Robert P. Myers

Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C

SummaryBackgroundRecent studies strongly suggest that due to the limitations and risks of biopsy, as well as the improvement of the diagnostic accuracy of biochemical markers, liver biopsy should no longer be considered mandatory in patients with chronic hepatitis C. In 2001, FibroTest ActiTest (FT-AT), a panel of biochemical markers, was found to have high diagnostic value for fibrosis (FT range 0.00–1.00) and necroinflammatory histological activity (AT range 0.00–1.00). The aim was to summarize the diagnostic value of these tests from the scientific literature; to respond to frequently asked questions by performing original new analyses (including the range of diagnostic values, a comparison with other markers, the impact of genotype and viral load, and the diagnostic value in intermediate levels of injury); and to develop a system of conversion between the biochemical and biopsy estimates of liver injury.ResultsA total of 16 publications were identified. An integrated database was constructed using 1,570 individual data, to which applied analytical recommendations. The control group consisted of 300 prospectively studied blood donors. For the diagnosis of significant fibrosis by the METAVIR scoring system, the areas under the receiver operating characteristics curves (AUROC) ranged from 0.73 to 0.87. For the diagnosis of significant histological activity, the AUROCs ranged from 0.75 to 0.86. At a cut off of 0.31, the FT negative predictive value for excluding significant fibrosis (prevalence 0.31) was 91%. At a cut off of 0.36, the ActiTest negative predictive value for excluding significant necrosis (prevalence 0.41) was 85%. In three studies there was a direct comparison in the same patients of FT versus other biochemical markers, including hyaluronic acid, the Forns index, and the APRI index. All the comparisons favored FT (P < 0.05). There were no differences between the AUROCs of FT-AT according to genotype or viral load. The AUROCs of FT-AT for consecutive stages of fibrosis and grades of necrosis were the same for both moderate and extreme stages and grades. A conversion table was constructed between the continuous FT-AT values (0.00 to 1.00) and the expected semi-quantitative fibrosis stages (F0 to F4) and necrosis grades (A0 to A3).ConclusionsBased on these results, the use of the biochemical markers of liver fibrosis (FibroTest) and necrosis (ActiTest) can be recommended as an alternative to liver biopsy for the assessment of liver injury in patients with chronic hepatitis C. In clinical practice, liver biopsy should be recommended only as a second line test, i.e., in case of high risk of error of biochemical tests.

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

BACKGROUND AIMSnLiver 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.nnnMETHODSnThe 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).nnnRESULTSnTwo 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.nnnCONCLUSIONSnThe aminotransferases and an index including five biochemical markers are accurate noninvasive markers of HBV-related activity and fibrosis, respectively.

FibroTest and FibroScan for the Prediction of Hepatitis C-Related Fibrosis: A Systematic Review of Diagnostic Test Accuracy

BACKGROUND:The accurate diagnosis of hepatitis C virus (HCV)-related fibrosis is crucial for prognostication and treatment decisions. Due to the limitations of biopsy, noninvasive alternatives including FibroTest and FibroScan have been developed. Our objective was to systematically review studies describing the accuracy of these tests for predicting HCV-related fibrosis.METHODS:Studies comparing FibroTest or FibroScan versus biopsy in HCV patients were identified via an electronic search. Random effects meta-analyses and areas under summary receiver operating characteristics curves (AUC) were examined to characterize test accuracy for significant fibrosis (F2-4) and cirrhosis. Heterogeneity was explored using meta-regression.RESULTS:Twelve studies were identified, 9 for FibroTest (N = 1,679) and 4 for FibroScan (N = 546). In heterogeneous analyses for significant fibrosis, the AUCs for FibroTest and FibroScan were 0.81 (95% CI 0.78–84) and 0.83 (0.03–1.00), respectively. At a threshold of ∼0.60, the sensitivity and specificity of the FibroTest were 47% (35–59%) and 90% (87–92%). For FibroScan (threshold ∼8 kPa), corresponding values were 64% (50–76%) and 87% (80–91%), respectively. Methodological quality, the length of liver biopsy specimens, and inclusion of special populations did not explain the observed heterogeneity. However, the diagnostic accuracy of both measures was associated with the prevalence of significant fibrosis and cirrhosis in the study populations. For cirrhosis, the summary AUCs for FibroTest and FibroScan were 0.90 (95% CI not calculable) and 0.95 (0.87–0.99), respectively.CONCLUSIONS:FibroTest and FibroScan have excellent utility for the identification of HCV-related cirrhosis, but lesser accuracy for earlier stages. Refinements are necessary before these tests can replace liver biopsy.

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.)

Neurolytic celiac plexus block for pain control in unresectable pancreatic cancer

BACKGROUND:A major focus of palliation in patients with unresectable pancreatic cancer is pain control. The aim of this systematic review was to examine the efficacy and safety of neurolytic celiac plexus blockade (NCPB) compared with standard treatment in randomized controlled trials (RCTs) involving patients with unresectable pancreatic cancer.METHODS:An electronic search was completed (1966 through August, 2005) for RCTs comparing NCPB versus control (standard treatment and/or sham NCPB) in patients with unresectable pancreatic cancer. The primary outcome was pain measured on a 10-point visual analogue scale (VAS). Secondary outcomes included opioid usage, adverse effects, quality of life (QOL), and survival. All outcomes were assessed at 2, 4, and 8 wk.RESULTS:Five RCTs involving 302 patients (NCPB, N = 147; control, N = 155) met the inclusion criteria. Mean age was 61.0 ± 4.3 yr. Compared with control, NCPB was associated with lower VAS scores for pain at 2, 4, and 8 wk (weighted mean difference [WMD] −0.60, 95% CI −0.82 to −0.37). Opioid usage (in mg/d oral morphine) was also reduced at 2, 4, and 8 wk (WMD −85.9, 95% CI −144.0 to −27.9). NCPB was associated with a reduction in constipation (relative risk 0.67, 95% CI 0.49–0.91), but not other adverse events. No differences in survival were observed. QOL could not be adequately analyzed due to differences in outcome scales among studies.CONCLUSIONS:In patients with unresectable pancreatic cancer, NCPB is associated with improved pain control, and reduced narcotic usage and constipation compared with standard treatment, albeit with minimal clinical significance.

Biochemical Markers of Fibrosis in Patients with Chronic Hepatitis C: A Comparison with Prothrombin Time, Platelet Count, and Age–Platelet Index

As an alternative to liver biopsy, an index of five biochemical markers (α2-macroglobulin, apolipoprotein A1, haptoglobin, total bilirubin, γ-glutamyl-transpeptidase) has been shown to predict the severity of hepatitis C-related fibrosis. The objective of this study was to compare this index with other markers frequently used for this purpose (prothrombin time, platelets, age–platelet index). In 323 hepatitis C-infected patients, the discriminative values of these markers for F2–F4 fibrosis (by the METAVIR classification) were compared. By multiple logistic regression analysis, only the five-marker index (P < 0.0001) and prothrombin time (P = 0.02) were independently predictive of F2–F4 fibrosis. For this outcome, the area under the receiver operating characteristic curve was significantly higher for the five-marker index (0.836 ± 0.024) than the age-platelet index (P = 0.002), and the platelet count and prothrombin time (P < 0.001), indicating greater diagnostic value. The addition of the latter markers to the five-marker index proved unhelpful for increasing its accuracy. In conclusion, an index of five biochemical markers accurately predicts significant hepatitis C-related fibrosis and is superior to traditional markers.

Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C

BACKGROUND/AIMSnFatigue and other extra hepatic manifestations of hepatitis C have never been studied prospectively in a large cohort. The aim was to assess the prevalence of these symptoms prior to any treatment, and on prolonged follow-up in treated and untreated patients.nnnMETHODSnA single-center cohort of consecutive patients with chronic hepatitis C was investigated prior to any treatment. A questionnaire was completed every 6 months for 18 months of follow-up.nnnRESULTSnOf 1614 patients, 431 met the inclusion criteria (56% male; age 49 years; 60% with significant fibrosis or cirrhosis; 46% with cryoglobulinemia). Seventy-six were untreated; of the treated patients, 83 were sustained responders, 47 relapsers and 225 non-responders. At baseline, fatigue and other extrahepatic manifestations were present in 254 (59%) and 225 (52%) patients. Fatigue was improved in 29 of 83 (35%) responders versus 75 of 348 (22%) patients with detectable hepatitis C virus (HCV)-RNA (P=0.01). The impact of virologic response on fatigue persisted after adjusting for age, gender, fibrosis stage, and depression (odds ratio: 0.34, P<0.001). A cryoglobulin was detectable in two of 34 (6%) responders versus 38 of 115 (33%) patients with detectable HCV-RNA (P<0.001).nnnCONCLUSIONSnIn hepatitis C, a sustained virologic response is associated with a reduction in fatigue and cryoglobulin, but fatigue frequently persists despite a virologic response.

Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy.

Background: Pegylated interferon alfa (PEG-IFN-α) and ribavirin is the most effective available treatment for chronic hepatitis C virus (HCV) infection. Its role in HIV/HCV-co-infected patients who have failed IFN-based therapy is unclear. Objective: The aim of this study was to determine the safety and efficacy of this therapy in HIV/HCV-co-infected non-responders and relapsers. Design: An open-label cohort study of 32 non-responders and relapsers to IFN (with or without ribavirin). Patients were treated for 48 weeks with PEG-IFN-α2b and ribavirin. Main outcome measure: A sustained virological response (SVR) defined as a negative HCV-RNA level 24 weeks after the end of treatment. Results: The mean age of the patients was 40 years; 78% were men, 67% had genotype 1, and 36% had bridging fibrosis or cirrhosis. The majority had a CD4 cell count greater than 200 cells/μl (97%) and an undetectable HIV-RNA level (81%). Fifteen patients (47%) withdrew because of adverse events, predominantly neuropsychiatric. In an intention-to-treat analysis, a SVR was observed in five patients (16%); 9% with genotype 1 versus 29% with genotype 3 and 33% with genotype 4 (P = NS). Additional, but statistically non-significant, univariate predictors of response were lower serum HCV-RNA (P = 0.07) and higher alanine aminotransferase levels (P = 0.055) at baseline. No patient with bridging fibrosis or cirrhosis responded. Treatment had a minimal impact on HIV parameters. Conclusion: PEG-IFN-α2b and ribavirin is a potentially useful therapy in HIV/HCV-co-infected patients who have failed standard IFN-based regimens. Strategies to improve adherence are vital so as to maximize long-term response rates.

Acute interstitial nephritis due to omeprazole.

Omeprazole is a proton pump inhibitor that is used commonly in the treatment of acid-peptic disorders. Although omeprazole is generally well tolerated, serious adverse effects such as renal failure have been reported. Thus far, 17 cases of acute interstitial nephritis (AIN) secondary to omeprazole have been described. Another case of AIN is described in a 36-yr-old woman presenting with nausea, vomiting, weight loss, and a rising serum creatinine concentration. Omeprazole therapy had ceased 2 wk before admission. AIN was diagnosed by renal biopsy and corticosteroid therapy was initiated. After 4 wk of therapy the serum creatinine concentration had normalized. Among the reported cases in the literature, AIN was diagnosed after an average of 2.7 months of therapy with 20–40 mg of omeprazole daily. Recurrence was universal on rechallenge. Common symptoms included fatigue, fever, anorexia, and nausea. The classic triad of fever, rash, and eosinophilia was uncommon. Typical laboratory features included hematuria, proteinuria, pyuria, eosinophilia, and anemia. Management consisted of withdrawal of omeprazole and corticosteroid therapy in some patients. All but one patient recovered normal renal function. Corticosteroid therapy was well tolerated and may have been beneficial.

Rituximab for the treatment of patients with autoimmune hepatitis who are refractory or intolerant to standard therapy

BACKGROUNDnAlthough most patients with autoimmune hepatitis (AIH) respond to treatment with prednisone and⁄or azathioprine, some patients are intolerant or refractory to standard therapy. Rituximab is an anti-CD20 monoclonal antibody that depletes B cells and has demonstrated efficacy in other autoimmune conditions.nnnAIMSnTo evaluate the safety and efficacy of rituximab in patients with refractory AIH in an open-label, single-centre pilot study.nnnMETHODSnSix patients with definite, biopsy-proven AIH who failed prednisone and azathioprine treatment received two infusions of rituximab 1000 mg two weeks apart and were followed for 72 weeks.nnnRESULTSnRituximab was well tolerated with no serious adverse events. By week 24, mean (± SD) aspartate aminotransferase (AST) levels had significantly improved (90.0±23.3 U⁄L versus 31.3±4.2 U⁄L; P=0.03) and mean immunoglobulin G levels had fallen (16.4±2.0 g⁄L versus 11.5±1.1 g⁄L; P=0.056). The prednisone dose was weaned in three of four subjects, with one subject flaring after steroid withdrawal. Inflammation grade improved in all four subjects who underwent repeat liver biopsy at week 48. Regulatory T cell levels examined by FoxP3 immunohistochemistry paralleled inflammatory activity and did not increase on follow-up biopsies. There was no significant change in serum chemokine or cytokine levels from baseline to week 24 (n=5), although interferon-gamma-induced protein 10 levels improved in three of five subjects.nnnCONCLUSIONSnRituximab was safe, well tolerated and resulted in biochemical improvement in subjects with refractory AIH. These results support further investigation of rituximab as a treatment for AIH.