In this review we develop the argument that cholestatic liver diseases, particularly primary biliary cholangitis and primary sclerosing cholangitis (PSC), evolve over time with anatomically an ...ascending course of the disease process. The first and early lesions are in “downstream” bile ducts. This eventually leads to cholestasis, and this causes bile salt (BS)–mediated toxic injury of the “upstream” liver parenchyma. BS are toxic in high concentration. These concentrations are present in the canalicular network, bile ducts, and gallbladder. Leakage of bile from this network and ducts could be an important driver of toxicity. The liver has a great capacity to adapt to cholestasis, and this may contribute to a variable symptom‐poor interval that is often observed. Current trials with drugs that target BS toxicity are effective in only about 50%‐60% of primary biliary cholangitis patients, with no effective therapy in PSC. This motivated us to develop and propose a new view on the pathophysiology of primary biliary cholangitis and PSC in the hope that these new drugs can be used more effectively. These views may lead to better stratification of these diseases and to recommendations on a more “tailored” use of the new therapeutic agents that are currently tested in clinical trials. Apical sodium‐dependent BS transporter inhibitors that reduce intestinal BS absorption lower the BS load and are best used in cholestatic patients. The effectiveness of BS synthesis–suppressing drugs, such as farnesoid X receptor agonists, is greatest when optimal adaptation is not yet established. By the time cytochrome P450 7A1 expression is reduced these drugs may be less effective. Anti‐inflammatory agents are probably most effective in early disease, while drugs that antagonize BS toxicity, such as ursodeoxycholic acid and nor‐ursodeoxycholic acid, may be effective at all disease stages. Endoscopic stenting in PSC should be reserved for situations of intercurrent cholestasis and cholangitis, not for cholestasis in end‐stage disease. These are arguments to consider a step‐wise pathophysiology for these diseases, with therapy adjusted to disease stage. An obstacle in such an approach is that disease stage–defining biomarkers are still lacking. This review is meant to serve as a call to prioritize the development of biomarkers that help to obtain a better stratification of these diseases. (Hepatology 2017;65:722‐738).
Summary MicroRNAs (miRNAs) are evolutionary conserved small non-coding RNAs that regulate gene expression by mediating post-transcriptional silencing of target genes. Since miRNAs are involved in ...fine-tuning of physiological responses, they have become of interest for diagnosis and therapy of a number of diseases. Moreover, the role of dysregulated miRNAs in maintaining the malignant phenotype has profound implications for cancer therapy. We will review the best defined cellular miRNAs and changes in their expression profile in hepatocellular carcinoma (HCC). Cellular miRNAs can also be released into the circulation, and these miRNAs are detected in most body fluids. Circulating miRNAs are associated with HCC and are possible biomarkers. Finally, by affecting several clinically relevant targets, artificially increasing or decreasing the expression level of a given miRNA offers fascinating therapeutic perspectives. We will therefore highlight recent developments in miRNA-based gene therapy with a focus on their therapeutic potential for HCC.
The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. ...These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications.
Adenosine triphosphate (ATP)‐binding cassette (ABC) transporters are drug efflux pumps responsible for the multidrug resistance phenotype causing hepatocellular carcinoma (HCC) treatment failure. ...Here we studied the expression of 15 ABC transporters relevant for multidrug resistance in 19 paired HCC patient samples (16 untreated, 3 treated by chemotherapeutics). Twelve ABC transporters showed up‐regulation in HCC compared with adjacent healthy liver. These include ABCA2, ABCB1, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC10, ABCC11, ABCC12, and ABCE1. The expression profile and function of some of these transporters have not been associated with HCC thus far. Because cellular microRNAs (miRNAs) are involved in posttranscriptional gene silencing, we hypothesized that regulation of ABC expression in HCC might be mediated by miRNAs. To study this, miRNAs were profiled and dysregulation of 90 miRNAs was shown in HCC compared with healthy liver, including up‐regulation of 11 and down‐regulation of 79. miRNA target sites in ABC genes were bioinformatically predicted and experimentally verified in vitro using luciferase reporter assays. In total, 13 cellular miRNAs were confirmed that target ABCA1, ABCC1, ABCC5, ABCC10, and ABCE1 genes and mediate changes in gene expression. Correlation analysis between ABC and miRNA expression in individual patients revealed an inverse relationship, providing an indication for miRNA regulation of ABC genes in HCC. Conclusion: Up‐regulation of ABC transporters in HCC occurs prior to chemotherapeutic treatment and is associated with miRNA down‐regulation. Up‐regulation of five ABC genes appears to be mediated by 13 cellular miRNAs in HCC patient samples. miRNA‐based gene therapy may be a novel and promising way to affect the ABC profile and overcome clinical multidrug resistance. (Hepatology 2012)
This review focuses on the hypothesis that biliary HCO 3− secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled ...membrane permeation of protonated glycine‐conjugated bile acids. Functional impairment of this biliary HCO 3− umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y‐ and bile salt/TGR5‐mediated Cl−/ HCO 3− exchange and HCO 3− secretion, and alkaline phosphatase–mediated ATP breakdown may guarantee a stable biliary HCO 3− umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO 3− umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. (HEPATOLOGY 2010)
Bile duct ligation (BDL) is an experimental procedure that mimics obstructive cholestatic disease. One of the early consequences of BDL in rodents is the appearance of so‐called bile infarcts that ...correspond to Charcot‐Gombault necrosis in human cholestasis. The mechanisms causing bile infarcts and their pathophysiological relevance are unclear. Therefore, intravital two photon–based imaging of BDL mice was performed with fluorescent bile salts (BS) and non‐BS organic anion analogues. Key findings were followed up by matrix‐assisted laser desorption ionization imaging, clinical chemistry, immunostaining, and gene expression analyses. In the acute phase, 1‐3 days after BDL, BS concentrations in bile increased and single‐cell bile microinfarcts occurred in dispersed hepatocytes throughout the liver caused by the rupture of the apical hepatocyte membrane. This rupture occurred after loss of mitochondrial membrane potential, followed by entry of bile, cell death, and a “domino effect” of further death events of neighboring hepatocytes. Bile infarcts provided a trans‐epithelial shunt between bile canaliculi and sinusoids by which bile constituents leaked into blood. In the chronic phase, ≥21 days after BDL, uptake of BS tracers at the sinusoidal hepatocyte membrane was reduced. This contributes to elevated concentrations of BS in blood and decreased concentrations in the biliary tract. Conclusion: Bile microinfarcts occur in the acute phase after BDL in a limited number of dispersed hepatocytes followed by larger infarcts involving neighboring hepatocytes, and they allow leakage of bile from the BS‐overloaded biliary tract into blood, thereby protecting the liver from BS toxicity; in the chronic phase after BDL, reduced sinusoidal BS uptake is a dominant protective factor, and the kidney contributes to the elimination of BS until cholemic nephropathy sets in.
Long term liver-related complications of type-1 Gaucher disease (GD), a lysosomal storage disorder, include fibrosis and an increased incidence of hepatocellular carcinoma. Splenectomy has been ...implicated as a risk factor for the development of liver pathology in GD. High ferritin concentrations are a feature of GD and iron storage in Gaucher cells has been described, but iron storage in the liver in relation to liver fibrosis has not been studied. Alternatively, iron storage in GD may be the result of iron supplementation therapy or regular blood transfusions in patients with severe cytopenia. In this pilot study, comprising 14 type-1 GD patients (7 splenectomized, 7 non-splenectomized) and 7 healthy controls, we demonstrate that liver stiffness values, measured by Transient Elastography and MR-Elastography, are significantly higher in splenectomized GD patients when compared with non-splenectomized GD patients (p = 0.03 and p = 0.01, respectively). Liver iron concentration was elevated (>60±30 µmol/g) in 4 GD patients of whom 3 were splenectomized. No relationship was found between liver stiffness and liver iron concentration. HFE gene mutations were more frequent in splenectomized (6/7) than in non-splenectomized (2/7) participants (p = 0.10). Liver disease appeared more advanced in splenectomized than in non-splenectomized patients. We hypothesize a relationship with excessive hepatic iron accumulation in splenectomized patients. We recommend that all splenectomized patients, especially those with evidence of substantial liver fibrosis undergo regular screening for HCC, according to current guidelines.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objective
To compare the diagnostic accuracy of TE and MRE and establish cutoff levels and diagnostic strategies for both techniques, enabling selection of patients for liver biopsy.
Methods
One ...hundred three patients with chronic hepatitis B or C and liver biopsy were prospectively included. Areas under curves (AUROC) were compared for TE and MRE for METAVIR fibrosis grade ≥ F2 and ≥F3. We defined cutoff values for selection of patients with F0–F1 (sensitivity >95 %) and for significant fibrosis F2–F4 (specificity >95 %).
Results
Following exclusions, 85 patients were analysed (65 CHB, 19 CHC, 1 co-infected). Fibrosis stages were F0 (
n
= 3), F1 (
n
= 53), F2 (
n
= 15), F3 (
n
= 8) and F4 (
n
= 6). TE and MRE accuracy were comparable AUROC
TE
≥ F2: 0.914 (95 % CI: 0.857–0.972) vs. AUROC
MRE
≥ F2: 0.909 (0.840–0.977),
P
= 0.89; AUROC
TE
≥ F3: 0.895 (0.816–0.974) vs. AUROC
MRE
≥ F3: 0.928 (0.874–0.982),
P
= 0.42. Cutoff values of <5.2 and ≥8.9 kPa (TE) and <1.66 and ≥2.18 kPa (MRE) diagnosed 64 % and 66 % of patients correctly as F0–F1 or F2–F4. A conditional strategy in inconclusive test results increased diagnostic yield to 80 %.
Conclusion
TE and MRE have comparable accuracy for detecting significant fibrosis, which was reliably detected or excluded in two-thirds of patients. A conditional strategy further increased diagnostic yield to 80 %.
Key Points
•
Both ultrasound-based transient elastography and magnetic resonance elastography can assess hepatic fibrosis.
•
Both have comparable accuracy for detecting liver fibrosis in viral hepatitis.
•
The individual techniques reliably detect or exclude significant liver fibrosis in 66 %.
•
A conditional strategy for inconclusive findings increases the number of correct diagnoses.
Fibroblast growth factor 19 (FGF19) plays a crucial role in the negative feedback regulation of bile salt synthesis. In the postprandial state, activation of ileal farnesoid X receptor (FXR) by bile ...salts results in transcriptional induction of FGF19 and elevation of circulating FGF19 levels. An intestinal‐liver axis of FGF19 signaling results in down‐regulation of bile salt synthesis. The aim of this study was to explore a broader signaling activity of FGF19 in organs engaged in the enterohepatic circulation of bile salts. For this aim, FGF19 expression and aspects of FGF19 signaling were studied in surgical specimens and in cell lines of hepatobiliary and intestinal origin. FGF19 messenger RNA was found to be abundantly expressed in the human gallbladder and in the common bile duct, with only minor expression observed in the ileum. Interestingly, human gallbladder bile contains high levels of FGF19 (21.9 ± 13.3 versus 0.22 ± 0.14 ng/mL in the systemic circulation). Gallbladder explants secrete 500 times more FGF19 than FXR agonist‐stimulated ileal explants. Factors required for FGF19 signaling (i.e., FGFR4 and βKlotho) are expressed in mucosal epithelial cells of the gallbladder and small intestine. FGF19 was found to activate signaling pathways in cell lines of cholangiocytic, enteroendocrine, and enterocytic origin. Conclusion: The combined findings raise the intriguing possibility that biliary FGF19 has a signaling function in the biliary tract that differs from its established signaling function in the portal circulation. Delineation of the target cells in bile‐exposed tissues and the affected cellular pathways, as well as a possible involvement in biliary tract disorders, require further studies. (HEPATOLOGY 2012)
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