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Adenosine Deaminase (ADA) in Peritoneal Tuberculosis

Adenosine Deaminase (ADA) in Peritoneal Tuberculosis


Tahiri Joutei Hassani Mohammed
Associate professor of gastroenterology
Medicine School of Casablanca – Hassan II University

Hliwa Wafaa
Professor of Gastroenterology
Medicine School of Casablanca – Hassan II University

Badre Wafaa
Professor of Gastroenterology
Medicine School of Casablanca – Hassan II University

Summary
Tuberculosis (TB) is a global public health issue. Peritoneal tuberculosis (PT) is the most common form of abdominal tuberculosis and leading cause of ascites in developing countries. PT has become a real concern in all countries because of the HIV epidemic. Peritoneal tuberculosis is more often seen in patients with advanced renal or liver disease. Although it is an invasive procedure, laparoscopy is still considered to be the gold standard for PT diagnosis. The diagnosis of peritoneal tuberculosis remains a real challenge because of the lack of non-invasive and reliable diagnostic tests. Nowadays, ascitic adenosine deaminase can be a good, non-invasive test for PT diagnosis.

Introduction
Tuberculosis (TB) is a global pandemic caused by Mycobacterium tuberculosis. Tuberculosis can involve all tissues and organs with a large spectrum.  Most TB localizations are pulmonary; however, extrapulmonary tuberculosis accounts for about 20 % of total cases 1. Extrapulmonary TB has increased worldwide due to many factors such as the HIV pandemic and malnutrition 2, 3. Abdominal TB is defined by the involvement of gastrointestinal tract and/or peritoneum and/or the mesenteric lymph nodes and it is the sixth most common extrapulmonary site in the United States 4.  HIV infection is a major risk factor for the development of TB 1.

Furthermore, patients with underlying end-stage renal disease and continuous ambulatory peritoneal dialysis (CAPD) are at risk to develop PT 5.

In Western countries alcoholic liver disease (ALD) seems to be is a significant risk factor of developing PT, whereas in developing countries underlying liver disease is not linked to increased incidence of PT 6, 7.

Peritoneal tuberculosis appears to be a consequence of hematogenous spread of Mycobacterium tuberculosis from a primary pulmonary site. Mycobacteria may rarely spread from adjacent organs such as the intestine or the fallopian tubes; ingesting contaminated food such as milk or swallowing the sputum of pulmonary TB can lead to intestinal tuberculosis 8.

Clinical features
Peritoneal tuberculosis is a real medical challenge because of its insidious and non-specific symptoms and the variability and paucity of its signs.  Unless there is a high index of suspicion, PT diagnosis can easily be delayed or even missed. PT mortality rate is high, ranging from 15 to 30% 9.   Delay in diagnosis is a major factor for the high mortality from TP 10.

There are many presentations that will make the diagnosis of this life threatening infectious disease difficult.

PT frequently occurs in patients with comorbid conditions such as renal failure or cirrhosis; this fact further adds to the diagnostic difficulty.  Three different forms of peritoneal tuberculosis are described: the wet-ascitic, fibrotic-fixed and the dry-plastic ones 11.  The wet-ascitic type is characterized by free or loculated ascites. The fibrotic-fixed type is characterized by abdominal masses composed of mesenteric and omental thickening. The dry-plastic type is characterized by dense adhesions, caseous nodules, and fibrous peritoneal reaction.

Ascites is a common finding except in dry-plastic form. Fever accompanied by night sweats usually occurs in PT whereas absence of fever should not exclude the diagnosis.  Weight loss, anorexia and malaise can be also noted in peritoneal tuberculosis.

Vague abdominal pain is a frequent symptom that can be accompanied by abdominal distension or intermittent subacute intestinal obstruction. Diarrhea or constipation are uncommon 12.

Tenderness on palpation, less often palpable masses, enlarged liver or splenomegaly can be detected by abdominal examination

Ascites is the usual finding. Yet, a small percentage of patients have only very mild ascites, which can only be detected by ultrasonography or during laparoscopy.

The diagnostic approaches
Changes of hematological indices including white cell count, erythrocyte sedimentation rate are non-specific. Usually in PT, the ascitic fluid is straw colored with protein >30g/L, and total cell count of 500-1500/ìl, the cells are predominantly lymphocytes (>70%). However, ascitic fluid total protein levels <25 g/L can be seen when PT complicates cirrhosis 6.  A low serum-ascites albumin gradient (<11 g/L) is seen in 100% of patients with PT but its specificity remains low.  Due to its low accuracy, ascitic LDH measurement is not used routinely 13.

The detection of MT in the ascites fluid is extremely insensitive and Mycobacterium detection is positive on smear in fewer than 3% of cases. A culture is positive in less than 20% of cases and takes 6 to 8 weeks. 14, 15. The polymerase chain reaction (PCR) test is another technique that has been introduced for detecting specific regions of bacterial genome; PCR detection of MTB from ascites fluid samples showed poor sensitivity 16.

An abnormal chest X-ray can be seen in about 38% of cases, however, coexistent active pulmonary disease is uncommon 14.  Ultrasonography can be very useful for PT diagnosis. Intra-abdominal fluid, which may be free or encysted, clear or with septae can be seen. In certain cases, only interloop ascites is noticed.  Additionally, discrete or matted lymphadenopathy may be concomitant. Abdominal CT scan can be more accurate in demonstrating peritoneal, mesenteric or omental involvement. Commonly, the peritoneum is thickened and nodular; thickened mesentery associated with mesenteric lymph nodes may be seen in early cases 17. All radiologic findings are nonspecific and cannot confirm the diagnosis. Laparoscopy, an invasive procedure and not exempt from complications, is usually considered as the gold standard for the diagnosis. Laparoscopy allows direct observation of the entire peritoneal space and allows peritoneal biopsies that can detect epithelioid granulomata with caseation. The peritoneal biopsies PCR showed higher diagnostic sensitivity compared to ascitic fluid 18.

Three categories of laparoscopic appearance can be seen in peritoneal tuberculosis: (i) thickened peritoneum with multiple, yellowish white, and uniform sized (4–5mm) tubercles scattered over the peritoneum; (ii) thickened peritoneum and adhesions; and (iii) markedly thickened peritoneum and multiple thick adhesions fixing intra-abdominal organs. Laparoscopy with combination of visual and histologic study has shown high sensitivity and specificity rates of 93% and 98% respectively 19. But, laparoscopy cannot be performed in approximately 14% of cases due to poor general condition or previous surgery with adhesions 20.

Furthermore, complications can occur in 2.6 to 6.5% of cases including bleeding, infection and intestinal perforation. And laparoscopy mortality can reach 5 % of cases 6, 18.

Moreover, laparoscopy requires a stay in the hospital. It is expensive and is not available in all hospitals in developing countries.  Therefore, it is critical to find alternative non-invasive, rapid accurate tests to diagnose PT. 

This brings us to usefulness of ascitic adenosine deaminase (ADA) determination for diagnosis of peritoneal tuberculosis. Among these tests adenosine deaminase (ADA) in the ascitic fluid has been widely studied.  ADA is an enzyme found in lymphocytes, erythrocytes, and in the cerebral cortex 21.  ADA is a purine-degrading enzyme that catalyzes the deamination of adenosine.  Inosine is the result of this reaction. Number, maturation, and stimulation of lymphocytes increase ADA activity in body fluids; thus, ADA activity is increased in body fluids in infections, in rheumatological diseases, and malignant lymphomas 21.

Thus, immune cellular response against Mycobacterium tuberculosis intensifies the stimulation and the maturation of lymphocyte and increases ADA levels.  In fact, many studies have investigated the diagnostic value of ascitic ADA for PT.  In a recent meta-analysis including seventeen studies and 1,797 patients, ascitic ADA determination pooled sensitivity and specificity were 0.93 and 0.94, respectively, for diagnosing PT indicating a high diagnostic accuracy. In this meta-analysis, the diagnostic accuracy was not affected by the study setting (low or high TB prevalence areas) and the ADA cut-off (>35 or <35 U/L) 22.

Former studies had concerns about ADA accuracy in cirrhotic patients 23.  But in more recent studies, ascitic ADA had sensitivity and specificity levels over 90% 24, 25.  Ascitic ADA levels can be influenced by HIV infection status, but even if adenosine deaminase levels in PT are lower in HIV positive patients compared to HIV negative patients, ADA still remains useful for PT diagnosis 26.  Even if ADA level as diagnostic criteria for PT is more sensitive than empirical antituberculous therapy 25, in many areas especially in those with high TB prevalence areas, treatment for PT still remains empirical and is only based on clinical judgment 24, 27.  When laparoscopy is not available, not affordable, and if patients are inoperable, ascitic ADA can be crucial to make a quick diagnosis and to start empirical antituberculosis drugs 28.  Otherwise, ADA can also orient the selection of patients who should have more invasive procedures such as laparoscopy.

Conclusion
PT is a real public health problem in endemic areas and remains a clinical challenge.  Ascitic ADA determination is an accurate, non-invasive, inexpensive, and rapid test that should be considered as a useful routine exam to indicate more invasive procedures such as laparoscopy.  ADA may be used in very selective cases as an alternative to laparoscopy.

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