Background and Aims
Liver fibrosis is the static and main (70%‐80%) component of portal hypertension (PH). We investigated dynamic components of PH by a three‐dimensional analysis based on ...correlation of hepatic collagen proportionate area (CPA) with portal pressure (PP) in animals or HVPG in patients.
Approach and Results
Different animal models (bile duct ligation: n = 31, carbon tetrachloride: n = 12, thioacetamide: n = 12, choline‐deficient high‐fat diet: n = 12) and patients with a confirmed single etiology of cholestatic (primary biliary cholangitis/primary sclerosing cholangitis: n = 16), alcohol‐associated (n = 22), and metabolic (NASH: n = 19) liver disease underwent CPA quantification on liver specimens/biopsies. Based on CPA‐to‐PP/HVPG correlation, potential dynamic components were identified in subgroups of animals/patients with lower‐than‐expected and higher‐than‐expected PP/HVPG. Dynamic PH components were validated in a patient cohort (n = 245) using liver stiffness measurement (LSM) instead of CPA. CPA significantly correlated with PP in animal models (Rho = 0.531; p < 0.001) and HVPG in patients (Rho = 0.439; p < 0.001). Correlation of CPA with PP/HVPG varied across different animal models and etiologies in patients. In models, severity of hyperdynamic circulation and specific fibrosis pattern (portal fibrosis: p = 0.02; septa width: p = 0.03) were associated with PH severity. In patients, hyperdynamic circulation (p = 0.04), vascular dysfunction/angiogenesis (VWF‐Ag: p = 0.03; soluble vascular endothelial growth factor receptor 1: p = 0.03), and bile acids (p = 0.04) were dynamic modulators of PH. The LSM‐HVPG validation cohort confirmed these and also indicated IL‐6 (p = 0.008) and hyaluronic acid (HA: p < 0.001) as dynamic PH components.
Conclusions
The relative contribution of “static” fibrosis on PH severity varies by type of liver injury. Next to hyperdynamic circulation, increased bile acids, VWF‐Ag, IL‐6, and HA seem to indicate a pronounced dynamic component of PH in patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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Severe cholestasis may cause cholemic nephropathy that can be modeled in common bile duct ligated (CBDL) mice. We aimed to explore the therapeutic efficacy and mechanisms of ...norursodeoxycholic acid (norUDCA) in cholemic nephropathy.
In 8-week CBDL mice fed with norUDCA (prior or post CBDL) or chow we evaluated serum urea levels, urine cytology and urinary neutrophil gelatinase associated lipocalin (uNGAL), kidney and liver tissue quantification of fibrosis by hydroxyproline content and gene chip expression looking at key genes of inflammation and fibrosis. Moreover, we comprehensively analysed bile acid profiles in liver, kidney, serum and urine samples.
NorUDCA-fed CBDL mice had significantly lower serum urea and uNGAL levels and less severe cholemic nephropathy as demonstrated by normal urine cytology, significantly reduced tubulointerstitial nephritis, and renal fibrosis as compared to controls. NorUDCA underwent extensive metabolism to produce even more hydrophilic compounds that were significantly enriched in kidneys.
NorUDCA ameliorates cholemic nephropathy due to the formation of highly hydrophilic metabolites enriched in kidney. Consequently, norUDCA may represent a medical treatment for cholemic nephropathy.
The term cholemic nephropathy describes renal dysfunction together with characteristic morphological alterations of the kidney in obstructive cholestasis that can be mimicked by ligation of the common bile duct in mice. Feeding the hydrophilic bile acid norUDCA to bile duct ligated mice leads to a significant amelioration of the renal phenotype due to the formation of highly hydrophilic metabolites enriched in the kidney and may therefore represent a medical treatment for cholemic nephropathy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Patients with advanced chronic liver disease (ACLD) may develop a prothrombotic phenotype that seems to be more pronounced with more severe liver dysfunction. An imbalance of endogenous pro- and ...anticoagulants is not fully captured by routine coagulation assays.
In a cohort of ACLD patients undergoing hepatic venous pressure gradient (HVPG) measurement, we assessed thrombin generation (TGA) using two commercially available assays (Technothrombin and Thrombinoscope) with and without addition of soluble thrombomodulin (TM), as well as thrombin activity, alongside a panel of coagulation parameters.
The cohort encompassed 37 patients (median age 55.3 years, mean HVPG 16 ± 5 mm Hg). In the TM-modified Thrombinoscope TGA, the endogenous thrombin generation potential (ETP) was significantly increased in Child-Pugh-Score (CPS) B/C patients (N = 23, 62 %) compared to CPS A patients (N = 14, 38 %) (ETP: 546 nM∗min (443–696) vs. 404 nM∗min (289–573), p = 0.028). Using the Technothrombin TGA without TM, patients with CPS B/C had decreased ETP compared to CPS A patients (ETP: 2792 ± 1336 nM∗min vs. 5040 ± 816 nM∗min, p < 0.001) and with addition of TM (final concentration: 5 nM; ETP: 2545 ± 1327 nM∗min vs. 4824 ± 929 nM∗min, p < 0.001). Thrombin activity levels were 0.6pM in median (0.2–1.6pM) and above the level of detectability (0.10pM) in 94.6 % of patients but were not correlated to severity of cirrhosis (CPS A 0.7pM vs CPS B/C 0.4pM, p = 0.377) nor to parameters of TGA.
Thrombin plasma levels are elevated in liver disease patients without apparent correlation to TGA or severity of cirrhosis. TGAs can be modified with TM to enable protein C-dependent anticoagulation, but result in differences with regard to severity of liver disease.
•Patients with advanced liver disease have an increased risk of thrombosis and bleeding.•Thrombin generation (TG) increases with liver disease severity.•TM-modified TG elucidates the hemostatic disbalance in liver disease.•Thrombin plasma levels are increased in liver disease patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of ...BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity.
We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes.
Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed ‘futile cycling’ of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity.
APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication.
Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.
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•APAP overdose causes a breach of the blood-bile barrier prior to hepatocyte death.•Bile acids leak into the sinusoidal blood and are then taken up by hepatocytes and repeatedly cycled.•Due to cycling, bile acid concentrations in hepatocytes exceed cytotoxic thresholds.•Blocking the hepatocyte bile acid uptake carriers ameliorates APAP-induced toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Salas JT, Banales JM, Sarvide S, Recalde S, Ferrer A, Uriarte I, Oude Elferink RP, ...Prieto J, Medina JF. Background/aims Cl(−)/HCO(3)(−) anion exchanger 2 (AE2) is involved in intracellular pH (pH(i)) regulation and transepithelial acid–base transport, including secretin-stimulated biliary bicarbonate excretion. AE2 gene expression was found to be reduced in liver biopsy specimens and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic nonsuppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. In mice with widespread Ae2 gene disruption, we previously reported altered spermiogenesis and reduced gastric acid secretion. We now describe the hepatobiliary and immunologic changes observed in these Ae2(a,b)-deficient mice. Methods In this murine model, splenocyte pH(i) and T-cell populations were studied by flow cytometry. CD3-stimulated cytokine secretion was estimated using cytokine arrays. AMA were evaluated by immunoblotting and proteomics. Hepatobiliary changes were assessed by immunohistopathology, flow cytometry, and serum biochemistry. Cholangiocyte gene expression was analyzed by real-time polymerase chain reaction. Results Ae2(a,b)(−/−) mice exhibit splenomegaly, elevated pH(i) in splenocytes, increased production of interleukin-12p70 and interferon gamma, expanded CD8(+) T-cell population, and under represented CD4(+)FoxP3(+)/regulatory T cells. Most Ae2(a,b)(−/−) mice tested positively for AMA, showing increased serum levels of immunoglobulin M and G, and liver-specific alkaline phosphatase. About one third of Ae2(a,b)(−/−) mice had extensive portal inflammation with CD8(+) and CD4(+) T lymphocytes surrounding damaged bile ducts. Cholangiocytes isolated from Ae2(a,b)(−/−) mice showed gene expression changes compatible with oxidative stress and increased antigen presentation. Conclusions Ae2 deficiency alters pH(i) homeostasis in immunocytes and gene expression profile in cholangiocytes, leading to immunologic and hepatobiliary changes that resemble PBC. Abstract reproduced by permission of Gastroenterology 2008;134:1482–1493
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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