Management of Sinistral Portal Hypertension after Pancreaticoduodenectomy.

BACKGROUND: Sinistral, or left-sided, portal hypertension (SPH) is a rare cause of upper gastrointestinal (GI) hemorrhage resulting from obstruction of the splenic vein. Venous drainage from the spleen via collaterals can result in venous hemorrhage into both the retroperitoneal and intra-abdominal spaces due to increased venous blood pressure in peripancreatic and gastroduodenal vasculature. SPH can occur secondary to pancreatitis with thrombosis of the splenic vein. Another possible cause is the surgical ligation of the splenic vein as part of pancreaticoduodenectomy (PD). Although splenectomy has been traditionally considered as the treatment of choice to relieve venous hypertension, individual concepts for each patient have to be developed. Considering the venous collateral drainage pathways, a comprehensive approach involving surgical, endoscopic, and interventional radiology interventions may be necessary to address the underlying cause of variceal bleeding. Among these approaches, splenic artery embolization (SAE) has demonstrated efficacy in mitigating the adverse effects associated with elevated venous outflow pressure. SUMMARY: This review summarizes key imaging findings in SPH patients after PD and highlights the potential of minimally invasive embolization for curative treatment of variceal hemorrhage. KEY MESSAGES: (i) SPH is a potential consequence after major pancreas surgery. (ii) Collateral flow can lead to life-threatening abdominal bleeding. (iii) Depending on the origin and localization of the bleeding, a dedicated management is required, frequently involving interventional radiology techniques.

Portal hypertension and variceal bleeding in patients with liver cancer: Evidence gaps for prevention and management.

BACKGROUND AND AIMS: Portal hypertension (PHT) and HCC are 2 major complications of cirrhosis that often coexist in the same patient and impact the prognosis, especially in patients with acute variceal bleeding. In this review, we aim to discuss the best strategy for PHT screening and primary prophylaxis, as well as the management of acute variceal bleeding, to improve the management of PHT in HCC patients. RESULTS: Recent therapeutic advances observed in the management of HCC, notably through the advent of immunotherapy, have led to a clear improvement in the survival of patients. The prevention of complications related to underlying cirrhosis, such as PHT and acute variceal bleeding, is now part of the management of HCC patients. The Baveno VII conference recently redefined screening and prophylaxis in patients with cirrhosis. However, data regarding the applicability of these criteria in patients with HCC have been sparse. From our point of view, the Baveno criteria are not appropriate to exclude high-risk esophageal varices (EV) in HCC patients, and endoscopy should be performed except in HCC patients with a liver stiffness measurement (LSM) ≥25 kPa, who should benefit from nonselective beta-blockers (NSSBs) without performing endoscopy. We are also in favor of using NSBBs as primary prophylaxis in patients with EV regardless of the size and with gastric varices since these patients display clinically significant PHT. CONCLUSIONS: Appropriate evaluation and treatment of PHT remain major issues in improving the outcomes of HCC patients. Many questions remain unanswered, opening the field to many areas of research.

Endoscopic procedures in hepatology: Current trends and new developments.

Gastrointestinal endoscopy has long been a reliable backbone in the diagnosis and management of hepatobilary disorders and their complications. However, with evolving non-invasive testing, personalised medicine has reframed the utility and necessity of endoscopic screening. Conversely, the growing interest and use of endoscopic ultrasound (EUS) and advanced endoscopy within gastrointestinal units has also opened novel diagnostic and therapeutic avenues for patients with various hepatobiliary diseases. The integration of "advanced endoscopy" within the practice of hepatology is nowadays referred to as "endo-hepatology". In essence, endo-hepatology consists of two pillars: one focusing primarily on disorders of the liver parenchyma, vascular disorders, and portal hypertension, which is mainly captured via EUS, while the other targets the hepatobiliary tract via endoscopic retrograde cholangiopancreatography and advanced imaging. Applications under the umbrella of endo-hepatology include, amongst others, EUS-guided liver biopsy, EUS-guided portal pressure gradient measurement, coil and glue embolisation of gastric varices as well as cholangioscopy. As such endo-hepatology could become an attractive concept wherein advanced endoscopy might reinforce the medical management of patients with hepatobiliary disorders and their complications after initial basic work-up. In this review, we discuss current trends and future developments within endo-hepatology and the remaining hurdles to overcome.

Long-Term Impact of Direct-Acting Antivirals on Liver Fibrosis and Survival in HCV-Infected Liver Transplant Recipients.

(1) Background: Little is known about the long-term impact of sustained virological response (SVR) on fibrosis progression and patient survival in liver transplantation (LT) recipients treated with direct-acting antivirals (DAAs). We investigated liver fibrosis evolution and patient survival in hepatitis C virus (HCV)-infected patients receiving DAAs after LT. (2) Methods: All consecutive HCV-infected patients treated with DAAs after LT between May 2014 and January 2019 were considered. The clinical and virological features were registered at the baseline and during the follow-up. The liver fibrosis was assessed by liver biopsy and/or transient elastography (TE) at the baseline and at least 1 year after the end of treatment (EoT). (3) Results: A total of 136 patients were included. The SVR12 was 78% after the first treatment and 96% after retreatment. After the SVR12, biochemical tests improved at the EoT and remained stable throughout the 3-year follow-up. Liver fibrosis improved after the SVR12 (p < 0.001); nearly half of the patients with advanced liver fibrosis experienced an improvement of an F ≤ 2. The factors associated with lower survival in SVR12 patients were the baseline platelet count (p = 0.04) and creatinine level (p = 0.04). (4) Conclusions: The long-term follow-up data demonstrated that SVR12 was associated with an improvement in hepatic function, liver fibrosis, and post-LT survival, regardless of the baseline liver fibrosis. The presence of portal hypertension before the DAAs has an impact on patient survival, even after SVR12.

Clinical manifestations and approach to the management of patients with common variable immunodeficiency and liver disease.

Purpose: The clinical spectrum of common variable immunodeficiency (CVID) includes predisposition to infections, autoimmune/inflammatory complications and malignancy. Liver disease is developed by a proportion of patients with CVID, but limited evidence is available about its prevalence, pathogenesis and prognostic outcome. This lack of evidence leads to the absence of guidelines in clinical practice. In this study, we aimed at defining the characteristics, course and management of this CVID complication in Spain. Methods: Spanish reference centers were invited to complete a cross-sectional survey. Thirty-eight patients with CVID-related liver disease from different hospitals were evaluated by a retrospective clinical course review. Results: In this cohort, abnormal liver function and thrombocytopenia were found in most of the patients (95% and 79% respectively), in keeping with the higher incidence of abnormal liver imaging and splenomegaly. The most common histological findings included nodular regenerative hyperplasia (NRH) and lymphocytic infiltration, which have been associated with portal hypertension (PHTN) leading to a poorer prognosis. Autoimmune/inflammatory complications occurred in 82% of the CVID patients that developed liver disease and 52% of the patients treated with immunomodulators showed a reduction in the liver function tests' abnormalities during treatment. Among the experts that conducted the survey, there was 80% or more consensus that the workup of CVID-related liver disease requires liver profile, abdominal ultrasound and transient elastography. The majority agreed that liver biopsy should be essential for diagnosis. There was 94% consensus that endoscopic studies should be performed in the presence of PHTN. However, there was 89% consensus that there is insufficient evidence on the management of these patients. Conclusion: Liver disease varies in severity and may contribute substantially to morbidity and mortality in patients with CVID. Hence the importance of close follow-up and screening of this CVID complication to prompt early targeted intervention. Further research is needed to evaluate the pathophysiology of liver disease in patients with CVID to identify personalized treatment options. This study emphasizes the urgent need to develop international guidelines for the diagnosis and management of this CVID complication.

Liver Cirrhosis and Portal Hypertension: How to Deal with Esophageal Varices?

The understanding of pathogenesis of portal hypertension in patients with liver cirrhosis continues to evolve. In addition to progressive fibrosis, cirrhosis is characterized by parenchymal extinction and vascular remodelling, causing architectural distortion. Existence of prothrombotic state and more recently, intestinal bacterial dysbiosis are recently described in the pathogenesis of portal hypertension. Clinically significant portal hypertension (CSPH) is an important prognostic milestone in patients with liver cirrhosis. This is a pre-symptomatic phase that predicts the development of varices, ascites and importantly increased risk of Hepatocellular carcinoma (HCC). CSPH is associated with significantly reduced survival. Endoscopic surveillance is necessary in these patients. Non-selective Beta-blocker is the preferred therapy for primary prophylaxis in the management of portal hypertension. Patients with acute variceal bleed should be resuscitated appropriately, followed by vasoactive drugs and endoscopic therapy. Early TIPS should be considered in those with refractory bleed or in endoscopic treatment failure. Application of artificial intelligence and machine learning may be useful in future for identifying patients at risk of variceal hemorrhage.

Two Cases of Gastric Varices with Left-sided Portal Hypertension Due to Essential Thrombocythemia Treated with Gastric Devascularization or Partial Splenic Embolization.

Left-sided portal hypertension (LSPH) is a condition of extrahepatic portal hypertension that often results in bleeding from isolated gastric varices (GVs). LSPH is sometimes caused by myeloproliferative diseases, such as essential thrombocythemia (ET). We herein report two cases of GVs with LSPH due to ET that were successfully controlled by gastric devascularization (GDS) or partial splenic embolization (PSE). Since each patient with LSPH due to ET has a different pathology, optimal treatment should be performed depending on the patient's condition, such as platelet counts, hemodynamics, or the prognosis. We believe that these cases will serve as a reference for future cases.

Interventional Management of Portal Hypertension in Cancer Patients.

PURPOSE OF REVIEW: To provide an overview of the classifications and clinical hallmarks of common cancer-related conditions that contribute to the high incidence of portal hypertension in this population and provide an update on currently available interventional radiology therapeutic approaches. RECENT FINDINGS: In the last few decades, there have been significant advancements in understanding the pathophysiology of portal hypertension. This knowledge has led to the development of safer and more effective minimally invasive approaches. The main objective is to provide alternatives to prevent life-threatening complications from clinically significant portal hypertension and to allow the continuation of cancer treatment interventions that would otherwise be stopped. Clinicians involved in cancer care should be aware of risk factors, associated complications, and management of portal hypertension in cancer patients. Interventional radiology offers minimally invasive alternatives that play a central role in improving clinical outcomes and survival of these patients, allowing the continuation of cancer treatments.

Presentation, Management, and Outcome of Congenital Portosystemic Shunts in Children: The Boston Children's Hospital Experience.

OBJECTIVES: Congenital portosystemic shunts (CPSS) are rare vascular malformations. We describe presentations, complications, associations, and outcomes of CPSS at Boston Children's Hospital (BCH). METHODS: This was a retrospective review of children with CPSS at BCH from 2000 to 2020. RESULTS: Twenty-nine patients had CPSS (17 girls): 14 extrahepatic (EH) and 15 intrahepatic (IH). At diagnosis, 15 were ≤5 days, 7 <1 year, and 7 >1 year (range 1-19). Median follow-up duration was 5.2 years (interquartile range [IQR] 1.6-10.9) in EH and 2.2 years (0.2-4.2) in IH CPSS. The most common presentation was antenatal ultrasound 13 (45%) followed by hyperammonemia 10 (34%), whereas 6 (21%) were asymptomatic. Complications were noted in 17 (12/14 EH vs 6/15 IH, P = 0.008). Associated anomalies were present in 25 (14/14 EH vs 11/15 IH, P = 0.10). Spontaneous closure was observed in 8 (28%) patients with IH CPSS, all <12 months of age. Ten patients underwent shunt closure 3 (30%) by interventional radiology (IR) and 5 (50%) by surgery, whereas 2 (20%) required both. After therapeutic closure; 8 had improvement, 1 had portal hypertension, and 1 had sepsis and thrombosis. The remaining 11 patients, 8 (42%) were followed without closure: 6 of 8 (75%) EH versus 2 of 11 (18%) IH ( P = 0.02), 2 lost follow-up and 1 with complicated EH CPSS died, unsuitable for therapeutic closure. CONCLUSIONS: CPSS may be asymptomatic or present with complications. Spontaneous closure of IH shunts may occur in infancy, thus therapeutic closure may be deferred until age ≥ 2 years. IR and surgical closure of CPSS are associated with improvement in the majority of cases.

[Expert consensus on clinical diagnosis and treatment of portal hypertension with hepatocellular carcinoma (2022)].

At present, there is no uniform standard for diagnosis and treatment of portal hypertension complicated with hepatocellular carcinoma internationally. Although in recent years, with the significant advances of surgical technique and the positive progress of targeted and immunotherapy in the field of hepatocellular carcinoma, the survival of hepatocellular carcinoma patients has improved, but the risk of surgery in patients with portal hypertension complicated with hepatocellular carcinoma remains high, and surgical treatment is still controversial. Therefore, based on the existing evidence, the Chinese Society of Spleen and Portal Hypertension Surgery, Chinese Society of Surgery, Chinese Medical Association has organized relevant experts to develop the consensus on clinical diagnosis and treatment of portal hypertension with hepatocellular carcinoma (2022) after full discussion. This consensus aims to provide the latest guidance for the standardized diagnosis and treatment of portal hypertension with hepatocellular carcinoma in China. Given that most portal hypertension originates from cirrhosis, this consensus only addresses the diagnosis and treatment of cirrhosis-related portal hypertension with hepatocellular carcinoma.

Electroacupuncture attenuates vascular hyporeactivity in a rat model of portal hypertension induced by bile duct ligation.

BACKGROUND: A hyperdynamic circulation and impaired vascular responsiveness to vasoconstrictors are observed in portal hypertension (PHT) rats. Inflammation is a major contributor to the hyperdynamic circulation state in murine models of PHT. Electroacupuncture (EA) may ameliorate the inflammatory response and limit arterial vasodilatation and portal pressure. This study investigated the possible mechanisms underlying putative hemodynamics effects of EA in normal and PHT rats. METHODS: PHT was induced by bile duct ligation (BDL) surgery over 4 weeks in rats. Sham-operated and BDL rats were treated with low-frequency EA (2 Hz) at ST36 10 min three times weekly for one or two consecutive weeks (for a total of 3 or 7 treatments, respectively). Serum tumor necrosis factor-α (TNF-α), nitrite/nitrate (NOx) and 6-keto-prostaglandin F1α (6-keto-PGF1α) were analyzed, and hemodynamic variation and contractile responses to phorbol-12,13-dibutyrate and phenylephrine in aortic and superior mesenteric arterial rings were recorded. Inducible (i) and endothelial (3) nitric oxide synthase (NOS), cyclooxygenase-1 (COX-1), and protein kinase C-α (PKC-α) levels were determined by Western blotting. RESULTS: EA significantly reduced portal pressure and serum TNF-α, NOx and 6-keto-PGF1α levels compared to the untreated BDL group, enhanced maximum contractile responses in the aorta, up-regulated PKC-α, and down-regulated iNOS and COX-1 levels. In addition, EA decreased the aortic angiogenesis signaling cascade, reflected by down-regulation of vascular endothelial growth factor (VEGF) abundance and transforming growth factor ß receptor (TGFßR)I/II expression, as assessed by immunostaining. CONCLUSION: EA attenuates TNF-α, NO and 6-keto-PGF1α overproduction, modulates the vascular levels of constitutive NOS and PKC-α, blunts the development of the angiogenesis cascade, and enhances vascular contractile force in PHT rats.

Combined Use of Transjugular Intrahepatic Portosystemic Shunt and Transarterial Chemoembolization in the Treatment of Esophageal and Gastric Variceal Bleeding: A Retrospective Study of 80 Patients with Hepatocellular Carcinoma and Portal Hypertension.

BACKGROUND The main cause of death in patients with hepatocellular carcinoma (HCC) with portal hypertension is esophageal and gastric variceal bleeding caused by severe portal hypertension; therefore, the treatment of portal hypertension is particularly important to prolong the survival of patients. The therapeutic efficacy and safety of transarterial chemoembolization (TACE) combined with a transjugular intrahepatic portosystemic shunt (TIPS) for HCC with esophageal and gastric variceal bleeding has been rarely reported. The aim of this study was to analyze the clinical efficacy of TIPS combined with TACE in the treatment of HCC with esophageal and gastric variceal bleeding. MATERIAL AND METHODS A total of 80 patients with HCC with esophageal and gastric variceal bleeding from July 2015 to November 2019 were retrospectively investigated. Clinical outcomes, biochemical indexes, and complications were compared between TIPS plus TACE and endoscopy plus TACE treatments. RESULTS Gastrointestinal rebleeding and adverse reactions (P<0.05) after TIPS combined with TACE were lower than that after endoscopy combined with TACE treatment. Furthermore, TIPS plus TACE had superior clinical outcomes than endoscopy plus TACE, which was associated with promising progression-free survival, overall survival, objective response rate, and disease control rate, and improved liver function. CONCLUSIONS TIPS combined with TACE was better than endoscopy combined with TACE in the treatment of patients with HCC and esophageal and gastric variceal bleeding. TIPS combined with TACE had a better therapeutic effect on improving liver function and prolonging patient survival time.

Trans-jugular intrahepatic portosystemic shunt in patients with hepatic cellular carcinoma: A preliminary study.

PURPOSE: To analyze the effects of trans-jugular intrahepatic portosystemic shunt (TIPS) on portal hypertension and liver function in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Thirteen patients with hemorrhage caused by portal hypertension and HCC who received TIPS and antitumor treatment were retrospectively analyzed. Trans-arterial chemoembolization, microwave ablation, target therapy, and immunetherapy or combined therapy were performed to treat HCC. Child-Pugh score was applied to estimate liver functions before and after TIPS. Shunting patency, overall survival (OS), and progression-free survival were analyzed. RESULTS: The median age was 58 (interquartile range: 52.5-62.5) years. The ratio with ascites before and after TIPS was 84.6% (11/13) and 7.7% (1/13), with P < 0.001. The ratio with Child-Pugh A before and after TIPS were 61.5% (8/13) and 84.6% (11/13) respectively, with P = 0.179. Mean portal vein pressure before and after TIPS was 27.85 ± 7.02 mmHg and 16.23 ± 6.61 mmHg, respectively, with P = 0.001. Two-year shunting patency rate was 61.5%. Median OS was 29.8 ± 11.5 months (95% confidence interval [CI] 22.8-36.7), and median progression-free survival was 20.2 ± 13.2 months (95% CI 12.2-28.1). CONCLUSION: TIPS could reduce ascites, down-regulate the Child-Pugh score, and give a chance for further anti-tumor therapy.

Efficacy and safety of transjugular intrahepatic portosystemic shunt combined with transcatheter embolization/chemoembolization in hepatocellular carcinoma with portal hypertension and arterioportal shunt.

OBJECTIVES: This study seeks to assess the efficacy and safety of transjugular intrahepatic portosystemic shunt (TIPS) combined with transarterial embolization/transarterial chemoembolization (TAE/TACE) in hepatocellular carcinoma (HCC) with portal hypertension and arterioportal shunt (APS). METHODS: Consecutive hospitalized patients having HCC accompanied by portal hypertension and APS were retrospectively analyzed. A total of 103 patients were enrolled. Of them, 26 patients were in Group A and 77 patients were in Group B according to the treatment protocol (Group A: TIPS plus TAE/TACE; Group B: TAE/TACE alone). The clinical outcomes and survival rate were compared between the two groups. RESULTS: The mean survival time in Group A and Group B were 14 mo and 9.9 mo, respectively, with statistical difference (p = 0.043). The immediate APS improvement rate was 95.2% in Group A and 91.9% in Group B, respectively, with no signficant difference (p = 1.000). However, the first follow-up consultation revealed that APS improvement rate in Group A was more obvious (66.7% vs 27.4%, p = 0.001). Objective response rate of HCC tended to be greater in Group A compared with Group B (65.4% vs 38.7%, p = 0.019). Liver function parameters significantly increased in Group A than those in Group B. After TIPS placement, the mean portal pressure gradient decreased from 32.61 ± 8.87 mmHg to 15.61 ± 8.15 mmHg, with significant difference (p = 0.000). The rate of absorption of ascites and control of variceal bleeding were statistically different between the two groups (p = 0.045 and 0.039, respectively). CONCLUSION: Our research suggests that TIPS combined with TAE/TACE seems to be safe and efficacious in patients with HCC accompanied by portal hypertension and APS, albeit may be accompanied by liver function damage.

Relaxin in hepatic fibrosis: What is known and where to head?

Relaxin (RLX) is a heterodimeric, polypeptide hormone that has natural anti-fibrotic activity in many organs. During the chronic liver injury, hepatic stellate cells (HSCs) are phenotypically transformed into myofibroblasts. This process is known as activation of HSCs. Activated HSCs play a central role in hepatic fibrosis. Quiescent HSCs were shown to express low levels of RLX receptors such as RXFP1 and RXFP2. Upon chronic liver injury, HSCs are activated and express high levels of the RLX receptors. ML290, an agonist of RXFP1 has been reported to have antifibrotic effect in vitro as well as in vivo. Serelaxin, a recombinant human RLX-2 treatment has reduced hepatic fibrosis and portal hypertension in experimental models due to its vasodilation properties by inducing intrahepatic nitric oxide level. Serelaxin has also produced a neutral effect when studied against human cirrhosis-related portal hypertension in clinical trials. RLX is a potent collagen synthesis inhibitor and it has extracellular matrix (ECM) remodeling properties by promoting matrix metalloproteinases and downregulating expression of metalloproteinases inhibitors. Available reports suggest that RLX could induce ECM remodeling and suppress the profibrogenic transforming growth factor-ß signaling and thereby regress hepatic fibrosis. Though RLX has natural antifibrotic activity, its antifibrotic molecular mechanisms especially in hepatic fibrosis condition are not reported. This review exclusively focuses antifibrotic effect of RLX on hepatic fibrosis.

Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality.

BACKGROUND & AIMS: Distinct prognostic stages of advanced chronic liver disease (ACLD) are defined by severity of portal hypertension (PH) and the presence/absence of clinical complications. We characterised the degree of liver dysfunction, PH, and systemic inflammation across the distinct prognostic stages and assessed their relative impact on decompensation and mortality. METHODS: A single-centre, prospective cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement between 01/2017 and 08/2019 were classified into 6 prognostic stages: mild PH (HVPG 6-9 mmHg, S0), clinically significant PH (HVPG ≥10 mmHg without varices, S1), presence of varices (S2), history of variceal bleeding (S3), first non-bleeding decompensation (S4), and further decompensation (S5). The model for end-stage liver disease (MELD), C-reactive protein (CRP), and IL-6 levels were assessed in relation to their predictive value for decompensation and death. RESULTS: Among 168 ACLD patients 78 had compensated (cACLD, S0 = 13; S1 = 21; S2 = 44) and 90 had decompensated (dACLD, S3 = 10; S4 = 58; S5 = 22) disease. MELD increased across all stages (p <0.001), whereas HVPG mostly increased within cACLD substages. Significant increases in CRP and IL-6 levels were only noted across dACLD substages. IL-6 was an independent predictor of decompensation at 1-year follow-up in cACLD (hazard ratio [HR] 1.06, 95% CI 1.01-1.10; p = 0.013). In dACLD patients, IL-6 levels predicted death/transplantation after 1-year of follow-up (HR 1.02, 95% CI 1.01-1.03; p = 0.004). CONCLUSION: HVPG progression occurs mostly in cACLD patients, whereas systemic inflammation, as reflected by IL-6 levels, only increases substantially across dACLD stages. IL-6 levels correlate with the risk of first decompensation in cACLD and of death/transplantation in dACLD patients. LAY SUMMARY: Patients with advanced chronic liver disease (ACLD; i.e. liver cirrhosis) have a certain risk of mortality according to their stage of disease. Progression of disease is greatly influenced by increased pressure in the portal venous system (i.e. portal hypertension) and occurrence of clinical complications (i.e. decompensation). Our study demonstrates that systemic inflammation markedly increases across highest disease stages, and the inflammation biomarker IL-6 in blood may specifically indicate risk of disease progression in patients with ACLD. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT03267615).