Overlapping of Primary Biliary Cirrhosis and Small Duct Primary Sclerosing Cholangitis: First Case Report

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are both autoimmune cholestatic liver disease and the association of these two conditions in the same patient is very rare. We report the case of a female patient presenting with a cholestatic liver disease and a panel of autoantibodies specific for PBC, including antibodies to mitochondrial E2-pyruvate dehydrogenase, gp-210 and Sp-100. Beside these findings, the liver biopsy revealed concentric fibrosis of small biliary ducts and the magnetic resonance cholangiography presented no abnormal findings. Diagnosis of small duct PSC/PBC overlapping was done. No description of this association was found in the literature. Clinical and serological features of this unusual finding are discussed.


Introduction
Although the etiology of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) remains unknown, there are several case reports of association of these hepatic autoimmune conditions in the same patient [1][2][3][4]. The expression "overlapping syndrome" has been used to describe forms of auto-immune disease, generally AIH/PBC or AIH/PSC, that present typical characteristics of more than one condition in the same patient, occurring simultaneously or sequentially, and sometimes migrating from one to another clinical presentation [3][4][5][6]. However, overlapping between PBC/PSC is much less described.
PBC is mostly prevalent among women, causing destruction of biliary ducts, resulting in progressive ductopenia and cirrhosis. AMA is considered a specific biomarker of PBC and some authors describe it as the serologic signature of the disease [7,8]. PSC, in its turn, is also a chronic cholestatic liver disease of unknown etiology, typically marked by progressive inflammation and concentric fibrosis of intraor extra-hepatic biliary ducts, causing cirrhosis, liver failure and high incidence of cholangiocarcinoma [9][10][11]. So far, there are no specific serological markers for PSC and AMA is virtually absent in PSC patients [12][13][14].
To our knowledge, there are only five PBC/PSC overlapping cases reported in the literature, none of them corresponding to small biliary duct PSC [15][16][17][18].
Here we describe a patient with clinical, biochemical and serological markers of PBC, whose biopsy was compatible with small duct PSC.

Case Report
A 48-year-old woman was referred to the hepatologist in order to investigate elevated levels of liver enzymes. Except for a treated systemic hypertension, mild obesity and a tenyear irregular use of amfepramone, she had no remarkable medical history. She also had no familiar history of liver disease or alcohol consumption. Physical examination revealed only mild hepatomegaly.

Discussion
The classically described overlapping syndrome is charac-terized by diagnosis of more than one form of autoimmune liver disease in the same patient [1][2][3][4][5]. If not correctly diagnosed and appropriately treated, its course can be more aggressive as compared to isolated forms [20,21]. It is a matter of discussion if overlapping syndromes are isolated entities or different manifestations of a unique autoimmune liver disease [1,2,6].
The patient herein reported presented an unremarkable clinical picture represented by the incidental finding of biochemical evidence of cholestatic disease, which might be suitable to both PBC and PSC. The serologic investigation initially performed was vigorously suggestive of PBC, with a positive a panel of autoantibodies specific for this disease, including antibodies to mitochondrial E2-pyruvate dehydrogenase (AMA M2), gp-210 and Sp-100.
Despite all these evidences for the diagnosis of PBC in the present case, the histological examination was not char-   acteristic of the disease; instead, it showed typical onion-skin lesions in biliary ducts, with concentric fibrosis, compatible with PSC, a non-expected finding in face of the serological findings.
The diagnosis of PSC is confirmed by the demonstration of typical lesions of the biliary tree, either by histological analysis or by imaging techniques (endoscopic cholangiography or MRI) [31,32]. Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC [31,33]. The histological hallmark of PSC is represented by concentric fibrosis of bile ducts; however, this finding is detected in only 30 to 40% of patients with PSC [31,[34][35][36]. Onion-skin fibrosis can also be found in secondary sclerosing cholangitis, but the patient reported here had no identified cause to this condition [31].
Description of overlapping between PBC and PSC is very uncommon. After revision of literature, only five reports of PBC/PSC overlapping syndromes were identified [15][16][17][18]. MRI was normal in the present patient, leading to the diagnosis of small duct PSC/PBC overlapping. To the best of our knowledge, this is the first report of small duct PSC overlapping with PBC. As she presented positivity to gp210, prognosis is a matter of awareness, even in the presence of small duct PSC, a condition with better prognosis than large duct PSC [38,39]. We have not enough follow up for evaluating prognosis in this case. After five years, response to treatment has been satisfactory.
In conclusion, we describe a female patient with features of PBC and small duct PSC, a diagnosis that would remain undiscovered if histology was not performed. This finding has important and controversial clinical implications, such as the management of treatment and the need of screening for cholangiocarcinoma [32]. This case is emblematic of how complex diagnosis of liver autoimmune diseases can be, and reinforces the impression that these are polymorphic entities that can express different patterns of autoantibodies and histological findings, making the diagnosis of these conditions particularly challenging.

Conflicts of Interest
There are no conflicts of interest.