Exercise training improves serum biomarkers of liver fibroinflammation in patients with metabolic dysfunction-associated steatohepatitis.

BACKGROUND AND AIMS: Exercise training is recommended for all patients with metabolic dysfunction-associated steatotic liver disease and may reverse liver fibrosis. Whether exercise training improves liver fibrosis without body weight loss remains controversial. We further investigated this relationship using serum biomarkers of liver fibroinflammation in a post hoc analysis of an exercise trial where patients did not lose significant body weight. METHODS: In the NASHFit trial, patients with metabolic dysfunction-associated steatohepatitis were randomized to receive either moderate-intensity aerobic exercise training or standard clinical care for 20 weeks. Mediterranean-informed dietary counselling was provided to each group. Change in serum biomarkers was measured and compared between the two groups. RESULTS: Exercise training led to improvement in serum biomarkers of liver fibroinflammation, including (1) ≥17 IU/L reduction in alanine aminotransferase (ALT) in 53% of individuals in the exercise training group compared to 13% in the standard clinical care group (p < 0.001; mean reduction 24% vs. 10% respectively) and (2) improvement in CK18 (-61 vs. +71 ng/mL, p = 0.040). ALT improvement ≥17 IU/L was correlated with ≥30% relative reduction in magnetic resonance imaging-measured liver fat and PNPLA3 genotype. CONCLUSION: Exercise training improves multiple serum biomarkers of liver fibroinflammation at clinically significant thresholds of response without body weight loss. This study provides further evidence that exercise training should be viewed as a weight-neutral intervention for which response to intervention can be readily monitored with widely available non-invasive biomarkers that can be applied at the population level.

NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH.

BACKGROUND AND AIMS: NASH is a common disease associated with increased rates of thromboembolism (TE). Although exercise training can lessen thrombotic risk in patients with vascular disease, whether similar findings are observed in patients with NASH is open for study. APPROACH AND RESULTS: We conducted a 20-week randomized controlled clinical trial involving patients with biopsy-confirmed NASH. Patients were randomly assigned (2:1 ratio) to receive either an exercise training program or standard clinical care. The primary endpoint was change in plasminogen activator inhibitor 1 (PAI-1) level, an established thrombotic biomarker. Twenty-eight patients were randomly assigned (18 exercise training and 10 standard clinical care). PAI-1 level was significantly decreased by exercise training when compared to standard clinical care (-40 ± 100 vs. +70 ± 63 ng/ml; p = 0.02). Exercise training decreased MRI proton density fat fraction (MRI-PDFF; -4.7 ± 5.6 vs. 1.2 ± 2.8% absolute liver fat; p = 0.01); 40% of exercise subjects had a ≥30% relative reduction in MRI-PDFF (histological response threshold) compared to 13% for standard of care (p < 0.01). Exercise training improved fitness (VO2 peak, +3.0 ± 5.6 vs. -1.8 ± 5.1 ml/kg/min; p = 0.05) in comparison to standard clinical care. CONCLUSIONS: This clinical trial showed that, independent of weight loss or dietary change, exercise training resulted in a significantly greater decrease in thrombotic risk than standard clinical care in patients with NASH, in parallel with MRI-PDFF reduction and improvement in fitness. Future studies are required to determine whether exercise training can directly impact patient outcomes and lower rates of TE.

Porto-Sinusoidal Vascular Disease in Congenital Erythropoietic Porphyria Needing Liver Transplantation.

Porphyria caused by inherited disorders in heme biosynthesis can lead to accumulation of porphyrins in various organs. Liver involvement due to porphyria mostly results in cholestasis leading to liver cirrhosis or hepatocellular carcinoma. Congenital erythropoietic porphyria (CEP), a rare porphyria due to deficiency of uroporphyrinogen III synthase, mostly results in cutaneous manifestations. There are reports of liver involvement including varying degree of fibrosis in patients with CEP. We report a unique case of a patient with CEP who developed porto-sinusoidal vascular disease with complications of portal hypertension that necessitated liver transplantation.

Prospective evaluation of patients with non-cirrhotic portal hypertension: A single centre study.

BACKGROUND: Non-cirrhotic portal hypertension (NCPH) is a spectrum of liver diseases, including porto-sinusoidal vascular disorder, with portal hypertension (PH) in the absence of cirrhosis. The natural history and diagnostic approach to NCPH are not well understood. AIM: We aimed to evaluate disease progression and outcomes in NCPH. METHODS: Patients with or at risk for NCPH were enrolled in a single centre prospective study; two groups were formed based on the presence of specific features of PH, such as varices, collaterals, portal hypertensive gastropathy or portal hypertensive bleeding. All participants underwent a baseline liver biopsy. Liver stiffness measurement (LSM), and imaging were repeated every 6-12 months. RESULTS: Fifteen patients without specific features of PH (Group I), and 35 patients with specific features (Group II) were enrolled. The median follow-up time was 50 months. Group II had higher hepatic venous pressure gradients, non-invasive measures of PH and a lower platelet count (PLT) when compared to Group I. Rates of survival and decompensation were similar in both groups. Patients with PLT ≤100 K/mcL had lower survival compared to those with PLT >100 K/mcL. Patients with LSM ≥10 kPa had lower survival and survival without decompensation when compared to patients with LSM <10 kPa. CONCLUSIONS: Patients irrespective of specific features of PH had similar survival or survival without decompensation. Patients without specific features are at risk for disease progression and should be monitored closely. Thrombocytopenia and increased LSM are associated with severe forms of liver disease, which are strongly associated with outcomes.

Utilization of a Directly Supervised Telehealth-Based Exercise Training Program in Patients With Nonalcoholic Steatohepatitis: Feasibility Study.

BACKGROUND: Most patients with nonalcoholic fatty liver disease (NAFLD) are physically inactive despite the well-known benefits of physical activity. Telehealth offers promise as a novel way to deliver an exercise training program and increase physical activity. However, the feasibility, safety, and efficacy of telehealth-based exercise programs is unknown in patients with NAFLD. OBJECTIVE: The aim of this study was to determine the feasibility of a directly supervised exercise training program delivered exclusively with telehealth to patients with nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. METHODS: In response to COVID-19 research restrictions, we adapted an existing clinical trial and delivered 20 weeks of moderate-intensity aerobic training 5 days a week under real-time direct supervision using an audio-visual telehealth platform. Aerobic training was completed by walking outdoors or using a home treadmill. Fitness activity trackers with heart rate monitors ensured exercise was completed at the prescribed intensity with real-time feedback from an exercise physiologist. RESULTS: Three female patients with biopsy-proven NASH were enrolled with a mean age of 52 (SD 14) years. The mean body mass index was 31.9 (SD 5.1) kg/m2. All patients had metabolic syndrome. All patients completed over 80% of exercise sessions (mean 84% [SD 3%]) and no adverse events occurred. Body weight (mean -5.1% [SD 3.7%]), body fat (mean -4.4% [SD 2.3%]), and waist circumference (mean -1.3 in. [SD 1.6 in.]) all improved with exercise. The mean relative reduction in magnetic resonance imaging-proton density fat fraction (MRI-PDFF) was 35.1% (SD 8.8%). Mean reductions in hemoglobin A1c and Homeostatic Model Assessment for Insulin Resistance were also observed (-0.5% [SD 0.2%] and -4.0 [SD 1.2], respectively). The mean peak oxygen consumption (VO2peak) improved by 9.9 (SD 6.6) mL/kg/min. CONCLUSIONS: This proof-of-concept study found that supervised exercise training delivered via telehealth is feasible and safe in patients with NASH. Telehealth-based exercise training also appears to be highly efficacious in patients with NASH, but this will need to be confirmed by future large-scale trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT03518294; https://clinicaltrials.gov/ct2/show/NCT03518294.

Excellent outcomes with liver transplantation in hepatopulmonary syndrome across pre-transplant PaO2 spectrum.

BACKGROUND & AIMS: Significantly worse survival has been reported in patients with hepatopulmonary syndrome (HPS) and partial pressure of arterial oxygen (PaO2) <45 mmHg undergoing liver transplantation. Long-term pre- and post-transplant outcomes based on degree of hypoxaemia were re-examined. METHODS: A retrospective analysis of 1,152 HPS candidates listed with an approved HPS model for end-stage liver disease (MELD) exception was performed. A Fine and Gray competing risks model was utilised to evaluate pre-transplant outcomes for PaO2 thresholds of <45, 45 to <60, and ≥60 mmHg. Post-transplant survival was analysed using the Kaplan-Meier method. RESULTS: Patients with a PaO2 <45 mmHg were significantly more likely to undergo transplantation (hazard ratio [HR] 1.51; 95% CI 1.12-2.03), whereas patients with higher MELD scores had lower hazard of transplant (HR 0.80, 95% CI 0.67-0.95, p = 0.011) and higher hazard of pre-transplant death (HR 2.29, 95% CI 1.55-3.37, p <0.001). Post-transplantation, patients with a PaO2 <45 mmHg had lower survival (p = 0.04) compared with patients with a PaO2 ≥45 to <50 mmHg, with survival curves significantly different at 2.6 years (75% survival compared with 86%) and median survival of 11.5 and 14.1 years, respectively. Cardiac arrest was a more likely (p = 0.025) cause of death for these patients. Cardiac arrest incidence in patients who died with a PaO2 >50 mmHg was 6.2%. CONCLUSIONS: Patients with a PaO2 <45 mmHg had a significantly higher rate of transplantation, and higher calculated MELD scores were associated with significantly higher pre-transplant mortality. Although post-transplant survival was lower in patients with a PaO2 <45 mmHg, the median survival was 11.5 years, and survival curves only became significantly different at 2.6 years. This suggests that patients with HPS do benefit from transplantation up to 2-3 years post-transplant regardless of the severity of pre-transplant hypoxaemia. LAY SUMMARY: A total of 1,152 patients with hepatopulmonary syndrome listed for liver transplant were analysed. Patients with a low PaO2 <45 mmHg had a high likelihood of transplantation. If associated with advanced liver disease, the mortality risk was higher for patients with hepatopulmonary syndrome on the wait list. After liver transplantation, patients with a PaO2 <45 mmHg had a lower survival, but this only became significant after 2.6 years, and the median survival was 11.5 years. This suggests that patients with hepatopulmonary syndrome do benefit from transplantation.

Drug-Induced Liver Disease: Clinical Course.

Drug-induced liver injury (DILI) is a term used to describe a spectrum of clinical presentations and severity that ranges from mild elevation of liver enzymes on routine blood work to acute liver failure and death. Approximately 10% of all patients with DILI develop acute liver failure resulting in death or liver transplantation. DILI may be prolonged with persistence of elevated liver enzymes for longer than 6 months in approximately 5% to 20% of cases. Cirrhosis and long-term liver-related morbidity and mortality have also been described but are rare, occurring in 1% to 3% of cases.