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Primary biliary cirrhosis in adults Expert Rev. Gastroenterol. Hepatol. 8(4), 427–433 (2014)

Njideka Momah1 and Keith D Lindor*2 1 University of Kentucky, Lexington, KY, USA 2 College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA *Author for correspondence: Tel.: +1 602 496 0789 Fax: +1 602 496 0544 [email protected]

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bile ducts, impaired biliary secretion and stasis of toxic endogenous bile acids within the liver with progression to liver fibrosis and cirrhosis. It has an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1. In most cases, diagnosis relies on a positive antimitochondrial antibody in the context of chronic cholestasis, without the need for a liver biopsy. Ursodeoxycholic acid improves survival even in patients with advanced liver disease. Certain findings such as fatigue, anti-nuclear antibodies, anti-centromere antibodies and the GP210 antinuclear antibody predict a poor outcome. Up to 40% of patients do not respond satisfactorily to ursodeoxycholic acid therapy and should be considered for adjunctive therapies. Several adjunctive and newer therapies are being tested and some appear promising. We provide a review of PBC with a focus on advances in therapies that may impact the management of PBC in the near future. KEYWORDS: adjunctive therapy • farnesoid X receptor agonist • obeticholic acid • primary biliary disease • ursodeoxycholic acid


Primary biliary cirrhosis (PBC) was first described in 1851 and named in 1949, long before the early precirrhotic stages of the disease were described [1,2]. The prevalence was initially thought to be as rare as 18 per million but may be rising worldwide and is reported to be as high as 400 per million [3–5]. The increase in prevalence may be related to longer survival with treatment, though it is also suggested that the incidence may be rising [5]. Regardless, there are more people with PBC now than there were ever before. PBC is more likely to be seen in women than men at a ratio of 10:1 [5]. The disease is clearly related to a varied genetic predisposition with environmental factors including infection and toxic waste also implicated [6–11]. In an animal model, xenobiotics were shown to induce PBC-like features [12]. Natural history

PBC is a chronic cholestatic liver disease with an autoimmune basis, leading to inflammatory changes and slow destruction of small intrahepatic bile ducts. The resultant decreased bile acid secretion and retention of toxic endogenous


bile acids exacerbate the liver injury. PBC progresses at varying rates to cirrhosis and the need for liver transplantation or death. The natural history has been refined in recent years. Increased awareness and testing for the disease have led to the diagnosis being more frequently detected in the asymptomatic stage. Medical therapy has significantly improved survival, leading to fewer liver transplantations and longer survival [13]. Preursodeoxycholic era

In the 19th century and early 20th century, PBC was often diagnosed when patients presented with symptoms and at advanced stages of the disease. The mean survival of an individual with advanced disease in the absence of ursodeoxycholic acid (UDCA) therapy was 6 months) cholestatic liver biochemistry. AMA is highly specific for PBC and is present in up to 95% of patients. Less than 1% of the healthy population has this antibody [21]. About 5–10% of individuals with PBC are AMA negative or may have low titers of AMA of 1: £80 [22]. The presence of antibody, not its magnitude, is the important factor in making a diagnosis [23]. Autoantibodies to the mitochondria as well as autoantibodies to the nuclear antigens can be present in PBC in the absence of overlapping autoimmune hepatitis. Accumulation of components of the inner mitochondrial membrane enzyme, 2-oxo-acetic dehydrogenase complex, especially the E2 subunit of pyruvate dehydrogenase complex at the plasma membrane of biliary epithelial cell is unique to PBC and may precede the development of characteristic clinicopathological features of PBC. Autoantibodies to the three components of 2-oxo-acetic dehydrogenase complex-E2 (E2 subunit of pyruvate dehydrogenase complex, 2-oxo-glutaric acid dehydrogenase complex and branched-chain oxoacid dehydrogenase complex) can be detected by ELISA or western blotting techniques in both AMA-positive and AMA-negative individuals with PBC [24,25]. Most patients diagnosed with PBC have abnormal liver biochemistries. The liver biochemistries tend to reflect the histological severity of the disease. The degree of elevation of alkaline phosphatase (ALP) usually reflects the severity of ductopenia and inflammation. Aminotransferases and IgG levels reflect the degree of inflammation, periportal and lobular necrosis. Hyperbilirubinemia is usually indicative of the severity of ductopenia. Rising bilirubin, g-globulin and hyaluronic acid levels associated with falling albumin (Alb) levels and platelet count are markers of early cirrhosis and portal hypertension [23]. Elevated cholesterol is a feature of cholestatic diseases in general and is not specific for PBC [26]. The combination of chronic cholestasis, especially in a woman, who has positive AMA, ALP >1.5-times the upper limit of normal ( ULN), and aspartate aminotransferase (AST) 98% (sensitivity 80%, specificity 92%). Liver biopsy is usually not needed for the diagnosis of PBC and is reserved for cases in which the diagnosis is not clear or for patient stratification in clinical trials [27]. 428

Predictors of prognosis

The prognosis of PBC can vary in different individuals. Various models have been proposed to predict progression of the disease. The Mayo Clinic model is consistently able to predict the progression of PBC in patients with advanced disease [31,32]. The presence of antinuclear antibodies such as anticentromere antibodies, antinuclear pore complexes (anti-GP210) or antidot proteins antibodies (anti-SP100) predicts poor outcome [33–35]. Good biochemical response to UDCA is associated with both improved survival and improved liver histology [17,18,27]. The liver biochemistry profile is a widely available test and a reasonable way to assess treatment response. Several studies have proposed various criteria as predictors of treatment success [17,18,36–38]. ALP < three-times ULN, AST < two-times ULN and bilirubin 40) is associated with increased mortality in patients with PBC [40]. Fatigue does not respond to UDCA [41]. Altered central neurotransmission of serotonergic and noradrenaline pathways may mediate fatigue in chronic disease states [42]. However, neither norfluoxetine, a selective serotonin Expert Rev. Gastroenterol. Hepatol. 8(4), (2014)

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PBC in adults

reuptake inhibitor nor ondansetron, a serotonin receptor antagonist, has been helpful in improving fatigue in individuals with PBC [43,44]. Sleep abnormality was noted to be present in a significant proportion of individuals with PBC in one study [45]. Modafinil, used to treat shift work associated daytime somnolence, was reportedly helpful in alleviating fatigue in PBC patients in one trial. However, the trial was a nonrandomized, observational study without a placebo control [46]. In a randomized double-blind, placebo-controlled trial, the end-of-treatment FIS scores were lower than baseline in both a group of patients on modafinil and the placebo group. In this randomized clinical trial, the decrease in FIS scores following treatment that was noted in both the modafinil group and the placebo group did not reach statistical significance. The randomized clinical trial concluded that although modafinil was fairly well tolerated, it did not result in statistically significant improvement in fatigue in patients with PBC compared with placebo [47]. There is currently no medication recommended specifically for the treatment of PBC-associated fatigue. Pruritus

Pruritus is a symptom of PBC and not regarded as a prognostic factor. It is more common in the precirrhotic stages. In the past, up to 70% of PBC patient had pruritus, but this has decreased with the increased diagnosis of asymptomatic patients. Pruritus in an individual with PBC is usually associated with a decrease in severity over time. However, it does not usually disappear completely without treatment. The pathophysiology of pruritus may be related to bile acids and/or opioidergic neurotransmission. However, the cause of pruritus is not very clear. A recent study suggests that autotaxin and its product, lysophosphatidic acid, play a significant role in pruritus of cholestasis and could provide therapeutic targets [48]. Cholestyramine is a bile resin shown to ameliorate pruritus and is well tolerated. Rifampicin is also helpful but its hepatotoxic, nephrotoxic, hemolytic adverse effects and drug interactions dictate that caution should be used with this medication. Severe pruritus not responsive to oral therapy has been treated with procedures that filter the pruritogens from the plasma. Naltrexone decreases opioidergic tone and should decrease pruritus [23]. Therapies in PBC Ursodeoxycholic acid

UDCA is a bile acid first found in a bear (‘ursus’ in Latin) and is the 7-b isomer of the primary bile acid, chenodeoxycholic acid (CDCA) [49]. It is found in very small quantities in human bile. UDCA has been fully characterized and synthesized [50]. It is less hepatotoxic than the dominant human endogenous bile acids. UDCA competes with endogenous bile acids for absorption mostly in the small intestine but is also absorbed to a small extent in the colon [51]. It solubilized at a pH close to 8, which is found in the postprandial proximal jejunum in the presence of endogenous bile acids [52], so it is best taken with


food. UDCA enrichment in bile increases with chronic and adequate dosage use and can reach up to 60% in the hepatic bile of patients with PBC [14]. UDCA at a dose of 13–15 mg/kg/day divided doses is approved by the US FDA and recommended by practice guidelines for the treatment of PBC [40,53]. Liver biopsy, in the absence of other indications, is not required before institution of UDCA therapy but may impact other management strategies. UDCA as mentioned, improves liver biochemistries, slows histological progression, improves survival free of liver transplantation and improves overall survival in individuals with PBC [15–20]. UDCA positively impacts survival regardless of the stage of liver disease. Long-term UDCA can improve survival free of liver transplantation, most easily demonstrated in patients with stage IV disease [19]. Initiation of UDCA in individuals with early stages of disease can lead to a normal life expectancy in patients with PBC [20]. Given the known mortality benefits of UDCA, UDCA therapy should be initiated once a diagnosis of PBC is made [23]. The use of liver biochemistry is recommended for monitoring response to UDCA therapy. Liver biopsy is not used to monitor treatment response [39]. Up to a third of patients with PBC normalize their liver biochemistries within 5 years of UDCA therapy [23]. A recent study in the UK of 215 PBC patients challenged the use of liver biochemistry to define treatment response in early PBC. Papastergiou et al. reported increased survival rates free of adverse outcome over a period of 20 years in patients with early PBC on UDCA that did not reach statistical significance compared with patients with early PBC who were not on UDCA therapy. In that study, they showed that untreated patients, who did not achieve the Paris 1 criteria (as described below), had a significantly poorer outcome [54]. However, another study in the UK of over two thousand PBC patients showed that the degree of response to UDCA was affected by age and sex with younger females two-times ULN, or bilirubin_1 mg/dl after 1 year of UDCA as reflectors of the long-term risk of death or LT in PBC and those patients with such response should be targeted for further therapies [36]. Momah/Lindor from Mayo Clinic proposed ALP ‡ two-times 429


Momah & Lindor

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ULN or bilirubin >1 mg/dl at 12 months of UDCA therapy as optimal criteria for identifying patients most likely to benefit from therapies adjunctive to UDCA [37,38]. In patients on adjunctive therapies based on the Momah/Lindor criteria, ALP £1.67-times ULN and bilirubin £1 mg/dl were suggested as appropriate criteria to define treatment success [38]. Adjunctive therapies

Up to 40% of patients may have unsatisfactory biochemical response to recommended doses of UDCA [17,18,36]. Doubling of the recommended UDCA dose is not helpful in PBC [56]. Several therapies such as colchicine [57], methotrexate [58], silymarin [59], moexipril [60], tetrathiomolybdate [61], azathioprine [62], chlorambucil [63] and rituximab [64] have been tried off-label in the past but not shown to have additive survival benefits. Prednisolone and cyclosporine have been found to be detrimental without significant added benefit in PBC [65,66]. More therapies such as tauro-UDCA acid [67] and which is a synthetic bile acid that is less toxic than UDCA as well as apical sodium-dependent bile acid transporter inhibitor [68] are being studied. Nuclear receptors involved in bile acid homeostasis are discussed further below and some appear promising in the management of PBC. Fibrates

Fibrates (fenofibrate and bezafibrate) were incidentally found to lower liver biochemistries when used to treat hypercholesterolemia in PBC patients. Fibrates are known to activate the peroxisome proliferator-activated receptor a that is a member of the nuclear hormone receptor family. They also facilitate the expression of multidrug resistance-associated proteins in rats. Multidrug resistance-associated proteins are involved in inflammatory responses and bile acid metabolism [69,70]. Studies have shown a decrease in ALP in patients on fibrates who previously had unsatisfactory response to UDCA monotherapy [71–73]. However, to date, no survival benefit has been shown with fibrate therapy.

Farnesoid X receptor agonists

Farnesoid X receptor (FXR) is one of the key nuclear receptors involved in bile acid homeostasis [76]. It is highly expressed in the liver (as well as intestine, adrenal gland and kidney) [77]. FXR collaborates with another nuclear receptor, retinoid X receptor, to induce the synthesis of a suppressor protein, the short heterodimeric partner (SHP). SHP displaces hepatocyte nuclear factor 4 from the promoter region of cholesterol 7a hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, thereby inhibiting bile acid biosynthesis. FXR also acts through SHP to decrease bile acid uptake in the liver. It is also known to modulate liver regeneration, carcinogenesis and inflammation [78]. FXR agonists have been shown in animal models to decrease serum ALP levels [79,80]. FXR can be activated by bile acids. CDCA is a human bile acid and is the most potent endogenous activator of human FXR [78]. Obeticholic acid (OCA) is a novel 6-ethyl semisynthetic derivative of CDCA. OCA is selective for FXR and is 100-times more potent than CDCA as an agonist of FXR [81]. Animal studies suggested that 6-ethyl semi-synthetic derivative of CDCA may have choleretic and antifibrotic properties with the potential of reversing portal hypertension [82]. In an international Phase II clinical trial, 165 PBC patients were randomized to receive placebo, 10, 25 and 50 mg of OCA adjunctive to UDCA therapy. Enrolled patients were patients with PBC who had persistently elevated ALP >1.5-times ULN while on stable doses of UDCA. Patients with conjugated bilirubin > two-times ULN were excluded from the study. Following 12 weeks, patients on OCA were noted to have a 21–25% drop in ALP compared with 3% drop in the placebo group. Pruritus was the most notable side effect, most pronounced at the two higher doses of OCA. Severe pruritus was most noted in patients on 50 mg of obeticholic acid and led to the most number of drug discontinuations [83,84]. A Phase III trial of obeticholic acid on PBC patients with unsatisfactory response to UDCA or intolerant of UDCA is ongoing. Criteria for treatment success will be defined as ALP

Primary biliary cirrhosis in adults.

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bil...
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