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Martini A, Ceranto E, Gatta A, Angeli P, Pontisso P. Occult liver disease burden: Analysis from a large general practitioners' database. United European Gastroenterol J 2017; 5:982-986. [PMID: 29163964 DOI: 10.1177/2050640617696402] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 02/06/2017] [Indexed: 11/15/2022] Open
Abstract
Background Cirrhosis represents the end stage of chronic liver disease, characterized by high mortality and morbidity. The prevalence of liver disease is difficult to assess, given its clinical latency up to the late stage. Objective We aimed to assess the prevalence of unrecognized chronic liver disease and cirrhosis using surrogate indicators from medical records of family physicians. Methods Medical records of 139,104 subjects, collected from 99 family physicians of the Veneto region, were used. Persistently high transaminases were used as indicators of occult chronic liver disease; thrombocytopenia, unrelated to haematological malignancies, was used as indicator of occult cirrhosis. Diagnosis of chronic liver disease and cirrhosis was assessed using ICD9-CM-1997 codes. Results Alteration of transaminases was found in 32.7% of the subjects, and among them only one-third had an already diagnosed liver disease. Patients with diagnosis of cirrhosis were 0.3%, while thrombocytopenia, indicator of occult cirrhosis, was detected in 1.3% of the remaining population. Patients with overt and occult cirrhosis showed a higher metabolic profile, with significantly higher prevalence of arterial hypertension, obesity and diabetes than the general population. Conclusion A large proportion of patients with chronic liver disease is still undiagnosed. Surrogate biochemical indicators might be useful for disease recognition.
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Affiliation(s)
- Andrea Martini
- Internal Medicine and Hepatology, Regional Referral Center for Liver Disease, Department of Medicine, University of Padua, Italy
| | - Elena Ceranto
- Internal Medicine and Hepatology, Regional Referral Center for Liver Disease, Department of Medicine, University of Padua, Italy
| | - Angelo Gatta
- Internal Medicine and Hepatology, Regional Referral Center for Liver Disease, Department of Medicine, University of Padua, Italy
| | - Paolo Angeli
- Internal Medicine and Hepatology, Regional Referral Center for Liver Disease, Department of Medicine, University of Padua, Italy
| | - Patrizia Pontisso
- Internal Medicine and Hepatology, Regional Referral Center for Liver Disease, Department of Medicine, University of Padua, Italy
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2
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Dufour MC. Are there net health benefits from moderate alcohol consumption? morbidity and other parameters of health. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/009145099402100115] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Mary C. Dufour
- (National Institute on Alcohol Abuse and Alcoholism, 6000 Executive Blvd., Rockville, MD 20892–7003), Division of Biometry and Epidemiology at the U.S. National Institute on Alcohol Abuse and Alcoholism
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Cramer JD, Patel UA, Samant S, Yang A, Smith SS. Liver disease in patients undergoing head and neck surgery: Incidence and risk for postoperative complications. Laryngoscope 2016; 127:102-109. [PMID: 27240547 DOI: 10.1002/lary.26044] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 03/24/2016] [Accepted: 03/28/2016] [Indexed: 12/23/2022]
Abstract
OBJECTIVES/HYPOTHESIS Head and neck cancer patients have multiple risk factors for liver disease. However, little is known about the incidence of liver disease or the safety of surgery in these patients. STUDY DESIGN We conducted a retrospective cohort study using the American College of Surgeons National Surgical Quality Improvement Program from 2005 to 2013. METHODS We identified patients undergoing head and neck surgery and excluded them if preoperative laboratory data were missing. Patients were classified as having liver disease if their preoperative aspartate aminotransferase-to-platelet ratio index was ≥ 0.7, and as having advanced liver disease if their Model for End-Stage Liver Disease-Sodium score was ≥ 10. We compared the rate of postoperative complications using multivariable logistic regression. RESULTS Among 19,138 eligible patients, the incidence of any degree of liver disease was 6.8% for aerodigestive tract surgery and 3.3% for controls. The 30-day mortality rate after major head and neck surgery, which included composite resection; free tissue transfer; and total laryngectomy with advanced, mild, and no liver disease, was 14.6%, 3.0%, and 0.9%, respectively (P < 0.001). For nonmajor surgery, the mortality rate was 3.0%, 0.3%, and 0.3%, respectively (P < 0.001). On multivariable analysis, patients with advanced liver disease experienced a six-fold higher rate of 30-day mortality (odds ratio 6.1; 95% confidence interval, 2.9-12.8). CONCLUSION There is a high risk to detect liver disease in patients undergoing head and neck surgery of the aerodigestive tract. Those with advanced liver disease are at high risk for perioperative mortality, and this risk should be judiciously considered in medical/surgical decision making and postoperative care. LEVEL OF EVIDENCE 2c. Laryngoscope, 127:102-109, 2017.
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Affiliation(s)
- John D Cramer
- Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A
| | - Urjeet A Patel
- Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.,Division of Otolaryngology Head and Neck Surgery, John H. Stroger Hospital of Cook County, Chicago, Illinois, U.S.A
| | - Sandeep Samant
- Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A
| | - Amy Yang
- Biostatistics Collaboration Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A
| | - Stephanie Shintani Smith
- Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A.,Center for Healthcare Studies, Northwestern University Feinberg School of Medicine, Chicago, Illinois, U.S.A
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Rex KF, Krarup HB, Laurberg P, Andersen S. Liver biochemistry and associations with alcohol intake, hepatitis B virus infection and Inuit ethnicity: a population-based comparative epidemiological survey in Greenland and Denmark. Int J Circumpolar Health 2016; 75:29528. [PMID: 26928535 PMCID: PMC4772703 DOI: 10.3402/ijch.v75.29528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 01/05/2023] Open
Abstract
Background Hepatitis B virus (HBV) infection is common in Arctic populations and high alcohol intake has been associated with an increased risk of a number of diseases. Yet, a description of the influence of alcohol intake in persons with HBV infection on liver biochemistry is lacking. Objective We aimed to describe the association between reported alcohol intake and liver biochemistry taking into account also HBV infection, ethnicity, Inuit diet, body mass index (BMI), gender and age in an Arctic population. Design and methods Population-based investigation of Inuit (n=441) and non-Inuit (94) in Greenland and Inuit living in Denmark (n=136). Participants filled in a questionnaire on alcohol intake and other life style factors. Blood samples were tested for aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), bilirubin, albumin, hepatitis B surface antigen, hepatitis B surface antibody and hepatitis B core antibody. We also performed physical examinations. Results Participation rate was 95% in Greenland and 52% in Denmark. An alcohol intake above the recommended level was reported by 12.9% of non-Inuit in Greenland, 9.1% of Inuit in East Greenland, 6.1% of Inuit migrants and 3.4% of Inuit in the capital of Greenland (p=0.035). Alcohol intake was associated with AST (p<0.001) and GGT (p=0.001), and HBV infection was associated with ALP (p=0.001) but not with AST, GGT, bilirubin or albumin in the adjusted analysis. Inuit had higher AST (p<0.001), GGT (p<0.001) and ALP (p=0.001) values than non-Inuit after adjustment for alcohol, diet, BMI and HBV exposure. Ethnic origin modified the association between alcohol and AST, while HBV infection did not modify the associations between alcohol and liver biochemistry. Conclusions Non-Inuit in Greenland reported a higher alcohol intake than Inuit. Ethnic origin was more markedly associated with liver biochemistry than was alcohol intake, and Greenlandic ethnicity modified the effect of alcohol intake on AST. HBV infection was slightly associated with ALP but not with other liver biochemistry parameters.
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Affiliation(s)
- Karsten Fleischer Rex
- Department of Internal Medicine, Queen Ingrid's Hospital, Nuuk, Greenland.,Arctic Health Research Centre, Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark;
| | - Henrik Bygum Krarup
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Peter Laurberg
- Arctic Health Research Centre, Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark.,Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Stig Andersen
- Department of Internal Medicine, Queen Ingrid's Hospital, Nuuk, Greenland.,Arctic Health Research Centre, Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark.,Department of Geriatric Medicine, Aalborg University Hospital, Aalborg, Denmark
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Abdelmegeed MA, Banerjee A, Jang S, Yoo SH, Yun JW, Gonzalez FJ, Keshavarzian A, Song BJ. CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. Free Radic Biol Med 2013; 65:1238-1245. [PMID: 24064383 PMCID: PMC3859835 DOI: 10.1016/j.freeradbiomed.2013.09.009] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 09/12/2013] [Accepted: 09/17/2013] [Indexed: 02/07/2023]
Abstract
Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator-activated receptor-α, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis.
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Affiliation(s)
- Mohamed A Abdelmegeed
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Atrayee Banerjee
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Sehwan Jang
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Seong-Ho Yoo
- Department of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Jun-Won Yun
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ali Keshavarzian
- Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Byoung-Joon Song
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
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Daneshpour N, Griffin M, Collighan R, Perrie Y. Targeted delivery of a novel group of site-directed transglutaminase inhibitors to the liver using liposomes: a new approach for the potential treatment of liver fibrosis. J Drug Target 2010; 19:624-31. [PMID: 21067461 DOI: 10.3109/1061186x.2010.531731] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Liver fibrosis and its end-stage disease cirrhosis are a main cause of mortality and morbidity worldwide. Thus far, there is no efficient pharmaceutical intervention for the treatment of liver fibrosis. Liver fibrosis is characterized by excessive accumulation of the extracellular matrix (ECM) proteins. Transglutaminase (TG)-mediated covalent cross-linking has been implicated in the stabilization and accumulation of ECM in a number of fibrotic diseases. Thus, the use of tissue TG2 inhibitors has potential in the treatment of liver fibrosis. Recently, we introduced a novel group of site-directed irreversible specific inhibitors of TGs. Here, we describe the development of a liposome-based drug-delivery system for the site-specific delivery of these TG inhibitors into the liver. By using anionic or neutral-based DSPC liposomes, the TG inhibitor can be successfully incorporated into these liposomes and delivered specifically to the liver. Liposomes can therefore be used as a potential carrier system for site-specific delivery of the TG2 inhibitors into the liver, opening up a potential new avenue for the treatment of liver fibrosis and its end-stage disease cirrhosis.
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Affiliation(s)
- Nooshin Daneshpour
- Medicines Research Unit, School of Life and Health Sciences, Aston University, Birmingham, UK
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Şengül C, Okay T, Açıkgöz Ç, Ozan G, Dilbaz N. Prevalence of Alcohol Dependence and
Abuse in a General Hospital;
Sensitivity and Specificity of MAST. ELECTRONIC JOURNAL OF GENERAL MEDICINE 2010. [DOI: 10.29333/ejgm/82787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Najman JM, Williams GM, Room R. Increasing socioeconomic inequalities in male cirrhosis of the liver mortality: Australia 1981-2002. Drug Alcohol Rev 2009; 26:273-8. [PMID: 17454016 DOI: 10.1080/09595230701247699] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Liver cirrhosis mortality is an indicator of harms associated with high levels of alcohol consumption. There is good evidence that changes in political and economic systems can lead to changing patterns of liver cirrhosis mortality. Socioeconomic inequalities in liver cirrhosis mortality have been periodically reported but there are few studies of changes in socioeconomic inequalities in liver cirrhosis mortality over time. This paper examines changes in socioeconomic inequalities in liver cirrhosis mortality in Australia for the period 1981 - 2002. Age standardised, liver cirrhosis mortality rates were calculated for occupational groupings for Australia 1981 - 2002. Occupations were grouped into non-manual and manual categories, and there was imputation for missing data. Despite decreasing overall liver cirrhosis mortality rates over time, liver cirrhosis mortality continues to account for about 3% of all deaths. Manual workers have consistently experienced liver cirrhosis mortality rates which are twice or more the rate experienced by non-manual workers. These inequalities appear to have increased in recent years and currently appear to be at historic highs (manual workers have mortality rates of about 2.5 times those of non-manual workers). Increasing socioeconomic inequalities in liver cirrhosis mortality in Australia suggest that lower SES groups have, over time, increased their level of harmful alcohol consumption relative to middle and higher SES groups. It is suggested that this might be attributed to a relative improvement in the affordability of alcohol over time.
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Affiliation(s)
- Jake M Najman
- School of Social Science, University of Queensland, St Lucia, Brisbane, Queensland, Australia.
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Dalton SR, Lee SML, King RN, Nanji AA, Kharbanda KK, Casey CA, McVicker BL. Carbon tetrachloride-induced liver damage in asialoglycoprotein receptor-deficient mice. Biochem Pharmacol 2009; 77:1283-90. [PMID: 19185565 DOI: 10.1016/j.bcp.2008.12.023] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2008] [Revised: 12/22/2008] [Accepted: 12/22/2008] [Indexed: 02/09/2023]
Abstract
The asialoglycoprotein (ASGP) receptor is an abundant hepatocyte-specific receptor involved in receptor-mediated endocytosis. This receptor's abundance and function is decreased by chronic ethanol administration prior to the appearance of pathology such as necrosis or inflammation. Hence, this study aimed to determine if ASGP receptor function is required to protect against liver injury by utilizing a knockout mouse model lacking functional ASGP receptor in the setting of carbon tetrachloride (CCl(4)) hepatotoxicity. Briefly, ASGP receptor-deficient (RD) mice and wild-type (WT) mice were injected with 1ml/kg body weight of CCl(4). In the subsequent week, mice were monitored for liver damage and pathology (aspartate transaminase (AST), alanine transaminase (ALT) and light microscopy). The consequences of CCl(4) injection were examined by measuring alpha-smooth muscle actin (alpha-SMA) deposition, contents of malondialdehyde and the percentage of apoptotic hepatocytes. After CCl(4) injection, RD mice showed increased liver pathology together with significantly increased activities of AST and ALT compared to that in WT mice. There were also significantly more apoptotic bodies, lipid peroxidation and deposition of alpha-SMA in RD mice versus WT mice following CCl(4) injection. Since these two mouse strains only differ in whether or not they have the ASGP receptor, it can be concluded that proper ASGP receptor function exerted a protective effect against CCl(4) toxicity. Thus, receptor-mediated endocytosis by the ASGP receptor could represent a novel molecular mechanism that is responsible for subsequent liver health or injury.
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Affiliation(s)
- Shana R Dalton
- Department of Internal Medicine, University of Nebraska Medical Center, Omaha, 68198-2000, USA
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Bell BP, Manos MM, Zaman A, Terrault N, Thomas A, Navarro VJ, Dhotre KB, Murphy RC, Van Ness GR, Stabach N, Robert ME, Bower WA, Bialek SR, Sofair AN. The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance. Am J Gastroenterol 2008; 103:2727-36; quiz 2737. [PMID: 18684170 DOI: 10.1111/j.1572-0241.2008.02071.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Chronic liver disease (CLD) is an important cause of morbidity and mortality, but the epidemiology is not well described. We conducted prospective population-based surveillance to estimate newly diagnosed CLD incidence, characterize etiology distribution, and determine disease stage. METHODS We identified cases of CLD newly diagnosed during 1999-2001 among adult county residents seen in any gastroenterology practice in New Haven County, Connecticut; Multnomah County, Oregon; and Northern California Kaiser Permanente Medical Care Program (KPMCP, Oakland, California [total population 1.48 million]). We defined CLD as abnormal liver tests of at least 6 months' duration or pathologic, clinical, or radiologic evidence of CLD. Consenting patients were interviewed, a blood specimen obtained, and the medical record reviewed. RESULTS We identified 2,353 patients with newly diagnosed CLD (63.9 cases/100,000 population), including 1,225 hepatitis C patients (33.2 cases/100,000). Men aged 45-54 yr had the highest hepatitis C incidence rate (111.3/100,000). Among 1,040 enrolled patients, the median age was 48 yr (range 19-86 yr). Hepatitis C, either alone (442 [42%]) or in combination with alcohol-related liver disease (ALD) (228 [22%]), accounted for two-thirds of the cases. Other etiologies included nonalcoholic fatty liver disease (NAFLD, 95 [9%]), ALD (82 [8%]), and hepatitis B (36 [3%]). Other identified etiologies each accounted for <3% of the cases. A total of 184 patients (18%) presented with cirrhosis, including 44% of patients with ALD. CONCLUSIONS Extrapolating from this population-based surveillance network to the adult U.S. population, approximately 150,000 patients with CLD were diagnosed in gastroenterology practices each year during 1999-2001. Most patients had hepatitis C; heavy alcohol consumption among these patients was common. Almost 20% of patients, an estimated 30,000 per year, had cirrhosis at presentation. These results provide population-level baseline data to evaluate trends in identification of patients with CLD in gastroenterology practices.
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Affiliation(s)
- Beth P Bell
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, Sexually Transmitted Diseases and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA
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Thieringer F, Maass T, Czochra P, Klopcic B, Conrad I, Friebe D, Schirmacher P, Lohse AW, Blessing M, Galle PR, Teufel A, Kanzler S. Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A. Gene 2008; 423:23-8. [PMID: 18598744 DOI: 10.1016/j.gene.2008.05.022] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Revised: 05/09/2008] [Accepted: 05/21/2008] [Indexed: 12/13/2022]
Abstract
Platelet derived growth factor (PDGF) plays a central role in repair mechanisms after acute and chronic tissue damage. To further evaluate the role of PDGF-A in liver fibrogenesis in vivo, we generated transgenic mice with hepatocyte-specific overexpression of PDGF-A using the CRP-gene promoter. Transgenic but not wildtype mice showed expression of PDGF-A mRNA in the liver. Hepatic PDGF-A overexpression was accompanied by a significant increase in hepatic procollagen III mRNA expression as well as TGF-beta1 expression. Liver histology showed increased deposition of extracellular matrix in transgenic but not in wildtype mice. PDGF-A-transgenic mice showed positive sinusoidal staining for alpha-SMA indicating an activation of hepatic stellate cells. Since the profibrogenic effect of PDGF-A was accompanied by increased TGF-beta1 protein concentration in the liver of transgenic mice, it can be postulated that PDGF-A upregulates expression of TGF-beta1 which is a strong activator of hepatic stellate cells. Thus, these results point towards a fibrosis induction by PDGF-A via the TGF-beta1 signalling pathway. In conclusion, expression and functional analysis of PDGF-A in the liver of transgenic mice suggest a relevant profibrogenic role of PDGF-A via TGF-beta1 induction. Counteracting PDGF-A may therefore be one of the effects of tyrosine kinase inhibitors which showed protective effects in animal models of liver fibrosis.
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Affiliation(s)
- Florian Thieringer
- 1st Department of Medicine, Johannes-Gutenberg-University, Mainz, Germany
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12
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Abstract
Chronic ethanol consumption is associated with serious and potentially fatal alcohol-related liver injuries such as hepatomegaly, alcoholic hepatitis and cirrhosis. Moreover, it has been documented that the clinical progression of alcohol-induced liver damage may be associated with an increase in hepatocellular death that involves apoptotic mechanisms. Although much information has been learned about the clinical manifestations associated with alcohol-related diseases, the search continues for a better understanding of the molecular and/or cellular mechanisms by which ethanol exerts its deleterious effects such as the induction of pro-apoptotic mechanisms and related cell damaging events. As part of the effort to enhance our understanding of those particular cellular pathways and mechanisms associated with ethanol toxicity, researchers over the years have utilized a variety of model systems. Recently, work has come forth demonstrating the utility of a hybrid cell line (WIF-B) as a cell culture model system for the study of alcohol-associated alterations in hepatocellular mechanisms. Success with such emerging model systems could aid in the development of potential therapeutic treatments for the prevention of alcohol-induced apoptotic cell death that may ultimately serve as a significant target in delaying the onset and/or progression of clinical symptoms of alcohol-mediated liver disease. This review article summarizes the current understanding of ethanol-mediated modifications in cell survival and thus the promotion of pro-apoptotic events with emphasis on analyses made in various experimental model systems, particularly the more recently characterized WIF-B cell system.
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Affiliation(s)
- Benita L McVicker
- Veterans Affairs Medical Center, Research Service (151), 4101 Woolworth Avenue, Omaha, NE 68105, USA.
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McVicker BL, Tuma DJ, Kharbanda KK, Kubik JL, Casey CA. Effect of chronic ethanol administration on the in vitro production of proinflammatory cytokines by rat Kupffer cells in the presence of apoptotic cells. Alcohol Clin Exp Res 2007; 31:122-9. [PMID: 17207110 DOI: 10.1111/j.1530-0277.2006.00270.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chronic ethanol consumption can lead to a variety of pathological consequences by as yet undefined mechanisms. Recently, it has been noted that alcohol-associated liver disease is often accompanied by morphological liver changes that include the increased production of apoptotic cells. Additionally, it has been demonstrated that hepatocellular uptake and removal of potentially damaging apoptotic cells is impaired after ethanol treatment. The aim of the present study was to determine whether the presence of apoptotic cells leads to Kupffer cell (KC) production and release of proinflammatory cytokines that have been linked to hepatocyte damage, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha). METHODS Kupffer cells were isolated from female rats after an 8-week oral administration of a dextrose control or ethanol-containing fish-oil diet. The isolated KCs were cultured for up to 24 hours in the absence or presence of apoptotic or nonapoptotic hepatoma cells, or lipopolysaccharide. After incubation, media from the cultures were assayed for the presence of TNF-alpha and IL-6 by immunoassay detection. Also, the expression of these cytokines was measured in KC lysates by a quantitative real-time polymerase chain reaction. RESULTS Kupffer cells cultured for up to 24 hours in the presence of apoptotic cells produced significantly more TNF-alpha and IL-6 (80 and 60%, respectively, p<0.05) when the cells were isolated from ethanol-fed animals compared with controls. Additionally, after as early as 4 hours in culture with apoptotic cells, mRNA levels of both cytokines were increased (2-5-fold) in KCs isolated from ethanol-fed animals compared with controls. CONCLUSIONS The presence of apoptotic cells results in the in vitro activation of KCs. Additionally, chronic ethanol administration results in an enhanced responsiveness of KCs to produce proinflammatory cytokines indicated by the increased production of inflammatory mediators from KCs obtained from ethanol-fed animals.
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Affiliation(s)
- Benita L McVicker
- Liver Study Unit, Department of Veterans Affairs Medical Center, and Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68105, USA
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McVicker BL, Tuma DJ, Kubik JL, Tuma PL, Casey CA. Ethanol-induced apoptosis in polarized hepatic cells possibly through regulation of the Fas pathway. Alcohol Clin Exp Res 2006; 30:1906-15. [PMID: 17067356 DOI: 10.1111/j.1530-0277.2006.00235.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND It has been noted that alcohol-related liver diseases can be associated with an increase in apoptotic hepatocellular death. Moreover, the promotion of hepatocyte apoptosis may be linked to signals emanating from death receptors, particularly Fas [CD95/apoptosis-inducing protein 1 (APO-1)]. In the present study, we utilized an in vitro hepatic culture model [hybrid of human fibroblast (WI 38) and rat hepatoma (Fao) cells, WIF-B cells] to study potential contributing mechanisms involved in hepatocellular apoptosis following ethanol administration. METHODS WIF-B cultures (differentiated hepatic cells that efficiently metabolize alcohol) were treated with or without ethanol and specific inhibitors of alcohol metabolism and cysteine protease activity, followed by morphological and biochemical examination of proapoptotic parameters. RESULTS The results of this work demonstrated that ethanol administration leads to an increase (45%-60%) in caspase-3 activity and that the induction of apoptosis was found to be linked to the metabolism of alcohol. Additionally, increases were observed in the activity of upstream initiator caspases (caspase-2 and caspase-8) that are directly related to membrane signaling events of death receptors such as Fas. Moreover, it was determined that the activation of caspase-3 could be blocked by the presence of a specific caspase-8 inhibitor, again linking death receptor-associated proteases to downstream effector caspase activity in alcohol-related death. Finally, ethanol administration was found to result in an increase in the amount of Fas protein present in the membrane fraction of the cell. The increase in membrane Fas protein indicates ligand-independent membrane targeting of Fas in the alcohol-treated cells that could potentially be a key signaling event in the induction of the proapoptotic caspase cascade. CONCLUSIONS The data presented here indicate that alcohol metabolism induces apoptosis in WIF-B cells that occurs, in part, by mechanisms involving signals emanating from death receptors.
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Affiliation(s)
- Benita L McVicker
- The Liver Study Unit, Department of Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, NE 68105, USA.
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15
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Abstract
Hepatic fibrogenesis is the common result of injury to the liver. It is believed to be a critical factor that leads to hepatic dysfunction and may be important in portal hypertension. The fibrogenic response is a complex process in which accumulation of extracellular matrix proteins, tissue contraction, and alteration in blood flow are prominent. A critical event in fibrogenesis is activation of resident perisinusoidal cells that are termed "hepatic stellate cells". Stellate cell activation is characterized by many important phenotypes, including enhanced extracellular matrix synthesis and prominent contractility. Given the central role of stellate cell activation in hepatic fibrogenesis (and portal hypertension), effective therapy for hepatic fibrogenesis is most likely will be directed at this event.
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Affiliation(s)
- Don C Rockey
- Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8887, USA.
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16
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Johnson TP, Booth AL, Johnson P. Physician beliefs about substance misuse and its treatment: findings from a U.S. survey of primary care practitioners. Subst Use Misuse 2005; 40:1071-84. [PMID: 16040369 DOI: 10.1081/ja-200030800] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Primary care physicians are in a unique position to detect patients with substance use related problems and initiate treatment at an early stage when it may be more successful. To evaluate current knowledge, attitudes, and practices of primary care physicians in the United States regarding the detection of substance use related problems, a national telephone survey of practicing primary care physicians was conducted in 1999. A total of 648 randomly selected family and general practitioners, internists, pediatricians, and OB-GYNs were interviewed regarding their perceived preparation to diagnose selected health conditions, their perceived difficulty discussing selected health conditions with patients, and their perceptions of the effectiveness of available treatments for selected health conditions. Findings suggest that primary care physicians in the United States perceive themselves as being less prepared to diagnose substance "abuse" than other chronic conditions. They additionally find it more difficult to discuss this topic with their patients, and are more skeptical about the effectiveness of available treatments. Because the social, economic, and health consequences of untreated substance misuse negatively affect the quality of life for so many patients and their families, developing new approaches to improving the attitudes and screening behaviors of primary care providers vis-à-vis substance use disorders should continue to be an important priority.
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Affiliation(s)
- Timothy P Johnson
- Survey Research Laboratory, College of Urban Planning and Public Affairs, University of Illinois at Chicago, 412 S. Peoria Street, Chicago, IL 60607, USA.
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17
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Abstract
BACKGROUND/AIMS Alcohol use and hepatitis C are prominent risk factors for liver injury and this review offers the current understanding of each factor's effects on liver disease. METHODS A Medline database search was preformed for English articles with a focus on alcohol, hepatitis C and liver disease. Article citations were also considered for further applicable articles, and the strongest studies were included in our review. RESULTS Up to 60% of patients with hepatitis C have a past history of alcohol use. In patients with hepatitis C, chronic alcohol consumption of more than 5 drinks/day increases the rate of liver fibrosis, risk for cirrhosis, hepatocellular carcinoma, and, possibly, death from liver disease. Numerous studies have further found that even moderate amounts of alcohol can be detrimental to hepatitis C patients. The prevalence of hepatitis C is higher in alcoholics with advanced liver disease than in alcoholics without liver disease. Also, recent alcohol use decreases the response rate to interferon treatment. CONCLUSIONS Hepatitis C and alcohol use are often co-occurring risk factors for liver disease, and though their interaction is not clear, it is known that heavy drinking significantly promotes liver disease progression.
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Affiliation(s)
- M Mazen Jamal
- Long Beach VA Medical Center and University of California, Irvine, Long Beach, CA 90822, USA.
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18
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Tao N, Sussman S, Nieto J, Tsukamoto H, Yuan JM. Demographic characteristics of hospitalized patients with alcoholic liver disease and pancreatitis in los angeles county. Alcohol Clin Exp Res 2004; 27:1798-804. [PMID: 14634496 DOI: 10.1097/01.alc.0000095862.30777.d9] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND This study sought to identify demographic characteristics of hospitalized patients with alcoholic liver disease (ALD) in Los Angeles County for the purpose of implementing new preventive and educational programs. Another specific aim of the study was to characterize demographic and comorbid differences between patients with ALD and patients with pancreatitis, another alcohol-related disease. METHODS Analyses were performed on discharge data from all nonfederal short-stay hospitals within Los Angeles County, released for the year 1999 by the Office of Statewide Health Planning and Development. Repeated hospital stays for ALD by the same patients were deleted from the data analysis based on individual identification numbers. For the analysis of medical costs of ALD, repeated hospital stays were included. RESULTS Primary diagnosis of ALD accounted for 1.2% of total deaths among hospitalized patients and was the eighth most common cause of death among diseases examined. Moreover, the fatality rate of primary ALD among ALD hospital visits was the second highest, behind septicemia. ALD was most prevalent in the middle-aged (45-65 years old) and low- to middle-income men. The age-standardized hospitalization rate of ALD was highest in Hispanic men (61.1 per 100,000 per year), whereas that of chronic pancreatitis, another common complication of alcohol abuse, was most prevalent in African American men. CONCLUSIONS Middle-aged Hispanic men with low- to middle-income status were identified as a high-risk group for ALD in Los Angeles County. These data will guide us to develop a new strategy for future preventative and educational programs for ALD.
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Affiliation(s)
- Nico Tao
- Department of Pathology, University of Southern California/University of California-Los Angeles Research Center for Alcoholic Liver and Pancreatic Diseases, 90033, USA
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19
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Abstract
It has been suggested that the ability to drive a car is impaired in patients with cirrhosis of the liver and minimal hepatic encephalopathy (MHE). However, the only study using an on-road driving test did not reveal such an impairment. In a prospective controlled study, we evaluated patients with cirrhosis of the liver for MHE and the ability to drive a car. MHE was diagnosed using three psychometric tests: Number Connection Test Part A, Digit Symbol Test, and a Complex Choice Reaction Test. In a standardized on-road driving test (22 miles, 90 minutes), designed for patients with brain impairment, a professional driving instructor blind to the subjects' diagnosis and test results assessed the driving performance. Four global driving categories (car handling, adaptation to traffic situation, cautiousness, maneuvering), 17 specific driving actions (e.g., changing lanes, overtaking, etc.), and a total score of driving performance were rated using a 6-point scale. Of 274 consecutive patients with liver cirrhosis, 48 fulfilled the medical and driving inclusion criteria, 14 of them with and 34 without MHE. Forty-nine subjects in a stable phase of chronic gastroenterological diseases and with normal liver findings served as controls. The total driving score of patients with MHE was significantly reduced in comparison to either cirrhotic patients without MHE or to controls (P <.05). Significant differences in ratings were found in the following driving categories: car handling, adaptation, and cautiousness. Significant differences were also found in specific driving actions. The instructor had to intervene in the driving of 5 of the 14 MHE patients to avoid an accident, significantly more than in cirrhotic patients without MHE and in controls. There was no significant difference in any driving category or specific driving action in cirrhotic patients without MHE compared to controls. In conclusion, fitness to drive a car can be impaired in patients with MHE. Therefore, patients with liver cirrhosis should be tested for MHE and informed in the case of abnormal test results. Therapy known to improve psychometric test results should be initiated.
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Affiliation(s)
- Christian Wein
- Department of Psychology, University of Hamburg, Von-Melle-Park 11, 20146 Hamburg, Germany.
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20
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Abstract
Portal hypertension bleeding is a common and serious complication of cirrhosis. All patients with cirrhosis should undergo endoscopy and be evaluated for possible causes of current or future portal hypertensive bleeding. Possible causes of bleeding include esophageal varices, gastric varices, and PHG. Patients with esophageal varices at high risk of bleeding should be treated with nonselective beta-blockers for primary prevention of variceal hemorrhage. HVPG measurements represent the optimal way to monitor the success of pharmacologic therapy. EVL may be used in those with high-risk varices who do not tolerate beta-blockers. When active bleeding develops, simultaneous and coordinated attention must be given to hemodynamic resuscitation, prevention and treatment of complications, and active control of bleeding. In cases of acute esophageal variceal (Fig. 5) and PHG bleeding, terlipressin, somatostatin, or octreotide should be started. Endoscopic treatment is provided for those with bleeding esophageal varices. If first-line therapy fails, TIPS or surgery may need to be performed. Unlike esophageal variceal or PHG bleeding, there is no established optimal treatment for gastric variceal bleeding. Individual and specific treatment modalities for acute gastric variceal bleeding must be calculated carefully after considering side effects.
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Affiliation(s)
- Kevin M Comar
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, MCV Box 980711, Sanger Hall 12011, Richmond, VA 23298-0711, USA
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Zhou Z, Wang L, Song Z, Lambert JC, McClain CJ, Kang YJ. A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-alpha production. THE AMERICAN JOURNAL OF PATHOLOGY 2003; 163:1137-46. [PMID: 12937155 PMCID: PMC1868249 DOI: 10.1016/s0002-9440(10)63473-6] [Citation(s) in RCA: 154] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Tumor necrosis factor-alpha (TNF-alpha) production is a critical factor in the pathogenesis of alcoholic liver injury. Both oxidative stress and endotoxin have been implicated in the process of alcohol-induced TNF-alpha production. However, a cause-and-effect relationship between these factors has not been fully defined. The present study was undertaken to determine the mediators of acute alcohol-induced TNF-alpha production using a mouse model of acute alcohol hepatotoxicity. Alcohol administration via gavage at a dose of 6 g/kg to 129/Sv mice induced hepatic TNF-alpha production in Kupffer cells as demonstrated by measuring protein levels, immunohistochemical localization, and mRNA expression. Alcohol intoxication caused liver injury in association with increases in plasma endotoxin and hepatic lipid peroxidation. Treatment with an endotoxin neutralizing protein significantly suppressed alcohol-induced elevation of plasma endotoxin, hepatic lipid peroxidation, and inhibited TNF-alpha production. Treatment with antioxidants, N-ACETYL-L-CYSTEINE, or dimethylsulfoxide, failed to attenuate plasma endotoxin elevation, but significantly inhibited alcohol-induced hepatic lipid peroxidation, TNF-alpha production and steatosis. All treatments prevented alcohol-induced necrotic cell death in the liver. This study thus systemically dissected the relationship among plasma endotoxin elevation, hepatic oxidative stress, and TNF-alpha production following acute alcohol administration, and the results demonstrate that oxidative stress mediates endotoxin-induced hepatic TNF-alpha production in acute alcohol intoxication.
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Affiliation(s)
- Zhanxiang Zhou
- Department of Medicine, University of Louisville School of Medicine, 511 South Floyd Street, MDR 525, Louisville, KY, USA.
| | - Lipeng Wang
- From the Departments of Medicine* and Pharmacology and Toxicology,† University of Louisville School of Medicine, Louisville; the Veterans Affairs Medical Center, Louisville;‡ and the Jewish Hospital Heart and Lung Institute,§ Louisville, Kentucky
| | - Zhenyuan Song
- From the Departments of Medicine* and Pharmacology and Toxicology,† University of Louisville School of Medicine, Louisville; the Veterans Affairs Medical Center, Louisville;‡ and the Jewish Hospital Heart and Lung Institute,§ Louisville, Kentucky
| | - Jason C. Lambert
- From the Departments of Medicine* and Pharmacology and Toxicology,† University of Louisville School of Medicine, Louisville; the Veterans Affairs Medical Center, Louisville;‡ and the Jewish Hospital Heart and Lung Institute,§ Louisville, Kentucky
| | - Craig J. McClain
- From the Departments of Medicine* and Pharmacology and Toxicology,† University of Louisville School of Medicine, Louisville; the Veterans Affairs Medical Center, Louisville;‡ and the Jewish Hospital Heart and Lung Institute,§ Louisville, Kentucky
| | - Y. James Kang
- From the Departments of Medicine* and Pharmacology and Toxicology,† University of Louisville School of Medicine, Louisville; the Veterans Affairs Medical Center, Louisville;‡ and the Jewish Hospital Heart and Lung Institute,§ Louisville, Kentucky
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Abstract
The prevalence of hepatitis C is 7-10-fold higher in alcoholics than it is in the general population. Among alcoholics, the prevalence of hepatitis C is higher in alcoholics with advanced liver disease. Serum ALT and hepatitis C viral load may improve if alcoholic patients with hepatitis C stop drinking for more than 4 months.Up to 60% of patients with hepatitis C have a past history of alcohol use. In patients with hepatitis C, chronic alcohol consumption of more than 5 drinks per day increases the rate of liver fibrosis. Hepatitis C patients who ingest more than 5 alcoholic drinks per day are at increased risk for cirrhosis, hepatocellular carcinoma and, possibly, death from liver disease. Recent alcohol use decreases the response rate to interferon treatment. The detrimental effects of small amounts (3 or fewer drinks per day) of alcohol consumption in patients with hepatitis C are not known.
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Affiliation(s)
- M Mazen Jamal
- Division of Gastroenterology and Hepatology, VA Medical Center, 5901 E. Seventh Street-111, Long Beach, CA 90822, USA.
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23
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Abstract
There has been great progress made in our understanding of the cellular mechanisms of hepatic fibrosis. The recognition that the hepatic stellate cell, (formerly know as lipocyte, Ito, or fat-storing cell), played a central role in the fibrotic response was key to our understanding. Stellate cells undergo a process known as activation, in response to any insult. Activation is a broad phenotypic response, characterized by distinct functional changes in proliferation, fibrogenesis, contractility, cytokine secretion, and matrix degradation. Insights gained into the molecular regulations of stellate cell activation may lead to new antifibrotic therapies, which may reduce morbidity and mortality in patients with chronic liver injury.
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Affiliation(s)
- E Albanis
- Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York, USA
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Affiliation(s)
- U S Karnam
- University of Miami School of Medicine, Florida, USA
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26
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Meister KA, Whelan EM, Kava R. The health effects of moderate alcohol intake in humans: an epidemiologic review. Crit Rev Clin Lab Sci 2000; 37:261-96. [PMID: 10894186 DOI: 10.1080/10408360091174222] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
A large body of scientific evidence associates the moderate intake of alcohol with reduced mortality among middle-aged and older people in industrialized societies. This association is due largely to a reduced risk of death from coronary heart disease, which appears to outweigh any possible adverse effects of moderate drinking. The regular consumption of small amounts of alcohol is more healthful than the sporadic consumption of larger amounts. No beneficial effect of moderate drinking on mortality has been demonstrated in young adults (premenopausal women and men who have not reached their forties). It is theoretically possible that moderate drinking in young adulthood might reduce the risk of later heart disease; however, this has not been clearly demonstrated. For some individuals (e.g., those who cannot keep their drinking moderate, pregnant women, and those who are taking medications that may interact adversely with alcoholic beverages), the risks of alcohol consumption, even in moderation, outweigh any potential benefits. Because even small amounts of alcohol can impair judgment and coordination, no one should drink alcoholic beverages, even in moderation, before driving a motor vehicle or performing other activities that involve attention and skill.
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Affiliation(s)
- K A Meister
- American Council on Science and Health, New York, NY, USA
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27
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Rockey DC. The cell and molecular biology of hepatic fibrogenesis. Clinical and therapeutic implications. Clin Liver Dis 2000; 4:319-55. [PMID: 11232195 DOI: 10.1016/s1089-3261(05)70113-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Much has been learned in the past 2 decades about the cellular and molecular mechanisms underlying hepatic fibrogenesis and about potential therapeutic approaches in patients with liver disease. The central event in fibrogenesis seems to be the activation of hepatic stellate cells. Stellate cell activation is characterized by several important features, including enhanced matrix synthesis and a prominent contractile phenotype, processes that probably contribute to the physical distortion and dysfunction of the liver in advanced disease. It is important to emphasize that the factors controlling activation are multifactorial and complex. The extracellular matrix is a dynamic, active constituent of the fibrogenic response and undergoes active remodeling, including synthesis and degradation. Effective therapy for hepatic fibrogenesis will probably also be multifactorial, based on the basic mechanisms underlying the fibrogenic process. The most effective therapies will probably be directed at the stellate cell. Approaches that address matrix remodeling (i.e., by enhancing matrix degradation or by inhibiting factors that prevent matrix breakdown) may be effective.
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Affiliation(s)
- D C Rockey
- Departments of Medicine and Cell Biology, Liver Center, Duke University Medical Center, Durham, North Carolina, USA.
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28
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Lieber CS. Carbohydrate deficient transferrin in alcoholic liver disease: mechanisms and clinical implications. Alcohol 1999; 19:249-54. [PMID: 10580515 DOI: 10.1016/s0741-8329(99)00042-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Carbohydrate-deficient transferrin (CDT) is now considered to be the most sensitive and specific biological marker of alcohol abuse. The mechanism by which chronic alcohol consumption causes an elevation of CDT levels in serum is discussed. The sensitivity and specificity of various test procedures are compared, with special emphasis on the impact of liver disease. Clinical applications are reviewed, including the utility of CDT as a marker of relapse in alcoholic patients, and the use of CDT for the systematic screening of drinking in vulnerable populations as part of a public health approach to alcoholism.
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Affiliation(s)
- C S Lieber
- Mount Sinai School of Medicine and Alcohol Research and Treatment Center, Bronx Veterans Affairs Medical Center, New York 10468, USA.
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Duh MS, Walker AM, Kronlund KH. Descriptive epidemiology of acute liver enzyme abnormalities in the general population of central Massachusetts. Pharmacoepidemiol Drug Saf 1999; 8:275-83. [PMID: 15073920 DOI: 10.1002/(sici)1099-1557(199907)8:4<275::aid-pds427>3.0.co;2-d] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
OBJECTIVES This study quantifies the incidence of liver enzyme abnormalities in the general population of central Massachusetts. METHODS Computerized data files from a health maintenance organization were used to ascertain potential subjects during the study period of 1 July 1992-30 June 1993. Medical records and laboratory tests results were reviewed to confirm the diagnoses. RESULTS The incidence rates were 40.6 cases per 100,000 persons per year for drug-associated liver enzyme abnormalities, 39.0 per 100,000 persons per year for liver enzyme abnormalities secondary to biliary pathologies, 25.2 per 100,000 persons per year for liver enzyme abnormalities secondary to mononucleosis, 25.2 per 100,000 persons per year for liver enzyme abnormalities of unknown aetiology, 15.4 per 100,000 persons per year for alcoholic liver enzyme abnormalities, 12.2 per 100,000 persons per year for liver malignancy, and 7.3 per 100,000 persons per year for viral hepatitis (HAV, HBV and HCV). Men were more commonly affected by alcoholic liver enzyme abnormalities and viral hepatitis, with respective incidence rates approximately 5 and 2 times higher than women. Liver enzyme abnormalities secondary to mononucleosis occurred predominantly between the ages of 15-24 years. In contrast, liver diseases secondary to biliary pathologies, liver malignancies and drug-associated liver enzyme abnormalities were found most frequently among the elderly. CONCLUSION Liver enzyme abnormalities occurred with a higher incidence in this general population than reported previously in selected patients. Drug-associated liver enzyme abnormality was the most common type. The magnitude of drug-associated liver enzyme abnormality could be much higher as an appreciable proportion of the liver cases of unknown aetiology are potentially drug-attributable.
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Affiliation(s)
- M S Duh
- Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA 02115, USA.
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Yang SQ, Lin HZ, Yin M, Albrecht JH, Diehl AM. Effects of chronic ethanol consumption on cytokine regulation of liver regeneration. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:G696-704. [PMID: 9756499 DOI: 10.1152/ajpgi.1998.275.4.g696] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Ethanol ingestion may interrupt the proregenerative signal transduction that is initiated by injury-related cytokines such as tumor necrosis factor (TNF)-alpha and TNF-alpha- inducible cytokines including interleukin (IL)-6. To test this theory, liver regeneration, TNF-alpha and IL-6 expression, and cytokine-regulated prereplicative events were compared in ethanol-fed rats and isocalorically fed controls after 70% partial hepatectomy (PH). Ethanol feeding inhibits hepatocyte replication and recovery of liver mass after PH but generally promotes induction of both cytokines in the liver and extrahepatic tissues (i.e., white adipose tissue). Cytokine-regulated events that occur early in the prereplicative period are influenced differentially. TNF-alpha-dependent increases in hepatic nuclear factor-kappaB (NF-kappaB) p50 and p65 expression and DNA binding activity are prevented, whereas IL-6-dependent inductions of hepatic Stat-3 phosphorylation and DNA binding activity occur normally. In contrast, events (e.g., induction of cyclin D1, cdk-1, cyclin D3, and p53 mRNA) that occur at the end of the prereplicative period are uniformly inhibited. These findings indicate that chronic ethanol ingestion arrests the regenerative process during the prereplicative period and demonstrate that increased TNF-alpha, IL-6 and Stat-3 are not sufficient to assure hepatocyte proliferation after PH.
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Affiliation(s)
- S Q Yang
- Johns Hopkins University, Baltimore, Maryland 21205, USA
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Abstract
OBJECTIVE The aim of this study was to perform a cost analysis of different strategies of long term antibiotic prophylaxis for spontaneous bacterial peritonitis (SBP) in patients with cirrhosis and ascites. The study involved a cost analysis using a decision analysis model and patients with cirrhosis and ascites who are at risk for developing SBP. METHODS Two different strategies of antibiotic prophylaxis were compared with a "no prophylaxis" strategy in patients with cirrhosis and ascites using a decision analysis model. In strategy I, antibiotic prophylaxis was administered in all patients with cirrhosis and ascites and in strategy II, patients were stratified into a low risk and a high risk group on the basis of serum bilirubin and ascitic fluid protein levels; only patients in the high risk group received antibiotic prophylaxis. The cost per patient treated for 1 yr was the outcome measure compared in the different strategies. Clinical input probabilities and ranges used were obtained by searching the MEDLINE database for English language articles. Cost estimates were obtained from a university hospital setting. Cost analysis was done with a societal perspective, and only direct costs were taken into account. Sensitivity analyses were performed to evaluate the effect of variations in the key clinical probabilities and cost estimates ranging from a best case to a worst case scenario on the outcome measure. RESULTS The estimated cost per patient treated in strategy I, strategy II, and strategy III (the strategy of "no prophylaxis") were $1311, $1123, and $3509, respectively. Over a broad range of clinical and cost variables, the strategy of risk stratification and restriction of antibiotic prophylaxis to the subgroup of patients with cirrhosis and ascites who were at high risk for SBP (as identified by serum bilirubin >2.5 mg/dl and ascitic fluid protein <1 g/dl) was the most favored strategy. However, when the cost of prophylaxis was low or the probability of a primary episode of SBP was at the lower end of the range reported in the literature, administering antibiotic prophylaxis to all patients with cirrhosis and ascites was the least costly strategy. CONCLUSION This cost analysis indicates that antibiotic prophylaxis particularly when restricted to a subgroup of patients who, by simple laboratory parameters, are identified to be at high risk for SBP, is very cost-effective in the prevention of SBP in patients with cirrhosis and ascites.
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Affiliation(s)
- A Das
- Division of Gastroenterology, University Hospitals of Cleveland, Ohio, USA
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35
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Abstract
Alcohol has been implicated in the genesis of liver disease for centuries. Significant progress has been made in our understanding of the pathogenesis of ALD. It is now apparent that both the consumption and the metabolism of alcohol promote the production of inflammatory mediators (cytokines) that result in hepatotoxicity and fibrogenesis. With time, this leads to progressively severe liver injury and, eventually, causes cirrhosis. Unfortunately, effective therapies for most individuals with ALD have not been found. High per capita consumption of alcohol, coupled with the dearth of effective treatments and the failure of most affected individuals to abstain from alcohol, explains why ALD is one of the most prevalent forms of disabling, chronic liver disease in the United States.
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Affiliation(s)
- A M Diehl
- Johns Hopkins University, Baltimore, Maryland 21205, USA
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Berneis K, Ninnis R, Keller U. Ethanol exerts acute protein-sparing effects during postabsorptive but not during anabolic conditions in man. Metabolism 1997; 46:750-5. [PMID: 9225827 DOI: 10.1016/s0026-0495(97)90118-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Ethanol abuse is frequently associated with protein malnutrition. To assess the acute effects of ethanol on whole-body protein metabolism, [1-13C]leucine kinetics were measured in eight postabsorptive normal male subjects three times, ie, during administration of two doses of ethanol (dose 1, 0.52 g/kg during 2 hours and 0.3 g/kg during 3 hours; dose 2, 0.69 g/kg during 2 hours and 0.3 g/kg during 3 hours) and during saline (controls). During the last 2 hours of the studies, glucose, insulin, and amino acids were infused to assess the effects of ethanol on protein kinetics under anabolic conditions (euglycemic clamp). The decreases in leucine flux (reflecting whole-body protein breakdown) and nonoxidative leucine disappearance (a parameter of protein synthesis) during saline infusion were abolished in both ethanol protocols (P < .05 or less v saline). The rate of leucine oxidation decreased during the higher dose of ethanol compared with saline (P < .005), indicating an anticatabolic effect. During anabolic conditions (clamp), leucine flux and nonoxidative leucine disappearance were significantly higher in both ethanol studies compared with saline (P < .05). Resting energy expenditure (REE) and oxygen consumption (VO2) during the euglycemic clamp increased to a greater degree during both ethanol studies than during saline (P < .05 or less). Thus, an elevation of blood ethanol concentrations to the levels observed in social drinking results in a net anticatabolic effect (diminished leucine oxidation) when ethanol is administered alone. However, during administration of other nutritional substrates, the anticatabolic effect was not detectable, possibly because ethanol enhanced nutrient-induced thermogenesis.
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Affiliation(s)
- K Berneis
- Department of Research, University Hospital Basel, Switzerland
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37
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Abstract
Tremendous insights into the understanding of hepatic fibrosis have taken place over the past ten years. Foremost among these is the recognition that hepatic stellate cells (formerly known as lipocytes, Ito cells, or fat-storing cells) play a central role based on their ability to undergo activation following liver injury of any cause. Stellate cell activation is a broad phenotypic response, characterized by distinct functional changes in proliferation, contractility, fibrogenesis, cytokine secretion, and matrix degradation. Insights gained into the molecular regulation of hepatic stellate cell activation will lead to new, targeted approaches to hepatic fibrosis in the future, and could lead to reduced morbidity and mortality in patients with chronic liver injury.
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Abstract
More than 7 percent of all adults in the United States have met diagnostic criteria for alcohol abuse and alcohol dependence. Many of these people and even occasional users of alcohol may exhibit medical complexities, particularly liver disease, that can adversely affect provision of routine dental care. This article highlights some of the important clinical topics associated with alcoholic liver disease as it relates to dental care and provides guidelines on treatment of affected people.
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Affiliation(s)
- M Glick
- University of Pennsylvania School of Dental Medicine, Philadelphia 19104, USA
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39
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Affiliation(s)
- S Sherlock
- Department of Surgery, Royal Free Hospital School of Medicine, London, UK
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Bellentani S, Tiribelli C, Saccoccio G, Sodde M, Fratti N, De Martin C, Cristianini G. Prevalence of chronic liver disease in the general population of northern Italy: the Dionysos Study. Hepatology 1994; 20:1442-9. [PMID: 7982643 DOI: 10.1002/hep.1840200611] [Citation(s) in RCA: 321] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Data on the prevalence of chronic liver disease, derived from selected series of hospitalized patients or from mortality registers, underestimate the prevalence of chronic liver disease. The Dionysos Study is a cohort study that investigated for the first time the prevalence of chronic liver disease in a general population. All the citizens of two towns in northern Italy, Campogalliano and Cormons, aged 12 to 65 yr were contacted by letter. From March 1991 through March 1993, 6,917 of a total of 10,150 citizens were enrolled (compliance, 69%). The standardized protocol for each enrollee included (a) a color-illustrated food questionnaire on dietary habits and alcohol intake; (b) a detailed medical history, including questions on risk factors for chronic liver disease; (c) a physical examination; and (d) blood tests for AST, ALT, gamma-glutamyltranspeptidase, mean cell volume, platelet count and hepatitis B virus and hepatitis C virus markers. Signs suggestive of chronic liver disease were seen in 21.3% of the subjects, and who then underwent further liver function tests, upper abdominal ultrasonography and, when necessary, liver biopsy. Persistent signs of chronic liver disease were present in 17.5% of the subjects, including 1.1% with cirrhosis and 0.07% with hepatocellular carcinoma. The prevalence rates of hepatitis B virus and hepatitis C virus positivity (second-generation enzyme-linked immunosorbent assay) were 1.3% and 3.2%, respectively. Alcohol abuse was the etiological agent in 23%.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S Bellentani
- Centro Studi fegato, Fondo per lo Studio delle Malattie del Fegato, Italy
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