Publications by authors named "Hartmut H-J Schmidt"

66 Publications

Association of contact to small children with a mild course of COVID-19.

Int J Infect Dis 2020 Nov 5;100:314-315. Epub 2020 Sep 5.

Medizinische Klinik B (Gastroenterologie, Hepatologie, Endokrinologie, Klinische Infektiologie), University Hospital Münster, Germany.

It is known that severe COVID-19 cases in small children are rare. If a childhood-related infection were protective against a severe course of COVID-19, it would be expected that adults with intensive and regular contact with small children also may have a mild course of COVID-19 more frequently. To test this hypothesis, a survey among 4010 recovered COVID-19 patients was conducted in Germany. 1186 complete answers were collected. 6.9% of these patients reported frequent and regular job-related contact with children below ten years of age, and 23.2% had their own small children, which was higher than expected. In the relatively small subgroup with intensive care treatment (n = 19), patients without contact with small children were overrepresented. These findings are not well explained by age, gender, or BMI distribution of those patients and should be validated in other settings.
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http://dx.doi.org/10.1016/j.ijid.2020.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832519PMC
November 2020

SERPINA1 modulates expression of amyloidogenic transthyretin.

Exp Cell Res 2020 10 5;395(2):112217. Epub 2020 Aug 5.

Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany. Electronic address:

Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum TTR, achieved via silencing oligonucleotides, was introduced as therapy of ATTR amyloidosis. We explored the impact of Serpin Family A Member 1 (SERPINA1) on TTR mRNA and protein expression. Oncostatin M (OSM) induced SERPINA1 in hepatoma cells and mice, while concomitantly TTR expression was significantly reduced. SERPINA1 knockdown resulted in specific elevated TTR expression in hepatoma cells; however other genes belonging to the group of acute phase proteins were unaffected. In mice, serum TTR was elevated after mSERPINA1 knockdown throughout antisense treatment. Following SERPINA1 knockdown, TTR deposition in several tissues, including dorsal root ganglia and intestine, was found to be increased, however numbers did not exceed significance levels. The data suggest that SERPINA1 is a co-factor of TTR expression. Our findings provide novel insight in the regulation of TTR and reveal a role of SERPINA1 in the pathogenesis of ATTR amyloidosis.
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http://dx.doi.org/10.1016/j.yexcr.2020.112217DOI Listing
October 2020

Immune-Mediated Hepatitis Induced by Therapy With Alemtuzumab in a Patient With Multiple Sclerosis.

Hepatology 2021 Jan 14;73(1):460-463. Epub 2020 Dec 14.

Department of Internal Medicine B, University Hospital Münster, Münster, Germany.

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http://dx.doi.org/10.1002/hep.31435DOI Listing
January 2021

Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

Amyloid 2020 Sep 4;27(3):153-162. Epub 2020 Mar 4.

Assistance Publique-Hôpitaux de Paris (APHP), French National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire Bicêtre, Universite Paris-Sud, INSERM Unite, Paris, France.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, fatal, multisystem disease leading to deteriorating quality of life (QOL). The impact of patisiran on QOL in patients with hATTR amyloidosis with polyneuropathy from the phase 3 APOLLO study (NCT01960348) is evaluated. Patients received either patisiran 0.3 mg/kg ( = 148) or placebo ( = 77) intravenously once every three weeks for 18 months. Multiple measures were used to assess varying aspects of QOL. At 18 months, compared with placebo, patisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score; (least squares [LS] mean difference: -21.1;  = 1.10 × 10; improved across all domains), EuroQoL 5-dimensions 5-levels (LS mean difference: 0.2;  = 1.4 × 10), EuroQoL-visual analog scale (LS mean difference: 9.5; =.0004), Rasch-built Overall Disability Scale (LS mean difference: 9.0;  = 4.07 × 10) and Composite Autonomic Symptom Score-31(COMPASS-31; LS mean difference: -7.5; =.0008). Placebo-treated patients experienced rapid QOL deterioration; treatment effects for patisiran were observed as early as 9 months. At 18 months, patisiran improved Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline. Consistent benefits were also observed in the cardiac subpopulation. The benefits of patisiran across all QOL measures and the rapid deterioration observed with placebo, highlight the urgency in early treatment for patients with hATTR amyloidosis with polyneuropathy.
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http://dx.doi.org/10.1080/13506129.2020.1730790DOI Listing
September 2020

Silymarin as Supportive Treatment in Liver Diseases: A Narrative Review.

Adv Ther 2020 04 17;37(4):1279-1301. Epub 2020 Feb 17.

Department of Medicine B for Gastroenterology and Hepatology, University Hospital Muenster, Muenster, Germany.

Silymarin, an extract from milk thistle seeds, has been used for centuries to treat hepatic conditions. Preclinical data indicate that silymarin can reduce oxidative stress and consequent cytotoxicity, thereby protecting intact liver cells or cells not yet irreversibly damaged. Eurosil 85 is a proprietary formulation developed to maximize the oral bioavailability of silymarin. Most of the clinical research on silymarin has used this formulation. Silymarin acts as a free radical scavenger and modulates enzymes associated with the development of cellular damage, fibrosis and cirrhosis. These hepatoprotective effects were observed in clinical studies in patients with alcoholic or non-alcoholic fatty liver disease, including patients with cirrhosis. In a pooled analysis of trials in patients with cirrhosis, silymarin treatment was associated with a significant reduction in liver-related deaths. Moreover, in patients with diabetes and alcoholic cirrhosis, silymarin was also able to improve glycemic parameters. Patients with drug-induced liver injuries were also successfully treated with silymarin. Silymarin is generally very well tolerated, with a low incidence of adverse events and no treatment-related serious adverse events or deaths reported in clinical trials. For maximum benefit, treatment with silymarin should be initiated as early as possible in patients with fatty liver disease and other distinct liver disease manifestations such as acute liver failure, when the regenerative potential of the liver is still high and when removal of oxidative stress, the cause of cytotoxicity, can achieve the best results.
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http://dx.doi.org/10.1007/s12325-020-01251-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140758PMC
April 2020

APOE polymorphism in ATTR amyloidosis patients treated with lipid nanoparticle siRNA.

Amyloid 2020 Mar 25;27(1):45-51. Epub 2019 Oct 25.

Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, Münster, Germany.

The novel class of compounds represented by lipid nanoparticle (LNP)-encapsulated siRNA formulations has an enormous potential to target disease, notably of the liver. Endocytosis of LNPs is believed to be mediated by APOE, an important serum protein of lipoprotein homeostasis. APOE polymorphisms affect binding to hepatic receptors and have been associated with development of specific disease. Here, the role of APOE was investigated with regard to the efficacy of Patisiran, the first LNP-siRNA recently approved for clinical use in patients having transthyretin amyloidosis (ATTR amyloidosis). Patisiran was evaluated in the human hepatoma cell line HepG2 after knockdown of APOE. The APOE genotype was determined in ATTR amyloidosis patients treated with Patisiran. TTR knockdown was monitored in consecutive plasma up to week 12. Downregulation of APOE suppressed efficacy of Patisiran in HepG2 cells. TTR levels were found to be robustly reduced (84.7% ± 1%) following Patisiran treatment in patients plasma. Analysis of APOE polymorphisms in ATTR amyloidosis patients revealed three most frequent genotypes E3/3, E3/4 and E3/2. APOE stratification of patients did not show significant differences of TTR plasma concentrations following treatment. Our results suggest that APOE is an important mediator of TTR silencing by Patisiran, however efficacy is independent of the APOE genotype.
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http://dx.doi.org/10.1080/13506129.2019.1681392DOI Listing
March 2020

Hepatocyte-like cells reveal novel role of SERPINA1 in transthyretin amyloidosis.

J Cell Sci 2018 11 26;131(23). Epub 2018 Nov 26.

Medizinische Klinik B für Gastroenterologie und Hepatologie, Universitätsklinikum Münster, 48149 Münster, Germany

Transthyretin (TTR)-related familial amyloid polyneuropathy (ATTR) results from aggregation and extracellular disposition of misfolded TTR mutants. Growing evidence suggests the importance of hepatic chaperones for the modulation of pathogenesis. We took advantage of induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from ATTR patients (ATTR-HLCs) to compare chaperone gene expression to that in HLCs from healthy individuals (H-HLCs). From the set of genes analyzed, chaperones that are predominantly located extracellularly were differently expressed. Expression of the chaperones showed a high correlation with in both ATTR-HLCs and H-HLCs. In contrast, after knockdown, the correlation was mainly affected in ATTR-HLCs suggesting that differences in TTR expression triggers aberrant chaperone expression. Serpin family A member 1 (SERPINA1) was the only extracellular chaperone that was markedly upregulated after knockdown in ATTR-HLCs. Co-immunoprecipitation revealed that SERPINA1 physically interacts with TTR. assays indicated that SERPINA1 can interfere with TTR aggregation. Taken together, our results suggest that extracellular chaperones play a crucial role in ATTR pathogenesis, in particular SERPINA1, which may affect amyloid formation.
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http://dx.doi.org/10.1242/jcs.219824DOI Listing
November 2018

[Transthyretin Familial Amyloid Polyneuropathy - Disease Profile of a Multisystem Disorder].

Dtsch Med Wochenschr 2018 Mar 15;143(6):427-430. Epub 2018 Mar 15.

Transthyretin-related Familial Amyloid Polyneuropathy (ATTR Amyloidosis, former FAP, here called TTR-FAP) is a rare, progressive autosomal dominant inherited amyloid disease ending fatal within 5 - 15 years after final diagnosis. TTR-FAP is caused by mutations of transthyretin (TTR), which forms amyloid fibrils affecting peripheral and autonomic nerves, the heart and other organs. Due to the phenotypic heterogeneity and partly not specific enough clinical symptoms, diagnosis of TTR-FAP can be complicated. False diagnoses can include idiopathic polyneuropathy, chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy as well as paraneoplastic syndrome. Hence, it is assumed that many cases remain unreported. Early and correct diagnosis of TTR-FAP is crucial, since appropriate therapeutic options exist. TTR-FAP should always be differentially diagnosed, when apart from a progressive peripheral polyneuropathy, additional symptoms as autonomic dysfunction, cardiomyopathy, gastrointestinal disorders, unexpected loss of weight, carpal tunnel syndrome, restrictions of renal function, epileptic fits, and corneal and vitreous body clouding occur. Histological evidence of amyloid and successive immunohistochemical evidence of transthyretin as well as genetic testing for transthyretin mutations, lead to an accurate diagnosis.
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http://dx.doi.org/10.1055/s-0043-123681DOI Listing
March 2018

Spatial investigation of the elemental distribution in Wilson's disease liver after d-penicillamine treatment by LA-ICP-MS.

J Trace Elem Med Biol 2017 Dec 29;44:26-31. Epub 2017 May 29.

Institute of Inorganic and Analytical Chemistry, University of Münster, Corrensstraße 30, 48149 Münster, Germany. Electronic address:

At present, the copper chelator d-penicillamine (DPA) is the first-line therapy of Wilson's disease (WD), which is characterized by an excessive copper overload. Lifelong DPA treatments aim to reduce the amount of detrimental excess copper retention in the liver and other organs. Although DPA shows beneficial effect in many patients, it may cause severe adverse effects. Despite several years of copper chelation therapy, discontinuation of DPA therapy can be linked to a rapidly progressing liver failure, indicating a high residual liver copper load. In order to investigate the spatial distribution of remaining copper and additional elements, such as zinc and iron, in rat and human liver samples after DPA treatment, a high resolution (spotsize of 10μm) laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method was applied. Untreated LPP rats, an established animal model for WD, appeared with a high overall copper concentration and a copper distribution of hotspots distributed over the liver tissue. In contrast, a low (>2-fold decreased) overall copper concentration was detected in liver of DPA treated animals. Importantly, however, copper distribution was highly inhomogeneous with lowest concentrations in direct proximity to blood vessels, as observed using novel zonal analysis. A human liver needle biopsy of a DPA treated WD patient substantiated the finding of an inhomogeneous copper deposition upon chelation therapy. In contrast, comparatively homogenous distributions of zinc and iron were observed. Our study indicates that a high resolution LA-ICP-MS analysis of liver samples is excellently suited to follow efficacy of chelator therapy in WD patients.
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http://dx.doi.org/10.1016/j.jtemb.2017.05.008DOI Listing
December 2017

Molecular Adsorbent Recirculating System Can Reduce Short-Term Mortality Among Patients With Acute-on-Chronic Liver Failure-A Retrospective Analysis.

Crit Care Med 2017 Oct;45(10):1616-1624

1Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatology, University Hospital Muenster, Muenster, Germany. 2Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany. 3Department of Transplant Medicine, University Hospital Muenster, Muenster, Germany. 4Data Management Center of the EASL-CLIF Consortium, CIBEReHD, Barcelona, Spain. 5Liver Unit, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain. 6Liver Unit, Hospital General Universitario Gregorio Maranon, IiSGM, Madrid, Spain.

Objectives: Acute-on-chronic liver failure is associated with numerous consecutive organ failures and a high short-term mortality rate. Molecular adsorbent recirculating system therapy has demonstrated beneficial effects on the distinct symptoms, but the associated mortality data remain controversial.

Design: Retrospective analysis of acute-on-chronic liver failure patients receiving either standard medical treatment or standard medical treatment and molecular adsorbent recirculating system. Secondary analysis of data from the prospective randomized Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial by applying the recently introduced Chronic Liver Failure-criteria.

Setting: Medical Departments of University Hospital Muenster (Germany).

Patients: This analysis was conducted in two parts. First, 101 patients with acute-on-chronic liver failure grades 1-3 and Chronic Liver Failure-C-Organ Failure liver subscore equals to 3 but stable pulmonary function were identified and received either standard medical treatment (standard medical treatment, n = 54) or standard medical treatment and molecular adsorbent recirculating system (n = 47) at the University Hospital Muenster. Second, the results of this retrospective analysis were tested against the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial.

Interventions: Standard medical treatment and molecular adsorbent recirculating system.

Measurements And Main Results: Additionally to improved laboratory variables (bilirubin and creatinine), the short-term mortality (up to day 14) of the molecular adsorbent recirculating system group was significantly reduced compared with standard medical treatment. A reduced 14-day mortality rate was observed in the molecular adsorbent recirculating system group (9.5% vs 50.0% with standard medical treatment; p = 0.004), especially in patients with multiple organ failure (acute-on-chronic liver failure grade 2-3). Concerning the affected organ system, this effect of molecular adsorbent recirculating system on mortality was particularly evident among patients with increased kidney, brain, or coagulation Chronic Liver Failure-C-Organ Failure subscores. Subsequent reanalysis of the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure dataset with adoption of the Chronic Liver Failure-classification resulted in similar findings.

Conclusions: Molecular adsorbent recirculating system treatment was associated with an improved short-term survival of patients with acute-on-chronic liver failure and multiple organ failure. Among these high-risk patients, molecular adsorbent recirculating system treatment might bridge to liver recovery or liver transplantation.
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http://dx.doi.org/10.1097/CCM.0000000000002562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5598913PMC
October 2017

Molecular adsorbent recirculating system (MARS) in acute liver injury and graft dysfunction: Results from a case-control study.

PLoS One 2017 12;12(4):e0175529. Epub 2017 Apr 12.

Department of Transplant Medicine, University Hospital Muenster, Muenster, Germany.

Background: The primary therapeutic goals in the treatment of liver injury are to support liver regeneration or bridge the gap to liver transplantation (LT). Molecular adsorbent recirculating system (MARS) therapy has shown beneficial effects for specific symptoms of liver failure; however, general survival advantages have not yet been demonstrated.

Aim: We studied the effects of MARS therapy compared to standard medical treatment (SMT) in two patient cohorts: in patients with an acute liver injury and in those with graft dysfunction (GD).

Methods: We report on our experience over a 6.5-year period with 73 patients treated with SMT or with SMT and MARS (MARS group). In total, 53 patients suffered from acute liver injury in their native liver without a preexisting liver disease (SMT: n = 31, MARS: n = 22), and 20 patients showed a severe GD after LT (SMT: n = 10, MARS: n = 10).

Results: The entire cohort was predominantly characterized by hemodynamically and respiratorily stable patients with a low hepatic encephalopathy (HE) grade and a model of end-stage liver disease (MELD) score of 20.57 (MARS) or 22.51 (SMT, p = 0.555). Within the MARS group, the median number of extracorporeal therapy sessions was four (range = 3-5 sessions). Independent of the underlying etiology, MARS improved the patients' bilirubin values in the short term compared to SMT alone. In patients with acute liver injury, this response was sustained even after the end of MARS therapy. By contrast, the majority of patients with GD and an initial response to MARS therapy experienced worsened hyperbilirubinemia. No differences in 28-day mortality were observed with respect to acute liver injury (MARS 5.3% (95% CI: 0-15.3); SMT 3.3% (95% CI: 0-9.8), p = 0.754) or GD (MARS 20.0% (95% CI: 0-44.7), SMT 11.1% (95% CI: 0-31.7), p = 0.478).

Conclusions: Although it did not improve 28-day mortality, MARS therapy improved the short-term response in patients with acute liver injury as well as in those with GD. In cases of acute hepatic injury, the use of MARS therapy resulted in the sustained stabilization of liver function and improved liver regeneration. A short-term response to MARS may predict the future course of the disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175529PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389829PMC
April 2017

In Reply.

Dtsch Arztebl Int 2017 02;114(8):137-138

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http://dx.doi.org/10.3238/arztebl.2017.0137bDOI Listing
February 2017

[Extracorporeal Liver Replacement Therapy: Already Standard Procedure].

Dtsch Med Wochenschr 2017 Mar 10;142(5):367-368. Epub 2017 Mar 10.

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http://dx.doi.org/10.1055/s-0042-113860DOI Listing
March 2017

Intragenic Deletions in ATP7B as an Unusual Molecular Genetics Mechanism of Wilson's Disease Pathogenesis.

PLoS One 2016 19;11(12):e0168372. Epub 2016 Dec 19.

Department of Transplantation Medicine, University of Muenster, Germany.

Wilson's disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B resulting in copper overload in the liver and brain. Direct sequencing is routinely used to confirm WD diagnosis; however, partial and whole gene deletions in the heterozygous state cannot be detected by exon amplification since the normal allele will mask its presence. The aim of the present work was to search for unusual mutational events in the unexplained WD cases and to provide insight into the mechanisms. Out of 1420 clinically and biochemically confirmed WD samples received between 2000 and 2014 for routine mutation analysis, we were unable to detect mutant alleles in 142 samples, after extensive sequencing analysis. We used selective amplification and MLPA to identify the partial gene deletions and identified three different partial gene deletions in seven different families. All three deletions were fully characterized at the DNA sequence level. We report the first hemizygous case with WD due to intragenic deletion in the ATP7B (c.3134_3556+689del). This novel deletion resulted from an excision event mediated by consensus sequences in an AluSq2 repeat element and could be traced to micro homologous end joining (MMEJ). Finally, we determined the prevalence of the three deletions in DNA samples from a multinational group of WD patients. Our results emphasize the need for searching mutant alleles beyond routine methods and highlight that large ATP7B deletions are rare, but account for a detectable proportion in some WD patients. Screening for gene aberrations will further improve mutation detection in patients with unidentified ATP7B mutations presenting with clinical manifestations of WD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168372PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167361PMC
July 2017

Organ-Protective Intensive Care in Organ Donors.

Dtsch Arztebl Int 2016 Aug;113(33-34):552-8

Department of Anesthesiology and Intensive Care Medicine, University Medicine Greifswald, German Organ Transplantation Foundation, North-East Donor Region, Berlin, Department of General and Visceral Surgery, University Hospital Münster, Department of Thoracic and Cardiovascular Surgery, University Hospital Münster, Department of Anaesthesiology and Intensive Care, University Hospital Leipzig, Department of Transplant Medicine, University Hospital Münster.

Background: The ascertainment of brain death (the irreversible, total loss of brain function) gives the physician the opportunity to limit or stop further treatment. Alternatively, if the brain-dead individual is an organ donor, the mode of treatment can be changed from patient-centered to donationcentered. Consensus-derived recommendations for the organ-protective treatment of brain-dead organ donors are not yet available in Germany.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, and on the authors' clinical experience.

Results: Brain death causes major pathophysiological changes, including an increase in catecholamine levels and a sudden drop in the concentration of multiple hormones, among them antidiuretic hormone, cortisol, insulin, and triand tetraiodothyronine. These changes affect the function of all organ systems, as well as the hemodynamic state and the regulation of body temperature. The use of standardized donor management protocols might well increase the rate of transplanted organs per donor and improve the quality of the transplanted organs. In addition, the administration of methylprednisolone, desmopressin, and vasopressin could be a useful supplement to treatment in some cases. Randomized controlled trials have not yet demonstrated either improved organ function or prolonged survival of the transplant recipients.

Conclusion: The evidence base for organ-protective intensive care is weak; most of the available evidence is on the level of expert opinion. There is good reason to believe, however, that the continuation of intensive care, in the sense of early donor management, can make organ transplantation more successful both by increasing the number of transplantable organs and by improving organ quality.
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http://dx.doi.org/10.3238/arztebl.2016.0552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015577PMC
August 2016

Evaluation of Therapeutic Oligonucleotides for Familial Amyloid Polyneuropathy in Patient-Derived Hepatocyte-Like Cells.

PLoS One 2016 1;11(9):e0161455. Epub 2016 Sep 1.

Klinik für Transplantationsmedizin, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1, Gebäude A14, D-48149, Münster, Germany.

Familial amyloid polyneuropathy (FAP) is caused by mutations of the transthyretin (TTR) gene, predominantly expressed in the liver. Two compounds that knockdown TTR, comprising a small interfering RNA (siRNA; ALN-TTR-02) and an antisense oligonucleotide (ASO; IONIS-TTRRx), are currently being evaluated in clinical trials. Since primary hepatocytes from FAP patients are rarely available for molecular analysis and commercial tissue culture cells or animal models lack the patient-specific genetic background, this study uses primary cells derived from urine of FAP patients. Urine-derived cells were reprogrammed to induced pluripotent stem cells (iPSCs) with high efficiency. Hepatocyte-like cells (HLCs) showing typical hepatic marker expression were obtained from iPSCs of the FAP patients. TTR mRNA expression of FAP HLCs almost reached levels measured in human hepatocytes. To assess TTR knockdown, siTTR1 and TTR-ASO were introduced to HLCs. A significant downregulation (>80%) of TTR mRNA was induced in the HLCs by both oligonucleotides. TTR protein present in the cell culture supernatant of HLCs was similarly downregulated. Gene expression of other hepatic markers was not affected by the therapeutic oligonucleotides. Our data indicate that urine cells (UCs) after reprogramming and hepatic differentiation represent excellent primary human target cells to assess the efficacy and specificity of novel compounds.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161455PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008816PMC
August 2017

Successful Anti-HCV Therapy of a Former Intravenous Drug User with Sofosbuvir and Daclatasvir in a Peritranspant Setting: A Case Report.

Am J Case Rep 2016 Aug 24;17:605-10. Epub 2016 Aug 24.

Department of Transplantation Medicine, University Hospital Münster, Münster, Germany.

BACKGROUND Direct-acting antivirals (DAAs) represent a new hallmark in antiviral therapy of hepatitis C virus (HCV). DAAs have been shown to be safe and effective after liver transplantation (LT), but there is little information about their use in peritransplant settings. Former intravenous drug users represent an increasing group seeking HCV treatment. This case report demonstrates the successful peritransplant antiviral treatment of a former intravenous drug user who had been treated in a methadone maintenance program. CASE REPORT The patient was diagnosed with Child B cirrhosis for the first time in 2009. He had a Model for End-stage Liver Disease (MELD) score of 21 and started antiviral therapy with sofosbuvir (SOF) and daclatasvir (DCV) in March 2014. Due to hepatic decompensation, he received a LT in April 2014. Immunosuppression was performed with tacrolimus (TAC) and mycophenolate-mofetil (MMF), and boosted with prednisolone in the initial stage. Four weeks after his LT, the patient presented with an acute renal injury. The patient was discharged one week later after sufficient hydration, discontinuation of non-steroidal anti-phlogistics therapy, and adjustments to his immunosuppressive regimen. At the beginning of his therapy, the number of RNA copies was 13,000 IU/mL. He received 24 weeks of anti-HCV treatment with SOF and DCV; the antiviral treatment was successful and his LT was well tolerated.  CONCLUSIONS Treatment of HCV is feasible in a peritransplant setting. The antiviral regimen we used did not seem to have any relevant interactions with the patient's immunosuppressive regimens. Still, the peritransplant setting is a very demanding environment for anti-HCV therapy, and further studies are needed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4999016PMC
http://dx.doi.org/10.12659/ajcr.895839DOI Listing
August 2016

 Early initiation of MARS® dialysis in Amanita phalloides-induced acute liver injury prevents liver transplantation.

Ann Hepatol 2016 Sep-Oct;15(5):775-87

Department for Transplant Medicine, University Hospital Münster, Münster, Germany.

 Amanita phalloides is the most relevant mushroom intoxication leading to acute liver failure. The two principal groups of toxins, the amatoxins and the phallotoxins, are small oligopeptides highly resistant to chemical and physical influences. The amatoxins inhibit eukaryotic RNA polymerase II causing transcription arrest affecting mainly metabolically highly active cells like hepatocytes and renal cells. The clinically most characteristic symptom is a 6-40 h lag phase before onset of gastrointestinal symptoms and the rapid progression of acute liver failure leading to multi-organ failure and death within a week if left untreated. Extracorporeal albumin dialysis (ECAD) was reported to improve patient's outcome or facilitate bridging to transplantation. In our tertiary center, out of nine intoxicated individuals from five non-related families six patients presented with acute liver injury; all of them were treated with ECAD using the MARS® system. Four of them were listed on admission for high urgency liver transplantation. In addition to standard medical treatment for Amanita intoxication we initiated ECAD once patients were admitted to our center. Overall 16 dialysis sessions were performed. All patients survived with full native liver recovery without the need for transplantation. ECAD was well tolerated; no severe adverse events were reported during treatment. Coagulopathy resolved within days in all patients, and acute kidney injury in all but one individual. In conclusion, ECAD is highly effective in treating intoxication with Amanita phalloides. Based on these experiences we suggest early initiation and repeated sessions depending on response to ECAD with the chance of avoiding liver transplantation.
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http://dx.doi.org/10.5604/16652681.1212613DOI Listing
February 2017

Methanobactin reverses acute liver failure in a rat model of Wilson disease.

J Clin Invest 2016 07 20;126(7):2721-35. Epub 2016 Jun 20.

In Wilson disease (WD), functional loss of ATPase copper-transporting β (ATP7B) impairs biliary copper excretion, leading to excessive copper accumulation in the liver and fulminant hepatitis. Current US Food and Drug Administration- and European Medicines Agency-approved pharmacological treatments usually fail to restore copper homeostasis in patients with WD who have progressed to acute liver failure, leaving liver transplantation as the only viable treatment option. Here, we investigated the therapeutic utility of methanobactin (MB), a peptide produced by Methylosinus trichosporium OB3b, which has an exceptionally high affinity for copper. We demonstrated that ATP7B-deficient rats recapitulate WD-associated phenotypes, including hepatic copper accumulation, liver damage, and mitochondrial impairment. Short-term treatment of these rats with MB efficiently reversed mitochondrial impairment and liver damage in the acute stages of liver copper accumulation compared with that seen in untreated ATP7B-deficient rats. This beneficial effect was associated with depletion of copper from hepatocyte mitochondria. Moreover, MB treatment prevented hepatocyte death, subsequent liver failure, and death in the rodent model. These results suggest that MB has potential as a therapeutic agent for the treatment of acute WD.
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http://dx.doi.org/10.1172/JCI85226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922707PMC
July 2016

Management of asymptomatic gene carriers of transthyretin familial amyloid polyneuropathy.

Muscle Nerve 2016 09;54(3):353-60

Pfizer, Inc., New York, New York, USA.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, severe, and irreversible, adult-onset, hereditary disorder caused by autosomal-dominant mutations in the TTR gene that increase the intrinsic propensity of transthyretin protein to misfold and deposit systemically as insoluble amyloid fibrils in nerve tissues, the heart, and other organs. TTR-FAP is characterized by relentless, progressively debilitating polyneuropathy, and leads to death, on average, within 10 years of symptom onset without treatment. With increased availability of disease-modifying treatment options for a wider spectrum of patients with TTR-FAP, timely detection of the disease may offer substantial clinical benefits. This review discusses mutation-specific predictive genetic testing in first-degree relatives of index patients diagnosed with TTR-FAP and the structured clinical follow-up of asymptomatic gene carriers for prompt diagnosis and early therapeutic intervention before accumulation of substantial damage. Muscle Nerve 54: 353-360, 2016.
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http://dx.doi.org/10.1002/mus.25210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113802PMC
September 2016

"Red-flag" symptom clusters in transthyretin familial amyloid polyneuropathy.

J Peripher Nerv Syst 2016 Mar;21(1):5-9

Global Medical Affairs, Global Innovative Pharma, Pfizer Inc, New York, NY, USA.

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a rare, progressive, life-threatening, hereditary disorder caused by mutations in the transthyretin gene and characterized by extracellular deposition of transthyretin-derived amyloid fibrils in peripheral and autonomic nerves, heart, and other organs. TTR-FAP is frequently diagnosed late because the disease is difficult to recognize due to phenotypic heterogeneity. Based on published literature and expert opinion, symptom clusters suggesting TTR-FAP are reviewed, and practical guidance to facilitate earlier diagnosis is provided. TTR-FAP should be suspected if progressive peripheral sensory-motor neuropathy is observed in combination with one or more of the following: family history of a neuropathy, autonomic dysfunction, cardiac hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel syndrome, renal impairment, or ocular involvement. If TTR-FAP is suspected, transthyretin genotyping, confirmation of amyloid in tissue biopsy, large- and small-fiber assessment by nerve conduction studies and autonomic system evaluations, and cardiac testing should be performed.
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http://dx.doi.org/10.1111/jns.12153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788142PMC
March 2016

Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis.

J Am Coll Cardiol 2015 Dec;66(21):2451-2466

Department of Molecular Medicine, University of Pavia, Pavia, Lombardy, Italy.

Transthyretin amyloidosis is a fatal disorder that is characterized primarily by progressive neuropathy and cardiomyopathy. It occurs in both a mutant form (with autosomal dominant inheritance) and a wild-type form (with predominant cardiac involvement). This article guides clinicians as to when the disease should be suspected, describes the appropriate diagnostic evaluation for those with known or suspected amyloidosis, and reviews the interventions currently available for affected patients.
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http://dx.doi.org/10.1016/j.jacc.2015.09.075DOI Listing
December 2015

Interferon-Free Sofosbuvir-Based Anti-HCV Therapy After Liver Transplantation.

Ann Transplant 2015 Sep 22;20:561-8. Epub 2015 Sep 22.

Department of Transplantation Medicine, University Hospital Münster, Münster, Germany.

Background: Therapy for HCV-infected patients after orthotopic liver transplantation (OLT) is based on interferon (IFN) as the gold standard, but sustained virologic response (SVR) and safety profiles of the IFN-based therapies are very unsatisfactory. The aim of this continuing analysis is evaluation of the impact of an IFN-free sofosbuvir (SOF)-based therapy in HCV-infected liver transplant recipients.

Material And Methods: Post-OLT patients with a proven recurrence of HCV were treated with SOF and ribavirin (RBV) for 24 weeks (n=10). Laboratory parameters and FibroScan® are continuously evaluated at weeks 0, 12, 24, and 36. A retrospectively analyzed HCV patient cohort who received antiviral therapy with pegylated INF and RBV± telaprevir (TLV) were used as a control group.

Results: All patients who finished their treatment with SOF/RBV at least 12 weeks ago showed an SVR. The SOF-based therapy showed a significantly higher rate of rapid virologic response (RVR) and sustained virologic response (SVR) compared to the IFN-based therapies (RVR: p=0.007; SVR: p=0.009). According to temporary data on FibroScan® analysis, regression of fibrosis was observed in 8 patients treated with SOF/RBV. No premature termination of SOF became necessary.

Conclusions: In this small group of patients, the preliminary results indicate that a regression of fibrosis is achievable within 24 weeks of therapy with SOF after OLT. SOF seems to be effective and safe in the treatment of OLT patients infected with HCV and will likely improve patient and transplant survival.
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http://dx.doi.org/10.12659/AOT.893640DOI Listing
September 2015

Donor-Specific Anti-HLA Antibodies and Endothelial C4d Deposition-Association With Chronic Liver Allograft Failure.

Transplantation 2015 Sep;99(9):1869-75

1 Department of Transplant Medicine, University Hospital Münster, Münster, Germany. 2 Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany. 3 Fundeni Clinical Institute of Digestive Diseases and Liver Transplantation, Bucharest, Romania. 4 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany. 5 Institute for Transfusion Medicine, University Hospital Essen, Essen, Germany. 6 Institute of Pathology, University Hospital Essen, Essen, Germany.

Background: The significance of humoral immune response for allograft survival after liver transplantation (LT) is still a matter of debate. The aim of this cross-sectional study was to assess immunological and clinical factors associated with advanced fibrosis (F3-F4) and chronic graft failure in LT recipients.

Methods: Serum samples from 174 patients prospectively enrolled and followed up for 12 months were tested for anti-HLA antibodies and compared against donor HLA types. Immunohistochemical C4d staining was performed on formalin-fixed, paraffin-embedded liver tissue.

Results: Mean time period from LT to enrollment was 66.9 ± 51.9 months. Independent predictive factors for graft failure included donor-positive cytomegalovirus serostatus (P = 0.02), donor-specific antibodies (DSA) against HLA class II (P = 0.03), donor age (P = 0.01), hepatitis C virus allograft reinfection (P = 0.0008), and biliary complications (P = 0.003). HLA class II DSA and HLA class I antibody positivity, hepatitis C virus reinfection, and mycophenolate mofetil-free regimens were significant risk factors for advanced fibrosis after LT. There was a significant association between C4d deposition on allograft endothelial cells and presence of class II DSA (P < 0.0001). Patients with C4d deposits had a 4.3 times higher risk of graft failure than those with negative staining and a significantly lower median time to graft failure (94.6 months [range, 3.6-158.9 months] vs 176.4 months [range, 9.4-217.8 months], P < 0.0001).

Conclusions: Screening for HLA DSA might be useful for early identification of LT recipients at increased risk of graft failure who could benefit from closer surveillance and tailored immunosuppressive regimens.
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http://dx.doi.org/10.1097/TP.0000000000000613DOI Listing
September 2015

The effect of zinc and D-penicillamine in a stable human hepatoma ATP7B knockout cell line.

PLoS One 2014 3;9(6):e98809. Epub 2014 Jun 3.

Clinic for Transplantation Medicine, Münster University Hospital, Münster, Germany.

Mutations in the copper (Cu) transporter gene ATP7B, the primary cause of Wilson disease (WD), result in high liver Cu and death of hepatocytes. Cu chelators and zinc salts are the two most important drugs used in the treatment of WD patients; however, the molecular mechanisms of the drugs with regard to ATP7B expression have not been determined. A targeted knockout of ATP7B (KO) was established in the most widely used human hepatoma cell line, HepG2 for molecular studies of the pathogenesis and treatment of the disease. KO cells showed similar growth, Cu uptake, release, and gene expression as compared to parental cells. However, in the presence of Cu, morphological changes, oxidative stress, apoptosis, and loss of viability were observed. Induction of metallothionein (MT1X) after Cu exposure was significantly reduced in KO cells. Following zinc treatment, MT1X expression was strongly induced and a high percentage of KO cells could be rescued from Cu induced toxicity. D-penicillamine treatment had a minor effect on the viability of KO cells whereas the parental cell line showed a pronounced improvement. Combined treatment displayed a highly synergistic effect in KO cells. The data suggest that zinc has a previously unrecognized effect on the viability of hepatocytes that lack ATP7B due to a high induction of MT1X expression that compensates low gene expression after Cu exposure. A combination therapy that simultaneously targets at MT1X induction and Cu chelation improves the overall survival of hepatocytes for most efficient therapy of patients having WD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098809PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4044041PMC
January 2015

Concentrated green tea extract induces severe acute hepatitis in a 63-year-old woman--a case report with pharmaceutical analysis.

J Ethnopharmacol 2014 Aug 24;155(1):165-70. Epub 2014 May 24.

Department of Transplantation Medicine, University Hospital of Münster, Münster, Germany.

Unlabelled: ETNOPHARMACOLOGICAL RELEVANCE: The popularity of concentrated green tea extracts as dietary supplements for a wide range of applications is increasing due to their health-promoting effects attributed to the high amounts of catechins they contain. The most important of the green tea catechins is (-)-epigallocatechin-3-O-gallate (EGCG). While their beneficiary effects have been studied extensively, a small number of adverse events have been reported in the medical literature. Here we present a typical reversible course of severe hepatitis after green tea consumption.

Materials And Methods: The case study describes in a 63-year old woman during treatment with green tea-capsules upon recommendation of a cancer support group.

Results: The histological finding was consistent with drug induced hepatitis, and other possible causes of hepatitis were excluded. According to the CIOMS/RUCAM score the causality was assessed as "probable". After discontinuation of medication, followed by extracorporal albumin dialysis, rapid and sustained recovery occurred. Pharmaceutically analysis (HPLC) of the green tea capsules did not give evidence for contaminants but revealed the two typical compounds of green tea, namely (-)-epigallocatechin-3-O-gallate (EGCG, 93.2%) and epicatechin (EC, 6.8%) at a very high dose level.

Conclusion: The present case highlights the fact that such concentrated herbal extracts from green tea may not be free of adverse effects under certain circumstances. There is still a lack of a uniform European Union-wide surveillance system for adverse drug reactions of herbal products. Therefore this case underlines the importance of public awareness in the potential risks in use of herbal products.
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http://dx.doi.org/10.1016/j.jep.2014.05.015DOI Listing
August 2014

Small bowel transplantation complicated by cytomegalovirus tissue invasive disease without viremia.

J Clin Virol 2014 Jun 15;60(2):177-80. Epub 2014 Mar 15.

Department of Transplant Medicine, University Hospital Münster, Münster, Germany. Electronic address:

We report on a small bowel transplant patient, donor/recipient seropositive (D+/R+) for cytomegalovirus (CMV), with a clinical course complicated by CMV disease. Anti-CMV prophylaxis was given for 100 days. Immunosuppression consisted of alemtuzumab, tacrolimus, mycophenolate mofetil and prednisolone. Five months posttransplant, CMV tissue invasive disease of the upper gastrointestinal tract was evident without the presence of viremia, tested by quantitative polymerase chain reaction (PCR). Complete viral load suppression was achieved with intravenous ganciclovir, followed by valganciclovir for secondary prophylaxis. Mycophenolate mofetil and prednisolone were discontinued. Shortly thereafter the patient presented with recurrent CMV and candida esophagitis. While on ganciclovir and caspofungin, the patient developed CMV tissue invasive disease of the ileal graft, with persistent absence of viremia. Foscarnet and CMV immunoglobulin were added. Viral load declined to undetectable levels; however, clinical improvement did not occur due to occurrence of graft rejection. Despite infliximab and high dose prednisolone, graft rejection was progressive, requiring surgical explantation of the graft. This case highlights the importance of additional diagnostic tools such as endoscopy including PCR analysis of tissue samples. Extension of primary antiviral prophylaxis interval up to 6 months and prolonged retreatment for recurrent CMV disease may be useful to avoid severe CMV-related complications.
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http://dx.doi.org/10.1016/j.jcv.2014.03.005DOI Listing
June 2014

Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy.

J Neurol 2013 11 22;260(11):2802-14. Epub 2013 Aug 22.

Unidade Clinica de Paramiloidose, Hospital de Santo António, Largo Prof Abel Salazar, 4099-001, Porto, Portugal,

Tafamidis, a transthyretin (TTR) kinetic stabilizer, delayed neuropathic progression in patients with Val30Met TTR familial amyloid polyneuropathy (TTR-FAP) in an 18-month randomized controlled trial (study Fx-005). This 12-month, open-label extension study evaluated the long-term safety, tolerability, and efficacy of tafamidis 20 mg once daily in 86 patients who earlier received blinded treatment with tafamidis or placebo. Efficacy measures included the Neuropathy Impairment Score in the Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy total quality of life (TQOL) score, and changes in neurologic function and nutritional status. We quantified the monthly rates of change in efficacy measures, and TTR stabilization, and monitored adverse events (AEs). Patients who continued on tafamidis had stable rates of change in NIS-LL (from 0.08 to 0.11/month; p = 0.60) and TQOL (from -0.03 to 0.25; p = 0.16). In patients switched from placebo, the monthly rate of change in NIS-LL declined (from 0.34 to 0.16/month; p = 0.01), as did TQOL score (from 0.61 to -0.16; p < 0.001). Patients treated with tafamidis for 30 months had 55.9 % greater preservation of neurologic function as measured by the NIS-LL than patients in whom tafamidis was initiated later. Plasma TTR was stabilized in 94.1 % of patients treated with tafamidis for 30 months. AEs were similar between groups; no patients discontinued because of an AE. Long-term tafamidis was well tolerated, with the reduced rate of neurologic deterioration sustained over 30 months. Tafamidis also slowed neurologic impairment in patients previously given placebo, but treatment benefits were greater when tafamidis was begun earlier.
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http://dx.doi.org/10.1007/s00415-013-7051-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825212PMC
November 2013

Evaluation of domino liver transplantations in Germany.

Transpl Int 2013 Jul 14;26(7):715-23. Epub 2013 May 14.

Klinik für Transplantationsmedizin, Universitätsklinikum Münster, Münster, Germany.

A retrospective multicenter study has been conducted to evaluate domino liver transplantations (DLTs) in Germany. The study provides insight into survival and features having an impact on the assessment of neuropathy after DLT. In addition, a neurologic follow-up program with a scheme to estimate the likelihood of de novo amyloidosis is presented. A series of 61 DLTs at seven transplant centers in Germany was enrolled. The mean age of domino recipients at the time of transplantation was 58 years, 46 of them being men, and 15 being women. The median follow-up was 46 months. The overall 1-, 3-, and 5-year survival of domino recipients was 81.6%, 70.8% and 68.8%, respectively. Causes of death were primarily not related to familial amyloidosis. The main indication of DLT was hepatocellular carcinoma. Two of the reported domino recipients developed symptoms and signs of de novo amyloidosis within 10 years after transplantation. A total of 30 domino graft recipients (49.18%) presented with diabetes post transplantation. In conclusion, an advanced follow-up program is crucial to evaluate the risk of transmitting familial amyloidosis by DLT and to establish more strict selection criteria for domino recipients.
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http://dx.doi.org/10.1111/tri.12110DOI Listing
July 2013