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1.  Non-Markov Multistate Modeling Using Time-Varying Covariates, with Application to Progression of Liver Fibrosis due to Hepatitis C Following Liver Transplant* 
Multistate modeling methods are well-suited for analysis of some chronic diseases that move through distinct stages. The memoryless or Markov assumptions typically made, however, may be suspect for some diseases, such as hepatitis C, where there is interest in whether prognosis depends on history. This paper describes methods for multistate modeling where transition risk can depend on any property of past progression history, including time spent in the current stage and the time taken to reach the current stage. Analysis of 901 measurements of fibrosis in 401 patients following liver transplantation found decreasing risk of progression as time in the current stage increased, even when controlled for several fixed covariates. Longer time to reach the current stage did not appear associated with lower progression risk. Analysis of simulation scenarios based on the transplant study showed that greater misclassification of fibrosis produced more technical difficulties in fitting the models and poorer estimation of covariate effects than did less misclassification or error-free fibrosis measurement. The higher risk of progression when less time has been spent in the current stage could be due to varying disease activity over time, with recent progression indicating an “active” period and consequent higher risk of further progression.
PMCID: PMC2836212  PMID: 20305705
fibrosis; hepatitis C; liver transplant; memoryless assumptions; multistate modeling
2.  Fibrosis Progression in African Americans and Caucasian Americans with Chronic Hepatitis C 
Background & Aims
Prior studies suggest the rate of liver fibrosis progression is slower in African-Americans (AA) than Caucasian-Americans (CA) with chronic hepatitis C virus (HCV) infection.
Using a multi-state Markov model, fibrosis progression was evaluated in a well-characterized cohort of 143 AA and 157 CA adults with untreated chronic HCV genotype 1 infection. In subjects with a history of injection drug use, duration of infection was imputed from a fitted risk model rather than assumed to be the reported first year of use.
The distribution of Ishak fibrosis stages were 0 (8.7%), 1/2 (55.7%), 3/4 (29.3%) and 5/6 (6.3%), and was similar in AA and CA (p= 0.22). After adjusting for biopsy adequacy, AA had a 10% lower rate of fibrosis progression than did CA, but the difference was not statistically significant (hazard ratio = 0.90, 95% confidence intervals = 0.72, 1.12). The overall 20-year estimates of probabilities of progression from stage 0 to stages 1/2, 3/4 and 5/6 were 59.3%, 28.8% and 4.7%. The estimated median time from no fibrosis to cirrhosis was 79 years for the entire cohort, and 74 and 83 years for CA and AA, respectively. In 3-variable models including race and biopsy adequacy, the factors significantly associated with fibrosis progression were age when infected, steatosis, ALT level, and necroinflammatory score.
The rates of fibrosis progression were slow and did not appear to differ substantially between AA and CA.
PMCID: PMC3166617  PMID: 19081528
3.  Progression of liver cirrhosis to HCC: an application of hidden Markov model 
Health service databases of administrative type can be a useful tool for the study of progression of a disease, but the data reported in such sources could be affected by misclassifications of some patients' real disease states at the time. Aim of this work was to estimate the transition probabilities through the different degenerative phases of liver cirrhosis using health service databases.
We employed a hidden Markov model to determine the transition probabilities between two states, and of misclassification. The covariates inserted in the model were sex, age, the presence of comorbidities correlated with alcohol abuse, the presence of diagnosis codes indicating hepatitis C virus infection, and the Charlson Index. The analysis was conducted in patients presumed to have suffered the onset of cirrhosis in 2000, observing the disease evolution and, if applicable, death up to the end of the year 2006.
The incidence of hepatocellular carcinoma (HCC) in cirrhotic patients was 1.5% per year. The probability of developing HCC is higher in males (OR = 2.217) and patients over 65 (OR = 1.547); over 65-year-olds have a greater probability of death both while still suffering from cirrhosis (OR = 2.379) and if they have developed HCC (OR = 1.410). A more severe casemix affects the transition from HCC to death (OR = 1.714). The probability of misclassifying subjects with HCC as exclusively affected by liver cirrhosis is 14.08%.
The hidden Markov model allowing for misclassification is well suited to analyses of health service databases, since it is able to capture bias due to the fact that the quality and accuracy of the available information are not always optimal. The probability of evolution of a cirrhotic subject to HCC depends on sex and age class, while hepatitis C virus infection and comorbidities correlated with alcohol abuse do not seem to have an influence.
PMCID: PMC3087702  PMID: 21457586
4.  Prospective Assessment of Genetic Effects on Progression to Different Stages of Age-Related Macular Degeneration Using Multistate Markov Models 
Multistate Markov models were used to examine the effects of several candidate genes on progression from normal to intermediate stages and then to advanced stages of AMD in a large prospective study, controlling for baseline demographic and behavioral factors.
Understanding the effect of genes on progression to different stages of age-related macular degeneration (AMD) may suggest stage-specific therapeutic targets and more precise prediction of the development of this disease.
Progression events and time to each stage of AMD were derived from the longitudinal data of 2560 subjects without advanced AMD. SNPs in 12 AMD risk loci were genotyped. A multistate Markov model for progression from normal to intermediate drusen, then to large drusen, and eventually to neovascular disease (NV) or geographic atrophy (GA) was applied to estimate stage-specific hazard ratios for each SNP. The effects of these genetic factors were also estimated by a multivariate multistate Markov model adjusted for baseline age, sex, smoking, body mass index (BMI), education, antioxidant treatment, and the status of AMD in the fellow eye.
Controlling for demographic and behavioral factors and other SNPs, the TT genotype of rs10468017 in LIPC was associated with decreased risk of progression from large drusen to NV (HR = 0.57, P = 0.04) and tended to reduce the risk of progression from normal to intermediate drusen (HR = 0.72, P = 0.07). The SNP rs1883025 (T allele) in ABCA1 was associated with decreased risk of progression from normal to intermediate drusen (HR per allele = 0.82 per allele, P = 9.7 × 10−3) and from intermediate drusen to large drusen (HR per allele = 0.77, P = 5.2 × 10−3). The genes CFH, C3, CFB, and ARMS2/HTRA1 were associated with progression from intermediate drusen to large drusen and from large drusen to GA or NV.
Genes in different pathways influence progression to different stages of AMD.
PMCID: PMC3339916  PMID: 22247473
5.  Cost Effectiveness of Fibrosis Assessment Prior to Treatment for Chronic Hepatitis C Patients 
PLoS ONE  2011;6(12):e26783.
Background and Aims
Chronic hepatitis C (HCV) is a liver disease affecting over 3 million Americans. Liver biopsy is the gold standard for assessing liver fibrosis and is used as a benchmark for initiating treatment, though it is expensive and carries risks of complications. FibroTest is a non-invasive biomarker assay for fibrosis, proposed as a screening alternative to biopsy.
We assessed the cost-effectiveness of FibroTest and liver biopsy used alone or sequentially for six strategies followed by treatment of eligible U.S. patients: FibroTest only; FibroTest with liver biopsy for ambiguous results; FibroTest followed by biopsy to rule in; or to rule out significant fibrosis; biopsy only (recommended practice); and treatment without screening. We developed a Markov model of chronic HCV that tracks fibrosis progression. Outcomes were expressed as expected lifetime costs (2009 USD), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER).
Treatment of chronic HCV without fibrosis screening is preferred for both men and women. For genotype 1 patients treated with pegylated interferon and ribavirin, the ICERs are $5,400/QALY (men) and $6,300/QALY (women) compared to FibroTest only; the ICERs increase to $27,200/QALY (men) and $30,000/QALY (women) with the addition of telaprevir. For genotypes 2 and 3, treatment is more effective and less costly than all alternatives. In clinical settings where testing is required prior to treatment, FibroTest only is more effective and less costly than liver biopsy. These results are robust to multi-way and probabilistic sensitivity analyses.
Early treatment of chronic HCV is superior to the other fibrosis screening strategies. In clinical settings where testing is required, FibroTest screening is a cost-effective alternative to liver biopsy.
PMCID: PMC3229483  PMID: 22164204
6.  Thrombotic risk factors and extent of liver fibrosis in chronic viral hepatitis 
Gut  2003;52(3):404-409.
Background and aims: Thrombosis of the small intrahepatic veins has been suggested to trigger liver tissue remodelling. We evaluated the prevalence of multiple thrombotic risk factors and their association with the extent of fibrosis in chronic viral hepatitis.
Methods: Ninety consecutive patients with chronic hepatitis B or C without malignancy, a history of venous thrombosis, or antiviral/immunosuppressive therapy within the last six months were included. Thrombophilic and coagulation factors were evaluated on the liver biopsy day.
Results: One or more thrombotic risk factors were found in 68% and ≥2 factors in 37% of patients. Higher necroinflammatory activity was independently associated with higher prothrombin time (p=0.003), alanine aminotransferase level (p=0.011), and histological staging (p=0.018). Patients with staging scores of 4–6 compared with those with scores of 0–3 more frequently had deficiency of protein C (24% v 3%; p=0.007), antithrombin III (28% v 5%; p=0.005), and plasminogen (19% v 2%; p=0.03), and a trend for more frequent activated protein C resistance (8% v 0%; p=0.075). The presence of ≥1 significant thrombotic risk factor was observed in 11/25 (44%) patients with staging scores of 4–6 and in 6/65 (9%) patients with scores of 0–3 (p<0.001), being the only variable independently associated with advanced staging (odds ratio 2.4, p=0.02).
Conclusions: Thrombotic risk factors are frequently detected in patients with chronic viral hepatitis and the presence of ≥1 significant factor is associated with more advanced fibrosis. Whether the association of such thrombophilic conditions with advanced fibrosis is a primary or secondary phenomenon and whether their development in combination with local inflammation accelerate the progression of liver fibrosis need further evaluation.
PMCID: PMC1773539  PMID: 12584224
antithrombin III; chronic hepatitis; liver fibrosis; thrombotic risk factors
7.  Estimating past hepatitis C infection risk from reported risk factor histories: implications for imputing age of infection and modeling fibrosis progression 
Chronic hepatitis C virus infection is prevalent and often causes hepatic fibrosis, which can progress to cirrhosis and cause liver cancer or liver failure. Study of fibrosis progression often relies on imputing the time of infection, often as the reported age of first injection drug use. We sought to examine the accuracy of such imputation and implications for modeling factors that influence progression rates.
We analyzed cross-sectional data on hepatitis C antibody status and reported risk factor histories from two large studies, the Women's Interagency HIV Study and the Urban Health Study, using modern survival analysis methods for current status data to model past infection risk year by year. We compared fitted distributions of past infection risk to reported age of first injection drug use.
Although injection drug use appeared to be a very strong risk factor, models for both studies showed that many subjects had considerable probability of having been infected substantially before or after their reported age of first injection drug use. Persons reporting younger age of first injection drug use were more likely to have been infected after, and persons reporting older age of first injection drug use were more likely to have been infected before.
In cross-sectional studies of fibrosis progression where date of HCV infection is estimated from risk factor histories, modern methods such as multiple imputation should be used to account for the substantial uncertainty about when infection occurred. The models presented here can provide the inputs needed by such methods. Using reported age of first injection drug use as the time of infection in studies of fibrosis progression is likely to produce a spuriously strong association of younger age of infection with slower rate of progression.
PMCID: PMC2238758  PMID: 18070362
8.  Estimating Complex Multi-State Misclassification Rates for Biopsy-Measured Liver Fibrosis in Patients with Hepatitis C 
For both clinical and research purposes, biopsies are used to classify liver damage known as fibrosis on an ordinal multi-state scale ranging from no damage to cirrhosis. Misclassification can arise from reading error (misreading of a specimen) or sampling error (the specimen does not accurately represent the liver). Studies of biopsy accuracy have not attempted to synthesize these two sources of error or to estimate actual misclassification rates from either source. Using data from two studies of reading error and two of sampling error, we find surprisingly large possible misclassification rates, including a greater than 50% chance of misclassification for one intermediate stage of fibrosis. We find that some readers tend to misclassify consistently low or consistently high, and some specimens tend to be misclassified low while others tend to be misclassified high. Non-invasive measures of liver fibrosis have generally been evaluated by comparison to simultaneous biopsy results, but biopsy appears to be too unreliable to be considered a gold standard. Non-invasive measures may therefore be more useful than such comparisons suggest. Both stochastic uncertainty and uncertainty about our model assumptions appear to be substantial. Improved studies of biopsy accuracy would include large numbers of both readers and specimens, greater effort to reduce or eliminate reading error in studies of sampling error, and careful estimation of misclassification rates rather than less useful quantities such as kappa statistics.
PMCID: PMC2810974  PMID: 20104258
9.  Estimating Complex Multi-State Misclassification Rates for Biopsy-Measured Liver Fibrosis in Patients with Hepatitis C* 
For both clinical and research purposes, biopsies are used to classify liver damage known as fibrosis on an ordinal multi-state scale ranging from no damage to cirrhosis. Misclassification can arise from reading error (misreading of a specimen) or sampling error (the specimen does not accurately represent the liver). Studies of biopsy accuracy have not attempted to synthesize these two sources of error or to estimate actual misclassification rates from either source. Using data from two studies of reading error and two of sampling error, we find surprisingly large possible misclassification rates, including a greater than 50% chance of misclassification for one intermediate stage of fibrosis. We find that some readers tend to misclassify consistently low or consistently high, and some specimens tend to be misclassified low while others tend to be misclassified high. Non-invasive measures of liver fibrosis have generally been evaluated by comparison to simultaneous biopsy results, but biopsy appears to be too unreliable to be considered a gold standard. Non-invasive measures may therefore be more useful than such comparisons suggest. Both stochastic uncertainty and uncertainty about our model assumptions appear to be substantial. Improved studies of biopsy accuracy would include large numbers of both readers and specimens, greater effort to reduce or eliminate reading error in studies of sampling error, and careful estimation of misclassification rates rather than less useful quantities such as kappa statistics.
PMCID: PMC2810974  PMID: 20104258
fibrosis; hepatitis C; kappa statistic; latent variables; misclassification
10.  Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome 
American Journal of Hematology  2013;88(7):581-588.
Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages. Am. J. Hematol. 88:581–588, 2013. © 2013 Wiley Periodicals, Inc.
PMCID: PMC3736162  PMID: 23606215
11.  Early transcriptional programming links progression to hepatitis C virus-induced severe liver disease in transplant patients 
Hepatology (Baltimore, Md.)  2012;56(1):17-27.
Liver failure due to chronic hepatitis C virus infection is a major cause for liver transplantation worldwide. Recurrent infection of the graft is universal in HCV patients following transplant and results in rapid progression to severe fibrosis and end-stage liver disease in one-third of all patients. No single clinical variable, or combination thereof, has so far proven accurate in identifying patients at risk of hepatic decompensation in the transplant setting. A combination of longitudinal, dimensionality reduction, and categorical analysis of the transcriptome from 111 liver biopsy specimens taken from 57 HCV-infected patients over time identified a molecular signature of gene expression of patients at risk of developing severe fibrosis. Significantly, alterations in gene expression occur prior to histologic evidence of liver disease progression, suggesting that events which occur during the acute phase of infection influence patient outcome. Additionally, a common precursor state for different severe clinical outcomes was identified. Hence, based on this patient cohort, incidence of severe liver disease is a process initiated early during HCV infection of the donor organ. The probable cellular network at the basis of the initial transition to severe liver disease was identified and characterized.
PMCID: PMC3349763  PMID: 22278598
viral hepatitis; microarray; hepatic fibrosis
12.  Wilson disease: Histopathological correlations with treatment on follow-up liver biopsies 
AIM: To investigate the progression of hepatic histopathology in serial liver biopsies from Wilson disease (WD) patients.
METHODS: We report a group of 12 WD patients treated with zinc and/or penicillamine who underwent multiple follow-up liver biopsies. Demographic, clinical and laboratory data were gathered and all patients underwent an initial biopsy and at least one repeat biopsy.
RESULTS: Time to repeat biopsy ranged from 2 to 12 years. Six patients (non-progressors) showed stable hepatic histology or improvement. In one case, we observed improvement of fibrosis from stage 2 to 0. Six patients (progressors) had worsening of fibrosis. There was no significant correlation between the histological findings and serum aminotransferases or copper metabolism parameters. The hepatic copper concentration reached normal levels in only two patients: one from the non-progressors and one from the progressors group. The estimated rate of progression of hepatic fibrosis in the entire group was 0 units per year in the time frame between the first and the second liver biopsy (4 years), and 0.25 between the second and the third (3 years). In the progressors group, the rate of progression of liver fibrosis was estimated at 0.11 fibrosis units per year between the first and second biopsy and, 0.6 fibrosis units between the second and third biopsy.
CONCLUSION: The inability of clinical tools to detect fibrosis progression in WD suggests that a liver biopsy with hepatic copper quantification every 3 years should be considered.
PMCID: PMC2846254  PMID: 20333789
Wilson disease; Copper; Liver biopsy; Histopathology
13.  A health technology assessment of transient elastography in adult liver disease 
An estimated one in 10 Canadians have some form of liver disease. The reference standard for staging and monitoring liver fibrosis is percutaneous liver biopsy – an invasive procedure associated with risks and complications. Transient elastography (TE) represents a noninvasive, ultrasound-based alternative.
To assess the efficacy of TE compared with liver biopsy for fibrosis staging in adults with five common types of liver disease: hepatitis B, hepatitis C, nonalcoholic fatty liver disease, cholestatic liver disease and complications post-liver transplantation.
A systematic review of published and grey literature from 2001 to June 2011 was conducted. Included were observational studies evaluating the accuracy of TE using liver biopsy as the comparator. An economic model was developed to estimate the cost per correct diagnosis gained with liver biopsy compared with TE. Identification of moderate fibrosis (stages 2 to 4) and cirrhosis (stage 4) were considered.
Fifty-seven studies were included in the review. The diagnostic accuracy of TE for the five clinical subgroups had sensitivities ranging from 0.67 to 0.92 and specificities ranging from 0.72 to 0.95. Liver biopsy was associated with an additional $1,427 to $7,030 per correct diagnosis gained compared with TE. The model was sensitive to the sensitivity and specificity of TE and the prevalence of fibrosis.
TE is an accurate diagnostic method in patients with moderate fibrosis or cirrhosis. TE is less effective but less expensive than liver biopsy. Systemic implementation of TE should be considered for the noninvasive assessment of liver fibrosis.
PMCID: PMC3732152  PMID: 23516679
Health technology assessment; Liver biopsy; Liver disease; Transient elastography
14.  A Novel Fibrosis Index Comprising a Non-Cholesterol Sterol Accurately Predicts HCV-Related Liver Cirrhosis 
PLoS ONE  2014;9(4):e93601.
Diagnosis of liver cirrhosis is essential in the management of chronic hepatitis C virus (HCV) infection. Liver biopsy is invasive and thus entails a risk of complications as well as a potential risk of sampling error. Therefore, non-invasive diagnostic tools are preferential. The aim of the present study was to create a model for accurate prediction of liver cirrhosis based on patient characteristics and biomarkers of liver fibrosis, including a panel of non-cholesterol sterols reflecting cholesterol synthesis and absorption and secretion. We evaluated variables with potential predictive significance for liver fibrosis in 278 patients originally included in a multicenter phase III treatment trial for chronic HCV infection. A stepwise multivariate logistic model selection was performed with liver cirrhosis, defined as Ishak fibrosis stage 5–6, as the outcome variable. A new index, referred to as Nordic Liver Index (NoLI) in the paper, was based on the model: Log-odds (predicting cirrhosis) = −12.17+ (age×0.11) + (BMI (kg/m2)×0.23) + (D7-lathosterol (μg/100 mg cholesterol)×(−0.013)) + (Platelet count (x109/L)×(−0.018)) + (Prothrombin-INR×3.69). The area under the ROC curve (AUROC) for prediction of cirrhosis was 0.91 (95% CI 0.86–0.96). The index was validated in a separate cohort of 83 patients and the AUROC for this cohort was similar (0.90; 95% CI: 0.82–0.98). In conclusion, the new index may complement other methods in diagnosing cirrhosis in patients with chronic HCV infection.
PMCID: PMC3974766  PMID: 24699777
15.  Fibrosis progression in paired liver biopsies from HIV/HCV co-infected patients 
Hepatitis Monthly  2011;11(7):525-531.
Chronic hepatitis C is more aggressive during HIV infection. Available data about risk factors of liver fibrosis in HIV/HCV co-infected patients derive from studies based on a single liver biopsy.
To evaluate the risk factors of liver fibrosis progression (LFP) and to investigate the role of antiretroviral therapy (ARV) in HIV/HCV patients who underwent paired liver biopsy.
Patients and Methods
We retrospectively studied 58 patients followed at two Infectious Diseases Departments in Northern Italy during the period 1988-2005. All specimens were double-blinded and centrally examined by two pathologists. LFP was defined when an increase of at least one stage occurred in the second biopsy, according to the Ishak-Knodell classification.
In a univariate analysis, serum levels of alanine aminotransferase (ALT) > 150 IU/L at the first biopsy (P = 0.02), and a > 20% decrease in CD4+ cell count between the two biopsies (P = 0.007), were significantly associated with LFP. In multivariate analysis, a > 20% decrease in CD4+ cell count remained independently associated to LFP (Odds Ratio, 3.99; 95% confidence interval, 1.25-12.76; P < 0.02). Analysis of life survival curves confirmed the correlation between CD4+ cell count and LFP.
Our findings highlight that in HIV/HCV coinfected patients, an effective antiretroviral therapy that assures a good immune-virological profile contributes to reducing the risk of LFP.
PMCID: PMC3212761  PMID: 22706343
HIV; HCV; Liver fibrosis; Antiretroviral therapy
16.  Measurement and determinants of the natural history of liver fibrosis in hepatitis C virus infection: a cross sectional and longitudinal study 
Gut  2003;52(4):574-579.
Introduction: The rate of development of liver fibrosis in hepatitis C virus (HCV) infection varies between individuals. This accounts for the variation in duration of progression to cirrhosis. The aims of this study were: (1) to determine whether fibrosis progresses linearly through the grading scales and (2) to identify factors which influence the rate of fibrosis.
Methods: HCV infected patients who had undergone at least one liver biopsy were identified. Biopsies were scored using the modified HAI (Ishak) and METAVIR systems, which were compared. Patients were treatment naïve at first biopsy. Demographic features were examined for their relationship to fibrosis rate (defined as fibrosis stage/infection duration) using univariate and multivariate analysis. A subgroup of patients with two biopsies was examined to test the assumption that fibrosis progresses in a linear fashion.
Results: A total of 917 patients were included. Male sex (p<0.00001), older age at infection (p⩽0.00001), and viral genotype non-1 (p=0.005) were all associated with a rapid rate of fibrosis. On multiple linear regression they accounted for 29.5% of the variability in fibrosis rate (r2=0.295). METAVIR and Ishak scores were highly correlated (r=0.935, p<0.0001). In 137 patients who had two biopsies, the predicted probability for an increase of 1 on the fibrosis score was too low to assess linearity.
Conclusions: Demographic features account for a minority of fibrosis rate variability. The Ishak and METAVIR scoring systems are equivalent. Linearity of fibrosis progression cannot be assessed in biopsies only a few years apart.
PMCID: PMC1773621  PMID: 12631672
hepatitis C; biopsy; fibrosis; natural history
17.  Clinical Features of Hepatitis C Virus Carriers With Persistently Normal Alanine Aminotransferase Levels 
Hepatitis Monthly  2012;12(2):77-84.
Hepatitis C virus (HCV) infection causes chronic hepatitis, which frequently leads to hepatic fibrosis and hepatocellular carcinoma (HCC). Alanine aminotransferase (ALT) is a biomarker of hepatocyte injury and is associated with the progression of hepatic fibrosis. Advanced hepatic fibrosis also predisposes HCV carriers to a risk of HCC. In contrast, some cases with persistent HCV infection have normal ALT levels that persist for a long time, and these HCV carriers have no or mild hepatitis and hepatic fibrosis. These HCV carriers are defined as persistent normal ALT (PNALT) cases and their risk of HCC is low compared to HCV carriers with abnormal ALT. However, there are various definitions of normal ALT and PNALT, and advanced hepatic fibrosis may be missed without a liver biopsy. In addition, there is also a risk of ALT elevation in HCV carriers with PNALT, which increases the risk of progression to hepatic fibrosis and HCC. Most HCV carriers with PNALT have asymptomatic or nonspecific symptoms. HCV carriers with PNALT are also considered to be responsive to interferon-based treatment. Thus, assessment of hepatic fibrosis is important in HCV carriers, and the eradication of HCV infection is more likely in HCV carriers with evidence of hepatic fibrosis, regardless of their ALT levels.
PMCID: PMC3321325  PMID: 22509183
Hepatitis C; Alanine Transaminase; Clinical Protocols; Liver Cirrhosis
18.  Similar Progression of Fibrosis between HIV/HCV- and HCV-Infected Patients: Analysis of Paired Liver Biopsy Samples 
Background and Aims
Fibrosis progression might be accelerated in patients that are co-infected with HIV and hepatitis C virus (HIV/HCV). However, no studies have directly compared fibrosis progression by paired liver biopsy between patients infected with HIV and HCV vs. those infected with only HCV.
Liver biopsy samples were collected from patients with HIV/HCV (n=306) and those with HCV; biopsies from 59 without a sustained virologic response (SVR) or cirrhosis were matched with those from patients with only HCV (controls) for initial fibrosis stage, demographics, and HCV treatment. For HIV/HCV patients, categorical variables at baseline and the area under the curve of continuous variables per unit time were analyzed for associations with fibrosis progression.
Liver biopsies from HIV/HCV patients had more piecemeal necrosis than controls (P=.001) and increased lobular inflammation (P=.002); HIV/HCV patients also had shorter intervals between liver biopsies (4.7 vs. 5.9 yrs, P<.0001). Between the 1st and 2nd biopsies, fibrosis remained unchanged or progressed 1 or 2 units in 55%, 18%, and 18% of HIV/HCV patients, respectively, compared with 45%, 30%, and 9% of controls. The fibrosis progression rate was similar between HIV/HCV and control patients (0.12±0.40 vs. 0.091±0.29 units/yr; P=.72). In paired biopsies from 66 patients, including those with SVR, there were no associations between fibrosis progression and demographics; numbers of CD4+ T cells; levels of aspartate aminotransferase or alanine aminotransferase; use of highly-active anti-retroviral therapy; response to HCV therapy (no treatment, SVR, or non-response); baseline levels of FIB-4; or histological features including inflammation, fibrosis, or steatosis.
Based on analysis of liver biopsy samples, fibrosis progression was similar between HIV/HCV- and HCV-infected patients; no clinical or laboratory parameters predicted disease progression.
PMCID: PMC2997143  PMID: 20728569
Hepatitis C disease progression; co-infection; human immunodeficiency virus
19.  Advancing donor liver age and rapid fibrosis progression following transplantation for hepatitis C 
Gut  2002;51(2):248-252.
Background and aims: Cirrhosis with liver failure due to hepatitis C virus (HCV) infection is the most common indication for liver transplantation (LT). Reinfection of the transplanted liver by HCV is inevitable, and aggressive hepatitis with accelerated progression to graft cirrhosis may be observed. Of concern, recent reports suggest that the outcome of LT for HCV may have deteriorated in recent years. Determinants of rate of progression to cirrhosis in the immunocompetent non-transplant patient are well defined, and the most powerful determinant is patient age at the time of infection. Following LT for HCV, recipient age does not affect outcome of HCV reinfection. However, the impact of donor age on graft fibrosis progression rate following LT has not been examined.
Methods: We have examined post-transplant biopsies to assess histological activity, including fibrosis stage (scored 0–6 units, 6 representing established cirrhosis), and to calculate fibrosis progression rates in 101 post-transplant specimens from 56 HCV infected LT patients. Univariate and multivariate analyses examined the impact of parameters including recipient and donor age and sex on fibrosis progression rate, and on predicted time to cirrhosis.
Results: For the cohort, median fibrosis progression rate was 0.78 units/year, and median interval from transplantation to development of cirrhosis was 7.7 years. In multivariate analysis, donor age (not recipient age) was a powerful determinant (p=0.02) of fibrosis progression rate. When the liver donor was younger than 40 years, median progression rate was 0.6 units/year and interval to cirrhosis was 10 years. When the donor was aged 50 years or more, median progression rate was 2.7 units/year and interval to cirrhosis only 2.2 years. During the observation period there has been a significant increase in donor age (p=0.01) but date of transplantation per se is not a determinant of progression rate when included in multivariate analyses.
Conclusions: Donor age has a major influence on graft outcome following transplantation for HCV. The changing organ donor profile will affect the long term results of LT for HCV. These observations have important implications for donor liver allocation.
PMCID: PMC1773334  PMID: 12117889
hepatitis C virus; liver transplantation; donor age; fibrosis progression
20.  Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study 
Gut  2004;53(3):451-455.
Background: The natural history of hepatitis C virus (HCV) infection remains uncertain. Previous data concerning rates of progression are from studies using estimated dates of infection and single liver biopsy scores. We prospectively studied the rate of progression of fibrosis in HCV infected patients by repeat liver biopsies without intervening treatment.
Patients: We studied 214 HCV infected patients (126 male; median age 36 years (range 5–8)) with predominantly mild liver disease who were prospectively followed without treatment and assessed for risk factors for progression of liver disease. Interbiopsy interval was a median of 2.5 years. Paired biopsies from the same patient were scored by the same pathologist.
Results: Seventy of 219 (33%) patients showed progression of at least 1 fibrosis point in the Ishak score; 23 progressed at least 2 points. Independent predictors of progression were age at first biopsy and any fibrosis on first biopsy. Factors not associated with progression were: necroinflammation, duration of infection, alcohol consumption, alanine aminotransferase levels, current or past hepatitis B virus infection, ferritin, HCV genotype, and steatosis or iron deposition in the initial biopsy.
Conclusions: One third of patients with predominantly mild hepatitis C showed significant fibrosis progression over a median period of 30 months. Histologically, mild hepatitis C is a progressive disease. The overall rate of fibrosis progression in patients with hepatitis C was low but increased in patients who were older or had fibrosis on their index biopsy. These data suggest that HCV infection will place an increasing burden on health care services in the next 20 years.
PMCID: PMC1773967  PMID: 14960533
hepatitis C virus; fibrosis; hepatic fibrosis
21.  Steatosis and fibrosis in patients with chronic hepatitis C 
Journal of Clinical Pathology  2004;57(4):402-406.
Background: Steatosis is present on liver biopsy in approximately 50% of patients with hepatitis C; its association with stage of fibrosis has been reported, but its relation to other fibrosis associated factors is unknown.
Aim: To study the relation between steatosis and other histological features in patients with hepatitis C, and changes in steatosis with time.
Methods: Cross sectional study: 233 routine liver biopsies from 219 patients with hepatitis C; hepatectomy specimens from 65 patients transplanted for hepatitis C cirrhosis. Longitudinal study: 41 patients with two biopsies and 10 patients with three biopsies performed over 2–8 years. Biopsies were scored by the Ishak scheme, and degree of steatosis assessed subjectively. Multivariate analysis was used to study the interaction of fibrosis associated factors. Changes in steatosis over time in individual patients were explored in the longitudinal study.
Results: Steatosis was present in 50% of biopsies. It correlated strongly with fibrosis in non-cirrhotic samples, but declined in cirrhosis, and was unusual in transplant hepatectomy specimens. On multivariate analysis of non-cirrhotic biopsies, steatosis was associated with increasing patient age and remained significantly associated with fibrosis independent of portal inflammation and interface hepatitis. In the longitudinal study, steatosis persisted and increased over time, except in patients developing cirrhosis.
Conclusions: Steatosis is associated with fibrosis independently of necroinflammation, but declines in cirrhosis. It may represent a pathogenic pathway distinct from necroinflammatory activity in the generation of liver fibrosis, and should be included in the assessment of biopsies for clinical and research purposes.
PMCID: PMC1770262  PMID: 15047745
hepatitis C; steatosis; fibrosis
22.  Transient elastography: Kill two birds with one stone? 
World Journal of Hepatology  2013;5(5):264-274.
Assessment of liver fibrosis and steatosis is crucial in chronic liver diseases in order to determine the prognosis, the need of treatment, as well as monitor disease progression and response to treatment. Liver biopsy is limited by its invasiveness and patient acceptability. Transient elastography (TE, Fibroscan®) is a non-invasive tool with satisfactory accuracy and reproducibility to estimate liver fibrosis and steatosis. TE has been well validated in major liver diseases including chronic hepatitis B and C, non-alcoholic fatty liver disease, alcoholic liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis. As alanine aminotransferase (ALT) is one of the major confounding factors of liver stiffness in chronic hepatitis B, an ALT-based algorithm has been developed and higher liver stiffness measurements (LSM) cutoff values for different stages of liver fibrosis should be used in patients with elevated ALT levels up to 5 times of the upper limit of normal. Otherwise falsely-high LSM results up to cirrhotic range may occur during ALT flare. TE is also useful in predicting patient prognosis such as development of hepatocellular carcinoma (HCC), portal hypertension, post-operative complications in HCC patients, and also survival. Unfortunately, failed acquisition of TE is common in obese patients. Furthermore, obese patients may have higher LSM results even in the same stage of liver fibrosis. The new XL probe, a larger probe with lower ultrasound frequency and deeper penetration, increases the success rate of TE in obese patients. The median LSM value with XL probe was found to be lower than that by the conventional M probe, hence cutoff values approximately 1.2 to 1.3 kPa lower than those of M probe should be adopted. Recent studies revealed a novel ultrasonic controlled attenuation parameter (CAP) of the machine is a useful parameter to detect even low-grade steatosis noninvasively. CAP may also be used to quantify liver steatosis by applying different cutoff values. As both LSM and CAP results are instantly available at same measurement, this makes TE a very convenient tool to assess any patients who are suspected or confirmed to suffer from chronic liver diseases.
PMCID: PMC3664284  PMID: 23717737
Biopsy; Cirrhosis; Fibrosis; Hepatitis; Fatty liver; Steatosis of liver
23.  Novel Biomarker Candidates to Predict Hepatic Fibrosis in Hepatitis C Identified by Serum Proteomics 
Digestive diseases and sciences  2011;56(11):3305-3315.
Liver biopsy remains the gold standard to assess hepatic fibrosis. It is desirable to predict hepatic fibrosis without the need for invasive liver biopsy. Proteomic techniques allow unbiased assessment of proteins and might be useful to identify proteins related to hepatic fibrosis.
We utilized two different proteomic methods to identify serum proteins as candidate biomarkers to predict hepatic fibrosis stage in patients with chronic hepatitis C virus (HCV) infection.
Serum was obtained from 24 people with chronic HCV at time of liver biopsy and from 6 normals. Liver biopsy fibrosis was staged 1–4 (Batts–Ludwig). Pooled serum samples (six in each of four fibrosis groups and controls) were analyzed with 4- and 8-plex isobaric tags for relative and absolute quantitation (iTRAQ), determining protein identification (ID) and ratios of relative protein abundance. Nonpooled samples were analyzed with two-dimensional (2-D) gels and difference in gel electrophoresis (DIGE) comparing different samples on the same gel and across gels. Spots varying among groups were measured with densitometry, excised, digested, and submitted for tandem mass spectrometry (MS/MS) protein ID.
iTRAQ identified 305 proteins (minimum 99% ID confidence); 66 were increased or decreased compared with controls. Some proteins were increased or decreased for specific fibrosis scores. From 704 DIGE protein spots, 66 were chosen, 41 excised, and 135 proteins identified, since one gel spot often identified more than one protein.
Both proteomic methods identified two proteins as biomarker candidates for predicting hepatic fibrosis: complement C4-A and inter-alpha-trypsin inhibitor heavy chain H4.
PMCID: PMC3181275  PMID: 21590334
Hepatic fibrosis; Hepatitis C; iTRAQ; DIGE; Gel electrophoresis; Mass spectroscopy
24.  A comparison of four fibrosis indexes in chronic HCV: Development of new fibrosis-cirrhosis index (FCI) 
BMC Gastroenterology  2011;11:44.
Hepatitis C can lead to liver fibrosis and cirrhosis. We compared readily available non-invasive fibrosis indexes for the fibrosis progression discrimination to find a better combination of existing non-invasive markers.
We studied 157 HCV infected patients who underwent liver biopsy. In order to differentiate HCV fibrosis progression, readily available AAR, APRI, FI and FIB-4 serum indexes were tested in the patients. We derived a new fibrosis-cirrhosis index (FCI) comprised of ALP, bilirubin, serum albumin and platelet count. FCI = [(ALP × Bilirubin) / (Albumin × Platelet count)].
Already established serum indexes AAR, APRI, FI and FIB-4 were able to stage liver fibrosis with correlation coefficient indexes 0.130, 0.444, 0.578 and 0.494, respectively. Our new fibrosis cirrhosis index FCI significantly correlated with the histological fibrosis stages F0-F1, F2-F3 and F4 (r = 0.818, p < 0.05) with AUROCs 0.932 and 0.996, respectively. The sensitivity and PPV of FCI at a cutoff value < 0.130 for predicting fibrosis stage F0-F1 was 81% and 82%, respectively with AUROC 0.932. Corresponding value of FCI at a cutoff value ≥1.25 for the prediction of cirrhosis was 86% and 100%.
The fibrosis-cirrhosis index (FCI) accurately predicted fibrosis stages in HCV infected patients and seems more efficient than frequently used serum indexes.
PMCID: PMC3098184  PMID: 21507271
25.  Prevalence and risk factors for significant liver fibrosis among HIV-monoinfected patients 
BMC Infectious Diseases  2010;10:116.
HIV-monoinfected patients may be at risk for significant liver fibrosis, but its prevalence and determinants in these patients are unknown. Since HIV-monoinfected patients do not routinely undergo liver biopsy, we evaluated the prevalence and risk factors of significant hepatic fibrosis in this group using the aspartate aminotransferase (AST)-to-platelet ratio index (APRI).
We conducted a cross-sectional study among HIV-infected patients negative for hepatitis B surface antigen and hepatitis C antibody in the Penn Center for AIDS Research Adult/Adolescent Database. Clinical and laboratory data were collected from the database at enrollment. Hypothesized determinants of significant fibrosis were modifiable risk factors associated with liver disease progression, hepatic fibrosis, or hepatotoxicity, including immune dysfunction (i.e., CD4 T lymphocyte count <200 cells/mm3, HIV viremia), diseases associated with hepatic steatosis (e.g., obesity, diabetes mellitus), and use of antiretroviral therapy. The primary outcome was an APRI score >1.5, which suggests significant hepatic fibrosis. Multivariable logistic regression identified independent risk factors for significant fibrosis by APRI.
Among 432 HIV-monoinfected patients enrolled in the CFAR Database between November 1999 and May 2008, significant fibrosis by APRI was identified in 36 (8.3%; 95% CI, 5.9 - 11.4%) patients. After controlling for all other hypothesized risk factors as well as active alcohol use and site, detectable HIV viremia (adjusted OR, 2.56; 95% CI, 1.02 - 8.87) and diabetes mellitus (adjusted OR, 3.15; 95% CI, 1.12 - 10.10) remained associated with significant fibrosis by APRI.
Significant fibrosis by APRI score was found in 8% of HIV-monoinfected patients. Detectable HIV viremia and diabetes mellitus were associated with significant fibrosis. Future studies should explore mechanisms for fibrosis in HIV-monoinfected patients.
PMCID: PMC2876168  PMID: 20465840

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