Optimising risk stratification in primary biliary cirrhosis: AST/platelet ratio index predicts outcome independent of ursodeoxycholic acid response.

BACKGROUND & AIMS: Outcomes in primary biliary cirrhosis (PBC) can be predicted by biochemical response to ursodeoxycholic acid (UDCA). Such stratification inadequately captures cirrhosis/portal hypertension, recognised factors associated with adverse events. METHODS: We evaluated a cohort of PBC patients (n=386) attending the Liver Unit in Birmingham (derivation cohort), seeking to identify risk-variables associated with transplant-free survival independent of UDCA-response. A validation cohort was provided through well-characterised patients attending the Toronto Center for Liver Diseases (n=479) and Jena University Hospital (n=150). RESULTS: On multivariate analysis, factors at diagnosis associated with liver transplant (LT)/death were patient age (HR:1.06; p<0.001), elevated bilirubin (HR:1.27; p<0.001), early-onset cirrhosis (HR:2.40; p<0.001) and baseline AST/platelet ratio index (APRI) (HR:1.95; p<0.001). At 1-year, UDCA biochemical non-response predicted poorer transplant-free survival, and additional factors (multivariate) associated with adverse outcome were age (HR:1.02; p<0.05) and 1-year APRI (HR:1.15; p<0.001). Obtaining a cut-point from our derivation cohort, APRI >0.54 at baseline was predictive of LT/death (adjusted HR: 2.40; p<0.001), and retained statistical significance when applied at 1-year (APRI-r1, adjusted HR:2.75; p<0.001) despite controlling for UDCA-response. Across both cohorts, transplant-free survival was poorer for biochemical-responders with an APRI-r1 >0.54 vs. biochemical-responders with a lower APRI-r1 (p<0.01 and p<0.001, respectively); non-responders with high APRI-r1 had the poorest outcomes (p<0.001 and p<0.001). CONCLUSION: In PBC, elevated APRI is associated with future risk of adverse events, independently and additively of UDCA-response. This cross-centre, robustly validated observation will contribute to ongoing efforts to refine existing risk-stratification tools, as well as direct focus for new therapies in patients with PBC.

Good maternal and fetal outcomes for pregnant women with primary biliary cirrhosis.

BACKGROUND & AIMS: Up to 25% of patients diagnosed with primary biliary cirrhosis (PBC) are of childbearing age. However, little is known about disease course during pregnancy. METHODS: We performed a retrospective analysis of women with PBC during pregnancy using a representative large cohort of patients attending the Liver Center at Toronto Western hospital from January 1979 through June 2009 (n = 306). Statistical analysis was performed by using R statistical software. RESULTS: We identified 32 women (50 pregnancies) who either became pregnant after a diagnosis of PBC or in whom pregnancy led to diagnosis. Liver biochemistry remained stable in most patients (70%) throughout pregnancy. However, 23 of 32 patients (72%) had a flare in biochemical disease activity post partum, which was unrelated to biochemical disease activity before conception (P = .53), or during the gestational period (P = .14). No adverse maternal events were observed during pregnancy or post partum, and only 2 of 32 of women (6%) developed progressive disease after delivery. De novo pruritus developed during pregnancy in 17 of 32 women (53%), whereas itch that existed before conception worsened for 4 patients. Fifteen of 21 women (71%) with pregnancy-related pruritus required symptom-specific therapy. Twenty-nine of 32 women (91%) had at least 1 successful live birth; adverse fetal outcome was not influenced by biochemical disease activity before conception (P = .24) or during pregnancy (P = 1.00). CONCLUSION: Pregnancy in women with PBC is frequently symptomatic but mostly uneventful. The majority of women maintain stable liver biochemistry during pregnancy, although postpartum biochemical exacerbations are common.

Natural history and management of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. It is a rare disease with prevalence of less than one in 2000. Its prevalence in developing countries is increasing presumably because of growth in recognition and knowledge of the disease. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The prognosis of PBC has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches.

The spectrum of sclerosing cholangitis and the relevance of IgG4 elevations in routine practice.

OBJECTIVES: American Association for the Study of Liver Diseases (AASLD) guidance recommends measurement of IgG4 in patients with sclerosing cholangitis (SC). The objective of this study was to evaluate this by analyzing our SC practice. METHODS: Characteristics were collected on 168 patients with radiological or biopsy proven SC; IgG4 was measured and magnetic resonance cholangiopancreatography studies were reviewed. RESULTS: In all, 49% of patients were females and 55% had inflammatory bowel disease. Large duct disease was present in 63%, small duct disease in 8%, overlap with AIH in 11%, and secondary SC in 18%. Secondary etiologies included autoimmune pancreatitis (AIP) (8%), intra-hepatic cholelithiasis (3%), portal vein thrombosis (2%), and neonatal Kasai (2%). In all, 101 patients had sufficient radiology and serology for re-evaluation. IgG4 was elevated (>104 mg/dl) in 22% of patients. This was associated with male gender (73%; P=0.016), a past history of pancreatitis (27% vs. 5%; P=0.007), a higher alkaline phosphatase (ALP) value, median 338.5 U/l vs. 160 (P=0.005), and a higher primary sclerosing cholangitis (PSC) Mayo risk score, mean 0.6 vs. -0.2 (P=0.0008). Prior biliary intervention was more likely (36 vs. 13%; P=0.023), while abnormal pancreatic imaging was noted in 15%, more frequently if IgG4 was elevated (40 vs. 8%; P=0.0007). After excluding those with pancreatic disease on magnetic resonance imaging, 14 patients had elevated IgG4. This group had higher ALP 379 U/l vs. 155.5 (P=0.0006), aspartate aminotransferase (AST) 72.5 U/l vs. 34 (P=0.0005), alanine aminotransferase (ALT) 90.5 U/l vs. 36 (P=0.004), and PSC Mayo risk score values 0.4 vs. -0.2 (P=0.017). CONCLUSIONS: SC is a heterogeneous liver injury. IgG4 testing may be clinically important in all patients, since it appears to identify a distinct patient population, more so than just those with AIP.

The specificity of fatigue in primary biliary cirrhosis: evaluation of a large clinic practice.

UNLABELLED: Quality of life is an important concern for patients with chronic liver disease. We sought to describe the frequency, severity, and associations of fatigue, in patients with primary biliary cirrhosis (PBC). We performed association testing between PBC-40 multidomain disease-specific quality of life responses and clinical findings. Three hundred twenty-seven patients from a single clinic with PBC (94% female, 92% AMA-positive) were evaluated. The average age was 57 years and average disease duration 7.2 years. Verbally reported fatigue was noted in 48% but present in the overwhelming majority on PBC-40 completion, with 44% having moderate or severe symptoms. Of those not complaining of fatigue clinically, 25% documented moderate or severe fatigue by questionnaire. Age had an inverse relationship with fatigue (P < 0.01), whereas body mass index (BMI) was positively associated (P < 0.01), as was the presence of pruritus (P < 0.001), sicca symptoms (P < 0.001), depression (P < 0.001), fibromyalgia (P < 0.004), and scleroderma (P < 0.05). For those with varices (P < 0.05) or cirrhosis clinically (P < 0.05), higher fatigue scores were noted, although those who initially presented with noncirrhotic disease had higher scores at the time of testing (P < 0.005). Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta-blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05). In a multivariate model, calcium and vitamin D use, BMI, stage of disease at diagnosis, as well as symptomatic fatigue or pruritus, were significant. Biochemical response to UDCA was not associated with lower fatigue scores. CONCLUSION: Attempts at defining the biological basis of fatigue in patients with PBC, and improving its treatment, must account for its multifactoral causes.