Introduction

Research about sarcopenia in primary biliary cholangitis (PBC) patients is limited while sarcopenia commonly occurs in cirrhotic patients. Concomitant sarcopenia in noncirrhotic PBC patients has been rarely explored yet.

Aims & Methods

This study aimed to investigate the prevalence of sarcopenia and the associations between concomitant sarcopenia at baseline and biochemical response to UDCA treatment and clinical outcomes in noncirrhotic primary biliary cholangitis (PBC) patients.
Between January 2009 and July 2022, consecutive PBC patients were retrospectively enrolled. Sarcopenia was assessed via pretreatment CT or MRI scans at the L3 level by the skeletal muscle index. Baseline characteristics, the response rate after 6 and 12 months of ursodeoxycholic acid (UDCA) administration, liver-related adverse events and baseline CRP and IL-6 levels in liver tissue and serum were evaluated.

Results

A total of 142 noncirrhotic PBC patients were included, with sarcopenia identified in 58 (40.8%) patients. The median duration of follow-up was 5.25 (3.23, 6.50) years. The group of PBC patients with sarcopenia demonstrated a lower biochemical response rate (44.9% vs. 64.8%; P=.031) according to the Paris-II criteria after 12 months of UDCA treatment, as well as higher incidence of new-onset ascites (28.1% vs. 13.1%, P=.027) during follow-up. Higher expression levels of baseline CRP and IL-6 in liver tissue and serum were observed in PBC patients with sarcopenia (P<.05).

Conclusion

Sarcopenia was highly prevalent in noncirrhotic PBC patients. Expression levels of baseline CRP and IL-6 in liver tissue and serum were elevated in noncirrhotic PBC patients with sarcopenia. Concomitant sarcopenia at baseline may adversely affect the biochemical response to UDCA treatment and occurrence of liver-related adverse events in PBC patients without cirrhosis.

Introduction

​In 2022 the BCLC staging and treatment algorithm for hepatocellular carcinoma (HCC) management has been updated (BCLC_2022), granting for higher flexibility and customized management for HCC patients as compared to the 2018 version.

Aims & Methods

Aim of the study was to evaluate the feasibility of BCLC_2022 in daily clinical practice (BCLC_2018 as benchmark), its impact on response to treatment and on overall survival (OS).
We retrospectively evaluated data of 798 prospectively followed (year 2006 to 2022) patients with de novo HCC: 187 0, 371 A, 132 B, 87 C and 21 D, according to BCLC. First line treatment allocations were discussed by a multidisciplinary team (MTD), following updated recommendations. All patients were followed until death or end of follow-up (12/2022).

Results

Overall, the feasibility if BCLC increased from 51% for the BCLC_2018 to 69% for the BCLC_2022 (p<0.001): 56% to 73% stage 0 (p=0.001), 45% to 72% stage A (p<0.001), 51% to 65% stage B (p=0.02), while no changes were registered for stage C and D. Among BCLC 0 /A patients, 130 (23%) were treated with TACE, which is a “lower priority option” for these stages according to BCLC_2022. The rate of "downward stage migration" was significantly lower with BCLC_2022 (33% to 16%, p<0.001). “Downward stage migration” without curative intent was associated with a lower proportion of complete response to first line treatment in the early stages (0% vs 77%, p=0.003 in BCLC0; 0% vs 57%, p=0.001 in BCLC A) and to a shorter OS [6 months (IQR 2-16) vs 82 months (IQR 42-132), p<0.001 in BCLC 0] as compared to BCLC_2022. Similarly in early stages patients treated with a “lower priority option” had a lower proportion of complete response (82% vs 60%, p=0.01 in BCLC 0 and 74% vs 20%, p<0.001 in BCLC A) and a shorter OS [33 (IQR 23-61) vs 74 months (IQR 42-137) p<0.001 in BCLC A] as compared to those undergoing first choice treatments. In BCLC B and C, an upward stage migration was associated to a higher achievement of complete response (17% vs 52%, p<0.001 in BCLC B and 2% vs 41% p<0.001 in BCLC C), and granted a longer OS [(63 months (IQR 36-72) vs 28 (IQR 18-44), p=0.003 in BCLC B and 21 months (IQR 15-44) vs 11 months (IQR 4-25) in BCLC C] as compared to BCLC 2022. In BCLC 0 and undergoing a “downward stage migration” without curative intent was an independent predictor of mortality [HR 6.94 (95% CI 2.27-21.20) p=0.001], alongside with age [HR 1.08 (95% CI 1.06-1.13), p<0.001] and ALBI grade 3 [HR 9.34 (95% CI 1.21-72.19), p=0.03. Conversely, “upward stage migration” was independently associated to a lower mortarlity risk both in BCLC B” [HR 0.46 (95% CI 0.27-0.80), p=0.006] and C [HR 0.50 (95% CI 0.27-0.92) p=0.03].

Conclusion

The BCLC_2022 updated version of HCC staging and treatment system allowed a greater adherence to the algorithm in clinical practice, without adversely affecting the survival of patients. Choosing a “curative option” for early HCC granted longer survival, as well as the access to treatments with curative intent permits a survival benefit in selected patients in more advanced stages.

Introduction

G-protein coupled receptor-119 (GPR119) agonism is known to modulate non-alcoholic fatty liver disease physiology. However, due to off-target effects, challenges remain for successful GPR119 agonist pharmacotherapy.
Designing a non-systemic drug candidate that locally targets gut-located receptors for incretin secretion is suggested as a safer approach to minimise conventional side effects. This strategy may potentially limit the direct action on pancreatic β-cells; however, chronic use may lead to beneficial outcomes.
We developed a novel small-molecule agent as an oleoyl-lysophosphatidylinositol derivative that stimulates intestinal glucagon-like peptide-1 (GLP-1) secretion by coupling with gut receptors at the orthosteric site.

Aims & Methods

The present study was designed to investigate the chronic impact of novel GPR119 agonist agent ps297 alone and in combination with Sitagliptin on liver health in high-fat diet (HFD)-induced obese mice.
Five-week-old healthy male C57BL6/J mice were fed with HFD for 20 weeks. Normal control mice were maintained on a standard chow diet. A dose-escalation protocol was followed during the treatment phase. Oral administration of the test compound commenced with an initial dose of 10 mg/kg/day for the first week, followed by weekly dose escalations of 10 mg/kg for the subsequent ten weeks until reaching a maximum dose concentration of 90 mg/kg/day. Sitagliptin was gavaged at a fixed dose of 20 mg/kg/day. Vehicle control mice received an equal volume of 0.25% carboxymethyl cellulose in water.
After ten weeks of treatment, blood samples were collected from each 4-hour fasted mice. Biochemical parameters including plasma glucose, triglycerides (TG), cholesterol (CHO), alanine aminotransferase (ALT), and aspartate transaminase (AST) were analysed using an automated analyser. Plasmatic concentrations of metabolic hormones were determined in a multiplex assay platform. Hepatic TG, CHO, and hydroxyproline concentrations were determined in frozen liver tissue samples by colourimetric assay. Liver histology was studied in tissue stored in 10% neutral buffered formalin. Hepatic ballooning was assessed in hematoxylin and eosin-stained sections, imaged using a slide scanner.

Results

Ten-week co-administration of compound ps297 with sitagliptin resulted in higher plasmatic GLP-1 levels compared to the HFD control arm, which led to a significant (p<0.05) reduction in fasting plasma glucose levels in this group. Moreover, combination group exhibited a significant reduction in liver weights (p<0.0001), plasma CHO (p<0.05), ALT (p<0.0001), and AST (p<0.01) levels. Furthermore, combination treatment showed a significant reduction in hepatic TG (p<0.0001) and CHO (p<0.001) concentrations compared to the HFD control group. Elevated hepatic hydroxyproline levels in HFD control mice were attenuated by combination treatment. Additionally, the hepatic ballooning score was found to be significantly reduced in the combination treatment mice.

Conclusion

Sitagliptin combination of ps297, improved glucose homeostasis in HFD-fed obese mice. Additionally, a prominent improvement in liver health status was observed in this group, as evident by reductions in liver weight, plasma liver enzymes, hepatic TG and CHO, and hydroxyproline levels. These findings were further supported by liver histological examination. The overall findings suggest the pharmacological potential of the GPR119 agonist compound ps297 in combination with gliptins to alleviate fatty liver disease, warranting further molecular investigation in disease-specific animal models.

References

Paternoster S, Simpson PV, Kokh E, Kizilkaya HS, Rosenkilde MM, Mancera RL, Keating DJ, Massi M, Falasca M. Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics. Pharmacol. Res. 172 (2021) 105822.

Bahirat UA, Shenoy RR, Talwar R, Goel RJ, Nemmani KVS. Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet. Biochem Biophys Res Commun 495 (2018) 1608-1613

Disclosure

MF and MM are inventors of a patent related to oleoyl-LPI mimetics. Curtin University received funding from Little Green Pharma Pty Ltd. to support MF to conduct the submitted work. LW is a paid employee of Little Green Pharma Pty Ltd. No other relationships or activities that could appear to have influenced the submitted work.

Introduction

Transjugular intrahepatic portosystemic shunt (TIPS) reduces the portal vein blood flow into the liver while declining portal venous pressure, resulting in liver ischemia injury and even liver failure.

Aims & Methods

This study aimed to verify the impact of the post-TIPS early liver injury on survival through large sample retrospective analysis and explore the risk factors of post-TIPS liver injury. The data of patients undergoing TIPS in West China Hospital from November 2009 to March 2021 were collected. We analysed the predictive ability of end-stage liver disease model score (MELD) on the 90-day, 1-year and 3-year survival rates after TIPS and screened out the independent predictive factors of post-TIPS liver injury by regression analysis.

Results

A total of 1108 patients were included. The post-TIPS MELD score was superior to other scoring systems, with a better predictive effect on the 90-day survival rate and 1-year survival rate. The 90-day survival rate (98.3% vs. 87.2%, HR 15.9, 95% CI 7.9-31.9, P < 0.001), 1-year survival rate (95.1% vs. 79.2%, HR 8.3, 95% CI 5.0-13.7, P < 0.001) and 3-year survival rate (86.5% vs. 68.8%, HR 4.0, 95% CI 2.8-5.7, P < 0.001) were significantly higher in patients with a post-MELD score less than 15. Preoperative total bilirubin, serum creatinine, INR and change of portosystemic pressure gradient were independent predictors of early liver injury after TIPS.

Conclusion

Baseline liver function and pressure reduction contribute to the occurrence of early liver injury after TIPS. Post-TIPS MELD score can accurately predict short-term and long-term survival.

Introduction

Metabolic dysfunction-associated fatty liver disease (MAFLD) has become the most common chronic liver disease in recent years. However, medications to improve MAFLD has no standard. Several potential agents have been widely investigated for the treatment of MAFLD. Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator, has been reported to improve dyslipidemia. Sodium-glucose cotransporter-2 inhibitor (SGLT2i) is an oral antidiabetes drug that promotes glucose excretion into the urine. These medications have potential therapeutic effects on MAFLD.

Aims & Methods

This retrospective study aimed to evaluate the effects of long-term administration of pemafibrate plus SGLT2i in patients with dyslipidemia and type 2 diabetes complicated by MAFLD. Transient elastography (FiboScan; Echosens, Paris, France) was used for liver stiffness measurement (LSM) and assessment of the controlled attenuation parameter (CAP). In total, 594 patients with dyslipidemia and type 2 diabetes complicated by MAFLD started pemafibrate plus SGLT2i treatment between 2019 and 2020 at our hospital. Pre- and post-treatment transient elastography data were compared.

Results

Following 3 years of pemafibrate plus SGLT2i treatment, the median LSM significantly decreased from 10.1 kPa to 6.4 kPa (P < 0.001) and the median CAP significantly decreased from 321 dB/m to 219 dB/m (P < 0.001), in spite of no significant reductions of the studied patients’ weight. Moreover, serum parameters, including hemoglobin A1c, alanine aminotransferase, and gamma-glutamyl transferase, significantly decreased over the study period.

Conclusion

The findings of our study confirm that long-term administration of pemafibrate plus SGLT2i can improve hepatic fibrosis by ameliorating hepatic steatosis and inflammation in patients with dyslipidemia and type 2 diabetes complicated by MAFLD.

References

Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008; 48(5): 835-847.
Yamashita S, Masuda D, Matsuzawa Y. Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases. J Atheroscler Thromb. 2019; 26(5): 389-402.
Mantovani A, Petracca G, Csermely A, et al. Sodium-Glucose Cotransporter-2 Inhibitors for Treatment of Nonalcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials. Metabolites. 2020; 11(1): 22.
Murakami K, Sasaki Y, Asahiyama M, et al. Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis. Cells. 2022;11(4):720.

Introduction

Gastric linitis is a kind of adenocarcinoma that invades the stomach and is composed of separate cells. The predicted survival rate for this condition over a five-year period ranges from 3 to 10%. The excessive cell growth that characterizes gastric linitis also results in the formation of fibrous tissue, which makes the stomach wall thicker and less flexible. Consequently, mucous biopsies frequently do not provide useful information.

Aims & Methods

The aim of this study is to evaluate the diagnostic performance of echo-endoscopic biopsy puncture (EUS-FNB) in the diagnosis of gastric linitis.This study is an observational retrospective monocentric analysis conducted over a period of 4 years from January 2018 to December 2022. It includes all patients who underwent a parietal gastric and/or ganglionary puncture under echo endoscopic guidance using a 20G or 22G Procore® or Acquire® type 22G FNB needle. The purpose of the procedure was to investigate suspected cases of gastric linitis. The study is conducted at the University Hospital Centre in Marrakech, which serves as a tertiary care department and is a point of reference for all regional and provincial hospitals. The appearance of parietal gastric thickness, abdominal DMT, an infiltrated aspect of the stomach, folds, or gastric stenosis in high digestive endoscopy led to the suspicion of gastric linitis.The data was obtained from various sources, including hospital registers, patient medical records, the computerized system "Hosix" for morphological and anatomopathological data, and the collaboration of the medical and paramedical staff from the departments of gastroenterology, visceral surgery, and anatomopathology. The statistical analysis was conducted using SPSS version 22.0. Socio-demographic, clinical and para-clinical data were collected taking into account the global ethical rules relating to confidentiality and protection of patient-specific data.

Results

Out of 42 patients who performed biopsy puncture under high echo-endoscopy on suspicion of diagnosis, ten patients had gastric linitis. The diagnosis of gastric linitis was obtained by puncture in 90% of cases (9/10). Eight patients (80%) had previously undergone at least one oeso-gastro-duodenal fibroscopy with returning negative mucous biopsies. Six patients were diagnosed as early as 1st EEH while 3 others required a second series of biopsies. While the mucous biopsies were also unsuccessful, echo-guided biopsy allowed the diagnosis of other more serious diseases in 43% of cases (n = 18/42) including gastric metastases of a breast cancer (n=2), other gastric adenocarcinomas of the intestinal type (N=8), and cases of T-type gastric lymphoma in one case and MALT type in 2 cases.

Conclusion

In case of suspicion of gastric linitis, guided biopsy puncture under echo-endoscopy is a cost-effective approach in 90% of cases, without noticeable side effects. It should be considered the procedure of choice for early diagnosis of gastric linitis when mucous biopsies return negative.