Liver stiffness: a novel parameter for the diagnosis of liver disease

Abstract

The noninvasive quantitation of liver stiffness (LS) by ultrasound based transient elastography using FibroScan® has revolutionized the diagnosis of liver diseases, namely liver cirrhosis. Alternative techniques such as acoustic radiation impulse frequency imaging or magnetic resonance elastography are currently under investigation. LS is an excellent surrogate marker of advanced fibrosis (F3) and cirrhosis (F4) outscoring all previous noninvasive approaches to detect cirrhosis. LS values below 6 kPa are considered as normal and exclude ongoing liver disease. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. LS highly correlates with portal pressure, and esophageal varices are likely at values >20 kPa. Many other factors may also increase LS such as hepatic infiltration with tumor cells, mast cells (mastocytosis), inflammatory cells (all forms of hepatitis) or amyloidosis. In addition, LS is directly correlated with the venous pressure (eg, during liver congestion) and is increased during mechanic cholestasis. Thus, LS should always be interpreted in the context of clinical, imaging and laboratory findings. Finally, LS has helped to better understand the molecular mechanisms underlying liver fibrosis. The novel pressure-stiffness-fibrosis sequence hypothesis is introduced.

Keywords: fibrosis; liver disease; liver stiffness; transient elastography.

Figure 1

Invasive and noninvasive methods to determine liver fibrosis hepatic venous pressure gradient.

Figure 2

FibroScan® vibration consists of a period with a center frequency of 50 Hz. The standard M probe has a 2 mm peak-to-peak amplitude.

Figure 3

Liver stiffness measurements are performed on the right lobe of the liver in intercostal position using FibroScan®.

Figure 4

FibroScan® operator uses A) A-mode and B) M-mode images to locate the liver. The shear wave velocity is deduced from the C) elastogram which represents the strains induced in the liver by the shear wave propagation as a function of time and depth.

Figure 5

Liver stiffness range caused by matrix deposition (fibrosis) and pressure changes (osmotic, hydrostatic, intra-abdominal).

Figure 6

Not only matrix but also pressure-associated conditions influence liver stiffness.

Figure 7

Relation of liver stiffness with clinical fibrosis-related entities such as fibrosis stage, portal hypertension and esophageal bleeding.

Figure 8

Liver stiffness is increased in post-sinusoidal thrombosis (eg, Budd-Chiari-Syndrome) but not in pre-sinusoidal thrombosis (eg, portal vein thrombosis). Additional measurement of spleen stiffness closes the diagnostic gap.

Figure 9

Estimated increase of liver stiffness by various clinical conditions irrespective of fibrosis. Note: *alcohol withdrawal.

Figure 10

Present diagnostic algorithm of liver stiffness. For details see text. *Arrows indicate cured hepatitis eg, detoxification from alcohol or cure from hepatitis C virus.

Figure 11

Pressure-stiffness-matrix sequence hypothesis. Either hydrostatic (venous or bile) or osmotic (eg, inflammation) pressure increases liver stiffness which, in turn, initiates increased matrix deposition via mechanical intercellular signaling. Matrix deposition finally leads to an irreversible increase of liver stiffness that is independent of pressure. These events may ultimately enter a vicious cycle causing end-stage liver disease. For more details see text.