Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms

Abstract

Portal hypertension in cirrhosis is defined as an increase in the portal pressure gradient (PPG) between the portal and hepatic veins and is traditionally estimated by the hepatic venous pressure gradient (HVPG), which is the difference in pressure between the free-floating and wedged positions of a balloon catheter in the hepatic vein. By convention, HVPG≥10 mmHg indicates clinically significant portal hypertension, which is associated with adverse clinical outcomes. Nonalcoholic fatty liver disease (NAFLD) is a common disorder with a heterogeneous clinical course, which includes the development of portal hypertension. There is increasing evidence that portal hypertension in NAFLD deserves special considerations. First, elevated PPG often precedes fibrosis in NAFLD, suggesting a bidirectional relationship between these pathological processes. Second, HVPG underestimates PPG in NAFLD, suggesting that portal hypertension is more prevalent in this condition than currently believed. Third, cellular mechanoresponses generated early in the pathogenesis of NAFLD provide a mechanistic explanation for the pressure-fibrosis paradigm. Finally, a better understanding of liver mechanobiology in NAFLD may aid in the development of novel pharmaceutical targets for prevention and management of this disease.

Keywords: Hepatic vascular resistance; Hepatic venous pressure gradient; Mechanobiology; Mechanotransduction; Portal venous pressure; Sinusoidal microcirculation.

Fig. 1. Portal pressure measurement in NAFLD.

Schematic illustration of sinusoidal circulation and a retrograde balloon-tipped catheter inserted into a hepatic vein branch for the assessment of portal venous pressure (PVP) by the wedged hepatic venous pressure (WHVP) in various liver conditions. (A) WHVP has an excellent correlation with directly measured PVP in cirrhosis, where the wedged catheter detects upstream pressure transmitted by a static vascular column created between the portal and hepatic veins. (B) In advanced cirrhosis, increased hepatic vascular resistance (HVR) may cause reverse (hepatofugal) blood flow in the portal vein, resulting in overestimation of PVP by WHVP. (C) By contrast, PVP is underestimated by WHVP in nonalcoholic fatty liver disease (NAFLD), which is likely due to the presence of intact intersinusoidal channels. These anastomoses allow pressure equilibration with adjacent areas in the noncirrhotic liver and may persist in cirrhotic NAFLD, accounting for diminished accuracy of indirect PVP assessment by WHVP. It has also been speculated that increased presinusoidal resistance in NAFLD may contribute to the underestimation of PVP. White arrows indicate the direction of blood flow in the portal vein. NAFLD, nonalcoholic fatty liver disease; PVP, portal venous pressure; WHVP, wedged hepatic venous pressure.

Fig. 2. Etiology of increased hepatic vascular resistance in NAFLD.

Schematic illustration of extraluminal and intraluminal causes of impaired sinusoidal flow between the portal tract and the pericentral region that result in increased hepatic vascular resistance, which is the primary factor in the development of sinusoidal portal hypertension in advanced chronic liver disease. Barriers to sinusoidal flow may also be classified as structural and functional factors. Please see details in the main text. NAFLD, nonalcoholic fatty liver disease.

Fig. 3. Overview of cellular mechanotransduction.

Mechanotransduction is a fundamental biological process by which cells perceive their physical environment and convert mechanical information into biological response. Key components of mechanotransduction include: physical forces that serve as mechanical cues; cell surface mechanosensors at interfaces of cells with other cells, bodily fluids, and ECM; intracellular spread of mechanical information via biochemical intermediates (mechanosignaling) and via the physical continuum between the cell membrane, the cytoskeleton, and the nucleus (mechanotransmission); and nuclear integration of this complex information with generation of a variety of mechanoresponses. In NAFLD, mechanoresponses have been implicated in disease progression. ECM, extracellular matrix, NAFLD, nonalcoholic fatty liver disease.

Fig. 4. Sinusoidal pressure-liver fibrosis paradigm.

Schematic illustration of the bidirectional relationship between subclinical portal hypertension and fibrosis, implicating the contribution of mechanocrine signals, such as increased sinusoidal pressure, in the development and progression of fibrosis through cell-cell communication and self-amplification mechanisms, ultimately resulting in clinically significant portal hypertension. Further research is needed to explore the cellular and molecular details of this process.