How Hepatologists Use Liver Biopsy in the Evaluation of Liver Disease?

This article focuses on how hepatologists view the role of liver biopsy in diagnosis, assessment, and management of chronic and acute liver disease, and its variable use among different etiologies of liver disease and in the evaluation of liver fibrosis.

Portal Hypertension in Nonalcoholic Fatty Liver Disease: Challenges and Paradigms.

Portal hypertension in cirrhosis is defined as an increase in the portal pressure gradient (PPG) between the portal and hepatic veins and is traditionally estimated by the hepatic venous pressure gradient (HVPG), which is the difference in pressure between the free-floating and wedged positions of a balloon catheter in the hepatic vein. By convention, HVPG≥10 mmHg indicates clinically significant portal hypertension, which is associated with adverse clinical outcomes. Nonalcoholic fatty liver disease (NAFLD) is a common disorder with a heterogeneous clinical course, which includes the development of portal hypertension. There is increasing evidence that portal hypertension in NAFLD deserves special considerations. First, elevated PPG often precedes fibrosis in NAFLD, suggesting a bidirectional relationship between these pathological processes. Second, HVPG underestimates PPG in NAFLD, suggesting that portal hypertension is more prevalent in this condition than currently believed. Third, cellular mechanoresponses generated early in the pathogenesis of NAFLD provide a mechanistic explanation for the pressure-fibrosis paradigm. Finally, a better understanding of liver mechanobiology in NAFLD may aid in the development of novel pharmaceutical targets for prevention and management of this disease.

Mechanotransduction in the pathogenesis of non-alcoholic fatty liver disease.

Mechanobiology is a domain of interdisciplinary research that aims to explore the impact of physical force, applied externally or internally, on cell and tissue function, including development, growth, and differentiation. Mechanotransduction is a term that describes how cells sense physical forces (such as compression, stretch, and shear stress), convert them into biochemical signals, and mount adaptive responses integrated by the nucleus. There is accumulating evidence that mechanical forces extensively inform the biological behaviour of liver cells in health and disease. Recent research has elucidated many cellular and molecular mechanisms involved in this process including the pleiotropic control and diverse effects of the paralogous transcription co-activators YAP/TAZ, which play a prominent role in mechanotransduction. The liver sinusoids represent a unique microenvironment in which cells are exposed to mechanical cues originating in the cytoskeleton and at interfaces with adjacent cells, the extracellular matrix, and vascular or interstitial fluids. In non-alcoholic fatty liver disease (NAFLD), hepatocellular lipid accumulation and ballooning, activation of inflammatory responses, dysfunction of liver sinusoidal endothelial cells, and transdifferentiation of hepatic stellate cells into a pro-contractile and pro-fibrotic phenotype have been associated with aberrant cycles of mechanosensing and mechanoresponses. The downstream consequences of disrupted mechanical homeostasis likely contribute to the progression of NAFLD and promote the development of portal hypertension, cirrhosis, and hepatocellular carcinoma. Identification of molecular targets involved in pathogenic mechanotransduction will allow for the development of novel strategies to prevent the progression of liver disease in NAFLD.

Microbiota transplantation in portal hypertension: promises and pitfalls.

In this commentary, we discuss new findings indicating that microbiota transplantation has favorable impact on portal hypertension (PH) in the experimental model of cirrhosis induced by bile duct ligation (BDL) (Huang et al.; Clin Sci (Lond) (2021) 135(24): 2709-2728, doi: 10.1042/CS20210602). Sinusoidal PH is an ominous outcome of advanced chronic liver disease, characterized by increased intrahepatic vascular resistance (IHVR), splanchnic hyperemia, and the development of portosystemic collaterals. In the work of Huang et al., microbiota transplantation not only alleviated splanchnic hyperdynamic circulation by improving vascular responsiveness and decreasing mesenteric angiogenesis, but also reduced blood flow in portosystemic collaterals. Surprisingly, however, microbiota transplantation had no effect on intrahepatic vasoconstriction in this experimental model. We discuss these observations in the context of recent literature showing that manipulation of the gut microbiota (either by transplantation or through the use of probiotics) may improve IHVR, which is one of the earliest abnormalities in the pathogenesis of sinusoidal PH. Further research is needed to explore the specific molecular and cellular targets associated with the correction of dysbiosis in liver disease.

Effects of Sodium Restriction on Activation of the Renin-Angiotensin-Aldosterone System and Immune Indices During HIV Infection.

BACKGROUND: Human immunodeficiency virus (HIV)-infected patients demonstrate increased activation of the renin-angiotensin-aldosterone system (RAAS). We evaluated changes in immune markers with physiological RAAS activation. METHODS: Immune activation markers were assessed serially in 18 HIV-infected and 7 non-HIV-infected subjects consuming an ad libitum diet followed by a standardized low-sodium diet. RESULTS: Levels of CCL-2 (P = .0004) and soluble CD163 (P = .0001) significantly increased with sodium restriction and RAAS activation, compared with levels in individuals with ad libitum sodium intake, among chronically treated HIV-infected subjects (mean duration of ART [±SEM], 11 ± 1 years), but not among non-HIV-infected subjects of similar age and sex. CONCLUSIONS: Dietary sodium restriction, which activates RAAS, uniquely stimulates critical indices of immune activation during HIV infection. CLINICAL TRIALS REGISTRATION: NCT01407237.

Fructose ingestion acutely stimulates circulating FGF21 levels in humans.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a hormone with pleiotropic metabolic activities which, in rodents, is robustly regulated by fasting and ketogenic diets. In contrast, similar dietary interventions have either no or minimal effects on circulating FGF21 in humans. Moreover, no intervention or dietary challenge has been shown to acutely stimulate circulating FGF21 in either humans or animals. Recent animal data suggest that the transcription factor Carbohydrate Responsive-Element Binding Protein (ChREBP) stimulates hepatic FGF21 expression and that fructose may activate hepatic ChREBP more robustly than glucose. Here, we examined whether fructose ingestion can acutely stimulate FGF21 in humans. METHODS: We measured serum FGF21, glucose, insulin, and triglyceride levels in ten lean, healthy adults and eleven adults with the metabolic syndrome following oral ingestion of 75 g of glucose, fructose, or a combination of the two sugars. RESULTS: FGF21 levels rose rapidly following fructose ingestion, achieved a mean 3.4-fold increase at two hours (P < 0.01), and returned to baseline levels within five hours. In contrast, FGF21 did not increase in the first two hours following ingestion of a glucose load, although more modest increases were observed after three to four hours. Both baseline and fructose-stimulated FGF21 levels were 2-3 fold elevated in subjects with metabolic syndrome. CONCLUSIONS: Fructose ingestion acutely and robustly increases serum FGF21 levels in humans in a pattern consistent with a hormonal response. While FGF21 appears to be critical for the adaptive response to fasting or starvation in rodents, these findings suggest that in humans, FGF21 may play an important role in fructose metabolism.

Matrix metalloproteinases (MMPs) are required for wound closure and healing during larval leg regeneration in the flour beetle, Tribolium castaneum.

Regenerative abilities are found ubiquitously among many metazoan taxa. To compare mechanisms underlying the initial stages of limb regeneration between insects and vertebrates, the roles of matrix metalloproteinases (MMPs) and fibroblast growth factor (FGF) signaling were investigated in the red flour beetle, Tribolium castaneum. RNA interference-mediated knockdown of MMP2 expression delayed wound healing and subsequent leg regeneration. Additionally, pairwise knockdown of MMP1/2 and MMP2/3, but not MMP1/3, resulted in inhibition of wound closure. Wound healing on the dorsal epidermis after injury was also delayed when MMPs were silenced. Our findings show that functionally redundant MMPs play key roles during limb regeneration and wound healing in Tribolium. This MMP-mediated wound healing is necessary for the subsequent formation of a blastema. In contrast, silencing of FGF receptor did not interfere with the initial stages of leg regeneration despite the alterations in tanning of the cuticle. Thus, insects and vertebrates appear to employ similar developmental processes for the initial stages of wound closure during limb regeneration, while the role of FGF in limb regeneration appears to be unique to vertebrates.

Short-term exenatide treatment leads to significant weight loss in a subset of obese women without diabetes.

OBJECTIVE: To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women. RESEARCH DESIGN AND METHODS: Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m(2)) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight. RESULTS: Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (-7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (-2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss. CONCLUSIONS: Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.