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Sökning: L773:0270 9139 OR L773:1527 3350 > Marschall Hanns Ulrich

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1.
  • Abu-Hayyeh, Shadi, et al. (författare)
  • Intrahepatic cholestasis of pregnancy levels of sulfated progesterone metabolites inhibit farnesoid X receptor resulting in a cholestatic phenotype.
  • 2013
  • Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 57:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here we report that the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate is supraphysiologically raised in the serum of ICP patients. Mice challenged with cholic acid developed hypercholanemia and a hepatic gene expression profile indicative of FXR activation. However, coadministration of epiallopregnanolone sulfate with cholic acid exacerbated the hypercholanemia and resulted in aberrant gene expression profiles for hepatic bile acid-responsive genes consistent with cholestasis. We demonstrate that levels of epiallopregnanolone sulfate found in ICP can function as a partial agonist for FXR, resulting in the aberrant expression of bile acid homeostasis genes in hepatoma cell lines and primary human hepatocytes. Furthermore, epiallopregnanolone sulfate inhibition of FXR results in reduced FXR-mediated bile acid efflux and secreted FGF19. Using cofactor recruitment assays, we show that epiallopregnanolone sulfate competitively inhibits bile acid-mediated recruitment of cofactor motifs to the FXR-ligand binding domain. Conclusion: Our results reveal a novel molecular interaction between ICP-associated levels of the 3β-sulfated progesterone metabolite epiallopregnanolone sulfate and FXR that couples the endocrine component of pregnancy in ICP to abnormal bile acid homeostasis. (HEPATOLOGY 2012;).
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2.
  • Abu-Hayyeh, S., et al. (författare)
  • Prognostic and Mechanistic Potential of Progesterone Sulfates in Intrahepatic Cholestasis of Pregnancy and Pruritus Gravidarum
  • 2016
  • Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 0270-9139 .- 1527-3350. ; 63:4, s. 1287-1298
  • Tidskriftsartikel (refereegranskat)abstract
    • A challenge in obstetrics is to distinguish pathological symptoms from those associated with normal changes of pregnancy, typified by the need to differentiate whether gestational pruritus of the skin is an early symptom of intrahepatic cholestasis of pregnancy (ICP) or due to benign pruritus gravidarum. ICP is characterized by raised serum bile acids and complicated by spontaneous preterm labor and stillbirth. A biomarker for ICP would be invaluable for early diagnosis and treatment and to enable its differentiation from other maternal diseases. Three progesterone sulfate compounds, whose concentrations have not previously been studied, were newly synthesized and assayed in the serum of three groups of ICP patients and found to be significantly higher in ICP at 9-15 weeks of gestation and prior to symptom onset (group 1 cases/samples: ICP n = 35/80, uncomplicated pregnancy = 29/100), demonstrating that all three progesterone sulfates are prognostic for ICP. Concentrations of progesterone sulfates were associated with itch severity and, in combination with autotaxin, distinguished pregnant women with itch that would subsequently develop ICP from pruritus gravidarum (group 2: ICP n = 41, pruritus gravidarum n = 14). In a third group of first-trimester samples all progesterone sulfates were significantly elevated in serum from low-risk asymptomatic women who subsequently developed ICP (ICP/uncomplicated pregnancy n = 54/51). Finally, we show mechanistically that progesterone sulfates mediate itch by evoking a Tgr5-dependent scratch response in mice. Conclusion: Our discovery that sulfated progesterone metabolites are a prognostic indicator for ICP will help predict onset of ICP and distinguish it from benign pruritus gravidarum, enabling targeted obstetric care to a high-risk population. Delineation of a progesterone sulfate-TGR5 pruritus axis identifies a therapeutic target for itch management in ICP.
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4.
  • Hirschfield, Gideon M, et al. (författare)
  • Ustekinumab for patients with primary biliary cholangitis who have an inadequate response to Ursodeoxycholic Acid: a proof-of-concept study.
  • 2016
  • Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 64:1, s. 189-199
  • Tidskriftsartikel (refereegranskat)abstract
    • The interleukin (IL)-12 signaling cascade has been associated with primary biliary cholangitis (PBC). This multicenter, open-label, proof-of-concept study evaluated the anti-IL12/23 monoclonal antibody ustekinumab (90 mg subcutaneous at weeks 0 and 4, then every 8 weeks through week 20) in adults with PBC and an inadequate response to ursodeoxycholic acid therapy (i.e., alkaline phosphatase [ALP] >1.67x upper limit of normal [ULN] after ≥6 months). ALP response was defined as a >40% decrease from baseline, and ALP remission as ALP normalization (if baseline ALP 1.67x-2.8x ULN) or <1.67x ULN (if baseline ALP >2.8x ULN). Changes in Enhanced Liver Fibrosis (ELF) scores and serum bile acids were also assessed. At baseline, patients had median disease duration of 3.2 years, median ELF score of 9.8, and highly elevated total bile acid concentration (median: 43.3 µmol/L); 13/20 (65%) patients had baseline ALP >3x ULN. Although steady-state serum ustekinumab concentrations were reached by week 12, no patient achieved ALP response or remission. The median percent ALP reduction from baseline to week 28 was 12.1%. The ELF score decreased slightly from baseline to week 28 (median reduction: 0.173), and total serum bile acid concentrations decreased from baseline to week 28 (median reduction: 8.8 µmol/L). No serious infections or discontinuations due to adverse events were reported through week 28. One patient had a serious upper gastrointestinal hemorrhage considered unrelated to test agent by the investigator.
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6.
  • Kowdley, Kris V, et al. (författare)
  • A randomized trial of obeticholic acid monotherapy in patients with primary biliary cholangitis.
  • 2018
  • Ingår i: Hepatology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 67:5, s. 1890-1902
  • Tidskriftsartikel (refereegranskat)abstract
    • Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus.OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2017).
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7.
  • Ludvigsson, Jonas F., 1969-, et al. (författare)
  • Pregnancy Outcome in Women Undergoing Liver Biopsy During Pregnancy: A Nationwide Population-Based Cohort Study.
  • 2018
  • Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 68:2, s. 625-633
  • Tidskriftsartikel (refereegranskat)abstract
    • Liver biopsy is an important procedure in the investigation of liver disease. We examined pregnancy outcomes in women who underwent liver biopsy during pregnancy. In a nationwide population-based cohort study we linked data from the Swedish Medical Birth Registry (for births between 1992 and 2011) with those from the Swedish Patient Registry. We identified 23 pregnancies exposed to liver biopsy. We calculated relative risks (RRs) for adverse pregnancy outcomes according to liver biopsy status using 1,953,887 unexposed pregnancies with and without a record of liver disease as reference. Our main outcome measures were stillbirth and preterm birth. There were no stillbirths in pregnancies exposed to liver biopsies compared with 0.3% stillbirths in unexposed pregnancies. 3/23 (13%) exposed pregnancies were preterm (RR=2.6; 95%CI=0.9-7.5). Compared with women with a record of liver disease, preterm birth was not increased in those exposed to liver biopsy (RR=0.9; 95%CI=0.1-6.0). Except for an increased risk of small for gestational age birth in pregnancies exposed to liver biopsy (RR=5.2; 95%CI=1.8-14.8), other adverse pregnancy outcomes were independent of liver biopsy status when the analysis was restricted to women with a diagnosis of liver disease. Compared with unexposed sibling pregnancies, pregnancies with a liver biopsy were 7 days shorter, but birth weights did not differ between the siblings (-67g; p>0.05).Apart from a moderately increased risk of preterm birth and small for gestational age, there was no association between liver biopsy during pregnancy and adverse pregnancy outcome. Potential excess risks should be weighed against the advantages of having a liver biopsy that may influence clinical management of the patient indirectly influencing fetal health. This article is protected by copyright. All rights reserved.
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8.
  • Mahlapuu, Margit, 1972, et al. (författare)
  • FGF21 signaling - the liver in focus.
  • 2016
  • Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 64:2
  • Tidskriftsartikel (refereegranskat)
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10.
  • Marschall, Hanns-Ulrich, et al. (författare)
  • Intrahepatic cholestasis of pregnancy and associated hepatobiliary disease: A population based cohort study.
  • 2013
  • Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 58:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease in pregnancy. We aimed to estimate the risk of developing hepatobiliary diseases in women with ICP and the odds of developing ICP in women with prevalent hepatobiliary diseases. We analyzed data of women with births between 1973 and 2009 and registered in the Swedish Medical Birth Register. By linkage with the Swedish Patient Register, we identified 11,388 women with ICP who were matched to 113,893 women without this diagnosis. Diagnoses of preexisting or later hepatobiliary disease were obtained from the Patient Register. Main outcome measures were hazard ratios (HRs) for later hepatobiliary disease in women with ICP and odds ratios (ORs) for developing ICP in preexisting hepatobiliary disease. Risk estimates were calculated through Cox and logistic regression analyses. Women with ICP were more often diagnosed with later hepatobiliary disease (HR 2.62; 95% CI 2.47-2.77; increment at 1% per year), hepatitis C or chronic hepatitis (HR 4.16; 3.14-5.51 and 5.96; 3.43-10.33, respectively), fibrosis/cirrhosis (HR 5.11; 3.29 -7.96), gallstone disease or cholangitis (HR 2.72; 2.55-2.91, and 4.22; 3.13-5.69, respectively) as compared to women without ICP (p<0.001 for all HRs). Later ICP was more common in women with prepregnancy hepatitis C (OR 5.76; 1.30-25.44; p=0.021), chronic hepatitis (OR 8.66; 1.05-71.48; p=0.045), and gallstone disease, (OR 3.29; 2.02-5.36; p<0.0001). Conclusion: Women with ICP have substantially increased risk for later hepatobiliary disease. We found beyond gallstone-related morbidity a strong positive association between ICP and hepatitis C both before and after ICP diagnosis. Thus, we advocate testing for hepatitis C in women with ICP, in particular, since this potentially life-threatening infection can be treated successfully in the majority of patients. (HEPATOLOGY 2013.).
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