Ascitits Bk

Systematic review: tuberculous peritonitis – presenting features,diagnostic strategies and treatment

F. M. SANAI & K. I. BZEIZI

Division of Hepatology, Department of Internal Medicine, Riyadh, Saudi Arabia

Accepted for publication 27 July 2005

SUMMARY

The peritoneum is one of the most common extrapulmo-

nary sites of tuberculous infection. Peritoneal tuberculo-

sis remains a significant problem in parts of the world

where tuberculosis is prevalent. Increasing population

migration, usage of more potent immunosuppressant

therapy and the acquired immunodeficiency syndrome

epidemic has contributed to a resurgence of this disease in

regions where it had previously been largely controlled.

Tuberculous peritonitis frequently complicates patients

with underlying end-stage renal or liver disease that

further adds to the diagnostic difficulty.

The diagnosis of this disease, however, remains a

challenge because of its insidious nature, the variability

of its presentation and the limitations of available

diagnostic tests. A high index of suspicion is needed

whenever confronted with unexplained ascites,

particularly in high-risk patients.

Based on a systematic review of the literature, we

recommend: tuberculous peritonitis should be consid-

ered in the differential diagnosis of all patients present-

ing with unexplained lymphocytic ascites and those

with a serum-ascites albumin gradient (SAAG) of

<11 g/L; culture growth of Mycobacterium of the ascitic

fluid or peritoneal biopsy as the gold standard test;

further studies to determine the role of polymerase

chain reaction, ascitic adenosine deaminase and the

BACTEC radiometric system for acceleration of myco-

bacterial identification as means of improving the

diagnostic yield; increasing utilization of ultrasound

and computerized tomographic scan for the diagnosis

and as a guidance to obtain peritoneal biopsies; low

threshold for diagnostic laparoscopy; treatment for

6 months with the first-line antituberculous drugs

(isoniazid, rifampicin, ethambutol and pyrazinamide)

in uncomplicated cases.

INTRODUCTION

The first documented case of ancient ‘tuberculosis (TB)

peritonitis’ was described in humans in 1843.1 Intro-

duction of antituberculous chemotherapy and more

importantly, the improvement in the socioeconomic

status, led to a decline in all forms of TB, including

tuberculous peritonitis (TBP). Although abdominal TB

continues to be a significant health problem in the

developing world, recently there has been an increase in

the number of patients diagnosed with abdominal TB in

parts of the world where TB generally was rare. This is

partly a result of increasing travel and migration and

also to the rising number of HIV patients who are

susceptible to opportunistic infections.2 There has been

a cumulative evidence of relative increase in the

incidence of the extrapulmonary TB.3–5

Abdominal TB may involve the gastrointestinal tract,

peritoneum or the mesenteric lymph nodes. Occasional

overlaps between these forms have also been described.

Peritoneum and its reflections are common sites of

tuberculous involvement of the abdomen and it is the

Correspondence to: Dr F. M. Sanai, Division of Hepatology (A41),

Department of Internal Medicine, Armed Forces Hospital, PO Box 7897,

Riyadh 11159, Saudi Arabia.

E-mail: [email protected]

Aliment Pharmacol Ther 2005; 22: 685–700. doi: 10.1111/j.1365-2036.2005.02645.x

� 2005 Blackwell Publishing Ltd 685

sixth most common extrapulmonary site in the United

States.5 It occurs in up to 3.5% of cases of pulmonary

TB and comprises 31–58% of cases of abdominal TB.6–9

In western Europe and North America, a frequent

association between TBP and cirrhosis has been des-

cribed.10–12 Other groups of patients at increased risk of

developing TBP include chronic renal failure patients on

continuous ambulatory peritoneal dialysis (CAPD) and

HIV patients.13, 14 Several reports have also highlighted

the remarkable similarity between this illness and

ovarian carcinoma,15 carcinomatosis peritonii16 and

complicated portal hypertensive ascites.

The diagnosis of this disease continues to pose

significant challenges. This is partly due to the lack of

specific clinical features that would otherwise help in

pursuing the diagnosis when suspected and also to the

limited yield of the commonly used diagnostic tests.

Isolation of mycobacteria from the ascitic fluid is difficult

and frequently laparoscopy is needed for the diagnosis.

In this review we aim to address the variability of

disease presentation, the associated risk factors of the

disease and will review the current knowledge of the

diagnostic measures available and treatment options.

Search strategy for identification of studies

We reviewed the literature available on this subject by

performing a Medline search limited to the English

language (January 1966–October 2004). The search

terms used were: ‘tuberculous peritonitis’, ‘peritoneal

tuberculosis’, ‘tuberculosis and ascites’, ‘abdominal

tuberculosis’ and ‘tuberculosis and laparoscopy’.

Abstracts of the articles selected in each of these multiple

searches were identified and those dealing particularly

with the subject were recorded and reviewed in full form.

Reference lists from trials previously selected by elec-

tronic searching were manually searched to identify

further relevant trials. Other publications known to the

authors were also reviewed. In addition, we electronic-

ally scanned major gastroenterology journals for the

most recent studies dealing with the subject. Studies

including paediatric subjects were not excluded.

EPIDEMIOLOGY

The reported incidence of TBP among all forms of TB

varies from 0.1% to 0.7% worldwide.17 Both sexes are

equally affected and the disease is seen most commonly

in patients between 35 and 45 years of age.

Variable methods have been used to study TB world-

wide and this might explain the discrepancies of data

available. Increasing migration and also the constant

changes of disease pattern are other factors that made

accurate assessments of the extent of this disease even

more complex. Examples of the methods used to study

TB prevalence include, mortality data, tuberculin skin

test and field surveillance by chest X-ray and sputum

cultures. BCG vaccination has limited the usefulness of

tuberculin skin testing in the diagnosis of TB because a

significant proportion of vaccinated but uninfected

patients will return a positive skin reaction.18 Similarly,

deriving meaningful epidemiological data on this dis-

ease by Mantoux skin testing has also become difficult

because of the vaccination programmes undertaken in

the third world. This trend is observed across all age

groups where non-vaccinated subjects had lower rates

of positive Mantoux test in uninfected patients than

those who had received BCG vaccination.18 The peak

prevalence of a positive skin reaction in those who had

previously been vaccinated occurs in 70% for the age

groups between 45 and 64 years. It is expected that the

rate of positive skin test for future generations will be

significantly higher as current immunization pro-

grammes in most of the third world countries include

BCG vaccination at child-birth. The newly developed

interferon (IFN)-c-based test would help overcome this

problem of detecting latent infection since previous BCG

vaccination does not affect its results.19 However, at

present there is no large-scale epidemiological data

available utilizing this test.

A significant correlation exists between the socioeco-

nomic status and disease prevalence. Poor hygiene and

overcrowding have consistently been shown to have a

causative relationship with TB. Ingestion of unpas-

teurized milk might also be another reason for the

increased prevalence of this disease in the rural

populations. On the contrary, the effective tuberculin

testing of dairy herds and a shift from the norm of

drinking unpasteurized milk in cities, has most likely

contributed to the overall reduction in cases of primary

abdominal TB.

Alcoholic liver disease (ALD) is frequently linked to

increased incidence of TBP particularly in the western

countries. In one study, 62% of patients with TBP had

an underlying ALD,10 a contrast to the findings of

studies from developing countries where the reported

underlying liver diseases was found in <13% of patients

with TBP.20–23

686 F. M. SANAI AND K. I. BZEIZI

� 2005 Blackwell Publishing Ltd, Aliment Pharmacol Ther 22, 685–700

The recent dramatic increase in the number of TB

cases globally is linked to the HIV/AIDS pandemic.24

About 9% of all new TB cases (31% in Africa) in adults

were attributable to HIV/AIDS.24 TB accounts for about

13% of all HIV-related deaths worldwide.24, 25

The incidence of extrapulmonary TB in Unites States

over a 5-year period has risen to 20% compared with

the incidence of 3% for pulmonary TB.26 Of the

5.1 million HIV patients in India, about half of them

are co-infected with TB.27 In India, it is estimated that

15–20% of all TB cases are extrapulmonary in site

amongst the HIV-negative adult population.28 Simi-

larly, Saudi Arabia reported increasing rates of extra-

pulmonary TB (abdominal TB 16%) from 1993 at

which point the incidence was 1.7 cases per 100 000

population, to 4.7 cases in 1997. During the same time

frame, reported pulmonary TB was decreasing.29

PATHOGENESIS

Infection of the peritoneum is usually secondary to

haematogenous spread of tubercles from a pulmonary

focus. Although an abnormal chest X-ray (CXR) is

frequently seen, however coexistent active pulmonary

disease is rare30 (Table 2). Spread of the mycobacteria

may rarely occur from lesions in the adjacent organs

such as the intestine or the fallopian tubes. Intestinal TB

occurs as a result of ingesting contaminated milk or

from swallowing the sputum of active lung disease.31

Alcoholic liver disease is a significant risk factor of

developing TBP.10–12 Shakil et al. found that alcohol

was the underlying cause in 90% of patients with

cirrhosis who developed TBP.10 The mechanism behind

the increased susceptibility of ALD patients to this

disease remains unknown. Unlike spontaneous bacterial

peritonitis, factors such as impaired opsonization,

complement deficiency, low immunoglobulin levels in

the ascitic and low serum albumin level do not appear

to explain the onset of TBP, which is related to impaired

cell-mediated immunity. Also, there is no evidence to

suggests that the impaired humoral immunity of

cirrhosis would play any role in the evolution of this

opportunistic infection. Theoretically, the presence of

stagnant ascitic fluid could potentially predispose to the

onset of opportunistic infections, as might be the case

with patients on CAPD. Against that is the fact that

cellular immunity is impaired in patients with uraemia

and this would be a likely explanation for the increased

susceptibility to TB. Tuberculosis is more common in

haemodialysis patients than in patients undergoing

CAPD (28% vs. 4.8%),13, 32, 33 which further negates

the hypothesis that the stagnant ascitic fluid is a

significant risk factor of TBP.

Malnutrition frequently develops in cirrhotic patients

and is more prominent in patients ALD due to a number

of reasons. Previous studies have documented the

poorer nutritional health of patients with ALD in

comparison with non-alcoholics.34 Additionally, these

patients demonstrate cutaneous anergy to a variety of

antigens, suggesting impaired T cell-dependent func-

tions, and this immune defect is again more commonly

seen in ALD compared with cirrhosis from other

causes.35 Therefore, it is likely that an interaction

between immunological dysfunction and malnutrition

produces the higher prevalence of TBP in patients with

cirrhosis.

The HIV infection is the strongest of all known risk

factors for the development of TB. HIV patients have

impaired Th1 type immune response, a crucial defence

against Mycobacterium tuberculosis.36, 37 The interaction

between TB and HIV is synergistic. The relative risk of

death and development of other opportunistic infections

is higher in the HIV–TB co-infected patients when

compared with CD4+ count-matched HIV-infected

controls without TB.38

CLINICAL MANIFESTATIONS

TBP is a subacute disease and its symptoms evolve over

a period of several weeks to months. Presence of

comorbid conditions such as cirrhosis result in atypical

presentations that may lead to delayed diagnosis.

Elderly patients with TBP may manifest minimal

constitutional symptoms, which again might cause a

delay in the diagnosis. The disease can present in three

different forms which are: the wet-ascitic, fibrotic-fixed

and the dry-plastic form.39 They have similar clinical

manifestations except for abdominal distension which

does not occur in the dry-plastic form. A considerable

degree of overlap does occur, whereby more than one

form may coexist. The clinical features of this illness

from 35 different studies of TBP have been tabulated

and presented in Table 1. Systemic and constitutional

symptoms are common. Low-grade fever occurs in

about 59% of the cases and it is usually accompanied by

night sweats. Patients may not report fever and in 49%

of the cases it is only documented during hospitaliza-

tion.7, 11, 40 Other systemic features of the disease

SYSTEMATIC REVIEW: TUBERCULOUS PERITONITIS 687


include weight loss, anorexia and malaise. The super-

imposition of this illness on other chronic conditions-

like uraemia, cirrhosis and AIDS make these symptoms

more difficult to quantify. Weight loss is seen in about

61% of cases and investigators have reported reversi-

bility of this manifestation as one of the markers of

disease resolution.7

Abdominal pain is a common presenting symptom and

frequently accompanied by abdominal distension. It is

usually non-localized and vague in nature. The pain is

largely due to the tuberculous inflammation of the

peritoneum and mesentery. Less often, it could be a

manifestation of intermittent subacute intestinal

obstruction, a result of matted bowel loops caused by

adhesions of the mesentery and omentum. The matted

bowel loops could be felt as palpable masses on

abdominal examination. Abdominal symptoms such as

vomiting, diarrhoea and constipation are uncommon.

The pathophysiology of diarrhoea is unknown and it is

very unlikely to be due to direct intestinal involvement

as TBP rarely occurs simultaneously with tuberculous

enteritis.1, 11, 41 Khuroo and Khuroo42 suggested that

the stagnation in dilated segments of intestinal loops

caused by adhesions between mesentery and small

bowel may result in small bowel bacterial overgrowth.

The evidence for this plausible mechanism is however,

not yet available.

Tenderness on palpation is common in TBP and occurs

in almost 48% of the cases and this might help in

differentiating it from spontaneous bacterial perito-

nitis, which complicates portal hypertensive ascites.43

Rebound tenderness is rare as the presence of ascitic

fluid prevents approximation of the parietal with the

visceral peritoneum.

Ascites is the predominant finding and it is present in

about 73% of the patients. A smaller percentage of

patients (5–13%) present with the classical ‘doughy’

abdomen. This is described as the dry or plastic type of

TBP and the patients have very little ascites, which can

only be detected by ultrasonography or during laparos-

copy.39, 44 The ascitic fluid is usually straw coloured, and

although red blood cells are frequently seen on micro-

scopic examination, however, frank haemorrhagic fluid

is seen only in 9% of the cases.21 The dialysate fluid of

patients on CAPD becomes cloudy upon infection with

TBP and this could be the earliest sign of the infection.

Interestingly, from the cumulative data of six large series

compiled by Marshall, it evolved that in 18% of patients,

ascites was detected primarily by radiological means or at

the time of surgery.30 The inaccuracy of detecting ascites

combined with the vague nature of the abdominal pain

and the paucity of other abdominal signs may errone-

ously cause the condition to be mislabelled as a mental

illness. Therefore, a high index of suspicion is required in

diagnosing these patients and a liberal utilization of

imaging studies may be warranted.

An enlarged liver or splenomegaly is uncommon

(Table 1), and presence of hepatomegaly suggests a

direct involvement of the liver.7 Splenomegaly is likely

to reflect presence of portal hypertension. Hepato-

splenomegaly is common in patients with an underlying

ALD except in advanced cirrhosis which results in a

shrunken liver.10, 11, 40

DIAGNOSIS

The insidious nature of this disease makes the diagnosis

a clinical challenge. With the ever-increasing demogra-

phic shift, more cases are now seen in areas of the world

where TB was a rarity. Unless a high degree of suspicion

is maintained, the diagnosis can easily be missed or

inappropriately delayed. The indolent nature of this

Table 1. Cumulative data of clinical features compiled from 35 studies of tuberculous peritonitis (TBP)

Clinical feature Number of cases Average (%)

Abdominal pain 12841, 7, 11–13, 15, 20–23, 39–41, 44, 45, 47, 51, 52, 60, 94–104 64.5

Fever 13931, 7, 10–13, 20–23, 40, 41, 44, 45, 47, 51, 52, 60, 94–105 59

Weight loss 7741, 7, 10–13, 20–23, 39–41, 51, 52, 95–99, 106 61

Diarrhoea 6301, 7, 11, 12, 21, 23, 40, 94, 96, 98, 104 21.4

Constipation 31911, 12, 21, 40, 47 11

Ascites 14051, 7, 10–12, 15, 20–23, 39, 40, 41, 44, 45, 47, 51, 52, 94–105, 107 73

Abdominaltenderness 3297, 11, 12, 20, 22, 40, 94–96 47.7

Hepatomegaly 3197, 10–12, 20, 39, 40, 95, 103 28.2

Splenomegaly 18910, 11, 39, 40, 52, 103 14.3



disease was illustrated by the recent case series, which

consistently reported a prolonged period of symptoms

before the diagnosis was established.13, 45–47 In areas of

high prevalence, it is a routine practice to screen for

Mycobacterium by the special staining and culture of

the ascitic fluid. It would be impractical to perform

this test routinely in areas of the world where TBP is

rare except of course in cases where TB is considered

in the differential diagnosis. The reported incidence

of TBP as a cause for ascites is only 2%.48 However,

the index of suspicion should be high if the patient

has lived or traveled from an endemic area. The same

applies for patients with ALD and those who are

immunosuppressed or undergoing CAPD. Patients with

ascites who have an abnormal CXR or had prior

exposure to open TB should also be screened for

TB.17, 40 The sensitivity patterns of various tests used

to diagnose TBP have been compiled in a tabulated form

based on the cumulative data of 39 series.

Laboratory investigations

Haematological indices. Changes of haematological indi-

ces are non-specific and therefore of little diagnostic

yield. Mild to moderate normochromic, normocytic

anaemia and thrombocytosis are frequent find-

ings.10, 21, 30 The white cell count (WBC) is usually

normal but, lymphomonocytosis is not uncommon.11, 21

The erythrocyte sedimentation rate is almost always

raised but in at least 50% of the cases, the values do not

exceed 60 mm/h.21 Raising the cut-off value does not

alter the specificity of this test as patients with ascites in

general may have similarly raised values.

Ascitic fluid analysis. Ascitic fluid analysis is routinely

performed in evaluating all patients presenting with

ascites. The WBC in TBP varies widely ranging from

counts of <100 cells/mm3 to as high as 5000 cells/

mm3.10, 13 Most patients however, have cell counts

between 500 and 1500 cells/mm3. The cells are

predominantly lymphocytes with the possible exception

of patients with underlying renal failure where, for

unknown reasons, the cells are mostly neutrophils.13, 49

As such, the possibility of TBP cannot be negated in the

presence of a neutrophil-predominant ascitic fluid. The

cumulative data from 13 series of TBP reviewed by us

(Table 2) showed lymphocytic predominance in 68% of

patients. A lymphocytic predominance may also be seen

in portal hypertensive ascites at the end of diuresis or

immediately after antibiotic therapy in previously

unrecognized spontaneous bacterial peritonitis. The

presence of lymphomonocytic ascites therefore is not a

reliable marker for TB and should be considered merely

as an indication for further investigations.

Ascitic fluid biochemistry. Ascitic glucose values is repor-

ted to be slightly low in some studies10, 11 however, there

is no sufficient evidence to support routine ascitic fluid

glucose measurement in patients with suspected TBP.

Ascitic lactate dehydrogenase (LDH) has been reported to

be high in some studies. The ascitic fluid concentration of

LDH is usually less than half of the serum level in

Table 2. Sensitivity patterns of various diagnostic tests from the cumulative data of 39 studies of TBP

Diagnostic

test

Sensitivity

(%) Remarks

Abnormal CXR 38 1002 patients with TBP1, 10–13, 20–22, 39–41, 44, 45, 47, 51, 52, 60, 94–96, 98–101

Positive PPD 53.16 380 patients studied;10, 11, 20–22, 39, 40, 51, 52, 96 authors used various induration sizes for positivity

Ascitic fluid tests

Predominant lymph 68.34 477 patients;10, 11, 13, 20, 23, 40, 41, 44, 45, 47, 51, 61, 96 investigators had differing definitions

for predominance

LDH 77 87 patients;10, 11, 51, 52 investigators used varying LDH range

ADA (>30 U/L) 94 1305 patients studied; 205 with TBP11, 39, 61, 62, 108–114 Hillebrand et al.61 used >7 U/L as cut-off

Smear 2.93 615 patients1, 10–13, 20–23, 41, 47, 51, 52, 95, 100, 101, 103, 104, 114–118

Culture 34.75 446 patients;1, 10–13, 20, 22, 23, 51, 52, 85, 95, 96, 99–101, 103, 104, 114–116, 118 studies using

BACTEC radiometric system not included

Laparoscopy

Visual diagnosis 92.7 397 patients;10, 20, 21, 23, 39, 51, 119–122 most series did not report specificity

Histology 93 402 patients;10, 20–23, 39, 51, 96, 119–121 patients with intent-to-biopsy included

TBP, tuberculous peritonitis; CXR, chest X-ray; LDH, lactate dehydrogenase; ADA, adenosine deaminase.



uncomplicated cirrhotic ascites. In infection, including

TBP, the ascitic fluid LDH level rises because of the release

of LDH from neutrophils. Shakil et al.10 showed that

raised LDH above 90 U/L carries a sensitivity of 90% and

a specificity of 14% for TBP. Such high degree of

sensitivity was not reproduced by another similar

study.11 Data tabulated by us from four different studies

(Table 2) suggest a sensitivity of 77% for LDH. Raised

ascitic LDH with similar degrees of sensitivity also occur

in patients with peritoneal carcinomatosis, pancreatic

ascites and about 20% of those with cirrhosis or

congestive cardiac failure.50 It does appear therefore that

ascitic LDH measurement is not of discriminatory value

and should not necessary be used routinely.

Ascitic fluid proteins. Ascitic fluid total protein levels

>25 g/L is seen in almost 100% of patients with iso-

lated TBP. However, the sensitivity of this test is

significantly reduced (42–70%) when TBP complicates

cirrhosis.10, 11, 51, 52 Ascitic fluid total protein >25 g/L is

found in 100% of nephrogenous ascites,53 22% of

cirrhotics, almost 100% of cardiac ascites50, 54 and 95%

of peritoneal carcinomatosis.54 The serum-ascites albu-

min gradient (SAAG) has more diagnostic yield than

ascitic fluid total protein measurement.50 It is calculated

by measuring both serum and ascitic fluid albumin on

the same day and subtracting the ascitic albumin from

the serum one. A low SAAG (<11 g/L) is seen in 100%

of patients with TBP, although the specificity remains

low.10, 51, 52, 54 Moreover, the sensitivity is greatly

reduced (29–88%) when TBP complicates chronic liver

disease leading to further diagnostic confusion.10, 51

The main advantage of calculating the SAAG is in its

specificity for portal hypertension induced ascites. SAAG

of 11 g/L or greater indicates portal hypertension with

97% of accuracy.54 This is of great significance as

majority of ascites is due to portal hypertension and

therefore specific investigation for other aetiologies such

as TB could be applied to a small group of patients with

unexplained ascites.

Elevation of CA-125 has been documented in the

majority of patients with TBP and created consider-

able confusion by mimicking advanced ovarian carci-

noma.15, 52 Subsequently, this test was recommended

as an indirect marker for TBP. Recent reports have

shown that serum and ascitic CA-125 levels are

elevated in almost all patients with ascites regardless

of the underlying cause.55–57 Patients commenced on

antituberculous treatment have shown rapid falls in

CA-125 levels paralleling clinical response and reso-

lution of ascites. Based on the available evidence, this

test does not seem to offer any particular advantage

in the diagnosis of TBP.

Microbiological diagnosis

Ziehl–Neelsen (ZN) staining of the ascitic fluid for

mycobacterial detection is positive in only about 3% of

cases with proven TBP (Table 2). To allow for the

detection of mycobacteria in stained smears, presence of

at least 5000 bacilli/mL of specimen is required,

whereas for positive culture as few as 10 organisms

might be sufficient for the diagnosis.58, 59 The current

‘gold standard’ for the diagnosis of TB entails culturing

the mycobacteria from clinical specimens. Culture

methods based on a combination of liquid or biphasic

media, together with solid media, are used to ensure

maximum sensitivity of detection. Studies reporting on

the microbiological diagnosis have used varied report-

ing methodology. While most have reported on the

regular method of culturing 10–50 mL of ascitic fluid,

others have recommended culturing 1 L of centrifuged

fluid. This is based on the above principle of increasing

yield by increasing the concentration of the bacilli.

Culture of the fluid by the regular method is positive in

35% based on our cumulative data comprising of 446

patients from 22 case series (Table 2), although the

yield has been shown to significantly improve (66–83%)

when 1 L of fluid is centrifuged and then cultured,

either by traditional culture media or the BACTEC

system.41, 47, 60 In clinical practice this is not practical

as the biggest available aliquots for centrifugation have

a capacity of 50 mL. This problem is further compoun-

ded by the 4–8 weeks requirement by the conventional

culture media. The recently introduced BACTEC radio-

metric system is a rapid method for detecting mycobac-

teria in clinical specimens, with a mean time to

detection of 14 days, and can be used to complement

conventional methods.47 A further 7 days are required

for drug susceptibility testing. Other newer methods of

identifying mycobacteria isolates include liquid chro-

matography and DNA probes for which the typical

turnaround time for confirmation is 21 days. Although,

the concept of culturing a litre of centrifuged ascitic fluid

is attractive, it may not be feasible in the regular clinical

setting. Hence, at least in resource-rich settings, the

BACTEC radiometric system should be made available

in routine clinical practice.



New diagnostic tools

Adenosine deaminase. With the persisting diagnostic

difficulties surrounding TBP, there has been an ongoing

search for alternative rapid and non-invasive tests.

Amongst these, adenosine deaminase (ADA) activity in

the ascitic fluid has been studied the most. ADA is an

aminohydrolase that converts adenosine to inosine and

its activity is more in T than in B lymphocytes, this

being proportional to the degree of T-cell differentiation.

ADA is increased in tuberculous ascitic fluid because of

the stimulation of T cells by the mycobacterial antigens.

Sensitivity and specificity levels over 90% have been

reported (Table 2) with the exception of a study by

Hillebrand et al.61 who reported a sensitivity of 59%.

They postulated that their lower sensitivity may have

been related to the higher incidence of cirrhosis in their

group of patients. These observations were countered by

Burgess et al.62 when they evaluated cirrhotic patients

with TBP in their study and reported a sensitivity of

94%, comparable with the findings of previous studies.

This study also demonstrated that raising the ADA level

above 30 U/L did not affect either the sensitivity or the

diagnostic efficiency of this test. At present, an ascitic

ADA activity of ‡30 U/L is generally accepted as the

cut-off level expected to yield the best results. Given its

high rate of diagnostic accuracy and easy availability,

we do recommend increasing the utilization of this test

in the diagnostic work-up of patients with suspected

TBP.

Gene amplification. Another technological advancement

has been the introduction of rapid amplification-based

tests for detecting specific regions of bacterial DNA or

RNA. The polymerase chain reaction (PCR) is a

technique that uses nucleic acid amplification to detect

M. tuberculosis in body tissues. Reports suggest that the

performance of the various PCR tests is reasonably

good with sensitivity reaching up to 95% in smear-

positive patients. The same success has not been

duplicated in smear-negative patients and the sensitiv-

ity attained has been disappointingly low (48%).63 As

the ZN stain in patients with TBP is positive in only

3%, these figures suggest that PCR sensitivity would be

similarly very low. To date, excluding a few case

reports there are no controlled studies of PCR in

patients with TBP.64–66 The issue of false-positives as a

result of cross-contamination of samples has raised

concerns of over-diagnosing TB in areas of endemicity.

Samples from sites with a possible latent infection

focus or DNA from dead bacilli may also give a positive

reaction.

The ligase chain reaction (LCR) DNA amplification

method has recently been introduced into practice. This

assay has been shown to provide valuable and rapid

information for the diagnosis of extrapulmonary TB and

with a higher diagnostic accuracy than PCR.67 Further

studies are needed to determine the clinical use of PCR

and/or LCR in the diagnosis of TBP. The cost of utilizing

these techniques will be another major issue to consider

particularly in poor countries where TB is endemic.

Immunodiagnostic tests. The search for reliable, repro-

ducible and specific serological tests for the diagnosis of

TBP has been an area of active research for many years.

Various antigens have been targeted in numerous

studies, however few have dealt with the issue of TBP.

In a South African study dealing with active disease, an

enzyme-linked immunosorbent assay to detect IgG to a

43 kDa antigen of M. tuberculosis found it to be highly

sensitive (approaching 100%) and 97% specific for

pleural and ascitic fluids.68 In another report from

India, the seropositivity of the IgA and IgG antibody

directed against A60 antigen was 88.4% in active

gastrointestinal TB.69 However, it is unclear from the

methodology if any of these 26 patients had TBP. High

IFN-c levels in tuberculous ascites have been reported to

be useful diagnostically.70 Although such assays hold

great potential, concerns remain regarding costs, low

positive predictive value and the ability to distinguish

from atypical mycobacterial infection.

Tuberculin skin test

The utilization of tuberculin skin testing has become

controversial and perhaps redundant. Various studies

from different parts of the world have reported positivity

rates ranging between 24 and 100%, and averaging at

53% based on the reported figures of 10 studies (Table 2).

A breakdown along demographic lines of high and low

endemicity areas did not reveal any differences in these

rates. Surprisingly, studies arising from the same regions

have revealed vast differences in their rates of positivi-

ty.20, 51, 52 Possible explanations for this may be linked to

the method of testing, strength of the reagent utilized and

the methodology of interpretation by the investigators in

different studies. Unfortunately, none of these study offer

any of these details. Generally, about 47%of patientswith



TBP would have false-negative reactions to tuberculin

skin testing.

As the tuberculin skin test has many potential sources

of error and variability, it has become imperative to

standardize the reagent, reading of the test itself, and

the interpretations derived. Recent recommendations by

the American Thoracic Society and the US Centers for

Disease Control and Prevention have placed the cut

point for the induration for those at low risk at 15 mm;

in people at moderate risk the cut point is 10 mm and

those at high risk the cut point is 5 mm.71 Additionally,

the issue of tuberculin testing has shifted away from

detecting active TB to one of screening for latent

infection. Some studies dealing with TBP have

addressed the issue of anergy testing reported to be

positive in about 9% of the cases.10 Anergy testing was

proposed initially to measure the overall ability to

mount a delayed-type hypersensitivity response. How-

ever, anergy testing as a routine adjunct to tuberculin

testing is no longer recommended as it may yield

misleading information.

Despite the high specificity of this test (between 95 and

99%), the low sensitivity, and the low positive predictive

value of 50–67% should obviate the clinician from

placing undue importance to this test.72 Skin testing is

now consigned to detecting latent infection and there

are no recommendations for using this test to diagnose

active disease like TBP. Diagnosis of TB is a clinical

responsibility and tuberculin skin testing, at best, offers

only auxiliary support.

A major scientific advance in detecting latent infection

has been the development of an IFN-c-based test which

yielded a sensitivity of 89%.19 Interferon-c test is a

quantitative in vitro assay that evaluates the cell-

mediated immune response to M. tuberculosis. The test

is based upon the principle that previously sensitized T

lymphocytes release IFN-c in response to stimulation by

purified protein derivative (PPD). This assay has been

shown to have excellent agreement with tuberculin skin

testing. A novel assay that is not widely available, it

measures the amount of IFN-c released by T lympho-

cytes following exposure to the antigen ESAT-6 (nor-

mally absent in BCG) and may be useful for diagnosing

latent TB in patients previously vaccinated with BCG.

Imaging studies

Various studies have reported an abnormal CXR in

19–83% of cases averaging to about 38% based on our

cumulative data of over 1000 patients (Table 2). Active

concomitant pulmonary disease however, occurs in

only 14% of patients.30 Although TBP represents one of

the disseminated forms of TB, miliary shadowing is

rarely seen or even reported in the literature. Aguado

et al.,11 found miliary mottling in only one patient out of

20 who had an abnormal CXR.

Ultrasound (US) changes include echogenic debris seen

as fine mobile strands or particulate matter within the

ascitic fluid. Calcifications in the walls of encysted

ascitic fluid are rare and when present, could be

detected by US imaging.73–76

The ascitic fluid has high attenuation values on

computerized tomographic (CT) imaging (20–45 HU).

The peritoneum is commonly thickened and nodular

(Figure 1).73, 75, 77 The fibrotic-fixed type of TBP is

characterized by a hypervascular peritoneum, matting

of the loops, and omental masses. CT seems more

capable of delineating omental changes which occur

in 36–82% of cases.74, 75, 77–80 Thickened mesentery

(>15 mm) with mesenteric lymph nodes is seen in

most cases and this combination may be an early sign

of abdominal TB.81 Loss of normal mesenteric confi-

guration is better demonstrated by CT scan.74, 75, 77, 80

Several studies have compared US and CT findings

in TBP and found them to be complementary to each

other as they provide different information. US is

superior to CT in revealing the multiple, fine, mobile

septations characteristically found in TBP, while CT

can highlight the peritoneal, mesenteric or omental

involvement.75, 82 Ha et al.80 reported 69% sensitivity

in the diagnosis of TBP by CT scan. On the contrary,

another group analysed retrospectively the CT images

of their TBP patients over a 3-year period and found

that the disease had been missed in all cases.83 The

CT abnormalities described above might be seen in

other diseases with peritoneal infiltration notably

peritoneal carcinomatosis. The presence of a smooth

peritoneum with minimal thickening and pronounced

enhancement on CT suggests TBP, whereas nodular

implants and irregular peritoneal thickening suggests

carcinomatosis.

Imagining modalities are increasingly used to help in

obtaining peritoneal biopsies. They provide a safer and

inexpensive alternative to diagnostic laparoscopy. Ear-

lier reports had suggested limited diagnostic sensitiv-

ity59, 83 but a recent report by Vardareli et al.

demonstrated a high diagnostic yield approaching

95% and without any complications.52 This is of vital



importance for centres with limited laparoscopic avail-

ability or expertise.84

Laparoscopy

Laparoscopy is the diagnostic tool of choice in patients

with suspected TBP. Not only does it allows inspection

of the peritoneum but also offers the option of obtaining

specimens for histology. The well-described laparoscopic

appearance by Bhargava et al.39 classifies it into three

types: thickened, hyperaemic peritoneum with ascites

and whitish miliary nodules (<5 mm) scattered over the

parietal peritoneum (Figure 2), omentum and bowel

loops (66%); thickened and hyperaemic peritoneum

with ascites and adhesions (21%); markedly thickened

parietal peritoneum with possibly yellowish nodules and

cheesy material along with multiple thickened adhe-

sions (fibro-adhesive type – 13%). The diagnostic yield

of laparoscopic examination is very high with a

sensitivity of the macroscopic appearances approaching

93%. The cumulative data of 402 patients from 11

studies (Table 2) showed impressive sensitivity and

specificity rates of 93% and 98% respectively when

the macroscopic appearances are combined with the

histological findings (epitheliod granulomata with case-

ation or mycobacterial identification).

Peritoneal biopsies should always be examined when-

ever possible for culture and sensitivity. It is the gold

standard test that provides diagnostic accuracy and

helps in optimizing the selection of the anti-TB

therapy. Surprisingly, few studies from the ones that

we reviewed did report results of mycobacterial culture

on specimens obtained at laparoscopy. ZN stain was

positive 3–25%10, 11, 39 while the yield of culture

sensitivity was between 38 and 92%.10, 39, 85

Peritoneal carcinomatosis, sarcoidosis, starch perito-

nitis and Crohn’s disease may occasionally mimic the

laparoscopic features of TBP, hence the importance of

taking biopsies. Granulomatous changes might be seen

in sarcoidosis or Crohn’s disease, however presence of

caseating changes would support the diagnosis of TB.

Complications of laparoscopy are rare, seen in <3% of

cases including bleeding, infection and bowel perfora-

tion. The reported mortality is up to 0.04%.86–88 The

procedure requires expertise and should only be per-

formed by competent surgeons. Moreover, this proce-

dure requires hospitalization and is more expensive

than image-guided peritoneal biopsy.

Failure to obtain tissue for microbiological or histolog-

ical assessment should not deter us from initiating

treatment as studies have consistently reported a

specificity in excess of 96% on the laparoscopic

appearance alone.17 At present there are no random-

ized-controlled trials comparing image guided biopsy,

laparoscopy and laparotomy; and the high number of

patients required would make such a trial unlikely

in the near future. We believe that laparotomy is

unnecessary and is only considered for patients with the

Figure 1. A computerized tomographic

(CT) image of a 34-year-old male with fever

and abdominal pain showing a thickened

peritoneum (arrow) with mild ascites. His-

tology was consistent with tuberculous

peritonitis (TBP).



fibro-adhesive type of TBP when there is an indication

for a peritoneal biopsy. Although the ideal diagnostic

test requires the demonstration of mycobacteria, how-

ever, the characteristic laparoscopic appearance itself,

even in the absence of bacteriological confirmation,

would be sufficient grounds for the diagnosis of TBP.

TREATMENT

The treatment of TBP is solely pharmacological. The

available data strongly suggest that regimens, which

are curative for pulmonary TB, are also sufficient for

TBP. There are currently five drugs that are considered

first-line medications: isoniazid (INH), rifampicin (RIF),

pyrazinamide (PZA), ethambutol (EMB) and streptomy-

cin (SM). Thiacetazone is widely used in the developing

world because of its low cost, but has substantial

toxicity and limited efficacy. In most circumstances, the

treatment regimen for adult patients with previously

untreated TB should consist of a 2-month initial phase

of INH, RIF, PZA and EMB given on a daily basis. This is

followed by a continuation phase where INH and RIF

are again given on a daily basis for another 4 months.89

There are various second-line drugs-like rifabutin,

fluoroquinolones, ethionamide, aminosalicylic acid and

cycloserine. The treatment of TBP in HIV-infected adults

is the same as that of HIV-uninfected patients, except for

the INH-rifapentine once weekly, continuation phase

which is contraindicated because of high relapse

rates.89 However, because HIV-infected patients are

often taking multiple medications, some of which may

interact with antituberculous ones, it is strongly

encouraged that experts in the treatment of HIV-related

TB be consulted.

Response to therapy is manifested by resolution of

symptoms and disappearance of ascites. All laboratory-

based tests of disease activity return to normal values,

usually within 3 months of treatment initiation. The

rate of drug resistance varies in different countries and

within different ethnic or regional denominations.

Overall primary resistance rates to standard first-line

medications in low prevalence areas tends to be below

5%, whereas multidrug resistance rates as high as 48%

have been described in high prevalence areas such as

Nepal.90 Drug resistance occurs usually when there is a

large bacillary population, or when an inadequate drug

regimen is prescribed. It also occurs as a result of

malabsorption of the antituberculous drug(s). As the

type of drugs used in resistant forms need to be modified

(along with an extension of the duration of treatment),

conducting drug sensitivities to the organism is essen-

tial. This should not forestall initiation of treatment

because the drugs can be modified as the sensitivity

patterns become available. In the presence of resistance

to first-line therapy, a single drug should not be added to

the failing regimen. Revising therapy in such instances

should be attempted with at least three unused drugs

(one of whom is injectable) to which there is in vitro

Figure 2. Laparoscopic image of an 18-

year-old girl with fever and ascites showing

multiple whitish nodules (<5 mm) covering

the peritoneum. The biopsy was consistent

with caseating granuloma and acid-fast

bacilli (courtesy: N. Azzam and

A. K. Al-Aska).



susceptibility. Usage of drugs with demonstrated in vitro

resistance is not encouraged. It is also preferable to use

hospital-based or directly observed therapy.89

Delay in treatment initiation can lead to significant

mortality. Chow et al.47 reported a considerable deteri-

oration in clinical condition of more than 80% of

patients during the diagnostic work-up. The overall

mortality in this study was 35%, while in the subset of

patients with underlying cirrhosis was 73%. Average

mortality from the cumulative data of 18 series

comprising of more than 800 patients was 19%.17

Although, current recommendation for treatment dur-

ation in TBP is only for 6 months, most reported studies

have given treatment for 12 months. There is however,

no evidence to support a recommendation of treatment

beyond 6 months. Some studies that used the 6- or

9-month regimen found almost all of their patients

responded equally to the treatment.51, 52 One study

compared different durations of treatment (9 months to

beyond 12 months) and found no difference in outcome

in either group.11 As such, 6 months of phased therapy

with the standard first line of antituberculous medica-

tions would be adequate for the treatment of TBP.

Role of corticosteroids

Corticosteroids reduce the polymorphonuclear inflam-

matory response, and decrease the peripheral blood

lymphocytes, monocytes, eosinophils and basophils. The

inflammatory fibrotic process of the disease results in

adhesions and subsequent intestinal obstruction.

Adjunctive steroids may offer benefit by minimizing

the inflammation and preventing the postinflammatory

fibrosis. Early trials showed that when corticosteroids

were given in combination with antituberculous med-

ications there was no progression of the TB.91 Over the

decades, this has prompted four trials of adjuvant

corticosteroids use in TBP and all of them cited modest

benefit.40, 51, 60, 85 Alrajhi et al.85 reported considerably

low morbidity and complications in those treated with

corticosteroids. There is a pending need for prospective,

well-controlled clinical trials with long-term follow-ups

to identify the category of patients most likely to benefit

from such therapy. Based on the limited data available,

it is presently difficult to make any firm recommenda-

tions regarding steroid use in TBP patients.

Drug-induced hepatotoxicity

One of the main concerns of clinicians in treating TB is

the hepatotoxic effect of the antituberculous drugs. The

risk is higher in patients with cirrhosis that is commonly

associated with TBP. Asymptomatic elevation of aspar-

tate transaminase (AST) occurs in 20% of patients with

the standard 4-drug regimen for pulmonary TB.92

According to recent recommendations by the American

Clinical features suggestive

IGPB

Histology conclusive

Histology inconclusive

Laparotomy

Anti-TB treatment

Lymphocyte dominant

SAAG <11 g/L

ADA < 30 IU/L

ADA > 30 IU/L

TB culture positive

TB culture negative

Laparoscopy

Appearancesuggestive; histology

inconclusive

Appearance suggestive; histology

conclusive

Ascites absentAscites present

Peritoneal disease (-)

Malignant cells positive

Neutrophildominant

Spontaneous bacterial peritonitis RxAscitic fluid

analysis

SAAG ≥11 g/L

Imaging Studies

Peritoneal disease (+)

Figure 3. Algorithm for evaluation of

patients with suspected tuberculous

peritonitis (TBP).



Thoracic Society, Centers for Disease Control and

Infectious Disease Society of America, in such situations

drug therapy need not be altered but the frequency

of clinical and laboratory monitoring should be

increased.89 Stoppage of treatment is recommended if

AST is elevated fivefolds; or threefolds in the presence of

symptoms.89 An increase in bilirubin or alkaline

phosphatase is also a serious adverse event. Restarting

treatment should be attempted when AST values are

less than twofolds and the drug to be introduced first is

RIF, followed by introductions of INH and PZA a week

apart. Asides from this, it is important to consider other

causes of impaired liver functions such as the pre-

existing liver disease or less commonly, direct dissem-

ination of TB to the liver.

Pre-existing liver disease

The treatment of TBP in patients with background liver

disease is problematic. The incidence of drug-induced

hepatitis may be greater and the implications of

hepatotoxicity for patients with cirrhosis are potentially

serious. One study of patients with TB and underlying

liver disease used INH, RIF, EMB and ofloxacin for

2 months followed by INH and RIF for 10 months and

found 0% hepatotoxicity in this group, while another

cohort utilizing a standard regimen developed hepato-

toxicity in 26%.93 The aforementioned recent recom-

mendations89 suggested using any of the following four

regimens in such a scenario.

1 RIF, PZA and EMB for 6 months.

2 INH, RIF, EMB for 2 months followed by INH and

RIF for another 7 months.

3 RIF, EMB, a fluoroquinolone, cycloserine/injectible

agents for 12–18 months.

4 EMB, SM, a fluoroquinolone and another second-line

oral drug.

CONCLUSION

Peritoneal TB remains a common problem in parts of

the world where TB is prevalent. The incidence

worldwide is likely to increase, largely as a consequence

of population migrations, increased immunosuppres-

sant therapy and the AIDS epidemic. Patients with

underlying cirrhosis particularly of alcoholic aetiology

are at higher risk of developing this infection. The risk is

also relatively higher in chronic renal failure patients on

CAPD. The diagnosis of this disease requires a high

index of suspicion because of the subtle nature of the

symptoms and signs. TBP should be considered in the

differential diagnosis of all patients presenting with a

lymphocytic ascites and those with a SAAG of <11 g/L.

Ascitic fluid analysis is non-specific and culture growth

of the Mycobacterium remains the ‘gold standard’ for

diagnosis. Ascitic ADA is a relatively new test with

excellent sensitivity and specificity patterns. Further

studies are needed to determine its role as a diagnostic

tool for TBP. Lately, the advent of molecular biology

techniques has led to the introduction of rapid amplifica-

tion-based tests like PCR and LCR. These are yet to be

tested in patients with TBP. The BACTEC radiometric

system for acceleration of mycobacterial identification

does increase the diagnostic yield and we recommend its

wider introduction in clinical practice. Ultrasound and CT

scan are increasingly used for the diagnosis of TBP and

could help in providing guided peritoneal biopsies. Lapar-

oscopy, however, remains the best means of diagnosing

the disease, either by visualization alone or in combination

with biopsy and histological examination. It should be

considered at an early stage whenever TBP is suspected.

It is essential to recognize that a combination of

different diagnostic tests is used in order to arrive at the

diagnosis of TBP. There is no single test that can

consistently yield a diagnosis by itself. Selective screen-

ing of ascitic fluid samples by more defining tests along

with laparoscopic visualization; or histological and

microbiological analysis of tissue obtained would be

required for definitive disease diagnosis in most cases.

The algorithm (Figure 3) outlines the suggested

investigational plan of patients with TBP.

Six months of treatment with the usual first-line

antituberculous drugs is considered sufficient in uncom-

plicated cases.

ACKNOWLEDGEMENT

The authors thank Drs MA Al-Karawi and Al-Barrak

for critically reviewing the manuscript.

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