Tropical Liver Diseases: An Overview

Answer questions and earn CME

Abbreviations

ACLF

acute‐on‐chronic liver failure

AIH

autoimmune hepatitis

ALF

acute liver failure

ALT

alanine aminotransferase

AST

aspartate aminotransferase

ATT

anti‐tuberculosis treatment

CLD

chronic liver disease

DIC

disseminated intravascular coagulation

DILI

drug‐induced liver injury

INR

international normalized ratio

LT

liver transplantation

NAFLD

nonalcoholic fatty liver disease

PBS

peripheral blood smear

UDCA

ursodeoxycholic acid

ULN

upper limit of normal

Listen to an audio presentation of this article.

Several infectious diseases are endemic in tropical countries but rare in developed countries. ¹ About 50 million people who travel from developed countries to these areas can also acquire these diseases. Hepatologists encounter such diseases when the clinical presentation is dominated by jaundice or other derangements of liver functions. Common tropical infections that can involve liver include dengue, scrub typhus, malaria, leptospirosis, amoebic liver abscess, hydatid disease of liver, and many other bacterial, protozoal, or fungal infections. Some diseases may be related to cultural practices prevalent in developing nations, such as the use of herbal or indigenous medicines. Liver abscess and biliary obstruction by worms are other common presentations. ²

Clinical Approach

In developing tropical countries, unhygienic conditions are not uncommon and can lead to residents and visitors being prone to food‐ or water‐borne, as well as mosquito‐borne, diseases. A high index of suspicion is required to recognize such tropical infections. A history of travel to tropical areas becomes of great importance. Fever may be a dominant symptom. In viral hepatitis, fever usually subsides with the appearance of jaundice. In patients with ongoing fever together with jaundice in the absence of biliary obstruction, alternate possibilities must be considered. Clinical syndrome at presentation often points to the possible etiology (Table 1). ³ , ⁴

TABLE 1.

Common Clinical Syndromes and the Common Etiologies Seen in Tropical Areas

Clinical Syndrome	Presentation	Common Etiology	Reference
Acute hepatitis/severe acute liver injury	Fever/prodrome followed by jaundice with rice in ALT >5× ULN; in severe acute liver injury, INR is also increased >1.5	Viral hepatitis A, B, or E	Anand et al. 3
		Drug‐induced hepatitis (acetaminophen toxicity is rare, ATT‐induced DILI or rodenticide poisoning relatively common)
Jaundice with encephalopathy	Patient has altered sensorium and is noted to have jaundice, with or without fever	ALF, malarial hepatopathy, dengue fever, typhoid fever, leptospirosis, scrub typhus	Beeching and Dassanayake 4
CLD	Liver function derangements lasting >6 months followed by fibrosis in liver	Hepatitis B and C	Anand and Puri 5
		Also, alcohol, NAFLD
Portal hypertension in the absence of cirrhosis	Esophageal varices and variceal bleeding	Schistosomiasis, noncirrhotic portal hypertension, extrahepatic portal vein obstruction in young patients	Devarbhavi et al. 6
Liver abscess	Right upper quadrant pain with thick‐walled liquifying lesions in liver with or without fever	Amoebic liver abscess, pyogenic liver abscess	Praharaj and Anand 7
		Also, hydatid cysts
Biliary obstruction with cholangitis	Fever, obstructive jaundice, dilated intrahepatic biliary radicles	Biliary ascariasis, hepatic lithiasis with or without Clonorchis sinensis and Opisthorchis viverrini	Khim et al. 8
		Also, gallstones
Fever and hepatomegaly	Without liver abscess	Granulomatous liver disease caused by tuberculosis, sarcoidosis	Khuroo et al. 9

Severe Acute Liver Injury and Acute Liver Failure

Many tropical infections can lead to severe acute liver injury or acute liver failure (ALF). ALF in the tropics is commonly due to hepatitis A, B, or E. Acetaminophen‐induced ALF is distinctly rare, although antituberculosis drugs are sometimes the culprit. A syndrome of jaundice and encephalopathy can be seen in severe malaria, dengue fever, typhoid fever, leptospirosis, and scrub typhus. ⁴ In most such cases, jaundice is a part of multisystem dysfunction syndrome, and diagnosis can be made by using appropriate investigations when suspected (Fig. 1).

FIG 1.

An outline approach to a patient with jaundice and encephalopathy in the tropics. Adapted with permission from Journal of Clinical and Experimental Hepatology. ¹⁰ Copyright 2015, Elsevier.

Malaria is the most common of these infections. Liver dysfunction in malaria is common (prevalence rate, 2.6%‐37%) ⁵ and presents with jaundice (malarial hepatopathy). It is usually seen in relation to Plasmodium falciparum infection and results from lysis of red cells and cytoadherence of parasites to the sinusoidal wall, causing ischemic injury. Patients often present in coma as a result of associated cerebral malaria, and the presentation may be confused with ALF. ⁶ Table 2 outlines the differences from ALF. ⁴

TABLE 2.

Severe Malaria Presenting With Coma and Jaundice Should Be Differentiated from Acute Liver Failure in Endemic Areas

	Malaria	ALF
Common clinical presentation	Cerebral malaria (coma) associated with malarial hepatopathy and nonoliguric renal failure	Viral hepatitis followed by hepatic coma
Fever	From onset, persistent but may be irregular	Mostly in prodrome
Liver size	Hepatomegaly with or without splenomegaly	Usually shrinks, not palpable
AST/ALT	≤5× ULN	↑↑↑ (>10×) ULN
Bilirubin	May be unconjugated or mixed	Often conjugated
INR	Normal unless DIC associated	↑↑↑
Anemia	Common	Absent
Hemolysis	Common	Absent
Specific tests	PBS, malaria antigen	Viral hepatitis markers
Histopathology	Reticuloendothelial cell hyperplasia and pigmentation	Massive or submassive necrosis of hepatocytes

Dengue fever is also associated with liver dysfunction. Elevated transaminases are nearly universal, and the degree of elevation usually correlates with the severity of illness. Patients with underlying chronic liver disease (CLD) have more severe liver dysfunction. ⁹ Leptospirosis is acquired through exposure to stagnant water and presents with biphasic illness consisting of fever, jaundice, conjunctival hemorrhage, elevated creatinine kinase, and mildly elevated transaminases.

CLD

CLD implies continuous or intermittent liver dysfunction for more than 6 months and progression to liver fibrosis. Hepatitis B and C are common causes in endemic areas, although alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) are also common causative factors in the tropics. There are pockets where sickle cell disease is common, and such patients may present with sickle hepatopathy. ⁷ Many patients present with portal hypertension and variceal bleeding in young age in the absence of cirrhosis, caused by noncirrhotic portal fibrosis, extrahepatic portal vein obstruction, or schistosomiasis. ⁶

Liver Abscess and Other Presentations

Even in 2021, liver abscess remains a common presentation in tropical countries and is frequently caused by a protozoal infection (i.e., Entamoeba histolytica). More details are discussed elsewhere in this issue of Clinical Liver Disease. Klebsiella pneumoniae, Escherichia coli, and Burkholderia pseudomallei are emerging causes of pyogenic liver abscess. Fortunately, wide availability of ultrasound has made the diagnosis and drainage easy. ⁸

Hydatid disease of the liver is caused by Echinococcus granulosus and multilocularis infections. The course of illness is typically slow (cyst grows at 1‐5 mm/year), and most patients remain asymptomatic for years before being diagnosed. Dull, aching pain in the right upper abdominal area may be a presentation. Rarely they can communicate with the biliary tree (Fig. 2). Secondary bacterial infection of these cysts can occur, and the patient can present with liver abscess. ⁹

FIG 2.

Hydatid disease of liver with biliary communication in a patient with cholangitis. Endoscopy‐directed clearance of common bile duct was done followed by symptomatic improvement. A small daughter cyst emerging from ampulla is shown.

Hepatobiliary ascariasis is caused by the nematode Ascaris lumbricoides leading to liver abscess, cholelithiasis, choledocholithiasis, cholangitis, or rarely, cholecystitis. Ascarides repeatedly traverse the bile duct (Fig. 3) and get trapped inside, forming hepatic lithiasis or abscess. In endemic regions, ascariasis is the causative factor for 36.7%, 23%, 14.5%, and 12.5% of all biliary diseases, acute pancreatitis, liver abscesses, and biliary lithiasis, respectively. ⁹

FIG 3.

Hepatobiliary ascariasis. The patient presented with intermittent biliary‐type pain for 2 months. Gastroduodenoscopy showed round worm (Ascaris lumbricoides) in the second part of duodenum (left panel). One ascarid worm was protruding from the papilla (middle panel). It was gently removed with help of forceps (right panel). The patient was started on albendazole. Afterward the patient improved.

Tuberculosis is a common infection in the tropics and can involve the liver by hematogenous spread that has been shown in about 50% to 80% of all patients dying of pulmonary tuberculosis. It leads to the formation of multiple granulomas in the liver causing granulomatous hepatitis. ⁹ Common symptoms include abdominal pain (65%‐87%), nonspecific symptoms (fever, anorexia, weight loss; 55%‐90%), hepatomegaly (70%‐96%), and splenomegaly (25%‐55%). Jaundice (20%‐35%) usually occurs as a result of biliary strictures or extrahepatic biliary obstruction by porta hepatitis lymph nodes.

Toxins and Indigenous Drugs

In developing nations, liver diseases due to over‐the‐counter availability of indigenous drugs is common (Table 3). ¹¹ Old age, malnutrition, alcohol consumption, and infection with human immunodeficiency virus have been considered predisposing factors for drug‐induced liver injury (DILI). Common clinical presentation is with jaundice, although a wide range of presentations are possible.

TABLE 3.

Commonly Prescribed Herbal Medicines in South Asia That Are Known to Cause Liver Disease ¹¹

Ayurvedic Herbs	Bioactive Ingredients	Hepatic Injury Described	Histopathology	Natural Course of Illness
Withania somnifera (Ashwagandha)	Steroidal lactone triterpenoids (withanolides)	Acute cholestatic hepatitis	Severe cholestatic hepatitis/bland cholestasis with intrahepatic bile plugs	Spontaneous recovery in 2‐5 months with UDCA/phenobarbitone
	Alkaloids (cuscohygrine and anhygrine, flavonoids, phytosteroids, and coagulins)
Bacopa monnieri and Centella asiatica (Brahmi/Gotu Kola)	Bacosides, brahmine, herpestine, nicotine, brahmoside, brahminiside, and various glycosides	Acute severe cholestatic hepatitis/ACLF/immune‐related DILI/ALF	Granulomatous hepatitis	Spontaneous recovery in 12 months with UDCA/steroids
			Eosinophilic degeneration in zone 3, lymphoplasmacytic infiltrates
Curcuma longa (Turmeric)	Curcumin, desmethoxycurcumin, bisdemethoxycurcumin	Drug‐induced AIH	Lobular inflammation and interface hepatitis (compatible with AIH)	Spontaneous recovery after withdrawal and recurrence after rechallenging
		Acute hepatitis
		Cholestatic hepatitis
Commiphora wightii or mukul Boswellia serrata (guggulu, guggul, or guggulipid)	Guggulsterone, guggul sterol, boswellic acid, and guggulipid	Acute severe hepatitis
Aloe barbadensis mille (aloe vera)	Acemannan, alprogen, aloin, emodin, auxins, and gibberellins	Acute cholestatic hepatitis	Portal and lobular lymphoplasmacytic infiltrates	Spontaneous recovery is usual
		Acute decompensation of CLD	Eosinophilic granuloma	Rarely prolonged morbidity may occur
			Bilirubin stasis
Morinda citrifolia (Indian mulberry or noni juice)	Alkaloids (xeronine)	Acute hepatitis	Mixed inflammation of portal tract and lobules, centrilobular necrosis	Spontaneous recovery in cases of acute hepatitis
	Anthraquinones (damnacanthal, morindone)	ALF	Hepatocellular cholestasis	LT in ALF
	Glycosides (citrifolinoside)
Symphytum species (Comfrey)	Pyrrolizidine alkaloids	Sinusoidal hemorrhages, constriction of central veins and fibrosis, later cirrhosis	Injury to centrilobular veins	ALF requiring LT
Senecio species (used in Bush teas)			Centrilobular sinusoidal hemorrhage/congestion
			Centrilobular/focal hepatocellular necrosis

Conclusions

Hepatotropic viral infections, tropical systemic infections, and herbal medications constitute the most common causes of liver disease in tropical countries. Many common tropical infections can be confused with severe acute liver injury or ALF. Hepatobiliary ascariasis, amoebiasis, and hydatid diseases are also common. Effective treatments are available for most of these infections; however, diagnosis can be made only if they are suspected. Delay in diagnosis may lead to liver failure or death.