Irinotecan as salvage chemotherapy for advanced small bowel adenocarcinoma: a series of three patients.

Small bowel adenocarcinoma (SBA) is a relatively rare disease. Because of its rarity the role of chemotherapy either as adjuvant or for advanced disease has not been clearly defined. Therefore any information, including case reports, is warranted. We report on three patients with adenocarcinoma of the jejunum and ileum. Two patients with positive lymph nodes received postoperative adjuvant chemotherapy with 5-fluorouracil-folinic acid (5FU-FA) for 12 months but they developed metastatic disease 3 and 8 months later, respectively. The third patient was initially treated with the same agents but for metastatic disease. All patients were subsequently treated for tumor recurrence with irinotecan 350 mg/m2 i.v. every 3 weeks as salvage chemotherapy supported by Granulocyte Colony Stimulating Factor (GCSF) for 5 days. Two patients achieved a minor response and had a dramatic improvement of their symptoms. Their survival times after irinotecan administration were 14 and 6 months with an overall survival after primary diagnosis of 29 and 27 months, respectively. The third patient who had a tumor refractory to 5FU-FA progressed also on irinotecan and had an 8-month overall survival. Although conclusions cannot be drawn regarding the role of adjuvant chemotherapy in SBA, it seems reasonable to extrapolate from large bowel carcinoma experience. Irinotecan seems to have some degree of activity in the treatment of SBA but further studies are warranted.

Cholestatic syndrome with bile duct damage and loss in renal transplant recipients with HCV infection.

BACKGROUND/AIMS: Bile duct cells are known to be susceptible to hepatitis B and C virus, while it has been recently suggested that hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may have a direct role in the pathogenesis of vanishing bile duct syndrome (VBDS) after liver transplantation. We report the development of a cholestatic syndrome associated with bile duct damage and loss in four HCV-infected renal transplant recipients. METHODS: All four patients were followed up biochemically, serologically and with consecutive liver biopsies. Serum HCV RNA was quantitatively assessed and genotyping was performed. RESULTS: Three patients were anti-HCV negative and one was anti-HCV/HBsAg positive at the time of transplantation and received the combination of methylprednisolone, azathioprine and cyclosporine A. Two patients became anti-HCV positive 1 year and one patient 3 years post-transplantation. Elevation of the cholestatic enzymes appeared simultaneously with seroconversion, or 2-4 years later, and was related to lesions of the small-sized interlobular bile ducts. Early bile duct lesions were characterized by degenerative changes of the epithelium. Late and more severe bile duct damage was associated with bile duct loss. The progression of the cholestatic syndrome coincided with high HCV RNA serum levels, while HCV genotype was 1a and 1b. Two patients (one with HBV co-infection) developed progressive VBDS and died of liver failure 2 and 3 years after biochemical onset. One patient, despite developing VBDS within a 10-month period, showed marked improvement of liver function after cessation of immunosuppression because of graft loss. The fourth patient, who had mild biochemical and histological bile duct changes, almost normalized liver function tests after withdrawal of azathioprine. CONCLUSION: A progressive cholestatic syndrome due to bile duct damage and loss may develop in renal transplant patients with HCV infection. The occurrence of the lesions after the appearance of anti-HCV antibodies and the high HCV RNA levels are indicative of viral involvement in the pathogenesis. Withdrawal of immunosuppressive therapy may have a beneficial effect on the outcome of the disease.

Overlap syndrome of primary sclerosing cholangitis and autoimmune hepatitis.

We report a 46-year-old patient with the typical biochemical, histological and cholangiographic findings of primary sclerosing cholangitis (PSC) whose clinical and laboratory findings would also qualify her for the diagnosis of definite autoimmune hepatitis (AIH), according to the aggregate score of the International Autoimmune Hepatitis Group. We suggest that this patient may represent an example of the overlapping syndrome of PSC and AIH.

Cholestatic syndromes in renal transplant recipients with HCV infection.

We present two distinct types of cholestatic syndrome identified in eight renal transplant (RTx) patients with HCV infection. Four patients developed fibrosing cholestatic hepatitis (FCH) and four, vanishing bile duct syndrome (VBDS). All patients with FCH were anti-HCV (-) at the time of Tx and developed a cholestatic profile 1-4 months post-Tx, with high HCV-RNA levels. Immunosuppressive therapy was drastically reduced. Two patients died of sepsis and liver failure 16 and 18 months post-Tx, and the other two showed marked improvement and seroconverted to anti-HCV. Regarding the patients with VBDS, three were anti-HCV (-) and one was anti-HCV (+)/HBsAg (+) at the time of RTx. Two patients became anti-HCV (+) 1 year, and one patient, 3 years post-Tx. Two patients developed progressive VBDS and died of liver failure 2 and 3 years after onset, and two showed marked improvement after withdrawal of immunosuppression. In two of the patients, the progression of the disease coincided with elevation in serum HCV RNA levels. We concluded that a progressive cholestatic syndrome acquiring features of FCH or VBDS may develop in HCV-infected RTx patients. The association with high viral load implicated the virus in the pathogenesis. Drastic reduction of immunosuppression may favourably affect the outcome.

Fibrosing cholestatic hepatitis in renal transplant recipients with hepatitis C virus infection.

Fibrosing cholestatic hepatitis (FCH) has been described as a specific manifestation of hepatitis B virus (HBV) infection in liver allograft recipients characterized by a rapid progression to liver failure. Only sporadic cases have been reported in other immunocompromised groups infected with HBV and in a few transplant recipients with hepatitis C virus (HCV) infection. We present the occurrence of FCH in 4 HCV-infected renal transplant recipients within a series of 73 renal transplant recipients with HCV infection followed up closely serologically and with consecutive liver biopsies. All 4 patients received the triple-immunosuppressive regimen (azathioprine, cyclosporine A, methylprednisolone). The interval from transplantation to the appearance of liver dysfunction was 1 to 4 months and to histological diagnosis, 3 to 11 months. The biochemical profile was analogous to a progressive cholestatic syndrome in 3 patients, whereas the fourth patient had only slightly increased alanine aminotransferase and gamma-glutamyl transferase (gammaGT) levels. Liver histological examination showed the characteristic pattern of FCH in 2 patients, whereas the other 2 patients had changes compatible with an early stage. All patients were anti-HCV negative at the time of transplantation, whereas 2 patients, 1 with incomplete and 1with complete histological FCH features, seroconverted after 3 and 31 months, respectively. The patients were HCV RNA positive at the time of the first liver biopsy and showed high serum HCV RNA levels (14 to 58 x 10(6) Eq/mL, branched DNA). HCV genotype was 1b in 3 patients and 3a in 1 patient. After histological diagnosis, immunosuppression was drastically reduced. Two patients died of sepsis and liver failure 16 and 18 months posttransplantation, whereas the seroconverted patients showed marked improvement of their liver disease, which was histologically verified in 1 patient. In conclusion, FCH can occur in HCV-infected renal transplant recipients. It seems to develop as a complication of a recent HCV infection during the period of maximal immunosuppression and is associated with high HCV viremia levels. There are indications that drastic reduction of immunosuppression may have a beneficial effect on the outcome of the disease.

Factors associated with severity and disease progression in chronic hepatitis C.

BACKGROUND/AIMS: Chronic hepatitis C appears to have a highly variable natural course with 20% of patients developing cirrhosis within 20 years, while the majority of them run a relatively mild course. We studied the relationships of epidemiological, biochemical and virological features with histological severity (grade) and liver disease progression (stage). METHODOLOGY: Liver histology, serum HCV RNA level and HCV genotype were determined in a well-defined cohort of 152 consecutive (100 males, 52 females) patients with chronic hepatitis C. RESULTS: Patients with minimal or mild chronic hepatitis were significantly younger than those with moderate or severe chronic hepatitis (mean age: 41.1 vs 49.5 years respectively, p=0.003). On the other hand, patients with no or mild fibrosis compared to those with moderate or severe fibrosis and to those with cirrhosis were significantly more frequently males (73%, 64% and 43%, p=0.01), parenteral drug users (36%, 11% and 11%, p=0.01) and infected with other than 1b genotype (86%, 52% and 33%, p<0.0001), significantly younger (mean age: 37, 48 and 58 years, p<0.0001) and had significantly lower HCV RNA levels (geometric mean: 6.9, 19.2 and 17.5 x 10(5) eq/ml, p=0.007). Multivariate analysis showed that stage was significantly related only to patient age (p<0.0001), HCV genotype (p=0.0025) and HCV RNA level (p=0.044). CONCLUSIONS: In chronic hepatitis C, histological severity seems to be associated only with patient age, while progression of the disease is mainly associated with patient age, HCV genotype and viremia level.

Significance of IgM anti-HCV core level in chronic hepatitis C.

AIM: To investigate the significance of IgM antibody to hepatitis C virus (HCV) core antigen (IgM anti-HCV core) in chronic hepatitis C. METHODS: In a group of 112 patients with histologically proven chronic hepatitis C positive for HCV RNA, IgM anti-HCV core level was studied by a sensitive semi-quantitative enzyme immunoassay. Quantitation of serum HCV RNA was done by a second generation bDNA assay and determination of HCV genotype by RT-PCR and reverse hybridization. RESULTS: IgM anti-HCV core was detected in 72 (64.3%) of the 112 patients. ALT levels were significantly higher in IgM anti-HCV core positive than negative patients. No other significant difference was observed in any of the patients' characteristics between IgM anti-HCV core positive and negative groups. On the contrary, IgM anti-HCV core level was found to be significantly higher in females than in males, in patients with moderate or severe chronic hepatitis, in patients with high HCV RNA levels and in patients infected with HCV genotype 1b. Moreover, IgM anti-HCV core level was significantly correlated with age and ALT level. Multiple regression analysis showed that IgM anti-HCV core level was significantly related only to the HCV genotype (p=0.001), histological grade (p=0.017) and ALT level (p=0.038). CONCLUSIONS: Our data support the hypothesis that IgM anti-HCV core level is associated mainly with HCV genotype and secondly with liver disease necroinflammatory activity. These associations may have implications in the pathogenesis of chronic hepatitis C.

Differential diagnosis of acute HBsAg positive hepatitis using IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay.

BACKGROUND/AIMS: We determined the diagnostic significance of IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay (IMx CORE-M) in acute HBsAg positive hepatitis. METHODS: We studied prospectively for at least 6 months 100 patients with acute self-limited hepatitis B (group A) and 40 patients with acute hepatitis superimposed on histologically confirmed chronic hepatitis B (group B). On admission, all patients in group A were positive and those in group B were negative for IgM anti-HBc by a commercially available enzyme immunoassay. RESULTS: Based on the assay criteria, the rates of IMx CORE-M (> 1.2) positive serum samples on admission, 4, 12 and 24 weeks later were: in group A: 100%, 95%, 72%, 44% and in group B: 20%, 27.5%, 17.5%, and 15%, respectively. Misclassification was observed in 20-27.5% of the acute on chronic hepatitis B cases. However, the mean IMx CORE-M index value was found to be significantly higher in group A during the whole follow-up. In particular, on admission the mean IMx CORE-M index value was 2.504 +/- 0.435 (range: 1.508-3.482) in group A and 0.747 +/- 0.346 (range: 0.062-1.384) in group B (p < 0.001). Discriminant function analysis showed that the cutoff level between the two groups for IMxCORE-M index on admission was 1.5. Four to 12 weeks from admission, in the group with acute on chronic hepatitis B cases, 13 patients with HDV and/or HCV superinfection had significantly lower IMx-CORE M index values compared with 27 patients with acute hepatitis due to exacerbation of chronic hepatitis B. CONCLUSIONS: IMx CORE-M appears to be an accurate diagnostic test to differentiate acute from acute on chronic HBsAg positive hepatitis, but the cut-off level seems to be higher (1.5 instead of 1.2).

Comparative efficacy of a high or low dose of interferon alpha 2b in chronic hepatitis C: a randomized controlled trial.

OBJECTIVES: Our objective was to determine the relative efficacy of 6 months of treatment with 10 MU versus 3 MU of interferon-alpha 2b (IFN-alpha), three times weekly, in chronic hepatitis C (HCV) in a randomized trial. METHODS: Ten megaunits of IFN-alpha were given to 28 patients (group A), and 3 MU were given to 30 patients (group B). After treatment ended, follow-up was continued for 26 wk. RESULTS: Overall, the sustained response rate was higher in group A than in group B (16/26 or 61.5% vs. 12/28 or 42.9%, p = 0.17), but the difference did not reach statistical significance. However, it was higher in group A than in group B among patients with minimal or mild chronic hepatitis (15/20 or 75% vs. 9/24 or 37.5%, p = 0.013) and among those with mild or moderate fibrosis (15/17 or 88.2% vs. 11/19 or 57.9%, p = 0.042). IFN-alpha treatment significantly reduced histological activity index (HAI) scoring and all its parameters, except fibrosis, but the decrease was similar in the two groups. Sex, age, stage, and HCV genotype were statistically significant predictors of sustained response in univariate analysis. However, multiple logistic regression analysis revealed that advanced histological stage (severe fibrosis and cirrhosis) was the only significant prognostic factor of poor sustained response (RR = 31.0, 95% CI 2-460, p = 0.01), whereas the presence of genotype 1 had marginal statistical significance (RR = 5.0, 95% CI 0.9-28, p = 0.07). CONCLUSIONS: 1) A larger dose of IFN-alpha does not improve the sustained response rate; however, it may be of benefit in early stages of chronic hepatitis C. 2) Pretreatment, histological stage, and possibly HCV genotype appear to be the main prognostic factors of sustained response.

Amineptine induced liver injury. Report of two cases and brief review of the literature.

Two cases of amineptine induced liver injury in patients treated with the drug for 18 and 15 days respectively, are reported. Hepatic reaction lasted 60 days in the first case and 120 days in the second one, with the latter considered unusually prolonged. The patients history, the course of the reaction and the histologic findings were compatible with the diagnosis of drug induced liver disease in both cases. Furthermore, every other possible origin of hepatobiliary injury such as disorders of bile ducts, ongoing viral hepatitis and autoimmune hepatitis were excluded. The mechanism of amineptine induced liver injury and the influence of a possible genetic predisposition to amineptine hepatotoxicity are also discussed.

Terbinafine-induced cholestatic liver disease.

Hepatobiliary disorders associated with orally administered terbinafine have rarely been reported. We describe a case of prolonged terbinafine-induced cholestatic liver disease. Extrahepatic cholestasis, viral hepatitis and autoimmune liver disorders were excluded. The histological findings of marked cholestasis without evidence of extrahepatic biliary obstruction or acute hepatitis were compatible with the diagnosis of drug-induced liver disease. Biochemical parameters of liver cell damage returned to normal levels 6 months later.

Biochemical and virological response of chronic hepatitis C after treatment with interferon-alpha for 6 or 12 months: predictors of sustained remission.

OBJECTIVE: To evaluate the biochemical and virological response in chronic hepatitis C patients treated with interferon-alpha at the usual dosage of 3 MU thrice weekly for 6 or 12 months, and to analyse the significance of clearance of serum HCV RNA and of HCV genotype in the prediction of sustained biochemical remission. SETTING: Liver Unit, Western Attica General Hospital, Athens, Greece. PARTICIPANTS: Sixty consecutive patients with histologically confirmed chronic hepatitis C. INTERVENTIONS: All patients received interferon-alpha-2b in a dose of 3 MU thrice weekly for 6 (n = 26) or 12 (n = 34) months. Serial serum samples were retrospectively tested for the presence of HCV RNA by a polymerase chain reaction assay and pretreatment serum samples for the determination of HCV genotype. RESULTS: Sustained biochemical response rate was significantly higher in the 12-month group (62% vs. 35%, P = 0.037). Clearance of serum HCV RNA at the end of treatment was achieved in 33 (58.9%) of the 56 patients with detectable pretreatment HCV RNA. HCV RNA reappeared in serum significantly more often in patients treated for 6 than for 12 months (35.7% vs. 5.3%, P = 0.037). Serum HCV RNA after 6 months of therapy was a prognostic factor of sustained biochemical response, which was observed in 75% of the HCV RNA-negative and in only 16.7% of the HCV RNA-positive patients (OR 0.067, P < 0.001). Moreover, in patients negative for HCV RNA after 6 months of therapy, 12 months' treatment resulted in a higher sustained response rate than did 6 months' (89% vs. 57%, P = 0.05). HCV genotype 1 was associated with a significantly lower sustained response rate (30% vs. 60.7%, P = 0.035), whereas 12 months' treatment induced sustained remission significantly more often only in patients with genotype 1 (6/12 vs. 0/8, P = 0.024). CONCLUSION: In chronic hepatitis C treatment HCV genotype and serum HCV RNA after 6 months of therapy are strong predictive factors of a sustained response, and a 12-month rather than a 6-month interferon regimen may induce a more persistent clearance of HCV RNA in total and a higher sustained response rate in patients with HCV genotype 1 and in those who clear HCV RNA after 6 months of therapy.

Histopathology of chronic hepatitis C in relation to epidemiological factors.

BACKGROUND/AIMS: To evaluate the clinicopathological features of chronic hepatitis C, 170 liver biopsies were studied and histological grade and stage (degree of fibrosis) of hepatitis were correlated with epidemiological features and characteristic histological findings. METHODS/RESULTS: Normal liver was found in 3 (1.8%), minimal chronic hepatitis in 40 (23.5%), mild chronic hepatitis in 104 (61.2%) and moderate chronic hepatitis in 23 (13.5%) cases. Cirrhosis was observed in 24 (14.1%) patients and was more frequently encountered among patients more than 40 years old (34.4% vs 2.8%, p < 10(-6) and rarely among intravenous drug users in comparison with post-transfusion and sporadic cases (3% vs 25% and 20% respectively, p < 0.005). Minimal chronic hepatitis was more frequently observed among patients 40 years old or younger (30.3% vs 11.5%, p < 0.01)), while moderate chronic hepatitis was significantly more common in older age groups (24.6% vs 7.3%, p < 0.005). Multiple regression analysis revealed that only age was statistically related to histological grade and stage of hepatitis (p < 10(-5). The frequency of the histological features more likely seen in chronic hepatitis C, including steatosis (57.6%), lymphoid follicles and/or aggregates (F/A) (47.1%) and bile duct lesions (22.9%), increased with hepatitis grade and the latter two features were more often encountered in moderate chronic hepatitis (p < 0.005); in addition, both lesions statistically coexisted (p < 0.005). No correlation was found between histological findings and possible source of infection. CONCLUSIONS: More than half of the chronic hepatitis C patients presented mild histological lesions. Age was proven to be the only independent epidemiological factor related to histological grade and stage of hepatitis. Lymphoid F/A and bile duct damage are important diagnostic findings associated with hepatitis activity.

Fulminant hepatitis due to Epstein-Barr virus infection.

Epstein-Barr virus infection is a benign disease, which may occasionally be fatal, particularly in children. Epstein-Barr virus infection is rare in elderly subjects and appears to have a self-limited course. An unusual case of fulminant hepatitis due to primary Epstein-Barr virus infection in a 62-year-old male 18 days after a cardiosurgical operation and blood transfusions is described in the present paper. Post-mortem examination of the liver showed massive hepatic necrosis. The etiology was established by increase in IgM antibodies to Epstein-Barr virus (titer 1:3.120) in serum and by cellular expression of Epstein-Barr virus DNA in liver tissue.

Ductular structures in acute hepatitis with panacinar necrosis.

The development of ductular structures in acute hepatitis with panacinar necrosis was studied in 15 cases of fulminant hepatitis with variable clinical duration, using immunohistochemical markers. The immunophenotype of ductular structures was assessed by the expression of two bile duct epithelium determinants, wide spectrum cytokeratin and epithelial membrane antigen (EMA), and by their glycoconjugate expression using the specific binding lectins Dolichos biflorus agglutinin (DBA) and soybean agglutinin (SBA). Ductular structures showed a predilective, but not a strictly selective location in acinar zone 1 and at the periphery of newly formed parenchymal nodules. All were positive for keratin, while EMA and the lectins were identified less frequently. Cytokeratin expression was additionally observed in hepatic cells with no other phenotypic alteration: this occurred along isolated hepatic cords, within parenchymal remnants, in the spared parenchyma in acinar zone 1 and occasionally at the periphery of parenchymal nodules. The presence of cytokeratin expression in liver cell plates in association with intermediate morphological stages of tubular remodelling speaks in favour of biliary metaplasia of hepatocytes. This process may represent a phenotypic-functional accommodation of hepatocytes to an altered microenvironment, due to loss of parenchymal integrity. During the phenotypic shift, altered cytokeratin expression appears as one of the earliest biliary features, while EMA and the expression of glycoconjugates represent maturation markers.

HBcAg and HBsAg expression in ductular cells in chronic hepatitis B.

The possible involvement of bile duct epithelium (BDE) in chronic hepatitis B was examined by immunohistochemical investigation of HBcAg and HBsAg expression in biliary cells in 47 liver biopsies with both viral antigens detectable in hepatocytes. HBcAg- and HBsAg-positive cells were identified in nine and five cases, respectively, in atypical and occasionally in typical ductules in cases of acute exacerbation, chronic active hepatitis and active cirrhosis. Atypical ductules were usually located in areas of periportal fibrosis and in cirrhotic septa. Liver cell plates expressing viral markers and undergoing ductular transformation (positive reaction of hepatocytes to BDE-specific, wide-spectrum keratin) were also observed in acinar zone 1, at the periphery and within parenchymal nodules in a number of cases. The presence of both viral antigens in atypical ductules in cases of advanced chronic liver disease most probably expresses the persistence of the virus in cells deriving from biliary metaplasia of infected hepatocytes. However, the detection of the virus in a few typical ductules is indicative of a direct viral infection. According to these findings, ductular cells seem to serve as a suitable host for HBV, their genotype permitting viral replication and antigen production.

Portal tract lipogranulomas in liver biopsies.

Portal lipogranulomas in liver biopsy specimens were investigated. The incidence of biopsies containing portal lipogranulomas was 2.4%. Out of 20 biopsies with lipogranulomas 10 biopsies contained only one lipogranuloma. Portal lipogranulomas show a distinctive morphology with fat vacuoles surrounded by macrophages. They are consistently found together with parenchymal steatosis and probably originate from parenchymal fat being transported to portal tracts. Portal lipogranulomas are of importance in the differential diagnosis from other granulomas.