A Novel Association Between Primary Biliary Cholangitis and Idiopathic Pulmonary Arterial Hypertension

Abstract

Background and Hypothesis Idiopathic Pulmonary Arterial Hypertension (IPAH) and Primary Biliary Cholangitis (PBC) are both rare diseases that are progressive and may be fatal when left untreated. Furthermore, mitochondrial dynamics are fundamental to the pathogenesis of both conditions. An association between the two in the form of an overlap syndrome has never been previously described. Despite this, observations from the Pulmonary Hypertension clinic at the University of Alberta indicate a number of patients with both conditions, raising suspicion for a possible overlap syndrome. We hypothesize that IPAH and PBC may co-exist in some patients as an overlap syndrome as opposed to simply co-occurring by chance. Methods The PBC patient database at the University of Alberta was reviewed, identifying patients with echocardiograms showing a right ventricular systolic pressure (RVSP) of >30mmHg. Within these cases we identified PBC patients with IPAH by identifying and subsequently excluded those with left heart disease, chronic lung disease, connective tissue disease, hyperdynamic circulation secondary to liver disease, and portal hypertension since these are all causes of secondary pulmonary hypertension. We used a control group of patients with primary sclerosing cholangitis (PSC), as this is a chronic immune mediated cholestatic liver disease, much like PBC. Results A total of 211 patients were analyzed, 134 with PBC and 77 with PSC. 5 patients with PBC also had concurrent IPAH (3.73%), compared to none in the PSC group (0%). Compared to the prevalence of IPAH in the general population of roughly 0.005%, the prevalence of IPAH in PBC patients was over seven hundred times higher. Of all patients with RVSP >30mmHg, 60.4% of PBC patients had portal hypertension, compared to 89% in the PSC group. Of patients without hyperdynamic circulation or heart disease, and RVSP>30mmHg, and secondary signs of PAH on echocardiogram, portopulmonary hypertension was observed at a proportion of 50% in PBC compared to 0% in PSC. Conclusions Given a 700 fold increased prevalence of IPAH in PBC compared to the general population, and also when compared to PSC, it is likely that PBC and IPAH can co-exist in a previously undescribed overlap syndrome. The underlying pathogenesis is unclear, but may involve mitochondrial suppression and a differential response of the immune system in the pulmonary arteries and biliary epithelial cells. Further epidemiological studies are warranted to confirm our findings of an overlap between IPAH and PBC, as well as laboratory studies to explore the underlying pathophysiology of such a condition.