A 61-year-old patient presented to the Hepatology clinic in September of 2008 with a six-month history of elevated alkaline phosphatase levels. He gave a history of malaise, low-grade fever, night sweats and a 50 lbs weight loss (Figure ). His prior workup included laboratory, radiologic and endoscopic tests, including ultrasound, esophago-gastro-duodenoscopy (EGD) and endoscopic retrograde choledochopancreatography (ERCP), all of which were unrevealing. Serological tests for viral or autoimmune hepatitis, primary biliary cirrhosis, and other concomitant liver diseases were negative.
Patient's weight and Alkaline Phosphatase changes prior to BCG instillation, during and after antimycobacterial treatment (BCG Rx: BCG treatment; First Sx: first symptom; TB Rx: TB treatment)
The patient had no history of immunodeficiencies. He had been diagnosed with superficial transitional cell carcinoma (TCC) of the bladder (Stage T1 with invasion into the lamina propria) in 2007. His initial treatment consisted of cystoscopic fulguration of the tumor. However, follow-up examinations revealed a local recurrence. Intravesical immunotherapy with weekly instillations of BCG (150 mg lyophilized Pasteur strain) was administered for a total of 6 weeks, starting in May, 2007. No immediate complications or traumatic instillations were reported.
On further laboratory testing, the patient's alkaline phosphatase level rose to and peaked at 1100 IU/L (Figure ). This was associated with mild increase in transaminases (AST 56 IU/L, ALT 60 IU/L). On physical exam, the patient was anicteric. Tender hepatomegaly was present. Aerobic and anaerobic bacterial blood cultures were negative, as was a PCR serum assay for cytomegalovirus. The patient was admitted to the hospital for further workup.
Computed tomography of the chest, abdomen and pelvis was performed to exclude recurrent transitional cell cancer and other malignancies. The lung images revealed multiple small nodules distributed randomly throughout both lungs, suggestive of an infiltrative, possible infectious process. Given the history of prior BCG treatment, the possibility of pulmonary or disseminated mycobacterial infection was raised. A liver biopsy was performed because of the marked liver enzyme elevations, and showed multiple, non-caseating granulomas with Langerhans giant cells (Figure ); Ziehl-Neelson staining of the liver tissues for acid-fast bacilli (AFB), and Gomori's methamine silver (GMS) staining for fungal organisms with appropriate controls were negative. Because of the continued concern over mycobacterial infection, bone marrow and repeat liver biopsies with mycobacterial culture were performed one month later. Noncaseating granulomas were present on both liver and bone marrow biopsies (Figure and ). AFB stains were again negative, but mycobacterial cultures were positive in both cases. Mycobacterial isolates from both sources were sensitive to streptomycin, isoniazid, rifampin, and ethambutol. PCR analysis of liver tissue confirmed the presence of Mycobacterium bovis BCG DNA, and susceptibility testing demonstrated the expected resistance to pyrazinamide.
Pathological features of liver biopsy of granulomatous hepatitis. Multiple non-caseating granulomas (A, ×10) and typical Langerhans giant cells (B, ×40).
Bone marrow involvement with Mycobacterium bovis. Multiple non-caseating granulomas (arrows) with Langerhans giant cells (A. ×10). B. Higher magnification (×20).
During this stage of his evaluation, the patient reported the new onset of vision changes, consisting of intermittent, painless, blurred vision in both eyes. On ophthalmologic examination, the best corrected visual acuity was 20/20 in the right eye, and 20/30 in the left eye. Vision acuity in the left eye was reduced from pre-existing strabismic amblyopia. Examination of the anterior segment was unremarkable, and intraocular pressures were normal. Fundoscopic examination demonstrated multiple, circumscribed, yellow-creamy lesions of the choroids bilaterally (Figure ). No vitritis or retinal edema was present. A diagnosis of bilateral, multifocal choroiditis was made and attributed to a rare manifestation of intraocular BCG involvement [6
Ophthalmoscopic findings (multiple, circumscribed yellow-creamy lesions) of bilateral choroiditis with greater severity in the left eye.
Triple anti-mycobacterial therapy was initiated consisting of rifampin (600 mg daily), isoniazid (300 mg daily), and ethambutol (1200 mg daily) for a total of 12 months. On treatment, the patient regained his prior weight, and his physical exam and liver tests normalized (Figure ). On ophthalmologic examination, the previously noted choroidal lesions had faded. The visual acuity remained unchanged. A follow-up liver biopsy was performed after the completion of anti-mycobacterial therapy. Scattered Langerhans cells were still present, but repeat PCR testing for Mycobacterium bovis was now negative.
Two months after the completion of anti-mycobacterial therapy, the patient presented to our hospital with an acute upper gastrointestinal hemorrhage. Emergency endoscopy revealed an adherent clot in the third portion of the duodenum. Abdominal CT examination revealed a previously documented abdominal aortic aneurysm. Compared to a study from one year prior, the diameter of the aneurysm had increased from 2.8 cm in the prior year to 4.1 cm and the aneurysm was impinging upon the third portion of the duodenum (Figure ). The patient underwent emergency laparotomy, where an aortoduodenal fistualization with fresh clots was encountered. Aortic reconstruction and primary fistula repair were performed successfully. The surgical specimen was sent for pathologic and microbiological studies. Histological examination revealed multifocal, non-caseating granulomas with multinucleated giant cells (Figure ). Special stains for AFB and fungal organisms were negative. In light of the patient's history of disseminated BCG infection and the presence of multiple granulomas on histological examination, it was felt that the patient warranted retreatment for Mycobacterium bovis. He was started on a repeat course of rifampin, isoniazid ethambutol and pyridoxine/B6. The patient is tolerating his treatment well and is currently asymptomatic.
Figure 5 Duodenal pathology of aorto-duodenal fistula. A. (×4) single, small, non-caseating granuloma with multinucleated foreign body giant cell reaction (arrow) and chronic transmural inflammation with vascular congestion, consistent with a fistula. (more ...)
The patient's cultures and stains are all negative but the pathology showed "multifocal, non-caseating small granulomas with multinucleated foreign body giant cell reaction and transmural chronic inflammation with mild vascular congestion, clinically fistula".