Cirrhosis and other liver disease in cystic fibrosis

Cystic fibrosis (CF) is a common lethal genetic disease in the North American population, affecting 1:2500 births. There are about 30,000 individuals in the United States with CF, and approximately 1,000 new cases annually. Although declining lung function is the most common cause of mortality in CF [1–3], liver disease is the third leading cause of death, accounting for 2.5% of overall mortality [4,5]. In this review, we will outline proposed definitions of liver disease in CF and review the epidemiology, diagnosis, proposed pathogenesis, management and outcome of liver disease in CF focusing on multilobular cirrhosis with or without portal hypertension. While the liver is likely involved to some degree in all individuals with CF, most individuals will not develop cirrhosis, which is what most authors consider clinically significant liver disease. CF related liver disease (CFLD) is a nonspecific term without a consistent definition that has been used to refer to several liver disorders often with wide a spectrum of severity and impact on outcome, leading to confusion when comparing disease history, treatment, and outcomes. The spectrum of liver disease in variably included in CFLD has included neonatal cholestasis, elevated aminotransferases, hepatic steatosis, hepatic fibrosis, focal biliary cirrhosis and multilobular cirrhosis with or without portal hypertension. We suggest that uniform definitions would lead to consistently defined clinical and pathologic manifestations and contribute to clarity in research on the prevalence, natural history and treatment of liver disease in CF. The identification of individuals with CF who are at risk for or who will subsequently develop cirrhosis has been difficult [6]. As new therapies including those that improve the function of the cystic fibrosis transmembrane regulator protein (CFTR) become available, there will be the potential to prevent or reverse clinically significant liver disease in CF. Thus there will be a new impetus to identify individuals at risk for advanced liver disease and those with pre-cirrhotic hepatic fibrosis. Broad definitions and classifications of CFLD have been traditionally been used. The 1999 CF guidelines defined liver disease as the presence of either clinical or biochemical liver disease [7]. Several recent publications have used the following definition: The presence of at least 2 of the following conditions on 2 or more consecutive examinations over a 6–12 month period [8–10]: 1. hepatomegaly, with liver edge >2 cm below costal margin in the midclavicular line and confirmed by ultrasound. 2. at least 2 of the 3 of AST, ALT and GGTP above the upper limit of normal and 3. William's score of ultrasound abnormalities ≥4 [11] Both definitions include many disparate types of liver disease variable impact on outcome. Recent reports on the prevalence of CFLD using the broader criteria listed above, found a 30–40% prevalence of liver involvement in children and adults with CF [9,10,12]. However, longitudinal studies found that only 20–30% of individuals with CF develop focal biliary cirrhosis and at most 5–10% will develop multilobular cirrhosis [4,5,10]. Thus the broad definitions of CFLD above tend to overestimate the impact of liver disease in CF. In part due to the variability in definitions, in 2007 the CF Foundation convened a group of hepatologists who proposed the classification of liver involvement in CF shown in Table 1. Table 1 Proposed classification of CFLD. This classification separates cirrhosis with or without portal hypertension from other forms of liver disease such as elevated aminotransferases, hepatic steatosis and imaging abnormalities and defines the criteria for considering an individual as having no current clinical evidence for liver involvement in CF, primarily for the purposes of research. The definitions, clinical presentations and prevalence data for each of the categories are described below.