LIVER DISORDERS, SERIES #4 Rad Agrawal, MD, FACP, FACG, AGAF, FASGE Primary Biliary Cholangitis Duminda Suraweera Courtney Reynolds Shehan Thangaratnam Gaurav Singhvi Primary biliary cholangitis, previously known as primary biliary cirrhosis, is a chronic, cholestatic, inflammatory liver disease characterized by destruction of intrahepatic bile ducts resulting in progressive liver damage. The etiology of primary biliary cholangitis is still not fully understood but likely involves both environmental and genetic factors. If symptomatic, patients often present with fatigue and pruritus. About 95% of individuals with primary biliary cholangitis will have a positive anti- mitochondrial antibody. Current treatment options are limited primarily to ursodeoxycholic acid, while those with decompensated liver disease will require liver transplantation. We provide a review of the etiology, pathogenesis, natural history, diagnosis and management of primary biliary cholangitis. EPIDEMIOLOGY, ETIOLOGY AND PATHOGENESIS rimary biliary cholangitis (PBC) has an incidence The etiology of PBC is not fully understood, but rate of 0.9 to 5.8 per 100,000 people with an both genetic predisposition and environmental triggers Pestimated female to male ratio of 10 to 1.1-3 PBC likely play an important role. The prevalence of PBC is is more common in patients in Northern Europe, the higher in families with an affected member, indicating United Kingdom and the northern United States. The a possible genetic component. Approximately 1.2% of prevalence seems to have increased over time, currently children of PBC patients develop PBC, with the highest ranging from 1.91 to 40.2 per 100,000 people.3 The risk in daughters of women with PBC.4 Monozygotic increase in prevalence is likely multifactorial with twins have a high concordance rate of 0.63 for PBC.5 increased disease diagnosis and increased survival with Additionally, several studies have shown a link between improved treatment. HLA alleles and PBC.6-9 Several studies have shown increased incidence in areas of heavy pollution in both the US and UK, Duminda Suraweera1 Courtney Reynolds1 Shehan suggesting that environmental toxins may play a role in Thangaratnam2 Gaurav Singhvi3 1Department the development of PBC.10,11 Furthermore PBC has also of Medicine, Olive View-UCLA Medical Center, been associated with infections, reproductive hormone Sylmar, CA 2Department of Chemistry, University replacement, hair dyes, nail polish, xenobiotics and of California Berkeley, CA 3David Geffen tobacco use.4,12,13 School of Medicine at UCLA, Los Angeles, CA (continued on page 50) 48 Practical GastroenteroloGy • January 2016 Agrawal Jan 16.indd 48 1/11/16 11:28 AM Primary Biliary Cholangitis LIVER DISORDERS, SERIES #4 LIVER DISORDERS, SERIES #4 (continued from page 48) The hallmark of PBC is the destruction of small bile duct epithelial cells leading to ductopenia and persistent cholestasis. This is believed to be largely mediated by T-cell destruction.14 Hepatic damage and eventual liver failure results from ongoing retention of toxic substances.15 It is still unclear as to why biliary epithelial cells in particular are affected. Biliary epithelial cells express T-cell ligands that play a key role in induction of autolysis and may even act as antigen presenting cells, thereby amplifying the immune response.9 While it is unknown what initially triggers PBC, potential candidates include viral or bacterial infection, xenobiotics and human immunoregulatory 16 defects. Figure 1. Diagnosis is not necessary in establishing the diagnosis. A liver biopsy should be obtained when AMA is absent or if Laboratory Markers there is a mixed biochemical or clinical picture. When PBC should be considered in patients with an elevated pursuing a biopsy, it is important to obtain an adequate alkaline phosphatase level when other intrahepatic and sample, as the distribution of bile duct destruction can extrahepatic causes of cholestasis have been excluded be patchy. Generally, it is recommended that at least (Figure 1). Often abnormal laboratory markers are 10-15 portal tracts should be examined to rule out found incidentally prior to any symptom development.1 pathology.1 The characteristic histologic finding in PBC While serum aminotransferases are often elevated, is an inflammatory infiltrate centered around the bile this is not always the case. Total bilirubin may also ducts.2 Infiltrating cells form granulomas consisting be normal in early stages of the disease. Serum anti- of lymphocytes, neutrophils, macrophages and plasma mitochondrial antibody (AMA) is highly sensitive for cells. This inflammatory process mainly affects the PBC, with a positive result in 95% of patients with interlobular and septal bile ducts, sparing the large PBC and less than 1% in non-PBC patients.17-19 The extrahepatic ducts. The degree of duct deformity can targets of the anti-mitochondrial antibody all belong to be staged using Ludwig’s staging criteria (Table 1).24 the 2-oxo-acid dehydrogenase complex enzymes. They Stage 1 is described as portal inflammation, with stage function to catalyze oxidative decarboxylation of keto 2 described as an extension of this inflammation to the acid substrates in the inner mitochondrial membrane.20,21 periportal areas. Stage 3 consists of septal fibrosis or Approximately 5-10% of patients will have a negative or inflammatory bridging, and stage 4 is cirrhosis. low titer AMA. In these patients, antibodies to the major M2 components, such as PDC-E2 or 2-oxo-glutaric acid Imaging dehydrogenase complex, may be present. Antinuclear Abdominal imaging should be part of the workup for antibodies have also been shown to be present in PBC, PBC and should be pursued at the onset of laboratory though the sensitivity is typically around 40-50%.22 abnormalities or symptoms. Ultrasound is a cost- Anti-Sp100 and anti-gp210 have high specificity to effective, non-invasive test for the initial evaluation PBC and their presence is generally associated with of liver cirrhosis and has a sensitivity and specificity of more aggressive disease.22,23 Often these are specialized about 80%.25 The use of Doppler can further enhance tests that are not readily available, thus AMA should ultrasound leading to an increased sensitivity of 97% be used as a primary method for screening for PBC. and specificity of 93%.26 Ultrasound is typically the modality of choice to screen for hepatocellular carcinoma Histology in patients with cirrhosis, typically every 6-12 months.1 While liver biopsy can be helpful, in patients with a Computer tomography can aid in the exclusion of other cholestatic liver profile and positive AMA, a biopsy etiologies such as mechanical biliary duct obstruction 50 Practical GastroenteroloGy • January 2016 Agrawal Jan 16.indd 50 1/11/16 11:28 AM Primary Biliary Cholangitis LIVER DISORDERS, SERIES #4 LIVER DISORDERS, SERIES #4 Table 1. Ludwig’s Histological Staging of Primary Biliary Cholangitis Stage 1 Portal inflammation Stage 2 Inflammation of portal and periportal areas Stage 3 Septal fibrosis or inflammatory bridging Stage 4 Cirrhosis Table 2. Clinical Stages of Primary Biliary Cholangitis Pre-clinical Positive anti-mitochondrial antibody Asymptomatic Liver function test abnormalities Symptomatic Symptoms of pruritus and fatigue Advanced Cirrhosis as well as help assess for advanced disease such as predictive value of the GLOBE score for transplantation fibrosis or portal hypertension. Cholangiography may or death, calculated via C-statistics, was 0.81 (CI be pursued to exclude other biliary tract diseases such as 95%). Without treatment, the 10-year survival is 50- sclerosing cholangitis. Recently, transient elastography 70% for asymptomatic patients and estimated at 5-8 has been utilized to evaluate liver fibrosis and has been years if symptomatic; liver failure develops in 15- found to have over 90% sensitivity and specificity for 25% of patients within 5 years.1 Interestingly, portal detecting advanced fibrosis in patients with PBC.27-29 hypertension can develop prior to cirrhosis in PBC patients and most commonly manifests with esophageal Natural History varices that are present in up to a third of untreated PBC is a progressive cholestatic liver disease that in its advanced patients. The etiology is unclear but is thought end stage can progress to cirrhosis. By clinical stage, to be due to nodular regeneration.1 Thus, screening PBC can be divided into pre-clinical, asymptomatic, with endoscopy for esophageal varices should begin symptomatic and advanced, which correspond to prior to development of cirrhosis, with initiation of positive AMA only; positive AMA with liver function a non-selective beta-blocker if needed. Initiation test abnormalities; the former along with symptoms of of standardized treatment with urseodeoxycholic pruritus and fatigue; and cirrhosis, respectively (Table acid (UDCA) in the 1990s has been shown to delay 2).1 Progression is determined by whether patients progression: one trial in France showed 7% vs 34% undergo treatment and by response to treatment.30 progression from stage I or II to stage III or IV in the Recently a new scoring system has been developed to UDCA vs placebo groups.32 Nonetheless, improvement risk stratify patients with PBC using age and several in survival has been inconsistently demonstrated.33-35 laboratory markers.31 The GLOBE score is calculated Poor prognostic factors include continued elevated as follows: 0.044378 x age at start of UDCS therapy + alkaline phosphatase while on UDCA treatment, higher 0.93982 x bilirubin times the upper limit of normal at bilirubin levels, low albumin and high IgG levels.36 1-year follow-up + 0.335648 x alkaline phosphatase Lack of response to UDCA has also been linked to time the upper limit of normal at 1-year follow- higher risk of hepatocellular carcinoma once cirrhosis up – 0.002581 x platelet counts per 109/L at 1 year develops. follow-up + 1.21685. The authors found the overall Other common complications of PBC include Practical GastroenteroloGy • January 2016 51 Agrawal Jan 16.indd 51 1/11/16 11:28 AM Primary Biliary Cholangitis LIVER DISORDERS, SERIES #4 hyperlipidemia, osteoporosis and vitamin deficiencies.