- Email: [email protected]
528 INCREASED HEPCIDIN SECRETION BY INFLAMMATORY CYTOKINES IN PATIENTS WITH ALCOHOLIC LIVER DISEASE
POSTERS 526 RAISED COMBINED SERUM FREE LIGHT CHAINS ARE ASSOCIATED WITH LIVER TRANSPLANTATION IN ALCOHOLIC LIVER DISEASE J.M. Faint1 , L.K. Assi1 , B.K. Gunson2 , E.A. Darlow2 , D.H. Adams2 . 1 Clinical R+D, The Binding Site Group, Ltd., 2 NIHR BRU in Liver Disease and Centre for Liver Research, University of Birmingham, Birmingham, UK E-mail: [email protected] Background and Aims: It is well known that some inflammatory markers are elevated in alcoholic liver disease (ALD) but they are not routinely used to predict survival or select for transplantation. Dysregulated antibody secretion and increased circulating levels of IgG, IgM and particularly IgA are associated with ALD. Recent studies report raised combined ú+l serum free light chains (cFLC) in patients with chronic inflammatory disease leading us to investigate their use compared with MELD scores as prognostic markers in ALD. Methods: cFLC (Combylite™, The Binding Site Group Ltd, Birmingham UK) was measured in stored sera from 340 ALD patients (157/340 (46%) with alcoholic cirrhosis (AC); 70/340 (21%) required transplant)) median follow up 9.9 months (range 0–46 months). Results were compared to patients MELD scores at sample collection (median 12; range 6–37) and cFLC concentrations from healthy controls (median 20 mg/L; range 9–50 mg/L). Results: In all patients, median cFLC levels were 49.9 mg/L (range, 11.0–337.4). Patients progressing to transplant had higher cFLC levels and MELD scores (cFLC: 61.9 mg/L, 21.3–164.2 mg/L vs 47 mg/L, 11–337.4 mg/L; p = 0.001; MELD: 16, 6–25 vs 11, 6–37; p < 0.001). Raised concentrations of cFLC (>50 mg/L) were associated with shorter time to transplant (TTT, Hazard Ratio=1.8; 95% CI=1.1–3.0, p = 0.014, transplants in 25% patients >50 mg/L=9 months, <50 mg/L=23 months, p = 0.012) as were elevated MELD levels (>11) (TTT Hazard Ratio=2.9; 95% CI=1.7–4.8, p < 0.001). A simple model including raised cFLC (>50 mg/L) and MELD (>11) as categorical risk factors identified patients with 0 (n = 102), 1 (n = 132) or 2 (n = 106) risk factors with transplant in 25% patients after 30 vs 13 vs 7 months, respectively p < 0.0001. In addition, the model stratified AC patients more effectively than MELD alone. Patients with 0 risk factors had a longer TTT than those with a high MELD score (>11) with transplants in 25% patients after 30 vs 23 months (3/38, 8% vs 10/71, 14%) respectively. Conclusion: The addition of cFLC measurements improved the prediction of TTT of the MELD score in ALD. Prospective studies will determine the role of cFLC and MELD in predicting outcome in patients with ALD but our data suggest a model incorporating cFLC will improve predictive capacity in liver. 527 VALPROIC ACID INDUCED MITOCHONDRIAL CHOLESTEROL LOADING AND SUBSEQUENT GSH DEPLETION SENSITIZES TO ACETAMINOPHEN TOXICITY 1,2 1 ´ . Cell Death and A. Baulies1,2 , C. Garc´ıa-Ruiz1,2 , J. Fernandez-Checa Proliferation, Instituto de Investigaciones Biomedicas de Barcelona, CSIC, 2 Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Universitat Barcelona, Barcelona, Spain E-mail: [email protected] Background: The branched short-chain fatty acid valproic acid (VPA) is widely used as an anticonvulsant, primarily in the treatment of epilepsy, bipolar disorder and migraine prophylaxis. The mechanisms of action remain unclear, although it has been shown to alter a wide variety of signaling pathways and a small number of direct targets (e.g. GSKa/b). Moreover, VPA targets mitochondria and induces mitochondrial permeability transition. There is evidence that glutathione (GSH) homeostasis may be altered as a consequence of reactive metabolites and/or reactive oxygen species produced during VPA treatment and may play an S216
important role in VPA-induced hepatotoxicity. Therefore, VPA use in patients is associated with mitochondrial dysfunction, weight gain and hepatic steatosis. Thus, the aim of our study was to investigate the role of VPA in cholesterol homeostasis and intracellular trafficking, in particular, if VPA induces mitochondrial cholesterol accumulation and mitochondrial GSH (mGSH) depletion, and if this effect sensitizes to acetaminophen (APAP) toxicity. Methods: Mitochondrial cholesterol trafficking and GSH levels were analyzed in F2-CHO cells transfected with Cyp11a1 treated with VPA (100–1000 mM), measuring mitochondrial cholesterol loading by confocal imaging and pregnonoleone levels by ELISA. Expression of StAR, MLN64, ER stress markers and lipogenic transcription factors were examined by qPCR and WB. Liver damage, cholesterol trafficking, GSH homeostasis and mitochondrial function was examined in mice following VPA treatment (400 mg/Kg). VPAtreated mice were administered APAP (300 mg/kg) and liver injury examined by ALT and H&E. Results: VPA selectively depleted mGSH levels (40–50%) in F2-CHO cell line and increased pregnenolone levels, indicating enhanced mitochondrial cholesterol levels. In parallel to these observations, VPA induced the expression of MLN64, StAR and mitochondrial cholesterol accumulation was observed by confocal imaging after VPA treatment. Hepatic extracts from VPA treated wild type mice exhibited microvesicular steatosis, liver injury, mitochondrial cholesterol accumulation and mGSH depletion. VPA treatment significally induced ER stress markers and the expression of lipogenic transcription factors. Importantly, VPA treatment in fed mice sensitized to APAP treatment (4000U/dL in VPA-treated mice vs 30U/dL in control mice). Conclusions: VPA-induced mitochondrial cholesterol trafficking leading to subsequent mitochondrial GSH depletion, which in turn sensitized to APAP mediated liver injury. 528 INCREASED HEPCIDIN SECRETION BY INFLAMMATORY CYTOKINES IN PATIENTS WITH ALCOHOLIC LIVER DISEASE N. Fujita1 , H. Miyachi1 , R. Sugimoto1 , R. Moroka1 , H. Tanaka1 , M. Iwasa1 , N. Tomosugi2 , Y. Takei1 . 1 Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, 2 Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan E-mail: [email protected] Background and Aims: Patients with alcoholic liver disease (ALD) are frequently associated with iron overload, but little is known about its causative mechanism. Recent work has established the importance of hepatocyte produced-hepcidin in iron homeostasis as a negative regulator of iron release from duodenal enterocytes. Hepatocytes respond to variety signals to hepcidin secretion, such as iron loading and inflammatory stimuli. To evaluate the hepcidin secretion in ALD, we measured the serum hepcidin, and its sequential changes after abstaining of alcohol. Methods: Serum hepcidin was measured in 67 ALD (M/F = 62/5, age = 56.5±13.0 yr, drinking ethanol = 141±66 g/day at entry) by SELDITOF-MS, and compared to those of healthy controls (M/F = 6/4, age = 49.2±11.3 yr). Serum IL-6 and IL-1b were also measured by ELISA. Serum hepcidin and cytokines were monitored after abstaining. Results: Many ALD patients had iron overload condition at entry (serum ferritin = 323±461 ng/ml, hepatic iron score = 7.6±8.1). Serum hepcidin was positively correlated with serum ferritin (r = 0.941) and the degree of hepatic iron deposit (r = 0.697). Serum hepcidin was significantly higher in ALD than in controls at entry (89.5±114.0 vs. 21.8±9.4 ng/ml, P = 0.01), and immediately decreased after abstaining (35.6±22.8 ng/ml after 3 months). Serum hepcidin-to-ferritin ratio was significantly higher in ALD than in controls (0.35±0.20 vs. 0.23±0.10, P = 0.03), and this ratio was also decreased after abstaining (0.27±0.13 after 3 months). Patients with
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POSTERS positive serum C reactive protein (CRP) had high hepcidin-to-ferrtin ratio compared to those with negative CRP (0.45±0.5 vs. 0.31±0.15, P < 0.01). Serum IL-6 of ALD was also decreased after abstaining (from 3.15±2.23 to 2.20±1.16 pg/ml during 3 month). Conclusions: Hepcidin secretion responds to iron condition and this response is enhanced by systemic inflammation in ALD. Because the enhanced hepcidin secretion is usually causative to iron deficiency, iron overload seen in ALD may be caused by bluntness of duodenal enterocytes to hepcidin by ethanol. 529 ETHANOL STIMULATES PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN HEPATIC STELLATE CELLS A. Gackowska, D. Mann, J. Mann. Newcastle University, Newcastle Upon Tyne, UK E-mail: [email protected] Background: Consumption of alcohol is a leading cause of liver fibrosis; however the mechanisms underlying ethanol-induced liver fibrosis are still unknown. Transdifferentiation of hepatic stellate cells (HSC) generates hepatic myofibroblasts, which are the key cells responsible for onset and progression of liver fibrosis. We investigated epigenetic regulation that causes expression changes of extracellular matrix (ECM) proteins in ethanol treated cultures of primary rat HSC. Methods: Rat hepatic stellate cells were treated at day 1, 2, 3, 5, 7 and 10 of culture for 24h and 48h with 86mM ethanol (dose equivalent to heavy drinking in humans). Expression levels of collagen I, III, IV, elastin and fibronectin were assessed and measured by qRT-PCR. Chromatin immunoprecipitation assay (ChIP) was used to examine epigenetic events at the ECM proteins. Results: Expression of ECM proteins is upregulated during HSC transdifferentiation, however ethanol treatment causes further increase in mRNA expression for collagen I, III, IV and elastin. The biggest changes were observed during early stages of HSC transdiferentiation (day1–3) at 48h of ethanol treatment. Small or no difference was seen in expression of fibronectin. ChIP assay showed that ethanol-induced gene expression is associated with altered methylation patterns of histone H3. Conclusions: There were significant differences in ECM proteins expression between ethanol-treated and control HSCs. Changes in expression of ECM proteins in ethanol-stimulated HSC appear to be regulated by modifications in epigenetic events. Evidence for epigenetic changes in ethanol-induced liver fibrosis might be helpful in diagnosis and may provide a future target for treatment of liver fibrosis. 530 CURCUMIN NANOPARTICLES: A POTENTIAL ORAL FORMULATION IN PREVENTING ALCOHOL INDUCED LIVER DAMAGE IN RAT MODEL D. Ghosh. Cancer Biology & Inflammatory Disorder, Indian Institute of Chemical Biology (CSIR), Kolkata, India E-mail: [email protected] Background and Aims: Alcoholic liver disease results from dose and time dependent exposure to alcohol. Alcohol mediated liver cirrhosis is growing at an alarming rate in the western world. Massive oxidative stress and depressed antioxidant status induced by ethanol metabolism play a major role in alcohol manifestation and liver damage. Curcumin, a very well known dietary antioxidant is known to have beneficial effect in circumventing alcohol induced liver damage. However its poor oral bioavailability is a major drawback limiting its potency and impelling the use of large doses for having beneficial effects. To overcome this limitation our aim was to investigate the efficacy of consuming oral curcumin encapsulated nanoparticles at a much lower dose as compared to free curcumin in preventing alcohol induced liver damage.
Methods: Alcoholic liver damage was induced in rats by consumption of ethanol. Biodegradable curcumin nanoparticles were given orally daily prior to alcohol consumption. ROS generation, membrane lipid peroxidation, microviscosity, antioxidant enzymes, NF-úB translocation, inflammatory proteins like NOS-2 and Cox-2 and mitochondrial cytochrome C release in the cytosol were measured in the liver tissue. Histopathology of the liver sections was done. Results: Alcohol consumption led to a massive generation of ROS. Alcohol induced liver damage was confirmed by histopathological analysis of liver sections and factors related to cell degeneration. NF-úB translocation in the nucleus, increase in Nos-2 and Cox-2 expression and release of cytochrome C in the cytosol were seen in alcohol induced control group of rats. Nanoparticulated curcumin treatment however prevented increased ROS, restored membrane integrity, prevented downregulation of membrane microviscosity and antioxidant enzymes with an inhibition of NF-úB activation and reduced the expression of inflammatory proteins. Histopathological analysis confirmed the pathological improvement of the liver. Free curcumin at the same dose was ineffective. Conclusion: Delivering a herb origin antioxidant curcumin in biodegradable nanoparticles containing a very low dose of the compound proved to be useful in overcoming the limitation of free curcumin and may be recommended as a very potent formulation in preventing alcohol induced liver damage. Acknowledgements: Council of Scientific & Industrial Research. 531 DEVELOPMENT OF DECOMPENSATED ALCOHOLIC LIVER DISEASE (ALD) IS ASSOCIATED WITH STARTING HEAVY DRINKING AT AN OLDER AGE: A CASE–CONTROL STUDY D. Gleeson1 , A.K. Ali1 , J.S. Jones1 , M.P. Bradley1 , R.J. Peck2 , K.M. McCormack3 . 1 Liver Unit, 2 Department of Radiology, 3 Research, Sheffield Teaching Hospitals Foundation NHS Trust, Sheffield, UK E-mail: [email protected] Background and Aims: The relationship between development of ALD (which affects only 10–15% of heavy drinkers) and rate, duration and age of onset of alcohol consumption is incompletely understood. We have previously (J Hepatol 2012; 56:S530) reported on total lifetime alcohol consumption in two cohorts of heavy drinkers (>60 Units/wk (M) or >40 Units/wk (F) for >5 years): one (patients) with decompensated ALD (Child Grade B or C, negative tests for other liver diseases) and one (controls) without serious liver disease on clinical, laboratory and ultrasound examination. Here, we aimed to compare alcohol consumption patterns in these cohorts in more detail. Methods: Subjects (330 patients, 234 male, mean age 48 yr and 238 heavy-drinking controls, 187 male, mean age 48 yr) completed a lifetime alcohol questionnaire. Alcohol consumption was calculated at home and outside home, and during Monday–Thursday and Friday–Sunday. Data were summed over each stable drinking period during the subject’s lifetime. We calculated total duration, and age at start and at cessation of all periods during which the subject drank >0, >40, >80, >120 and >160 units (U)/wk. Results: Neither total duration of periods consuming >0, >40, >80, >120, and >160 U alcohol/wk (table) nor mean weekly consumption during those periods (not shown) differed between patients and controls. However, patients first started drinking over each level at an older age than did controls (table). The relationships between ALD and age of starting drinking >0, >40, >80, >120 and >160 U/week persisted in multivariate analysis (p = 0.00–0.013). Conclusions: Development of decompensated ALD in heavy drinkers is associated with starting heavy drinking at an older age.
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important role in VPA-induced hepatotoxicity. Therefore, VPA use in patients is associated with mitochondrial dysfunction, weight gain and hepatic steatosis. Thus, the aim of our study was to investigate the role of VPA in cholesterol homeostasis and intracellular trafficking, in particular, if VPA induces mitochondrial cholesterol accumulation and mitochondrial GSH (mGSH) depletion, and if this effect sensitizes to acetaminophen (APAP) toxicity. Methods: Mitochondrial cholesterol trafficking and GSH levels were analyzed in F2-CHO cells transfected with Cyp11a1 treated with VPA (100–1000 mM), measuring mitochondrial cholesterol loading by confocal imaging and pregnonoleone levels by ELISA. Expression of StAR, MLN64, ER stress markers and lipogenic transcription factors were examined by qPCR and WB. Liver damage, cholesterol trafficking, GSH homeostasis and mitochondrial function was examined in mice following VPA treatment (400 mg/Kg). VPAtreated mice were administered APAP (300 mg/kg) and liver injury examined by ALT and H&E. Results: VPA selectively depleted mGSH levels (40–50%) in F2-CHO cell line and increased pregnenolone levels, indicating enhanced mitochondrial cholesterol levels. In parallel to these observations, VPA induced the expression of MLN64, StAR and mitochondrial cholesterol accumulation was observed by confocal imaging after VPA treatment. Hepatic extracts from VPA treated wild type mice exhibited microvesicular steatosis, liver injury, mitochondrial cholesterol accumulation and mGSH depletion. VPA treatment significally induced ER stress markers and the expression of lipogenic transcription factors. Importantly, VPA treatment in fed mice sensitized to APAP treatment (4000U/dL in VPA-treated mice vs 30U/dL in control mice). Conclusions: VPA-induced mitochondrial cholesterol trafficking leading to subsequent mitochondrial GSH depletion, which in turn sensitized to APAP mediated liver injury. 528 INCREASED HEPCIDIN SECRETION BY INFLAMMATORY CYTOKINES IN PATIENTS WITH ALCOHOLIC LIVER DISEASE N. Fujita1 , H. Miyachi1 , R. Sugimoto1 , R. Moroka1 , H. Tanaka1 , M. Iwasa1 , N. Tomosugi2 , Y. Takei1 . 1 Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, 2 Medical Research Institute, Kanazawa Medical University, Kanazawa, Japan E-mail: [email protected] Background and Aims: Patients with alcoholic liver disease (ALD) are frequently associated with iron overload, but little is known about its causative mechanism. Recent work has established the importance of hepatocyte produced-hepcidin in iron homeostasis as a negative regulator of iron release from duodenal enterocytes. Hepatocytes respond to variety signals to hepcidin secretion, such as iron loading and inflammatory stimuli. To evaluate the hepcidin secretion in ALD, we measured the serum hepcidin, and its sequential changes after abstaining of alcohol. Methods: Serum hepcidin was measured in 67 ALD (M/F = 62/5, age = 56.5±13.0 yr, drinking ethanol = 141±66 g/day at entry) by SELDITOF-MS, and compared to those of healthy controls (M/F = 6/4, age = 49.2±11.3 yr). Serum IL-6 and IL-1b were also measured by ELISA. Serum hepcidin and cytokines were monitored after abstaining. Results: Many ALD patients had iron overload condition at entry (serum ferritin = 323±461 ng/ml, hepatic iron score = 7.6±8.1). Serum hepcidin was positively correlated with serum ferritin (r = 0.941) and the degree of hepatic iron deposit (r = 0.697). Serum hepcidin was significantly higher in ALD than in controls at entry (89.5±114.0 vs. 21.8±9.4 ng/ml, P = 0.01), and immediately decreased after abstaining (35.6±22.8 ng/ml after 3 months). Serum hepcidin-to-ferritin ratio was significantly higher in ALD than in controls (0.35±0.20 vs. 0.23±0.10, P = 0.03), and this ratio was also decreased after abstaining (0.27±0.13 after 3 months). Patients with
Journal of Hepatology 2013 vol. 58 | S63–S227
POSTERS positive serum C reactive protein (CRP) had high hepcidin-to-ferrtin ratio compared to those with negative CRP (0.45±0.5 vs. 0.31±0.15, P < 0.01). Serum IL-6 of ALD was also decreased after abstaining (from 3.15±2.23 to 2.20±1.16 pg/ml during 3 month). Conclusions: Hepcidin secretion responds to iron condition and this response is enhanced by systemic inflammation in ALD. Because the enhanced hepcidin secretion is usually causative to iron deficiency, iron overload seen in ALD may be caused by bluntness of duodenal enterocytes to hepcidin by ethanol. 529 ETHANOL STIMULATES PRODUCTION OF EXTRACELLULAR MATRIX PROTEINS IN HEPATIC STELLATE CELLS A. Gackowska, D. Mann, J. Mann. Newcastle University, Newcastle Upon Tyne, UK E-mail: [email protected] Background: Consumption of alcohol is a leading cause of liver fibrosis; however the mechanisms underlying ethanol-induced liver fibrosis are still unknown. Transdifferentiation of hepatic stellate cells (HSC) generates hepatic myofibroblasts, which are the key cells responsible for onset and progression of liver fibrosis. We investigated epigenetic regulation that causes expression changes of extracellular matrix (ECM) proteins in ethanol treated cultures of primary rat HSC. Methods: Rat hepatic stellate cells were treated at day 1, 2, 3, 5, 7 and 10 of culture for 24h and 48h with 86mM ethanol (dose equivalent to heavy drinking in humans). Expression levels of collagen I, III, IV, elastin and fibronectin were assessed and measured by qRT-PCR. Chromatin immunoprecipitation assay (ChIP) was used to examine epigenetic events at the ECM proteins. Results: Expression of ECM proteins is upregulated during HSC transdifferentiation, however ethanol treatment causes further increase in mRNA expression for collagen I, III, IV and elastin. The biggest changes were observed during early stages of HSC transdiferentiation (day1–3) at 48h of ethanol treatment. Small or no difference was seen in expression of fibronectin. ChIP assay showed that ethanol-induced gene expression is associated with altered methylation patterns of histone H3. Conclusions: There were significant differences in ECM proteins expression between ethanol-treated and control HSCs. Changes in expression of ECM proteins in ethanol-stimulated HSC appear to be regulated by modifications in epigenetic events. Evidence for epigenetic changes in ethanol-induced liver fibrosis might be helpful in diagnosis and may provide a future target for treatment of liver fibrosis. 530 CURCUMIN NANOPARTICLES: A POTENTIAL ORAL FORMULATION IN PREVENTING ALCOHOL INDUCED LIVER DAMAGE IN RAT MODEL D. Ghosh. Cancer Biology & Inflammatory Disorder, Indian Institute of Chemical Biology (CSIR), Kolkata, India E-mail: [email protected] Background and Aims: Alcoholic liver disease results from dose and time dependent exposure to alcohol. Alcohol mediated liver cirrhosis is growing at an alarming rate in the western world. Massive oxidative stress and depressed antioxidant status induced by ethanol metabolism play a major role in alcohol manifestation and liver damage. Curcumin, a very well known dietary antioxidant is known to have beneficial effect in circumventing alcohol induced liver damage. However its poor oral bioavailability is a major drawback limiting its potency and impelling the use of large doses for having beneficial effects. To overcome this limitation our aim was to investigate the efficacy of consuming oral curcumin encapsulated nanoparticles at a much lower dose as compared to free curcumin in preventing alcohol induced liver damage.
Methods: Alcoholic liver damage was induced in rats by consumption of ethanol. Biodegradable curcumin nanoparticles were given orally daily prior to alcohol consumption. ROS generation, membrane lipid peroxidation, microviscosity, antioxidant enzymes, NF-úB translocation, inflammatory proteins like NOS-2 and Cox-2 and mitochondrial cytochrome C release in the cytosol were measured in the liver tissue. Histopathology of the liver sections was done. Results: Alcohol consumption led to a massive generation of ROS. Alcohol induced liver damage was confirmed by histopathological analysis of liver sections and factors related to cell degeneration. NF-úB translocation in the nucleus, increase in Nos-2 and Cox-2 expression and release of cytochrome C in the cytosol were seen in alcohol induced control group of rats. Nanoparticulated curcumin treatment however prevented increased ROS, restored membrane integrity, prevented downregulation of membrane microviscosity and antioxidant enzymes with an inhibition of NF-úB activation and reduced the expression of inflammatory proteins. Histopathological analysis confirmed the pathological improvement of the liver. Free curcumin at the same dose was ineffective. Conclusion: Delivering a herb origin antioxidant curcumin in biodegradable nanoparticles containing a very low dose of the compound proved to be useful in overcoming the limitation of free curcumin and may be recommended as a very potent formulation in preventing alcohol induced liver damage. Acknowledgements: Council of Scientific & Industrial Research. 531 DEVELOPMENT OF DECOMPENSATED ALCOHOLIC LIVER DISEASE (ALD) IS ASSOCIATED WITH STARTING HEAVY DRINKING AT AN OLDER AGE: A CASE–CONTROL STUDY D. Gleeson1 , A.K. Ali1 , J.S. Jones1 , M.P. Bradley1 , R.J. Peck2 , K.M. McCormack3 . 1 Liver Unit, 2 Department of Radiology, 3 Research, Sheffield Teaching Hospitals Foundation NHS Trust, Sheffield, UK E-mail: [email protected] Background and Aims: The relationship between development of ALD (which affects only 10–15% of heavy drinkers) and rate, duration and age of onset of alcohol consumption is incompletely understood. We have previously (J Hepatol 2012; 56:S530) reported on total lifetime alcohol consumption in two cohorts of heavy drinkers (>60 Units/wk (M) or >40 Units/wk (F) for >5 years): one (patients) with decompensated ALD (Child Grade B or C, negative tests for other liver diseases) and one (controls) without serious liver disease on clinical, laboratory and ultrasound examination. Here, we aimed to compare alcohol consumption patterns in these cohorts in more detail. Methods: Subjects (330 patients, 234 male, mean age 48 yr and 238 heavy-drinking controls, 187 male, mean age 48 yr) completed a lifetime alcohol questionnaire. Alcohol consumption was calculated at home and outside home, and during Monday–Thursday and Friday–Sunday. Data were summed over each stable drinking period during the subject’s lifetime. We calculated total duration, and age at start and at cessation of all periods during which the subject drank >0, >40, >80, >120 and >160 units (U)/wk. Results: Neither total duration of periods consuming >0, >40, >80, >120, and >160 U alcohol/wk (table) nor mean weekly consumption during those periods (not shown) differed between patients and controls. However, patients first started drinking over each level at an older age than did controls (table). The relationships between ALD and age of starting drinking >0, >40, >80, >120 and >160 U/week persisted in multivariate analysis (p = 0.00–0.013). Conclusions: Development of decompensated ALD in heavy drinkers is associated with starting heavy drinking at an older age.
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