• hepatitis;
  • hepatopathy;
  • jaundice;
  • malaria;
  • Plasmodium falciparum


  1. Top of page
  2. Abstract

Jaundice is not an unusual accompaniment of malaria. It can occur due to intravascular hemolysis, disseminated intravascular coagulation, and, rarely, ‘malarial hepatitis’. Although the primary schizogony of the malarial parasite always leads to the rupture of the infected hepatocyte, alteration of the hepatic functions is uncommonly recorded due to this event. Histologically, the hepatitis or the actual inflammation in the liver has never been demonstrated. Nonetheless, the term ‘malarial hepatitis’ (MH) has been used in the literature to describe the occurrence of hepatocellular jaundice in patients with Plasmodium falciparum infection. The authors’ own data and review of the literature indicate that it is not an uncommon entity. In endemic areas, jaundice is seen in approximately 2.5% of patients with falciparum malaria. It also appears to be a heterogeneous syndrome and one can recognize two clinical subsets. In one group there was an acute, virulent presentation with coma, renal failure and in some cases even hemorrhagic manifestations. It is only in this setting that jaundice signified a ‘severe’ disease as noted by the World Health Organization action program. This presentation is often confused with acute viral hepatitis and acute hepatic failure in non-endemic areas, but can be clinically differentiated.

© 2005 Blackwell Publishing Asia Pty Ltd


  1. Top of page
  2. Abstract

Malaria remains a major problem in many parts of the world. Approximately 500 million people are affected annually, and approximately 3 million, mostly children, die of falciparum malaria each year.1,2 The liver plays a key role in the life cycle of the malarial parasite and in some cases it is seriously affected. Although hemolytic jaundice is not uncommon in malaria, there are reports of a spectrum of hepatocellular dysfunction varying from mild derangement of liver function tests to those describing liver failure as a complication of falciparum malarial infection.3–5 The term ‘malarial hepatitis’ is often used to describe hepatocellular jaundice in patients with malarial infection; the clinical significance of this entity is yet to be clearly elucidated.6–8

Historical perspective

Several historical papers suggest that malaria was suspected to be a cause of liver disease for more than 100 years. Dr Patrick Manson in 1898 wrote the following.

Under the influence of succession of acute attacks, hepatic congestion may acquire a more or less permanent character. If this . . . be long maintained, it tends to bring about various kinds and degrees of chronic hepatitis and hypertrophy, or to different forms of atrophic cirrhosis. Thus, irremediable organic disease of the liver, portal obstruction and ascites may ensue.9

Later, Lucius Nicholls in 1913 wrote, ‘Cirrhosis of the liver is a common condition of many tropical countries, and numerous authorities have asserted that some cases are caused by repeated attacks of malaria . . .’10 Ronald Ross elucidated the host–mosquito–host cycle of avian malaria in 1898.11 It was only in 1948 that the hepatocyte stage of the life cycle of malaria was clearly described when it was first discovered that malaria parasites infect and developmentally mature in hepatocytes of the liver.12

Role of the liver in the plasmodium life cycle

The liver is affected in two stages in the life cycle of the malarial parasite: initially the pre-erythrocytic cycle and then in the erythrocytic phase. The latter is responsible for the clinical manifestations of malaria. The life cycle of the malaria parasite is depicted in Fig. 1.


Figure 1. Outline of the life cycle of malaria. 1. Sporozoites injected with saliva of female Anopheles mosquito migrate to liver. 2. Pre-erythrocytic schizogony in liver cells leads to release of merozoites. 3. Merozoites released into circulation invade red blood cells. 4. Erythrocytic schizogony in red blood cells leads to release of tides of merozoites causing periodic fever. 5. Some of the released cells develop into gametocytes; and 6. are ingested again by mosquito during a bite. Sexual cycle completed in the mosquito. It releases fresh sporozoites, which migrate to the salivary glands of the mosquito.

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Pre-erythrocytic cycle

Female Anopheles mosquitoes transmit malaria parasites to humans. During the bite, the invasive form known as a sporozoite, is injected into the dermis. These sporozoites reach the liver through the blood stream and infect the hepatocytes.11,13 The possible molecular basis enabling the sporozoites to find their way into the liver has been determined recently.14 The circumsporozoite protein (CSP-A protein that covers the surface of the sporozoite) and TRAP (a sporozoite organellar protein inducibly translocated to the sporozoite surface) bind to hepatocytes via the heparan sulfate glycosylaminoglycans (GAG) expressed specifically on the surface of hepatocytes.15 Malaria sporozoites have been shown in rats to actively enter and pass through Kupffer cells prior to hepatocyte invasion.16

In the hepatocyte, the sporozoite undergoes schizogony to form a schizont, which divides to produce tens of thousands of merozoites. Schizogony takes place in the liver without any obvious effect on its function. The exo-erythrocytic cycle lasts for 6–15 days and is clinically silent. Rupture of the infected hepatocyte releases the merozoites into the blood stream where they invade red blood cells (RBC) to begin the erythrocytic phase of the malarial life cycle. Infection with Plasmodium falciparum and P. malariale is not associated with any residual liver stage after release of merozoites while P. vivax and P. ovale are associated with a persistent exo-erthrocytic stage, the hypnozoite, which can persist in the liver and on activation mature into schizonts.

Erythrocytic cycle

The merozoites multiply in parasitized RBC to produce new merozoites that rupture from the RBC, and invade new RBC to perpetuate the infection. A few of the merozoites differentiate into male and female gametocytes. When a feeding mosquito ingests these gametocytes, they undergo fertilization in the midgut of the mosquito to form a zygote that transforms into another invasive stage termed an ookinete. The ookinete differentiates into an oocyst that replicates its nucleus thousands of times to form sporozoites. When the oocyst ruptures the sporozoites migrate to the salivary glands thereby priming the mosquito to be able to transmit malaria to another human host.15,17,18

Incidence of jaundice in malaria

There is a wide variation in the report of jaundice in malaria. In a study of 732 patients with falciparum malaria in an endemic area, we have shown that jaundice occurs in 5.3% of all such cases.19 Mehta et al. in a study of 425 cases of falciparum malaria have also reported jaundice in only 2.58%.20 In epidemics, the reported incidence of jaundice is higher and varies from 11.5% to 62%.21–23 Murthy et al. found jaundice in 62% of patients with falciparum malaria.22 Wilairatana et al. from Thailand reported an incidence of jaundice in 32% of falciparum malaria although the bilirubin was predominantly unconjugated.24 Harris et al. from South India found that 37% of cases of falciparum malaria had hyperbilirubinemia.25 In children, Bag et al. found ‘hepatitis’ in 8% children with complicated falciparum malaria.26

Jaundice has been found to be more common in falciparum as compared to vivax malaria. Hazra et al. found an association of jaundice in 40% and 9.09% cases with P. falciparum and P. vivax, respectively, from Calcutta.27 Echeverri et al. in a study of vivax malaria from Colombia have reported an incidence of jaundice in 15%.28 Seth et al. found jaundice in 7.7% cases of falciparum malaria while they did not find jaundice in vivax malaria.29

Some possible reasons for such a wide variation in reports of jaundice could include endemic versus epidemic areas, age group, vivax versus falciparum/mixed infection and analyzing only complicated cases where the incidence is higher. A study from Thailand has suggested that pre-existing helminth infections are associated with protection from malaria-related acute renal failure and jaundice by influencing sequestration.30 Another possible factor could be associated viral hepatitis, which could also be endemic.

Although unconjugated hyperbilirubinemia is common in malaria, we reported hepatocellular jaundice or the so-called ‘malarial hepatitis’ with an incidence of approximately 2.6%from North-East India.19 Murthy et al. have reported malarial hepatitis in 22% cases of falciparum malaria from Hyderabad.22 Harris et al. found that 72% of patients with jaundice had direct hyperbilirubinemia and elevated liver enzymes suggesting hepatocellular damage.25 Higher incidence of hepatitis reported by some authors may be due to inclusion of only admitted cases, of which 50% had cerebral malaria and other complications that indicate severe infection.22 While hepatomegaly and mild elevation of enzymes can be observed in a significant proportion of patients, involvement of liver leading to acute hepatitis or liver cell necrosis is a relatively uncommon complication in P. falciparum malaria.31

Aetiopathogenesis of jaundice in malaria

While jaundice in malaria is often labeled as ‘malarial hepatitis’, jaundice can be multifactorial. It may be caused by intravascular hemolysis, disseminated intravascular coagulation (DIC) or hepatocellular dysfunction. The common causes of jaundice in malaria are outlined in Table 1.

Table 1.  Causes of jaundice in malaria
  1. DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; RBC, red blood cell.

Direct cause:Malarial hepatitis
Intravascular hemolysis of parasitized RBC
Septicemic hepatitis
Indirect cause:Microangiopathic hemolysis associated with DIC
G6PD-related hemolysis
Anti-malarial-drug induced
Unrelated cause:Coexisting acute viral hepatitis
Underlying chronic hepatitis

Malarial hepatitis

Hepatocellular dysfunction ranging from conjugated hyperbilirubinemia with or without mild elevation in transaminases to fulminant hepatic failure has been described in falciparum malaria. A diagnosis of malarial hepatitis can be made in a patient who fulfills the following criteria: (i) demonstration of P. falciparum infection; (ii) at least threefold rise in transaminases, particularly alanine aminotranferase (ALT), demonstrated on two consecutive blood samples taken over 24 h apart with or without conjugated hyperbilirubinemia; (iii) absence of clinical and serological evidence to suggest drug or viral hepatitis; and finally (iv) clinical response to antimalarial drugs or autopsy evidence of disseminated falciparum infection.

Although the term ‘malarial hepatitis’ has been used to describe the occurrence of jaundice in patients with falciparum malaria, the exact pathogenesis of jaundice is not clearly understood. Malaria can coexist with viral hepatitis and the very diagnostic criteria of ‘malarial hepatitis’ mandates the exclusion of other viral infections. However, in reports of malarial hepatitis, detailed work-up for viral markers are not available. Histological data, however, do not suggest a significant role of viral infection in fatal cases. For the same reason hepatitis due to drugs is also not a likely cause.

The peripheral parasitemia in P. falciparum may be scanty and intermittent mainly due to cytoadherent properties and sequestration of parasitized RBC accounting for the negative smears found. Organ damage in falciparum malaria is said to be related to cytoadherence of parasitized RBC to the vascular and sinusoidal endothelium, leading to ‘stagnant anoxemia’.32 Even reversible reductions in portal venous flow have been described during the acute phase of falciparum malaria, presumably as a consequence of microocclusion of portal venous branches by parasitized erythrocytes.33 However, parasitized RBC in the sinusoids are not universally seen in histological samples.

Liver function abnormalities have also been reported in severe systemic infections and endotoxemia. Endotoxemia with or without a concomitant bacterial infection has been reported in complicated falciparum malaria.34 Hepatic dysfunction due to intrahepatic cholestasis because of reticuloendothelial blockage and disturbance of hepatic microvilli is an additional mechanism proposed.35 Although the hepatocellular dysfunction is labeled as ‘malarial hepatitis’, biochemical and histological evidence of hepatocellular injury is minimal in these patients. A question that is asked regarding malarial hepatitis is where the inflammation is in falciparum hepatitis.8,36 It appears that hepatocellular jaundice in falciparum malaria is not because of hepatitis but may be because of suppression of bilirubin excretion due to either effect of parasitemia on the hepatocytes, or endotoxemia or metabolic acidosis or a combination of these abnormalities. Electron microscopy of liver tissue in severe falciparum malaria has shown hypertrophy of Kupffer cells and sinusoidal macrophages. Hepatocyte swelling, changes in endoplasmic reticulum and mitochondria, and loss of microvilli at the sinusoidal pole were reported.37 The damage to the canalicular membrane on electron microscopic examination may be responsible for passive back-diffusion of conjugated bilirubin. It still needs to be resolved as to whether the centrizonal necrosis observed in some recent cases was related to malarial infection or terminal hypotension/preservation artifact.36

Several reports have loosely used the term ‘fulminant hepatic failure’ with severe malaria. However, coma in a patient with cerebral malaria may be related to cerebral malaria rather than hepatic encephalopathy. Although hepatocellular jaundice can occur in severe and complicated malaria, ‘severe liver disease’, which is one of the criteria for diagnosis of fulminant hepatic failure, has not been shown histologically on post-mortem examination. Hence, the current usage of the term ‘malarial hepatitis’ appears to be a misnomer and the term ‘malarial hepatopathy’ may more aptly describe our current knowledge of hepatocellular dysfunction in these patients.

One thing, however, that cannot be disputed is that patients with malarial hepatitis usually have evidence of significant dysfunction of other organs. Murthy et al. studied 95 consecutive patients admitted with falciparum malaria.22 Of these, 20 had evidence of malarial hepatitis. Patients with malarial hepatitis had a significantly higher incidence of complications such as renal failure, adult respiratory distress syndrome, septicemia and mortality. They concluded that the presence of hepatitis in patients with falciparum malaria indicates a more severe illness with a higher incidence of complications and a poor prognosis.

Other causes of jaundice in severe malaria

Intravascular hemolysis of parasitized red blood cells

Massive intravascular hemolysis has been recognized as the pathogenic mechanism of jaundice in falciparum malaria. This accounts for the common occurrence of unconjugated hyperbilirubinemia.30

Coexisting acute viral hepatitis

In endemic areas it is important to be aware that jaundice may be a part of malaria per se or acute viral hepatitis. In a patient with fever and jaundice with or without altered sensorium, disproportionate hyperbilirubinemia but with only mild elevation of liver enzymes could help differentiate these cases of malaria from viral hepatitis.23 However acute hepatitis E and malaria are both common infections in tropical countries and can coexist. Ghoshal et al. reported a case of a 20-year-old girl who presented with fulminant hepatic failure and had combined infection with acute hepatitis E as well as falciparum malaria.38 Although their case had a fatal outcome, Bansal et al. reported a case of coexistence of complicated vivax malaria with coexisting acute hepatitis E with a favorable outcome.39 In general hepatic failure is seen only in association with concomitant acute viral hepatitis or with severe P. falciparum malaria.40 Association of hepatitis A with malaria has also been reported.41 Viral hepatitis may be ‘atypical’ when associated with other infections (malaria, typhoid fever etc.), mostly in patients from tropical countries.42

Underlying chronic hepatitis

Seroepidemiological associations have been found between malaria and hepatitis B.43 Barcus et al. investigated the prevalence of infection with hepatitis B virus (HBV) among adult Vietnamese patients hospitalized for severe P. falciparum malaria.44 They found that the overall prevalence of hepatitis B surface antigen (HBsAg) was 23.77% as compared to the estimated prevalence of 9.8% in the general catchment population. No association was found between risk of death caused by severe malaria and HBsAg. Patients admitted with cerebral malaria had a slightly greater risk of registering positive for HBsAg relative to other manifestations of severe malaria. Chronic infection with HBV may be a risk factor for severe malaria. Souto et al. in a survey on Plasmodium infection carried out in goldmine camps in the Brazilian Amazon, found that 82.9% had HBV markers, and 7.1% were HBsAg positive.45 Antibody against P. falciparum ring-infected erythrocyte surface antigen (RESA) titers were significantly lower in HBV carriers than in people with resolved HBV infection, suggesting that the anti-RESA immune response could be suppressed by HBV carrier status.

Malaria, like HBV and hepatitis C virus (HCV), can be transmitted via syringes in intravenous drug users,46 as well as through blood transfusions.47,48 A case of chronic active viral hepatitis B combined with HIV carriage, malaria and syphilis has also been reported.49 Falciparum malaria may modulate viremia in chronic HBV infection.50 Thursz et al. reported an association of HBsAg carriage with severe malaria in Gambian children.51 They suggested that this association might relate to impaired clearance of liver stage parasites in the presence of the reduced level of human leukocyte antigen (HLA) class I antigen expression on hepatocytes infected by HBV. If this association is causal and viral carriage predisposes to severe malaria, widespread vaccination against HBV may reduce mortality from severe malaria.

Interestingly, a severe flare-up of chronic hepatitis B infection with liver cell insufficiency has been observed after discontinuation of chloroquine administered as malaria prophylaxis. Chloroquine is known to inhibit the association of the major histocompatibility complex (MHC) type II with HBV antigens; thereby inhibiting T-cell-mediated lysis of infected cells. Furthermore, it inhibits uptake of duck HBV by duck liver cells. These in vitro studies suggest that chloroquine inhibits the lysis of HBV-infected hepatocytes. Withdrawal of chloroquine in patients with chronic HBV infection can lead to a rebound immune response manifesting as a reactivation of hepatitis B, similar to that observed after steroid withdrawal.52 Malaria infection might influence the course and pathogenesis of HBV infection in co-infected humans.53

Jaundice due to drugs

Mefloquine is an effective drug for prophylaxis and treatment of malaria caused by P. falciparum. It is generally well-tolerated with few side-effects. Minimal elevation of liver function tests has been reported after exposure to mefloquine, especially in susceptible individuals with prior abnormal liver function tests. Gotsman et al. reported a patient who had had elevated liver function tests attributed to heart failure, who experienced an acute elevation of liver transaminases 6 weeks after exposure to mefloquine 250 mg/week.54 Cessation of the drug caused test results to return to normal. Mefloquine should be prescribed cautiously in patients with liver disease. Drug-induced hepatitis with considerable morbidity has also been reported with chloroguanide prophylaxis.55 Fatal acute hepatitis due to amodiaquine has been reported.56,57

Combination antimalarial therapy is being explored to delay development of resistance to falciparum malaria. Orrell et al. reported acute asymptomatic hepatitis in a healthy normal volunteer exposed to two oral doses of amodiaquine and artesunate.58 Acute hepatitis has been reported following administration of pyrimethamine-sulfadoxine.59 Granulomatous hepatitis attributed to the combination pyrimethamine–chloroquine for prophylaxis has also been reported.60 Use of these combinations should be closely monitored.

The pharmacokinetics of quinine inpatients with hepatitis show that terminal elimination half-life was prolonged (17 and 15 vs 10 h) and there was lower clearance (2.9 and 2.3 vs 3.5 mL/min per kg). The present data suggest that current dosage regimens of quinine used in the treatment of falciparum malaria may not be suitable for malaria patients with acute hepatitis or those who have had hepatitis within the past 3 months.61

Glucose-6-phosphate dehydrogenase deficiency

While glucose-6-phosphate dehydrogenase (G6PD) deficiency may confer protection against malaria,62 it may also be a cause of hemolysis and jaundice. In a study of 35 children with G6PD deficiency who presented with acute intravascular hemolysis, malaria was the incriminating factor responsible for hemolysis in four children.63 Antimalarial drugs may precipitate hemolysis in G6PD deficiency.

Microangiopathic hemolysis associated with disseminated intravascular coagulation

Hemolysis and DIC are common causes of jaundice in severe and complicated malaria.64 DIC is associated with severe manifestation of malarial illness.

Clinical profile

Malarial hepatopathy is a heterogeneous syndrome with at least two clinical subsets. The fulminant clinical illness (type A) with coma, deep jaundice, purpura and renal failure can be confused with fulminant hepatic failure. A relatively milder form illness (type B) occurs where the patients have a relatively mild illness with only fever, headache and vomiting.19 The comparison of the clinical course of a typical patient from group A with that of another from group B is shown in Fig. 2.


Figure 2. Comparison of clinical features of two types of malarial hepatitis. Horizontal axis shows time in days, while vertical axis shows severity of clinical abnormality. Malarial hepatitis can be classified into two clinical types. Type B is a relatively benign condition while type A is associated with multiorgan failure.

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Mimic of fulminant hepatic failure

Imported falciparum malaria presenting to emergency departments in the USA is frequently misdiagnosed as hepatitis and gastroenteritis.65 The common association of jaundice along with hepatomegaly in conjunction with nausea and/or vomiting leads to clinical mimicry with infective hepatitis.24 The full-blown picture of falciparum malaria with jaundice and altered sensorium may often be confused with fulminant hepatic failure. Three pointers to the etiology being malaria are associated oligoanuria, disproportionate anemia and normal or increased liver span. In addition, persistent fever and only mild elevation of liver enzymes should help differentiate these patients from cases of fulminant hepatic failure. Demonstration of P. falciparum rings or antigen and a prompt response to antimalarial drugs are points in favor of malarial syndrome.3,5,19,66 It is important that this severe disease should not be mistaken for fulminant hepatic failure because there is a better response to therapy. Although there are reports of severe P. falciparum leading to fulminant hepatic failure, clinical liver failure is unlikely unless the patient has concomitant viral hepatitis.67


According to the World Health Organization (WHO), bilirubin > 3 mg% and death due to hepatic encephalopathy is rare, but bilirubin up to 25 mg% and death due to ‘hepatic coma’ have been reported.68,69 Unconjugated bilirubin is often elevated and may be associated with evidence of intravascular hemolysis in the form of hemoglobinemia and hemoglobinuria. However, malarial hepatopathy with rise in conjugated bilirubin is not uncommon. Enzyme elevation, however, is only mild.

Differential diagnosis of fever with jaundice is depicted in Table 2. Conventionally malaria is diagnosed by demonstration of malarial parasite on peripheral blood smear. Microscopy is relatively inexpensive and is the most affordable test for use in developing countries However, in falciparum malaria the parasite may not be easily demonstrable on peripheral blood smear. In such cases rapid tests for malaria may help in reaching to the diagnosis. These tests are based on the detection of antigens derived from malaria parasites in lyzed blood, using immunochromatographic methods.

Table 2.  Differential diagnosis of fever with jaundice
  Clinical and biochemical featuresSpecific investigations
  1. ALT, alanine aminotransferase; AP, alkaline phosphatase; EB, Epstein–Barr; GGT, γ-glutamyl transpeptidase; h/o, history of; IFA, indirect immunofluorescence assay; PBS, peripheral blood smear; USG, ultrasound.

Viral infectionsViral hepatitis A, B,C, D, EFever in prodrome with anorexia, nausea, vomiting; transaminases [UPWARDS ARROW][UPWARDS ARROW][UPWARDS ARROW]Serology (HBsAg, IgM anti-HAV, IgM anti-HEV, IgM anti-HBc etc.)
Lymphadenopathy, sore throat, jaundice in 5%, mild rise in ALT, APPaul Bunnel, atypical lymphocytes on PBS, IgM antibodies to EB virus
Yellow feverTravel to Africa, South America 
Rare causes: herpes simplex, Cytomegalovirus  
Bacterial infectionsLeptospiraRenal failure, bleeding manifestations, [UPWARDS ARROW]creatinine kinase in 50%, [UPWARDS ARROW] AP, ALT < 200 IU/L, mild rise in ALT, APELISA, isolation of leptospira from blood/CSF (first 10 days) and urine (after 1 week for several weeks)
Typhoid feverComplications in 3rd−4th week,Widal, blood culture
CholangitisBiliary colicUSG dilated biliary radicals
Septicemic hepatitisSepsis source may be obvious, other organ dysfunction, bilirubin usually between 5 and 10 mg%, discrepancy between bilirubin and enzymesBlood cultures
RickettsiaTyphusRash, pulmonary manifestations, thrombocytopenia; jaundice uncommonWeil felix, IFA
ProtozoaMalariaQuartan/tertian fever pattern, mild rise in ALT, AP; often [UPWARDS ARROW] in indirect bilirubinMalarial parasite on PBS
Amebic liver abscessPleuritic pain, pain abdomen, jaundiceUSG liver abscess, amebic serology
Non infectiveAlcoholic hepatitisAST > ALT, ALT < 200 IU/L, [UPWARDS ARROW]GGT 
Adverse drug reactions or transfusion-related hemolysish/o transfusion/drug intake 


The spectrum of histological changes reported in malaria include centrizonal necrosis, Kupffer cell hyperplasia, deposition of brown malarial pigment (hemozoin), portal infiltration with lymphocytes, steatosis and finding parasitized RBC. Rarely cholestasis, spotty necrosis and submassive necrosis have been reported. While centrizonal necrosis has been reported by some authors to be the characteristic histological abnormality in malarial hepatitis,3,70 others have found only non-specific histological features on biopsy/autopsy, with centrizonal necrosis being rare.19,31,71,72 Joshi et al. studied liver histology in patients with acute liver failure due to P. falciparum liver injury, which was identical in all eight, showing centrizonal necrosis and hyperplastic Kupffer cells loaded with malarial pigment.3 Seth et al. studied histology in eight patients with fatal falciparum malaria and found Kupffer cell hyperplasia and deposition of malarial pigment in all eight, portal infiltration with lymphocytes in five (63%), steatosis in two (25%) and parasitized RBC in four (50%).29 Chawla et al. also found that histologically the most consistent finding in liver biopsies was reticuloendothelial cell hyperplasia.71 Pigmentation in Kupffer cells, fatty change, sinusoidal and portal infiltration and cholestasis were the other features seen. Kachawaha et al. studied post-mortem liver tissue in four patients and found swollen hepatocytes, presence of hemozoin deposits, portal infiltrates by mononuclear cells, Kupffer cell hyperplasia, centrizonal necrosis, bile stasis and fatty change.72 Srivastava et al. studied post-mortem liver biopsy in four patients with fatal falciparum malaria and found Kupffer cell hyperplasia, pigment deposition, foci of steatosis and necrosis along with submassive necrosis in one case.66 Anand et al. found centrizonal necrosis in only one out of five patients; reticuloendothelial cell hyperplasia and deposition of brown malarial pigment was seen in four of five patients, and parasitized RBC in the sinusoids were seen in only two patients.19

However, demonstration of parasites is seen in half or fewer of the patients on histology. Sepsis is often associated with severe falciparum malaria and may play a role in histological non-specific changes. However, patients with sepsis often have marked cholestasis and may show mid-zonal or peripheral necrosis.72–74 Cholestasis, however, is rare and is not a dominant manifestation. Liver histology showing hepatocytes laden with brown malarial pigment is shown in Fig. 3. The prevalence of jaundice and histopathology found by various authors is shown in Table 3.3,22,23,25,27–29,66,68,71,72,75


Figure 3. Histopathology of liver in falciparum hepatopathy. HE stained (×450) section shows Kupffer cell hyperplasia and malarial pigment deposit.

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Table 3.  Prevalence of jaundice and histopathology in malaria
StudyNo. casesSetting of the studyJaundiceHistopathology
  1. FHF, fulminant hepatic failure.

Joshi et al. 198639FHF in falciparum malaria; patient selected on basis of features of liver failureAlln = 8: centrizonal necrosis and hyperplastic Kupffer cells with malarial pigment
Chawla et al. 19897132Retrospective study of falciparum malaria with jaundice21.8% Conjugated 65.5% Serum transaminases [UPWARDS ARROW]in 21.8%Reticuloendothelial cell hyperplasia in all. Pigmentation in Kupffer cells, fatty change, sinusoidal and portal infiltration and cholestasis were other features seen
Anand et al. 199219732Prospective study of falciparum malaria, all patients investigated for jaundice5.3% Malarial hepatitis in 18 (2.5%)n = 5 Kuppfer cell hyperplasia, malarial pigment deposition in 4, centrizonal necrosis in 1, parasites in 2
Srivastava et al. 1996664Selected on basis of coexistence of falciparum malaria and jaundiceAlln = 4 Reticuloendothelial cell hyperplasia, focal steatosis, pigment deposition
Seth et al. 199729213Prospective study; Falciparum n = 169, vivax n = 44Falciparum: 7.7%, Vivax 0% Conjugated 41%, unconjugated 3.6%n = 8; Kuppfer cell hyperplasia in all; lymphomononuclear portal infiltration 5, parasitized sinusoidal RBC 4, steatosis 2
Murthy et al. 19982295Consecutive cases of falciparum malaria58.9% Malarial hepatitis in 20n = 1 Kupffer cell hyperplasia, deposition of malarial pigment, portal lymphomononuclear infiltrate
Hazra et al. 199827225Falciparum n = 60, Vivax n = 165Falciparum 40% Vivax 9.09% 
Harris et al. 20012586Complicated falciparum malaria: retrospective study37% (72% had malarial hepatitis) 
Echeverri et al. 200128104Vivax malaria15% 
Asthana et al. 200175211Efficacy of arte-ether in complicated falciparum multicentric study29.4% Majority hemolytic jaundice 
Kochar 200268, 200336411Prospective study of cerebral malaria6.8%2003 study reported histopathological examination in 20 patients. Showed evidence of swollen hepatocytes (100%), malarial pigment deposition (75%), inflammatory infiltrates (60%), congestion of hepatocyte (50%) along with centrizonal necrosis in 25% of cases
Mazumder et al. 200323212Prospective study of falciparum malaria17%; conjugated in all; transaminases [UPWARDS ARROW] in 78% 
Kachawaha et al. 20037229Ultrasonography in malarial hepatitisAlln = 4 swollen hepatocytes, hemazoin deposits, portal mononuclear infiltrate, congestion, Kupffer cell hyperplasia, centrizonal necrosis, bile stasis and fatty change

Imaging scans

Kachawaha et al. studied ultrasound in 29 patients with malarial hepatitis and found hepatomegaly with low echogenicity and thick gallbladder wall similar to those seen in acute viral hepatitis.72 There are no data to show if computed tomography or magnetic resonance imaging of liver in patients with malarial hepatopathy differ from those without liver dysfunction.

Treatment and follow up

Although the presence of hepatocellular jaundice signifies severe malaria, there is no evidence that treatment of malaria should change in these cases. Mild cases would improve with antimalarial therapy, to which the primary infection would respond. The guidelines for treatment of chloroquin-resistant malaria would vary from place to place depending on the sensitivity patterns. Ghoda studied 56 patients with falciparum hepatopathy and found reversible and transient hepatic involvement with treatment of falciparum malaria leading to quick reversal of liver function tests.76 We found no evidence of residual hepatic damage in the survivors at 8 weeks and 6 months follow up.19


  1. Top of page
  2. Abstract

Jaundice is common in severe malaria and may be multifactorial. Hepatocellular jaundice in malaria should be more appropriately labeled as malarial hepatopathy rather than malarial hepatitis. Although the significance of malarial hepatopathy in causing morbidity in its own right may be in question, there is no doubt about its association with severe dysfunction of other organs, overall morbidity and mortality. Clinical relevance of malarial hepatopathy also lies in the fact that the more severe presentation with cerebral malaria can be misdiagnosed as fulminant hepatic failure.


  1. Top of page
  2. Abstract
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