Introduction

The first and further decompensation mark the natural history and the risk of mortality in patients with cirrhosis. We assessed the cumulative incidence of first and further (acute and non-acute) decompensation and evaluated their impact on liver-related death (LR-D) in patients with compensated advanced chronic liver disease (cACLD) due to metabolic dysfunction-associated steatotic liver disease (MASLD).

Aims & Methods

International multicenter retrospective study (17 centers) on 6,061 consecutive patients with clinical (LSM>10 kPa) or biopsy-proven (F3-F4 fibrosis) diagnosis of cACLD due to MASLD. First and further decompensation were defined according to Baveno VII criteria. Competing risk analysis by cumulative incidence functions and Cause-specific Cox models with baseline and time-dependent variables were performed. A multistate model was built to better assess the clinical course of cACLD due to MASLD.

Results

The cumulative incidence of the first decompensation was 3.5% (95% C.I 3.0-4.1) at 5 years, increasing 19-fold the risk of LR-D using Cox analysis; the cumulative incidence of further decompensation was 43.9% (95% C.I 37.2-50.2) at 5 years among patients with first decompensation, additionally increasing 1.5-times the risk of LR-D. Ascites, followed by variceal bleeding, were the most common events in both first and further decompensation. Hepatocellular carcinoma (HCC) further independently increased the risk of LR-D by 3- and 1.4-fold in the whole cohort of cACLD due to MASLD and in those who experienced first decompensation, respectively.

Conclusion

The first and further decompensations represent tipping points in the clinical course of patients with cACLD due to MASLD, increasing 19-times and additionally 1.5-times the risk of LR-D. HCC is an independent predictor of LR-D in patients with cACLD due to MASLD, resulting in an additional risk of LR-D when associated with both first and further decompensation.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are recommended for individuals with a PDAC lifetime-risk ≥5% to improve outcomes.¹ While familial adenomatous polyposis (FAP) is linked to increased PDAC risk, robust data to guide surveillance recommendations is lacking.^2,3 This study evaluates PDAC risk in a large FAP-cohort and cost-effectiveness of PDAC-surveillance in this group.

Aims & Methods

Data were collected from FAP cohorts in the United States (US) and the Netherlands (NL), including individuals (≥18 years) with a confirmed (likely) pathogenic APC variant. To minimize ascertainment bias, individuals whose initial visit or registration was prompted by a PDAC diagnosis were excluded from the analysis. Cumulative PDAC incidence, adjusted for death as competing risk, was calculated for the FAP cohorts and compared with control data from the Netherlands Cancer Registry and Statistics Netherlands. The cost-effectiveness of surveillance was evaluated using our previously developed Markov model.⁴ In comparison to the previous study, the model was modified by setting the inflation rate at 3%, discontinuing surveillance at age 75 and incorporating the relative risk derived from our FAP cohort.

Results

The US-cohort (n=357) and the NL-cohort (n=1000) had a median age at the end of follow-up of 46 years (IQR, 32.0-60.0) and 60 years (IQR, 47.5-72.5), respectively. Female participants comprised 52.9% of the US-cohort and 47.2% of the NL-cohort. Within the US-cohort, three PDAC cases were identified, however, two individuals had been referred to the Mayo Clinic at the time of PDAC diagnosis and were subsequently excluded from the analysis to reduce the risk of ascertainment bias. When combining both FAP-cohorts, the cumulative risk of PDAC by age 70 was 0.7% (95% CI, 0.3-1.8). Detailed cumulative risk estimates, stratified by cohort and age, are presented in Table 1. For comparison, the cumulative incidence of PDAC in the general population at age 70 was 0.32% (95% CI, 0.31-0.33), corresponding to a relative risk of 2.2 (95% CI, 0.9-5.7) for individuals with FAP. The cost-effectiveness analysis estimated that annual magnetic resonance imaging-based PDAC surveillance, starting at age 40, would be considered cost-effective if the relative risk reached at least 4.0, based on a willingness-to-pay threshold of $100 000.

Table 1. Adjusted cumulative incidence of pancreatic ductal adenocarcinoma in individuals with familial adenomatous polyposis

Conclusion

This is the largest cohort study to date to assess PDAC risk in individuals with FAP. Our findings indicate that PDAC risk in FAP patients is not significantly higher than in the general population. Moreover, their surveillance is shown not to be cost-effective.

References

1. Goggins M, Overbeek KA, Brand R, Syngal S, Del Chiaro M, Bartsch DK, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7-17.
2. Giardiello FM, Offerhaus GJ, Lee DH, Krush AJ, Tersmette AC, Booker SV, et al. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34(10):1394-6.
3. Karstensen JG, Bülow S, Højen H, Jelsig AM, Jespersen N, Andersen KK, et al. Cancer in Patients With Familial Adenomatous Polyposis: A Nationwide Danish Cohort Study With Matched Controls. Gastroenterology. 2023;165(3):573-81.e3.
4. Corral JE, Das A, Bruno MJ, Wallace MB. Cost-effectiveness of Pancreatic Cancer Surveillance in High-Risk Individuals: An Economic Analysis. Pancreas. 2019;48(4):526-36.

Disclosure

None