Introduction

The incidence of liver cancer has shown different temporal trends across regions around the world. The incidence of liver cancer has shown an increasing trend in many western populations, while it has shown a decreasing trend in some Asian countries, while the underlying reasons remain unclear.

Aims & Methods

Using data from population-based cancer registries, we examined temporal trends in the incidence of liver cancer in the United States, Hong Kong, and Sweden since the 1970s through 2021, using joinpoint regression. We further performed an age-period-cohort analysis to address possible underlying causes for the observed temporal trends.

Results

The age-standardized incidence rate of primary liver cancer in the United States increased on average by 2.4% (95% confidence interval [CI] 1.7% to 3.1%) per year in men and by 2.2% (95% CI 1.7% to 2.6%) in women during the period 1975-2019, but decreasing trends were noted in 2015-2019 in both sexes (annual percent change [APC] -5.9%, 95% CI -8.1% to -3.6% in men; APC -4.9%, 95% CI -9.4% to -0.1% in women). The rate in Hong Kong steadily decreased in men (APC -2.1%, 95% CI -2.5% to -1.8%) and in women (APC -2.2%, 95% CI -3.2% to -1.1%) during the period 1983-2020. The rate in Sweden increased on average by 0.8% (95% CI 0.2% to 1.4%) per year in men and was generally stable in women (APC 0.2%, 95% CI -0.9% to 1.4%) per year in 1970-2021.We observed distinct changes in trends across age groups in the three populations and different trends across generations (birth cohorts).

Conclusion

The incidence of liver cancer has shown increasing trends in the United States and Sweden, while the incidence has decreased in Hong Kong population. Such disparities across populations may be explained by different etiology and implementation of preventive measures, such as vaccination against hepatitis virus infection, in different populations.

Introduction

Recent findings suggest a higher risk of progressive liver disease and hepatocellular cancer in first-degree relatives of individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). The familial risk of extrahepatic cancer is, however, unclear.

Aims & Methods

We conducted a nationwide multigenerational cohort study involving all family members of Swedish adults with biopsy-proven MASLD (1969−2017) and of matched general population comparators. We included 36,684 first-degree relatives (FDRs: parents, siblings, offspring) and 8,788 spouses of MASLD individuals as well as 190,501 FDRs and 44,694 spouses of matched comparators without previous diagnosis of any cancer. Cox proportional hazards models were used to calculate multivariable adjusted hazard ratios (aHR) and 95% CIs.

Results

Over a median of 24.6 years the incidence rate for any extrahepatic cancer was slightly higher in MASLD FDRs than in comparator FDRs (72.3 vs. 71.9/10,000 person years (PY); aHR 1.04, 95%CI, 1.01−1.08). They were also at slightly higher risk of cancer-related mortality (24.0 vs. 23.6/10,000PY; aHR 1.08, 95% CI, 1.01−1.16). Compared to FDRs of comparators, largest differences were observed in rates of esophagus/stomach cancer (1.8 vs. 1.5/10,000PY; aHR 1.26, 95% CI, 1.01−1.58) and lung cancer (4.9 vs. 4.3/10,000PY; aHR 1.18, 95% CI 1.03−1.35). Across generations of FDRs, the risk of cancer was uniformly increased with no differences by relationship (i.e., parents, siblings, and offspring; p>0.05). MASLD spouses were also at a slightly increased risk of extrahepatic cancer (119.1 vs. 113.4/10,000PY; aHR 1.07, 95%CI, 1.00−1.14) and cancer-related mortality (43.9 vs. 38.8/10,000PY; aHR 1.21, 95%CI, 1.07−1.38). Compared to spouses of comparators, largest differences were observed in rates of colorectal cancer (17.0 vs. 13.4/10,000PY; aHR 1.34, 95% CI, 1.15−1.56).

Conclusion

First-degree relatives and spouses of individuals with biopsy-proven MASLD were at slightly higher risks of incident extrahepatic cancers, suggesting that shared lifestyle factors may contribute to the associations. Absolute cancer risks for family members were low and thus do not motivate implementation of screening programs.

Disclosure

Dr F. Ebrahimi has served as an advisory board member for Boehringer Ingelheim. Dr Ludvigsson has coordinated an unrelated study on behalf of the Swedish IBD quality register (SWIBREG). That study received funding from Janssen Corporation. Dr Ludvigsson has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. Ludvigsson has also a research collaboration on celiac disease with Takeda. The other authors have nothing to disclose.

Introduction

A growing proportion of the general population is affected by Metabolic dysfunction-associated steatotic liver disease (MASLD). The relationship between MASLD and breast cancer is not sufficiently understood. The question, whether MASLD is a risk factor for breast cancer has become of great interest. The other way round, the question to what extent breast cancer therapy with tamoxifen leads to MASLD needs to be addressed.

Aims & Methods

In order to investigate the relationship between MASLD and breast cancer, we analyzed data from the liver Magnetic Resonance Imaging (MRI) subset of the United Kingdom Biobank (UK Biobank) (20,601 women, 3,817 MASLD and 1,048 breast cancer cases) and data from the Mayo Clinic Biobank and Tapestry studies (7,943 women, 1,976 MASLD and 634 breast cancer cases). MRI data were used to differentiate between MASLD and controls in the UK Biobank cohort. In the Mayo Clinic cohort, International Classification of Diseases (ICD) 9 and 10 codes, natural language processing and chart review were used. In the UK Biobank cohort we adjusted the analysis for age and Body Mass Index (BMI) by multivariable logistic regression, whereas in the Mayo Clinic cohort the controls were matched by age and BMI.

Results

We found an association between MASLD and breast cancer among lean women in both cohorts independent of age and BMI (both p<0.001). Most women with breast cancer and MASLD were diagnosed with breast cancer before they were diagnosed with MASLD. Significantly more women used tamoxifen in the MASLD group compared to the control group in the UK Biobank cohort (p=0.002) and the Mayo Clinic cohort (p=0.008) independent of age and BMI. In a subgroup analysis of the women, who were diagnosed with breast cancer after the study MRI of the liver in the UK Biobank, there was no significant association of MASLD and breast cancer independent of age and BMI (p=0.219). This was also not the case among lean or overweight women.

Conclusion

In this study we observed an association between MASLD and breast cancer among lean women. The use of tamoxifen in breast cancer therapy offers a possible explanation for the association. This study raises awareness that the development of hepatic steatosis through breast cancer therapy with tamoxifen might also be relevant for lean women.

Disclosure

financial support:
C.V.S. is supported by a grant from the Interdisciplinary Centre for Clinical Research within the faculty of Medicine at the RWTH Aachen University (PTD 1-13/IA 532313), the Junior Principal Investigator Fellowship program of RWTH Aachen Excellence strategy and the NRW Rueckkehr Programme of the Ministry of Culture and Science of the German State of North Rhine-Westphalia. K.M.S. is supported by the Federal Ministry of Education and Research (BMBF) and the Ministry of Culture and Science of the German State of North Rhine-Westphalia under the Excellence strategy of the federal government and the Laender as well as the NRW Rueckkehr Programme of the Ministry of Culture and Science of the German State of North Rhine-Westphalia. C.D., C.V.S. and K.M.S. are supported by the CRC 1382 project A11 and B09 funded by Deutsche Forschungsgesellschaft (DFG, German Research Foundation) – Project-ID 403224013 – SFB 1382. K.J.W. is supported by the U.S. National Cancer Institute through grant R37CA259201 and the Mayo Clinic Hepatobiliary SPORE (P50 CA210964).

Introduction

Chronic liver disease—including alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and liver fibrosis/cirrhosis (LFC)—has emerged as a major global health challenge, accounting for over 2 million deaths annually^1-2. Often progressing silently, chronic liver disease is frequently diagnosed at advanced stages, underscoring the urgent need for early identification of at-risk populations through reliable markers³. While recognized risk factors such as insulin resistance, alcohol overuse, and aging contribute to disease development, recent attention has focused on biological ageing acceleration (BioAgeAccel) as a comprehensive, integrative metric reflecting physiological decline, yet the utility in large populations remains underexplored^4-6. In parallel, genetic susceptibility and phenotypic data hold promise for identifying individuals predisposed to chronic liver disease⁷.

Aims & Methods

We conducted research to explore the association between BioAgeAccel, the risk of chronic liver diseases, incorporating genetic susceptibility.

This study included participants from the UK Biobank (UKB) and the All of Us (AoU) two cohort databases. BioAgeAccel was defined as the deviation between an individual’s phenotypic age (PhenoAge) or Klemera-Doubal age (KDMAge) and chronological age. Cox proportional hazards models analyzed the associations between BioAgeAccel and the risk of MASLD, ALD, and LFC, with hazard ratios (HRs) and 95% confidence intervals (CIs), and combined polygenic risk scores (PRS) to quantify genetic predisposition to chronic liver diseases.

Results

In the UKB cohort, accelerated PhenoAge was associated with significantly higher risks of ALD (HR 2.29; 95% CI 2.03-2.58), MAFLD (1.10; 1.04-1.16), and LFC (2.22; 2.01-2.46). Similarly, in the AoU cohort, accelerated PhenoAge was associated with higher risks of ALD (1.97; 1.00-3.88), MAFLD (1.35; 1.15-1.58), and LFC (2.19; 1.48-3.22). Comparable trends were observed for KDMAgeAccel in the UKB. Greater BioAgeAccel was associated with progressively higher risks of ALD and LFC, with these trends consistently. In the UKB, accelerated biological ageing was associated with chronic liver diseases independently of genetic risk and remained significant across PRS levels. Furthermore, compared to individuals with biologically younger ages and low genetic risk, participants with high genetic risk and accelerated PhenoAgeAccel exhibited the highest risk of developing chronic liver diseases, and LDSC revealed a positive genetic correlation between ageing and ALD, with SMR identifying three shared genes.

Table 1: Association between biological ageing acceleration (PhenoAgeAccel) and incident of chronic liver diseases in two datasets

Conclusion

Accelerated biological ageing was associated with increased risk of chronic liver diseases, independently of genetic risk. Identifying individuals with higher BioAgeAccel is crucial for predicting the risk of chronic liver diseases, and indicators related to the calculation of BioAgeAccel can serve as potential targets for interventions.

References

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-1222. doi:10.1016/S0140-6736(20)30925-9
2. Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023;79(2):516-537. doi:10.1016/j.jhep.2023.03.017
3. Wang Y, Huang Y, Chase RC, et al. Global Burden of Digestive Diseases: A Systematic Analysis of the Global Burden of Diseases Study, 1990 to 2019. Gastroenterology. 2023;165(3):773-783.e15. doi:10.1053/j.gastro.2023.05.050
4. Lee YB, Ha Y, Chon YE, et al. Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B. Clin Mol Hepatol. 2019;25(1):52-64. doi:10.3350/cmh.2018.0040
5. Klemera P, Doubal S. A new approach to the concept and computation of biological age. Mech Ageing Dev. 2006;127(3):240-248. doi:10.1016/j.mad.2005.10.004
6. Cohen AA, Milot E, Yong J, et al. A novel statistical approach shows evidence for multi-system physiological dysregulation during aging. Mech Ageing Dev. 2013;134(3-4):110-117. doi:10.1016/j.mad.2013.01.004
7. Martin K, Hatab A, Athwal VS, Jokl E, Piper Hanley K. Genetic Contribution to Non-alcoholic Fatty Liver Disease and Prognostic Implications. Curr Diab Rep. 2021;21(3):8. doi:10.1007/s11892-021-01377-5

Disclosure

The authors have declared no conflict of interest.

Introduction

Hepatocellular carcinoma (HCC) is one of the main indication for liver transplantation (LT) worldwide, however, despite various proposed selection criteria, HCC recurrence rate after LT remains up to 20%. An earlier diagnosis allows for more effective treatments and survival benefit. Recently, the RETREAT score has been proposed showing high accuracy.

Aims & Methods

Our aim was to validate the RETREAT score in a single center cohort.
This is a retrospective study including patients who underwent LT for HCC at Padua University-Hospital between January 2016 and December 2018. Clinical and radiological data before and after LT (aFP, liver function according to MELD and CHILD score, tumor morphology, downstaging and/or bridging treatments) and explant pathology features were collected. RETREAT and TTV/aFP scores, based on explant pathology, were calculated. Cox regression and LogRank models have been used for the association between HCC scores and tumor recurrence.

Results

During the study period, 123 patients underwent LT for HCC (HCV 35%, median MELD 11). After HCC diagnosis, 115 patients (93%) underwent downstaging (47% ≥2 treatments), and 64 of them (56%) received bridging therapies. The median aFP at LT was 4.8 ng/mL. On explant pathology, microvascular invasion was found in 27%, G3 nodules in 30%. On explant pathology, 65 patients (53%) were Milan-out, 44 patients (36%) were TTV/aFP-out, 77 patients (62%) had a RETREAT score ≥2. During the follow-up of 50 months (IQR 39-60), 16 patients (13%) showed post-transplant HCC recurrence, at median time of 14 months (IQR 8-36); 75% of them had extrahepatic recurrence. RETREAT score was associated with the risk of HCC recurrence (p<0.001, HR 1.703, 95%CI 1.30-2.22). Patients with RETREAT score 0-1, 2-4 and 5-8 had a 1 year-HCC recurrence of 2%, 4% and 21%, respectively (log-rank<0.001). TTV/AFP has not been associated with HCC recurrence (p=0.680).

Conclusion

RETREAT score is a reliable tool to improve the selection of patients at higher risk of HCC recurrence and to guide the post-LT management, defining shorten tumor surveillance post-LT. Thus, an earlier diagnosis of tumor recurrence might allow more efficacious treatments and patient survival benefit.

Introduction

MASLD patients is increasing worldwide and the clinical outcomes of different phenotypes had shown varied especially the occurrence of of liver related events (LRE) or major cardiovascular events (MACE)(Eslam M, et al. Hepato Inter 2020, 14:889–919) In addition, the prognostic factors for LRE. or MACE. are not well studied.

Aims & Methods

Aims: We aimed to study the rate of LRE. or MACE and the predictors for LRE. Or MACE. in MASLD patients with liver biopsy proven.
Methods: In a single-tertiary-center prospective cohort, we collected data of MASLD patients with biopsy-proven who were followed up of at least 1 years at King Chulalongkorn Memorial Hospital during 2005-2022. The primary outcome was the presence of LRE. or MACE. which included cirrhotic complications: acute decompensations; EV/GV bleeding, ascites, hepatic encephalopathy or HCC or acute complications requiring liver transplantation or death. MACE was defined by the occurrence of stroke or acute coronary disease or myocardial infarction. Related baseline characteristics, LSM, FIB-4, and liver biopsy were collected.

Results

Among 286 MASLD patients, the MASLD patients with mean age of 50.1 +/- 14.5 years old (range 19-80 yr.) Male and female were 44% and 56 % respectively. MASLD patients were categorized into 3 groups which were type 2 diabetes mellitus (T2DM) in 119 (41.6%), overweight or obese group in 149 (52.1%), and lean MASLD (BMI<23) in 18 (6.3%). Their baseline characteristics were shown in Table 1.
The average BMI was 41.3 kg/m² (range 19.1-88.7). Other metabolic abnormalities were hypertension in 165 (57.7%), and dyslipidemia in 157 (54.9%). There were 6 cirrhotic cases (2.1%) at diagnosis. Presence of advanced liver fibrosis (TE>12KPA) was found in 15 cases (5.2%). After a mean follow-up of 9.5 years (range 1-19); there were 11 cases (3.8%) developed coronary artery disease and 3 cases (1%) developed stroke. LRE. were present in 7 cases (2.4%) which included acute decompensation (3 cases; 1%), HCC (3 cases; 1%), and death (1 cases; 0.3%). The overall complications of LRE. or MACE. were present in 16 cases (5.6%). By using multivariate analysis, the predictors of LRE. or MACE. were in presence of hypertriglyceridemia (aOR 1.01 (1.00-1.01); p =0.002) and older age (aOR 1.06 (1.01-1.11); p =0.023).

Conclusion

The overall complication of LRE. or MACE. was not uncommon (5.6% of this cohort with a mean follow-up of 9.5 years). Older age and hypertriglyceridemia were predictors of LRE. or MACE. occurrence.

References

Eslam M, et al. Hepato Inter 2020, 14:889–919.