Genetic and lifestyle risk factors for advanced liver disease among men and women

Background and Aim Liver disease is traditionally categorized as alcoholic and non-alcoholic. We studied various risk factors predictive of advanced non-viral liver disease in general population and analyzed the interaction between these factors and alcohol consumption. Methods Persons without underlying liver disease who participated in the Health2000 or FINRISK studies 1992-2012 comprised a cohort of 41 260 individuals. Pattern of alcohol consumption and metabolic, lifestyle-related, and anthropometric parameters were analyzed with Cox regression analysis using severe liver disease hospitalization, cancer, or death as end-point. Viral liver diseases were excluded. Results A total of 355 liver events occurred during the mean 12.4-year follow-up (511 789 person-years). In the multivariate model, age (hazard ratio [HR] 1.03, P = 0.0083 for men; HR 1.04, P = 0.0198 for women), waist-to-hip ratio (WHR) (HR 1.52, P = 0.0006 for men; HR 1.58, P = 0.0167 for women), patatin-like phospholipase-containing domain 3 mutations (HR 1.9, P = 0.024 for men; HR 2.7, P = 0.0109 for women), and weekly binge drinking (HR 2.4, P = 0.0024 for men; HR 7.4, P <0.0001 for women) predicted development of severe liver disease. Among men, diabetes (HR 2.7, P = 0.0002), average alcohol consumption (HR for 10 g/day 1.1, P = 0.0022), non-married status (HR 1.9, P = 0.0397 for single; HR 2.4, P = 0.0002 for widowed/separated), and serum high-density lipoprotein (HR 2.2, P = 0.0022) and non-high-density lipoprotein cholesterol (HR 1.2, P = 0.0237) were additional risk factors. Alcohol intake increased the risk especially among persons with high WHR (P for interaction 0.009). Conclusions Age, patatin-like phospholipase-containing domain 3 haplotype, and WHR increase the risk for development of severe liver disease. We found strong synergism between alcohol and central obesity. Binge drinking is an additional risk factor.Peer reviewe

Alcoholic liver disease : epidemiology, prognosis and risk factors

The most severe manifestations of alcoholic liver disease (ALD) are alcoholic liver cirrhosis and alcoholic hepatitis (AH). The purpose of this study was to examine incidence, risk factors, prognosis and malignant comorbidities of ALD in a cohort of patients with alcoholic liver cirrhosis (n=7746) and AH (n=4127) as an inpatient diagnosis during years 1996-2012 identified from the national Hospital Discharge Registry and followed until death or incidence of cancer (41209 person-years). There was increase in incidence of alcoholic liver cirrhosis (by 66% among men and 75% among women) and AH (by 76% among men and 108% among women) during the study period. Survival of the patients was poor, 5-year relative survival rates for male and female alcoholic liver cirrhosis patients being 0.28 (95%CI 0.27-0.30) and 0.39 (95%CI 0.36-0.41), and for all patients with AH 0.46 (95%CI: 0.44-0.48) without difference between sexes. Majority of the patients died from alcohol-related causes. Risk for mortality from several other causes was increased: cancers (standardised mortality ratio [SMR] 6.82; 95%CI 6.35-7.29), digestive diseases (SMR 27.95; 95%CI 24.78–31.31), respiratory diseases (SMR 7.86; 95%CI 6.70–9.10) and circulatory diseases (SMR 6.13; 95%CI 5.74–6.52). The risk of accidental or violent death was increased (11.12; 95%CI 10.13-12.15), as well. Standardised cancer incidence among patients with advanced ALD was 2.86 (95%CI 2.69-3.03) There was increased risk for cancer of liver (SIR 59.20; 95%CI 53.11–65.61) pancreas (SIR 3.71; 95%CI 2.72-24.94), pharynx (SIR 9.25; 95%CI 6.05–13.56), mouth (SIR 8.31; 95%CI 4.84–13,29), tongue (SIR 7,21; 95%CI 3.60–12.89), oesophagus (SIR 7.92; 95%CI 5.49–11.07), larynx (SIR 5.20; 95%CI 2.77–8.89), lung (SIR 2.77; 95%CI 2.27– 3.32), stomach (SIR 2.76; 95%CI 1.79–4.07), kidney (SIR 2.69; 95 CI 1.84–3.79), colon (SIR 2.33; 95%CI 1.70–3.11), cervix uteri (SIR 4.93; 95%CI 1.34–12.63) and non-melanoma skin cancer (SIR 1.89; 95%CI 1.18–2.86) . Alterations in cholesterol metabolism in severe AH were studied among 24 hospitalised patients with severe AH treated with prednisolone and randomised to get either prednisolone alone or in combination with ciprofloxacin to identify potential prognostic factors to predict response to corticosteroid therapy at baseline. AH patients had a distinct profile of sterol metabolism compared to patients with primary sclerosing cholangitis and healthy individuals. Certain non-cholesterol sterols (i.e. plant sterols) putatively reflecting the nutritional status of the patients were related to response to corticosteroids. High serum level of ferritin at baseline predicted poor response to corticosteroid therapy. Potential risk factors besides alcohol for advanced liver disease were studied in a cohort of 41260 individuals comprised of persons participating Health2000 or FINRISK studies 1992-2012 without an underlying liver disease. Age, PNPLA3 haplotype and WHR increased the risk for advanced liver disease. There is synergism between alcohol intake and central obesity to the risk. Binge drinking poses an additional risk factor.Alkoholimaksasairaus on keskeisimpiä alkoholin liikakäytön haittoja. Sen vaikeimmat muodot ovat alkoholimaksakirroosi ja alkoholihepatiitti. Tässä tutkimuksessa selvitettiin alkoholimaksasairauden ilmaantuvuutta, ennustetta ja alkoholimaksasairauteen liittyvää syöpäriskiä vuosina 1996-2012 sairaalahoidossa olleiden potilaiden muodostamassa kohortissa (41209 potilasvuotta). Alkoholimaksakirroosin ilmaantuvuus lisääntyi vuosina 2001-2012 miehillä 66% ja naisilla 75%, alkoholihepatiitin ilmaantuvuus miehillä 75% ja naisilla 108%. Vaikean alkoholimaksasairauden ennuste osoittautui huonoksi. Viiden vuoden suhteellinen elossaolo alkoholimaksakirroosia sairastavilla miehillä oli 28% ja naisilla 39% ja alkoholihepatiitin sairastaneilla 46% ilman selviä eroja sukupuolten välillä. Suurin osa kuolemista oli alkoholiin liittyviä. Kuolemanriski syöpiin oli 6,82-kertainen muuhun väestöön verrattuna, ruoansulatuselinten sairauksiin 27,95-kertainen, hengityselinten sairauksiin 7.86-kertainen verenkiertoelinten sairauksiin 6,13-kertainen. Tapaturmaisen ja väkivaltaisen kuoleman riski oli 11,12-kertainen. Vaikea alkoholimaksasairaus lisäsi syövän riskiä 2,86-kertaiseksi taustaväestöön verrattuna. Maksasyövän riski oli 59,2-kertainen. Myös haimasyövän, nielusyövän, suusyövän, kielisyövän, ruokatorvisyövän, kurkunpään syövän, keuhkosyövän, mahasyövän, munuaissyövän, paksusuolen syövän, kohdunkaulan syövän ja ei-melanooma-tyyppisen ihosyövän riski oli suurentunut. Alkoholihepatiittiin liittyviä kolesterolimetabolian muutoksia tutkittiin 24 vaikean alkoholihepatiitin takia sairaalahoitoon joutuneella potilaalla osana satunnaistettua tutkimusasetelemaa, jossa potilaat saivat joko pelkkää prednisolonia tai prednisolonia yhdistettynä siprofloksasiiniin. Alkoholihepatiittipotilailla todettiin poikkeava ei-kolesterolisteroleiden metabolia terveisiin verrokkeihin ja primaaria sklerosoivaa kolangiittia sairastaviin verrattuna. Seerumin matalilla kasvisterolipitoisuuksilla oli yhteys huonoon kortiokosteroidihoidon vasteeseen. Seerumin korkea ferritiinipitoisuus liittyi huonoon hoitovasteeseen. Alkoholista riippumattomia vakavan maksasairauden riskejä tutkittiin 41260 henkilön muodostamassa kohortissa, joka koostui 1992-2012 Finriski- ja Terveys2000 -tutkimuksiin osallistuneista. Ikä, PNPLA3-geenin variaatiot ja korkea vyötärön-lantionympäryssuhde lisäsivät vakavan maksasairauden riskiä. Keskivartalolihavuus lisäsi alkoholista johtuvaa maksasairauden riskiä. Humalahakuinen juominen oli vakavan maksasairauden erillinen riskitekijä