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World J Gastroenterol. Dec 28, 2016; 22(48): 10482-10501
Published online Dec 28, 2016. doi: 10.3748/wjg.v22.i48.10482
Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis
Sebastian Mueller
Sebastian Mueller, Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstr, 69121 Heidelberg, Germany
Author contributions: Mueller S solely contributed to the conception and design, writing the paper, critical reading and final approval.
Conflict-of-interest statement: No conflict of interest to report.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sebastian Mueller, MD, PhD, Professor of Medicine, Vice Head, Co-Director, Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstraße 11 - 33, 69121 Heidelberg, Germany. sebastian.mueller@urz.uni-heidelberg.de
Telephone: +49-6221-483210 Fax: +49-6221-484494
Received: July 27, 2016
Peer-review started: August 1, 2016
First decision: September 28, 2016
Revised: October 10, 2016
Accepted: November 23, 2016
Article in press: November 28, 2016
Published online: December 28, 2016
Processing time: 151 Days and 23.1 Hours
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 fibrosis via biomechanic 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.

Keywords: Liver stiffness; Stretch force; Sinusoidal pressure hypothesis; Liver cirrhosis; Hepatic arterial buffer response; Biomechanics; Arterialization; Hepatic stellate cells; Fibroblasts; Cellular and intercellular mechano-signaling

Core tip: This paper introduces the sinusoidal pressure hypothesis, which identifies an elevation of sinusoidal pressure (SP) as cause of fibrosis/cirrhosis. Accordingly, elevated SP is the major upstream event that initiates fibrosis progression via biomechanic signaling by stretching of perisinusoidal cells. Fibrosis progression is determined by the degree and time of elevated SP. The cirrhotic extracellular matrix eventually matches the degree of pressure. Arterialization of the stiff cirrhotic liver represents the final self-perpetuating key event exposing the low-pressure-organ to pathologically high pressures. It also defines the “point of no return” where fibrosis progression becomes irreversible.