The Pathophysiology of Portal Hypertension.

This article reviews the pathophysiology of portal hypertension that includes multiple mechanisms internal and external to the liver. This article starts with a review of literature describing the cellular and molecular mechanisms of portal hypertension, microvascular thrombosis, sinusoidal venous congestion, portal angiogenesis, vascular hypocontractility, and hyperdynamic circulation. Mechanotransduction and the gut-liver axis, which are newer areas of research, are reviewed. Dysfunction of this axis contributes to chronic liver injury, inflammation, fibrosis, and portal hypertension. Sequelae of portal hypertension are discussed in subsequent studies.

Hepatic Venous Pressure Gradient: Measurement and Pitfalls.

Measurement of hepatic venous pressure gradient (HVPG) effectively mirrors the severity of portal hypertension (PH) and offers valuable insights into prognosis of liver disease, including the risk of decompensation and mortality. Additionally, HVPG offers crucial information about treatment response to nonselective beta-blockers and other medications, with its utility demonstrated in clinical trials in patients with PH. Despite the widespread dissemination and validation of noninvasive tests, HVPG still holds a significant role in hepatology. Physicians treating patients with liver diseases should comprehend the HVPG measurement procedure, its applications, and how to interpret the results and potential pitfalls.

Pulmonary Complications of Portal Hypertension.

Portopulmonary hypertension (POPH), hepatopulmonary syndrome, and hepatic hydrothorax constitute significant complications of portal hypertension, with important implications for management and liver transplantation (LT) candidacy. POPH is characterized by obstruction and remodeling of the pulmonary resistance arterial bed. Hepatopulmonary syndrome is the most common pulmonary vascular disorder, characterized by intrapulmonary vascular dilatations causing impaired gas exchange. LT may improve prognosis in select patients with POPH. LT is the only effective treatment of hepatopulmonary syndrome. Hepatic hydrothorax is defined as transudative pleural fluid accumulation that is not explained by primary cardiopulmonary or pleural disease. LT is the definitive cure for hepatic hydrothorax.

Noninvasive Assessment of Portal Hypertension.

The progressive use of noninvasive tests (NITs) has changed the way hepatologists diagnose and manage patients with chronic liver disease, mainly because of their easiness to use and the ability to be repeated during follow-up. Liver stiffness measurement is the NIT with more scientific evidence. NITs have demonstrated to be useful to detect not only liver fibrosis but also the presence of clinically significant portal hypertension. Moreover, current evidence supports they can also be useful to evaluate the prognosis of patients with chronic liver disease.

Pharmacologic Treatment of Portal Hypertension.

Portal hypertension is the key mechanism driving the transition from compensated to decompensated cirrhosis. In this review, the authors described the pathophysiology of portal hypertension in cirrhosis and the rationale of pharmacologic treatment of portal hypertension. We discussed both etiologic and nonetiologic treatment of portal hypertension and the specific clinical scenarios how nonselective beta-blocker can be used in patients with cirrhosis. Finally, the authors summarized the evidence for emerging alternatives for portal hypertension in patients with cirrhosis.

Renal Complications in Portal Hypertension.

Acute kidney injury (AKI) is a common complication among patients with decompensated cirrhosis and its development is associated with worse prognosis in terms of survival. Patients with decompensated cirrhosis may develop a unique type of AKI, known as hepatorenal syndrome (HRS-AKI), characterized by marked impairment of kidney function due to haemodynamic changes that occur in late stages of liver cirrhosis. Besides, patients with cirrhosis also may develop chronic alterations of kidney function (chronic kidney disease, CKD), the incidence of which is increasing markedly and may be associated with clinical complications. The aim of this review is to provide the reader with an update of the most relevant aspects of alterations of kidney function in patients with cirrhossi that may be useful for theri clinical practice.

Cerebral Aspects of Portal Hypertension: Hepatic Encephalopathy.

Portal hypertension has cerebral consequences via its causes and complications, namely hepatic encephalopathy (HE), a common and devastating brain disturbance caused by liver insufficiency and portosystemic shunting. The pathogenesis involves hyperammonemia and systemic inflammation. Symptoms are disturbed personality and reduced attention. HE is minimal or grades I to IV (coma). Bouts of HE are episodic and often recurrent. Initial treatment is of events that precipitated the episode and exclusion of nonhepatic causes. Specific anti-HE treatment is lactulose. By recurrence, rifaximin is add-on. Anti-HE treatment is efficacious also for prophylaxis, but emergence of HE marks advanced liver disease and a dismal prognosis.

Enhancing liver cirrhosis varices and CSPH risk prediction with spleen stiffness measurement using 100-Hz probe.

Managing complications of liver cirrhosis such as varices needing treatment (VNT) and clinically significant portal hypertension (CSPH) demands precise and non-invasive diagnostic methods. This study assesses the efficacy of spleen stiffness measurement (SSM) using a 100-Hz probe for predicting VNT and CSPH, aiming to refine diagnostic thresholds. A retrospective analysis was conducted on 257 cirrhotic patients, comparing the diagnostic performance of SSM against traditional criteria, including Baveno VII, for predicting VNT and CSPH. The DeLong test was used for statistical comparisons among predictive models. The success rate of SSM@100 Hz was 94.60%, and factors related to SSM failure were high body mass index and small spleen volume or length. In our cohort, the identified SSM cut-off of 38.9 kPa, which achieved a sensitivity of 92% and a negative predictive value (NPV) of 98% for detecting VNT, is clinically nearly identical to the established Baveno threshold of 40 kPa. The predictive capability of the SSM-based model for VNT was superior to the LSM ± PLT model (p = 0.017). For CSPH prediction, the SSM model notably outperformed existing non-invasive tests (NITs), with an AUC improvement and significant correlations with HVPG measurements (obtained from 49 patients), highlighting a correlation coefficient of 0.486 (p < 0.001) between SSM and HVPG. Therefore, incorporating SSM into clinical practice significantly enhances the prediction accuracy for both VNT and CSPH in cirrhosis patients, mainly due to the high correlation between SSM and HVPG. SSM@100 Hz can offer valuable clinical assistance in avoiding unnecessary endoscopy in these patients.

The autoimmune landscape of Porto-sinusoidal vascular disorder: What the rheumatologist needs to know.

Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions of the portal venules and sinusoids with clinical manifestations ranging from non-specific abnormalities in serum liver enzymes to clinically overt portal hypertension and related complications. Several reports have documented cases of PSVD in patients with systemic autoimmune conditions, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. It is of note that these diseases share specific pathophysiological features with PSVD, including endothelial dysfunction, vascular inflammation, and molecular signatures. This narrative review aims to summarize the current knowledge on the association between PSVD and systemic autoimmune diseases, emphasizing the importance of promptly recognizing this condition in the rheumatological practice, and highlighting the key aspects where further research is necessary from both pathogenic and clinical perspectives.

Transjugular intrahepatic portosystemic shunt: A promising therapy for recompensation in cirrhotic patients.

This is a retrospective study focused on recompensation after transjugular intrahepatic portosystemic shunt (TIPS) procedure. The authors confirmed TIPS could be a treatment for recompensation of patients with cirrhosis according to Baveno VII. The paper identified age and post-TIPS portal pressure gradient as independent predictors of recompensation in patients with decompensated cirrhosis after TIPS. These results need to be validated in a larger prospective cohort.

[Liver cirrhosis as a multisystem disease]. / Die Leberzirrhose als Multisystemerkrankung.

In recent years, the pathophysiological concept of decompensated liver cirrhosis has undergone significant changes. Until a few years ago, the focus of pathophysiological considerations was on the hyperdynamic circulation resulting from portal hypertension. In recent years, emerging data suggests that increased bacterial translocation leading to systemic inflammation plays an important role in patients with decompensated liver cirrhosis. This inflammation affects a variety of extrahepatic organs. Nowadays, liver cirrhosis is considered not only a condition confined to the liver but rather an inflammatory-triggered multisystem disease. The existing inflammation serves as the common pathophysiological explanation for the diverse impact of liver cirrhosis on several extrahepatic organs. It plays a significant role in the development of conditions such as hepatorenal syndrome, cirrhotic cardiomyopathy, hepatopulmonary syndrome, hepatic encephalopathy, and even in the emergence of cirrhosis-associated relative adrenal insufficiency. These new pathophysiological insights hold clinical significance as they influence the prophylaxis and treatment of patients with decompensated liver cirrhosis.

Non-Invasive Diagnostic Tests for Portal Hypertension in Patients with HBV- and HCV-Related Cirrhosis: A Comprehensive Review.

Clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease indicates an increased risk of decompensation and death. While invasive methods like hepatic venous-portal gradient measurement is considered the gold standard, non-invasive tests (NITs) have emerged as valuable tools for diagnosing and monitoring CSPH. This review comprehensively explores non-invasive diagnostic modalities for portal hypertension, focusing on NITs in the setting of hepatitis B and hepatitis C virus-related cirrhosis. Biochemical-based NITs can be represented by single serum biomarkers (e.g., platelet count) or by composite scores that combine different serum biomarkers with each other or with demographic characteristics (e.g., FIB-4). On the other hand, liver stiffness measurement and spleen stiffness measurement can be assessed using a variety of elastography techniques, and they can be used alone, in combination with, or as a second step after biochemical-based NITs. The incorporation of liver and spleen stiffness measurements, alone or combined with platelet count, into established and validated criteria, such as Baveno VI or Baveno VII criteria, provides useful tools for the prediction of CSPH and for ruling out high-risk varices, potentially avoiding invasive tests like upper endoscopy. Moreover, they have also been shown to be able to predict liver-related events (e.g., the occurrence of hepatic decompensation). When transient elastography is not available or not feasible, biochemical-based NITs (e.g., RESIST criteria, that are based on the combination of platelet count and albumin levels) are valid alternatives for predicting high-risk varices both in patients with untreated viral aetiology and after sustained virological response. Ongoing research should explore novel biomarkers and novel elastography techniques, but current evidence supports the utility of routine blood tests, LSM, and SSM as effective surrogates in diagnosing and staging portal hypertension and predicting patient outcomes.

Pathophysiology of Hepatorenal Syndrome.

Hepatorenal syndrome type 1 (HRS-1) is a unique form of acute kidney injury that affects individuals with decompensated cirrhosis with ascites. The primary mechanism leading to reduction of kidney function in HRS-1 is hemodynamic in nature. Cumulative evidence points to a cascade of events that led to a profound reduction in kidney perfusion. A state of increased intrahepatic vascular resistance characteristic of advanced cirrhosis and portal hypertension is accompanied by maladaptive peripheral arterial vasodilation and reduction in systemic vascular resistance and mean arterial pressure. As a result of a fall in effective arterial blood volume, there is a compensatory activation of the sympathetic nervous system and the renin-angiotensin system, local renal vasoconstriction, loss of renal autoregulation, decrease in renal blood flow, and ultimately a fall in glomerular filtration rate. Systemic release of nitric oxide stimulated by the fibrotic liver, bacterial translocation, and inflammation constitute key components of the pathogenesis. While angiotensin II and noradrenaline remain the critical mediators of renal arterial and arteriolar vasoconstriction, other novel molecules have been recently implicated. Although the above-described mechanistic pathway remains the backbone of the pathogenesis of HRS-1, other noxious elements may be present in advanced cirrhosis and likely contribute to the renal impairment. Direct liver-kidney crosstalk via the hepatorenal sympathetic reflex can further reduce renal blood flow independently of the systemic derangements. Tense ascites may lead to intraabdominal hypertension and abdominal compartment syndrome. Cardio-hemodynamic processes have also been increasingly recognized. Porto-pulmonary hypertension, cirrhotic cardiomyopathy, and abdominal compartment syndrome may lead to renal congestion and complicate the course of HRS-1. In addition, a degree of ischemic or toxic (cholemic) tubular injury may overlap with the underlying circulatory dysfunction and further exacerbate the course of acute kidney injury. Improving our understanding of the pathogenesis of HRS-1 may lead to improvements in therapeutic options for this seriously ill population.

Prospective evaluation of patients with non-cirrhotic portal hypertension: A single centre study.

BACKGROUND: Non-cirrhotic portal hypertension (NCPH) is a spectrum of liver diseases, including porto-sinusoidal vascular disorder, with portal hypertension (PH) in the absence of cirrhosis. The natural history and diagnostic approach to NCPH are not well understood. AIM: We aimed to evaluate disease progression and outcomes in NCPH. METHODS: Patients with or at risk for NCPH were enrolled in a single centre prospective study; two groups were formed based on the presence of specific features of PH, such as varices, collaterals, portal hypertensive gastropathy or portal hypertensive bleeding. All participants underwent a baseline liver biopsy. Liver stiffness measurement (LSM), and imaging were repeated every 6-12 months. RESULTS: Fifteen patients without specific features of PH (Group I), and 35 patients with specific features (Group II) were enrolled. The median follow-up time was 50 months. Group II had higher hepatic venous pressure gradients, non-invasive measures of PH and a lower platelet count (PLT) when compared to Group I. Rates of survival and decompensation were similar in both groups. Patients with PLT ≤100 K/mcL had lower survival compared to those with PLT >100 K/mcL. Patients with LSM ≥10 kPa had lower survival and survival without decompensation when compared to patients with LSM <10 kPa. CONCLUSIONS: Patients irrespective of specific features of PH had similar survival or survival without decompensation. Patients without specific features are at risk for disease progression and should be monitored closely. Thrombocytopenia and increased LSM are associated with severe forms of liver disease, which are strongly associated with outcomes.

Evaluation and clinical significance of contrast-enhanced ultrasound on changes in liver blood flow perfusion after TIPS surgery.

To investigate the clinical value of contrast-enhanced ultrasound in the prediction of hepatic encephalopathy (HE) in patients with hepatitis B cirrhosis after intrahepatic portal-systemic shunt via jugular vein. In this retrospective study, we collected data from 75 patients with hepatitis B, cirrhosis, and portal hypertension who underwent jugular intrahepatic portosystemic shunt from February 2019 to February 2022. The diagnostic instrument used was the TOSHIBA Aplio500 color Doppler ultrasound with contrast-enhanced ultrasound capabilities. The trial group comprised 20 patients with HE within 3 months postsurgery, while the control group (CG) included 55 patients without HE within the same postoperative period. All patients underwent various examinations before and within 48 hours after surgery, including observation of liver and spleen size and stent position, as well as assessment of blood flow direction in portal and hepatic veins. Subsequently, contrast-enhanced ultrasound was employed to examine and observe perfusion changes of contrast agents in hepatic veins, hepatic arteries, and portal veins (PV). Changes in PV pressure gradient, intrahepatic, and stent blood flow perfusion (BFP) were explored in both postoperative trials and CGs. The trial group exhibited higher BFP volume, PV pressure gradient difference, and percentage decrease compared to the CG. A weak positive correlation was observed between blood flow within the liver stent and PV pressure gradient difference, as well as the percentage decrease in PV pressure gradient. The correlation coefficient between blood flowing perfusion volume within the stent and the difference in PV pressure gradient was R = 0.415 (P = .000). The correlating coefficient between BFP amount within the stent and the percentage decrease in PV pressure gradient was R = 0.261 (P = .027). The area under the receiver operating characteristic curve for stent perfusion volume, difference in PV pressure gradient, and percentage decrease in PV pressure gradient was 0.691, 0.759, and 0.742, respectively. An increase in PV pressure gradient accelerates blood flow within the stent, predisposing to HE. Changes in hepatic BFP following transjugular intrahepatic portosystemic shunt can effectively predict the occurrence of HE, demonstrating significant clinical relevance.

Pathophysiology and therapeutic options for cirrhotic portal hypertension.

Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy. Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome. Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension. Data also suggest that the phenotype of hepatic cells could be further impaired due to the altered mechanical properties of the cirrhotic liver itself, creating a deleterious cycle that worsens portal hypertension in the advanced stages of liver disease. In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options.

Portal hypertension-like pattern in coronavirus disease 2019 acute respiratory distress syndrome.

OBJECTIVES: Although respiratory failure is the most common feature in coronavirus disease 2019 (COVID-19), abdominal organ involvement is likewise frequently observed. To investigate visceral and thoracic circulation and abdominal organ damage in COVID-19 patients. MATERIALS AND METHODS: A monocentric observational study was carried on. In COVID-19 patients affected by acute respiratory distress syndrome (ARDS) (n = 31) or mild pneumonia (n = 60) thoracoabdominal circulation was evaluated using Doppler-ultrasound and computed tomography. The study also included non-COVID-19 patients affected by ARDS (n = 10) or portal hypertension (n = 10) for comparison of the main circulatory changes. RESULTS: Patients affected by COVID-19 ARDS showed hyperdynamic visceral flow and increased portal velocity, hepatic artery resistance-index, and spleen diameter relative to those with mild-pneumonia (p = 0.001). Splanchnic circulatory parameters significantly correlated with the main respiratory indexes (p < 0.001) and pulmonary artery diameter (p = 0.02). The chest and abdominal vascular remodeling pattern of COVID-19 ARDS patients resembled the picture observed in the PH group, while differed from that of the non-COVID ARDS group. A more severe COVID-19 presentation was associated with worse liver dysfunction and enhanced inflammatory activation; these parameters both correlated with abdominal (p = 0.04) and chest imaging measures (p = 0.03). CONCLUSION: In COVID-19 ARDS patients there are abdominal and lung vascular modifications that depict a portal hypertension-like pattern. The correlation between visceral vascular remodeling, pulmonary artery enlargement, and organ damage in these critically ill patients is consistent with a portal hyperlfow-like syndrome that could contribute to the peculiar characteristics of respiratory failure in these patients. CLINICAL RELEVANCE STATEMENT: our data suggest that the severity of COVID-19 lung involvement is directly related to the development of a portal hyperflow-like syndrome. These observations should help in defining the need for a closer monitoring, but also to develop dedicated therapeutic strategies.

Review article: Recent advances in ascites and acute kidney injury management in cirrhosis.

BACKGROUND: Better understanding of disease pathophysiology has led to advances in managing ascites and its associated complications including hepatorenal syndrome-acute kidney Injury (HRS-AKI), especially medicinal and interventional advances. AIM: To review the latest changes in the management of ascites and HRS-AKI. METHODS: A literature search was conducted in Pubmed, using the keywords cirrhosis, ascites, renal dysfunction, acute kidney injury, hepatorenal syndrome, beta-blockers, albumin, TIPS and vasoconstrictors, including only publications in English. RESULTS: The medicinal advances include earlier treatment of clinically significant portal hypertension to delay the onset of ascites and the use of human albumin solution to attenuate systemic inflammation thus improving the haemodynamic changes associated with cirrhosis. Furthermore, new classes of drugs such as sodium glucose co-transporter 2 are being investigated for use in patients with cirrhosis and ascites. For HRS-AKI management, newer pharmacological agents such as vasopressin partial agonists and relaxin are being studied. Interventional advances include the refinement of TIPS technique and patient selection to improve outcomes in patients with refractory ascites. The development of the alfa pump system and the study of outcomes associated with the use of long-term palliative abdominal drain will also serve to improve the quality of life in patients with refractory ascites. CONCLUSIONS: New treatment strategies emerged from better understanding of the pathophysiology of ascites and HRS-AKI have shown improved prognosis in these patients. The future will see many of these approaches confirmed in large multi-centre clinical trials with the aim to benefit the patients with ascites and HRS-AKI.

Obliteration of portal venules contributes to portal hypertension in biliary cirrhosis.

The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, n = 63), primary biliary cholangitis (PBC, n = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, n = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl4) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, p < 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl4 models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl4 model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the 'territory' originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.