Iwao Ariyama

A Relationship between the Evolution of Hepatitis C Virus Variants, Liver Damage, and Hepatocellular Carcinoma in Patients with Hepatitis C Viremia

To clarify the mechanism of liver damage induced by hepatitis C virus (HCV) and to determine whether the damage is related to hepatocellular carcinoma (HCC), HCV RNA levels were measured serially, and HCV genome mutations were analyzed from serum of 274 Japanese patients with chronic HCV viremia during 1993-1998. All patients had alanine aminotransferase (ALT) levels measured during 1986-1998. Patients with consistently normal ALT levels had identical and highly conserved HCV core regions; however, those with consistently abnormal ALT levels had quasi species, and the population of the quasi species changed over time. HCV RNA levels did not change in the 274 patients. HCC developed in 31% of 80 patients with consistently abnormal ALT levels and in 4% of 92 patients with intermittently abnormal ALT levels but never in 102 patients with ALT levels consistently normal during 1993-1998. In patients with chronic HCV viremia, persistent liver damage plays an important role in the development of HCC.

Maintenance hemodialysis decreases serum Hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection

OBJECTIVE:Hepatitis C virus (HCV) infection is a major complication among hemodialysis patients the world over. To determine the natural course of HCV viremic levels in patients on maintenance hemodialysis, we prospectively quantified the HCV RNA levels in serial blood samples from hemodialysis patients and compared them with those in nonuremic subjects.METHODS:The population studied included 98 hemodialysis patients and 228 nonuremic subjects with chronic HCV infection. HCV RNA was detected by polymerase chain reaction (PCR) and the levels were determined by branched DNA probe assay. HCV RNA genotypes were determined by PCR using type-specific primers.RESULTS:HCV RNA levels were significantly lower in hemodialysis patients (median, 0.4 × 106 genome equivalent [Meq;[sol;ml) than in nonuremic subjects (median, 3.0 Meq/ml) (p < 0.05). HCV of genotype 1b was prevalent in the hemodialysis patients (81.6%) and nonuremic subjects (88.6%). HCV RNA levels in 20 hemodialysis patients with genotype 1b were significantly reduced after each hemodialysis procedure (p < 0.05). The 3-yr prospective observation from 1995 to 1998 showed a significant decrease of HCV RNA levels in 47 hemodialysis patients with genotype 1b (median, 1.9–0.9 Meq/ml, p < 0.05), whereas levels in 155 nonuremic subjects with genotype 1b did not decrease (median, 2.6–3.0 Meq/ml). There were no patients or nonuremic subjects with undetectable HCV RNA by a PCR assay during the observation period.CONCLUSIONS:These observations suggest that maintenance hemodialysis decreases the HCV RNA levels in hemodialysis patients with chronic HCV infection, but does not produce clearance of the viremia.

Acute hepatitis C among Japanese hemodialysis patients: a prospective 9-year study.

Abstract OBJECTIVES: The aims of this prospective survey were to determine the incidence and clinical characteristics of newly acquired hepatitis C virus (HCV) infection in hemodialysis patients after the start of antibody to HCV (anti-HCV) screening for blood products in Japan in 1989. METHODS: In serial serum samples from 269 hemodialysis patients who were followed over a mean period of 6.6 yr (± 2.1 yr) from 1990 to 1998, HCV RNA and anti-HCV were detected by reverse transcription-polymerase chain reaction and second generation ELISA, respectively. RESULTS: During the observation period, newly acquired HCV infection was found in 26 (15.4%) of the 169 hemodialysis patients without anti-HCV or HCV RNA at entry, an annual incidence rate of 2.59%. Of these 26, only four had a history of blood transfusion, one of whom had received the blood transfusion after 1992, the year in which screening of blood products for anti-HCV by second-generation ELISA was introduced in Japan. Persistent HCV viremia was found in 17 (65.4%) of the 26 patients; the other nine (34.6%) had transient HCV infection. The mean period of continuous ALT abnormality was significantly longer in the former (12.4 ± 13.6 months) than in the latter (1.9 ± 3.5 months) ( p = 0.0067). However, only three (17.6%) of 17 patients with chronic HCV viremia had continuous ALT abnormality for more than 24 months; in all of them, ALT eventually normalized. CONCLUSIONS: These findings indicate that newly acquired HCV infection has continued to occur in hemodialysis patients after the initiation of anti-HCV screening of blood products and that the abnormal ALT found in these patients is related to HCV chronicity.

Liver damage in hemodialysis patients with hepatitis C virus viremia : A prospective 10-year study

Hepatitis C virus (HCV) infection is a major problem associated with hemodialysis. The extent of liver damage in hemodialysis patients with chronic HCV infection has not been thoroughly documented. The aim of this study was to evaluate liver damage of hemodialysis patients infected with HCV. A total of 233 hemodialysis patients were categorized into two groups at entry: group X, 80 positive for serum HCV RNA, and group Y, 153 negative for serum HCV RNA. All were tested for serum alanine aminotransferase (ALT) serially from 1989 to 1998, and serum hyaluronic acid (HA), serum type-IV collagen (IV-C), platelet counts, and ultrasonographic examination of the liver was done in 1998. In group X, 61.3% had continuously abnormal ALT levels for over six months followed by normal ALT levels. Of the group X patients, 11.3% had abnormal ALT levels in 1998, and in three, hepatocellular carcinoma occurred. Mean HA and IV-C levels in group X (648.8 and 188.7 ng/ml, respectively) were significantly higher than in group Y (213.1 and 165.5 ng/ml, respectively) (P < 0.05). Ultrasonographic findings significantly correlated with serum HA level and platelet counts and showed significantly more abnormalities in group X than in group Y (P < 0.05). From these findings, a combined examination with ultrasonography and serum fibrogenesis markers is useful for detection of liver damage in hemodialysis patients with HCV viremia.

Hepatitis C virus infection in institutionalized psychiatric patients: Possible role of transmission by razor sharing

The objective of this study was to determine if HCV can be transmitted from patient to patient in psychiatric institutions and to determine possible routes of infection. We did a cross-sectional survey of 196 Japanese psychiatric patients tested for HCV and HBV markers and 400 age- and sex-matched controls. Anti-HCV was detected in 10.2% and antibody to hepatitis B core antigen was detected in 44.4% of the patients, a significantly higher prevalence than found among matched controls. A multiple regression logistic analysis was used to identify risk factors that could indicate the route of infection by HCV. Duration of hospitalization, age, razor sharing, and history of surgery proved to be statistically significant independent risk factors associated with positive anti-HCV results [odds ratio (OR), 4.00; 95% confidence interval (CI), CI, 1.74–9.19; OR, 2.19; 95% CI, 1.27–1.3.77; OR, 4.90; 95% CI, 1.29–18.86; OR, 3.35; 95% CI, 0.997–11.3, respectively]. These observations suggest that razor sharing played an important role in the spread of the HCV infection in the institutionalized psychiatric patients we studied.

Differences between interferon-α and -β treatment for patients with chronic hepatitis C virus infection

To compare virological, biochemical, and immuneresponses to human lymphoblastoid interferon(IFN-α) and human fibroblast interferon(IFN-β) in patients with chronic hepatitis C virus(HCV) infection, 120 patients were randomly assigned to threegroups (group A, 60 patients receiving IFN-α, 6million units (MU) once a day, daily for one month andthrice weekly for five months; group B, 40 patients receiving 6 MU IFN-β once a day daily fortwo months; and group C, 20 patients receiving 3 MUIFN-β twice a day (6 MU/day) daily for two months).Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured byenzyme-linked immunosorbent assay. Patients withsustained clearance of serum HCV RNA detected bypolymerase chain reaction (PCR) at six months after IFNtreatment were defined as having complete response to IFNtreatment. A low level of HCV RNA (≤10-4copies/50 mul, measured by competitive PCR) and HCV RNAof genotype 2a were favorable factors for a completeresponse to both IFNs. Complete response in group Atreatment was strongly associated with early HCV RNAclearance, in contrast with group B. A significantlyhigher HCV RNA negativity at the second week from start of treatment was noted in group C (80.0%),compared with groups A (41.6%) and B (27.5%). sIL-2Rlevels rose in each group during IFN administration. Ingroup C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findingsindicate that timing of serum HCV RNA negativity insustained response differs between IFN-α andIFN-β administrations and that early HCV RNAclearance was induced by twice-a-day IFN-βtreatment.

Evidence of B Cell Clonal Expansion in HIV Type 1-Infected Patients

HIV-1 infection results in a gradual decrease in CD4(+) T cell counts and progressive immune deficiency. Increased T cell turnover in HIV-1-infected patients, which can be interpreted as T cell clonal expansion, has been thought to be relevant to its pathogenesis. To investigate whether B cell clonal expansion also occurs in HIV-1-infected patients, we examined the expressed V(H)DJ(H) gene sequences of peripheral B cells in HIV-1-infected patients with hypergammaglobulinemia. Identical V(H)DJ(H) gene rearrangements with additional nucleotide differences in V(H) genes were analyzed as a marker of clonally related B cells. From healthy individuals and HIV-1-uninfected patients with hypergammaglobulinemia, clonally related B cells were detected in none of 10 (0%) and 2 of 10 (20%), respectively. No clonally related B cells were detected in any of the nine HIV-1-infected patients with detectable viral loads and normal Ig levels (0%). In contrast, from 9 of 14 HIV-1-infected patients with hypergammaglobulinemia (64%), clonally related B cells were detected. In addition, no HIV-1-infected patients who exhibited normal Ig levels after antiretroviral therapy had clonally related B cells. These findings suggest that B cell clonal expansion is present in HIV-1-infected patients with hypergammaglobulinemia.

Seroepidemiology of TT Virus Infection and Relationship Between Genotype and Liver Damage

TT virus (TTV) has been identified in patients with posttransfusion hepatitis of unknown etiology and is thought to be a new hepatitis virus. We determined the extent of TTV infection in the Japanese general population and the relationship between TTV DNA genotype and liver damage. In 1998, we tested 847 serum samples for TTV. TTV DNA was assayed by a nested polymerase chain reaction and classified into three different genotypes and eight subtypes. TTV DNA was detected in 25.3% and 32.4% of the inhabitants of the two areas studied, respectively. The genotype distribution was similar in both areas. G1, G2, and G3 were 60%, 20%, and 5%, respectively. Of the 20 subjects with TTV DNA alone and elevated serum ALT levels, 18 were G1, one was G2, and one was G3. TTV infection is endemic in the Japanese general population studied. The main TTV genotype, G1, may be related to the ensuing liver damage.

Hepatitis G virus in the general population and in patients on hemodialysis.

To determine the routes of transmission ofhepatitis G virus (HGV) and the relationship between HGVand hepatitis C virus (HCV) infections, we tested forHGV RNA by polymerase chain reaction and antibody to HCV (anti-HCV) in 494 hemodialysis patients,638 inhabitants of two HCV endemic areas, and in 400blood donors in Japan. HGV RNA was detected in 6.9% ofhemodialysis patients, in 1.4% of inhabitants, and in 0.8% of donors, and anti-HCV wasdetected in 39.3%, 12.4%, and 1.8%, respectively. Of HGVRNA-positive hemodialysis patients, and HGV RNA-positiveinhabitants, 64.7% and 11.1%, respectively, had been given blood transfusions. Theprevalences of HGV RNA and anti-HCV significantlyincreased with the duration of hemodialysis. Of all HGVRNA positives, 74.4% were coinfected with HCV andsubjects with HGV RNA alone had normal liver function.In conclusion, HGV is transmitted by blood transfusionand within the hemodialysis unit itself. HGV does notseem to injure hepatocytes.

Serum soluble interleukin-2 receptor levels before and during interferon treatment in patients with chronic hepatitis B virus infection

To determine the role of serum solubleinterleukin-2 receptor (sIL-2R) in chronic hepatitis Bvirus (HBV) infection, the level of serum sIL-2R wasmeasured in sera of 105 patients with chronic HBVinfection and in 21 healthy controls, using enzyme-linkedimmunosorbent assay. Serum sIL-2R levels weresignificantly higher in chronic HBV-infected patientswith chronic hepatitis (508 ± 310 units/ml) andliver cirrhosis (543 ± 283 units/ml) than inhealthy controls (331 ± 106 units/ml, P <0.05). Moreover, serum sIL-2R levels were significantlyhigher in patients with chronic hepatitis or livercirrhosis than in asymptomatic HBV carriers (341 ±150 units/ml, P < 0.01). There was no difference inserum sIL-2R levels between asymptomatic HBV carriersand healthy controls or between patients with chronic hepatitis and liver cirrhosis. A significantrelationship was found between serum sIL-2R and ALTlevels (P < 0.05) in patients with chronic HBVinfection, although there was no correlation betweensIL-2R and HBV DNA levels. Serum sIL-2R levels in mostpatients decreased to the same level as asymptomatic HBVcarriers and healthy controls at 48 weeks after the endof treatment, and serum ALT and HBV DNA levels were decreased to within the normal range at 96weeks. Thus, serum sIL-2R levels indicate the degree ofliver damage among patients with chronic HBV infection.The serum sIL-2R levels one year after interferon administration may be a useful marker ofdetermined at the effectiveness by thistreatment.