MALARIA WITH HYPERBILIRUBINEMIA IN MINAHASA, INDONESIA

Paul N. Harijanto, Carta A. Gunawan, Stephanus A. Nugroho

Division of Infectious and Tropical Diseases, Department of Medicine,
Sam Ratulangi University School of Medicine/Manado General Hospital, Indonesia

Abstract
Malaria is the most important parasitic infection in the world, especially in tropical
countries. Data from some hospitals in Minahasa, North Sulawesi showed that malaria with
jaundice ranked first of all severe malaria cases.
A retrospective study was done on severe malaria patients with hyperbilirubinemia/
jaundice treated at Bethesda Hospital and Gunung Maria Hospital, North Sulawesi in a period of
10 years (January 1991 – December 2000).
There were 271 severe malaria patients. Patients with serum bilirubin above
normal/hyperbilirubinemia (> 1 mg/dL) were 77.1 %, whereas those with jaundice that fulfilled
WHO criteria (bilirubin > 3 mg/dL) were 54.2 %. Total bilirubin ranged from 1.01
to 36.40 mg/dL. Mean total bilirubin level was 6.64 mg/dL. Most patients were in the group with
bilirubin 5.01 – 10.00 mg/dL (24.9 %). Malaria patients with hyperbilirubinemia who had
another complication were 47.7 %, while those with 3 or more complications were found in only
4.8 % of patients. Other complications were most often found in patients with bilirubin level
> 10.00 mg/dL, namely 41 of 46 patients (89.1 %), however there was no correlation between
bilirubin level and the number of other complications. Patients with hyperbilirubinemia/ jaundice
were frequently accompanied with renal dysfunction/ acute renal failure (56.9 %). Mean SGOT
level was 57.8 IU/L, mean SGPT level was 37.9 IU/L and de Ritis ratio was 1.52. Mean alkaline
phosphatase level was 176.5 IU/L. There were significant positive correlations between bilirubin
level and SGOT, SGPT, alkaline phosphatase, creatinine, parasite count and significant negative
correlation between bilirubin and platelet count. There were no correlations between bilirubin
level and consciousness (GCS), hemoglobin, or reticulocyte count. Mortality was 36 of 271
patients (13.3 %). Patients who died with two complications were the same number as those
who died with 3 or more complications (6.3 %). Sixteen of 36 patients who died (44.4 %) were
those with hyperbilirubinemia accompanied with renal dysfunction/ acute renal failure. There was
no difference in effectiveness of quinine and artemether in treating severe malaria.

1
 Malaria with hyperbilirubinemia/ jaundice is the most common complication in severe
malaria patients. Liver parenchymal disorder and cholestasis play a more important role in the
development of jaundice compared with hemolysis. Malaria with hyperbilirubinemia is
frequently accompanied with renal dysfunction/ acute renal failure. Mortality is most often found
in patients with hyperbilirubinemia accompanied with renal dysfunction/ acute renal failure.
There is no correlation between bilirubin level and mortality rate.
Key words : malaria, hyperbilirubinemia, jaundice, complication, mortality.

INTRODUCTION
Malaria is the most important parasitic infection in the world, especially in
tropical countries where it is a leading cause of morbidity and mortality. Approximately
250 million people in the world are infected with malaria and this disease results in 1 – 2
million deaths in children each year.1 Mortality is caused by complications in various
organ systems.1
In Southeast Asia, the most frequent severe malaria manifestations are cerebral
2
malaria, malaria with jaundice and malaria with acute renal failure. Wenas et al in a
prospective study at Bethesda Hospital, North Sulawesi during 32 months (1990 – 1993)
reported that 46 % of severe malaria patients were classified as malaria with jaundice. At
the Department of Medicine, Sam Ratulangi University School of Medicine/ Manado
General Hospital, in 1995 it was found that 36.8 % of severe malaria cases were malaria
with jaundice, whereas cerebral malaria accounted for 21.2 % and malaria with acute
renal failure 20.6 % of severe cases. In 1997 and 1998 malaria with jaundice also ranked
as the highest percentage of severe malaria cases, namely 42.1 % and 41.6 %,
respectively, followed by cerebral malaria and malaria with acute renal failure.3,4 In
5
Thailand Harinasuta et al (1992) reported that 20 – 30 % of malaria patients treated at
hospitals were classified as malaria with jaundice.
Severe malaria with jaundice is characterized by intermittent fever, nausea,
yellow eyes, brownish-yellow urine, and liver enlargement with pain on palpation.
Laboratory examination characteristically reveals liver dysfunction including elevated
SGOT, SGPT, alkaline phosphatase, -glutamyl transpeptidase, total bilirubin, conjugated
bilirubin, and unconjugated bilirubin levels.5-7 Jaundice in malaria may be caused by

2
hemolysis, liver parenchymal disorder and cholestasis.8 Jaundice is also positively
associated with cerebral malaria, acute renal failure, pulmonary edema, shock and other
complications.6 Acute liver failure is very uncommon, except when there is concomitant
viral hepatitis, but Joshi et al 9 (1986) in India reported 9 patients with acute liver failure
caused by Plasmodium falciparum and Srivastava et al 10 (1996) from India also reported
7 cases of falciparum malaria with acute liver failure, in which 4 of the patients died.

METHODS
A retrospective study was performed by collecting data from the case records of
severe malaria patients treated at Bethesda Hospital and Gunung Maria Hospital,
Minahasa (North Sulawesi) over a period of 10 years (January 1991 – December 2000).
Data collected included age, sex, level of consciousness (based on Glasgow Coma Scale),
total bilirubin, conjugated bilirubin, unconjugated bilirubin, alkaline phosphatase, SGOT,
SGPT, creatinine levels, parasite count, hemoglobin, platelet count, reticulocyte count,
drugs used for treatment (quinine or artemether injection), outcome of treatment
(recovered or died). The diagnosis of severe malaria was based on World Health
Organization (WHO) criteria and was defined as asexual stage of Plasmodium
falciparum infection accompanied with one or more specified complications meeting
WHO criteria. Data were analyzed with descriptive statistics and statistical tests (z test,
x2 test and t test for regression/ correlation analysis) .
Corespondence this article :
Dr. Paul. N. Harijanto, internist, consultant tromped & infect.dis,
Depart. Medicine Bethesda Hospital, Tomohon, North Sulawesi, Indonesia.
Div. Trop Medicine & Infectious Diseases, depart. Medicine, Univ. Sam Ratulangi faculty
of Medicine. Phone : +62431-351065/351105 ext 114 (tomohon); +62431841581
( manado), Cell : +628124302869; email : paul@manado.wasantara.net.id
RESULTS
Records were identified for 271 severe malaria patients hospitalized during this
ten year period. Patients with hyperbilirubinemia (total bilirubin level > 1 mg/dL, where
normal values range from 0.2 – 1.0 mg/dL) were 209 (77.1 %), whereas those who
fulfilled WHO criteria for jaundice (total bilirubin > 3 mg/dL) were 147 (54.2 %). Other

3
complications found in these 271 severe malaria patients were cerebral malaria 58 (21.4
%), acute renal failure 52 (19.2 %) and hyperparasitemia (parasite > 5%) 48 (17.7 %).

Table 1. Distribution of falciparum malaria patients with hyperbilirubinemia according

to age and sex

Age (years) Male (n) Female (n) Total Percentage

< 21 19 11 30 14.4
21 – 30 28 17 45 21.5
31 – 40 26 23 49 23.4
41 – 50 11 20 31 14.8
51 – 60 9 7 16 7.7
> 60 14 24 38 18.2
Total 107 102 209 100.0

Among the 209 patients with bilirubin levels greater than 1.0 mg/dL, male
patients were 107 (51.2 %) and females were 102 (48.8 %). The male to female ratio was
1.05 : 1. There was no difference in the incidence of falciparum malaria with
hyperbilirubinemia between males and females (p > 0.05). Patients` ages ranged from 13
to 87 years with mean age 39.59 years. Malaria with hyperbilirubinemia occurred in all
decades of life but occurred most commonly between the ages of 21 - 50, with the
highest level occurring in patients in the 31 – 40 year age group (23.4 %) and the lowest
level in the 51 – 60 year age group (7.7 %).

Table 2. Distribution of falciparum malaria patients with hyperbilirubinemia according to

total bilirubin level.

Total bilirubin (mg/dL) No. patients Percentage

1.1 – 2.00 37 17.7
2.01 – 3.00 24 11.5
3.01 – 5.00 50 23.9
5.01 – 10.00 52 24.9
> 10.00 46 22.0
Total 209 100.0

4
 Total bilirubin levels on admission ranged from 1.01 to 36.40 mg/dL with mean
total bilirubin level 6.64 mg/dL. According to total bilirubin level, most patients were
found in the group with total bilirubin level 5.01 – 10.00 mg/dL (24.9 %), followed by the
group with total bilirubin level 3.01 – 5.00 mg/dL (23.9 %) and bilirubin >
10.00 mg/dL (22.0 %). Conjugated bilirubin ranged from 0.08 to 27.60 mg/dL (normal
value 0.1 – 0.3 mg/dL) with mean value 3.99 mg/dL. Unconjugated bilirubin ranged from
0.08 to 8.80 mg/dL (normal value 0.1 – 0.7 mg/dL) with mean value 2.65 mg/dL.
The majority of patients with hyperbilirubinemia experienced complications, as
defined by meeting one or more criteria for severe malaria. Ninety-nine of 209 patients
(47.4 %) experienced one complication, 37 patients (17.7 %) experienced 2
complications, whereas those with 3 or more complications were only found in 10 cases
(4.8 %). Complications were more frequent in those with total bilirubin
> 10.00 mg/dL, namely 41 of 46 patients (89.1 %). However, the number of other
complications was not associated with total bilirubin level.

Table 3. Number of other complications in falciparum malaria with hyperbilirubinemia

and mortality according to total bilirubin level.

Total bilirubin No. of other complications Death Percentage

(mg/dL) 0 1 2 3

1.1 – 2.00 12 18 7 0 6 16.2

2.01 – 3.00 4 14 4 2 4 16.7
3.01 – 5.00 25 14 8 3 5 10.0
5.01 – 10.00 17 25 7 3 6 11.5
> 10.00 5 28 11 2 15 32.6
Total 63 99 37 10 36

5
Figure 1. Percentage of falciparum malaria with hyperbilirubinemia without other
complications and those with other complications according to total
bilirubin level.
Falciparum malaria patients with hyperbilirubinemia/ jaundice accompanied with
renal dysfunction (creatinine > 1.5 mg/dL)/ acute renal failure were 119 (56.9 %),
hyperbilirubinemia and cerebral malaria (GCS < 11) were 43 (20.6 %),
hyperbilirubinemia and hyperparasitemia were also 43 (20.6 %).

16 400

14

300

12

10 200

100

6
SGOT
GCS

4 0
-10 0 10 20 30 40 -10 0 10 20 30 40

Bilirubin Bilirubin

Figure 2. The correlation between bilirubin Figure 3. The correlation between

and GCS bilirubin and SGOT

6
 300 10

200
6

4
100

Creatinine
SGPT

0 0
-10 0 10 20 30 40 -10 0 10 20 30 40

Bilirubin Bilirubin

Figure 4. The correlation between bilirubin Figure 5. The correlation between

and SGPT bilirubin and creatinine

600 300000

500

200000

400

300 100000
Alkaline Phosphatase

200

100
Platelet

0 -100000
-10 0 10 20 30 40 -10 0 10 20 30 40

Bilirubin Bilirubin

Figure 6. The correlation between bilirubin Figure 7. The correlation between

and alkaline phosphatase bilirubin and platelet count

In the 209 patients with hyperbilirubinemia, levels of SGOT ranged from 6 to

297 IU/L (normal value 0 – 35 IU/L) with mean SGOT level 57.8 IU/L. Levels of SGPT
ranged from 4 to 238 IU/L (normal value 0 – 35 IU/L) with mean SGPT level 37.9 IU/L.
The ratio of mean SGOT to SGPT level was 1.52. Alkaline phosphatase levels ranged

7
from 15 to 535 IU/L (normal value 30 – 120 IU/L) with mean alkaline phosphatase level
176.5 IU/L. There were significant positive correlations identified between total bilirubin
level and SGOT (p < 0.01), SGPT (p < 0.01) and alkaline phosphatase (p < 0.05).
There were no correlations between total bilirubin level and level of
consciousness (GCS), hemoglobin or reticulocyte count (p > 0.05). It was found
significant positive correlation between bilirubin and creatinine (p < 0.01), parasite count
(p < 0.05), and a significant negative correlation was identified between bilirubin and
platelet count (p < 0.01).
Mortality was 36 of 271 severe malaria patients (13.3 %). Among patients who
died, all had at least one complication as defined by WHO criteria. Patients who died
with one complication were 0.7 %, and patients who died with 2 complications were the
same as those who died with 3 or more complications (6.3 % each). The highest mortality
was found in patients with total bilirubin level > 10.00 mg/dL (32.6 %), but there was no
correlation between total bilirubin level and mortality rate (p > 0.05).
Complication features in the 36 patients who died were as follows :
- hyperbilirubinemia and renal dysfunction/ acute renal failure 16 (44.4 %)
- hyperbilirubinemia and cerebral malaria 1 (2.8 %)
- hyperbilirubinemia and renal dysfunction/ acute renal failure, cerebral malaria 7
(19.4 %)
- hyperbilirubinemia and renal dysfunction/ acute renal failure, hyperparasitemia 9
(25.0 %)
- hyperbilirubinemia and cerebral malaria, hyperparasitemia 1 (2.8 %)
- hyperbilirubinemia and renal dysfunction/ acute renal failure, cerebral malaria,
hyperparasitemia 2 (5.6 %)
In this study, patients were treated with either quinine infusion continued with
quinine orally when tolerated or artemether injection. Quinine was given as a loading
dose of 20 mg/kg body weight in 100 – 200 ml dextrose 5 %/ normal saline for 4 hours
continued with 10 mg/kg in 200 ml dextrose 5 % for 4 hours, continued every 8 hours
for patients who had not taken quinine or mefloquine in the last 24 hours before
treatment. These latter patients were treated with the same regimen, but did not receive
the loading dose. After 48 hours if patients could take medicine orally, quinine infusion

8
was changed to sulphate quinine tablet 400 – 600 mg (10 mg/ kg body weight) three
times a day until the seventh day counted from the first day of parenteral dose.
Artemether was given intramuscularly with a dose of 1.6 mg/ kg body weight every 12
hours for the first day and then the same dose once daily for the next 4 days with total
dose of 480 mg in 5 days.

Table 4. Effectiveness of quinine and artemether

Therapy Alive Percentage Death Percentage

Quinine 210 86.8 32 13.2

Artemether 25 86.2 4 13.8

The effectiveness of quinine was 86.8 % compared with artemether 86.2 %. There
was no significant difference in the effectiveness of these two drugs (p > 0.05).

DISCUSSION
Hospital based studies conducted in Minahasa, North Sulawesi indicate that
severe malaria accounts for 1.7 –11.9 % of malaria cases. 4 In this study, malaria patients
with jaundice accounted for the highest percentage (54.2 %), followed by cerebral
malaria (21.4 %), severe malaria with acute renal failure (19.2 %) and malaria with
hyperparasitemia (17.7 %). Similar results were found in earlier studies at Bethesda
Hospital 1990 – 1993 and at Manado General Hospital. 2,4 These results reflect the
features of severe malaria in North Sulawesi generally, where severe malaria with
jaundice is the most common presentation of severe malaria. Studies in Vietnam and
Thailand showed a different result, where cerebral malaria accounted for about 50 % of
severe malaria cases.6
Jaundice in malaria appears to have hemolytic, hepatic and cholestasic
components.8 Liver dysfunction is caused by decrease of hepatic blood flow.2 Gamma-
glutamyl transpeptidase, 5-nucleotidase, SGOT, SGPT can be elevated and prothrombin
time is moderately prolonged. An important index of liver dysfunction is a low or falling
serum albumin level. Other liver disorders associated with liver dysfunction are lactic
acidosis, hypoglycemia, change of triglyceride, phospholipid, free fatty acid, cholesterol

9
levels.6 Study by Datau et al quoted from 2 showed that the most common type of jaundice was
mixed-type, a combination of parenchymal disorder, hemolysis and obstruction (78.6
%). Liver biopsy in jaundiced patients usually shows Kupffer cell hyperplasia, sinusoidal
dilatation, mononuclear cell infiltration, pigment deposition, hepatocyte swelling and
even centrizonal necrosis, although in some patients liver histology is remarkably
normal.5-8 Acute liver failure is very unusual, however Joshi et al 9 and Srivastava et al 10

reported 9 and 7 malaria patients with acute liver failure.

The highest total bilirubin level in this study was 36.40 mg/dL and the mean total
bilirubin level was 6.64 mg/dL, whereas most patients were found in the group with total
bilirubin 5.01 – 10.00 mg/dL (24.4 %). Mild jaundice may be caused by hemolysis, but
very high bilirubin level shows liver dysfunction. 6 In this study both conjugated and
unconjugated bilirubin were increased, however mean conjugated bilirubin level
(3.99 mg/dL) was higher than mean unconjugated bilirubin level (2.65 mg/dL).
From table 3 we can see that patients with hyperbilirubinemia were most often
accompanied with another complication (47.7 %), while 3 or more complications were
only found in 4.8 % of patients. Patients with hyperbilirubinemia who most frequently
experienced additional complications were those with total bilirubin level > 10.00 mg/dL
(89.1 %), however there was no correlation between the number of complications and
bilirubin level. Wenas et al 2 found that patients with bilirubin level > 3 mg/dL had more
complications compared with those with bilirubin level < 3 mg/dL.
In this study, malaria with hyperbilirubinemia was frequently accompanied with
renal dysfunction/ acute renal failure (56.9 %). Studies in Vietnam showed that 63 %
of patients with acute renal failure were jaundiced.6
Transaminases (SGOT and SGPT) can rise to as high as 10 times the upper
normal limit in severe malaria, considerably smaller elevations than can be found with
viral hepatitis.6 In this study the highest SGOT level was 297 IU/L, mean SGOT level
was 57.8 IU/L, whereas the highest SGPT level was 238 IU/L, mean SGPT level was
37.9 IU/L. De Ritis ratio was 1.52 (normal < 0.7). Serum glutamic-oxaloacetic
transaminase (SGOT) is present in both the cytosol and mitochondria of hepatocytes
while SGPT is localized to the cytosol. This ratio indicates that hepatocyte damage
involved primarily the mitochondria and tended to be necrotic type rather than

10
 2
inflammatory type. Wenas et al reported de Ritis ratio 1.5 in malaria patients with
jaundice.
There were positive correlations between total bilirubin level and SGOT, SGPT,
alkaline phosphatase (this enzyme is a usual marker to identify cholestasis) while no
correlations were found between total bilirubin level and hemoglobin or reticulocyte
quoted from 5
count. Hall et al reported that total bilirubin level correlated positively with
SGPT and alkaline phosphatase. These results support the evidence that liver
parenchymal disorder and cholestasis are more important than hemolysis in the
development of jaundice.7
In this study there was positive correlation between serum bilirubin level and
2 quoted from 5
parasite count. Wenas et al reported a similar finding. Hall et al found that
jaundice occurred in 5 % of patients with parasite density < 1000/L, but it reached 45 %
in those with parasite density > 100,000/L. In this study 71 % of patients with parasite
density > 100.000/L were jaundiced.
Total bilirubin correlated positively with creatinine. This is the same as Hall
quoted from 5
et al`s study. We also found that jaundiced patients accompanied with renal
dysfunction/ acute renal failure were 56.9 %.
Total bilirubin correlated negatively with platelet count. This means bleeding
tendency rises with a high bilirubin level, likely due to liver dysfunction (impaired
clotting factor synthesis produced by liver which is characterized by prolonged
prothrombin time) and decreased platelet count.
Mortality rate of severe malaria at Manado General Hospital in 1995 was 15.8 %
and in 1998 11.4 %. In this study 36 of 271 patients died (13.3 %). Patients who died with
one complication were 0.7 %, those who died with 2 complications were 6.3 % and
patients who died with 3 or more complications were also 6.3 %. This indicated that the
presence of more than one complication led to increased mortality rate. The majority of
patients who died were those with hyperbilirubinemia and renal dysfunction/ acute renal
failure, 16 of 36 patients (44.4 %). This was compatible with data that the most common
combination of complications were hyperbilirubinemia/ jaundice along with renal
dysfunction/ acute renal failure and there was positive correlation between total bilirubin
level and creatinine level. Another study reported that a parasite count > 100,000/L was

11
associated with increased mortality and 50 % of malaria patients with parasite count
> 500,000/L died.7 In this study 38 % of patients with parasite count > 500,000/ L
died. Worldwide the mortality rate of cerebral malaria is 10 – 50 %.6 Studies in North
Sulawesi showed that the mortality of cerebral malaria was 30.5 %. 4 In this study there
was no correlation between total bilirubin level and mortality. This shows that other
factors such as hyperparasitemia, cerebral malaria, acute renal failure and complications
in other organs play a role in the increase in mortality. According to WHO (1990), the
main causes of death in patients with severe malaria were pulmonary edema, acute renal
failure, and metabolic acidosis with circulation failure. 7 Wenas et al 2
reported that
mortality in patients with bilirubin > 3 mg/dL was 33 %, bilirubin 2 – 3 mg/dl 29 %,
bilirubin 1.2 – 2 mg/dL 17 % and bilirubin < 1.2 mg/dL 11 %.
Quinine is an antimalarial drug from the group of chincona alkaloid which is
blood schizonticide for all types of Plasmodium and gametocide for P. vivax and P.
malariae.8,11 Artemether is an antimalarial drug derived from Artemesia annua extract
(qinghaosu), which is blood schizonticide for P. falciparum and P. vivax, and known as
the most rapidly acting of antimalarials. This drug is recommended for uncomplicated
malaria that is multidrug resistant, and severe malaria unresponsive to quinine. From two
large comparative studies, artemether accelerated parasite clearance, but slightly
prolonged recovery from coma and did not reduce mortality significantly in comparison
with quinine.1 In this study we used either quinine or artemether. There was no difference
in the effectiveness of quinine and artemether in treating severe malaria, but our power to
detect a difference was small.

CONCLUSION
Malaria with hyperbilirubinemia/ jaundice is the most common complication in
severe malaria (77.1 %) in Minahasa, North Sulawesi. Hyperbilirubinemia with other
complications is most frequently found in patients with total bilirubin level
> 10.00 mg/dL, however there is no correlation between bilirubin and the number of
other complications. Malaria with hyperbilirubinemia/ jaundice is often accompanied
with renal dysfunction/ acute renal failure (56.9 %). Bilirubin correlates positively with
SGOT, SGPT, alkaline phosphatase, parasite count, and creatinine and correlates

12
negatively with platelet count. There is no difference in mortality in patients with 2
complications and those with 3 or more complications. The highest mortality is found in
patients with hyperbilirubinemia accompanied with renal dysfunction/acute renal failure
(44.4 % of patients who died). There is no correlation between bilirubin level and
mortality rate. This shows that other factors play a role.

REFERENCES
1. White NJ. The treatment of malaria. N Engl J Med 1996; 335: 800-6.
2. Wenas NT, Harijanto PN, Moeis ET. Liver dysfunction in severe malaria. (in Indonesian).
Acta Medica Indonesiana 1995; XXVII (suppl 1) : 282-90.
3. Gunawan CA, Harijanto PN, Sutjipto. Malaria in North Sulawesi. In : Harijanto PN (Ed).
Malaria. Epidemiology, Pathogenesis, Clinical Manifestation and Management. (in
Indonesian). Jakarta : EGC, 1999 : 26-37.
4. Harijanto PN. The clinical presentations of severe malaria. In : Harijanto PN (Ed). Malaria.
Epidemiology, Pathogenesis, Clinical Manifestation and Management. (in Indonesian).
Jakarta : EGC, 1999 : 166-84.
5. Harinasuta T, Bunnag D. The clinical features of malaria. In : Wensdorfer WH, McGregor SI
(Eds). Malaria. Principles and Practice of Malariology. Vol 1. Edinburg : Churchill
Livingstone, 1988 : 709-207.
6. World Health Organization. Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000; 94
(suppl 1) : 11-15.
7. White NJ., Ho M. The pathophysiology of malaria. Advances in Parasitology 1992 ; 31 :
126-7.
8. White NJ. Protozoan infections. In : Cook Gc (Ed). Manson`s Tropical Diseases. 20 th ed.
Philadelphia : WB Saunders Company, 1996 : 1087-1164.
9. Joshi YK, Tandon BN, Archarya SK, Babu S, Tandon M. Acute hepatic failure due to
Plasmodium falciparum liver injury. Liver 1986; 6 : 357-60.
10. Srivastava A, Khanduri A, Lakhtakia S, Pandey R, Chouduri G. Falciparum malaria with
acute liver failure. Trop Gastroenterol 1996; 17 : 172-5.
11. Tjitra E. Anti-malarial drugs. In : Harijanto PN (Ed). Malaria. Epidemiology, Pathogenesis,
Clinical Manifestation and Management. (in Indonesian). Jakarta : EGC, 1999 : 194-223.

13
14