ISSN 1007-9327 CN 14-1219/R World J Gastroenterol 2010 August 7; 16(29): 3687-3691
BRIEF ARTICLE
Dominique Larrey, Marie-Cécile Bozonnat, Ihab Kain, Georges-Philippe Pageaux, Eric Assenat
Dominique Larrey, Georges-Philippe Pageaux, Liver Unit and INSERM Unit 632, Saint-Eloi Hospital, Montpellier University, 34295 Montpellier Cedex 5, France
Marie-Cécile Bozonnat, Department of Biostatistics, Intitut Universitaire de Recherche Clinique, Montpellier University, 34295 Montpellier Cedex 5, France
Ihab Kain, Liver Unit, Saint-Eloi Hospital, Montpellier University, 34295 Montpellier Cedex 5, France
Eric Assenat, Medical Oncology Unit, Saint-Eloi Hospital, Montpellier University, 34295 Montpellier Cedex 5, France
Author contributions: Larrey D performed the major contribution; Bozonnat MC performed statistical analysis; Kain I reviewed data of some of the patients; Pageaux GP reviewed the manuscript; Assenat E provided help for cancer aspects.
Correspondence to: Dominique Larrey, MD, PhD, Professor of Hepatology, Liver Unit and INSERM Unit 632, Saint-Eloi Hospital, Montpellier University, 80 rue Augustin Fliche, 34295 Montpellier Cedex 5, France. dom-larrey@chu-montpellier.fr
Telephone: +33-4-67337061 Fax: +33-4-67330257
Received: September 17, 2009 Revised: December 22, 2009
Accepted: December 29, 2009
Published online: August 7, 2010
Abstract
AIM: To evaluate the prevalence of breast tumors in adult females with chronic hepatitis C virus (HCV) infection.
METHODS: Prospective, single-center study, based on female outpatients consulting in a liver unit, for 1 year. The study group included females with present and/or past history of chronic infection by HCV. Patients with spontaneous recovery were excluded. Chronic hepatitis had been proved by liver biopsy in the majority of cases and/or biological markers of inflammation and fibrosis. The control group included female patients with other well documented chronic liver diseases: chronic hepatitis B, alcoholic liver disease, autoimmune hepatitis, hemochromatosis, non alcoholic liver disease, chronic cholangitis. Participating patients were prospectively questioned during consultation about past breast history and follow-up by mammography.
RESULTS: Breast carcinoma was recorded in 17/294 patients with HCV infection (5.8%, 95% CI: 3.1-8.4) vs 5/107 control patients (4.7%, 95% CI: 0.67-8.67). Benign tumors of the breast (mastosis, nodules, cysts) were recorded in 75/294 patients with HCV infection (25.5%, 95% CI: 20.5-30.5) vs 21/107 (19.6%, 95% CI: 12.1-27.1) in the control group. No lesion was noted in 202 patients with HCV (68.7%, 95% CI: 63.4-74) vs 81 control patients (75.7%, 95% CI: 67.6-83.8). Despite a trend to an increased prevalence in the group with HCV infection, the difference was not significant compared to the control group (P = NS). In patients over 40 years, the results were, respectively, as follows: breast cancer associated with HCV: 17/266 patients (6.3%, 95% CI: 3.4-9.3) vs 5/95 patients (5.2%, 95% CI: 0.7-9.7) in the control group; benign breast tumors: 72/266 patients with HCV infection (27%, 95% CI: 21.7-32.4) vs 18/95 patients (18.9%, 95% CI: 11-26.8) in the control group; no breast lesion 177/266 (66.5%, 95% CI: 60.9-72.2) in patients with HCV infection vs 72/95 (75.7%, 95% CI: 67.1-84.4) in the control group. The differences were not significant (P = NS).
CONCLUSION: These results suggest that chronic HCV infection is not a strong promoter of breast carcinoma in adult females of any age.
© 2010 Baishideng. All rights reserved.
Key words: Breast tumors; Breast cancer; Hepatitis C virus infection; Risk factor
Peer reviewer: Edmund J Bini, Professor, Division of Gastroenterology (111D), VA New York Harbor Healthcare System, 423 East 23rd Street, New York, NY 10010, United States
Larrey D, Bozonnat MC, Kain I, Pageaux GP, Assenat E. Is chronic hepatitis C virus infection a risk factor for breast cancer? World J Gastroenterol 2010; 16(29): 3687-3691 Available from: URL: http://www.wjgnet.com/1007-9327/full/v16/i29/3687.htm DOI: http://dx.doi.org/10.3748/wjg.v16.i29.3687
INTRODUCTION
Several viruses have been involved in the occurrence of cancers[1]. For instance, human papilloma virus has been directly implicated in uterus cancer; poliomavirus in mesothelioma and brain tumors; Epstein-Barr virus in B-cell lymphoproliferative disease and nasopharyngeal carcinoma; herpes virus in Kaposi sarcoma[1]. Hepatitis C virus (HCV) is well-known to cause chronic hepatitis, cirrhosis and hepatocarcinoma[2-5]. The prevalence of HCV in France, as in other Western European countries, is around 1% and is estimated to be 1.6% in the United States[6-8]. The potential link between HCV infection and the risk of developing malignancy other than hepatocarcinoma has been recently raised in several studies[9-13]. There are several lines of evidence showing a role in the occurrence in non-Hodgkin lymphoma and lymphoproliferative diseases[9,10]. Recent studies argue for an increasing risk of intra-hepatic cholangiocarcinoma[11] and thyroid cancer[12]. The prevalence of HCV has been evaluated in elderly patients with tumors different from hepatocarcinoma and non-Hodgkin lymphoma (colorectal, prostate, breast, bladder, kidney)[13]. Among 236 patients, 87 (36%) were positive for HCV, a higher prevalence than in the patients of the control group (10%)[13]. A statistically significant difference was observed with kidney cancer, prostate cancer, and bladder cancer[13]. Finally, the link between hepatocarcinoma and another tumor has been assessed in a retrospective study including 37 patients[14]. Five patients (13.5%) had developed another primary cancer before or after hepatocarcinoma: kidney cancer, breast cancer, colorectal cancer, prostate cancer, or lymphoma. A common point between these 5 patients was HCV chronic infection. This suggested that HCV chronic infection may not only promote hepatocarcinoma, but also other solid tumors[14].
Therefore the aim of this study was to assess the frequency of breast tumors in adult females with chronic infection by HCV and whether this disease may be a promoting factor for the onset of benign or malignant breast tumors.
MATERIALS AND METHODS
This was a prospective, single-center study performed over 1 year in female patient aged ≥ 20 years, consulting in the Liver Unit of Montpellier School of Medicine, France, for chronic liver diseases. The study group included patients with present or past chronic infection by HCV.
Patients
Inclusions criteria: Age ≥ 20 years, the evidence of chronic infection by HCV based on the presence of serum anti-HCV antibodies, detection of serum HCV RNA by PCR tested on several occasions for a period longer than 1 year; chronic hepatitis C proved by liver biopsy (75% of patients) or non-invasive methods (25% of patients) including biological markers of inflammation and fibrosis of the liver such as Fibrotest-Actitest® and/or elastographic examination (Fibroscan®) as recently published[15-17]; agreement of the patient for participation in the study.
Exclusion criteria: A spontaneous recovery from HCV; co-infection by hepatitis B virus or human immunodeficiency virus; absence of capacity to understand or to answer the questions in the inquiry.
The control group included females seen sequentially and prospectively during the same period and affected by chronic liver disease over 1 year, with well defined characteristics based on clinical, radiological and histological features [chronic hepatitis B, chronic alcoholic liver disease, auto-immune hepatitis, hemochromatosis, non alcoholic fatty liver disease (NAFLD), chronic cholangitis, etc.].
Methods
The following information was collected during the consultation by using a questionnaire: past history of breast cancer or benign breast tumor; which type if any (adenoma, mastosis, cyst); performed examinations or treatment (mammography, biopsy, surgery); potential participation in a tumor detection program by mammography. Indeed, in our geographic area, there is a detection program for breast lesions with systematic mammography every 2 years for females over 40 years.
Statistical analysis
The data processing was performed using SAS software packages version 8.1. A general descriptive analysis was done for every parameter of the study. The distribution of qualitative variables (such as breast tumors) between groups was compared using c2 test. When the calculated frequency of the categorical data of the contingency table did not allow the use of the c2 test, Fisher’s exact test was performed. A P level < 0.05 was considered as significant. Stratification was performed according to age brackets: 20 to 40 years, 41 to 60 years and more than 60 years. Unilateral and bilateral power was calculated a posteriori.
RESULTS
Four hundred and one patients fulfilled inclusion criteria and all agreed to participate in the study. The study group with HCV infection included 294 patients; the control group included 107 patients with the following chronic liver diseases: NAFLD, 32 cases; chronic hepatitis B, 10 cases; primary biliary cirrhosis, 17 cases; auto-immune chronic hepatitis, 13 cases; chronic alcoholic liver disease, 4 cases; chronic cholangitis, 9 cases; hemochromatosis, 4 cases; and other chronic liver diseases, 18 cases.
Patients’ ages ranged from 21 to 84 years (median 58 years) in the HCV group and from 23 to 84 years (median 56 years) in the control group. The distribution by age was comparable in the two groups with a predominance of patients between 40 and 70 years: 20-40 years, n = 36 (8.9%) vs n = 15 (9.7%); 41-60 years, n = 132 (33%) vs n = 52 (45.9%); > 60 years, n = 126 (42.8%) vs n = 40 (37.4%). Other main characteristics of patients with chronic HCV infection, including genotype, severity of fibrosis and anti-viral treatment history, are shown in Table 1. They are similar to the features collected in the data bank of patients with HCV infection in our regional HCV network (3280 patients)[18]. In the control group, the percentage of chronic liver diseases reaching the stage of cirrhosis (stage F4 of METAVIR scale) was 13% (14/107 cases), which was similar to the HCV group (14%) (Table 1).
The programme of mammography for patient aged over 40 years was followed in 212/266 patients (79.7%) of the HCV group and in 74/99 patients (77.8%) of the control group. In younger patients, mammography had only been performed because of symptoms, in less than 15% of patients of both groups.
The prevalence of breast tumors is shown in Table 2. Among all patients, breast cancer was recorded in 5.8% (95% CI: 3.1-8.4) of HCV group patients vs 4.7% (95% CI: 0.67-8.67), a benign breast tumor in 25.5% (95% CI: 20.5-30.5) in the HCV group vs 19.6% (95% CI: 12.1-27.1) in the control group, no evidence of breast lesion in 68.7% (95% CI: 63.4-74) of patients in the HCV group vs 75.7% (95% CI: 67.6-83.8) in the control group. Despite a trend for a higher prevalence of malignant or benign tumors in the HCV group, there was no significant statistical difference with the control group (Table 2). Familial history of breast cancer was recorded only in 1 of the 17 patients in the HCV group and none in the 5 cases of the control group.
The same analysis was performed according age brackets as presented in Table 3. No breast cancer was recorded in females younger than 40 years in the two groups. The frequency was low for females between 41 and 60 years, with a mild predominance but no significant difference in the HCV group compared to the control group: 3.4% (95% CI: 0.5-6.4) vs 1.8% (95% CI: 0-5.3). Females older than 60 years exhibited the highest prevalence with 10.0% without any difference between the two groups. In all patients over 40 years, breast cancer in the HCV group was 17/266 patients (6.3%, 95% CI: 3.4-9.3) vs 5/95 (5.2%, 95% CI: 0.7-9.7) in the control group.
For benign breast tumors, frequency also varied according to age brackets: it was slightly lower in the HCV group vs the control group for females between 20 and 40 years. In contrast, it was slightly higher in the other two age brackets but the difference was not statistically significant.
The absence of breast tumors was slightly higher in females aged between 41 and 60 years, and older than 60 years in the control group vs the HCV group but the difference was not statistically significant.
DISCUSSION
In many parts of the world, breast cancer is the most frequent form of cancer in females[19-22]. Similarly in France, there are 49 000 new cases/year and 11 000 deaths for a population of 60 million inhabitants[23-25]. The incidence is 101 cases/100 000 females[25]. Overall, cancer occurs in one female out of 11. As with many other cancers, the risk increases with age (less than 10% of breast cancers are detected in patients younger than 40 years[21-24]. Then the incidence increases with age[21-24]. These observations justify a systematic detection in females from 50 years. The causes of breast cancer are poorly known. Nevertheless, some risk factors have been identified[25-28]: benign breast diseases, fertility (females without pregnancy or with first pregnancy later than 30 years old exhibit a higher risk), obesity particularly after menopause[25]. Familial and genetic factors may also increase the risk, in particular through a gene mutation (BRCA1-BRCA2)[28]. The role of oral contraceptives has been discussed[21-27]. The increase in risk has been mainly observed in oral contraceptive users with a family history of breast cancer[28].
The role of HCV in breast cancer has been recently raised[14] for the following reasons. Chronic HCV infection is clearly involved in the occurrence of hepatocarcinoma and lymphoma[3,4-10] and in several other solid tumors[11-13]. Some cases of breast cancer were observed in a recent study of patients with HCV[14] and several cases have been recorded during the regular follow-up of the large cohort of patients with chronic HCV infection seen in the Liver Unit of Montpellier School of Medicine (personal observation). This led to the present prospective study knowing that a program of systematic detection of breast tumors by mammography every 2 years in all females older than 40 years has been in place in our geographic area for nearly 20 years.
Global results of this study show a breast cancer frequency of 5.8% in adult females with chronic HCV infection. Intentionally, we included a group of young females, aged 20-40 years, to detect a potential signal in an age population known to not exhibit a particular risk. No malignant lesion was recorded. However, only a small proportion of these patients had undergone mammography. Therefore, the detection of a tumor was mainly based on its clinical expression. This sub-group representing about 10% of the overall group has slightly lowered the global prevalence. Indeed, the prevalence of all patients aged more than 40 years is 6.3% and reaches its highest rate, 10%, in females aged more than 60 years. The prevalence may have been underestimated since the mammography program was not followed in 20% of patients. Results observed in the HCV group were similar to those found in the control group, including females with other types of chronic liver diseases and having the same breast tumor detection program. We observed a similar low frequency in younger patients and the same proportion of patients who did not follow the mammography program. Therefore, this did not influence the comparison between groups. Finally, a familial history of breast cancer was recorded in a single patient with breast cancer (in the HCV group). This factor does not appear to have influenced the result of our study. Overall, these data do not support the idea that HCV chronic infection is a factor which contributes markedly to breast cancer. This view is also reinforced by the fact that prevalence of breast cancer found in this study is within the range of those found in general French and occidental populations[19-24]. Nevertheless, the interpretation of the results needs to be balanced by some limitations, in particular the relatively low number of patients in the control group and the absence of a priori calculation of the number of patients required to show a significant difference between groups with high power. This is largely caused by the fact that the prevalence of breast cancer in patients with chronic liver diseases in general and in HCV infection in particular, was completely unknown when the study was started. Therefore, our study does not allow us to draw definite conclusions. Nevertheless, it may serve as basis to set a more powerful study with matched control groups.
In summary, results of this study allowed the evaluation of the prevalence of breast cancer in patients with HCV chronic infection and suggest that HCV is not a strong promoter of breast carcinoma in adult females of any age.
COMMENTS
Background
Chronic infection by hepatitis C virus (HCV) exhibits a high frequency worldwide and represents a major cause of chronic liver disease leading to cirrhosis and hepatocarcinoma. Its influence on the onset of malignant tumors is under investigation.
Research frontiers
Several recent studies suggest that HCV chronic infection can not only cause hepatocarcinoma and lymphoma but may also promote the onset of several other solid tumors involving biliary ducts, thyroid, prostate, kidney and bladder.
Innovations and breakthroughs
The prevalence of breast cancer in patients with chronic liver diseases in general and HCV chronic infection in particular, is unknown. The relationship between HCV infection and breast cancer has been recently suggested by anecdotal cases. This is the first study designed to evaluate the prevalence of breast malignant and benign tumors in female patients and to assess whether HCV chronic infection is a risk factor. The study has been performed prospectively, using other chronic liver diseases as the control group. The results show the same prevalence of breast tumors in both groups which suggests that HCV does not appear as a strong promoting factor.
Applications
This study has allowed us to estimate the prevalence of breast cancer in females with chronic HCV infection. The interpretation of the results is balanced by the number of patients included in the study and statistical power. Nevertheless, this constitutes a step to design new studies with matched control groups including a much larger number of patients to evaluate a potential low impact of HCV in breast malignancy.
Peer review
The authors evaluated the association between HCV infection and breast cancer. The study included 294 patients with HCV infection. Control subjects were 107 women seen in the same liver clinic over a 1-year period. Overall, there was no difference in the frequency of breast cancer or benign breast lesions between HCV-infected patients and control subjects. The hypothesis is interesting, but the study has limitations as discussed.
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13 Malaguarnera M, Gargante MP, Risino C, Ranno S, Berretta M, Cannizzaro MA, Costanzo M, Fricia T, Rampello E, Romano M. Hepatitis C virus in elderly cancer patients. Eur J Intern Med 2006; 17: 325-329
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S- Editor Wang JL L- Editor O’Neill M E- Editor Ma WH
Source
August 5, 2010
Hepatitis C Virus Infection, Age, and Hispanic Ethnicity Increase Mortality From Liver Cancer in the United States
Clinical Gastroenterology and Hepatology
Volume 8, Issue 8 , Pages 718-723, August 2010
Zobair M. Younossi, Maria Stepanova
published online 03 May 2010.
Abstract
Backround & Aims
We performed a population-based study to assess factors that are associated independently with hepatocellular carcinoma (HCC)-related mortality.
Methods
We evaluated clinicodemographic, laboratory, and mortality data collected from 15,866 individuals in the Third National Health and Nutrition Examination Survey from 1988 to 1994. The etiology of chronic liver disease was determined using serologic tests to measure hepatitis C virus (HCV) RNA, hepatitis B surface antigen, and iron; excessive alcohol consumption and nonalcoholic fatty liver disease (NAFLD) were determined. Cohorts were compared with controls using a stratum-specific chi-square test. The Cox proportional hazard model was used to identify independent predictors of HCC-related mortality.
Results
After a follow-up period of 160 months, 14.55% of the individuals died; 83 deaths were liver-related (25 HCC and 58 non-HCC liver related). Factors that independently predicted HCC-related mortality were age (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.04–1.16; P = .0021), Hispanic ethnicity (HR, 5.14; 95% CI, 1.75–15.06; P = .0036), and HCV infection (HR, 18.12; 95% CI, 3.57–91.98; P = .0008). Factors that independently predicted non-HCC liver-related mortality included age (HR, 1.07; 95% CI, 1.04–1.10; P < .0001), male sex (HR, 3.29; 95% CI, 1.15–9.42; P = .0277), alcoholic liver disease (HR, 10.81; 95% CI, 1.32–88.26; P = .0271), HCV (HR, 27.00; 95% CI, 4.70–155.1; P = .0004), iron overload (HR, 6.18; 95% CI, 1.82–20.97; P = .0043), or NAFLD (HR, 11.56; 95% CI, 3.21–41.67; P = .0004).
Conclusions
This population-based study showed that HCV infection and Hispanic ethnicity independently increase the risk for HCC-related mortality. All liver diseases, including NAFLD, increase the risk for non-HCC liver-related mortality.
Keywords: Hepatocelluar Carcinoma, Liver-Related Mortality, Liver Neoplasm
Abbreviations used in this paper: ALD, alcoholic liver disease, CH-C, chronic hepatitis C, CI, confidence interval, DM, diabetes mellitus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HR, hazard ratio, ICD, International Classification of Diseases, NAFLD, nonalcoholic fatty liver disease, NDI, National Death Index, NHANES III, Third National Health and Nutrition Examination Survey, SEER, Surveillance, Epidemiology End Result
Conflicts of interest The authors disclose no conflicts.
Funding This study was supported in part by the Liver Outcomes Research Fund, The Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia.
PII: S1542-3565(10)00431-3
doi:10.1016/j.cgh.2010.04.017
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Volume 8, Issue 8 , Pages 718-723, August 2010
Zobair M. Younossi, Maria Stepanova
published online 03 May 2010.
Abstract
Backround & Aims
We performed a population-based study to assess factors that are associated independently with hepatocellular carcinoma (HCC)-related mortality.
Methods
We evaluated clinicodemographic, laboratory, and mortality data collected from 15,866 individuals in the Third National Health and Nutrition Examination Survey from 1988 to 1994. The etiology of chronic liver disease was determined using serologic tests to measure hepatitis C virus (HCV) RNA, hepatitis B surface antigen, and iron; excessive alcohol consumption and nonalcoholic fatty liver disease (NAFLD) were determined. Cohorts were compared with controls using a stratum-specific chi-square test. The Cox proportional hazard model was used to identify independent predictors of HCC-related mortality.
Results
After a follow-up period of 160 months, 14.55% of the individuals died; 83 deaths were liver-related (25 HCC and 58 non-HCC liver related). Factors that independently predicted HCC-related mortality were age (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.04–1.16; P = .0021), Hispanic ethnicity (HR, 5.14; 95% CI, 1.75–15.06; P = .0036), and HCV infection (HR, 18.12; 95% CI, 3.57–91.98; P = .0008). Factors that independently predicted non-HCC liver-related mortality included age (HR, 1.07; 95% CI, 1.04–1.10; P < .0001), male sex (HR, 3.29; 95% CI, 1.15–9.42; P = .0277), alcoholic liver disease (HR, 10.81; 95% CI, 1.32–88.26; P = .0271), HCV (HR, 27.00; 95% CI, 4.70–155.1; P = .0004), iron overload (HR, 6.18; 95% CI, 1.82–20.97; P = .0043), or NAFLD (HR, 11.56; 95% CI, 3.21–41.67; P = .0004).
Conclusions
This population-based study showed that HCV infection and Hispanic ethnicity independently increase the risk for HCC-related mortality. All liver diseases, including NAFLD, increase the risk for non-HCC liver-related mortality.
Keywords: Hepatocelluar Carcinoma, Liver-Related Mortality, Liver Neoplasm
Abbreviations used in this paper: ALD, alcoholic liver disease, CH-C, chronic hepatitis C, CI, confidence interval, DM, diabetes mellitus, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HR, hazard ratio, ICD, International Classification of Diseases, NAFLD, nonalcoholic fatty liver disease, NDI, National Death Index, NHANES III, Third National Health and Nutrition Examination Survey, SEER, Surveillance, Epidemiology End Result
Conflicts of interest The authors disclose no conflicts.
Funding This study was supported in part by the Liver Outcomes Research Fund, The Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia.
PII: S1542-3565(10)00431-3
doi:10.1016/j.cgh.2010.04.017
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Compliance With Practice Guidelines and Risk of a First Esophageal Variceal Hemorrhage in Patients With Cirrhosis
Clinical Gastroenterology and Hepatology
Volume 8, Issue 8 , Pages 703-708, August 2010
Jayavani Moodley, Rocio Lopez, William Carey
published online 12 March 2010.
Abstract
Background & Aims
Esophageal variceal hemorrhage (EVH) is a serious complication of cirrhosis, with 20% mortality per episode. The 2007 American Association for the Study of Liver Disease and American College of Gastroenterology practice guidelines regarding esophageal varices in patients with cirrhosis recommend screening and intervention to prevent EVH. We assessed practice guideline compliance and its impact on the rate of first EVH.
Methods
An institutional review board-approved retrospective chart review was conducted on a random sample of adult patients newly evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006 (n = 179). Exclusion criteria were a previous diagnosis of esophageal varices or EVH and/or treatment with β-adrenergic antagonists. Patients were followed for 23 months (range, 9–38 months). Conformity with practice guidelines and subsequent bleeding rates were determined. Observed bleeding rates were compared to the North Italian Endoscopy Club (NIEC) model.
Results
Of the patients, 94% had a screening endoscopy, 80% within 6 months of the initial visit. Varices were present in 50% of the patients; 68% of all patients screened and 91% with large varices received a practice guideline-recommended treatment. Twelve patients (7%) had an episode of EVH; 82% of subjects without bleeding had their screening endoscopy within 6 months versus 50% of those with bleeding (P = .016). Actuarial likelihood of bleeding at 2 years was 13% versus 27% predicted by the NIEC model (P < .05).
Conclusion
Compliance with practice guideline recommendations is associated with reduction in first EVH in the first 2 years.
Keywords: Practice Guideline Compliance, Cirrhosis, Esophageal Varices, Hemorrhage
Abbreviations used in this paper: AASLD, American Association for the Study of Liver Disease, ACG, American College of Gastroenterology, BB, beta blocker, CPS, Child–Pugh Score, EGD, endoscopy, EV, esophageal varices, EVH, esophageal variceal hemorrhage, EVL, esophageal variceal ligations, IGV, isolated gastric varices, NIEC, North Italian Endoscopy Club, PG, practice guideline
Conflicts of interest The authors disclose no conflicts.
PII: S1542-3565(10)00228-4
doi:10.1016/j.cgh.2010.02.022
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Volume 8, Issue 8 , Pages 703-708, August 2010
Jayavani Moodley, Rocio Lopez, William Carey
published online 12 March 2010.
Abstract
Background & Aims
Esophageal variceal hemorrhage (EVH) is a serious complication of cirrhosis, with 20% mortality per episode. The 2007 American Association for the Study of Liver Disease and American College of Gastroenterology practice guidelines regarding esophageal varices in patients with cirrhosis recommend screening and intervention to prevent EVH. We assessed practice guideline compliance and its impact on the rate of first EVH.
Methods
An institutional review board-approved retrospective chart review was conducted on a random sample of adult patients newly evaluated for cirrhosis at the Cleveland Clinic from 2003 to 2006 (n = 179). Exclusion criteria were a previous diagnosis of esophageal varices or EVH and/or treatment with β-adrenergic antagonists. Patients were followed for 23 months (range, 9–38 months). Conformity with practice guidelines and subsequent bleeding rates were determined. Observed bleeding rates were compared to the North Italian Endoscopy Club (NIEC) model.
Results
Of the patients, 94% had a screening endoscopy, 80% within 6 months of the initial visit. Varices were present in 50% of the patients; 68% of all patients screened and 91% with large varices received a practice guideline-recommended treatment. Twelve patients (7%) had an episode of EVH; 82% of subjects without bleeding had their screening endoscopy within 6 months versus 50% of those with bleeding (P = .016). Actuarial likelihood of bleeding at 2 years was 13% versus 27% predicted by the NIEC model (P < .05).
Conclusion
Compliance with practice guideline recommendations is associated with reduction in first EVH in the first 2 years.
Keywords: Practice Guideline Compliance, Cirrhosis, Esophageal Varices, Hemorrhage
Abbreviations used in this paper: AASLD, American Association for the Study of Liver Disease, ACG, American College of Gastroenterology, BB, beta blocker, CPS, Child–Pugh Score, EGD, endoscopy, EV, esophageal varices, EVH, esophageal variceal hemorrhage, EVL, esophageal variceal ligations, IGV, isolated gastric varices, NIEC, North Italian Endoscopy Club, PG, practice guideline
Conflicts of interest The authors disclose no conflicts.
PII: S1542-3565(10)00228-4
doi:10.1016/j.cgh.2010.02.022
© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source
Metabolic disorders associated with chronic hepatitis C: impact of genotype and ethnicity
Liver International
Volume 30 Issue 8, Pages 1131 - 1136
Published Online: 9 Jun 2010
© 2010 John Wiley & Sons A/S
CLINICAL STUDIES
Thomas Sersté 1,2 , Marcel Nkuize 1 , Rami Moucari 2 , Marc Van Gossum 1 , Marijke Reynders 3 , Robert Scheen 3 , Françoise Vertongen 4 , Michel Buset 1 , Jean Pierre Mulkay 1 and Patrick Marcellin 2
1 Hépato-Gastroentérologie, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
2 AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France
3 Microbiologie, Biologie Moléculaire, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
4 Biochimie, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
Correspondence
Thomas Sersté, Hépato-Gastroentérologie, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgique.
Tel: +322 535 4109
Fax: +322 535 4135
e-mail: thomas.serste@skynet.be
KEYWORDS
chronic hepatitis C • ethnicity • genotype • insulin resistance
ABSTRACT
Background & aim: Patients with hepatitis C virus (HCV) infection, especially those with genotypes 1 and 4, have an increased risk of developing metabolic disorders. The aim of this study was to evaluate the associations among metabolic disorders, ethnicity and genotype in a large cohort of patients with chronic hepatitis C (CHC).
Patients and Methods: All consecutive patients with CHC who were seen in our hepato-gastroenterology unit between January 2002 and September 2008 were included. Demographical data and variables related to the metabolic syndrome were collected. Insulin resistance was assessed using the homeostasis model for the assessment of insulin resistance test (HOMA-IR) test.
Results: Among the 454 CHC patients, the prevalence of the metabolic syndrome was 12.4%. The HOMA-IR test was performed in 140 patients, and 35.0% had insulin resistance. There were more Black Africans among the patients with genotypes 1/4 than among those with genotypes 2/3 (32.0 vs 1.2%, P<0.0001). Insulin resistance was more common in patients with genotypes 1/4 than in those with genotypes 2/3 (17 vs 1.7%, P=0.0001 and 43.3 vs 16.3%, P=0.001, respectively). Genotypes 1/4 were more frequently present in patients with insulin resistance than in those without insulin resistance (85.7 vs 60.5%, P=0.001). By logistic regression, genotypes 1/4 [odds ratio (OR)=2.79; 95% confidence interval (CI): 1.09–7.12, P=0.032] and older age (OR=1.03; 95% CI: 1.004–1.06, P=0.024) were independently associated with the presence of insulin resistance.
Conclusions: In CHC, insulin resistance is independently associated with the presence of genotypes 1/4. Ethnicity is not independently associated with metabolic disorders in patients with CHC.
Received 12 December 2009
Accepted 11 May 2010
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1478-3231.2010.02291.x About DOI
Source
Volume 30 Issue 8, Pages 1131 - 1136
Published Online: 9 Jun 2010
© 2010 John Wiley & Sons A/S
CLINICAL STUDIES
Thomas Sersté 1,2 , Marcel Nkuize 1 , Rami Moucari 2 , Marc Van Gossum 1 , Marijke Reynders 3 , Robert Scheen 3 , Françoise Vertongen 4 , Michel Buset 1 , Jean Pierre Mulkay 1 and Patrick Marcellin 2
1 Hépato-Gastroentérologie, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
2 AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France
3 Microbiologie, Biologie Moléculaire, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
4 Biochimie, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
Correspondence
Thomas Sersté, Hépato-Gastroentérologie, Hôpital Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgique.
Tel: +322 535 4109
Fax: +322 535 4135
e-mail: thomas.serste@skynet.be
KEYWORDS
chronic hepatitis C • ethnicity • genotype • insulin resistance
ABSTRACT
Background & aim: Patients with hepatitis C virus (HCV) infection, especially those with genotypes 1 and 4, have an increased risk of developing metabolic disorders. The aim of this study was to evaluate the associations among metabolic disorders, ethnicity and genotype in a large cohort of patients with chronic hepatitis C (CHC).
Patients and Methods: All consecutive patients with CHC who were seen in our hepato-gastroenterology unit between January 2002 and September 2008 were included. Demographical data and variables related to the metabolic syndrome were collected. Insulin resistance was assessed using the homeostasis model for the assessment of insulin resistance test (HOMA-IR) test.
Results: Among the 454 CHC patients, the prevalence of the metabolic syndrome was 12.4%. The HOMA-IR test was performed in 140 patients, and 35.0% had insulin resistance. There were more Black Africans among the patients with genotypes 1/4 than among those with genotypes 2/3 (32.0 vs 1.2%, P<0.0001). Insulin resistance was more common in patients with genotypes 1/4 than in those with genotypes 2/3 (17 vs 1.7%, P=0.0001 and 43.3 vs 16.3%, P=0.001, respectively). Genotypes 1/4 were more frequently present in patients with insulin resistance than in those without insulin resistance (85.7 vs 60.5%, P=0.001). By logistic regression, genotypes 1/4 [odds ratio (OR)=2.79; 95% confidence interval (CI): 1.09–7.12, P=0.032] and older age (OR=1.03; 95% CI: 1.004–1.06, P=0.024) were independently associated with the presence of insulin resistance.
Conclusions: In CHC, insulin resistance is independently associated with the presence of genotypes 1/4. Ethnicity is not independently associated with metabolic disorders in patients with CHC.
Received 12 December 2009
Accepted 11 May 2010
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1478-3231.2010.02291.x About DOI
Source
A simpler score of routine laboratory tests predicts liver fibrosis in patients with chronic hepatitis B
Journal of Gastroenterology and Hepatology
Published Online: 14 May 2010
Journal compilation © 2010 Blackwell Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation
ZHOU Kun 1,4▵ , GAO Chun-fang 3▵ , ZHAO Yun-peng 3 , LIU Hai-lin 4 , ZHENG Rui-dan 5 , XIAN Jian-chun 6 , XU Hong-tao 6 , MAO Yi-min 1 , ZENG Min-de 1 , LU Lun-gen 1,2*
1 Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200001; 2 Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080,China
E-mail: lungenlu1965@yahoo.com
4 Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China
3 Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai 200433, China
5 Research and Therapy Center for Liver Diseases, Southeast Hospital, Zhangzhou, Fujian 363000,China
6 Department of Infectious Disease, Taizhou People's Hospital, Jiangsu 225300, China
Correspondence to *Dr. LU Lun-gen
▵These two authors contributed equally to this work.
Financial Support: This study was supported by the National Key Technologies Research and Development Program of China during the 11th Five-year Plan Period (2008ZX10002-006), the National High Technology Research and Development Program of China (863 Program,No:2006AA02A411), Science and Technology Commission of Shanghai Municipality (No:064119519), the Key Project of Shanghai Medical Development Foundation (No: 99ZDI001), and Shanghai Leading Academic Discipline Project (No:Y0205).
The funding sources had no involvement in study design, in the collection, analysis, and interpretation of data and so on.
This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Gastroenterology and Hepatology, but has yet to undergo copy-editing and proof correction. Please cite this article as an "Accepted Article"; doi: 10.1111/j.1440-1746.2010.06383.x
KEYWORDS
liver biopsy • liver fibrosis • cirrhosis • noninvasive diagnosis • assessment
ABSTRACT
Background: In recent years, a great interest has been dedicated to the development of noninvasive predictive models to substitute liver biopsy for fibrosis assessment and follow-up.
Aims: To provide a simpler model consisting of routine laboratory markers for predicting liver fibrosis in patients chronically infected with hepatitis B virus (HBV) in order to optimize their clinical management.
Methods: Liver fibrosis was staged in 386 chronic HBV carriers who underwent liver biopsy and routine laboratory testing. Correlations between routine laboratory markers and fibrosis stage were statistically assessed. After logistic regression analysis, a novel predictive model was constructed. This S index was validated in an independent cohort of 146 chronic HBV carriers in comparison to the SLFG model, Fibrometer, Hepascore, Hui model, Forns score and APRI using receiver operating characteristic (ROC) curves.
Results: The diagnostic values of each marker panels were better than single routine laboratory markers. The S index consisting of γ-glutamyltransferase (GGT), platelets (PLT) and albumin (ALB) (S-index: 1000 × GGT / (PLT × ALB2)) had a higher diagnostic accuracy in predicting degree of fibrosis than any other mathematical model tested. The areas under the ROC curves (AUROC) were 0.812 and 0.890 for predicting significant fibrosis and cirrhosis in the validation cohort, respectively.
Conclusions: The S index, a simpler mathematical model consisting of routine laboratory markers predicts significant fibrosis and cirrhosis in patients with chronic HBV infection with a high degree of accuracy, potentially decrease the need for liver biopsy.
Accepted: 02 May 2010
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1440-1746.2010.06383.x About DOI
Source
Published Online: 14 May 2010
Journal compilation © 2010 Blackwell Publishing Asia Pty Ltd and Journal of Gastroenterology and Hepatology Foundation
ZHOU Kun 1,4▵ , GAO Chun-fang 3▵ , ZHAO Yun-peng 3 , LIU Hai-lin 4 , ZHENG Rui-dan 5 , XIAN Jian-chun 6 , XU Hong-tao 6 , MAO Yi-min 1 , ZENG Min-de 1 , LU Lun-gen 1,2*
1 Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200001; 2 Department of Gastroenterology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080,China
E-mail: lungenlu1965@yahoo.com
4 Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, China
3 Department of Laboratory Medicine, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai 200433, China
5 Research and Therapy Center for Liver Diseases, Southeast Hospital, Zhangzhou, Fujian 363000,China
6 Department of Infectious Disease, Taizhou People's Hospital, Jiangsu 225300, China
Correspondence to *Dr. LU Lun-gen
▵These two authors contributed equally to this work.
Financial Support: This study was supported by the National Key Technologies Research and Development Program of China during the 11th Five-year Plan Period (2008ZX10002-006), the National High Technology Research and Development Program of China (863 Program,No:2006AA02A411), Science and Technology Commission of Shanghai Municipality (No:064119519), the Key Project of Shanghai Medical Development Foundation (No: 99ZDI001), and Shanghai Leading Academic Discipline Project (No:Y0205).
The funding sources had no involvement in study design, in the collection, analysis, and interpretation of data and so on.
This is an Accepted Article that has been peer-reviewed and approved for publication in the Journal of Gastroenterology and Hepatology, but has yet to undergo copy-editing and proof correction. Please cite this article as an "Accepted Article"; doi: 10.1111/j.1440-1746.2010.06383.x
KEYWORDS
liver biopsy • liver fibrosis • cirrhosis • noninvasive diagnosis • assessment
ABSTRACT
Background: In recent years, a great interest has been dedicated to the development of noninvasive predictive models to substitute liver biopsy for fibrosis assessment and follow-up.
Aims: To provide a simpler model consisting of routine laboratory markers for predicting liver fibrosis in patients chronically infected with hepatitis B virus (HBV) in order to optimize their clinical management.
Methods: Liver fibrosis was staged in 386 chronic HBV carriers who underwent liver biopsy and routine laboratory testing. Correlations between routine laboratory markers and fibrosis stage were statistically assessed. After logistic regression analysis, a novel predictive model was constructed. This S index was validated in an independent cohort of 146 chronic HBV carriers in comparison to the SLFG model, Fibrometer, Hepascore, Hui model, Forns score and APRI using receiver operating characteristic (ROC) curves.
Results: The diagnostic values of each marker panels were better than single routine laboratory markers. The S index consisting of γ-glutamyltransferase (GGT), platelets (PLT) and albumin (ALB) (S-index: 1000 × GGT / (PLT × ALB2)) had a higher diagnostic accuracy in predicting degree of fibrosis than any other mathematical model tested. The areas under the ROC curves (AUROC) were 0.812 and 0.890 for predicting significant fibrosis and cirrhosis in the validation cohort, respectively.
Conclusions: The S index, a simpler mathematical model consisting of routine laboratory markers predicts significant fibrosis and cirrhosis in patients with chronic HBV infection with a high degree of accuracy, potentially decrease the need for liver biopsy.
Accepted: 02 May 2010
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1440-1746.2010.06383.x About DOI
Source
Nonalcoholic Steatohepatitis: A Review of the Literature and Updates in Management
From Southern Medical Journal
Lakshmi Pasumarthy, MD, FACP; James Srour, MD
Posted: 08/05/2010; South Med J. 2010;103(6):547-550. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Nonalcoholic steatohepatitis is a common cause of liver inflammation and is associated with obesity, insulin resistance, and hyperlipidemia. There are concerns that it may turn out to be the most common cause of liver failure as prevalence of obesity increases. It leads to increased morbidity and mortality. Other causes of liver inflammation, especially alcoholic liver disease, must be ruled out. The diagnosis is suggested by abnormalities in the blood work and metabolic panel in an obese patient. Despite advances made in our understanding regarding the pathogenesis and trials with multiple drugs targeting mechanisms in pathogenesis, there are no consistent guidelines regarding treatment. However, multiple sources advocate weight reduction, optimum blood glucose control, and elimination of medications that cause fatty infiltration. The purpose of our article is to detail advances made in identifying disease mechanisms and treatment modalities, including surgery to promote weight loss.
Introduction
Fatty infiltration of the liver was described a long time ago and was initially felt to be linked with alcohol-related liver damage. The term nonalcoholic steatohepatitis (NASH) was introduced by Ludwig in 1980 and recognized in the absence of alcohol intake.[1] In the 1990s the incidence of nonalcoholic fatty liver disease (NAFLD) began to increase, paralleling the increase in obesity rates, and it is now recognized widely. The entity includes NAFLD which presents with simple steatosis, NASH, and cirrhosis. It is the most common cause of chronic liver disease. The estimated prevalence of NAFLD and NASH is 20–30% and 3.5–5%, respectively.[2] There is a higher prevalence of NASH in Mexican-Americans compared with non-Hispanic whites, even after controlling for obesity and body fat distribution.[3] The importance of NASH becomes more apparent when reviewing available data, which shows that 10–15% of patients with histologically proven NASH progress to cirrhosis and its complications such as liver failure and hepatocellular carcinoma. Furthermore, patients with NASH have lower survival rates.[4] Unfortunately, even though the prevalence of NASH threatens to increase, there are no approved medications for its treatment. There are many medications being evaluated currently, many targeting different steps in the development of hepatic steatosis or its progression to steatohepatitis. The laboratory and histologic profile of NASH and alcoholic liver disease are very similar. Distinction should be made carefully, since the treatment and prognosis are quite different.
Pathogenesis
The "two hit" hypothesis is a commonly described pathway by which fatty liver progresses to nonalcoholic steatohepatitis (NASH). The first hit involves macrovesiclular steatosis due to increased hepatic lipid synthesis and reduced transfer of lipids from the liver. Though insulin resistance plays an important role in this process, once the steatosis develops, it frequently worsens the insulin resistance and triggers a vicious cycle.[5] The role of insulin resistance in the pathogenesis of this disease is supported by pilot studies demonstrating beneficial effects of glucose-sensitizing medications in patients with NASH. Receptors in the cell nucleus that are involved in triggering the effects of insulin may fail, thus leading to insulin resistance, hepatic inflammation, and, ultimately, hepatic scarring. Treatment with rosiglitazone reduces the expression of hepatic acute phase reactants (C-reactive protein and serum amyloid A), suggesting that improvements in insulin sensitivity correspond with a reduction in inflammation.[6]
The second hit occurs due to increased hepatic oxidative stress, perhaps arising from increased free fatty acid metabolism, decreased antioxidant activity, increased activity of mitochondrial uncoupling proteins, and/or increased endotoxin levels in the liver. Oxidative stresses—mainly as a consequence of mitochondrial dysfunction—and proinflammatory cytokines are thought to play a central role in the progression from simple steatosis to steatohepatitis and cirrhosis.[7]
Accumulating evidence supports the role of antioxidants in preventing oxidative liver injury. In a study by Harrison et al,[8] a 6-month course of combination therapy with vitamin E and vitamin C resulted in significant histologic improvement. In another study, dietary intake of antioxidant vitamins was significantly lower in patients with NASH compared with controls matched for age and body mass index.[9] Genetic causes of increased fatty acid input promote excessive hepatic lipogenesis. These include mutations that cause leptin deficiency or leptin receptor inhibition and mutations that induce insulin, insulin-like growth factors, or insulin-responsive transcription factors.[10] Leptin signals "fullness" postprandially and also promotes insulin sensitivity. Despite elevated plasma levels of leptin, patients with NASH often do not experience normal satiety, and they also have insulin resistance. Thus, hyperinsulinemia and defective leptin signaling are conspicuous at early stages of NASH. It has also been shown that leptin is clearly related to stellate cell activation.[11] Inflammation of hepatocytes causes activation of hepatic stellate cells which are important in the pathogenesis of fibrosis. Increased levels of insulin cause upregulation of fibrogenic growth factor secreted by the hepatic stellate cells.
There is evidence to support the hypothesis that angiotensin II promotes activation, and dedifferentiation of the stellate cells into myofibroblasts. Furthermore, angiotensin II encourages myofibroblast contraction and proliferation and promotes release of inflammatory cytokines as well as the deposition of extracellular matrix.[12]
Presentation
Type 2 diabetes, insulin resistance, central obesity, and dyslipidemia are risk factors associated with development of NASH.[13] Initially, most patients with NASH are asymptomatic and present with abnormal liver tests obtained after routine screening. Rarely patients present with symptoms such as fatigue and nonspecific right upper quadrant pain. A careful history to exclude significant alcohol intake is extremely important.[14] This is defined as more than two alcoholic drinks a day for a male (20 gm/day) and more than one alcoholic drink a day for a female (10 gm/day). Fatty infiltration is also found in the context of other liver disorders, therefore it is important to go through the differential diagnoses. Finally, it is important to review the patient's medication list including over the counter medications, herbal remedies, and vitamin supplements. Many drugs can precipitate or exacerbate steatohepatitis in the presence of other risk factors.
As the fibrosis advances, the patients present with the typical manifestations of cirrhosis such as spider telangiectasiae, ascites, ankle edema, and easy bruising. It has been proposed that what was once classified as cryptogenic cirrhosis was probably underrecognized "burned out" NASH.
Diagnosis
The diagnosis of NAFLD is suspected in patients with elevated aminotransferases and evidence of the metabolic syndrome, although the levels fluctuate and patients may have normal enzyme levels on several occasions. The distinction between NASH and simple steatosis cannot reliably be made without liver biopsy, but this is not practical as a population-based approach.[15]
A multivariable model that included age, body mass index, platelet count, albumin, and aspartate aminotransferase/alanine transaminase (AST/ALT) ratio had good discriminant ability to identify individuals with advanced fibrosis in a study of 733 patients.[16] In addition, the diagnosis is suggested by ruling out other causes of elevated liver enzymes coupled with the patient's metabolic profile.
In NAFLD, the alanine aminotransferase (ALT) is initially greater than the aspartate aminotransferase (AST), and the trend is found reversing with onset of cirrhosis.[17] Transaminase values are usually increased less than fourfold, though normal values do not exclude the diagnosis. These values correlate poorly with the severity of underlying liver disease. Interest has been generated by SteatoTest for the diagnosis of hepatic steatosis and by NashTest for the diagnosis of NASH. These tests utilize noninvasive biomarkers such as gamma glutamyl-transferase (GGTP), total bilirubin, haptoglobin, α2-macroglobulin, and apolipoprotein A1. However, these are still not recommended in routine clinical practice.[18]
There is no single pathognomonic histological lesion in NASH and, instead, the disease presents with a constellation of findings. Three histological lesions are necessary for the diagnosis of NASH: zone 3 macrosteatosis, hepatocyte ballooning, and mixed lobular inflammation. Other findings that are common, but not necessary, include mild-moderate portal inflammation, acidophil bodies, glycogenated nuclei, periodic acid stain after diastase Kupffer cells, lipogranulomas and perisinusoidal zone 3 fibrosis, and Mallory hyaline in hepatocytes and megamitochondria.[19] A liver biopsy yields a very small sample of the liver and may not accurately reflect the extent or diagnosis because the histological lesions of NASH are unevenly distributed throughout the liver parenchyma.[20]
Noninvasive radiologic modalities like ultrasound (US), computerized tomography (CT) and magnetic resonance imaging (MRI) are sensitive in diagnosing steatosis but they are not able to differentiate the nonprogressive form of NAFLD from fibrosis.[21] CT and US are very sensitive only when there is more than 33% fat in the hepatic parenchyma.
Treatment
Nonpharmacologic
Factors that increase hepatic oxidative stress promote progression from hepatic steatosis to steatohepatitis. Avoidance of alcohol, weight loss, a low-fat diet, exercise, and tight glycemic control of diabetes help inhibit disease progression.
Weight loss as achieved through diet and exercise should be gradual, aiming for no more than 2 lbs of weight loss per week. Weight loss and exercise help improve insulin resistance. Exercise can also improve muscular insulin sensitivity, which may improve the impact of insulin resistance on NASH.
Though weight loss is rapid, bariatric surgery for morbid obesity does help NASH significantly. For example, Dixon et al showed that NASH resolved in 82% of patients undergoing laparoscopic adjustable gastric banding after losing approximately 40 kg. Patients who had metabolic syndrome showed a greater improvement in steatosis, necroinflammation, and fibrosis with weight loss showcasing the fact that improvements in several components of metabolic syndrome are expected to have a beneficial impact on the liver disease. This is probably because of the decrease in cytokines and chronic inflammation associated with obesity.[22]
Pharmacologic
Orlistat/Sibutramine. A clinical trial using orlistat showed a mean decrease in body weight of 10.3 kg and significant reductions in serum transaminase levels in obese patients with NASH. A 6-month pilot study of sibutramine reported weight loss, improved insulin resistance, and biochemical profiles.[23]
Vitamins. Some hepatologists utilize vitamin E based on trials in which decrements in ALT were demonstrated either with vitamin E alone or in combination with pioglitazone or with vitamin C.[8,24,25] However, given more recent concerns related to an increase in mortality with vitamin E supplementation and the weak evidence supporting its benefit in NASH, vitamin E is not advocated strongly.
Medications Addressing Insulin Resistance. Metformin and thiazolidinediones are insulin sensitizing and work by decreasing insulin resistance. Since this issue is closely associated with the pathogenesis of NASH, much interest and work has been devoted to these medications.
Metformin acts by decreasing hepatic glucose production and increasing peripheral glucose uptake by muscles. Metformin can also increase fatty acid oxidation and suppress lipogenesis. Trials involving lipid and calorie-restricted diet with or without metformin for six months[26] showed decreased aminotransferase levels, insulin, and C-peptide levels to a significantly greater extent in the metformin group. In another randomized trial, metformin alone resulted in normalization of aminotransferases as compared with vitamin E and weight loss. Despite some gastrointestinal intolerance, metformin was well tolerated. On the other hand, though biochemical improvement was shown, histological data remain very limited. It must be avoided in patients with congestive heart failure and renal insufficiency.[27]
Thiazolidinediones reduce insulin resistance by acting on peroxisome proliferator-activated receptors (PPAR)—gamma in adipose tissue. Both pioglitazone and rosiglitazone have been studied and demonsrated improvements in transaminases and liver histology in multiple studies[28,29] Concerns for cardiovascular effects, congestive heart failure and weight gain have limited their long term use. Nateglinide, muraglitazar, and rimonabant have helped with weight loss in the obese but data to support their use for NASH are limited.
Lipid Lowering Medications. Both fibrates and statins have been studied for treatment of NASH since hyperlipidemia is one of the components of metabolic syndrome. Gemfibrozil has shown an improvement in aminotransferases in a trial, though no other fibrate has replicated this result. Fibrates have a complex mechanism of action affecting several pathways resulting in lowering triglycerides and increasing high-density lipoprotein (HDL).[30]
Both pravastatin and atorvastatin act by inhibiting hydroxymethylglutaryl-CoA reductase, a key step in cholesterol metabolism, and showed an improvement in aminotransferases and, as expected, in the lipid panels.[31,32] The use of statins raises concerns for hepatotoxicity, but this was not seen with standard doses used in the study.[33]
Antioxidants. Vitamins E and C are mentioned above.
Betaine is a metabolite of choline that assists with the synthesis of S-adenosylmethionine, which is a powerful antioxidant. It has been studied in a small trial and showed improvements in liver biochemistries and histology.[34]
Tumor necrosis factor (TNF)-α is a pro-inflammatory mediator and plays a distinct role in hepatocyte inflammation and cell death. Pentoxifylline is a TNF-α inhibitor and has shown improvement in transaminases and insulin resistance; nausea was also a significant concern.[35]
Ursodeoxycholic acid (UDCA) is a cytoprotective medication tried by Lindor and coworkers[36] and did not reveal any significant benefits in a double-blind, placebo-controlled trial.
Others. Animal studies have demonstrated a marked decrease in hepatic fibrosis and stellate cell activation with inhibition of renin-angiotensin system. Stellate cells are important in the pathogenesis of liver fibrosis. Losartan has been studied in patients with NASH and hypertension and has shown improvements in markers of fibrosis.[37]
Conclusion
In summary, NASH is poised to become the leading cause of liver failure and continues to be the source of much discussion regarding the etiopathogenesis. Though many medicines have been evaluated closely and more are being researched, there are no uniform guidelines for treatment. The main focus of treatment still involves weight loss, and modifying risks such as insulin resistance.
References
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2.Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960–967.
3.Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2003;124:71–79.
4.Ekstedt M, Franzén L, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865–873.
5.Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis 2007;11:75–104, ix.
6.Ryan MW, Harrison SA, Neuschwander-Tetri BA. Serum amyloid A and C-reactive protein diminish after treatment of NASH with rosiglitazone (abstract). Gastroenterology 2003;124:A747.
7.Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000;343:1467–1476.
8.Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C in the treatment of nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98:2485–2490.
9.Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003;37:909–916.
10.Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001;21:089–104.
11.Ikejima K, Takei Y, Honda H, et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 2002;122:1399–1410.
12.Jonsson JR, Clouston AD, Ando Y, et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001;121:148–155.
13.Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74–80.
14.Falck-Ytter Y, Younossi ZM, Marchesini G, et al. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001;21:17–26.
15.Oh MK, Winn J, Poordad F. Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;28:503–522.
16.Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846–854.
17.Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–1362.
18.Gressner AM, Gao CF, Gressner OA. Non-invasive biomarkers for monitoring the fibrogenic process in liver: a short survey. World J Gastroenterol 2009;15:2433–2440.
19.Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3–20.
20.Ratziu V, Charlotte F, Heurtier A, et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898–1906.
21.Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–750.
22.Dixon JB, Bhathal PS, Hughes NR, et al. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 2004;39:1647–1654.
23.Sabuncu T, Nazligul Y, Karaoglanoglu M, et al. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol 2003;12:189–192.
24.Lavine, JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000;136:734–738.
25.Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004;2:1107–1115.
26.Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537–544.
27.Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082–1090.
28.Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;38:1008–1017.
29.Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297–2307.
30.Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999;31:384.
31.Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193–196.
32.Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, et al. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006;23:1643–1647.
33.Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;41:690–695.
34.Abdelmalek MF, Angulo P, Jorgensen RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001;96:2711–2717.
35.Adams LA, Zein CO, Angulo P, et al. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365–2368.
36.Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464–1467.
37.Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004;40:1222–1225.
Source
Lakshmi Pasumarthy, MD, FACP; James Srour, MD
Posted: 08/05/2010; South Med J. 2010;103(6):547-550. © 2010 Lippincott Williams & Wilkins
Abstract and Introduction
Abstract
Nonalcoholic steatohepatitis is a common cause of liver inflammation and is associated with obesity, insulin resistance, and hyperlipidemia. There are concerns that it may turn out to be the most common cause of liver failure as prevalence of obesity increases. It leads to increased morbidity and mortality. Other causes of liver inflammation, especially alcoholic liver disease, must be ruled out. The diagnosis is suggested by abnormalities in the blood work and metabolic panel in an obese patient. Despite advances made in our understanding regarding the pathogenesis and trials with multiple drugs targeting mechanisms in pathogenesis, there are no consistent guidelines regarding treatment. However, multiple sources advocate weight reduction, optimum blood glucose control, and elimination of medications that cause fatty infiltration. The purpose of our article is to detail advances made in identifying disease mechanisms and treatment modalities, including surgery to promote weight loss.
Introduction
Fatty infiltration of the liver was described a long time ago and was initially felt to be linked with alcohol-related liver damage. The term nonalcoholic steatohepatitis (NASH) was introduced by Ludwig in 1980 and recognized in the absence of alcohol intake.[1] In the 1990s the incidence of nonalcoholic fatty liver disease (NAFLD) began to increase, paralleling the increase in obesity rates, and it is now recognized widely. The entity includes NAFLD which presents with simple steatosis, NASH, and cirrhosis. It is the most common cause of chronic liver disease. The estimated prevalence of NAFLD and NASH is 20–30% and 3.5–5%, respectively.[2] There is a higher prevalence of NASH in Mexican-Americans compared with non-Hispanic whites, even after controlling for obesity and body fat distribution.[3] The importance of NASH becomes more apparent when reviewing available data, which shows that 10–15% of patients with histologically proven NASH progress to cirrhosis and its complications such as liver failure and hepatocellular carcinoma. Furthermore, patients with NASH have lower survival rates.[4] Unfortunately, even though the prevalence of NASH threatens to increase, there are no approved medications for its treatment. There are many medications being evaluated currently, many targeting different steps in the development of hepatic steatosis or its progression to steatohepatitis. The laboratory and histologic profile of NASH and alcoholic liver disease are very similar. Distinction should be made carefully, since the treatment and prognosis are quite different.
Pathogenesis
The "two hit" hypothesis is a commonly described pathway by which fatty liver progresses to nonalcoholic steatohepatitis (NASH). The first hit involves macrovesiclular steatosis due to increased hepatic lipid synthesis and reduced transfer of lipids from the liver. Though insulin resistance plays an important role in this process, once the steatosis develops, it frequently worsens the insulin resistance and triggers a vicious cycle.[5] The role of insulin resistance in the pathogenesis of this disease is supported by pilot studies demonstrating beneficial effects of glucose-sensitizing medications in patients with NASH. Receptors in the cell nucleus that are involved in triggering the effects of insulin may fail, thus leading to insulin resistance, hepatic inflammation, and, ultimately, hepatic scarring. Treatment with rosiglitazone reduces the expression of hepatic acute phase reactants (C-reactive protein and serum amyloid A), suggesting that improvements in insulin sensitivity correspond with a reduction in inflammation.[6]
The second hit occurs due to increased hepatic oxidative stress, perhaps arising from increased free fatty acid metabolism, decreased antioxidant activity, increased activity of mitochondrial uncoupling proteins, and/or increased endotoxin levels in the liver. Oxidative stresses—mainly as a consequence of mitochondrial dysfunction—and proinflammatory cytokines are thought to play a central role in the progression from simple steatosis to steatohepatitis and cirrhosis.[7]
Accumulating evidence supports the role of antioxidants in preventing oxidative liver injury. In a study by Harrison et al,[8] a 6-month course of combination therapy with vitamin E and vitamin C resulted in significant histologic improvement. In another study, dietary intake of antioxidant vitamins was significantly lower in patients with NASH compared with controls matched for age and body mass index.[9] Genetic causes of increased fatty acid input promote excessive hepatic lipogenesis. These include mutations that cause leptin deficiency or leptin receptor inhibition and mutations that induce insulin, insulin-like growth factors, or insulin-responsive transcription factors.[10] Leptin signals "fullness" postprandially and also promotes insulin sensitivity. Despite elevated plasma levels of leptin, patients with NASH often do not experience normal satiety, and they also have insulin resistance. Thus, hyperinsulinemia and defective leptin signaling are conspicuous at early stages of NASH. It has also been shown that leptin is clearly related to stellate cell activation.[11] Inflammation of hepatocytes causes activation of hepatic stellate cells which are important in the pathogenesis of fibrosis. Increased levels of insulin cause upregulation of fibrogenic growth factor secreted by the hepatic stellate cells.
There is evidence to support the hypothesis that angiotensin II promotes activation, and dedifferentiation of the stellate cells into myofibroblasts. Furthermore, angiotensin II encourages myofibroblast contraction and proliferation and promotes release of inflammatory cytokines as well as the deposition of extracellular matrix.[12]
Presentation
Type 2 diabetes, insulin resistance, central obesity, and dyslipidemia are risk factors associated with development of NASH.[13] Initially, most patients with NASH are asymptomatic and present with abnormal liver tests obtained after routine screening. Rarely patients present with symptoms such as fatigue and nonspecific right upper quadrant pain. A careful history to exclude significant alcohol intake is extremely important.[14] This is defined as more than two alcoholic drinks a day for a male (20 gm/day) and more than one alcoholic drink a day for a female (10 gm/day). Fatty infiltration is also found in the context of other liver disorders, therefore it is important to go through the differential diagnoses. Finally, it is important to review the patient's medication list including over the counter medications, herbal remedies, and vitamin supplements. Many drugs can precipitate or exacerbate steatohepatitis in the presence of other risk factors.
As the fibrosis advances, the patients present with the typical manifestations of cirrhosis such as spider telangiectasiae, ascites, ankle edema, and easy bruising. It has been proposed that what was once classified as cryptogenic cirrhosis was probably underrecognized "burned out" NASH.
Diagnosis
The diagnosis of NAFLD is suspected in patients with elevated aminotransferases and evidence of the metabolic syndrome, although the levels fluctuate and patients may have normal enzyme levels on several occasions. The distinction between NASH and simple steatosis cannot reliably be made without liver biopsy, but this is not practical as a population-based approach.[15]
A multivariable model that included age, body mass index, platelet count, albumin, and aspartate aminotransferase/alanine transaminase (AST/ALT) ratio had good discriminant ability to identify individuals with advanced fibrosis in a study of 733 patients.[16] In addition, the diagnosis is suggested by ruling out other causes of elevated liver enzymes coupled with the patient's metabolic profile.
In NAFLD, the alanine aminotransferase (ALT) is initially greater than the aspartate aminotransferase (AST), and the trend is found reversing with onset of cirrhosis.[17] Transaminase values are usually increased less than fourfold, though normal values do not exclude the diagnosis. These values correlate poorly with the severity of underlying liver disease. Interest has been generated by SteatoTest for the diagnosis of hepatic steatosis and by NashTest for the diagnosis of NASH. These tests utilize noninvasive biomarkers such as gamma glutamyl-transferase (GGTP), total bilirubin, haptoglobin, α2-macroglobulin, and apolipoprotein A1. However, these are still not recommended in routine clinical practice.[18]
There is no single pathognomonic histological lesion in NASH and, instead, the disease presents with a constellation of findings. Three histological lesions are necessary for the diagnosis of NASH: zone 3 macrosteatosis, hepatocyte ballooning, and mixed lobular inflammation. Other findings that are common, but not necessary, include mild-moderate portal inflammation, acidophil bodies, glycogenated nuclei, periodic acid stain after diastase Kupffer cells, lipogranulomas and perisinusoidal zone 3 fibrosis, and Mallory hyaline in hepatocytes and megamitochondria.[19] A liver biopsy yields a very small sample of the liver and may not accurately reflect the extent or diagnosis because the histological lesions of NASH are unevenly distributed throughout the liver parenchyma.[20]
Noninvasive radiologic modalities like ultrasound (US), computerized tomography (CT) and magnetic resonance imaging (MRI) are sensitive in diagnosing steatosis but they are not able to differentiate the nonprogressive form of NAFLD from fibrosis.[21] CT and US are very sensitive only when there is more than 33% fat in the hepatic parenchyma.
Treatment
Nonpharmacologic
Factors that increase hepatic oxidative stress promote progression from hepatic steatosis to steatohepatitis. Avoidance of alcohol, weight loss, a low-fat diet, exercise, and tight glycemic control of diabetes help inhibit disease progression.
Weight loss as achieved through diet and exercise should be gradual, aiming for no more than 2 lbs of weight loss per week. Weight loss and exercise help improve insulin resistance. Exercise can also improve muscular insulin sensitivity, which may improve the impact of insulin resistance on NASH.
Though weight loss is rapid, bariatric surgery for morbid obesity does help NASH significantly. For example, Dixon et al showed that NASH resolved in 82% of patients undergoing laparoscopic adjustable gastric banding after losing approximately 40 kg. Patients who had metabolic syndrome showed a greater improvement in steatosis, necroinflammation, and fibrosis with weight loss showcasing the fact that improvements in several components of metabolic syndrome are expected to have a beneficial impact on the liver disease. This is probably because of the decrease in cytokines and chronic inflammation associated with obesity.[22]
Pharmacologic
Orlistat/Sibutramine. A clinical trial using orlistat showed a mean decrease in body weight of 10.3 kg and significant reductions in serum transaminase levels in obese patients with NASH. A 6-month pilot study of sibutramine reported weight loss, improved insulin resistance, and biochemical profiles.[23]
Vitamins. Some hepatologists utilize vitamin E based on trials in which decrements in ALT were demonstrated either with vitamin E alone or in combination with pioglitazone or with vitamin C.[8,24,25] However, given more recent concerns related to an increase in mortality with vitamin E supplementation and the weak evidence supporting its benefit in NASH, vitamin E is not advocated strongly.
Medications Addressing Insulin Resistance. Metformin and thiazolidinediones are insulin sensitizing and work by decreasing insulin resistance. Since this issue is closely associated with the pathogenesis of NASH, much interest and work has been devoted to these medications.
Metformin acts by decreasing hepatic glucose production and increasing peripheral glucose uptake by muscles. Metformin can also increase fatty acid oxidation and suppress lipogenesis. Trials involving lipid and calorie-restricted diet with or without metformin for six months[26] showed decreased aminotransferase levels, insulin, and C-peptide levels to a significantly greater extent in the metformin group. In another randomized trial, metformin alone resulted in normalization of aminotransferases as compared with vitamin E and weight loss. Despite some gastrointestinal intolerance, metformin was well tolerated. On the other hand, though biochemical improvement was shown, histological data remain very limited. It must be avoided in patients with congestive heart failure and renal insufficiency.[27]
Thiazolidinediones reduce insulin resistance by acting on peroxisome proliferator-activated receptors (PPAR)—gamma in adipose tissue. Both pioglitazone and rosiglitazone have been studied and demonsrated improvements in transaminases and liver histology in multiple studies[28,29] Concerns for cardiovascular effects, congestive heart failure and weight gain have limited their long term use. Nateglinide, muraglitazar, and rimonabant have helped with weight loss in the obese but data to support their use for NASH are limited.
Lipid Lowering Medications. Both fibrates and statins have been studied for treatment of NASH since hyperlipidemia is one of the components of metabolic syndrome. Gemfibrozil has shown an improvement in aminotransferases in a trial, though no other fibrate has replicated this result. Fibrates have a complex mechanism of action affecting several pathways resulting in lowering triglycerides and increasing high-density lipoprotein (HDL).[30]
Both pravastatin and atorvastatin act by inhibiting hydroxymethylglutaryl-CoA reductase, a key step in cholesterol metabolism, and showed an improvement in aminotransferases and, as expected, in the lipid panels.[31,32] The use of statins raises concerns for hepatotoxicity, but this was not seen with standard doses used in the study.[33]
Antioxidants. Vitamins E and C are mentioned above.
Betaine is a metabolite of choline that assists with the synthesis of S-adenosylmethionine, which is a powerful antioxidant. It has been studied in a small trial and showed improvements in liver biochemistries and histology.[34]
Tumor necrosis factor (TNF)-α is a pro-inflammatory mediator and plays a distinct role in hepatocyte inflammation and cell death. Pentoxifylline is a TNF-α inhibitor and has shown improvement in transaminases and insulin resistance; nausea was also a significant concern.[35]
Ursodeoxycholic acid (UDCA) is a cytoprotective medication tried by Lindor and coworkers[36] and did not reveal any significant benefits in a double-blind, placebo-controlled trial.
Others. Animal studies have demonstrated a marked decrease in hepatic fibrosis and stellate cell activation with inhibition of renin-angiotensin system. Stellate cells are important in the pathogenesis of liver fibrosis. Losartan has been studied in patients with NASH and hypertension and has shown improvements in markers of fibrosis.[37]
Conclusion
In summary, NASH is poised to become the leading cause of liver failure and continues to be the source of much discussion regarding the etiopathogenesis. Though many medicines have been evaluated closely and more are being researched, there are no uniform guidelines for treatment. The main focus of treatment still involves weight loss, and modifying risks such as insulin resistance.
References
1.Ludwig J, Viggiano TR, McGill DB, et al. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434–438.
2.Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003;98:960–967.
3.Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2003;124:71–79.
4.Ekstedt M, Franzén L, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:865–873.
5.Edmison J, McCullough AJ. Pathogenesis of non-alcoholic steatohepatitis: human data. Clin Liver Dis 2007;11:75–104, ix.
6.Ryan MW, Harrison SA, Neuschwander-Tetri BA. Serum amyloid A and C-reactive protein diminish after treatment of NASH with rosiglitazone (abstract). Gastroenterology 2003;124:A747.
7.Tilg H, Diehl AM. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000;343:1467–1476.
8.Harrison SA, Torgerson S, Hayashi P, et al. Vitamin E and vitamin C in the treatment of nonalcoholic steatohepatitis. Am J Gastroenterol 2003;98:2485–2490.
9.Musso G, Gambino R, De Michieli F, et al. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 2003;37:909–916.
10.Koteish A, Diehl AM. Animal models of steatosis. Semin Liver Dis 2001;21:089–104.
11.Ikejima K, Takei Y, Honda H, et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 2002;122:1399–1410.
12.Jonsson JR, Clouston AD, Ando Y, et al. Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 2001;121:148–155.
13.Powell EE, Cooksley WG, Hanson R, et al. The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years. Hepatology 1990;11:74–80.
14.Falck-Ytter Y, Younossi ZM, Marchesini G, et al. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis 2001;21:17–26.
15.Oh MK, Winn J, Poordad F. Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2008;28:503–522.
16.Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45:846–854.
17.Angulo P, Keach JC, Batts KP, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology 1999;30:1356–1362.
18.Gressner AM, Gao CF, Gressner OA. Non-invasive biomarkers for monitoring the fibrogenic process in liver: a short survey. World J Gastroenterol 2009;15:2433–2440.
19.Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis 2004;24:3–20.
20.Ratziu V, Charlotte F, Heurtier A, et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128:1898–1906.
21.Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology 2002;123:745–750.
22.Dixon JB, Bhathal PS, Hughes NR, et al. Nonalcoholic fatty liver disease: improvement in liver histological analysis with weight loss. Hepatology 2004;39:1647–1654.
23.Sabuncu T, Nazligul Y, Karaoglanoglu M, et al. The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Rom J Gastroenterol 2003;12:189–192.
24.Lavine, JE. Vitamin E treatment of nonalcoholic steatohepatitis in children: a pilot study. J Pediatr 2000;136:734–738.
25.Sanyal AJ, Mofrad PS, Contos MJ, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol 2004;2:1107–1115.
26.Uygun A, Kadayifci A, Isik AT, et al. Metformin in the treatment of patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2004;19:537–544.
27.Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol 2005;100:1082–1090.
28.Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, et al. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 2003;38:1008–1017.
29.Belfort R, Harrison SA, Brown K, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355:2297–2307.
30.Basaranoglu M, Acbay O, Sonsuz A. A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J Hepatol 1999;31:384.
31.Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174:193–196.
32.Gómez-Domínguez E, Gisbert JP, Moreno-Monteagudo JA, et al. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther 2006;23:1643–1647.
33.Chalasani N. Statins and hepatotoxicity: focus on patients with fatty liver. Hepatology 2005;41:690–695.
34.Abdelmalek MF, Angulo P, Jorgensen RA, et al. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study. Am J Gastroenterol 2001;96:2711–2717.
35.Adams LA, Zein CO, Angulo P, et al. A pilot trial of pentoxifylline in nonalcoholic steatohepatitis. Am J Gastroenterol 2004;99:2365–2368.
36.Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 1996;23:1464–1467.
37.Yokohama S, Yoneda M, Haneda M, et al. Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis. Hepatology 2004;40:1222–1225.
Source
OraSure delays filing for oral version of hep C test
CORRECTED - UPDATE 1-OraSure delays filing for oral version of hep C test
Wed Aug 4, 2010 7:50pm EDT
(Corrects paragraphs two and six to OraQuick HCV instead of OraQuick)
* Says filing for oral version of HCV test delayed
* Says FDA commented on lower sensitivity of tests
* Q2 loss/shr $0.01 vs. est loss/shr $0.07
* Q2 rev $19.2 mln vs. est $17.5 mln
Aug 4 (Reuters) - OraSure Technologies Inc (OSUR.O) said it has delayed the filing of a new version of its recently approved hepatitis C virus test after the U.S. health regulator commented on its lower sensitivity.
The primary comments from regulators were related to the lower sensitivity of the oral fluid and fingerstick whole blood versions of the test, OraQuick HCV, compared to the venous whole blood version, which is already on the market.
The company said, based on the comments it has decided to separate the filing for the two claims.
A supplemental application for the fingerstick version was recently sent to the regulator, OraSure said, adding that the filing for the oral fluid has been delayed pending additional discussions with the U.S. Food and Drug Administration.
The company also said it is likely that more clinical data will be needed to support an oral fluid application for the test.
Marketing approval of the test in June had raised hopes of OraQuick HCV getting the nod for multiple specimen types such as oral fluid and fingerstick whole blood sample types. [ID:nSGE65O0GB]
OraSure also posted a narrower-than-expected quarterly loss on higher sales and early receipt of a milestone payment from its partner Merck & Co (MRK.N). [ID:nWNAB3728]
Shares of the company closed at $4.45 Wednesday on Nasdaq. (Reporting by Krishnakali Sengupta in Bangalore; Editing by Unnikrishnan Nair)
Source
Wed Aug 4, 2010 7:50pm EDT
(Corrects paragraphs two and six to OraQuick HCV instead of OraQuick)
* Says filing for oral version of HCV test delayed
* Says FDA commented on lower sensitivity of tests
* Q2 loss/shr $0.01 vs. est loss/shr $0.07
* Q2 rev $19.2 mln vs. est $17.5 mln
Aug 4 (Reuters) - OraSure Technologies Inc (OSUR.O) said it has delayed the filing of a new version of its recently approved hepatitis C virus test after the U.S. health regulator commented on its lower sensitivity.
The primary comments from regulators were related to the lower sensitivity of the oral fluid and fingerstick whole blood versions of the test, OraQuick HCV, compared to the venous whole blood version, which is already on the market.
The company said, based on the comments it has decided to separate the filing for the two claims.
A supplemental application for the fingerstick version was recently sent to the regulator, OraSure said, adding that the filing for the oral fluid has been delayed pending additional discussions with the U.S. Food and Drug Administration.
The company also said it is likely that more clinical data will be needed to support an oral fluid application for the test.
Marketing approval of the test in June had raised hopes of OraQuick HCV getting the nod for multiple specimen types such as oral fluid and fingerstick whole blood sample types. [ID:nSGE65O0GB]
OraSure also posted a narrower-than-expected quarterly loss on higher sales and early receipt of a milestone payment from its partner Merck & Co (MRK.N). [ID:nWNAB3728]
Shares of the company closed at $4.45 Wednesday on Nasdaq. (Reporting by Krishnakali Sengupta in Bangalore; Editing by Unnikrishnan Nair)
Source
Kerry Introduces Bill to Fight Viral Hepatitis
For Immediate Release: Thursday, August 5, 2010
CONTACT: DC Press Office, (202) 224-4159
WASHINGTON, D.C. – Senator John Kerry (D-Mass.), today introduced the Viral Hepatitis and Liver Cancer Control and Prevention Act of 2010, which calls for a national strategy to prevent and control Hepatitis B and C. Congressman Mike Honda (D-CA) is the legislation’s lead sponsor in the House of Representatives. The bill has been endorsed by over 100 hepatitis focused organizations from across the nation.
“Viral hepatitis is a silent killer,” Senator Kerry said. “Most people don’t even know they have hepatitis until it causes liver damage or even cancer years after the initial infection. We can easily avoid these needless tragedies with prevention, surveillance programs, and by educating Americans about this deadly disease. The bill I’m introducing today will help create a national strategy to combat and prevent hepatitis, hopefully ending this silent affliction’s often deadly consequences.”
Viral Hepatitis contributes to the death of 15,000 Americans a year and threatens the health of 5.3 million more. It is more common than HIV/AIDS and is the leading cause of liver cancer. Most people don’t know they have hepatitis until it causes cancer or liver disease years after infection. This is largely because there is currently no federal funding of core public health services for viral hepatitis. Nor is there any federally funded chronic Hepatitis B and C surveillance system.
The Viral Hepatitis and Liver Cancer Control and Prevention Act aims to correct this by authorizing nearly $600 million over the next five years to fund a national strategy to prevent and control viral hepatitis. It directs the Secretary of Health and Human Services to develop a national plan for the prevention, control and medical management of viral hepatitis in coordination with the Centers for Disease Control and Prevention (CDC), the National Institutes for Health (NIH), the National Cancer Institute (NCI), the Health Resources and Services Administration (HRSA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Agency for Healthcare Research and Quality (AHRQ) and the Department of Veterans Affairs (VA).
The legislation requires the development of a national plan that must include the following components:
• education and awareness programs;
• an expansion of current vaccination programs;
• counseling regarding the ongoing risk factors associated with viral hepatitis;
• support for medical evaluation and ongoing medical management;
• increased support for adult viral hepatitis coordinators; and
• the establishment of an epidemiological surveillance program to identify trends in incidence and prevalence in the disease.
The Viral Hepatitis and Liver Cancer Control and Prevention Act of 2010 also enhances SAMHSA’s role in hepatitis activities by providing the agency with the authority to develop educational materials and intervention strategies to reduce the risks of hepatitis among substance abusers and individuals with mental illness.
Source
CONTACT: DC Press Office, (202) 224-4159
WASHINGTON, D.C. – Senator John Kerry (D-Mass.), today introduced the Viral Hepatitis and Liver Cancer Control and Prevention Act of 2010, which calls for a national strategy to prevent and control Hepatitis B and C. Congressman Mike Honda (D-CA) is the legislation’s lead sponsor in the House of Representatives. The bill has been endorsed by over 100 hepatitis focused organizations from across the nation.
“Viral hepatitis is a silent killer,” Senator Kerry said. “Most people don’t even know they have hepatitis until it causes liver damage or even cancer years after the initial infection. We can easily avoid these needless tragedies with prevention, surveillance programs, and by educating Americans about this deadly disease. The bill I’m introducing today will help create a national strategy to combat and prevent hepatitis, hopefully ending this silent affliction’s often deadly consequences.”
Viral Hepatitis contributes to the death of 15,000 Americans a year and threatens the health of 5.3 million more. It is more common than HIV/AIDS and is the leading cause of liver cancer. Most people don’t know they have hepatitis until it causes cancer or liver disease years after infection. This is largely because there is currently no federal funding of core public health services for viral hepatitis. Nor is there any federally funded chronic Hepatitis B and C surveillance system.
The Viral Hepatitis and Liver Cancer Control and Prevention Act aims to correct this by authorizing nearly $600 million over the next five years to fund a national strategy to prevent and control viral hepatitis. It directs the Secretary of Health and Human Services to develop a national plan for the prevention, control and medical management of viral hepatitis in coordination with the Centers for Disease Control and Prevention (CDC), the National Institutes for Health (NIH), the National Cancer Institute (NCI), the Health Resources and Services Administration (HRSA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Agency for Healthcare Research and Quality (AHRQ) and the Department of Veterans Affairs (VA).
The legislation requires the development of a national plan that must include the following components:
• education and awareness programs;
• an expansion of current vaccination programs;
• counseling regarding the ongoing risk factors associated with viral hepatitis;
• support for medical evaluation and ongoing medical management;
• increased support for adult viral hepatitis coordinators; and
• the establishment of an epidemiological surveillance program to identify trends in incidence and prevalence in the disease.
The Viral Hepatitis and Liver Cancer Control and Prevention Act of 2010 also enhances SAMHSA’s role in hepatitis activities by providing the agency with the authority to develop educational materials and intervention strategies to reduce the risks of hepatitis among substance abusers and individuals with mental illness.
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