A systematic review of hepatic tuberculosis with considerations in human immunodeficiency virus co-infection
Hickey et al. BMC Infectious Diseases
A systematic review of hepatic tuberculosis with considerations in human immunodeficiency virus co-infection
Andrew J Hickey 0
Lilishia Gounder 1 2
Mahomed-Yunus S Moosa 2
Paul K Drain 3 4
0 University of Maryland School of Medicine , 655 W. Baltimore Street, Baltimore, MD 21201 , USA
1 Department of Virology, National Health Laboratory Service, Inkosi Albert Luthuli Central Hospital , Durban , South Africa
2 Department of Infectious Diseases, Nelson Mandela School of Medicine, University of KwaZulu-Natal , Durban , South Africa
3 Medical Practice Evaluation Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School , Boston , USA
4 Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School , Boston , USA
Background: Mycobacterium tuberculosis (TB) infection of the liver, known as hepatic TB, is an extrapulmonary manifestation of TB. Hepatic TB has become more prevalent, likely as a result of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic. We sought to review case series to characterize the epidemiology, pathophysiology, clinical features, diagnosis, and treatment of hepatic TB and to comment on the impact of HIV co-infection on these characteristics. Results: We obtained data on 618 hepatic TB patients from 14 case series. The most common reported signs and symptoms were hepatomegaly (median: 80%, range: 10-100%), fever (median: 67%, range: 30-100), respiratory symptoms (median: 66%, range: 32-78%), abdominal pain (median: 59.5%, range: 40-83%), and weight loss (median: 57.5%, range: 20-100%). Common laboratory abnormalities were elevated alkaline phosphatase and gamma-glutamyl transferase. Ultrasound and computerized tomography (CT) were sensitive but non-specific. On liver biopsy, smear microscopy for acid-fast bacilli had a median sensitivity of 25% (range: 0-59%), histology of caseating granulomas had a median sensitivity of 68% (range: 14-100%), and polymerase chain reaction for TB had a median sensitivity of 86% (range: 30-100%). Standard anti-tuberculous chemotherapy for 6 to 12 months achieved positive outcomes for nearly all patients with drug-susceptible TB. Conclusions: Clinicians in TB-endemic regions should maintain a high index of suspicion for hepatic TB in patients presenting with hepatomegaly, fever, respiratory symptoms, and elevated liver enzymes. The most sensitive imaging modality is a CT scan, while the most specific diagnostic modality is a liver biopsy with nucleic acid testing of liver tissue samples. Upon diagnosis, 4-drug anti-TB therapy should promptly be initiated. HIV co-infected patients may have more complex cases and should be closely monitored for complications.
Tuberculosis; Liver; Extrapulmonary tuberculosis; HIV/AIDS
Mycobacterium tuberculosis (TB) usually infects the lungs,
called pulmonary TB, but can infect almost any organ in
the body, causing an extrapulmonary infection. TB
infection of the liver, called hepatic TB, is an extrapulmonary
manifestation of an active infection. The first recorded
case of hepatic TB was reported in 1858 by Dr. John Syer
Bristowe, an English physician . In 1905, more than
20 years after Kochs discovery of the TB bacillus, Drs.
Rolleston and McNee had classified hepatic TB into
miliary (disseminated) and local (isolated) forms .
Since then, several case reports and few limited case series
have described patients with both forms of hepatic TB,
but there has been no systematic review of hepatic TB.
The incidence of TB underwent a resurgence in the
1980s, and the World Health Organization (WHO)
estimates that 8.7 million people develop active TB disease
and 1.4 million die from TB annually [3,4]. While the
incidence of active TB likely peaked in 2004, the
proportion of extrapulmonary TB cases continues to rise [5,6].
In the United States, the proportion of extrapulmonary
TB cases nearly tripled from 7.6% in 1962 to 21% in
2006 . The HIV/AIDS pandemic, coupled with poor
health care delivery in many resource-limited countries,
has fueled the resurgence of TB . High TB incidence
rates occur where HIV is most prevalent, and the
immunosuppression caused by HIV leads to a reactivation
of latent TB . HIV/AIDS has also contributed to the
relative rise in extrapulmonary TB rates , as the risk
of extrapulmonary TB increases with decreasing CD4
counts . Over 50% of HIV and TB co-infected people
present with extrapulmonary involvement, which
includes hepatic TB .
A clearer understanding of hepatic TB will help clinicians
with diagnostic and management decisions in order to
improve patient outcomes. There have been no prior
systematic reviews of hepatic TB to facilitate this understanding;
therefore, the aim of this systematic review is to synthesize
the existing data on the epidemiology, pathophysiology,
clinical features, diagnosis, and treatment of hepatic TB, and to
highlight additional considerations in HIV co-infection.
Literature search and inclusion criteria
We conducted a systematic literature search in PubMed
and ScienceDirect for articles pertaining to hepatic TB
(Figure 1). The primary search term used was hepatic
tuberculosis. We included all articles published between
1960 and July 2013. There were a total of 965 hits (806
in PubMed, 159 in ScienceDirect). Of these, there were
21 duplicate articles which were removed, leaving 944 to
be screened. Of the 944 articles screened, 840 were
excluded under the following criteria: published in
language other than English, non-human animal study,
subject of study was not hepatic TB, and study was not
a case report or case series. The remaining 104 articles
were assessed for eligibility for quantitative analysis.
For the purpose of our study, we included only hepatic
TB case series, and we defined a case series as having
five or more patients diagnosed with hepatic TB. We
also required that the case series have sufficient data to
perform quantitative analysis on clinical presentation,
diagnosis, and treatment of hepatic TB. Of the 104
articles assessed for eligibility, 14 met our inclusion criteria
for quantitative analysis, and the remaining 90 were
excluded for the following reasons: patients had
tuberculosis infections that did not include the liver, fewer than
5 patients with hepatic TB in study, and insufficient
data on presentation, diagnosis, and treatment to perform
quantitative analysis. We also reviewed references from
the selected manuscripts to obtain additional information
relevant to the epidemiology, pathophysiology, clinical
features, diagnosis, and treatment of hepatic TB. These
references were published any time prior to July 2013.
Figure 1 Flow diagram of literature search and study selection.
number of patients receiving that regimen, median
treatment duration, and outcomes were assessed and
This study was a systematic review of the medical
literature and did not involve any human subjects. As such, no
approval from an ethics committee was required.
Results and Discussion
Our search identified 14 manuscripts, describing 618
cases of hepatic TB that occurred before or during the
HIV/AIDS epidemic. The global distribution of reported
hepatic TB cases was concentrated in Sub-Saharan Africa
and Southeast Asia, which is similar to the distribution of
pulmonary TB (Table 1) . Approximately 79% of all
reported hepatic TB cases were due to systemic
dissemination of bacilli, called miliary hepatic TB. However, several
cases of local hepatic TB, which are isolated infections
of the liver, have been reported in South Africa, the
Philippines, and India [11,13-16]. Since hepatic TB is
underreported in published literature, any regional
clustering of described hepatic TB cases may reflect a
reporting bias, and the distribution of hepatic TB likely mirrors
the global epidemiology of active pulmonary TB cases.
The prevalence of hepatic TB has been estimated in
several studies. An early case series published in 1930
estimated TB liver involvement in 50-80% of patients with
advanced pulmonary TB . Over a six-year period from
19781984, Essop et al. diagnosed hepatic TB by liver
biopsy and/or autopsy in 1.2% (96/8,342) of all patients
with active TB in a South African hospital, some of
From identified manuscripts and case series, we abstracted
data on the epidemiology, pathogenesis, clinical features,
diagnosis, and treatment. The method of analysis varied
by the aspect of hepatic TB being examined and the data
available from the manuscripts. The epidemiology of
hepatic TB was evaluated by abstracting the year of the study,
geographic location, proportion of male patients, and
mean age of cases. The incidence and mortality of hepatic
TB were approximated using data available from some
of the larger case series. Pathological features were
determined by calculating the proportion of total hepatic
TB cases that were miliary hepatic TB and those that
were local hepatic TB. Where available, we also abstracted
information on pathogenesis from the introduction and
discussion sections, as well as from other manuscripts
referenced in the studies. To determine the key clinical
features of hepatic TB, we determined the most common
signs and symptoms by calculating the proportion of
patients with each sign and symptom from each of the
case series, and we then presented the median value
and range of these percentages. For assessing liver
function test abnormalities, the median values from
each case series were calculated, and the range of
these medians, rounded to the nearest 50 U/L, were
reported. The diagnosis of hepatic TB was evaluated
by calculating the median proportion and range of
positive diagnostic findings on chest radiograph,
abdominal ultrasound, abdominal computerized
tomography (CT), and liver biopsy. The treatment of hepatic
TB cases was not provided in all cases series. When
treatment information was provided, the regimen,
Table 1 Reported case series of hepatic tuberculosis
Alvarez & Carpio 
Essop et al. 
Maharaj et al. 
Chien et al. 
Kok et al. 
Huang et al. 
Desai et al. 
Hwang et al. 
Gounder et al. 
Vilaichone et al. 
Amarapurkar et al.  2008 India
1964 South Africa 200
1984 South Africa 96
1987 South Africa 41
2009 South Korea 12
2012 South Africa 20
Total (N) Male (%) Age (Mean) Miliary (%) Local (%) Comments
PCR = Polymerase chain reaction; HIV = Human immunodeficiency virus; SLE = Systemic lupus erythematosus; CT = Computerized tomography; MRI = Magnetic
resonance imaging; US = Ultrasound.
#Approximate majority age range.
Primarily diagnosed at autopsy
Two groups: w/ and w/o jaundice
+/ prognostic groups
22-month prospective study
Comparison of miliary and local forms
Brief cases and literature review
Retrospective PCR analysis
10 HIV+, 2 SLE, 8 immunocompetent
CT, MRI, US findings
2-year retrospective; 1 HIV+
Study excluded patients with HIV
15-year retrospective study
3 immunocompromised (HIV-)
whom might have been HIV-positive . Tai et al. found
a similar proportion of hepatic TB (0.8%; 10/1,251) among
patients with active TB during a 15-year period in Taiwan
. At one South African hospital in 1986, nearly 10% of
patients (whose HIV status was unknown or not reported)
with unexplained hepatomegaly were diagnosed with
hepatic TB by liver biopsy . The incidence of hepatic
TB remains unknown, likely due to unfamiliarity of the
disease, since historically most hepatic TB was diagnosed
upon surgery or autopsy . A conservative estimate of
the incidence can be made using data from the studies
conducted by Essop et al. and Tai et al., who found hepatic
TB in approximately 1% of all active TB cases [18,19].
Applying this percentage to the worlds TB incidence,
8.7 million per year , suggests there may be
approximately 87,000 new cases of hepatic TB each year.
The proportion of extrapulmonary TB, which includes
hepatic TB, has increased in the last 30 years , due
largely to increases in the global prevalence of HIV/
AIDS [11,21-26]. In a study of 164 patients with
disseminated TB, hepatic TB was observed in 17.4% (4/23) of
HIV-infected people and 4.3% (6/141) of HIV-uninfected
people . In an autopsy study on 39 patients who died
of HIV complications in Johannesburg, South Africa, TB
was the cause of death in 69% (27/39) of cases, and among
those, 33% (9/27) had TB cultured from their liver
specimen . In an autopsy study from Nigeria, histologic
evidence of TB was found in 37.3% (25/67) of liver tissue
samples from patients who died of HIV/TB co-infection
complications . These studies suggest that hepatic TB
may be underdiagnosed and commonly associated with
mortality in HIV and TB co-infected patients.
Among HIV-uninfected patients, the case fatality rate
of hepatic TB was between 12 and 42% [18,29]. However,
Essop et al. reported 95% (35/37) of untreated patients
died in their case series . Poor prognostic factors
included age <20 years, miliary TB, predisposing factors
(treatment with steroids, chronic renal failure, diabetes,
systemic lupus erythematosus, and significant alcohol
Table 2 Contrasting miliary and local hepatic TB
intake), coagulopathy, low prothrombin index, and greater
extent of caseation on histology . There was no
definitive data on the mortality rate for HIV-infected hepatic
TB patients. In our recent study of 20 HIV-infected
hepatic TB patients in South Africa, the mortality was
40% despite prompt initiation of standard 4-drug
antituberculosis therapy . Although this was comparable
to the observed mortality among HIV-uninfected adults,
the results are limited by a small sample size.
Dissemination and pathophysiology of hepatic
Tuberculous bacilli can reach the liver via hematogenous
dissemination, generally from the lungs, or by local spread
from the gastrointestinal tract (Table 2) [2,3,31,32]. Among
reported hepatic TB cases, miliary form accounted for 79%
of cases, while local hepatic TB accounted for 21% of cases
(Table 1). TB infection of the biliary tree, or biliary TB, is
another form of TB infection in the liver and is considered
Hematogenous dissemination, or miliary disease, from
a pulmonary focus is the most common etiology of
hepatic TB . The source of miliary dissemination may be
from another extrapulmonary site, such as an abdominal
lymph node, but this is rare. In miliary hepatic TB, bacilli
reach the liver via the hepatic artery [2,32,33]. Miliary
hepatic TB is characterized by diffuse seeding of the liver with
tubercles ranging from 0.6 to 2.0 mm in diameter situated
in the lobules of the liver .
In local hepatic TB, which has also been called
tuberculoma, macronodular hepatic TB, or pseudotumoral
hepatic TB, dissemination primarily occurs via the portal
vein from a focus in the gastrointestinal tract . Local
hepatic TB is typically characterized by tubercles greater
than 2 mm in diameter situated near the portal triad
region [2,32]. A TB liver abscess commonly arises from
local hepatic TB, but may also occur following miliary
hepatic TB . Local hepatic TB tends to cause more
hepatocellular damage than miliary hepatic TB . In
0.6-2.0 mm in diameter
>2.0 mm in diameter
Near portal triad
Location of tubercles
Clinical signs/symptoms Cough, sputum production, hepatomegaly
Weight loss, hepatomegaly, jaundice
CT scan; liver biopsy is less helpful
Liver biopsy more helpful
Multiple, dispersed, low-density micronodules Large, low-density nodules with calcification and peripheral enhancement
4-drug regimen; consider drainage of abscess or surgery
contrast to miliary hepatic TB, those with local hepatic
TB do not generally have evidence of active pulmonary
The characteristic histological feature of both miliary
and local forms of hepatic TB is the granuloma [11,34].
Hepatic granulomas are due to cell-mediated
immunological responses to TB antigens and consist of focal
aggregates of macrophages, including Kupffer cells that may
coalesce to form Langerhans giant cells with surrounding
lymphocytes and fibroblasts [34-37]. Granulomas may be
necrotizing or non-necrotizing, and caseating (where
necrotic tissue appears cheese-like on gross examination)
or non-caseating. Hepatic granulomas in response to TB
tend to be necrotizing with central caseation . In three
large case series, caseating granulomas were found in
51-83% of hepatic TB patients [18,20,29]. Multiple
granulomas may coalesce to form a large tuberculoma, and
caseation and liquefaction necrosis of a tuberculoma may
lead to a tubercular abscess .
TB was the most common etiology of hepatic
granulomas in TB-endemic countries [36,38,39]. In Iran, India,
and Saudi Arabia, TB was the cause of hepatic
granulomas among 51% (37/72), 55% (28/51), and 43% (26/61)
of cases, respectively [36,38,39]. In Turkey, TB was among
the most common causes of hepatic granulomas (15%)
. Therefore, in TB-endemic countries, presence of
hepatic granulomas was highly suggestive of hepatic TB.11
In low-prevalence TB regions and among patients with no
risk factors for TB, non-communicable causes, such as
primary biliary cirrhosis or sarcoidosis, may be more
common etiologies for hepatic granulomas [35,37].
HIV alters the pathophysiology of hepatic TB.
Immunocompromised HIV-infected patients not only have
increased susceptibility to TB reactivation and dissemination,
but their manifestations of extrapulmonary TB tend to be
Table 3 Presenting signs and symptoms of hepatic TB patients
more severe [8,22]. HIV-infected patients with
extrapulmonary TB are also more likely to have concomitant
pulmonary TB . An increased risk of dissemination and
development of abdominal TB among HIV-infected people
may explain their greater risk of developing hepatic TB
than HIV-uninfected persons . The isolated local form
of hepatic TB is more common in immunocompromised
patients [41,42]. In addition, granulomas in AIDS patients
are typically absent or poorly formed and lack necrosis
due to a dysfunctional immune system . Hepatic TB
in HIV-infected and -uninfected patients differs both
clinically and pathologically.
Clinical features of hepatic tuberculosis
Clinical features of hepatic TB are nonspecific, which
often leads to a diagnostic delay . Analysis of eleven
hepatic TB case series revealed the most common
presenting signs/symptoms were hepatomegaly (median: 80%,
range: 10-100%), fever (median: 67%, range: 30-100%),
respiratory symptoms (median: 66%, range: 32-78%),
abdominal pain (median: 59.5%, range: 40-83%), and weight
loss (median: 57.5%, range: 20-100%) (Table 3). Other
signs included splenomegaly (median: 30%, range: 0-40%),
ascites (median: 23%, range: 5-25%), and jaundice
(median: 20%, range: 0-60%). Local hepatic TB and miliary
TB may differ in presentation. Local hepatic TB may
present primarily as diffuse abdominal pain, while
patients with miliary hepatic TB may present with acute
respiratory symptoms such as a cough, with or
without sputum production [2,19,44,45]. Jaundice is also
more common in cases of local hepatic TB and biliary
TB . Presenting signs and symptoms are similar in
HIV-infected and HIV-uninfected patients [11,46-48].
However, as before, HIV-infected patients are more
likely to have a concomitant pulmonary TB infection .
N Frequency of presenting sign/symptom (%)
Hepatomegaly Fever Respiratory SX ABD pain
143 74 97 66 55
Alvarez (1983) 
Essop (1984) 
Maharaj (1987) 
Vilaichone (2004)  20
67 (30100) 66 (3278)
59.5(4083) 57.5 (20100) 30 (040)
23 (525) 20 (060)
The most common abnormalities associated with hepatic
TB included elevated alkaline phosphatase (ALP) (typical
range: 200750 U/L) and gamma-glutamyl transferase
(GGT) (typical range: 100400 U/L), and occasional
elevation of alanine transaminase (ALT) (typical range: 0200
U/L) and aspartate transaminase (AST) (typical range:
0200 U/L) [2,18,23,32,44,45,49,50]. Higher levels of
ALT and AST were observed in jaundiced patients .
Mild hyperbilirubinemia has been reported in both miliary
and local hepatic TB cases . Hepatic TB patients often
had an inverted albumin to globulin ratio (A/G), in which
the serum globulin was reported to be 1.25-1.86 times
higher than serum albumin [14,18,20,45].
Laboratory abnormalities are generally similar between
HIV-infected and -uninfected hepatic TB patients. In one
small study, HIV-infected people had significantly higher
levels of ALP (1,374.6 714.4 U/L), as compared to
HIV-uninfected people (472.2 209.6 U/L) . While
abnormal liver function enzymes typically improve
with treatment, in our review of 20 HIV-infected
hepatic TB patients, we found normalization of liver
enzymes lagged by months to years behind the clinical
Diagnosis of hepatic tuberculosis
A high index of clinical suspicion is required to make a
diagnosis of hepatic TB. In TB-endemic regions, hepatic
TB should be considered in patients who present with
any combination of chronic right upper quadrant pain,
Table 4 Diagnostic findings in hepatic TB case series
hepatomegaly, fever, and weight loss . An
infiltrative pattern on liver function test with elevated ALP
and GGT, as well as an inverted albumin/globulin ratio,
would further support a clinical diagnosis of hepatic TB
[2,14,18,20,23,32,44,45,49,50]. Where available,
radiography and liver biopsy should be considered in addition
to a clinical examination and laboratory tests.
Plain x-ray radiography and ultrasound are generally the
most widely available and first imaging tests to be
obtained, but they both lack diagnostic specificity [15,20,52].
Plain abdominal radiography may show a focal hepatic
lesion and/or hepatomegaly, but features may be similar
to viral hepatitis, vascular disorders, systemic infections,
other granulomatous diseases, or malignancy [15,52]. In
one study, plain abdominal radiography revealed
abnormalities in 86% (102/119) of cases, with diffuse hepatic
calcifications in 49% (58/119) of patients . A positive
chest radiograph may also prompt additional
investigations for hepatic TB, but a negative chest radiograph
should not be used to exclude hepatic TB [18,20,29,44].
The median proportion of patients with abnormal chest
radiographs was 42.5% (range: 0-88%) among hepatic TB
case series (Table 4). Ultrasound has the benefit of being
easily operated in TB-endemic resource-limited settings
. The median proportion of patients with abnormal
abdominal ultrasound was 76% (range: 6-100%) among
hepatic TB case series. However, abdominal ultrasound
generally showed a round, non-specific hypoechoic region
in the liver, and is therefore not an optimal test for hepatic
130 65 (83/128)
Alvarez (1983) 
Essop (1984) 
Maharaj (1987) 
Huang (2003) 
Vilaichone (2004) 
Desai (2006) 
Amarakpurkar (2008)  38
TB = Tuberculosis; ABN = Abnormal; CXR = Chest x-ray; ABD = Abdominal; US = Ultrasound; CT = Computed tomography; AFB = Acid-fast bacilli; PCR = Polymerase
chain reaction; ND = Not documented or not done, &Minimum abnormal, given documentation; #Granulomas present, caseation not specified.
TB [54,55]. Echogenic lesions of hepatic TB have also
been described [56,57]. The primary value of plain
radiographs or ultrasound would be to prompt further
investigation and/or identify correct location for percutaneous
liver biopsy [15,18,58,59].
The optimal radiographic test for diagnosing hepatic
TB is a contrast-enhanced abdominal CT scan or a
dedicated triple-phase liver CT scan. The median
proportion of patients with abnormal abdominal CT was 88%
(range: 40-100%) among hepatic TB case series (Table 4).
The CT findings are different for miliary and local hepatic
TB. Miliary hepatic TB, which has smaller tubercles, is
visualized on a CT scan as multiple, low-density
micronodules dispersed throughout the liver . CT imaging for
miliary hepatic TB may also reveal hepatomegaly without
nodular intrahepatic lesions, or it may reveal abdominal
lymphadenopathy with peripheral lymph node
enhancement and/or calcifications [59-61]. By contrast, local
hepatic TB generally appears on CT as one large solitary
nodule or 23 low-density nodules [54,60].
There were too few studies to recommend magnetic
resonance imaging (MRI) as an appropriate imaging
modality for hepatic TB, and the cost and accessibility
of MRI scanning further limits its utility in TB-endemic
Liver biopsy with mycobacterial culture is considered the
most specific diagnostic test for hepatic TB [18,51,32].
While liver biopsy may not always be necessary,
microbiological and histological findings can allow for a more
accurate diagnosis [11,24]. A liver biopsy is indicated in any
person with a constellation of clinical, laboratory, and
radiographic suspicion of hepatic TB [32,58]. These may
include, but are not limited to, hepatomegaly of unknown
origin, fever of unknown origin, and abnormal liver
enzymes in any patient from a TB-endemic region
[32,58,62]. A liver biopsy can be performed as a
percutaneous transthoracic procedure along the mid-axillary line
or as a subcostal abdominal procedure in patients with
hepatomegaly . Ultrasound guided liver biopsy is
generally preferred to improve the sampling and increase
the diagnostic accuracy [58,61]. The diagnostic yield of a
liver biopsy may also be increased by using a large aspiration
needle and performing more passes into the liver, but these
should be weighed against the risk of complications .
Liver biopsies should be sent for both microbiological
and histological evaluation. Microbiological methods
include smear microscopy for acid-fast bacilli (AFB) and
mycobacterial culture. AFB smear had a median
sensitivity of 25% (range: 0-59%) among hepatic TB case series
(Table 4). A positive AFB result may be from another
Mycobacterium infection such as Mycobacterium avium,
a common opportunistic infection of the liver in AIDS
Treatment of hepatic tuberculosis
Anti-TB therapy should be initiated upon diagnosing
hepatic TB, and considered in cases where clinical
Table 5 Traditional and updated diagnostic criteria for hepatic TB
Diagnostic criteria in 1984  Updated diagnostic criteria in 2014*
Acid fast bacilli on smear of liver tissue Culture of liver tissue demonstrating M. tuberculosis
Culture of liver tissue demonstrating M. tuberculosis
Acid fast bacilli on smear or nucleic acid (PCR) positive for TB (IS6110 insertion sequence)
from liver tissue sample
Typical appearance at laparotomy
Autopsy confirmation of hepatic TB
Response to specific therapy
Caseating hepatic granulomata with a positive
Abdominal CT demonstrating low-density hepatic nodule(s) (<2 mm: miliary; >2 mm: local)
in patient with confirmed pulmonary TB or in a TB-endemic region
Hepatic granulomata with demonstration of TB bacilli
anywhere else in the patient
Clinical presentation of right upper quadrant pain, hepatomegaly, fever, and weight loss in
patient with confirmed pulmonary TB or in a TB-endemic region**
Resolution of elevated liver enzymes following anti-TB therapy
TB = Tuberculosis; PCR = Polymerase chain reaction; CT = Computed tomography.
*Diagnostic criteria are presented from the strongest evidence to the weakest evidence.
**When available, other diagnostic tools such as radiography and liver biopsy should be employed to confirm clinical diagnosis.
suspicion of hepatic TB is high . Treatment of hepatic
TB has been most successful with multi-drug regimens
containing rifampin, isoniazid, and other anti-TB agents
such as pyrazinamide, ethambutol, and/or streptomycin
(Table 6). In one cohort of 96 hepatic TB patients, those
receiving monotherapy had higher mortality (20% vs. 0%)
compared to patients receiving a multi-drug regimen
containing isoniazid and rifampin . In another
cohort, positive clinical responses, including improved
appetite and reduced hepatomegaly, were seen in 67%
(87/130) of patients receiving multi-drug therapy .
The WHO recommendation for the treatment of
drugsusceptible pulmonary TB (rifampin, isoniazid, ethambutol,
and pyrazinamide for two months, followed by 4 months
of rifampin and isoniazid) [68,69] has been applied to
hepatic TB with positive outcomes (Table 6). The
optimal duration for treating hepatic TB is controversial,
but 612 months appears to be effective for most
patients (Table 6). The American Thoracic Society
recommends 69 months for any extrapulmonary site, except
the meninges . Treatment has resulted in improved
appetite and weight gain, resolution of fever, reduced
jaundice, and decreased hepatosplenomegaly within the
first two to three months [14,19,29,44]. Resolution of fever
has been noted to occur within two weeks of initiating
treatment, and appetite generally improved earlier .
Monitoring hepatic TB patients is important to
ensure response to treatment and detect complications.
Table 6 Treatment regimens, outcomes, and mortality in hepatic TB case series
Lead Author (Year) N Treatment regimens (n) Median Outcomes
Alvarez (1983)  ND
Essop (1984) 
Huang (2003) 
Desai (2006) 
Hwang (2009) 
Amarapurkar (2008)  38
<2 drugs (10); >2 drugs
(no R, H) (29); R, H, +others
(16); no TX (37);
ATT (3), lobectomy (1),
hepatectomy (2); no TX (2)
R, H, Z, E for 2 months,
then R, H for 4 months (7)
R, H, Z, E for 2 months, then 12
R, H for 10 months (38)
ATT (10), left hepatic
Gounder (2012) 
R, H, Z, E (20)
TB = Tuberculosis; H = Isoniazid; S = Streptomycin; E = Ethambutol; PAS = Paraaminosalicylic acid; ND = Not documented; R = Rifampin; TX = Treatment; ATT = Anti
tuberculous therapy; Z = Pyrazinamide; LTFU = Lost to follow-up; MDR/XDR-TB = Multiple/extensively drug-resistant tuberculosis.
52 improved; 40 died;
4 improved; 1 died
6 improved; 1 died
9 improved; 1 LTFU
10 improved; 2 had
12 improved; 8 died
Author recommends treatment
for 12 months
No TX mortality: 95%; <2 drug
mortality: 20%; R, H, +others
All local hepatic TB
All local hepatic TB
All local hepatic TB
Disease persisted in patients
w/ liver abscesses
2 patients died from MDR/XDR-TB
Hepatotoxicity, or drug-induced liver injury (DILI), is
the most common adverse effect among patients receiving
isoniazid, rifampin, and pyrazinamide [71,72]. However,
the incidence and management of DILI among hepatic TB
patients has been poorly studied. Managing hepatic TB in
HIV co-infected patients involves additional challenges,
and may require the assistance of an infectious diseases
specialist. The WHO recommends initiating antiretroviral
therapy (ART) 28 weeks after starting anti-TB therapy
. In addition to complex drug-drug interactions of
concurrent ART and anti-TB therapy, clinicians should be
aware of DILI and TB-related immune reconstitution
inflammatory syndrome (TB-IRIS). Both entities can cause a
worsening clinical picture and elevated liver enzymes after
initiating ART, and can be difficult to distinguish .
TB-IRIS is an inflammatory reaction to TB antigens by
the host immune system while receiving ART.
Approximately one-sixth of co-infected patients starting ART
will develop TB-IRIS . Hepatic TB-IRIS presents with
hepatomegaly (56% of patients), right upper quadrant
pain, fever, nausea/vomiting, and elevated liver enzymes
. However, patients with hepatic TB-IRIS do not
typically present with jaundice . Differentiating DILI from
hepatic TB-IRIS can be challenging in the absence of a
liver biopsy . Making this distinction is critical since
DILI is managed with treatment cessation and drug
rechallenge, while TB-IRIS requires persistence of treatment
with the possible addition of corticosteroids [74,75].
Hepatic TB is an extrapulmonary expression of active
TB disease, and the incidence has likely increased during
the era of HIV/AIDS, but definitive clinical studies are
lacking. Clinicians in TB-endemic regions should have a
high index of suspicion in patients presenting with
hepatomegaly, fever, respiratory symptoms, and elevated liver
enzymes. Abdominal radiography and ultrasound are
nonspecific imaging modalities, and a CT scan can be more
accurate and should be preferred if available. Liver biopsy
with mycobacterial culture and histology is the most
specific test for diagnosing hepatic TB, but has poor sensitivity
(or a high false negative rate). PCR of biopsy specimens
has demonstrated high sensitivity and specificity for
diagnosing hepatic TB. Patients with definitive or clinically
suggestive hepatic TB should be promptly initiated on 4-drug
anti-TB therapy, and clinicians should observe closely
for drug toxicity and complications, such as DILI and
TB-IRIS. Co-infection with HIV can complicate the
management of hepatic TB, and clinicians must be knowledgeable
of differences in pathophysiology, treatment, and disease
management. A high index of suspicion for hepatic TB is
important if clinicians are to make an early diagnosis and
initiate prompt treatment to improve clinical outcomes.
TB: Tuberculosis; HIV: Human immunodeficiency virus; AIDS: Acquired
immunodeficiency syndrome; CT: Computerized tomography; WHO: World
Health Organization; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl
transferase; ALT: Alanine transaminase; AST: Aspartate transaminase;
MRI: Magnetic resonance imaging; AFB: Acid-fast bacilli; PCR: Polymerase
chain reaction; RIF: Rifampin; DILI: Drug-induced liver injury; ART: Anti-retroviral
therapy; TB-IRIS: Tuberculosis-related immune reconstitution inflammatory
The authors declare that they have no competing interests.
AJH undertook the acquisition of data, performed the analysis and
interpretation of data, and drafted the manuscript. LG and MYSM provided
critical revision of the manuscript for important intellectual content. PKD
developed the study concept and design, provided critical revision of the
manuscript, and provided study supervision. All authors read and approved
the final manuscript.
This research was supported by the Duke University Deans Summer
Research Fellowship. PKD is supported by the Harvard Global Health
Institute, the Infectious Disease Society of America Education & Research
Foundation (IDSA ERF) and National Foundation for Infectious Diseases
(NFID), Massachusetts General Hospital Executive Committee on Research,
the National Institute of Allergy and Infectious Diseases K23 AI108293, and
the Harvard University Center for AIDS Research P30 AI060354.
We thank our research staff and nurses who carried out the study.
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