Duodenal gastric-type neoplasm with uncertain malignant potential in a lipoma.

The pathologic diagnosis of duodenal tumors is a developing field; however, its overview remains unclear. We describe a rare case of a duodenal gastric-type neoplasm in a 50-year-old woman. She visited her primary care doctor with complaints of upper abdominal pain, tarry stools, and shortness of breath on exertion. She was admitted owing to a stalked polyp with erosion and hemorrhage in the descending part of the duodenum. Endoscopic mucosal resection (EMR) was performed on the polyp. Histologically, the resected polyp was a lipomatous lesion in the submucosal layer, composed of mature adipose tissues. Scattered irregular lobules of Brunner's gland-like structures with well-preserved construction but mildly enlarged nuclei and occasional conspicuous nucleoli of the constituent cells were observed. The resection margin was negative. EMR findings of the duodenal polyp showed a gastric epithelial tumor within a lipoma, a rare histological type that has not been reported previously. This tumor may be classified as a "neoplasm with uncertain malignant potential" in a lipoma, an intermediate category between adenoma and invasive adenocarcinoma. There is no consensus on treatment, and careful follow-up is recommended. This is the first report of a duodenal gastric-type neoplasm with uncertain malignant potential in a lipoma.

Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection.

The outcome of acute hepatitis B virus (HBV) infection is variable, influenced by host and viral factors. From 1982 through 2004, 301 patients with acute HBV infection entered a multi-center cross-sectional study in Japan. Patients with fulminant hepatitis (n = 40) were older (44.7 +/- 16.3 vs. 36.0 +/- 14.3 years, P < .0017), less predominantly male (43% vs. 71%, P = .0005), less positive for hepatitis B e antigen (HBeAg) (23% vs. 60%, P < .0001), less infected with subgenotype Ae (0% vs. 13%, P < .05), and more frequently with Bj (30% vs. 4%, P < .0001) than those with acute self-limited hepatitis (n = 261). Precore (G1896A) and core-promoter (A1762T/G1764A) mutations were more frequent in patients with fulminant than acute self-limited hepatitis (53% vs. 9% and 50% vs. 17%, P < .0001 for both). HBV infection persisted in only three (1%) patients, and they represented 2 of the 23 infected with Ae and 1 of the 187 with the other subgenotypes (9% vs. 0.5%, P = .032); none of them received antiviral therapy. In multivariate analysis, age 34 years or older, Bj, HBeAg-negative, total bilirubin 10.0 mg/dL or greater, and G1896A mutation were independently associated with the fulminant outcome. In in vitro transfection experiments, the replication of Bj clone was markedly enhanced by introducing either G1896A or A1762T/G1764A mutation. In conclusion, persistence of HBV was rare (1%) and associated with Ae, whereas fulminant hepatitis was frequent (13%) and associated with Bj and lack of HBeAg as well as high replication due to precore mutation in patients with acute HBV infection.

T1653 mutation in the box alpha increases the risk of hepatocellular carcinoma in patients with chronic hepatitis B virus genotype C infection.

BACKGROUND: Most patients with chronic hepatitis B virus infection become carriers of inactive virus after hepatitis B e antigen seroconversion; however, a subgroup of patients have persistent abnormal transaminase levels and develop hepatocellular carcinoma after seroconversion. METHODS: In an age-matched case-control study, 40 carriers of inactive virus (mean age+/-standard deviation [SD], 50.9 +/- 11.1 years), 40 patients with chronic hepatitis (mean age+/-SD, 50.2 +/- 8.9 years), and 40 patients with hepatocellular carcinoma (mean age+/-SD, 50.7 +/- 9.4 years) who were infected with hepatitis B virus genotype C and had test results positive for antibody to hepatitis B e antigen were analyzed. RESULTS: The prevalence of T1653 in the box alpha was significantly higher among patients with hepatocellular carcinoma than among carriers of inactive virus who did not have hepatocellular carcinoma (70% vs. 25%; P < .0001) or chronic hepatitis (70% vs. 35%; P = .003). Mutations in the basic core promoter region (T1762/A1764) were frequently found in all groups, regardless of clinical status (in 77.5% of carriers of inactive virus, 77.5% of patients with chronic hepatitis, and 90% of patients with hepatocellular carcinoma). In the multivariate analysis, the presence of T1653, an alanine aminotransferase level of > or = 37 U/L, and a platelet count of < 18 x 10(4) platelets/mm3 were independent predictive values for hepatocellular carcinoma (odds ratio [95% confidence interval], 5.05 [1.56-16.35], 12.56 [3.05-51.77], and 11.5 [3.47-38.21], respectively). High alpha -fetoprotein level was the only independent predictive value for T1653 in patients with hepatocellular carcinoma (odds ratio, 12.67; 95% confidence interval, 1.19-134.17]). Among patients with test results positive for antibody to hepatitis B e antigen who had hepatocellular carcinoma and were infected with different genotypes of hepatitis B virus, the prevalence of T1653 was 40%, 15%, 25%, 25%, 67%, and 23% in patients infected with hepatitis B virus genotypes Aa, Ae, Ba, Bj, C, and D, respectively (P<.05 for genotype C vs. genotypes Ae, Ba, Bj, or D). CONCLUSIONS: Our data indicate that the addition of T1653 mutation in the box alpha to the basic core promoter mutation increases the risk of hepatocellular carcinoma in patients with hepatitis B virus genotype C.

Factors regarding increase of platelet counts in chronic hepatitis C patients with sustained virological response to interferon-Relation to serum thrombopoietin levels.

UNLABELLED: Thrombocytopenia is frequently found in patients with chronic liver disease, and associated with advanced fibrosis stage and with decreased liver function. Serum thrombopoietin (TPO) levels also decrease as the disease progresses from mild fibrosis to cirrhosis. On the other hand, platelet counts increase associated with improvement of fibrosis in chronic hepatitis C (CH-C) patients with sustained virological response (SVR) to interferon (IFN) therapy. Then, we studied if the increase of platelet counts in SVR associate with elevated TPO production or a reduction of spleen size. Liver fibrosis, spleen size, serum TPO levels, albumin, zinc turbidity test (ZTT), platelet counts were compared in fifteen CH-C patients with SVR before and after IFN therapy. RESULTS: Albumin increased from 4.2+/-0.3 to 4.3+/-0.3g/dl (p=0.067), ZTT decreased from 17.7+/-5.9 to 8.9+/-3.9K-U (p<0.001), platelet counts increased from 15.5+/-6.8x10(4) to 19.9+/-5.8x10(4)/mul (p<0.01) and serum TPO levels increased from 1.65+/-0.94 to 2.06+/-1.22fmol/ml (p=0.073). Spleen size was measured by ultrasonography, and the spleen index was calculated by multiplication of the long and short axes from hilus, which decreased from 14.6+/-5.0 to 10+/-3.1 (p<0.001) after IFN therapy. In conclusion, increase of platelet counts in SVR may be related to the reduction of spleen size and increased serum TPO levels associated with improvement of fibrosis after IFN therapy.

Risk factors for the development of hepatocellular carcinoma among patients with chronic hepatitis C who achieved a sustained virological response to interferon therapy.

BACKGROUND AND AIM: Hepatitis C virus (HCV)-infected patients who responded to interferon (IFN) treatment with clearance of serum HCV RNA may rarely develop hepatocellular carcinoma (HCC). The aim of the present study was to elucidate the risk factors for liver carcinogenesis among such patients. METHODS: In total, 126 patients with chronic hepatitis C (CHC) who achieved a sustained virological response (SVR) to IFN monotherapy, which was defined as the absence of detectable HCV RNA in the serum at 6 months after completion of treatment, were enrolled and possible risk factors for HCC were analyzed. RESULTS: During the observation period of 66 +/- 36 months after cessation of IFN treatment, five (4.0%) of the 126 patients developed HCC. The cumulative incidence of HCC at 3, 5 and 10 years was estimated to be 0.9, 4.7 and 7.5%, respectively. The cumulative incidence of HCC was significantly higher among patients with severe fibrosis (F3 or F4) than among patients with no or mild fibrosis (F0 to F2) in the liver before treatment (P = 0.007); among patients with alcohol intake of > or = 27 g/day than among patients with that of < 27 g/day (P = 0.015); and among patients who were > or = 65 years old than among patients who were < 65 years old at the start of treatment (P = 0.026). CONCLUSIONS: Patients with CHC who had severe fibrosis, who had regularly taken moderate amounts of alcohol, or who were > or = 65 years at the start of IFN treatment should be carefully followed to detect small and controllable HCC, even after eradication of HCV.

Late liver-related mortality from complications of transfusion-acquired hepatitis C.

Although several cohort studies have been reported in individuals with chronic hepatitis C virus (HCV) infection, little is known about liver-related mortality among the elderly. We conducted a cohort study in 302 patients with tuberculosis sequelae who had received a blood transfusion at a young age and had subsequently been treated at a chest clinic. The cohort consisted of 147 patients with antibody to HCV (anti-HCV), of whom 81% were positive for HCV RNA, and 155 without anti-HCV. The cohort was followed for a mean duration of 5.7 years. There were no differences between the two groups in the mean age of the patients at the time of transfusion (31 vs. 34 years) or at the time of entry into the study (65 vs. 66 years). The outcome of 143 patients with, and 145 without, anti-HCV could be traced; 92 (64%) and 82 (57%) had died, respectively. The main cause of death was tuberculosis sequelae in 61 (42%) and 66 (46%) patients, respectively. Eight (6%) of the 143 patients with anti-HCV died of liver disease (hepatocellular carcinoma: seven; rupture of varices: one). The average annual mortality from liver disease from study entry in the patients with anti-HCV was 9.8 per 1,000 person-years. The patients with anti-HCV had a significantly lower cause-specific survival probability for liver disease (92% vs. 100% at 10 years, P < .005). In conclusion, in our study, liver-related mortality appeared to be high among elderly HCV-infected individuals.

Two subtypes of genotype B (Ba and Bj) of hepatitis B virus in Japan.

We have previously reported 2 subtypes of hepatitis B virus (HBV) genotype B, one of which has the recombination with genotype C over the precore region plus core gene (Ba) and the other of which does not (Bj). A restriction fragment-length polymorphism method with 2 endonucleases was newly developed for distinguishing between subtypes Ba and Bj and was applied to 313 carriers of HBV genotype B in Japan. Subtype Ba was detected in 38 (12%) and subtype Bj in 275 (88%) of the carriers of HBV genotype B. Hepatitis B e antigen in serum was found more frequently in patients with chronic infection with subtype Ba than in those with chronic infection with subtype Bj (8 [32%] of 25 vs. 25 [9%] of 273; P<.01). The new method for distinguishing between Ba and Bj by restriction fragment-length polymorphism would be useful in examining the distribution of these 2 subtypes in situations in which HBV genotype B is prevalent.

Circulating KL-6 level at baseline is a predictive indicator for the occurrence of interstitial pneumonia during interferon treatment for chronic hepatitis C.

Interstitial pneumonia (IP) is a serious adverse event of interferon alpha (IFNalpha) treatment for chronic hepatitis C (CH-C). Among 558 CH-C patients who received IFNalpha treatment with or without ribavirin between January 1992 and June 2002, six patients (1.1%) developed IP, including one patient who developed IP in 1993 and again in 2002. Among the seven cases who contracted IP, at the onset of IP, seven (100%), five (71%), and two cases (29%) had elevated serum levels of KL-6, surfactant protein A (SP-A), and surfactant protein D (SP-D), respectively. Prior to starting IFN treatment (baseline), the serum SP-A and SP-D levels were within the normal range in all seven cases, but the serum KL-6 level was elevated in five of the seven cases, contrasting with that in three of 48 age-adjusted CH-C patients who did not develop IP during IFN treatment (71 vs. 6%; P=0.0003). Furthermore, the circulating KL-6 level at baseline was significantly higher among the seven cases than among the controls (543+/-105 vs. 304+/-98 U/ml, P=0.0001). These results indicate that measurement of the circulating KL-6 level in CH-C patients before IFN treatment may be useful for predicting the occurrence of IP during IFN treatment.

Molecular and serological characterization of sporadic acute hepatitis E in a Japanese patient infected with a genotype III hepatitis E virus in 1993.

Serum samples collected periodically from a 40-year-old Japanese woman who had not travelled abroad and who had contracted sporadic acute hepatitis E in 1993 were semi-quantitatively tested by enzyme immunoassay for IgM, IgA and IgG antibodies to hepatitis E virus (HEV). Anti-HEV IgM and IgA antibody levels were the highest (1 : 2400 dilution and 1 : 3400 dilution, respectively) on day 9 after the onset of hepatitis and then decreased rapidly in a parallel manner. Anti-HEV IgG antibody levels were the highest (1 : 17000 dilution) on day 145 and then decreased gradually but remained at high titres (1 : 2200 dilution) even 8.7 years after the onset of hepatitis. An HEV isolate, HE-JA10, recovered from the patient's serum at admission was closely related to a genotype III strain isolated in the United States (US1), with 92.2% identity over the full-length genome, and was most closely related to the JMY-Haw isolate of Japanese origin (95.4% identity).

Polyphyletic strains of hepatitis E virus are responsible for sporadic cases of acute hepatitis in Japan.

Among 87 patients who were previously treated for acute hepatitis of unknown etiology between 1992 and 2001 at five hospitals in Japan, 11 (13%) patients were positive for immunoglobulin M-class antibodies to hepatitis E virus (HEV) by enzyme immunoassay and had detectable HEV RNA by reverse transcription-PCR with two independent sets of primers derived from well-conserved genomic areas in open reading frames 1 and 2. Clinical HEV infection was significantly associated with male sex (9 of 11 versus 29 of 76 patients [P < 0.01]) and older age (52 +/- 11 [mean +/- standard deviation] versus 41 +/- 17 years [P < 0.05]), and its prevalence differed by geographic region (6 to 25%), with a higher rate in the northern part of Japan. At admission, the 11 patients with HEV-associated hepatitis had elevated alanine aminotransferase levels of 914 to 4,850 IU/liter, and all but 1 had elevated bilirubin levels of 1.5 to 24.0 mg/dl. The 11 HEV isolates were of genotype III or IV and were segregated into three groups with intergroup nucleotide differences of 9.5 to 22.0%. Phylogenetic analysis revealed that four isolates of genotype III were closely related to a Japanese isolate, while the other four isolates of the same genotype were nearest those from the United States. The remaining three isolates were close to known isolates of genotype IV in China and Taiwan but shared less than 88% identity with them. These results indicate that multiple genotypes of HEV cocirculate in Japan and contribute to the development of sporadic acute hepatitis, with the prevalence differing by age, sex, and geographic region.

High TT virus load as an independent factor associated with the occurrence of hepatocellular carcinoma among patients with hepatitis C virus-related chronic liver disease.

The TT virus (TTV) load was estimated in sera obtained from 237 patients with hepatitis C virus (HCV)-related chronic liver disease including 42 patients with hepatocellular carcinoma (HCC), by real-time detection PCR using primers and a probe derived from the well-conserved untranslated region of the TTV genome, which can detect all known TTV genotypes. Of the 237 patients studied, 18 (8%) were negative for TTV DNA, 87 (37%) had low TTV viremia (1.3 x 10(2)-9.9 x 10(3) copies/ml), and 132 (56%) had high TTV viremia (1.0 x 10(4)-2.1 x 10(6) copies/ml). Various features were compared between the patients with high TTV load (n = 132) and those with no TTV viremia or low viral load (n = 105). High TTV viremia (> or =10(4) copies/ml) was significantly associated with higher age (P < 0.05), past history of blood transfusion (P < 0.001), complication of cirrhosis (P < 0.05) or HCC (P < 0.0005), lower HCV RNA titer (P < 0.05), and lower platelet count (P < 0.01). On multivariate logistic regression analysis, high TTV viral load was a significant risk factor for HCC (P < 0.05), independent from known risk factors such as complication of liver cirrhosis (P < 0.0001) and high age (> or =65 years, P < 0.05), among all 237 patients. Furthermore, high TTV viral load was an independent risk factor for HCC among the 90 cirrhotic patients (P < 0.05). These results suggest that a high TTV viral load is associated independently with the complication of HCC and may have prognostic significance in patients with HCV-related chronic liver disease, although whether high TTV viremia mediates the progression of HCV-related chronic liver disease remains to be defined.

TT virus of certain genotypes may reduce the platelet count in patients who achieve a sustained virologic response to interferon treatment for chronic hepatitis C.

The platelet count increases after a sustained response to interferon (IFN) treatment for chronic hepatitis C (CH-C). However, the extent of the increase differs by patient. We investigated whether concurrent TT virus (TTV) infection interferes with the improvement of thrombocytopenia. Serial serum samples were obtained from 85 noncirrhotic CH-C patients who achieved a sustained virologic response for hepatitis C virus (HCV) upon IFN treatment, and tested for TTV DNA by three polymerase chain reaction (PCR) methods (UTR, N22 and TTV genotype-1). UTR PCR can detect essentially all TTV genotypes, whereas N22 PCR primarily detects four major TTV genotypes (1-4). Eighty-four patients (84/85, 99%) were positive for TTV DNA by UTR PCR, 27 (32%) by N22 PCR and 18 (21%) by TTV genotype-1 PCR just before IFN treatment was started (baseline). A sustained virologic response for TTV was observed in 6% (5/84) by UTR PCR, 52% (14/27) by N22 PCR and 56% (10/18) by TTV genotype-1 PCR. The platelet count was significantly lower in the N22 PCR-positive group than in the N22 PCR-negative group not only at baseline (14.9+/-3.8 vs. 18.1+/-6.4x10(4)/&mgr;l, P<0.05), but also at the non-HCV-viremic state one year after the completion of IFN treatment (15.5+/-2.8 vs. 18.6+/-5.5x10(4)/&mgr;l, P<0.05), the differences also being statistically significant by TTV genotype-1 PCR, but not by UTR PCR. These results suggest that certain TTV genotypes including genotype 1 may play a role in aggravating the thrombocytopenia of CH-C patients, either alone or in concert with HCV.