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Puoti C, Elmo MG, Ceccarelli D, Ditrinco M. Liver steatosis: The new epidemic of the Third Millennium. Benign liver state or silent killer? Eur J Intern Med 2017; 46:1-5. [PMID: 28688543 DOI: 10.1016/j.ejim.2017.06.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Accepted: 06/29/2017] [Indexed: 12/15/2022]
Abstract
Until the end of the 90's of the last century, rather little attention was paid to the issue of the non-alcoholic fatty liver disease (NAFLD), perhaps due to the fact that the newly discovered hepatitis C virus did attract a paramount interest of hepatologists and researchers. On the other side, fatty liver was considered a relatively uncommon cause of liver damage, occurring almost exclusively in obese females, often associated with non-insulin dependent diabetes mellitus (NIDDM), and with a relatively benign prognosis. Due to the complexity of international available guidelines, we decide to approach the main unsolved issues on this topic in the form of a dialog between a hepatologist and a man suffering from NAFLD, trying to give evidence-based answers to the more frequently asked questions from patients and their GPs. This is the third instalment of the Trilogy of Dr. Calm, a skilled hepatologist who will try to clearly explain to his patient Mr. Frightened the natural history of NAFLD, the diagnostic workup, indications for liver biopsy and suggested medical treatments, advicing him on the importance of dietary intervention and lifestyle modifications.
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Affiliation(s)
- Claudio Puoti
- Liver Unit, INI Research Institute and Clinics, Grottaferrata, Rome, Italy; N. Cusano University, Rome, Italy.
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Omata M, Kanda T, Wei L, Yu ML, Chuang WL, Ibrahim A, Lesmana CRA, Sollano J, Kumar M, Jindal A, Sharma BC, Hamid SS, Dokmeci AK, Al-Mahtab M, McCaughan GW, Wasim J, Crawford DHG, Kao JH, Yokosuka O, Lau GKK, Sarin SK. APASL consensus statements and recommendations for hepatitis C prevention, epidemiology, and laboratory testing. Hepatol Int 2016; 10:681-701. [PMID: 27229718 PMCID: PMC5003900 DOI: 10.1007/s12072-016-9736-3] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023]
Abstract
The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on "APASL consensus statements and recommendations for management of hepatitis C" in March 2015 to revise the "APASL consensus statements and management algorithms for hepatitis C virus infection" (Hepatol Int 6:409-435, 2012). The working party consisted of expert hepatologists from the Asian-Pacific region gathered at the Istanbul Congress Center, Istanbul, Turkey on 13 March 2015. New data were presented, discussed, and debated during the course of drafting a revision. Participants of the consensus meeting assessed the quality of the cited studies. The finalized recommendations for hepatitis C prevention, epidemiology, and laboratory testing are presented in this review.
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Affiliation(s)
- Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan.
- The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Tatsuo Kanda
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Lai Wei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing, China
| | - Ming-Lung Yu
- Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
| | - Wang-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Alaaeldin Ibrahim
- GI/Liver Division, Department of Internal Medicine, University of Benha, Banha, Egypt
| | | | - Jose Sollano
- University Santo Tomas Hospital, Manila, Philippines
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Saeed S Hamid
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Mamun Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh
| | - Geofferey W McCaughan
- Royal Prince Alfred Hospital, Centenary Institute, University of Sydney, Sydney, Australia
| | - Jafri Wasim
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Darrell H G Crawford
- University of Queensland, School of Medicine, Woolloongabba, QLD, 4102, Australia
| | - Jia-Horng Kao
- National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan
| | - Osamu Yokosuka
- Graduate School of Medicine, Chiba University, Chiba, Japan
| | - George K K Lau
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Szereday L, Meggyes M, Halasz M, Szekeres-Bartho J, Par A, Par G. Immunological changes in different patient populations with chronic hepatitis C virus infection. World J Gastroenterol 2016; 22:4848-4859. [PMID: 27239111 PMCID: PMC4873877 DOI: 10.3748/wjg.v22.i20.4848] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/05/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate killer inhibitory and activating receptor expression by natural killer (NK), natural killer T-like (NKT-like) and CD8+ T lymphocytes in patients with chronic hepatitis C virus (HCV) infection with elevated and with persistently normal alanine aminotransferase (PNALT).
METHODS: The percentage of peripheral blood Treg cells, KIR2DL3, ILT-2, KIR3DL1, CD160, NKG2D, NKG2C expressing NK, T and NKT-like cells, cytokine production and NK cytotoxicity were determined by flow cytometry. Twenty-one patients with chronic HCV infection with elevated alanine aminotransferase, 11 HCV carriers with persistently normal alanine aminotransferase and 15 healthy volunteers were enrolled.
RESULTS: No significant differences were observed in the percentage of total T, NK or NKT-like cells between study groups. Comparing the activating and inhibitory receptor expression by NK cells obtained from HCV carriers with PNALT and chronic HCV hepatitis patients with elevated alanine aminotransferase, NKG2D activating receptor expression was the only receptor showing a significant difference. NKG2D expression of NK cells was significantly lower in patients with elevated alanine aminotransferase. The expression of CD160, NKG2D and NKG2C activating receptor by CD8+ T cells were significantly lower in patients with chronic HCV hepatitis than in healthy controls and in HCV carriers with PNALT. Plasma TGF-β1 levels inversely correlated with NKG2D expression by NK cells. In vitroTGF-β1 treatment inhibited NK cells cytotoxic activity and downregulated NKG2D expression. CD8+ T cells from HCV carriers with PNALT showed significantly elevated expression of CD160, NKG2D and NKG2C activating receptors compared to chronic HCV patients with elevated alanine aminotransferase. Enhanced expression of inhibitory KIR2DL3 receptor, and decreased ILT-2 expression on NK cells were also found in chronic hepatitis C patients compared to healthy controls.
CONCLUSION: Our study demonstrated a complex dysregulation of activating and inhibitory receptor expression, such as decreased NKG2D and CD160 activating receptor expression and increased KIR2DL3 inhibitory receptor expression by NK and cytotoxic T cells and may provide further mechanism contributing to defective cellular immune functions in chronic hepatitis C. Increased NKG2D receptor expression in HCV patients with persistently normal ALT suggests an important pathway for sustaining NK and CD8 T cell function and a protective role against disease progression.
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Jin YJ, Shim JH, Kim GA, Yu E, Kim KM, Lim YS, Lee HC. Clinicobiochemical prediction of biopsy-proven cases of severe hepatic fibrosis in patients with chronic hepatitis C infection. BMJ Open 2014; 4:e006255. [PMID: 25431223 PMCID: PMC4248083 DOI: 10.1136/bmjopen-2014-006255] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To evaluate clinicobiochemical factors predicting severe hepatic fibrosis in patients with chronic hepatitis C virus (HCV) infection. SETTING Tertiary institution. PARTICIPANTS 859 treatment-naïve Korean patients with HCV who underwent liver biopsy. Severe fibrosis was defined as fibrosis stage ≥3 based on the METAVIR system. PRIMARY OUTCOME MEASURES Clinicobiochemical factors predicting severe hepatic fibrosis. RESULTS The median serum alanine aminotransferase (ALT) level was 68 IU/L and body mass index (BMI) was 24.2 kg/m(2). Severe fibrosis was observed in 326 (39.7%) of the 859 patients. The frequencies of severe fibrosis were 0%, 37.8%, 41.9% and 42% in patients with serum ALT concentrations (IU/L) of ≤20, 20-30, 30-40 and >40 (p<0.01), respectively, and 10.7%, 19.8%, 30.5%, 39.2% and 55.6% in patients <30, 30-40, 40-50, 50-60 and ≥60 years old, respectively (p<0.01). Categorised age in years (50-60 (OR 4.26, p=0.03) and ≥60 (OR 7.53, p<0.01) compared with <30), categorised ALT level in IU/L (20-30 (OR 16.76, p<0.01), 30-40 (OR 20.02, p<0.01) and >40 (OR 21.49, p<0.01) compared with ≤20) and BMI >27.5 kg/m(2) (OR 1.65, p=0.03) were independently related to severe fibrosis in patients with chronic HCV. The severe fibrosis rate was 60.6% in patients aged ≥50 years with ALT >20 IU/L and BMI >27.5 kg/m(2). CONCLUSIONS More advanced age (≥50 years), obesity and serum ALT>20 IU/L are associated with severe fibrosis in patients with chronic HCV. Anti-HCV therapy may be considered for these patients without histological confirmation, regardless of HCV genotype. A wait-and-see policy may be justified for patients with serum ALT ≤20 IU/L.
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Affiliation(s)
- Young-Joo Jin
- Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Liver Center, Asan Medical Center, Seoul, Republic of Korea
| | - Gi Ae Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Liver Center, Asan Medical Center, Seoul, Republic of Korea
| | - Eunsil Yu
- Department of Pathology, University of Ulsan College of Medicine, Asan Liver Center, Asan Medical Center, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Liver Center, Asan Medical Center, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Liver Center, Asan Medical Center, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Liver Center, Asan Medical Center, Seoul, Republic of Korea
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Puoti C, Bellis L, Costanza OM, Elmo MG. Liver disease progression in hepatitis C virus carriers with normal alanine aminotransferase levels. Hepatology 2014; 60:1448-9. [PMID: 24700090 DOI: 10.1002/hep.27052] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2013] [Accepted: 01/08/2014] [Indexed: 01/25/2023]
Affiliation(s)
- Claudio Puoti
- Department of Internal Medicine and Liver Unit, Marino General Hospital, Rome, Italy
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Histological and clinical characteristics of patients with chronic hepatitis C and persistently normal alanine aminotransferase levels. HEPATITIS RESEARCH AND TREATMENT 2014; 2014:760943. [PMID: 24891947 PMCID: PMC4033356 DOI: 10.1155/2014/760943] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 04/23/2014] [Accepted: 04/23/2014] [Indexed: 01/05/2023]
Abstract
Patients with chronic hepatitis C virus (HCV) infection and persistently normal alanine aminotransferase (PNALT) are generally described to have mild liver disease. The aim of this study was to compare clinical and histological features in HCV-infected patients with PNALT and elevated ALT. Patients presenting to the University of Illinois Medical Center, Chicago, who had biopsy proven HCV, an ALT measurement at the time of liver biopsy, at least one additional ALT measurement over the next 12 months, and liver biopsy slides available for review were identified. PNALT was defined as ALT ≤ 30 on at least 2 different occasions over 12 months. Of 1200 patients with HCV, 243 met the study criteria. 13% (32/243) of patients had PNALT while 87% (211/243) had elevated ALT. Significantly more patients with PNALT had advanced fibrosis (F3 and F4) compared to those with elevated ALT (P = 0.007). There was no significant difference in the histology activity index score as well as mean inflammatory score between the two groups. In conclusion, in a well-characterized cohort of patients at a tertiary medical center, PNALT did not distinguish patients with mild liver disease.
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7
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Vajro P, Maddaluno S, Veropalumbo C. Persistent hypertransaminasemia in asymptomatic children: A stepwise approach. World J Gastroenterol 2013; 19:2740-2751. [PMID: 23687411 PMCID: PMC3653148 DOI: 10.3748/wjg.v19.i18.2740] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Revised: 12/20/2012] [Accepted: 01/19/2013] [Indexed: 02/06/2023] Open
Abstract
We aimed to examine the major causes of isolated chronic hypertransaminasemia in asymptomatic children and develop a comprehensive diagnostic flow diagram. A MEDLINE search inclusive of publications throughout August 2012 was performed. We found only a small number of publications that had comprehensively investigated this topic. Consequently, it was difficult to construct a diagnostic flowchart similar to those already available for adults. In children, a “retesting panel” prescription, including gamma-glutamyl transpeptidase and creatine kinase in addition to aminotransferases, is considered a reasonable approach for proficiently confirming the persistence of the abnormality, ruling out cholestatic hepatopathies and myopathies, and guiding the subsequent diagnostic steps. If re-evaluation of physical and historical findings suggests specific etiologies, then these should be evaluated in the initial enzyme retesting panel. A simple multi-step diagnostic algorithm incorporating a large number of possible pediatric scenarios, in addition to the few common to adults, is available. Accurately classifying a child with asymptomatic persistent hypertransaminasemia may be a difficult task, but the results are critical for preventing the progression of an underlying, possibly occult, condition later in childhood or during transition. Given the high benefit/cost ratio of preventing hepatic deterioration, no effort should be spared in diagnosing and properly treating each case of persistent hypertransaminasemia in pediatric patients.
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Sinn DH, Gwak GY, Shin JU, Choi MS, Lee JH, Koh KC, Paik SW, Yoo BC. Disease progression in chronic hepatitis C patients with normal alanine aminotransferase levels. World J Gastroenterol 2013; 19:2256-2261. [PMID: 23599653 PMCID: PMC3627891 DOI: 10.3748/wjg.v19.i14.2256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2012] [Revised: 01/18/2013] [Accepted: 02/06/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether the disease progression of chronic hepatitis C patients with normal alanine aminotransferase (ALT) levels differs by ALT levels.
METHODS: A total of 232 chronic hepatitis C patients with normal ALT (< 40 IU/L) were analyzed. The patients were divided into “high-normal” and “low-normal”ALT groups after determining the best predictive cutoff level associated with disease progression for each gender. The incidence of disease progression, as defined by the occurrence of an increase of ≥ 2 points in the Child-Pugh score, spontaneous bacterial peritonitis, bleeding gastric or esophageal varices, hepatic encephalopathy, the development of hepatocellular carcinoma, or death related to liver disease, were compared between the two groups.
RESULTS: Baseline serum ALT levels were associated with disease progression for both genders. The best predictive cutoff baseline serum ALT level for disease progression was 26 IU/L in males and 23 IU/L in females. The mean annual disease progression rate was 1.2% and 3.9% for male patients with baseline ALT levels ≤ 25 IU/L (low-normal) and > 26 IU/L (high-normal), respectively (P = 0.043), and it was 1.4% and 4.8% for female patients with baseline ALT levels ≤ 22 IU/L (low-normal) and > 23 IU/L (high-normal), respectively (P = 0.023). ALT levels fluctuated during the follow-up period. During the follow-up, more patients with “high-normal” ALT levels at baseline experienced ALT elevation (> 41 IU/L) than did patients with “low-normal” ALT levels at baseline (47.7% vs 27.9%, P = 0.002). The 5 year cumulative incidence of disease progression was significantly lower in patients with persistently “low-normal” ALT levels than “high-normal” ALT levels or those who exhibited an ALT elevation > 41 U/L during the follow-up period (0%, 8.3% and 34.3%, P < 0.001).
CONCLUSION: A “high normal” ALT level in chronic hepatitis C patients was associated with disease progression, suggesting that the currently accepted normal threshold of serum ALT should be lowered.
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9
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Nunnari G, Pinzone MR, Cacopardo B. Lack of clinical and histological progression of chronic hepatitis C in individuals with true persistently normal ALT: the result of a 17-year follow-up. J Viral Hepat 2013; 20:e131-7. [PMID: 23490382 DOI: 10.1111/jvh.12029] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 09/01/2012] [Indexed: 12/28/2022]
Abstract
Thirty to 40% of patients with chronic hepatitis C have persistently normal alanine aminotransferase (PNALT). Even though traditionally considered as healthy people, most PNALT carriers actually have some degree of clinical progression and histological liver damage. We evaluated the clinical and histological outcome of a 17-year follow-up on a cohort of patients with chronic HCV infection and PNALT. Between 1994 and 2011, 70 PNALTs and 55 Hyper-alanine aminotransferase (ALT) subjects underwent a clinical, biochemical, virological and histological follow-up. At the end of the follow-up, all patients were alive. In the PNALT group, none of the patients developed hepatic decompensation, while 14.5% of Hyper-ALTs were diagnosed as affected by decompensated cirrhosis. No significant variation of the Metavir grading and staging scores was observed among PNALTs by comparing pre- and post-follow-up liver specimens. On the contrary, a significant increase in both Metavir grading and staging scores was noticed within the Hyper-ALT group. Finally, the analysis of IL28B single-nucleotide polymorphism rs12979860 revealed no difference between Hyper-ALTs and PNALTs in terms of frequency of C/C genotype. In conclusion, progression of chronic hepatitis C among PNALTs is slow or even absent, because at the end of the 17-year follow-up histological and clinical parameters had not worsened significantly.
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Affiliation(s)
- G Nunnari
- Division of Infectious Diseases, Department of Clinical and Molecular Biomedicine, University of Catania, Catania, Italy
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Puoti C. How to manage HBeAg-negative chronic HBV infection with normal alanine aminotransferase levels in clinical practice? Eur J Intern Med 2013; 24:100-3. [PMID: 23167981 DOI: 10.1016/j.ejim.2012.10.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2012] [Revised: 10/28/2012] [Accepted: 10/30/2012] [Indexed: 02/08/2023]
Abstract
Many HBsAg-positive/HBeAg-negative patients show normal alanine aminotransferase levels. However, in this group of patients two different virological and clinical subsets do exist: inactive HBV carriers and patients with chronic hepatitis B with transient virological and biochemical remission. Natural history and outcome, severity of liver damage and need for liver biopsy and antiviral treatment differ significantly between these groups of patients. It is not always easy to distinguish between inactive HBV carriers and patients suffering from HBeAg-negative chronic hepatitis with transient disease remission, as they share similar biochemical (normal serum ALT values) and virological (HBeAg negativity and low HBV DNA levels) features. In clinical practice, it is very important to differentiate inactive carriers from patients with chronic hepatitis B with spontaneous transient remission, as the former have a good prognosis with a very low risk of complications, while the latter have active liver disease with a high risk of progression to advanced hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Thus, a careful assessment and adequate follow-up periods are needed. The aim of this review, written in the form of a dialog between a hepatologist and a newly diagnosed patient with HBV infection and normal alanine aminotransferase levels, is to give evidence-based suggestions for the management in clinical practice of HBsAg patients, on the basis of more recent international guidelines, covering many aspects of the condition, including advice on lifestyle and vaccination, indications for liver biopsy and treatment, the types and side effects of treatment and treatment endpoints.
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Affiliation(s)
- Claudio Puoti
- Dept. of Internal Medicine and Liver Unit, Marino General Hospital, Rome, Italy.
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11
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Uehara T, Kosyk O, Jeannot E, Bradford BU, Tech K, Macdonald JM, Boorman GA, Chatterjee S, Mason RP, Melnyk SB, Tryndyak VP, Pogribny IP, Rusyn I. Acetaminophen-induced acute liver injury in HCV transgenic mice. Toxicol Appl Pharmacol 2012. [PMID: 23200774 DOI: 10.1016/j.taap.2012.11.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility.
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Affiliation(s)
- Takeki Uehara
- Department of Environmental Sciences & Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
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Coffin PO, Scott JD, Golden MR, Sullivan SD. Cost-effectiveness and population outcomes of general population screening for hepatitis C. Clin Infect Dis 2012; 54:1259-71. [PMID: 22412061 PMCID: PMC3404694 DOI: 10.1093/cid/cis011] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2011] [Accepted: 12/06/2011] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Current US guidelines recommend limiting hepatitis C virus (HCV) screening to high-risk individuals, and 50%-75% of infected persons remain unaware of their status. METHODS To estimate the cost-effectiveness and population-level impact of adding one-time HCV screening of US population aged 20-69 years to current guidelines, we developed a decision analytic model for the screening intervention and Markov model with annual transitions to estimate natural history. Subanalyses included protease inhibitor therapy and screening those at highest risk of infection (birth year 1945-1965). We relied on published literature and took a lifetime, societal perspective. RESULTS Compared to current guidelines, incremental cost per quality-adjusted life year gained (ICER) was $7900 for general population screening and $4200 for screening by birth year, which dominated general population screening if cost, clinician uptake, and median age of diagnoses were assumed equivalent. General population screening remained cost-effective in all one-way sensitivity analyses, 30 000 Monte Carlo simulations, and scenarios in which background mortality was doubled, all genotype 1 patients were treated with protease inhibitors, and most parameters were set unfavorable to increased screening. ICER was lowest if screening was applied to a population with liver fibrosis similar to 2010 estimates. Approximately 1% of liver-related deaths would be averted per 15% of the general population screened; the impact would be greater with improved referral, treatment uptake, and cure. CONCLUSIONS Broader screening for HCV would likely be cost-effective, but significantly reducing HCV-related morbidity and mortality would also require improved rates of referral, treatment, and cure.
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Affiliation(s)
- Phillip O Coffin
- Division of Allergy and Infectious Diseases, Department of Medicine, University of Washington, Seattle, WA 98104, USA.
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13
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Puoti C, Guarisco R, Spilabotti L, Bellis L, Mitidieri Costanza O, Dell' Unto O, Elmo MG. Should we treat HCV carriers with normal ALT levels? The '5Ws' dilemma. J Viral Hepat 2012; 19:229-35. [PMID: 22404720 DOI: 10.1111/j.1365-2893.2011.01485.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Approximately 30% of patients with chronic HCV infection have persistently normal ALT levels. Although formerly referred to as 'healthy' or 'asymptomatic' HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of cases and might progress towards a more severe degree of liver fibrosis. A significant proportion of patients experience periods of increased serum ALT associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of 'persistent' ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of noninvasive tools for the assessment of liver fibrosis, the natural history and the usefulness of antiviral treatment. The advent of new therapeutic options (pegylated interferon plus ribavirin) has shifted treatment targets towards the eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review is aimed at approaching the main unresolved issues on this topic, trying to give evidence-based answers to the more frequently asked questions from patients and their physicians.
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Affiliation(s)
- C Puoti
- Department of Internal Medicine and Liver Unit, Marino Hospital, Rome, Italy.
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14
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Soluble serum CD81 is elevated in patients with chronic hepatitis C and correlates with alanine aminotransferase serum activity. PLoS One 2012; 7:e30796. [PMID: 22355327 PMCID: PMC3280260 DOI: 10.1371/journal.pone.0030796] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 12/29/2011] [Indexed: 02/07/2023] Open
Abstract
Aim Cellular CD81 is a well characterized hepatitis C virus (HCV) entry factor, while the relevance of soluble exosomal CD81 in HCV pathogenesis is poorly defined. We performed a case-control study to investigate whether soluble CD81 in the exosomal serum fraction is associated with HCV replication and inflammatory activity. Patients and Methods Four cohorts were investigated, patients with chronic hepatitis C (n = 37), patients with chronic HCV infection and persistently normal ALT levels (n = 24), patients with long term sustained virologic response (SVR, n = 7), and healthy volunteers (n = 23). Concentration of soluble CD81 was assessed semi-quantitatively after differential centrifugation ranging from 200 g to 100,000 g in the fifth centrifugation fraction by immunoblotting and densitometry. Results Soluble CD81 was increased in patients with chronic hepatitis C compared to healthy subjects (p = 0.03) and cured patients (p = 0.017). Patients with chronic HCV infection and persistently normal ALT levels and patients with long term SVR had similar soluble CD81 levels as healthy controls (p>0.2). Overall, soluble CD81 levels were associated with ALT levels (r = 0.334, p = 0.016) and severe liver fibrosis (p = 0.027). Conclusion CD81 is increased in the exosomal serum fraction in patients with chronic hepatitis C and appears to be associated with inflammatory activity and severity of fibrosis.
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Uto H, Mawatari S, Kumagai K, Ido A, Tsubouchi H. Clinical Features of Hepatitis C Virus Carriers With Persistently normal Alanine Aminotransferase Levels. HEPATITIS MONTHLY 2012; 12:77-84. [DOI: 10.5812/hepatmon.4851] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Bihrer V, Friedrich-Rust M, Kronenberger B, Forestier N, Haupenthal J, Shi Y, Peveling-Oberhag J, Radeke HH, Sarrazin C, Herrmann E, Zeuzem S, Waidmann O, Piiper A. Serum miR-122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection. Am J Gastroenterol 2011; 106:1663-9. [PMID: 21606975 DOI: 10.1038/ajg.2011.161] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection. METHODS RNA was extracted from sera of patients with chronic HCV infection (CHC) and healthy controls and was analyzed for miR-22 content by quantitative real-time reverse-transcription polymerase chain reaction. miR-122 serum levels were correlated with standard parameters of liver function. Liver biopsies from the same patients were examined for the histologic activity index (HAI) and the degree of fibrosis. RESULTS Sera from patients with CHC contained higher levels of miR-122 than sera from healthy controls. Serum miR-122 levels correlated well with markers of liver inflammatory activity, that is, the serum levels of alanine leucine transaminase (ALT) and aspartate transaminase, and the HAI score. In patients with persistently normal ALT levels, serum miR-122 levels did not differ from healthy controls. There was no correlation of serum miR-122 levels with serum albumin, international normalized ratio, liver fibrosis, or serum HCV RNA. CONCLUSIONS The serum level of miR-122 strongly correlates with serum ALT activity and with necroinflammatory activity in patients with CHC and elevated ALT levels, but not with fibrosis stage and functional capacity of the liver.
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Affiliation(s)
- Verena Bihrer
- Department of Medicine I, University of Frankfurt/M., Frankfurt, Germany
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Derbala MF, Amer AM, Almohanadi M, John A, Amin A, John A, Sharma M, Alkaabi SR, Al Dweik NZ, Pasic F, Yaqoob R, Butt MT, Shebl FM. Hepatitis C virus genotype 4 with normal transaminases: histological changes, schistosomiasis and response to treatment. J Viral Hepat 2011; 18:e258-62. [PMID: 21108700 PMCID: PMC3101275 DOI: 10.1111/j.1365-2893.2010.01403.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Among individuals with chronic hepatitis C virus (HCV) infection, approximately 30% of patients show persistently normal alanine aminotransferase (PNALT). Individuals with PNALT have been historically excluded from antiviral treatment. However, some studies have reported sudden worsening of disease in patients with PNALT, suggesting the need to treat such individuals. To evaluate this further, we compared fibrosis severity and response to treatment in patients with PNALT to patients with abnormal ALT. In addition, we investigated whether liver histology and schistosomiasis affect response to treatment differently in those with PNALT and abnormal ALT. A retrospective cohort study of 176 HCV-Genotype 4 (HCV-G4) patients treated with pegylated interferon (PEG-IFN) and ribavirin. Of 176 cases studied, 53 (30.1%) had normal ALT. Prevalence of pretreatment severe fibrosis, sustained virological response (SVR) and relapse were not significantly different in patients with PNALT (26%, 66% and 5.7% respectively) compared to those with abnormal ALT (32.5%, 60.7%, and 6.6% respectively). Multivariable logistic regression revealed that pretreatment ALT, pretreatment viral load, inflammation and schistosomiasis were not significantly associated with SVR [OR (95% CI), 0.75 (0.34-1.65); 0.92 (0.61-1.37); 1.64 (0.64-4.18); 0.90 (0.44-1.84) respectively]. Severe fibrosis was the only significant predictor of SVR [OR (95% CI), 0.38 (0.14-0.99)]. PNALT does not reflect the degree of fibrotic changes or predict SVR. Furthermore, schistosomiasis is a predictor of neither fibrosis nor poor response in patients with PNALT. Severe fibrosis is a strong and independent predictor of response to treatment. Therefore, it is important to treat individuals with PNALT levels regardless of schistosomiasis.
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Affiliation(s)
- M F Derbala
- Department of Gastroenterology and Hepatology, Hamad Hospital and Weill Cornell Medical College in Qatar, Egypt.
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Puoti C, Barbarini G, Picardi A, Romano M, Pellicelli A, Barlattani A, Mecenate F, Guarisco R, Costanza OM, Spilabotti L, Bellis L, Bonaventura ME, Dell' Unto O, Elmo MG, Nicolini AM, Nosotti L, Soccorsi F. Rapid virological response as a predictor of sustained response in HCV-infected patients with persistently normal alanine aminotransferase levels: A multicenter study. J Viral Hepat 2011; 18:393-399. [PMID: 20546499 DOI: 10.1111/j.1365-2893.2010.01319.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV-1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV-1, 90% HCV-2 and 64% HCV-3). An end-of-treatment response was observed in 86% of the patients (68% HCV-1, 100% HCV-2 and 91% HCV-3). SVR was maintained in 91 patients (46% HCV-1, 97% HCV-2 and 82% HCV-3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV-1 patients with baseline HCV RNA <400×10(3) IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.
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Affiliation(s)
- C Puoti
- Department of Internal Medicine and Liver Unit, Marino Hospital, Rome, Italy.
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Puoti C, Guarisco R, Spilabotti L, Bellis L. Sustained virological response following extremely short antiviral treatment in selected HCV carriers with persistently normal ALT. Dig Liver Dis 2010; 42:745. [PMID: 20303840 DOI: 10.1016/j.dld.2010.01.024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2010] [Revised: 01/20/2010] [Accepted: 01/31/2010] [Indexed: 12/11/2022]
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Sárváry E, Gerlei Z, Dinya E, Tóth E, Varga M, Chmel R, Molnar M, Remport A, Nemes B, Kobori L, Görög D, Fazakas J, Gaal I, Járay J, Perner F, Langer R. Hepatitis C infected hemodialysis and renal transplant patients with elevated α-glutathione S-transferase have increased risk for liver damage. Interv Med Appl Sci 2010. [DOI: 10.1556/imas.2.2010.2.5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
AbstractPatients on hemodialysis (HD) and renal transplant recipients (RT) have a high prevalence of HCV infection. Theaimof our study was to determine the prevalence of HCV-RNA in the anti-HCV positive patients and to compare the biochemical parameters of PCR(+) and PCR(−) subgroups.Methods:The 525 sera were screened for anti-HCV. HCV-RNA was detected by polymerase chain reaction (PCR) and liver enzymes [SGOT, SGPT, GGT,α-glutathione S-transferase (GST)] were measured.Results:Active viraemia was found only in 187 of 289 (65%) seropositive HD patients in contrast to 53 of 53 (100%) of seropositive RT patients. Significantly increased (p<0.05) GST values (9.9 μg/l) were found in the PCR(+) subgroups compared to GST levels (2.7 μg/l) of the PCR(−) subgroups. Elevated GST concentration was found in 80% (208/251) of PCR(+) patients. The measured enzymes were not elevated in HCV infected patients. Six percent of HD and 11% of RT patients were screened before seroconversion. Diagnostic sensitivity (80%) and specificity (79%) of GST were calculated as good for early liver damage caused by HCV. In contrast, the sensitivity of the measurement of other liver enzymes were very weak (SGOT: 8%; SGPT: 10%; GGT: 42%).Conclusion:The significantly higher viraemia of the RT subgroup could be related to the immunosuppressive therapy. Increased GST level may be a useful indicator of tissue damage during HCV infection. If HCV infection is suspected, PCR and GST measurement should be performed, even if anti-HCV result is negative.
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Affiliation(s)
- Enikő Sárváry
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
- 4 Transplantation and Surgical Clinic, Semmelweis University, Baross u. 23–25, H-1082, Budapest, Hungary
| | - Zs. Gerlei
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - E. Dinya
- 2 EGIS Pharmacenticals LTD., Budapest, Hungary
| | - E. Tóth
- 3 EUROCARE Dialysis Center, Békéscsaba, Hungary
| | - M. Varga
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - R. Chmel
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - M. Molnar
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - A. Remport
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - B. Nemes
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - L. Kobori
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - D. Görög
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - J. Fazakas
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - I. Gaal
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - J. Járay
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - F. Perner
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
| | - R. Langer
- 1 Semmelweis University Transplantation and Surgical Clinic, Budapest, Hungary
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