Category Archives: Hepatology

Improving Liver Organ Transplantation Allocation with Artificial Intelligence

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AM Gomez-Orellana et al. Clin Gastroenterol Hepatol 2025; 23: 2187-2196. Open Access! Gender-Equity Model for Liver Allocation Using Artificial Intelligence (GEMA-AI) for Waiting List Liver Transplant Prioritization

Background: “The current gold standard for ranking patients in the waiting list according to their mortality risk is the Model for End-Stage Liver Disease corrected by serum sodium (MELD-Na), which combines 4 serum analytic and objective parameters, namely bilirubin, international normalized ratio (INR), creatinine, and sodium…2“

“The Model for End-Stage Liver Disease (MELD) 3.0 was developed and internally validated in the United States,4 and the gender-equity model for liver allocation corrected by serum sodium (GEMA-Na) was trained and internally validated in the United Kingdom and externally validated in Australia.5… GEMA-Na was associated with a more pronounced discrimination benefit than MELD 3.0, probably owing to the replacement of serum creatinine with the Royal Free Hospital cirrhosis glomerular filtration rate (RFH-GFR)6 in the formula.5“

Methods:

Key findings:

  • GEMA-AI made more accurate predictions of waiting list outcomes than the currently available models, and could alleviate gender disparities for accessing LT

Discussion Points:

  • The components of the current scores available for waiting list prioritization provide objective and reproducible information…which in turn are associated with the probability of mortality or clinical deterioration resulting in transplant unsuitability.18 However, this relationship is nonlinear…at a certain point, for the highest values typically found in the sickest patients, the relationship with the outcome risk becomes exponential.5 …GEMA-AI was the only adequately calibrated model and showed the greatest advantage on discrimination”
  • An “advantage of nonlinear methodologies, and particularly of ANNs [artificial neural network], is their ability to identify patterns of combinations of values that are associated with an increased risk of death or delisting due to clinical worsening. While linear models give a fixed weight to each variable irrespective of its value or the value of other variables in the model, ANNs could capture specific combinations to modulate the weighting.19“

My take: In the movie, iRobot, Detective Spooner instructs the robot: “Sonny, save Calvin.” While things worked out in the movie, it turns out that the robot would usually make a better decision. This study shows that AI has the potential to reduce waiting list mortality by taking advantage of weighing non-linear variables.

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Primary Sclerosing Cholangitis (PSC) – Medical Treatment, Therapeutic Window and Relationship to Colitis

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A recent Hepatology issue with reviews on cholestatic diseases featured three articles focused on Primary Sclerosing Cholangitis (PSC). These in-depth reviews spanned ~60 pages with more than 500 references.

TH Karlsen et al. Hepatology 2025; 82: 927-948. Open Access! Medical treatment of primary sclerosing cholangitis: What have we learned and where are we going?

As an aside, all of the articles include a short AI-generated plain language summary. I am a little surprised that the journal put in a disclaimer for them: “Text is machine generated and may contain inaccuracies.” The authors and editors have the expertise to assure accuracy of the summary of their published article. (I am the one who needs a disclaimer.)

A Few Points:

  • “It has proven difficult to establish robust evidence for significant clinical benefits of medical treatment in primary sclerosing cholangitis (PSC). For ursodeoxycholic acid, clinical practice guidelines only offer vague recommendations”
  • “Norucholic acid (previously denominated nor-UDCA) is a side chain–shortened homologue of UDCA that has shown superior anticholestatic, anti-inflammatory, and antifibrotic properties compared to UDCA in animal models.9  In PSC, norucholic acid was compared to placebo in a randomized multicenter phase II trial that evaluated the safety and efficacy of 12 weeks of treatment with oral norucholic acid (500, 1000, or 1500 mg/d) compared with placebo.10 … Norucholic acid significantly reduced ALP values in all treatment arms compared to placebo, and the safety profile was comparable across groups…An ongoing phase III placebo-controlled study compares oral treatment with 1500 mg/d norucholic acid with placebo on PSC disease progression assessed by a decrease in ALP and liver histology as a combined primary endpoint (NCT03872921)”
  • Other therapies are reviewed in depth
  • LJ Horst et al. Hepatology 2025; 82: 960-984. Open Access! PSC and colitis: A complex relationship “The clinical phenotype, genetic, and intestinal microbiota associations strongly argue for PSC-IBD being a distinct form of IBD, existing alongside ulcerative colitis and Crohn’s disease. In fact, the liver itself could contribute to intestinal pathology, clinically overt in 60%–80% of patients. Recent studies suggested that on a molecular level, almost all people with PSC have underlying colitis…complex pathophysiological relationships, where factors such as genetic predisposition, changes in the intestinal microbiota, altered bile acid metabolism, and immune cell migration are among the suspected contributors.”

My take: These are good reviews that highlight how much we have learned about PSC but also details the challenges ahead.

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New Era in Cholestatic Liver Diseases

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H Sutton, RJ Sokol, BM Kamath. Hepatology 2025; 82: 985-995. Open Access! IBAT inhibitors in pediatric cholestatic liver diseases: Transformation on the horizon?

This review article is one of many in the same issue (#4) of Hepatology.

Key points:

  • “In the last few years, a novel class of agents, intestinal bile acid transporter (Ileal bile acid transporter (IBAT); also known as apical sodium-dependent bile acid transporter [ASBT]) inhibitors, has emerged and gained approval from the FDA… the pivotal studies on which these approvals were granted were all performed in rare pediatric cholestatic diseases, namely Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC).3 Additional expansion of these approvals will possibly follow as there are ongoing trials of IBAT inhibitors in primary biliary cirrhosis, primary sclerosing cholangitis, and biliary atresia.”
  • “The role of bile acids in promoting hepatic injury in cholestasis is perhaps best illustrated in human infants with ABCB11 (bile salt export pump; BSEP) disease or PFIC type 2…The response to IBAT inhibition in this disease further supports the notion that retained bile acids are a key factor leading to progressive liver injury and cholestatic symptoms including pruritus, fat-soluble vitamin deficiencies, and growth failure.4“
  • These medications may improve liver histology and not just reduce pruritic symptoms: “Using the MDR2−/− mouse cholangiopathy model, Miethke et al22 demonstrated that ASBT inhibition led to a reduction in both serum and intrahepatic bile acid concentrations by 98% and 65%, respectively. These reductions in bile acid concentrations were associated with improved liver biochemistry and a reduction in peri-portal inflammation and fibrosis on histology. The histopathologic improvements seen in these treated MDR2−/− are important to highlight, as they support the rationale of this therapeutic approach: that lowering serum bile acid (sBA) with IBAT inhibition leads to a reduction in intrahepatic bile acid accumulation and toxicity, improvements in liver inflammation and fibrosis, and ultimately improved liver disease biology.”
  • Numerous clinical trials are listed in Table 1 (completed trials) and Table 2 (ongoing).
  • Physiology: “Bile acids are key regulators of their own enterohepatic circulation, predominately through activation of the farnesoid X receptor (FXR)…the fecal elimination of bile acids in IBAT inhibitor–treated patients appears to far exceed the rate of synthesis of new bile acids in the liver; thus, IBAT inhibitors reduce the total bile acid pool size and the bile acid load presented to the liver.22,34,39“
  • Alagille syndrome (ALGS): Key trials are summarized including the ICONIC trial with maralixibat and the ASSERT trial with odevixibat.
  • PFIC (Type 1 and 2) Trials: Key trials are summarized including the MARCH-PFIC trial with maralixibat and the PEDFIC1 & PEDFIC 2 trialswith odevixibat.
  • Safety: These medications are well-tolerated with self-limiting diarrhea and abdominal pain especially at the initiation of these medications. Liver blood test abnormalities have been noted in up to 20%. “This is an interesting finding, and the underlying etiology is unknown. Maralixibat is largely luminally restricted and so, without systemic absorption, a direct hepatotoxic effect is unlikely. It may reflect an alteration in the speciation of the bile acid pool with increasing bile acid synthesis or alterations in the gut-liver axis signaling. More importantly, it is not known if there are any clinical consequences to the increase in ALT.”
  • Cost: The authors note that ursodeoxycholic acid and antihistamines are frequently used for management of pruritus. They also not that “from a cost standpoint, it seems appropriate to offer rifampin before IBAT inhibitors in the treatment of cholestatic pruritus.”
  • Conclusions: “The clinical trial data are encouraging. As more physicians gain experience prescribing IBAT inhibitors, we will continue to learn how to best apply them to our patient populations. Like any new drug, there are still several unknowns. One of these unknowns is the potential for loss of efficacy…The short-term to medium-term clinical effects of IBAT inhibitors are clear, but we have not yet begun to see the long-term benefits. Whether durable reductions in oncogenic and fibrogenic bile acids reduce rates of HCC or slow the progression of (or reverse) portal hypertension remains to be seen.”

Related article: M Trauner, SJ Karpen, PA Dawson. Hepatology 2025; 82: 855-876. Open Access! Benefits and challenges to therapeutic targeting of bile acid circulation in cholestatic liver disease

“Recent advances in understanding bile acid (BA) transport in the liver… This has led to new treatments targeting BA transport and signaling. These include inhibitors of BA transport systems in the intestine and kidney (IBAT/ASBT inhibitors) and liver (NTCP inhibitors), as well as receptor agonists that modify BA synthesis and transport genes. BA analogs like norucholic acid also show promise. This review discusses the molecular and clinical basis for these therapies, particularly for cholestatic liver disorders.

Principal therapeutic targets within the entero-nephro-hepatic circulation of BAs in cholestasis.

My take (borrowed from Trauner et al): “We have arrived at a new era in the treatment of cholestatic disorders. This has been made possible by incorporating findings from discoveries into the molecular pathogenesis of cholestasis and adaptive processes that direct rational therapeutics to improve patients’ lives.”

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Liver Transplantation is Getting More Costly in U.S

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A Kaplan et al. Liver Transplantation 2025; 31: 1165-1175. Open Access! The rising cost of liver transplantation in the United States

Key points:

  • LT is resource-intensive and costly, with expenditures rising dramatically in recent years. Factors contributing to this increase in cost include expanded transplant criteria (higher risk recipients), utilization of marginal organs, and broader organ distribution, resulting in significant logistical expenses
  • Advanced technologies like organ perfusion devices, while promising better outcomes, further inflate costs due to their high price and market monopolization
  • Despite rising costs, reimbursement has remained largely stagnant, putting financial strain on transplant programs, and threatening their sustainability. “In fact, there has been an observed decline (−32%) in adjusted reimbursement of LT by Medicare over the past decade.62“

Increased Costs Associated with Recipient Characteristics:

  • “According to the latest annual SRTR report, patients aged 65 or older undergoing LT accounted for 21.9% of transplants in 2022, up from 14.6% a decade prior.18 One study looking at the cost burden of hospitalizations associated with liver transplants from 2016 to 2019 found mean costs increasing by nearly $10,000 per hospitalization in the group aged >65 over the study period”
  • “Increasing numbers of patients are being transplanted for steatotic liver disease… LT associated with metabolic dysfunction–associated steatotic liver disease has been demonstrated to be associated with higher costs, largely attributable to longer posttransplant lengths of stay.21–23 Similarly, LT associated with AH/ALD is very expensive—at 1 transplant program, net revenue from LT admission to 90 days after LT was −5.0% for AH compared to +1.4% for acute-on-chronic liver failure.24“

Organ distribution:

  • “In 2019, the OPTN implemented further changes in liver allocation from a regional-based system to an acuity circle model. This model was intended to create a more equitable allocation system and to reduce waitlist mortality for patients across the United States…This has been associated with a 77% increase in fly-out costs, amounting to an increase in $47,010,190 across all LT centers by recent estimates.4“
  • “1 study found that the cost for private jets ranged from $6850 to $27,350 depending on the distance traveled.29 In this same study, commercial flights, as opposed to private jets, were found to be safe and only around 10% of the cost.”

Perfusion devices:

“The FDA’s approval of organ perfusion and preservation devices has ushered in a new era in organ transplantation, enabling medical teams to extend the geographical reach for organ procurement. These devices enhance the utilization of organs that may have previously been discarded… It has been suggested that the average cost of using normothermic regional perfusion for DCD organs is around $10,000 per donor, compared to the $40,000–$80,000 per donor for use of NMP [normothermic machine perfusion].”

My take: Transplant centers are getting squeezed financially. In addition, ~25% of liver transplant patients experience a high financial burden. Pretty soon, along with checking organs for suitability, it may be necessary to assess liver transplant centers for viability.

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Osaka Garden in Jackson Park (Chicago)

AI for GI

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This month’s Gastroenterology issue is devoted solely to the use/expected uses as well as risks of artificial intelligence (AI) for gastroenterology and hepatology.

DL Shung, M Iacucci. Gastroenterol 2025; 169: 391-392. Artificial Intelligence in Gastroenterology and Hepatology: Potential and Perils

An excerpt:

“AI is reshaping the landscape of gastroenterology and hepatology with the promise of better, faster, more objective, and standardized care of delivery. However, behind the algorithms lies a more insidious risk: the erosion of trust in human providers…Information risk …include both error commission (ie, when the models generate false statements, introduce nonsensical concepts, or fabricate sources) and error omission (ie, summaries that omit critical information)…

When AI becomes the center of care, patients may perceive their doctors as intermediaries…diminishing the therapeutic effect of the patient-physician relationship…This arrangement can dilute clinical training, increase physician burnout, and lead to medicolegal implications…Other risks include perpetuating bias from nonrepresentative training data and amplifying uncertainty of AI due to lack of real-world validation…

We hope that AI systems will allow us to spend more, not less, time with patients and empower us to provide personalized care by leveraging high-quality multimodal data.”

Most of the articles are behind a paywall in this issue. There are five that are open access articles:

My take: These articles provide a good deal of information about the applications and risks of AI. In my view, physicians will be needed more than ever to help interpret/manage the huge amount of information available.

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FDA Approves Semaglutide for MASH

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Dani Blum, NY Times 8/18/25: A Common Weight Loss Drug Can Treat Severe Liver Disease, F.D.A. Says

An excerpt:

Roughly 15 million people — six percent of adults in the United States — have metabolic dysfunction-associated steatohepatitis, known as MASH. Rates of the disease are rising…

Wegovy, which is a weekly injection, is now approved for adults with MASH and moderate-to-advanced levels of fibrosis, or excessive scar tissue in the liver. The drug is not intended for people with cirrhosis…

Wegovy will be a welcome addition to the options doctors can prescribe — as long as their patients can access them. The drug carries a list price of over $1,300 a month, although most people do not pay that full amount. Many people have lost insurance coverage for weight-loss drugs, as plans struggle to keep up with the costs.

Related review article: G Targher et al. NEJM 2025; 393: 683-698. Metabolic Dysfunction–Associated Steatotic Liver Disease. This review article succinctly covers the epidemiology, manifestations, disease progression and pivotal pharmacologic advances.

Related blog post: Semaglutide’s Efficacy in Phase 3 MASH Trial

Liver Transplantation for PSC: Long-term Outcomes and Complications

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M Mouchli et al. Liver Transplantation 2025; 31: 781-792. Long-term (15 y) complications and outcomes after liver transplantation for primary sclerosing cholangitis: Impact of donor and recipient factors

Methods: Using Mayo clinic prospectively maintained transplant database, 293 adult patients (>18 y, mean age 47 yrs) with PSC who underwent LT from 1984-2012 were identified. Patients with cholangiocarcinoma were excluded. One hundred and thirty-four patients received LT before 1995, and 159 were transplanted after 1995.

Key findings:

  • The 1-, 5-, 10-, and 15-year cumulative incidence of recurrent PSC was 1.0%, 8.0%, 23.5%, and 34.3%, respectively.
  • Vascular and biliary complications are frequent: hepatic artery thrombosis (N = 30), portal vein stenosis/thrombosis (N = 48), biliary leak (N = 47), biliary strictures (N = 87)
  • Graft failure occurred in 70 patients
  • Donor age >60 years was associated with an increased risk of recurrent PSC. 

My take: Overall, there was a good survival rate despite the increased frequency of vascular and biliary complications. Also, 2/3rds of patients did NOT have recurrent PSC. Older donor age was associated with higher graft failure in this cohort.

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Advanced Liver Disease: Global Statistics and Risk Factors

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M Zamani et al. Clin Gastroenterol Hepatol 2025; 23:1123 – 1134. Open Access! Open Access! Global Prevalence of Advanced Liver Fibrosis and Cirrhosis in the General Population: A Systematic Review and Meta-analysis

A total of 46 studies fulfilled the eligibility criteria, comprising approximately 8 million participants from 21 countries.

Key findings:

  • The pooled prevalence rates of advanced liver fibrosis and cirrhosis in the general population were 3.3% (95% CI, 2.4%–4.2%) and 1.3% (95% CI, 0.9%–1.7%) worldwide, respectively
  • Risk factors for cirrhosis were viral hepatitis, diabetes, excessive alcohol intake, obesity, and male sex
  • Limitations: 1. All included studies used noninvasive tests to diagnose advanced fibrosis and cirrhosis, which might overestimate prevalence in general populations. The diagnostic performance of these tests is influenced by baseline prevalence, leading to a higher rate of false positives in low-prevalence populations 2. Significant differences in prevalence by geographic region and time period. However, these differences could be influenced by variations in health care infrastructure, access to health care, and disease awareness, which may only partially reflect the true prevalence of advanced liver fibrosis and cirrhosis. In addition, the data is influenced by the number of studies (eg. Oceania had only 1 individual study).
Map of Global Prevalence of Advanced Fibrossi
Map of Global Prevalence of Cirrhosis

My take: This study provides estimates of the high and increasing prevalence of advanced liver fibrosis and cirrhosis. This data is essential in determining if we are making progress and how to mitigate the disorders leading to advanced liver disease.

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EAT-Lancet Diet Associated with Reduced Risk of MASLD

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From the commentary: “In 2019, the EAT-Lancet Commission on Food, Plant, and Health proposed a planetary health diet, known as the EAT-Lancet reference diet, that promotes human health and sustainable food production globally…and recommends fruits, vegetables, whole grains, plant-based proteins (eg. legumes, nuts) and unsaturated plant oils, with limited or moderate amounts of animal-based proteins such as meat and dairy….[it] has been associated with multiple health benefits, including reducing the risks of type 2 diabetes, cardiovascular disease, certain cancers, and all-cause mortality.”

Methods: This prospective multicohort study comprised more than 191,000 adults from several cohorts. In addition, 228 Chinese adults from the Prospective Epidemic Research Specifically of Non-alcoholic Steatohepatitis (PERSONS) with biopsy-proven MASLD were included.

Key findings:

  • Participants in the highest tertiles of the EAT-Lancet diet index had a lower risk of MASLD compared with those in the lowest tertiles with HR ranging in different cohorts from 0.73 to 0.87
  • Liver-controlled attenuation parameter decreased with increasing the diet index in individuals with biopsy-proven MASLD (β = −5.895

My take (borrowed from the authors): Adherence to the EAT-Lancet reference diet was inversely associated with the risk of MASLD as well as its severity.

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Semaglutide’s Efficacy in Phase 3 MASH Trial

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AJ Sanyal et al. NEJM 2025; DOI: 10.1056/NEJMoa2413258. Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis

The results of this just-published study were alluded to in a previous post: More Data Indicating GLP-1 Efficacy for MASH

Methods:  In this phase 3, multicenter, randomized, double-blind, placebo-controlled trial, the authors assigned 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3 in a 2:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo for 240 weeks

Key findings:

  • Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the 534 patients in the semaglutide group and in 34.3% of the 266 patients in the placebo group (P<0.001)
  • A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (P<0.001). 
  • The mean change in body weight was −10.5% with semaglutide and −2.0% with placebo (P<0.001)
  • Gastrointestinal adverse events were more common in the semaglutide group. The incidence of acute pancreatitis was similar in the two groups: Nausea 290/800 (36.2%) vs. 52/395 (13.2%), Diarrhea 215/800 (26.9%) vs. 48/395 (12.2%), Constipation 178/800 (22.2%) vs. 33/395 (8.4%) and Vomiting 149/800 (18.6%) vs. 22/395 (5.6%)
  • Semaglutide improved multiple cardiometabolic features, including glycemic control and insulin resistance. “These findings are important because metabolic dysfunction is an upstream event driving hepatic lipotoxicity and, subsequently, steatohepatitis and fibrogenesis. Thus, semaglutide treatment addressed the primary pathogenic driver of MASH”
  • Side effects leading to people dropping out of the trial were 2.6% for the semaglutide group and 3.3% for the placebo group

Discussion notes that “although semaglutide can be safely used in patients with
cirrhosis, its efficacy in this population has not been established.”

My take: Semaglutide appears to be effective in patients with MASH.with stage 2 or 3 fibrosis.

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