Recognizing and addressing the challenges of gastrointestinal tuberculosis

Abstract

In this editorial, we comment on the article by Ali et al published in the recent issue of the World Journal of Clinical Cases. This case report shed light on a particularly rare manifestation of this disease-primary gastrointestinal tuberculosis (GTB) presenting as gastric outlet obstruction. GTB presents diagnostic challenges due to its nonspecific symptoms and lack of highly accurate diagnostic algorithms. This editorial synthesizes epidemiological data, risk factors, pathogenesis, clinical presentations, diagnostic methods, and therapies to raise awareness about GTB. GTB constitutes 1%-3% of all tuberculosis cases globally, with 6%-38% of patients also having pulmonary tuberculosis. Pathogenesis involves various modes of Mycobacterium tuberculosis complex entry into the gastrointestinal system, with the terminal ileum and ileocecal valve commonly affected. Clinical presentation varies, often resembling other intra-abdominal pathologies, necessitating a high index of suspicion. Diagnostic tools include a combination of biochemical, microbiological, radiological, and endoscopic assessments. Anti-tubercular medication remains the cornerstone of treatment, supplemented by surgical intervention in severe cases. Multidisciplinary management involving gastroenterologists, surgeons, pulmonologists, and infectious disease specialists is crucial for optimal outcomes. Despite advancements, timely diagnosis and management challenges persist, underscoring the need for continued research and collaboration in addressing primary GTB.

Key Words: Gastrointestinal tuberculosis, Tuberculosis, Infectious diseases, Diagnostic challenge, Mycobacterium

Core Tip: Gastrointestinal tuberculosis (GTB) poses diagnostic challenges due to nonspecific symptoms and lack of definitive tests. This editorial synthesizes epidemiological data, clinical challenges, diagnostic methods, and therapeutic approaches for GTB management. Despite advancements, delays in diagnosis lead to complications, emphasizing the need for heightened awareness and a multidisciplinary approach involving gastroenterologists, surgeons, and infectious disease specialists. Improved understanding and collaboration are essential for timely diagnosis and optimal treatment outcomes in primary GTB cases.

INTRODUCTION

Tuberculosis (TB) persists as a significant global health concern, representing one of the foremost contributors to illness and death on a worldwide scale. Its etiology lies in the infection by Mycobacterium tuberculosis complex (MTC) bacteria, encompassing strains such as M. tuberculosis and M. bovis[1]. Notably, approximately a quarter of the global populace has encountered the M. tuberculosis bacillus, carrying a lifetime risk ranging from 5% to 10% of transitioning from latent infection to active disease[2].

Gastrointestinal TB (GTB) is characterized including of any part of the digestive system and its related organs[2]. Most TB patients with intestinal involvement are asymptomatic. When patients become symptomatic, they have vague symptoms and are mostly nonspecific[3,4]. It has common features with many inflammatory and infectious diseases; complaints often become chronic and have a slow course. Also, diagnosing GTB is challenging due to the lack of a direct diagnostic test[5]. Research indicates that physicians entertained the diagnosis in fewer than 40% of patients upon their initial presentation[6,7]. The recent case report by Ali et al[8] shed light on an infrequent yet significant manifestation of this disease-primary GTB presenting as gastric outlet obstruction[8]. Delays in diagnosis, as in this case, lead to the development of complications, resulting in serious morbidity and mortality. Therefore, this editorial will focus on epidemiology, risk factors, pathogenesis, clinical presentation, diagnostic methods, and therapy to increase awareness about GTB and help clinicians diagnose.

EPIDEMIOLOGY AND RISK FACTORS

In 2021, it is estimated that 10.6 million patients worldwide infected with TB, which corresponds to approximately 134 cases per 100000 people. Geographically, the majority of cases were located in South-East Asia (45%), Africa (23%) and the Western Pacific (18%)[9]. The incidence of TB is high in low-income countries and causes serious health problems[9]. Accompanying factors of illiteracy and malnutrition also contribute to this situation[10]. Its incidence is higher in people with immunodeficiency[11]. In developing countries, the most common cause is human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome, and HIV infection can increase TB risk up to 30-fold[11-13]. In addition, with the increase in transportation opportunities and many migrations, these patients are also encountered in developed countries[9,12].

Approximately a quarter of the world's population is thought to be infected with TB, and 10%-15% of these are at risk of reactivation[2]. Solid organ transplantation increases the risk of TB by 20-fold[14], and the use of immunomodulatory drugs, especially anti-tumor necrosis factor-alpha (anti-TNF alpha)[15], are the most important risk factors in the reactivation of latent TB[12]. In regions with low TB incidence, such as the United States, most of active TB cases arise from the reactivation of latent TB[16]. So, in developed countries, reactivation of latent TB comes to the fore as a risk factor[17].

Extrapulmonary TB comprises approximately 12% of the total TB caseload, with gastrointestinal TB constituting approximately 1% to 3% of all TB cases globally[12]. Regional characteristics are the most important factor affecting this rate, and significant differences are observed according to geographical regions. For example, in a study conducted in Pakistan, 6.1% (3313/54092) of all TB cases were GTB, while in the USA, where TB is seen with a lower incidence, this rate was reported as 1.2% (140/11088)[17]. The most important reasons for this geographical difference are socioeconomic status, malnutrition, and the higher prevalence of untreated immunodeficiency syndrome[10,18]. Between 6% and 38% of patients with GTB may also have pulmonary TB[12]. Although there have been studies showing that extrapulmonary TB is more common in women[19], there has been no significant gender difference specific to GTB.

In an autopsy study conducted in Colombia, 4500 autopsy patients were evaluated, and 484 of these patients were histopathologically reported as having TB. Forty-eight of the patients were reported to have GTB[2]. Therefore, it is thought that there are more GTB patients than detected but not diagnosed. However, since the mid-20th century, GTB cases have started to decrease. The main reasons include pasteurization of milk, better living conditions, and advances in antibiotics[20].

PATHOGENESIS

MTC bacteria are the main microorganisms that cause GTB, and their evolution can occur in several ways. MTC can enter the gastrointestinal system (1) via the hematogenous spread of active foci of pulmonary or miliary TB; (2) ingestion of contaminated sputum in patients with pulmonary TB; (3) ingestion of contaminated food (mainly M. bovis in contaminated raw milk); and (4) contiguous spread from adjacent organs[5,21,22].

The terminal ileum and the ileocecal valve are frequently affected (44%-93%), attributed to several factors unique to this anatomical region[5]. These include a narrow luminal diameter, heightened physiological stasis facilitating bacterial absorption, minimal digestive activity, and the presence of specialized M cells within the lymphoid tissue, facilitating the uptake of tubercle bacilli[12,23].

The bactericidal properties of gastric acid, intact gastric mucosa, relative absence of lymphoid tissue and rapid transit time typically protect against gastric TB[12]. However, factors such as treatment with H2 blockers may predispose individuals to gastric involvement[24]. Pathological GTB can present in various forms, such as ulcerative, hypertrophic, or fibrotic manifestations. Upon invasion of the submucosa by Mycobacterium, a granulomatous inflammatory reaction characterized by vasculitis accompanied by thickening of the submucosal and serosal layers occurs. This cascade may accelerate ulceration, leading to perforation, or undergo healing through fibrotic processes. Scarring from ulcers can lead to diffuse narrowing, causing gastric outlet obstruction[25]. Complications resulting from these different forms manifest as hemorrhage, strictures resulting in obstruction, and perforations, including fistula formation[26].

CLINICAL PRESENTATION

Diagnosing GTB poses a significant challenge due to its propensity to present with nonspecific symptoms, lacking pathognomonic signs[23,27]. Family history of TB may be absent, and concomitant pulmonary TB or past medical history of TB may not be present in all cases[28]. Consequently, GTB should be considered even in the absence of a history of TB.

Patients usually have chronic complaints or chronic problems are accompanied by nonspecific acute complaints. The duration of onset of complaints before diagnosis varies but averages around eight weeks[11,29,30]. Common symptoms include recurrent epigastric pain, nausea, vomiting, weight loss, and changes in bowel habits[5,31]. However, some patients may remain asymptomatic[32]. On physical examination, pallor, anemia, rectal bleeding, abdominal distension and ascites, hepatosplenomegaly, lymphadenopathy, and abdominal mass can be detected[1,5,12]. These symptoms and findings can mimic many other intra-abdominal pathologies, leading to delays in diagnosis. As in the case of Ali et al[8], patients may also present with complaints caused by complications. Although the patient had complaints for a long time, he could not access effective treatment did not comply with empirically initiated antituberculosis treatment, and finally; when surgery was performed for gastric outlet obstruction, the definitive diagnosis was made with the pathology results[8]. Obstruction, perforation, fistula, abdominal collection-abscess, and gastrointestinal bleeding may also be observed due to complications[33].

CURRENT DIAGNOSTIC TOOLS

Diagnosing primary gastric TB requires a high index of suspicion and the use of various diagnostic modalities. A single test may rarely be sufficient to make the diagnosis. A combination of biochemistry and microbiological, radiological, and endoscopic results with the patient's history and physical examination can confirm the diagnosis.

Patients with GTB mainly have decreased hemoglobin and albumin levels, increased C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR)[12]. CRP, ESR, and fecal calprotectin can also be used in treatment monitoring[34]. Although the positivity of these tests is helpful in diagnosis, their negativity is insufficient to exclude the diagnosis[12]. Although these tests indicate inflammation, none are specific to TB and are usually not helpful in the differential diagnosis[35].

Mycobacterium-specific tests may help in the differential diagnosis[12]. Acid-fast stain, culture, nucleic acid amplification, quantitative, interferon gamma release assay, adenosine deaminase (ADA) measurements, mycobacterial cultures and polymerase chain reaction tests are some of these tests[1,16,17]. The availability of these tests and policies for requesting them are determined locally, and clinicians should be familiar with the capabilities of their health institution.

The World Health Organization recommends a test for the diagnosis of TB that amplifies genomic DNA with PCR testing, with results available within two hours[12]. This test also has a high specificity for extrapulmonary TB. In case of non-specific results, more invasive procedures may be required. Endoscopic biopsy and paracentesis of ascitic fluid (if present) help diagnose[36,37]. Cell counts and biochemistry tests from these clinical specimens are recommended. The advantages are that cell counts and biochemistry are inexpensive and can be completed within hours. However, its use can be limited by the need for invasive procedures to obtain the sample and the fact that not all patients have suspicious areas that can be sampled[38]. Depending on the capacity of the health institution, ADA and interferon-γ levels can also be measured from these samples. The sensitivity and specificity of these tests vary according to the threshold used. The Infectious Disease Society of America states that these tests can help the clinician but do not specify a clear cut-off value due to a lack of data[38]. Nucleic acid amplification tests and mycobacterial cultures have low false positive rates. Thus, with positive results, they can be used as evidence of extrapulmonary TB. However, it should be kept in mind that false negativity is insufficient to exclude the diagnosis, especially in extrapulmonary TB[38].

People diagnosed with TB on clinical and history basis without bacteriologic confirmation are classified as "clinically diagnosed" TB cases[9]. However, bacteriologic confirmation is necessary to diagnose correctly and provide the most effective treatment[9]. But in some cases, despite intensive efforts, it may not always be possible to confirm the diagnosis of TB[39]. When clinical suspicion is highly in favor of TB, empirical antituberculosis treatment is a valid diagnostic and therapeutic option and remains an established tool in clinical practice[17].

Radiologic imaging modalities do not generally provide definitive diagnostic information, but they may help in the diagnosis and may also help in the demonstration of complications[40]. For example, abdominal computed tomography (CT) scans can reveal gastric distension and wall thickening, but definitive diagnosis often relies on histopathological examination of gastroduodenal biopsy specimens obtained via endoscopy. CT scan has high specificity for identifying obstruction, perforations, fistulae, abscess collection, and the presence of ascites[40]. Other modalities, including endoscopic ultrasound and intraoperative fine-needle aspiration cytology, may aid in diagnosis[12,41,42].

TREATMENT

The treatment of primary gastric TB involves a multidisciplinary approach, including medical management with anti-tubercular medications and, in some cases, surgical intervention. Anti-tubercular medication therapy is the cornerstone of treatment, aiming to eradicate the infection and prevent disease progression the same as pulmonary TB. A standard therapy includes a four-drug regimen. Isoniazid, rifampicin, pyrazinamide, and ethambutol are used thrice weekly for the first two months. For the next four months, isoniazid and rifampicin are used, completing the treatment in six months. Often, this treatment has a high cure rate[43]. Clinical response should be evaluated after 2-3 months of treatment. In responding patients, drug treatment should be completed to six months, and an endoscopy should be performed to show mucosal healing[44]. In drug-resistant cases or in cases that worsen despite treatment, referral should be made to the reference hospital and laboratory[9]. Surgical intervention may be necessary in cases of severe complications such as gastric outlet obstruction, with procedures like gastrojejunostomy often performed to relieve obstruction and restore gastrointestinal function[45]. Similarly, in the case of Ali et al[8], antrectomy, roux-en-y reconstruction, and gastrojejunostomy were performed. In cases where the diagnosis has not been fully established, it is important to examine these pathological samples histopathologically with appropriate mycobacterial tests[8].

The case report also emphasizes the importance of multidisciplinary management in such cases. From initial presentation to surgical intervention and subsequent anti-tubercular treatment, a coordinated effort involving gastroenterologists, surgeons, pulmonologists, and infectious disease specialists is crucial for optimal patient outcomes.

CONCLUSION

The case report presented by Ali et al[8] highlights the complexities involved in diagnosing and managing primary gastric TB. As we strive to eliminate TB globally, it is essential to enhance awareness and understanding of this disease's diverse manifestations. Continued research and collaboration are vital in improving diagnostic strategies and treatment outcomes for patients with primary GTB.