DIAGNOSTIC PUZZLER

Abdominal pain and bloating in two 20-something patients

By Andrew Berchuck, MD, Angeles A. Alvarez, MD, and Jason E. Stout, MD

Two women in their late 20s present to you with histories of abdominal swelling, vomiting, and diarrhea. In both cases, CT scan reveals ascites. Is this ovarian cancer...or something else? You make the diagnosis.

Case 1

Initial presentation. Ms. JD, 27 years old, presents to her local physician with a 3-month history of nausea, vomiting, abdominal pain, and increased abdominal girth without weight gain. She also complains of irregular menstrual cycles for the 2 months prior to presentation but denies having any fever, chills, or cough. An ultrasound and CT scan demonstrate no abnormalities of the gallbladder or liver, but do show marked ascites, bilateral complex adnexal masses, and omental thickening consistent with peritoneal carcinomatosis (Figure 1). Presuming a diagnosis of disseminated ovarian carcinoma, her physician refers Ms. JD to the gynecologic oncology service at Duke University Medical Center, where this medical mystery is unraveled.

Clues in the history and physical exam? In talking with the patient, we learned that 6 years ago, she moved to the United States from a small town in Mexico, where she had casual exposure to domestic and farm animals. She did not recall having consumed any unpasteurized milk or raw meat in Mexico, but she did frequently eat soft cheese (queso fresco) made from unpasteurized cow's milk. As part of an employment examination, Ms. JD had recently undergone a Mantoux skin test, the results of which were negative, and she denied exposure to persons with active tuberculosis. The results of an examination at our medical center were remarkable only for minimal epigastric tenderness, and a chest radiograph showed no abnormalities. Ms. JD's serum CA 125 level was markedly elevated at 1,853 U/mL. An HIV test was negative.

More testing reveals the answer. Our next step was diagnostic laparoscopy, which found multiple peritoneal implants that appeared suspicious for carcinomatosis, as well as viscous-appearing ascites. But intraoperative frozen-section showed only granulomas and no evidence of carcinoma. The final pathology report noted the presence of a single acid-fast bacillus. Two days later, the results of a tuberculosis skin test that had been performed on the day of the surgery pointed to the correct diagnosis: peritoneal TB. JD's TB test was positive—induration, 22 mm! Mycobacterial culture of the peritoneal implant specimen yielded an organism that was identified as Mycobacterium tuberculosis complex by DNA probe. This "bug" was susceptible to streptomycin, isoniazid, ethambutol, and rifampin but was resistant to pyrazinamide. Further biochemical testing and high-performance liquid chromatography revealed the mycobacterium to be a non-BCG strain of Mycobacterium bovis. We immediately began Ms. JD on isoniazid, rifampin, pyrazinamide, and ethambutol, and she ultimately completed a 9-month course of therapy with isoniazid and rifampin. Her symptoms resolved completely.

Case 2

Initial presentation. Ms. LB, a 25-year-old nulliparous black woman, was admitted to an outlying hospital with a 2-month history of high fevers, abdominal swelling, vomiting, and diarrhea. A CT scan revealed ascites and peritoneal thickening consistent with carcinomatosis, but her ovaries were not enlarged and her serum CA 125 level was 571 U/mL. Paracentesis was performed and revealed a straw-colored exudate with inflammatory cells.

Clues in the history and physical exam. Ms. LB's medical history revealed one spontaneous and two therapeutic abortions. She lived alone and denied any travel outside North Carolina. When transferred to Duke University Medical Center, we found that she had a positive TB skin test and a temperature of 39.3°C. Her hematocrit was 27% and a white blood cell count was 3,700. She was HIV negative. CXR showed a small left pleural effusion.

Additional tests reveal the answer. Ms. LB was taken to the operating room for diagnostic laparoscopy and found to have an inflamed peritoneum with numerous small nodules scattered throughout (Figure 2). Peritoneal biopsy revealed noncaseating granuloma and there was no evidence of malignancy (Figure 3). Although histochemical staining for acid-fast bacilli was negative, we started Ms. LB empirically on multidrug TB therapy with isoniazid, pyrazinamide, rifampin, ethambutol, and vitamin B₆. Two weeks postoperatively, Mycobacterium tuberculosis was isolated from her peritoneal biopsy cultures. At a follow-up visit 1 month later, the patient reported that her fever and abdominal swelling had regressed.

A more in-depth look at peritoneal TB

TB is caused by one of five organisms in the Mycobacterium tuberculosis complex: M tuberculosis, M africanum, M microti, M canetti, or M bovis. M tuberculosis is by far the most common cause ofTB worldwide. While the incidence of the disease has declined within the US to an all-time low of 5.8 cases/100,000 persons per year (a total of 16,377 cases were reported to the Centers for Disease Control and Prevention in 2000) [ http://www.cdc.gov/nchstp/tb/surv/surv2000/content/table1.htm ], the disease continues to be a major problem worldwide, with an estimated 8 million new cases of active disease reported each year and 2 million deaths.¹ The global burden of TB remains high, mainly because of poor control in Southeast Asia, sub-Saharan Africa, and eastern Europe, and because of high rates of M tuberculosis and HIV co-infection in some African countries. As a result, an increasing proportion of TB disease in the US occurs among foreign-born persons who emigrate from endemic areas; 46% of patients in the US with active TB were foreign-born in 2000.

To adequately treat TB requires at least 6 months of therapy. Patients with suspected or confirmed TB should be started on four-drug therapy (isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin). If the organism is susceptible to all drugs, then the ethambutol/streptomycin can be discontinued. Pyrazinamide is continued for the first 2 months, followed by 4 months of isoniazid plus rifampin. Extrapulmonary disease is treated in the same fashion as pulmonary disease. In some cases, drug resistance prolongs and complicates therapy significantly; patients infected with resistant TB may require treatment for 2 years or more with multiple drugs ( http://www.cdc.gov/nchstp/tb/pubs/corecurr/CoreCurronTB.pdf ).

Approximately 80% of TB among patients in the US is pulmonary disease, with the remaining cases affecting other parts of the body. The most common extrapulmonary sites infected in decreasing order of frequency are lymph nodes (8%), pleura (4%), bone and joint (2%), the genitourinary tract (1%), peritoneum (1%), and the meninges (1%). Pulmonary disease often presents with chronic cough, fevers, night sweats, and weight loss. The diagnosis can be difficult because of the nonspecific symptoms, the fact that only about half of patients have a positive sputum smear for acid-fast bacilli, and the long time (up to 8 weeks) required for the organism to grow in culture. Extrapulmonary disease may be even more difficult to diagnose because the symptoms are often nonspecific and clinical signs are lacking.

Our experience with Ms. JD and Ms. LB illustrates the difficulties inherent in diagnosing peritoneal TB. As you can see from the case presentations, peritoneal TB can resemble ovarian cancer. The most common signs and symptoms include abdominal swelling, fever, weight loss, and abdominal tenderness.² Peritoneal TB is much less common than ovarian cancer, with only 136 cases reported in the US in 1999, compared with an estimated 26,800 cases of ovarian cancer.³ Radiographic studies indicating ascites and carcinomatosis and elevated serum CA 125 levels in patients with peritoneal TB suggest ovarian cancer. That was the case here, and both patients were referred to the gynecologic oncology service. It is worth noting that in a study of 11 patients with tuberculous peritonitis, all had elevated CA 125 levels (mean 317 U/mL).⁴ Because ovarian cancer is rare in young women, we performed diagnostic laparoscopy on both Ms. JD and Ms. LB Peritoneal TB generally can be diagnosed using laparoscopy, whereas we would normally perform a laparotomy during the initial management of ovarian cancer.²

Ms. JD's peritoneal TB was attributable to M bovis, which accounts for less than 3% of cases of the disease in industrialized countries.⁵ The relatively low incidence of this organism can be attributed to control of TB among cattle and to widespread pasteurization of milk before it is consumed by humans.⁶ In developing countries, this organism may be a more common cause of TB because of less stringent programs to control disease in animals and inadequate pasteurization. The exact prevalence of M bovis in such countries is difficult to determine, however, because diagnosis of TB is usually based on clinical findings plus the presence of acid-fast bacilli on sputum smears. Mycobacterial cultures are not routinely performed in developing countries, precluding speciation of isolates. In recent years, an increasing proportion of cases of TB in the US have been attributable to individuals born in other countries.¹

A recent study in San Diego revealed that only 2.6% of TB cases were attributable to M bovis.⁵ The patients described in these series were overwhelmingly Mexican. The most likely means of exposure was via consumption of unpasteurized dairy products, such as milk or cheese, or undercooked meat from cattle infected with M bovis. Queso fresco is popular in Mexico and among people of Mexican descent. Unpasteurized milk and cheeses are likely vectors for M bovis; 16% of a recent random sample of 2,500 Mexican dairy cattle from the six primary dairy regions of Mexico had lesions that were typical of bovine TB.⁶

M bovis infection presents two challenges to clinicians in addition to those posed by M tuberculosis. The first is the organism's universal resistance to pyrazinamide.⁵ Resistance to pyrazinamide alone in a mycobacterial isolate that has been identified asM tuberculosis complex by DNA hybridization strongly suggests M bovis infection and should prompt further testing of the isolate to determine the exact species. There is no well-defined standard course of therapy for TB caused by M bovis, but clinicians usually treat the disease for 9 to 12 months. The second challenge is the organism's predilection to infect extrapulmonary sites and 50% of adults have only extrapulmonary disease with this pathogen.⁵ Some of this variation in disease site has been attributed to the mode of infection. Patients in countries with long-standing programs for control of TB among cattle seem to be more likely to have pulmonary reactivation or to acquire their infection from other persons whose latent M bovis pulmonary infection has been reactivated.

On the other hand, patients who acquire their infection as a result of consuming contaminated food are likely to have primary gastrointestinal infection, including infection in the mesenteric lymph nodes and peritoneum. Although isolated peritoneal TB is a rare manifestation of M tuberculosis disease, it has been reported in about 10% of cases of M bovis disease.⁵ Finally, in a series of 26 cases of abdominal TB among children from San Diego, 80% of cultures were positive for M bovis.⁷

REFERENCES

1. Dye C, Scheele S, Dolin P, et al. Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project. JAMA. 1999;282:677-686.

2. Marshall JB. Tuberculosis of the gastrointestinal tract and peritoneum. Am J Gastroenterol. 1993;88:989-999.

3. Reported tuberculosis in the United States, 1999. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/nchstp/tb/surv/surv99/surv99.htm . Accessed June 13, 2002.

4. Simsek H, Savas MC, Kadayifci A, et al. Elevated serum CA 125 concentration in patients with tuberculous peritonitis: a case-control study. Am J Gastroenterol. 1997;92:1174-1176.

5. Dankner WM, Waecker NJ, Essey MA, et al. Mycobacterium bovis infections in San Diego: a clinicoepidemiologic study of 73 patients and a historical review of a forgotten pathogen. Medicine (Baltimore). 1993;72:11-37.

6. Milian-Suazo F, Salman MD, Ramirez C, et al. Identification of tuberculosis in cattle slaughtered in Mexico. Am J Vet Res. 2000;61:86-89.

7. Veeragandham RS, Lynch FP, Canty TG, et al. Abdominal tuberculosis in children: review of 26 cases. J Pediatr Surg. 1996;31:170-175; discussion 175-176.

Dr. Berchuck is F. Bayard Carter Distinguished Professor of Obstetrics and Gynecology, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, N.C.

Dr. Alvarez is Assistant Professor, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, N.C.

Dr. Stout is Associate, Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, N.C.

 

Andrew Berchuck, Angeles Alvarez, Jason Stout. Diagnostic Puzzler: Abdominal pain and bloating in two 20-something patients. Contemporary Ob/Gyn 2003;1:51-58.