Algorithms for Early Detection of Silent Liver Fibrosis in the Primary Care Setting.

More than one-third of the adult world population has steatotic liver disease (SLD), with a few percent of individuals developing cirrhosis after decades of silent liver fibrosis accumulation. Lack of systematic early detection causes most patients to be diagnosed late, after decompensation, when treatment has limited effect and survival is poor. Unfortunately, no isolated screening test in primary care can sufficiently predict advanced fibrosis from SLD. Recent efforts, therefore, combine several parameters into screening algorithms, to increase diagnostic accuracy. Besides patient selection, for example, by specific characteristics, algorithms include nonpatented or patented blood tests and liver stiffness measurements using elastography-based techniques. Algorithms can be composed as a set of sequential tests, as recommended by most guidelines on primary care pathways. Future use of algorithms that are easy to interpret, cheap, and semiautomatic will improve the management of patients with SLD, to the benefit of global health care systems.

Using liver stiffness to predict and monitor the risk of decompensation and mortality in patients with alcohol-related liver disease.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD). METHODS: We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10 kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10 kPa or <20 kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10 kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable. RESULTS: We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1 kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n = 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p = 0.004) and mortality (hazard ratio 3.22, p = 0.01). CONCLUSION: LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring. IMPACT AND IMPLICATIONS: Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII.

Sphingolipids Are Depleted in Alcohol-Related Liver Fibrosis.

BACKGROUND & AIMS: Alcohol disturbs hepatic lipid synthesis and transport, but the role of lipid dysfunction in alcohol-related liver disease (ALD) is unclear. In this biopsy-controlled, prospective, observational study, we characterized the liver and plasma lipidomes in patients with early ALD. METHODS: We performed mass spectrometry-based lipidomics of paired liver and plasma samples from 315 patients with ALD and of plasma from 51 matched healthy controls. We associated lipid levels with histologic fibrosis, inflammation, and steatosis with correction for multiple testing and adjustment for confounders. We further investigated sphingolipid regulation by means of quantitative real-time polymerase chain reaction sequencing of microRNA, prediction of liver-related events, and tested causality with Mendelian randomization. RESULTS: We detected 198 lipids in the liver and 236 lipids in the circulation from 18 lipid classes. Most sphingolipids (sphingomyelins and ceramides) and phosphocholines were co-down-regulated in both liver and plasma, where lower abundance correlated with higher fibrosis stage. Sphingomyelins showed the most pronounced negative correlation to fibrosis, mirrored by negative correlations in both liver and plasma with hepatic inflammation. Reduced sphingomyelins predicted future liver-related events. This seemed to be characteristic of "pure ALD," as sphingomyelin levels were higher in patients with concomitant metabolic syndrome and ALD/nonalcoholic fatty liver disease overlap. Mendelian randomization in FinnGen and UK Biobanks indicated ALD as the cause of low sphingomyelins, and alcohol use disorder did not correlate with genetic susceptibility to low sphingomyelin levels. CONCLUSIONS: Alcohol-related liver fibrosis is characterized by selective and progressive lipid depletion in liver and blood, particularly sphingomyelins, which also associates with progression to liver-related events.

Screening for Fibrosis Promotes Lifestyle Changes: A Prospective Cohort Study in 4796 Individuals.

BACKGROUND AND AIMS: Early detection of liver fibrosis is believed to promote lifestyle changes. We evaluated self-reported changes in alcohol intake, diet, exercise, and weight after participating in a screening study for liver fibrosis. METHODS: We conducted a prospective screening study of individuals at risk of alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD). We provided lifestyle advice to all participants and evaluated lifestyle changes by questionnaires after 1 week and 6 months, with re-examination of a subgroup after 2 years. RESULTS: A total of 1850 at risk of ALD and 2946 at risk of MASLD were included, of whom 383 (8%) were screening positive (transient elastography ≥8 kPa). A total of 84% replied to the 6-month questionnaire. In ALD participants, excessive drinking decreased from 46% to 32% after 6 months. Only 15% reported increased drinking, without differences between screening positive and negative individuals (P = .698). In high-risk drinkers, a positive screening test predicted abstinence or decreased alcohol use after 6 months (odds ratio, 2.45; 95% confidence interval, 1.32-4.57; P = .005). After 2 years, excessive drinking decreased from 52% to 41% in a subgroup of 752 individuals and a positive screening test predicted abstinence or decreased alcohol use after 2 years (odds ratio, 1.84; 95% confidence interval, 1.09-3.11, P = .023). MASLD participants showed similar improvements: 35% improved their diet, 22% exercised more, and 13% reported a weight loss ≥5% after 6 months. CONCLUSIONS: Screening for liver fibrosis is associated with sustained improvements in alcohol consumption, diet, weight, and exercise in at-risk ALD and MASLD. The changes are most pronounced in screening positive participants but not limited to this group.

Effect of Calorie-Unrestricted Low-Carbohydrate, High-Fat Diet Versus High-Carbohydrate, Low-Fat Diet on Type 2 Diabetes and Nonalcoholic Fatty Liver Disease : A Randomized Controlled Trial.

BACKGROUND: It remains unclear if a low-carbohydrate, high-fat (LCHF) diet is a possible treatment strategy for type 2 diabetes mellitus (T2DM), and the effect on nonalcoholic fatty liver disease (NAFLD) has not been investigated. OBJECTIVE: To investigate the effect of a calorie-unrestricted LCHF diet, with no intention of weight loss, on T2DM and NAFLD compared with a high-carbohydrate, low-fat (HCLF) diet. DESIGN: 6-month randomized controlled trial with a 3-month follow-up. (ClinicalTrials.gov: NCT03068078). SETTING: Odense University Hospital in Denmark from November 2016 until June 2020. PARTICIPANTS: 165 participants with T2DM. INTERVENTION: Two calorie-unrestricted diets: LCHF diet with 50 to 60 energy percent (E%) fat, less than 20E% carbohydrates, and 25E% to 30E% proteins and HCLF diet with 50E% to 60E% carbohydrates, 20E% to 30E% fats, and 20E% to 25E% proteins. MEASUREMENTS: Glycemic control, serum lipid levels, metabolic markers, and liver biopsies to assess NAFLD. RESULTS: The mean age was 56 years (SD, 10), and 58% were women. Compared with the HCLF diet, participants on the LCHF diet had greater improvements in hemoglobin A1c (mean difference in change, -6.1 mmol/mol [95% CI, -9.2 to -3.0 mmol/mol] or -0.59% [CI, -0.87% to -0.30%]) and lost more weight (mean difference in change, -3.8 kg [CI, -6.2 to -1.4 kg]). Both groups had higher high-density lipoprotein cholesterol and lower triglycerides at 6 months. Changes in low-density lipoprotein cholesterol were less favorable in the LCHF diet group than in the HCLF diet group (mean difference in change, 0.37 mmol/L [CI, 0.17 to 0.58 mmol/L] or 14.3 mg/dL [CI, 6.6 to 22.4 mg/dL]). No statistically significant between-group changes were detected in the assessment of NAFLD. Changes were not sustained at the 9-month follow-up. LIMITATION: Open-label trial, self-reported adherence, unintended weight loss, and lack of adjustment for multiple comparisons. CONCLUSION: Persons with T2DM on a 6-month, calorie-unrestricted, LCHF diet had greater clinically meaningful improvements in glycemic control and weight compared with those on an HCLF diet, but the changes were not sustained 3 months after intervention. PRIMARY FUNDING SOURCE: Novo Nordisk Foundation.

Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease.

BACKGROUND & AIMS: There is a need for accurate biomarkers of fibrosis for population screening of alcohol-related and non-alcoholic fatty liver disease (ALD, NAFLD). We compared the performance of the enhanced liver fibrosis (ELF) test to the fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS), using transient elastography as the reference standard. METHODS: We prospectively included participants from the general population, and people at risk of ALD or NAFLD. Screening positive participants (TE ≥8 kPa) were offered a liver biopsy. We measured concomitant ELF, FIB-4, and NFS using validated cut-offs: ≥9.8, ≥1.3, ≥-1.45, respectively. RESULTS: We included 3,378 participants (1,973 general population, 953 at risk of ALD, 452 at risk of NAFLD), with a median age of 57 years (IQR: 51-63). Two hundred-and-forty-two were screening positive (3.4% in the general population, 12%/14% who were at-risk of ALD/NAFLD, respectively). Most participants with TE <8 kPa also had ELF <9.8 (88%) despite a poor overall correlation between ELF and TE (Spearman´s rho = 0.207). ELF was associated with significantly fewer false positives (11%) than FIB-4 and NFS (35% and 45%), while retaining a low rate of false negatives (<8%). A screening strategy of FIB-4 followed by ELF in indeterminate cases resulted in false positives in 8%, false negatives in 4% and the correct classification in 88% of cases. We performed a liver biopsy in 155/242 (64%) patients who screened positive, of whom 54 (35%) had advanced fibrosis (≥F3). ELF diagnosed advanced fibrosis with significantly better diagnostic accuracy than FIB-4 and NFS: AUROC 0.85 (95% CI 0.79-0.92) vs. 0.73 (0.64-0.81) and 0.66 (0.57-0.76), respectively. CONCLUSION: The ELF test alone or combined with FIB-4 for liver fibrosis screening in the general population and at-risk groups reduces the number of futile referrals compared to FIB-4 and NFS, without overlooking true cases. IMPACT AND IMPLICATIONS: We need referral pathways that are efficient at detecting advanced fibrosis from alcohol-related and non-alcoholic fatty liver disease in the population, but without causing futile referrals or excessive use of resources. This study indicates that a sequential test strategy of FIB-4 followed by the ELF test in indeterminate cases leads to few patients referred for confirmatory liver stiffness measurement, while retaining a high rate of detected cases, and at low direct costs. This two-step referral pathway could be used by primary care for mass, targeted, or opportunistic screening for liver fibrosis in the population. CLINICAL TRIAL NUMBER: Clinicaltrials.gov number NCT03308916.

Binge drinking episode causes acute, specific alterations in systemic and hepatic inflammation-related markers.

BACKGROUND: Frequent binge drinking is a known contributor to alcohol-related harm, but its impact on systemic and hepatic inflammation is not fully understood. We hypothesize that changes in immune markers play a central role in adverse effects of acute alcohol intake, especially in patients with early liver disease. AIM: To investigate the effects of acute alcohol intoxication on inflammation-related markers in hepatic and systemic venous plasma in people with alcohol-related liver disease (ArLD), non-alcoholic fatty liver disease (NAFLD) and healthy controls. METHODS: Thirty-eight participants (13 with ArLD, 15 with NAFLD and 10 healthy controls) received 2.5 mL of 40% ethanol per kg body weight via a nasogastric tube. Seventy-two inflammation-related markers were quantified in plasma from hepatic and systemic venous blood, at baseline, 60 and 180 min after intervention. RESULTS: Alcohol intervention altered the levels of 31 of 72 and 14 of 72 markers in the systemic and hepatic circulation. All changes observed in the hepatic circulation were also identified in the systemic circulation after 180 min. Only FGF21 and IL6 were increased after alcohol intervention, while the remaining 29 markers decreased. Differences in response to acute alcohol between the groups were observed for 8 markers, and FGF21 response was blunted in individuals with steatosis. CONCLUSION: Acute alcohol intoxication induced changes in multiple inflammation-related markers, implicated in alcohol metabolism and hepatocellular damage. Differences identified between marker response to binge drinking in ArLD, NAFLD and healthy controls may provide important clues to disease mechanisms and potential targets for treatment. CLINICAL TRIAL NUMBER: NCT03018990.

Hepatorenal Index by B-Mode Ratio Versus Imaging and Fatty Liver Index to Diagnose Steatosis in Alcohol-Related and Nonalcoholic Fatty Liver Disease.

OBJECTIVES: We aimed to evaluate the accuracy of the hepatorenal index by B-mode ratio to diagnose hepatic steatosis, compared to ultrasound steatosis score, controlled attenuation parameter, and the fatty liver index using histology as the gold standard. METHODS: We prospectively included participants with alcohol-related or nonalcoholic fatty liver disease for same-day noninvasive investigations and liver biopsy. RESULTS: We included 137 participants, 72% male, median age 60 years (53-65) and body mass index 32 kg/m2 (28-38). Eighty percent had steatosis (S0/S1/S2/S3 = 20/37/24/19%). B-mode ratio had moderate diagnostic accuracy for any steatosis (≥S1, area under the receiver operating characteristics curve [AUROC] = 0.79; 95% confidence interval 0.70-0.88), significant steatosis (≥S2, AUROC = 0.76; 0.66-0.85), and severe steatosis (=S3, AUROC = 0.74; 0.62-0.86), independent of disease etiology. The cutoff values to rule-out and rule-in any steatosis were 1.09 and 1.45. While B-mode ratio and controlled attenuation parameter correlated poorly, their diagnostic accuracies were comparable to each other and to ultrasound steatosis scoring. Fatty liver index did not differ from B-mode ratio in detecting any steatosis but had poor accuracy to detect higher steatosis grades. B-mode ratio measurements failed in 12% of patients, compared to 1% for ultrasound steatosis scoring and 2% for controlled attenuation parameter. CONCLUSION: The hepatorenal index by B-mode ratio diagnose steatosis with moderate accuracy in patients with alcohol-related or nonalcoholic fatty liver disease, comparable to B-mode ultrasound steatosis scoring and controlled attenuation parameter. However, its clinical use is limited by a high failure rate.

Only one-third of referrals for fatty liver disease are on time: real-world study reveals opportunities to avoid unnecessary and delayed referrals.

BACKGROUND AND AIMS: Fatty liver disease is a global health concern, but in the absence of specific guidelines, current referral patterns differ according to the preferences of the general practitioners. Outpatient Gastroenterology clinics spend futile resources on liver-healthy patients while diagnosing decompensated patients delayed. We aimed to describe referral patterns to a regional outpatient Gastroenterology clinic. METHODS: We reviewed 9684 referrals from primary care for suspected liver disease in the years 2016-2017, during two years. Data were extracted from the patients' hospital records to assess the clinical workup and patient outcomes until a mean of 43 months after the time of referral. Referrals were categorized as unnecessary (no signs of liver disease), timely (significant fibrosis/compensated cirrhosis), or delayed (decompensated cirrhosis). RESULTS: We included 375 patient referrals from primary care. The main reason for referral was elevated transaminases. More than half (54%) of patients had no signs of liver disease, being unnecessarily referred for evaluation, while 17% had decompensated liver disease and were thus referred too late. CONCLUSIONS: Only one-third of patients referred on suspicion of liver disease were referred on time, either before presenting with decompensated liver cirrhosis or with some evidence of significant liver disease, e.g., liver fibrosis. There is a huge unmet need for clinical referral pathways in primary care. Strengths and Limitations of this StudyA strength of this study is the complete mapping of all potential referrals to the outpatient clinic in the two-year period. Instead of retrieving the historic data by ICD-10 diagnosis codes, and reflecting only those patients where the GP clearly suspects liver disease, we have a strong reliance on our methods. We screened all potentially relevant referrals, e.g., referrals due to weight loss or fatigue, which may reflect symptoms of cirrhosis. Thereby we are confident that we have not missed any patients that originally were referred with unspecific symptoms, but after evaluation are diagnosed with liver disease.Another strength of our study is the long follow-up period, which allows us to fully evaluate the course for the individual patient, and the potential later coming diagnoses.Finally, it is a strength of the study that we were not exclusive to one liver disease etiology, both ALD and NAFLD etiology were included in the study.A limitation of this study is the use of historic data, and the fact that it is a single-center study, showing only the referral patterns in one outpatient Gastroenterology clinic.

Prognostic performance of 7 biomarkers compared to liver biopsy in early alcohol-related liver disease.

BACKGROUND & AIMS: Alcohol is the most common cause of liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking. METHODS: We performed a prospective cohort study in patients with early, compensated alcohol-related liver disease. At baseline, we obtained a liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent AUC for prognostication. We used validated cut-off points to create 3 risk groups for each test: low, intermediate and high risk. RESULTS: We followed 462 patients for a median of 49 months (IQR 31-70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE <10 kPa, the hazard ratios for liver-related events for TE 10-15 kPa were 8.1 (3.2-20.4), and 27.9 (13.8-56.8) for TE >15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to liver-related events, except for patients in the low-risk groups. CONCLUSION: TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with alcohol-related liver disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles. LAY SUMMARY: Alcohol is the leading cause of death and illness due to liver disease. In this study, we assessed the ability of biomarkers to predict the risk of developing symptomatic liver disease in patients with early stages of alcohol-related liver disease. We found that several tests accurately predicted the risk of liver-related events such as ascites, esophageal varices and hepatic encephalopathy during an average follow-up of 4.1 years. Liver stiffness measurements by ultrasound elastography and the enhanced liver fibrosis test performed best. By using them, we were able to stratify patients into 3 groups with significantly different risks.

Ketamine as an Anesthetic for Patients with Acute Brain Injury: A Systematic Review.

For years, the use of ketamine as an anesthetic to patients suffering from acute brain injury has been debated because of its possible deleterious effects on the cerebral circulation and thus on the cerebral perfusion. Early studies suggested that ketamine could increase the intracranial pressure thus lowering the cerebral perfusion and hence reduce the oxygen supply to the injured brain. However, more recent studies are less conclusive and might even indicate that patients with acute brain injury could benefit from ketamine sedation. This systematic review summarizes the evidence regarding the use of ketamine in patients suffering from traumatic brain injury. Databases were searched for studies using ketamine in acute brain injury. Outcomes of interest were mortality, intracranial pressure, cerebral perfusion pressure, blood pressure, heart rate, spreading depolarizations, and neurological function. In total 11 studies were included. The overall level of evidence concerning the use of ketamine in brain injury is low. Only two studies found a small increase in intracranial pressure, while two small studies found decreased levels of intracranial pressure following ketamine administration. We found no evidence of harm during ketamine use in patients suffering from acute brain injury.

New nomenclature for fatty liver disease.

This review investigates that, in 2023, fatty liver disease underwent a name change to "steatotic liver disease" (SLD). SLD now includes metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and metabolic and alcohol-related liver disease (MetALD). The renaming aims to better incorporate alcohol intake and metabolic risk factors into disease classification and to diminish the stigma associated with the previous nomenclature. Early identification of the patient's aetiology is important for the prognosis which can be improved by interventions against the causative risk factors.

Validation of the new nomenclature of steatotic liver disease in patients with a history of excessive alcohol intake: an analysis of data from a prospective cohort study.

BACKGROUND: Steatotic liver disease is a new overarching term that includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-related steatotic liver disease (MetALD), and alcohol-related liver disease (ALD). We aimed to validate the prognostic importance of MASLD, MetALD, and ALD as steatotic liver disease subclasses. METHODS: Between April 18, 2013, and Sept 17, 2018, we prospectively recruited patients aged 18-75 years with current or previous excessive alcohol intake (>24 g/day for women and >36 g/day for men) for at least a year and no previous hepatic decompensation from the Department of Gastroenterology and Hepatology at Odense University Hospital (Odense, Denmark). Participants were followed up until Sept 15, 2022. Here, we characterise these patients according to steatotic liver disease subclasses. We classified patients as having MASLD, MetALD, or ALD in accordance with the nomenclature definitions, on the basis of metabolic comorbidity and self-reported average alcohol intake in the 3 months leading up to inclusion. Histological scoring was done by a pathologist who was masked to the clinical data. We compared prognoses between classes using Cox regression analyses on hepatic decompensation and overall mortality as the two outcome measures. Patients not meeting the criteria for steatotic liver disease were classified as no steatotic liver disease and served as a reference group. FINDINGS: We enrolled 446 patients with a history of excessive alcohol intake were included in this analysis (334 [75%] were male and 112 [25%] were female; median age 56 years [SD 10]). Cirrhosis was present in 58 (13%), and 435 (98%) had at least one cardiometabolic risk factor. 321 (72%) met steatotic liver disease criteria and 125 (28%) did not have steatotic liver disease, meaning no evident liver steatosis and no significant fibrosis (≥F2). Of the 321 patients with steatotic liver disease, six (2%) were identified as having ALD due to the absence of cardiometabolic risk factors. The remaining 315 (98%) patients presented with at least one cardiometabolic risk factor. Of these patients, 153 (49%) had MASLD, 76 (24%) had MetALD, and 86 (27%) had ALD. During follow-up, 67 (15%) of 446 patients decompensated and 97 (22%) died (median follow-up 70 months [IQR 53-94]). Patients with steatotic liver disease had a significantly higher risk of hepatic decompensation and overall mortality than those without steatotic liver disease, independent of age, sex, and liver stiffness. The risk of decompensation increased in a stepwise manner from MASLD (hazard ratio 4·73 [95% CI 1·03-21·6]), through MetALD (7·69 [1·66-35·6]), to ALD (10·2 [2·24-46·4]). Similarly, overall mortality increased from MASLD (HR 2·30 [95% CI 1·08-4·90]), through MetALD (2·94 [1·31-6·58]), to ALD (3·57 [1·64-7·80]), independent of age, sex, and liver stiffness. INTERPRETATION: Steatotic liver disease and its subclasses portend distinct prognoses. There is a need to specify how historical alcohol intake should be integrated into the nomenclature and risk stratification of steatotic liver disease. FUNDING: EU Horizon 2020 Research and Innovation Program.

Rifaximin-α for liver fibrosis in patients with alcohol-related liver disease (GALA-RIF): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Alcohol is the leading cause of liver-related mortality worldwide. The gut-liver axis is considered a key driver in alcohol-related liver disease. Rifaximin-α improves gut-barrier function and reduces systemic inflammation in patients with cirrhosis. We aimed to compare the efficacy and safety of rifaximin-α with placebo in patients with alcohol-related liver disease. METHODS: GALA-RIF was an investigator-initiated, randomised, double-blind, placebo-controlled, single-centre, phase 2 trial done at Odense University Hospital in Denmark. Eligible participants were adults (aged 18-75 years) who had current or previous alcohol overuse (at least 1 year with ≥24 g of alcohol per day for women and ≥36 g of alcohol per day for men), biopsy-proven alcohol-related liver disease, and no previous hepatic decompensation. Patients were randomly allocated (1:1) through a web-based randomisation system to receive oral rifaximin-α (550 mg) twice daily or matched placebo for 18 months. Randomisation was done in blocks of four and stratified according to fibrosis stage and alcohol abstinence. Participants, sponsor, investigators, and nurses involved in the study were masked to the randomisation outcome. The primary endpoint was a histological decrease from baseline to 18-month treatment of at least one fibrosis stage, according to the Kleiner fibrosis score. We also assessed the number of patients with progression by at least one fibrosis stage from baseline to 18 months. Primary analyses were done in the per-protocol and modified intention-to-treat populations; safety was assessed in the full intention-to-treat population. The per-protocol population was defined as all randomly assigned patients who did not present serious protocol violations, who ingested at least 75% of the treatment, and who were not withdrawn from the study due to non-adherence (interruption of treatment for 4 weeks or more). Participants receiving at least one dose of the intervention were included in the modified intention-to-treat analyses. This completed trial is registered with EudraCT, number 2014-001856-51. FINDINGS: Between March 23, 2015, and Nov 10, 2021, we screened 1886 consecutive patients with a history of excessive alcohol consumption and no previous hepatic decompensation, of whom 136 were randomly assigned to either rifaximin-α (n=68) or placebo (n=68). All patients were White (100%), 114 (84%) were men, and 22 (16%) were women. 133 (98%) patients received at least one dose of the intervention and were included in the modified intention-to-treat analysis; 108 (79%) completed the trial per protocol. In the per-protocol analysis, 14 (26%) of 54 patients in the rifaximin-α group and 15 (28%) of 54 patients in the placebo group had a decrease in fibrosis stage after 18 months (odds ratio 1·10 [95% CI 0·45-2·68]; p=0·83). In the modified intention-to-treat analysis, 15 (22%) of 67 patients in the rifaximin-α group and 15 (23%) of 66 patients in the placebo group had a decrease in fibrosis stage at 18 months (1·05 [0·45-2·44]; p=0·91). In the per-protocol analysis, increase in fibrosis stage occurred in 13 (24%) patients in the rifaximin-α group and 23 (43%) patients in the placebo group (0·42 [0·18-0·98]; p=0·044). In the modified intention-to-treat analysis, increase in fibrosis stage occurred in 13 (19%) patients in the rifaximin-α group and 23 (35%) patients in the placebo group (0·45 [0·20-1·02]; p=0·055). The number of patients with adverse events (48 [71%] of 68 patients in the rifaximin-α group; 53 [78%] of 68 in the placebo group) and serious adverse events (14 [21%] in the rifaximin-α group; 12 [18%] in the placebo group) was similar between the groups. No serious adverse events were deemed related to treatment. Three patients died during the trial, but none of the deaths were considered treatment related. INTERPRETATION: In patients with alcohol-related liver disease, rifaximin-α might reduce progression of liver fibrosis. These findings warrant confirmation in a multicentre phase 3 trial. FUNDING: The EU Horizon 2020 Research and Innovation Program and The Novo Nordisk Foundation.

Management of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease in the world, affecting 25% of the population. Around 6% of people with NAFLD will be at risk of developing advanced fibrosis, but symptoms often first occur very late from a decompensated cirrhosis. We need better referral pathways to identify and treat patients with advanced fibrosis. Non-invasive tests such as FIB-4 and NFS can be used in primary care to identify patients who will benefit from a referral to secondary care.

Serum keratin-18 detects hepatic inflammation and predicts progression in compensated alcohol-associated liver disease.

Alcohol-associated liver fibrosis accumulates over decades, driven by hepatic inflammation and cell death. We investigated the diagnostic accuracy of keratin-18 degradation, measured using serum M30 and M65 levels, and the ActiTest for hepatic inflammatory activity in patients with compensated alcohol-associated liver disease (ALD). Furthermore, we evaluated the prognostic accuracy of markers for liver-related events and all-cause mortality. All findings were compared with routine liver function tests: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase. Our prospective, biopsy-controlled, single-center study included 265 patients with ongoing or prior excessive alcohol intake, representing the full spectrum of compensated ALD. We defined hepatic inflammatory activity as a combined score of lobular inflammation and ballooning. For severe hepatic inflammatory activity (n = 40), we found excellent diagnostic accuracy for M30 (area under the receiver operating characteristics curve [AUROC] = 0.90), M65 (AUROC = 0.86), and AST (AUROC = 0.86). Elevated M30 (M30 > 240 U/L) had the highest positive predictive value (PPV) and specificity, significantly higher than M65, ActiTest and ALT, but not AST (M30: sensitivity = 83%, specificity = 82%, positive predictive value = 45%, negative predictive value = 95%). Patients were followed up for 1445 patient-years. All markers, except for ALT, significantly predicted liver-related events and all-cause mortality. After adjusting for advanced fibrosis, drinking behavior and body mass index, M30 and M65 remained significant predictors of liver-related events, whereas M30 and AST were significant predictors of all-cause mortality. Conclusion: M30 and AST accurately detect severe hepatic inflammatory activity in patients with compensated ALD. M30 was the only significant predictor of both liver-related events and all-cause mortality after adjusting for advanced fibrosis, body mass index, and drinking behavior at inclusion.

Allocation of patients with liver cirrhosis and organ failure to intensive care: Systematic review and a proposal for clinical practice.

AIM: To propose an allocation system of patients with liver cirrhosis to intensive care unit (ICU), and developed a decision tool for clinical practice. METHODS: A systematic review of the literature was performed in PubMed, MEDLINE and EMBASE databases. The search includes studies on hospitalized patients with cirrhosis and organ failure, or acute on chronic liver failure and/or intensive care therapy. RESULTS: The initial search identified 660 potentially relevant articles. Ultimately, five articles were selected; two cohort studies and three reviews were found eligible. The literature on this topic is scarce and no studies specifically address allocation of patients with liver cirrhosis to ICU. Throughout the literature, there is consensus that selection criteria for ICU admission should be developed and validated for this group of patients and multidisciplinary approach is mandatory. Based on current available data we developed an algorithm, to determine if a patient is candidate to intensive care if needed, based on three scoring systems: premorbid Child-Pugh Score, Model of End stage Liver Disease score and the liver specific Sequential Organ Failure Assessment score. CONCLUSION: There are no established systems for allocation of patients with liver cirrhosis to the ICU and no evidence-based recommendations can be made.

How do bacteraemic patients present to the emergency department and what is the diagnostic validity of the clinical parameters; temperature, C-reactive protein and systemic inflammatory response syndrome?

OBJECTIVE: Although blood cultures are often ordered based on the presence of fever, it is a clinical challenge to identify patients eligible for blood cultures. Our aim was to evaluate the diagnostic value of temperature, C-reactive-protein (CRP), and Systemic Inflammatory Response Syndrome (SIRS) to identify bacteraemic patients in the Medical Emergency Department (MED). METHODS: A population-based cohort study including all adult patients at the MED at Odense University Hospital between August 1st 2009 - August 31st 2011. RESULTS: 11,988 patients were admitted to the MED within the study period. Blood cultures were performed on 5,499 (45.9%) patients within 2 days of arrival, of which 418 (7.6%) patients were diagnosed with bacteraemia. This corresponded to 3.5% of all patients. 34.1% of the bacteraemic patients had a normal rectal temperature (36.0°-38.0 °C) recorded at arrival, 32.6% had a CRP < 100 mg/L and 28.0% did not fulfil the SIRS criteria.For a temperature cut-point of >38.0 °C sensitivity was 0.64 (95% CI 0.59-0.69) and specificity was 0.81 (0.80-0.82) to identify bacteraemic patients. CONCLUSION: One third of the acute medical bacteraemic patients had a normal temperature at arrival to the MED. A normal temperature combined with a CRP < 100 mg/L and no SIRS criteria, ruled out bacteraemia.