Hepatic steatosis, metabolic dysfunction and risk of mortality: findings from a multinational prospective cohort study.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are implicated in the aetiology of non-communicable diseases. Our study aimed to evaluate associations between NAFLD and MetS with overall and cause-specific mortality. METHODS: We used dietary, lifestyle, anthropometric and metabolic biomarker data from a random subsample of 15,784 EPIC cohort participants. NAFLD was assessed using the fatty liver index (FLI) and MetS using the revised definition. Indices for metabolic dysfunction-associated fatty liver disease (MAFLD) were calculated. The individual associations of these indices with overall and cause-specific mortality were assessed using multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). As a subobjective, risk associations with adaptations of new classifications of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic and alcohol-related liver disease (MetALD) were also assessed. RESULTS: Among the 15,784 sub-cohort participants, a total of 1997 deaths occurred (835 due to cancer, 520 to CVD, 642 to other causes) over a median 15.6 (IQR, 12.3-17.1) years of follow-up. Compared to an FLI < 30, FLI ≥ 60 was associated with increased risks of overall mortality (HR = 1.44, 95%CI = 1.27-1.63), and deaths from cancer (HR = 1.32, 95%CI = 1.09-1.60), CVD (HR = 2.06, 95% CI = 1.61-2.63) or other causes (HR = 1.21, 95%CI = 0.97-1.51). Mortality risk associations were also elevated for individuals with MAFLD compared to those without. Individuals with MetS were at increased risk of all mortality endpoints, except cancer-specific mortality. MASLD and MetALD were associated with higher risk of overall mortality. CONCLUSIONS: Our findings based on a prospective cohort suggest that individuals with hepatic steatosis or metabolic dysfunction have a higher overall and cause-specific mortality risk.

Severe obesity is associated with worse outcomes than lean metabolic dysfunction-associated steatotic liver disease.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in people with obesity. We aimed to study the association of body mass index (BMI) with clinical outcomes in patients with MASLD. METHODS: A retrospective cohort of 32,900 patients with MASLD, identified through the International Classification of Diseases-9 and 10 codes within the electronic health records of a large US-based health system, with a mean follow-up of 5.5 years (range: 1-15 y), was stratified into 6 BMI categories, <25, 25-<30, 30-<40, 40-<50, and ≥50 kg/m2. RESULTS: The risk of liver decompensation and extrahepatic obesity-associated cancers had a J-shaped profile (both ps for linear and quadratic terms <0.05). Compared to patients with BMI 25-<30 kg/m2, the adjusted HRs (95% CIs) for liver decompensation of patients with BMI <25 and BMI ≥50 kg/m2 were 1.44 (1.17-1.77) and 2.27 (1.66-3.00), respectively. The corresponding figures for obesity-associated extrahepatic cancer were 1.15 (0.97-1.36) and 1.29 (1.00-1.76). There was an inverse association for BMI with liver transplantation and non-obesity-associated cancer (both ps for linear terms <0.05), but no association with HCC or all types of cancers combined. A similar J-shaped association between BMI and all-cause mortality was observed; adjusted HRs (95% CIs) for BMI <25 and ≥50 kg/m2 were 1.51 (1.32-1.72) and 3.24 (2.67-3.83), respectively, compared with BMI 25-<30 kg/m2 (both ps for linear and quadratic terms <0.001). CONCLUSIONS: Patients with MASLD and very severe obesity (BMI ≥50 kg/m2) had the highest risk, exceeding that of patients with lean MASLD, for developing liver decompensation, obesity-associated extrahepatic cancers, or dying from any cause.

Steatotic liver disease-associated all-cause/cause-specific mortality in the United States.

BACKGROUND: Recently, a panel of multi-society experts proposed steatotic liver disease (SLD) as an alternative terminology for metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD). AIMS: We compared the impact of SLD, subtype of SLD, MAFLD and NAFLD on all-cause and cause-specific mortality. METHODS: A total of 7811 individuals in the third National Health and Nutrition Examination Survey and linked mortality through 2019 were analysed. SLD was defined based on ultrasonographic hepatic steatosis. SLD, subtype of SLD and MAFLD were defined using the proposed definitions. The Cox proportional hazard model assessed all-cause/cause-specific mortality. RESULTS: During a median follow-up of 27.1 years, individuals with SLD and MAFLD experienced approximately 13%-23% higher risk of all-cause mortality (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.02-1.29 for SLD; HR: 1.23, 95% CI: 1.09-1.38 for MAFLD; HR: 1.13, 95% CI: 1.01-1.27 for metabolic dysfunction-associated steatotic liver disease [MASLD]). Individuals with MetALD demonstrated a higher risk of all-cause (HR: 1.68, 95% CI: 1.10-2.57) and cancer-related mortality (HR: 2.40, 95% CI: 1.23-4.66). MASLD with advanced fibrosis had an increased risk of all-cause mortality compared to MASLD without advanced fibrosis. CONCLUSIONS: SLD, especially MASLD and MetALD, is associated with increased all-cause mortality among adults in the US. Given this significant association between SLD or subtype of SLD (MASLD and MetALD) and all-cause mortality, adopting the proposed SLD criteria may help identify a sub-group of individuals with SLD who are at an increased risk for all-cause mortality.

Long-term clinical outcomes in steatotic liver disease and incidence of liver-related events, cardiovascular events and all-cause mortality.

BACKGROUND: A multi-society consensus group proposed a new nomenclature for steatotic liver disease (SLD) including metabolic-dysfunction associated steatotic liver disease (MASLD), MASLD and increased alcohol intake (MetALD) and alcohol-associated liver disease (ALD). However, the risk of liver-related events, major adverse cardiovascular events (MACE) and all-cause mortality among various sub-groups is unknown. AIMS: To evaluate the risk of liver-related events, MACE and death among patients with SLD. METHODS: We conducted a nationwide, population-based study and enrolled 761,400 patients diagnosed with MASLD, MetALD or ALD. The primary endpoint was the occurrence of liver-related events, MACE and death in patients with MASLD, MetALD and ALD. RESULTS: The cumulative incidence of liver-related events and death were highest in ALD, followed by MetALD and MASLD (p < 0.001 for both liver-related events and death), while the incidence of MACE was highest in MASLD, followed by MetALD and ALD (p < 0.001). Using MASLD as the reference and adjusting for age, sex, smoking, diabetes mellitus, dyslipidaemia and hypertension, the adjusted hazard ratios (95% confidence intervals) for liver-related events, MACE and death in MetALD were 1.42 (1.1-1.8), 0.68 (0.63-0.73) and 1.13 (0.98-1.3), respectively. In ALD, they were 3.42 (2.6-4.6), 0.58 (0.49-0.67) and 1.60 (1.3-2.0), respectively, for liver-related events, MACE and death. CONCLUSIONS: The new consensus nomenclature can be used to stratify the risk of complications and prognosis. The nomenclature is beneficial for risk stratification and identifying new mechanisms for disease-specific therapeutic implications.

The impact of county-level food access on the mortality and post-transplant survival among patients with steatotic liver disease.

BACKGROUND: The impact of county-level food access on mortality associated with steatotic liver disease, as well as post-liver transplant outcomes among individuals with steatotic liver disease, have not been characterized. METHODS: Data on steatotic liver disease-related mortality and outcomes of liver transplant recipients with steatotic liver disease between 2010 and 2020 were obtained from the Centers for Disease Control Prevention mortality as well as the Scientific Registry of Transplant Recipients databases. These data were linked to the food desert score, defined as the proportion of the total population in each county characterized as having both low income and limited access to grocery stores. RESULTS: Among 2,710 counties included in the analytic cohort, median steatotic liver disease-related mortality was 27.3 per 100,000 population (interquartile range 24.9-32.1). Of note, patients residing in counties with high steatotic liver disease death rates were more likely to have higher food desert scores (low: 5.0, interquartile range 3.1-7.8 vs moderate: 6.1, interquartile range, 3.8-9.3 vs high: 7.6, interquartile range 4.1-11.7). Among 28,710 patients who did undergo liver transplantation, 5,310 (18.4%) individuals lived in counties with a high food desert score. Liver transplant recipients who resided in counties with the worst food access were more likely to have a higher body mass index (>35 kg/m2: low food desert score, 17.3% vs highest food desert score, 20.1%). After transplantation, there was no difference in 2-year graft survival relative to county-level food access (food desert score: low: 88.4% vs high: 88.6%; P = .77). CONCLUSION: Poor food access was associated with a higher incidence rate of steatotic liver disease-related death, as well as lower utilization of liver transplants. On the other hand, among patients who did receive a liver transplant, there was no difference in 2-year graft survival regardless of food access strata. Policy initiatives should target the expansion of transplantation services to vulnerable communities in which there is a high mortality of steatotic liver disease.

Hepatic inflammation and fibrosis are profiles related to mid-term mortality in biopsy-proven MASLD: A multicenter study in Japan.

AIMS: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan. METHODS: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis. RESULTS: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD. CONCLUSIONS: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD.

Anatomopathological findings of Testudines necropsied in the Distrito Federal, Brazil / Achados anatomopatológicos de Testudines necropsiados no Distrito Federal, Brasil

In order to determine the main anatomopathological findings of Testudines necropsied in the Distrito Federal, all necropsy records performed at the "Laboratório de Patologia Veterinária" of the "Universidade de Brasília" (LPV-UnB) on Testudines during the period from January 2008 to July 2020 were reviewed. The 72 cases reviewed were grouped and classified according to species, sex, origin, season of occurrence, and diagnosis. In 69.44% of the cases the species was informed in the necropsy protocols, which included Phrynops geoffroanus (38%), Trachemys dorbigni (36%), Chelonoidis carbonaria (14%), Chelonoidis denticulata (10%) and Podocnemis expansa (2%). In 30.55% of the cases this parameter was not informed and were classified only as Testudines. In 41.66% of the cases the sex was informed, being female 22.22%, male 19.44%, and 58.33% were not informed. Of these animals 79.16% were from environmental agencies and 20.84% from zoos and/or guardians. In 70.83% of the animals analyzed they were directly related to the autumn and winter seasons, with June being the most frequent month (29.17%). The conclusive diagnosis was possible in 68.05% of the cases. The category of disorders caused by injurious agents (48.97%) was the most prevalent, followed by inflammatory disorders (32.65%) and nutritional and metabolic disorders (28.57%). The main diagnoses were carapace and/or plastron fracture with 30.61%, hepatic steatosis (20.40%) and pneumonia (10.22%). Most cases of carapace or plastron fracture and hepatic steatosis occurred in animals from environmental agencies.

Com o objetivo de determinar os principais achados anatomopatológicos de Testudines necropsiados no Distrito Federal, foram revisadas todas as fichas de necropsia realizadas no Laboratório de Patologia Veterinária da Universidade de Brasília (LPV-UnB) em Testudines, durante o período de janeiro de 2008 a julho de 2020. Os 72 casos revisados foram agrupados e classificados quanto à espécie, sexo, procedência, estação do ano de ocorrência e diagnóstico. Em 69,44% dos casos havia a espécie informada nos protocolos de necropsia, que incluíam Phrynops geoffroanus (38%), Trachemys dorbigni (36%), Chelonoidis carbonaria (14%), Chelonoidis denticulata (10%) e Podocnemis expansa (2%). Em 30,55% dos casos não tiveram esse parâmetro informado e foram classificados apenas como Testudines. Em 41,66% casos foi informado o sexo, sendo fêmea 22,22%, macho 19,44% e não informados 58,33%. Destes animais 79,16% eram de órgão ambiental e 20,84% de zoológicos e ou tutores. Em 70,83% dos animais analisados tiveram direta relação com as estações de outono e inverno, sendo o mês de junho o mais frequente (29,17%). O diagnóstico conclusivo foi possível em 68,05% dos casos. A categoria de distúrbios causados por agentes lesivos (48,97%) foi a mais prevalente, seguido por distúrbios inflamatórios (32,65%) e dos distúrbios nutricionais e metabólicos (28,57%). Os principais diagnósticos foram fratura de carapaça e ou plastrão com 30,61%, esteatose hepática (20,40%) e pneumonia (10,22%). A maior parte dos casos de fratura de carapaça ou plastrão e de esteatose hepática ocorreram em animais provenientes de órgão ambiental.

Anatomopathological findings of Testudines necropsied in the Distrito Federal, Brazil / Achados anatomopatológicos de Testudines necropsiados no Distrito Federal, Brasil

In order to determine the main anatomopathological findings of Testudines necropsied in the Distrito Federal, all necropsy records performed at the "Laboratório de Patologia Veterinária" of the "Universidade de Brasília" (LPV-UnB) on Testudines during the period from January 2008 to July 2020 were reviewed. The 72 cases reviewed were grouped and classified according to species, sex, origin, season of occurrence, and diagnosis. In 69.44% of the cases the species was informed in the necropsy protocols, which included Phrynops geoffroanus (38%), Trachemys dorbigni (36%), Chelonoidis carbonaria (14%), Chelonoidis denticulata (10%) and Podocnemis expansa (2%). In 30.55% of the cases this parameter was not informed and were classified only as Testudines. In 41.66% of the cases the sex was informed, being female 22.22%, male 19.44%, and 58.33% were not informed. Of these animals 79.16% were from environmental agencies and 20.84% from zoos and/or guardians. In 70.83% of the animals analyzed they were directly related to the autumn and winter seasons, with June being the most frequent month (29.17%). The conclusive diagnosis was possible in 68.05% of the cases. The category of disorders caused by injurious agents (48.97%) was the most prevalent, followed by inflammatory disorders (32.65%) and nutritional and metabolic disorders (28.57%). The main diagnoses were carapace and/or plastron fracture with 30.61%, hepatic steatosis (20.40%) and pneumonia (10.22%). Most cases of carapace or plastron fracture and hepatic steatosis occurred in animals from environmental agencies.(AU)

Com o objetivo de determinar os principais achados anatomopatológicos de Testudines necropsiados no Distrito Federal, foram revisadas todas as fichas de necropsia realizadas no Laboratório de Patologia Veterinária da Universidade de Brasília (LPV-UnB) em Testudines, durante o período de janeiro de 2008 a julho de 2020. Os 72 casos revisados foram agrupados e classificados quanto à espécie, sexo, procedência, estação do ano de ocorrência e diagnóstico. Em 69,44% dos casos havia a espécie informada nos protocolos de necropsia, que incluíam Phrynops geoffroanus (38%), Trachemys dorbigni (36%), Chelonoidis carbonaria (14%), Chelonoidis denticulata (10%) e Podocnemis expansa (2%). Em 30,55% dos casos não tiveram esse parâmetro informado e foram classificados apenas como Testudines. Em 41,66% casos foi informado o sexo, sendo fêmea 22,22%, macho 19,44% e não informados 58,33%. Destes animais 79,16% eram de órgão ambiental e 20,84% de zoológicos e ou tutores. Em 70,83% dos animais analisados tiveram direta relação com as estações de outono e inverno, sendo o mês de junho o mais frequente (29,17%). O diagnóstico conclusivo foi possível em 68,05% dos casos. A categoria de distúrbios causados por agentes lesivos (48,97%) foi a mais prevalente, seguido por distúrbios inflamatórios (32,65%) e dos distúrbios nutricionais e metabólicos (28,57%). Os principais diagnósticos foram fratura de carapaça e ou plastrão com 30,61%, esteatose hepática (20,40%) e pneumonia (10,22%). A maior parte dos casos de fratura de carapaça ou plastrão e de esteatose hepática ocorreram em animais provenientes de órgão ambiental.(AU)

Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.

BACKGROUND & AIMS: Recently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults. METHODS: We analyzed data from 7,761 participants in the Third National Health and Nutrition Examination Survey and their linked mortality through 2015. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other known liver diseases. MAFLD was defined based on the criteria proposed by an international expert panel. The Cox proportional hazard model was used to study all-cause mortality and cause-specific mortality between MAFLD and NAFLD, with adjustments for known risk factors. RESULTS: During a median follow-up of 23 years, individuals with MAFLD had a 17% higher risk of all-cause mortality (hazard ratio [HR] 1.17; 95% CI 1.04-1.32). Furthermore, MAFLD was associated with a higher risk of cardiovascular mortality. NAFLD per se did not increase the risk of all-cause mortality. Individuals who met both definitions had a higher risk of all-cause mortality (HR 1.13, 95% CI 1.00-1.26), while individuals who met the definition for MAFLD but not NAFLD had a 1.7-fold higher risk of all-cause mortality (HR 1.66, 95% CI 1.19-2.32). Estimates for all-cause mortality were higher for those with advanced fibrosis and MAFLD than for those with advanced fibrosis and NAFLD. CONCLUSIONS: In this US population-based study, MAFLD was associated with an increased risk of all-cause mortality, while NAFLD demonstrated no association with all-cause mortality after adjusting for metabolic risk factors. LAY SUMMARY: Our findings provide further support for the idea that non-alcoholic fatty liver disease (NAFLD) is a part of a broader multi-system disease that also includes obesity, diabetes, high blood pressure, and high cholesterol. Therefore, re-defining NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD) may help improve our understanding of predictors that increase the risk of death.

Fatty Liver Index as a Simple and Useful Predictor for 10-year Cardiovascular Disease Risks Determined by Framingham Risk Score in the General Korean Population.

BACKGROUND AND AIMS: The fatty liver index (FLI) is a simple and non-invasive method for the diagnosis of fatty liver disease with an increased risk of cardiovascular disease (CVD) as well as liver-related mortality. We examined the association between FLI and 10-year CVD risk as determined by the Framingham risk score. METHODS: This cross-sectional study included 7,240 individuals aged 30 to 69 years who underwent a health examination between 2015 and 2017. The FLI was calculated using an algorithm based on triglyceride, γ-glutamyltransferase, body mass index (BMI), and waist circumference. Multiple linear and logistic regression analyses were performed to assess independent relationships between the FLI and Framingham risk score after adjusting for confounding variables. RESULTS: The overall prevalence of fatty liver disease among study participants as assessed by an FLI ≥ 60 was 19.7%. Compared with non-hepatic steatosis (FLI < 30), the odds ratio (95% confidence interval) for a high Framingham 10-year CVD risk ≥ 10% in individuals with hepatic steatosis (FLI ≥ 60) was 2.56 (1.97-3.33) after adjusting for age, gender, fasting plasma glucose, high-density and low-density lipoprotein cholesterol, blood pressure, C-reactive protein, regular exercise, alcohol-drinking, and current smoking. CONCLUSIONS: The FLI was positively and independently associated with a Framingham 10-year CVD risk in the general Korean population. Our findings suggest that the FLI, a simple, useful, and economical index, may be an indicator of CVD events.

Renal hyperfiltration, fatty liver index, and the hazards of all-cause and cardiovascular mortality in Finnish men.

OBJECTIVES: Renal hyperfiltration (RHF) and fatty liver are separately associated with adverse health outcomes. In this study, we investigated the mortality hazard of coexisting RHF and fatty liver. METHODS: Middle-aged men from the Kuopio Ischaemic Disease Risk Factor Study (n=1,552) were followed up for a median of 29 years. Associations among RHF, fatty liver index (FLI) score, age, body mass index, smoking status, alcohol consumption, and hypertension status were assessed using logistic regression. Cox proportional hazards models were used to determine the hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality with respect to RHF and fatty liver. RESULTS: Of the men, 5% had RHF (n=73), whereas a majority had fatty liver (n=848). RHF was associated specifically with smoking, and fatty liver was associated specifically with overweight. The all-cause mortality hazard was highest (HR, 1.96; 95% confidence interval [CI], 1.27 to 3.01) among men with RHF and fatty liver (n=33). Among men with RHF but normal FLI (n=40), the HR of all-cause mortality was 1.67 (95% CI, 1.15 to 2.42). Among men with fatty liver but a normal estimated glomerular filtration rate (n=527), the HR of all-cause mortality was 1.35 (95% CI, 1.09 to 1.66). CVD mortality hazard was associated with RHF, but not fatty liver. We detected no interaction effect between RHF and fatty liver for all-cause (synergy index, 0.74; 95% CI, 0.21 to 2.67) or CVD (synergy index, 0.94; 95% CI, 0.34 to 2.60) mortality. CONCLUSIONS: RHF and fatty liver are independently associated with all-cause and CVD mortality.

Liver failure in pregnancy: a review of 25 cases.

We retrospectively reviewed the medical records from 25 pregnant women with liver failure from May 2009 to July 2019. Data describing clinical symptoms and manifestations, routine blood analyses, coagulation, and liver and kidney function were extracted. Swansea criteria were assessed to identify variables with prognostic significance for maternal mortality. The results showed that acute fatty liver was the primary cause of liver failure and 8 (88.89%) patients died within 7 days. Swansea diagnostic criteria for assessing the severity of liver failure were consistent with Chinese guidelines and were more systematic and convenient. The incidence of postpartum haemorrhage was 76%, and the velocity of bleeding was approximately 600 mL per hour. Increased Swansea score, hepatic encephalopathy and decreased PWR were important prognostic indicators for mortality. Recovery during the 7 days postpartum period was an important determinant of maternal outcomes.Impact statementWhat is already known on this subject? Liver failure in pregnant women is a rare but potentially devastating disease with a high rate of short-term morbidity and mortality. There are limited reports about clinical predictors of maternal-foetal outcomes and the dilemmas faced in the term of delivery.What the results of this study add? The incidence of postpartum haemorrhage was 76% in pregnant women with liver failure, but the velocity of bleeding was approximately 600 mL per hour. Our study revealed the Swansea score and the ratio of hepatic encephalopathy were significantly higher and platelet-to-white blood cell ratio (PWR) was lower in women who died compared to those who survived. During treatment period, 8 (88.89%) patients died within 7 days.What the implications are of these findings for clinical practice and/or further research? Swansea score, hepatic encephalopathy and PWR were important prognostic indicators for mortality in pregnant women with liver failure. Recovery during the 7 days postpartum period was an important determinant of maternal outcomes. Our findings may prompt researchers to conduct a large multicentre study to evaluate the prognostic indicators for mortality in pregnant women with liver failure.

Fatty liver, cardiometabolic disease and mortality.

PURPOSE OF REVIEW: We discuss the findings of the most recent metanalyses on the association between nonalcoholic fatty liver disease (NAFLD), cardiometabolic disease and mortality. RECENT FINDINGS: Recent metanalyses have shown that NAFLD is associated with incident type 2 diabetes mellitus (T2DM) and incident cardiovascular disease (CVD). Nonalcoholic steatohepatitis, which can be diagnosed by liver biopsy only in tertiary care centers, is often associated with liver fibrosis, which has been shown by metanalyses to increase both cardiovascular and liver-related mortality. Hyperlipidemia, lipotoxicity and impaired insulin secretion are among the possible mechanisms underlying the association of NAFLD with T2DM and CVD. Metanalyses of the association between NAFLD and mortality in the general population, where risk stratification cannot be performed on the basis of liver biopsy, have given contradictory results. SUMMARY: To establish conclusively whether NAFLD adds to known prognostic factors of death in the general population will require a shared operational definition of NAFLD, purposefully designed cohort studies, and the use of clinically relevant measures of effect size.

Fatty liver and mortality: a cohort population study in South Italy.

OBJECTIVE: Alcoholic fatty liver (AFLD) and non-alcoholic fatty liver (NAFLD) are two common conditions. However, if they can increase the risk of death is poorly explored. We therefore aimed to investigate the potential association between the presence and severity of liver steatosis and mortality in a large sample of older people. DESIGN: Prospective. SETTING: Community. PARTICIPANTS: Women and men randomly sampled from the electoral rolls of the population of Castellana Grotte, a town in Southern Italy (Apulia region) between 2005 and 2006. Among 1942 initially contacted, 1708 (=87.9%) participated to the baseline survey (Multicentrica Colelitiasi III (MICOL III)). This specific study included 1445 older participants (mean age=65.2 years, females=44.2%). EXPOSURE: NAFLD or AFLD. PRIMARY AND SECONDARY OUTCOMES: Mortality (all-cause and specific-cause). RESULTS: After a median of 12 years, 312 participants (=21.6%) died. After adjusting for nine potential confounders, the presence of steatosis was not associated with any increased risk of death in both NAFLD and AFLD. The severity of liver steatosis was not associated with any increased risk of mortality in NAFLD, while in AFLD, the presence of moderate steatosis significantly increased the risk of overall (HR=2.16; 95% CI 1.19 to 3.91) and cancer-specific (HR=3.54; 95% CI 1.16 to 10.87) death. CONCLUSIONS: Liver steatosis is not associated with any increased risk of death in NAFLD, while moderate steatosis could be a risk factor for mortality (particularly due to cancer) in people affected by AFLD.

CHD1L is associated with poor survival and promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma.

Chromodomain helicase/ATPase DNA­binding protein 1­like gene (CHD1L) is a new oncogene which has been confirmed to be crucial to the progression of many solid tumors. In the present study, the expression of CHD1L was found to be upregulated in intrahepatic cholangiocarcinoma (ICC), which was significantly associated with histological differentiation (P=0.011), vascular invasion (P=0.002), lymph node metastasis (P=0.008) and TNM stage (P=0.001). Kaplan­Meier survival analysis revealed that ICC patients with positive CHD1L expression had shorter overall and disease­free survival than those with negative CHD1L expression. Functional study found that CHD1L exhibited strong oncogenic roles, including increased cell growth by CCK­8 assay, colony formation by plate colony formation assay, G1/S transition by flow cytometry and tumor formation in nude mice. In addition, RNAi­mediated silencing of CHD1L inhibited ICC invasion and metastasis by wound healing, Transwell migration and Matrigel invasion assays in vitro and in vivo. Collectively, our results show that CHD1L is upregulated and promotes the proliferation and metastasis of ICC cells. CHD1L acts as an oncogene and may be a prognostic factor or therapeutic target for patients with ICC.

Fatal diffuse pulmonary fat microemboli following reperfusion in liver transplantation with the use of marginal steatotic allografts.

Organ shortage is a major cause of delayed liver transplantation and increased waitlist time. The level of donor steatosis is a significant determinant in organ selection. Scarcity of organs has led some programs to expand their acceptable criteria for the percentage of steatosis. We report two cases of liver transplantation of steatotic donor organs that resulted in mortality within hours from transplantation. Postmortem analysis showed evidence of diffuse pulmonary fat microemboli likely originating from the donor organ, with marked preservation reperfusion injury. The mechanism of diffuse fat microemboli in this setting and possible relationship to other perioperative syndromes (transfusion-related lung injury, acute kidney injury, and postreperfusion syndrome) is discussed.

Transient steatosis assessed by magnetic resonance imaging predicts outcome after extended hepatectomy in mice.

RATIONALE AND OBJECTIVES: Posthepatectomy liver failure (PHLF) remains challenging to diagnose and difficult to treat. The extent of transient regeneration-associated steatosis (TRAS) differs between successful liver regeneration and PHLF. This study aims to quantify TRAS by magnetic resonance imaging (MRI) after hepatectomy in mice. MATERIALS AND METHODS: Mice (C57BL/6) underwent either extended hepatectomy (EH) or standard hepatectomy (SH). Serial MRI on postoperative days 1-7 was used to compare TRAS and liver remnant growth between groups. Survival was also assessed. RESULTS: EH was associated with decreased survival and impaired proliferation when compared to SH (p = 0.02 and p = 0.03). MRI showed increased TRAS 48 h after EH compared to SH (11.8 ±â€¯6% vs. 4.3 ±â€¯2%, p < 0.001). Compared to EH survivors, death after EH was associated with increased TRAS 48 h postoperatively (16.4 ±â€¯6% vs. 9.2 ±â€¯5%, p = 0.02). CONCLUSIONS: EH is associated with increased TRAS and inferior outcomes when compared to SH. MRI may help to predict PHLF after hepatectomy.

Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver.

BACKGROUND: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. METHODS: Severe hepatic steatosis was performed by 12-14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. RESULTS: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%). CONCLUSIONS: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.

Systematic review of the influence of chemotherapy-associated liver injury on outcome after partial hepatectomy for colorectal liver metastases.

BACKGROUND: The impact of chemotherapy-associated liver injury (CALI) on postoperative outcome in patients undergoing partial hepatectomy for colorectal liver metastases (CRLM) remains controversial. The objective of this study was to clarify the effect of CALI (sinusoidal dilatation (SD), steatosis and steatohepatitis) on postoperative morbidity and mortality by investigating a large data set from multiple international centres. METHODS: PubMed and Embase were searched for studies published between 1 January 2004 and 31 December 2013 with keywords 'chemotherapy', 'liver resection', 'outcome' and 'colorectal metastases' to identify potential collaborating centres. Univariable and multivariable analyses were performed using binary logistic regression models, with results presented as odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: A consolidated database comprising 788 patients who underwent hepatectomy for CRLM in eight centres was obtained. In multivariable analyses, severe SD was associated with increased major morbidity (Dindo-Clavien grade III-V; OR 1·73, 95 per cent c.i. 1·02 to 2·95; P = 0·043). Severe steatosis was associated with decreased liver surgery-specific complications (OR 0·52, 95 per cent c.i. 0·27 to 1·00; P = 0·049), whereas steatohepatitis was linked to an increase in these complications (OR 2·08, 1·18 to 3·66; P = 0·012). Subgroup analysis showed that lobular inflammation was the sole component associated with increased overall morbidity (OR 2·22, 1·48 to 3·34; P = 0·001) and liver surgery-specific complications (OR 3·35, 2·11 to 5·32; P < 0·001). Finally, oxaliplatin treatment was linked to severe SD (OR 2·74, 1·67 to 4·49; P < 0·001). CONCLUSION: An increase in postoperative major morbidity and liver surgery-specific complications was observed after partial hepatectomy in patients with severe SD and steatohepatitis. Postoperative liver failure occurred more often in patients with severe SD.

The Risk of Cardiovascular Disease, Diabetes, Liver-Related Outcomes, and Death Over 10 Years in HIV/HCV-Coinfected Patients With and Without Steatosis.

BACKGROUND: Coinfection with HIV/HCV is associated with more severe liver disease, including increased frequency of steatosis and significant fibrosis, compared to patients mono-infected with HCV or HIV. We sought to explore the impact of steatosis on cardiovascular disease (CVD), liver-related outcomes, and survival. METHODS: An IRB-approved, single-center retrospective cohort study was undertaken to analyze 10-year clinical outcomes in HIV/HCV-coinfected patients. Liver biopsy was performed at study entry for the evaluation of HCV disease; a study pathologist graded samples for fibrosis and steatosis. Clinical outcomes, including cardiac events, liver function with FIB-4, AST to Platelet Ratio Index, and survival were assessed over 10 years. RESULTS: At cohort entry N = 105, mean age 45 ± 7 years, 70% male, and 56% had steatosis present on biopsy. During the 10-year follow-up, no association was found between incident CVD, changes in noninvasive liver fibrosis measures, or survival in the steatosis group compared to nonsteatosis group. However, nonsignificant trends were noted. Overall, mortality for this coinfected population was 25% over 10 years, with liver disease as the most common cause of death. CONCLUSIONS: Given the prevalence of steatosis in approximately half of coinfected patients, larger studies are warranted to determine if steatosis is associated with cardiac disease, diabetes, or liver disease progression in this population. Furthermore, 10-year mortality for this population was very high, underscoring the importance of HCV treatment and need for a better understanding of other variables responsible for decreased survival in this population.