Reviews and Overviews

Neuropsychiatric Symptoms Associated With Hepatitis C and Interferon Alpha: A Review Eric Dieperink, M.D. Mark Willenbring, M.D. Samuel B. Ho, M.D. HEPATITIS C AND INTERFERON DIEPERINK, WILLENBRING, AND HO

Objective: Neuropsychiatric symptoms are commonly associated with chronic hepatitis C virus infection, its sequelae, and its treatment. In particular, interferon, a primary component of treatment for chronic hepatitis C, has been strongly associated with depressive symptoms. This review summarizes current knowledge about the etiology, course, and treatment of neuropsychiatric problems associated with hepatitis C and interferon alpha (IFN-α) treatment. Method: Studies were identified by computerized searches, and further references were obtained from bibliographies of the reviewed articles. Results: Chronic infection with the hepatitis C virus is a common and growing problem, often affecting persons with psychiatric and substance use problems.

Although changes in cognition, mood, and personality have been described in association with hepatitis C and with IFN-α treatment, there has been little systematic study of these changes. Conclusions: Psychiatrists should become familiar with the clinical spectrum associated with hepatitis C virus infection as well as the neuropsychiatric symptoms related to hepatitis C and IFNα treatment. More studies are necessary to define the neuropsychiatric syndromes associated with this population and to find possible effective treatments. Furthermore, research is needed so that patients with psychiatric problems are not excluded from effective treatments for this growing medical problem. (Am J Psychiatry 2000; 157:867–876)

T

he hepatitis C virus is a major public health problem. Although the incidence of new infection is declining, a large asymptomatic population with chronic hepatitis C exists. Over the next 10–20 years many of these patients will develop clinical symptoms. It is estimated that 4 million Americans are currently infected by the virus, and in 2000 more people will die from hepatitis C than from AIDS. Management of chronic hepatitis C infection involves monitoring liver function tests, liver biopsy, and education regarding the transmission and progression of the disease. Treatment with interferon alpha (IFN-α) is reserved for the patients who are likely to progress to cirrhosis.

Neuropsychiatric symptoms are widely reported in association with both hepatitis C and IFN-α treatment. Furthermore, hepatitis C disproportionately infects psychiatric patients. Fearing psychiatric vulnerability, practitioners may withhold IFN-α inappropriately. It is important that psychiatrists become familiar with hepatitis C infection and the psychiatric management of its complications. In this article we examine the available studies regarding neuropsychiatric symptoms in chronic hepatitis C infection and IFN-α treatment. Studies were identified by computerized searches, and further references were obtained from bibliographies of the reviewed articles. We first describe the epidemiology and natural history of the hepatitis C virus, treatment with IFN-α, and the associated neuroAm J Psychiatry 157:6, June 2000

psychiatric symptoms. We then review the mechanisms of interferon-associated neuropsychiatric symptoms, with particular attention to depressive symptoms. Finally, we discuss treatment and future research directions.

Epidemiology of Hepatitis C The incidence of infection with the hepatitis C virus in the United States peaked in 1989 with 175,000 new cases per year (1). The current incidence is approximately 30,000 cases per year. The prevalence of serum antibodies to the hepatitis C virus in the United States (1%–2%) is similar to the rates in other developed countries, but rates vary elsewhere, with a maximum prevalence of 9.6%–13.6% in North Africa (2). Before effective screening of blood donors, transfusions accounted for 15%–20% of newly acquired hepatitis C infections. The risk of hepatitis C transmission in the United States through transfusion is now estimated at 1 in 103,000 (3). Intravenous drug use is the most common route of transmission and currently accounts for the majority of new cases (4). Hepatitis C infection is frequently found in 50%–80% of intravenous drug users (1). In populations with alcoholic liver disease, the frequency of antibody to hepatitis C virus has been reported to be as high as 46%, even when individuals with intravenous drug use and those with a history of blood transfusions are excluded (5). Alcoholics without liver disease

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have a hepatitis C rate slightly higher than that in the general population, approximately 4.8% (6). Mother-to-infant transmission also occurs, although the risk is 6% or less (1). Other risk factors associated with transmission of hepatitis C include multiple sexual partners and occupational exposure (needle-stick injury). The rate of infection with no identified risk factor is quite low, approximately 2% (7).

Clinical Spectrum and Natural History of Hepatitis C Most acute infections with the hepatitis C virus are asymptomatic, despite elevations in liver enzyme levels. Approximately 30% of the people with newly acquired hepatitis C infection develop symptoms, such as malaise, loss of appetite, and jaundice. Only rarely does acute hepatitis C cause fulminant liver failure. The acute episode resolves in approximately 15% of patients, while the rest develop chronic hepatitis (1). Chronicity is defined as evidence of persistent infection for at least 6 months after exposure to the virus. In the chronic phase of hepatitis C, 20% of infected persons have clinical liver disease and complain of fatigue and malaise, 50% are asymptomatic but have increased liver enzyme levels, and 30% are asymptomatic and have normal liver enzyme levels (1). The progression of chronic hepatitis C is slow; often the first clinical indication of chronic infection is liver failure, hepatic encephalopathy, jaundice, or ascites. In the United States, hepatitis C currently is the leading cause of chronic liver disease and the most common indication for liver transplantation (8). Cirrhosis develops in approximately 20% of chronic carriers, and subsequent liver failure, portal hypertension, and hepatocellular carcinoma may develop. Once cirrhosis develops, the risk of hepatocellular carcinoma increases, occurring at a rate of approximately 1%–4% per year (9). A variety of extrahepatic manifestations have been associated with hepatitis C, including a mixed cryoglobulinemia and glomerulonephritis. Other associated syndromes include porphyria cutanea tarda, Sjogren’s syndrome, and hypo- and hyperthyroidism (10). It is not clear how hepatitis C is related to the pathogenesis of these conditions or how frequently they occur. Clinicians should be aware of the varied symptomatic complaints and possible clinical presentations of hepatitis C, so that the diagnosis is not overlooked. Several studies have shown that heavy drinking of alcohol worsens hepatic injury and may accelerate progression of hepatitis C infection (11). However, the threshold for injury from alcohol is not determined, so it is unclear whether light or moderate drinking accelerates liver damage. Unfortunately, excessive drinking appears to be common among individuals infected with hepatitis C. Lee et al. (12) found that 29% of individuals with hepatitis C reported heavy alcohol use and an additional 34% con-

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sumed alcohol regularly. Alcohol not only increases the risk of cirrhosis but also enhances the risk of hepatocellular carcinoma.

Neuropsychiatric Symptoms Associated With Hepatitis C Neuropsychiatric symptoms have been reported in association with both hepatitis C and IFN-α treatment. During both the acute and chronic stages of hepatitis C, malaise, fatigue, and depressive symptoms are frequently reported. Among 309 drug users not receiving substance abuse treatment (13), depressive symptoms were reported in 57.2% of those with hepatitis C, compared to 48.2% in patients without the hepatitis C virus, as determined with the Center for Epidemiologic Studies Depression Scale (14). The group with hepatitis C also scored lower on the subscale for positive affect and higher on the subscale for somatic/retarded activity. However, only the difference in positive affect was statistically significant. Malaguarnera and colleagues (15) found elevated mean scores, representing “mild depression,” on the Zung Self-Rating Depression Scale (16) before IFN-α treatment. In patients with and without hepatitis C who were awaiting liver transplantation, Singh et al. (17) found significantly more mood disturbance, tension and anxiety, confusion and bewilderment, and pain and higher Beck Depression Inventory (18) scores in the patients with hepatitis C, none of whom had been treated with interferon. Others (19–22) have reported depression in 2%–30% of hepatitis C patients. In a retrospective review, Lee et al. (12) reported that 24% of 359 untreated hepatitis C patients were depressed and that of those 24%, two-thirds required antidepressant treatment. In this study group, depression was the disorder most commonly associated with chronic hepatitis C.

Treatment of Hepatitis C IFN-α has been the mainstay of treatment for chronic hepatitis C. Interferons are used to treat a wide variety of illnesses, including several malignancies, viral illnesses, and multiple sclerosis. Despite interferon’s varied uses, no other patient population as potentially large as that with hepatitis C has required it for treatment. Treatment of hepatitis C is aimed at reducing inflammation and liver cell damage, thus preventing cirrhosis and hepatocellular carcinoma (23, 24). However, IFN-α alone produces a response in only 40% of the patients with hepatitis C, as measured by the serum concentration of alanine aminotransferase and the presence or absence of hepatitis C RNA in serum. Furthermore, more than 90% of patients relapse soon after stopping therapy (25). Recently, a synthetic nucleoside analogue, ribavirin, has been used in combination with IFN-α (26, 27), and this combination improves outcomes in both initial treatment and retreatment after relapse following monotherapy. Am J Psychiatry 157:6, June 2000

DIEPERINK, WILLENBRING, AND HO

These improved response rates are likely to result in increases in the numbers of patients seeking and receiving treatment. Physicians are also more likely to attempt to keep patients in treatment in spite of side effects such as depression.

Quality of Life With Hepatitis C and Interferon Treatment Several studies have shown that patients with chronic hepatitis C have a reduced quality of life (28–31). Reduction in quality of life is not associated with how the infection is acquired or with the severity of the liver disease (30, 31). Although a history of intravenous drug use is independently associated with reduced quality of life, patients without a history of drug use still show a reduction in quality of life. Quality of life for patients with chronic hepatitis C appears to be worse than for patients with hypertension and comparable to that for patients with type II diabetes (29, 31). The impact of IFN-α treatment is less clear. Hunt et al. (20) prospectively followed patients with hepatitis C who were treated with IFN-α and found that the health status of these patients was similar to that of the general U.S. population and did not change during IFN-α therapy. In contrast, Bonkovsky et al. (31), in a much larger study, showed that successful therapy with IFN-α improves quality of life and that the degree of improvement is related to sustained virological or biochemical response to treatment. However, the patients were not blinded to their state of infection. Further study is needed to establish whether eradication of hepatitis C improves quality of life.

TABLE 1. General Medical Symptoms Associated With Interferon Alphaa Condition Flu-like symptoms Headache Fatigue/asthenia Malaise Arthralgia Musculoskeletal pain Fever Rigors Gastrointestinal symptoms Anorexia Dyspepsia Vomiting Nausea Diarrhea Abdominal pain Weight loss Respiratory symptoms Cough Dyspnea Pharyngitis Sinusitis Rhinorrhea Dermatological symptoms Alopecia Pruritus Rash Dry mouth Hematologic disorders Anemia Thrombocytopenia Granulocytopenia High triglyceride levels Hypo- or hyperthyroidism Immune disordersd

Approximate Prevalence (%) 27–67 39–90 5–10 9–36 26–32 10–20 10–20 13–19 5–10 5–10 18–35 13–26 15–20 5–10 5–10 5–10 5–10 7–14 2–5 5–28 5–10 5–10 2–5 1b < 3c