Q J Med 2003; 96: 505-512
© 2003 Association of Physicians
Hepatocyte dysfunction and hepatic encephalopathy in Plasmodium falciparum malaria
From the Departments of Medicine, 1Gastroenterology, 2Radiodiagnosis and 3Neurology, S.P. Medical College, Bikaner, India
Received 12 November 2002 and in revised form 29 March 2003
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionReferences |
|---|
Background: According to the WHO, signs of hepatic dysfunction are unusual, and hepatic encephalopathy is never seen in malaria. However, in recent years, isolated cases have been reported from different parts of world.
Aim: To identify the evidence for hepatocyte dysfunction and/or encephalopathy in jaundiced patients with falciparum malaria.
Design: Prospective observational study.
Methods: We studied 86 adult patients of both sexes who had malaria with jaundice (serum bilirubin > 3 mg%). The main outcome measures were: flapping tremor, deranged psychometric test, level of consciousness, serum bilirubin level, serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, blood ammonia level, viral markers for hepatitis, ultrasonography of liver and gall bladder and electroencephalography (EEG).
Results: The range of serum bilirubin was 3–48.2 mg% (mean ± SD 10.44 ± 8.71 mg%). The ranges of AST and ALT levels were 40–1120 IU/l (294.47 ± 250.67 IU/l) and 40–1245 IU/l (371.12 ± 296.76 IU/l), respectively. Evidence of hepatic encephalopathy was seen in 15 patients. Asterexis was observed in 9 patients, impaired psychometric tests in 12 and altered mental state in 13. Arterial blood ammonia level was 120–427 meq/l (310 ± 98.39 meq/l). EEG findings included presence of large bilateral synchronous slow waves, pseudo burst suppression and triphasic waves. Four patients died due to multiple organ dysfunction; the others made rapid recoveries.
Discussion: There is strong evidence of hepatocyte dysfunction and hepatic encephalopathy in some of these patients, with no obvious non-malarial explanation. Current guidelines may need to be revised.
|
Introduction |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
Malaria is endemic in 91 countries, and about 40% of the world's population is at risk of acquiring the infection. Each year, there are 300–500 million cases of malaria and 1.5–2.7 million deaths. According to the WHO, the majority of deaths occur due to severe malaria, which is defined as the presence of one or more complications in a patient showing asexual parasitaemia of Plasmodium falciparum in a peripheral blood film (PBF).1 Jaundice and renal failure have been observed more commonly in recent years in patients with falciparum malaria in Thailand and Vietnam.2 Similar observations have also been reported by many Indian workers in recent years. According to the WHO, apart from jaundice, signs of hepatic dysfunction are unusual, and clinical signs of liver failure such as asterexis or ‘liver flap’ are never seen unless there is concomitant viral hepatitis.1 However, in recent years many isolated case reports with definite evidence of hepatic encephalopathy have been reported from different parts of the world, including India.3–7 Bearing in mind the paucity of such cases in the available literature, and the frequent observation of such patients in our institution, we planned a systematic study to identify the evidence for hepatocyte dysfunction and/or encephalopathy in jaundiced patients with falciparum malaria.
|
Methods |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
During an outbreak of falciparum malaria, in August–September 2001, 190 adult patients of both sexes with PBF evidence of falciparum malaria were admitted to our tertiary care centre, attached to the Medical College, Bikaner (north-west India). The present study included 86 patients who had serum bilirubin > 3 mg%. Any patient with evidence of liver disease (e.g. viral hepatitis, cirrhosis liver, portal hypertension, amoebic liver abscess, unexplained hepatomegaly, ascites, history of alcoholism, taking hepatotoxic drugs, past history of jaundice) were excluded. Three patients had a history of regular consumption of alcohol over > 10 years and two patients were on anti-tubercular drug: all five were also excluded.
Apart from routine relevant clinical examination, a detailed examination was done in all the jaundiced patients for clinical evidence of encephalopathy at the time of admission and daily thereafter. All patients were underwent a set of investigations, including blood for haemoglobin, bleeding time, clotting time, prothrombin time, total leukocyte count, PBF for detailed morphology of RBC and parasite count, total serum bilirubin, conjugated and unconjugated bilirubin, and serum AST and ALT levels. Urine was examined for urobilinogen, bile pigment and bile salt. Blood tests for markers of hepatitis B, C, and leptospirosis were done in all patients. To rule out any possibility of acute viral hepatitis in the patients with signs of encephalopathy, a detailed serological investigation was done which included IgM anti-hepatitis-A-virus antibody (IgM anti-HAV), hepatitis B surface antigen (HBsAg), IgM anti-hepatitis-B-core antibody (IgM anti-HBc) and IgM anti-hepatitis-E-virus antibody (IgM anti-HEV). Detailed ultrasonography was done to check the size and echo-texture of the liver, and check for gall bladder abnormality, intrahepatic or extrahepatic bile duct dilatation and signs of portal hypertension in all the patients having serum bilirubin >10 mg%.
In those patients who had clinical evidence of hepatic encephalopathy, grading was done daily on the basis of examination of asterexis, mental state examination and psychometric test (number connection test and handwriting).8 EEG and blood ammonia level was measured on the first day of observation; however, EEG was also repeated when patient started showing improvement and at the time bilirubin levels returned to normal. Arterial blood ammonia was measured by use of the ektochem DT slides, which are dry, multi-layered, self-contained analytical elements coated on a plastic support. The analysis is based on the selective migration of ammonia through a semi-permeable membrane into a layer containing an indicator dye. The ammonia reacts with an indicator to produce a highly coloured dye. The intensity of the colour measured by the analyser is proportional to the amount of ammonia in the sample. Liver biopsy was done in four patients just after death for detailed histopathological examination.
All patients received specific treatment in the form of i.v./oral quinine using the standard regimen, along with the usual specific supportive care.1 Quinine was administered as a loading dose of 20 mg/kg followed by 10 mg/kg intravenously every 8 h until the patient was able to take it orally. Loading dose was not administered if the patient was taking quinine from the primary/secondary health care centre.
|
Results |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
All patients had a history of fever for the last 5–15 days. Of the 190 adult patients of both sexes with PBF evidence of falciparum malaria, 91 had jaundice (serum bilirubin > 3 mg/dl), 50 had severe anaemia (Hb < 5 g/dl), 49 had spontaneous bleeding, 21 had cerebral malaria (Glasgow Coma Scale < 9), 21 had shock (systolic BP < 80 mmHg), 13 had macroscopic haemoglobinuria, 12 had renal failure (serum creatinine > 3 mg/dl), 11 patients had thrombocytopenia (total platelet count < 20 000/µl), four had ARDS, three had impaired consciousness, three had hypoglycaemia (blood glucose < 40 mg/dl) and three had generalized convulsions. Many of these patients had concomitant multiple organ dysfunction. Serum bilirubin levels ranged from 3 to 48.2 mg% (mean ± SD 10.44 ± 8.71 mg%) (Figure 1), with AST levels 40–1120 IU/l (mean ± SD 294.47 ± 250.67 IU/l) and ALT levels 40–1245 IU/L (mean ± SD 371.12 ± 296.76 IU/l), respectively (Figure 2). These values were normally distributed. Blood markers of hepatitis B and C and leptospirosis were negative in all the patients. The detailed ultrasonography done in 29 patients having serum bilirubin > 10 mg% revealed hepatomegaly in 25, splenomegaly in 24 and both hepatomegaly and splenomegaly in 20. Seven patients with hepatomegaly also had decreased echogenicity. Gall bladder wall thickness was increased in five patients. There was no evidence of intrahepatic or extrahepatic bile duct dilatation (Table 1). The AST and ALT levels in these patients were 99–1120 IU/l (mean ± SD 563.03 ± 303.13 IU/l) and 128–1245 IU/l (mean ± SD 669.83 ± 368.08 IU/l), respectively.
|
|
|
During the course of illness, a clinical picture of hepatic encephalopathy was observed in 15 patients. The range of serum bilirubin in these patients was 5–48.2 mg% (mean ± SD 22.18 ± 10.62 mg%) with serum AST level 120–998 IU/l (mean ± SD 594 ± 268.45 IU/l) and serum ALT level 320–1160 IU/l (mean ± SD 758.8 ± 269.95 IU/l), respectively. Intellectual deterioration varied from slight impairment of mental function to gross confusion. Hypersomnia and inversion of the sleep rhythm and delirium was present in some patients. An important neurological abnormality of hepatic encephalopathy—the ‘flapping tremor’ was observed in nine patients (60%). The details of EEG observation in these patients are shown in Table 2, Figure 3 and Figure 4. Triphasic waves, which were once considered characteristic of hepatic encephalopathy, were present in three patients. Range of arterial blood ammonia was 120–427 meq/l (mean ± SD 310 ± 98.39 meq/l). The Reiten trail-making test, handwriting and asterexsis were assessed serially. The grading of hepatic encephalopathy was done according to level of mental state examination, asterexsis, psychometric test, arterial blood ammonia and EEG changes.8 The EEG done after the disappearance of all signs of encephalopathy in survivors was normal in all patients. The histopathological examination of liver biopsy, which was done in four patients, revealed swollen hepatocytes, malarial pigment (haemozoin) deposition in RE cells, portal infiltration by mononuclear cells, Kupffer cell hyperplasia and intrahepatic cholestasis. Focal areas of necrosis were also seen in one patient.
|
|
|
All patients were treated with i.v. quinine, along with supportive treatment. The patients who had no complication other than jaundice recovered very quickly. All patients with serum bilirubin < 10 mg% had complete disappearance of jaundice within 10 days, whereas those with serum bilirubin 10–20 mg% took about 15 days, and those with serum bilirubin levels > 20 mg% took longer. Clearance of jaundice was also delayed in patients with renal failure. The prognosis for encephalopathy was also dependent on associated illness, and all four patients who died had multiple organ dysfunction All other patients receiving quinine and adequate supportive therapy had quick regression of signs of hepatic encephalopathy, with a fall in serum bilirubin. The mental state examination of all the surviving patients was normal in 7 days. The patients with jaundice who were in coma from the beginning (n = 4) were not included in this study, because the cause of coma could have been cerebral malaria, malarial fulminant liver failure, or both. No patient was using traditional (herbal/ayurvedic) remedies before admission.
|
Discussion |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
According to the WHO, jaundice is one of the cardinal manifestations of severe malaria. It results from the intravascular haemolysis of parasitized erythrocytes, hepatic dysfunction and possibly an element of microangiopathic haemolysis associated with disseminated intravascular coagulation.1 The changes in liver may result from alteration in blood flow through the organ as parasitized red blood cells adhere to endothelial cells, blocking the sinusoids and obstructing the intrahepatic blood flow. The histopathological changes reported in the malaria patients include hepatocyte necrosis, cholestasis, bile stasis, granulomatous lesions and malarial nodules. The bile stasis is due to impairment of bilirubin transport because of reticulo-endothelial blockage and disturbance of hepatocyte microvilli.3–7
Intravascular haemolysis of parasitized and non-parasitized red blood cells has been considered as an important factor in the causation of mild to moderate jaundice, but there the bilirubin is predominantly unconjugated and its levels do not rise very high. According to the WHO, in severe falciparum malaria patients, serum bilirubin levels remain in the range 7–10 mg%, but in our study 29 patients (out of 86) had serum bilirubin levels > 10 mg%. The maximum value of serum bilirubin observed in this study was 48.2 mg%. Chawla et al.9 studied 31 patients, of whom 14 had serum bilirubin > 10 mg%, with predominantly conjugated hyperbilirubinaemia. They attributed these elevated serum bilirubin levels to intravascular haemolysis and associated renal failure, leading to decreased excretion of bilirubin. Anand et al.3 studied 39 patients, out of whom 13 had serum bilirubin in the range 16 ± 6.3 mg%, and most had predominantly conjugated hyperbilirubinaemia. Apart from intravascular haemolysis and disseminated intravascular coagulation, the authors observed evidence of hepatocellular jaundice secondary to histopathological changes of liver in malaria as an important contributory factor. Murthy et al.10 in their study of 95 patients observed that high serum bilirubin levels in malaria were associated with a more severe course of illness, and with higher incidence of complications and poor prognosis because of histopathological changes to the liver.
In this study, we observed predominantly conjugated hyperbilirubinaemia, with a proportionate rise in AST and ALT levels. The AST/ALT levels were 158.11 ± 76.79 IU/l and 202.98 ± 120.00 IU/l, respectively, in patients with serum bilirubin < 10 mg%, vs. 563.03 ± 303.13 IU/l and 669.83 ± 368.08 IU/l, respectively, in patients with serum bilirubin > 10 mg%. Similar observations have been made by other workers.3,9 Hepatic bilirubin excretion involves the secretion of conjugated pigment across the canalicular membrane. This rate-limiting step in bilirubin excretion is an active, energy-dependent transport process.11 When large amounts of bilirubin saturate the secretory apparatus, there is regurgitation of conjugated bilirubin from the liver cells in the plasma. The effect of parasitaemia on hepatocytes in experimental P. berghi infection in mice showed a 30–40% decrease in hepatic cytochrome P-450 and associated monooxygenase activity.12 Similar effect on bilirubin excretion may be responsible for conjugated hyperbilirubinaemia. These changes, which show a linear increase of hepatic enzymes according to the increase in serum bilirubin levels, are a direct indicator of hepatocyte dysfunction associated with falciparum malaria.
Hepatic encephalopathy is defined as an alteration of the mental state due to impaired liver function and/or abnormal shunting of blood from the portal to the systemic circulations. The most logical approach to the assessment of encephalopathy is a series of semi-quantitative evaluations of each of the components of the hepatic encephalopathy syndrome, and some type of integration of the individual scores. Each of the five components, i.e. asterexis, mental state examination, psychometric test, EEG and blood ammonia concentration can be semi-quantitatively scored in a relatively rapid and easy manner, and can be arbitrarily arranged in a simple 0 to 4 scale.8 Although blood ammonia concentration is not necessarily proportional to the degree of encephalopathy, there is a positive linear correlation between arterial ammonia and the uptake of ammonia by the brain.8
Severe jaundice associated with plasmodium falciparum malaria is now a well-known entity, and high incidences are being reported from many countries of south-east Asia, but according to the WHO (2000) the signs of gross hepatocyte dysfunction and hepatic encephalopathy do not occur in these patients.1 However, in this study based on different semi-quantitative tests, we encountered 15 patients with hepatic encephalopathy of different grades. Our observation of linear elevation of AST and ALT levels in patients with different bilirubin levels, and of hepatomegaly with low echogenicity and increased gall bladder wall thickness on ultrasound examination in a few patients, are important evidence of widespread hepatocyte dysfunction. The liver biopsies on four patients just after their deaths also revealed changes similar to those reported in malaria by other workers3,10 (Figures 5– 8). The presence of asterexis, deranged psychometric tests, deranged mental state examination, increased arterial blood ammonia level and a definite pattern of EEG changes in these patients are important indicators of hepatic encephalopathy. Four patients with hepatic encephalopathy died during the course of illness, primarily due to multiple organ dysfunction; however, there was no death in any patient with jaundice (with or without hepatic encephalopathy) as the sole complication of falciparum malaria. Recovery in the surviving patients was evident after 3–4 days, and complete in the next few days. Serum bilirubin levels returned to normal in all the surviving patients at further follow-up.
|
|
|
|
|
Footnotes |
|---|
Address correspondence to Professor D.K. Kochar, C-54, Sadul Ganj, Bikaner (Raj) 334 003, India. e-mail: drdkkochar{at}indiatimes.com
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionReferences |
|---|
1. WHO Communicable Disease Cluster. Severe falciparum malaria. Trans Roy Soc Med Hyg 2000; 94(Suppl.):1–90.
2. Willairatana, P., Looareesuwan, S. & Charoenlarp, P. Liver profile changes and complications in jaundiced patients with falciparum malaria. Trop Med Parasitol 1994; 45:298–302.[Medline]
3. Anand AC, Ranji C, Narula AS, Singh W. Histopathological changes of liver in malaria: a heterogenous syndrome? Natl Med J India 1992; 5:59–62.[Medline]
4. Mishra SK, Mohanty S, Das BS, Patnaik JK, Satpathy SK, Mohanty D, Bose TK, Hepatic changes in Plasmodium Falciparum Malaria. Indian J Malariol 1992; 29:167–71.[Medline]
5. Ashan T, Rab SM, Sheekhani MS. Falciparum malaria or fulminant hepatic failure? J Pak Med Ass 1993; 43:206–8.[Medline]
6. Srivastava A, Khanduri A, Lakhtakia S, Pandey R. Falciparum malaria with acute liver failure. Trop Gastroenterol 1996; 17:172–4.[Medline]
7. Premaratna R, Gunatilake AK, Desilva NR, Tilakaratney, Fonreka MM, Desilva HJ. Severe hepatic dysfunction associated with falciparum malaria. Southeast Asian J Trop Med Public Health 2001; 32:70–2.[Medline]
8. Conn HO. Quantifying the severity of hepatic encephalopathy. In: Conn HO, Bircher J, eds. Hepatic Encephalopathy: Syndromes & Therapies. Illinois, Medi-Ed Press, 1994:13–26.
9. Chawla LS, Sidhu G, Sabharwal BD, Bhatia KL, Sood A. Jaundice in Plasmodium falciparum. J Assoc Phys India 1989; 37:390–2.
10. Murthy GL, Sahay RK, Sreenivas DV, Sundaram C, Shantaram V. Hepatitis in falciparum malaria. Trop Gastroenterol 1998; 19:152–4.[Medline]
11. Seymour R, Reycraft DW, Hano JE, Barry W. The liver in malaria. Arch Path 1967; 83:271–7.[Medline]
12. Taliaferro WH, Mulligan HW. The histopathology of malaria with special reference to the function and origin of the macrophages in defence. Indian M Res Mem 1937; 39:1.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. K. Kochar, A. Das, S. K. Kochar, V. Saxena, P. Sirohi, S. Garg, A. Kochar, M. P. Khatri, and V. Gupta Severe Plasmodium vivax Malaria: A Report on Serial Cases from Bikaner in Northwestern India Am J Trop Med Hyg, February 1, 2009; 80(2): 194 - 198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-F. Penet, F. Kober, S. Confort-Gouny, Y. Le Fur, C. Dalmasso, N. Coltel, A. Liprandi, J.-M. Gulian, G. E. Grau, P. J. Cozzone, et al. Magnetic Resonance Spectroscopy Reveals an Impaired Brain Metabolic Profile in Mice Resistant to Cerebral Malaria Infected with Plasmodium berghei ANKA J. Biol. Chem., May 11, 2007; 282(19): 14505 - 14514. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guha, S. Kumar, V. Choubey, P. Maity, and U. Bandyopadhyay Apoptosis in liver during malaria: role of oxidative stress and implication of mitochondrial pathway FASEB J, June 1, 2006; 20(8): 1224 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Devarbhavi, J. F. Alvares, and K. S. Kumar Severe Falciparum Malaria Simulating Fulminant Hepatic Failure Mayo Clin. Proc., March 1, 2005; 80(3): 355 - 358. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||