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World J Gastroenterol. 2016 Dec 28;22(48):10482-10501. doi: 10.3748/wjg.v22.i48.10482.

Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis.

Author information

1
Sebastian Mueller, Department of Medicine and Center for Alcohol Research, Salem Medical Center, University of Heidelberg, Zeppelinstr, 69121 Heidelberg, Germany.

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:

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

PMID:
28082801
PMCID:
PMC5192260
DOI:
10.3748/wjg.v22.i48.10482
[Indexed for MEDLINE]
Free PMC Article

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