Download Diagnosis and treatment of adrenocorticotrophic hormone

Diagnosis and treatment of adrenocorticotrophic hormone independent
macronodular adrenocortical hyperplasia: 23 cases of experience in a single
center
LI Jiang, YANG Chang-hai
Department of Urology, Tianjin Medical University General Hospital, Tianjin 300052, China
Corresponding author: YANG Chang-hai, Department of Urology, Tianjin Medical University
General Hospital, No 154, Anshan Street, Heping district, Tianjin 300052, China
Tel: 86- 22-60362443
Fax: 86- 22-60362444
E-mail: [email protected]
Abstract
AIM: We aim to report our experience in treatment of adrenocorticotrophic hormone
(ACTH)-independent macronodular adrenal hyperplasia (AIMAH) in a single medical center.
Methods: A total of 23 AIMAH cases were retrospectively reviewed according to patient’s
clinic features. All cases have physical signs and biochemical evidence of Cushing’s
syndrome. High and low dose dexamethas failed to suppress cortisone secretion on
suppression tests and ACTH levels were low in all cases. Bilateral massively enlarged adrenal
glands were screened on CT scan in 23 cases and all were bilateral adrenal macronodular
hyperplasia by pathological examination.
Results: There were 8 cases have normal blood pressure after 2~8 years of bilateral
adrenalectomy. Fifteen cases underwent single side adrenalectomy and their blood pressures
were remarkable decrease in 3 years after operation, 12 cases of them (12/15) had medicine
treatment; Three cases of them (3/15) underwent the contralateral adrenalectomy, then have
normal blood pressure. There was no Nelson’s syndrome in all cases.
Conclusions: AIMAH had unique endocrinological, radiological and pathological features,
presenting as an independent etiological factor of Cushing’s syndrome. Diagnosis of AIMAH
mostly derived from pathological examination. Long term remission can be achieved by
unilateral adrenalectomy. Contralateral adrenalectomy should be performed in case of
recurrence when followed with periodical examination of symptom and serum concentration
of cortisol.
Key words: Adrenocortical Macronodular Hyperplasia; Cushing's syndrome
Introduction
Adrenocorticotrophic hormone (ACTH)-independent macronodular adrenal hyperplasia
(AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the
adrenal glands and increased cortisol production with subclinical or overt Cushing’s
syndrome (CS). (1, 2) AIMAH represents less than 1% of cases of endogenous CS; however,
as 10% of incidentally found adrenal lesions are bilateral, AIMAH with subclinical cortisol
secretion is being increasingly recognized. (3) Patients with AIMAH are identified either
following an incidental radiological finding or the investigation of an adrenal over-secretion
syndrome. (4, 5) The most common clinical presentation is subclinical, followed by clinical
Cushing’s syndrome (CS).
So far the most common cause (in 95% of patients) of AIMAH is adrenocortical adenoma or
carcinoma. Most of the remaining patients have primary pigmented nodular adrenal disease, a
syndrome that is characterized by multiple small bilateral pigmented adrenocortical nodules
and is often associated with the Carney complex.(6) The diagnosis and management of
patients with ACTH-independent Cushing’s syndrome and bilateral adrenal masses are
problematic, (7, 8) particularly for the bilateral adrenal adenomas. In this report, we present
23 cases of AIMAH; these patients were admitted from July 1994 to 2010 in our hospital
diagnosed by pathology.
Patients and methods
There 23 patients (14 males and 9 females, mean age 49 years) were admitted to our hospital
from July 1994 to 2010. All patients presented with several symptoms characteristic of
Cushing’s syndrome, and hypertension were discovered incidentally during the examination.
The duration of their disease ranged from 1 to 5 years. Diabetes occurred in 10 cases (10/23),
Central obesity occurred in 8 cases. Sanguine appearance occurred in 6 cases. Fourteen
patients have purple stripes.
The levels of plasma cortisol, ACTH, and urinary free cortisol (UFC) were measured in all
patients, the patients were treated by high-dose and low-dose dexamethasone suppression test
(HDDST and LDDST), the results of HDDST and LDDST were negative. There were 4
patients received plasma cortisol rhythm determination, and the other 19 cases only examined
at 8:00. Measurement results showed that plasma cortisol levels elevated in 20 patients and
UFC increased and ACTH levels lowered in all 23 patients (Table 1).
Imaging examination
MRI examination showed pituitary was normal in 17 patients; however, pituitary MRI
examination didn’t been performed in another 6 patients. On CT scan, bilateral adrenal
nodules of soft tissue density, measuring up to 5 cm, distort the normal adrenal glands appear
diffusely enlarged but lack. CT scan results in these patients showed that the adrenal lesion
with macronodularity were significantly enlarged (Figure 1), and the largest diameter of
adrenal nodular was 6 cm.
Operative procedures
Bilateral adrenallectomy was performed in 8 patients and unilateral adrenalectomy was
performed in another 15 cases. The operative procedure has been described by Shinbo et al.(9)
Briefly, under general anesthesia, patient underwent right adrenalectomy were placed in a left
lateral position. A 10/12-mm trocars at the mid-clavicular line below the costal margin and at
the median line 5 cm above the umbilicus and 5-mm trocars were placed at approximately
three finger-widths below the xyphoid process and at the anterior axillary line 5 cm below the
costal margin. Laparosonic coagulating shears with suction and irrigation device with cautery
and L-hook tip were used when necessary. The two trocars at median line remained on the
abdominal wall while skin wounds at the other trocar sites were closed.
Left laparoscopic adrenalectomy was performed as follows: patient was repositioned to the
right half lateral position and two 5-mm trocars were placed at the left below the costal
margin and at the midclavicular line below the costal margin. The left adrenal gland was
isolated similarly to right side and enclosed in an endoscopic pouch. Skin wounds were
closed.
Results
Operation and discharge
After operation, all resected samples were confirmed positive by histopathological
examination (Figure 2), the nodules composed of bright cells. The normal cortical structure
disappeared. We summarized the general clinical and biochemical conditions of these patients
in Table 2. The lumbar open operations were performed in 9 patients; retroperitoneal
laparoscopic operations were performed in 7 patients; Single abdominal open operations were
performed in 3 patients; multiple lumbar open operations were performed in 2 patients and
the Laparoscopic operations were performed in 2 patients. Only1 patient occurred in infection
after operation, and soon got control after treatment. The resected adrenal nodular mass of all
patients was diffused grayish yellow or golden yellow (Figure 3). The largest nodular was 6 ×
4 × 4 cm with 40g of weight and no clear coat. The surface of resected slide was golden
brown with diameter of 0.6~1.7cm. Patients with unilateral resection were not treated with
hormone drug therapy at discharge, while bilateral resection patients received dose of 5 or 10
mg of prednisone treatment.
Postoperative follow-up
After surgery, hypertension of these patients alleviated significantly. The 8 patients received
bilateral adrenallectomy were followed up for 2 to 8 years, treated by glucocorticoid
replacement, and they had normal blood pressure and breath. Their obesity and sanguine
appearance alleviated.
Decreased blood pressure after surgery was observed in others 15 patients. However, only
three years later, 12 cases of 15 patients had hypertension about 150~170/90~100mmHg and
maintained at 130~150/70~85mmHg after taking oral antihypertensive drugs. The other 3
patients (Case 11, 12, 23) had no response on oral antihypertensive drugs and their blood
pressure reached to 170~180/90~110 mm Hg. Plasma cortisol, UFC, ACTH and CT
examination were performed, and their contralateral adrenal increased up to 35 ml, 32ml and
38ml respectively. Their blood pressure returned to normal after their contralateral adrenal
being removed and underwent hormone replacement therapy. No Nelson syndrome occurred
after therapy.
Discussion
Cushing's syndrome is due to excess cortisol secretion and is associated to increased mortality
and severe morbidity that are not fully reversible despite biochemical control. CS is
characterized by loss of the normal feedback regulation and circadian rhythm of the
hypothalamic-pituitary axis due to inappropriate secretion of ACTH from a pituitary tumor
(Cushing's disease, CD) or an ectopic source (ectopic ACTH secretion, EAS). The remaining
causes (20%) are ACTH independent. As soon as the diagnosis is established, the therapeutic
goal is the removal of the tumor. Whenever surgery is not curative, management of patients
with CS requires a major effort to control hypercortisolemia and associated symptoms. (10)
The diagnosis of Cushing’s syndrome is based on the clinical features of hypercortisolism,
absence of serum cortisol diurnalrhythm, elevated midnight sleeping cortisol levels, and
incomplete cortisol suppression test.(11) Cushing’s syndrome due to AIMAH was first
reported in an isolated case.(12)
AIMAH is characterized by bilateral macronodular hyperplasia of the adrenal glands and is
one of the causes of Cushing’s syndrome.(13) Clinical manifestations include hypertension,
weight gain, impaired glucose tolerance or diabetes mellitus, osteoporosis, and bruisability.
Hypogonadism and gynecomastia have been reported occurred in males and hirsutism
occurred in females.(14) The precise etiology of AIMAH is unknown, recent studies have
demonstrated that the aberrant adrenal expression and aberrant function of one to several
peptide hormone receptors, such as receptors for glucose-dependent insulinotropic hormone
(GIP), vasopressin, luteinzing hormone/human chorionic gonadotropin (LH/hCG), beta
adrenergic agonists, and serotonin, can lead to adrenal cell proliferation and abnormal
regulation of steroidogenesis in AIMAH.(15, 16)
Cross sectional imaging is commonly used to identify adrenaldisease in patients have
Cushing’s syndrome. CT scan and MR imaging are used to document the lesion size and
shape; presence or absence of calcification, hemorrhage, and necrosis; On MRI, T1-weighted
images are hypointense relative to the liver and isointense relative to muscle. T2-weighted
images tend to be hyperintense relative to the liver.(17, 18) In contrast, the nodules of patients
with chronic ACTH stimulation appear isointense relative to the liver on T2-weighted MR
images. (19)
On histology, a remarkable increase in the number of small clear cells, which are mostly
derived from the upper fascicularzone. The amount of cortisol produced by each cell is slight,
so that significant enlargement of the adrenal gland is necessary before excessive cortisol
production causes Cushing’s syndrome.(20) The definitive treatment of CS consists in
surgical resection of the tumor secreting ACTH. When the source of the excessive secretion is
the pituitary gland, the standard approach is to perform an endoscopic endonasal
trans-sphenoidal exploration, with excision of the tumor, if found. This surgical procedure is
demanding and should only be performed in centers with extensive experience, to minimize
operative risks, reduce the possibility of remission, and maintain other pituitary functions.
Bilateral adrenalectomy by overt or laparoscopic approach is the most useful treatment in
patients with AIMAH and hormonal hypersecretion.(21, 22) However, in patients with
moderately increased hormonal production, unilateral adrenalectomy is proposed as a safe
and effective alternative; it is expected that, as the cell mass increases in the contralateral
adrenal, a second adrenalectomy may be necessary.(23, 24)
In this report, we presented 23 cases of that were diagnosed with AIMAH. High and low dose
dexamethas failed to suppress cortisone secretion on suppression tests and ACTH levels were
low in all cases. Bilateral massively enlarged adrenal glands could be seen on CT scan, and all
were bilateral adrenal macronodular hyperplasia confirmed by pathological examination.
Consistent with previous case report content, our result showed AIMAH had unique
endocrinological, radiological and pathological features. Diagnosis of AIMAH mostly derived
from pathological examination. Long term remission can be achieved by unilateral
adrenalectomy. Contralateral adrenalectomy should be performed in case of recurrence when
followed with periodical examination of symptom and serum concentration of cortisol.
Conflict of interest
The authors declare there is no conflict of interest.
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Figure legend
Figure 1 CT result of one patient, whose bilateral adrenal demonstrated irregular nodular
masses after enhancement.
Figure 2 Histopathological analysis of the resected adrenal specimen.
Figure 3 Macroscopic appearance of the adrenal glands of a patient.