The Liver and Cystic fibrosis.

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.

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.

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.

Liver disease appears to be less frequent in pancreatic sufficient patients and could be associated with severe mutations of the CFTR gene.

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.


A spectrum of hepatobiliary lesions is observed in CF.

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.

    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.