Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis
Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome...
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| creator | Taubert, Richard Hardtke-Wolenski, Matthias Noyan, Fatih Lalanne, Claudine Jonigk, Danny Schlue, Jerome Krech, Till Lichtinghagen, Ralf Falk, Christine S Schlaphoff, Verena Bantel, Heike Muratori, Luigi Manns, Michael P Jaeckel, Elmar |
| description | Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins ( |
| doi_str_mv | 10.1371/journal.pone.0179074 |
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The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87-24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635-0.863) and internal validation cohort (AUC = 0.741; CI 0.558-0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0179074</identifier><identifier>PMID: 28594937</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Animals ; Area Under Curve ; Bacterial infections ; Biochemistry ; Biology and Life Sciences ; Biopsy ; Care and treatment ; Chronic active hepatitis ; Cohort Studies ; Cytokines ; Damage ; Deregulation ; Diagnostic systems ; Diseases ; Dosage and administration ; Endocrinology ; Ferritin ; Ferritins - blood ; Gastroenterology ; Gene expression ; Growth factors ; Hepatitis ; Hepatitis, Autoimmune - blood ; Hepatitis, Autoimmune - complications ; Hepatitis, Autoimmune - therapy ; Hepatocyte growth factor ; Hepatocyte Growth Factor - pharmacology ; Hepatology ; Hepcidin ; Hepcidins - metabolism ; Histology ; Homeostasis ; Humans ; Hypergammaglobulinemia ; Hypergammaglobulinemia - blood ; Hypergammaglobulinemia - complications ; Hypotheses ; Hypotheses (Scientific method) ; Immunoglobulins ; Immunosuppression ; Immunosuppressive agents ; Incidence ; Infections ; Iron ; Laboratories ; Liver ; Liver diseases ; Liver transplantation ; Medical prognosis ; Medical schools ; Medicine and Health Sciences ; Metabolism ; Mice ; Pathology ; Patients ; Reference Standards ; Remission ; Remission Induction ; ROC Curve ; Therapy ; Training ; Transferrin ; Transferrins ; Transplantation ; Transplants & implants ; Treatment Outcome</subject><ispartof>PloS one, 2017-06, Vol.12 (6), p.e0179074-e0179074</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Taubert et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Taubert et al 2017 Taubert et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-413443e75fc22b5ec2d5d8d14fe6319c5a7f32cf2340e63965e9c11af3548d6a3</citedby><cites>FETCH-LOGICAL-c692t-413443e75fc22b5ec2d5d8d14fe6319c5a7f32cf2340e63965e9c11af3548d6a3</cites><orcidid>0000-0001-9270-2496</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464635/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464635/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28594937$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Taubert, Richard</creatorcontrib><creatorcontrib>Hardtke-Wolenski, Matthias</creatorcontrib><creatorcontrib>Noyan, Fatih</creatorcontrib><creatorcontrib>Lalanne, Claudine</creatorcontrib><creatorcontrib>Jonigk, Danny</creatorcontrib><creatorcontrib>Schlue, Jerome</creatorcontrib><creatorcontrib>Krech, Till</creatorcontrib><creatorcontrib>Lichtinghagen, Ralf</creatorcontrib><creatorcontrib>Falk, Christine S</creatorcontrib><creatorcontrib>Schlaphoff, Verena</creatorcontrib><creatorcontrib>Bantel, Heike</creatorcontrib><creatorcontrib>Muratori, Luigi</creatorcontrib><creatorcontrib>Manns, Michael P</creatorcontrib><creatorcontrib>Jaeckel, Elmar</creatorcontrib><title>Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87-24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635-0.863) and internal validation cohort (AUC = 0.741; CI 0.558-0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.</description><subject>Adult</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Bacterial infections</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Biopsy</subject><subject>Care and treatment</subject><subject>Chronic active hepatitis</subject><subject>Cohort Studies</subject><subject>Cytokines</subject><subject>Damage</subject><subject>Deregulation</subject><subject>Diagnostic systems</subject><subject>Diseases</subject><subject>Dosage and administration</subject><subject>Endocrinology</subject><subject>Ferritin</subject><subject>Ferritins - blood</subject><subject>Gastroenterology</subject><subject>Gene expression</subject><subject>Growth factors</subject><subject>Hepatitis</subject><subject>Hepatitis, Autoimmune - blood</subject><subject>Hepatitis, Autoimmune - complications</subject><subject>Hepatitis, Autoimmune - therapy</subject><subject>Hepatocyte growth factor</subject><subject>Hepatocyte Growth Factor - pharmacology</subject><subject>Hepatology</subject><subject>Hepcidin</subject><subject>Hepcidins - metabolism</subject><subject>Histology</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Hypergammaglobulinemia</subject><subject>Hypergammaglobulinemia - blood</subject><subject>Hypergammaglobulinemia - complications</subject><subject>Hypotheses</subject><subject>Hypotheses (Scientific method)</subject><subject>Immunoglobulins</subject><subject>Immunosuppression</subject><subject>Immunosuppressive agents</subject><subject>Incidence</subject><subject>Infections</subject><subject>Iron</subject><subject>Laboratories</subject><subject>Liver</subject><subject>Liver diseases</subject><subject>Liver transplantation</subject><subject>Medical prognosis</subject><subject>Medical schools</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Pathology</subject><subject>Patients</subject><subject>Reference Standards</subject><subject>Remission</subject><subject>Remission Induction</subject><subject>ROC Curve</subject><subject>Therapy</subject><subject>Training</subject><subject>Transferrin</subject><subject>Transferrins</subject><subject>Transplantation</subject><subject>Transplants & implants</subject><subject>Treatment 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Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Taubert, Richard</au><au>Hardtke-Wolenski, Matthias</au><au>Noyan, Fatih</au><au>Lalanne, Claudine</au><au>Jonigk, Danny</au><au>Schlue, Jerome</au><au>Krech, Till</au><au>Lichtinghagen, Ralf</au><au>Falk, Christine S</au><au>Schlaphoff, Verena</au><au>Bantel, Heike</au><au>Muratori, Luigi</au><au>Manns, Michael P</au><au>Jaeckel, Elmar</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-06-08</date><risdate>2017</risdate><volume>12</volume><issue>6</issue><spage>e0179074</spage><epage>e0179074</epage><pages>e0179074-e0179074</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Autoimmune hepatitis (AIH) is a chronic hepatitis with an increasing incidence. The majority of patients require life-long immunosuppression and incomplete treatment response is associated with a disease progression. An abnormal iron homeostasis or hyperferritinemia is associated with worse outcome in other chronic liver diseases and after liver transplantation. We assessed the capacity of baseline parameters including the iron status to predict the treatment response upon standard therapy in 109 patients with untreated AIH type 1 (AIH-1) in a retrospective single center study. Thereby, a hyperferritinemia (> 2.09 times upper limit of normal; Odds ratio (OR) = 8.82; 95% confidence interval (CI): 2.25-34.52) and lower immunoglobulins (<1.89 times upper limit of normal; OR = 6.78; CI: 1.87-24.59) at baseline were independently associated with the achievement of complete biochemical remission upon standard therapy. The predictive value increased when both variables were combined to a single treatment response score, when the cohort was randomly split into a training (area under the curve (AUC) = 0.749; CI 0.635-0.863) and internal validation cohort (AUC = 0.741; CI 0.558-0.924). Patients with a low treatment response score (<1) had significantly higher cumulative remission rates in the training (p<0.001) and the validation cohort (p = 0.024). The baseline hyperferritinemia was accompanied by a high serum iron, elevated transferrin saturations and mild hepatic iron depositions in the majority of patients. However, the abnormal iron status was quickly reversible under therapy. Mechanistically, the iron parameters were not stringently related to a hepatocellular damage. Ferritin rather seems deregulated from the master regulator hepcidin, which was down regulated, potentially mediated by the elevated hepatocyte growth factor. In conclusion, baseline levels of serum ferritin and immunoglobulins, which are part of the diagnostic work-up of AIH, can be used to predict the treatment response upon standard therapy in AIH-1, although confirmation from larger multicenter studies is pending.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28594937</pmid><doi>10.1371/journal.pone.0179074</doi><tpages>e0179074</tpages><orcidid>https://orcid.org/0000-0001-9270-2496</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-06, Vol.12 (6), p.e0179074-e0179074 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1907553752 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adult Animals Area Under Curve Bacterial infections Biochemistry Biology and Life Sciences Biopsy Care and treatment Chronic active hepatitis Cohort Studies Cytokines Damage Deregulation Diagnostic systems Diseases Dosage and administration Endocrinology Ferritin Ferritins - blood Gastroenterology Gene expression Growth factors Hepatitis Hepatitis, Autoimmune - blood Hepatitis, Autoimmune - complications Hepatitis, Autoimmune - therapy Hepatocyte growth factor Hepatocyte Growth Factor - pharmacology Hepatology Hepcidin Hepcidins - metabolism Histology Homeostasis Humans Hypergammaglobulinemia Hypergammaglobulinemia - blood Hypergammaglobulinemia - complications Hypotheses Hypotheses (Scientific method) Immunoglobulins Immunosuppression Immunosuppressive agents Incidence Infections Iron Laboratories Liver Liver diseases Liver transplantation Medical prognosis Medical schools Medicine and Health Sciences Metabolism Mice Pathology Patients Reference Standards Remission Remission Induction ROC Curve Therapy Training Transferrin Transferrins Transplantation Transplants & implants Treatment Outcome |
| title | Hyperferritinemia and hypergammaglobulinemia predict the treatment response to standard therapy in autoimmune hepatitis |
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