The main stages of advanced chronic liver disease (ACLD) are compensated (cACLD) and decompensated (dACLD), which can be followed by a stage of further decompensation. Clinically significant portal hypertension (CSPH) is a key determinant of disease progression. a, cACLD is a long stage with a low mortality rate. cACLD can be delineated into substages based on hepatic venous pressure gradient (HVPG) measures or endoscopy. b, dACLD is a short-stage that is associated with high mortality. It is often substaged based on manifestations at presentation (such as ascites, acute variceal bleeding (AVB) and hepatic encephalopathy (HE)) or whether hospital admission is needed. c, Further decompensation is a very short stage that is associated with high mortality. Several severe complications, such as spontaneous bacterial peritonitis (SBP) and other bacterial infections, acute kidney injury (AKI) and hepatorenal syndrome (HRS), hepatocellular carcinoma (HCC), portal vein thrombosis (PVT) or acute-on-chronic liver failure (ACLF), can occur. Some of these complications, such as bacterial infections, HCC, PVT or ACLF can be present at earlier stages (cACLD or dACLD) and may trigger progression from one stage to the next.
Compensated CLD
a, Increased intrahepatic resistance, associated with both structural and dynamic changes, is a primary factor leading to portal hypertension, which is a key determinant of the progression from compensated advanced chronic liver disease (cACLD) to decompensated ACLD (dACLD). b, When hepatic venous pressure gradient (HVPG) reaches a value of 10 mmHg, portal–systemic shunts (PSS) and varices begin to form, due to the combined effect of the increased portal pressure and vascular endothelial growth factor (VEGF)-driven angiogenesis. c, Splanchnic vasodilation is an adaptive response, characterized by increased levels of VEGF and nitric oxide (NO) among others, which leads to an increased portal blood inflow contributing to aggravation of portal hypertension. There is reduced sensitivity to vasoconstrictors and altered intestinal vascular barrier function that results in translocation of intestinal bacteria and bacterial products from the intestinal lumen into the portal circulation and splanchnic lymph nodes. d, Splanchnic vasodilation results in effective hypovolaemia causing increased heart rate and cardiac output and activating vasoactive neurohumoral factors. This causes renal sodium and water retention, expanding blood volume. A particularly relevant mechanism of disease progression is systemic inflammation promoted by bacterial translocation, which contributes to worsening ACLD mainly after decompensation. The discontinuous arrows indicate effects on portal pressure that are not direct, but are instead mediated by aggravating liver disease through increased intrahepatic resistance and/or increased portal blood inflow. Portal hypertension and liver failure lead to decompensating events, such as ascites, variceal bleeding and hepatic encephalopathy. Failure of homeostatic mechanisms or aggravation of liver disease leads to other complications such as acute-on-chronic liver failure, acute kidney injury/hepatorenal syndrome or spontaneous bacterial peritonitis, all increasing the risk of death. Systemic vasodilation may also cause pulmonary ventilation or perfusion mismatch, which can lead to hepatopulmonary syndrome (HPS). Portopulmonary hypertension (PoPH), characterized by pulmonary vasoconstriction, may also occur.
CO, carbon monoxide; CSPH, clinically significant portal hypertension; GFR, glomerular filtration rate; HS, hydrogen sulfide; IVC, inferior vena cava.
a, Noninvasive criteria to identify clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease (cACLD). b, Invasive and noninvasive criteria for the prediction of decompensation. dALCD, decompensated ACLD; ELF, enhanced liver fibrosis; FIB-4, fibrosis 4; HVPG, hepatic venous pressure gradient; LSM, liver stiffness measurement; MRE, magnetic resonance elastography; NIT, noninvasive test; SSM, splenic stiffness measurement; VITRO, von Willebrand factor antigen to platelet ratio. aViral and/or alcohol-related liver disease or non-obese (BMI <30 kg/m2) metabolic dysfunction-associated steatotic liver disease. bSSM has been validated to reduce the grey zone (liver stiffness 15–24.9 kPa and/or platelet count <150 × 109/l) and improve the precision of detecting CSPH (performing endoscopy (to identify varices) in patients with indeterminate findings from NITs may also improve diagnostic performance and risk stratification).