Cirrhosis, age may shape HCC risk in PSC
Investigators followed 3,071 patients for a mean of 12.5 years.
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12/29/2025
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by Doug Brunk
Hepatocellular carcinoma (HCC) appears to be an uncommon complication of primary sclerosing cholangitis (PSC), especially in patients without cirrhosis and those younger than 50 years, results from a large international cohort study suggests.
Reporting in Hepatology, Magnus Holmer, PhD, of the Unit of Gastroenterology and Hepatology, Karolinska Institute, Stockholm, Sweden, and fellow investigators from the International PSC Registry analyzed longitudinal data from 3,071 patients with well-characterized PSC followed at 12 European centers for more than 38,000 person-years. They had a mean age of 36.2 years at the time of PSC diagnosis and 48.7 years at the conclusion of follow-up. During a mean follow-up of 12.5 years, 39 patients (1.3%) developed HCC, corresponding to an overall incidence of 1.01 cases per 1,000 person-years. The mean time from PSC diagnosis to HCC was 16.4 years.
Cirrhosis and age emerged as the dominant determinants of risk. In multivariable Poisson regression models, cirrhosis was associated with an approximately 11-fold higher HCC risk (incidence rate ratio [IRR], 10.8), while each additional year of age conferred a 5% increase in risk. Two-thirds of patients with HCC had documented cirrhosis before cancer diagnosis, and most cases occurred in men. By contrast, HCC risk in noncirrhotic PSC patients remained low across all age groups and both sexes.
Age-stratified analyses showed that annual HCC incidence exceeded commonly cited cost-effectiveness thresholds for surveillance only in older patients with cirrhosis. Among men with cirrhosis, the annual incidence rate reached 0.81 at age 50 and increased to 2.22 by age 70; corresponding rates in women were lower but followed a similar age-dependent pattern. In non-cirrhotic patients, annual incidence rate remained well below 0.3 even at older ages.
“Our findings indicate that HCC surveillance may be less cost-effective in young patients with PSC and cirrhosis compared to those aged 50 years or older,” the authors concluded. “Further research is needed to determine appropriate age thresholds for initiating HCC specific surveillance in patients with PSC.”
The study was funded by the Bengt Ihre Fund and the Swedish Cancer Society, Stockholm County. Several authors reported potential conflicts of interest.
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The guidelines emphasize four-hour gastric emptying studies over two-hour testing. How do you see this affecting diagnostic workflows in practice?
Dr. Staller: Moving to a four-hour solid-meal scintigraphy will actually simplify decision-making. The two-hour reads miss a meaningful proportion of delayed emptying; standardizing on four hours reduces false negatives and the “maybe gastroparesis” purgatory that leads to repeat testing. Practically, it means closer coordination with nuclear medicine (longer slots, consistent standardized meal), updating order sets to default to a four-hour protocol, and educating front-line teams so patients arrive appropriately prepped. The payoff is fewer equivocal studies and more confident treatment plans.
Metoclopramide and erythromycin are the only agents conditionally recommended for initial therapy. How does this align with what is being currently prescribed?
Dr. Staller: This largely mirrors real-world practice. Metoclopramide remains the only FDA-approved prokinetic for gastroparesis, and short “pulsed” erythromycin courses are familiar to many of us—recognizing tachyphylaxis limits durability. Our recommendation is “conditional” because the underlying evidence is modest and patient responses are heterogeneous, but it formalizes what many clinicians already do: start with metoclopramide (lowest effective dose, limited duration, counsel on neurologic adverse effects) and reserve erythromycin for targeted use (exacerbations, bridging).
Several agents, including domperidone and prucalopride, received recommendations against first-line use. How will that influence discussions with patients who ask about these therapies?
Dr. Staller: Two points I share with patients: evidence and access/safety. For domperidone, the data quality is mixed, and US access is through an FDA IND mechanism; you’re committing patients to EKG monitoring and a non-trivial administrative lift. For prucalopride, the gastroparesis-specific evidence isn’t strong enough yet to justify first-line use. So, our stance is not “never,” it’s just “not first.” If someone fails or cannot tolerate initial therapy, we can revisit these options through shared decision-making, setting expectations about benefit, monitoring, and off-label use. The guideline language helps clinicians have a transparent, evidence-based conversation at the first visit.
The guidelines suggest reserving procedures like G-POEM and gastric electrical stimulation for refractory cases. In your practice, how do you decide when a patient is “refractory” to medical therapy?
Dr. Staller: I define “refractory” with three anchors.
1. Adequate trials of foundational care: dietary optimization and glycemic control; an antiemetic; and at least one prokinetic at appropriate dose/duration (with intolerance documented if stopped early).
2. Persistent, function-limiting symptoms: ongoing nausea/vomiting, weight loss, dehydration, ER visits/hospitalizations, or malnutrition despite the above—ideally tracked with a validated instrument (e.g., GCSI) plus nutritional metrics.
3. Objective correlation: delayed emptying on a standardized 4-hour solid-meal study that aligns with the clinical picture (and medications that slow emptying addressed).
At that point, referral to a center with procedural expertise for G-POEM or consideration of gastric electrical stimulation becomes appropriate, with multidisciplinary evaluation (GI, nutrition, psychology, and, when needed, surgery).
What role do you see dietary modification and glycemic control playing alongside pharmacologic therapy in light of these recommendations?
Dr. Staller: They’re the bedrock. A small-particle, lower-fat, calorie-dense diet—often leaning on nutrient-rich liquids—can meaningfully reduce symptom burden. Partnering with dietitians early pays dividends. For diabetes, tighter glycemic control can improve gastric emptying and symptoms; I explicitly review medications that can slow emptying (e.g., opioids; consider timing/necessity of GLP-1 receptor agonists) and encourage continuous glucose monitor-informed adjustments. Pharmacotherapy sits on top of those pillars; without them, medications will likely underperform.
The guideline notes “considerable unmet need” in gastroparesis treatment. Where do you think future therapies or research are most urgently needed?
Dr. Staller: I see three major areas.
1. Truly durable prokinetics: agents that improve emptying and symptoms over months, with better safety than legacy options (e.g., next-gen motilin/ghrelin agonists, better-studied 5-HT4 strategies).
2. Endotyping and biomarkers: we need to stop treating all gastroparesis as one disease. Clinical, physiologic, and microbiome/omic signatures that predict who benefits from which therapy (drug vs G-POEM vs GES) would transform care.
3. Patient-centered trials: larger, longer RCTs that prioritize validated symptom and quality-of-life outcomes, include nutritional endpoints, and reflect real-world medication confounders.
Our guideline intentionally highlights these gaps to hopefully catalyze better trials and smarter referral pathways.
Dr. Staller is with the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston.