Alcohol-associated liver disease-Global epidemiology.

Alcohol-associated liver disease (ALD), as highlighted in this narrative review, is a major public health concern, increasingly impacting global disease burden and premature mortality. In 2019, ALD accounted for the loss of 11 million life-years worldwide. The rising number of deaths and disability-adjusted life-years attributed to ALD, particularly pronounced in the United States, are alarming. Projections suggest that the economic impact of ALD, as seen in the United States, could potentially double by 2040. ALD is increasingly prevalent among younger adults (20-45 y) and has become the leading cause of liver transplantation in both United States and Europe. During the COVID-19 pandemic, the existing trend was further amplified as high-risk drinking patterns coincided with a rise in hospital admissions for alcohol-associated hepatitis and increased ALD-related mortality. The prevalence of ALD is estimated at 3.5% in the general population, 26.0% among hazardous drinkers, and 55.1% among those with alcohol use disorders. Alarmingly, 5-year mortality rates for patients with ALD exceed 50%, with even higher rates in more advanced disease stages. Methodological challenges, such as underreporting, diagnostic difficulties, and variability in registry data quality, complicate the accurate assessment of the impact of ALD. Additionally, the contribution of alcohol to the progression of other liver diseases is often under acknowledged in health care registries, leading to a significant underestimation of its broader implications for liver health. Addressing the growing ALD concern requires robust public health initiatives, heightened awareness, refined diagnostic techniques, and comprehensive epidemiological studies. These measures are vital to tackle the increasing prevalence of ALD and mitigate its extensive impact on individuals and health care systems.

Protocol liver biopsy predicts graft survival after liver transplantation.

BACKGROUND: The use of protocol liver biopsy to monitor liver allograft status remains controversial. There is limited data from modern transplantation populations that includes protocol biopsies to evaluate its value in predicting clinical outcomes. METHODS: All protocol liver biopsies were identified from 875 patients who underwent liver transplantation at Helsinki University Hospital between 2000 and 2019. Each histologic component was analyzed for its ability to predict long-term outcomes, especially graft survival. We determined the frequency of significant biopsy findings based on the Banff working group definition. Liver function tests (LFTs) and clinical markers were evaluated for their ability to predict significant biopsy findings. RESULTS: In total, 867 protocol liver biopsies were analyzed. Significant findings were identified in 20.1% of the biopsies. In the first protocol biopsy, steatohepatitis (hazard ratio [HR] 3.504, p = .03) and moderate or severe congestion (HR 3.338, p = .04) predicted graft loss. The presence of cholangitis (HR 2.563, p = .04), necrosis (HR 7.635, p < .001), mild congestion (HR 4.291, p = .009), and significant biopsy finding (HR 2.540, p = .02) predicted inferior death-censored graft survival. While the degree of elevation of LFTs was positively associated with significant biopsy findings, the discrimination was poor (AUC .572-.622). Combined LFTs and clinical risk factors remained suboptimal for discriminating significant biopsy findings (AUC .696). CONCLUSIONS: Our findings support the use of protocol liver biopsies after liver transplantation since they frequently revealed changes associated with long-term outcomes, even when LFTs were normal.

Serum ferritin level is associated with liver fibrosis and incident liver-related outcomes independent of HFE genotype in the general population.

BACKGROUND & AIMS: Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. METHODS: The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. RESULTS: Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02-1.21]; p = 0.012 and HR 1.11 [95% CI 1.02-1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. CONCLUSION: Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia.

The future of International Classification of Diseases coding in steatotic liver disease: An expert panel Delphi consensus statement.

BACKGROUND: Following the adoption of new nomenclature for steatotic liver disease, we aimed to build consensus on the use of International Classification of Diseases codes and recommendations for future research and advocacy. METHODS: Through a two-stage Delphi process, a core group (n = 20) reviewed draft statements and recommendations (n = 6), indicating levels of agreement. Following revisions, this process was repeated with a large expert panel (n = 243) from 73 countries. RESULTS: Consensus ranged from 88.8% to 96.9% (mean = 92.3%). CONCLUSIONS: This global consensus statement provides guidance on harmonizing the International Classification of Diseases coding for steatotic liver disease and future directions to advance the field.

Risk and prediction of kidney failure early after liver transplantation.

BACKGROUND: Kidney disease is common after liver transplantation (LT), but postoperative kidney failure is difficult to predict. Current guidelines recommend simultaneous liver-kidney transplantation (SLKT) in patients with pre-LT estimated glomerular filtration rate (eGFR) below 30-40 mL/min, which might be too liberal. The aim of this study was to evaluate the risk of kidney failure after LT. We also assessed the predictive ability of pretransplantation eGFR using various equations. METHODS: This single-center study included patients undergoing primary LT 2006-2020. Patients undergoing simultaneous liver-kidney transplantations or on dialysis before LT were analysed separately. We calculated 5 different eGFR equations measured just before LT and assessed their predictive ability using Kaplan-Meier cumulative incidence estimates. RESULTS: Among 556 LT patients with a median follow-up of 5.0 years (IQR 2.0-8.5), 20 developed kidney failure during follow-up, 7 of them within 1-year post LT. Six of these 7 suffered from major perioperative complications. Depending on the eGFR equation used, the incidence of kidney failure within 1-year was 3.9-6.7% at pre-LT eGFR-values <30 mL/min, 1.2-3.1% at eGFR 30-60 mL/min, and 0.6-0.9% at eGFR >60 mL/min. CONCLUSIONS: Kidney failure within 1-year post-LT could not be reliably predicted by pre-LT eGFR. However, kidney failure was uncommon even in patients with severely reduced pre-LT glomerular filtration rate (eGFR <30 mL/min), and extremely rare in patients unaffected by major perioperative complications. Our data prompts further consideration regarding the guidelines for SLKT in patients with a reduced preoperative eGFR.

Cyclosporine vs. tacrolimus after liver transplantation for primary sclerosing cholangitis - a propensity score-matched intention-to-treat analysis.

BACKGROUND & AIMS: There is controversy regarding the optimal calcineurin inhibitor type after liver transplant(ation) (LT) for primary sclerosing cholangitis (PSC). We compared tacrolimus with cyclosporine in a propensity score-matched intention-to-treat analysis based on registries representing nearly all LTs in Europe and the US. METHODS: From the European Liver Transplant Registry (ELTR) and Scientific Registry of Transplant Recipients (SRTR), we included adult patients with PSC undergoing a primary LT between 2000-2020. Patients initially treated with cyclosporine were propensity score-matched 1:3 with those initially treated with tacrolimus. The primary outcomes were patient and graft survival rates. RESULTS: The propensity score-matched sample comprised 399 cyclosporine-treated and 1,197 tacrolimus-treated patients with PSC. During a median follow-up of 7.4 years (IQR 2.3-12.8, 12,579.2 person-years), there were 480 deaths and 231 re-LTs. The initial tacrolimus treatment was superior to cyclosporine in terms of patient and graft survival, with 10-year patient survival estimates of 72.8% for tacrolimus and 65.2% for cyclosporine (p <0.001) and 10-year graft survival estimates of 62.4% and 53.8% (p <0.001), respectively. These findings were consistent in the subgroups according to age, sex, registry (ELTR vs. SRTR), time period of LT, MELD score, and diabetes status. The acute rejection rates were similar between groups. In the multivariable Cox regression analysis, tacrolimus (hazard ratio 0.72, p <0.001) and mycophenolate use (hazard ratio 0.82, p = 0.03) were associated with a reduced risk of graft loss or death, whereas steroid use was not significant. CONCLUSIONS: Tacrolimus is associated with better patient and graft survival rates than cyclosporine and should be the standard calcineurin inhibitor used after LT for patients with PSC. IMPACT AND IMPLICATIONS: The optimal calcineurin inhibitor to use after liver transplantation in patients with primary sclerosing cholangitis has yet to be firmly established. Since randomized trials with long follow-up are unlikely to be performed, multicontinental long-term registry data are essential in informing clinical practices. Our study supports the practice of using tacrolimus instead of cyclosporine in the initial immunosuppressive regimen after liver transplantation for patients with primary sclerosing cholangitis. The retrospective registry-based design is a limitation.

Combined use of the CLivD score and FIB-4 for prediction of liver-related outcomes in the population.

BACKGROUND AND AIMS: A need exists for effective and practical tools to identify individuals at increased risk of liver-related outcomes (LROs) within the general population. APPROACH AND RESULTS: We externally validated the chronic liver disease (CLivD) score for LROs in the UK Biobank cohort. We also investigated the sequential combined use of CLivD and fibrosis-4 (FIB-4) scores. Our analysis included 369,832 adults without baseline liver disease and with available data for CLivD and FIB-4 computation. LROs reflecting compensated or decompensated liver cirrhosis or HCC were ascertained through linkages with electronic health care registries. Discriminatory performance and cumulative incidence were evaluated with competing-risk methodologies. Over a 10-year follow-up, time-dependent AUC values for LRO prediction were 0.80 for CLivD lab (including gamma-glutamyltransferase), 0.72 for CLivD non-lab (excluding laboratory values), and 0.75 for FIB-4. CLivD lab demonstrated AUC values exceeding 0.85 for liver-related death and severe alcohol-associated liver outcomes. The predictive performance of FIB-4 increased with rising CLivD scores; 10-year FIB-4 AUC values ranged from 0.60 within the minimal-risk CLivD subgroup to 0.81 within the high-risk CLivD subgroup. Moreover, in the minimal-risk CLivD subgroup, the cumulative incidence of LRO varied from 0.05% to 0.3% across low-to-high FIB-4 strata. In contrast, within the high-risk CLivD subgroup, the corresponding incidence ranged from 1.7% to 21.1% (up to 33% in individuals with FIB-4 >3.25). CONCLUSIONS: The CLivD score is a valid tool for LRO risk assessment and improves the predictive performance of FIB-4. The combined use of CLivD and FIB-4 identified a subgroup where 1 in 3 individuals developed LROs within 10 years.

Erratum to: "Enhanced Liver Fibrosis® test predicts liver-related outcomes in the general population" (JHEP Reports 2023; 5: 100765).

[This corrects the article DOI: 10.1016/j.jhepr.2023.100765.].

Association Between Pre-Transplant Oral Health and Post-Liver Transplant Complications.

Oral disease is linked with systemic inflammation and various systemic conditions, including chronic liver disease. Liver transplantation (LT) candidates often need dental infection focus eradication, and after LT, there is high risk of many inflammation-related complications. We studied whether pre-LT dental status is associated with the occurrence of post-LT complications. This study included 225 adult LT recipients whose teeth were examined and treated before LT, and 40 adult LT recipients who did not have pre-LT dental data available. Data on post-LT complications were collected from the national liver transplant registry and followed up until the end of July 2020. Worse pre-LT dental status was associated with a higher risk of acute rejection post-LT compared to patients with good dental status. Worse dental status was also associated with higher 1-year-post-LT ALT levels and lower albumin levels. In conclusion, poor pre-LT oral health seems to associate with an increased risk of post-LT acute rejection and with elevated ALT levels and decreased albumin levels, suggesting an effect on post-LT liver health. Therefore, prevention and treatment of oral and dental diseases should be promoted early in the course of liver disease.

Waist-hip ratio is superior to BMI in predicting liver-related outcomes and synergizes with harmful alcohol use.

BACKGROUND: Obesity is associated with liver disease, but the best obesity-related predictor remains undefined. Controversy exists regarding possible synergism between obesity and alcohol use for liver-related outcomes (LRO). We assessed the predictive performance for LROs, and synergism with alcohol use, of abdominal obesity (waist-hip ratio, WHR), and compared it to overall obesity (body mass index, BMI). METHODS: Forty-thousand nine-hundred twenty-two adults attending the Finnish health-examination surveys, FINRISK 1992-2012 and Health 2000 studies, were followed through linkage with electronic healthcare registries for LROs (hospitalizations, cancers, and deaths). Predictive performance of obesity measures (WHR, waist circumference [WC], and BMI) were assessed by Fine-Gray models and time-dependent area-under-the-curve (AUC). RESULTS: There are 355 LROs during a median follow-up of 12.9 years (509047.8 person-years). WHR and WC emerge as more powerful predictors of LROs than BMI. WHR shows significantly better 10-year AUC values for LROs (0.714, 95% CI 0.685-0.743) than WC (0.648, 95% CI 0.617-0.679) or BMI (0.550, 95% CI 0.514-0.585) both overall and separately among men and women. WHR is predictive also in BMI strata. Absolute 10-year risks of LROs are more dependent on WHR than BMI. Moreover, WHR shows a significant supra-additive interaction effect with harmful alcohol use for liver-related outcomes (excess 10-year cumulative incidence of 2.8% from the interaction), which is not seen between BMI and harmful alcohol use. CONCLUSIONS: WHR is a better predictor than BMI or WC for LROs, and WHR better reflects the synergism with harmful alcohol use. WHR should be included in clinical assessment when evaluating obesity-related risks for liver outcomes.

Obesity has been linked to liver disease, but the most accurate measure for predicting obesity-related liver disease outcomes remains uncertain. In this study, we analyzed data from over 40,000 adults to compare the extent to which different measures of obesity can predict liver-related outcomes, such as severe liver disease, liver failure, or death from liver disease. The measures of obesity were the ratio of waist circumference to hip circumference (waist-hip ratio, WHR), waist circumference (WC), and body mass index (BMI). Our findings reveal that WHR and WC are stronger predictors of these outcomes than BMI. In particular, WHR demonstrated superior predictive ability and this predictive ability was influenced by harmful alcohol use. This study suggests that WHR may be a relatively simple but useful measure for clinicians to use when predicting obesity-related risks for liver health.

Four-fold increased mortality rate in patients with Wilson's disease: A population-based cohort study of 151 patients.

BACKGROUND AND AIMS: Few studies have investigated mortality rates in patients with Wilson's disease and compared these to the general population. Here, we examined several clinical outcomes (including cardiovascular, psychiatric, neurologic conditions) in a population-based study of patients with Wilson's disease. METHOD: We used nationwide registers to identify all patients with a first diagnosis of Wilson's disease between 2002 and 2020 in Sweden. Each patient was matched by age, sex, and municipality with up to 10 reference individuals from the general population. Validated registers were used to investigate outcomes up to 19 years after baseline in patients and reference individuals. RESULTS: We identified 151 patients with Wilson's disease matched with 1441 reference individuals. Median age at baseline was 26 years (IQR 17-42) and 50% were males. During a median follow-up of 6.6 years (IQR 2.9-12.9), 10 (6.6%) patients with Wilson's disease died compared with 31 (2.2%) reference individuals. This translated to a hazard ratio (HR) of 3.8 (95%CI = 1.8-8.1). Mortality was higher among Wilson's disease patients with baseline neuropsychiatric diagnoses (HR 7.9, 95%CI = 2.9-21.8). Cumulative mortality over 10 years was 9.3% (95%CI = 5.0-16.8) in Wilson's disease, compared to 2.4% (95%CI = 1.6-3.6) in reference individuals. We observed significantly elevated risks in the Wilson's disease group for incident cardiovascular disease, and incident psychiatric and neurological conditions when considering liver transplantation or death from other causes as competing events. CONCLUSION: In this large population-based cohort study, patients with Wilson's disease had an almost four-fold increased mortality rate compared with matched individuals from the general population.

Combined use of the ELF test and CLivD score improves prediction of liver-related outcomes in the general population.

BACKGROUND AND AIMS: Effective and feasible population screening strategies are needed for the early detection of individuals at high risk of future severe liver-related outcomes. We evaluated the predictive performance of the combination of liver fibrosis assessment, phenotype profile, and genetic risk. METHODS: Data from 5795 adults attending the Finnish Health 2000 Survey were linked with healthcare registers for liver-related outcomes (hospitalization, hepatocellular cancer, and death). Fibrosis was assessed using the enhanced liver fibrosis (ELF) test, phenotype profile by the chronic liver disease (CLivD) risk score, and genetic risk by a validated Polygenic Risk Score (PRS-5). Predictive performance was assessed by competing-risk analyses. RESULTS: During a median 13-year follow-up, 64 liver-related outcome events were recorded. ELF, CLivD score, and PRS-5 were independently associated with liver-related outcomes. The absolute 10-year risk of liver-related outcomes at an ELF value of 11.3 ranged from 0.3% to 33% depending on the CLivD score. The CLivD score added 51% of new predictive information to the ELF test and improved areas under the curve (AUCs) from 0.91, 0.81, and 0.71 for ELF alone to 0.95, 0.85, and 0.80, respectively, for ELF combined with the CLivD score at 1, 5, and 10 years. The greatest improvement was for 10-year predictions (delta-AUC 0.097, p < .0001). Adding PRS-5 did not significantly increase predictive performance. Findings were consistent in individuals with obesity, diabetes, or alcohol risk use, and regardless of whether gamma-glutamyltransferase was used in the CLivD score. CONCLUSION: A combination of ELF and CLivD score predicts liver-related outcomes significantly better than the ELF test alone.

Enhanced liver Fibrosis® test predicts liver-related outcomes in the general population.

Background & Aims: The Enhanced Liver Fibrosis® (ELF) test exhibits good discriminative performance in detecting advanced liver fibrosis and in predicting liver-related outcomes in patients with specific liver diseases, but large population-based studies are missing. We analysed the predictive performance of the ELF test in a general population cohort. Methods: Data were sourced from the Health 2000 study, a Finnish population-based health examination survey conducted in 2000-2001. Subjects with baseline liver disease were excluded. The ELF test was performed on blood samples collected at baseline. Data were linked with national healthcare registers for liver-related outcomes (hospitalisation, cancer, and death). Results: The cohort comprised 6,040 individuals (mean age 52.7. 45.6% men) with 67 liver-related outcomes during a median 13.1-year follow-up. ELF predicted liver outcomes (unadjusted hazards ratio 2.70, 95% CI 2.16-3.38). with 5- and 10-year AUCs of 0.81 (95% CI 0.71-0.91) and 0.71 (95% CI 0.63-0.79) by competing-risk methodology. The 10-year risks for liver outcomes increased from 0.5% at ELF <9.8 to 7.1% at ELF ≥11.3, being higher among men than women at any given ELF level. Among individuals with body mass index ≥30 kg/m2, diabetes, or alanine aminotransferase >40 U/L. Five-year AUCs for ELF were 0.85, 0.87, and 0.88, respectively. The predictive ability of the ELF test decreased with time: the 10-year AUCs were 0.78, 0.69, and 0.82, respectively. Conclusions: The ELF test shows good discriminative performance in predicting liver-related outcomes in a large general population cohort and appears particularly useful for predicting 5-year outcomes in persons with risk factors. Impact and implications: The Enhanced Liver Fibrosis test exhibits good performance for predicting liver-related outcomes (hospitalisation, liver cancer, or liver-related death) in the general population, especially in those with risk factors.

Persistent organic pollutants associate with liver disease in a Finnish general population sample.

BACKGROUND AND AIMS: Persistent organic pollutants (POPs) have multiple adverse effects on human health. Recent studies show a possible association with liver disease, but population-based data are scarce. In this population-based study, we studied the associations between POPs and biomarkers of liver disease and incident liver disease. METHODS: This study consisted of 2789 adults that participated in the environmental toxin subset of the Finnish health-examination survey, FINRISK 2007. Toxins were measured from serum samples, and standard liver tests and dynamic aspartate aminotransferase-alanine aminotransferase ratio (dAAR) were measured as biomarkers of liver function. Associations between POPs and the biomarkers were then analysed using linear regression. Associations between POPs and incident liver disease (n = 36) were analysed by Cox regression. RESULTS: Organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and several perfluorinated alkyl substances exhibited statistically significant positive associations with several biomarkers of liver injury (betacoefficient per SD 0.04-0.14, p < 0.05). These associations were stronger in subgroups of individuals with obesity or non-alcoholic fatty liver disease. OCPs, PCBs and perfluoro-octanoic acid also had significant positive associations with dAAR, which can be used to predict risk of incident severe liver outcomes (beta coefficient per SD 0.05-0.08, p < 0.05). OCPs and PCBs were also significantly and positively associated with incident liver disease (hazard ratio per SD 1.82 95% CI 1.21-2.73, p < 0.01 and hazard ratio per SD 1.69, 95% CI 1.07-2.68, p < 0.05 respectively). CONCLUSIONS: Several POPs show positive associations with markers of liver injury and incident liver disease, suggesting that environmental toxins are important risk factors for chronic liver disease.

Persistent oral mucosal lesions preceding diagnosis of Crohn's disease and primary sclerosing cholangitis.

Oral mucosal lesions may persist years before symptoms or diagnosis of inflammatory bowel disease (IBD) and subsequent primary sclerosing cholangitis (PSC). Since a dental practitioner may be the first clinician to suspect IBD with extraintestinal manifestations (EIMs), early referral, and close collaboration with a gastroenterologist are recommended.