Dranoff, Jonathan A.

This practice recommendation serves as an update to the 2023 AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction–associated steatotic liver disease (MASLD), and provides implementable guidance on patient selection for treatment, consideration of comorbidities, and monitoring of treatment safety and efficacy of semaglutide. FDA-indication and Practice Recommendation: The Wegovy formulation, whose main ingredient is semaglutide, received accelerated FDA approval in August 2025 for treating MASH with moderate-to-advanced fibrosis (consistent with stages F2–F3 fibrosis), based on interim results of the phase 3 ESSENCE trial where 72 weeks of 2.4 mg/week subcutaneous injection resulted in achievement of both primary histologic endpoints: (1) resolution of MASH without worsening of fibrosis (62.9% vs. 34.3% placebo, p <0.001) and (2) ≥1 stage reduction in liver fibrosis without worsening of MASH (36.8% vs. 22.4% placebo, p <0.001); final approval awaits long-term outcomes. Patient Selection: Candidates should have MASH with stage 2–3 fibrosis, identified using non-invasive tests (NITs) such as VCTE (8–15 kPa), MRE (3.1–4.4 kPa), or ELF (9.2–10.5), rather than liver biopsy, which is impractical and unnecessary for most patients. In those with VCTE (15–20 kPa), MRE (4.4–5 kPa), or ELF (10.5–11.3), an individualized decision to treat should be based on exclusion of cirrhosis with another confirmatory NIT, or cross-sectional imaging excluding nodular-appearing liver contour and signs of portal hypertension, or a platelet count of <150,000/mm 3 . While semaglutide is not approved to treat patients with MASH cirrhosis (VCTE >20 kPa, MRE>5.0 kPa, ELF>11.3, and/or evidence of portal hypertension), those with compensated cirrhosis who are receiving semaglutide for another FDA-approved indication should be monitored carefully. Monitoring and Safety: Semaglutide showed a favorable hepatic safety profile in the ESSENCE trial, with no discontinuations due to liver enzyme elevations. Routine hepatic panels are recommended only as clinically indicated. The most common adverse events were gastrointestinal (nausea, diarrhea, constipation, vomiting), generally mild and transient; patient education and dose titration help improve tolerance. Clinicians should monitor for rare but serious risks, including acute kidney injury (from dehydration), symptomatic gallbladder disease, pancreatitis, thyroid C-cell tumors, retinopathy progression, and lean mass loss. Treatment Response and Concomitant Therapy: Lifestyle modification remains the cornerstone of MASLD/MASH management alongside semaglutide. Combination use of resmetirom with semaglutide 2.4mg/week has not been studied. While no NITs reliably predict histologic response at the individual patient level, reductions from baseline to 72 weeks of treatment suggest significant improvement in MASH resolution (ALT ≥17 U/L or ≥20%) and fibrosis improvement (VCTE LSM ≥30%; MRE LSM ≥20%; ELF ≥0.5). Non-response may be suspected if ALT or NITs worsen. The benefit is uncertain if a suboptimal response occurs, and may require an individualized approach and further follow-up.

Background and Aims: Blood-based biomarkers have been proposed as an alternative to liver biopsy for noninvasive liver disease assessment in chronic liver disease. Our aims for this systematic review were to evaluate the diagnostic utility of selected blood-based tests either alone, or in combination, for identifying significant fibrosis (F2-4), advanced fibrosis (F3-4), and cirrhosis (F4), as compared to biopsy in chronic liver disease. Approach and Results: We included a comprehensive search of databases including Ovid MEDLINE(R), EMBASE, Cochrane Database, and Scopus through to April 2022. Two independent reviewers selected 286 studies with 103,162 patients. The most frequently identified studies included the simple aspartate aminotransferase-to-platelet ratio index and fibrosis (FIB)-4 markers (with low-to-moderate risk of bias) in HBV and HCV, HIV-HCV/HBV coinfection, and NAFLD. Positive (LR+) and negative (LR−) likelihood ratios across direct and indirect biomarker tests for HCV and HBV for F2-4, F3-4, or F4 were 1.66–6.25 and 0.23–0.80, 1.89–5.24 and 0.12–0.64, and 1.32–7.15 and 0.15–0.86, respectively; LR+ and LR− for NAFLD F2-4, F3-4, and F4 were 2.65–3.37 and 0.37–0.39, 2.25–6.76 and 0.07–0.87, and 3.90 and 0.15, respectively. Overall, the proportional odds ratio indicated FIB-4 <1.45 was better than aspartate aminotransferase-to-platelet ratio index <0.5 for F2-4. FIB-4 >3.25 was also better than aspartate aminotransferase-to-platelet ratio index >1.5 for F3-4 and F4. There was limited data for combined tests. Conclusions: Blood-based biomarkers are associated with small-to-moderate change in pretest probability for diagnosing F2-4, F3-4, and F4 in viral hepatitis, HIV-HCV coinfection, and NAFLD, with limited comparative or combination studies for other chronic liver diseases.

Extracellular nucleotides may be important regulators of bile ductular secretion, because cholangiocytes express P2Y ATP receptors and nucleotides are found in bile. However, the expression, distribution, and function of specific P2Y receptor subtypes in cholangiocytes are unknown. Thus our aim was to determine the subtypes, distribution, and role in secretion of P2Y receptors expressed by cholangiocytes. The molecular subtypes of P2Y receptors were determined by RT-PCR. Functional studies measuring cytosolic Ca2+(Ca[Formula: see text]) signals and bile ductular pH were performed in isolated, microperfused intrahepatic bile duct units (IBDUs). PCR products corresponding to P2Y1, P2Y2, P2Y4, P2Y6, and P2X4receptor subtypes were identified. Luminal perfusion of ATP into IBDUs induced increases in Ca[Formula: see text] that were inhibited by apyrase and suramin. Luminal ATP, ADP, 2-methylthioadenosine 5′-triphosphate, UTP, and UDP each increased Ca[Formula: see text]. Basolateral addition of adenosine 5′- O-(3-thiotriphosphate) (ATP-γ-S), but not ATP, to the perifusing bath increased Ca[Formula: see text]. IBDU perfusion with ATP-γ-S induced net bile ductular alkalization. Cholangiocytes express multiple P2Y receptor subtypes that are expressed at the apical plasma membrane domain. P2Y receptors are also expressed on the basolateral domain, but their activation is attenuated by nucleotide hydrolysis. Activation of ductular P2Y receptors induces net ductular alkalization, suggesting that nucleotide signaling may be an important regulator of bile secretion by the liver.