Takefumi Nakamura

Antibody to hepatitis B core antigen and risk for hepatitis C-related hepatocellular carcinoma : A prospective study

Context Retrospective studies suggest that exposure to hepatitis B virus (HBV) may contribute to the development of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)positive patients with cirrhosis. Contribution These investigators prospectively studied patients with chronic HCV infection and evidence of occult HBV infection (negative results for hepatitis B surface antigen and HBV DNA but positive results for antibody to hepatitis B core antigen [anti-HBc] on serologic testing). Patients with HCV-related cirrhosis and positive results for anti-HBc on serologic testing were at high risk for HCC. Anti-HBc positivity was associated with increased risk for HCC, even in patients with a virologic response to interferon therapy. Caution The effect of alcohol cannot be fully assessed because of the small number of study patients who drank moderately. Implication Anti-HBc serologic testing may be a valuable indicator of special risk for HCC in patients with HCV-related cirrhosis. The Editors Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide, and its incidence has been increasing (1, 2). In Japan, an endemic area for hepatitis B virus (HBV) and hepatitis C virus (HCV), it is well known that more than 75% of cases of HCC are attributable to HCV-related chronic liver disease, and nearly 15% are attributable to HBV-related liver disease (3). Several reports have focused on the clinical role of HBV as a unique infection, in which HBV DNA is detectable in the liver despite the absence of serum hepatitis B surface antigen (HBsAg) (46). It is increasingly recognized that after a person is exposed to HBV, infection persists in the liver for a prolonged period (710). This unique persistent infection, known as occult (or latent) HBV infection, is characterized by HBV DNA in the liver but no HBsAg in the serum (1113). In most cases, antibody to hepatitis B core antigen (anti-HBc) is detectable, and thus anti-HBc is believed to be a surrogate marker for latent carriers (14). In fact, we recently showed that HBV infection invariably occurred through grafts from anti-HBcpositive donors in HBV-naive recipients through living-donor liver transplantation (15). In addition to our data, other reports showing frequent HBV transmission from anti-HBcpositive cadaveric donors to recipients indicate that most healthy persons who are positive for anti-HBc, even at low titers, have latent HBV infection in liver tissue (11, 1618). Indeed, we have shown that most anti-HBcpositive healthy persons have a latent episomal form of HBV infection accompanied by ongoing viral replication (19, 20). In contrast, the prevalence of latent HBV infection in anti-HBcpositive patients with HCV-related chronic liver disease, including chronic hepatitis, cirrhosis, and HCC, remains controversial (21). However, several reports have revealed that the HBV genome is frequently detectable in liver tumors in anti-HBcpositive, HBsAg-negative patients with HCV-related liver disease, which suggests that occult HBV infection may contribute to the progression of liver damage and the development of HCC in HCV-positive patients (14, 2227). In a large-scale retrospective study of the prevalence of anti-HBc among 2014 patients with chronic HCV infection, we found that nearly 50% of patients with HCV-related liver disease had anti-HBc (28). Moreover, we found a strong correlation between the prevalence of anti-HBc and the clinical progression of liver disease. The prevalence of anti-HBc was approximately 60% in patients with HCV-related HCC (28). This high prevalence of anti-HBc in HCV-positive patients, particularly those with HCC, strongly suggests that previous exposure to HBV plays an important role in the development of HCC in patients with HCV-related chronic liver disease. Therefore, we performed a prospective study to determine whether previous exposure to HBV affects the clinical course, especially in development of HCC, in patients with chronic HCV infection. Methods Patients Patients with chronic HCV infection who presented to Kyoto University, Kyoto, Japan, and 14 affiliated core hospitals from May 1995 to June 1995 were enrolled. To be eligible, patients had to have serologically confirmed HCV infection without HBsAg and HBV DNA in sera. All patients had been followed with biochemical tests, including -fetoprotein, and ultrasonography or computed tomography (CT) every 3 to 6 months before and after enrollment. We excluded patients who had elevated -fetoprotein levels or those in whom HCC had been diagnosed before enrollment. As a result, 872 patients with chronic HCV infection were enrolled. We discontinued follow-up in patients who moved from the study districts but included their clinical data until they moved. The end of follow-up was defined as the date of diagnosis of HCC, date of death, date of move from the study district, or the closing date of the study (15 May 2005). A total of 384 patients were classified into the hepatitis group or cirrhosis group on the basis of histologic findings on liver biopsy. The differential diagnosis of cirrhosis or hepatitis was made in the remaining 488 patients by using the cirrhosis discriminant score (29, 30). This score is based on 3 laboratory variables: platelet count, alanine aminotransferaseaspartate aminotransferase ratio, and prothrombin time. It has been shown to be highly sensitive in identifying cirrhosis in patients with HCV infection. In accordance with the original definition, patients with a high score (8) were classified into the cirrhosis group. Patients with ascites confirmed by ultrasonography or CT or previous variceal bleeding were given a diagnosis of cirrhosis, regardless of their score, because these findings are strong indicators of portal hypertension and most likely cirrhosis. As a result, 597 (68.5%) patients had a diagnosis of chronic hepatitis and 275 (31.5%) patients had a diagnosis of cirrhosis at the time of enrollment. The patients had regular clinical assessments, biochemical tests, and ultrasonography or CT of the liver every 3 to 6 months during the follow-up period. Patients were stratified into 3 categories according to their smoking habits: nonsmokers, light smokers who smoked fewer than 20 pack-years, and heavy smokers who smoked 20 pack-years or more. Similarly, we stratified patients into 3 categories according to their drinking habits: nondrinkers, moderate drinkers with an average ethanol intake less than 30 g/d, and heavy drinkers with an average ethanol intake greater than 30 g/d. Information on average alcohol intake was based on the patients drinking habits during the 15 years before study entry. All patients provided informed consent to participate in the study, and the study was designed in accordance with the Declaration of Helsinki (31). Serologic Studies At study entry, serum samples from each patient were tested for serologic markers of HCV. Detection of HBsAg, anti-HBc, and antibody to hepatitis B surface antigen (anti-HBs) was performed by using commercial enzyme immunoassay kits (Dainabot, Tokyo, Japan) (28). Results of the anti-HBc assays were expressed as the percentage of inhibition, and the specimen was considered to be anti-HBc positive when the percentage of inhibition was greater than 50% (19). Detection of HBV DNA was done by using DNA probe assay (32). Anti-HCV was assessed by using second-generation assays (Dainabot) (28). Serum HCV RNA levels were determined in 254 patients by using a competitive reverse transcriptionpolymerase chain reaction assay, and positivity of HCV RNA was confirmed in all patients who were examined at study entry (33). History of Interferon Therapy Of the 576 patients with chronic hepatitis, 224 had a history of interferon therapy. One hundred ninety-two patients received 5 to 10 million U of interferon- intramuscularly every day for the first 2 weeks and then 3 times weekly for the following 22 weeks. The remaining 32 patients were treated with 3 to 6 million U of interferon- intravenously every day for 8 weeks. No patient received pegylated interferon or combination therapy with ribavirin. Patients who received interferon were divided into 3 groups based on their virologic response to therapy. Patients with a sustained virologic response were defined as those with no detectable HCV RNA by qualitative assay at least 24 weeks after cessation of therapy. Patients with relapse were defined as those with disappearance of viremia at the end of treatment followed by reappearance of viremia with 24 weeks. Nonresponders included patients whose serum HCV RNA remained positive during therapy. Statistical Analysis The incidence rates for HCC are expressed as the number of HCC cases per 1000 person-years. Incidence rate ratios were calculated by dividing rates, and the exact 95% CIs for the rate ratios were calculated on the basis of a binomial distribution, which is a conditional distribution for 2 independent Poisson distributions. The Cox proportional hazards model was used to calculate the incidence rate ratios for the association between HBc seropositivity and HCC incidence. The multivariate model, with adjustment for potential risk factors, included male sex, age, alcohol intake (none, 0 to 30 g/d, and 30 g/d), smoking (none, 0 to 20 pack-years, and 20 pack-years), and history of interferon therapy (yes or no). The associated 95% Wald CIs were calculated. Analyses were done by using PC-SAS, version 8.2 (SAS Institute, Inc., Cary, North Carolina) and JMP, version 4.0 (SAS Institute, Inc.). Role of the Funding Source The Japan Society for the Promotion of Science provided funding for the study. The funding source had no role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Characteristics of Patients at Enrollment We followed 846 of the 872 enrolled patients. The remaining 26 patients were excluded from the analysis. Twenty-on

Measurement of Portal Vascular Resistance in Patients With Portal Hypertension

Portal vascular resistance was measured percutaneously in 60 patients with chronic liver disease and in 5 control subjects. The portal vascular resistance (PVR) was calculated, using the following equation, from the portal blood flow (QPV), portal venous pressure (PPV), and hepatic venous pressure (PHV): PVR = (PPV - PHV)/QPV. The portal blood flow was measured using an ultrasonic Doppler duplex system, and the portal venous and hepatic venous pressures were measured using percutaneous transhepatic catheterization and venous catheterization, respectively. The wedged hepatic venous pressure was measured by occluding the hepatic venous branch using a balloon catheter. The portal vascular resistance was 0.25 +/- 0.13 mmHg X ml-1 X min X kg body weight (mean +/- SD, n = 5) in the control group, 0.64 +/- 0.29 mmHg X ml-1 X min X kg body wt (n = 13) in the chronic active hepatitis group, 1.34 +/- 0.79 mmHg X ml-1 X min X kg body wt (n = 30) in the cirrhosis group, and 0.85 +/- 0.69 mmHg X ml-1 X min X kg body wt (n = 13) in the idiopathic portal hypertension group.

Gray scale second harmonic imaging of the liver: A preliminary animal study

Gray scale second harmonic imaging (2.5 MHz/5.0 MHz) was evaluated in preliminary animal studies with a new ultrasound contrast agent (FS069). FS069 was administered intravenously in 10 rabbits (6 with normal liver, and 4 with implanted VX-2 tumors) and two woodchucks with hepatocellular carcinomas. The vasculature (including tumor vessels) and liver parenchyma were clearly enhanced at a low dosage (optimal dose was from 0.1 to 0.2 mL/kg) in all cases. Enhancement was reproducible and generally dose-dependent. Tumors were enhanced well during the early phase and tumor enhancement disappeared earlier than that of surrounding normal liver. Arterial phase and portal phase were easily distinguished and patterns of enhancement were diagnostic of the tumors. Gray scale second harmonic imaging is useful in the detection of hepatic tumors and in diagnosis of their hemodynamics.

Quantitative measurement of portal blood flow in patients with chronic liver disease using an ultrasonic duplex system consisting of a pulsed doppler flowmeter and B-mode electroscanner

SummaryPortal blood flow (PBF) can be measured quantitatively using a B-mode combined pulsed Doppler (BCD) system. This system combines a real time B-mode linear type electroscanner and a pulsed Doppler (D-mode) flowmeter. Since both modes are displayed in realtime, Dopper blood flow signals can be retrieved at will from any depth. The blood flow velocity determined by the Doppler spectrogram and the vascular cross-sectional area measured from the B-mode tomographic image enables the quantitative calculation of blood flow volume. Using this system,PBF was measured quantitatively in 88 healthy adults, 54 patients with chronic hepatitis, 65 with cirrhosis of the liver, 27 with primary hepatoma and 12 with idiopathic portal hypertension (IPH). Results ofPBF volume measurement were as follows: 889±284 ml/min (mean ± S.D.) for healthy adults, 851 ± 237 ml/min for patients with chronic hepatitis, 870 ± 289 ml/min for cirrhosis of the liver, 966 ± 375 ml/min for primary hepatoma and 1,047 ± 381 ml/min forIPH.These preliminary results demonstrated that this ultrasonic Duplex system is clinically useful to determine the quantitative amount of PBF.

Hemodynamics of splenic artery aneurysm

Blood flow volume of the portal venous system of 3 patients with splenic artery aneurysm, an uncommon disease, was measured using an ultrasonic duplex system. A huge increase in splenic blood flow volume was found in each case. A large portasystemic shunt through which the portal blood flowed hepatofugally was present in 2 cases. We suspect the shunt is partially responsible for an increase in splenic blood flow volume, which would lead to the formation of splenic artery aneurysm together with portal hypertension.

Risk of HCV transmission after needlestick injury, and the efficacy of short-duration interferon administration to prevent HCV transmission to medical personnel

Background. We carried out this study to assess the risk of hepatitis C virus (HCV) transmission after needlestick injuries in medical personnel, and to evaluate the efficacy of short-duration interferon administration to prevent HCV transmission. Methods. A total of 684 personnel who had been occupationally exposed to an anti-HCV-positive source and followed for more than 3 months were retrospectively examined. Results. Of the 684 subjects, 279 (41%) were treated with 1 to 3 days of interferon either just after or 1 to 12 days after the injury. One case of HCV infection was found in each of the treated (1/279; 0.4%) and nontreated (1/405; 0.2%) groups. There was no significant difference in the transmission of HCV between the two groups. Both infected patients were treated with interferon after developing acute hepatitis, and HCV was subsequently cleared. Conclusions. There is a lower risk of HCV transmission after needlestick accident than previously reported, and short-duration interferon administration at an early stage after the needlestick injury, to prevent HCV transmission, is unnecessary.

Acute pancreatitis secondary to 5-aminosalicylic acid therapy in a patient with ulcerative colitis

SummaryTherapy with oral 5-aminosalicylic acid (5-ASA) for uicerative colitis has been reported to be effective and safe. We describe a case of biochemically proven mild acute pancreatitis occurring after 9 d of oral 5-ASA therapy for uicerative colitis. A hypersensitivity mechanism seemed to be involved in the development of pancreatitis probably owing to erratic systemic absorption of the drug. We suggest clinical and biochemical monitoring for early diagnosis of pancreatitis in patients with uicerative colitis receiving 5-ASA administration. This is the first report of acute pancreatitis developed by oral 5-ASA therapy for the treatment of uicerative colitis in the literature of Japan.

Regression of B-Cell Lymphoma of the Liver with Hepatitis C Virus Infection After Treatment with Pegylated Interferon-α and Ribavirin

The pathogenesis of human B-cell lymphoma is not well understood, although some types of B-cell lymphoma seem to be related to infection with pathogens such as Helicobacter pylori [1]. Accumulating evidence reveals a high incidence of B-cell lymphoma in patients with hepatitis C virus (HCV) infection, suggesting a link between HCV infection and the development of B-cell lymphoma [2–6]. We describe here a case of primary B-cell lymphoma of the liver with HCV infection that regressed following the eradication of HCV.

Ultrasonographic arterial portography with second harmonic imaging: Evaluation of hepatic parenchymal enhancement with portal venous flow

Ultrasonographic arterial portography was evaluated with second harmonic and conventional gray scale imaging after the administration of 0.001 to 0.1 ml/kg of FS069 (Optison) in 10 dogs (four dogs with ligation of the portal vein branch) and two woodchucks with hepatocellular carcinomas. Harmonic imaging was required to obtain good liver parenchymal enhancement for ultrasonographic arterial portography to be useful. The tumors were visible as regions of greater enhancement after intravenous injection and as hypoechoic regions after superior mesenteric artery injection. The segments with portal vein ligation were not detected after intravenous injection but were clearly seen after superior mesenteric artery injection. Doppler signal measurement verified a significant difference between the portal vein and hepatic vein after superior mesenteric artery injection and in the femoral artery after intravenous versus superior mesenteric artery injection, demonstrating that minimal levels of FS069 pass through the liver.

Sinusoidal obstructive syndrome with hypereosinophilia successfully treated with prednisolone

A 60-year-old man was admitted to Tenri Hospital complaining of erythema and abdominal distention. There were marked liver damage and hypereosinophilia. The patient was suffering from portal hypertension and coagulation disorder. We diagnosed the patient clinically as suffering from veno-occlusive disease, or sinusoidal obstructive syndrome (SOS). The pathological finding of the liver biopsy specimen was compatible with SOS. All of the manifestations, liver function test, and hemodynamics subsided shortly after administration of steroid treatment and ursodeoxycholic acid. The pathogenesis was not identified but some allergic reaction was suspected.