Please use this identifier to cite or link to this item:
https://www.arca.fiocruz.br/handle/icict/12029
Type
ArticleCopyright
Open access
Collections
- IOC - Artigos de Periódicos [12696]
Metadata
Show full item record
A NEW HYPOTHESIS ON THE MANIFESTATION OF CEREBRAL MALARIA: THE SECRET IS IN THE LIVER
Affilliation
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Malária. Centro de Pesquisa Diagnóstico e Treinamento em Malária. Rio de Janeiro, RJ, Brasil / Albert Einstein College of Medicine. Department of Pathology. The Bronx, NY, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Malária. Centro de Pesquisa Diagnóstico e Treinamento em Malária. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Pesquisa em Malária. Centro de Pesquisa Diagnóstico e Treinamento em Malária. Rio de Janeiro, RJ, Brasil.
Abstract
Despite the abundance of information on cerebral malaria (CM), the pathogenesis of this disease is not
completely understood. At present, two nonexclusive dominant hypotheses exist to explain how the neurological
syndrome manifests: the sequestration (or mechanical) hypothesis and the inflammatory
hypothesis. The sequestration hypothesis states that sequestration of Plasmodium falciparum-parasitized
red blood cells (pRBCs) to brain capillary endothelia causes obstruction of capillary blood flow followed
by brain tissue anoxia and coma. The inflammatory hypothesis postulates that P. falciparum infection
releases toxic molecules in the circulation, inducing an imbalanced systemic inflammatory response that
leads to coagulopathy, brain endothelial cell dysfunction, accumulation of leukocytes in the brain microcirculation,
blood brain barrier (BBB) leakage, cerebral vasoconstriction, edema, and coma. However, both
hypotheses, even when considered together, are not sufficient to fully explain the pathogenesis of CM.
Here, we propose that the development of acute liver failure (ALF) together with BBB breakdown are
the necessary and sufficient conditions for the genesis of CM. ALF is characterized by coagulopathy
and hepatic encephalopathy (HE) in a patient without pre-existing liver disease. Signs of hepatic dysfunction
have been shown to occur in 2.5–40% of CM patients. In addition, recent studies with murine models
demonstrated that mice presenting experimental cerebral malaria (ECM) had hepatic damage and brain
metabolic changes characteristic of HE. However, the occurrence of CM in patients with mild or without
apparent hepatocellular liver damage and the presence of liver damage in non-CM murine models indicate
that the development of ALF during malaria infection is not the single factor responsible for neuropathology.
To solve this problem, we also propose that BBB breakdown contributes to the pathogenesis of
CM and synergizes with hepatic failure to cause neurological signs and symptoms. BBB dysfunction
would thus occur in CM by a mechanism similar to the one occurring in sepsis and is in agreement with
the inflammatory hypothesis. Nevertheless, differently from in the inflammatory hypothesis, BBB leakage
would facilitate the penetration of ammonia and other toxins into the brain parenchyma, but would not
be sufficient to cause CM when occurring alone. We believe our hypothesis better explains the pathogenesis
of CM, does not have problems to deal with the exception data not explained by the previous hypotheses,
and reveals new targets for adjunctive therapy.
Share