Introduction

This study aims to investigate the causal estimates of the correlation between liver cirrhosis and colorectal cancer (CRC) and assess the mediation effect of modifiable risk factors direct to clinical treatments.

Aims & Methods

We performed a two-step mendelian randomization (MR) analysis using publicly accessible summary-level data on liver cirrhosis and modifiable risk factors from databases except for the FinnGen, as well as CRC from the FinnGen. Single-nucleotide polymorphisms (SNPs) significantly related to exposures were selected as instrumental variables. A random-effects inverse variance weighted (IVW) method was used in the primary analysis and sensitivity analyses were complemented to ensure the reliability of causal associations. Gene set enrichment analysis (GSEA) was performed to explore the potential biological mechanisms of the causal associations.

Results

In the IVW analysis, liver cirrhosis was causally associated with CRC without adjusting for confounding factors (OR = 1.193, 95%CI = 1.008, 1.411, p =0.040). Multivariate MR analysis showed that body mass index, whole body fat mass, waist to hip ratio (WHR) and alcohol consumption were independent risk factors of CRC (p values < 0.05). The estimate of the mediator, WHR, is 0.013 and the standard error is 0.006. WHR explained 7.45% of the total effect of cirrhosis on CRC risk. GSEA analysis identified two intersection genes which worked both in liver cirrhosis and CRC tissues, namely SERPINE1 and ARKND1. The potential biological mechanisms might include epithelial–mesenchymal transition, coagulation, inflammatory response, and etc.

Table 1 The mediator effect of modified risk factors on the causal association between liver cirrhosis and colorectal cancer.

Conclusion

Genetically predicted liver cirrhosis had potentially risk causal effect on CRC with the mediation by WHR. SERPINE1 and ARKND1 might be candidate targets for preventing CRC in patients with liver cirrhosis.

Introduction

Alcoholic liver cirrhosis (ALC) is a complex condition marked by numerous complications, often leading to a poor prognosis and high mortality rates^​. This study evaluates the clinical characteristics, causes of hospitalization, and factors associated with prolonged hospital stay and in-hospital mortality among patients with alcoholic liver cirrhosis.

Aims & Methods

A retrospective study was conducted on 357 patients diagnosed with alcoholic liver cirrhosis in a tertiary gastroenterology department. The mean age was 57.8 ± 9.8 years, and 85% were male. Data on causes of hospital admission, length of stay, and clinical complications were analyzed. Associations with prolonged hospitalization (defined as >3 days) and in-hospital mortality were assessed using univariate and multivariate statistical analyses.

Results

The overall in-hospital mortality rate was 21.5%. The most common causes of admission included urinary tract infections (57.7%), hepato-renal syndrome (28.2%), digestive hemorrhage (22.6%), acute alcoholic hepatitis (19.3%), spontaneous bacterial peritonitis (8.4%), and pulmonary infections (5.6%). The median hospital stay was 6.6 days.
Variables significantly associated with prolonged hospitalization in univariate analysis included ascites (p<0.0001), spontaneous bacterial peritonitis (p=0.01), hepatic encephalopathy (p<0.0001), urinary tract infections (p<0.0001), and hepato-renal syndrome (p=0.09). In multivariate analysis, only urinary tract infection was independently associated with prolonged hospital stay.
Regarding in-hospital mortality, significant associations in univariate analysis were found with spontaneous bacterial peritonitis (p<0.0001), acute alcoholic hepatitis (p<0.0001), digestive hemorrhage (p<0.0001), and hepato-renal syndrome (p<0.0001). In multivariate analysis, only hepato-renal syndrome remained independently associated with mortality (p<0.0001).

Conclusion

Urinary tract infection is an independent predictor of prolonged hospitalization in patients with alcoholic liver cirrhosis, while hepato-renal syndrome is the only independent predictor of in-hospital mortality. These findings highlight the importance of early recognition and management of infections and renal complications in this high-risk population.

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

Transplantation techniques and immunosuppression treatments have been increasing notably in the past years, particularly when considering liver transplant (LT). LT is the preferred treatment for early-stage hepatocellular carcinoma (HCC). Despite the use of the Milan criteria, recurrence remains a major concern, with an estimated incidence ranging from 5% to 20%. Therefore, our objective is to assess potential risk factors, including clinical, laboratory and pathological parameters, as well as prognosis of HCC recurrence in LT recipients.

Aims & Methods

Retrospective evaluation of medical records from a Brazilian tertiary hospital, including adults who were submitted to LT due to HCC, during the period of 01/01/2002 up to 31/12/2021. Patients who had a LT for other causes, who presented a follow-up less than 1 year or with incidental detection of HCC in the liver explants were excluded. Data collection included demographic information, immunosuppressive treatments, clinical, radiological and histhopathological findings related to the HCC, as well as characteristics associated with the post-transplant follow-up and tumoral recurrence, including death. Primary outcome was recurrence of HCC, whereas secondary outcomes were survival and adopted treatments after cancer recurrence, as well as time elapsed until HCC recrudescence.

Results

150 patients were included (males 95 [63.3%], median age 60 years-old [IQR 56-66]), 130 (86.6%) were classified as Milan-in. The main cirrhosis etiologies were viral (88%) and metALD (10%). Half of patients presented an A CHILD score (50%) and a median MELDNa score of 12 (IQR 9-14). Main locoregional therapies included transarterial chemoembolization (TACE) and percutaneous ethanol injection (PEI), accounting for 48 (32%) and 45 (30%) respectively. 47 (31.33%) patients underwent two or more locoregional therapy modalities, and downstaging was achieved in 20 patients (13.3%). Explant analysis with microvascular invasion and Milan-out were detected in 18 (12%) and 30 (20.1%) individuals, respectively. HCC recurrence occurred in 21/150 patients (14%), while non-HCC neoplasias in 27/150 (18.1%) after LT. The median time to recurrence was 30 months (IQR 20-43), and systemic therapy to HCC with sorafenib was used in 12/21 patients (57.14%). Among those who presented recurrence, 19/21 died (90.4%), and prognosis after recurrence was dismal (median survival of 14.5 months, IQR 3.25-33.5). Evaluation of possible associations between HCC recurrence and clinical, laboratorial, imaging and histopathological parameters was performed, but none showed impact on HCC recurrence after LT. However, there was a trend to an association between recurrence and CHILD score (p = 0.06) and smoking (p = 0.08). Also, when evaluating patients who presented early recurrence (less than 24 months after LT), a trend of an association with the number of involved liver segments was found (p = 0.07).

Conclusion

Identifying patients at risk of HCC recurrence after LT remains as a great challenge. There are some parameters previously suggested as possible predictors, but, in accordance to literature findings, our study didn't identify significant associations. Nonetheless, the possible association between early recurrence and the number of affected liver segments hasn't been studied yet, and this is the first study that suggests an association. Thus, evaluating the number of liver segments affected by HCC might help physicians to identify patients with higher risk of recurrence, as well as giving another possible parameter to investigate in further studies.

Introduction

Autoimmune liver diseases (AILDs) includes primary biliary cholangitis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC), in which the immune system produces an inappropriate response to self-antigens leading to chronic liver disease. Gallstone disease is one of the most commonly occurring gastrointestinal disorders. The prevalence of gallbladder stones in patients with chronic liver disease is 22%-54%, higher than the general population¹. Chronic liver disease in most studies mainly refers to viral hepatitis and alcoholic liver disease, and there are no studies on AILDs complicating gallstones. Previous studies have shown that gallstones were associated with autoimmune disease² and were a common cause of secondary sclerosing cholangitis³, but the association between AIH, PBC and gallstones has not been reported yet. We have observed that the combination of AILDs and gallstones are a common phenomenon in clinical practice. Therefore, our study was intended to analyze the proportion and the clinical characteristics of gallstones in patients with AILDs as a reference for clinical decision making in patients with AILDs complicated by gallstones.

Aims & Methods

We investigated the comorbidity of gallstones and risk factors associated with gallstones in patients with AILDs. AILDs patients attending the General Hospital of Tianjin Medical University from November 2012 to October 2022 were retrospectively included. Analysis of the proportion of AILDs patients with gallstones (including patients who underwent cholecystectomy for gallstones), clinical characteristics, and laboratory test. Logistic regression analysis was used to assess the risk factors for the combination of gallstones in patients with AILDs.

Results

A total of 560 patients with AILDs were enrolled, including 207 patients with PBC, 289 with AIH and 64 with PBC-AIH overlap syndrome (PBC-AIH). The proportion of patients with AILDs, PBC, AIH and PBC-AIH complicated by gallstones was 32.50%, 35.75%, 28.37% and 40.63%, respectively. Multiple stones predominate in patients with AILDs complicated by gallstones (43.41%), followed by single stones (32.42%) and sludge (6.04%). Age at first visit (p=0.007) and serum biochemical markers associated with bile duct injury such as GGT (p=0.003) and ALP (p=0.001) were significantly higher in patients with AILDs complicated by gallstones compared to those without gallstones. Age (odd ratio [OR] = 1.024; 95% confidence interval [CI] =1.006-1.042 and serum ALP levels (OR = 1.001; 95% CI = 1-1.002) were independent risk factors for patients with AILDs complicated by gallstones, while serum GGT levels (OR = 1.002; 95% CI = 1-1.003) were independent risk factors for patients with AIH complicated by gallstones. Significantly higher prevalence of gallstones in patients with AILDs older than 61.5 years (p=0.003).

Conclusion

Gallstones are more common comorbidity in AILDs patients, predominantly multiple stones. Age and serum ALP levels were independent risk factors for patients with AILDs complicated by gallstones. Patients with AILDs complicated by gallstones present with significantly elevated serum biochemical parameters associated with bile duct injury. The comorbidity of gallstones tends to delay the initial diagnosis of patients with AILDs.

References

1 Li X, Gao P. Hepatitis C Virus Infection Increases Risk of Gallstone Disease in Elderly Chinese Patients with Chronic Liver Disease. Sci Rep. 2018;8(1):4636. Published 2018 Mar 15. doi:10.1038/s41598-018-22896-4
2 Chapman MH, Thorburn D, Hirschfield GM, et al. British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis. Gut. 2019;68(8):1356-1378. doi:10.1136/gutjnl-2018-317993
3 Shabanzadeh DM, Linneberg A, Skaaby T, Sørensen LT, Jørgensen T. Screen-detected gallstone disease and autoimmune diseases - A cohort study. Dig Liver Dis. 2018;50(6):594-600. doi:10.1016/j.dld.2018.01.12
B4

Introduction

Chronic liver disease (CLD) is a disease of the liver that involves progressive destruction and regeneration of the liver parenchyma, leading to fibrosis and cirrhosis. Although liver fibrosis and cirrhosis have been considered irreversible, it has recently been suggested that even advanced fibrosis and cirrhosis may be reversible. The use of platelet-rich plasma (PRP) in tissue regeneration is a developing area of research for clinicians and specialists. Platelets contain proteins required for hemostasis as well as numerous growth factors. They have a prominent role in suppressing the progression of liver fibrosis in vitro and in vivo. Elevating growth factors induced by platelet transfusion can enhance liver function in patients with CLD and cirrhosis. However, PRP could increase the risk of rejection or immune response in allogenic transfusion; therefore, searching for effective therapeutic strategies is much needed.

Aims & Methods

This study evaluated the possible regenerative effect of purified platelet-derived growth factors on an experimentally induced model of liver cirrhosis. Purified Platelet Derived Growth Factors were prepared using a patented method (Gooris & Fahmy, 2019). Twenty-eight mice were included and categorized into four groups. The 1^st group acted as a normal control group. The 2^nd group acted as a Purified Platelet Derived Growth Factors control group and was injected subcutaneously with Purified Platelet Derived Growth Factors only twice weekly for eight weeks. The 3^rd group acted as a pathological control group and was injected intraperitoneally with thioacetamide (TAA) three times a week for eight weeks. At the same time, the 4^th group was injected with both Purified Platelet Derived Growth Factors and TAA for eight weeks. After eight weeks, animals were euthanized, and liver specimens and blood samples were collected for pathological and biochemical assessment.

Results

Our results showed that Purified Platelet Derived Growth Factors administration could improve the hepatic status of the mice, as cirrhotic livers were regenerated back into normal-appearing parenchyma when compared to the pathological control group. In addition, the levels of ALT, AST, and total bilirubin decreased significantly (P<0.001), and the Relative expression of hepatic Alpha-SMA was significantly down-regulated (P<0.001) after Purified Platelet Derived Growth Factors administration.

Conclusion

Purified Platelet Derived Growth Factors can be used as a new therapeutic modality for liver cirrhosis.

References

• Gooris T and Fahmy HM (2019): A method for preparing a growth factors containing platelet releasate. United States patent application US 16/462,452. Oct 24.

Introduction

Steatotic liver disease (SLD) is a common problem after liver transplantation (LT). Previous studies have confirmed the role of donor PNPLA3 rs738409 G allele as a risk factor for post-LT SLD, but the role of other recipient and donor genetic risk variants is largely unknown.

Aims & Methods

Aims: To study the prevalence of genetic risk variants for SLD in LT recipients and donors and their impact on development of post-LT SLD.
Methods: Of 807 adult patients undergoing LT in Finland between 2000–2019, 56 SLD-associated genetic risk variants were extracted from genotype data for 666 donor-recipient-pairs. Recipient genotypes were compared with ~10 000 Finnish population controls from gnomAD database. Incident post-LT SLD was assessed from protocol liver biopsies. The impact of donor and recipient genetic variants was studied in multivariate Cox regression analysis adjusted for phenotype factors.

Results

Of 56 risk variants, the minor allele frequencies (MAFs) of 17 variants were significantly different between LT recipients and population controls. The greatest MAF differences were observed for PNPLA3 rs738409-G (0.33 vs 0.22, p = 2.56 x 10^-20), TNF rs1800629-A (0.19 vs 0.12, p = 1.48 x 10^-12), IFNL4 rs12979860-T (0.29 vs 0.24, p = 7 x 10^-6 ), CD14 rs2569190-A (0.41 vs 0.37, p = 0.005) and MERTK rs4374383-A (0.36 vs 0.33, p = 0.014).
Patients transplanted for metabolic dysfunction-associated steatohepatitis (MASH) (n = 42) exhibited high prevalence of PNPLA3 rs738409-G (0.63 vs 0.22, p = 1.47 x 10^-19) and low prevalence of the protective HSD17B13 rs6834314-G (0.07 vs 0.21, p = 0.001) and MARC1 rs2642438-A (0.14 vs 0.29, p = 0.002)
Incidence of post-LT SLD was 29.1% in median follow-up time of 7.6 years. The lowest incidence (14.8%) was observed among patients transplanted for acute liver failure, and the highest (52.9%) in patients transplanted for MASH.
Final multivariate regression model to predict post-LT SLD included high SLD-risk indication (HR 2.03, p < 0.001), BMI (HR 1.10, p < 0.001), diabetes (HR 1.37, p = 0.016) and alcohol consumption (HR 2.01, p < 0.001). Table 1 shows the hazard ratios of the donor and recipient genetic variants most strongly predicting post-LT SLD after adjusting for recipient phenotype factors (high-SLD risk indication, BMI, diabetes, and alcohol consumption).

Conclusion

SLD-associated risk alleles were common in LT recipients, especially in MASH. Post-LT SLD incidence was high (29.1%), but with large variation across transplantation indications. Donor, but not recipient, PNPLA3 allele was most strongly associated with post-LT SLD. Several other donor and recipient genetic variants also contributed to post-LT SLD. Both LT recipient and donor genotypes provide novel insights into the genetic determinants of SLD after LT, providing help in future individual risk assessment.