Toward prevention of hepatocellular carcinoma developing in chronic hepatitis C

Abstract

See article on page 789 Worldwide, 170 million people are infected with hepatitis C virus (HCV) persistently. Like hepatitis B virus (HBV) that infects approximately 350 million individuals in the world, HCV is transmitted parenterally, typically by transfusions and illicit intravenous drugs. The differences between these two hepatitis viruses are that HBV infection, except when introduced to hosts in infancy, goes on to become chronic in only a few percent, while HCV infection evolves into being chronic much more frequently and persists in approximately 70% of the infected. In contrast to chronic hepatitis B that is mostly self-limited, chronic hepatitis C is an ever progressive disease. Consequently, hepatocellular carcinoma (HCC), the most dreadful sequel of persistent hepatitis virus infection, develops much more often in individuals chronically infected with HCV than HBV. Unlike HBV, which is a DNA virus and integrated into the host genome, HCV, being an RNA virus not reverse-transcribed to DNA, is hardly carcinogenic per se. Hence, HCC almost always develops in the background of chronic hepatitis C and associated liver cirrhosis in the long run. It is estimated to take 30 years before HCC develops in patients who are followed up and who are presumed to have contracted the infection by transfusions.1 In comparison with other malignancies, HCC is unique in that the individuals at risk for developing it can be identified and followed closely; they are persistently infected with HBV or HCV and suffering from chronic hepatitis. Moreover, therapeutic interventions for preventing HCC are possible by either exterminating hepatitis viruses or controlling the inflammatory process leading to hepatocarcinogenesis. Hepatocellular carcinoma associated with hepatitis virus infections is most prevalent in Asia and Africa. Experiences with recognition and prevention of HCV-associated HCC, which have accumulated in Japan during the past 30 years, are hoped to help plan strategies in Western countries where HCV infection prevails at the present and will advance into HCC in the foreseeable decades. In Japan, HCC occurs at an incidence of 35 cases per 100 000 people annually at present, which is much higher than that in Europe and the United States of America. However, the incidence of HCC was not so high 30 years ago even in Japan. Figure 1 depicts the annual death of patients caused by HCC, estimated from the national reports issued biyearly. A clear trend for the increase in death because of HCC is seen since 1975. Etiologic analysis became possible from the mid-1970s for HBV, and as of 1990 for HCV, which had been classified in a non-A, non-B category until then. Increasing incidence of death because of hepatocellular carcinoma in Japan. (▪) Represents the cases positive for hepatitis B surface antigen (HBsAg) and () represents the cases positive for antibodies to hepatitis C virus (anti-HCV). The cases negative for both HBsAg and anti-HCV are presented by (□). Over the past 25 years, the proportion of HBV infection, identified by hepatitis B surface antigen (HBsAg) in serum, has stayed constant and accounted for less than five deaths caused by HCC per 100 000 people/ year. A rapid biyearly increase since 1975 is ascribable to the etiology that is unrelated to HBV, although a role of HBV is not to be excluded in the patients seronegative for HBsAg. Serologic tests for HCV infection by antibody to HCV (anti-HCV) and HCV-RNA introduced since 1990 have disclosed that by far the highest number of cases negative for HBsAg were infected with HCV. Today, markers of ongoing HCV are detected in approximately 80% and those of HBV in approximately 20% in HCC patients in Japan; the etiology remains unknown in only a few percent. Taken together, HCV is reasonably considered to be responsible for the rapid biyearly increase of death caused by HCC ever since 1975 in Japan. The reason why HCV has spread in the past, eventuating in a high incidence of HCV-associated HCC today, is not yet fully established. According to the reasoning by Dr Hiroshi Yoshizawa (pers. comm., 2000) of the University of Hiroshima, the following scenario is likely. He postulates an HCV epidemic in a restricted population in Japan that started just after the end of World War II in 1945. Intravenous injections with methamphetamine was popular among ex-soldiers to keep them awake and promote their fighting spirit in the war. It would not have taken much time for them to be infected with HCV, with transmission expected from HCV infection among illicit intravenous drug users. The subpopulation kept selling blood, so as to support themselves and secure intravenous drugs, which unselectively transmitted HCV infection to the recipients of transfusions. In that age, tuberculosis prevailed in Japan, and plastic surgery was popular; it involved transfusions for dissemination of HCV among the patients with pulmonary tuberculosis. In addition, HCV is considered to have spread by medical and paramedical practices by means of contaminated needles and syringes until recently. Besides all these transmission routes, the post-transfusion non-A, non-B hepatitis was not contained until November, 1989 when the exclusion of blood units positive for anti-HCV was introduced in Japan; it was earlier than any other countries in the world. Now that post-transfusion hepatitis C is completely prevented, and with a fortunate uncommon abuse of illicit drugs, de novo HCV infection has become infrequent in Japan. Dr Yoshizawa predicts that the incidence of HCV-associated HCC will reach a plateau by the year 2010, and then decline thereafter. How and when HCV infection started to prevail in Europe and the United States of America is not known. In the wake of what is ongoing in Japan, it is not difficult to speculate that turmoil with the Vietnam War during the 1960s would have had some impact on a rapid spread of HCV in the United States of America. Should that be the case, the experiences with HCV-associated HCC in Japan would be mirrored in the United States of America, with an expected time lag of approximately 20 years (Fig. 1). There are two means of preventing HCC that is associated with HBV or HCV infection. One is to halt the invasion at the coast, which is being accomplished for HBV infection. In Asia, the persistent carrier state of HBV in immune-competent individuals is established by the perinatal transmission of HBV to babies from mothers who are seropositive for hepatitis B e antigen (HBeAg). Since 1986, the Japanese Ministry of Health and Welfare launched a national program to prevent the perinatal HBV infection by protecting the babies born to HBeAg-positive carrier mothers with a combined hepatitis B immune globulin and hepatitis B vaccine. As a consequence, the perinatal HBV transmission decreased from approximately 4000 cases to merely a few hundred cases per year nowadays; the immunoprophylaxis does not work on approximately 4% of babies who receive it because of transplacental infection in utero. The screening of blood units for HBsAg was started in 1972, and it has consequently decreased the incidence of post-transfusion HBV infection in Japan dramatically. The residual risk of transmitting HBV by transfusions has been curtailed by implementing tests for hepatitis B core antibodies (anti-HBc) in 1989, as well as tests for HBV-DNA by using molecular biological techniques starting at the turn of the millennium. Both these tests can identify blood donors in the ‘window’ period of HBV infection before serological markers such as HBsAg and anti-HBc appear in the circulation. Likewise, the screening of blood donors for anti-HCV since 1989, and better still for HCV-RNA initiated very recently, has been most efficient and decreased the risk of post-transfusion hepatitis C infinitely to zero. At present, however, there are no means of preventing perinatal transmission of HCV that occurs in approximately 4% of babies born to carrier-mothers who are not coinfected with human immunodeficiency virus type 1. Passive immunoprophylaxis with anti-HCV immunoglobulins and active immunoprophylaxis with hepatitis C vaccines are eagerly awaited, not only to prevent perinatal transmission, but also for the protection of groups with increased professional or recreational risk of contracting HCV infection. The other approach for prevention of HCC, associated with HBV or HCV infection, is directed towards patients with chronic viral hepatitis who have already been infected and run a high risk of developing HCC. The mechanism of how HCC develops in patients with chronic viral hepatitis/cirrhosis is not known. The present consensus is that necroinflammatory changes in the liver of patients with chronic viral hepatitis endows it with a ‘hypercarcinogenic state’,2 probably through regenerative force and oxidative injury to host DNA in hepatocytes. Hence, two ways of preventing HCC in the high-risk population can be envisaged, one of which is radical, while the other is palliative. Ideally, HBV or HCV should be eradicated from the patients for radical cure of chronic viral hepatitis. This can be achieved by interferons in concert with lamivudine for HBV, and in combination with ribavirin for HCV. Accumulating lines of evidence indicate that HCC occurs rarely, if ever, in the patients who have cleared HCV from their sera.3 A current impediment to this protocol is that not all patients respond to these antiviral therapies by clearing viral infections. A complete and sustained response to antiviral therapies is accomplished in one-half of the patients infected with HCV, at best. Hence, attending physicians are left with the other half of patients in whom HCV infection continues accompanied by active liver diseases along with ongoing necroinflammatory changes and increasing fibrosis. Licorice is a crude extract from the root of Glycyrrhiza glabra, and has been a popular Chinese medicine with a history going back to the BC era. The active principle of licorice is glycyrrhizin, which is composed of one molecule of glycyrrhetinic acid and two molecules of glucuronic acid. The medicine has been commercially available as Stronger Neo-Minophagen C (SNMC; Minophagen Pharmaceutical Co., Tokyo, Japan) for the past 60 years, as an aqueous solution containing 40 mg glycyrrhizin supplemented with glycine (400 mg) and cysteine (20 mg) in a 20 mL ampoule. It has mainly been used for the treatment of allergic diseases, represented by chronic dermatitis and urticaria. Since the late 1960s, SNMC has gained increasing attention for its possible use in patients with chronic hepatitis. In 1977, Suzuki et al. conducted the first prospective double-blind and placebo-controlled trial for the efficacy of SNMC on a cohort of 133 patients with chronic hepatitis in Japan, most of whom were infected with HCV in retrospect.4 Their results were introduced to the Western medical society in 1983. They found that SNMC significantly reduces the levels of alanine aminotransferase (ALT) and γ-glutamyl transpeptidase in the patients who received SNMC during 4 weeks of the trial. The effects of SNMC were transient, however, and liver enzymes swiftly returned to pretreatment levels after the withdrawal of SNMC. There is an apparent dose-effect of SNMC in nomalization of liver function tests. A higher efficacy in decreasing ALT levels is observed in patients with chronic hepatitis C who received 100 mL (five ampoules) than those who received 40 mL (two ampoules) of SNMC intravenously.5 A prospective trial starting with a daily injection of 100 mL SNMC has been conducted by Arase et al.6 in a liver clinic in Japan headed by Dr Hiromitsu Kumada, for a timespan extending to 15–20 years. They gave SNMC to 84 patients for whom a daily intravenous injection was feasible, and oral herbal medicines to the other 109 patients who did not have handy facilities for a daily injection around them. They found that the patients who received SNMC ran a 2.5-fold lower risk of developing HCC than those who did not receive SNMC. Therefore, they have demonstrated the ability of SNMC to prevent HCC, most likely by controlling or retarding necroinflammatory and fibrotic processes that occur with continuing HCV infection in the liver. It is not known how SNMC inhibits the progression of chronic hepatitis C. It does not seem to have antiviral effects, because HCV-RNA titers in serum do not change appreciably in patients who receive it.7 Two distinct actions of SNMC are postulated. One is its immediate effects capable of decreasing ALT levels within a matter of hours, and may be ascribed to the cytoprotective capacity of glycyrrhizin. The other pharmaceutical effects include an anti-inflammatory activity of glycyrrhetinic acid, representing the final metabolite of glycyrrhizin. Orally administered glycyrrhizin is converted to glycyrrhetinic acid in the intestine and then absorbed. The unavailability of glycyrrhizin in the circulation would be responsible for less efficacy of orally than parenterally administered glycyrrhizin preparations. Pseudo-aldosteronism has long been noted in individuals on a large dose of glycyrrhizin. The mechanism how it induces pseudo-aldosteronism was determined only recently.8 Glycyrrhetinic acid, as well as the metabolite of glycyrrhizin with one glucronic acid,9 interferes with the enzyme that catalyzes the conversion of cortisol to cortisone. Resulting excessive cortisol stimulates the mineralocorticoid receptor leading to pseudo-aldosteronism. Therefore, in principle, glycyrrhizin would have much less activity to induce pseudo-aldosteronism than its metabolites with one or no glucuronic acid components on them. This seems to be the case because pseudo-aldosteronism is more frequent in patients who receive an oral than an intravenous preparation of glycyrrhizin. The report in this issue seems to resolve undue concerns for an activity of SNMC to induce pseudo-aldosteronism. van Rossum et al. placed patients with chronic hepatitis C on two SNMC regimens with five ampoules at six times a week (weekly dose: 1200 mg) or six ampoules at three times a week (720 mg) for 4 weeks.10 None of the patients developed full-blown pseudo-aldosteronism; only a few of them on a higher dose of SNMC showed minor reversible symptoms of pseudo-aldosteronism without the need for medication. Based on their observation, they warn against a weekly dose of SNMC greater than 1200 mg. Arase et al. noted moderate hypokalemia (< 3 mEq/mL) in nine (11%) patients, and increased blood pressure (> 160/90 mmHg) in three (4%) of the 84 patients who were started on a daily dose of 100 mL SNMC (weekly dose: 1400 mg) during a period ranging from 15 to 20 years.6 As the indication of SNMC widens in the future, pseudo-aldosteronism occurring in minor predisposed individuals may come to the fore. Physicians have to keep their eyes open to the signs and symptoms of pseudo-aldosteronism, which are corrected easily and safely by antagonists to aldosterone. More than 90% of the patients with HCV-associated liver cirrhosis die of HCC developing later in their lives. With the advent of modern medicine, it has become increasingly less frequent for patients to die because of the complications of decompensated liver cirrhosis, such as hepatic encephalopathy and variceal bleeding. Hence, the main goal of treatment would be to prevent HCC or retard its occurrence until or close to the life expectancy of the patient. Antiviral agents are the principal resort to this end, because they are capable of eradicating the cause of hepatocarcinogenesis. For the patients who poorly respond to antiviral therapies, other measures need to be used to protect them from HCC. Although intravenous glycyrrhizin (SNMC) can contribute toward this goal, its use on chronic viral hepatitis has been restricted to Japan, Holland, China and Germany so far.4–8,10–12 The administration of SNMC through intravenous injection poses considerable constraints against its life-long use in patients with chronic hepatitis C. The development of oral or intramuscular preparations of SNMC is awaited, for an easier administration to millions of people infected with HCV over the world in whom the development of HCC has to be prevented or delayed.