Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context
Background: Liver injury is a known feature of severe malaria, but is only incidentally investigated in uncomplicated disease. In such cases, drug-induced hepatotoxicity is often thought to be the primary cause of the observed liver injury, and this can be a major concern in antimalaria drug develop...
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Elsevier
2018-10-01
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Series: | EBioMedicine |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Isaie J. Reuling Gerdie M. de Jong Xi Zen Yap Muhammad Asghar Jona Walk Lisanne A. van de Schans Rob Koelewijn Anna Färnert Quirijn de Mast Andre J. van der Ven Teun Bousema Jaap J. van Hellemond Perry J.J. van Genderen Robert W. Sauerwein |
spellingShingle |
Isaie J. Reuling Gerdie M. de Jong Xi Zen Yap Muhammad Asghar Jona Walk Lisanne A. van de Schans Rob Koelewijn Anna Färnert Quirijn de Mast Andre J. van der Ven Teun Bousema Jaap J. van Hellemond Perry J.J. van Genderen Robert W. Sauerwein Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context EBioMedicine |
author_facet |
Isaie J. Reuling Gerdie M. de Jong Xi Zen Yap Muhammad Asghar Jona Walk Lisanne A. van de Schans Rob Koelewijn Anna Färnert Quirijn de Mast Andre J. van der Ven Teun Bousema Jaap J. van Hellemond Perry J.J. van Genderen Robert W. Sauerwein |
author_sort |
Isaie J. Reuling |
title |
Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context |
title_short |
Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context |
title_full |
Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context |
title_fullStr |
Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context |
title_full_unstemmed |
Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in context |
title_sort |
liver injury in uncomplicated malaria is an overlooked phenomenon: an observational studyresearch in context |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2018-10-01 |
description |
Background: Liver injury is a known feature of severe malaria, but is only incidentally investigated in uncomplicated disease. In such cases, drug-induced hepatotoxicity is often thought to be the primary cause of the observed liver injury, and this can be a major concern in antimalaria drug development. We investigated liver function test (LFT) abnormalities in patients with imported uncomplicated malaria, and in Controlled Human Malaria Infection (CHMI) studies. Methods: Clinical and laboratory data from 484 imported malaria cases and 254 CHMI participants were obtained from the Rotterdam Malaria Cohort database, and the Radboud University Medical Center database (between 2001 and 2017), respectively. Routine clinical LFTs, clinical profiles, parasite densities, hematological, and inflammation parameters were assessed in 217 patients with imported falciparum malaria upon admission, and from longitudinal data of 187 CHMI participants. Findings: Upon admission, the proportion of patients with imported uncomplicated malaria and elevated liver enzymes was 128/186 (69%). In CHMI, 97/187 (52%) participants showed LFT abnormalities, including mild (64%, >1.0 ≤ 2.5× upper limit of normal (ULN)), moderate (20%, >2.5 ≤ 5.0xULN) or severe (16%, >5.0xULN). LFT abnormalities were primarily ALT/AST elevations and to a lesser extent γGT and ALP. LFT abnormalities peaked shortly after initiation of treatment, regardless of drug regimen, and returned to normal within three to six weeks. Positive associations were found with parasite burden and inflammatory parameters, including cumulative inflammatory cytokine responses and oxidative stress markers (r = 0·65, p = 0·008, and r = −0·63, p = 0·001, respectively). Interpretation: This study shows that reversible liver injury is a common feature of uncomplicated falciparum malaria, most likely caused by an enduring pro-inflammatory response post treatment. The recognition of this phenomenon is of clinical relevance for individual patient care as well as clinical development of (new) antimalarial drugs. Fund: PATH Malaria Vaccine Initiative (MVI) Keywords: Malaria, Liver injury, Pathogenesis, Inflammation, Oxidative stress |
url |
http://www.sciencedirect.com/science/article/pii/S235239641830375X |
work_keys_str_mv |
AT isaiejreuling liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT gerdiemdejong liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT xizenyap liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT muhammadasghar liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT jonawalk liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT lisanneavandeschans liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT robkoelewijn liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT annafarnert liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT quirijndemast liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT andrejvanderven liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT teunbousema liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT jaapjvanhellemond liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT perryjjvangenderen liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext AT robertwsauerwein liverinjuryinuncomplicatedmalariaisanoverlookedphenomenonanobservationalstudyresearchincontext |
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doaj-c814598894534a568eda2dfff0839c1a2020-11-25T02:32:52ZengElsevierEBioMedicine2352-39642018-10-0136131139Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational StudyResearch in contextIsaie J. Reuling0Gerdie M. de Jong1Xi Zen Yap2Muhammad Asghar3Jona Walk4Lisanne A. van de Schans5Rob Koelewijn6Anna Färnert7Quirijn de Mast8Andre J. van der Ven9Teun Bousema10Jaap J. van Hellemond11Perry J.J. van Genderen12Robert W. Sauerwein13Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands; Corresponding author.Harbour Hospital, Institute for Tropical Diseases, Rotterdam, the Netherlands; Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, the NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, the NetherlandsDivision of Infectious Diseases, Department of Medicine Solna, Karolinska Institute, Stockholm, SwedenDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, the NetherlandsDivision of Infectious Diseases, Department of Medicine Solna, Karolinska Institute, Stockholm, SwedenDepartment of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.Department of Internal Medicine, Radboud university medical center, Nijmegen, the Netherlands.Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the NetherlandsDepartment of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, the NetherlandsHarbour Hospital, Institute for Tropical Diseases, Rotterdam, the Netherlands; Department of Medical Microbiology and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, the NetherlandsDepartment of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands; Corresponding author.Background: Liver injury is a known feature of severe malaria, but is only incidentally investigated in uncomplicated disease. In such cases, drug-induced hepatotoxicity is often thought to be the primary cause of the observed liver injury, and this can be a major concern in antimalaria drug development. We investigated liver function test (LFT) abnormalities in patients with imported uncomplicated malaria, and in Controlled Human Malaria Infection (CHMI) studies. Methods: Clinical and laboratory data from 484 imported malaria cases and 254 CHMI participants were obtained from the Rotterdam Malaria Cohort database, and the Radboud University Medical Center database (between 2001 and 2017), respectively. Routine clinical LFTs, clinical profiles, parasite densities, hematological, and inflammation parameters were assessed in 217 patients with imported falciparum malaria upon admission, and from longitudinal data of 187 CHMI participants. Findings: Upon admission, the proportion of patients with imported uncomplicated malaria and elevated liver enzymes was 128/186 (69%). In CHMI, 97/187 (52%) participants showed LFT abnormalities, including mild (64%, >1.0 ≤ 2.5× upper limit of normal (ULN)), moderate (20%, >2.5 ≤ 5.0xULN) or severe (16%, >5.0xULN). LFT abnormalities were primarily ALT/AST elevations and to a lesser extent γGT and ALP. LFT abnormalities peaked shortly after initiation of treatment, regardless of drug regimen, and returned to normal within three to six weeks. Positive associations were found with parasite burden and inflammatory parameters, including cumulative inflammatory cytokine responses and oxidative stress markers (r = 0·65, p = 0·008, and r = −0·63, p = 0·001, respectively). Interpretation: This study shows that reversible liver injury is a common feature of uncomplicated falciparum malaria, most likely caused by an enduring pro-inflammatory response post treatment. The recognition of this phenomenon is of clinical relevance for individual patient care as well as clinical development of (new) antimalarial drugs. Fund: PATH Malaria Vaccine Initiative (MVI) Keywords: Malaria, Liver injury, Pathogenesis, Inflammation, Oxidative stresshttp://www.sciencedirect.com/science/article/pii/S235239641830375X |