Introduction

The canonical pathogenesis of hepatic encephalopathy (HE) in liver cirrhosis pivots on the amino acid metabolism. HE subsequent to transjugular intrahepatic portosystemic shunt (TIPS) is distinct from the common HE in liver cirrhosis, and the metabolism knowledge of post-TIPS HE is not fully understood.

Aims & Methods

The aim of this study is to investigate the metabolic profile of pre-TIPS metabolomics and to determine most-altered pre-TIPS metabolites to alert the onset of post-TIPS HE. Serum samples, which were harvested before TIPS in liver cirrhosis patients, were randomly chosen from the ongoing cohort study (ChiCTR2000039616). Ten samples each with and without overt HE within 6 months after TIPS was measured by ultrahigh performance liquid chromatography–tandem mass spectrometry, and thereafter untargeted metabolomics and targeted lipidomics analyses were performed.

Results

There were no significant differences in the baseline characteristics between patients with and without overt HE after randomized sampling. In the untargeted metabolomics analysis, 46 (0.08%) out of 1255 metabolites were significantly associated with post-TIPS HE according to OPLS-DA (P < 0.1 and vip > 1), of which 12 and 34 metabolites were up-regulated and down-regulated in the post-TIPS HE, respectively. These metabolites are tightly related with alanine, aspartate and glutamate metabolism, fatty acid biosynthesis, and glyceropholipid metabolism pathways. Intriguingly, of 46, 14 (30.4%) differential metabolites came from the lysophosphatide family, which were mainly down-regulated in post-TIPS HE. Further targeted lipidomics identified 44 (7.8%) differential lipids out of 564 lipid metabolites by OPLS-DA (P < 0.05 and vip > 1). Of 15 up-regulated lipid metabolites in post-TIPS HE group, 12 (80%) were triacylglycerols. In contrast, there were 17 (58.6%) phospholipids and 9 (31%) lysophosphatides out of 29 down-regulated lipid metabolites in post-TIPS HE. Post-TIPS HE was related to the increased triacylglycerols and decreased glyceropholipids before TIPS.

Conclusion

Lipid metabolism disturbances, features as up-regulated triacylglycerols and down-regulated glycerophospholipds, are associated with the onset of post-TIPS HE in liver cirrhosis.

References

None.

Introduction

Hepatic encephalopathy (HE) after Transjugular Intrahepatic Portosystemic Shunt (TIPS) affect 35-50% of patients. The use of prophylactic agents (Lactulose and Rifaximin) to prevent post-TIPS HE remains controversial and currently not recommended by professional guidelines. Our aim was to assess real world practice and identify potential predictors for post-TIPS HE and benefit from post-TIPS prophylaxis.

Aims & Methods

Retrospective cohort study of patients undergoing TIPS at the Tel-Aviv Medical Center (2016-2024). The primary outcome was overt HE, with secondary outcomes of liver transplantation (LT) and mortality.

Results

Seventy-nine patients underwent TIPS, median age was 60 years and 52% were male. Primary liver disease was metabolic dysfunction-associated steatohepatitis (MASH) in 34%, viral (20%), and alcohol-related liver disease (ALD) (16.5%). Indications for TIPS were variceal bleeding (52%) and refractory ascites (38%). Prior to the procedure 31% had ≥ 1 episodes of HE, 21.5% were treated with Lactulose and/or Rifaximin, and 58% were on betablocker treatment. At the time of the procedure, the patient's Child-Pugh score was A/B/C in 19%/66%/11% respectively, with a median MELD-Na of 10.9. Median follow up was 22.75 months. Overall, 22 patients died during follow-up and 8 underwent liver transplantation. 45 patients (57%) developed post-TIPS HE, 60% of them during the first three months. Early post-TIPS HE treatment was given to 49%: 10% Lactulose, 5% Rifaximin, and 34% both. Among those patients, 44% were previously (pre-TIPS) on HE treatment. Development of HE was not predicted by pre-or post-TIPS MELD-Na or Child-Pugh score, TIPS diameter, postTIPS gradient, or post-procedure ammonia levels. Rates of HE also did not differ according to initial prophylaxis treatment (59% with treatment, 56% without, p=1). Pre-TIPS AST and albumin were associated with post-TIPS HE (36.6U/L vs. 60.44 U/L, p=0.03; 34.6g/dl vs. 31.8g/dl, p = 0.05). Prior beta-blocker treatment was associated with post-TIPS HE (14% vs 32%, p = 0.01) but not varices as the indication for TIPS. Mortality rate was not affected by the occurrence of post-TIPS HE (28% among those who developed HE vs. 26% among those who didn't, p = 1).

Conclusion

Early post-TIPS preventive treatment was mostly given to patients previously treated with Lactulose/Rifaximin, however it did not affect the rate of post-TIPS HE. Development of HE did not increase mortality.

References

1. Wolfgang el al. ASSLD practice Guidance, Hepatology (2024)
2. Yao el al.J Gastrointestin Liver Dis (2015)

Introduction

Transjugular intrahepatic portosystemic shunt (TIPS) is now an effective and standard procedure to prevent variceal bleeding and recurrent ascites in decompensated cirrhosis (1). Moreover, there is increasing evidence (2, 3) showing that TIPS is feasible in patients with partial or occlusive portal vein thrombosis (PVT). However, thrombosis may develop at intrahepatic branches of the portal vein after TIPS, even in patients without PVT before the procedure. Our retrospective study showed that warfarin could prevent portal branch PVT and might improve liver function among cirrhosis patients receiving TIPS (4). Thus, to obtain clinical evidence with higher quality, a prospective study on post-TIPS de novo PVT regarding the incidence, risk factors, and impact on liver function is necessary.

Aims & Methods

Aim: We aimed to assess the incidence and risk factors for thrombosis developed at branches of the portal vein after TIPS in cirrhosis patients without preexisting PVT. In addition, we aimed to evaluate the influence of post-TIPS PVT on liver function and cirrhosis-related events.
Methods: A total of 70 decompensated cirrhosis patients who received TIPS without PVT were included. Routine laboratory and radiological examinations and assessment of cirrhosis-related complications proceed at 1, 3, 6 and 12 months after TIPS. For the primary outcome, the presence of post-TIPS PVT was assessed by doppler ultrasound showing that the blood flow signal partially or completely disappeared or by contrast-enhanced computed tomography showing filling defects or occlusion in the portal vein branches. For the liver function and complications comparison within 1 year after TIPS (secondary outcome), a 1:1 match using propensity score matching (PSM) based on age, sex and preoperative Child‒Pugh score was conducted between patients with and without post-TIPS PVT.

Results

Among 70 patients, 34 (48.6%) were Child‒Pugh class A, and the median Child‒Pugh score was 7 (5-8). The most common indication for TIPS was variceal bleeding (76.8%), followed by refractory ascites (21.4%). During the follow-up, 25 (35.7%) patients developed post-TIPS PVT, with incidences of 8.0%, 16.0% and 26.8% at 1, 2 and 3 months after TIPS, respectively. Univariate analysis showed that lower serum albumin (p = 0.023), Child‒Pugh B/C class (p = 0.029) and stenting at the left branch of the portal vein (p = 0.020) were significantly associated with post-TIPS PVT. Multivariate analysis showed that lower serum albumin (OR 0.87, p = 0.022) and stenting at the left branch of the portal vein (OR 6.56, p = 0.020) were independent risk factors. Twenty four of 25 patients with post-TIPS PVT were matched with 24 of 45 patients without post-TIPS PVT. Preoperative clinical characteristics of the matched patients were compared, and no significant differences were shown between the two groups. However, the Child‒Pugh score was significantly higher in the PVT group at 1 year after TIPS compared with non-PVT group [7 (6-8) vs 8 (7-9), p = 0.044]. In addition, the incidence of overt hepatic encephalopathy (50.0% vs 20.8%, p = 0.035) and the presence of ascites (54.2% vs 25.0%, p = 0.039) at 1 year after TIPS were significantly higher in the PVT group.

Conclusion

PVT may develop at intrahepatic branches of the portal vein early in the post-TIPS period in cirrhosis, leading to further liver damage and cirrhosis-related complications. Lower serum albumin levels and stenting at the left branch of the portal vein were independent risk factors for de novo PVT within 1 year after TIPS.

References

1.de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C; Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol. 2022 Apr;76(4):959-974.
2.Lv Y, Bai W, Li K, Wang Z, Guo W, Luo B, Wang J, Wang Q, Wang E, Xia D, Li X, Yuan J, Han N, Niu J, Yin Z, Fan D, Han G. Anticoagulation and Transjugular Intrahepatic Portosystemic Shunt for the Management of Portal Vein Thrombosis in Cirrhosis: A Prospective Observational Study. Am J Gastroenterol. 2021 Jul 1;116(7):1447-1464.
3.Guo DF, Fan LW, Le Q, Huang CB. Transjugular intrahepatic portosystemic shunt for the prevention of rebleeding in patients with cirrhosis and portal vein thrombosis: Systematic review and meta-analysis. Front Pharmacol. 2022 Aug 16;13:968988.
4.Zhang L, Huan H, Tong H, Wei B, Wang Z, Liu C, Wu H. Warfarin prevented de novo portal vein thrombosis after transjugular intrahepatic portosystemic shunt: A retrospective study. Medicine (Baltimore). 2020 Jan;99(2):e18737.

Introduction

Liver fibrosis, characterized by diffuse fibrous deposition and distortion of hepatic vascular architecture in histology, is an intermediate step in the development of cirrhosis resulting from chronic liver disease. Liver sinosoidal endothelial cells (LSECs) are critical gatekeepers of sinusoidal homeostasis. Following injury, LSECs are the first to be affected and initiate a cascade of reactions within the sinusoidal, which contribute to the development and progression of liver fibrosis and portal hypertension. Our preliminary studies have shown that hepatic cyclooxygenase-2 (COX-2) expression was correlated with the severity of inflammation and fibrosis, and its inhibitor could ameliorate intrahepatic fibrosis.

Aims & Methods

The present study aimed to investigate the role of COX-2 on LSECs function and its underlying molecular mechanism.

Results

Ptgs2 deficiency attenuates liver fibrosis
In both inducible and non-inducible mouse models, Ptgs2 knockdown resulted in a reduction in collagen deposition. TAA- or DDC-induced fibrosis-related protein expression (collagen I and α-SMA) was significantly reduced by Ptgs2 deletion.
Ptgs2 deficiency alleviates hepatic inflammatory injury
RNA-seq analysis indicated that down-regulated DEGs by Ptgs2 knockdown were enriched in leukocyte chemotaxis, leukocyte migration, and leukocyte cell-cell adhesion. Consistently, significantly decreased numbers of infiltrating neutrophils and macrophages were observed in Ptgs2-deficient mice. In addition to inflammatory cell infiltration, liver function was also improved suggested by significant decreases in serum levels of ALT and AST.
COX-2 expression is elevated in LSECs in reponse to liver injury
D-IF showed that COX-2 expression was elevated in injury liver tissues. The immunofluorescence for COX-2 in TAA-A and TAA-C groups was also co-stained with LYVE1, a LSEC-specific maker. RNA-seq data from the GEO database further confimed the COX-2 overexpression in murine LSECs isolated from various fibrotic models. In vivo study, COX-2-mPGES-1-EP2 pathway could be up-regulated by pro-inflammatory factor TNFα.
COX-2-PGE2-EP2 promotes leukocyte recruitment through NF-κB pathway
RNA-seq analysis found that inhibition of COX-2 supressed TNF-induced gene transcription which were enriched in leukocyte recruitment, TNFα pathway, and NF-κB pathway. In HHSEC, TNFα activated NF-κB signaling pathway and increased expression levels of chemokines (CXCL1 and CCL2) and adhesion molecules (ICAM1 and VCAM1). This TNFα-induced effect could be potently suppressed by COX-2 inhibitor (Celecoxib), mPGES-1 inhibitor (MF63) or EP2 receptor antagonist (TG4-155). PGE2 also activated NF-κB pathway, which was abolished after EP2 blockage.
COX-2 inhibitors attenuate fibrosis and liver injury
Both Celecoxib and Etoricoxib (both were selective COX-2 inhibitors) were able to decrease collagen deposition, fibrosis-related protein expression, inflammatory cell infiltration and serum transaminase levels in TAA or DDC models.

Conclusion

COX-2 expression in LSECs is up-regulated in liver fibrosis. Upon inflammatory stimulation, COX-2-PGE2-EP2 axis increases chemokines and adhesion molecules through the synergistic activation of NF-κB signaling pathway, leading to leukocyte recruitment and hepatic inflammation. Inhibition of COX-2 by Celecoxib or Etoricoxib attenuate fibrosis and liver injury. The present study sheds light on the regulation of LSECs on leukocyte recruitment through a cyclooxygenase-2-dependent mechanism. Taken together, our results suggest COX-2 as a potential therapeutic target in the treatment of liver fibrosis.

Disclosure

The authors disclose no conflicts.

Introduction

Transjugular intrahepatic portosystemic shunt (TIPS) is a well-established procedure frequently employed to manage portal hypertension associated conditions such as variceal bleeding, ascites, and hydrothorax. However, despite its benefits, TIPS placement is frequently complicated by post-TIPS hepatic encephalopathy (HE), a condition that can significantly impact patient outcomes and quality of life. Currently, there is a lack of consensus and robust evidence regarding the optimal prophylactic treatments for post-TIPS HE. There is a recommendation suggesting the use of rifaximin, which is based solely on a single randomized controlled trial^1,2. Thus, more data are needed to assess the efficacy of prophylactic therapies in a real-world clinical setting.

Aims & Methods

This work aims to compare the efficacy of different prophylactic treatments (lactulose, rifaximin or both) and identify predictive factors for post-TIPS HE.
A retrospective study was conducted at a tertiary TIPS referral centre, including all adult patients who undergone TIPS placement between January/2021 and June/2024. Clinical records were reviewed to collect demographic data, prior decompensations, analytical results, medication and episodes of post-TIPS HE. A minimum of 6 months of follow-up was required. Statistical analysis was performed using SPSS Statistics version 26®.

Results

We included 83 patients, most of them male (n=69;83.1%) with a mean age of 60.1±1.3 years old. Most patients had alcoholic liver disease (n=58; 69.9%), followed by metabolic dysfunction and alcohol-related liver disease (n=6;7.2%). Prior to the procedure 22 (26.5%) patients had previous episodes of HE: 12 (14.5%) were medicated with lactulose, 2 (2.4%) with rifaximin and 8 (9.6%) with both. The remaining 61 (73.5%) had no previous medication. The primary indications for TIPS placement were variceal haemorrhage (n=50; 60.2% [pre-emptive n=21;42.0%]) and refractory ascites or hepatic hydrothorax (n=27;32.5%). The mean pre-TIPS and post-TIPS direct portal pressure were 31.0±0.9 mmHg and 22.2±0.7 mmHg, respectively. After TIPS placement 19 (22.9%) were discharged with lactulose, 3 (3.6%) with rifaximin, 20 (24.1%) with both and 41 (49.4%) with no medication. The mean follow-up time after TIPS placement was 22.3±2.0 months. Twenty-five (30.1%) patients had post-TIPS HE and there were no differences between therapeutic strategies in preventing such episodes (lactulose: OR 2.6 (95%CI 0.7-9.2) p-value 0.14; rifaximin: OR 1.1 (95%CI 0.1-19.0) p-value 0.94; both OR 2.4 (95%CI 0.7-8.2) p-value 0.15). Those discharged with no medication had less post-TIPS HE (OR 0.2 (95%CI 0.1-0.6) p-value 0.008), although these had also less pre-TIPS HE (p-value 0,046). Previous variceal haemorrhage (OR 3.2 (95%CI 1.0-9.9) p-value 0.046) and lower glomerular filtration rate (OR 0.98 (95%CI 0.96-0.99) p-value 0.03) were associated with higher risk for post-TIPS HE.

Conclusion

Our study found no significant differences between prophylactic treatments for post-TIPS HE. Notably, patients who did not receive prophylaxis had lower incidence of post-TIPS HE, although they also had fewer pre-TIPS episodes of HE. This raises questions about the universal application of these treatments and suggests the need for a more individualized approach. The identification of risk factors such as a history of variceal haemorrhage and lower glomerular filtration rate may guide treatment decisions, emphasizing the need for tailored management strategies. Future studies with larger sample sizes and multicentre participation are needed to refine prophylactic recommendations.

References

1. Bureau C, Thabut D, Jezequel C, Archambeaud I, D’Alteroche L, Dharancy S, et al. The use of rifaximin in the prevention of overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled trial. Ann Intern Med. 2021;174:633-40;
2. Lee EW, Eghtesad B, Garcia-Tsao G, Haskal ZJ, Hernandez-Gea V, Jalaeian H, Kalva SP, Mohanty A, Thabut D, Abraldes JG. AASLD Practice Guidance on the use of TIPS, variceal embolization, and retrograde transvenous obliteration in the management of variceal hemorrhage. Hepatology. 2024 Jan 1;79(1):224-250.

Introduction

Liver cirrhosis, the end stage of chronic liver diseases, is associated with high morbidity, mortality, and medical costs worldwide(1). The progression of liver cirrhosis from compensated to decompensated cirrhosis, portal hypertension (PHT) with complications is developed(2). Transjugular intrahepatic portosystemic shunt (TIPS) is an effective procedure for treating PHT. Whereas complications of post-TIPS, especially hepatic encephalopathy and stent dysfunction, limit the application of TIPS as a first-line treatment for liver cirrhosis.
Osteoarthritis (OA) and rheumatoid arthritis (RA) are characterized by chronic polyarticular inflammation which may cause irreversible joint damage. The conventional agent of modifying antirheumatic drugs and corticosteroids are associated with hepatotoxicity and are contraindicated in chronic hepatitis (3,4). Treatment of liver cirrhosis combined OA/RA should be carefully considered.
Systemic inflammation is tightly associated with the progression of liver cirrhosis and RA/OA. Selective COX-2 inhibitor is one of the most well-investigated anti-inflammation drugs with antifibrotic effects (5,6,7). However, there are no relevant studies about the anti-inflammatory concept of cirrhotic patients with RA or OA after TIPS.

Aims & Methods

Aim：To assess the effects and safety of anti-inflammatory therapy of selective cyclooxygenase-2 (COX-2) inhibitors in patients with decompensated liver cirrhosis undergone transjugular intrahepatic portosystemic shunt (TIPS) accompanied with rheumatoid arthritis (RA) or osteoarthritis (OA).
Methods：Clinic data from patients with liver cirrhosis underwent TIPS were collected from January 2017 to October 2022 for a retrospective analysis. According to whether receiving selective COX-2 inhibitors orally for arthritis, patients were divided into the TIPS and TIPS+COX-2-I group. Occurrences of clinic adverse events were examined.

Results

Eligible patients in the TIPS (n=95) and TIPS+COX-2-I group (n=51) were analyzed. Clinic events containing variceal rebleeding, hepatic encephalopathy, ascites (>grade 2), hepatocellular carcinoma (HCC) and stent dysfunction in the TIPS+COX-2-I group was less than the TIPS group (5.88% vs. 27.37%, p=0.002). Among those patients in the TIPS+COX-2-I group, 1.96% (1/51) patient experienced esophageal and gastric variceal bleeding (EGVB) again. No patients occurred HE with only 1 patient experienced ascites relapse, and 1 patient finally progressed to HCC. However, in the TIPS group, the rates of clinic adverse events including EGVB, HE, ascites, HCC and stents dysfunction were all higher, which were 10.53%, 4.21%, 4.21%, 2.11%, 6.32% respectively. No concerned side effects related to selective COX-2 inhibitors mainly including cardiovascular events and gastrointestinal hemorrhage occurred during follow-up periods.
Table 1. Clinic advers events between two groups

Conclusion

Anti-inflammatory therapy of selective COX-2 inhibitors for post-TIPS patients with RA or OA, not only can reduce the occurrence of adverse clinic events, but also safe in those patients, which is a completely effective and safe therapy.

References

1. Smith A, Baumgartner K, Bositis C. Cirrhosis: diagnosis and management.Am Fam Physician. 2019; 100:759–770.
2. 2.Ginès P, Krag A, Abraldes JG, Solà E, Fabrellas N, Kamath PS. Liver cirrhosis. Lancet. 2021; 398:1359-1376.
3. Olsson-White DA, Olynyk JK, Ayonrinde OT, Paramalingam S, Keen HI. Assessment of liver fibrosis markers in people with rheumatoid arthritis on methotrexate. Intern Med J. 2022;52(4):566-573.
4. Kim PS, Ho GY, Prete PE, Furst DE. Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B. Arthritis Care Res (Hoboken). 2012;64(8):1265-8.
5. Su W, Tai Y, Tang SH, Ye YT, Zhao C, Gao JH, et al. Celecoxib attenuates hepatocyte apoptosis by inhibiting endoplasmic reticulum stress in thioacetamide-induced cirrhotic rats. World J Gastroenterol. 2020; 26:4094-4107.
6. Tai Y, Zhao C, Zhang L, Tang S, Jia X, Tong H, et al. Celecoxib reduces hepatic vascular resistance in portal hypertension by amelioration of endothelial oxidative stress. J Cell Mol Med. 2021 Nov;25(22):10389-10402.
7. Gao JH, Wen SL, Yang WJ, Lu YY, Tong H, Huang ZY, et al. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. PLoS One. 2013; 8: e69309.
   

Disclosure

There is no conflict of interest.