4 
4
Hepatobiliary Diseases
Mark Danta, Arthur Y. Kim
KEY FEATURES
• Hepatobiliary abnormalities are common in
resource-limited and tropical settings.
• Liver disease can be divided into pre-hepatic, involving
the portal vein or hepatic artery; hepatic, involving the
parenchymal lobule, including hepatocytes and biliary
and vascular sinusoids; and post-hepatic, involving the
hepatic vein or biliary systems.
• Characterizing liver abnormalities involves a
combination of clinical, biochemical, serologic,
microbiologic, radiologic, and histologic investigations.
• Hepatitis is common, and most frequently due to viral
infections and toxins.
• Parasitic infection of the liver may be seen during
echinococcosis, schistosomiasis, and liver fluke infection,
among other processes.
• Many tropical diseases may result in cholestasis and
jaundice, through varied mechanisms.
• Focal liver diseases may be due to infection or neoplasia.
• Hepatitis B and hepatitis C can lead to chronic liver
disease, especially in the setting of HIV co-infection.
• Non-alcoholic fatty liver disease is an increasing
problem in developing countries.
• Chronic liver disease can lead to cirrhosis, liver failure,
and cancer.
INTRODUCTION
Given the prevalence of hepatotropic infections and the exposure
of the liver to gastrointestinal organisms and toxins, it is not
surprising that many tropical diseases manifest primarily in the
liver. Acute and chronic diseases of the hepatobiliary system pose
major threats to the health of people living within, and travelers
to, endemic regions. The World Health Organization (WHO)
has estimated that the age-standardized mortality rate related to
cirrhosis is >20/100,000 in Africa, Asia, and South America.1 This
chapter provides a framework to approach common presentations
of liver diseases in the tropics. Each primary clinical presentation
is discussed with emphasis on differential diagnosis; for individual
conditions, the reader is referred to the specific chapter.
APPROACH TO LIVER DISEASE
The liver has a great capacity to regenerate; however, hepatic
dysfunction and failure, which usually occur in the context of
cirrhosis, carry a poor prognosis. Specific etiologic agents cause
a variety of liver injuries. The functional unit of the liver is the
hepatic lobule. Blood enters from either the portal (70%) or
systemic (30%) circulation, flowing across the liver sinusoids to
the central vein, and then back to the heart via the hepatic veins.
The hepatocyte microvilli, which project basally into the peri-
sinusoidal space and apically into the bile canaliculi, actively secrete
and absorb fluids and solutes. The liver is integrally involved in
the synthesis of proteins; metabolism of amino acids, fat, and
carbohydrate; and the detoxification of many compounds, receiving
blood from the intestine, spleen, and pancreas via the portal circula-
tion. As a result, the liver is exposed to numerous potential infective
and toxic pathogens from the gastrointestinal tract, particularly
in the tropics and developing world. Hepatic infections most
commonly spread to the liver hematogenously, but can also ascend
via the biliary tract. Gastrointestinal organisms enter the liver via
the portal circulation or biliary tract and include pathogenic ameba,
enteric bacteria, hydatids, liver flukes (Fasciola, Opisthorchis, and
Clonorchis), and schistosomes. Systemic infections seed the liver
via the hepatic artery and include Mycobacterium tuberculosis,
Burkholderia pseudomallei (the cause of melioidosis), syphilis, and
fungal infections.
Characterization of the interaction between the gastrointestinal
microbiome and the liver has led to a greater understanding of
some liver diseases.2 The microbiota are the organisms that make
up the microenvironment of the gastrointestinal tract; the genetic
composition is termed the microbiome. Studies are providing strong
evidence that microbial factors influence the pathophysiology of
specific liver diseases, particularly non-alcoholic fatty liver disease
(NAFLD), alcoholic liver disease, primary sclerosing cholangitis
(PSC), HIV-related liver disease, and the complications of cirrhosis
such as infection and encephalopathy.
The spectrum of liver disease varies from asymptomatic liver
lesions and abnormalities detected on routine blood tests to hepatic
failure. Chronic inflammation and subsequent hepatic fibrosis can
lead to cirrhosis, characterized by the formation of fibrous tissue
and regenerative nodules in the liver that disrupt hepatocyte and
biliary function and obstruct flow through canaliculi and sinusoids.
These histologic changes result in the clinical manifestations of
liver disease. Acute and chronic liver failure are defined by the
inability of the liver to maintain normal metabolic and synthetic
function with manifestations that include hyperbilirubinemia
(leading to jaundice), coagulopathy (leading to bleeding), increased
nitrogenous waste products (associated with encephalopathy), and
hypoalbuminemia (contributing to edema and ascites).3 Vascular
obstructions that affect sinusoidal blood flow can lead to portal
hypertension, which itself then contributes to ascites and formation
of varices, both of which are major complications of cirrhosis.4
The evaluation of the liver should determine the site of hepatic
injury, the underlying etiology, and the severity of the liver disease.
Conceptually, liver disease can be divided into pre-hepatic, involving
the portal vein or hepatic artery; hepatic, involving the parenchymal
lobule, including hepatocytes and biliary and vascular sinusoids;
and post-hepatic, involving the hepatic vein or biliary systems.
Characterizing liver abnormalities may involve a combination of
clinical, biochemical, serologic, microbiologic, radiologic, and
histologic investigations. These evaluations should be refined by
knowledge of the geographic distribution of each condition and
an understanding of risk factors for each disease. Evaluation should
include a detailed history encompassing a review of symptoms
(including right upper quadrant pain or discomfort, anorexia,
jaundice, darkened urine, pruritus, fever), underlying conditions,
past vaccination history, and epidemiologic exposures (including
exposures to water, food, blood, animals, and sexual practices).
Examination should include assessment of signs and findings
consistent with liver disease, including jaundice, occurrence
of smooth-surfaced white spots or patches under the nails
27
28 PART 1  Clinical Practice in the Tropics

(leukonychia), palmar erythema, spider nevi, and gynecomastia.
Hepatomegaly can be associated with most causes of hepatitis and
liver lesions, whereas splenomegaly in the context of liver disease
represents either portal hypertension or an underlying cause, such
as malaria.
The inaccurately termed liver function tests (LFTs) can be used
to refine the site of liver disease (Fig. 4.1). Bilirubin is a breakdown
product of hemoglobin, which is conjugated by the liver. Elevation
can result from an increased load (pre-hepatic), reduced hepatic
conjugation or transport, or post-hepatic biliary obstruction.
Elevation of hepatic cytosolic alanine aminotransferase (ALT) and
mitochondrial aspartate aminotransferase (AST) indicates paren-
chymal inflammation and hepatocyte injury. In contrast, alkaline
phosphatase (ALP), lining the hepatic canalicular membrane, and
gamma-glutamyl transpeptidase (GGT), expressed on the epithe-
lium of the bile ducts, are cholestatic enzymes that increase in
biliary disease. However, ALP also increases in some parenchymal
and granulomatous disease, and GGT can also be elevated after
injury mediated by alcohol and drugs, such as phenytoin. By using
these biochemical markers, however, patterns of liver injury can
be characterized as hepatocellular (ALT/AST), cholestatic (ALP/
GGT), or mixed. The true functional tests of hepatic function
include assessing blood levels of albumin, bilirubin, and coagulation
factors. Thrombocytopenia in chronic liver disease is often second-
ary to portal hypertension. In the tropics, peripheral blood
eosinophilia can be useful in suggesting certain parasitic infections.
Based on clinical and blood parameters, two scoring systems exist
that relate the severity of chronic liver disease and prognosis: the
Childs–Pugh classification and the Model for End-stage Liver
Disease (MELD) score5 (Table 4.1).
The primary approach to the differential diagnosis depends
on the results of the initial examination and laboratory testing as
outlined in Fig. 4.1. Further investigations may include a hepatitis
screen and imaging. A hepatitis screen usually includes viral
serologies (hepatitis A, B, and C), immune serologies (including
anti-nuclear antibody [ANA], anti-mitochondrial antibody [AMA],
and anti-smooth muscle antibody), and metabolic markers such
as iron or copper studies. Applicability of tests will depend on
local resources and prevalence of specific conditions. An ultrasound
is a useful, usually accessible investigation that can identify

Clinical liver disease

Abnormal LFTs
ALT/AST ALP/GGT

Hepatocellular Jaundice Cholestatic

ALT/AST ALP/GGT
Hepatitis screen Unconjugated Conjugated Imaging
bilirubin bilirubin

Normal
ALT/AST

Imaging Hemolysis No biliary dilation Biliary dilation

screen (Intrahepatic) (Extrahepatic)
Haptoglobin
(Prehepatic)

Red cell defect - G6PD deficiency

Infection - malaria, babesiosis,
Bartonella, hemoglobinopathies
Gilbert’s syndrome, hemolysis

Biopsy Hepatitis ERCP

screen MRCP
Acute or chronic hepatitis:
Viral hepatitis, Alcohol, Drugs Gallstones
Medications, Autoimmune hepatitis Granulomatous disease Tumor – pancreatic,
NASH (Non-Alcoholic Steatohepatitis) Immune PBC/PSC cholangiocarcinoma
Helminth infection
Fig. 4.1  The initial screening tests for hepatic injury are liver function tests, which are abnormal in a variety of
tropical conditions. When jaundiced, the total bilirubin should be fractionated into unconjugated (also termed
indirect) and conjugated (also termed direct). Imaging is an important diagnostic tool to look for both biliary
dilation and mass lesions (see Table 4.4) and to assess hepatic vasculature, with ultrasound more available in
resource-limited settings than computed tomography. ERCP, or endoscopic retrograde
cholangiopancreatography and MRCP, or magnetic resonance cholangiopancreatography, are useful for
assessment of biliary disease. ALP, Alkaline phosphatase; ALT, alanine aminotransferase (also termed SGPT
or serum glutamic pyruvic transaminase); AST, aspartate aminotransferase (also termed SGOT or serum
glutamic oxaloacetic transaminase); GGT, gamma-glutamyl transpeptidase; PBC/PSC, primary biliary cirrhosis/
primary sclerosing cholangitis.
 CHAPTER 4  Hepatobiliary Diseases 29

parenchymal and biliary disease and cirrhosis. It may also detect resonance cholangiopancreatography (MRCP) and endoscopic
evidence of portal hypertension, including reversal of portal vein retrograde cholangiopancreatography (ERCP) for biliary disease. 4
flow and splenomegaly. More detailed investigations include Finally, liver biopsy may be required for definitive diagnosis and
computed tomography (CT) and magnetic resonance imaging staging of disease.6 Interestingly, a recent modeling study of U.S.
(MRI) for parenchymal and vascular disease, and magnetic and UK cohorts suggested that a test of all possible causes of liver
disease was less expensive than a staggered approach to potential
etiologies.7
TABLE 4.1  Modified Childs–Pugh Classification
Points Assigned HEPATITIS AND JAUNDICE
Parameter 1 2 3
Acute Hepatitis
Ascites Absent Slight Moderate
Bilirubin, mg/dL ≤2 2–3 >3
Acute hepatitis can be defined as any syndrome that causes elevation
of LFTs for less than 6 months. This can be caused by a variety
Albumin, g/dL >3.5 2.8–3.5 <2.8
of infections, toxin/drug exposures, or metabolic diseases, often
Prothrombin time with a typical hepatocellular, cholestatic, or mixed picture on LFTs.
  Seconds over control 1–3 4–6 >6 A variety of viruses, bacteria, and other organisms can cause an
 INR <1.8 1.8–2.3 >2.3
acute elevation in liver enzymes, either due to direct infection (as
Encephalopathy None Grade 1–2 Grade 3–4 in the viral hepatitides) or indirectly as a response to systemic
infection (e.g., during sepsis, malaria, typhoid fever). These and
One-Year Two-Year
Patient Patient other common toxins and drugs that commonly cause hepatitis
Grade Points Survival (%) Survival (%) are summarized in Table 4.2. Because distinguishing causality by
clinical presentation alone is difficult, knowledge of the geographic
A (total 5–6): 5–6 100 85
distribution of infections and a history eliciting particular risk
well-compensated
disease
factors is critical in determining the likelihood of each entity and
guiding evaluation and treatment.
B (total 7–9): 7–9 80 60
Hepatitis A virus (HAV), a non-enveloped RNA virus in the
significant functional
compromise
Picornavirus family, is the most common cause of viral hepatitis
worldwide. HAV infection is transmitted by the fecal–oral route,
C (total 10–15): 10–15 45 35
and in the developing world often occurs in the first years of
decompensated
disease
life. HAV infection is usually asymptomatic when acquired in
childhood and confers lifelong immunity. In adults, acute HAV

TABLE 4.2  Etiology of Hepatitis

Hepatic (Hepatocellular or Intra-Hepatic
Pre-Hepatic Cholestatic) Post-Hepatic
INFECTIOUS
Fecal–oral Hepatitis A virus Microsporidiosis
Hepatitis E virus Cryptosporidiosis
Typhoid Ascariasis
Q fever
Brucellosis
Inhalation Tuberculosis
Adenovirus
Psittacosis
Water-borne Schistosomiasis Leptospirosis Liver fluke:
Fasciola
Clonorchis
Opisthorchis
Ascariasis
Parenteral and Hepatitis B virus
peri-mucosal Hepatitis D virus
Hepatitis C virus
Syphilis
Vector-borne Malaria Dengue
Babesiosis Yellow fever
Bartonellosis Hemorrhagic Fevers: Lassa, Ebola, Marburg,
yellow fever, dengue
Saliva Epstein–Barr virus Cytomegalovirus

NON-INFECTIOUS Hemolysis Drug reaction Cholangiocarcinoma

G6PD deficiency Toxins—alcohol, aflatoxins, carbon tetrachloride Gallbladder cancer
Hemoglobinopathy Immune—primary biliary cirrhosis/primary Pancreas: pancreatic tumor or pancreatitis
sclerosing cholangitis Cholelithiasis
Non-Hodgkin’s lymphoma
Non-alcoholic fatty liver disease (NAFLD)
VASCULAR Ischemic hepatitis Sinusoidal obstruction syndrome (SOS) Budd–Chiari syndrome
Portal vein Nodular regenerative hyperplasia (NRH) Cardiac hepatopathy
thrombosis Peliosis
30 PART 1  Clinical Practice in the Tropics
is more likely to cause symptomatic illness, including prolonged
jaundice with cholestasis and, rarely, fulminant hepatitis and
liver failure, especially with older age. Tender hepatomegaly and
splenomegaly may be present on physical examination. Overall,
recovery and lack of sequelae are the outcomes in the vast majority
of cases, especially among young children. Due to the unlikelihood
of exposure that would generate natural immunity in many people
in the developed world, HAV remains a significant risk to travelers
from low-prevalence countries. Proper use of pooled immuno-
globulin (Ig) and inactivated hepatitis A vaccine can reduce
the risk of acute infection significantly, and may be used for
post-exposure prophylaxis8; restricting food preparation among
infected individuals is also important to prevent further household
transmission.
Hepatitis E virus (HEV), a calicivirus, is another virus that
also has a fecal–oral route of transmission. HEV has a more
localized distribution than HAV (Mexico, Asia, Africa, and the
Middle East) and should be considered in people living in areas
with outbreaks or in travelers returning from those countries.9
Most cases are self-limited, but fulminant hepatitis can occur,
with overall mortality rates of about 0.5% to 4%. Pregnancy is
a risk factor for severe HEV infection, with mortality as high as
20% if acquired during the third trimester. Diagnoses of both
HAV and HEV rely on detection of specific IgM antibodies from
sera (see Chapter 35).
In contrast, hepatitis B virus (HBV) and hepatitis C virus (HCV)
are transmitted primarily through parenteral, sexual, or perinatal
exposure. In high-prevalence areas, HBV is primarily transmitted
by vertical exposure from mother to child, and acute congenital
infection is often asymptomatic with higher rates of chronicity
(90%) than infections acquired later in life.10 This course contrasts
with the clinical outcome of HBV acquired during adulthood,
generally through parenteral or sexual exposures. In this latter
setting, symptomatic hepatitis is more prevalent along with
spontaneous clearance of the virus (anti-HBs positive with clearance
of HBsAg). Thus travelers or expatriates are at greater risk for
acute HBV via occupational exposures (contact with blood),
nosocomial exposures (contact with contaminated needles or
medical equipment), or unprotected sexual contacts. Recombinant
vaccines, immunoglobulin for neonates, universal precautions, and
safer sex are key to preventing HBV infection. Superinfection
with hepatitis D virus (HDV) requires co-existing HBV infection
and is generally transmitted by parenteral exposure. Diagnosis of
acute HBV can be made by detection of surface antigen (HBsAg)
and, more specifically for the acute stage, by detection of IgM
against the core protein (anti-HBc-IgM).
HCV is most efficiently transmitted via the parenteral route
and in the majority (≈75%) of infected people causes a lifelong
chronic infection.11 HCV is endemic throughout the world, but
some countries and regions have a higher prevalence (e.g., Egypt
has a prevalence of >10%), because the epidemic has been amplified
due to previous unsafe injection practices. Most acute infections
are asymptomatic and thus do not come to medical attention, but
acute symptomatic hepatitis with or without jaundice may occur.
Fulminant hepatitis and mortality due to acute HCV are very
rare; however, chronic liver disease that develops over decades is
a major cause of morbidity and mortality. There is no approved
prophylactic HCV vaccine. Diagnosis of acute HCV may be
difficult, but ideally is made by documentation of seroconversion
and/or the presence of HCV RNA via molecular testing techniques
in the presence of negative antibody.
Other tropical viral infections that affect the liver include
vector-borne causes such as yellow fever, where hepatic necrosis
may accompany up to 20% of cases (see Chapter 37.1) and dengue
fever (see Chapter 36.1). A variety of viral hemorrhagic fevers
may also involve the liver; some of these viruses (e.g., Lassa fever,
Ebola virus; see Chapters 37.2 and 37.4) may require strict isolation
precautions if suspected. Herpesviruses not specific to the tropics
TABLE 4.3  LFT Patterns With Drugs
Cholestatic Hepatocellular
Amoxicillin/clavulanic acid Acetaminophen
Anabolic steroids Antiretroviral therapy (ART)
Chlorambucil Allopurinol
Chlorpromazine Amiodarone
Chlorpropamide Aspirin and non-steroidal
Erythromycin anti-inflammatory drugs (NSAIDs)
Estrogen (oral contraceptives) Carbamazepine
Tricyclics Halothane
Isoniazid
Ketoconazole
Nitrofurantoin
Phenytoin
Propylthiouracil
Rifampin
Statins
Sulfonamides
Tetracycline
Valproic acid
(particularly cytomegalovirus and Epstein–Barr virus, which can
also cause splenomegaly) can also affect the liver.
Elevation of transaminases can occur during various systemic
infections, including sepsis. Specific bacterial causes of acute
hepatitis include spirochetal illness such as leptospirosis and
relapsing fever, or syndromes caused by gram-negative bacteria
such as melioidosis, typhoid fever, and tularemia, as well as scrub
typhus and Q fever. Accompanying pulmonary symptoms may
result from bacterial pneumonia, sepsis, Q fever, or tuberculosis.
Rarely, miliary tuberculosis may be associated with acute elevation
in transaminases, but is more commonly associated with granu-
lomatous hepatitis. Granulomatous hepatitis can be caused by
several infectious and non-infectious etiologies, but primary
diagnostic considerations should include tuberculosis (see Chapter
43), brucellosis (see Chapter 75), and Q fever (see Chapter 71).
Eosinophilia may be caused by a variety of parasitic infections,
but eosinophilia in the setting of symptomatic hepatitis or hepa-
tomegaly may suggest schistosomiasis, trichinellosis, capillariasis,
or fascioliasis (see Chapters 126, 119, 111, and 128).
Non-infectious causes of liver enzyme abnormalities include
acute hepatic injury from medications (Table 4.3) such as isoniazid
or pyrazinamide; commonly used antimycobacterial drugs;
acetaminophen; or toxins such as alcohol, mushrooms, carbon
tetrachloride, or aflatoxins.
Chronic Liver Disease
Chronic hepatitis is arbitrarily defined as abnormal LFTs for more
than 6 months. The major consequence of chronic hepatitis is
cirrhosis with its concomitant risk of liver failure and cancer. The
most common cause of chronic hepatitis worldwide is HBV, with
an estimated 400 million people currently chronically infected
worldwide. Untreated, about 20% to 25% of people with chronic
HBV may die of complications of cirrhosis and/or hepatocellular
carcinoma (HCC), and this course may be accelerated by co-existing
HDV infection. Chronic HCV is also a cause of significant morbid-
ity and mortality worldwide, with an estimated 71 million people
chronically infected.12 Although effective treatments have been
developed for each of these viruses, particularly direct-acting
anti-viral treatment for HCV, their cost is often prohibitive.13
Schistosomiasis (see Chapter 126) is another major cause of
chronic liver disease.14 Adult schistosome worms live in draining
veins of the intestine or urinary tract. Eggs secreted by adult
worms in mesenteric vessels can be flushed into the liver and
become trapped in pre-sinusoidal portal venules, leading to intense
inflammation, granulomas, and a “pipe-stem” fibrosis. This can
 CHAPTER 4  Hepatobiliary Diseases 31

result in portal hypertension out of proportion to the level of fibrosis of the inferior vena cava or hepatic veins; portal vein thrombosis;
and hepatic dysfunction. Given the prevalence and geographic sinusoidal obstruction syndrome (previously termed veno-occlusive 4
overlap with chronic viral hepatitis, alternative causes of liver disease disease); nodular regenerative hyperplasia; and peliosis.18 Other
should be considered when true cirrhosis is found in the setting of causes include ischemic hepatitis and congestive hepatopathy as
chronic schistosomiasis. Moreover, given that each may be clinically a result of cardiac failure, for example, right heart failure related
silent for years to decades, a high index of suspicion is needed to to mycobacterial constrictive pericarditis. Usually, these vascular
diagnose these conditions. Early treatment with praziquantel can lesions are associated with portal hypertension, which precedes
lead to regression of fibrosis due to schistosomiasis. hepatic synthetic failure. Doppler ultrasound or contrast CT are
Other causes of chronic liver disease leading to hepatic failure useful imaging techniques for delineating the vessels of the liver.
include granulomatous diseases, metabolic diseases, and alcoholic
liver disease. Systemic infections can be associated with granulomas
in the liver. In addition to schistosomiasis, these include myco-
FOCAL LIVER LESIONS
bacteriosis, leishmaniasis, histoplasmosis, brucellosis, and syphilis. The evaluation of a focal liver lesion includes non-invasive tests,
Non-infectious causes include sarcoidosis, lymphoma, primary such as serology, blood parameters, tumor markers, and micro-
biliary cirrhosis, and drug reactions. High environmental copper biologic assessment, as well as further imaging with ultrasound,
ingestion in children can also lead to cirrhosis (copper-associated CT, or MRI, which should be contrast enhanced.19 Determining
childhood cirrhosis or Indian childhood cirrhosis); recognition of the size and whether the lesion is solid or cystic is useful in
how to prevent and treat this entity has decreased the incidence stratifying the diagnostic approach (Table 4.4). As a rule, small
of this disease. African Bantu hemosiderosis is a disease of iron lesions (<1 cm) are often benign, whereas larger lesions and those
overload similar in manifestations to hemochromatosis; the occurring in the context of chronic liver disease have a higher
presumed genetic basis of this disease is currently unknown. It is potential for malignancy. Biopsy may be required to differentiate
important to counsel those with chronic liver disease to avoid lesions; however, in a large study of focal liver lesions, pre-operative
additional hepatic insults via prevention of exposures to infectious assessment was correct in 221 of the 225 cases (98.2%), suggesting
agents and toxins, as well as provision of vaccination against hepatitis that fine needle aspiration for diagnosis is not necessary in the
A and hepatitis B viruses. majority of cases.20 In surgical candidates this may lead to tumor
An increasing problem in the developing world is NAFLD. It seeding if the lesion is malignant.
has been estimated that the rate of obesity has doubled since 1980 In an individual presenting with a cystic liver lesion associated
with 2 billion people overweight and 600 million obese.15 A recent with right upper quadrant pain and fever, consideration should
systematic review of global NAFLD found that the overall preva- be given to differentiating amebic from pyogenic abscesses.
lence is approximately 25%, with the highest prevalence 30.5% Although both are associated with significant mortality, treatment
in South America and the lowest 13.5% in Africa.16 Although a differs. The typical imaging appearance of a pyogenic abscess is
major contribution is excess calorie intake, other factors such as a fluid-filled lesion with surrounding parenchymal edema. However,
genetic variants linked to obesity and NAFLD such as PNPLA3 imaging could not satisfactorily differentiate pyogenic from amebic
variants are likely contributing.17 The overall incidence of liver- abscesses in a large series.21 In this series, multi-variate analysis
related mortality in NAFLD has been estimated at 2%—the large identified pyogenic abscesses to be associated with older age (>50
and increasing denominator means that this will become a significant years), pulmonary findings on examination, multiple lesions, and
problem into the future. negative amebic serology (<1 : 256 IU). The major route of seeding
in both is the portal circulation. Pyogenic liver abscesses are
commonly polymicrobial, usually caused by mixed enteric facultative
Jaundice and Biliary Obstruction and anaerobic species. Klebsiella pneumoniae and Streptococcus milleri
Many tropical diseases may result in cholestasis and jaundice, through are common pathogens.22 Focal liver abscesses can also complicate
varied mechanisms. Overload of unconjugated bilirubin can occur melioidosis (caused by the gram-negative bacillus Burkholderia
during acute hemolysis due to malaria, babesiosis, Oroya fever pseudomallei). Melioidosis occurs in Southeast Asia, China, and
(caused by Bartonella bacilliformis), hemolytic uremic syndrome northern Australia populations, particularly in patients with diabetes,
caused by Escherichia coli O157:H7 or Shigella dysenteriae, and sepsis alcoholism, or renal failure.23
related to Clostridium perfringens. Hemolytic crises can also complicate
hemoglobinopathies and may be precipitated by infections. Jaundice
may also be caused by processes that result in impaired conjugation TABLE 4.4  Focal Liver Lesions
and/or excretion of bilirubin by the liver. Some tropical diseases Infection Tumor
may be associated with both hemolysis and impaired excretion (i.e.,
Cystic Abscess Simple cyst
leptospirosis). Non-obstructive causes include any causes of general-
Pyogenic Polycystic liver disease
ized liver dysfunction (i.e., during fulminant acute hepatitis or Amebic
subsequent to chronic liver disease/cirrhosis). Obstructive causes Hydatid
include non-infectious causes (gallstones and tumors), helminthic
Solid Tuberculosis Hepatocellular carcinoma
infection (such as those caused by Ascaris lumbricoides or Clonorchis Syphilitic gumma (HCC)
sinensis and other liver flukes), and certain protozoa (such as Liver fluke: Adenoma
Cryptosporidium hominis/parvum, particularly in those with HIV or Fasciola Fibronodular hyperplasia
other states of immunosuppression). Any biliary obstruction can Clonorchis (FNH)
be complicated by bacterial cholangitis. Some of these entities Opisthorchis Hemangioma
often cause obstruction by mass lesions (see the later section) that Regenerative nodule
may also involve blockage of the pancreatic duct; serum pancreatic Metastatic disease
enzymes and ultrasound and/or other imaging may be useful tests Lymphoma
to help identify specific etiologies. Biliary Liver fluke: Cholangiocarcinoma
obstruction Fasciola Gallbladder cancer
Clonorchis Pancreas: pancreatic
VASCULAR LIVER DISEASE (SEE TABLE 4.2) Opisthorchis tumor or pancreatitis
Microsporidiosis Gallstone
Vascular diseases of the liver are uncommon and include Budd– Cryptosporidiosis
Chiari syndrome, which is obstruction of the intra-hepatic portion
32 PART 1  Clinical Practice in the Tropics

Pyogenic abscesses require early percutaneous drainage and or endoscopic ultrasound (EUS) with cytology can be diagnostic
broad-spectrum antibiotics. Studies do not support a difference in biliary tract malignancies. Finally, in the context of systemic
between intermittent versus continuous drainage of these abscesses.24 disease, metastatic malignancy and lymphoma should be
In contrast, amebic abscesses are usually treated medically. Liver considered.
abscess is the most common extra-intestinal manifestation of
Entamoeba histolytica infection (see Chapter 94), occurring in
endemic areas such as Central and South America, West and South
HIV AND THE LIVER
Africa, and India.25 Amebic abscesses may be solitary or multiple, The majority of people infected with HIV live in resource-limited
and often occur in the right hepatic lobe (75%). Diagnosis is settings (see Chapter 31). HIV is associated with a number of
usually based on detection of antibody in blood or antigen in stool specific diseases of the liver related to immunosuppression, immune
or hepatic aspirates, as well as response to empiric treatment with reconstitution, and drug effects. Broadly, the spectrum of liver
metronidazole or its analogs, followed by a luminal amebicide disease relates to CD4 count and antiretroviral therapy (ART)
such as paromomycin, iodoquinol, or diloxanide furoate to eliminate exposure. In areas where ART is available, the burden of disease
infection.25 Drainage, however, should be considered if there has shifted from opportunistic infection and malignancy to chronic
is impending rupture or involvement of the pleura or diseases, with liver disease related to viral hepatitis becoming a
pericardium. leading cause of morbidity and mortality.40 Chronic viral hepatitis
Other cystic lesions of the liver include simple hepatic cysts and HIV co-infection are associated with reduced spontaneous
and cystic hydatid disease caused by Echinococcus granulosus (see clearance and accelerated progression of viral hepatitis to cirrhosis,
Chapter 132).26,27 Hydatid cysts have a typical radiologic appearance, hepatic decompensation, and HCC.41 A recent global meta-analysis
which has led to a staging classification based on imaging appear- regarding HIV-HCV co-infection estimated a worldwide global
ance. Generally, hydatid cysts have thick pericystic walls that may burden of 2.3 million cases, highest in people who inject drugs.42
be calcified. The cysts usually have septa and may contain “daughter” The introduction of the new combination HCV direct-acting
cysts.28 Unlike abscesses, surrounding liver tissue is normal. Anti- E. anti-viral therapies will have a significant impact on the mortality
granulosus antibodies are positive in a majority of cases.27 Current and morbidity of HIV/HCV co-infection43 (see Fig. 4.1). However,
treatment usually involves albendazole with or without mechanical in those who do not have access to ART, opportunistic infection
drainage or removal. and malignancy are still prevalent. Most conditions associated
Primary malignant hepatobiliary tumors in the developing with liver disease are systemic and have spread hematogenously
world often relate to underlying infectious etiologies. HCC is the from other sites to involve the liver. These can be stratified by
second most common cause of cancer-related death, with an annual CD4 count, as most serious opportunistic infections occur with
global incidence of 850,000, usually occurring in the context of severe immunodeficiency (CD4 <100 cells/µL). However, tuber-
chronic liver disease.29,30 An estimated 85% of cases are associated culosis, non-Hodgkin’s lymphoma (NHL), and Kaposi’s sarcoma
with chronic viral hepatitis (HBV and HCV), which currently (KS) can occur at moderate levels (CD4 >200 cells/µL) of
infects over 500 million people worldwide.31 Levels of HBV viremia immunodeficiency.44 Of the opportunistic infections infecting the
correlate with the risk of developing HCC,32 and successful anti- liver, Mycobacterium avium complex is the most common. Other
HBV vaccination programs lead to a significant reduction in the infections include Cryptococcus neoformans, Pneumocystis jirovecii,
incidence of HCC.33 Eradication of HCV is associated with a cytomegalovirus, and tuberculosis (Table 4.5). In particular geo-
reduced incidence of HCC.34 Other risk factors for HCC include graphic areas, visceral or disseminated leishmaniasis is also prevalent.
alcohol and aflatoxins, which may in part explain the higher AIDS cholangiopathy is associated with cryptosporidial and
incidence of HCC in West African and Chinese populations without microsporidial infection in patients with CD4 counts <100 cells/µL,
underlying HBV-related cirrhosis.31 Diagnosis usually involves a and can lead to biliary obstruction.45 Although the presentation
combination of consistent findings on imaging studies and elevated is variable, it is usually a variation of cholangitis with diarrhea,
alpha-fetoprotein (AFP) levels in the setting of chronic liver disease. which is the result of the intestinal infection with these
Typically, HCCs appear as hyper-vascular lesions on imaging, a pathogens.
result of neovascularization from the hepatic artery. Approximately After the initiation of ART in individuals with low CD4 T-cell
70% of cases are associated with an elevated AFP. In the largest counts (<100 cells/µL), approximately 10% to 30% of individuals
randomized study of ultrasound and AFP screening in over 18,000
Chinese patients, bi-annual screening reduced HCC mortality by
37%.35 However, the benefit of screening in resource-limited TABLE 4.5  HIV Infection and the Liver
settings is controversial. The role of AFP is also controversial, Infection Tumor Other
and in some national recommendations it has been removed as a
CD4 Mycobacterium Non-Hodgkin’s
recommended screening test.36
<100 avium lymphoma
To date, HCC treatment involves either locoregional therapies, cells/µL infection (NHL)
including alcohol injection, radiofrequency ablation, or trans-arterial Cryptococcosis Kaposi’s
chemoembolization (TACE), or surgical resection in those with Cytomegalovirus sarcoma
small tumors and sufficient hepatic reserve without portal hyperten- (KS)
sion. However, overall prognosis of HCC is usually poor. Newer CD4 Tuberculosis Non-Hodgkin’s
targeted chemotherapies include sorafenib and regorafenib, but >200 lymphoma
their current cost precludes use in resource-limited settings.37,38 cells/µL Kaposi’s
New immune therapies, such as the PD1 blockade, also look sarcoma
promising, but cost will limit future access. Benign parenchymal CD4 Viral hepatitis Hepatocellular Drug-induced liver
liver tumors include adenomas, fibronodular hyperplasia, and >500 (hepatitis B carcinoma injury (DILI)
hemangiomas. Chronic biliary inflammation associated with cells/µL virus, Lipodystrophy and
persistent Salmonella infection of the biliary tract and hepatitis C non-alcoholic
Clonorchis/Opisthorchis liver flukes has also been associated with virus) fatty liver
gallbladder cancer and cholangiocarcinoma, respectively.39 Individu- disease
(NAFLD)
als with these entities may usually eventually present with biliary
Immune
obstruction, with elevation of ALP and GGT, with or without reconstitution
jaundice, and biliary dilation on ultrasound, CT, or MRCP. ERCP

present with a new opportunistic infection or worsening clinical
symptoms of an already established infection, termed immune
reconstitution syndrome.46 This is of particular relevance for those
co-infected with viral hepatitis with advanced hepatic fibrosis, as
fatal hepatic flares have been reported.47 Finally, drug-induced
liver injury (DILI) is commonly associated with ART, and this
entity is more likely when there is co-infection with viral
hepatitis.48
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