Frequency and Pathophysiology of Acute Liver Failure in Ornithine Transcarbamylase Deficiency (OTCD)
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{"title"=>"Frequency and pathophysiology of acute liver failure in ornithine transcarbamylase deficiency (OTCD)", "type"=>"journal", "authors"=>[{"first_name"=>"Alexander", "last_name"=>"Laemmle", "scopus_author_id"=>"24474518700"}, {"first_name"=>"Renata C.", "last_name"=>"Gallagher", "scopus_author_id"=>"55828714600"}, {"first_name"=>"Adrian", "last_name"=>"Keogh", "scopus_author_id"=>"15923479500"}, {"first_name"=>"Tamar", "last_name"=>"Stricker", "scopus_author_id"=>"55917404200"}, {"first_name"=>"Matthias", "last_name"=>"Gautschi", "scopus_author_id"=>"56333340400"}, {"first_name"=>"Jean Marc", "last_name"=>"Nuoffer", "scopus_author_id"=>"6602500161"}, {"first_name"=>"Matthias R.", "last_name"=>"Baumgartner", "scopus_author_id"=>"7101704024"}, {"first_name"=>"Johannes", "last_name"=>"Häberle", "scopus_author_id"=>"7003808409"}], "year"=>2016, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84963736938", "sgr"=>"84963736938", "pui"=>"609839750", "pmid"=>"27070778", "doi"=>"10.1371/journal.pone.0153358"}, "id"=>"070d1684-035e-3dfe-b74e-13ff4c7bf8b9", "abstract"=>"BACKGROUND: Acute liver failure (ALF) has been reported in ornithine transcarbamylase deficiency (OTCD) and other urea cycle disorders (UCD). The frequency of ALF in OTCD is not well-defined and the pathogenesis is not known. AIM: To evaluate the prevalence of ALF in OTCD, we analyzed the Swiss patient cohort. Laboratory data from 37 individuals, 27 females and 10 males, diagnosed between 12/1991 and 03/2015, were reviewed for evidence of ALF. In parallel, we performed cell culture studies using human primary hepatocytes from a single patient treated with ammonium chloride in order to investigate the inhibitory potential of ammonia on hepatic protein synthesis. RESULTS: More than 50% of Swiss patients with OTCD had liver involvement with ALF at least once in the course of disease. Elevated levels of ammonia often correlated with (laboratory) coagulopathy as reflected by increased values for international normalized ratio (INR) and low levels of hepatic coagulation factors which did not respond to vitamin K. In contrast, liver transaminases remained normal in several cases despite massive hyperammonemia and liver involvement as assessed by pathological INR values. In our in vitro studies, treatment of human primary hepatocytes with ammonium chloride for 48 hours resulted in a reduction of albumin synthesis and secretion by approximately 40%. CONCLUSION: In conclusion, ALF is a common complication of OTCD, which may not always lead to severe symptoms and may therefore be underdiagnosed. Cell culture experiments suggest an ammonia-induced inhibition of hepatic protein synthesis, thus providing a possible pathophysiological explanation for hyperammonemia-associated ALF.", "link"=>"http://www.mendeley.com/research/frequency-pathophysiology-acute-liver-failure-ornithine-transcarbamylase-deficiency-otcd-1", "reader_count"=>11, "reader_count_by_academic_status"=>{"Researcher"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Researcher"=>1, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Other"=>2, "Student > Master"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>4, "Nursing and Health Professions"=>1, "Medicine and Dentistry"=>3, "Agricultural and Biological Sciences"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/4943254"], "description"=>"<p>Following treatment with NH<sub>4</sub>Cl, several parameters were determined in cell culture supernatant: <b>A,</b> Cell viability showed no significant differences between various treatment groups (0; 0.1; 1; 10 mM NH<sub>4</sub>Cl for 24 h) compared to non-treated control cells as assessed by MTT assay. <b>B,</b> Albumin secretion was quantified by ELISA. While control cells secreted 1944 ± 235 μg/L albumin in 24 hours, cells treated with 10 mM NH<sub>4</sub>Cl secreted only 1471 ± 25 μg/L and after 48 hours controls secreted 2820 ± 464 μg/L versus 1666 ± 53 μg/L in treated cells. <b>C,</b> Quantification of urea: while in untreated hepatocytes urea in supernatant increases slightly from 0.42 mmol/L at 24 h to 0.64 mmol/L at 48 h, in NH<sub>4</sub>Cl-treated cells urea production increases from 0.82 mmol/L to 1.31 mmol/L, respectively. <b>D,</b> Quantification of ASAT reveals a potential negative effect of ammonia on mitochondrial integrity.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174241, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.g004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Effects_of_NH_sub_4_sub_Cl_exposure_on_human_primary_hepatocytes_/3174241", "title"=>"Effects of NH<sub>4</sub>Cl exposure on human primary hepatocytes.", "pos_in_sequence"=>4, "defined_type"=>1, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943221"], "description"=>"<p>Fig 3 illustrates laboratory values from patient 21.1 with neonatal onset of OTCD causing acute liver failure (ALF) and fatal disease course. Concomitant with massive hyperammonemia (max. 2569 μmol/L; upper left y-axis in grey colour), INR was drastically elevated (max. 4.1; lower left y-axis in red colour) while both liver transaminases (here only ALAT is shown; max. 25 U/L) remained normal. After suspicion of OTCD, this patient immediately received specific treatment including hemodialysis resulting in rapid normalization of plasma ammonia levels after two days of treatment. However, INR remained elevated despite application of fresh frozen plasma and the patient deceased from multiorgan failure.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174214, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/INR_is_a_sensitive_parameter_of_ammonia_related_liver_dysfunction_/3174214", "title"=>"INR is a sensitive parameter of ammonia-related liver dysfunction.", "pos_in_sequence"=>3, "defined_type"=>1, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943167"], "description"=>"<p>In the urea cycle the “toxin” ammonium (NH<sub>4</sub><sup>+</sup>) is converted to non-toxic urea by five consecutive enzymatic reactions in the liver. In hepatocytes, the rate-limiting, ATP-dependent enzyme carbamoyl phosphate synthetase 1 (CPS1), which is allosterically activated by N-acetyl glutamate (NAG), produced by N-acetyl glutamate synthase (NAGS), not shown, and ornithine transcarbamylase (OTC) are located in the mitochondria, while argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase (ARG) are in the cytoplasm. Inherited defects in any of these enzymes can cause recurrent episodes of hyperammonemia. Defects in two mitochondrial transporters, not shown, may also result in hyperammonemia.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174172, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Urea_cycle_/3174172", "title"=>"Urea cycle.", "pos_in_sequence"=>1, "defined_type"=>1, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943308"], "description"=>"<p>Laboratory values of OTCD patients suffering from acute liver failure.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174286, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Laboratory_values_of_OTCD_patients_suffering_from_acute_liver_failure_/3174286", "title"=>"Laboratory values of OTCD patients suffering from acute liver failure.", "pos_in_sequence"=>6, "defined_type"=>3, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943341"], "description"=>"<p>Unresponsiveness to vitamin K in coagulopathy occurring in OTCD.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174322, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.t004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Unresponsiveness_to_vitamin_K_in_coagulopathy_occurring_in_OTCD_/3174322", "title"=>"Unresponsiveness to vitamin K in coagulopathy occurring in OTCD.", "pos_in_sequence"=>8, "defined_type"=>3, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943197"], "description"=>"<p>From 37 cases, 29 were eligible for further studies regarding occurrence of acute liver failure (ALF). Male patients are shown as neonatal (onset in the first month of life) and late onset (symptoms beyond the first month of life) cases. Females are classified as symptomatic or asymptomatic. The bottom boxes indicate the occurrence of ALF.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174199, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.g002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Overview_of_included_patients_and_occurrence_of_acute_liver_failure_/3174199", "title"=>"Overview of included patients and occurrence of acute liver failure.", "pos_in_sequence"=>2, "defined_type"=>1, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943320"], "description"=>"<p>Association of coagulopathy and acute liver failure with hyperammonemia.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174298, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.t003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Association_of_coagulopathy_and_acute_liver_failure_with_hyperammonemia_/3174298", "title"=>"Association of coagulopathy and acute liver failure with hyperammonemia.", "pos_in_sequence"=>7, "defined_type"=>3, "published_date"=>"2016-04-12 14:15:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/4943281"], "description"=>"<p>Summary of the Swiss cohort of OTC deficient patients.</p>", "links"=>[], "tags"=>["urea cycle disorders", "hepatic protein synthesis", "Background Acute liver failure", "Acute Liver Failure", "ornithine transcarbamylase deficiency", "INR", "cell culture studies", "liver involvement", "hepatic coagulation factors", "ALF", "cell culture experiments", "Ornithine Transcarbamylase Deficiency", "ammonium chloride", "UCD", "Swiss patient cohort", "OTCD"], "article_id"=>3174268, "categories"=>["Biochemistry", "Medicine", "Microbiology", "Cell Biology", "Physiology", "Biotechnology", "Chemical Sciences not elsewhere classified", "Immunology", "Developmental Biology", "Cancer", "Hematology", "Infectious Diseases", "Virology"], "users"=>["Alexander Laemmle", "Renata C. Gallagher", "Adrian Keogh", "Tamar Stricker", "Matthias Gautschi", "Jean-Marc Nuoffer", "Matthias R. Baumgartner", "Johannes Häberle"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0153358.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Summary_of_the_Swiss_cohort_of_OTC_deficient_patients_/3174268", "title"=>"Summary of the Swiss cohort of OTC deficient patients.", "pos_in_sequence"=>5, "defined_type"=>3, "published_date"=>"2016-04-12 14:15:31"}

PMC Usage Stats | Further Information

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Relative Metric

{"start_date"=>"2016-01-01T00:00:00Z", "end_date"=>"2016-12-31T00:00:00Z", "subject_areas"=>[]}
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