RESUMEN
Various factors are involved in the pathogenesis of alcoholic liver disease (ALD) and ethanol-mediated carcinogenesis. In addition to genetic, epigenetic and immunologic mechanisms, acetaldehyde-associated toxicity, oxidative stress as well as cytokine-mediated inflammation are of major importance. Oxidative stress, with the generation of reactive oxygen species (ROS), develops either in inflammation (alcoholic hepatitis) or during oxidation of ethanol via cytochrome P4502E1 (CYP2E1). CYP2E1 is induced by ethanol, oxidizes ethanol to acetaldehyde, and generates ROS during this process. ROS results in protein damage, enhanced fibrogenesis and DNA lesions. Furthermore, CYP2E1 induction results in an enhanced activation of various procarcinogens and an increased degradation of retinol and retinoic acid (RA), a compound responsible for cell differentiation and proliferation. An inhibition of CYP2E1 results in an improvement of ALD and chemically induced carcinogenesis in animal experiments. In humans, CYP2E1 is induced following the consumption of 40 grams of ethanol per day after one week. However, the induction varies inter-individually. The mechanism for this is still unclear. Patients with ALD show a significant correlation between CYP2E1, the occurrence of highly carcinogenic etheno DNA adducts and the severity of fibrosis. First results on the effect of CYP2E1 inhibition by chlormethiazole, a specific CYP2E1 inhibitor on ALD, can be expected soon.
Asunto(s)
Carcinogénesis/inducido químicamente , Citocromo P-450 CYP2E1/metabolismo , Etanol/efectos adversos , Hepatopatías Alcohólicas/metabolismo , Neoplasias/inducido químicamente , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Animales , Citocromo P-450 CYP2E1/fisiología , Humanos , Hígado , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND & AIMS: Controlled attenuation parameter (CAP) is a novel non-invasive measure of hepatic steatosis, but it has not been evaluated in alcoholic liver disease. Therefore, we aimed to validate CAP for the assessment of biopsy-verified alcoholic steatosis and to study the effect of alcohol detoxification on CAP. METHODS: This was a cross-sectional biopsy-controlled diagnostic study in four European liver centres. Consecutive alcohol-overusing patients underwent concomitant CAP, regular ultrasound, and liver biopsy. In addition, we measured CAP before and after admission for detoxification in a separate single-centre cohort. RESULTS: A total of 562 patients were included in the study: 269 patients in the diagnostic cohort with steatosis scores S0, S1, S2, and S3â¯=â¯77 (28%), 94 (35%), 64 (24%), and 34 (13%), respectively. CAP diagnosed any steatosis and moderate steatosis with fair accuracy (area under the receiver operating characteristic curve [AUC] ≥S1â¯=â¯0.77; 0.71-0.83 and AUC ≥S2â¯=â¯0.78; 0.72-0.83), and severe steatosis with good accuracy (AUC S3â¯=â¯0.82; 0.75-0.88). CAP was superior to bright liver echo pattern by regular ultrasound. CAP above 290â¯dB/m ruled in any steatosis with 88% specificity and 92% positive predictive value, while CAP below 220â¯dB/m ruled out steatosis with 90% sensitivity, but 62% negative predictive value. In the 293 patients who were admitted 6.3â¯days (interquartile range 4-6) for detoxification, CAP decreased by 32⯱â¯47â¯dB/m (pâ¯<0.001). Body mass index predicted higher CAP in both cohorts, irrespective of drinking pattern. Obese patients with body mass index ≥30â¯kg/m2 had a significantly higher CAP, which did not decrease significantly during detoxification. CONCLUSIONS: CAP has a good diagnostic accuracy for diagnosing severe alcoholic liver steatosis and can be used to rule in any steatosis. In non-obese but not in obese, patients, CAP rapidly declines after alcohol withdrawal. LAY SUMMARY: CAP is a new ultrasound-based technique for measuring fat content in the liver, but has never been tested for fatty liver caused by alcohol. Herein, we examined 562 patients in a multicentre setting. We show that CAP highly correlates with liver fat, and patients with a CAP value above 290â¯dB/m were highly likely to have more than 5% fat in their livers, determined by liver biopsy. CAP was also better than regular ultrasound for determining the severity of alcoholic fatty-liver disease. Finally, we show that three in four (non-obese) patients rapidly decrease in CAP after short-term alcohol withdrawal. In contrast, obese alcohol-overusing patients were more likely to have higher CAP values than lean patients, irrespective of drinking.
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Abstinencia de Alcohol , Hígado Graso Alcohólico/diagnóstico por imagen , Hígado Graso Alcohólico/terapia , Ultrasonografía/métodos , Adulto , Alcoholismo/diagnóstico por imagen , Biopsia , Estudios de Cohortes , Estudios Transversales , Diagnóstico por Imagen de Elasticidad , Femenino , Humanos , Hígado/diagnóstico por imagen , Masculino , Síndrome Metabólico/diagnóstico por imagen , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
Liver stiffness (LS) as measured by transient elastography is widely used to screen for liver fibrosis. However, LS also increases in response to pressure changes like congestion but no data on portal pressure are available. We study here the effect of rapid portal pressure changes on LS. Therefore, LS was assessed directly prior and after ligation of esophageal varices ( n = 11) as well as transjugular intrahepatic portosystemic shunt (TIPS) implantation in patients with established cirrhosis ( n = 14). Additionally, we retrospectively analyzed changes in LS and variceal size in patients with sequential gastroscopic monitoring and LS measurements ( n = 14). To study LS and portal pressure in healthy livers, LS (µFibroscan; Echosens, Paris, France) and invasive pressures (Powerlab, AD Instruments, New Zealand) were assessed in male Wistar rats after ligation of single liver lobes. Ligation of esophageal varices caused an immediate and significant increase of LS from 40.3 ± 19.0 to 56.1 ± 21.5 kPa. Likewise, LS decreased significantly from 53.1 ± 16.6 to 43.8 ± 17.3 kPa after TIPS placement, which correlated significantly with portal pressure ( r = 0.558). In the retrospective cohort, the significant LS decrease from 54.9 ± 23.5 to 47.9 ± 23.8 kPa over a mean observation interval of 4.3 ± 3 mo was significantly correlated with a concomitant increase of variceal size ( r = -0.605). In the animal model, LS and portal pressure increased significantly after single lobe ligation without changes of arterial or central venous pressure. In conclusion, rapid changes of portal pressure are a strong modulator of LS in healthy and cirrhotic organs. In patients with stable cirrhosis according to the model for end-stage liver disease (MELD), a decrease of LS may be indicative for enlarging varices. NEW & NOTEWORTHY Liver stiffness (LS) immediately increases after variceal ligation while it decreases after transjugular intrahepatic portosystemic shunt (TIPS) implantation due to portal pressure changes. LS and portal pressure rapidly increase after single lobe ligation in Wistar rats without changes of arterial or central venous pressure. Collateral formation may be one cause for a transient decrease in LS in the absence of other confounders. Such pressure changes should be considered when interpreting LS in clinical practice.
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Várices Esofágicas y Gástricas/cirugía , Hemorragia Gastrointestinal/cirugía , Técnicas Hemostáticas , Hipertensión Portal/cirugía , Cirrosis Hepática/fisiopatología , Hígado/irrigación sanguínea , Derivación Portosistémica Intrahepática Transyugular , Adulto , Anciano , Animales , Circulación Colateral , Diagnóstico por Imagen de Elasticidad , Várices Esofágicas y Gástricas/diagnóstico , Várices Esofágicas y Gástricas/etiología , Várices Esofágicas y Gástricas/fisiopatología , Femenino , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/fisiopatología , Gastroscopía , Humanos , Hipertensión Portal/diagnóstico , Hipertensión Portal/etiología , Hipertensión Portal/fisiopatología , Ligadura , Hígado/diagnóstico por imagen , Circulación Hepática , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/etiología , Masculino , Persona de Mediana Edad , Presión Portal , Valor Predictivo de las Pruebas , Estudios Prospectivos , Ratas Wistar , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Liver stiffness (LS) as measured by transient elastography is increasingly used to noninvasively assess liver fibrosis. However, LS is efficiently modulated by confounders like arterial and portal pressure (PP). We here study the effect of acute hemodynamic changes on LS (measured by µFibroscan) in a rodent model of cirrhosis in response to pharmacological modulation of PP by losartan, nitric oxide donors, and propranolol. Additionally, changes of LS and the hepatic venous pressure gradient (HVPG) under propranolol therapy were assessed with regard to clinical outcomes in a human cohort of n = 38 cirrhotic patients. In the animal model, cirrhosis induction resulted in a significant increase of LS and PP. After losartan or NO application, a LS decrease of 25% was strongly correlated with a concomitant decrease of mean arterial pressure (MAP) and PP. In contrast, acute propranolol administration decreased heart rate but not MAP resulting in stable LS. In the human cohort, most patients ( n = 25, 66%) showed a LS decrease after propranolol treatment initiation which significantly correlated to HVPG ( r = 0.518, P < 0.01) but was not accompanied by statistically significant changes in transaminases or model of end-stage liver disease (MELD). On multivariate analysis, patients with decreasing LS on propranolol had a decreased risk for experiencing a transplantation or death than patients with increasing LS irrespective of HVPG. In conclusion, LS changes after pharmacological interventions are influenced by hemodynamic effects on arterial and portal pressure. In humans, a LS decrease may be predictive of improved outcome irrespective of MELD scores and may serve as an additional follow-up tool in the future. NEW & NOTEWORTHY Liver stiffness (LS) is efficiently modulated by changes in portal venous and systemic pressures in an animal model of liver cirrhosis irrespective of baseline LS and portal pressure values. In humans, most patients show a decrease in LS after propranolol treatment initiation without statistically significant changes in transaminases or model of end-stage liver disease (MELD) scores. A decrease in LS may be associated with improved outcome and thus another valuable tool in the follow-up of patients after propranolol treatment initiation.
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Antihipertensivos/uso terapéutico , Circulación Hepática , Cirrosis Hepática/tratamiento farmacológico , Hígado/efectos de los fármacos , Losartán/uso terapéutico , Propranolol/uso terapéutico , Adulto , Anciano , Animales , Antihipertensivos/farmacología , Presión Arterial , Diagnóstico por Imagen de Elasticidad , Femenino , Humanos , Hígado/diagnóstico por imagen , Hígado/patología , Cirrosis Hepática/epidemiología , Losartán/farmacología , Masculino , Persona de Mediana Edad , Óxido Nítrico/farmacología , Óxido Nítrico/uso terapéutico , Presión Portal , Propranolol/farmacología , Ratas , Ratas WistarRESUMEN
BACKGROUND: One mechanism by which alcoholic liver disease (ALD) progresses is oxidative stress and the generation of reactive oxygen species, among others due to the induction of cytochrome P-4502E1 (CYP2E1). Experimental data underline the key role of CYP2E1 because ALD could be partially prevented in rats by the administration of the specific CYP2E1 inhibitor chlormethiazole. As CYP2E1 is linked to the formation of carcinogenic etheno DNA adducts in ALD patients, a causal role of alcohol-induced CYP2E1 in hepatocarcinogenesis is implicated. The purpose of this study was to investigate CYP2E1 induction in ALD, and its correlation with oxidative DNA lesions and with hepatic histology. METHODS: Hepatic biopsies from 97 patients diagnosed with ALD were histologically scored for steatosis, inflammation, and fibrosis. CYP2E1 and the exocyclic etheno DNA adduct 1,N6 -etheno-2'deoxyadenosine (εdA) were determined immunohistochemically. In addition, in 42 patients, 8-hydroxydeoxyguanosine (8-OHdG) was also evaluated using immunohistochemistry. RESULTS: A significant positive correlation was found between CYP2E1 and εdA (p < 0.0001) as well as between CYP2E1 and 8-OHdG (p = 0.039). Both CYP2E1 (p = 0.0094) and ÉdA (p < 0.0001) also correlated significantly with the stage of hepatic fibrosis. Furthermore, a significant correlation between the fibrosis stage and the grade of lobular inflammation (p < 0.0001) was observed. However, the amount of alcohol consumed did not correlate with any of the parameters determined. CONCLUSIONS: These data suggest an important role of CYP2E1 in the generation of εdA, in the fibrotic progression of ALD, and thus in alcohol-mediated hepatocarcinogenesis. CYP2E1 may be a target in the treatment of ALD and a potential prognostic marker for disease progression.
Asunto(s)
Carcinogénesis , Citocromo P-450 CYP2E1/metabolismo , Desoxiadenosinas/metabolismo , Hepatopatías Alcohólicas/metabolismo , Hígado/metabolismo , 8-Hidroxi-2'-Desoxicoguanosina , Carcinoma Hepatocelular , Desoxiguanosina/análogos & derivados , Desoxiguanosina/metabolismo , Femenino , Fibrosis , Humanos , Inmunohistoquímica , Inflamación/metabolismo , Inflamación/patología , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Hígado/patología , Cirrosis Hepática Alcohólica/metabolismo , Cirrosis Hepática Alcohólica/patología , Hepatopatías Alcohólicas/patología , Neoplasias Hepáticas , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND & AIMS: Liver iron accumulates in various chronic liver diseases where it is an independent factor for survival and carcinogenesis. We tested a novel room-temperature susceptometer (RTS) to non-invasively assess liver iron concentration (LIC). METHODS: Two hundred and sixty-four patients with or without signs of iron overload or liver disease were prospectively enrolled. Thirty-five patients underwent liver biopsy with semiquantitative iron determination (Prussian Blue staining), atomic absorption spectroscopy (AAS, n=33), or magnetic resonance imaging (MRI, n=15). RESULTS: In vitro studies demonstrated a highly linear (r2=0.998) association between RTS-signal and iron concentration, with a detection limit of 0.3mM. Using an optimized algorithm, accounting for the skin-to-liver capsule distance, valid measurements could be obtained in 84% of cases. LIC-RTS showed a significant correlation with LIC-AAS (r=0.74, p<0.001), LIC-MRI (r=0.64, p<0.001) and hepatocellular iron (r=0.58, p<0.01), but not with macrophage iron (r=0.32, p=0.30). Normal LIC-RTS was 1.4mg/g dry weight. Besides hereditary and transfusional iron overload, LIC-RTS was also significantly elevated in patients with alcoholic liver disease. The areas under the receiver operating characteristic curve (AUROC) for grade 1, 2 and 3 hepatocellular iron overload were 0.72, 0.89 and 0.97, respectively, with cut-off values of 2.0, 4.0 and 5.0mg/g dry weight. Notably, the positive and negative predictive values, sensitivity, specificity and accuracy of severe hepatic iron overload (HIO) (grade ≥2) detection, were equal to AAS and superior to all serum iron markers. Depletion of hepatic iron could be efficiently monitored upon phlebotomy. CONCLUSIONS: RTS allows for the rapid and non-invasive measurement of LIC. In comparison to MRI, it could be a cost-effective bedside method for LIC screening. Lay summary: Novel room-temperature susceptometer (RTS) allows for the rapid, sensitive, and non-invasive measurement of liver iron concentration. In comparison to MRI, it could be a cost-effective bedside method for liver iron concentration screening.
Asunto(s)
Hierro/análisis , Hígado/química , Adulto , Anciano , Femenino , Humanos , Hierro/metabolismo , Hígado/metabolismo , Hígado/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Espectrofotometría Atómica , TemperaturaRESUMEN
Chronical alcohol abuse causes more than 200 diseases and/or symptoms and among these alcoholic liver disease (ALD) is of special importance since it occurs frequently and may be life-threatening. In Europe alcohol consumption as well as ALD increased as compared to the rest of the world. It has been estimated that in Europe approximately 500â000 people die every year due to ALD. ALD consists of alcoholic fatty liver, alcoholic steatohepatitis (ASH), alcoholic cirrhosis and hepatocellar cancer (HCC ). Alcohol hepatitis (AH) is a clinical feature with jaundice and liver failure and a high mortality. The course of ALD is variable and depends among others, on genetics, gender, the presence of other liver diseases as well as exposure towards toxic substances and drugs. The treatment of ALD mainly consists of alcohol abstinence which may be difficult to achieve in the alcoholic. The results of the therapy improve by cognitive psychotherapy as well as antigraving medication. The treatment of AH with poor prognosis is limited. Although a number of therapeutic approaches in AH have been tried, the present therapy consists of intensive care in association with the administration of steroids, hyperalimentation and possibly the administration of N-acetylcystein. Presently it is discussed whether liver transplantation is an option for these patients. New therapeutic approaches focuses on pathopyhsiologically identified targets in ALD. This includes elimination of endotoxines, cytokines, and chemokines as well as an inhibition oxidative stress. Antigraving substances, such as Nalmafen also may improve liver function since their administration degreases alcohol consumption. In addition, betain to stimulate methyltransfer as well the inhibition of apoptosis have been investigated. Stimulation of liver regeneration by granulozytecolony stimulating factor as well as mesenchymalcell and bone marrow transplantation have shown some positive results. Nevertheless new therapeutic strategies are urgently needed. Especially in AH with its high mortality.
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Acetilcisteína/administración & dosificación , Abstinencia de Alcohol , Terapia Cognitivo-Conductual/métodos , Hepatopatías Alcohólicas/diagnóstico , Hepatopatías Alcohólicas/terapia , Trasplante de Hígado/métodos , Esteroides/administración & dosificación , Trasplante de Médula Ósea/métodos , Terapia Combinada/métodos , Medicina Basada en la Evidencia , Predicción , Humanos , Resultado del TratamientoRESUMEN
Noninvasive measurement of liver stiffness (LS) has been established to screen for liver fibrosis. Since LS is also elevated in response to pressure-related conditions such as liver congestion, this study was undertaken to learn more about the role of arterial pressure on LS. LS was measured by transient elastography (µFibroscan platform, Echosens, Paris, France) during single intravenous injections of catecholamines in anesthetized rats with and without thioacetamide (TAA)-induced fibrosis. The effect of vasodilating glycerol trinitrate (GTN) on LS was also studied. Pressures in the abdominal aorta and caval and portal veins were measured in real time with the PowerLab device (AD Instruments, Dunedin, New Zealand). Baseline LS values in all rats (3.8 ± 0.5 kPa, n = 25) did not significantly differ from those in humans. Epinephrine and norepinephrine drastically increased mean arterial pressure (MAP) from 82 to 173 and 156 mmHg. Concomitantly, LS almost doubled from 4 to 8 kPa, while central venous pressure remained unchanged. Likewise, portal pressure only showed a slight and delayed increase. In the TAA-induced fibrosis model, LS increased from 9.5 ± 1.0 to 25.6 ± 14.7 kPa upon epinephrine injection and could efficiently be decreased by GTN. We finally show a direct association in humans in a physiological setting of elevated cardiac output and MAP. During continuous spinning at 200 W, MAP increased from 84 ± 8 to 99 ± 11 mmHg while LS significantly increased from 4.4 ± 1.8 to 6.7 ± 2.1 kPa. In conclusion, our data show that arterial pressure suffices to increase LS. Moreover, lowering MAP efficiently decreases LS in fibrotic livers that are predominantly supplied by arterial blood.
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Presión Arterial/fisiología , Diagnóstico por Imagen de Elasticidad/métodos , Cirrosis Hepática/diagnóstico por imagen , Hígado/diagnóstico por imagen , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/fisiopatología , Catecolaminas/farmacología , Epinefrina/farmacología , Hígado/efectos de los fármacos , Hígado/fisiopatología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/fisiopatología , Masculino , Norepinefrina/farmacología , Ratas , Ratas WistarRESUMEN
The peptide hormone hepcidin regulates mammalian iron homeostasis by blocking ferroportin-mediated iron export from macrophages and the duodenum. During inflammation, hepcidin is strongly induced by interleukin 6, eventually leading to the anemia of chronic disease. Here we show that hepatoma cells and primary hepatocytes strongly up-regulate hepcidin when exposed to low concentrations of H(2)O(2) (0.3-6 µM), concentrations that are comparable with levels of H(2)O(2) released by inflammatory cells. In contrast, bolus treatment of H(2)O(2) has no effect at low concentrations and even suppresses hepcidin at concentrations of >50 µM. H(2)O(2) treatment synergistically stimulates hepcidin promoter activity in combination with recombinant interleukin-6 or bone morphogenetic protein-6 and in a manner that requires a functional STAT3-responsive element. The H(2)O(2)-mediated hepcidin induction requires STAT3 phosphorylation and is effectively blocked by siRNA-mediated STAT3 silencing, overexpression of SOCS3 (suppressor of cytokine signaling 3), and antioxidants such as N-acetylcysteine. Glycoprotein 130 (gp130) is required for H(2)O(2) responsiveness, and Janus kinase 1 (JAK1) is required for adequate basal signaling, whereas Janus kinase 2 (JAK2) is dispensable upstream of STAT3. Importantly, hepcidin levels are also increased by intracellular H(2)O(2) released from the respiratory chain in the presence of rotenone or antimycin A. Our results suggest a novel mechanism of hepcidin regulation by nanomolar levels of sustained H(2)O(2). Thus, similar to cytokines, H(2)O(2) provides an important regulatory link between inflammation and iron metabolism.
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Péptidos Catiónicos Antimicrobianos/metabolismo , Peróxido de Hidrógeno/farmacología , Mediadores de Inflamación/farmacología , Factor de Transcripción STAT3/metabolismo , Regulación hacia Arriba , Acetilcisteína/farmacología , Péptidos Catiónicos Antimicrobianos/genética , Sitios de Unión , Proteína Morfogenética Ósea 6/fisiología , Línea Celular Tumoral , Depuradores de Radicales Libres/farmacología , Hepcidinas , Humanos , Interleucina-6/fisiología , Fosforilación , Regiones Promotoras Genéticas , Procesamiento Proteico-Postraduccional , Transducción de Señal , Transcripción GenéticaRESUMEN
BACKGROUND: Enhanced drug elimination in alcoholics remains largely indefinable. In contrast, the reduced elimination of drugs in patients with advanced alcoholic liver disease (ALD) is normally owing to hepatic end-stage disease such as cirrhosis. We here study the mRNA expression of various hepatic drug metabolizing enzymes and transporters in association with liver stiffness (LS) being a novel noninvasive parameter for the assessment of cirrhosis to unravel the dynamic relationship between ALD and determinants of pharmacokinetics such as drug metabolizing enzymes and transporters. METHODS: We quantified mRNA expression levels of various cytochrome P-450 isoenzymes (CYPs) and drug transporters in 26 liver specimens of chronic alcoholics and 5 controls by quantitative polymerase chain reaction. In addition, liver histology, clinical data, and LS evaluated by transient elastography (Fibroscan) were obtained. RESULTS: Eighteen patients had a normal or moderate LS < 8 kPa (69.2%), while in the remaining 8 patients (30.7%) advanced F3 or F4 fibrosis could be established with an LS > 8 kPa. Overall, CYP3A4, CYP2E1, and solute carrier organic anion transporter 1B1 (SLCO1B1) were negatively correlated with increasing LS. CYPs and drug transporters tended to be up-regulated in alcoholics without advanced fibrosis (LS < 8.0 kPa) compared to healthy controls supporting data of boosted drug elimination in alcoholics without advanced ALD. However, in alcoholics with severely increased LS (>8 kPa), expression levels of CYP2E1, SLC22A2, and SLCO1B1 were significantly lower. CONCLUSIONS: In conclusion, CYPs and drug transporters seem to be induced in chronic alcoholics without irreversible liver damage but decline in case of manifest cirrhosis. Our study also suggests that noninvasive measurements of LS could be useful for pharmacokinetic predictions and individualized pharmacotherapy.
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Sistema Enzimático del Citocromo P-450/farmacocinética , Cirrosis Hepática/metabolismo , Hepatopatías Alcohólicas/metabolismo , Hígado/metabolismo , Transportadores de Anión Orgánico/farmacocinética , Adulto , Sistema Enzimático del Citocromo P-450/biosíntesis , Sistema Enzimático del Citocromo P-450/genética , Diagnóstico por Imagen de Elasticidad/métodos , Femenino , Regulación de la Expresión Génica , Humanos , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/patología , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico/biosíntesis , Transportadores de Anión Orgánico/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Mensajero/farmacocinéticaRESUMEN
Drug-induced liver injury became one of the most important liver disorders and diagnostic challenge for clinicians and pathologists. Here, we report a rare case of ashwagandha-induced acute liver injury. The patient developed jaundice 2 weeks after starting ashwagandha intake and recovered within 5 months after withdrawal without any specific treatment.
RESUMEN
UNLABELLED: A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 × 10(-5) ; P(allelic) = 1.6 × 10(-6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. CONCLUSION: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians.
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Lipasa/genética , Hepatopatías Alcohólicas/genética , Proteínas de la Membrana/genética , Adulto , Anciano , Alanina Transaminasa/sangre , Alcoholismo/genética , Hígado Graso Alcohólico/genética , Femenino , Frecuencia de los Genes , Alemania , Humanos , Cirrosis Hepática Alcohólica/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población Blanca/genéticaRESUMEN
BACKGROUND & AIMS: Liver stiffness (LS) as measured by transient elastography [Fibroscan] offers a novel non-invasive approach to assess liver cirrhosis. Since Fibroscan seems to be unreliable in patients with congestive heart failure, it remains to be determined whether hemodynamic changes affect LS irrespective of fibrosis. METHODS & RESULTS: Using landrace pigs, we studied the direct relationship between the central venous pressure and LS measured by Fibroscan. Clamping of the inferior caval vein increased LS from 3.1 to 27.8kPa while reopening reversed LS within 5min to almost normal values of 5.1kPa. We then studied LS as a function of venous pressure in the isolated pig liver by clamping the upper and lower caval, portal vein and hepatic artery. The stepwise increase of intravenous pressure to 36cm of water column (3.5kPa) linearly and reversibly increased LS to the upper detection limit of 75kPa. We finally measured LS in 10 patients with decompensated congestive heart failure before and after recompensation. Initial LS was elevated in all patients, in 8 of them to a degree that suggested liver cirrhosis (median 40.7kPa). Upon recompensation with a median weight loss of 3.0kg, LS decreased in all 10 patients down to a median LS of 17.8kPa. Inflammation could not account for increased LS since initial liver enzyme counts were only slightly elevated and did not change significantly. CONCLUSION: LS is a direct function of central venous pressure which should be considered when assessing the degree of fibrosis.
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Presión Venosa Central/fisiología , Elasticidad/fisiología , Cirrosis Hepática/diagnóstico , Hígado/irrigación sanguínea , Hígado/fisiología , Anciano , Anciano de 80 o más Años , Animales , Diagnóstico por Imagen de Elasticidad , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Cirrosis Hepática/fisiopatología , Masculino , Persona de Mediana Edad , Sus scrofaRESUMEN
UNLABELLED: Iron in association with reactive oxygen species (ROS) is highly toxic, aggravating oxidative stress reactions. Increased iron not only plays an important role in the progression of hereditary hemochromatosis (HH) but also in common liver diseases such as chronic hepatitis C. The underlying mechanisms of hepatitis C virus (HCV)-mediated iron accumulation, however, are poorly understood. We introduce an in vitro-targeted approach to identify ROS/iron-regulated genes in patients with HCV using a genome-wide DNA microarray. The sensitivity of the 32,231 complementary DNA clone-carrying microarray was approximately 20% as estimated by detecting target genes of the genome-wide transcription factor hypoxia inducible factor 1alpha. Upon in vitro challenge to iron and oxidative stress, 265 iron-related and 1326 ROS-related genes could be identified in HepG2 cells; 233 significantly regulated genes were found in patients with mild (HCV) or severe (HH) iron deposition. Notably, 17 of the in vitro-selected genes corresponded to the genes identified in patients with HCV or HH. Among them, natriuretic peptide precursor B (NPPB) was the only iron-regulated gene identified in vitro that was differentially regulated between HCV and HH. Reverse-transcription polymerase chain reaction confirmed most of the microarray-identified genes in an even larger group of patients (n = 12). In patients with HCV, these included genes that are associated with RNA processing (MED9/NFAT, NSUN2), proliferation, differentiation, hypoxia, or iron metabolism (ISG20, MIG6, HIG2, CA9, NDRG1), whereas none of the nine known iron-related genes showed significant differences between HCV and HH. CONCLUSION: Although high-density microarray technology is less suitable for routine liver diagnosis, its use in combination with prior in vitro selection is a powerful approach to identify candidate genes relevant for liver disease.
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Genoma Humano , Hepatitis C/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Adulto , ADN Complementario/genética , Progresión de la Enfermedad , Hemocromatosis/genética , Hepatitis C/complicaciones , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hierro/metabolismo , Cirrosis Hepática/epidemiología , Persona de Mediana Edad , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Receptores del Factor Natriurético Atrial/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVES: To present a rare case of propofol-induced hepatitis. MATERIALS AND METHODS: A 59-year old man was referred to our department because of suspicion of toxic hepatitis after propofol anaesthesia for endoscopic colonoscopy. RESULTS: The patient had jaundice, increased transaminases demonstrating liver necrosis, and liver stiffness of 18 kPa. Liver biopsy revealed bridging necrosis and initial post-collapse fibrosis. Following therapy with steroids and N-acetyl cysteine, the patient was discharged on the seventh day after admission in good general condition. CONCLUSION: Although propofol is considered safe, it can cause acute hepatitis, the seventh published case of which is reported here. Importantly, treatment with N-acetyl cysteine, a radical scavenger, but especially with steroids resulted in hepatic improvement. LEARNING POINTS: Drug-induced hepatitis is a severe illness caused by a large variety of agents, including many considered safe.It can occur in the absence of predisposing liver abnormality or disease.If the condition is correctly identified, clinical and laboratory abnormalities can be reversed with appropriate treatment.
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The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.
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UNLABELLED: Transient elastography (FibroScan [FS]) is a novel non-invasive tool to assess liver fibrosis/cirrhosis. However, it remains to be determined if other liver diseases such as extrahepatic cholestasis interfere with fibrosis assessment because liver stiffness is indirectly measured by the propagation velocity of an ultrasound wave within the liver. In this study, we measured liver stiffness immediately before endoscopic retrograde cholangiopancreatography and 3 to 12 days after successful biliary drainage in patients with extrahepatic cholestasis mostly due to neoplastic invasion of the biliary tree. Initially elevated liver stiffness decreased in 13 of 15 patients after intervention, in 10 of them markedly. In three patients, liver stiffness was elevated to a degree that suggested advanced liver cirrhosis (mean, 15.2 kPa). Successful drainage led to a drop of bilirubin by 2.8 to 9.8 mg/dL whereas liver stiffness almost normalized (mean, 7.1 kPa). In all patients with successful biliary drainage, the decrease of liver stiffness highly correlated with decreasing bilirubin (Spearman's rho = 0.67, P < 0.05) with a mean decrease of liver stiffness of 1.2 +/- 0.56 kPa per 1 g/dL bilirubin. Two patients, in whom liver stiffness did not decrease despite successful biliary drainage, had advanced liver cirrhosis and multiple liver metastases, respectively. The relationship between extrahepatic cholestasis and liver stiffness was reproduced in an animal model of bile duct ligation in landrace pigs where liver stiffness increased from 4.6 kPa to 8.8 kPa during 120 minutes of bile duct ligation and decreased to 6.1 kPa within 30 minutes after decompression. CONCLUSION: Extrahepatic cholestasis increases liver stiffness irrespective of fibrosis. Once extrahepatic cholestasis is excluded (e.g., by liver imaging and laboratory parameters) transient elastography is a valuable tool to assess liver fibrosis in chronic liver diseases.
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Conductos Biliares/patología , Colestasis Extrahepática/patología , Ictericia Obstructiva/patología , Cirrosis Hepática/patología , Hígado/patología , Adulto , Anciano , Anciano de 80 o más Años , Colestasis Extrahepática/diagnóstico por imagen , Diagnóstico por Imagen de Elasticidad/métodos , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Ictericia Obstructiva/etiología , Cirrosis Hepática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Neoplasias Gástricas/patología , Tomografía Computarizada por Rayos XRESUMEN
The exact regulation of the liver-secreted peptide hepcidin, the key regulator of systemic iron homeostasis, is still poorly understood. It is potently induced by iron, inflammation, cytokines or H2O2 but conflicting results have been reported on hypoxia. In our current study, we first show that pronounced (1%) and mild (5%) hypoxia strongly induces hepcidin in human Huh7 hepatoma and primary liver cells predominantly at the transcriptional level via STAT3 using two hypoxia systems (hypoxia chamber and enzymatic hypoxia by the GOX/CAT system). SiRNA silencing of JAK1, STAT3 and NOX4 diminished the hypoxia-mediated effect while a role of HIF1α could be clearly ruled out by the response to hypoxia-mimetics and competition experiments with a plasmid harboring the oxygen-dependent degradation domain of HIF1α. Specifically, hypoxia drastically enhances the H2O2-mediated induction of hepcidin strongly pointing towards an oxidase as powerful upstream control of hepcidin. We finally provide evidences for an efficient regulation of hepcidin expression by NADPH-dependent oxidase 4 (NOX4) in liver cells. In summary, our data demonstrate that hypoxia strongly potentiates the peroxide-mediated induction of hepcidin via STAT3 signaling pathway. Moreover, oxidases such as NOX4 or artificially overexpressed urate oxidase (UOX) can induce hepcidin. It remains to be studied whether the peroxide-STAT3-hepcidin axis simply acts to continuously compensate for oxygen fluctuations or is directly involved in iron sensing per se.
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Hepcidinas/genética , NADPH Oxidasa 4/genética , Factor de Transcripción STAT3/genética , Hipoxia Tumoral/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Humanos , Peróxido de Hidrógeno/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Hierro/metabolismo , Janus Quinasa 1/genética , Oxígeno/metabolismo , Peróxidos/metabolismo , Transducción de Señal/genética , Urato Oxidasa/genéticaRESUMEN
Alcoholic liver disease (ALD) is a leading health risk worldwide. Hepatic iron overload is frequently observed in ALD patients and it is an important and independent factor for disease progression, survival, and the development of primary liver cancer (HCC). At a systemic level, iron homeostasis is controlled by the liver-secreted hormone hepcidin. Hepcidin regulation is complex and still not completely understood. It is modulated by many pathophysiological conditions associated with ALD, such as inflammation, anemia, oxidative stress/H2O2, or hypoxia. Namely, the data on hypoxia-signaling of hepcidin are conflicting, which seems to be mainly due to interpretational limitations of in vivo data and methodological challenges. Hence, it is often overlooked that hepcidin-secreting hepatocytes are physiologically exposed to 2-7% oxygen, and that key oxygen species such as H2O2 act as signaling messengers in such a hypoxic environment. Indeed, with the recently introduced glucose oxidase/catalase (GOX/CAT) system it has been possible to independently study hypoxia and H2O2 signaling. First preliminary data indicate that hypoxia enhances H2O2-mediated induction of hepcidin, pointing towards oxidases such as NADPH oxidase 4 (NOX4). We here review and discuss novel concepts of hypoxia signaling that could help to better understand hepcidin-associated iron overload in ALD.
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AIM: To investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology. METHODS: Caucasian heavy drinkers (n = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients. RESULTS: The PNPLA3 rs738409 genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005) and less with steatosis (r = 0.264, P < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r = 0.828, P < 0.005), ballooning (r = 0.516, P < 0.005), steatohepatitis (r = 0.319, P < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% vs 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3 G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers. CONCLUSION: In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers.