Comparison of transient elastography (FibroScan), FibroTest, APRI and two algorithms combining these non-invasive tests for liver fibrosis staging in HIV/HCV coinfected patients: ANRS CO13 HEPAVIH and FIBROSTIC collaboration.

OBJECTIVES: Combining noninvasive tests increases diagnostic accuracy for staging liver fibrosis in hepatitis C virus (HCV)-infected patients, but this strategy remains to be validated in HIV/HCV coinfection. We compared the performances of transient elastography (TE), Fibrotest (FT), the aspartate aminotransferase-to-platelet ratio index (APRI) and two algorithms combining TE and FT (Castera) or APRI and FT (SAFE) in HIV/HCV coinfection. METHODS: One hundred and sixteen HIV/HCV-coinfected patients (64% male; median age 44 years) enrolled in two French multicentre studies (the HEPAVIH cohort and FIBROSTIC) for whom TE, FT and APRI data were available were included in the study. Diagnostic accuracies for significant fibrosis (METAVIR F ≥ 2) and cirrhosis (F4) were evaluated by measuring the area under the receiver-operating characteristic curve (AUROC) and calculating percentages of correctly classified (CC) patients, taking liver biopsy as a reference. RESULTS: For F ≥ 2, both TE and FT (AUROC = 0.87 and 0.85, respectively) had a better diagnostic performance than APRI (AUROC = 0.71; P < 0.005). Although the percentage of CC patients was significantly higher with Castera's algorithm than with SAFE (61.2% vs. 31.9%, respectively; P < 0.0001), this percentage was lower than that for TE (80.2%; P < 0.0001) or FT (73.3%; P < 0.0001) taken separately. For F4, TE (AUROC = 0.92) had a better performance than FT (AUROC = 0.78; P = 0.005) or APRI (AUROC = 0.73; P = 0.025). Although the percentage of CC patients was significantly higher with the SAFE algorithm than with Castera's (76.7% vs. 68.1%, respectively; P < 0.050), it was still lower than that for TE (85.3%; P < 0.033). CONCLUSIONS: In HIV/HCV-coinfected patients, TE and FT have a similar diagnostic accuracy for significant fibrosis, whereas for cirrhosis TE has the best accuracy. The use of the SAFE and Castera algorithms does not seem to improve diagnostic performance.

[Cholangiocarcinoma: epidemiology and global management]. / Cholangiocarcinomes: épidémiologie et prise en charge globale.

SCOPE: Cholangiocarcinoma, or biliary tract tumors, are rare tumors for which survival is short, as diagnosis is often made at an advanced stage. Indeed, diagnosis remains difficult, since symptoms are often unspecific and appear at latest stages. This article presents an update of recent data and therapeutic options. CURRENT SITUATION AND SALIENT POINTS: Several etiologic factors have been identified, but for most patients, none of these factors can be found. Prognosis is often poor, and remains difficult to establish because of the lack of sufficient large-scale studies looking at the impact on preexisting tumor characteristics on overall survival. Surgery remains when possible the gold standard. When tumor removal is impossible, due to a local extension, the appropriate care of patients remains to be defined. Chemotherapy has been proposed with evidence of objective response but limited data on its ability to prolong overall survival and to enhance quality of life. Active chemotherapies appear to be made from combination of an antimetabolite, such as 5-fluorouracile or gemcitabine, and a platinum drug. PERSPECTIVES: In the near future, indications of chemotherapy could be enlarged and targeted therapy might also be used, since several molecules have been tested in preclinical studies, and be offered to patients in clinical trials.

UDP-glucuronosyltransferase UGT1A7 genetic polymorphisms in hepatocellular carcinoma: a differential impact according to seropositivity of HBV or HCV markers?

BACKGROUND: We conducted a case-control study to evaluate the role of UDP-glucuronosyltransferase 1A7 (UGT1A7) polymorphisms in the onset of hepatocellular carcinoma (HCC). METHODS: The study included 165 patients with HCC, 134 with cirrhosis and 142 controls without liver disease, matched for age and hospital. All were men younger than 75 years. HCC and cirrhosis patients were stratified according to time since cirrhosis diagnosis. RESULTS: We found a positive association between the UGT1A7*3/*3 genotype and HCC when the comparison was restricted to patients whose disease was of viral origin [OR = 3.4 (0.3-45)] but a negative association when it included only alcoholic patients [OR = 0.1 (0.02-0.6), p = 0.01]. CONCLUSION: Our study shows that UGT1A7 may play a role in hepatocellular carcinogenesis and that this role may differ according to the primary cause of the cirrhosis.

Epidemiology of hepatitis C virus in Europe.

Epidemiology of Hepatitis C virus (HCV) infection in Europe is changing very rapidly since the main source of contamination was blood transfusion and the use of surrogate markers allowed to diminish dramatically the number of patients contaminated through HCV post transfusion hepatitis. The recent description of several genotypes with different distributions over Europe and different pathogenicity will allow to explain various evolutive aspects of the disease. At present, groups at risk are drug addicts (70%), hemophiliacs (contaminated with blood products before 1985), hemodialysis patients (20%) and patients with cirrhosis with or without hepatocellular carcinoma. The detection of HCV markers prior to blood transfusion allowed to detect asymptomatic carriers of HCV, some of them with latent chronic hepatitis which can be predicted by the detection of HCV RNA in the serum. Vertical and sexual transmission are rare but possible events observed with certainty in patients co-infected with HIV and controversial in other situations.

Fulminant hepatitis in renal transplant recipients. The role of the delta agent.

In a series of about 300 renal transplant patients followed from 1972 to 1983, 3 cases of fulminant hepatitis were observed in HBs Ag-positive patients. In the liver biopsies of 2/3 of them, the delta antigen was detected by direct immunofluorescence with a specific anti-delta serum. This result demonstrates the responsibility of the delta agent for the development of fulminant hepatitis, and emphasizes the possibility of delta infection in HBs Ag-positive transplant patients with severe hepatitis.

Recurrence of Fabry's disease in a renal allograft eleven years after successful renal transplantation.

A case of Fabry's disease in a renal transplant recipient with a follow-up period of 11 years is reported. The patient suffered from renal, skin, peripheral nerve lesions, and asymptomatic cardiomegaly. Fabry's disease symptoms disappeared after transplantation. Improvement of renal function was rapidly observed, and it remained satisfactory during the whole posttransplantation period. The patient died of a severe, uncontrolled infection and of biliary peritonitis. Autopsy showed a polyvisceral accumulation of sphingolipids deposits. The engrafted kidney was histologically free of disease. Ultrastructurally, it revealed numerous sphingolipid inclusions in the endothelial cells of capillaries. The explanation of this complication could be attributed to: (1) high circulating levels of plasma substrates locally overwhelming the enzymatic capability of the graft endothelial cells; and (2) the endothelial cells originated from the recipient but not from the donor, an occurrence that has been described after transplantation. Rejection and the newly formed deposits in the endothelial cells may lead to the loss of the engrafted organ. As a consequence of the increasing possibility of organ transplantation, this complication should be detected by studying the blood vessels ultrastructurally in order to evaluate the condition of the transplant.

Is renal transplantation involved in post-transplantation liver disease? A prospective study.

Various lesions of the liver commonly observed in renal transplant recipients are usually considered as a consequence of the transplantation procedures (immunosuppression, drug toxicity, alteration of immune responses to various viruses). A group of 64 patients all treated with corticosteroids and azathioprine was studied prospectively, and serial liver biopsies were performed on the day of transplantation and at 1 and 3 years after transplantation. Chronic hepatitis was already present in 40% of the patients on the day of transplantation and an increase of only 15% in the frequency of this condition was observed 3 years later. The presence of HBsAg in 45% of the patients at the time of transplantation was significantly associated with liver lesions. In about 3% of the cases, transplantation was directly responsible for a liver disease (peliosis hepatitis). During the followup period an evolution from chronic persistent hepatitis to chronic active hepatitis was observed with an abnormally high frequency (25%). We conclude that most of the liver diseases observed in transplant recipients are the consequence of events before transplantation and probably related to hemodialysis.

Restriction of V beta gene usage of liver-derived lymphocytes in chronic hepatitis B and C.

T lymphocytes have been reported to be the predominant inflammatory cells in the liver of patients with chronic viral hepatitis. Their presence may reflect either nonspecific inflammation or a virus-specific immune response. To assess the repertoire of intra-hepatic T cells, we investigated the TCR V beta gene usage of T cells in 10 patients with chronic hepatitis B and 15 with chronic hepatitis C. Liver-derived lymphocytes and peripheral blood lymphocytes were analyzed by flow cytometry. Five out of the 10 hepatitis B patients were found to have an accumulation of certain V beta T cells in the liver (V beta 6.7; V beta 6.7; V beta 3.1, V beta 5.1, and V beta 6.7; V beta 3.1; V beta 12.1, respectively). Four out of the 15 hepatitis C patients were found to have an accumulation of certain V beta T cells in the liver (V beta 5.1; V beta 8 and V beta 5.2 and 5.3; V beta 3.1 and V beta 5.2 and 5.3; V beta 3.1 and V beta 12.1, respectively). Despite a limited screening of V beta subfamilies, this study indicates that, in patients with chronic hepatitis B and C, T cells using a certain V beta gene may accumulate in the liver. This suggests that intra-hepatic T cells are oligoclonal and possibly virus specific. Our results argue against the role of a superantigen in perpetuating liver disease. In addition, this study supports a role for T lymphocytes in the pathogenesis of chronic hepatitis C.

The hepatic sinusoid in hairy cell leukemia: an ultrastructural study of 12 cases.

Ultrastructural lesions of the liver were studied in 12 cases of hairy cell leukemia, with the alterations of the sinusoidal barrier receiving special emphasis. Portal and sinusoidal tumoral infiltration was observed in all cases. It was associated with angiomatous lesions of the sinusoids in eight cases; these lesions consisted of randomly distributed cavities lined by hairy cells and containing hairy cells and erythrocytes. In addition to the attachment of hairy cells to the sinusoidal wall, other striking electron microscopic abnormalities of the sinusoids included 1) wide areas of communication between the sinusoidal lumen and Disse's space, allowing extravasation of blood cells; 2) focal disruption of the sinusoidal wall; and 3) replacement of the sinusoidal cell lining by tumor cells in close contact with hepatocytes. Most of these changes closely resembled those observed in peliosis hepatis. As in peliosis, sinusoidal alterations in hairy cell leukemia might be due to the destruction of the sinusoidal wall, and tumor cells could play a role in the pathogenesis of the lesions. The pattern of liver involvement in hairy cell leukemia, which is peculiar among hepatic localizations of blood malignancies, might reflect the unique phenotype of the tumor cells.

Chronic cholestasis in patients after allogeneic bone marrow transplantation: several diseases are often associated.

From 1984 to 1991, 514 patients were treated by BMT in 1 center. 254 patients survived more than 3 months and, in 38 patients, 47 liver biopsies were performed for chronic liver dysfunction characterized by cholestasis. The aim of the present study was to evaluate the possible causes of liver disease at the time of biopsy. One clinician analyzed clinical data and was able to propose up to 3 diagnoses including GVHD, viral hepatitis, drug-related hepatitis, chronic veno-occlusive disease (VOD) or other. Two pathologists reviewed histologic sections and were also able to propose up to 3 diagnoses. Clinically, 1, 2 or 3 diagnoses were proposed in 30, 60 and 10% of cases, respectively. Pathologically, 1, 2 or 3 diagnoses were proposed in 13, 62 and 25%, respectively. Histologic changes of GVHD were present in 40 of 47 biopsies and concordance between the clinician and the pathologists on the presence of GVHD lesions was found in 77% of biopsies. Viral hepatitis was proposed 22 times by the clinician and 19 times by pathologists. Viral hepatitis, usually hepatitis C, was associated with GVHD in 16 cases. Diagnoses of chronic VOD and drug-related hepatitis were proposed less often. In summary, more than 1 diagnosis was suggested for many of the patients studied, GVHD being the most frequent. The simultaneous presence of GVHD, viral diseases, chronic VOD and drug-induced diseases could explain the high incidence of cholestasis in the long-term post-BMT.

Relationship between composition of lymphoid cell infiltrates in the liver and replication status in chronic hepatitis B: an immunohistochemical study.

The purpose of this in situ immunophenotyping study was to assess the nature of lymphoid cells involved in chronic hepatitis B with various levels of replication. Replicative status was studied in 25 patients with chronic hepatitis B. Different subsets of T cells, B cells, natural killer cells, and follicular dendritic cells were counted with a computerized image analyzer. Twelve patients had chronic hepatitis B with a high level of replication, nine without replication, and four with a low level of replication. The number of CD3+ T cells was significantly higher in the liver of patients with replication. In all cases, CD8+ T cells were the most numerous cells in the lobules and CD4+ T cells were the most numerous cells in the portal tract. Intra-portal lymphoid follicles were observed in 33% of patients with a high level of replication. The CD57+ natural killer cells were more numerous in patients with a low level of replication. This study suggests that in immunocompetent patients, the intensity and type of hepatic immune response are directly determined by the HBV replication.

[In vitro supplementation of pyridoxal phosphate for the optimisation of the determination of the catalytic activity of alanine aminotransferase and aspartate aminotransferase in kidney transplant patients (author's transl)]. / Intérêt de l'addition in vitro de phosphate de pyridoxal dans la détermination de l'activité catalytique des amino-transférases dans une population de transplantés rénaux.

Pyridoxal phosphate (PLP) is the coenzyme of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Thus, in vitro supplementation with PLP is important for the optimisation of the determination of catalytic activity of both enzymes. It patients with kidney transplants, stimulation by PLP is very important for ALT activity, which could be affected by plasma PLP deficiency. Furthermore, in this population catalytic activities are more frequently found increased using methods with PLP supplementation than without PLP supplementation (56% and 71% of patients for AST and ALT, respectively). These differences are not related to HBs antigen.

Plasma cell variant of Castleman's disease localized to the liver: a case report.

Localized plasma cell variant of Castleman's disease is an uncommon lymphoproliferative disorder. It is characterized by numerous, evenly distributed germinal centres with moderate or extensive sheets of plasma cells in between. It may be associated with a wide variety of systemic manifestations that disappear after removal of lesion. Rare cases of Castleman's disease have been reported in extranodal locations, i.e. muscle, larynx, vulva, lung, pericardium and cranium. We report the first the case of a liver tumour with clinico-pathological features of the plasma cell variant of Castleman's disease. This tumour differs from the hepatic inflammatory pseudotumour, which is frequently associated with infectious conditions.

Hepatitis B vaccine: randomized trial of immunogenicity in hemodialysis patients.

In order to determine whether reinforced vaccinations improve the immune response among uremic patients, three vaccination schedules with hepatitis B surface antigen vaccine (Institut Pasteur Production) were compared. A total of 215 hemodialysis patients treated in HBV free units were randomly allocated to Group I (3 injections of 1 ml), Group II (3 injections of 2 ml) and Group III (4 injections of 1 ml). Immune response was evaluated in 204 patients. The percentages of responders within 12 months after the first injection (greater than = 10 mIU/ml on 2 successive blood specimens) were: 45.6%, 75.0% and 69.4% in Group I, Group II and Group III respectively. The geometric mean peak values of anti-HBs observed 6 months after the first injection among the responders were: 60, 192 and 268 mIU/ml respectively. One month after a booster dose given to 182 patients 14 months after the first injection, anti-HBs levels were 144, 1123, 524 mIU/ml respectively, and the frequency of patients with an anti-HBs titer greater than = 50 mIU/ml was 68%, 82% and 75% respectively. These results led us to discard the use of Protocol I for these immuno-depressed patients while it is quite satisfactory in healthy subjects; they also show that Protocol II and III give better results than Protocol I, but that they cannot be statistically differentiated. We conclude that response rates and anti HBs antibody titers can be significantly improved in chronic hemodialysis patients with reinforced vaccination protocols.

Relationship between the effector T-cell response and viremia in symptomatic chronic hepatitis C.

OBJECTIVE: The purpose of this study was to assess the relationship between hepatitis C virus (HCV) viremia, HCV genotype, histologic activity index, and intrahepatic densities of immunocompetent lymphoid cells in chronic hepatitis C. METHOD: Liver biopsy specimens from patients with chronic hepatitis and anti-HCV antibodies, 5 with low-level HCV viremia and 26 with high-level HCV viremia, were studied. Sections of snap-frozen specimens were immunostained with monoclonal antibodies directed against different subsets of B cells, follicular reticulum cells, and T cells, including CD45RA-naive cells and CD45RO-primed cells. The densities of each subset of lymphoid cells were calculated with a computerized image analyzer. Hepatitis C virus RNA was measured with a quantitative branched DNA signal amplification assay, and HCV genotypes were determined with the line probe assay. RESULTS: A statistical correlation was found between the level of HCV viremia and the histologic activity index (P = .002). There were also significant correlations between the densities of CD3+ T cells and CD45RO+-primed cells in the liver and the histologic activity index and (P = .024 and P = .005, respectively), and significant correlations were found between the densities of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45RO+-primed cells and HCV viremia (P = .005, P = .03, P = .03, and P = .02, respectively). Whatever the viremia status, CD45RO-primed cells were more numerous than CD45RA-naive cells in lobules and portal tracts. The CD45RO/CD45RA ratio was significantly higher when intraportal lymphoid aggregates were present. Eight patients were infected with genotype 1b, and 11 were infected with genotype 3b. There were no statistical differences in the histologic activity index, viremia, and density of immunocompetent cells in the liver between these two HCV genotypes. CONCLUSIONS: The results of this study suggest that the density of antigen-primed effector T cells in the liver of symptomatic patients with chronic hepatitis C is adapted to HCV viremia but is independent of the occurrence of genotypes 1b or 3a, the most frequent genotypes found in France.

Resection of hepatocellular carcinoma: a European experience on 328 cases.

BACKGROUND/AIMS: Surgical liver resection has been demonstrated in Asian countries to be the best therapeutic option in patients with hepatocellular carcinoma. Because the value of this treatment is still debated in Western countries, the aim of this paper was to report a European experience of resection for hepatocellular carcinoma. METHODOLOGY: From 1990 to 1999, 239 men and 61 women aged from 15 to 77 years old underwent 328 resections including major resection in 138 (42%) cases. Normal liver was present in 53 patients (17%) and chronic liver disease was present in 247 including 152 (50%) with cirrhosis. RESULTS: In-hospital mortality was 6.4% and was significantly influenced by the presence of chronic liver disease (1.7% vs. 7.4%). Mortality after resection in alcoholic patients (14%), in patients with hepatitis C (9%) was significantly higher than in patients chronic hepatitis B (1%) (P < 0.05). The overall survival rates were 81%, 57%, 37%, and 13% at 1, 3, 5 and 10 years. Five-year survival rate was significantly higher (P < 0.05) in patients with normal liver as compared to chronic liver disease (50% vs. 34%). In patients with chronic liver disease parameters, which significantly influenced survival rate, were vascular invasion, tumor differentiation and the extent of resection. CONCLUSIONS: In this European study with varied profile of etiologies associated with hepatocellular carcinoma we showed that a five-year survival rate of 40% can be expected after resection and that chronic liver disease is a major factor influencing short and long-term prognosis.

[Ineffectiveness of corticosteroids in cholestatic forms of chronic active hepatitis]. / Inefficacité des corticostéroïdes au cours des formes cholestatiques de l'hépatite chronique active.

Four cases of chronic active hepatitis with cholestasis resembling primary biliary cirrhosis are reported. Two patients were women and two were men; their age ranged from 18 to 52 years. They had recurrent jaundice with pruritus, and, in two cases, xanthelasma or xanthomas. All patients had hyperbilirubinemia, a moderate increase in serum aspartate aminotransferase activity, an increase in serum alkaline phosphatase activity and immunoglobulins G levels. Hepatitis B surface antigen was present in one patient. Histological examination of the liver revealed active chronic hepatitis with cholestasis. Moderate doses of prednisone had no effect on clinical or biochemical signs in any of the patients.

[Practices of transcutaneous liver biopsies in France. Results of a retrospective nationwide study]. / Pratiques de la ponction-biopsie hépatique transpariétale en France. Résultats d'une étude nationale.

OBJECTIVES: Few nationwide studies have evaluated the number of transcutaneous liver biopsies performed for diffuse parenchymal liver diseases and the practices of this procedure. The aims of this retrospective nationwide survey were to precise these data. METHODS: In 1997, a confidential questionnaire was mailed to all AFEF and ANGH members. Parameters studied were annual number of transcutaneous liver biopsies performed by center for diffuse parenchymal liver diseases, sedation and/or premedication, haemostasis parameters required for choosing transcutaneous liver biopsy route, fasting liver biopsy, use of venous access, ultrasonography use during liver biopsy (determination of puncture site), modalities of follow-up after liver biopsy, number of biopsies performed as day-care procedure. RESULTS: Sixty seven centers were involved in the study. About 12 000 transcutaneous liver biopsies are performed each year in France for diffuse liver parenchymal diseases. Mean number of biopsies per center is 130 (median 70, ranges 5-600). Sedation is routinely used before liver biopsy in 31% of centers; APTT is not measured in 20% of centers and bleeding time is measured in 30% of centers before liver biopsy. Ultrasonography for determination of puncture site is used in 41% of centers. Venous access is implemented in 36% of centers. Outpatient liver biopsies are performed in less than 15% of cases by 64% of centers whereas 30% of centers practice outpatient liver biopsy of more than 50% of cases. Heterogeneity of biopsy practices are related to individual choices rather than the type or location of medical practice. CONCLUSIONS: Many transcutaneous liver biopsies are performed each year in France for diffuse parenchymal liver diseases, and practices vary greatly. Ultrasonography use and outpatient liver biopsy should be developed.

[Primary biliary cirrhosis: current modes of presentation. Clinical, biochemical, immunologic and histologic study of 206 patients seen from 1978 to 1988]. / La cirrhose biliaire primitive: modes actuels de présentation. Etude clinique, biochimique, immunologique et histologique de 206 malades observés de 1978 à 1988.

The aim of this study, based on a series of 206 patients (186 women and 20 men) with primary biliary cirrhosis seen from 1978 to 1988, was to assess the current modes of presentation of the disease. In approximately 30 percent of patients, primary biliary cirrhosis was recognized at an asymptomatic stage. Two thirds of these patients remained asymptomatic: they were older (mean age 57 years) and had less severe histological lesions than the patients who became symptomatic (mean age 45 years). The modes of presentation were not markedly different in the male and female patients of our series. The prevalence of cholelithiasis seemed to be particularly high (more than 20 percent in our patients). Complications of portal hypertension (bleeding esophageal varices or ascites) were the initial manifestations of primary biliary cirrhosis in 8 percent of our symptomatic patients. Alkaline phosphatase level was normal or only slightly increased in 15 percent of our patients: a normal level or a slight increase in alkaline phosphatases is not an argument against the diagnosis of primary biliary cirrhosis. Antinuclear antibodies with perinuclear fluorescence were demonstrated in 26 percent of our patients; in most of these patients, an antibody to a 200 kD protein of the nuclear envelope was present; in patients with this antibody, asthenia, arthralgias and associated extrahepatic diseases were less common and the titers of antibodies to mitochondria were lower than in the patients without this antibody.

[Encephalopathy following portal shunting in nodular regenerative hyperplasia of the liver]. / Encéphalopathie après dérivation portale au cours de l'hyperplasie nodulaire régénérative du foie.

Two patients with nodular hyperplasia of the liver developed a chronic disabling encephalopathy after an interposition mesocaval shunt. Both had a low total hepatic blood flow-rate postoperatively. Encephalopathy disappeared following surgical occlusion of the shunt. These observations emphasize the risk of postshunt encephalopathy in patients with non-cirrhotic intrahepatic portal hypertension.