Hepatology Update for Gastroenterologists

1. Does my patient benefit with MASLD benefit from pharmacotherapy?

Rashmee Patil, of Pinnacle Clinical Research, discussed current approaches to diagnosis and treatment of MASLD, which affects 25-30% of US population. She defined patients with metabolic dysfunction-associated steatohepatitis (MASH) and F2-F3 fibrosis as having “at risk” MASH that is likely to progress to MASLD. Identifying these at-risk patients is key to intervention that can slow progression. Risk factors include diabetes, obesity, and other signals of dysregulated metabolism. Diagnosis with liver biopsy is the gold standard but is not practical in clinical practice. Various non-invasive tests (NITs) are commonly used, including FIB-4 (age, AST, ALT, and platelets), which is readily available and validated. For patients with a FIB-4 score that falls in the indeterminate range of 1.3 to 2.67, referral for secondary testing is warranted. Second-line tests include predictive blood tests (ELF, Fibrosure, LIverFASt) and fibrosis imaging with magnetic resonance (MR) elastography or vibration-controlled transient elastography (VCTE or FibroScan), which can be used together to calculate more precise disease scores. Goals for MASH management have changed in last 10 years, from lifestyle changes and watch-and-wait to addition of liver-directed treatment to halt and reverse fibrosis and delay or prevent major adverse liver outcomes (MALO). Resmetirom is a thyroid hormone receptor beta receptor agonist that modifies signaling in the liver, with efficacy demonstrated in the MAESTRO-NASH. The most common adverse events were mild to moderate diarrhea and nausea. Semaglutide is a GLP-1 receptor agonist with known effects in multiple systems; the ESSENCE trial reported efficacy in reducing MASH in the liver. Adverse events were nausea, diarrhea, constipation, vomiting, and decreased appetite. Of note, neither option is appropriate for use in patients with cirrhosis (later stage MASH). The same NITs used at baseline should be used to assess treatment response at 6 months. These treatments should be presented to patients as a complement to diet and exercise, along with their NIT results.

2. How do I manage PBC beyond prescribing ursodeoxycholic acid?

Craig Lammert, MD, of Indiana University, described a shift from a reactive “wait to fail” model for patients with PBC to a proactive individualized approach that involves risk stratification, staging, and symptom management from the time of diagnosis. Symptoms of PBC include fatigue, pruritis, and elevated antimitochondrial antibody (AMA) and IgM, though some patients have AMA-negative disease. NITs for PBC include liver stiffness via ultrasound, bilirubin, and alkaline phosphatase (ALP). However, dichotomous yes/no diagnostic models based on these tests do not fully capture the spectrum of disease, and new continuous predictive models, including the GLOBE score and UK-PBC risk score, use thresholds for markers and can be used for diagnosis, treatment response, and monitoring. Ursodeoxycholic acid (UDCA) is the first-line treatment to improve survival and slow progression, but is not effective in all patients. PPAR agonists are now available as second-line therapies for PBC, and each target the receptor subunits differently. The efficacy of elafibranor was established in the ELATIVE study and seladelpar in the RESPONSE trial, both in 2024, with sustained effects on biochemical markers and symptoms out to years of follow-up. Neither treatment is appropriate for patients with decompensated cirrhosis or bile duct obstruction. Linerixibat is an ileal bile acid transporter inhibitor (IBAT) that treats cholestatic pruritic (itching) in patients with PBC. Patients need to be monitored for bone health, hypercholesterolemia (particularly lipoprotein X and HDL as markers of cholestatic pruritis), and co-morbid autoimmune diseases such as Hashimoto’s and Sjogren’s. In PBC, an adequate biochemical treatment response is no longer the goal, and partial responders may improve with tighter controls. Treatment today is focused on personalized care based on risk and the patient’s aspirational goals. This involves sharing test results with patients and setting normal results as a goal. Treatment should aim to achieve the deepest, sustained response across symptoms, fibrosis, comorbidities, and quality of life.

3. Should I prescribe a beta blocker or perform a screening esophagogastroduodenoscopy (EGD) in my patient with cirrhosis?

Brett E. Fortune, MD, from the Miami Transplant Institute, presented the current debate on whether a screening upper endoscopy is needed in patients with cirrhosis. Chronic liver disease is prompted by an injury (alcohol, metabolic dysfunction, obesity, viral hepatitis, or autoimmune response) to become compensated cirrhosis. With clinically significant portal hypertension, cirrhosis becomes decompensated, leading to liver transplantation or death. With treatment, patients can move back to “recompensated” cirrhosis.

Dr. Fortune also introduced new terms that depart from “cirrhosis,” which refers to histology, and instead distinguish between compensated or decompensated advanced chronic liver disease (cACLD and dACLD). Portal hypertension is a point of treatment for dACLD. Traditional methods to diagnose portal hypertension include radiology, endoscopy, and clinical findings (ascites, variceal bleeding, hepatic encephalopathy), and the gold standard measure of hepatic venous pressure gradient (HVPG). The field has turned to more practical NITs, including VCTE, shear wave elastography, MR elastography, and blood markers. Every 5 kPa increase in liver stiffness increases disease severity. For those who fall in the intermediate zone, stiffness of the spleen can be used as an additional marker. The prediction model “NICER” includes liver stiffness, platelets, splenic stiffness, and BMI. Dr. Fortune felt that upper endoscopy is also an option; however, the importance of preventing decompensation and ascites outweighs treatment of variceal bleeding. Beta blockers directly affect portal hypertension to prevent decompensation. At least 20 meta-analyses of EGD versus beta blockers have found no difference in survival; however, the PREDESCI trial showed that improvement in ascites lowered risk of decompensation, as well as increased decompensation-free survival with beta blockers. Beta blockers are also cheaper, with fewer risks, and preferred by patients. This move away from EGD-based risk stratification and towards beta blockers to prevent hepatic decomposition represents a paradigm shift in practice that will be included in the Baveno VIII Consensus statements, which will be released soon.

4. When and how should I screen my patients for HCC?

Nicole E. Rich, MD, from UT Southwestern Medical Center, discussed the underuse of HCC surveillance and consequent late-stage liver cancer diagnosis. Curative treatments are available for early-stage HCC, which is asymptomatic. HCC surveillance is not recommended by the USPSTF because of a lack of evidence-based test.

Most patients are followed in primary care clinics, where HCC surveillance would be most effective. Most patients with HCC have cirrhosis, so any patient with cirrhosis should be screened for HCC. However, 20-30% of MASLD-related HCC occur in those without cirrhosis. In the U.S., HBV/HVC in no longer the primary cause of HCC; alcohol use, MASLD, and MetALD are the most common causes today. These are much larger populations that would benefit from HCC surveillance, though these groups have a smaller risk of HCC compared to the risk conferred by HBV/HCV. Currently, patients without cirrhosis are candidates for surveillance if they have HBV infection and other risk factors (e.g., from an endemic country). Gray areas for surveillance include patients with HCV infection with fibrosis, non-cirrhotic MASLD, those with discordant NIT results, and family history. In all cases, shared decision-making about surveillance is recommended. HCC surveillance is not recommended for individuals with low life expectancy or low risk to avoid harms such as unnecessary additional testing for false positives, anxiety, and cost. Screening involves ultrasound plus AFP testing every 6 months. Ultrasound should have a confirmed LI-RADS visualization score for use in screening. Low-visibility ultrasounds should be followed up with CT or MRI. Blood-based biomarkers are the future of HCC surveillance; for example, GALAD combines gender, age, and the blood-based makers AFP-L3, AFP, and DCP (PIVKA-II). An ongoing challenge in HCC screening is the ability to recall previous results to compare over time.