**2. Primary Biliary Cholangitis**

PBC is a chronic autoimmune cholestatic liver disease that predominantly affects women. It is characterized by cholestasis, serologic reactivity to antimitochondrial antibodies (AMA) or to specific antinuclear antibodies (ANA) such as Sp100 and Gp210, and histologic evidence of chronic non-suppurative, granulomatous, lymphocytic small bile duct cholangitis. Many aspects of the aetiology and the pathogenesis of the disease are still uncertain, and the disease is often progressive, resulting in chronic cholestasis and possibly cirrhosis [1,2]. The main treatment goals include the prevention of the progression of the disease and the management of the symptoms, which may have a strong negative impact

**Citation:** Mazzetti, M.; Marconi, G.; Mancinelli, M.; Benedetti, A.; Marzioni, M.; Maroni, L. The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities. *J. Clin. Med.* **2021**, *10*, 1763. https://doi.org/ 10.3390/jcm10081763

Academic Editor: Pierluigi Toniutto

Received: 21 March 2021 Accepted: 15 April 2021 Published: 18 April 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

on the quality of life of patients. The only two medications approved by the Food and Drug Administration (FDA) are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). However, over the past years, given the strong support of randomized clinical studies, new therapies entered into the clinical practice of many experts in the field. Moreover, others molecules are actively being investigated in different clinical trials with promising results [3]. In this section, we are going to review the principal drugs in clinical use, in clinical trial, an in a preclinical phase for PBC.

#### *2.1. Therapies in Clinical Use*

### 2.1.1. UDCA

UDCA, at a dosage of 13–15 mg/kg/day, is the first-line treatment for PBC [1]. It is the 7-β epimer of the chenodeoxycholic acid, a human bile acid. The complex mechanisms of action of UDCA and the evidence for its clinical use are extensively reviewed elsewhere [2,4]. Several molecular mechanisms contribute to the beneficial effect of UDCA in PBC patients. Indeed, many studies have shown that UDCA has anti-cholestatic effects due to complex post-transcriptional molecular mechanisms, a cytoprotective property, thanks to its action on endoplasmic reticulum stress, and an anti-inflammatory activity, inhibiting prostaglandin E2 [5]. UDCA administration also makes the endogenous bile acid pool more hydrophilic, and it improves therefore the biliary bicarbonate (HCO3−) umbrella, which is thought to create a protective layer on the apical surface of cholangiocytes against the permeation of protonated bile acids [6]. Moreover, UDCA interferes with the pathogenesis of autoimmune diseases by decreasing the expression of Major Histocompatibility Complex (MHC) class I and class II, the eosinophil levels in blood, and the immune reaction against PAMPs [7]. The administration of UDCA in PBC patients induces a reduction in markers of cholestasis, IgM, and AMA level [8]; improves liver histology [9]; and decreases mortality, especially when started at early stage [10]. Unfortunately, one-third of the patients have an inadequate response to UDCA treatment, defined according to several scoring systems, including the Barcelona, Paris I, Paris II, Rotterdam, Toronto, Ehime, GLOBE, and UK-PBC scoring systems [1]. Recently, the UDCA Response Score (URS), calculated with pre-treatment parameters, was used to predict the UDCA response [11]. A lower probability of UDCA response was significantly associated with a higher level of ALP (*p* < 0.0001), higher levels of total bilirubin (*p* = 0.0003), lower aminotransferase concentration (*p* = 0.0012), younger age (*p* < 0.0001), longer gap from diagnosis to UDCA treatment (*p* < 0.0001), and worsening of ALP from diagnosis (*p* < 0.0001). Based on these variables, the score reached an area under the receiver operating characteristic curve of 0.83 in predicting UDCA response. Other factors that contribute to the response to treatment are male sex [12], PBC-specific ANA positivity [1], and histology [11].

#### 2.1.2. Steroidal FXR Agonist: Obethicolic Acid (OCA)

OCA is an analogue of chenodeoxycholic acid (CDCA), with the addition of an ethyl group which gives a strong affinity for the nuclear farnesoid X receptor (FXR). FXR is the primary regulator of bile acid homeostasis, thanks to its effect on reducing production and reabsorption and increasing excretion [13]. After the good results of two phase II studies and one phase III clinical trial (POISE), in October 2016, OCA reached the EMA authorization for PBC treatment. The POISE study was a 12-month, double-blind, randomized, placebo-controlled phase III trial, evaluating 216 patients. The study included three treatment arms: OCA 10 mg ± UDCA, titration arm (OCA 5 mg ± UDCA for six months and then OCA 10 mg for the following six months), and placebo ± UDCA. The primary endpoint (i.e., ALP < 1.67 together with ALP reduction of at least 15% from baseline and normalization in total bilirubin) was reached by 46% and 47% of patients in the 5–10 mg and 10 mg OCA arms, respectively, and by 10% in the placebo group. Treatment arms also had a reduction in ALP, AST, and GGT that reached their lowest levels after three months of treatment and were maintained up to 48 months. The main adverse event was pruritus, which caused the study interruption for 7 out of 73 patients in the

OCA 10 mg group, and in 1 out of 70 in the titration arm. Concerning the lipid profile, a transient increase in LDL and a decrease in HDL, VLDL, total cholesterol, and triglycerides were detected [14,15]. The long-term efficacy and safety of OCA for PBC patients who are intolerant to UDCA or have an inadequate response to UDCA were confirmed in the three-year interim analysis of the five-year open-label extension of the pivotal phase 3 POISE trial [16]. Moreover, a sub-analysis of data from the POISE study showed that OCA treatment was associated with improvement or stabilization of histological features of the disease (ductular injury, fibrosis, and collagen deposition), but final analyses of fibrosis-related endpoints are ongoing [17]. OCA monotherapy (10 mg and 50 mg) was also studied in a double-blind, placebo-controlled phase 2 study in patients with PBC. After three months, a significant decrease in ALP was observed in both of the groups, and a similar effect was detected through six years of open-label extension treatment [18]. Thus, OCA is recommended by international guidelines as a first-line therapy in patients who are intolerant to UDCA, and as a second-line therapy in addition to UDCA in patients with an incomplete response to UDCA. Of note, special attention should be paid in cirrhotic patients. In fact, severe liver injury or death was reported in patients treated with incorrectly high doses, and the FDA has issued a Black Box Warning for OCA. Guidelines recommend starting OCA at a dose of 5 mg weekly (with a maximum dose of 10 mg twice weekly) in Child Pugh B or C cirrhotic patients, and to use caution in Child Pugh A patients [1,19,20].
