Surgical Experience with Cushing's Disease H. WILLIAM SCOTT, JR., M.D., GRANT W. LIDDLE, M.D., J. L. MULHERIN, JR., M.D., T. J. MCKENNA, M.D., S. L. STROUP, M.D. AND R. K. RHAMY, M.D.

I N 1932 HARVEY CUSHING2 described a syndrome of truncal obesity, hypertension, amenorrhea, hirsutism, purplish abdominal striae, polyphagia, polydipsia, polycythemia and susceptibility to infections. Four of the 8 patients in his series were found at autopsy to have basophil adenomas of the pituitary and Cushing attributed the syndrome to pituitary basophilism. Anderson et al.1 in 1938 brought evidence that the common denominator in Cushing's syndrome is hyperactivity of the adrenal cortex, and it has subsequently been clearly established that the fundamental hormonal basis of the syndrome described by

Cushing is hypercortisolism. If those cases due to the use of steroid hormones in medical therapy are excluded, hypercortisolism occurs most commonly from three causes: (1) bilateral adrenal cortical hyperplasia under the stimulatory effect of increased secretion of adrenocorticotropin (ACTH) by the pituitary which may or may not contain an adenoma, (2) bilateral adrenal cortical hyperplasia under the stimulus of ectopic ACTH secreted by a non-endocrine tumor such as oatcell carcinoma of the lung, (3) adrenocortical tumor, either benign or malignant. Despite the impression of certain physicians that the incidence of Cushing's syndrome is on the increase, it appears more likely that this represents implementation of better diagnostic methods which promote wider recognition of the disease rather than an absolute increase. It occurs more frequently in young adults and is two to three times more common in females than in males. This report summarizes our surgical experience with Cushing's disease, the variant of the syndrome caused by bilateral adrenal cortical hyperplasia secondary to excessive secretion of ACTH by the pituitary, also referred to as "pituitary-dependent hypercortisolism". Presented at the Annual Meeting of the Southern Surgical Association, December 5-8, 1976, Palm Beach, Florida.

524

From the Departments of Surgery, Medicine, Radiology and Urology, Vanderbilt University Medical Center, Nashville, Tennessee

Clinical Material During the last 24 years at Vanderbilt University Hospital, over 200 patients with spontaneous hypercortisolism, or Cushing's syndrome, have been observed. Excluding the iatrogenic syndrome secondary to the medicinal use of steroids, the most frequent cause of this disorder was pituitary-dependent hypercortisolism or Cushing's disease (63%) followed in frequency by Cushing's syndrome due to adrenocortical tumor (24%) and the ectopic ACTH variant (13%). Among the patients in this group, 119 who proved to have Cushing's disease were studied and treated from 1952 through 1976. The age range was 7 years to 68 years and two-thirds of the patients were females. The clinical features which were observed in this group of patients were similar to those with benign adrenocortical tumor causing Cushing's syndrome.11 The clinical manifestations in 29 patients with Cushing's disease who were treated by total bilateral adrenalectomy are summarized in Table 1. As can be readily seen in the table, several patients had only a few of the classic manifestations of the syndrome originally described by Cushing. Truncal obesity, hypertension, weakness and "moon facies" were the most frequently encountered features. Symptoms developed in these patients with Cushing's disease over a period of many months to a few years before the diagnosis was suspected. Excessive production of cortisol in Cushing's syndrome results in a catabolic state with protein depletion and diminution in the total mass of the patient's muscle and connective tissue. In addition to muscular weakness and osteoporosis with loss of strength of bones and pathologic fractures, children in this group showed

Vol. 185.o No. 5

CUSHING'S DISEASE

evidence of growth retardation. The thinness and delicacy of the skin with its increased capillary fragility were manifested by easy bruisability and abdominal striae which are characteristic of severe protein depletion. Cutaneous striae developed where the protein depleted corium of the skin was stretched and split by underlying accumulations of adipose tissue. The enhanced protein breakdown is associated with increased gluconeogenesis and diminished carbohydrate tolerance occasionally resulting in overt diabetes. Another common problem of altered protein and carbohydrate metabolism is impairment of wound healing. Accompanying the excessive breakdown of protein in Cushing's syndrome is an abnormal accumulation of fat and these patients had the characteristic pattern of deposition in the face, neck, back and trunk. The cervicodorsal fat pad has been characterized as a "buffalo hump" and accumulation of fat in the face often produces the typical "moon facies". Most patients showed the remarkable tendency to accumulate fat in the trunk, often strikingly severe, in contrast to the accompanying muscular wasting and thinning of the arms and legs. The weakness and easy fatiguability, which occurred in most patients, are clearly related to protein catabolism and the severe depletion of muscle mass. Hypertension, frequently with concomitant headaches, developed most likely because of salt and water retention with expansion of extra-cellular volume. In addition, a few patients developed metabolic alkalosis with accompanying hypokalemia. Unlike patients with primary aldosteronism, however, patients with Cushing's disease do not have suppressed plasma renin activity in association with their expanded extracellular fluid volume, and it has been suggested that the renin-angiotensin system contributes to the elevation of blood pressure in Cushing's disease. Menstrual abnormalities occurred in half of the premenopausal women. Hirsutism, acne and other aspects of mild virilization also occurred in women. Emotional instability was frequently observed in these patients with Cushing's disease and a few had more severe mental disorders, including psychoses.

Endocrinologic Diagnosis of Cushing's Syndrome Establishment of the diagnosis of Cushing's syndrome in patients who are suspected of having this disorder may be accomplished by precise studies of adrenocortical function and adrenal-pituitary relationships. These studies are of fundamental importance in differentiating Cushing's syndrome due to pituitarydependent adrenocortical hyperplasia, extra-endocrine tumor and adrenocortical tumor.

525

TABLE 1. Incidence of Clinical Manifestations in 29 Patients with Cushing's Disease

Central obesity

Hypertension Weakness Moon facies

Ecchymoses Osteoporosis Diabetes Protein wasting Hirsutism Mental aberrations Menstrual abnornalities Edema Striae

22/29 19/29 18/29 16/29 15/29 15/29 14/29 11/29 10/22 10/29 8/15 8/29 6/29

76% 70% 62% 55% 52%

52% 48% 38% 45% 34% 53% 28% 21%

Plasma cortisol levels in normal individuals show characteristic diurnal variations. Cortisol levels measured in the early morning are two to 6 times as high as those measured in the late evening. In normal subjects these diurnal variations in plasma cortisol levels correlate with plasma ACTH concentrations. Unstressed normal subjects characteristically have evening plasma cortisol concentrations less than 7 gg/ 100 ml. In contrast, patients with Cushing's syndrome do not have the normal diurnal variation in plasma cortisol levels. The early morning plasma cortisol level in patients with Cushing's syndrome may occasionally be within the normal range, but late evening values are distinctly elevated (usually well above 12 ,g/100 ml).4 Another laboratory estimation of the activity of the adrenal cortex in producing cortisol is measurement of the daily urinary excretion of 17-hydroxycorticosteroids (17-OHCS). Normal unstressed adults excrete three to 12 mg of 17-OHCS in 24 hours and patients with Cushing's syndrome usually excrete in excess of 12 mg/day. The accuracy of the urine collection and at the same time an adjustment for body size can be obtained by relating the quantity of 17-OHCS to the quantity of creatinine in the urine. Patients with Cushing's syndrome almost always excrete more than 10 mg of 17-OHCS per gram of creatinine while normal subjects excrete 3 to 7 mg of 17OHCS per gram of creatinine.4 Pavlatos, Smilo and Forsham10 have popularized a screening test for Cushing's syndrome which consists of giving the suspect 1 mg of the synthetic hormone, dexamethasone, at 11 p.m. and then drawing blood for plasma cortisol concentration at 8 a.m. Normal individuals will have suppression of plasma cortisol concentrations to 5 ,ug/l00 ml or less while patients with Cushing's syndrome maintain plasma cortisol concentrations in excess of this amount. The most reliable laboratory test for establishment of the diagnosis of Cushing's syndrome is the dexa-

526

SCOTT AND OTHERS r.

o0

,_

Ann. Surg. * May 1977

rz~~~~~~"

2Eq

*-

2 --

*.

u

u,= e

u

r"cis o4

0%1WI

0

00

NN-

~"-

t-W

0;

0 o x m r-

ll.

"

s-

"

2 ,

xo -4

cn

"0

la la

U2 4o

$O

2 =

"0"lala "l

"0

o

G

*--

00u)u

0o

N N00 ON oo u W W WI 0I_ 0o ON CN ce _ %i _- 0o% __" _l

ON

0

"0

"0

"10"0"0

"0"0

)l4)

o"0

AO

"la

4)

U=

OU u0

WuVC)W

=

_c,4e

(O W

_-

== =

en

** I_ * I_ oA _

crfi

_

0 I"

a"

oo oOso c4

la"0"

4L)

=U)u)

UUUR))

U

la0"

3

la0"0

"010

3

=

WuuUE

UU uC-)XX)

-4C'

n

..

o NNN%0%0 a%

nV)1, 1

%

S~ ~ al~s s s~s~ty

-

0

0 Z

0

0t

U'

. . C* i X *; 7 s iX*s

rl0 C)

04

Y ce;c

e

d

e cd c

.

X*

.*

> w

c

$

r M M r P rMM> $ AA2 .

:.

$

$ oX~~~~~~~~~~~~~~~~~4 >

..; s* -

*

03 %o -.

e"00 C14- 00 IR

U,D

0j

_-

_N0 0

ON O,N it _0 (O

~o 00 O

~oR

St

1N

cd

iL3

4

W

ec- i

1-

0

L.

-

00

,

00

o

rIt ro V-

CO

I-

e "C4 er

WI V )

t 't

en

^

\0

r)

F 03 'beN ^~~~~~v rt

2

N-

=0 0-,o

ON

e-^

IR

0

I'.in

00 00

.L.

(ON%

") 0 " 0%A

00 0%

!m

., cn U

Surgical experience with Cushing's disease.

Surgical Experience with Cushing's Disease H. WILLIAM SCOTT, JR., M.D., GRANT W. LIDDLE, M.D., J. L. MULHERIN, JR., M.D., T. J. MCKENNA, M.D., S. L. S...
3MB Sizes 0 Downloads 0 Views