Liver Injury in Uncomplicated Malaria is an Overlooked Phenomenon: An Observational Study

Abstract

BackgroundLiver 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.MethodsClinical 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.FindingsUpon 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).InterpretationThis 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.FundPATH Malaria Vaccine Initiative (MVI)

Liver injury in uncomplicated malaria: an overlooked phenomenon

“…However, it has been proposed that the increased prevalence of LFAs after ACT may be a consequence of the rapid parasiticidal activity of the artemisinin compound, leading to increased clearance of parasites by the reticuloendothelial system and increased release of relative oxygen species [ 2 ]. This is consistent with the reported patterns of bilirubin concentrations associated with haemolysis, where elevations occurred within the first days after treatment, did not amplify after administration of consecutive drug doses, and rapidly resolved after the clearance of parasitaemia [ 1 , 3 ]. Monitoring of bilirubin concentrations during drug therapy may therefore prove to be a useful parameter for differentiating malaria-associated changes from drug-induced toxicity, where a more delayed liver injury meeting Hy's Law would be expected [ 3 ].…”

“…In these studies, elevated enzyme levels are most often associated with antimalarial drug-induced liver toxicity, with little consideration given to the potential contribution of parasite-induced liver injury. The temporal pattern of liver abnormalities over the course of an infection is also unclear [ [1] , [2] , [3] ].…”

“…The study reported by Reuling et al in EBioMedicine presents a novel approach to characterise liver injury in uncomplicated falciparum malaria [ 3 ]. This was achieved by investigating longitudinal associations between routine clinical LFTs, parasite density, and haematological and immunological parameters in patients with naturally acquired falciparum malaria ( n = 217) and Controlled Human Malaria Infection (CHMI) volunteers ( n = 187).…”

Development and Evaluation of a New P. Falciparum 3D7 Blood Stage Malaria Cell Bank for Use in Malaria Volunteer Infection Studies

“…The adverse events reported for both studies are in keeping with previous IBSM studies [9][10][11]26,27]. The raised asymptomatic raised liver enzymes, with no associated signi cant rise in bilirubin, have been reported in previous IBSM studies [28,29], sporozoite VIS [30] and in naturally occurring malaria [28,31]. Similarly, the reduction in white cell counts, especially lymphopenia and neutropenia have previously been reported in IBSM VIS, sporozoite VIS and clinical malaria [12,16,[32][33][34].…”

Association of Plasmodium berghei With the Apical Domain of Hepatocytes Is Necessary for the Parasite's Liver Stage Development

“…Pharmacological modulation of hepatocyte polarity by welltolerated widely used drugs might fast track approaches to host-directed prophylactic therapeutics. Hepatic dysfunction is strongly associated with malaria (Reuling et al, 2018), with a significant number of malaria patients showing impaired liver functions including hyperbilirubinemia, and jaundice (Joshi et al, 1986;Kaeley et al, 2017). While the pathological basis of hepatic dysfunction during malaria is not clear, druginduced hepatotoxicity and clearance of infected RBC's have been proposed to play major roles in hepatic pathology (Reuling et al, 2018).…”