Ascites is a common finding in patients with cirrhosis of the liver but is also associated with noncirrhotic conditions, such as tuberculosis (TB), malignancy, congestive heart failure, and bowel obstruction.

Case Presentation

A 50-year-old Hispanic man presented with progressive abdominal distension, generalized weakness, dyspnea on exertion, and anorexia associated with a 20-lb weight loss during a 3-month period. He reported that just before the onset of these symptoms, he had subjective fever, chills, night sweats, and a productive cough that resolved after a few days.

He was not taking any medications, denied alcohol abuse and intravenous drug use, and had never received a blood transfusion. He grew up in Mexico, where he said he might have been exposed to TB. He had migrated to central California and for a short period worked on a ranch, where he had direct contact with cattle known to be infected with Mycobacterium bovis. He had repeatedly ingested raw cow's milk, which later tested positive for M bovis.

The patient was not in distress, and his vital signs were stable. Physical examination of the chest revealed crackles at the left lung base. The abdomen was nontender but distended, with shifting dullness. Abdominal organs were nonpalpable. He had generalized muscle wasting. Peripheral examination revealed no jaundice.

Complete blood cell count, serum electrolytes, and creatinine level were normal. Liver function tests were normal, except for a low serum albumin (2.1 g/dL) and a slightly elevated prothrombin time (14.5 seconds; international normalized ratio, 1.2). Screening tests for HIV and hepatitis B and C infections were negative.

Chest x-ray and computed tomography (CT) scan revealed a left lower-lobe infiltrate, with no masses or lymphadenopathy. Sputum and blood cultures did not grow any organism. A purified protein derivative (PPD) test was positive, with 18 mm induration. The patient was placed on respiratory isolation because of suspicion of active TB. Serial sputum acid-fast bacilli (AFB) screening was negative.

Since coccidioidomycosis was endemic in the area, serology for coccidioidomycosis was done, which was positive for immunoglobulin (Ig) G antibodies, negative for IgM antibodies, and showed high complement fixation titers suggestive of active disease.

To evaluate the etiology of the ascites, abdominal paracentesis was done, with aspiration of homogeneous straw-colored fluid. Peritoneal fluid analysis revealed a red blood cell count of 1.2 X 10¹²/L, a total nucleated cell count of 3.5 X 10⁹/L, and a neutrophil cell count of 10 X 10⁹/L—suggestive of spontaneous bacterial peritonitis.

The patient was started on empiric ceftriaxone sodium (Rocephin), which was later discontinued when the ascitic fluid cultures grew no organisms. The ascitic fluid albumin was 1.9 g/dL, and the serum-ascites albumin gradient (SAAG) was calculated at 0.2 g/dL, indicating that the ascites was likely from a noncirrhotic cause. An infectious or inflammatory etiology of the ascites was seriously considered. Disseminated Mycobacterium tuberculosis, M bovis, or coccidioidomycosis could all explain the lung findings, as well as the ascites. The possibility of concurrent infection with TB and coccidioidomycosis was also entertained.

Culture of the ascitic fluid did not grow any fungus and was negative for AFB and TB polymerase chain reaction (PCR). Results of adenosine deaminase activity determination were equivocal. CT scan of the abdomen and pelvis showed a large-volume ascites but otherwise normal hepatobiliary and abdominopelvic structures.

A laparoscopic intraabdominal examination with peritoneal biopsy was performed to establish a definitive diagnosis. Intraoperative visualization revealed generalized inflammation of the peritoneum, which was studded with nodular lesions (Figure 1).

Figure 1— Laparoscopic images showing the serosal surface of the peritoneum studded with nodular lesions, suggestive of peritoneal coccidioidomycosis.

Figure 2— Histopathology of peritoneal biopsy showing areas of caseating granulomas with Langhan's type giant cells (arrows), the classic findings in TB that may also appear in coccidioidomycosis and in some malignancies.

Figure 3— Gomori methenamine silver staining of the peritoneal biopsy specimen showing a double-walled Coccidioides spherule, with many endospores (arrow).

Histopathologic examination of the tissue sample showed Langhan's cell granulomas, with caseation necrosis, resembling that of TB (Figure 2). Closer inspection, however, revealed double-walled spherules with endospores, indicative of invasive coccidioidomycosis (Figure 3). Cultures of the peritoneal biopsy samples later grew Coccidioides immitis. Mycobacteria were never isolated, and malignancy was not identified.

A final diagnosis of coccidioidomycosis, with peritoneal dissemination, was made, and the patient was started on a high-dose oral fluconazole (Diflucan) regimen. His symptoms, as well as the ascites and lung infiltrate, all resolved several weeks after initiation of therapy. He was also later treated for latent TB (Class II) infection.

Discussion

Abdominal paracentesis with subsequent analysis of ascitic fluid is the first step in the evaluation of patients with ascites. The SAAG—calculated by subtracting the ascites albumin concentration from the serum value—is a very useful measurement in investigating the etiology of ascites. The SAAG directly correlates with portal pressure, with a 98% accuracy and a 95% sensitivity.^1,2 High-gradient ascites (≥1.1 g/dL) results from portal hypertension, most often from alcoholic liver cirrhosis, viral hepatitis, infiltrative disorders, or nonalcoholic steatohepatitis. Low-gradient ascites (<1.1 g/dL) is associated with noncirrhotic causes, including malignancy, heart failure, pancreatic disease, TB, and other infectious/inflammatory conditions (Table).

Tuberculous peritoneal
Peritoneal TB constitutes 3.3% of extrapulmonary tuberculous infections in the United States.³ PPD testing is positive in only about one fourth of cases,⁴ and concurrent pulmonary TB is present in between 2% and 35% of cases.^5,6 Most cases of peritoneal TB are caused by M tuberculosis, and a small proportion are caused by zoonotic M bovis.⁵

Tuberculous peritonitis is difficult to diagnose because of its nonspecific clinical presentation. It almost always presents with ascites. Ascitic fluid in abdominal TB usually shows a total nucleated cell count of 500 to 2000 cells/mm³, with lymphocytic predominance (polymorphonuclears may be more abundant early in the process).⁴ Acid-fast staining of the ascitic fluid, however, is almost always negative, whereas PCR of the fluid is positive in 40% to 60% of cases.⁷ Ascitic fluid culture for TB may eventually become positive in 33% of cases, but culture takes too long (usually 6 weeks) to be useful.⁸

Measurement of the activity of adenosine deaminase (a key enzyme in purine nucleotide degradation) in ascitic fluid has been used as a screening tool for tuberculous peritonitis. In highly endemic areas, adenosine deaminase activity has a sensitivity of 95% and a specificity of 98%.⁹ In the United States, however, where the prevalence of TB is low, its use is limited by its poor sensitivity (only 30%).¹⁰ Peritoneal sampling, either through laparoscopy or laparotomy, has been shown to be the most effective investigation, yielding the diagnosis in 92% of cases.¹¹

Coccidioidal peritonitis
Coccidioidomycosis, a systemic fungal disease, results from exposure either to C immitis or to Coccidioides posadasii. It is endemic in the southwestern United States, notably in California's San Joaquin Valley (where C immitis is more predominant)¹² and in the Sunbelt states, particularly Arizona, where the incidence of the disease increased by 281% between 1997 and 2004.¹³

Infection is primarily localized in the lung, presenting as pneumonia, and is often self-limited. In less than 1% of infections, mostly in high-risk groups (eg, immunocompromised persons, pregnant women, low-income populations), coccidioidomycosis may spread to extrapulmonary sites.¹⁴ Dissemination to any organ can occur. However, gastrointestinal involvement is rare, and this diagnosis is seldom suspected initially. As with tuberculous peritonitis, peritoneal coccidioidomycosis has a nonspecific clinical presentation.

A review of 26 cases of coccidioidal peritonitis determined that only half of the patients had concurrent respiratory findings; abdominal distension was found in 46% and ascites in 42% of the patients.¹⁴ Ascitic fluid in coccidioidal peritonitis shows lymphocytosis, with markedly elevated white blood cell counts, often reaching 4 X 10⁹/L. In that review, fungus was isolated from the ascitic fluid in 27% of the cases. In the majority of these cases, the diagnosis was confirmed by histopathologic and mycologic examination of surgical specimens using laparoscopy or laparotomy.

Laparoscopy
Laparoscopy is a minimally invasive procedure that permits visualization and biopsy of the organs and other structures to detect abdominal pathology. It offers advantages over open laparotomy, since it involves less tissue dissection and less disruption of tissue planes, which translates into fewer perioperative complications. In addition, laparoscopy permits better visualization of the pelvic cavity and the paracolic gutters than the classic laparotomy approach.

Because analysis of ascitic fluid is of limited value in the diagnosis of tuberculous peritonitis, laparoscopy with biopsy should be performed whenever TB is suspected as a cause of ascites. During laparoscopy, findings suggestive of abdominal TB (scattered whitish nodules over the peritoneum and adhesions between adjacent organs) may permit a presumptive visual diagnosis in 83% of cases and a positive diagnosis in 87%.¹⁵

Diagnosis
Definitive diagnosis can be made by identification of mycobacteria from microscopy and PCR of tissue samples taken during the procedure. TB cultures from tissue samples have a far greater yield than ascitic fluid samples, thus laparoscopy offers the added advantage of sensitivity testing to anti-TB drugs.

A diagnosis of coccidioidal peritonitis can sometimes be made on the basis of clinical findings, serologic data, and studies of the ascitic fluid. Nevertheless, in 85% of cases, tissue biopsy from a surgical procedure is required to establish the diagnosis.¹⁴ In abdominal coccidioidomycosis, the peritoneum is usually inflamed, with granular deposits in the serosal surface, a feature that may be visually indistinguishable from peritoneal TB or carcinomatosis. Definitive diagnosis is made by identification of thick-walled spherules containing endospores on histopathology or mycologic culture.¹⁴

The role of laparoscopy is less well-defined in suspected coccidioidal peritonitis than it is in TB. If the diagnosis of coccidioidal peritonitis remains uncertain after ascitic fluid analysis and other conservative tests, laparoscopy should be the next step.

Treatment
Coccidioidal peritonitis has historically been treated with amphotericin, ketoconazole, or fluconazole. Current guidelines for extrapulmonary coccidioidomycosis recommend initial therapy with oral azole antifungal agents, most often with fluconazole or itraconazole, and with amphotericin as an alternative agent. Fluconazole is the preferred agent, because it has excellent penetration into the peritoneal fluid. Some experts recommend using high doses of fluconazole, from 800 to 2000 mg/day.¹⁶ Remember that some cases of coccidioidal ascites may spontaneously resolve without treatment.

Conclusion

The evaluation of ascites begins with abdominal paracentesis and analysis of the ascitic fluid. The differential diagnosis can be narrowed by calculating the SAAG, which correlates with portal hypertension. Definitive diagnosis may require diagnostic laparoscopy or histologic examination of tissue samples. Our patient had all the earmarks of abdominal TB, based on his history and clinical findings. He was initially treated with anti-TB drugs, but when his ascitic fluid was negative for both AFB and TB PCR, additional investigation was conducted. Diagnostic laparoscopy and histopathology of a tissue sample revealed the diagnosis of coccidioidomycosis with peritoneal dissemination.

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