Direct and indirect methods for the assessment of portal hypertension. A. Several minimally invasive or non-invasive approaches (indicated by white circles) have been developed to estimate portal venous pressure, including endoscopic visualization or imaging of portal-systemic collaterals by various methods based on abdominal sonography [28, 63, 64, 79], computer tomography [80] and multi-parametric MR imaging [81]; tissue stiffness assessment of the liver and spleen by vibrationcontrolled transient elastography or 2-dimensional (gradient-recalled echo) MR elastography [65, 82-84]; and analysis of mucosal vascular pattern and flow by confocal endomicroscopy [78]. Direct access methods (indicated by blue circles) include HVPG measurement, which is the reference technique for measuring portal hypertension, and the occasional opportunity to obtain intraoperative access to the portal vein [57, 85, 86]. EUS-guided portal and hepatic vein access is an emerging method to provide safe and direct measurement of portal pressure gradient (PPG) [87, 88]; B. Comparison of the classic hepatic venous pressure gradient (HVPG) method using indirect access through the hepatic vein to estimate PVP and endoscopic ultrasound (EUS)-guided assessment of through direct access of the portal vein and hepatic vein. To calculate HVPG, a balloon-tipped central vein catheter is inserted into a hepatic vein tributary where retrograde occlusion detects WHVP and keeping the catheter "free" in the hepatic vein detects FHVP [57, 85]. In cirrhotic patients, WHVP is almost identical to PVP and the pressure difference between wedged and free-floating catheter positions defines HVPG [89]. To calculate PPG, the portal and hepatic vein is accessed through insertion of a digital pressure detection device by EUS-guided technique to calculate the difference between PVP and FHVP [87, 88]. SMV: superior mesenteric vein; IMV: inferior mesenteric vein; PV: portal vein; HV: hepatic vein

Direct and indirect methods for the assessment of portal hypertension. A. Several minimally invasive or non-invasive approaches (indicated by white circles) have been developed to estimate portal venous pressure, including endoscopic visualization or imaging of portal-systemic collaterals by various methods based on abdominal sonography [28, 63, 64, 79], computer tomography [80] and multi-parametric MR imaging [81]; tissue stiffness assessment of the liver and spleen by vibrationcontrolled transient elastography or 2-dimensional (gradient-recalled echo) MR elastography [65, 82-84]; and analysis of mucosal vascular pattern and flow by confocal endomicroscopy [78]. Direct access methods (indicated by blue circles) include HVPG measurement, which is the reference technique for measuring portal hypertension, and the occasional opportunity to obtain intraoperative access to the portal vein [57, 85, 86]. EUS-guided portal and hepatic vein access is an emerging method to provide safe and direct measurement of portal pressure gradient (PPG) [87, 88]; B. Comparison of the classic hepatic venous pressure gradient (HVPG) method using indirect access through the hepatic vein to estimate PVP and endoscopic ultrasound (EUS)-guided assessment of through direct access of the portal vein and hepatic vein. To calculate HVPG, a balloon-tipped central vein catheter is inserted into a hepatic vein tributary where retrograde occlusion detects WHVP and keeping the catheter "free" in the hepatic vein detects FHVP [57, 85]. In cirrhotic patients, WHVP is almost identical to PVP and the pressure difference between wedged and free-floating catheter positions defines HVPG [89]. To calculate PPG, the portal and hepatic vein is accessed through insertion of a digital pressure detection device by EUS-guided technique to calculate the difference between PVP and FHVP [87, 88]. SMV: superior mesenteric vein; IMV: inferior mesenteric vein; PV: portal vein; HV: hepatic vein

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Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pre...

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... addition to HVPG, there are other techniques to indirectly estimate portal pressure but none have entered clinical practice as a reliable substitute (Figure 4). Ultrasonographic detection of hemodynamic alterations consistent with increased IHVR may help in the diagnosis of portal hypertension associated with NAFLD [19]. ...

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... While most cases of PH are associated with cirrhosis, 12% have mild or absent fibrosis. The extent of steatosis is the only difference between non-cirrhotic NAFLD patients with and without PH [68]. In addition, a strong association has been reported between NASH and HCC [69,70], with a prevalence of 38% [71]. ...
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... As another example, portal hypertension may cause a buildup of pressure within the liver parenchyma; finding a nominal shear modulus for one group under specific conditions (presence of non-alcoholic fatty liver disease (NAFLD), no portal hypertension) may not be the same for another group with slightly altered conditions (presence of NAFLD, with portal hypertension). Several studies already show that there are measurable and highly correlated differences with hepatic venous pressure and measured stiffness within these patients and more severe progressions of the disease [20,21]. Without appreciation for prestress, distinct groups such as these could ruin standardization of liver stiffness due to the clear confounding factor of pressure changes, but with proper appreciation, there could be potential for high specificity screening. ...
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... These changes in portal perfusion could be the reason of less adequate enhancement in steatotic livers. In steatohepatitis there are fibrotic changes which could additionally contribute to portal hypertension and subsequent less adequate enhancement [16]. ...
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... To sum up, development of portal hypertension in NAFLD can occur through early sinusoidal compression and microcirculatory disruption without the presence of extensive fibrosis or tissue remodelling in cirrhosis. 8,10 As mentioned above, another important problem in NAFLD-related portal hypertension is the concept of portal hypertension without the presence of fibrosis or cirrhosis. A prospective study of 292 subjects with NAFLD showed that 17% of the subjects who did not have cirrhosis were found to have portal hypertension (HVPG >5 mmHg), in which 0.5% of the subjects had CSPH. ...
... Consequently, higher number of non-invasive options are still necessary to overcome the lack of portal pressure measurement methods in patients with early stages of advanced liver disease. 10,14 Magnetic resonance (MR)-based methods have demonstrated the ability to discern between portal hypertension with and without cirrhosis. In a retrospective evaluation of 41 subjects with non-cirrhotic portal hypertension, magnetic resonance elastography (MRE) also indicated a promising result, showing that increased liver stiffness measurement, as well as increased ratio of splenic stiffness measurement and liver stiffness measurement, can distinguish non-cirrhotic portal hypertension from cirrhotic portal hypertension. ...
... The study also showed that liver stiffness measurement was markedly lower in portal hypertension without cirrhosis, while the ratio between spleen stiffness measurement and liver stiffness measurement was markedly higher in portal hypertension without cirrhosis. 15 In addition, MR-based methods have been well-correlated with a wide range of HVPG measurements (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). A study by Gharib et al. 16 demonstrated an independent significant correlation (p=0.015) between HVPG and MRE of the liver, with a median HVPG of 6 mmHg from 23 subjects. ...
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... Supraphysiological pressure in the portal venous system, called portal hypertension (PH), is a detrimental complication in liver cirrhosis (65). The pathophysiology of PH is complex, involving hepatic (increased intrahepatic resistance to portal venous blood flow due to tissue remodeling) and/or extrahepatic (splanchnic arterial vasodilation) factors (65,66). Despite the fact that PH has mostly been discussed in the context of cirrhosis, elevated portal venous pressure has also been detected in experimental or human NAFLD, when fibrosis was less advanced and cirrhosis was absent (66,67). ...
... The pathophysiology of PH is complex, involving hepatic (increased intrahepatic resistance to portal venous blood flow due to tissue remodeling) and/or extrahepatic (splanchnic arterial vasodilation) factors (65,66). Despite the fact that PH has mostly been discussed in the context of cirrhosis, elevated portal venous pressure has also been detected in experimental or human NAFLD, when fibrosis was less advanced and cirrhosis was absent (66,67). Numerous earlier studies reported decreased hepatic blood flow and increased hepatic arterial and portal venous pressure after electric stimulation of the hepatic nerves in rat (68), dog (69), or cat (70). ...
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... The prime examples would be alcoholic fatty liver disease and NAFLD. There is growing evidence that PH can occur in alcoholic fatty liver disease and NAFLD even in the absence of significant fibrosis/cirrhosis and that it correlates with the degree of steatosis [95][96][97][98][99][100][101]. Although the exact etiopathogenesis remains unclear, multiple hypotheses have been proposed. ...
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Idiopathic non-cirrhotic portal hypertension (INCPH) is a clinicopathologic disease entity characterized by the presence of clinical signs and symptoms of portal hypertension (PH) in the absence of liver cirrhosis or known risk factors accountable for PH. Multiple hematologic, immune-related, infectious, hereditary and metabolic risk factors have been associated with this disorder. Still, the exact etiopathogenesis is largely unknown. The recently proposed porto-sinusoidal vascular disease (PSVD) scheme broadens the spectrum of the disease by also including patients without clinical PH who are found to have similar histopathologic findings on core liver biopsies. Three histomorphologic lesions have been identified as specific for PSVD to include obliterative portal venopathy, nodular regenerative hyperplasia and incomplete septal cirrhosis/fibrosis. However, these findings are often subtle, under-recognized and subjective with low interobserver agreement among pathologists. Additionally, the natural history of the subclinical forms of the disease remains unexplored. The clinical course is more favorable compared to cirrhosis patients, especially in the absence of clinical PH or liver dysfunction. There are no universally accepted guidelines in regard to diagnosis and treatment of INCPH/PSVD. Hence, this review emphasizes the need to raise awareness of this entity by highlighting its complex pathophysiology and clinicopathologic associations. Lastly, formulation of standardized diagnostic criteria with clinical validation is necessary to avoid misclassifying vascular diseases of the liver and to develop and implement targeted therapeutic strategies.
... PH and its derived complications represent the main cause of liver failure and transplantation in patients with advanced chronic liver diseases (García-Pagán et al., 2012). However, PH is not solely the consequence of cirrhosis, as sinusoidal microvascular dysfunction contributes also to increase IHVR, and consequently, sinusoidal portal pressure, which may impact disease progression in MAFLD (Ryou et al., 2020). Consistent with these data, our NASH model presents PH, together with a marked microvascular dysfunction characterized by decreased eNOS activation in LSECs and increased HSC contraction. ...
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Non-alcoholic fatty liver disease (NAFLD) is still and will become a major problem worldwide as its prevalence is increasing. The new proposed term metabolic associated fatty liver disease (MAFLD) has opening the new horizon from the old dominant liver disease to metabolic associated liver disease. Gut microbiota dysbiosis is considered as “a man behind the gun”, not only causing a problem in the gut but also in other organs. Since gut microbiota also has a strong link to metabolic dysfunction, this chapter discusses gut microbiota dysbiosis in NAFLD, starting from the basic science until the most recent clinical evidence.