Cholestasis is the earliest and most common manifestation of CF liver disease (CFLD), which is a diagnosis of exclusion. Cystic fibrosis liver disease is seen in 6% of infants with CF, but up to 25% of those with meconium ileus.1 Dysfunctional CFTR in cholangiocytes leads to inspissated bile and bile duct plugging. Additionally, up to one-third of neonates with CF have microgallbladder.15 Clinically, these findings can be confused with biliary atresia, which should be ruled out urgently. Infants with cholestasis benefit from a formula rich in medium-chain triglycerides, which do not require bile acids or micellular formation for absorption. Currently, there is no evidence supporting the routine use of ursodiol in CF.16 Cholestasis exacerbates fat-soluble vitamin malabsorption and leads to osteopenia, due to deficiency of vitamins D and K.15 Bone density scans are part of routine monitoring.
Gallbladder disease occurs in up to 50% of children with CF.15 In addition to microgallbladder, gallbladder hypokinesis is common as well. This predisposes patients to gallbladder stasis, which can lead to gallstones, with a prevalence up to 25%, including neonates. The evaluation and treatment are the same as for the general population and should be undertaken early in anticipation of progressive pulmonary operative risk over time. Biliary scintigraphy should be considered to evaluate emptying of the cystic duct, as bile duct strictures are not uncommon. Patients with biliary strictures are also at increased risk of cholangiocarcinoma.
Hepatic steatosis has a prevalence of 23% to 70% at any age.3 It is likely multifactorial, resulting from malnutrition; CFTR dysfunction; deficiencies of choline, carnitine, essential fatty acids; or poorly controlled CFRD.1 Other non–CF-related conditions also can result in steatosis. These patients should be referred to Gastroenterology.
Transient elevations of liver enzymes and gamma-glutamyl transferase (GGT) are exceedingly common and do not predict chronic liver disease.1,17 Elevations should be followed every 1 to 2 weeks until resolved or stable. Abnormalities persisting beyond 6 months should be evaluated with complete abdominal ultrasound with liver vascular duplex and referral to Gastroenterology. Hepatosplenomegaly should prompt earlier referral. Standard evaluation for chronic elevation of transaminases includes consideration of infectious hepatitis, drug-induced liver disease (from modulators, antibiotics, etc.), autoimmune hepatitis, Wilson disease, alpha-1-antitrypsin disease, and celiac disease.18
Cystic fibrosis liver disease is the 3rd-leading cause of death in CF following lung disease and transplant complications, and constitutes 2.5% of mortality in CF.16 Incidence increases every year from birth reaching 32% by age 25 years and then levels out. There is a higher prevalence among males, those homozygous for F508del, and those with a history of meconium ileus. Synthetic function is usually preserved. Cystic fibrosis liver disease is thought to be a consequence of bile ductule inspissation that starts out as areas of focal biliary cirrhosis with progression to multilobular cirrhosis and a nodular liver on exam. Five percent to 10% of patients have multilobular cirrhosis before adolescence.18 The most significant consequence of CFLD is progression to portal hypertension, which can lead to varices and hypersplenism. Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in this context due to resultant thrombocytopenia. Varices are treated with banding, and transjugular intrahepatic portosystemic shunt is considered with recurrent bleeding as bridge to liver transplantation.
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