title: Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis.
abstract: Independent of their etiology, all chronic liver diseases ultimately lead to liver cirrhosis, which is a major health problem worldwide. The underlying molecular mechanisms are still poorly understood and no efficient treatment strategies are available. This paper introduces the sinusoidal pressure hypothesis (SPH), which identifies an elevated sinusoidal pressure (SP) as cause of fibrosis. SPH has been mainly derived from recent studies on liver stiffness. So far, pressure changes have been exclusively seen as a consequence of cirrhosis. According to the SPH, however, an elevated SP is the major upstream event that initiates fibrosisviabiomechanic signaling by stretching of perisinusoidal cells such as hepatic stellate cells or fibroblasts (SPH part I: initiation). Fibrosis progression is determined by the degree and time of elevated SP. The SPH predicts that the degree of extracellular matrix eventually matches SP with critical thresholds > 12 mmHg and > 4 wk. Elevated arterial flow and final arterialization of the cirrhotic liver represents the self-perpetuating key event exposing the low-pressure-organ to pathologically high pressures (SPH part II: perpetuation). It also defines the "point of no return" where fibrosis progression becomes irreversible. The SPH is able to explain the macroscopic changes of cirrhotic livers and the uniform fibrotic response to various etiologies. It also opens up new views on the role of fat and disease mechanisms in other organs. The novel concept will hopefully stimulate the search for new treatment strategies.
authors.affiliation: Sebastian Mueller, Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstr, 69121 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mueller
mesh_terms: D000818:Animals; D001164:Arteriovenous Fistula / Q000150:complications; D001696:Biomechanical Phenomena; D015687:Cell Hypoxia; D018450:Disease Progression; D054459:Elasticity Imaging Techniques; D058625:End Stage Liver Disease / Q000209:etiology*; D005234:Fatty Liver / Q000150:complications; D005347:Fibroblasts / Q000502:physiology; D006333:Heart Failure / Q000150:complications*; D055166:Hepatic Stellate Cells / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000098:blood supply* / Q000166:cytology / Q000473:pathology; D008102:Liver Circulation; D008103:Liver Cirrhosis / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000150:complications*; D017082:Portal Pressure
keywords: Arterialization; Biomechanics; Cellular and intercellular mechano-signaling; Fibroblasts; Hepatic arterial buffer response; Hepatic stellate cells; Liver cirrhosis; Liver stiffness; Sinusoidal pressure hypothesis; Stretch force