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Emerging Therapies for PBC

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Emerging Therapies for PBC J Gastroenterol (2020) 55:261–272 https://doi.org/10.1007/s00535-020-01664-0 REVIEW Emerging therapies for PBC 1,2 3 David Maxwell Hunter Chascsa • Keith Douglas Lindor Received: 4 December 2019 / Accepted: 5 January 2020 / Published online: 22 January 2020 Ó The Author(s) 2020 Abstract Primary biliary cholangitis is an uncommon Background cholestatic liver disease predominantly affecting middle- aged women. Left untreated, there is a high risk of pro- Primary biliary cholangitis (PBC) is an uncommon chole- gression to end-stage liver disease. Few treatment options static liver disease predominantly affecting women with an exist. To date, ursodeoxycholic acid (UDCA) and obeti- overall prevalence of 6–402 per million persons; incidence cholic acid (OCA) are the only medical therapies approved may be on the rise [1–5]. The age of onset is typically in for use, other than symptomatic treatments and liver the fourth or fifth decade of life [6–8]. The exact patho- transplantation, the latter of which is reserved for those physiologic basis for the development of PBC is yet to be developing complications of cirrhosis or with fully elucidated; however, evidence supports an autoim- intractable pruritus. UDCA improves outcomes, but many mune-induced mechanism. This is supported by the pres- patients do not adequately respond. OCA therapy may ence of a hallmark autoantibody: anti-mitochondrial improve response, but long-term data are limited. New antibody (AMA), in nearly all PBC patients. Genetic risk therapies are desperately needed, but evaluation has been and environmental exposures have also been implicated limited by the fact that the disease is heterogeneous, hard [6–14]. end points take years to develop, and there are different criteria in use for determining therapeutic response based on surrogate biomarkers. Fibrates appear to be the most Diagnosis of PBC promising new therapy and have beneficially affected surrogate end points and are beginning to show improve- Diagnosis of PBC relies on fulfillment of two of three ment in clinical end points. hallmark criteria [15–18]. These include a persistently elevated alkaline phosphatase (ALP) in the absence of Keywords Primary biliary cholangitis Á Ursodeoxycholic other hepatobiliary pathology, detection of a positive anti- acid Á Obeticholic acid Á Fibrate Á Liver disease mitochondrial antibody (AMA), and/or a liver biopsy with characteristic findings [17]. After identification of an elevated ALP, assessment & David Maxwell Hunter Chascsa should be made to detect the presence or absence of an [email protected] elevated AMA. AMA is the hallmark antibody of PBC, and & Keith Douglas Lindor is found in over 95% of patients with the disease [email protected] [12, 19–27]. Approximately, 5% of PBC patients will lack 1 Department of Gastroenterology and Hepatology, Mayo a detectable AMA. Biopsy is not necessary for diagnosis Clinic, MD 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA and may be reserved for patients with high clinical suspi- 2 Department of Transplant Center, Mayo Clinic, MD 5777 E. cion but negative AMA, or to exclude coexistent liver Mayo Blvd, Phoenix, AZ 85054, USA disease such as autoimmune hepatitis. 3 Office of University Provost, Arizona State University, MD, 550 North 3rd Street, Phoenix, AZ 85004, USA 123 262 J Gastroenterol (2020) 55:261–272 Histologically, PBC is characterized by non-suppurative follow up on safety and efficacy. Liver transplantation has inflammation of the small intrahepatic bile ducts. An been used for the treatment of PBC-related cirrhosis, dis- inflammatory infiltrate is seen around the small intrahepatic ease refractory to control by UDCA or OCA and when bile ducts. The classic histologic finding is a florid duct symptomatic treatments fail to control pruritus, but carries lesion (Fig. 1), but it is only present in a minority of his- the real risk of transplant-related morbidity and mortality tologic samples [26, 28]. There is a spectrum of histologic and is thus reserved only for those patients who have changes. Over time, however, there is relatively slow progressed to cirrhosis with significant liver dysfunction to progression from inflammatory to fibrotic change with the warrant the surgical risk and long-term risks inherent to development of cirrhosis typically occurring within organ transplantation or for those patients who have approximately 1 to 2 decades from diagnosis. However, developed liver-related malignancy attributed to cirrhosis there is wide variation in clinical presentation and course. or with refractory pruritus. Interestingly, even liver trans- Left untreated, there is variable progression to end-stage plant does not appear to ‘‘cure’’ PBC. A small study liver disease. While there is no cure, current treatments showed that as many as 75% of patients may develop have been shown to delay or reduce the risk of end-stage recurrent disease after transplant, though the severity of the liver disease and its complications [29]. recurrence is usually of little clinical significance [30]. Need for additional treatment options Pitfalls in developing clinical trials for PBC PBC carries increased risk of morbidity and mortality as There is a clear need for the development of new agents to well as reduced indicators of quality of life. Medical treat PBC, but progress has been overall slow. One of the treatments for PBC are relatively new, having become likely explanations for the difficulty in developing new and available in the last 30 years. Until recently, 2016, effective agents is the lack of a clear understanding of what ursodeoxycholic acid (UDCA), a synthetic bile acid, the drives the pathology of PBC. PBC is thought to progress efficacy of which will be described in full detail later in this through three phases [31]. The first is an autoimmune phase manuscript, was the only approved medical therapy for with resultant immune-mediated inflammation and damage PBC. The identification of UDCA as PBC treatment was a to bile ducts. This chronic persistent damage leads to monumental breakthrough in medical science, but unfor- cholestasis. Bile acids are toxic to the hepatobiliary cells tunately approximately one-third of PBC patients lack an over time. This further drives hepatocellular inflammation. adequate biochemical response defined as a reduction in Hepatocellular and cholangio-cellular death leads to duc- the surrogate biomarker ALP to less than 40% of baseline topenia and irreversible biliary fibrosis and cirrhosis. The or less than 1.67–2 times the upper limit of normal [16]. difficulty in finding treatments is that many potential tar- Obeticholic acid (OCA) is the newest approved treatment, gets have been identified, but bile acid metabolism is which will also be discussed later, but lacks long-term complex and necessary for normal hepatic function. Fig. 1 Histologic features of PBC with overlap. The image demon- cirrhosis, but no bile duct anomaly. Diagnostic liver biopsy was strates a classic ‘‘florid duct lesion’’ of PBC. Typically, a biopsy is not pursued. Interestingly, the case demonstrates an overlap syndrome as required to make the diagnosis of PBC. In this particular case, a well, given the presence of interface hepatitis. This highlights the 70-year-old woman presented with a long-standing alkaline phos- need for diagnostic liver biopsy in cases of AMA-negative but phatase elevation 2–3 times the upper limit of normal. AMA testing suspected PBC, and when there is concern for an overlap syndrome. It was negative, but ANA was markedly positive at 4.6 units. further highlights the utility of ANA assessment in patients suspected Abdominal ultrasound was pursued showing findings suspicious for of PBC 123 J Gastroenterol (2020) 55:261–272 263 Complete blockage of function is not possible, as normal functional scores that predict outcomes such as the GLOBE bile acid metabolism and homeostasis are necessary for score and UK-PBC score are now also available. There are life. several PBC histologic scoring systems. However, given Furthermore, from a clinical standpoint, PBC represents the patchy nature of the disease and the invasiveness of a heterogeneous disease. While predominantly affecting liver biopsy, histology is felt to be an unfavorable means to middle-aged Caucasian females who possess a positive assess treatment response for any emerging therapy. AMA, it can present in other populations and with differ- Currently, a search for primary biliary cholangitis or ences in clinical severity. It is debatable whether AMA- primary biliary cirrhosis in the National Clinical Trials negative and AMA-positive biliary cholangitis even rep- Registry reveals slightly more than 100 clinical trials resent the same disease entity, though there appears to be a relating to the disease. Many have been completed or are genetic association. Younger age of onset and male gender not actively recruiting. Less than 20 appear actively as well as African and Hispanic descent portend a poorer assessing novel therapies. prognosis and it is not clear why [32–35]. Biomarkers of disease severity are otherwise lacking, or in their infancy of development, though autotaxins and the microbiome are Aim of this article being studied as well as other potential markers [36, 37]. Additionally, the efficacy of investigational agents was The aim of this current article is to highlight the fact that limited by lack of clearly defined treatment end points. PBC has few treatment options to date. Currently available Furthermore, the development of fibrosis and the associ- treatment options while effective in some patients may lack ated comorbidities of advanced liver disease such as cir- efficacy or lead to intolerable side effects in up to one-third rhosis-related portal hypertensive complications of of patients. The main goal is to review the currently portosystemic encephalopathy, development and progres- available treatment options, review those that have been sion of esophageal varices, and variceal bleeding, ascites shown to be less effective, and highlight the newest pos- formation, and hepatocellular carcinoma risk take years if sible agents which may be used to treat the disease.
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