Cystic Fibrosis-Associated Liver Disease
Catherine Lenaerts, MD
Gastroenterology and Hepatology Unit, Department of Pediatrics, Centre Hospitalier Universitaire, Amiens, France

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Pathogenesis and types of liver injury in CF
Frequency of hepatic and biliary disease
Clinical features of CF liver disease
Therapeutic approach
References

Introduction

Cystic fibrosis (CF), an inherited disorder of epithelial transport affecting primarily lungs, pancreas, gut, liver and exocrine glands, results from mutations of a gene located on chromosome 7. The defective protein coded by the mutated gene, cystic fibrosis transmembrane conductance regulator (CFTR), is a transmembrane chloride channel. Liver disease associated with cystic fibrosis has been increasingly diagnosed during recent years probably due to the combined effect of systematic hepatic assessment and reduced death from extra-hepatic causes of CF patients. Although the natural history of cystic fibrosis-associated liver disease suggests a benign and protracted course in most cases, it is considered a major complication of CF which may limit survival and quality of life.

Pathogenesis and types of liver injury in CF

CF-associated liver disease should be considered as the first inherited liver disorder in which the primary defect affects cholangiocyte transport systems. In the normal liver the CFTR gene is expressed in the epithelia of the intrahepatic and extrahepatic bile ducts and the gallbladder and the CFTR protein is localised to the apical domain of these cells (1). CFTR is not expressed in hepatocytes or other cells of the liver. It is therefore likely that CFTR is involved in chloride and water secretion into the bile at the ductal level (2). CFTR gene mutations cause reduced, dysfunctional or absent c-AMP-inducible chloride channel function in bile duct epithelia. Impaired or abolished CFTR-induced chloride efflux across these cells appears to result in concomitant reduction in water and sodium movement into bile. It is also possible that CFTR regulates other ion channels in bile duct epithelia. CFTR mutations most certainly lead to abnormalities in the composition, consistency, alkalinity or flow of bile which, in turn, contribute to the pathogenesis of the liver lesions observed in CF: the impaired secretory function of the biliary epithelium is considered responsible for reduced biliary fluidity and alkalinity and for subsequent bile duct damage by cytotoxic compounds or infectious agents. Although specific gene mutations have been associated with the severity of pancreatic involvement in CF, there is no relationship between genotype and clinically detectable liver disease in CF patients (3,4,5). Liver disease appears to be less frequent in pancreatic sufficient patients and could be associated with severe mutations of the CFTR gene (6). No clear association with specific CFTR mutations has been observed.

Because all CF patients have abnormal CFTR in the biliary tree, it is unclear why all patients do not develop significant liver disease. Most CF patients do not develop clinical symptoms or signs of liver disease despite the probable presence of focal biliary cirrhosis in the majority of older patients in autopsic series. The variable onset and severity of liver disease suggests that other modifying genetic or environmental factors determine if hepatobiliary involvement will be of clinical significance: polymorphisms or heterozygosity for other genes may be involved in bile flow or other modifier genes may increase the risk for the development of liver disease (7).

A spectrum of hepatobiliary lesions is observed in CF (Table I). The most important clinically is the development of biliary obstruction and periportal fibrosis. The mechanism causing these liver lesions in CF has been attributed to focal inspissation of biliary secretions in intrahepatic ducts leading gradually to the development of portal fibrosis, bridging and eventually to cirrhosis. Factors that contribute to the abnormal viscosity, decreased flow and increased concentration of components of bile in CF may be defective chloride transport, sodium reabsorption and bile dilution in intrahepatic bile ducts or increased glycine-conjugated bile acids. Altered bile composition or decreased bile flow causes obstruction of small biliary ductules that may induce collagen deposition in portal tracts in several ways: (a) secondary hepatocyte injury, e.g. by hydrophobic bile acids, may release pro-inflammatory cytokines, growth factors or lipid peroxide products that recruit and activate hepatic stellate cells to synthesize collagen. (b) injured bile duct epithelial cells may release cytokines and growth factors that induce collagen synthesis by stellate cells. (c) inflammation leads to recruitment of other cells, neutrophils, macrophages, lymphocytes, that generate cytokines responsible for the stellate cell recruitment and activation. This process begins focally in the liver, possibly because of interductal connections that may allow adequate bile drainage of some areas. As the fibrogenic process proceeds, bridging fibrosis develops into multilobular cirrhosis, so-called because of the large regenerative nodules formed as a result of the initial focal process. This progression from cholestasis to focal biliary cirrhosis to multilobular cirrhosis takes years to decades.

Other liver lesions present in CF include neonatal cholestasis and hepatic steatosis. Neonatal cholestasis occurs in conjunction with complicated meconium ileus and the use of parenteral nutrition and is characterized by inspissated, eosinophilic secretions in portal tract bile ducts. This lesion is rare in children who eventually develop cirrhosis and is not predictive of progressive liver disease (13). Hepatic steatosis is the most common hepatic lesion in CF. It occurs in about one third of the patients, is as common early in life than in older patients and occurs frequently in the presence of excellent nutritional status. Hepatic steatosis in CF may be related to malnutrition, essential fatty acid deficiency, other dietary factors, the effect of elevated levels of cytokines or the genetic defect itself. The relationship between steatosis and the development of fibrosis and cirrhosis in CF is unknown. Hepatic congestion may result from right sided congestive heart failure, not uncommon in older patients with CF. This lesion may progress to cirrhosis and liver failure.

Current prevalence rates of liver involvement in CF underestimate the true risk because of the lack of sensitive markers and because defining clinically significant liver disease in CF is difficult. Many patients with cirrhosis caused by CF are completely asymptomatic and may even have normal blood tests. In the recent literature the incidence of multilobular cirrhosis complicated with portal hypertension varies between 5 and 15%. The mean age at diagnosis of liver cirrhosis is 9 years in a series of 44 patients, 90% appearing before age 14 (8). In a larger series including the previous one, 39% of oesophageal varices are diagnosed between age 6 and 10 and 37% between age 10 and 15 ( 9).

The prevalence of focal biliary cirrhosis can only be estimated by autopsy series since this pathognomonic lesion seen only in CF is usually clinically silent and may be present with normal blood tests. It includes inspissated granular eosinophilic material within the portal ducts, bile duct proliferation, a chronic portal infiltration, variable fibrosis, and a focal distribution (10). The post-mortem incidence of focal biliary cirrhosis increases with age from more than 10% in infants dying during the first 3 months of life to 27% of children dying after 1 year of age (11) and 72% in adults (12). There is no relationship between this lesion and neonatal obstructive (13,14). Neonatal cholestasis occurs in less than 2% of infants with CF , associated with meconium ileus in half of the cases. Hepatic steatosis develops in 20-60% of CF patients and has not been correlated with outcome. Microgallbladder is present in 20-30% of patients and cholelithiasis in less than 1% of patients.

The most common clinical presentation of liver disease in CF is hepatomegaly or splenomegaly found in an asymptomatic child or adolescent on routine examination. The liver may be firm and nodular, frequently extends >2-3cm below the right costal margin or below the xiphoid, and its enlargement may be limited to either the right or left lobe. Jaundice is generally absent as are cutaneous signs of chronic liver disease and clubbing may be attributed to underlying pulmonary disease. Although clinical signs of portal hypertension such as splenomegaly, bruising may be present in less than 25%, gastrointestinal haemorrhage, ascites, porto-systemic encephalopathy are rarely the presenting features. However, complications of portal hypertension may develop and become the predominant clinical problem related to the liver disease. The other common mode of presentation of CF-related liver disease is the finding of elevated serum AST, ALT, alkaline phosphatase or GGT concentration on routine screening. Prolonged prothrombin time may be secondary to severe liver disease or vitamin K deficiency.

In the neonatal cholestasis presentation of CF, total and direct bilirubin are elevated, hepatomegaly may be present and stools have decreased pigments, leading to occasional confusion with the diagnosis of biliary atresia. The cholestatic jaundice resolves over time, however, residual fibrosis may remain. Hepatic steatosis usually presents clinically in a malnourished patient as an asymptomatic enlarged, smooth soft liver without splenomegaly or ascites and the liver appears hyperechogenic on ultrasound. Isolated steatosis is biologically silent. However, when associated with other histologic findings, liver function tests may be abnormal.

As focal biliary cirrhosis progresses to multilobular cirrhosis, portal hypertension may lead to the development of oesophageal and gastric varices presenting with hematemesis, melena or iron-deficiency anemia. Ascitis, splenomegaly and hypersplenism, encephalopathy, fatigue and coagulopathy occur late in the course as cirrhosis decompensate. Liver function tests do not reflect the severity of the disease. They are generally only slightly elevated early in the course of the disease and may be normal when portal hypertension becomes severe. Variceal bleeding is the most severe complication and occurs in one third of patients with cystic fibrosis associated liver cirrhosis, who often do not have severe respiratory failure. Injection sclerotherapy of esophageal varices does not prevent recurrence of bleeding. Elective surgical portosystemic shunting may be considered to relieve portal hypertension in patients without progressive liver failure and severe lung disease as an alternative to liver transplantation. Control of bleeding and variceal decompression allow prolonged post-operative survival up to 15 years or stabilization for many years until progression of liver or lung diseases indicates liver or lung and liver transplantation (15). Hepatic synthetic failure is a late finding and is the primary indication for liver transplantation. The presence of cystic fibrosis-associated liver disease with portal hypertension, in the setting of good synthetic function normal serum bilirubin, minimal varices, without ascites or encephalopathy, should not be an absolute contraindication to lung transplantation (16).

Ursodeoxycholic acid is a nontoxic exogenous, hydrophilic bile acid which possesses choleretic, hepatoprotective and immunomodulatory properties. Treatment with ursodeoxycholic acid, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the most useful therapeutic approach in CF-associated liver disease. Beneficial effects on liver biochemistry, hepatic excretory function, liver histology, and essential fatty acid status have been reported (17,18). In one long-term prospective study, 7 patients with hepatosplenomegaly developed no hepatic complications during a 10 year period with 20mg/kg/day and the ultrasonography remained unchanged while the size of the portal vein diameter and spleen remained stable or decreased (19). These results need to be confirmed and in the absence of randomized, placebo-controlled trials of sufficient duration, the effectiveness of ursodeoxycholic acid on clinically relevant outcomes, such as death or need for transplantation has to be demonstrated. Early diagnosis and identification of CF patients who are more liable to develop liver disease should be actively pursued (3).

References

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