Diagnostic efficacy of noninvasive liver fibrosis indexes in predicting portal hypertension in patients with cirrhosis

The Fontan operation is the current surgical procedure to treat single-ventricle congenital heart disease, by splitting the systemic and pulmonary circulations and thus permitting lifespan to adulthood for the majority of newborns. However, emerging data are showing that Fontan-associated liver disease (FALD) is an increasing related cause of morbidity and mortality in patients with the Fontan circuit. We described the clinical, laboratory, and transient elastography (TE) findings in a case series of adults with the Fontan circuit, and also correlated data with post-mortem histological features, aimed to define the prognostic value of TE in the staging of FALD. All patients presented signs of a long-standing Fontan failure, characterized by reoperation need, systemic ventricle dysfunction, and FALD stigmata (liver and spleen enlargement, portal vein and inferior vena cava dilation, and abnormal liver function tests). Liver and spleen stiffness (LS and SS) values were indicative of significant liver fibrosis/cirrhosis and the presence of suggestive portal hypertension (LS mean 35.9; range 27.3–44.7 kPa; SS mean 42.1, range 32.2–54.5 kPa). Post-mortem evaluations confirmed a gross hepatic architecture distortion in all cases. All patients died from severe complications related to liver dysfunction and bleeding. TE correlated well with pathological findings and FALD severity. We propose this validated and harmless technique to monitor liver fibrosis extension and portal hypertension over time in Fontan patients, and to identify the optimal timing for surgical reoperations or orthotopic-heart transplantation (OHT), avoiding a higher risk of morbidity and mortality in cases with severe FALD.

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Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00537.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. G877-G884 ◽

Cited By ~ 38

Author(s):

Pau Sancho-Bru ◽

Ramón Bataller ◽

Jordi Colmenero ◽

Xavier Gasull ◽

Montserrat Moreno ◽

...

Keyword(s):

Cell Proliferation ◽

Portal Hypertension ◽

Liver Fibrosis ◽

Hepatic Stellate Cells ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Stellate Cells ◽

Luciferase Reporter ◽

Dependent Manner ◽

Cell Contraction

Catecholamines participate in the pathogenesis of portal hypertension and liver fibrosis through α1-adrenoceptors. However, the underlying cellular and molecular mechanisms are largely unknown. Here, we investigated the effects of norepinephrine (NE) on human hepatic stellate cells (HSC), which exert vasoactive, inflammatory, and fibrogenic actions in the injured liver. Adrenoceptor expression was assessed in human HSC by RT-PCR and immunocytochemistry. Intracellular Ca2+ concentration ([Ca2+]i) was studied in fura-2-loaded cells. Cell contraction was studied by assessing wrinkle formation and myosin light chain II (MLC II) phosphorylation. Cell proliferation and collagen-α1(I) expression were assessed by [3H]thymidine incorporation and quantitative PCR, respectively. NF-κB activation was assessed by luciferase reporter gene and p65 nuclear translocation. Chemokine secretion was assessed by ELISA. Normal human livers expressed α1A-adrenoceptors, which were markedly upregulated in livers with advanced fibrosis. Activated human HSC expressed α1A-adrenoceptors. NE induced multiple rapid [Ca2+]i oscillations (Ca2+ spikes). Prazosin (α1-blocker) completely prevented NE-induced Ca2+ spikes, whereas propranolol (nonspecific β-blocker) partially attenuated this effect. NE caused phosphorylation of MLC II and cell contraction. In contrast, NE did not affect cell proliferation or collagen-α1(I) expression. Importantly, NE stimulated the secretion of inflammatory chemokines (RANTES and interleukin-8) in a dose-dependent manner. Prazosin blocked NE-induced chemokine secretion. NE stimulated NF-κB activation. BAY 11-7082, a specific NF-κB inhibitor, blocked NE-induced chemokine secretion. We conclude that NE stimulates NF-κB and induces cell contraction and proinflammatory effects in human HSC. Catecholamines may participate in the pathogenesis of portal hypertension and liver fibrosis by targeting HSC.

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Telmisartan relieves liver fibrosis and portal hypertension by improving vascular remodeling and sinusoidal dysfunction

European Journal of Pharmacology ◽

10.1016/j.ejphar.2021.174713 ◽

2021 ◽

pp. 174713

Author(s):

Lei Zheng ◽

Zhifeng Zhao ◽

Jiayun Lin ◽

Hongjie Li ◽

Guangbo Wu ◽

...

Keyword(s):

Portal Hypertension ◽

Liver Fibrosis ◽

Vascular Remodeling

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Non-invasive methods in the assessment of portal hypertension severity

Gastroenterologie a hepatologie ◽

10.48095/ccgh2021125 ◽

2021 ◽

Vol 75 (2) ◽

pp. 125-133

Author(s):

Soňa Franková ◽

Jan Šperl

Keyword(s):

Portal Hypertension ◽

Liver Fibrosis ◽

Shear Wave ◽

Transient Elastography ◽

Venous Pressure ◽

Liver Stiffness ◽

Invasive Technique ◽

Hepatic Veins ◽

Oesophageal Varices ◽

Non Invasive

Portal hypertension represents a wide spectrum of complications of chronic liver diseases and may present by ascites, oesophageal varices, splenomegaly, hypersplenism, hepatorenal and hepatopulmonary syndrome or portopulmonary hypertension. Portal hypertension and its severity predicts the patient‘s prognosis: as an invasive technique, the portosystemic gradient (HPVG – hepatic venous pressure gradient) measurement by hepatic veins catheterisation has remained the gold standard of its assessment. A reliable, non-invasive method to assess the severity of portal hypertension is of paramount importance; the patients with clinically significant portal hypertension have a high risk of variceal bleeding and higher mortality. Recently, non-invasive methods enabling the assessment of liver stiffness have been introduced into clinical practice in hepatology. Not only may these methods substitute for liver biopsy, but they may also be used to assess the degree of liver fibrosis and predict the severity of portal hypertension. Nowadays, we can use the quantitative elastography (transient elastography, point shear-wave elastrography, 2D-shear-wave elastography) or magnetic resonance imaging. We may also assess the severity of portal hypertension based on the non-invasive markers of liver fibrosis (i.e. ELF test) or estimate clinically signifi cant portal hypertension using composite scores (LSPS – liver spleen stiff ness score), based on liver stiffness value, spleen diameter and platelet count. Spleen stiffness measurement is a new method that needs further prospective studies. The review describes current possibilities of the non-invasive assessment of portal hypertension and its severity.

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Fibrospleen: Measuring spleen stiffness by transient elastography increases accuracy of staging of liver fibrosis and of portal hypertension in chronic viral hepatitis

Digestive and Liver Disease ◽

10.1016/j.dld.2008.12.078 ◽

2009 ◽

Vol 41 (3) ◽

pp. A38 ◽

Cited By ~ 1

Author(s):

V. Di Marco ◽

F. Bronte ◽

V. Calvaruso ◽

C. Cammà ◽

D. Cabibi ◽

...

Keyword(s):

Portal Hypertension ◽

Liver Fibrosis ◽

Viral Hepatitis ◽

Transient Elastography ◽

Chronic Viral Hepatitis ◽

Spleen Stiffness

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Short-Term Western Diet Aggravates Non-Alcoholic Fatty Liver Disease (NAFLD) With Portal Hypertension in TGR(mREN2)27 Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21093308 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3308 ◽

Cited By ~ 1

Author(s):

Carla Cremonese ◽

Robert Schierwagen ◽

Frank Erhard Uschner ◽

Sandra Torres ◽

Olaf Tyc ◽

...

Keyword(s):

Portal Hypertension ◽

Liver Disease ◽

Liver Fibrosis ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Western Diet ◽

Suitable Model ◽

Alcoholic Fatty Liver ◽

Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially, the development of fibrosis and portal hypertension in NAFLD patients requires treatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. As expected, WD induced obesity and liver fibrosis as confirmed by Sirius Red and Oil Red O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increased during feeding of WD, indicating infiltration of macrophages into the liver, even though this increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.

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