Vincent Di Martino

Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) – NCT01514890

BACKGROUND & AIMS In phase III trials, the safety profile of triple therapy (pegylated interferon/ribavirin with boceprevir or telaprevir) seems to be similar in HCV treatment-experienced cirrhotic and non-cirrhotic patients, but few cirrhotics were included. We report the week 16 safety and efficacy analysis in a cohort of compensated cirrhotics treated in the French Early Access Programme. METHODS 674 genotype 1 patients, prospectively included, received 48 weeks of triple therapy. The analysis is restricted to 497 patients reaching week 16. RESULTS A high incidence of serious adverse events (40.0%), and of death and severe complications (severe infection or hepatic decompensation) (6.4%), and a difficult management of anaemia (erythropoietin and transfusion use in 50.7% and 12.1%) were observed. Independent predictors of anaemia < 8 g/dl or blood transfusion were: female gender (OR 2.19, 95% CI 1.11-4.33, p=0.024), no lead-in phase (OR 2.25, 95% CI 1.15-4.39, p=0.018), age ≥ 65 years (OR 3.04, 95% CI 1.54-6.02, p=0.0014), haemoglobin level (≤ 12 g/dl for females, ≤ 13 g/dl for males) (OR 5.30, 95% CI 2.49-11.5, p=0.0001). Death or severe complications were related to platelets count ≤ 100,000/mm(3) (OR 3.11, 95% CI 1.30-7.41, p=0.0105) and albumin <35 g/dl (OR 6.33, 95% CI 2.66-15.07, p=0.0001), with a risk of 44.1% in patients with both. However, the on-treatment virological response was high. CONCLUSIONS The safety profile was poor and patients with platelet count ≤ 100,000/mm(3) and serum albumin <35 g/L should not be treated with the triple therapy.

Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B

BACKGROUND AIMS Liver biopsy is the gold standard for assessing hepatitis B virus (HBV)-related histology. The aim was to determine the diagnostic utility of noninvasive serum markers in patients with chronic hepatitis B. METHODS The aminotransferases and indices including alpha(2)-macroglobulin, apolipoprotein A1, haptoglobin, gamma-glutamyl-transpeptidase (GGT), and total bilirubin (Fibrotest), and ALT (Actitest) were compared with liver histology. The primary outcomes were A2-A3 activity and F2-F4 fibrosis (METAVIR). RESULTS Two hundred and nine patients were included. Forty-one patients (20%) had A2-A3 activity and 61 (29%) had F2-F4 fibrosis. AST and GGT (P<0.001) were independently associated with A2-A3 activity. AST, ALT, and Actitest accurately predicted activity ((areas under receiver operating characteristic (ROC) curves (AUROC), 0.81-0.82+/-0.04)); an AST or ALT< or =30IU/l excluded significant activity with 96% certainty. Fibrotest accurately predicted F2-F4 fibrosis (AUROC, 0.78+/-0.04). Fibrotest scores (range, 0-1.0) < or =0.20 and >0.80 had negative and positive predictive values of 92%, respectively. Restricting biopsy to patients with intermediate scores (>0.20 and < or =0.80) may prevent liver biopsies in 46% of patients while maintaining 92% accuracy. CONCLUSIONS The aminotransferases and an index including five biochemical markers are accurate noninvasive markers of HBV-related activity and fibrosis, respectively.

Progression of liver fibrosis in women infected with hepatitis C: Long‐term benefit of estrogen exposure

Female sex is a protective factor for the progression of fibrosis in patients with chronic hepatitis C virus (HCV) infection. Experimental data suggest that estrogens may have an antifibrotic effect. The objective of this study was to evaluate the influence of past pregnancies, oral contraceptives, menopause, and hormone replacement therapy (HRT) on liver fibrosis progression in HCV‐infected women. Four hundred seventy‐two HCV‐infected women received a survey regarding prior pregnancies, menopause, and the use of oral contraceptives and HRT. The impact of these variables on liver fibrosis and its progression were evaluated using multivariate analyses considering all putative confounding factors. Two hundred one women completed the survey (43% response rate), 157 of whom had an estimated date of HCV infection (96 postmenopausal women, 96 women with previous pregnancies, and 105 women with past use of oral contraceptives). Through multivariate analyses, the estimated rate of fibrosis progression was higher in postmenopausal (P < .05) and nulliparous (P = .02) women and was associated with greater histological activity (P < .001). Prior use of oral contraceptives had no significant influence. Among postmenopausal women, the estimated rate of fibrosis progression (±SE) was lower in women who received HRT compared with untreated patients (0.099 ± 0.016 vs. 0.133 ± 0.006 METAVIR units/yr; P = .02) and was similar to that of premenopausal women (0.093 ± 0.012 METAVIR units/yr; P value not significant). In conclusion, menopause appears to be associated with accelerated liver fibrosis progression in HCV‐infected women, an effect that may be prevented by HRT. Pregnancies may have a beneficial impact on the long‐term progression of liver fibrosis. (HEPATOLOGY 2004;40:1426–1433.)

Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis.

BACKGROUND & AIMS We performed a meta-analysis to evaluate the effects of ursodeoxycholic acid (UDCA) on pruritus, liver test results, and outcomes of babies born to women with intrahepatic cholestasis of pregnancy (ICP). METHODS We performed a systematic review of 9 published, randomized controlled trials (3 double blinded) that compared the effects of UDCA to other drugs, placebo, or no specific treatment (controls) in patients with ICP. We analyzed data from 454 patients: 207 received only UDCA, 70 received only placebo, 42 received cholestyramine, 36 received dexamethasone for 1 week and then placebo for 2 weeks, 65 received S-adenosyl-methionine, and 34 received no specific treatment. To achieve consistency among end points, a standard questionnaire was sent to all corresponding authors. For each end point, we performed pooled analysis that compared the effects of UDCA with those of all controls and UDCA with those of placebos. RESULTS In pooled analyses that compared UDCA with all controls, UDCA was associated with total resolution of pruritus (odds ratio [OR], 0.23; 95% confidence interval [CI], 0.07-0.74; P < .01), reduced pruritis (OR, 0.27; 95% CI, 0.13-0.55; P < .0001), normalization of serum levels of alanine aminotransferase (ALT) (OR, 0.23; 95% CI, 0.10-0.50; P < .001), decreased serum level of ALT (OR, 0.24; 95% CI, 0.11-0.52; P < .0001), reduced serum levels of bile acids (OR, 0.37; 95% CI, 0.19-0.75; P < .001), fewer premature births (OR, 0.44; 95% CI, 0.24-0.79; P < .01), reduced fetal distress (OR, 0.46; 95% CI, 0.25-0.86; P < .01), less frequent respiratory distress syndrome (OR, 0.30; 95% CI, 0.12-0.74; P < .01), and fewer neonates in the intensive care unit (OR, 0.49; 95% CI, 0.25-0.98; P = .046). In pooled analyses that compared the effects of UDCA with placebo, UDCA reduced pruritus (OR, 0.21; 95% CI, 0.07-0.62; P < .01), normalized (OR, 0.18; 95% CI, 0.06-0.52; P < .001) or decreased serum levels of ALT (OR, 0.12; 95% CI, 0.05-0.31; P < .0001), and reduced serum levels of bile acids (OR, 0.30; 95% CI, 0.12-0.73; P < .01). CONCLUSIONS Based on a meta-analysis, UDCA is effective in reducing pruritus and improving liver test results in patients with ICP; UDCA therapy might also benefit fetal outcomes.

Effect of terlipressin (Glypressin) on hepatorenal syndrome in cirrhotic patients: results of a multicentre pilot study.

Objectives Hepatorenal syndrome (HRS) is a severe complication of cirrhosis, leading to death in more than 90% of cases in the absence of liver transplantation. Several treatments have been attempted as a bridge to liver transplantation. Among such treatments, terlipressin has been studied in several reports, two prospective pilot studies and a double-blind, short-term, controlled haemodynamic study. Promising results have been shown with this drug. The purpose of this multicentre retrospective study was to evaluate the effects of terlipressin on renal function and survival of patients with HRS. Patients and methods Eighteen patients recruited in three liver units with type 1 HRS in 16 cases and type 2 HRS in two cases were given 4 mg/day terlipressin (range 1.5–12) for 7 days (range 2–16). Electrolytes, renal function, mean urinary output, natriuresis, liver function tests, and tolerance of the treatment were monitored regularly. Results A total of 13/18 (72%) patients responded with a mean decline in serum creatinine ranging from 31 to 75% from day 0 to day 5. Eight of these 13 patients had a normal serum creatinine level at day 5. Liver function tests remained unaffected by terlipressin administration. Three local necrosis complications were noted in patients receiving terlipressin continuously via an infusion pump. Two responder patients survived: one of these underwent orthotopic liver transplantation with a follow-up of 24 months; the other is alive with a follow-up of more than 36 months. Patients who responded to terlipressin had lower baseline serum bilirubin and significantly higher serum sodium concentrations than patients who did not respond. Conclusion In this pilot study, improvement in renal function was noted in 72% of cases after administration of terlipressin, and was associated with long-term survival in two patients. Parameters associated with response to terlipressin and increased survival should be defined better in a large cohort of cirrhotic patients with HRS.

C-Reactive protein predicts short-term mortality in patients with cirrhosis

BACKGROUND & AIMS We aimed at improving prediction of short-term mortality in cirrhotic inpatients by evaluating C-reactive protein (CRP) as a surrogate marker of systemic inflammatory response syndrome (SIRS). METHODS One-hundred and forty-eight consecutive cirrhotic patients with Child-Pugh score ≥ B8 and without hepatocellular carcinoma were prospectively included and followed for 182 days. The primary end point was 6-month survival. RESULTS Main baseline characteristics were as follows: alcoholic liver disease in 88.5%; bacterial infection in 37%; hepatorenal syndrome in 7% of cases. CRP range was 1-240 mg/L (median 26 mg/L); 42 patients (28.4%) had SIRS as defined by ACCP/SCCM-criteria. CRP levels were higher in patients with SIRS (50 vs. 21 mg/L; p<0.0001), infection (46 vs. 27 mg/L; p<0.0001), and alcoholic hepatitis (44 vs. 32 mg/L, p=0.049). Forty-two patients died within the first 6 months of follow-up. Short-term mortality was associated with extrahepatic co-morbidities (p=0.002), high MELD score (p<0.001; AUROC=0.67), renal failure (p=0.008), elevated blood lactates (p<0.001), and high baseline CRP levels (p=0.003; AUROC=0.63; best cut-off value at 29 mg/L). Among patients with baseline CRP ≥ 29 mg/L, 32 still had CRP ≥ 29 mg/L at day 15 (group A). Group A was associated with 6-month mortality in the overall population (p<0.001) and also through sensitivity analyses restricted to patients without infection or alcoholic hepatitis. Multivariate analysis (Cox) adjusted for age identified three predictors of mortality: high MELD score (HR=1.08; 95% CI: 1.03-1.12; p<0.001), extrahepatic co-morbidities (HR=2.51; 95% CI: 1.31-4.84; p=0.006), and CRP level (group A) (HR=2.73; 95% CI: 1.41-5.26; p=0.003). The performance of the three variables taken together for predicting death was 0.80 (AUROC). CONCLUSIONS In Child-Pugh score ≥ B8 cirrhotic patients, persistent CRP levels ≥ 29 mg/L predicted short-term mortality independently of age, MELD, and co-morbidities, and better than infection or clinically-assessed SIRS.

Truth survival in clinical research: An evidence-based requiem?

Science progresses through a series of paradigms that are held to be true until they are replaced by a better approximation of reality (1). Since the development of the steam engine in the late 18th century, economists have recognized 50-year cycles during which critical technological innovation is introduced (2). In 1997, Hall and Platell (3) estimated the half-life of dogma relating to the practice of surgery. From their analysis of 260 abstracts published from 1935 to 1994, they estimated that the half-life of truth for clinical conclusions in the surgical literature was 45 years. We hypothesized that some factors should be related to this truth survival. The first hypothesis was that conclusions derived from better methodology should have a longer half-life. If correct, this observation could be a validation of good methodology, often called evidence-based medicine (4). Therefore, we compared the survival of conclusions from meta-analyses with those from isolated, randomized trials or nonrandomized studies. For the conclusions from randomized trials (isolated trials or meta-analyses), we also compared the survival rate on the basis of high versus low methodologic scores. The second hypothesis was that survival of truth should be higher for negative conclusions than for positive conclusions. A negative conclusion has a better chance of survival because the only way it would not continue to be negative is if it were found to be false. A positive conclusion risks being found to be false or becoming obsolete. We also thought that publication of a negative conclusion in a reputable journal often indicated that a previous positive conclusion had been found to be false. We concluded, therefore, that this second-line analysis should be of higher quality. To reduce heterogeneity in sampling and evaluation, we chose a single medical disciplinecirrhosis and hepatitisand focused on two selective journals. We tried to categorize the conclusions into three groups: those that were true (referred to as true in this article), those that were not false but became obsolete (referred to as obsolete), and those that are now considered false (referred to as false). An example of an obsolete conclusion is the efficacy of immunoglobulins for preventing hepatitis A virus infection, since an effective vaccine is now available. An example of a false conclusion is the efficacy of corticosteroids for treating acute viral hepatitis. Methods We identified original articles about cirrhosis or hepatitis in adults from 1945 to 1999. The articles were divided into eleven 5-year periods. Nonoriginal studies and studies involving children were excluded. Selection of Nonrandomized Studies In each 5-year period, we selected 20 nonrandomized articles published in two journals10 from Lancet and 10 from Gastroenterology. We chose these journals because they have published clinical studies about hepatitis and cirrhosis since at least 1945, they are peer-reviewed and highly selective, and they have impact factors greater than 10. Articles from 1945 to 1985 were selected by a hand search. Because a true randomization was very difficult to organize, we selected by order of publication within each 5-year period. We selected the first article about cirrhosis or hepatitis that appeared within each 5-year period, then the last published article in the period, then the second article after the first, then the second-to-the-last article, and so on up to 20 articles. From 1985 to 1999, we used a PubMed electronic search and specified the following limits: cirrhosis or hepatitis, human, and Lancet or Gastroenterology. Abstracts were downloaded by using a similar selection method, stratified into 5-year periods. We selected the first abstract listed on the first electronic page, then the first on the last electronic page, then the last on the second electronic page, then the last on the next-to-the- last electronic page, and so on up to 20 articles. Selection of Randomized Trials In each 5-year period, we tried to select 20 randomized trials about cirrhosis or hepatitis, 10 from Lancet and 10 from Gastroenterology. This was possible from 1970 to 1999. From 1945 to 1969, we selected all randomized trials that could be identified in any journal (range, 4 trials [1945 to 1950] to 20 trials [1965 to 1969]). From 1945 to 1982, we used the hand searching method previously described (5). We completed the random selection by hand searching articles from 1982 to 1985 and using PubMed (as described for nonrandomized studies) to search for articles from 1985 to 1999. Selection of Meta-Analyses From 1945 to 1992, we used a hand-searching method, as described in a systematic review of meta-analyses (6). Thereafter, we used PubMed and specified the following limits: meta-analysis and cirrhosis or hepatitis. Because of the limited number of meta-analyses, we included all journals. All of the meta-analyses consisted solely of randomized trials. Database Development and Observer Review We obtained abstracts from all of the articles and selected the sentence from each abstract that seemed to best summarize the findings. These sentences were then copied to a database. Editing of these sentences was restricted to the rephrasing of outdated terminology and the elimination of redundant words. Six hepatologists, called observers, assessed a form that contained the selected conclusion sentences in a random order. Observers were full-time hepatologists with different clinical subspecialties (viral hepatitis, n = 2; HIV, n = 1; fibrosis, n = 1; alcoholic liver disease, n = 1; and transplantation, n = 1); worked in the same hospital; and were between 31 and 65 years of age. They had graduated from six different universities; three had worked in the United States, each in a different university. Observers were blinded to period, journal, authors, method (meta-analysis, randomized trial, or nonrandomized study), and the methodologic quality from which each conclusion was derived. They classified each conclusion into one of three categories: still true in 2000, obsolete but not false in 2000, or false in 2000. Quality Assessment of Methodology and Consideration of Prognostic Factors Independent of this study, the quality of the randomized trials was assessed by means of a scoring method (range, 2 to 14; mean, 12) that included 14 items (7, 8). Also independent of this study, the quality of the meta-analyses was assessed by means of a slightly modified version (6) of the scoring method established by Sacks and coworkers (9) and described in detail elsewhere (7). This scoring method (range, 0 to 54; mean, 27) included 27 items. We analyzed the meta-analyses that combined individual data as a separate category of research. In classic meta-analysis, the results of each trial are combined. In meta-analysis that combines individual data, the results for each patient are combined with the patients prognostic factors, thus permitting better adjustment of the treatment effect on prognostic factors. Articles were rated as high quality when the score was greater or equal to the mean (12 for randomized trials and 27 for meta-analyses) and as low quality when the score was less than the mean. The methodologic quality of nonrandomized studies was classified as low because no specific scoring method was available. In addition to methodologic quality, the following factors were considered: negative or positive conclusion, type of disease (hepatitis, portal hypertension, alcoholic liver disease, primary biliary cirrhosis, or miscellaneous), domain of clinical research (therapeutic, diagnostic, or cognitive study [cognitive studies were defined as explanatory studies that did not assess treatment or diagnostic tests]), journal of publication (Lancet, Gastroenterology, or other), and specialty (medicine or surgery). Statistical Analysis A conclusion was considered to be true, obsolete, or false when three or more observers stated it to be so. When there was a split decision (3 to 3) about whether conclusions were true or not true (9 of 474 articles [1.9%]), the conclusion was considered to be true. When there was a split decision (3 to 3) about whether conclusions were obsolete or not obsolete (26 of 474 articles [5.5%]), the conclusion was considered to be obsolete. When the article was not classified as either true or obsolete, it was considered to be false. Conclusions from older research are at greater risk for being refuted or becoming obsolete than are conclusions from more recent studies. Because the end points were highly time dependent, we used time-dependent analyses. The half-life was calculated according to the KaplanMeier method, using the censored time as the duration between the year of publication and the year 2000. The censored time is the time at risk for being refuted or found obsolete. For example, an article published in 1950 had a censored time of 50 years. First, we analyzed the truth survival: If the conclusion was assessed to be true, it was censored at 50 years. If the conclusion was assessed to be false or obsolete, it was considered a failure (death of truth). Second, we analyzed the nonfalse survival; true or obsolete conclusions were considered censored at 50 years. If the conclusion was false, it was considered a failure (death of nonfalse). The factors were compared by using the two-sided log-rank test and the multivariate proportional hazards regression analysis. Agreement among observers was analyzed by using statistics. Results Characteristics of the 474 identified articles are given in Table 1. All nonrandomized studies were published in Lancet (50%) or Gastroenterology (50%); randomized trials were published in Lancet (29%), Gastroenterology (41%), or other journals (30%); and 92% of meta-analyses were published in other journals. Compared with the total number of articles published every year about hepatitis or cirrhosis, this sample represents less than 0.1% of nonran

Hepatitis C in 6,865 patients 65 yr or older : A severe and neglected curable disease?

BACKGROUND:Few data are available on chronic hepatitis C (CHC) in elderly patients. The aim of this study was to compare the features and severity of CHC and the efficacy/safety of antiviral therapy in patients <65, between 65 and 80, and >80 yr old, and to determine the usefulness of biochemical markers (Fibrotest-Fibrosure/ActiTest [FT-AT]) in aged patients.METHODS:This was a retrospective study with two groups of patients: Group 1: prospective cohort including all hepatitis C virus patients from our institution (N = 4,182); Group 2: all consecutive patients who had FT-AT performed in France between 2002 and 2004 (N = 33,738).RESULTS:A total of 6,865 patients ≥65 yr old was included (Group 1 = 881, Group 2 = 5,984). Group 1: patients ≥65 had a longer duration of and a higher age at infection, more genotype 1, and a history of transfusion ( p < 0.001). Among the 2,169 patients who underwent liver biopsy, bridging fibrosis (F2,F3,F4) was more frequent in patients ≥65 yr old, regardless of the duration of infection. In multivariate analysis, ages at biopsy and at infection were associated with F2,F3,F4. Discovery of CHC by a complication was more frequent in patients ≥65 yr ( p < 0.001). One hundred seventy patients ≥65 yr received antiviral therapy. A sustained virologic response was obtained in 45% of patients ≥65 yr treated with pegylated interferon/ribavirin. Group 2: At FT, 58% of patients >80 yr, 37% of patients between 65 and 80 yr, and 14% of patients <65 yr ( p < 0.001) had cirrhosis. Patients >80 yr (43%) with cirrhosis had nonelevated alanine amino transferase (ALT), compared with 31% of patients <65 yr ( p < 0.001).CONCLUSION:In patients ≥65 yr, CHC is more severe and presents with lower ALT than in younger patients. Treatment is effective. Biochemical markers seem particularly useful as a noninvasive alternative to liver biopsy in this population.

Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: Meta-analyses of randomized, controlled trials and implications for the future†‡

Response‐guided pegylated interferon (peg‐IFN) plus ribavirin (P/R) therapy trials on genotype (G)1 and G2/G3 hepatitis C virus–infected patients provide contradictory results. We conducted meta‐analyses of randomized, controlled trials to address (1) the benefit of a 72‐week extended‐duration therapy in G1‐slow responders and (2) adequate shortened duration therapy in G1 and G2/G3‐rapid responders. Seventeen trials were selected, including 624 G1 rapid responders, 570 G1 slow responders, and 2,062 G2/G3 rapid responders. Virologic outcomes and treatment discontinuation data were collected from published articles and by asking investigators. Pooled estimates of sustained virologic response (SVR), relapse, and dropouts were calculated using the random effects model, considering the variability of shortened duration, ribavirin dose, genotype, and baseline viral load. In G1 slow responders, a 72‐week extended duration increased SVR (+10.7%; 95% CI [confidence interval]: +4.4% to + 17.1%), decreased relapse (−12.3%; 95% CI: −25.4% to 0%), and did not significantly increase drop‐out rates (+4.5%; 95% CI: −0.6% to + 9.6%). The benefit of extended duration was lower when using a weight‐based ribavirin regimen (+8.7%; 95% CI: +1.7% to + 15.8%). In G1 rapid responders, a 24‐week shortened duration decreased SVR (−12.5%; 95% CI: −19.2% to −5.8%) and increased relapse rates (+8.8%; 95% CI: +2.9% to + 14.8%). Such differences were not significant in patients with baseline viral load <400,000 UL/mL (−4.4%; 95% CI: −9.8% to + 1%). In G2/G3 rapid responders, SVR was more common for standard 24‐week duration than for shortened durations (+4.1%; 95% CI: +0.1% to + 8.5), but this benefit was not significant when ribavirin was weight‐adjusted and the short duration was 16 weeks (−1.7%; 95% CI: −6.1% to + 2.7%) and for G2 patients (+1.6%; 95% CI: −0.2% to + 5.5%). Conclusion: Long durations of P/R therapy improve SVR, regardless of genotype. This effect is nonetheless negligible in rapid responders, with the most favorable conditions for SVR (G2, G1 with low viral load, and G3 with weight‐adjusted ribavirin regimen). (HEPATOLOGY 2011;)

Focal neurological signs in hepatic encephalopathy in cirrhotic patients: an underestimated entity?

OBJECTIVES:Focal neurological signs have been poorly documented in the course of hepatic encephalopathy in cirrhotic patients because they are not mentioned in any textbooks of liver diseases. Having the opportunity to observe such cases, we underwent a prospective study to determine incidence, characteristics, associated factors, prognostic significance, and outcome of this rare form of hepatic encephalopathy.METHODS:Over a 12-month period, all cirrhotic patients hospitalized in the intensive care unit of our department for hepatic encephalopathy were prospectively studied. Patients with clinical and electroencephalogram evidences of hepatic encephalopathy were examined by a senior physician and, in cases of focal neurological signs, underwent examination by a neurologist, CT scan, lumbar punction, and cerebral magnetic resonance imaging and echo Doppler examination of neck and head vessels. Clinical and biological parameters were compared in patients during episodes with and without focal neurological signs, and outcome was noted.RESULTS:Thirty-four cirrhotic patients were hospitalized for 48 episodes of hepatic encephalopathy; two of these patients with cerebral hematoma were excluded. Twenty-four patients exhibited 38 hepatic encephalopathy episodes without focal neurological signs (82.6%), and eight patients exhibited eight hepatic encephalopathy episodes with focal neurological signs (17.4%) that were hemiplegia and hemiparesia in six patients (75%). In all patients, cerebral CT scan and cerebrospinal fluid examination disclosed no abnormalities, as neither did cerebral magnetic resonance imaging (n = 5) and echo Doppler examination of neck and head vessels(n = 5). Except for female sex, which was more often encountered in patients with focal neurological signs (p < 0.05), there were no differences between episodes with and without focal neurological signs for any of the parameters studied. In surviving patients who recovered from hepatic encephalopathy (7/8), focal neurological signs disappeared without recurrences after follow up of 6 months (3–12).CONCLUSIONS:Hepatic encephalopathy with focal neurological signs when carefully searched is not uncommon. It could be more frequent in cirrhotic females, is reversible, and has no prognostic significance.