Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels.

OBJECTIVE: A significant proportion of individuals with chronic hepatitis C virus (HCV) infection have persistently normal alanine aminotransferase (ALT) levels. Although data are controversial, such patients usually have weaker histological damage and a lower progression rate of fibrosis. The aims of this study were: (1) to compare demographic, virological, and histological parameters of HCV patients with normal ALT values with those of HCV patients with elevated ALT levels; and (2) to determine whether HLA class II alleles contribute to the persistence of normal ALT levels in HCV patients. PATIENTS AND METHODS: Eighty three patients with chronic HCV infection and persistently normal ALT values (group 1) and 233 patients with chronic HCV infection and elevated ALT levels (group 2) were studied. Histological features were expressed using Knodell and Metavir scores. HLA DRB1* and DQB1* genotyping was performed using hybridisation with sequence specific oligonucleotides after genomic amplification. The kappa2 and Fisher's exact tests were used to compare discrete variables and phenotype frequencies between the two groups, and Wilcoxon's test was used for continuous variables. A multivariate logistic regression model was used to determine which variables predicted normal ALT values. RESULTS: ALT levels were correlated with the severity of liver damage. In group 1, 93% of patients had an F0 or F1 Metavir index of fibrosis compared with 47% of patients in group 2 (p<0.001). A longer duration of infection (p<0.001) and increased DRB1*11 phenotype frequency (pc=0.03) were observed among patients with normal ALT. The two groups did not differ with regard to the mode of contamination or viral genotype. After logistic regression, young age (p=0.0008), female sex (p=0.01), long duration of infection (p=0.0001), and HLA DRB1*11 (p=0.050) were more strongly associated with persistence of normal ALT. CONCLUSIONS: Our study confirms that patients with chronic hepatitis C and normal ALT levels have less severe liver disease than those with elevated ALT levels. This particular biochemical outcome may be explained, at least in part, by host immunogenetic factors such as the presence of HLA-DRB1*11.

Non-invasive diagnosis of esophageal varices in chronic liver diseases.

BACKGROUND/AIMS: The primary prevention of bleeding from esophageal varices is a major therapeutic issue requiring early screening of esophageal varices. Our aim was to study the diagnostic accuracy of non-endoscopic means for the diagnosis of esophageal varices. METHODS: Sixty-three clinical, biochemical, endoscopic and Doppler ultrasound variables were prospectively recorded in 207 consecutive patients with chronic liver disease. Diagnostic accuracy was evaluated by discriminant analysis, first globally using all variables with diagnostic accuracy > or = 65% in univariate analysis, then by stepwise regression. RESULTS: A) whole group (n=207), 1) diagnosis of esophageal varices: diagnostic accuracy was globally 81%, and 81% with 1 variable: irregular liver surface at ultrasound, 2) Diagnosis of large esophageal varices (grades 2+3): diagnostic accuracy was globally 80%, and 79% with 2 variables: prothrombin index, gamma-globulins. B) patients with cirrhosis (n=116), 1) diagnosis of esophageal varices: diagnostic accuracy was globally 71%, and 72% with 2 variables: platelet count, prothrombin index, 2) diagnosis of large esophageal varices (grades 2+3): diagnostic accuracy was globally 71%, and 72% with 3 variables: platelet count, prothrombin index, spider naevi. The ROC curve showed that the best threshold for the diagnostic accuracy of platelet count was 160 G/l providing a sensitivity of 80% and a specificity of 58%. Platelet count > or = 260 G/l has a negative predictive value > or = 91%. CONCLUSIONS: Using a few non-endoscopic criteria, esophageal varices can be correctly diagnosed in 81% of patients with chronic liver disease and in 71% of patients with cirrhosis. These results show that the non-invasive screening of patients who are candidates for the primary prevention of variceal bleeding is possible, but should be improved before being used in a clinical setting.

Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis.

BACKGROUND/AIMS: Evaluation of the degree of hepatic fibrosis is especially important in patients with chronic liver disease. Our aim was to study the diagnostic accuracy of abdominal ultrasonography for cirrhosis or fibrosis. METHODS: Twenty-three clinical (n=12) and Doppler ultrasonic (n=11) variables were recorded in 243 patients with chronic (alcoholic and viral) liver disease under conditions close to those of clinical practice. Fibrosis was classified into six grades by two pathologists. Diagnostic accuracy was evaluated by discriminant analysis, first globally using all variables, then by stepwise analysis. RESULTS: A) Diagnosis of cirrhosis: 1) whole group (n=243): diagnostic accuracy was globally 84%, and 84% with two variables: spleen length, portal velocity; 2) compensated chronic liver disease (n=191): diagnostic accuracy was globally 85%, and 82% with two variables: liver surface, liver length (right kidney); 3) alcoholic compensated chronic liver disease (n=109): diagnostic accuracy was globally 86%, and 88% with two variables: spleen length, liver length (middle clavicle); 4) viral compensated chronic liver disease (n= 83): diagnostic accuracy was globally 86% and 86% with one variable: liver surface. By subtracting the proportion of patients who could not be investigated due to anatomical limitations, the highest calculated univariate diagnostic accuracy decreased by 7%. B) Diagnosis of fibrosis: diagnostic accuracy was globally 84% for extensive fibrosis. CONCLUSIONS: Cirrhosis can be correctly diagnosed in 82-88% of patients with chronic liver disease using a few ultrasonographic signs. However, the diagnostic accuracy of ultrasound is decreased by the anatomical limitations of this technique.

Measurement of collateral circulation blood flow in anesthetized portal hypertensive rats.

AIMS: The aim of this study was to develop a technique to measure collateral blood flow in portal hypertensive rats. METHODS: Morphological techniques included inspection, casts and angiographies of portosystemic shunts. The main hemodynamic measurements were splenorenal shunt blood flow (transit time ultrasound method), percentage of portosystemic shunts and regional blood flows (microsphere method). In study 1, a model of esophageal varices was developed by ligating the splenorenal shunt. In study 2, morphological studies of the splenorenal shunt were performed in rats with portal vein ligation. In study 3, the relationship between splenorenal shunt blood flow with percentage of portosystemic shunts was evaluated in dimethylnitrosamine cirrhosis. In study 4, secondary biliary, CCl4 and dimethylnitrosamine cirrhosis were compared. In study 5, rats with portal vein ligation received acute administration of octreotide. In study 6, rats with dimethylnitrosamine cirrhosis received acute administration of vapreotide. RESULTS: Blood flow of para-esophageal varices could not be measured. SRS blood flow was correlated with the mesenteric percentage of portosystemic shunts (r = 0.74, P < 0.05), splenic percentage of portosystemic shunts (r = 0.54, P < 0.05) and estimated portosystemic blood flow (r = 0.91, P < 0.01). Splenorenal shunt blood flow was 6 to 12 times higher in portal hypertensive rats, e.g., in portal vein ligated rats: 2.8 +/- 2.7 vs 0.3 +/- 0.1 mL.min-1 in sham rats (P < 0.01), and was similar in the different cirrhosis models but was higher in portal vein ligated rats than in cirrhotic rats (1.2 +/- 0.7 vs 0.6 +/- 0.6 mL.min-1.100 g-1, P = 0.05). Octreotide significantly decreased splenorenal shunt blood flow: -23 +/- 20% (P < 0.01) vs -6 +/- 8% (not significant) in placebo rats. The variation of splenorenal shunt blood flow after vapreotide was significant but not that of the splenic percentage of portosystemic shunts compared to placebo. CONCLUSIONS: The splenorenal shunt is the main portosystemic shunt in rats. The measurement of splenorenal shunt blood flow is easy, accurate and reproducible and should replace the traditional measurement of the percentage of portosystemic shunts in pharmacological studies.

Splenorenal shunt blood flow by transit-time ultrasound as an index of collateral circulation in portal hypertensive rats.

The aim of this study was to develop a technique that could serve as an index of portosystemic shunt (PSS) blood flow in portal hypertensive rats whose main shunt is the splenorenal shunt (SRS). The main hemodynamic measurements performed were: SRS blood flow by the transit-time ultrasound (TTU) method, percentage of PSS, and regional blood flows by the microsphere method. We determined the accuracy and reproducibility of SRS blood flow measurements under baseline and pharmacological (octreotide) conditions. SRS blood flow was compared with other hemodynamic characteristics. Two models of portal hypertension were used: secondary biliary and dimethylnitrosamine cirrhosis. The SRS blood flow was correlated with mesenteric (r = .76; P < .001) and splenic (r = .67; P < .01) PSS percentages. The intra- and interobserver agreements for SRS blood flow were excellent: ric = .99 and ric = .98, respectively. SRS blood flow was six times higher in portal hypertensive rats (0.6 +/- 0.7 mL . min-1 . 100 g-1) than in sham rats (0.1 +/- 0.1 mL . min-1 . 100 g-1 [P < .01]). Octreotide significantly decreased SRS blood flow but not mesenteric or splenic PSS percentages. SRS is the main PSS in rats. The measurement of SRS blood flow by TTU is accurate and reproducible. This method can be used to identify new mechanisms in hemodynamic studies that differ from those identified by the measurement of the percentage of PSS by the microsphere method, especially in pharmacological studies.

[Occurrence of non-Hodgkin's lymphoma in chronic viral hepatitis C]. / Survenue d'un lymphome non hodgkinien au cours d'une hépatite chronique virale C.

INTRODUCTION: We report the occurrence of non-Hodgkin's lymphoma during the course of chronic hepatitis C treated with alpha-interferon. EXEGESIS: Specific viruses such as Epstein-Barr virus and human T-cell leukemia viruses I and II may be at the origin of various lymphomas in human. The presence of B cell lymphoma in the course of chronic hepatitis C has already been described and could be related to the lymphoid tropism of hepatitis C virus. CONCLUSION: This new report of an association between chronic hepatitis C and B cell lymphoma should lead physicians to search for signs of lymphoma in patients with chronic hepatitis C.

[Suicidal impulses in patients with chronic viral hepatitis C during or after therapy with interferon alpha]. / Pulsions suicidaires chez des malades atteints d'hépatite chronique C au cours ou au décours du traitement par l'interféron alpha.

UNLABELLED: We report 5 cases of psychiatric side effects in patients treated with alpha interferon for chronic viral C hepatitis. The first case includes depression with suicidal impulses without a suicide attempt; there was a positive rechallenge of interferon. In the second and third cases, depression occurred during interferon therapy, but has not disappeared after interferon withdrawal. In the 4th and 5th cases, depression occurred after interferon withdrawal. Overall, suicide was attempted in 4 cases after interferon withdrawal and was responsible for 2 deaths. The prevalence of suicide attempts during the 6 to 12 months of interferon therapy was 0% compared to 1.3% during the 6 months after interferon therapy (P < 0.05) in 306 patients with chronic hepatitis C treated by interferon in our local area network during the same period. IN CONCLUSION: a) depression does not always disappear after interferon is discontinued; b) regular psychiatric follow-up is justified during treatment with interferon; c) psychiatric supervision should be continued, even more frequently after interferon withdrawal; d) the increased risk of psychiatric side-effect due to interferon as well as their severity suggest interferon should be administered with caution; e) the role of interferon can only be evaluated in controlled studies including the incidence and predictive value of emotional disorders.

[Recurrent stomal hemorrhage treated by transjugular intrahepatic portosystemic anastomosis and embolization of stomal varices]. / Hémorragies stomiales récidivantes traitées par anastomose portosystémique intrahépatique transjugulaire et embolisation des varices stomiales.

Bleeding stomal varices is a rare complication of portal hypertension. We report the case of a cirrhotic patient, with a history of colonic adenocarcinoma, who had recurrent bleeding stomal varices. Treatment with transjugular intrahepatic portosystemic shunt and stomal varice embolization was performed because failure of medical treatment of portal hypertension and sclerotherapy. Twenty six months later only one stomal hemorrhage was noted. This suggests that transjugular intrahepatic portosystemic shunt and stomal varice embolization is effective in case of recurrent bleeding of stomal varices.

Hemodynamic effects of terlipressin and octreotide administration alone or in combination in portal hypertensive rats.

BACKGROUND/AIMS: The action sites and kinetic effects of octreotide and terlipressin may be different. Therefore, we studied the hemodynamic effects of acute administration of these drugs alone or in combination in rats with portal hypertension due to portal vein ligation. METHODS: In a first study performed in anesthetized rats, hemodynamics were measured before and after drug administration (placebo, octreotide: 8 microg x kg(-1) x h(-1) for 30 min, terlipressin: 50 microg/kg bolus, terlipressin + octreotide at the same doses). The second study, performed in conscious rats, included the same groups and drug doses; hemodynamics were measured every 10 min for 1 h. The third study tested the effect of preinfusion of octreotide on responsiveness to terlipressin. RESULTS: Terlipressin produced more marked systemic effects than octreotide by decreasing heart rate and cardiac output and increasing mean arterial pressure. Terlipressin produced a greater decrease in portal pressure than octreotide: placebo: -3+/-5%, terlipressin: -42+/-8%, octreotide: -16+/-10%, combination: -44+/-8% (conscious rats at 20 min, p<10(-4)). The decrease in portal pressure was immediate and lasted at least 60 min with both drugs. Octreotide significantly decreased spleno-renal shunt blood flow (% variation): placebo: -6+/-8, terlipressin: -15.5+/-20, octreotide: -22.5+/-20, combination: -27+/-10 (p<10(-2)). Octreotide preinfusion significantly increased the responsiveness of arterial pressure and heart rate to terlipressin. CONCLUSIONS: Terlipressin decreases portal pressure significantly more than octreotide, while only octreotide significantly decreases collateral blood flow. Simultaneous administration of these drugs does not have significant additive effects but has complementary effects. The preadministration of octreotide alters systemic response to terlipressin.

Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores. Comparison with serum markers.

BACKGROUND/AIMS: Liver fibrosis is mainly evaluated by qualitative histological examination. Although histological semi-quantitative scores and quantitative determination with image analysis are now possible, these methods have not been fully validated and compared. Therefore, we evaluated these two methods prospectively in 243 patients with chronic liver disease. METHODS: The semi-quantitative fibrosis score was evaluated by two independent pathologists, using the Knodell fibrosis score and a 6-grade score derived from the Metavir score; the area of fibrosis was measured by image analysis. The serum levels of hyaluronate, N-terminal peptide of procollagen III, laminin, transforming growth factor-beta1, alpha2-macroglobulin, apolipoprotein A1, PGA score and prothrombin index were measured. RESULTS: There was a good correlation between the semi-quantitative fibrosis score and the area of fibrosis (r=0.84, p<10(-4)). Using multiple regression analysis, the semi-quantitative score was predicted by the 8 serum markers with R2=0.69 (R2=0.59 for hyaluronate at the 1st step) while the area of fibrosis was predicted with R2=0.79 (R2=0.76 for hyaluronate at the 1st step), and the Knodell fibrosis score was predicted with R2=0.65 (R2=0.31 for hyaluronate at the 1st step). CONCLUSIONS: The area of fibrosis, as determined by image analysis, and the semi-quantitative score are well correlated. However, for serum markers the correlation is higher with the area of fibrosis than with the semi-quantitative score. Other characteristics such as reproducibility, rapidity, simplicity, adaptability, and exhaustiveness also favor image analysis.

Noninvasive diagnosis of hepatic fibrosis or cirrhosis.

BACKGROUND & AIMS: The evaluation of the degree of hepatic fibrosis is especially important in patients with chronic liver disease. The aim of this study was to study the diagnostic accuracy of noninvasive means. METHODS: Sixty-three clinical, biochemical (prothrombin index, gamma-glutamyl transpeptidase and apolipoprotein A1 levels [PGA score]; and hyaluronate, alpha2-macroglobulin, N-terminal peptide of type III procollagen, laminin, and transforming growth factor beta1 levels), Doppler ultrasonic, and endoscopic variables were recorded in 243 patients who were divided into four groups: whole, compensated, alcohol-compensated, and viral-compensated liver disease. Diagnostic accuracy was evaluated by discriminant analysis; first globally, then by stepwise analysis. RESULTS: In three groups, hyaluronate and prothrombin index were the best predictive factors (accuracy, > or =85%). Accuracy for the diagnosis of cirrhosis varied from 89.5% to 95% with global discriminant analysis and from 91% to 94% with stepwise analysis according to the group. In the compensated group, hyaluronate concentration of > or =60 microg/L had a sensitivity of 97% and a specificity of 73%. Diagnostic accuracy was 87% globally for extensive fibrosis. Prothrombin index and hyaluronate were two independent variables predictive of the area of fibrosis (r2 = .66). CONCLUSIONS: With the use of a few noninvasive criteria, cirrhosis can be correctly diagnosed in 91%-94% of patients with chronic liver disease. Serum hyaluronate concentration is the most sensitive variable for screening.

Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation.

AIMS/METHODS: Our aim was to study the antifibrotic and hemodynamic effects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (SPN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension induced in rats by bile duct ligation. A blind study was performed in five groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg x kg(-1) x J(-1)), PTX (50 mg x kg(-1) x J(-1)) and SPN (100 mg x kg(-1) x J(-1)). Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the following parameters were evaluated: area of hepatic fibrosis by image analysis after staining collagen with picrosirius and plasma concentrations of hyaluronate, splanchnic and systemic hemodynamics (radiolabeled microspheres). RESULTS: Portal venous pressure (PL: 15.5+/-1.5, SMV: 15.8+/-2.5, PTX: 15.9+/-1.8, SPN: 13.5+/-2.1 mmHg, p<0.05) and porto-systemic shunts (PL: 30+/-31, SMV: 18+/-27, PTX: 25+/-24, SPN: 5+/-4%, p<0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. There was a significant correlation between portosystemic shunts and portal pressure (r(s)=0.47, p<0.01). The area of fibrosis was not significantly different among the four groups of bile duct ligated rats (PL: 8.7+/-3.9, SMV: 7.1+/-3.6, PTX: 7.8+/-2.7, SPN: 6.6+/-3.3%) but was higher than in sham rats (1.5+/-0.5%, p<0.001). Hyaluronate was significantly higher in bile duct ligated rats (from 374+/-162 to 420+/-131 microg/l, among the four groups) than in sham rats (52+/-16 microg/l, p<0.0001). CONCLUSIONS: In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and prevented porto-systemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

[Association of hepatic adenomatosis and hepatoportal sclerosis in a woman with incontinentia pigmenti]. / Association d'une adénomatose hépatique et d'une sclérose hépatoportale chez une femme atteinte d'incontinentia pigmenti.

We report the case of the association of three uncommon diseases in a young woman: incontinentia pigmenti, portal hypertension due to hepatoportal sclerosis, and liver adenomatosis. Incontinentia pigmenti is a hereditary genodermatosis with pigmentary cutaneous lesions and dysmorphic malformations. In our patient, among liver abnormalities, there were blood biochemical alterations, portal hypertension, and initially neo hepatic nodular lesions. Histological examination of the surgical liver specimen showed several adenomas and fibrosis of the portal tracts with portal vascular changes. The etiopathogenic nature of the adenomatosis and hepatoportal sclerosis is unclear. As a general rule, hepatic adenomatosis is associated with normal liver. We hypothesize that the adenomas could be secondary to changes in hepatic vascularisation.

[Hematologic manifestations related to hepatitis A virus. 3 cases]. / Manifestations hématologiques liées au virus de l'hépatite A. Trois cas.

We report 3 cases of acute hepatitis A infection with haematological manifestations. In the first case, severe aplastic anemia occurred in a 6 year-old child, who underwent 3 bone marrow grafts before responding favourably. In the second and third cases, severe anemia and thrombocytopenia occurred in a 42 year-old man with cholestatic hepatitis, and in a 66 year-old man with fulminant hepatitis; there was a favourable outcome in both cases. These cases demonstrate that haematological manifestations in hepatitis A can be severe, independent of the severity of liver disease. Although these manifestations seem to be rare, we suggest performing systematic haematological evaluations in cases of viral hepatitis A with unusual outcomes.