44

Journal of the association of physicians of india • june 2013 • VOL. 61

Review Article
Hepatobiliary Tuberculosis
Sanjay Bandyopadhyay1, Pranab K Maity2
Abstract
Hepatobiliary tuberculosis refers to the localized form of hepatic tuberculosis and is a distinct entity in which
hepatobiliary involvement overwhelmingly dominates the clinical picture. Presentations are often delayed,
and manifestations can be nonspecific. Fever is the most common symptom followed by abdominal pain, and
hepatomegaly is the most common abnormality found on clinical examination. Abnormalities of the liver function
tests are non-specific and hence not diagnostic. Ultrasound or computed tomography reveals single or complex
masses, and guided biopsy is diagnostic either by demonstrating caseating granuloma or the organism by staining
and culture. Treatment is with standard first-line antituberculous drugs. Endoscopic stenting gives an excellent
outcome for symptomatic biliary strictures. The outcome in patients infected with Human Immunodeficiency
virus depends on the level of underlying immunosuppression.

Introduction (and biliary) involvement overwhelmingly dominates the clinical

picture. Hepatobiliary tuberculosis is uncommon and accounts
T uberculosis is known to involve the liver in three different
forms.1 1. Miliary form, which is part of generalized miliary
tuberculosis, occurs in 50-80%, and usually has no signs or
for less than 1% of all tuberculous infections.2

symptoms relevant to the liver. 2. Granulomatous disease

Pathogenesis
(tuberculous hepatitis) that presents with unexplained fever, Normally the liver is an inhospitable place for tubercle bacillus
some with mild jaundice, with or without hepatomegaly, which, owing to its low tissue oxygen tension.3 If the organism reaches
on liver biopsy, shows caseating granuloma and improves with the hepatobiliary tract via the hepatic artery from a tuberculous
anti-tuberculous therapy (ATT). 3. Localized hepatic tuberculosis infection of the lungs (which may be active or inactive), it results
(with signs and symptoms relevant to the hepatobiliary tract): in miliary tuberculosis. 3 In some cases, however, infection
(i) without bile duct involvement, to include solitary or multiple could reach the liver via the portal vein especially if there is
nodules, tuberculoma and tuberculous hepatic abscess; and a concomitant involvement of the gastrointestinal tract. The
(ii) with bile duct involvement causing obstructive jaundice, tubercle bacilli may also reach the liver by lymphatic spread or
either by enlarged nodes surrounding the bile ducts or actual due to rupture of a tuberculous lymph node in the portal tract.
tuberculous processes in the ductal epithelium producing These latter cases result in localized hepatobiliary tuberculosis.3
inflammatory strictures. This difference in pathogenesis may explain the observation
that in miliary tuberculosis, lesions are concentrated near the
Hepatobiliary tuberculosis refers to the localized form of
hepatic veins, although in the local form, they are usually found
hepatic tuberculosis and is a distinct entity in which hepatic
periportally.4 The term primary hepatobiliary tuberculosis is
Table 1: Table showing outstanding clinical features, laboratory abnormalities and adverse outcome from seven large series of
hepatobiliary tuberculosis
Alvarez, et al5 Essop, et al6 Hersch7 Maharaj, et al8 Chong2 Saluja, et al9 Amarapurkar, et
(n=130) (n=96) (n=200) (n=41) (n=14) (n=18) al10 (n=38)
Abdominal pain 45 66 50 46 57 63 42
Fever 65 70 90 63 50 63 79
Weight loss 55 - 75 61 64 55 66
Jaundice 35 11 15 14 42 63 18
Loss of appetite - - - - 64 55 -
Hepatomegaly 96 80 95 95 - 55 49
Splenomegaly 25 40 57 32 - - -
Abnormal transaminases 35 70 - - - - 8
Increased alk. phosphatase 75 83 - - - - 23
Altered A:G ratio 81 63 - 95 - - -
Abnormal CXR 65 75 - 78 29 18 30
Calcification 50 - - - 64 - 5
Liver biopsy 78
Caseating granuloma 67 83 51 78
Non-caseating granuloma 13 22
AFB (+) 7 9 59 71 20 43
Culture (+) 92
PCR (+) 100
Mortality 42 14 0 0
Adverse effects of treatment 43 16 3
1
Assistant Professor, Division of Medical Gastroenterology, School inappropriate and the term ‘localized hepatobiliary tuberculosis’
of Digestive and Liver Diseases, IPGME and R, 244, AJC Bose Road,
may be preferred.
Kolkata 700020; 2Resident, Department of Medicine, Nil Ratan Sircar
Medical College and Hospital, 138, AJC Bose Road, Kolkata 700014.
Received: 06.05.2011; Revised: 30.06.2011; Accepted: 19.08.2011
404 © JAPI • june 2013 • VOL. 61
Journal of the association of physicians of india • june 2013 • VOL. 61 45
Fig. 1: CECT scan of liver showing a tuberculous liver abscess
penetrating into the skin.
Clinical Features
The majority of localized hepatic tuberculosis reported in the
literature occurs in the 30-50 years age group.2,5-8 Patients are
symptomatic for more than one year prior to admission.5 The
outstanding signs and symptoms of hepatobiliary tuberculosis
from several widely-quoted series are shown in Table 1.2,5-10
Fever is the most common (50 -90%) symptom followed by
abdominal pain (45 - 66%, mainly in the right upper quadrant).
Hepatomegaly is the most common abnormality found on
clinical examination, and in one series, it was nodular in 55%
and tender in 36% cases simulating liver abscess.5 Less than
one-third patients present with jaundice that is obstructive in
nature, simulating other conditions that exhibit extrahepatic
biliary obstruction.2,5-10 Pruritus is reported in 23%.10 Concomitant
tuberculous peritonitis is found in 9-14%, producing abdominal
distension and ascites.2,9
A significant decline in liver function is unusual and acute
liver failure is rare.11 The rarity of liver failure in hepatobiliary
tuberculosis may be owing to the fact that the presence of
tuberculous granulomas, even if massive, does not directly result
in the extensive destruction of hepatocytes.11 The liver may be
massively enlarged by the presence of granulomas, yet liver
metabolic function remains normal.
The nodular form of localized hepatic tuberculosis is a distinct
radiological entity.11,12 Two brilliant case series illustrated the
difficulty in reaching the correct diagnosis, unsuspected in
nearly all the cases and most often confused with carcinoma of
the liver. A greater awareness of this rare entity may prevent
needless surgical intervention.
Investigations
Abnormalities of the liver function tests are non-specific and
hence not diagnostic (Table 1).1 Alkaline phosphatase may be
markedly elevated, particularly in those cases presenting with
obstructive jaundice.5-7 Hypoalbuminaemia with polyclonal
hyperglobulinaemia are present in approximately 80% patients.1
In general, abnormalities in liver chemistry parameters confirm
the presence of hepatic involvement, but their levels have no
correlation with the extent of involvement.1 More than two-third
of cases show abnormalities in chest radiography,5,6,10 although
concomitant active pulmonary tuberculosis is rare (less than
10%).9 Liver calcification is rare though one series had reported
it to the extent of 50%.5 Calcifications seen in hepatobiliary
tuberculosis can easily be differentiated from other causes of
liver calcification.14 In hepatobiliary tuberculosis, large (8-12 mm
in size) “chalky” and confluent hepatic calcifications involving
both the lobes are seen. Other characteristic imaging finding is
the nodal-type calcifications along the course of the common
© JAPI • june 2013 • VOL. 61 405
bile duct. Histoplasmosis is differentiated from tuberculosis by
the presence of small, discrete, scattered calcifications. Benign
tumors of liver may show popcorn calcification. Liver cysts
show marginal calcification. Primary hepatocellular carcinoma
are usually solitary and show irregular calcification if any. On
the other hand calcification is unusual in hepatic metastasis.
Ultrasound of the liver shows hypoechoic lesions and
complex masses mimicking primary or metastatic hepatic
carcinoma or pyogenic abscess, particularly in those cases with
tuberculous liver abscess (Figure 1). 15,16 These lesions have
been referred by a variety of names, including tuberculoma,
macronodular tuberculosis or pseudotumoral tuberculosis.11
Liver calcifications can be detected earlier by ultrasound than
by plain radiographs.1 Dilated intrahepatic ducts in obstructive
jaundice can be demonstrated by ultrasound.1
Computed tomography (CT) scan of the liver can show
solitary or multiple focal masses due to a large tuberculoma or
tuberculous liver abscess, which can be difficult to differentiate
from malignancy. 17 CT-guided liver aspiration or biopsy
can confirm the diagnosis. Liver calcifications can also be
demonstrated by CT scan.18 Technetium-sulfa colloid liver scans
have generally been replaced by ultrasonography and CT.
Percutaneous blind aspiration liver biopsy is more useful for
the miliary form and tuberculous granulomatous disease of the
liver, where the success rate of a correct diagnosis is better. In
the localized form of hepatic tuberculosis, ultrasound-, CT- or
laparoscopic-guided liver biopsy yields a higher success (nearly
100%) than blind aspiration liver biopsy (67%).5 A hard gritty
sensation felt during liver biopsy is very suggestive but may also
occur in malignancy.1 Histologically, the finding of caseating
granuloma (found in 30-67%) in the liver biopsy specimen is
considered diagnostic of tuberculosis.5,6,8,19 However, it has also
occasionally been reported in Brucellosis, Coccidioidomycosis
and Hodgkin’s disease, but the clinical presentation is different.20
In the presence of non-caseating granuloma, a test for acid-fast
bacillus (AFB) and/or culture of Mycobacterium tuberculosis would
be required. AFB may be seen in tuberculous granulomas in
0-35% of cases.21 The yield of positive culture for M tuberculosis is
much lower. The overall positivity of PCR assay for M tuberculosis
in liver biopsy specimen is 88% (100% in those with caseating
granuloma).22 This is favorably higher when compared with
the conventional methods of AFB staining and culture (0-12%).1
In presence of non-caseating granuloma in liver biopsy,
distinction from sarcoidosis becomes difficult. 23 Sarcoid
granulomas are numerous, discrete, periportal in distribution,
with asteroid bodies or Schaumann bodies, with thin rim
of lymphocytes and with concentric hyalinized scar in old
granulomas. Criteria which favor tuberculosis are the presence of
Langhans’ giant cells, tendency to coalesce, no zonal predilection,
destruction of reticulin framework, and irregular contour with
a dense cuff of lymphocytes.23
Prior to availability of ultrasonography and CT, laparoscopy
was used extensively as the main diagnostic aid in visualizing
lesions on the surface of the liver and obtaining a direct vision
liver biopsy. The finding of cheesy white, sometimes chalky
white, irregular nodules of varying sizes (often resembling tumor
masses) are diagnostic.5 Laparoscopy has a diagnostic yield of
88%, and combined with guided-biopsy, nearly 100%.5
Presence of fatty liver is seen in 14 – 42% and amyloidosis
in 0 – 10% cases.10 Other non-specific changes in liver biopsy
include focal hepatocellular necrosis, Kupffer cell hyperplasia,
lymphohistiocytic aggregates, nodular regenerative hyperplasia,
mild periportal fibrosis and non-specific portal inflammation.19
46 Journal of the association of physicians of india • june 2013 • VOL. 61
Fig. 2 : ERCP showing stricture at mid-CBD caused by extrinsic
compression from tuberculous lymph nodes
Magnetic resonance cholangiopancreatography (MRCP) has
now replaced endoscopic retrograde cholangiopancreatography
(ERCP) or percutaneous transhepatic cholangiography (PTC)
as a diagnostic tool for biliary involvement.24 The bile ducts
involved shows irregular tortuous stricture with marked
proximal dilatation.14,24 While this cholangiographic appearance
is difficult to differentiate from malignancy, the presence of
associated scattered hepatic calcifications favors the diagnosis
of tuberculosis.1 Alternatively, the common bile duct may
appear beaded (19% in one series), with areas of dilatation and
constriction.25 Obstruction is usually found at porta (67-86%)
or at distal bile duct (14-33%).25 Constriction at the proximal
common bile duct or the hepatic ducts is rarely reported.
Biliary tract involvement in the majority of cases is due to
enlarged tuberculous lymph nodes located periductally at the
hepatoduodenal ligament and at the porta hepatis (Figure 2).26
Direct tubercular involvement of biliary epithelium is rare.27
ERCP or PTC is restricted for use in jaundiced patients with
therapeutic intentions.25
Treatment
Hepatobiliary tuberculosis is a treatable infection. Successful
therapy, however, requires an accurate microbiologic diagnosis
and compliance with a regimen of demonstrated efficacy.11
The treatment regimen does not differ from that of pulmonary
tuberculosis. Initially, quadruple therapy (containing isoniazid,
rifampicin, pyrazinamide and ethambutol) is recommended
for at least two months due to increasing incidence of drug
resistance.11 Total duration of therapy is generally one year.
For those patients with obstructive jaundice, in addition to
the use of ATT, biliary decompression should be done by stent
placement during ERCP.28 Strictures resulting from biliary
involvement or hepatic tuberculoma tend to be multiple and
may require multiple stent placements. Conversely, lymph node
compression tends to be at the hilum and is usually singular,
making stenting an ideal treatment.2 Percutaneous drainage
may be used as a temporary measure and later combined with
endoscopic internalization of the stents. Surgery is attempted
if there is dilated proximal common bile duct or hepatic ducts
accessible for biliary-enteric anastomosis.1
Prognostic factors for adverse outcome include age younger
than 20 years, acute presentation, coagulopathy, and high
mean caseation score.6 The outlook of patients with AIDS is
problematic. The level of underlying immunosuppression
appears to be the most important variable influencing long-term
survival in this group.29
A good clinical response is documented by reduction in the
size of the liver, and increases in appetite and weight gain.1
Quadruple therapy results in response in 67%.5 Despite ATT,
406 © JAPI • june 2013 • VOL. 61
overall mortality varies from 12-42%,5,6 and may be as high
as 75% in those with jaundice.7 Deaths usually results from
disseminated disease, complications of portal hypertension
(often due to underlying cirrhosis) or unrelieved cholangitis.1
Poor general condition of the patients, delayed presentation and
adverse effects of drug therapy are important contributors to
mortality.2 Hepatic failure is not a usual cause of death.30
Special Issues
Hepatobiliary tuberculosis in HIV infection
There has been a resurgence of tuberculosis in recent years,
primarily because of acquired immunodeficiency syndrome
(AIDS), and 50% of AIDS patients diagnosed with tuberculosis
have extrapulmonary involvement.31 AIDS patients may run
an unusually aggressive course. Unusual forms of hepatic
tuberculosis are more common as also high rate of disseminated
disease, drug resistance and adverse drug reactions.11 The
comparative incidence of M tuberculosis versus M avium-
intracellulare complex in various series differs greatly owing
to the fact that these infections occur in different stages of
immunosuppression. Geographic, racial and socioeconomic
factors may also influence these differences in comparative
incidence.31
Tuberculosis occurring in liver transplant patients
Both pediatric and adult liver transplant recipients appear
to be at risk because of their immunosuppressed state. The
prevalence of new onset tuberculosis in liver transplant
recipients is 0.7% over five year period. However, tuberculosis
is a rare cause of hepatic granuloma in post-transplant patients.32
Of greater concern is the risk of hepatotoxicity associated with
isoniazid therapy or prophylaxis. Hepatic enzyme abnormalities
associated with drug therapy can be confused with transplant
rejection.32
Associated and coincidental hepatic lesions)
Nearly 30% patients dying of cirrhosis have demonstrable
tuberculous infections.33 Korn et al suggested that the fatty
changes in the liver in patients with hepatic tuberculosis may
be the result of concomitant alcohol ingestion.19 Alcohol also
increases the risk of hepatotoxicity from INH and other anti-
tuberculous therapy.34 Cirrhosis has been described as a possible
risk factor for the development of drug-resistant tuberculosis.34
In patients with underlying liver disease, ofloxacin may be better
than traditional antituberculous therapy.34
Hepatic injury due to ATT
INH causes acute hepatocellular jaundice in about 1% of all
recipients, and at least 10% experience more trivial anicteric
hepatic injury.34 Clinical features are indistinguishable from
acute viral hepatitis.34 Case fatality rate may be as high as 10%.34
The mechanism appears to be metabolic idiosyncrasy rather
than hypersensitivity. Risk factors are advanced age, female
sex, alcoholism, concomitant use of other hepatotoxic drugs or
rifampicin and pyrazinamide.34
Rifampicin increases the likelihood of INH-induced hepatic
injury but occasionally can itself produce acute idiosyncratic
injury. It can also interfere with bilirubin uptake and excretion
as a benign physiologic effect.
Pyrazinamide also potentiates hepatotoxicity of INH and
rifampicin. Case fatality rate is higher (compared to those not
receiving pyrazinamide) and the survival is inversely related to
the time to onset of jaundice.34
Tuberculosis of the gallbladder
The gallbladder is an uncommon site of tuberculous infection.
Journal of the association of physicians of india • june 2013 • VOL. 61 47
The majority of patients are women over 30 years of age.35
Gallstones are present in more than two third of cases, and most
commonly reported symptoms and signs include epigastric pain
made worse by eating, and right hypochondriac tenderness.36
Most cases occur in association with other organ involvement,
including tuberculous peritonitis.36 Treatment usually requires
cholecystectomy in combination with ATT. Complications,
such as, tuberculous abscess of the gallbladder requires prompt
surgical attention.36
Conclusion
The term hepatobiliary tuberculosis refers to the localized
form of hepatic tuberculosis as a distinct clinical entity, with signs
and symptoms related to the hepatobiliary tract. Presentations
are often delayed, and manifestations can be nonspecific. The
diagnosis of hepatobiliary tuberculosis in endemic countries
should be considered in any patient with prolonged fever and
chronic right upper quadrant pain associated with hepatomegaly,
especially if accompanied by weight loss. The presence of
associated pulmonary lesions (active or inactive) by chest
radiography along with scattered hepatic calcifications by plain
abdominal radiograph will aid in the diagnosis. Liver biopsy
done either during laparoscopy, ultrasound- or CT-guided
biopsies will establish the diagnosis if the caseating granuloma
is seen. To confirm the diagnosis for a non-caseating granuloma,
a positive AFB and/or culture for Mycobacterium tuberculosis
would be needed. Identification of Mycobacterium tuberculosis
by PCR is more successful than by the conventional method of
AFB and culture. In patients with chronic recurrent obstructive
jaundice, especially when associated with an enlarged nodular
liver and in those who have had the condition for more than one
year, diagnosis of hepatobiliary tuberculosis should be highly
entertained. Nearly two-third of patients responds to standard
ATT given for one year. With the emergence of AIDS epidemic,
Physicians are likely to experience more aggressive, unusual
forms of hepatobiliary tuberculosis with a higher rate of drug
resistance and fatal outcome.
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