Sclerosing Cholangitis and Multiple Liver Abscesses in a Patient with Thymoma, Myasthenia Gravis, and Immune Deficiency (Good’s Syndrome)

Introduction

Sclerosing cholangitis (SC) is a rare hepatobiliary disorder that can occur spontaneously (primary SC, PSC), but most often is associated with inflammatory bowel diseases [1]. PSC-like secondary immune cholangiopathy has been encountered in additional conditions with altered innate immunity, such as IgG4 gammopathy [2], acquired immune deficiency syndrome [3], and HIV [4], with some features and pathophysiologic mechanisms shared with other autoimmune liver diseases [5,6].

Thymoma is associated with altered immunity, predisposing to autoimmune disorders and acquired immune deficiency, and has rarely been associated with SC [7,8]. Herein we report the case of a patient with relapsed metastatic thymoma, myasthenia gravis, and acquired hypogammaglobulinemia (Good’s syndrome) who developed SC, liver abscesses, and protracted gram-negative bacteremia.

Case Report

A 77-year-old woman was evaluated following E. coli bacteremia with liver abscesses and persistent abnormal levels of liver enzymes. Her past medical history included thymectomy for myasthenia gravis associated with thymoma, performed 15 years earlier, and relapsed myasthenia and metastatic thymoma with pleural involvement that was managed by irradiation, carboplatin, and etoposide. Acquired hypogammaglobulinemia (Good’s syndrome) [9] developed in parallel, associated with bronchiectasis and recurrent pneumonia following COVID-19 and myasthenia crises, which required transient tracheostomy and respiratory support with successful subsequent weaning. She was treated with prednisone and pyridostigmine, and with periodic administration of intravenous gamma globulins (IVIG), which allowed gradual attenuation of steroids, and achieved a MGFA class IIIa, requiring substantial support.

The acute illness (day 1) started shortly afterwards, as the patient developed E. coli bacteremia of undetermined source, manifested by low-grade fever and lassitude, with no localizing physical findings, and associated with leukocytosis and moderate elevation of hepatocellular and cholestatic enzymes (Figure 1). Imaging disclosed the gradual formation of multiple hepatic lesions, compatible with liver abscesses (Figure 2). She was treated with piperacillin/tazobactam for 6 weeks in parallel with rehabilitation for deconditioning, and recovered with the resolution of leukocytosis and stabilization of the size and distribution pattern of the hepatic cyst-like fluid-containing defects. Nevertheless, while liver transaminases nearly normalized, cholestatic markers gradually intensified, despite the patient’s generally good condition, the lack of indices of active infection, and the administration of ursodeoxycholic acid (Figure 1). Magnetic resonance cholangiopancreatography (MRCP) disclosed the evolution of intrahepatic biliary tract disease compatible with sclerosing cholangitis (SC) (Figure 3), with thickened bile duct walls, intraluminal filling defects and beading of intrahepatic bile ducts. As shown in Figure 1, reemergence of E. coli bacteremia led to resumption of piperacillin/tazobactam, followed by oral ciprofloxacin and metronidazole, without amelioration of cholestatic disturbances. Positron-emission computed tomography (PET-CT) showed a lack of glucose uptake at the hepatic parenchyma adjacent to the multiple unchanged cyst-like filling defects, as opposed to pronounced uptake along the dilated and inflamed intrahepatic biliary tract, presenting a pattern compatible with cholangitis, combined with forme fruste liver abscesses (Figure 4). Extensive laboratory evaluation was remarkable for very low levels of IgG, IgA, and IgA, lymphopenia, and near-absent CD-19- and CD-20-positive lymphocytes. Additional evaluation excluded other differential diagnoses for cholangitis-like changes, including anti-mitochondrial, anti-parietal-cell, and antinuclear antibody panels, ASCA antibodies, IgG4 levels, and echinococcal and amoebic antibodies. Synthetic liver function test results remained unaltered and there was no indication of relapsed malignancy. A couple of weeks following holding of oral antibiotics, the patient’s condition deteriorated again and she finally died due to repeated bacteremia and multiorgan failure, despite resumed courses of antibiotics and IVIG.

Remarkably, the patient ran a rather benign clinical course up to the final sepsis and multiorgan failure, despite active hepatobiliary infection with recurrent bacteremia, with the absence of high fever, jaundice, or tender hepatomegaly.

Discussion

Our patient with relapsed malignant thymoma, associated with myasthenia gravis and acquired hypogammaglobulinemia, achieved clinical remission and was stable on IVIG, steroids, and pyridoxamine. However, multiple liver abscesses developed in association with E. coli bacteremia, followed by a protracted course of relapsing bacteremia, recurring within weeks following holding of antibiotics. It has been debated whether this form of protracted suppressed bacteremia originates from active liver abscesses or from the biliary tree. Evaluation by different imaging techniques excluded ongoing active infection within stable, unresolved liver parenchymal defects. However, persistently elevated and gradually rising cholestatic enzymes were noted over a few months, with the development of radiological features of SC. The PET signature illustrated increased uptake restricted to the biliary tree and not including the liver parenchymal defects. Collectively, the clinical course was compatible with SC, with chronic non-resolving bacterial cholangitis, which eventually led to the patient’s death. The persistent hepatic defects conceivably were a sterile forme fruste of healed liver abscesses, independent of cholangitis.

A few published case reports [7,8] raised the possible causal association of thymoma and SC, which might be explained by dysregulation of the immune system in patients with thymoma. We explored this possibility using the TriNetX (Cambridge, USA) federated global health research network, which enables retrospective analysis of real-world clinical data from multiple health care organizations (https://doi.org/10.1016/j.jbi.2021.103847). The incidence of cholangitis (ICD-10 K83) was studied in patients with thymoma (ICD-10 C37; N=11 701) and compared to patients with meningioma serving as a control group (ICD-10 D32; N=232 973). Propensity-score matching was performed based on demographics and the presence of a history of biliary disease (ICD-10 K80-K87), liver disease (ICD-10 K70-K77), and inflammatory bowel disease (ICD-10 K50-K51), resulting in 10 706 patients in each matched cohort with a mean follow-up time of 1303±1390 and 1361±1469 days since the diagnosis of thymoma and meningioma, respectively. Kaplan-Meier analysis revealed that compared to meningioma, patients with thymoma were at increased risk for a diagnosis of cholangitis (hazard ratio 1.816 95% CI 1.066, 3.095; 0.355%, vs 0.196%, P=0.0260).

However, this evaluation could not be controlled for immune deficiencies that may have accompanied thymomas. Indeed, such altered immune systems, associated with thymoma, termed Good’s syndrome [10,11], specifically the acquired common variable immune deficiency variant, can lead to a variety of autoimmune disorders, including hematologic immune cytopenias, arthritis, psoriasis, vitiligo, celiac disease, and immune thyroid and gastric disorders. Primary SC is rarely encountered and has been reported in only 1.8% of such patients [12].

An alternative possibility, linking SC with Good’s syndrome, might be repeated bacterial or other viral infections, such as HCV or HIV. Indeed, cholangiopathy associated with primary immune deficiencies in children can be improved by hemopoietic stem cell transplantation, suggesting that clearance of chronic infection following the establishment of immune competence, including cell-mediated immunity, may play a role in its pathogenesis [13]. Similarly, antiretroviral therapy was found to ameliorate SC in liver transplant patients, suggesting the role of viral infection in this disorder [14].

Interestingly, while bacterial cholangitis can complicate SC [15], biliary infection is not considered a significant mechanism underlying the development of liver abscesses, at least in patients with SC related to inflammatory bowel diseases [16]. However, the initial transient prominent rise in cholestatic enzymes along with transaminasemia suggests that an initial bacterial infection did develop within the biliary tract and likely generated the widespread liver parenchymal abscesses. An early long-term antibiotic regimen eradicated infection within the liver filling defects, with a near-normalization of transaminase levels (with the exception of the terminal clinical event with sepsis and multiorgan failure). However, our patient subsequently had repeated and relapsing gram-negative bacteremia, likely originating from the biliary tract, with persistent and progressively elevated cholestatic enzymes (Figure 1). Infection plausibly contributed to the structural changes first caused by SC, which likely interfered with eradication of this bacterial infection.

Finally, we suggest that the rather benign clinical course up to the final sepsis, despite ongoing hepatobiliary infection with recurrent bacteremia, was due to a malfunctioning immune system and inflammatory response.

Conclusions

This report illustrates a rare association of infrequent disorders, namely recurrent malignant thymoma associated with myasthenia gravis, acquired immune deficiency, and SC. Gram-negative bacteremia with cholangitis and with clinically (but not morphologically) healed multiple liver abscesses could be a complication of SC and possibly played a role in its intensification, with a vicious feed-forward loop of infection, inflammation, and fibrosis.