Adrenal Tumors in Patients With Chronic Hepatitis C

We report 3 patients with chronic hepatitis C associated with adrenal adenomas, 2 of which were functional. Hepatitis C can be associated with insulin resistance, which leads to hyper-insulinemia, and with increased serum levels of insulin growth factor (IGF); both substances have been reported to increase adrenal fasciculate cell growth in vitro. Thus, the hepatitis C virus may trigger adrenal tumorigenesis, which, in some cases, may lead to hyperaldosteronism. Accordingly, hyperaldosteronism may be one of the extrahepatic manifestations of chronic hepatitis C.

Infection with the hepatitis C virus is one of the most common causes of chronic liver disease. In addition to liver disease, chronic hepatitis C can be associated with extrahepatic manifestations, including mixed cryo-globulinemia, glomerulonephritis, porphyria cutanea tarda, lichen planus, Sjögren syndrome, and, recently, cardiomyopathy.^1,2 In this report, we describe a series of 3 patients with chronic hepatitis C who were referred to the hepatologist for evaluation and treatment, and in whom adrenal adenomas were diagnosed. All relevant laboratory findings are reported in Table 1.

Table 1.

Summary of Relevant Clinical Work-Up of Patients

				Hepatitis C			Adrenal tumor investigations at diagnosis
Patient	Age (years)	Gender/race	Risk factors for hepatitis C	Viral load (Log IU/mL)	Genotype	Adrenal gland findings by CT scan	A (ng/dL)	PRA (ng/mL/hr)	A:PRA ratio
#1	54	Male/African American	Intravenous drug use	6.44	1A	Right mass, <1 cm	84	0.2	420
#2	78	Female/White	Blood transfusions	6.53	1A	Left mass, 2.4 cm	3	2.98	1.01
#3	43	Female/White	Intravenous drug use	7	1A	Left nodular adrenal lesion/left adrenal mass, 1.9 cm	32	<0.1	320

A=

aldosterone

CT=

computed tomography

PRA=

plasma renin activity

Case series

Patient #1

A 54-year-old African-American man was referred to the hepatologist for treatment of chronic hepatitis C, which had not responded to standard therapy 12 years prior to the evaluation. His risk factor for hepatitis C virus infection had been remote intravenous drug use. He had had hypertension for at least 3 years that had been managed with a calcium channel and a beta blocker, an alpha 2 adrenergic agonist, and an angiotensin-converting enzyme (ACE) inhibitor, diabetes mellitus managed with a second-generation sulfonylurea, and schizophrenia managed with olanzapine. During the process of evaluation for hepatitis C treatment, the patient was admitted for treatment of hypokalemia. Investigations for hypertension associated with hypokalemia revealed findings consistent with hyperaldosteronism (see Table 1). An abdominal computed tomography (CT) scan revealed a right adrenal tumor less than 1 cm in size. The administration of spironolactone was associated with gradual correction of hypokalemia and control of blood pressure. The patient underwent laparoscopic resection of the adrenal tumor associated with resolution of his hypokalemia. The serum aldosterone concentration after surgery was 3 ng/dL. The patient remained hypertensive and was treated with a diuretic and an ACE inhibitor.

Patient #2

A 78-year-old white woman was admitted to the hospital because of pneumonia associated with a loculated empy-ema. She reported having hypertension for many years, which had been managed by an ACE inhibitor and a diuretic, and chronic obstructive pulmonary disease. The patient had received blood transfusions 30 years prior to admission. As part of her evaluation for pneumonia, she underwent a chest CT scan, which revealed a vascular lesion in the left lobe of the liver suggestive of hepatocellular carcinoma. A CT scan of the abdomen confirmed the presence of a vascular mass suggestive of hepatocellular carcinoma, which was supported by the presence of a serum alpha-fetoprotein concentration of 510.8 ng/mL. In addition, a 2.4-cm adrenal tumor was detected. Liver disease work-up revealed chronic hepatitis C (see Table 1). The patient's plasma aldosterone concentration, plasma renin activity, and plasma renin activity ratio were not consistent with hyperaldosteronism. The patient did not wish to pursue evaluation of the liver mass at the time of the admission but agreed to follow-up at a later time.

Patient #3

A 43-year-old white woman was referred to the clinic for evaluation of chronic hepatitis C. She reported having hypertension for 17 years and had been treated in various emergency rooms for hypokalemia. Her risk factor for chronic hepatitis C had been previous intravenous drug use. Due to the suspicion of primary hyperaldosteronism, relevant investigations were requested. The patient underwent a CT scan, which revealed a left adrenal tumor suggestive of adenoma. Her serum aldosterone concentration was 32 ng/dL, and her plasma renin activity was less than 0.1 ng/mL/hr, yielding an aldosterone:plasma renin activity ratio of 320, which was consistent with hyperaldosteronism (see Table 1). The patient was lost to follow-up, and efforts to find her were unsuccessful. One year later, she was hospitalized because of weakness associated with uncontrolled hypertension and hypokalemia. A CT and magnetic resonance imaging scan of the abdomen confirmed the diagnosis of an adrenal tumor. Adrenal vein sampling indicated that the left adrenal was the source of the hyperaldosteronism. The patient underwent resection of the tumor. Postoperatively, her serum aldosterone concentration decreased to 3 ng/dL and her serum potassium level was within normal limits. Her blood pressure was normal during the immediate perioperative period but subsequently required medications to be controlled. She was discharged on a calcium channel blocker.

Discussion

We describe 3 patients with chronic hepatitis C and adrenal tumors, 2 of which were associated with hyper-aldosteronism. Two of the patients had reported a history of hypertension and hypokalemia for several years. In 2 patients, the hypokalemia had been of sufficient magnitude that admissions to the hospital were required.

Two of the patients (patients #1 and #3) had used intravenous drugs, which was the identified risk for hepatitis C infection, and which preceded the diagnosis of hypertension. Patient #2 had received blood transfusions 30 years prior to the diagnosis of chronic hepatitis C, which might have been the mode through which she contracted the infection. In all of the patients, the activity identified as the likely risk for hepatitis C virus infection, and hence the infection, preceded the diagnosis of hypertension by several years, suggesting that the patients had already contracted the hepatitis C virus infection and that the virus might have stimulated the development of the adrenal adenoma.

In patient #2, the adrenal tumor had not been associated with hyperaldosteronism. Indeed, 70% of adrenal tumors are not functioning, and according to reported small series of patients, less than 20% of adrenal tumors followed over time become functional.³ The possibility of an adrenal metastasis in this patient, in whom hepatocel-lular carcinoma was suspected, has to be considered in this discussion; however, the appearance on CT was most consistent with an adenoma, and the size (ie, less than 4 cm) was most suggestive of a benign tumor.³

The mechanism that mediates tumorigenesis and aldosterone production by adrenal adenomas is not known. Hepatitis C virus, however, has tropism for glandular tissue, as evidenced by its ability to cause hepatitis; thus, it is possible that what makes the virus thrive in the liver may be at play in its potential role in the formation of adrenal adenomas. In this regard, the immunoreactivities of IGF-I, insulin, and their respective receptors were reported to be expressed by adrenal tumors. In a published series of 23 tumors, 48% of adrenal adenomas expressed IGF-I and 56% expressed IGF-R immunoreactivities.⁴ In addition, insulin and insulin receptor immunoreactivities were detected in 69.5% and 100% of tumors, respectively.⁴ These results may suggest that IGF-I and insulin may mediate, to some degree, the growth of adrenal tumors. This idea may be relevant to the association of hepatitis C and adrenal tumors because it has been reported that serum levels of IGF are increased in patients with chronic viral hepatitis, including hepatitis C. Furthermore, insulin resistance, which has been reported in patients with chronic hepatitis C, is associated with an increase in secretion of insulin.^5-7 Both insulin and IGF-I are growth factors that have been associated with increased cell growth in a culture system of adrenal fasciculate cells.⁸ These observations may suggest that IGF-I, and perhaps insulin, can trigger adrenal tumorigenesis.

A genetic predisposition to develop adrenal tumors in association with chronic hepatitis C may be required; however, the small number of patients in the series does not allow for a strong statement in regard to predisposing factors.

summary

We report a case series of 3 patients with chronic hepatitis C and unilateral adrenal adenomas, of which 2 were functional. Primary hyperaldosteronism may be one of the extrahepatic manifestations of chronic hepatitis C virus infection and should lead to an expeditious diagnostic investigation to exclude this viral infection. The potential effect of interferon and ribavirin treatment, which is the standard of care for chronic hepatitis C, on adrenal tumorogenesis is unknown.