Fatigue is the most frequent and often debilitating symptom of chronic hepatitis C. It is unclear whether successful therapy of hepatitis C leads to its clinical improvement. In the Virahep-C study, patients with hepatitis C virus (HCV) genotype 1 infection were treated with peginterferon alfa-2a and ribavirin for up to 48 weeks while undergoing assessment of viral kinetics and clinical symptoms.Fatigue measurements were conducted, before, during and after therapy, as ‘presence’ (yes/no) and ‘severity’ (visual analog scale: 0–100 mm). The clinical, histologic, and virologic features that correlated with the presence and degree of fatigue were assessed focusing upon changes associated with sustained virological response (SVR).At baseline, 52% (n = 401) of participants reported having fatigue, which was more common in women than men (59% vs. 48%, p = 0.02) and slightly more severe (30 vs. 22 mm, p = 0.056). Fatigue was frequent and worse in cirrhotics versus those with lesser fibrosis (66% vs. 49%; 34 vs. 24 mm). Fatigue did not correlate with other parameters. The proportion of patients and median fatigue scores increased on treatment (52–78%; 25–40 mm, p <0.0001) with higher fatigue noted amongst those who ultimately achieved SVR (p <0.0001). On achieving SVR, there was a significant decrease in both frequency and severity of fatigue compared to their baseline (53–33%; 27–13 mm, both p <0.0001).Fatigue is common in patients with chronic hepatitis C but is poorly associated with biochemical parameters. Sustained response is accompanied by substantial improvement of fatigue.

GOALS:To evaluate the safety and efficacy of the combination of interferon and cyclosporine for the treatment of hepatitis C in previous nonresponder patients. BACKGROUND:Preliminary data indicated that adding the immunosuppressive agent cyclosporin A to interferon might improve response rates in patients with hepatitis C. STUDY:Ten previous virologic nonresponders with genotype 1 infection were included. Treatment consisted of interferon alfacon-1, 15 microg/d, and cyclosporine, 100 mg twice daily, for 4 weeks. The dose of interferon alfacon-1 was then decreased to 15 microg three times weekly, and cyclosporine was reduced to 50 mg twice daily. Therapy was continued for 48 weeks unless viremia persisted at week 24. RESULTS:Three of 10 subjects had an on-treatment virologic response, although one had a breakthrough with recurrent viremia during treatment and two relapsed after therapy was completed. On treatment responders had significantly higher trough cyclosporine levels at week 4 compared with nonresponders (P = 0.025). Serum creatinine levels remained stable, and no patient developed diabetes. Triglyceride levels increased during treatment. Cyclosporine was dose reduced in two patients for hypertension. CONCLUSIONS:Selected patients with hepatitis C tolerated therapy, including cyclosporine without severe or irreversible toxicity. Despite an association between higher cyclosporine levels and on-treatment response, the combination of cyclosporine and interferon was ineffective in producing a sustained response in previous nonresponder patients.

ABSTRACT OBJECTIVE: The aim of this retrospective analysis was to determine the natural history of hepatitis C virus infection in African Americans versus non-African Americans by evaluating the clinical, virological, and histological findings. METHODS: We examined in a retrospective manner the demographics, mode of infection, virological features, and histological progression of HCV infection in African Americans versus non-African Americans. There were 355 patients who met criteria based on adequate liver biopsy specimens and exclusion of other hepatic diseases. RESULTS: African Americans (n = 112) were significantly more likely to be infected with genotype 1 virus (88%) than were non-African Americans (n = 243; 67%; p ≤ 0.001). Baseline HCV RNA levels were similar, although baseline ALT values were significantly lower in African Americans (80.0 μl ± 5.5 vs 112.1 μl ± 6.2; p ≤ 0.001). African Americans were significantly older at the time of presentation and were significantly more likely to be women ( p ≤ 0.02). In African Americans, there was a trend toward less cirrhosis (22% vs 30%; p ≤ 0.1) and significantly less piecemeal necrosis on liver biopsy. Non-African Americans had significantly higher fibrosis scores, ALT values, and piecemeal necrosis ratings, and tended to progress more rapidly to cirrhosis. This difference in histological progression between the two groups was not explained by differences in alcohol consumption. CONCLUSION: The lower ALT, piecemeal necrosis scores, and slower progression of fibrosis in African Americans may reflect less immunological recognition of HCV-infected liver cells.

Spur cell anemia is an acquired form of hemolytic anemia caused by a structural abnormality of red cell membranes that results in spiculated erythrocytes. These peculiarly shaped red blood cells, called acanthocytes, have a shortened survival and undergo splenic sequestration and destruction. Spur cell anemia has been known to occur in several conditions, including chronic liver disease, and more specifically in alcoholic cirrhosis. Treatment of this disorder has been disappointing and usually indicates end-stage liver disease. Liver transplantation has been reported as the most effective treatment. We herein present a case of severe spur cell hemolytic anemia that successfully reverted after orthotopic liver transplantation and recurred secondary to resumption of alcohol intake and consequent liver graft failure. This case conclusively demonstrates the association among alcoholic cirrhosis, end-stage liver disease, and spur cell hemolytic anemia.

eradicate hepatitis C or prevent progression of disease, and we can all agree that there is a continuing need for more effective therapies, but at what point do you think that we should draw the line on potential new therapies that may be feasible to administer but do not seem to be either very practical nor reasonable given the current therapies that are available? C. R. (Timidly): Because the Japanese studies were started well before the availability of intereferon, before embarking on replicative long-term studies with glycyrrhizin in additional populations, you would have to hope that such patients would remain compliant in the current treatment environment for a decade or longer. I agree that this is not a very likely scenario with what we know about glycyrrhizin in contrast to the increasing data-base of interferon-based therapy results. R. U. (Kiddingly): Would you want to take daily glycyrrhizin infusions if you had hepatitis C? C. R. (Bashfully): Probably not, but the investigators are hoping that an oral glycyrrhizin product may be available to study in the future (13). R. U. (Wonderingly): No one would argue that oral agents are preferred over parenterally administered drugs, but with the introduction of pegylated interferons that need to be given only once weekly, and with their improved efficacy (15, 16), it is hard to imagine that an i.v. medication that fails to eradicate the hepatitis C virus would have many takers. C. R. (Boldly): You may well be right, but I wonder if patients who were willing to undergo interferon therapy might be willing to be treated with other parenterally administered medications if interferon-based therapies are ineffective. R. U. (Matter-of-factly): That remains to be seen, but I agree that van Rossum et al. have shown that it is feasible to do so with glycyrrhizin, at least on a short-term basis (13). Are you aware of any other parenteral hepatitis C therapies that we might be able to discuss at a future market research session? C. R. (Confidently): When we have some additional information, we are planning on talking about another natural product—histamine hydrochloride. I’ll be sure to call you to see if you’d be interested in that discussion. R. U. (Tongue-in-cheek): I can’t wait!

BACKGROUND: The distress imposed on family members of a patient with chronic disease, such as the inflammatory bowel disease, may predispose to mental disorders.Conversely, mental disorders in household members could contribute to stress-triggersd recurrences of the disease.Thus, our hypothesis was that.household-member of patients with inflammatory bowel disease have an increased frequency of mental disorders.AIM: to determine the prevalence of non-psychotic mental disorders in household-members of patients with inflammatory bowel disease.The 12-items version of the General Health Questionnaire (GHG) was administered to a group of 106 subjects from 52 families (53m/53w; mean age of 42 _+ 13 years) who lived with patients with inflammatory bowel disease.The 12-items GHQ is a standard questionnaire that assesses the predisposition to develop psychiatric non-psychotic disorders, and has been previously validated to Spanish.Its sensibility and specificity are 87 % and 91% respectively.The score of the GHQ ranges from 0 to 12 points.A score higher than 2 it is considered suggestive of mental disorder.Prevalence of mental disorders in household-members of patients with inflammatory bowel disease was compared with a previously analyzed unselected reference group of 12.245 controls who live in Catalunya (Gac Sanlt 1998;12:153).RESULTS: Prevalence of mental disorders in the 106 household-members was 39.0 %, whereas in the reference-control group was 17.4 %.In both groups, mental disorders were more prevalent in women (48.9 % in household-women vs 28.3 % in householdmen and 18.6 % in control-women vs 15.7 % in control-men).With regard to age, prevalence of mental disorders was higher (50.1%) in the subgroup of household-members 40 to 60 years old.In household-members younger than 40 years and older to 60 years the frequency of mental disorders was 30.0 %.Prevalence of mental disorders was similar for householdmembers of patients with Crohn's disease and ulcerative colitis (39.4 % vs 39.8% respectively).CONCLUSIONS: Household-members of patients with inflammatory bowel disease have an increased prevalence of non-psychotic mental disorders, specially affecting women and middleage household.These results reinforce the concept that global care of patients with inflammatory bowel disease should also include their household-members.

BACKGROUND:The majority of liver transplant centers require a 6-month abstinence period before listing candidates for liver transplantation with alcoholic cirrhosis and a persistent sobriety thereafter. We attempted to identify risk factors for failure to comply with these requirements.METHODS:Ninety-nine consecutive patients with alcoholic cirrhosis were referred for liver transplant evaluation between September 1996 and May 1998. The mean age was 49 years, 74% were male, and 54% were hepatitis C virus positive. To be listed, patients had to meet the following requirements. All patients received extensive psychosocial evaluations and were frequently monitored with random urine and blood alcohol tests; patients found positive were excluded or removed from the liver transplant waiting list. Detailed patient information was entered into a computerized database, and 36 discreet variables were analyzed in relation to success (patient listed and remained on the list) or failure (not listed or removed from the list based on noncompliance).RESULTS:Forty-nine patients were successfully listed. Nineteen received a transplant, with a 95% 1-year patient and graft survival rate and 21% alcohol relapse rate after transplantation. Twenty-two patients had either medical contraindication and/or died before transplant listing. Twenty-four patients were never listed and four were removed from the list due to recurrent alcoholism, for a total of 28 failures. Our statistical analysis identified five significant risk factors for failure: (I) living arrangement (alone/family versus community/friend), P=0.006; (II) history of suicide ideation, P=0.03; (III) history of previous alcohol-related hospitalization, P=0.01; (IV) lack of previous alcoholic rehabilitation before transplant evaluation, P=0.001; and (V) failure to accept further alcoholic rehabilitation before orthotopic liver transplantation, P=0.01.CONCLUSIONS:Our experience confirms that transplantation can be extremely successful in properly selected patients with alcoholic cirrhosis. We identified several predictive psychosocial factors of early alcoholic recidivism in transplant candidates.

G-25 chromatography as well as colorimetric immunoassays.Results: 1.In LR, maximal Itih-4 expression was observed at 30 minutes and 12 hours, predominantly centrizonal in distribution.2. Itih-4 expression was prominent in early liver development at day 9 and reached a second peak at day 16, being restricted to hepatoblasts, immature hepatncytes and differentiated hepatocytes.3. A marked increase in Itih-4 labeling was noted in proliferating hepatocytes, but not bile duct cells in liver explant cultures treated with I L-6 (100 units/ml).Itih-4 expression was not altered in explants cultured with TNF alpha.4. The fluorescence emission spectrum of metal free ITIH-4 showed a maximum at 332 nm with no change on addition of 5 mM Ca.The GST-fusion protein was recovered in the void fraction with no protein binding to the column.Similarly covalent binding of Itih-4 to hyaiuronic acid was not detected.Conclusions: In LR, Itih-4 expression corresponds to that of immediate early genes, such as c-myc, c-los, c-jun, IGFBP-2 and may contribute to the entry of normally quiescent hepetocytes into the early stages of the cell cycle.The markedly high expression of Itih-4 in early liver development and in explants treated with IL-6 suggest a prominent role for Itih-4 in the tissue remodeling that occurs during regenerative and developmental aspects of liver formation.

Background Hepatitis C (HCV) infects 1-3% of the United States population. African Americans(AA)are disproportionately infected with this virus (5%) and predominately infected with genotype 1 HCV. The natural history of this disease in AA has not been analyzed in a large number of HCV infected patients. Aim To analyze demographic, virolgical, biochemical and histological data in order to determine the natural history of liver disease in AA versus non-African Americans (non-AA). Methods We retrospectively reviewed the records of 289 patients with HCV seen at our institution from 1996 through 1999. We included patients who had adequate histological data to assess HAl and the degree of hepatic fibrosis. The following data were collected: age, gender, race, weight, baseline ALT, genotype, HCV RNA levels, mode and duration of infection. The duration of infection was estimated from earliest potential exposure to the virus. Liver biopsies were reviewed (blindly) and graded for histologic activity using the Knodell scoring system (HAl). Results There were 93 AA and 196 non-AA patients. There were no significant differences in mean baseline HCV RNA and weight. Although not significant, only 23% of AA's compared to 31% of non-Ax's were cirrhotic. There was a significant difference between AA and non-AA patients in piecemeal necrosis (PN)(2.5 vs. 3.1, p=.04), mean baseline ALT(86.55 vs. 112.41, p=.Ol), age (49 vs. 45, p=.OOI), and duration of infection(27 vs. 23, p=.(02). AA patients were more often infected with genotype 1 HCV (87.7% vs. 70.9%, p=.02) No AA patients were infected with genotype 3 HCV. When analyzing the data according to the duration of infection, AA patients had a lower ALT(56 vs. 134, p=.03), total HAI(3.1 vs. 4.8, p=.05), as well as portal inflammation(1.4 vs. 2.4,p=.02), PN(.8 vs. 3.1, p=.05), and HAl without fibrosis(3.5 vs. 6.6, p= .04) during the second decade of exposure (years 10-19). There were no AA patients with cirrhosis by the second decade compared to 26% of non-AA patients with cirrhosis, although this was not statistically significant. By the third decade (years 20-29), 18% of AA patients vs. 31% of non-Ax's were cirrhotic. The degree of fibrosis was significantly greater in non-AA patients (2.1 vs. 2.6, p=.04). Summary AA's are more likely to be infected with genotype 1 HCV and tend to progress more slowly to cirrhosis. In addtition, early in their exposure, AA's had lower HAl, baseline ALT, and percentage of cirrhosis, although mean baseline HCV RNA levels and weight were not significantly different.

IFNa is the only drug currently approved for treatment (Tx) of chronic hepatitis B. Aim of the present study was to compare the efficacy and safety of a combined therapy of IFNa plus lamivudine versus IFNa alone.

In patients with chronic HCV infection, higher initial and daily doses of IFN ex 2b (HOI) may help achieve early clearance of HCV RNA from serum.The value of HOI followed by IFN TIW dosing in combination with ribavirin (RBV) in non-responders (NR) to IFN is not known.AIM: To assess the efficacy and safety of HDI with IFN followed by combination therapy in achieving higher sustained virological response (SR) in pts.who failed IFN therapy.METHODS: Pts. who failed IFN were randomized to receive HOI with IFN the first 4 wks.(10MUqd x 14 d.then 5 MU qd x 14 d).Subsequently, IFN was given at 5 MU TIW along with RBV/placebo at doses of 800-1ooomg/d for a total of 48 wks.Pts.viremic at 24 wks.by NGI assay (negative < 100 copies /ml) were determined to be non-responders and blinding was broken.Pts. on placebo were offered open label RBV for additional 24-48 wks.Results are presented in an intention-to-treat analysis.RESULTS: All pts. at baseline (46 I+P and 47 I+R) had viremia and chronic hepatitis including 25% in both groups with either bridging fibrosis or cirrhosis.85% of I+P and 80% of I+R had Genotype I.After HDI (4 wks) results were comparable: HCV RNA was negative in 15% of both groups.No pt withdrew from treatment during HDI.Between wks 4 to 24, six pts in 1+ P (II %) and five pts in I+ R (11%) withdrew secondary to side effects or adverse events.See Table below.SUMMARY: In NR to IFN monotherapy, HOI followed by combination IFN + ribavirin are significantly more effective than HOI followed by IFN + placebo.CON-CLUSION: The role of HOI preceding combination therapy in achieving SR for NR to IFN monotherapy remains unclear.

In patients with chronic HCV infection, higher initial and daily doses of IFN ex 2b (HOI) may help achieve early clearance of HCV RNA from serum.The value of HOI followed by IFN TIW dosing in combination with ribavirin (RBV) in non-responders (NR) to IFN is not known.AIM: To assess the efficacy and safety of HDI with IFN followed by combination therapy in achieving higher sustained virological response (SR) in pts.who failed IFN therapy.METHODS: Pts. who failed IFN were randomized to receive HOI with IFN the first 4 wks.(10MUqd x 14 d.then 5 MU qd x 14 d).Subsequently, IFN was given at 5 MU TIW along with RBV/placebo at doses of 800-1ooomg/d for a total of 48 wks.Pts.viremic at 24 wks.by NGI assay (negative < 100 copies /ml) were determined to be non-respond-

Mathematical models have been used to study the dynamics of HIV. Using these same principles, the dynamics of hepatitis C virus (HCV) are reviewed during interferon (IFN) therapy. After initiating IFN treatment, there is an IFN dose-dependent exponential decline in viral RNA levels within the first 48 hours. This rapid 1.0 to 2.0 log decline was best explained by an effect of IFN in inhibiting viral production with a varying degree of effectiveness. By applying mathematical principles, viral serum half-life was estimated to be 3.0 hours and viral production rat was calculated to be 1.0 x 10(12) virions per day. After this rapid first-phase decline there was a slower second phase decline in viral levels that was highly variable between subjects. This phase was dependent on the rate of elimination of HCV-infected liver cells. The rapidity of the second phase proved to be the best predictor of early viral clearance. The use of these models to understand the life cycle of viruses and their response to therapy is reviewed.