Liver stiffness predicts progression to liver-related events in patients with chronic liver disease - A cohort study of 14 414 patients.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) is a non-invasive diagnostic biomarker of liver fibrosis. It is uncertain if LSM can predict risk for future liver-related outcomes in large, heterogenous populations. METHODS: This Swedish multi-centre cohort study included patients (n = 14 414) from 16 sites who underwent LSM by VCTE between 2008 and 2020. Outcomes were ascertained from national registers. We investigated progression to cirrhosis with portal hypertension or hepatocellular carcinoma (HCC), separately. Cox regression was used to obtain hazard ratios (HRs). Harrel's C-index was used to measure discrimination of VCTE. RESULTS: Included patients had a median age of 46 (interquartile range 34-57), median LSM of 5.9 kPa (4.6-8.0), 59% were male, and the majority had hepatitis C (50.1%). During a median follow-up of 5.9 (4.3-8.0) years, 402 patients (2.7%) developed cirrhosis with portal hypertension. In patients with an LSM ≥25 kPa, 28.7% developed cirrhosis with portal hypertension within 5 years of follow-up, while only .6% of patients with an LSM <10 kPa did. This translated to a HR of 48.3 (95% confidence interval = 37.6-62.0). VCTE had a high discriminative ability, with C-indices above .80 for most liver diseases, including .82 for MASLD. Similar findings were seen for incident HCC. CONCLUSIONS: Increased LSM by VCTE was associated with an increased risk of progression to both cirrhosis with portal hypertension, and to HCC, and had a high discriminative ability across different aetiologies of chronic liver diseases. These results support the use of VCTE to guide follow-up and treatment decisions.

Statin initiation after myocardial infarction in patients with alcohol-related liver disease: A nationwide population-based study.

BACKGROUND AND AIMS: Secondary prevention with statins improves clinical outcomes after myocardial infarction (MI). We aimed to compare odds of statin initiation after MI in patients with co-existing alcohol-related liver disease (ALD) to the general population, and the association between statin initiation and mortality in the patients with ALD. METHODS: All statin-naïve patients with ALD and a first-time MI between 2006 and 2020 were identified from Swedish healthcare registers and matched for age, sex, and year of MI with up to ten ALD-free general population controls with a first-time MI. Logistic regression was used to estimate adjusted odds ratios (OR) for statin initiation within 30 days after MI for ALD patients versus controls. Cox regression was used in patients with ALD to compare mortality between statin initiators and non-initiators. RESULTS: Of the 276 patients with a first-time MI and ALD, 206 (74.6%) were male, the median age was 67 (interquartile range 62-72), 151 (54.7%) had cirrhosis, and 62 (22.5%) had decompensated cirrhosis. 1769 matched controls were included. Initiation of statins was less common in ALD patients (50.0%) than controls (89.2%, adjusted OR = .15, 95% confidence interval [CI] = .10-.20). Among patients with ALD, statin initiators and non-initiators were followed for a median of 3.9 (interquartile range = 1.8-7.7) and 1.9 years (interquartile range = .5-4.4), respectively. Statin initiators had lower mortality than non-initiators (adjusted hazard ratio = .41, 95%CI = .28-.59). CONCLUSIONS: Patients with ALD less often initiated statins after MI than the general population. Statin initiation was associated with improved survival, suggesting that patients with ALD might be undertreated following MI.

Misclassified Alcohol-related Liver Disease is Common in Presumed Metabolic Dysfunction-associated Steatotic Liver Disease and Highly Increases Risk for Future Cirrhosis.

BACKGROUND & AIMS: Alcohol overconsumption is a risk factor for disease progression in patients with presumed metabolic dysfunction-associated steatotic liver disease (MASLD). How commonly this occurs and how it affects progression to major adverse liver outcomes (MALOs) is not well known. METHODS: We did a register-based cohort study, including all patients with a diagnosis of MASLD in Sweden between 1987 and 2020. Patients were stratified on co-occurrence of diagnoses of alcohol-related liver disease (ALD) or alcohol use disorder (AUD) prior to MASLD diagnosis. Incident MALOs were derived from national registers. Cox regression was used to calculate hazard ratios (HRs) for incident MALO. RESULTS: A total of 15,107 patients with MASLD were identified. The median age was 55 years, and 52% were female. Of the patients, 1843 (12%) had a prior diagnosis of ALD or AUD. During follow-up, a further 787 patients (5.2%) received a diagnosis of ALD or AUD. Patients with previous ALD or AUD diagnoses at or before baseline had considerably higher rates of MALOs compared with patients without (19.5% vs 7.8%; adjusted HR, 3.12; 95% confidence interval, 2.74-3.55). Acquiring an ALD or AUD diagnosis after MASLD diagnosis was associated with higher rates of MALOs (adjusted HR, 5.81; 95% confidence interval, 4.90-6.88). CONCLUSIONS: ALD or AUD is commonly diagnosed prior to or after MASLD diagnosis. Such patients have considerably higher rates of progression to MALOs. Correctly separating between MASLD and ALD is vital to assess prognosis.

Glucagon-like peptide-1 receptor agonists and risk of major adverse liver outcomes in patients with chronic liver disease and type 2 diabetes.

OBJECTIVE: Phase II trials suggest glucagon-like peptide-1 receptor (GLP1) agonists resolve metabolic dysfunction-associated steatohepatitis but do not affect fibrosis regression. We aimed to determine the long-term causal effect of GLP1 agonists on the risk of major adverse liver outcomes (MALO) in patients with any chronic liver disease and type 2 diabetes. DESIGN: We used observational data from Swedish healthcare registers 2010-2020 to emulate a target trial of GLP1 agonists in eligible patients with chronic liver disease and type 2 diabetes. We used an inverse-probability weighted marginal structural model to compare parametric estimates of 10-year MALO risk (decompensated cirrhosis, hepatocellular carcinoma, liver transplantation or MALO-related death) in initiators of GLP1 agonists with non-initiators. We randomly sampled 5% of the non-initiators to increase computational efficiency. RESULTS: GLP1 agonist initiators had a 10-year risk of MALO at 13.3% (42/1026) vs 14.6% in non-initiators (1079/15 633) in intention-to-treat analysis (risk ratio (RR)=0.91, 95% CI=0.50 to 1.32). The corresponding 10-year per-protocol risk estimates were 7.4% (22/1026) and 14.4% (1079/15 633), respectively (RR=0.51, 95% CI=0.14 to 0.88). The per-protocol risk estimates at 6 years were 5.4% (21/1026) vs 9.0% (933/15 633) (RR=0.60, 95% CI=0.29 to 0.90) and at 8 years 7.2% (22/1026) vs 11.7% (1036/15 633) (RR=0.61, 95% CI=0.21 to 1.01). CONCLUSION: In patients with chronic liver disease and type 2 diabetes who adhered to therapy over time, GLP1 agonists may result in lower risk of MALO. This suggests that GLP1 agonists are promising agents to reduce risk of chronic liver disease progression in patients with concurrent type 2 diabetes, although this needs to be corroborated in randomised trials.

Risk of injuries before and after a diagnosis of cirrhosis: A population-based cohort study.

BACKGROUND: Cirrhosis is often asymptomatic prior to decompensation. Still, cognitive impairment and sarcopenia may be present before decompensation, possibly increasing the risk of injuries. We estimated the risk of injuries during the period shortly before and after cirrhosis diagnosis. METHODS: All patients (N=59,329) with a diagnosis of cirrhosis from 1997 to 2019 were identified from the Swedish National Patient Register. We used a self-controlled case series design to compare the incidence rates (IR) of injuries during a "diagnostic period" (within 3 months before or after the cirrhosis diagnosis date) to a self-controlled "prediagnostic period" (the same 6 calendar months 3 years before diagnosis), using conditional Poisson regression. Injuries were ascertained from the National Patient Register. RESULTS: We identified 23,733 (40.0%) patients with compensated and 35,595 (60.0%) with decompensated cirrhosis. There were 975 injuries (IR 2.8/1000 person-months) during the prediagnostic period, and 3610 injuries (IR 11.6/1000 person-months) identified during the diagnostic period. The IR ratio was 8.1 (95% CI 7.5-8.7) comparing the diagnostic period with the prediagnostic period. For patients with compensated cirrhosis, the risk increment of injuries was highest just before the diagnosis of cirrhosis, whereas the risk increase was highest shortly after the diagnosis for those with decompensation. CONCLUSIONS: The incidence of injuries increases shortly before and after the diagnosis of cirrhosis. These findings indicate that cirrhosis is frequently diagnosed in conjunction with an injury, and highlight the need for injury prevention after cirrhosis diagnosis, especially in patients with decompensation.

Time trends in mortality and life expectancy in 22,658 patients hospitalized with alcohol-associated cirrhosis: A nationwide cohort study.

BACKGROUND: The management of alcohol-associated cirrhosis has improved in the last decades, but whether the prognosis has changed over time is uncertain. We aimed to assess time trends in mortality and life expectancy in patients hospitalized with alcohol-associated cirrhosis. METHODS: In this population-based cohort study, we used the Swedish national population and health registers to identify all patients with a first episode of in-hospital alcohol-associated cirrhosis from 1969 to 2019 (n = 22,658). Time trends in 1-year mortality were assessed with multivariable Cox regression. A flexible parametric model was fitted to evaluate loss in life expectancy. RESULTS: Crude mortality was similar in the 2010s and 1980s (unadjusted HR = 1.00, 95% CI = 0.93-1.08, ptrend = 0.767). However, when adjusting for baseline characteristics, mortality was lower in the 2010s than in the 1980s (adjusted HR = 0.74, 95% CI = 0.68-0.80), including both liver- and nonliver-related mortalities. These results were consistent in men but not in women, where only nonliver mortality had decreased. The average loss in life expectancy for patients with alcohol-associated cirrhosis compared with the general population was similar throughout the study period (in the 2010s: 14.3 y shorter (95% CI = 13.7-14.9) in men and 15.8 years shorter (95% CI = 14.9-16.7) in women). CONCLUSION: Mortality in patients hospitalized with alcohol-associated cirrhosis has improved somewhat when accounting for baseline characteristics, but the loss in life expectancy remains substantial. This underscores the need for new therapeutic options and health policy interventions to further improve the dismal prognosis and life expectancy of patients with alcohol-associated cirrhosis.

Porphyrin precursors and risk of primary liver cancer in acute intermittent porphyria: A case-control study of 188 patients.

Acute intermittent porphyria (AIP) is a rare hereditary metabolic disease characterized by acute attacks and accumulation of the porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Patients with AIP have a high risk of primary liver cancer (PLC). We aimed to assess the association between porphyrin precursor excretion and the risk for PLC in patients with AIP. We studied 48 patients with AIP who developed PLC between 1987 and 2015 and 140 age and sex matched controls with AIP but no PLC. Data on all available urinary PBG and ALA samples collected from 1975 until 1 year before PLC diagnosis were analyzed and compared between cases and controls using logistic regression. Porphyrin precursor excretion was higher in patients with PLC (PBG median 7.9 [IQR 4.4-21.9] mmol/mol creatinine) than in controls (3.8 [1.2-9.8]) (adjusted odds ratio 1.07, 95% confidence interval: 1.02-1.12). None of the 28 patients with all registered samples below the upper limit of normal (ULN) developed PLC, and only one of the 45 patients with all samples <2× ULN developed PLC. Among non-PLC controls, ALA and PBG levels decreased after age 50-60 while an increasing trend was observed after age 65 among those who developed PLC. Increased urinary porphyrin precursors are associated with a high risk of developing PLC. Patients with normal levels appear to have a low risk while high or increasing ALA and PBG after age 65 indicates high risk, which should be considered in surveillance decisions.

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.

Risk of infections in non-alcoholic fatty liver disease: A nationwide population-based cohort study.

BACKGROUND AND AIMS: Previous literature suggests an association between non-alcoholic fatty liver disease (NAFLD) and infections. We aimed to determine the rate and risk of severe infections in NAFLD compared to the general population. METHODS: In this population-based cohort study, we used national registers to identify all patients with a hospital-based diagnosis of NAFLD in Sweden 1987-2020 (n = 14 869). The patients were matched with ≤10 comparators from the general population for age, sex, municipality, and calendar year (n = 137 145). Cox regression was used to estimate hazard ratios (HR) for infections in patients with NAFLD compared to comparators. Cumulative incidences were calculated while accounting for competing risks (non-infection death and liver transplantation). RESULTS: Severe infections leading to death or hospitalization occurred in 1990 (13.4%) patients with NAFLD and 9899 (7.2%) comparators during a median of 4.5 and 6.1 years of follow-up, respectively. The rate of severe infections per 1000 person-years was higher in patients with NAFLD (21.0) than comparators (9.1) independently of components related to the metabolic syndrome (adjusted HR 1.9, 95% CI = 1.8-2.0). Infection-related mortality was also higher in NAFLD compared to comparators (adjusted HR 1.8, 95% CI = 1.6-2.2). The 10-year cumulative incidence of severe infections was 16.6% (95% CI = 15.8-17.4) in NAFLD and 8.0% (95% CI = 7.8-8.2) in comparators. CONCLUSION: NAFLD was associated with severe infections and infection-related mortality, independently of components associated with the metabolic syndrome. Increased clinical vigilance of severe infections in NAFLD may diminish the risk of premature death.

Secondary Prevention of Esophageal Variceal Bleeding Is Often Imperfect: A National, Population-Based Cohort Study of 3592 Patients.

BACKGROUND AND AIMS: Secondary prevention of esophageal variceal bleeding is important to improve prognosis, but uptake of guidelines is unknown in a real-world setting. Here, we determined the proportion of patients receiving appropriate nonselective beta-blocker treatment and repeat upper endoscopy after a first episode of esophageal variceal bleeding within a reasonable time frame. METHODS: Population-based registers were used to identify all patients with a first episode of esophageal variceal bleeding in Sweden from 2006 to 2020. Crosslinkage between registers was performed to receive information on the cumulative incidence of patients with a dispensation of nonselective beta-blockers and repeat upper endoscopy within 120 days from baseline. Overall mortality was investigated using Cox regression. RESULTS: In total, 3592 patients were identified, with a median age of 63 (interquartile range, 54-71) years. The cumulative incidence of a dispensation of nonselective beta-blockers and a repeat endoscopy within 120 days was 33%. A total of 77% received either of these treatments. Overall mortality was high, with 65% of patients dying after esophageal variceal bleeding during the full follow-up period (median 1.7 years). We observed an improved overall mortality during the later years of the study period (adjusted hazard ratio for the 2016-2020 period compared with the 2006-2010 period, 0.80; 95% confidence interval, 0.71-0.89). Patients with receipt of nonselective beta-blockers and repeat upper endoscopy had better overall survival compared with those without (adjusted hazard ratio, 0.80; 95% confidence interval, 0.72-0.90). CONCLUSIONS: Secondary prevention of esophageal variceal bleeding has not been widely undertaken, with many patients not receiving guideline-supported interventions within a reasonable time frame. This highlights a need to raise awareness on appropriate prevention strategies to clinicians and patients.

Risk of Severe Infection in Patients With Biopsy-proven Nonalcoholic Fatty Liver Disease - A Population-based Cohort Study.

BACKGROUND & AIMS: It has been suggested that patients with nonalcoholic fatty liver disease (NAFLD) might be at increased risk of severe infections, but large-scale data from cohorts with biopsy-proven NAFLD are lacking. METHODS: Population-based cohort study including all Swedish adults with histologically confirmed NAFLD (n = 12,133) from 1969 to 2017. NAFLD was defined as simple steatosis (n = 8232), nonfibrotic steatohepatitis (n = 1378), noncirrhotic fibrosis (n = 1845), and cirrhosis (n = 678). Patients were matched to ≤5 population comparators (n = 57,516) by age, sex, calendar year, and county. Swedish national registers were used to ascertain incident severe infections requiring hospital admission. Multivariable adjusted Cox regression was used to estimate hazard ratios in NAFLD and histopathological subgroups. RESULTS: Over a median of 14.1 years, 4517 (37.2%) patients with NAFLD vs 15,075 (26.2%) comparators were hospitalized for severe infections. Patients with NAFLD had higher incidence of severe infections than comparators (32.3 vs. 17.0/1000 person-years; adjusted hazard ratio [aHR], 1.71; 95% confidence interval, 1.63-1.79). The most frequent infections were respiratory (13.8/1000 person-years) and urinary tract infections (11.4/1000 person-years). The absolute risk difference at 20 years after NAFLD diagnosis was 17.3%, equal to one extra severe infection in every 6 patients with NAFLD. Risk of infection increased with worsening histological severity of NAFLD (simple steatosis [aHR, 1.64], nonfibrotic steatohepatitis [aHR, 1.84], noncirrhotic fibrosis [aHR, 1.77], and cirrhosis [aHR, 2.32]. Also compared with their full siblings, patients with NAFLD were at increased risk of severe infections (aHR, 1.54; 95% confidence interval, 1.40-1.70). CONCLUSIONS: Patients with biopsy-proven NAFLD were at significantly higher risk of incident severe infection requiring hospitalization both compared with the general population and compared with siblings. Excess risk was evident across all stages of NAFLD and increased with worsening disease severity.

Administrative coding for non-alcoholic fatty liver disease is accurate in Swedish patients.

Background and Aims: Epidemiological studies of non-alcoholic fatty liver disease (NAFLD) frequently use the International Classification of Disease (ICD) codes to identify patients. The validity of such ICD codes in a Swedish setting is unknown. Here, we aimed to validate the administrative code for NAFLD in Sweden.Methods: In total, 150 patients with an ICD-10 code for NAFLD (K76.0) from the Karolinska University Hospital between 1 January 2015 and 3 November 2021 were randomly selected. Patients were classified as true or false positives for NAFLD by medical chart review and the positive predictive value (PPV) for the ICD-10 code corresponding to NAFLD was calculated.Results: The PPV of the ICD-10 code for NAFLD was 0.82 (95% confidence interval [CI] = 0.76-0.89). After exclusion of patients with diagnostic coding for other liver diseases or alcohol abuse disorder (n = 14), the PPV was improved to 0.91 (95% CI 0.87-0.96). The PPV was higher in patients with coding for NAFLD in combination with obesity (0.95, 95%CI = 0.87-1.00) or type 2 diabetes (0.96, 95%CI = 0.89-1.00). However, in false-positive cases, a high alcohol consumption was common and such patients had somewhat higher Fibrosis-4 scores than true-positive patients (1.9 vs 1.3, p = 0.16)Conclusions: The ICD-10 code for NAFLD had a high PPV, that was further improved after exclusion of patients with coding for other liver diseases than NAFLD. This approach should be preferred when performing register-based studies to identify patients with NAFLD in Sweden. Still, residual alcohol-related liver disease might risk confound some findings seen in epidemiological studies which needs to be considered.

Risk of fractures and postfracture mortality in 3980 people with primary biliary cholangitis: A population-based cohort study.

BACKGROUND: Morbidity in primary biliary cholangitis (PBC) is multifactorial. Osteoporosis related to cholestasis is an extrahepatic complication of PBC. It is not fully established to what extent people with PBC have an increased risk for fractures, and if mortality after a fracture is increased, compared to the general population. METHODS: All Swedish people with PBC diagnosed between 2001 and 2016 were identified from the National Swedish Patient Register using ICD-10 codes. Incident fractures were ascertained in the same register and compared to matched controls from the Swedish general population (1:10 for age, sex, and municipality). Cox regression was used to investigate the rates of fractures and postfracture mortality. The cumulative incidence of fractures was calculated while accounting for competing risks (death or liver transplantation). RESULTS: People with PBC (n = 3980) showed a higher risk of fractures at all-time points during follow-up compared to matched controls (n = 37,196), which was seen both in men and women. At 5 years of follow-up, the cumulative incidence of any fracture in people with PBC was 16.8% (95% confidence interval [CI] = 15.6-18.1), compared to 11.6% (95%CI = 11.3-12.0) in controls. The rate of osteoporotic fractures was particularly high (adjusted Hazard ratio [aHR] = 1.9; 95% = CI 1.7-2.0). The 30-day as well as the 1-year mortality after a fracture was significantly higher in people with PBC compared to controls that also experienced a fracture (aHR = 2.2; 95%CI = 1.5-3.2; aHR = 2.0; 95%CI 1.7-2.4). CONCLUSION: People with PBC have a significantly higher risk of fractures and postfracture mortality compared to matched controls from the general population.

Risk of Fractures and Subsequent Mortality in Alcohol-Related Cirrhosis: A Nationwide Population-Based Cohort Study.

BACKGROUND AND AIMS: Alcohol-related cirrhosis is linked to increased risk of fractures, but this has seldom been quantified nationally or compared against control subjects without cirrhosis. Here, we determined the rate and risk of fractures and postfracture mortality in patients with alcohol-related cirrhosis compared with individuals from the general population. METHODS: In this nationwide population-based cohort study, data were retrieved from the Swedish National Patient Registry on 25,090 patients with alcohol-related cirrhosis from 1969-2016. Patients were matched for sex, age, and municipality with 239,458 control subjects from the Swedish Total Population Registry. Cox regression models were fitted to investigate the rates of fractures and postfracture mortality. The cumulative incidence of fractures was calculated while accounting for competing risks (death or liver transplantation). RESULTS: A total of 48,635 fractures occurred during 3,468,860 person-years of follow-up. Patients with alcohol-related cirrhosis had a higher fracture rate per 1000 person-years (38.7) than control subjects (13.3; adjusted hazard ratio, 3.8; 95% confidence interval, 3.6-3.9). The cumulative incidence of fractures was elevated for patients the first 19 years of follow-up, with a 5-year risk of 9.6% compared with 4.5% for control subjects. Patients with alcohol-related cirrhosis had a higher postfracture mortality rate compared with control subjects who also experienced a fracture, at both 30 days (adjusted hazard ratio, 1.6; 95% confidence interval, 1.4-1.8) and 1 year (adjusted hazard ratio, 1.8; 95% confidence interval, 1.7-2.0). CONCLUSIONS: Alcohol-related cirrhosis is associated with an almost 4-fold increased fracture rate, a higher risk of fractures the first 2 decades after initial diagnosis, and higher postfracture mortality. Preventive interventions to reduce modifiable fracture risk factors in this population are justified.

Three-fold Increased Risk of Death in Budd-Chiari Syndrome Compared to Matched Controls: A Population-based Cohort Study.

BACKGROUND & AIMS: Patients with Budd-Chiari syndrome (BCS) have an elevated risk of overall and liver-specific mortality, but this has not been quantified on a population level nor compared against a matched general population cohort. METHODS: We identified all patients in Sweden with a recorded diagnosis of BCS in the Swedish National Patient Register between 1987 and 2016. Patients with BCS were matched for age, sex, and municipality at baseline with up to 10 reference individuals from the general population. Data on cause-specific mortality were obtained from the Causes of Death Register. A Cox regression model was performed to investigate rates of all-cause and cause-specific mortality. RESULTS: A total of 478 patients with BCS were matched with 4603 reference individuals. Of the patients with BCS, 43% were men, the median age was 58 years, 39% had a recorded diagnosis of a precipitating risk factor, and 13% had underlying liver disease. During a follow-up of up to 29 years, 243 (51%) of the patients with BCS died compared with 1346 (29%) of the reference individuals. Overall mortality was 70 per 1000 person-years in patients with BCS compared with 28 per 1000 person-years in reference individuals, translating into an adjusted hazard ratio (aHR) of 3.1 (95% confidence interval [CI], 2.6-3.6). Although liver-related mortality was particularly high (aHR, 47.6; 95% CI, 16.5-137.4), liver disease accounted for only 10% of deaths in BCS. The most common cause of death was cardiovascular disease (aHR, 2.2; 95% CI, 1.7-2.9). CONCLUSIONS: Patients with BCS in Sweden had a 3-fold higher risk of death compared with general population reference individuals. Although mortality from liver diseases was high in relative terms, most patients died from cardiovascular causes.

FXR inhibition may protect from SARS-CoV-2 infection by reducing ACE2.

Preventing SARS-CoV-2 infection by modulating viral host receptors, such as angiotensin-converting enzyme 2 (ACE2)1, could represent a new chemoprophylactic approach for COVID-19 that complements vaccination2,3. However, the mechanisms that control the expression of ACE2 remain unclear. Here we show that the farnesoid X receptor (FXR) is a direct regulator of ACE2 transcription in several tissues affected by COVID-19, including the gastrointestinal and respiratory systems. We then use the over-the-counter compound z-guggulsterone and the off-patent drug ursodeoxycholic acid (UDCA) to reduce FXR signalling and downregulate ACE2 in human lung, cholangiocyte and intestinal organoids and in the corresponding tissues in mice and hamsters. We show that the UDCA-mediated downregulation of ACE2 reduces susceptibility to SARS-CoV-2 infection in vitro, in vivo and in human lungs and livers perfused ex situ. Furthermore, we reveal that UDCA reduces the expression of ACE2 in the nasal epithelium in humans. Finally, we identify a correlation between UDCA treatment and positive clinical outcomes after SARS-CoV-2 infection using retrospective registry data, and confirm these findings in an independent validation cohort of recipients of liver transplants. In conclusion, we show that FXR has a role in controlling ACE2 expression and provide evidence that modulation of this pathway could be beneficial for reducing SARS-CoV-2 infection, paving the way for future clinical trials.