Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges

Abstract

Portal hypertension (PH) has traditionally been observed as a consequence of significant fibrosis and cirrhosis in advanced non-alcoholic fatty liver disease (NAFLD). However, recent studies have provided evidence that PH may develop in earlier stages of NAFLD, suggesting that there are additional pathogenetic mechanisms at work in addition to liver fibrosis. The early development of PH in NAFLD is associated with hepatocellular lipid accumulation and ballooning, leading to the compression of liver sinusoids. External compression and intra-luminal obstacles cause mechanical forces such as strain, shear stress and elevated hydrostatic pressure that in turn activate mechanotransduction pathways, resulting in endothelial dysfunction and the development of fibrosis. The spatial distribution of histological and functional changes in the periportal and perisinusoidal areas of the liver lobule are considered responsible for the pre-sinusoidal component of PH in patients with NAFLD. Thus, current diagnostic methods such as hepatic venous pressure gradient (HVPG) measurement tend to underestimate portal pressure (PP) in NAFLD patients, who might decompensate below the HVPG threshold of 10 mmHg, which is traditionally considered the most relevant indicator of clinically significant portal hypertension (CSPH). This creates further challenges in finding a reliable diagnostic method to stratify the prognostic risk in this population of patients. In theory, the measurement of the portal pressure gradient guided by endoscopic ultrasound might overcome the limitations of HVPG measurement by avoiding the influence of the pre-sinusoidal component, but more investigations are needed to test its clinical utility for this indication. Liver and spleen stiffness measurement in combination with platelet count is currently the best-validated non-invasive approach for diagnosing CSPH and varices needing treatment. Lifestyle change remains the cornerstone of the treatment of PH in NAFLD, together with correcting the components of metabolic syndrome, using nonselective beta blockers, whereas emerging candidate drugs require more robust confirmation from clinical trials.

Keywords: Endothelial dysfunction; Hepatic venous pressure gradient; Mechanotransduction; Non-alcoholic fatty liver disease; Portal hypertension.

Figure 1

Development of portal hypertension in non-alcoholic fatty liver disease. A: Ballooning of hepatocytes are caused by excessive lipid uptake. Pathogen-associated molecular patterns (PAMPs), along with other products of intestinal dysbiosis, arrive at the liver via the portal blood flow and act on liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) from the luminal side of the sinusoid; B: Excessive lipid accumulation in hepatocytes and PAMPs trigger inflammation by cytokine secretion and immune cell infiltration; C: Immune cell infiltration leads to steatonecrosis, apoptosis and hepatic stellate cells (HSCs) activation; D: Hepatocytes dying by steatonecrosis and apoptosis release damage-associated molecular pattern molecules, causing the activation of KCs and subsequently HSCs. The destruction of lipid-laden hepatocytes incites lipid embolus liberation in the sinusoidal lumen. Lipid droplets participate in lipogranuloma formation, which interferes with sinusoidal blood flow and results in elevated intrahepatic vascular resistance (IHVR); E: Activated HSCs transdifferentiate to proliferative, contractile and collagen-producing myofibroblasts which secrete vascular endothelial growth factor (VEGF) and inflammatory chemokines such as neutrophil chemotactic chemokines and synthesize α-smooth muscle actin. Notch-dependent neutrophil chemotaxis is also activated by the stretching of LSECs caused by the enlargement of hepatocytes and the liver; F: Stretch-activated LSECs promote the creation of neutrophil extracellular traps (NETs), web-like structures composed primarily of DNA-histone complexes originating from neutrophils. NETs contribute to the creation of microthrombi; G: The activation of HSCs is a key event mediating the elevation of IHVR by contracting around the sinusoid. IHVR is also elevated by extrasinusoidal compression caused by swollen steatotic hepatocytes and increased shear stress produced by intraluminal obstacles such as NETs; H: Sinusoid capillarization and the endothelial dysfunction of LSECs are important events that promote the activation of HSCs and KCs, initiating liver fibrosis and inflammation promotion; I: Myofibroblasts and mechanical forces lead to collagen and hyaluronic acid deposition in the space of Disse, causing an excessive increase in extracellular matrix (ECM) stiffness. The cross-linking of ECM proteins and collagen leads to the formation of perisinusoidal fibrosis; J: Angiogenesis occurs as liver fibrosis progresses. Stretched lipid-laden hepatocytes, HSCs, portal myofibroblasts and macrophages stimulate angiogenesis by producing a greater amount of VEGF and other similar mediators as a response to shear stress, hypoxia and inflammation. qHSC: Quiescent hepatic stellate cell; aHSCs: Activated hepatic stellate cells; DAMPs: Damage-associated molecular pattern molecules; αSMA: α-smooth muscle actin; FA: Fatty acid; HA: Hyaluronic acid; CXCL: Chemokine (C-X-C motif) ligand 1; α-SMA: Alpha-smooth muscle actin; MPO: Myeloperoxidase; PAI-1: Plasminogen activator inhibitor-1; ATX: Autotaxin; LPA: Lysophosphatidic acid.

Figure 2

Development of endothelial dysfunction and capillarization. A: The initial step in the development of endothelial dysfunction is the reduced production of nitric oxide (NO) caused by decreased endothelial nitric-oxide synthase (eNOS) activity and the low response of liver sinusoidal endothelial cells (LSECs) to acetylcholine; B: Reduced NO bioavailability can be caused by insulin resistance, heightened intracellular levels of reactive oxygen species and the formation of eNOS, paracrine and competitive inhibitors such as asymmetric dimethylarginine; C: Low levels of NO paired with increased endothelin 1 (ET-1) synthesis lead to sinusoidal contraction through the activation of perisinusoidal hepatic stellate cells (HSCs), resulting in elevated intrahepatic vascular resistance and the elevation of portal pressure; D: As a response to shear stress, hypoxia and inflammation, lipid-laden hepatocytes, cholangiocytes, LSECs, activated HSCs and Kupffer cells stimulate angiogenesis by producing an excessive amount of vascular endothelial growth factor (VEGF); E: Hypoxia in fatty liver is induced by mechanical pressure on sinusoids and increased lipid metabolism. Elevated VEGF concentrations lead to the promotion of angiogenesis and fibrogenesis by the increased fibrogenic functions of HSC, as well as LSEC capillarization and the secretion of hepatocyte growth factor. Capillarization, marked by the formation of the basal membrane and loss of fenestration, occurs as a result of LSECs exposure to lipid accumulation in parenchymal cells and a great amount of circulating lipids in the blood; F: As a response to excessive lipid exposure, LSECs express lipid-induced adhesion molecules (VCAM-1, VAP-1, etc.), activate Kupffer cells through the secretion of pro-inflammatory cytokines and induce leukocyte recruitment and their translocation into the liver parenchyma; G: Capillarized LSECs also activate HSCs through the release of angiocrine signals such as VEGF, transforming growth factor and hedgehog signals. Activated HSCs begin to deposit extracellular matrix, which increases tissue stiffness, further stimulating HSC activation; H: Shear stress downregulates the expression of ET-1 via Krüppel-like factors 2 (KLF2) activation. LSECs overexpress KLF2 to maintain HSCs in a quiescent state as a compensatory mechanism to manage vascular dysfunction. Unfortunately, this is an insufficient mechanism for preventing portal hypertension development. ACh: Acetylcholine; aHSC: Activated hepatic stellate cell; KC: Kupffer cell; ROS: Reactive oxygen species; HIF: Hypoxia-inducible factor; M-CSF: Macrophage colony-stimulating factor; MCP1: Monocyte chemoattractant protein-1; IR: Insulin resistance; ADMA: Asymmetric dimethylarginine; HGF: Hepatocyte growth factor; VCAM-1: Vascular cell adhesion molecule 1; VAP-1: Vascular adhesion protein-1; IL-1: Interleukin-1; IL-6: Interleukin-6; TNFα: Tumor necrosis factor α; TGF-β: Transforming growth factor; Hh: Hedgehog signals.