Henning Wittenburg

HELIOS Klinikum Schleswig, Stadt Schleswig, Schleswig-Holstein, Germany

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Publications (53)231.33 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background. Hepatotoxicity is a major side effect of treatment with bosentan in patients with pulmonary hypertension (PH). Bosentan is metabolized by the cytochrome CYP2C9 and inhibits the bile salt export pump, which is encoded by ABCB11. This suggests that genetic variants of CYP2C9 and/or ABCB11 may predispose patients to bosentan-induced liver injury. Material and methods. PH patients with (n = 23) or without (n = 25) an increase of alanine aminotransferase (ALT) or aspartate-aminotransferase (AST) during bosentan therapy were included in our analysis. Functionally relevant alleles of CYP2C9 and 16 representative variants of ABCB11 were genotyped. Data were analyzed using logistic regression. Results. Variants of ABCB11 were not associated with bosentan-induced liver injury. In contrast, variant alleles of CYP2C9 were more common in patients with elevated transaminases (allele frequency 52%) compared to controls (allele frequency 24%, P = 0.04, odds ratio 3.5, 95% confidence interval 1.01-11.8). Conclusion. Our data indicate hepatotoxicity of bosentan from decreased hepatic metabolism due to common variants of CYP2C9.
    Annals of hepatology. 11/2014; 13(6):803-9.
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    ABSTRACT: Background/Aim: Aberrant adipokine serum concentrations are associated with a variety of obesity-related diseases. This study was designed to investigate the putative role of the adipokines adiponectin, chemerin, progranulin, vaspin, fibroblast growth factor 21 (FGF21) and adipocyte fatty acid binding protein (AFABP) in gallstone disease. Methods: Serum levels of adiponectin, chemerin, progranulin, vaspin, FGF21 and AFABP of 189 gallstone patients and 833 healthy controls were measured by enzyme-linked immunosorbent assays. Results: Increased adiponectin levels were nominally associated with lower gallstone risk in women (p=0.036, odds ratio (OR) 0.47, 95% confidence interval (CI) [0.23; 0.95]). Furthermore progranulin serum concentrations in men were significantly elevated in gallstone carriers in comparison to controls (p=0.012, OR 6.1, 95% CI [1.5; 24.9]). Serum levels of chemerin, vaspin, FGF21 and AFABP did not differ between controls and subjects with gallstones. Conclusion: Our data further support a protective effect of adiponectin on gallstone risk and suggest a role of progranulin in the pathophysiology of cholelithiasis. Nevertheless, longitudinal data and functional analyses would be required to assess the pathogenetic link between gallstone formation and adipokine serum levels.
    Experimental and Clinical Endocrinology & Diabetes 07/2014; · 1.56 Impact Factor
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    ABSTRACT: In some patients with tumors located in the pancreas or in the periampullary region, the decision to perform a surgical resection can be difficult. In patients with concomitant chronic pancreatitis this decision can be even more challenging, since a definitive preoperative differentiation between non-malignant and malignant tumors in many cases is not possible. Clinical symptoms or complications from the tumor often direct a rational treatment strategy. For therapeutic decisions, an interdisciplinary discussion of all diagnostic findings by experienced clinicians is needed. However, in rare cases, like the one presented here, an uncommon non-malignant entity like a periampullary hamartoma may be only diagnosed after surgical resection.
    Pancreatology 05/2013; 13(4):458-60. · 2.04 Impact Factor
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    ABSTRACT: BACKGROUND & AIMS: The sterolin locus (ABCG5/ABCG8) has been solidly shown to confer susceptibility for cholesterol gallstone disease in humans. Both the responsible variant and the molecular mechanism causing an increased incidence of gallstones in these patients have as yet not been identified. METHODS: Genetic mapping utilized patient samples from Germany (2808 cases, 2089 controls), Chile (680 cases, 442 controls), Denmark (366 cases, 766 controls), India (247 cases, 224 controls) and China (280 cases, 244 controls). Analysis of allelic imbalance in cDNA samples from human liver (N=22) was performed using pyrosequencing. Transiently transfected HEK293 cells were used for [3H]-cholesterol export assays, analysis of protein expression and localisation of allelic constructs. RESULTS: Through fine mapping in German and Chilean samples, a ∼250kB disease-associated interval could be defined for this locus. Lack of allelic imbalance or allelic splicing of the ABCG5 and ABCG8 transcripts in human liver limited the search to coding SNPs. Subsequent mutation detection and genotyping yielded two disease-associated variants ABCG5-R50C (p=4.94×10(-9) ) and ABCG8-D19H (p=1.74×10(-10) ) in high pair-wise LD (r(2) =0.95). [3H]-cholesterol export assays of allelic constructs harbouring these genetic candidate variants demonstrated increased transport activity (3.2-fold, p=0.003) only for the ABCG8-19H variant, which was also superior in nested logistic regression models in German (p=0.018), Chilean (p=0.030) and Chinese (p=0.040) patient samples. CONCLUSION: This variant thus provides a molecular basis for biliary cholesterol hypersecretion as the mechanism for cholesterol gallstone formation thereby drawing a link between "post-genomic" and "pre-genomic" pathophysiological knowledge about this common complex disorder. (HEPATOLOGY 2012.).
    Hepatology 08/2012; · 12.00 Impact Factor
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    ABSTRACT: Heme oxygenase 1 (HMOX1) is the rate limiting enzyme in heme degradation and a key regulator of inflammatory processes. In animal models the course of pancreatitis was ameliorated by up-regulation of HMOX1 expression. Additionally, carbon monoxide released during heme breakdown inhibited proliferation of pancreatic stellate cells and might thereby prevent the development of chronic pancreatitis (CP). Transcription of HMOX1 in humans is influenced by a GT-repeat located in the promoter. As such, HMOX1 variants might be of importance in the pathogenesis of pancreatitis. The GT-repeat and SNP rs2071746 were investigated with fluorescence labelled primers and by melting curve analysis in 285 patients with acute pancreatitis, 208 patients with alcoholic CP, 207 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and in 289 controls, respectively. GT-repeat analysis was extended to a total of 446 alcoholic CP patients. In addition, we performed DNA sequencing in 145 patients with alcoholic CP, 138 patients with idiopathic/hereditary CP, 147 patients with alcoholic liver cirrhosis, and 151 controls. Exon 3 screening was extended to additional patients and controls. S- and L-alleles of the GT-repeat, genotypes and alleles of SNP rs2071746 and non-synonymous variants detected by sequencing were found with similar frequencies in all groups. Although functional data implicate a potential influence of HMOX1 variants on the pathogenesis of pancreatitis, we did not find any association. As rare non-synonymous HMOX1 variants were found in patients and controls, it is rather unlikely that they will have functional consequences essential for pancreatitis development.
    PLoS ONE 01/2012; 7(5):e37981. · 3.53 Impact Factor
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    ABSTRACT: Chronic pancreatitis (CP) is an inflammatory disease that in some patients leads to exocrine and endocrine dysfunction. In industrialized countries the most common aetiology is chronic alcohol abuse. Descriptions of associated genetic alterations in alcoholic CP are rare. However, a common PNPLA3 variant (p.I148M) is associated with the development of alcoholic liver cirrhosis (ALC). Since, alcoholic CP and ALC share the same aetiology PNPLA3 variant (p.I148M) possibly influences the development of alcoholic CP. Using melting curve analysis we genotyped the variant in 1510 patients with pancreatitis or liver disease (961 German and Dutch alcoholic CP patients, 414 German patients with idiopathic or hereditary CP, and 135 patients with ALC). In addition, we included in total 2781 healthy controls in the study. The previously published overrepresentation of GG-genotype was replicated in our cohort of ALC (p-value <0.0001, OR 2.3, 95% CI 1.6-3.3). Distributions of genotype and allele frequencies of the p.I148M variant were comparable in patients with alcoholic CP, idiopathic and hereditary CP and in healthy controls. The absence of an association of PNPLA3 p.I148M with alcoholic CP seems not to point to a common pathway in the development of alcoholic CP and alcoholic liver cirrhosis.
    PLoS ONE 01/2012; 7(1):e29433. · 3.53 Impact Factor
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    Inflammatory Bowel Diseases 12/2011; 18(3):E599-600. · 5.12 Impact Factor
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    ABSTRACT: Recently, a single nucleotide polymorphism (SNP) rs9514089 in SLC10A2 (apical sodium-dependent bile acid transporter gene) has been identified as a susceptibility variant for cholelithiasis in humans. Here we assessed the effects of rs9514089 on gallstone risk and related phenotypes of the metabolic syndrome in the self-contained population of Sorbs (183 cases with gallstones/826 controls). Furthermore, we performed a meta-analysis for effects of rs9514089 on susceptibility for cholelithiasis in three independent cohorts (Stuttgart: 56 cases/71 controls, Aachen: 184 cases/184 controls and Sorbs). There was no significant association of rs9514089 with gallstone risk, serum lipid parameters and BMI in the Sorbs and in the meta-analysis of all three cohorts (p > 0.05). There was an effect trend in the subgroup of lean subjects but based on different effect directions in the three cohorts there was no significant association in the meta-analysis. We were not able to replicate the effect of rs9514089 on gallstone risk in the Sorbs. Further analyses in larger cohorts are required to finally assess the role of genetic variants in SLC10A2 in human gallstone development and lipid metabolism.
    BMC Medical Genetics 11/2011; 12:149. · 2.54 Impact Factor
  • H. Wittenburg, U. Tennert, T. Berg
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    ABSTRACT: Komplikationen im Rahmen der Leberzirrhose sind mit einem signifikanten Letalitätsrisiko assoziiert. Das rechtzeitige Erkennen von Komplikationen und deren Therapie ist daher für die Prognose der Patienten wesentlich. Bei Erstdiagnose jeder Leberzirrhose und bei Dekompensationen erfolgt eine Gastroskopie zur Erhebung des Varizenstatus. Zur Primärprophylaxe einer Varizenblutung stehen β-Rezeptorantagonisten und die Gummibandligatur zur Verfügung. Bei erstmaligem Auftreten von Aszites und bei weiteren Komplikationen der Leberzirrhose wie einer hepatischen Enzephalopathie oder eines hepatorenalen Syndroms erfolgt eine Parazentese zum Ausschluss einer spontan-bakteriellen Peritonitis. Das hepatorenale Syndrom kann mit einer Kombinationstherapie aus Vasokonstriktoren und Albumin erfolgreich behandelt werden. Zudem sollte bei Auftreten von Komplikationen der Leberzirrhose stets die Indikation zu einer Lebertransplantation überprüft werden. The occurrence of complications increases the mortality in patients with cirrhosis of the liver. Therefore, early detection and treatment of complications of cirrhosis is of major importance. Following diagnosis of cirrhosis, a screening gastroscopy detects esophageal varices. Primary prevention of variceal bleeding can be initiated with β-receptor antagonists or variceal band ligation. With the first episode of ascites or the manifestation of other complications of cirrhosis such as hepatic encephalopathy and hepatorenal syndrome, a paracentesis excludes spontaneous bacterial peritonitis. Hepatorenal syndrome can be treated with a combination of vasopressors and albumine. Furthermore, occurrence of complications in patients with cirrhosis of the liver should prompt the evaluation of an indication for liver transplantation. SchlüsselwörterÖsophagusvarizen–Aszites–Spontan-bakterielle Peritonitis–Hepatorenales Syndrom–Hepatische Enzephalopathie KeywordsEsophageal varices–Ascites–Spontaneous bacterial peritonitis–Hepatorenal syndrome–Hepatic encephalopathy
    Der Internist 09/2011; 52(9):1061-1072. · 0.33 Impact Factor
  • H Wittenburg, U Tennert, T Berg
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    ABSTRACT: The occurrence of complications increases the mortality in patients with cirrhosis of the liver. Therefore, early detection and treatment of complications of cirrhosis is of major importance. Following diagnosis of cirrhosis, a screening gastroscopy detects esophageal varices. Primary prevention of variceal bleeding can be initiated with β-receptor antagonists or variceal band ligation. With the first episode of ascites or the manifestation of other complications of cirrhosis such as hepatic encephalopathy and hepatorenal syndrome, a paracentesis excludes spontaneous bacterial peritonitis. Hepatorenal syndrome can be treated with a combination of vasopressors and albumine. Furthermore, occurrence of complications in patients with cirrhosis of the liver should prompt the evaluation of an indication for liver transplantation.
    Der Internist 05/2011; 52(9):1061-70; quiz 1071-2. · 0.33 Impact Factor
  • Gastroenterology 01/2011; 140(5). · 12.82 Impact Factor
  • Henning Wittenburg
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    ABSTRACT: Gallstones are common in Western countries and due to pain and complications pose a substantial burden on health care systems. In general, cholesterol gallstones are distinguished from bilirubin gallstones. Bilirubin gallstones form if the ion product of unconjugated bilirubin and calcium in gallbladder bile exceeds the solubilisation capacities of mixed micelles and vesicles. Cholesterol gallstones develop if the amount of cholesterol in gallbladder bile exceeds the maximum concentration that is soluble at the given concentration of bile salts and phospholipids. In addition, cholesterol gallstone formation requires hypomotility of the gallbladder and a mucin gel as nucleation matrix for monohydrate crystals. The individual risk of gallstone formation is determined by interactions of lithogenic alleles of gallstone susceptibility genes and multiple environmental factors. For asymptomatic gallstones, expectant management is recommended, whereas an episode of gallstone-associated pain substantially increases the risk of complications such as cholecystitis, cholangitis and pancreatitis and therefore necessitates cholecystectomy.
    Best practice & research. Clinical gastroenterology 10/2010; 24(5):747-56. · 2.48 Impact Factor
  • H. Wittenburg, U. Tennert, J. Mössner
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    ABSTRACT: Der Dünndarm besitzt zahlreiche hormonale und metabolische Funktionen, für die neben den Enterozyten enteroendokrine Zellen in der Mukosa verantwortlich sind. So führt eine Freisetzung von Cholezystokinin zu einer Sekretion von Pankreasenzymen und einer Gallenblasenkontraktion. Kürzlich wurde eine hormonelle Regulierung der Gallenblasenfüllung durch das Hormon FGF-15/19 beschrieben, das vermittelt durch Gallensalze aus Enterozyten des terminalen Ileums sezerniert wird und daneben eine Verminderung der Gallensäure- und Fettsäuresynthese sowie eine Hemmung der Glukoneogenese bewirkt. Mit Ghrelin ist ein intestinales Hormon bekannt, das die Nahrungsaufnahme steigert. Dem stehen eine Reihe von Sättigungshormonen wie z. B. Cholezystokinin und Glucagon-like Peptide gegenüber, durch deren Wirkung die Nahrungsaufnahme gehemmt wird. Die Kenntnis dieser Hormone und ihrer Funktionen ist für das Verständnis der Stoffwechselkontrolle und der Pathophysiologie zahlreicher Erkrankungen wesentlich. Hieraus ergeben sich pharmakologische Ansätze z.B. zur Behandlung von Motilitätsstörungen, des Diabetes mellitus Typ2, der nicht-alkoholischen Fettlebererkrankung und der Adipositas. The small intestine exhibits numerous hormonal and metabolic functions. These are mediated by enteroendocrine cells that are expressed in addition to enterocytes in the mucosa of the small intestine. The release of cholecystokinin causes the secretion of pancreatic enzymes and a contraction of the gallbladder. Recently, a hormonal regulation of gallbladder filling was confirmed. This is mediated by the hormone FGF15/19 which is secreted by enterocytes of the terminal ileum following induction of its expression by bile acids. In addition, FGF15/19 reduces synthesis of bile acids and fatty acids and inhibits gluconeogenesis. Ghrelin is the only intestinal hormone that increases food intake. Contrary, a number of hormones such as cholecystokinin and glucagon-like peptide are expressed in the small intestine and mediate satiation. Knowledge of the intestinal hormones and their functions is important for the full understanding of metabolic control and provides targets for innovative therapy of several diseases such as diabetes type2, non-alcoholic steatohepatitis and obesity. SchlüsselwörterDünndarm-Gallenblasenmotilität-Energiehaushalt-Sättigungshormon-Ghrelin KeywordsSmall intestine-Gallbladder motility-Energy balance-Satiation hormone-Ghrelin
    Der Internist 06/2010; 51(6):695-701. · 0.33 Impact Factor
  • H Wittenburg, U Tennert, J Mössner
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    ABSTRACT: The small intestine exhibits numerous hormonal and metabolic functions. These are mediated by enteroendocrine cells that are expressed in addition to enterocytes in the mucosa of the small intestine. The release of cholecystokinin causes the secretion of pancreatic enzymes and a contraction of the gallbladder. Recently, a hormonal regulation of gallbladder filling was confirmed. This is mediated by the hormone FGF15/19 which is secreted by enterocytes of the terminal ileum following induction of its expression by bile acids. In addition, FGF15/19 reduces synthesis of bile acids and fatty acids and inhibits gluconeogenesis. Ghrelin is the only intestinal hormone that increases food intake. Contrary, a number of hormones such as cholecystokinin and glucagon-like peptide are expressed in the small intestine and mediate satiation. Knowledge of the intestinal hormones and their functions is important for the full understanding of metabolic control and provides targets for innovative therapy of several diseases such as diabetes type 2, non-alcoholic steatohepatitis and obesity.
    Der Internist 04/2010; 51(6):695-701. · 0.33 Impact Factor
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    ABSTRACT: Human trypsinogens are post-translationally sulfated on Tyr154 by the Golgi resident enzyme tyrosylprotein sulfotransferase-2 (TPST2). Tyrosine sulfation stimulates the autoactivation of human cationic trypsinogen. Because increased trypsinogen autoactivation has been implicated as a pathogenic mechanism in chronic pancreatitis, we hypothesized that genetic variants of TPST2 might alter the risk for the disease. We sequenced the 4 protein-coding exons and the adjacent intronic sequences of TPST2 in 151 subjects with chronic pancreatitis and in 169 healthy controls. The functional effect of TPST2 variants on trypsinogen sulfation was analyzed in transfected HEK 293T cells. We detected 10 common polymorphic variants, including 6 synonymous variants and 4 intronic variants, with similar frequencies in patients and controls. None of the 8 common haplotypes reconstructed from the frequent variants showed an association with chronic pancreatitis. In addition, we identified 5 rare TPST2 variants, which included 3 synonymous alterations, the c.458G>A (p.R153H) nonsynonymous variant and the c.-9C>T variant in the 5' untranslated region. The p.R153H variant was found in a family with hereditary pancreatitis; however, it did not segregate with the disease. In functional assays, both the p.R153H and c.-9C>T TPST2 variants catalyzed trypsinogen sulfation as well as wild-type TPST2. Genetic variants of human TPST2 exert no influence on the risk of chronic pancreatitis.
    Pancreatology 01/2010; 10(2-3):165-72. · 2.04 Impact Factor
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    ABSTRACT: A sustained imbalance of pancreatic proteases and their inhibitors seems to be important for the development of chronic pancreatitis (CP). Mesotrypsin (PRSS3) can degrade intrapancreatic trypsin inhibitors that protect against CP. Genetic variants that cause higher mesotrypsin activity might increase the risk for CP. We analyzed all 5 exons and the adjacent non-coding sequences of PRSS3 by direct sequencing of 313 CP patients and 327 controls. Additionally, exon 4 was investigated in 855 patients and 1,294 controls and a c.454+191G>A variant in 855 patients and 1,467 controls. The c.499A>G (p.T167A) variant was analyzed functionally using transiently transfected HEK 293T cells. In the exonic regions, the previously described common c.94_96delGAG (p.E32del) variant and a novel p.T167A non-synonymous alteration were identified. Extended analysis of the p.T167A variant revealed no association to CP and in functional assays p.T167A showed normal secretion and activity. Variants of the intronic regions, including the extensively analyzed c.454+191G>A alteration, were not associated with the disease. Haplotype reconstruction using variants with a minor allele frequency of >1% revealed no CP-associated haplotype. Although the trypsin inhibitor-degrading activity qualified PRSS3 as a candidate for a novel CP susceptibility gene, we found no association between a specific variant or haplotype and CP in our cohort with a high suspicion of genetically determined disease.
    Pancreatology 01/2010; 10(2-3):243-9. · 2.04 Impact Factor
  • Zeitschrift Fur Gastroenterologie - Z GASTROENTEROL. 01/2010; 48(08).
  • Gastroenterology 01/2010; 138(5). · 12.82 Impact Factor
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    ABSTRACT: The spontaneous mouse mutation "thrombocytopenia and cardiomyopathy" (trac) causes macrothrombocytopenia, prolonged bleeding times, anemia, leukopenia, infertility, cardiomyopathy, and shortened life span. Homozygotes show a 20-fold decrease in platelet numbers and a 3-fold increase in platelet size with structural alterations and functional impairments in activation and aggregation. Megakaryocytes in trac/trac mice are present in increased numbers, have poorly developed demarcation membrane systems, and have decreased polyploidy. The thrombocytopenia is not intrinsic to defects at the level of hematopoietic progenitor cells but is associated with a microenvironmental abnormality. The trac mutation maps to mouse chromosome 17, syntenic with human chromosome 2p21-22. A G to A mutation in exon 10 of the adenosine triphosphate (ATP)-binding cassette subfamily G, member 5 (Abcg5) gene, alters a tryptophan codon (UGG) to a premature stop codon (UAG). Crosses with mice doubly transgenic for the human ABCG5 and ABCG8 genes rescued platelet counts and volumes. ABCG5 and ABCG8 form a functional complex that limits dietary phytosterol accumulation. Phytosterolemia in trac/trac mice confirmed a functional defect in the ABCG5/ABCG8 transport system. The trac mutation provides a new clinically significant animal model for human phytosterolemia and provides a new means for studying the role of phytosterols in hematologic diseases and testing therapeutic interventions.
    Blood 10/2009; 115(6):1267-76. · 9.78 Impact Factor
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    Annals of hepatology: official journal of the Mexican Association of Hepatology 09/2009; 8(4):388-9. · 1.67 Impact Factor

Publication Stats

646 Citations
231.33 Total Impact Points

Institutions

  • 2014
    • HELIOS Klinikum Schleswig
      Stadt Schleswig, Schleswig-Holstein, Germany
  • 2007–2014
    • University of Leipzig
      • • Interdisciplinary Centre for Clinical Research
      • • Klinik und Poliklinik für Gastroenterologie und Rheumatologie
      Leipzig, Saxony, Germany
  • 2006–2007
    • University of Western Australia
      • Western Australian Institute for Medical Research (WAIMR)
      Perth, Western Australia, Australia
  • 2002–2006
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
    • University Hospital RWTH Aachen
      Aachen, North Rhine-Westphalia, Germany
  • 2003
    • The Jackson Laboratory
      Bar Harbor, Maine, United States