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Background
For a very long time, this hepatitis had no identity except as non-A, non-B hepatitis. It was a diagnosis of exclusion. In 1989, the hepatitis C virus was discovered. It is one of the major causes of blood borne transmitted hepatitis as well as by inoculation by intravenous drug use. A significant percentage of patients progress to chronic disease with eventual cirrhosis, hepatocellular carcinoma, or death.
OUTLINE
Epidemiology General
IV Drug abuse
Race
Transfusion related
Transmission, nosocomial
Transmission, sexual
Transmission, vertical
TransplantationDisease Associations Autoimmune diseases
Lichen Planus
LymphomaPathogenesis RNA Flavivirus and genotypes
Progression to chronic diseaseLaboratory/
Radiologic/
Other Diagnostic TestingAutoantibodies
Viral load
Branched chain DNA
PCR
SerologyGross Appearance and Clinical Variants General
Pediatric
SkinHistopathological Features and Variants Acute
Chronic
With alcoholic hepatitis
Hepatitis B and C
SteatosisDifferential Diagnosis Hepatitis non-A, non-B, non-C Prognosis and Treatment General
CD34 positive cells
Infants born to HCV positive women
Interferon, predicting response
RNA measurement
Recurrence
TREATMENT
General
Antioxidants
Interferons
Ribavarin
Transplantation
Venesection for iron overloadCommonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS HCV
Non-A, Non-B hepatitisINCIDENCE Approximately 170,000,000 persons infected worldwide-about 3% of the world population
In developed nations, prevalence rates < 3%
Volunteer blood donors < 1%
Highly endemic areas of the world (eg, in Egypt), the prevalence rates range from 10% to 30%N Engl J Med 1999;341:556-62. Third National Health and Nutritional Examination Survey (NHANES II)
Overall prevalence of positivity was 1.8%, corresponding to an estimated 3.9 million persons nationwide
Serum samples from 21241 patients in United States between 1988 and 1994
The estimated annual incidence average rate of 50 per 100,000 (about 135,000 new cases per year) during the 1980's, but declined by more than 80% between 1989 and 1993, down to an estimated 28,000 new cases per year
8000 to 10,000 deaths per year AGE RANGE-MEDIAN In the most highly endemic areas of the world, prevalent among persons older than 40 years but is uncommon in those younger than 20 years Sixty-five percent of antibody-positive persons were 30 to 49 years old, and 74% were positive for HCV RNA, indicating that an estimated 2.7 million people in the United States were chronically infected, of whom 57% were infected with genotype 1a and 17% with genotype 1b EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION GENERAL RISK FACTORS Illicit drug use and high-risk sexual behavior
Poverty
Twelve or fewer years of education
Divorced or separatedInt J Epidemiol 1996;25:204-9.
Majority of the new HCV infections now occurring in the United States and other developed countries
Since 1992, at least two thirds of the new HCV infections in the United States
Transmission of hepatitis C occurs most often within the first few months of initiating drug abuse
RACIAL Neither sex nor racial/ethnic group was independently correlated with HCV infection
Incidence rates were highest among nonwhite personsSMOKING
Smoking and alanine aminotransferase levels in hepatitis C virus infection: implications for prevention of hepatitis C virus progression.Wang CS, Wang ST, Chang TT, Yao WJ, Chou P.
National Yang-Ming University, Institute of Public Health, Shih-Pai, Taipei 112, Taiwan, Republic of China.
Arch Intern Med 2002 Apr 8;162(7):811-5 Abstract quote BACKGROUND: Alcohol consumption is a well-known risk factor for elevated ALT levels, but the role of cigarette smoking is unclear.
METHODS: We collected a cross-sectional sample of 6095 inhabitants 35 years or older in a community with hyperendemic hepatitis B and C virus infections. We assayed levels of serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), and anti-hepatitis C virus antibody (anti-HCV). Multivariate logistic regression was performed to determine the factors for elevated ALT levels (> or =40 U/L) among people with different hepatitis infection statuses.
RESULTS: Prevalence of elevated ALT levels in individuals who were seronegative for both infections or seropositive for HBsAg or anti-HCV was 3.9%, 11.1%, and 30.8%, respectively. Subjects with elevated ALT levels were more likely to be seropositive for anti-HCV, male, and seropositive for HBsAg; to drink alcohol; to smoke; and to have undergone blood transfusion (P<.05). An association was found between elevated ALT levels and the consumption of cigarettes and alcohol among anti-HCV-seropositive subjects. In multivariate logistic analyses, alcohol consumption (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.2-4.1) and smoking (OR, 1.8; 95% CI, 1.1-2.7) were significantly associated with elevated ALT levels among anti-HCV-seropositive subjects, but no such association was found among HBsAg-seropositive subjects. The odds of elevated ALT levels were 7 times higher (95% CI, 2.7-18.8) for the anti-HCV-seropositive patients who smoked 1 or more packs of cigarettes per day and frequently drank alcohol than for those who did not.
CONCLUSIONS: Smoking and alcohol consumption are independently associated with elevated ALT levels among anti-HCV-seropositive individuals but not among HBsAg-seropositive individuals. Patients who are seropositive for anti-HCV are strongly advised not to smoke and drink alcohol to reduce the possible risk for aggravating the liver dysfunction.
TRANSFUSION RELATED Lancet 1995;345:95-6.
MMWR 1991;40:1-23.Blood transfused from an anti-HCV antibody-positive donor leads to 80% of the recipients infected
Routine screening of blood for anti-HCV antibodies has decreased the transmission of hepatitis C by blood product transfusion and now causes fewer than 4% of the new HCV infections in the United States
Transmission through infusion of blood products still remains a remote possibility (<1 in 100,000) from patients who have not yet developed antibodies or who test negative by the currently available assays for HCV RNA
TRANSMISSION, NOSOCOMIAL Hepatology 1993;17:5-8.
N Engl J Med 1996;334:555-8.
Hepatology 1992;16:1109-14.Introduction of universal precautions and screening of blood products for HCV, the annual incidence of hepatitis C in hemodialysis units has been reduced to 0.44%, lower in patients who are receiving ambulatory peritoneal dialysis
Transmission of HCV from health care providers to patients has also been documented. In one report, five of 6 patients had a genetically similar HCV strain that was later also found in the surgeon
Two percent to 8% of needlestick exposures from HCV-infected patients are followed by the development of HCV infection in health care workers, usually with hollow-bore needles
TRANSMISSION, SEXUAL Hepatol 1997;26(Suppl 1):66S-70S.
Low (~5%)
CDC have not recommended barrier precautions between stable, monogamous sexual partners when one is HCV positive but avoidance of potential exposure to blood (no sharing of razors, combs, or toothbrushes)
Coinfection with HIV increases the risk of sexual transmission of HCV
In a study of 147 HCV-infected patients, 98 of whom were also HIV infected, the prevalence of anti-HCV antibodies was 9.2% in the partners of the HIV-infected index cases but only 4.1% in the partners of the HIV-uninfected index cases
Scand J Gastroenterol 1993;28:343-6.
Nearly 15% of household contacts of patients with HCV-related chronic liver disease due to HCV developed HCV positivity, as compared with no infections among the household contacts of 30 asymptomatic HCV-infected blood donors
Stage of the liver disease, and not the length of relationship, may chiefly influence the risk of household transmission
TRANSMISSION, VERTICAL
Transmission of hepatitis C virus from mothers to infants. The Vertical Transmission of Hepatitis C Virus Collaborative Study Group.
Ohto H, Terazawa S, Sasaki N, Sasaki N, Hino K, Ishiwata C, Kako M, Ujiie N, Endo C, Matsui A, et al.
Blood Transfusion Service, Fukushima Medical College, Japan.
N Engl J Med 1994 Mar 17;330(11):744-50 Abstract quote
BACKGROUND. Although there are case reports of vertical transmission of hepatitis C virus (HCV), it remains uncertain to what extent infected mothers transmit this virus to their infants.
METHODS. We investigated the transmission of HCV from infected mothers to their babies by analyzing HCV RNA in the blood. Three independent studies were performed. First, 7698 parturient women were tested for anti-HCV antibodies; 53 were positive. Their 54 infants (including one set of twins) were followed prospectively for at least six months and tested for HCV disease were prospectively studied. Third, the families of three HCV-infected infants were examined retrospectively.
RESULTS. Of the 53 antibody-positive mothers, 31 were also positive for serum HCV RNA. Three of the 54 babies born to these mothers (5.6 percent) became positive for HCV RNA during the follow-up period. None of the babies of the 22 women who were antibody-positive but HCV RNA-negative became positive for HCV RNA. In the second study, HCV RNA was detected in one of the six infants of infected mothers. In the third study, HCV RNA was detected in the mothers of the three HCV-infected infants. In each of the seven infected infants we studied, the genomic sequence of HCV was almost identical to that from the mother. These seven mothers had significantly higher titers of HCV RNA than did the mothers of infants with no evidence of infection (mean [+/- SD], 10(6.4 +/- 0.5) vs. 10(4.4 +/- 1.5) per milliliter; P < 0.001).
CONCLUSIONS. HCV is vertically transmitted from mother to infant, and the risk of transmission is correlated with the titer of HCV RNA in the mother.
Hepatitis C virus infection in the mothers and infants cohort study.
Granovsky MO, Minkoff HL, Tess BH, Waters D, Hatzakis A, Devoid DE, Landesman SH, Rubinstein A, Di Bisceglie AM, Goedert JJ.
Division of Cancer Epidemiology and Genetics, Viral Epidemiology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20852, USA.
Pediatrics 1998 Aug;102(2 Pt 1):355-9 Abstract quote
OBJECTIVES: To estimate the hepatitis C virus (HCV) vertical transmission rate, the effect of potential risk factors, and the pattern of HCV antibody response and viremia in HCV-infected infants.
STUDY DESIGN: The Mothers and Infants Cohort Study enrolled both human immunodeficiency virus (HIV)-seropositive and HIV-seronegative pregnant women at five obstetric clinics in New York City in a prospective cohort study between January 1986 and January 1991. HCV-infected mothers and their 122 offspring were followed-up for a minimum of 12 months for evidence of HCV infection as determined by persistent HCV antibodies or detection of HCV RNA by reverse transcription polymerase chain reaction. Comparisons among groups for categorical variables were performed using the Fisher's exact test.
RESULTS: Seven (6%; 95% confidence interval, 2%-11%) of the 122 infants were HCV-infected. There was a tendency for increased risk of transmission with maternal viral and obstetrical factors, such as coinfection with HIV (7% vs 4%), high HIV viral load (13% vs 6%), HCV viremia (8% vs 3%), vaginal delivery (6% vs 0%), and female gender of offspring (8% vs 3%), although none of the associations reached statistical significance. After loss of maternal antibody, HCV antibody seroconversion occurred at a mean age of 26 months in 3 HIV-coinfected infants compared with 7 months of age in 4 HCV-infected HIV-uninfected infants. Serial samples showed that HCV RNA persisted in 6 infants for at least 18 to 54 months.
CONCLUSIONS: Our study is in accordance with other studies that have shown low overall HCV vertical transmission risk and a trend toward higher risk with maternal risk factors such as HIV-coinfection or HCV viremia. A delay in infant HCV antibody response may be associated with HIV coinfection although larger studies are needed to confirm these findings.
J Hepatol 1998;28:191-7.
Transmission by breast-feeding is unusual
Case-control study of 65 mother-infant pairs in whom mothers were anti-HCV positive, compared with 42 patients who were anti-HCV negative, 3 infants developed hepatitis C by 3 months of age
All 3 babies were born to symptomatic mothers with high serum viral loads, ranging from 2.5 × 108 to 4.5 × 109 copies/mL. HCV genotypes were concordant within each of these 3 mother/baby pairs. These 3 infants were delivered by elective cesarean section at term and had been breast-fed regularly.
Asymptomatic mothers do not seem to transmit the infection by breast-feeding, although symptomatic women, especially with high viral loads, may pose some risk to their infants
Consensus recommendations of the CDC do not proscribe breast-feeding by mothers with HCV infection.
J Hepatol 1998;28:191-7.
Household transmission of HCV remains an unlikely mode of transmission based on the currently available data, although one study reported a positive correlation with duration of exposure to the virus.
Follow-up of transmission of hepatitis C to babies of human immunodeficiency virus-negative women: the role of breast-feeding in transmission.
Ruiz-Extremera A, Salmeron J, Torres C, De Rueda PM, Gimenez F, Robles C, Miranda MT.
Pediatrics Department, San Cecilio Hospital, Granada, Spain.
Pediatr Infect Dis J 2000 Jun;19(6):511-6 Abstract quote
BACKGROUND: The studies on hepatitis C virus (HCV) vertical transmission, the effect of potential risk factors and the role of breast-feeding have reported conflicting results.
PATIENTS AND METHODS: Seventy-three infants of 63 anti-HCV-positive and anti-HIV-negative mothers were studied from 1993 to 1999 in the south of Spain. The mean period of follow-up in children was 29.2 +/- 19 months (range, 8 to 76 months); 6 (8%) children were lost to follow-up. Breast milk was studied for HCV-RNA in 68 samples of 35 mothers.
RESULTS: Alanine aminotransferase was high in 19 (26%) and HCV-RNA was positive in 46 (63%) pregnant woman. Breast milk HCV-RNA was negative in nonviremic mothers and positive in 20% of the viremic mothers. The overall rate of vertical HCV transmission was 11.9% (n = 8) (95% confidence interval, 6 to 23%) if HCV-RNA was positive one or more times, but only 1.5% (n = 1) (95% confidence interval, 0.1 to 9%) if HCV-RNA was permanently positive. Seven HCV-infected children did not develop antibodies to HCV, and they had a spontaneous clearance of the virus. A 10-month-old baby was HCV-RNA-positive from birth to the end of the follow-up. The genotype in each of the infants was consistent with that of their mother. The rate of HCV transmission was higher for infants of mothers with higher HCV viremia (P < 0.01) and also for infants whose mothers were HCV-RNA-positive in breast milk (P < 0.05). There were no statistically significant differences between other risk factors.
CONCLUSION: The presence of transitory viremia without seroconversion indicates that the vertical transmission of HCV is not important. This could be related to the viral charge and ingestion of milk of HCV-RNA-positive mothers. However, to advise avoidance of maternal breast feeding, it would be necessary to conduct larger studies.
Mother-to-child transmission of hepatitis C virus: evidence for preventable peripartum transmission.
Gibb DM, Goodall RL, Dunn DT, Healy M, Neave P, Cafferkey M, Butler K.
Medical Research Council Clinical Trials Unit, London, UK.
Lancet 2000 Sep 9;356(9233):904-7 Abstract quote
BACKGROUND: Little information is available about the timing of mother-to-child transmission of hepatitis C virus (HCV), and no interventions to decrease transmission rates have been identified. We examined the effect of risk factors, including mode of delivery, on the vertical transmission rate.
METHODS: Data from HCV-infected women and their infants from three hospitals in Ireland and from a British Paediatric Surveillance Unit study of infants born to HCV-infected mothers were used to estimate the vertical transmission rate and risk factors for transmission. We used a probabilistic model using methods that simultaneously estimated the time to HCV-antibody loss in uninfected infants and the diagnostic accuracy of PCR tests for HCV RNA.
FINDINGS: 441 mother-child pairs from the UK (227) and Ireland (214) were included. 50% of uninfected children became HCV-antibody negative by 8 months and 95% by 13 months. The estimated specificity of PCR for HCV RNA was 97% (95% CI 96-99) and was unrelated to age; sensitivity was only 22% (7-46) in the first month but rose sharply to 97% (85-100) thereafter. The vertical transmission rate was 6.7% (4.1-10.2) overall, and 3.8 times higher in HIV coinfected (n=22) than in HIV-negative women after adjustment for other factors (p=0.06). No effect of breastfeeding on transmission was observed, although only 59 women breastfed. However, delivery by elective caesarean section before membrane rupture was associated with a lower transmission risk than vaginal or emergency caesarean-section delivery (odds ratio 0 [0-0.87], p=0.04, after adjustment for other factors).
INTERPRETATION: The low sensitivity of HCV RNA soon after birth and the finding of a lower transmission rate after delivery by elective caesarean section suggest that HCV transmission occurs predominantly around the time of delivery. If the findings on elective caesarean section are confirmed in other studies, the case for antenatal HCV testing should be reconsidered.
Prospective study of mother-to-infant transmission of hepatitis C virus.
Tajiri H, Miyoshi Y, Funada S, Etani Y, Abe J, Onodera T, Goto M, Funato M, Ida S, Noda C, Nakayama M, Okada S.
Department of Pediatrics, Osaka University, Faculty of Medicine, Japan.
Pediatr Infect Dis J 2001 Jan;20(1):10-4 Abstract quote
BACKGROUND: Mother-to-infant transmission of hepatitis C virus (HCV) could become the main route of HCV infection in the future because there are no methods available to prevent vertical infection. The aim of this study was to determine the incidence of mother-to-infant transmission in infants born to mothers who tested positive for anti-HCV antibodies and to elucidate associated risk factors for transmission.
METHODS: Screening was conducted for 16,800 pregnant women with an anti-HCV antibodies test, and 154 mothers were positive. From the positive group 141 mothers were enrolled in the study and their 147 infants were followed from birth for serum alanine aminotransferase activity, anti-HCV antibodies and HCV RNA. HIV infection was tested in 73 of 141 mothers, all of whom were negative.
RESULTS: Thirty-three infants were dropped from the study because they were followed for <6 months or were not tested adequately. Of the 114 infants finally evaluated 9 (7.8%) had detectable HCV RNA. The transmission rate was not influenced by the mode of delivery [vaginal delivery, 8 of 90 vs. cesarean section, 1 of 24 (P = 0.396)] or by the type of feeding [9 of 98 for breast-fed infants vs. 0 of 16 for formula-fed infants (P = 0.243)]. All infected infants were born to mothers who had HCV viremia at the delivery (P = 0.040) and to those with a high viral load (P = 0.019).
CONCLUSIONS: Our prospective study showed that the transmission rate of mother-to-infant HCV infection was 7.8% in anti-HCV antibody-positive mothers. Risk was related to the presence of maternal HCV viremia at delivery and a high viral load in the mothers.
TRANSPLANTATION J Hepatol 1994;20:768-72.
If organ or bone marrow donors are HCV RNA positive, there are high rates of HCV infection among recipients of solid organs (liver, kidney, heart, lung) or bone marrow
This infection nearly always becomes chronic and leads to hepatitis in about half of the recipients
HCV infection has been transmitted by tissue transplantation of bone, ligament, and tendon allografts as well
Infection in recipients already infected with the HCV with a second strain of the virus from a donor organ has been demonstrated
Correlation of histology, viral load, and in situ viral detection in hepatic biopsies from patients with liver transplants secondary to hepatitis C infection.Nuovo GJ, Holly A, Wakely P Jr, Frankel W.
Department of Pathology, Ohio State University Medical Center, Columbus, OH.
Hum Pathol 2002 Mar;33(3):277-84 Abstract quote The diagnosis of hepatitis C infection in the setting of liver transplantation in based on several variables, including histopathologic changes and the presence of viral RNA in the serum. It may be difficult to differentiate acute rejection from recurrent viral hepatitis in liver biopsies from patients who received liver transplants for end-stage hepatitis C infection.
The purpose of this study was to analyzed the histologic features, viral load, and in situ viral detection in 37 biopsies taken from 25 people who underwent liver transplant for end-stage hepatitis C infection. Hepatitis C antigen was detected in 9 of 37 (24%) biopsies using immunohistochemistry; the detection rate increased to 19 of 37 (51%) using reverse transcriptase in situ polymerase chain reaction for viral cDNA. Hepatitis E cDNA was detected in 4 of 37 (11%) cases, hepatitis G cDNA in 3 of 37 (8%) cases and in 1 case cytomegalovirus was noted; with several cases of dual infection, 22 of 37 (59%) of tissues were positive for at least 1 virus.
Histologic parameters that significantly correlated with in situ viral detection included single-cell hepatocyte necrosis (P = 0.02), bile duct damage (P = 0.03), lymphoid aggregates (P = 0.02), and cholestasis (P = 0.01). Further, a serum viral load exceeding 1,250,000 viral equivalents/ml was strongly correlated with in situ viral detection in the liver (P = 0.01). We conclude that certain histologic features and an increased viral load are highly correlated with the in situ detection of viral RNA in the liver, which is consistent with recurrent viral infection.
DISEASE ASSOCIATIONS CHARACTERIZATION AIDS/HIV
- The role of liver biopsy in the management of chronic hepatitis C in patients infected with the human immunodeficiency virus.
Quereda C, Moreno S, Moreno L, Moreno A, Garca-Sanmiguel L, Perez-Elas MJ, Navas E, Dronda F, Moreno A, Casado J, Antela A, Lopez-San Roman A.
Department of Infectious Diseases, Hospital Ramon y Cajal, Madrid, Spain.
Hum Pathol. 2004 Sep;35(9):1083-7. Abstract quote
We evaluated the role of liver biopsy in the management of chronic hepatitis C in HIV-infected persons. Patients included had abnormal alanine transaminase (ALT) levels, detectable HCV RNA, and an interpretable liver biopsy. Demographic, epidemiologic, clinical, laboratory, histological, and therapeutic data were recorded in all patients.
We also registered the clinical diagnosis of cirrhosis (previous to biopsy) and whether the biopsy result deferred the decision of initiating therapy. During the 33-month duration of the study, 112 patients were included. The degree of fibrosis in liver biopsies was none or mild (F0 or F1) in 47 patients (42%) and was significant or severe in 65 (58%). Seventeen patients (15%) had histological cirrhosis. By logistic regression analysis, only portal hypertension (odds ratio [95% confidence interval], 5.3 [1.05-25.9], P = 0.04) was independently associated with significant fibrosis.
Overall, cirrhosis was predicted before biopsy in 29 patients (26%) by the caregiving physician, but only 8 of these were confirmed histologically. The clinical prediction of cirrhosis before biopsy had a sensitivity of 47%, a specificity of 78%, a positive predictive value of 28%, and a negative predictive value of 89%.
Histological findings changed the decision to initiate HCV therapy in 19 patients (17%) because of little or no fibrosis. Liver biopsy is a useful tool in the management of HCV-HIV-coinfected persons. In addition to allowing grading and staging of the disease far better than any other method or combination of methods, it is important for making management decisions for patients coinfected with HCV and HIV.
- Fibrosis is worse in HIV-HCV patients with low-level immunodepression referred for HCV treatment than in HCV-matched patients.
Rullier A, Trimoulet P, Neau D, Bernard PH, Foucher J, Lacoste D, Winnock M, Urbaniak R, Ballardini G, Balabaud C, Bioulac-Sage P, Le Bail B.
Department of Pathology, Bordeaux Hospital, Bordeaux, France.
Hum Pathol. 2004 Sep;35(9):1088-94. Abstract quote
Hepatitis C virus (HCV) infection is frequent in human immunodeficiency virus (HIV)-infected patients. It is known to have an aggressive course in significantly immunosuppressed patients, and cirrhosis C has become one of the main causes of mortality in HIV-HCV coinfected patients since the improvement of antiretroviral therapy. The reasons for this severe fibrotic evolution are unclear.
This prospective study compared chronic HCV lesions, liver immunocompetent cells, fibrosis and liver HCV loads in 2 cohorts of naive patients referred for HCV treatment: 33 HIV-HCV coinfected patients with CD4 >250/microL and 33 HCV-infected patients matched for the main risk factors of fibrosis. Fibrosis, particularly perisinusoidal fibrosis, was more marked in the coinfected patients. This occurred in the absence of a significant difference in disease activity. The number of CD3+ cells in the liver was higher in the HIV-HCV patients than in the HCV patients. Conversely, the number of liver CD4+ cells was lower in HIV-HCV patients than in HCV patients. The numbers of CD8+ and CD68+ cells were similar in the 2 groups. Finally, liver HCV load, assessed by immunostaining and reverse-transcription polymerase chain reaction, was similar in the 2 groups.
We conclude that in the population of HIV-HCV coinfected patients with low-level immunosuppression referred for HCV treatment, fibrosis is worse than in HCV patients and the proportion of CD4+ lymphocytes among CD3+ cells is markedly decreased in the liver, whereas intrahepatic viral load is similar. Our data confirm the need to treat such patients against HCV, and suggest that HIV infection could favor fibrosis via the modulation of the intrahepatic immune response.AUTOIMMUNE DISEASES Most common autoimmune disorder found in patients with CHC
Increased prevalence of antithyroid antibodies in patients with hepatitis C, even before treatment with interferon
Prevalent in older women
Interferon alfa (IFN-) therapy may induce autoimmune thyroiditis-develops more often in patients with pre-existing antithyroid antibodies than in those without and may resolve after cessation of IFN- therapy or it may persist even after IFN- has been discontinued
Not associated with typical primary Sjögren's syndrome, but a lymphocytic sialadenitis does occur with increased prevalence in patients with CHC
Often associated with xerostomia (8%-36%), but it is not associated with xeropthalmia or with anti-Ro(SS-A) antibodies
Relatively mild form of lymphocytic capillaritis of the salivary glands, and the infiltrating lymphocytes are predominantly CD8+, in contrast to those in primary Sjögren's syndrome
Elevated titers of platelet-associated IgG were described in 88% of patients with CHC
IFN- therapy leads to a decrease in the platelet count
Presence of pre-existent thrombocytopenia is not an absolute contraindication to the use of IFN
BILE DUCT DYSPLASIA
*Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD †Department of Pathology, University of Washington School of Medicine, WA ‡Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
Intrahepatic cholangiocarcinomas are rare and risk factors remain incompletely understood, but one recently identified potential risk factor is chronic hepatitis C (HCV) infection.
To further study this potential association, we searched for dysplasia in the intrahepatic bile ducts in native explanted livers in cases of chronic HCV and control groups. Cases of chronic biliary tract disease were excluded. A total of 1058 explants were reviewed: HCV (511), alcohol alone (112), HCV and alcohol (85), HBV (67), cirrhosis from other causes (149), and noncirrhotic livers, for example, cases transplanted for acute liver failure (134).
Dysplasia of the intrahepatic bile ducts was seen in 19/1058 (1.8%) of cases and was associated with chronic HCV infection and alcohol use, P=0.01. Ten out of 19 cases of dysplasia were in the setting of chronic HCV, 5/19 were in the setting of alcohol alone, and the remaining 4/19 were in the setting of combined HCV and alcohol. Seventeen out of 19 cases were classified as low-grade dysplasia and 2/19 as high-grade dysplasia. In all cases of dysplasia, the lesions were multifocal and involved septal-sized bile ducts. In 16/19 cases, the dysplasia was papillary whereas in 3/19 cases the dysplasia was flat.
In conclusion, dysplasia can be found within the intrahepatic bile ducts in chronic HCV cirrhosis, supporting recent epidemiologic studies identifying chronic HCV as a major risk factor for intrahepatic cholangiocarcinoma. Alcohol also seems to be a risk factor. The dysplastic changes are multifocal, involve septal sized bile ducts, and are typically papillary.LICHEN PLANUS LYMPHOMA A high prevalence (20%-40%) of antibodies against HCV has been described in patients with non-Hodgkin's B-cell lymphomas, but not in other hematologic malignancies
Low-grade malignancies associated with cryoglobulinemia and in mucosal-associated lymphoid tumors of the gastrointestinal tract (MALT syndrome)
PATHOGENESIS CHARACTERIZATION RNA Flavivirus Positivesense, single-stranded RNA genome within a nucleocapsid
The nucleocapsid and RNA are packaged in an envelope, derived from host membranes, into which viral-encoded glycoproteins are inserted
Two populations of virus have been described in sera of infected hosts:
A high-density fraction is believed to be composed of free or immunoglobulin-bound viral particles
Low-density fraction appears to be bound to low-density lipoproteinsHighly conserved 5´ and 3´ terminal regions that flank a large nucleotide open reading frame, which encodes a polyprotein of approximately 3300 amino acids
RNA polymerase introduces random nucleotide errors that the polymerase is not able to correct because it lacks a proofreading function
Frequency with which such errors occur is very high, estimated at between 1/100 to 1/1000 substitutions per nucleotide site per year
HCVs are heterogeneous, with only about 70% similarity among all known isolates
Genotypes Hepatology 1994;19:1321-4
Sequencing of relatively well-conserved regions (E1, NS4, or NS5), isolates of the same genotype have an average sequence similarity of 95%, with a range of 88% to 100%
Subtypes within the same genotype have an overall average sequence similarity of about 80%, whereas different genotypes have sequence similarities of the less well-conserved regions of only about 65% (range, 55%-70%)
Simmonds Classification scheme:
Major genotypes are assigned arabic numbers
Subtypes are assigned small letters
Genotype Percentage in US Characterization 1a ~50-60 Difficult to eradicate with currently available therapies 1b ~15-20 Most prevalent in Europe, Turkey, Japan, Taiwan 1c <1 2a/b/c ~10-15 Widely distributed; respond best to currently available therapies 3a/b ~4-6 Found mainly in India, Pakistan, Australia, Scotland 4 <5 Found mainly in Middle East, Africa 5 <5 Found mainly in South Africa 6 <5 Found mainly in Hong Kong, Macao
Assessment of hepatitis C virus RNA and genotype from 6807 patients with chronic hepatitis C in the United States.
Blatt LM, Mutchnick MG, Tong MJ, Klion FM, Lebovics E, Freilich B, Bach N, Smith C, Herrera J, Tobias H, Conrad A, Schmid P, McHutchison JG.
National Genetics Institute, Los Angeles, CA, USA.
J Viral Hepat 2000 May;7(3):196-202 Abstract quote
Hepatitis C virus (HCV) RNA status and HCV genotype have become important tools in the diagnosis and monitoring of therapy in chronic HCV infection. To establish a database with respect to HCV genotype and serum HCV RNA concentrations in chronic hepatitis C patients in the United States, we analysed 6807 chronic hepatitis C patients who had HCV RNA and HCV genotype tests conducted at a central laboratory.
The HCV RNA concentration cut-off for the lower 25th percentile of this population (low titre) was 0.9 x 106 copies ml-1. The median HCV RNA concentration was 3.5 x 106 copies ml-1 and the cut-off for the upper 25th percentile (high titre) was 5 x 106 copies ml-1. Male patients had a median HCV RNA concentration of 3.9 x 106 copies ml-1, which was significantly higher than the median HCV RNA level for females (2.75 x 106 copies ml-1; P < 0.001). HCV genotype 1 was detected in 73% of patients; genotype 2 in 14%; genotype 3 in 8%; mixed genotype in 4%; and genotypes 4, 5 and 6 with a frequency of < 1%.
Patients from the Northeast, Southeast and Midwest had significantly (P < 0.001) more infections with genotype 1 than patients from the Western and Southern regions. African-American patients were more likely to be infected with genotype 1 when compared with Caucasian, Hispanic or Asian Pacific Islanders (P < 0.001).
Patients infected with HCV genotype 1 and mixed HCV genotypes had significantly higher serum HCV RNA concentrations when compared with HCV genotypes 2 and 3 (P < 0.001 for all comparisons).
PROGRESSION TO CHRONIC DISEASE CHARACTERIZATION Relation of Hepatic Iron Distribution, HFE Genotype, and Disease Course
Chiara Corengia, MD, etal.
The aim of the present study was to describe the histopathologic features of hepatic iron accumulation in patients with chronic hepatitis C (CH-C) infection, the relation between HFE mutations and hepatic iron location and among iron distribution, HFE, and hepatic damage.
We studied 206 patients with CH-C infection. Of 101 patients with hemosiderin deposits, 90.1% had iron deposits in hepatocytes (alone or with sinusoidal and/or portal involvement). The hepatic iron score increased significantly as iron accumulation involved sinusoidal and portal tract compartments and according to HFE genotypes. Severe fibrosis and cirrhosis were associated more markedly with the presence of hemosiderin iron in the 3 hepatic compartments, HFE mutations, and high alcohol intake. We suggest that part of the iron accumulation in CH-C infection derives from increased iron absorption and release from storage cells and that the amount and distribution of hepatic iron deposits is related to hepatic damage.
HFE mutations favor both processes, but other factors, genetic or acquired, are involved.Viral factors J Hepatol 1998;28:939-44.
42 patients with diagnoses of acute hepatitis C who were followed up for up to 1 year, there was an overall rate of development of chronicity of 59.5%
Rate was 92% in persons infected with genotype 1b HCV and these had more severe histologic changes
HCV virus genotype 1b is independently associated with development of chronic hepatitis and greater likelihood of progression
Mode of acquisition Hepatology 1997;26:485-90.
Large inocula of HCV are associated with more severe disease
6664 patients with 21% had biopsy-proven cirrhosis
Prevalence of cirrhosis varied markedly according to the modes of transmission of HCV:
Recipients of blood transfusions (23%)
Users of illicit drugs (7%)Host immune responses J Virol 1999;73:2938-46.
5 patients who spontaneously cleared HCV were compared with 10 who had persistent viremia, the quasispecies complexity was higher and the apparent immune pressure was lower in those with persistent viremia
Presence of both characteristics increased the likelihood of chronic infection
Hepatology 1999;29:908-14.
142 patients with history of illicit drug use were followed up semiannually from 1988 through 1996
HCV infection was detected serologically in 43 (30%) of the participants over a median follow-up of 72 months
Spontaneous viral clearance was noted in 6 (14%) of the 43 who became infected, whereas viral persistence was observed in 37 (86%)
Those who spontaneously cleared the virus were more likely to be:
Caucasian
Developed jaundice (suggesting more severe acute hepatitis), and to have had a l
Lower peak viral titerOutcome for any given person could not be predicted reliably by analyses of these clinical features
The more vigorous the antibody and T-cell responses to acute HCV infection, the more likely will be spontaneous resolution of viral infection, and vice versa
N Engl J Med 1995;332:1463-6.
Am J Gastroenterol 1993;88:240-3.
Gut 1993;34(Suppl):S13-S16
Follow-up periods ranged from 4 to 11 years
Cirrhosis in 8% to 46% of the patients, and HCC developed in 11% to 19%
Hepatology 1998;28:1687-95.
838 patients with CHC were followed up for 50 ± 27 months
During follow-up 62 patients died (31 from liver disease, 31 from other causes), and 12 needed liver transplantation. When compared with an age- and sex-matched control population, those with CHC had increased mortality mainly when cirrhosis was present at baseline and in patients who were younger than 50 years at entry. During follow-up, an additional 30 patients developed nonlethal complications of cirrhosis
By multivariate analysis, survival was decreased by:
Cirrhosis
Long duration of disease
History of intravenous drug use
Excessive alcohol consumptionInterferon therapy was associated with improved survival
The risk of HCC was increased by:
Cirrhosis
Long duration of infection
Early elevations of serum bilirubin levels, even when cirrhosis was absent at diagnosisHepatology 1998;28:562-7.
Among 627 nonalcoholic North American patients with CHC:
282 patients (45%) were transfusion recipients
262 patients acquired the disease by other routes of percutaneous exposure
83 were without identified risk factorsDuration of follow-up was 1 to 25 years
Four hundred sixty-three patients had liver biopsies:
No cirrhosis in 59%
Cirrhosis in 37%
HCC in 4% (all the latter also had underlying cirrhosis)Of the patients with cirrhosis:
68% had acquired the infection via transfusion as compared with 23% who acquired it through other percutaneous exposuresOf the 215 patients with blood transfusions:
Cirrhosis was present in 55%Of the nontransfusion parenteral exposure group the corresponding figure was 21%.
During the follow-up period, hepatic decompensation developed in 31% of the patients with cirrhosis
By logistic regression analysis, only the mode of transmission (not the age or estimated disease duration) predicted the risk of liver failure:
Posttransfusion hepatitis C were more likely to develop decompensation than those who were not transfusion recipients, with a relative risk of 3.92Hepatology 1999;29:1311-6.
112 patients with compensated HCV cirrhosis and a documented history of either intravenous drug use or transfusion were followed up for a mean duration of 4.5 years
The cumulative probabilities of hepatic decompensation and development of HCC were 22.2% and 10.1%, respectively, with estimated yearly incidences of 4.4% and 2.0%
The cumulative 5-year survival probability was 83% from entry and 51% from onset of hepatic decompensation
The actuarial yearly rate of mortality was 3.4% and the yearly rate of liver transplantation was 9.8%
The incidence of decompensation was significantly lower in patients treated with interferon
J Hepatol 1997;27:201-5.
384 European patients with cirrhosis were enrolled and followed up for a mean period of 5 years
Entry criteria included biopsy-proven cirrhosis, abnormal serum aminotransferase levels, absence of complications of cirrhosis, and exclusion of HAV or HBV infections and other metabolic and toxin-induced liver diseases
During 5 years of follow-up, HCC developed in 7% and hepatic decompensation in 18%. Death occurred in 51 patients, constituting 13% of the cohort, with 70% dying of liver disease. The survival probabilities were 91% and 79% at 5 and 10 years, respectively
Ann Intern Med 2000;132:105-11.
Natural history of hepatitis C may be somewhat benign, especially if infection is acquired in childhood or early adulthood
Retrospective study of 8568 military recruits when serum was available from 1968 to 1954, a total of 17 were found to be anti-HCV positive, of whom only 2 developed liver disease (relative risk, 3.56) and one died of liver disease
N Engl J Med 1999;341:866-70.
Study of children infected at the time of cardiac surgery and followed up for nearly 20 years
Approximately 45% cleared the virus
In the remaining patients, only one had elevated liver tests
Biopsy specimens in 17 of these 67 patients showed histologic damage in only 3Hepatology 1997;26:485-90.
Excessive alcohol intake by patients with CHC increases the risk of development of cirrhosis (39.4% vs 18.2%), as does concurrent HBV infection (24.6% vs 21.1%)
HCC was observed in 3.6% of all patients and in 17.8% of patients with cirrhosis
Occurrence was strongly and mainly related to the presence of cirrhosis
In the typical patient, the progression of CHC is slow and protracted, and overtly serious disease typically first presents 2 to 3 decades after the initial infection
Rapid progression among chronically immunosuppressed patients (ie, long-term hemodialysis and bone marrow transplant recipients)
Immunohistochemical Detection of HCV in Cirrhosis, Dysplastic Nodules, and Hepatocellular Carcinomas with Parallel-Tissue Quantitative RT-PCR
Anne Rullier, etal.
Mod Pathol 2001;14:496-505 Abstract quote
Hepatitis C virus is a major risk factor for hepatocarcinogenesis in humans. In situ detection of the virus in early sequential lesions of hepatocarcinogenesis could provide information about the role of the virus in the transformation and promotion process.
Parallel in situ detection of HCV proteins and RNA in human tissues were performed in 55 posthepatitis C cirrhosis, 17 dysplastic nodules (DN), and 25 hepatocellular carcinomas (HCC), using immunohistochemistry and tissue quantitative RT-PCR.
A consistent cytoplasmic hepatocellular staining was obtained in 73% of cirrhosis cases (with or without HCC) and in 55% DN cases. A few tumoral hepatocytes were unambiguously stained in 28% HCC. The percentage of positive cells and the intensity of immunostaining significantly decreased from cirrhosis to HCC through DN, whereas there was no difference in the prevalence of positivity or the number of viral copies between cirrhosis and HCC using tissue-quantitative RT-PCR. Finally, RT-PCR levels were found parallel with the immunostaining in cirrhosis but not in HCC.
These results suggest that HCV protein synthesis may persist but be down-regulated during sequential hepatocarcinogenesis. A putative role of HCV proteins on cell proliferation and differentiation during the early steps of carcinogenesis cannot therefore be excluded.
Genomic instability in chronic viral hepatitis and hepatocellular carcinoma
Maria Pina Dore, MD Giuseppe Realdi, MD Daniela Mura, MD Angela Onida, MD Giovanni Massarelli, MD Giuseppe Dettori, MD David Yates Graham, MD Antonia Rogado Sepulveda, MD, PhD
Hum Pathol 2001;32:698-703. Abstract quote
Chronic hepatitis may progress to cirrhosis and hepatocellular carcinoma (HCC). Progressive accumulation of mutations and genomic instability in chronic viral hepatitis might flag an increased risk of HCC development. Genomic instability at dinucleotide microsatellite loci in chromosomes 2, 13, and 17 and at 2 mononucleotide repeat loci was examined in liver tissues from 41 patients, including 30 without HCC (18 patients with chronic hepatitis and 12 with cirrhosis) and 11 with HCC. Genomic instability was detected in 51% of the 41 cases. Allelic imbalance at informative dinucleotide loci occurred in 37% of the cases. In 14 cases (34%), allelic imbalance was detected in chronic hepatitis or cirrhosis without HCC. Allelic imbalance at the chromosome 13 locus was detected in 50% of the cases of chronic hepatitis C. Allelic imbalance at the TP53 chromosome locus and/or at the chromosome 13 locus was significantly more frequent than alterations at the chromosome 2 locus (P = .026). Low-level microsatellite instability was found in 20% of all cases examined and high-level microsatellite instability in 3 patients (7.5%), including 2 cases of chronic hepatitis and 1 case of cirrhosis.
Our results show that allelic imbalance occurs frequently in hepatitis-related HCC as well as in chronic hepatitis in patients without HCC. Allelic imbalance at the D13S170 chromosome 13 locus (13q31.2) occurs frequently in chronic hepatitis, suggesting that genomic alterations affecting the long arm of chromosome 13 might be used to monitor the natural progression of chronic hepatitis-associated liver carcinogenesis.
BCL-2
Potential role of bcl-2 and bax mRNA and protein expression in chronic hepatitis type B and C: a clinicopathologic study.
Tsamandas AC, Thomopoulos K, Zolota V, Kourelis T, Karatzas T, Ravazoula P, Tepetes K, Petsas T, Karavias D, Karatza C, Bonikos DS, Gogos C.
Departments of Pathology, University of Patras School of Medicine, Patras, Greece.
Mod Pathol. 2003 Dec;16(12):1273-88 Abstract quote.
Bcl-2 oncoprotein regulates programmed cell death by providing a survival advantage to rapidly proliferating cells, and bax protein promotes apoptosis by enchanting cell susceptibility to apoptotic stimuli.
In this study, we assessed the expression of bcl-2 and bax in liver biopsies from patients with chronic hepatitis (CH) Type B (HBV) and C (HCV). The study comprised 65 liver biopsies from 65 patients with HBV (n = 37) and HCV (n = 28) and 10 normal liver biopsies as controls. The HAI score ranged from 3/18-13/18, and the fibrosis Stage, from 1-6 (7 HBV/10 HCV). Pathologic examination included the following: (1) immunohistochemical stains in paraffin sections for bcl-2 and bax protein expression, (2) Western blot analysis (bcl-2 and bax protein levels evaluation), (3) ISH (detection of bcl-2 and bax mRNA), and (4) ISH (TUNEL-ABI [apoptotic body index]). In CH cases, both bcl-2 and bax protein and mRNA were detected in portal and intralobular lymphocytes and in cholangiolar epithelial cells in interface areas and fibrous bands. Bax protein and mRNA was expressed within hepatocytes and epithelial cells of interlobular ducts in portal tracts. Bcl-2 mRNA was present in periportal hepatocytes only in cases with Stage 5-6 fibrosis. Western blot analysis showed a decreased bcl-2 and an increased bax expression toward advanced fibrotic stages.
In CH cases, ABI was reverse correlated with the percentage of bcl-2 expression and was correlated directly with the percentage of bax expression (P <.001). The results of this study suggest that in cases of chronic HBV or HCV infection, bax may be involved in the hepatocyte cycle regulation during infection, whereas its expression in intraportal bile duct epithelium implies that this protein enhances susceptibility of these particular cells to apoptosis. The increased bax expression and ABI in fibrosis Stages 1-5, imply that they are responsible for hepatocytes depletion through apoptosis, during progress of liver fibrosis and fibrous tissue accumulation, until cirrhosis is established. Bcl-2 mRNA expression in periportal hepatocytes only in Stages 5 and 6 suggests that this oncogene is involved in the late stages of progressive liver fibrosis and failure and furthermore that periportal hepatocytes are resistant to apoptosis. Bcl-2 expression, in cholangioles of interface area, suggests that this oncoprotein may be involved in growth regulation of these epithelial cells.
Further research is warranted to specify the exact role of apoptosis and apoptotic genes involved in liver fibrosis process in cases of chronic HBV and HCV infection. This may lead to new strategies in the management of human liver disease to prevent the progression to chronic liver failure.
LABORATORY/
RADIOLOGY/
OTHER STUDIESCHARACTERIZATION LABORATORY AUTOANTIBODIES Titers of such autoimmune markers are higher in patients with autoimmune hepatitis than in those with chronic hepatitis C
Autoantibody presence does not influence the clinical presentation, the course of the disease, or its response to treatment
Associated with certain HLA types of the host, particularly HLA-A1, -B8, -DR3
Association of autoimmune serologic tests in CHC has been associated with HLA-DR4.62
There are reports of exacerbation of psoriasis
Anticardiolipin antibodies in patients with chronic hepatitis C virus infection: characterization in relation to antiphospholipid syndrome.
Ordi-Ros J, Villarreal J, Monegal F, Sauleda S, Esteban I, Vilardell M.
Department of Internal Medicine, Vall d'Hebron Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain.
Clin Diagn Lab Immunol 2000 Mar;7(2):241-4 Abstract quote
The antiphospholipid syndrome (APS) is usually defined by the association of clinical manifestations that comprise venous and/or arterial thrombosis, recurrent fetal losses, and thrombocytopenia, along with the presence of anticardiolipin (aCL) antibodies and/or lupus anticoagulant. Various infectious diseases can induce aCL; however, these antibodies are not usually associated with thrombotic events, as happens with autoimmune diseases, in which these antibodies need the presence of beta(2)-glycoprotein I.
Levels of immunoglobulin G (IgG) and IgM aCL antibodies were determined by enzyme-linked immunosorbent assay for 243 patients with chronic hepatitis C virus (HCV) infection and 100 healthy controls. Clinical events of APS, the level of beta(2)-glycoprotein dependence of aCL, the presence of cryoglobulins and other autoantibodies, and cross-reactivity between purified aCL and HCV were evaluated. Positive results for aCL antibodies were found more frequently (3. 3%) for the patients with HCV infection than for healthy controls (0%). All positive aCL antibodies were beta(2)-glycoprotein I independent. No significant association was found between aCL antibodies and clinical manifestations of APS, neither was one found between the presence of other autoantibodies or cryoglobulins and that of aCL. Finally, no cross-reactivity between aCL antibodies and HCV antigens was observed.
As previously reported, aCL antibodies seem to be an epiphenomenon, and they do not have clinical or laboratory significance in HCV patients.
PCR Detection of Hepatitis C Virus RNA in Formalin-Fixed, Paraffin-Embedded Thin-Needle Liver Biopsy Specimens
Stefanie Vogt, MD, Regine Schneider-Stock, PhD, Sabine Klauck, MD, Albert Roessner, MD, PhD, and Christoph Röcken, MD, PhDAm J Clin Pathol 2003;120:536-543 Abstract quote
We examined the feasibility of detecting hepatitis C virus (HCV) RNA in formalin-fixed, paraffin-embedded (FFPE) specimens obtained by thin-needle biopsy (TNB). Specimens obtained by large-needle biopsy (LNB) and unfixed frozen tissue served as controls.
A total of 23 biopsy specimens, 13 obtained by TNB and 10 by LNB, from 20 patients with chronic hepatitis C were included in the study. HCV RNA was detected by nested reverse transcription–polymerase chain reaction (RT-PCR). HCV RNA was found in FFPE archival specimens obtained by TNB (11 [85%]) or LNB (7 [70%]). The sensitivity was similar in unfixed tissue in which HCV RNA was found in 7 (88%) of 8 TNB specimens and 6 (86%) of 7 LNB specimens.
The detection of HCV RNA did not seem to be affected by storage of the paraffin blocks, the presence of advanced fibrosis and cirrhosis, or fragmentation of the core cylinder. TNB yields enough qualitative suitable material to detect HCV RNA by RT-PCR.
Detection of extrahepatic hepatitis C virus replication by a novel, highly sensitive, single-tube nested polymerase chain reaction.Hu Y, Shahidi A, Park S, Guilfoyle D, Hirshfield I.
Microbiological Sciences Branch, Northeast Regional Laboratory, US Food and Drug Administration, Jamaica, NY, USA.
Am J Clin Pathol 2003 Jan;119(1):95-100 Abstract quote We established a cell culture system for the replication of hepatitis C virus (HCV) by using human T and B leukemia cell lines.
These 2 cell lines were infected in vitro by using HCV-positive pooled patient serum samples. HCV RNA was extracted from infected cell lines at different times after infection, and a sequence of the virus 5' untranslated region was analyzed. Hepatitis C minus-strand RNA was detected in the infected cell lines by highly strand-specific rTth (recombinant Thermus thermophilus DNA polymerase)-based reverse transcription followed by a novel, highly sensitive, single-tube nested polymerase chain reaction (PCR) method. PCR products were analyzed by direct DNA sequencing.
These results indicate that the HCV can replicate in T and B lymphocytes. This model should represent a valuable tool for the detailed study of the initial steps of the HCV replication cycle and for the evaluation of antiviral molecules.
VIRAL LOAD Serum and liver HCV RNA levels in patients with chronic hepatitis C: correlation with clinical and histological features.
De Moliner L, Pontisso P, De Salvo GL, Cavalletto L, Chemello L, Alberti A.
Department of Clinical and Experimental Medicine, University of Padova, Italy.
Gut 1998 Jun;42(6):856-60 Abstract quote
BACKGROUND: Liver disease in chronic hepatitis C virus (HCV) infection ranges from minimal lesions to liver cirrhosis, eventually evolving to hepatocellular carcinoma. Whether and how HCV determines the different clinical and histological manifestations of the disease is not fully understood.
AIMS: To verify whether the amount of virus in individual patients could be related to the severity of liver injury.
PATIENTS AND METHODS: Levels of HCV RNA were measured in serum in 96 consecutive patients with chronic hepatitis type C using a signal amplification assay. The relation between viraemic values and the corresponding viral load in the liver was assessed in a subgroup of 21 patients in whom HCV RNA was measured in serum samples and liver specimens obtained at the same time.
RESULTS: A positive correlation was observed between the amount of viral nucleic acid in the two compartments, indicating that levels of viraemia reflect the amount of virus present in the liver. Viral load did not correlate with aminotransferase activities nor with histological diagnosis, and serum and liver levels of HCV RNA were not significantly different in patients infected by the various HCV genotypes.
CONCLUSIONS: Measurement of HCV replication in serum is a mirror of viral replication in the liver. The extent of replicative activity of HCV does not seem to play a role in the modulation of the associated hepatic disease.
Comparative study of a modified competitive RT-PCR and Amplicor HCV monitor assays for quantitation of hepatitis C virus RNA in serum.
Olmedo E, Costa J, Lopez-Labrador FX, Forns X, Ampurdanes S, Maluenda MD, Guilera M, Sanchez-Tapias JM, Rodes J, Jimenez de Anta MT.
Liver Unit, Hospital Clinic i Provincial, University of Barcelona, Catalonia, Spain.
J Med Virol 1999 May;58(1):35-43 Abstract quote
A modified competitive RT-PCR (mcRT-PCR) to measure HCV RNA in serum and the Amplicor HCV Monitor assay were compared.
For mcRT-PCR, the RNA extracted was retrotranscribed and coamplified in one step with a known amount of a DNA internal control (IC). Digoxigenin-labeled amplified products were hybridized to specific HCV DNA and IC-DNA probes and quantified by colorimetry. HCV RNA concentration was calculated by plotting the ratio of HCV/IC ODs against a calibration curve. Multiple samples were analyzed in the same round and tedious titration of each sample with a competitor was unnecessary. The mcRT-PCR assay was linear from 6 x 10(3) to 6 x 10(7) copies/ml, whereas Amplicor was linear up to 1-2 x 10(6) copies/ml. HCV RNA was measured in samples from 75 carriers. There was agreement between both methods in type 1 infections but not in type 2 or type 3 infections, in which the values measured by Amplicor were, on average, 15 times lower than those measured by the mcRT-PCR. HCV RNA measured by Amplicor was higher in type 1 infections than in type 2 or 3 infections, but no differences were found when viral load was assessed by mcRT-PCR. The binding efficiency of the Amplicor-probe was greater for type 1 than for types 2 or 3, suggesting Amplicor underestimates the viral load in the latter types. In contrast, the mcRT-PCR is not affected by genotype-related variation of HCV.
This study suggests that mcRT-PCR assay is reliable for sensitive and accurate measurement of HCV RNA over a broad range of values independently of the HCV genotype.
Assessment of viral loads in patients with chronic hepatitis C with AMPLICOR HCV MONITOR version 1.0, COBAS HCV MONITOR version 2.0, and QUANTIPLEX HCV RNA version 2.0 assays.
Martinot-Peignoux M, Le Breton V, Fritsch S, Le Guludec G, Labouret N, Keller F, Marcellin P.
Unite de Recherche INSERM U481, Centre de Recherche Claude Bernard sur les Hepatites Virales and Service d'Hepatologie, Hopital Beaujon, 92110 Clichy, France.
J Clin Microbiol 2000 Jul;38(7):2722-5 Abstract quote
The correlation between response to antiviral therapy and pretreatment viral load in patients with chronic hepatitis C has prompted the development of quantitative assays to measure viral load. The aim of our study was to assess the clinical relevance of the newly developed semiautomated PCR system COBAS HCV MONITOR version 2.0 in comparison with (i) the AMPLICOR HCV MONITOR version 1.0 assay, which underestimates RNA concentration of hepatitis C virus (HCV) genotypes 2 to 6, and (ii) the QUANTIPLEX HCV RNA version 2.0 assay, which achieves equivalent quantification for each HCV genotype, with samples from 174 patients diagnosed with chronic hepatitis C before therapy.
The level and range of quantification measured with AMPLICOR HCV MONITOR version 1.0 were 1 log lower than when measured with the COBAS HCV MONITOR version 2.0, at 0.261 x 10(6) RNA copies/ml (range, 0.001 x 10(6) to 2.50 x 10(6) RNA copies/ml) and 4.032 x 10(6) RNA copies/ml (range, 0.026 x 10(6) to 72.6 x 10(6) RNA copies/ml), respectively. The two assays showed a poor correlation (r(2) = 0.175). The level and range of quantification were similar when measured with the COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays, at 3.03 x 10(6) RNA copies/ml (range, 0.023 x 10(6) to 72.6 x 10(6) RNA copies/ml) and 4.91 Meq/ml (range, 0.200 to 49.5 Meq/ml), respectively. The two assays showed a strong correlation (r(2) = 0. 686) for each HCV genotype. The duration of treatment (6 or 12 months) is modulated according to HCV genotype and viral load.
Our results indicate that COBAS HCV MONITOR version 2.0 and QUANTIPLEX HCV RNA version 2.0 assays showing an equal dynamic range for each HCV genotype are suitable tools to assess patients before therapy.
Effective Management of Hepatitis C Molecular Testing Improves Test Use Without Compromising Patient Management
Sara Kukuczka, BS, MPH and Leonard E. Grosso, MD, PhD
From the Division of Molecular Pathology, Department of Pathology, Saint Louis University School of Medicine, Saint Louis, Mo.
Arch Pathol Lab Med 2002;Vol. 126, No. 1, pp. 100–102. Abstract quote
Context.—The availability of effective antiviral therapy for hepatitis C has increased the need for molecular detection and quantification of circulating hepatitis C viral particles. The limits of detection differ for the quantitative and qualitative reverse transcriptase polymerase chain reaction (RT-PCR) assays; furthermore, adequate patient assessment requires both detection of hepatitis C virus when it is present and quantitation of the viral load when possible. The combination of these factors promotes the simultaneous ordering of both tests with the possibility of generating redundant test information.
Objective.—To reduce the number of unnecessary hepatitis C tests performed. Methods.—We established a reflexive testing protocol for quantitative and qualitative RT-PCR testing for hepatitis C.
Results.—During a 3½-month interval, 170 qualitative RT-PCR hepatitis C tests were eliminated (a 59.4% reduction in the number of these tests). This reduction was achieved without a clinically significant change in turnaround time or a compromise of patient care.
Conclusions.—Establishing the quantitative and qualitative RT-PCR tests in-house and adopting the reflexive testing protocol was cost-effective and did not compromise patient management or care.
BRANCHED CHAIN DNA PROBE Comparison of HCV RNA levels by branched DNA probe assay and by competitive polymerase chain reaction to predict effectiveness of interferon treatment for patients with chronic hepatitis C virus.
Hayashi J, Kawakami Y, Nabeshima A, Kishihara Y, Furusyo N, Sawayama Y, Kinukawa N, Kashiwagi S.
Department of General Medicine, Kyushu University Hospital, Fukuoka, Japan.
Dig Dis Sci 1998 Feb;43(2):384-91 Abstract quote
To compare hepatitis C virus (HCV) RNA levels determined by branched DNA probe assay and by competitive polymerase chain reaction (PCR) as predictive markers of the response to interferon for treatment of patients with chronic HCV infection, we studied data on 140 patients treated for six months with natural interferon-alpha.
Serum samples were tested for HCV RNA by PCR. HCV RNA was grouped into four genotypes by PCR with type-specific primers, and HCV RNA level was measured by branched DNA probe assay and by competitive PCR. HCV RNA was detected in all patients prior to initiation of the treatment. A complete response, sustained elimination of HCV RNA, occurred in 51 patients (36.4%). With multiple logistic regression analysis assessment, when using competitive PCR, a low level of HCV RNA (P < 0.0001), younger age (P = 0.0054) and genotype 2a and 2b (P < 0.0158) were significant predictive markers for a complete response to interferon treatment. When using branched DNA probe assay, a low level of HCV RNA (P < 0.0001) and age (P = 0.0089) were predictive markers, but genotype was not. The branched DNA probe assay had a narrower linear range for quantitation of HCV RNA level than competitive PCR.
In conclusion, HCV RNA level determined by branched DNA probe assay proved to be useful for prediction of effects of interferon and it is cost effective as a marker of complete response to interferon treatment for patients with chronic HCV infection.
SEROLOGY Serum alpha-fetoprotein levels in patients with chronic hepatitis C. Relationships with serum alanine aminotransferase values, histologic activity index, and hepatocyte MIB-1 scores.
Goldstein NS, Blue DE, Hankin R, Hunter S, Bayati N, Silverman AL, Gordon SC.
Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.
Am J Clin Pathol 1999 Jun;111(6):811-6 Abstract quote
Patients with chronic viral hepatitis and cirrhosis often have elevated serum alpha-fetoprotein (AFP) values, the causes of which are unclear.
We studied 81 patients with chronic hepatitis C and the relationships of serum AFP and alanine aminotransferase (ALT) values, hepatic histologic features, and hepatocyte proliferation activity scores.
Twenty-two patients had nil to mild fibrosis, 34 had moderate fibrosis, and 25 had marked fibrosis-cirrhosis. The mean serum AFP value was significantly greater in patients with more fibrosis. Serum ALT values were slightly greater in the marked fibrosis-cirrhosis patient group. The differences in the HAI and in hepatocyte MIB-1 scores were not significant. Among all patients, increasing serum AFP values significantly correlated with increasing ALT values. However, there were no significant correlations with serum ALT or HAI and serum AFP values. There was no association between serum AFP values and immunohistochemical staining for AFP within hepatocytes.
These results suggest that elevated serum AFP values are the result of altered hepatocyte-hepatocyte interaction and loss of normal architectural arrangements. The presence of marked fibrosis or cirrhosis, a state of significant altered hepatocyte architecture, may be the underlying cause of increased serum AFP, rather than necrosis or active regeneration.
Diagnosis of hepatitis C virus (HCV) infection and laboratory monitoring of its therapy.
Erensoy S.
Department of Microbiology and Clinical Microbiology, Ege University, 35100, Bornova, Izmir, Turkey.
J Clin Virol 2001 Jun;21(3):271-81 Abstract quote
BACKGROUND: Just after the identification and characterization of hepatitis C virus (HCV) in 1989, tests for the detection of HCV antibodies or HCV RNA in serum were developed. The enzyme-linked immunosorbent assays (ELISAs) and confirmatory/supplemental analytical antibody tests were improved in sensitivity and specificity with the development of further generations of these assays. Application of molecular tests for detecting, quantifying, and characterization of the infecting virus became very important in management of HCV infection.
OBJECTIVE AND DESIGN: This review summarizes the assays developed for the diagnosis and management of HCV infection. Strategies for the diagnosis and monitoring with the advantages and disadvantages of the assays based on the setting and goal are discussed according to data in the literature and our experience.
RESULTS: Specific laboratory diagnostic tests for hepatitis C virus infection may be discussed under two titles: (i) Serological antibody tests which detect anti-HCV in serum or plasma; (ii) Molecular tests which detect HCV RNA genome, investigate viral load, and determine the characteristics of the genome. Strategies in different laboratory settings which screen populations with different HCV prevalences vary.
CONCLUSIONS: Anti-HCV positive result in a low-risk setting such as blood banks should be confirmed with an analytical antibody test. Then a HCV RNA test should be performed on serum of the person with a positive or indeterminate confirmatory test result. On the contrary, anti-HCV positive test result in high-risk population or a situation where HCV infection is suspected, it is likely to be true positive and confirmation with HCV RNA test will be significant. Quantitative HCV RNA test and genotyping should be performed if therapy is considered.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION VARIANTS In 75% of cases, chronic hepatitis develops
Defined as persistently abnormal serum amino-transferases (aspartate aminotransferase, ALT) for at least 6 months
Some subjects with chronic HCV infection have persistently normal serum aminotransferases but have evidence of persistent infection as shown by detectable HCV RNA in serum and compatible histopathologic abnormalities on liver biopsies
In those with chronic hepatitis, cirrhosis often develops (~20%-50%) and may culminate in the development of liver failure or hepatocellular carcinoma (HCC).
Incubation period for acute hepatitis C averages 6 to 7 weeks but may range from as short as 2 weeks to as long as 26 weeks
Among adults with acute HCV infection, only 30% to 40% have symptoms (usually mild) and/or develop jaundice
Usually milder than, but otherwise indistinguishable from, other types of acute viral hepatitis (HAV, HBV)
Majority of asymptomatic patients have fluctuating serum aminotransferase levels
Normalization of these levels may occur and may be followed later by elevations again, indicating chronic disease.
J Hepatol 1998;29:861-71.
Rare
HCV RNA was detected in 5 of 26 patients with fulminant hepatic failure
Not believed to be a major cause of fulminant hepatic failure
PEDIATRIC Serum levels of hepatitis C virus RNA in infants and children with chronic hepatitis C.
Azzari C, Resti M, Bortolotti F, Moriondo M, Crivellaro C, Lionetti P, Vierucci A.
Department of Pediatrics, University of Florence, Italy.
J Pediatr Gastroenterol Nutr 1999 Sep;29(3):314-7 Abstract quote
BACKGROUND: The role of serum hepatitis C virus (HCV) load in infectivity, disease activity, and response to interferon treatment has been investigated in adults, and controversial results have been obtained. Little is known about HCV load in infants and children with HCV infection.
PURPOSE: To investigate the relation between HCV load in serum and features of associated liver disease in infants and children with HCV infection.
METHODS: Hepatitis C viral load was investigated in serial samples in 43 children with chronic HCV infection, including 32 patients aged 4 to 16 years infected by different routes and 11 vertically infected infants observed prospectively since birth.
RESULTS: Overall viremia ranged between 2.7 and 6.9 log copies/ml (median, 5.56 log/ml) and fluctuated slightly during the follow-up. Median HCV RNA levels did not significantly differ among infants, children, and adolescents. Viral load was also independent of sex, route of infection, clinical manifestation, alanine aminotransferase levels, and liver histology. All 11 perinatally infected children became chronic HCV carriers, whatever their initial viral load; retrospective testing of sera taken in the first day of life in three infants showed high viremia levels.
CONCLUSIONS: Viremia levels observed in children were similar to those reported in adults, were independent of age, biochemical activity of liver disease, and chronicity of infection. They were also relatively stable, suggesting that serial measurement of viral load is useless in untreated infants and children. The detection of viremia at birth in children in whom chronic hepatitis developed later suggests the possibility of in utero infection.
Distribution of hepatitis C virus infection in liver biopsies from children and adults with chronic hepatitis C.
de Lucas S, Bartolome J, Rodriguez-Inigo E, Casqueiro M, Millan A, Ruiz-Moreno M, Oliva H, Carreno V.
Instituto de Hepatologia, Hospital Pardo de Aravaca, Madrid, Spain.
J Med Virol 2001 May;64(1):1-5 Abstract quote
Chronic hepatitis C in children is characterized by milder forms of liver damage than those found in adults. Such a difference has been attributed to a low viral load in children that may lead to poor recognition of infected cells by the immune system.
One approach that could be used to confirm this hypothesis may be to examine the number of infected hepatocytes in liver biopsies. Paraffin embedded liver biopsies from 21 children and 15 adults with chronic hepatitis C virus (HCV) infection (with a similar duration of the infection) were hybridized in situ and the percentage of infected hepatocytes was correlated with the histological activity index, alanine aminotransferase levels and HCV viraemia levels. Histological activity index and HCV viraemia levels were statistically higher (P < 0.05 and P < 0.01 respectively) in adults than in children, and the percentage of infected hepatocytes was higher in adults (11.0 +/- 19.7%) than in children (4.6 +/- 3.6%), although it did not reach statistical significance. Also, the percentage of infected hepatocytes correlated with HCV-RNA concentration in serum in both children (r = 0.683, P = 0.001) and adults (r = 0.768, P = 0.001).
The results show that liver damage in children with chronic hepatitis C is not related to the extent of infection in the liver. This findings support the hypothesis of that liver injury in chronic HCV infection is mediated by the host immune response.
SKIN
- Necrolytic acral erythema: a cutaneous sign of hepatitis C virus infection.
Abdallah MA, Ghozzi MY, Monib HA, Hafez AM, Hiatt KM, Smoller BR, Horn TD.
Department of Dermatology and Venereology, Faculty of Medicine Ain Shams University, Cairo, Egypt.
J Am Acad Dermatol. 2005 Aug;53(2):247-51. Abstract quote
BACKGROUND: Hepatitis C virus (HCV) infection is globally epidemic. Several mucocutaneous diseases are well established in association with HCV infection. Few case reports describe the recently recognized HCV-related skin disorder termed necrolytic acral erythema (NAE).
METHODS: Thirty patients with NAE were identified in a university-based dermatology clinic in Cairo, Egypt. These patients were observed over time to document the clinical and histologic findings of this disorder.
RESULTS: All patients were infected with HCV. Erythematous papules arose most commonly on the dorsal aspect of the feet, particularly the dorsal surface of the great toe. Progression resulted in confluence into erythematous dusky plaques with adherent scale and central erosion. The eruption extended to involve the lower leg and other regions in some patients but never affected palms or soles, the nail bed, nail plate, or mucous membranes. Skin biopsy specimens from fully evolved lesions displayed psoriasiform changes in association with more characteristic findings of keratinocyte necrosis and papillomatosis.
LIMITATIONS: We did not perform a prospective review of patients known to be infected with HCV. Patients were identified from a general clinic population and then assayed for HCV serology.
CONCLUSIONS: NAE is a distinctive skin disorder associated with HCV infection in all cases reported to date. Recognition of this disease should alert practitioners to the need for viral testing and appropriate counseling of patients.
The dermatopathologic manifestations of hepatitis C infection: A clinical, histological, and molecular assessment of 35 cases.Crowson AN, Nuovo G, Ferri C, Magro CM.
Hum Pathol. 2003 Jun;34(6):573-9. Abstract quote Cutaneous eruptions related to hepatitis C virus (HCV), a major cause of hepatitis in the setting of blood transfusion, intravenous drug abuse, organ transplantation, and hemodialysis, are typically reported as isolated cases.
We encountered 35 cases of HCV infection associated with cutaneous eruptions. The present study evaluates paraffin-embedded, formalin-fixed tissue sections stained with hematoxylin and eosin from biopsy specimens of skin lesions from 35 patients seropositive for HCV. In 20 cases, reverse transcriptase polymerase chain reaction (RT-PCR) was performed using a probe for HCV RNA; the RNA was detected through the action of alkaline phosphatase on the chromogen nitroblue tetrazolium and bromochloroindolyl phosphate.
The clinical spectrum comprised dermatomyositis-like photodistributed eruptions, palpable purpura, folliculitis, violaceous and perniotic acral lesions, ulcers, nodules, and urticaria.
Lesions were also classified histopathologically by the dominant reaction pattern: vasculopathies of neutrophilic, lymphocytic, and granulomatous vasculitis and pauci-inflammatory subtypes (15 patients); palisading granulomatous inflammation (3 patients); sterile neutrophilic folliculitis (5 patients); dermatitis herpetiformis (1 patient); lobular panniculitis composed of neutrophilic lobular panniculitis in 2 patients and benign cutaneous polyarteritis nodosa in 1 patient; neutrophilic dermatoses, including neutrophilic urticaria, neutrophilic eccrine hidradenitis, and pyoderma gangrenosum (3 patients); interface dermatitis (3 patients); and low-grade lymphoproliferative disease of B-cell lineage representing marginal zone lymphoma in 1 patient and a clonal plasmacellular infiltrate in another patient.
In most cases, whereas 1 of the aforementioned disorders defined the dominant reaction pattern, there was an accompanying secondary reaction pattern, defining a hybrid picture. Endothelial changes including endothelial cell enlargement and effaced heterochromatin with margination of the chromatin to the nuclear membrane were seen in several cases; in some cases similar cytopathic changes also involved the supporting pericytes, eccrine ductular cells, or keratinocytes.
The RT-PCR analyses in 8 of 20 cases examined revealed HCV RNA expression in a focal, weak fashion in endothelia and perivascular inflammatory cells in those cases showing vasculopathic changes. Viral parasitism of endothelia may be important in cutaneous lesional propagation in the setting of HCV infection. Cross-reactivity between endogenous and viral antigens, leading to cellular and/or type II immune reactions; viral tropism to B lymphocytes, resulting in B cell expansion with resultant autoantibody production; and circulating immune complexes containing monoclonal cryoglobulins may also be of pathogenetic importance.Tropism of the virus to B lymphocytes provides a mechanism for the development of low-grade clonal B cell lymphoproliferative disease in this setting.
Medicine 1994;73:53-67.
Two major hypotheses:
Low-grade malignant lymphoproliferative disorder:
Monoclonal T-cell populations have sometimes been found in patients with MC.Chronic stimulation of the immune system produced by a variety of infections:
Monoclonal rheumatoid factors that generally occur in the type II MC associated with CHC are thought to result from chronic stimulation of the immune system by complexes consisting of IgG bound to HCV antigensHepatology 1998;27:1661-9
All patients with PCT should be screened for HCV infection with measurement of antibodies against HCV
All should undergo HFE gene mutational analysis to look for either of the two mutations (C282Y or the H63D) that have been linked with iron overloadInt J Dermatol 1998;37:575-8.
Prevalence of antibodies to HCV in 263 patients with oral lichen planus to a control group of 100 patients who were receiving routine dental care. Twenty-nine percent of those with lichen planus were positive for HCV antibodies, as compared with 3% in the control group
Prevalence of HCV infection in patients with lichen planus varies considerably from one geographic area to another, ranging from 4% to 62% in Japan
When chronic liver disease is associated with lichen planus, CHC is generally the cause
No difference in prevalence of HCV between erosive and nonerosive forms of lichen planus
Arch Dermatol 1995;131:852-3.
Dig Dis Sci 1998;43:2177-83.978 consecutive patients presenting to a dermatology clinic were tested for serum markers of HCV infection
Of the 28 patients with prurigo, 11 (39%) had evidence of HCV infection by enzyme-linked immunosorbent assay compared with the remaining 950 patients of whom 49 (5%) had evidence of HCV infection
CHC with moderate to severe fibrosis may result in low-grade cholestasis with pruritus, possibly in association with bile duct disappearance
J Rheumatol 1993;20:304-9.
Rarely found in patients with CHC
Prevalences of 5% to 20% for HCV markers have been reported in patients with PAN
Lancet 1990;336:822-3. Lancet 1990;336:1377. Lancet 1991;337:428. J Hepatol 1998;28:161-4. Int J Dermatol 1996;35:252-6.
Erythema of the dorsal aspects of the feet
7 patients with necrolytic acral erythema, all were found to have the HCV infection by enzyme-linked immunoassay and polymerase chain reaction
Hepatitis C, cryoglobulinemia, and cutaneous vasculitis associated with unusual and serious manifestations.
Mendez P, Saeian K, Reddy KR, Younossi ZM, Kerdel F, Badalamenti S, Jeffers LJ, Schiff ER.
Department of Medicine, University of Miami School of Medicine, Florida 33136, USA.
Am J Gastroenterol 2001 Aug;96(8):2489-93 Abstract quote
Hepatitis C viral infection is currently the leading cause of chronic hepatitis and cirrhosis. It also is a major predisposing factor for the development of hepatocellular carcinoma. It is estimated that approximately 1-2% of patients with hepatitis C infection have nonhepatic manifestations that are protean in nature.
In this report, we describe six unusual cases of nonhepatic manifestations: abdominal vasculitis in two, peripheral neuropathy in two, and one patient each with central nervous system vasculitis and necrotizing cutaneous vasculitis.
All patients had cutaneous vasculitis and cryoglobulinemia. None of our patients had cirrhosis, yet three of the six patients died. Because of the severe manifestations, aggressive therapy was instituted with interferon, immunosuppressive medications, i.v. immunoglobulin, and plasmapheresis.
Our report underscores the importance of recognizing nonhepatic manifestations in patients with hepatitis C infection that may be associated with high morbidity and mortality.
HISTOLOGICAL TYPES CHARACTERIZATION General Acute disease Similar to those of acute hepatitis from other viral causes, although fatty change in hepatocytes is more commonly seen
Pleomorphism of hepatocytes
Foci of lobular necrosis and inflammation, Acidophilic (apoptotic) bodies
Portal tract inflammation with interface hepatitisChronic disease Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group.
Lefkowitch JH, Schiff ER, Davis GL, Perrillo RP, Lindsay K, Bodenheimer HC Jr, Balart LA, Ortego TJ, Payne J, Dienstag JL, et al.
College of Physicians and Surgeons, Columbia University, New York, New York.
Gastroenterology 1993 Feb;104(2):595-603 Abstract quote
BACKGROUND: Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain.
METHODS: In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens. RESULTS: Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1).
CONCLUSIONS: These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.
Histopathologic findings in chronic hepatitis C.
Fischer HP, Willsch E, Bierhoff E, Pfeifer U.
Institute of Pathology, University of Bonn, Germany.
J Hepatol 1996;24(2 Suppl):35-42 Abstract quote
Evaluation of liver biopsies in hepatitis C is aimed at confirming the clinical and serologic diagnosis, grading of necroinflammatory activity, staging of consecutive fibrosis, ruling out or confirming liver diseases of different etiology, and assessment of therapeutic effects. Usually, the course of chronic hepatitis C virus (HCV) infection is slow, with mild inflammatory changes. Nevertheless, even in mild asymptomatic chronic hepatitis C episodes of higher inflammatory activity associated with extensive piecemeal necrosis and porto-central bridging, necrosis can accelerate the course of the disease. For this reason, the traditional, morphologically based classification of chronic hepatitis and the term "chronic persistent hepatitis" have lost their predictive usefulness, especially in hepatitis C.
Chronic hepatitis should be characterized by etiologic designation as well as grade and stage of the disease. Portal lymphoid aggregates, some inflammatory bile duct damage and mild steatosis are the most characteristic features by which hepatitis C can be differentiated from other progressive inflammatory liver diseases. Antibodies directed against HCV antigens allow identification of viral proteins by immunohistochemistry. Immunostaining for hepatitis B antigens, for alpha-1-antitrypsin and copper staining are helpful in detecting hepatitis B and congenital liver diseases (Wilson's disease, alpha-1-antitrypsin deficiency) as possible causes of chronic progressive inflammatory liver disease. Centrilobular Mallory's hyalin, identified by immunostaining for ubiquitin in combination with perivenular fibrosis, is helpful in diagnosing concomitant alcoholic liver disease. In our own biopsy material (n = 100) and autopsy material (n = 58), HIV/HCV-coinfected patients have a significantly higher rate of fibrosis and cirrhosis than HIV patients without HCV infection. Hepatitis C can apparently aggravate the course of HIV infection.
Our morphologic findings support the clinical observation that chronic HCV infection seems to be the main cause of liver failure, especially in the risk group of HCV/HIV-coinfected hemophiliacs.
Histological damage in chronic hepatitis C is not related to the extent of infection in the liver.
Rodriguez-Inigo E, Bartolome J, de Lucas S, Manzarbeitia F, Pardo M, Arocena C, Gosalvez J, Oliva H, Carreno V.
Department of Hepatology, Fundacion Jimenez Diaz and Fundacion Estudio Hepatitis Virales, Madrid, Spain.
Am J Pathol 1999 Jun;154(6):1877-81 Abstract quote
It has not been completely elucidated whether the liver injury induced by the hepatitis C virus (HCV) is due to direct cytopathic damage or to an immune-mediated response against HCV-infected hepatocytes.
In this work, we have determined the percentage of HCV-infected hepatocytes, the histological activity index, and the viremia levels in chronically HCV-infected patients with different grades of liver injury to investigate any possible correlation between them. For that purpose, liver biopsies from 27 patients with HCV chronic hepatitis were analyzed by in situ hybridization. This technique revealed that the percentage of infected hepatocytes ranged from 0.04% to 83.6%. Regarding the viremia levels, HCV RNA concentration ranged from 1.8 x 10(3) to 1.4 x 10(6) genome copies/ml. A significant correlation (r = 0.54; P = 0.003) between the percentage of infected hepatocytes and the viremia levels was found. In contrast, no correlation was observed between the percentage of HCV-infected hepatocytes or the viremia levels and the histological activity index.
In conclusion, we have shown that the HCV viremia reflects the extent of the infection in the liver and that the liver injury in chronic HCV infection is not directly related to either the number of infected hepatocytes or the serum HCV RNA concentration.
VARIANTS ACIDOPHIL BODIES
Utilization of acidophil bodies in the diagnosis of recurrent hepatitis C infection after orthotopic liver transplantation.Saxena R, Crawford JM, Navarro VJ, Friedman AL, Robert ME.
Departments of Pathology (RS, JMC, MER), Medicine (VJN), and Surgery (ALF), Yale University School of Medicine, New Haven, Connecticut.
Mod Pathol 2002 Sep;15(9):897-903 Abstract quote BACKGROUND: The distinction between acute rejection and early recurrent hepatitis C infection (RHCV) in the setting of orthotopic liver transplantation is often difficult. In liver biopsies acidophil bodies and lobular hepatitis are used to suggest a diagnosis of RHCV over rejection, however, the reliability of this practice has not been established. Because portal tract changes in RHCV and rejection often overlap, we sought to determine whether the degree of hepatocyte acidophil body formation seen on liver biopsies could be used to distinguish between these two conditions.
METHODS: Quantification of acidophil bodies was performed on liver biopsies in orthotopic liver transplant patients with RHCV (n = 10), non-hepatitis C orthotopic liver transplant patients with uncomplicated rejection episodes (n = 10) and non-transplant patients with chronic hepatitis C infection (n = 10). Hematoxylin and Eosin stained slides from all three groups were randomized and tissue segments 1.0 cm in length and of variable width (0.04-0.13 cm) were examined at 200x magnification in a blinded fashion by two pathologists in order to quantify the number of acidophil bodies/cm(2). Lobular chronic inflammation was also graded on a 0-3+ scale.
RESULTS: Liver biopsies taken at the onset of RHCV exhibited 606 +/- 101 acidophil bodies/cm(2) (mean +/- standard error of mean, range 200-1390). These counts were significantly greater (P =.0061, paired 2-tailed t-test) than the 241 +/- 53 acidophil bodies/cm(2) (range 80-514) for acute rejection, and the 194 +/- 21 acidophil bodies/cm(2) (range 100-333) for non-liver transplant chronic hepatitis C infection (P =.0013). No difference in lobular inflammation between index RHCV and rejection biopsies was detected.
CONCLUSIONS: Although there is overlap, on average there are twice as many acidophil bodies in the initial stage of RHCV when compared with acute rejection (average of 55 per linear cm in RHCV versus 21 per linear cm for rejection). Lobular inflammation was not a reliable indicator of the initial onset of RHCV.
ALCOHOLIC LIVER DISEASE Clinicopathological analysis of alcoholic liver disease complicating chronic type C hepatitis.
Noguchi O, Yamaoka K, Ikeda T, Tozuka S, Sakamoto S, Kanayama M, Uchida T.
Department of Internal Medicine, Yokosuka Kyosai Hospital, Japan.
Liver 1991 Aug;11(4):225-30 Abstract quote
Seventy-six chronic alcoholics in Japan were evaluated for histological changes of liver needle biopsies, Chiron C100 antibody (C-100) for hepatitis C virus, as well as clinical and laboratory data.
In biopsies, the presence of necroinflammations within the parenchyma, lymphocytic reaction in the portal tracts, or both, might indicate non-A, non-B (NANB) chronic hepatitis. Using these histological criteria, the patients were previously classified into two groups: alcoholic liver disease (ALD) alone and ALD complicating NANB chronic hepatitis. The C100-positive ratio was found to be 12% in the former group and 69% in the latter. Further clinical and laboratory comparison revealed that there were significant differences in gamma-glutamyl transpeptidase, gamma-globulin, and adenosine deaminase levels in the sera between the ALD alone and the ALD complicating NANB chronic hepatitis groups.
Since some chronic alcoholics are also affected by chronic type C hepatitis, detailed evaluations of the liver biopsy and C-100 assay are required for the differentiation of these hepatic disorders.
A histopathological study of alcoholics with chronic HCV infection: comparison with chronic hepatitis C and alcoholic liver disease.
Uchimura Y, Sata M, Kage M, Abe H, Tanikawa K.
Second Department of Medicine, Kurume University School of Medicine, Japan.
Liver 1995 Dec;15(6):300-6 Abstract quote
To clarify the relationship between hepatitis C virus infection and excessive alcohol intake, we carried out histological examination of the liver in 46 alcoholics with chronic hepatitis C virus infection and compared the findings in 55 patients with chronic hepatitis C, 38 with alcoholic liver disease, and 27 with chronic hepatitis B.
The majority of alcoholics with chronic hepatitis C virus infection displayed virus-related histological changes very similar to those in chronic hepatitis C, including frequent lymphoid follicles (34.7%) or aggregates (93.3%) in the portal tracts, mild necroinflammatory change (76.1%) in the parenchyma, and lymphocytosis in sinusoids (83.7%). Liver cell dysplasia and irregular regenerative activity of hepatocytes were rarely observed. The effects of alcohol on the liver were found to be minimal in the majority.
These findings could suggest that the hepatic injury in the majority of alcoholics with chronic hepatitis C virus infection in Japan is due to persistent hepatitis C virus infection rather than to alcoholic injury. In addition, our study disclosed that the perivenular fibrosis which is designated as a histological characteristic of alcoholic liver disease is frequently observed in chronic hepatitis C. These similarities suggest that a similar fibrogenesis is present in chronic hepatitis C and alcoholic liver disease.
Effects of alcohol consumption on histological changes in chronic hepatitis C: a clinicopathological study.
Tamai T, Seki T, Shiro T, Nakagawa T, Wakabayashi M, Imamura M, Nishimura A, Yamashiki N, Takasu M, Inoue K, Okamura A.
Third Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, Japan
Alcohol Clin Exp Res 2000 Apr;24(4 Suppl):106S-111S Abstract quote
BACKGROUND: To assess the effects of alcohol on the histological changes in chronic hepatitis type C, we performed histopathological examination on liver biopsy specimens by using a semiquantitative method.
METHODS: Subjects were 91 patients with chronic hepatitis type C and 32 with alcoholic liver disease. The patients with chronic hepatitis type C were classified into three groups according to the total amount of alcohol intake: nondrinkers, moderate drinkers, and heavy drinkers. For each patient, we evaluated pathological changes of several items and awarded scores from 0 to 2 points, with severe to moderate scoring 2 points, mild 1, and negative 0; the total score was then compared between groups. The evaluated histological changes included virus-related histological changes (V1, inflammatory cell infiltration; V2, lymphoid follicle formation; and V3, bile duct damage) and alcohol-related changes (A1, perivenular fibrosis; A2, stellate/pericellular fibrosis; and A3, fatty change).
RESULTS: The total scores of the hepatitis C virus-related histological changes were significantly lower in patients with alcoholic liver disease (ALD group) (p < 0.05). However, we found no significant difference between the different alcohol intake groups. The total score for alcohol-related histological changes significantly increased in line with increases in total alcoholic intake regardless of the presence or absence of hepatitis type C virus infection (p < 0.05).
CONCLUSIONS: The results suggest that both alcoholic-related liver damage and virus-related liver damage have specific features; in a addition, alcohol was found to have little effect on the histological liver damage observed in chronic hepatitis type C.
ALLOGRAFTS
Recurrent Hepatitis C in Liver Allografts: Prospective Assessment of Diagnostic Accuracy, Identification of Pitfalls, and Observations About Pathogenesis.
Demetris AJ, Eghtesad B, Marcos A, Ruppert K, Nalesnik MA, Randhawa P, Wu T, Krasinskas A, Fontes P, Cacciarelli T, Shakil AO, Murase N, Fung JJ, Starzl TE.
Departments of *Pathology and daggerSurgery, Divisions of Transplantation, University of Pittsburgh Medical Center; double daggerGraduate School of Public Health, and section signDepartment of Medicine, Division of Hepatology, University of Pittsburgh, Pittsburgh, PA.
Am J Surg Pathol. 2004 May;28(5):658-669. Abstract quote
RATIONALE AND DESIGN:: The accuracy of a prospective histopathologic diagnosis of rejection and recurrent hepatitis C (HCV) was determined in 48 HCV RNA-positive liver allograft recipients enrolled in an "immunosuppression minimization protocol" between July 29, 2001 and January 24, 2003. Prospective entry of all pertinent treatment, laboratory, and histopathology results into an electronic database enabled a retrospective analysis of the accuracy of histopathologic diagnoses and the pathophysiologic relationship between recurrent HCV and rejection.
RESULTS:: Time to first onset of acute rejection (AR) (mean, 107 days; median, 83 days; range, 7-329 days) overlapped with the time to first onset of recurrent HCV (mean, 115 days; median, 123 days; range, 22-315 days), making distinction between the two difficult. AR and chronic rejection (CR) with and without co-existent HCV showed overlapping but significantly different liver injury test profiles. One major and two minor errors occurred (positive predictive values for AR = 91%; recurrent HCV = 100%); all involved an overdiagnosis of AR in the context of recurrent HCV. Retrospective analysis of the mistakes showed that major errors can be avoided altogether and the impact of unavoidable minor errors can be minimized by strict adherence to specific histopathologic criteria, close clinicopathologic correlation including examination of HCV RNA levels, and a conservative approach to the use of additional immunosuppression. In addition, histopathologic diagnoses of moderate and severe AR and CR were associated with relatively low HCV RNA levels, whereas relatively high HCV RNA levels were associated with a histopathologic diagnosis of hepatitis alone, particularly the cholestatic variant of HCV.
CONCLUSIONS:: Liver allograft biopsy interpretation can rapidly and accurately distinguish between recurrent HCV and AR/CR. In addition, the histopathologic observations suggest that the immune mechanism responsible for HCV clearance overlap with those leading to significant rejection.COMBINED HEPATITIS B AND C Chronic hepatitis in patients with active hepatitis B virus and hepatitis C virus combined infections: a histological study.
Villari D, Pernice M, Spinella S, Squadrito G, Rodino G, Brancatelli S, Longo G, Raimondo G.
Dipartimento di Patologia Umana, Universita di Messina, Italy.
Am J Gastroenterol 1995 Jun;90(6):955-8 Abstract quote
OBJECTIVES: To evaluate whether peculiar histological changes are present in liver tissue of patients with chronic hepatitis by hepatitis B and hepatitis C (HBV and HCV) virus combined infections.
METHODS: We studied liver biopsy specimens from 14 HB surface antigen/anti-HCV-positive patients consecutively admitted to hospital because of chronic liver disease from 1987 to 1992. Alcohol abusers, drug addicts, hepatitis delta virus- and HIV-infected subjects were excluded from the study. All of them were positive for serum HBV-DNA and/or intrahepatic HB core antigen and for serum HCV-RNA. Histological examination showed mild or moderate chronic hepatitis in nine cases and severe chronic hepatitis with cirrhosis in five cases. Two additional sets of liver biopsy specimens were also included in the study, consisting of liver samples from 14 patients with chronic liver disease due to active HBV infection alone (group B) and from 14 patients with active HCV infection alone (group C). Cases from group B and C matched for age, sex, and histological diagnosis with those from group B + C. Histological patterns of all the liver specimens of the three groups were re-examined by two authors who scored the found features using a scale from 0 to 3.
RESULTS: No peculiar histological pattern was revealed in group B + C, and most of the detected microscopic features were similarly present in all three groups. Bile duct lesions and well defined lymphoid follicles were found only in liver samples of patients from groups C and B + C. Ground-glass hepatocytes were observed only in cases from the groups B and B + C.
CONCLUSIONS: Histological examination of liver tissue from patients with chronic HBV and HCV combined infection does not show either typical patterns or evidence that this subgroup of chronic viral hepatitis is a more severe form of liver disease than that caused by a single virus infection. The observation in liver samples of peculiar lesions by HBV or HCV infection does not exclude a combined infection by both viruses.
STEATOSIS Liver steatosis in chronic hepatitis C: a morphological sign suggesting infection with HCV genotype 3.
Rubbia-Brandt L, Leandro G, Spahr L, Giostra E, Quadri R, Male PJ, Negro F.
Division of Clinical Pathology, University Hospital, 1 rue Michel Servet, 1211 Geneva, Switzerland.
Histopathology 2001 Aug;39(2):119-24 Abstract quote
AIMS: To identify factors associated with liver steatosis in chronic hepatitis C.
METHODS AND RESULTS: Occurrence and severity of liver steatosis in 254 chronic hepatitis C patients were compared with presence of alcohol abuse, body mass index (BMI) >26, history of intravenous drug addiction and hepatitis C virus (HCV) genotype. Steatosis was found in 109 (43%) patients. The occurrence of steatosis was significantly associated with ongoing alcohol abuse (P=0.03) or HCV genotype 3 (P= 0.003), but not with BMI >26. A moderate to severe steatosis was present in 60% of patients infected with HCV genotype 3, irrespective of the presence of alcohol abuse, BMI >26 or history of intravenous drug addiction. Using a multivariable stepwise logistic regression analysis, infection with genotype 3 had an odds ratio (OR) of 10 (95% confidence interval (CI)=4.56-22) for a liver steatosis, whereas the presence of a cirrhosis at histology had an OR=0.256 (95% CI=0.07-0.92).
CONCLUSIONS: A moderate to severe degree of steatosis of the liver is a morphological sign suggestive of infection with HCV genotype 3, independent of other risk factors of a fatty liver, but it may disappear at late stages of the disease.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES HEPATITIS NON-A, NON-B, NON-C Liver biopsy features of acute hepatitis C compared with hepatitis A, B, and non-A, non-B, non-C.
Kobayashi K, Hashimoto E, Ludwig J, Hisamitsu T, Obata H.
Institute of Gastroenterology, Tokyo Women's Medical College, Japan.
Liver 1993 Apr;13(2):69-72 Abstract quote
The diagnosis of acute hepatitis C (AHC) often can only be suspected because current serologic tests remain negative for over 3 months. Because histologic features might provide useful clues, we reviewed 85 liver biopsy specimens from 85 patients with acute viral hepatitis, comparing 22 cases of AHC with 23 cases of acute hepatitis A (AHA), 30 cases of acute hepatitis B (AHB), and 10 cases of acute hepatitis non-A, non-B, non-C (AHNC).
AHC was characterized by dense portal lymphoid aggregates (7 cases) and Poulsen-Christoffersen-type cholangitis (8 cases); these lesions were not found in any other type of acute viral hepatitis, and thus appeared to be diagnostic. Sinusoidal inflammatory infiltrates also were common in AHC, particularly in biopsy specimens obtained during the early phase of the disease. These inflammatory infiltrates did not appear to affect adjacent hepatocytes. Necrosis in AHC usually was spotty and accompanied by mixed inflammatory cells. In AHNC, necrosis was also spotty but, as an added feature, pigmented macrophages predominated in them. In AHA, necrosis was predominantly periportal, whereas in AHB, severe zone-3 necrosis predominated. Fatty changes were predominantly microvesicular; they were common in AHC but were also found in other groups.
Collectively, the described histologic features allowed diagnosis of AHC in biopsy specimens with reasonable confidence. However, histologic findings failed to predict the prognosis in individual cases.
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSTIC FACTORS Those most likely to respond to interferon and ribivarin therapy:
Young women who have not been infected for long
Little or no iron in the liver
Do not drink alcohol
Intact immune systems
Low serum ferritins
Little or no hepatic fibrosis
Robust hepatic inflammatory (T-cell) responses
Infected with non-type 1 strains of HCV, which are present in low numbers in the serum at baselineGENERAL Hepatitis activity index is a key factor in determining the natural history of chronic hepatitis C
Hélène Fontaine, MD Bertrand Nalpas, MD, PhD
Bruno Poulet, MD Françoise Carnot, MD Hervé Zylberberg, MD Christian Brechot, MD, PhD
Stanislas Pol, MD, PhDHum Pathol 2001;32:904-909 Abstract quote
To analyze the spontaneous pathologic progression of chronic hepatitis C, we analyzed the histopathologic semiquantitative scores (Metavir and Knodell) of sequential liver biopsies performed in untreated hepatitis C virus (HCV)–infected patients.
Subjects included 35 men and 41 women, with a mean age of 41 ± 12 years, a duration of HCV infection of 11 ± 5 years, and an interval between liver biopsies of 3.7 ± 2.5 years. Results obtained using the Knodell score and the Metavir score were similar. At the first biopsy, 78.9% of patients had a low activity score (A0-A1) and 82.9% had a low fibrosis score (F0-F2). At the second biopsy, the activity decreased in 9.2%, was unchanged in 72.4%, and increased in 18.5%. An increase in activity was more frequently observed in patients infected with genotype 1 (28.9%) than with others (7.7%; P = .04); the yearly progression of activity was significantly higher in patients with a low rather than high initial activity score (0.11 v –0.02; P < .01). An increase in fibrosis was noted in 13.3% of those with a low and 43.8% of those with a high initial activity score (P < .01), with a highest rate of yearly fibrosis progression (0.12 U).
In multivariate analysis, only a high activity score was significantly associated with an increased risk of fibrosis progression (relative risk, 25.5; 95% confidence interval, 2.7 to 238; P = .004). Spontaneous chronic hepatitis C evolution is worsening in only 20% of patients. Fibrosis progression is significantly associated with the necroinflammatory activity suggesting that this factor should be regarded as a major clue for deciding therapy.
Clinical course of hepatitis C virus during the first decade of infection: cohort study.Harris HE, Ramsay ME, Andrews N, Eldridge KP; HCV National Register Steering Group. Hepatitis C virus.
Public Health Laboratory Service Communicable Disease Surveillance Centre, London NW9 5EQ.
BMJ 2002 Feb 23;324(7335):450-3 Abstract quote OBJECTIVE: To determine the clinical course of hepatitis C virus in the first decade of infection in a group of patients who acquired their infections on a known date.
DESIGN: Cohort study.
SETTING: Clinical centres throughout the United Kingdom.
PARTICIPANTS: 924 transfusion recipients infected with the hepatitis C virus (HCV) traced during the HCV lookback programme and 475 transfusion recipients who tested negative for antibodies to HCV (controls).
MAIN OUTCOME MEASURES: Clinical evidence of liver disease and survival after 10 years of infection.
RESULTS: All cause mortality was not significantly different between patients and controls (Cox's hazards ratio 1.41, 95% confidence interval 0.95 to 2.08). Patients were more likely to be certified with a death related to liver disease than were controls (12.84, 1.73 to 95.44), but although the risk of death directly from liver disease was higher in patients than controls this difference was not significant (5.78, 0.72 to 46.70). Forty per cent of the patients who died directly from liver disease were known to have consumed excess alcohol. Clinical follow up of 826 patients showed that liver function was abnormal in 307 (37.2%), and 115 (13.9%) reported physical signs or symptoms of liver disease. Factors associated with developing liver disease were testing positive for HCV ribonucleic acid (odds ratio 6.44, 2.67 to 15.48), having acquired infection when older (at age > or = 40 years; 1.80, 1.14 to 2.85), and years since transfusion (odds ratio 1.096 per year, 1.00 to 1.20). For patients with severe disease, sex was also significant (odds ratio for women 0.38, 0.17 to 0.88). Of the 362 patients who had undergone liver biopsy, 328 (91%) had abnormal histological results and 35 (10%) of these were cirrhotic.
CONCLUSIONS: Hepatitis C virus infection did not have a great impact on all cause mortality in the first decade of infection. Infected patients were at increased risk of dying directly from liver disease, particularly if they consumed excess alcohol, but this difference was not statistically significant.
APOLIPOPROTEIN E-e4
Pierluigi Toniutto, MD, etal.Am J Clin Pathol 2004;122:428-433 Abstract quote
Carriage of the e4 allelic variant of the apolipoprotein E (ApoE) gene might affect the outcome of hepatitis C virus (HCV) infection. The liver transplantation setting offers the opportunity to verify the role of the donor's vs recipient's ApoE polymorphism.
Twenty-four patients (16 men) with recurrent hepatitis C, all infected by HCV-1b and treated with interferon and ribavirin, were genotyped for ApoE variants. Liver biopsies were done at baseline and 12 months later. After treatment, staging scores improved in 10 of 24 patients. Staging improvement was associated with recipient sex, completion of the full antiviral schedule, and recipient's e4 carriage. The beneficial effect of e4 carriage toward the progression of fibrosis was due entirely to the contribution given by male patients and was independent of the viral response.
Recipients', but not donors', carriage of at least 1 e4 allele might be associated with a better histologic outcome in recurrent HCV infection.CD34 POSITIVE CELLS High expression of CD34-positive sinusoidal endothelial cells is a risk factor for hepatocellular carcinoma in patients with HCV-associated chronic liver diseases
Shigeru Ohmori, MD
Katsuya Shiraki, MD
Kazushi Sugimoto, MD
Takahisa Sakai, MD
Katsuhiko Fujikawa, MD
Hidetaka Wagayama, MD
Koujiro Takase, MD
Takeshi Nakano, MDHum Pathol 2002;32:1363-1370. Abstract quote
CD34 has been widely used for the assessment of sinusoid-like neoangiogenesis in hepatocellular carcinoma (HCC). Recently, it was demonstrated that CD34-positive cells isolated from human peripheral blood differentiate into endothelial cells and contribute to neoangiogenesis in adults.
We investigated the localization and the substantial role of CD34-positive endothelial cells in the liver with hepatitis C virus (HCV)–associated chronic liver diseases. Liver tissue sections obtained by biopsy from 56 patients with HCV-associated chronic liver diseases by were examined immunohistochemically using anti-CD34, anti–von Willebrand factor (vWF), and anti–vascular endothelial growth factor (VEGF) antibodies. CD34 was stained in the sinusoid, showing dotty, linear, semicircular, or circular patterns. However, sinusoidal expression of vWF was not substantially identified in the same specimens, indicating the existence of sinusoidal CD34-positive but vWF-negative endothelial cells. We classified these cells as CD34 LI and found that CD34 LI was correlated with the expression of VEGF. Among 34 patients with advanced-stage disease, the cumulative incidence of HCC was significantly higher in patients with CD34 LI 12 (n = 16) than in those with CD34 LI < 12 (n = 18; P = .009). Moreover, among several clinicopathologic risk factors, CD34 LI could be recognized as an independently significant factor for development of HCC (relative risk, 7.36; P = .019).
We conclude that CD34-positive endothelial cells are regulated by several factors, such as VEGF, and might play a substantial role in hepatocarcinogenesis. Furthermore, high expression of CD34-positive sinusoidal endothelial cells is a risk factor for HCC in patients with HCV-associated chronic liver diseases.
INFANTS BORN TO HCV WOMEN Vertical transmission of hepatitis C virus and follow-up of newborns from infected mothers.
Polatti F, Viazzo F, Colleoni R, Belloni C, Zara F.
Department of Morphological, Eidological and Clinical Sciences, IRCCS S. Matteo Hospital, University of Pavia.
Minerva Ginecol 2000 Mar;52(3):59-62 Abstract quote
BACKGROUND: Aim of the study is to analyze the rate of vertical transmission of HCV and the time of clearance of maternal antibodies in non-infected babies serum.
METHODS: We have studied 36 babies born to HCV-positive and HIV-negative pregnant women at the University of Pavia. All mothers underwent blood tests to evaluate the presence of anti-HCV antibodies and viral RNA during pregnancy and after delivery. All babies underwent several tests at different times to evaluate the presence of viral RNA and the clearance of maternal antibodies.
RESULTS: All babies proved HCV-Ab positive at birth, but only one case (2.7%) proved infected at PCR analysis. Different patterns of HCV-Ab clearance were noted in the 35 non-infected babies. Of 24 babies from HCV-RNA-positive mothers, HCV-Ab reached zero in 24 months while in 11 babies from HCV-RNA-negative mothers, the antibodies disappeared at 12 months. A statistical difference was noted between the two groups of babies for the time of clearance of antibodies.
CONCLUSIONS: The risk of vertical transmission in babies born to HCV-RNA negative mothers is very low, and the clearance of maternal antibodies is set within 12 months of follow-up. Mothers positive to HCV-RNA have a higher risk of transmitting the virus to their offspring and the time of clearance of antibodies in non-infected babies seems to be longer. A correct follow-up of these children must be no shorter than 24 months
Outcome of infants born to hepatitis C infected women.
Healy CM, Cafferkey MT, Conroy A, Dooley S, Hall WW, Beckett M, Clarke TA, White MJ, Gorman WA, Butler KM.
Children's Hospital, Temple Street, Dublin, Ireland.
Ir J Med Sci 2001 Apr-Jun;170(2):103-6; discussion 92-3 Abstract quote
BACKGROUND: Hepatitis C virus (HCV) can be transmitted vertically from mother to infant, either late in pregnancy or at delivery. AIMS: To determine the outcome of infants born to HCV infected women, to characterise epidemiology and to design an appropriate infant monitoring schedule.
METHODS: Three hundred and fourteen infants, born to 296 HCV positive women between 1994 and 1999 were monitored for a median of 18 months (range 1-52).
RESULTS: Forty per cent of infants were small for age and 46% had neonatal abstinence syndrome (NAS). Of 173 infants of defined status, 11 were infected (vertical transmission rate [VTR] 6.4%, 95% CI 2.8-10). Infected infants were diagnosed at a median of three months (range 0.5-10). Liver transaminases elevation was documented in 8% of uninfected infants. A negative HCV PCR test before one month of age did not exclude infection but all infected patients had detectable HCV RNA when next tested (range 2-10 months).
CONCLUSIONS: 94% of infants born to HCV antibody positive women are not HIV infected. Liver transaminase elevation in exposed infants is not always indicative of infection. A minimum monitoring schedule of testing (PCR and antibody) at six to eight weeks, six and 18 months allows early diagnosis while detecting late seroconversions.
INTERFERON, PREDICTING RESPONSE A statistical analysis of predictive factors of response to human lymphoblastoid interferon in patients with chronic hepatitis C.
Hayashi J, Ohmiya M, Kishihara Y, Tani Y, Kinukawa N, Ikematsu H, Kashiwagi S.
Department of General Medicine, Kyushu University Hospital, Fukuoka, Japan.
Am J Gastroenterol 1994 Dec;89(12):2151-6 Abstract quote
OBJECTIVE: To determine markers predictive of effective interferon treatment for patients with chronic hepatitis C virus (HCV) infection, we studied 80 Japanese patients treated for 6 months with natural interferon-alpha.
METHODS: Serum samples were tested for HCV RNA by two-stage polymerase chain reaction (PCR). HCV RNA were grouped into four genotypes by amplification of core-gene sequences by PCR with type-specific primers, and the level of HCV RNA was measured by competitive PCR. HCV RNA was detected in all patients before the interferon treatment. For the purposes of this study, a complete response was defined as the elimination of HCV RNA for at least 6 months after termination of the treatment.
RESULTS: HCV RNA was eliminated from the sera of 27 patients (33.8%) at the termination of the interferon treatment, and the elimination was sustained throughout a 6-month follow-up (complete response). Four of eleven variables proved to be associated with a complete response when assessed by univariate analysis. With multiple logistic regression analysis assessment, however, only two variables (HCV RNA level (p < 0.001) and genotype (p = 0.048)) were significant.
CONCLUSION: These results suggest that factors associated with the HCV infection are more important than patient characteristics for effective interferon treatment of patients with chronic HCV infection and that a low level of HCV RNA and HCV of genotype III are useful predictors of a complete response.
Influence of pretreatment lesions on histologic response to interferon therapy in chronic hepatitis C.
Serra MA, Ferrandez A, Gilabert MS, Rodriguez F, Escudero A, Del Olmo JA, Compan A, Rodrigo JM.
Service of Hepatology, Hospital Clinico Universitario, Valencia, Spain
J Clin Gastroenterol 1998 Jun;26(4):296-9 Abstract quote
We have assessed the predictive value of the grade of pretreatment liver lesions on histologic response to interferon therapy in patients with chronic hepatitis C.
In 93 patients with chronic hepatitis C virus (HCV) infection who showed an initial response to interferon therapy, HCV RNA load and serum aminotransferase levels together with grade of liver histologic lesions were assessed at baseline and 6 months after treatment cessation. Regression of portal and periportal necroinflammation was observed only in sustained responders (normalization of aminotransferase levels and HCV RNA clearance). Neither short-term response nor the absence of virus was associated with significant histologic changes in the liver biopsies. Logistic regression analysis showed that pretreatment histologic lesion was an independent predictive factor of biologic response in the histologic regression of lesions 6 months after cessation of interferon treatment.
In conclusion, a dense inflammatory necrotic activity is a positive predictor of histologic response in interferon-treated patients with HCV.
Various scoring systems evaluating histologic features of chronic hepatitis C treated with interferon
Hirotsugu Ikawa, MD
Yoshitake Hayashi, MD
Toshiaki Ninomiya, MD
Yoshihiko Yano, MD
Miyuki Nakaji, MD
Hidenobu Nagano, MD
Yasushi Seo, MD
Yoshiko Kumon, MD
Seitetsu Yoon, MD
Masato Kasuga, MD
Hiroshi Itoh, MD
Chiho Ohbayashi, MDHum Pathol 2001;32:910-917 Abstract quote
Various scoring systems for chronic hepatitis have been proposed; however, there is no standard scoring system for studies of interferon (IFN) therapy in patients with chronic hepatitis C.
The aims of this study were to determine the most useful system reflecting histologic changes in biopsy specimens from complete responders and predicting the efficacy of IFN therapy.
Patients with chronic hepatitis C were administered IFN- for 6 months. Forty-six patients were included in this study and categorized as complete responders (n = 15), partial responders (n = 24), and nonresponders (n = 7) according to viral and biochemical responses to the therapy.
Biopsy specimens obtained from each patient before and after treatment were evaluated under 3 different systems: Histological Activity Index (HAI), modified HAI, and Scheuer classification. Complete responders showed considerable improvement in both grade and stage on the modified HAI and Scheuer classifications. On the HAI, a considerable improvement was observed in grade but not in stage. No significant change was observed in partial responders or nonresponders on any system.
Prediction of complete response was not possible under any system, but the pretreatment score reflecting piecemeal necrosis on any 1 of the 3 classifications and the fibrosis score on Scheuer classification were predictors of nonresponse.
The modified HAI system and Scheuer classification were amply useful in evaluating histologic changes in complete responders. Scores higher than 4 of the categories reflecting piecemeal necrosis on any system and fibrosis scores of 3 or 4 on Scheuer classification predicted nonresponse to IFN therapy.
RNA MEASUREMENT Hepatitis C viral RNA status at two weeks of therapy predicts the eventual response.
Yamaji K, Hayashi J, Kawakami Y, Furusyo N, Sawayama Y, Kishihara Y, Etoh Y, Kashiwagi S.
Department of General Medicine, Kyushu University Hospital, Fukuoka, Japan.
J Clin Gastroenterol 1998 Apr;26(3):193-9 Abstract quote
We investigated the timing of the disappearance and reappearance of serum hepatitis C viral (HCV) RNA in patients with chronic hepatitis C during interferon treatment and follow-up.
Serum samples were tested for HCV RNA by polymerase chain reaction in 62 patients with chronic hepatitis C treated with interferon-alpha for 24 weeks. We found that 17 patients obtained complete response, with absence of serum HCV RNA for 6 months after the treatment. Twenty-nine patients had a partial response, with reappearance of serum HCV RNA within 6 months of follow-up, and 16 patients were nonresponders who were positive for serum HCV RNA throughout the observation period. HCV RNA disappeared within 2 weeks of treatment in 31 patients, including all 17 (100%) complete responders and 14 (48.3%) of the 29 partial responders. The patients remaining positive for HCV RNA at the second week were 15 (51.7%) of the 29 partial responders and the 16 nonresponders. In all of the 29 partial responders, viremia recurred within 1 month after the treatment.
These results indicate that the status of HCV RNA at the second week of treatment is a useful predictor of effective treatment, whereas status at the first month after cessation of treatment is useful for assessing the effectiveness of interferon itself.
SURVIVAL RECURRENCE Approximately 50% of those who previously responded to standard-dose interferon, but relapsed after cessation of 6 months or less of therapy (“relapsers”), will have sustained responses to IFN-2b and ribavirin or to high-dose alfacon-1 (15 µg 3 times/wk ×48 weeks). Recurrence and accelerated progression of hepatitis C following liver transplantation.
Bernard PH, Le Bail B, Rullier A, Trimoulet P, Neau-Cransac M, Balabaud C, Bioulac-Sage P.
Service d'Anatomie Pathologique, laboratoire de Virologie, et Service de Chirurgie Digestive et de Transplantation Hepatique, Hopitaux Pellegrin et St Andre, C.H.U. Bordeaux, France.
Semin Liver Dis 2000;20(4):533-8 Abstract quote
The patient described had recurrent hepatitis C following OLT. This hepatitis appeared early postOLT and progressed to fibrosing cholestatic hepatitis, a severe form of HCV recurrence. Factors such as genotype 1, high viral load and severe damage on the first postOLT biopsy may indicate a more severe outcome.
We have hypothesized that, in parallel to what is known for hepatitis B, this rare form of recurrence was linked to a high expression of virus C proteins in the liver graft. Severe form of hepatitis C recurrence should be treated early with the best currently available treatment which is a combination of IFN and ribavirin. Large series of patients with comparable virological, histological and immunological inclusions criteria are necessary to evaluate the efficacy of this treatment.
TREATMENT The most effective therapy for CHC (IFN-2b and ribavirin or high-dose alfacon-1) produces cure in about 30% to 50% of patients
Cure is now usually defined as lack of detectable HCV RNA in serum by sensitive polymerase chain reaction assay at least 6 months after cessation of therapy
If patients achieve this, their chances of remaining free of detectable viral RNA during the ensuing several years are greater than 90%
Interferon and/or ribavirin have anti-inflammatory and antifibrotic effects on the liver even when they are not able to eradicate HCV
GENERAL
Cost-effectiveness of treatment for chronic hepatitis C infection in an evolving patient population.Salomon JA, Weinstein MC, Hammitt JK, Goldie SJ.
Harvard Center for Population and Development Studies, Cambridge, Mass 02138, USA.
JAMA. 2003 Jul 9;290(2):228-37. Abstract quote CONTEXT: Approximately 2.7 million US individuals are chronically infected with the hepatitis C virus (HCV). As public health campaigns are pursued, a growing number of treatment candidates are likely to have minimal evidence of liver damage.
OBJECTIVE: To examine the clinical benefits and cost-effectiveness of newer treatments for chronic hepatitis C infection in a population of asymptomatic, HCV sero-positive but otherwise healthy individuals.
DESIGN AND SETTING: Cost-effectiveness analysis using a Markov model of the natural history of HCV infection and impact of treatment. We used an epidemiologic model to derive a range of natural history parameters that were empirically calibrated to provide a good fit to observed data on both prevalence of HCV seropositivity and time trends in outcomes related to HCV infection.
PATIENTS: Cohorts of 40-year-old men and women with elevated levels of alanine aminotransferase, positive results on quantitative HCV RNA assays and serologic tests for antibody to HCV, and no histological evidence of fibrosis on liver biopsy.
INTERVENTIONS: Monotherapy with standard or pegylated interferon alfa-2b; combination therapy with standard or pegylated interferon plus ribavirin.
MAIN OUTCOME MEASURES: Lifetime costs, life expectancy, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.
RESULTS: The probability of patients with chronic HCV developing cirrhosis over a 30-year period ranged from 13% to 46% for men and from 1% to 29% for women. The incremental cost-effectiveness of combination therapy with pegylated interferon for men ranged from 26 000 dollars to 64 000 dollars per QALY for genotype 1 and from 10 000 dollars to 28 000 dollars per QALY for other genotypes; and for women ranged from 32 000 dollars to 90 000 dollars for genotype 1 and from 12 000 dollars to 42 000 dollars for other genotypes. Because the benefits of treatment were realized largely in the form of improvements in health-related quality of life, rather than prolonged survivorship, cost-effectiveness ratios expressed as dollars per year of life were substantially higher. Results were most sensitive to assumptions about the gains and decrements in health-related quality of life associated with treatment.
CONCLUSIONS: While newer treatment options for hepatitis C appear to be reasonably cost-effective on average, these results vary widely across different patient subgroups and depend critically on quality-of-life assumptions. As the pool of persons eligible for treatment for HCV infection expands to the more general population, it will be imperative for patients and their physicians to consider these assumptions in making individual-level treatment decisions.ANTIOXIDANTS Hepatology 1997;26(Suppl 1):143S-151S.
Use of antioxidants such as N-acetylcysteine or S-adenosylmethionine
Hepatology 1996;24:778-89.
Anti-HCV effects of interferon are modest, especially for patients with genotype 1a or 1b viruses and chronic infections
United States, such patients account for approximately 75% of all patients with known HCV infection
Response rates during therapy are 20% to 35%, but sustained virologic response rates are disappointingly low (~10%)
Side effects:
Fever, chills, headache, fatigue, arthralgias, and myalgia
Depression, moodiness, insomnia, and other neuropsychiatric problems
Granulocytopenia and thrombocytopenia
Leukopenia responds to granulocyte-macrophage colony-stimulating factor.Symptoms are sufficiently severe to require discontinuation of therapy in 2% to 10%
Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial.
Carrat F, Bani-Sadr F, Pol S, Rosenthal E, Lunel-Fabiani F, Benzekri A, Morand P, Goujard C, Pialoux G, Piroth L, Salmon-Ceron D, Degott C, Cacoub P, Perronne C; ANRS HCO2 RIBAVIC Study Team.
Groupe Hospitalier Universitaire Est, Universite Paris 6, INSERM U444, Paris, France.
JAMA. 2004 Dec 15;292(23):2839-48. Abstract quote
CONTEXT: Treatment of chronic hepatitis C virus (HCV) infection in human immunodeficiency virus (HIV)-infected patients is a growing concern. Most data on the virologic efficacy and safety of the combination of peginterferon alfa-2b and ribavirin in coinfected patients come from uncontrolled studies.
OBJECTIVE: To study the safety and efficacy of peginterferon alfa-2b plus ribavirin vs standard interferon alfa-2b plus ribavirin in HIV-HCV coinfected patients.
DESIGN AND SETTINGS: A multicenter, randomized, parallel-group, open-label trial. Patients were enrolled from February 2000 to February 2002 and followed up for 72 weeks.
PATIENTS: Four hundred twelve HIV-HCV coinfected patients with detectable serum HCV-RNA, abnormal liver histology, a CD4 cell count of at least 200 x 10(6)/L, and stable plasma HIV-RNA.
INTERVENTION: Treatment with ribavirin 400 mg twice a day, orally, plus either peginterferon alfa-2b (1.5 microg/kg subcutaneous injection once a week) or standard interferon alfa-2b (3 million units of subcutaneous injection 3 times a week) for 48 weeks.
MAIN OUTCOME MEASURES: Sustained virologic response, defined by undetectable serum HCV-RNA at week 72.
RESULTS: More patients had sustained virologic responses in the peginterferon group than in the standard interferon group (27% vs 20%, P = .047). This difference between the treatments was found in patients with HCV genotype 1 or 4 infection (17% for peginterferon vs 6% for standard interferon, P = .006) but was not found in patients with HCV genotype 2, 3, or 5 (44% for peginterferon vs 43% for standard interferon, P = .88). Together, a decline in HCV-RNA of less than 2 log10 from baseline and detectable serum HCV-RNA at week 12 predicted 99% of treatment failures. Histologic activity diminished and fibrosis stabilized in virologic responders. The 2 regimens showed similar tolerability although dose modifications for clinical and biological events were more frequent with peginterferon. Eleven cases of pancreatitis or symptomatic hyperlactatemia were observed, all in patients receiving didanosine-containing antiretroviral regimens.
CONCLUSION: In combination with ribavirin, treatment with peginterferon alfa-2b is more effective than standard interferon alfa-2b for HCV infection in HIV-infected patients.Effectiveness of interferon treatment for patients with chronic hepatitis C virus infection and normal aminotransferase levels.
Ohmiya M, Hayashi J, Ueno K, Furusyo N, Sawayama Y, Kawakami Y, Kinukawa N, Kashiwagi S.
Department of General Medicine, Kyushu University Hospital, Fukuoka, Japan.
Dig Dis Sci 2000 Oct;45(10):1953-8 Abstract quote
To determine the effects of interferon treatment, we studied 77 Japanese patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase (ALT).
Of 77 patients, 37 were given natural interferon-alpha for 24 weeks, and 40 not given interferon acted as controls. Serum samples were tested for HCV RNA and genotypes by polymerase chain reaction (PCR). HCV RNA levels were measured by competitive PCR. Of 37 treated patients, 11 (29.7%) had sustained elimination throughout a six-month follow-up, while HCV RNA was not eliminated in any untreated patients. At 24 months, the number of patients with elevated ALT was not significantly different between treated (13.5%) and untreated patients (15%).
Interferon eliminates HCV RNA in patients with normal ALT without severe side effects. The natural history of HCV infection should be clarified so that the interferon treatment regimen can be tailored to the needs of each patient.
RIBAVARIN N Engl J Med 1998;339:1485-92.
N Engl J Med 1998;339:1493-9.
Hepatology 1999;30:265A.Several recent studies have shown that adding ribavirin to standard IFN-2a or IFN-2b markedly improves the responses during and after therapy for 6 to 12 months
Major side effects of ribavirin:
Teratogenic effects
Hemolytic anemia
Skin rash
Contraindicated in patients with ischemic disease (eg, coronary artery disease, ischemic cerebrovascular disease, or peripheral vascular disease), renal insufficiency, or bothSeverity of such side effects is diminished by use of lower dose:
Lower doses (600 mg/d) are as effective and are better toleratedRIBAVARIN AND INTERFERON
Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, Haussinger D, Diago M, Carosi G, Dhumeaux D, Craxi A, Lin A, Hoffman J, Yu J.
University of North Carolina, Chapel Hill 27599, USA
N Engl J Med 2002 Sep 26;347(13):975-82 Abstract quote BACKGROUND: Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C.
METHODS: A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks.
RESULTS: A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin.
CONCLUSIONS: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone.
TRANSPLANTATION A 10-year experience of liver transplantation for hepatitis C: analysis of factors determining outcome in over 500 patients.
Ghobrial RM, Steadman R, Gornbein J, Lassman C, Holt CD, Chen P, Farmer DG, Yersiz H, Danino N, Collisson E, Baquarizo A, Han SS, Saab S, Goldstein LI, Donovan JA, Esrason K, Busuttil RW.
Dumont-UCLA Transplant Center, Department of Surgery, UCLA School of Medicine, Los Angeles, California 90095, USA.
Ann Surg 2001 Sep;234(3):384-93; discussion 393-4 Abstract quote
OBJECTIVE: To determine the factors affecting the outcome of orthotopic liver transplantation (OLT) for end-stage liver disease caused by hepatitis C virus (HCV) and to identify models that predict patient and graft survival.
SUMMARY BACKGROUND DATA: The national epidemic of HCV infection has become the leading cause of hepatic failure that requires OLT. Rapidly increasing demands for OLT and depleted donor organ pools mandate appropriate selection of patients and donors. Such selection should be guided by a better understanding of the factors that influence the outcome of OLT.
METHODS: The authors conducted a retrospective review of 510 patients who underwent OLT for HCV during the past decade. Seven donor, 10 recipient, and 2 operative variables that may affect outcome were dichotomized at the median for univariate screening. Factors that achieved a probability value less than 0.2 or that were thought to be relevant were entered into a stepdown Cox proportional hazard regression model.
RESULTS: Overall patient and graft survival rates at 1, 5, and 10 years were 84%, 68%, and 60% and 73%, 56%, and 49%, respectively. Overall median time to HCV recurrence was 34 months after transplantation. Neither HCV recurrence nor HCV-positive donor status significantly decreased patient and graft survival rates by Kaplan-Meier analysis. However, use of HCV-positive donors reduced the median time of recurrence to 22.9 months compared with 35.7 months after transplantation of HCV-negative livers. Stratification of patients into five subgroups, based on time of recurrence, revealed that early HCV recurrence was associated with significantly increased rates of patient death and graft loss. Donor, recipient, and operative variables that may affect OLT outcome were analyzed. On univariate analysis, recipient age, serum creatinine, donor length of hospital stay, donor female gender, United Network for Organ Sharing (UNOS) status of recipient, and presence of hepatocellular cancer affected the outcome of OLT. Elevation of pretransplant HCV RNA was associated with an increased risk of graft loss. Of 15 variables considered by multivariate Cox regression analysis, recipient age, UNOS status, donor gender, and log creatinine were simultaneous significant predictors for patient survival. Simultaneously significant factors for graft failure included log creatinine, log alanine transaminase, log aspartate transaminase, UNOS status, donor gender, and warm ischemia time. These variables were therefore entered into prognostic models for patient and graft survival.
CONCLUSION: The earlier the recurrence of HCV, the greater the impact on patient and graft survival. The use of HCV-positive donors may accelerate HCV recurrence, and they should be used judiciously. Patient survival at the time of transplantation is predicted by donor gender, UNOS status, serum creatinine, and recipient age. Graft survival is affected by donor gender, warm ischemia time, and pretransplant patient condition. The authors' current survival prognostic models require further multicenter validation.
THERAPEUTIC VENESECTION FOR IRON DEPLETION Hepatology 1997;26(Suppl 1):143S-151S.
Hepatology 1997;25:759-68.
Hepatology 2000;31:730-6.Generally encouraging results
Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
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