chicago, 1964 . Year Book Publishers, Inc . 6 . WATKINS, D . B . Pheochromocytoma : Review of the literature . J. Chron. Dis ., 6 : 510, 1957 . 7 . GREEN, D . M. Pheochromocytoma and chronic hypertension . J.A .M.A ., 131 : 1260, 1946 . 8 . SILVA, T . F . and SOMMERS, S . C, Renal biopsy with pheochromocytoma . Am . J. M. Sc., 236 : 700, 1958 . 9 . HOwaaD, J . E. and BARtER, W . H . Paroxysmal hypertension and other clinical manifestations' associated with benign chromaffin cell tumors

VOLUME 16, SEPTEMBER 196a

437

(pheochromocytoma) . Bull . Johns Hopkins Hosp ., 61 : 361, 10 . MACKEITH, R . Adrenal sympathetic syndrome . Brit . Heart J., 6 : 1, 1944 . 11 . GRAHAM, J . B . Collective review : Pheochromocytoma and hypertension . Internat . Abstr. Surg ., 92 : 105, 1951 . 12 . WILKINS, R. W . et al . Extensive laboratory studies of a patient with pheochromocytoma before and after successful operation . Arch . Jot . Med ., 86 : 51, 1950 . 13 . GROUT, R . J . and SJOERDSMA, A . A . The clinical and laboratory significance of serotonin and catecholamines in bananas . New England .7. Med ., 261 : 23-26, 1959 . 14 . HARRISON, T . R . et al . Principles of Internal Medicine, ed . 4, p. 631 . New York, 1962 . McCrawHill Book Co . 15 . CAHILL, G. F. and ARANOw, H . Pheochromocytoma : Diagnosis and treatment, Ann . IN . Med., 31 :389,1949 .