Q J Med 2003; 96:505512
doi:10.1093/qjmed/hcg091
Hepatocyte dysfunction and hepatic encephalopathy in
Plasmodium falciparum malaria
D.K. KOCHAR, P. AGARWAL, S.K. KOCHAR, R. JAIN, N. RAWAT, R.K. POKHARNA1,
S. KACHHAWA2 and T. SRIVASTAVA3
From the Departments of Medicine, 1Gastroenterology, 2Radiodiagnosis and
3
Neurology, S.P. Medical College, Bikaner, India
Received 12 November 2002 and in revised form 29 March 2003
Summary
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 electroencephalogra-
phy (EEG).
Introduction
Malaria is endemic in 91 countries, and about 40%
of the worlds population is at risk of acquiring the
infection. Each year, there are 300500 million
cases of malaria and 1.52.7 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 falci-
parum in a peripheral blood film (PBF).1 Jaundice
Address correspondence to Professor D.K. Kochar, C-54, Sadul Ganj, Bikaner (Raj) 334 003, India. e-mail:
drdkkochar@indiatimes.com
! Association of Physicians 2003; all rights reserved.
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Results: The range of serum bilirubin was 348.2
mg% (mean
SD 10.44
8.71 mg%). The ranges
of AST and ALT levels were 401120 IU/l (294.47

250.67 IU/l) and 401245 IU/l (371.12
296.76
IU/l), respectively. Evidence of hepatic encephalo-
pathy 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 120427 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.
and renal failure have been observed more com-
monly in recent years in patients with falciparum
malaria in Thailand and Vietnam.2 Similar observa-
tions 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
 506
years many isolated case reports with definite
evidence of hepatic encephalopathy have been
reported from different parts of the world, including
India.37 Bearing in mind the paucity of such cases
in the available literature, and the frequent observa-
tion 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
During an outbreak of falciparum malaria, in
AugustSeptember 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, unex-
plained hepatomegaly, ascites, history of alcohol-
ism, 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 encepha-
lopathy 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 encephalo-
pathy, 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 extra-
hepatic 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
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D.K. Kochar et al.
the basis of examination of asterexis, mental state
examination and psychometric test (number con-
nection 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
All patients had a history of fever for the last 515
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 bleed-
ing, 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 throm-
bocytopenia (total platelet count < 20 000/ml), 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 dysfunc-
tion. Serum bilirubin levels ranged from 3 to
48.2 mg% (mean
SD 10.44
8.71 mg%) (Figure 1),
with AST levels 401120 IU/l (mean
SD
294.47
250.67 IU/l) and ALT levels 401245 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,
 Hepatic complications of malaria 507

Figure 1. Serum bilirubin levels and hepatic encephalopathy (ordered by increasing serum bilirubin).

Figure 2. Comparison of serum AST and ALT levels with rising serum bilirubin levels.

splenomegaly in 24 and both hepatomegaly and
splenomegaly in 20. Seven patients with hepato-
megaly 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 991120 IU/l
(mean
SD 563.03
303.13 IU/l) and 1281245
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 548.2 mg% (mean
SD 22.18

10.62 mg%) with serum AST level 120998 IU/l
(mean
SD 594
268.45 IU/l) and serum ALT level
3201160 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
encephalopathythe 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

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 508 D.K. Kochar et al.

120427 meq/l (mean
SD 310
98.39 meq/l). The encephalopathy in survivors was normal in all
Reiten trail-making test, handwriting and asterexsis patients. The histopathological examination of liver
were assessed serially. The grading of hepatic biopsy, which was done in four patients, revealed
encephalopathy was done according to level of swollen hepatocytes, malarial pigment (haemozoin)
mental state examination, asterexsis, psychometric deposition in RE cells, portal infiltration by mono-
test, arterial blood ammonia and EEG changes.8 The nuclear cells, Kupffer cell hyperplasia and intrahe-
EEG done after the disappearance of all signs of patic cholestasis. Focal areas of necrosis were also
seen in one patient.
All patients were treated with i.v. quinine, along
Table 1 Ultrasonography findings in patients with serum
with supportive treatment. The patients who had
bilirubin > 10 mg% (n 29)
no complication other than jaundice recovered
Finding n % very quickly. All patients with serum bilirubin
< 10 mg% had complete disappearance of jaundice
Liver within 10 days, whereas those with serum bilirubin
Size enlarged 25 86.21 1020 mg% took about 15 days, and those with
Altered echo pattern 7 24.14 serum bilirubin levels > 20 mg% took longer. Clear-
Normal architecture 29 100.00 ance of jaundice was also delayed in patients with
Mid grey scale 20 68.96
renal failure. The prognosis for encephalopathy was
Low grey scale 7 24.14
Normal grey scale 2 6.90 also dependent on associated illness, and all four
patients who died had multiple organ dysfunction
Gall bladder All other patients receiving quinine and adequate
Increased wall thickness 5 19.23
supportive therapy had quick regression of signs of
Lumen sludge 11 37.93
hepatic encephalopathy, with a fall in serum
Clear lumen 17 58.62
Pericholecystic fluid 2 6.90 bilirubin. The mental state examination of all the
surviving patients was normal in 7 days. The
Intrahepatic and 0 0 patients with jaundice who were in coma from the
extrahepatic bile
beginning (n 4) were not included in this study,
duct dilatation
Spleen enlarged 24 82.76
because the cause of coma could have been
Kidney enlarged 5 19.23 cerebral malaria, malarial fulminant liver failure, or
Free peritoneal fluid 6 20.69 both. No patient was using traditional (herbal/
ayurvedic) remedies before admission.

Table 2 Semiquantitative grading of patients* with hepatic encephalopathy (n 15)

Psychometric
Patient Mental state Asterexis tests NH3 EEG**

1 2 2 3 412 Background  activity and triphasic waves

2 2 0 2 408 -activity
3 0 0 2 385 Mixed  and  activity
4 2 2 ND* 256 Background  activity
5 2 2 3 120 Background  activity
6 2 0 ND* 286 Background  activity and pseudo burst suppression
7 3 0 1 427 -activity
8 3 2 ND* 221 Background  activity with triphasic waves.
9 1 0 2 177 Background  activity
10 1 2 4 308 Background  activity with pseudo burst suppression
11 2 3 3 315 -activity
12 3 3 4 427 Background  activity
13 3 2 2 178 Background  activity and triphasic waves
14 0 0 2 315  waves
15 2 2 2 412 Background  activity with pseudoperiodic burst suppression

*Grading was according to the method described by Conn.8 *ND, not done; psychometric tests could not be performed
because of education standard. **Glasgow Coma Scale was > 11/14 in all patients at the time of examination. NH3, arterial
blood level of ammonia.

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 Hepatic complications of malaria 509

Figure 3. EEG showing intermittent delta activity and triphasic waves.

Figure 4. EEG showing delta activity and pseudoperiodic burst suppression.

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 510
Discussion
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 micro-
villi.37
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 710 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 hyperbi-
lirubinaemia. 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 intra-
vascular haemolysis and disseminated intravascular
coagulation, the authors observed evidence of
hepatocellular jaundice secondary to histopatholo-
gical 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 con-
jugated 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
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D.K. Kochar et al.
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 appara-
tus, 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 3040%
decrease in hepatic cytochrome P-450 and asso-
ciated monooxygenase activity.12 Similar effect on
bilirubin excretion may be responsible for conju-
gated hyperbilirubinaemia. These changes, which
show a linear increase of hepatic enzymes accord-
ing to the increase in serum bilirubin levels, are
a direct indicator of hepatocyte dysfunction asso-
ciated with falciparum malaria.
Hepatic encephalopathy is defined as an altera-
tion 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 encephalo-
pathy is a series of semi-quantitative evaluations of
each of the components of the hepatic encephalo-
pathy syndrome, and some type of integration of
the individual scores. Each of the five components,
i.e. asterexis, mental state examination, psycho-
metric 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 propor-
tional 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 dysfunc-
tion 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 dys-
function. The liver biopsies on four patients just after
their deaths also revealed changes similar to
those reported in malaria by other workers3,10
(Figures 58). The presence of asterexis, deranged
 Hepatic complications of malaria
Figure 5. Photomicrograph showing marked reticulo-
endothelial hyperplasia with large amounts of malaria
pigment in reticulo-endothelial cells. H&E, 200.
Figure 6. Photomicrograph showing marked pigmenta-
tion of hepatocytes due to cholestasis, especially on left.
There is also reticulo-endothelial hyperplasia, with
malaria pigment granules in Kupffer cells. H&E, 400.
psychometric tests, deranged mental state examina-
tion, 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 34 days, and complete
in the next few days. Serum bilirubin levels returned
to normal in all the surviving patients at further
follow-up.
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511
Figure 7. Photomicrograph showing marked pigmenta-
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malaria pigment granules in Kupffer cells. H&E, 1000.
Figure 8. Photomicrograph showing marked reticulo-
endothelial hyperplasia with large amounts of malaria
pigment in reticulo-endothelial cells. H&E, 1000.
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