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Miami, Florida. Hepatocellular ... Center/University of Miami School of Medicine, Miami, FL. Requests ... 3-month basis, using a-fetoprotein and ultrasound.
HEPATOCELLULAR CARCINOMA: AN EMERGING PROBLEM WITH HEPATITIS C Lennox Jeffers, MD, FACP Miami, Florida

Hepatocellular carcinom (HCC) is emerging as a major problem in the United States, primarily due to the development of liver cancer in patients with cirrhosis secondary to the hepatitis C virus. The diagnosis of HCC in patients with underlying cirrhosis can be achieved at an early stage if appropriate diagnostic measures are pursued by primary care physicians and gastroenterologists. African Americans are particularly vulnerable in developing HCC since their response to current therapy for chronic hepatitis C is less than optimal. (i Natl Med Assoc. 2000;92:369-371.)

Key words: hepatocellular carcinoma + cirrhosis * hepatitis The development of hepatocellular carcinoma (HCC) in the cirrhotic and noncirrhotic liver varies according to geographic regions. However, worldwide, it is the most common tumor in males, with a high prevalence in Asia and Southern Africa. Hepatitis B and C are the most common risk factors. Other risk factors include alcohol, hemochromatosis, a-antitrypsin deficiency, glycogen storage diseases, estrogens and androgens, and unknown etiologic agent's.' In the United States and Western Europe, hepatitis C with cirrhosis appears to be the predominant factors leading to the development of HCC. Alcohol along with hepatitis C virus (HCV) in a cirrhotic patient will lead to the rapid development of HCC. It is expected that the number of cases of HCC in the United States will increase from 5,000 per year to 15,000 in 10 to 15 years.' © 2000. From the Department of Hepatology, Miami VA Medical Center/University of Miami School of Medicine, Miami, FL. Requests for reprints should be addressed to Dr. Lennox Jeffers, Department of Hepatology, Miami VA Medical Center/University of Miami School of Medicine, 2500 NW, 12th Ave., Suite 110 1, Miami, FL 33136. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION

In most cases of HCC, the progression from hepatitis C to HCC is a slow process. The course is about 25 to 30 years from the initial HCV infection to the development of HCC. At the Miami VA Medical Center we have seen patients as early as 7 years after transfusion develop HCC. We believe that alcohol consumption definitely decreases the time period from hepatitis to HCC. The combination of alcohol and hepatitis C in the cirrhotic patient may increase the progression to as little as 10 years. The probability of the development of liver cancer in patients with long-term cirrhosis has been studied extensively in Italy. It has been shown that after 5 years of compensated cirrhosis, about 7% of patients will develop HCC, and after 10 years, about 14% of patients.2 How do we make the diagnosis of HCC in a patient with chronic hepatitis C and cirrhosis? The diagnosis is based on the combination of clinical and laboratory features together with radiologic and histopathologic findings. Mass screening for selected patients with a-fetoprotein and abdominal ultrasound is warranted in the United States, although it is not practiced based on the lack of supporting data. In Japan, on the other hand, patients with cirrhosis of the liver are screened on a 3-month basis, using a-fetoprotein and ultrasound. The a-fetoprotein test is commonly utilized in 369

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Figure 1. A large hypervascular mass in the right lobe of the liver. Note neovascularity of tumor and the potential danger of a needle biopsy. the United States to assist in the diagnosis; however, it lacks specificity. Individuals with levels greater than 400 ng/mL, and a mass in the liver should be considered as having HCC despite the lack of biopsy evidence. a-Fetoproteins may be normal despite the presence of HCC in about 30%-40% of patients with cirrhosis of the liver and HCC. One should suspect HCC in cirrhotic patients who decompensate, for example with variceal bleeding, development of ascites, hepatic encephalopathy, or blood in the peritoneal cavity. Hemoperitoneum is not an unusual complication of patients with HCC (Fig. 1). Some patients may have a paraneoplastic presentation, i.e., elevated calcium and hemoglobin and a decrease in glucose. These are usually patients with advanced end-stage cirrhosis. A retrospective study was conducted from January 1994 to December 1997 to evaluate the prevalence of HCV and hepatitis B virus (HBV) and alcohol in patients with HCC. Patients with a diagnosis of HCC were included from the University of Miami Center for Liver Diseases and Huntington Memorial Hospital in Southern California. 44% of the patients were Caucasians, 31% Asians, 20% Hispanics, 3% African Americans, and 2% others. The most common etiologies were HCV 41% and HBV 25%. Alcohol and HCV accounted for 10% of the patients, and unknown etiologies accounted for 24%. Hepatitis B was more prevalent among African Americans.3 There are a variety of treatments for HCC, including nonsurgical therapies, which include chemoembolization, alcohol injection, cryosurgery, microwave therapy, and systemic chemotherapy. Surgical resection is a viable option in patients with single lesions and well compensated cirrhosis. However, in the United States, solitary lesions are a 370

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Figure 2. Single tumor nodule in the right lobe in a patient with hepatocellular carcinoma. rarity, which is probably secondary to the lack of routine screening. Nevertheless, a single lesion less than 5 cm in the left lobe in patients with good synthetic function or a peripheral lesion in the right lobe, may be a potential surgical candidate (Fig. 2). Solitary small lesions centrally located in the right lobe should be treated with orthotopic liver transplant (OLT). Liver transplantation has become the treatment of choice in patients with three or less lesions in the liver of less than 3 cm in size. Metastatic liver disease or portal vein involvement is an absolute contraindication for OLT. Mazzafero et al.4 demonstrated the effectiveness of OLT in patients with HCC and HCV utilizing the above criteria and found there was no difference in survival in patients with HCC and those without HCC and cirrhosis. What about screening for HCC? Previous studies have focused on hepatitis B infection; two consensus panels have convened in the United States and Italy to draft recommendations. They suggested that cirrhotic patients be screened every 6 months with a-fetoprotein and ultrasound. Patients who are surface-antigen-positive and have a family history of HCC should be screened annually. There is considerable debate about cost-effectiveness of screening HCV patients who have cirrhosis. It is difficult at this particular time to undertake screening because of reimbursement issues with insurance companies and Medicare, which will not allow a-fetoprotein testing on such a frequent basis (i.e., every 3 months). In addition, there are probVOL. 92, NO. 8, AUGUST 2000

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lems surrounding the authorization of ultrasounds by most insurance carriers.

Americans with HCC, because they do not respond to current available therapy.

CONCLUSION

REFERENCES

We know that the hepatitis C viral RNA is found in cancerous and noncancerous tissue, although we do not know the exact mechanism by which individuals develop HCC. The underlying factor is always cirrhosis of the liver in patients with hepatitis C, and a subset of patients with HCV cirrhosis and alcohol as a cofactor will progress rapidly to develop HCC. New treatments are needed for patients with chronic hepatitis C who also have cirrhosis. Studies should be undertaken to evaluate the utility of a interferon on a long-term basis in compensated cirrhotic patients to prevent the development of HCC. Particular attention should be placed on African

1. Di Bisceglie A. Malignant neoplasms of the liver. In: Schiff ER, Sorrell MF, Madder WC, eds. Schiffs Diseases ofthe Liver, 8th ed. Philadelphia, PA: Lippincott-Raven Publishers; 1999:1281-1304. 2. Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463-472. 3. Reddy KR, Jeffers LJ, Tong M, et al. Comparison of etiologic characteristics of Asian and Hispanic populations with hepatocellular carcinoma from Los Angeles and Miami. In: Book of Abstracts-NIH Single Topic Conference on Hepatocellular Carcinoma, March 27-29, 1998, St. Louis, MO. 4. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. NEnglJMed. 1996;334:693-699.

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