Recommendations for Management of Liver and Biliary Tract Disease in Cystic Fibrosis

Although involvement of the liver and biliary tract has been recognized as a complication of cystic fibrosis (CF) since Anderson's initial description of CF in 1938 ⁽¹⁾, the clinical significance of hepatobiliary disease in CF has not been well characterized until recently. The clinically silent development of liver complications has often been eclipsed by the obvious manifestations of pulmonary and pancreatic abnormalities. Because of improved life expectancy in the past 2 decades, now reported to be 31 years, liver disease has assumed greater importance to patients with CF and those involved in their care. Unfortunately, clinical identification of liver disease in CF has been difficult and inaccurate because of the general absence of symptoms of the developing fibrotic liver lesion. Thus, early diagnosis and therapeutic intervention has not been possible. In recent years, advances in our understanding of the function of the cystic fibrosis transmembrane conductance regulator (CFTR) in bile duct epithelia and of the mechanisms of fibrogenesis in the liver have provided a stronger scientific basis for the pathogenesis of disease, leading to insights concerning potentially novel therapeutic approaches. For these reasons, the Cystic Fibrosis Foundation has recognized the need to revise the previous Recommendations for Management of Liver and Biliary Tract Disease in Cystic Fibrosis, published in 1989, to reflect the new scientific advances and clinical information in this area.

Basic Defect in Biliary Epithelium

The cftr gene in the normal human liver is expressed in the epithelia of the intrahepatic and extrahepatic bile ducts and the gallbladder, and the CFTR protein is localized to the apical domain of these cells ⁽²⁾. CFTR is not expressed in hepatocytes or other cells of the liver ⁽²⁾. It is therefore probable that CFTR is involved in chloride and water secretion into bile at the ductal level ⁽³⁾. CFTR gene mutations cause reduced, dysfunctional, or absent cyclic adenosine monophosphate-inducible chloride channel function in bile duct epithelia ⁽³⁾; thus, 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. The role of CFTR, relative to that of other chloride channels, in increasing bile flow and diluting biliary fluid remains to be determined. However, CFTR mutations most certainly cause abnormalities in the composition, consistency, alkalinity or flow of bile which, in turn, contribute to the pathogenesis of the liver lesions observed in CF. Although specific gene mutations (genotypes) have been associated with the severity of pancreatic involvement in CF, there is no correlation between the frequency of occurrence of the cftr mutation or genotype and clinically detectable liver disease in patients with CF ^(4-6). However, there appears to be a lower frequency of liver disease in pancreatic-sufficient patients with CF ^(7,8).

Because all patients with CF have abnormal CFTR in the biliary tree, it is unclear why significant liver disease does not develop in all patients. In fact, most patients with CF do not show clinical symptoms or signs of liver disease, despite the probable presence (based on autopsy series) of focal biliary cirrhosis in most older patients. This variable onset and severity of liver disease suggests that there are other modifying genetic or environmental factors that determine whether hepatobiliary involvement will be of clinical significance in a given case. In this regard, Duthie et al. ⁽⁹⁾ found that the HLA haplotype B7-DR15-DQ6 was associated with an increased risk of chronic liver disease in male patients with CF, implicating a possible immune pathogenesis of hepatobiliary injury in addition to the CFTR defect. It should be pointed out that, as the median survival improves in CF, a longer time is available for the progression of portal fibrosis and cirrhosis; thus, complications of liver disease and portal hypertension may become more common.

Pathogenesis of Hepatobiliary Injury in Cystic Fibrosis

A spectrum of hepatobiliary lesions is observed in CF (Table 1). 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 bile ducts, leading gradually to the development of portal fibrosis, bridging and, eventually, cirrhosis (Figure 1). 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; impaired secretion of mucins and other protective proteins from submucosal glands; 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: Secondary hepatocyte injury (e.g., by hydrophobic bile acids) may release proinflammatory cytokines, growth factors, or lipid peroxide products that recruit and activate hepatic stellate to synthesize collagen ⁽¹⁰⁾; injured bile duct epithelial cells ⁽¹¹⁾ may release cytokines and growth factors that induce collagen synthesis by stellate cells ⁽¹²⁾; and 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 ⁽¹³⁾. 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 (decreased bile flow) to focal biliary cirrhosis to multilobular cirrhosis takes years to decades and should be viewed as a continuum. The contribution of apoptosis (programmed cell death) of the bile duct epithelia or hepatocytes to the liver lesions in CF has not been determined, although it has been suspected in other biliary diseases ⁽¹⁴⁾. Although it has been claimed that extrahepatic stenosis of the common bile duct (as it courses through the pancreas) often contributes to the hepatic fibrosis in CF ⁽¹⁵⁾, subsequent reports indicate that this phenomenon is rare ^(16,17).

TABLE 1: Hepatobiliary manifestations of cystic fibrosis

FIG. 1: Proposed pathogenesis of hepatobiliary dysfunction, liver injury, and biliary fibrosis in cystic fibrosis. cftr = cystic fibrosis transmembrane conductance regulator gene.

Other liver lesions present in CF include neonatal cholestasis and hepatic steatosis. Neonatal cholestasis generally occurs in conjunction with complicated meconium ileus and the use of parenteral nutrition ⁽¹⁸⁾ and is characterized by inspissated, eosinophilic secretions in portal tract bile ducts. Among patients in whom cirrhosis eventually develops, this lesion is rare ⁽⁴⁾, thus raising the question of whether it is predictive of progressive liver disease. Hepatic steatosis in CF may be related to malnutrition ⁽¹⁹⁾, essential fatty acid deficiency ⁽²⁰⁾, other dietary factors ⁽²¹⁾, the effect of elevated blood levels of cytokines (e.g., tumor necrosis factor) ⁽²²⁾, ethanol ingestion in older patients, or perhaps the genetic defect itself. Curiously, many cases of steatosis occur in the presence of excellent nutritional status. The relationship between steatosis and the development of fibrosis and cirrhosis in CF is undetermined; however, in other clinical scenarios, steatosis may progress to cirrhosis ^(23,24). Hepatic congestion may result from right-side congestive heart failure, not uncommon in older patients with CF. Over years, this lesion may progress to cirrhosis and liver failure. The pathogenesis of microgallbladder in CF is unknown; however, the high expression of CFTR in fetal gallbladder ⁽²⁵⁾ suggests the possibility of a developmental abnormality.

Prevalence of Hepatic and Biliary Disease

Because there are no sensitive diagnostic markers of liver involvement in CF, current prevalence rates should be considered estimates that most likely underestimate the true risk (Table 1). Defining "clinically significant liver disease" in CF is problematic. Many patients with cirrhosis caused by CF are well compensated and completely asymptomatic and may even have normal readings in liver blood tests. However, these patients are prone to decompensation (development of gastrointestinal hemorrhage, ascites, fatigue, weight loss, anorexia, jaundice and pruritus, encephalopathy, hypersplenism) caused by disease progression, viral infection, or other poorly defined factors. Thus, current hepatology practice is to identify patients with portal fibrosis, cirrhosis, or portal hypertension of any cause early in its course; take measures to anticipate, prevent, and treat complications; and educate the patient and family about symptoms, complications, and treatment of liver disease and portal hypertension, even if intervention is to be delayed. Patients with CF should be treated no differently. The presence of hepatic disease may also influence the choice and dosage of antibiotics and other medications.

The literature contains recent prevalence data from three sources that provide different prevalence estimates: voluntary reporting to the CF Foundation National CF Registry from U. S. CF centers ⁽²⁶⁾, retrospective review of single-center experience ^(27,28), and prospective evaluation (including imaging studies) for frequency of hepatobiliary abnormalities ^(15,4). Data reported on 19,064 patients to the CF Foundation Registry in the U.S. in 1996 illustrate the underestimation of disease prevalence by voluntary reporting. The Registry data indicated a prevalence of hepatic cirrhosis (with portal hypertension) from a low of 0.1% in patients 2 to 5 years of age, to a peak of 1.7% in those 18 to 24 years of age, to 1.4% in those aged 45 or more years, for an overall prevalence rate of 1.0% ⁽²⁶⁾. Gallbladder disease requiring surgery was one third as common as cirrhosis. Elevated serum liver enzymes were reported in 2.4% of patients and liver disease that required gastroenterology consultation was reported in 2.0% of patients. Hepatic disease was the primary cause of death in 1.6% of deaths, the second most common cause of death after pulmonary decompensation. Fourteen patients underwent liver transplantation in 1996.

Scott-Jupp et al. ⁽²⁸⁾ retrospectively examined records of 1100 patients with CF from seven centers in the United Kingdom and found that 4.2% had clinical liver disease (defined as hepatomegaly, splenomegaly, or both). Elevated liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], or γ-glutamyl transpeptidase [GGT]) were present in 12.9% of those examined. Clinically apparent biliary tract disease (defined as biliary colic plus gallstones visible in imaging studies) was present in 0.55% of patients. Clinically apparent liver disease peaked in patients aged 16 to 20 years (8.7%) and declined among patients aged 20 or more years (4.1%), possibly because a larger proportion of older patients are more likely to have "milder" genetic mutations. In most patients, hepatomegaly was an incidental finding noted on examination. Feigelson et al. ⁽²⁷⁾ reported from Paris a prevalence of 7% of multilobular cirrhosis, 90% of which appeared in patients aged less than 14 years. In both of these studies, investigators found a slight predominance in males, possibly because of the survival advantage in males with CF. Cholelithiasis was present in 0.8% of patients and was unrelated to the presence of cirrhosis. Thirty percent of patients had a transient increase in liver enzymes in the absence of multilobular cirrhosis. In a retrospective review of 233 patients (aged more than 15 years) with CF, 24% were found to have hepatomegaly or persistently abnormal liver blood tests ⁽¹⁶⁾. Thirteen patients underwent cholangiography, two of which had common bile duct strictures.

In two prospective studies, investigators evaluated changes in serum concentrations of AST and alkaline phosphatase in infants and children with CF in North America. Sokol et al. ⁽²⁹⁾ studied a series of 99 infants in Denver, Colorado, identified by newborn screening for CF (excluding those with meconium ileus) for the first 8 years of life and found that, overall, 27% of alkaline phosphatase values and 38% of AST values were above the upper limit of normal for age. The frequency of elevated AST values was: age 6 months, 51%; 12 months, 56%; 2 years, 38%; 3 years, 23%; 4 years, 18%; 5 to 6 years, 15%; and 6 to 8 years, 13%. The frequency of elevated alkaline phosphatase values was: age 6 months, 39%; 12 months, 29%; 2 years, 25%; 3 to 6 years, 15%; and 7 to 8 years, 6%. Most patients had elevations less than 1.5 times the upper limit of normal. Kovesi et al. ⁽³⁰⁾ evaluated in Ontario the correlation of cftr mutations to the prevalence of abnormal AST and alkaline phosphatase levels in 526 patients with CF of all ages. Abnormal AST or alkaline phosphatase was present in 46% of 267 patients homozygous for ΔF₅₀₈ compared with 20% in 25 pancreatic-sufficient patients with mild missense mutations. The prevalence rate was 22% among all 69 pancreatic-sufficient patients, including those with unknown genotypes. Among other genotypes, the prevalence rate was 34% to 60%. Again, most patients had elevations of AST and alkaline phosphatase levels less than 1.5 times the upper limit of normal. Although the absolute frequencies of abnormal AST and alkaline phosphatase differed in these two studies, clearly, slight elevations of liver blood test results are common in patients with CF, and the significance of such increases should be determined.

In two prospective studies, investigators in other countries evaluated the frequency of liver abnormalities in patients with CF. In a prospective evaluation of 153 patients with CF aged 4 to 19 years in New South Wales, Australia, Gaskin et al. ⁽¹⁵⁾ found that 30% of patients had hepatomegaly, 9% had elevated liver enzyme without hepatomegaly, and 13% were judged to have multilobular cirrhosis by clinical, biochemical, and imaging criteria. In a similar study, Colombo et al. ⁽⁴⁾ prospectively evaluated 189 patients with CF over 3 years of age in Milan, Italy. Thirty percent of patients had hepatomegaly, 5.8% had splenomegaly, and 16.9% had abnormal levels of liver enzymes. Liver disease (defined as firm hepatomegaly, persistent elevation of at least two liver enzymes, and abnormal ultrasound features of the liver) was present in 17% of patients. Because the results of these two prospective studies are similar, although criteria used to define liver disease were different, the best current estimate for clinically significant liver disease (i.e., probable significant hepatic fibrosis leading to some degree of liver dysfunction) in children with CF is approximately 13% to 17%. However, the presence of hepatomegaly in 30% of patients in both studies suggests that the incidence of significant portal and biliary fibrosis may be higher. Historical data had suggested a prevalence of 5% in those aged more than 12 years, and 10% in those aged more than 25 years ⁽³¹⁾.

The prevalence of focal biliary cirrhosis can only be estimated by autopsy series, because this lesion is usually clinically silent and may be present with normal liver blood test results. The disease was identified after death in 10% of infants dying in the first 3 months of life, in 27% dying after 1 year ⁽³²⁾, and in 72% of adults ⁽³³⁾. Unfortunately, these are old data, gathered at a time when median survival in CF was low and malnutrition was common. However, more recent incidence figures have not been accumulated since the advent of improved treatments and prognosis in CF. Neonatal cholestasis occurs in less than 2% of infants with CF and is associated approximately 50% of the time with meconium ileus ⁽³⁴⁾. Cirrhosis has been reported to develop in 15% to 20% of such infants. Hepatic steatosis develops in 20% to 60% of patients with CF and has not been correlated with outcome. Microgallbladder is present in 20% to 30% of patients ⁽³⁵⁾ and cholelithiasis in less than 1% ^(26,27,30). Common bile duct stenosis is a rare complication of CF, occurring in less than 1% to 2% of patients at most centers. Sclerosing cholangitis is usually diagnosed on the basis of findings in endoscopic retrograde cholangiopancreatography (ERCP), which can be misleading in the face of biliary cirrhosis and inspissated, thickened biliary secretions. Therefore, the true incidence in CF is unknown but certainly is low. Cholangiocarcinoma has rarely been observed in patients with CF but must be considered in the adult with new onset of biliary obstruction or with worsening obstructive jaundice, abdominal pain, or weight loss in patients with long-standing hepatobiliary involvement ⁽³⁶⁾.

Clinical Features

One of the common clinical presentations of liver disease in CF is that of an asymptomatic child or adolescent who is found to have hepatomegaly or splenomegaly on routine physical examination. The liver may be firm and nodular, frequently extending more than 2 to 3 cm below the right costal margin or below the xiphoid, and its enlargement may be limited to the right or left lobe. Cutaneous signs of chronic liver disease (jaundice, palmar erythema, and spider hemangiomas) are rarely present, and peripheral cyanosis or clubbing may be attributed to underlying pulmonary disease. Jaundice is generally limited to patients with CF with neonatal cholestasis, cholelithiasis, and end-stage liver disease. Although clinical signs of portal hypertension (splenomegaly, bruising) may be present (in <25% of cases), gastrointestinal hemorrhage, ascites, portosystemic encephalopathy, and spontaneous bacterial peritonitis are rarely the initial symptoms. However, over time, complications of portal hypertension may develop and become the predominate clinical problem related to the liver disease. The other common manifestation of CF-related liver disease is elevated serum AST, ALT, alkaline phosphatase, or GGT concentrations on routine screening. Hyperbilirubinemia generally occurs late in the course of liver disease or from common bile duct obstruction or drug-induced hemolysis. Elevated blood ammonia is only present when liver disease is severe. Prolongation of the prothrombin time may be secondary to severe liver disease or vitamin K deficiency.

In neonatal cholestasis associated with CF, total and direct bilirubin levels are elevated, hepatomegaly may be present, and stools have decreased pigment, leading to occasional confusion with the diagnosis of biliary atresia. The cholestatic jaundice resolves over time; however, residual hepatic fibrosis may remain. Hepatic steatosis usually manifests clinically in a malnourished patient as an asymptomatically enlarged, smooth, soft liver without splenomegaly or ascites. Cholelithiasis is usually asymptomatic but has symptoms of right upper quadrant or right shoulder pain, jaundice, nausea and vomiting, or pruritus and elevated alkaline phosphatase, GGT, or bilirubin. Sclerosing cholangitis generally has features of hepatomegaly and pruritus, occasionally with fever, and elevated alkaline phosphatase and GGT. This manifestation is rare in patients with CF.

As focal biliary cirrhosis progresses to multilobular cirrhosis, complications of portal hypertension and nutritional deficiencies appear at an unpredictable pace. Portal hypertension may cause development of esophageal or gastric varices presenting with hematemesis, menena or iron-deficiency anemia. Ascites, splenomegaly and hypersplenism, encephalopathy, fatigue and coagulopathy occur late in the course as cirrhosis decompensates. Hepatic synthetic failure is a late finding and is the primary indication for liver transplantation. Impaired bile flow may enhance fat malabsorption and cause increased diarrhea, weight loss, and clinical signs of fat-soluble vitamin deficiencies (vitamin A, associated with night blindness, dry skin rash, xerophthalmia; vitamin D, with rickets, osteomalacia, bone fractures; vitamin E, with hemolytic anemia, hyporeflexia, ataxia, decreased vibratory and position sensations, opthalmoplegia; vitamin K, with bruising, epistaxis, bleeding) ⁽³⁷⁾.

Cholecystitis causes abdominal pain, classically in the right upper quadrant, back or right shoulder, and is exacerbated by meals. However, poorly localized abdominal pain may also be caused by chronic cholecystitis in CF. Colicky abdominal pain and/or acute onset of jaundice suggest common bile duct or cystic duct obstruction caused by stones or sludge. Fever, vomiting, and pale stools may also accompany complicated gallstone disease.

Several investigators have suggested that the presence of meconium ileus or distal intestinal obstruction syndrome is a risk factor for development of liver disease in CF. Maurage et al. ⁽³⁸⁾ reported this risk factor to be present in 50% of patients with CF-associated cirrhosis and 14% of those without. Similarly, Colombo et al. ⁽⁴⁾ described an incidence of 35.3% in patients with liver disease but of only 12.3% in patients with CF and no liver disease. Despite this apparent association, most patients with CF with significant liver disease do not have a history of meconium ileus.

Diagnostic Evaluation

In the past, liver disease in patients with CF was usually identified because of complications of liver involvement or at surgery or autopsy. Today, asymptomatic hepatomegaly or elevated serum liver enzymes obtained as screening tests are the typical scenarios for suspected liver disease. The extent and pace of the diagnostic evaluation depend on the suspected severity of liver involvement, the presence of complications, and the overall clinical status of the patient. Persistent hepatomegaly (increased span of the liver) or splenomegaly, a firm or hard consistency of the liver on palpation, persistently abnormal liver blood test results, complications of portal hypertension, or abnormal liver histology establish the presence of significant liver involvement. Other common liver diseases that should be considered in the differential diagnosis are listed in Table 2. The evaluation should include the following:

TABLE 2: Differential diagnosis of hepatobiliary disease in cystic fibrosis^a

Historical information obtained should include: a thorough neonatal history including incidence of jaundice or pruritus; change in activity or school performance; bruising or bleeding; anemia; edema or abdominal swelling; nausea or abdominal pain; change in stool color or frequency; poor weight gain or weight loss; fatigue; intake of medications, herbs, or nutrient supplements; alcohol ingestion; and family history of liver disease. The physical examination should include percussion and palpation of the entire liver and measurement of the liver span at the right midclavicular line ⁽³⁹⁾ (percussion should be used for the upper border of the liver and the lower border if the liver does not extend below the right costal margin); recording the distance that the liver edge extends below the right costal margin and below the xiphoid and the distance that the spleen extends below the left costal margin; noting the liver edge's texture and firmness; assessing the presence of dilated abdominal veins, ascites, and peripheral edema; and identifying cutaneous (e.g., palmar erythema, spider hemangiomas, scleral icterus, clubbing) and neurologic features of cirrhosis. Clinical signs of specific nutrient deficiencies should be sought (including hyporeflexia, ataxia, ophthalmoplegia, and decreased position and vibratory sensation with insufficient vitamin E; xerosis of the cornea and impaired night vision, vitamin A; and bruising or epistaxis, vitamin K). Nutritional status and cardiac function should be evaluated clinically.

Biochemical evaluation for liver injury and function should include serum AST, ALT, total and direct bilirubin, alkaline phosphatase, GGT, total protein, albumin, prothrombin time, blood ammonia, cholesterol, and glucose and a complete blood count to check for hypersplenism. There is a suggestion that fasting serum bile acid concentrations may be an early indicator of the presence of liver dysfunction in CF ⁽⁴⁰⁾. However, serum bile acid levels rarely influence clinical decision making, and should be regarded as a research tool at the present time. It has been suggested that elevated high-molecular-mass alkaline phosphatase is strongly predictive of liver disease ⁽⁴¹⁾, that serum glutathione S-transferase B₁ activity predicts liver dysfunction in CF ⁽⁴²⁾, and that elevations of serum collagen VI levels correlate with fibrosis in CF ⁽⁴³⁾; however, these observations remain to be confirmed. To screen for other causes of liver disease, a determination of anti-nuclear antibody, anti-smooth muscle antibody and anti-liver-kidney-microsomal antibody (autoimmune hepatitis); α₁-antitrypsin level and phenotype; HBsAg and hepatitis C antibody; ceruloplasmin (Wilson's disease); and iron and iron-binding capacity (hemochromatosis) should be considered when clinically appropriate.

Ultrasonography of the liver, biliary tract, gallbladder, spleen and hepatic vasculature provides useful information and should be performed initially in all patients in whom liver disease is suspected ⁽³⁵⁾. Ultrasound is most helpful in determining the presence of gallstones, common bile duct stones, ascites, and bile duct or hepatic vein dilatation. The test is less useful for the detection and quantification of hepatic fibrosis or cirrhosis because periportal steatosis can appear sonographically similar to focal fibrosis in the liver, both lesions being common in CF. Doppler ultrasound can detect dilatation and flow patterns of hepatic vasculature. Dilated hepatic veins suggest that increased right heart pressure (secondary to pulmonary disease and cor pulmonale) may be contributing to hepatomegaly. Portal hypertension is suggested by decreased portal venous flow velocities or reversal of flow (hepatofugal) in the portal veins. However, in one study, Doppler ultrasound was found to be an inaccurate assessment of portal hypertension and the presence of varices in CF ⁽⁴⁴⁾. Thrombosis of the portal or splenic veins as a cause of splenomegaly can also detected by ultrasound.

Hepatobiliary scintigraphy (iminodiacetic acid [IDA] derivatives) has limited clinical utility compared with ultrasound. ^99mTc-IDA derivatives administered intravenously are cleared from the circulation by hepatocytes, excreted into the canaliculus and bile ducts, stored in the gallbladder, and excreted into the duodenum. Liver uptake biliary secretion rates, and mean hepatic residence time can be calculated ⁽⁴⁵⁾. Thus IDA scanning may provide quantitative data about liver function in a research setting. Biliary tree obstruction, abnormal gallbladder function, and common bile duct stenosis can be determined, albeit with poor resolution compared with that provided by cholangiography ⁽⁴⁶⁾. Dilatation of the biliary tree cannot be accurately determined by scintigraphy. Scintigraphy may be helpful in demonstrating absence of gallbladder filling that is characteristics of cholecystitis. Although it has been claimed that scintigraphy should be used to determine whether ursodeoxycholic acid (UDCA) therapy should be initiated ⁽⁴⁷⁾ and that it is of value in monitoring the therapeutic response to this agent ⁽⁴⁸⁾, neither of these proposals has been validated in controlled clinical trials.

Endoscopic retrograde cholangiopancreatography can reveal strictures, dilatation, stones, and other abnormalities of the biliary tree. Because it is invasive and usually requires general anesthesia in children, ERPC is reserved for investigating dilated or narrowed bile ducts identified on ultrasonography or scintigraphy that may be causing clinical symptoms, suspected common bile duct or intrahepatic biliary stones, or suspected biliary colic. Although changes in intrahepatic bile ducts are common in CF liver disease ⁽¹⁶⁾, common bile duct stenosis is much less common (<10% of patients with advanced liver disease) ⁽¹⁶⁾ than initially reported ⁽¹⁵⁾. ERCP can also be used as a therapeutic intervention to dilate strictures, extract impacted biliary stones, and place biliary stents or perform sphincterotomy to improve common bile duct drainage. It should be pointed out that these procedures should be used only when there are clear clinical indications. In some centers, percutaneous transhepatic cholangiography is used instead of ERCP to delineate and intervene in the biliary tree.

Upper gastrointestinal endoscopy is the most sensitive way to detect esophageal varices, gastric varices, portal hypertensive gastropathy, or gastric and duodenal ulcers. It is indicated for upper gastrointestinal bleeding in a patient with CF. If esophageal variceal hemorrhage is suggested or present at the time of endoscopy, sclerosis or band ligation of varices should be performed endoscopically ⁽⁴⁹⁾. It is not recommended that all children or adolescents with suspected or known liver disease undergo endoscopy, because varices in children that have not bled are generally not treated, unless unusual circumstances prevail. In adults with esophageal varices caused by other forms of cirrhosis, β-blocker therapy reduces the risk of the first episode of variceal hemorrhage ^(50-52). Therefore, endoscopy should be considered in adults with CF and portal hypertension to determine whether prophylactic β-blocker therapy should be initiated to prevent variceal bleeding. Side effects of β-blockers are discussed in a later section.

Computed tomography is useful to exclude mass lesions in the liver or biliary tree and may help differentiate hepatic steatosis from fibrosis. However, it is used infrequently in the usual evaluation of suspected liver disease in the patient with CF. Magnetic resonance imaging cholangiography is a new noninvasive technique for visualizing the biliary tree that has not been tested in CF, but may prove to be helpful in examining the extrahepatic biliary tree, gallbladder, and major intrahepatic ducts ⁽⁵³⁾. Abdominal radiographs, upper gastrointestinal contrast radiographs, and oral cholecystography are generally not helpful in evaluating the patient with CF and associated liver disease.

Liver biopsy may be useful for determining whether steatosis or focal biliary cirrhosis is the predominant abnormality, for determining the extent of portal fibrosis or cirrhosis, and for demonstrating absence of other lesions. However, not all clinicians think that liver biopsy is indicated in investigating liver disease in CF, because there is no definitive therapy. In CF, percutaneous liver biopsy should be performed only after ultrasonographic determination of a safe location for the biopsy, avoiding the right lower lobe of the lung, and aiming toward sonographically involved liver. Percutaneous liver biopsy is contraindicated if significant dilatation of hepatic veins (indicative of cor pulmonale) or of intrahepatic bile ducts is present, if coagulopathy cannot be corrected, if significant ascites is present, if platelet count cannot be increased to more than 60,000-80,000/µl, or if the patient cannot be safely sedated because of lung involvement. Transjugular or laparoscopic liver biopsy should be considered under these circumstances, if deemed necessary.

Management of Liver Disease

A multidisciplinary team approach should be involved in the diagnosis and treatment of hepatobiliary complications of CF. This team should include the CF center team, a pediatric (for children or adolescents) or internist (for the older patients) gastroenterologist-hepatologist, a nutritionist-registered dietitian, a pediatric or adult surgeon experienced in hepatobiliary surgery, and a radiologist. The approach to managing CF hepatobiliary disease includes screening for liver disease, medical management, nutritional therapy, management of portal hypertension, management of liver failure, and prophylactic therapy. When the patient has reached the stage of decompensated cirrhosis, it is essential that there be a close working relationship with a liver transplantation center. It should be recognized that the following recommendations may be changed over time as new knowledge and information are acquired.

Screening for Liver Disease

The first component of managing CF-related liver disease is the identification of those patients with clinically significant liver involvement. Careful examination and measurement of the liver and spleen by palpation and percussion should be performed art each clinic visit. Both the right and left lobes of the liver should be palpated. Liver edge palpated more than 2 cm below the right costal margin is abnormal at any age; however, hyperexpansion of the chest in CF can push a normal-sized liver this distance below the costal margin. Therefore, measurement of the liver span at the right midclavicular line (in centimeters) is a more accurate method. The left lobe of the liver should also be palpated below the xiphoid, because it may be the only part of the liver that is enlarged. The liver span should be compared with age-related normative data ^(39,54). There is some dispute in the literature about the normal liver size at various ages. However, the normal mean liver span at the midclavicular line is 3.0 to 5.5 cm at birth, 4 to 6 cm at 1 year, 5 to 7 cm at 3 years, 6 to 8 cm at 5 years, and 7 to 9 cm at 12 years of life. The upper limit of normal is 1.5 to 2.0 cm higher than these mean values. In the adult, a liver span of more than 12 cm indicates hepatomegaly and less than 6 cm atrophy. The texture of the liver edge (soft, firm, hard), which is more important clinically than is the absolute size of the liver, should be recorded. A palpable spleen is abnormal; its distance below the left costal margin should also be recorded routinely. A firm or hard enlarged liver, particularly in the presence of splenomegaly, indicates clinically significant liver involvement. With advancing cirrhosis, the liver may shrink and not be palpable or enlarged. Thus, a small liver, when accompanied by splenomegaly, should alert the clinician that significant liver disease is present.

A panel of liver blood tests should be obtained yearly in all patients with CF. These tests should include determinations of serum AST, ALT, alkaline phosphatase, GGT, and bilirubin. It should be noted that none of these tests measures or correlates with the degree of hepatic fibrosis. Nevertheless, if any of these values is higher than 1.5 times the upper limit of normal, the test should be repeated at shorter intervals (3-6 months). Because fluctuations in the values of these tests are common in CF, only persistently elevated results should be investigated more completely. Thus, if levels remain elevated for more than 6 months, without another explanation for the elevation, they are indicative of probable clinically significant liver involvement. Tests of hepatic synthetic function should then be obtained, including serum albumin and prothrombin time (blood ammonia if significant portal hypertension is suspected clinically). It should be noted that in one series, elevated ALT and GGT had only 52% and 50% sensitivity and 77% and 74% specificity, respectively, as predictors of significant hepatic fibrosis in patients with CF who underwent liver biopsy ⁽⁵⁵⁾. In most surveys, 20% to 30% of patients with CF have elevation of at least one of these liver blood tests at a single point in time. Therefore, these tests should be used to screen for those patients who need a more complete evaluation, rather than to diagnose clinically significant liver disease. Exceptions would be those patients with high elevations (>3-5 times the upper limit or normal) of these readings, in whom significant liver disease is likely. Other causes of acute elevation of aminotransferases (hepatitis A virus, cytomegalovirus, Epstein-Barr virus, drugs or toxins, and, when appropriate, hepatitis B and C viruses) or elevated GGT or alkaline phosphatase (gallstones, cholecystitis, bone disease, hyperphosphatasia) should be excluded. If results of liver blood tests remain persistently elevated without another explanation, then hepatic ultrasound should be performed and consideration given to liver biopsy and other diagnostic methods discussed earlier.

Medical Management

After liver disease has been documented by the presence of hepatomegaly or hepatosplenomegaly, persistently abnormal results in liver blood tests, abnormal histologic findings in a liver biopsy specimen, or abnormalities observed in imaging studies, it should be determined whether the liver abnormalities are most likely caused by hepatic steatosis, hepatic congestion or the cholestasis-focal biliary cirrhosis-multilobular cirrhosis sequence. Each of these entities will be managed differently and is associated with its own set of complications.

Hepatic steatosis

Steatosis is suggested by a palpable softness of the liver, with concomitant malnutrition, or fat density seen on computer tomographic scanning and is confirmed by histologic study of a liver tissue specimen if a biopsy is deemed to be clinically indicated. Steatosis may also be present in conjunction with fibrosis or cirrhosis of the liver, in which case the liver will not be soft to palpation. Although it is not known what causes hepatic steatosis in most patients affected with CF, consideration should be made for evaluating and correcting deficiencies of essential fatty acids, carnitine, or choline, which may lead to steatosis. Medical management consists primarily of optimizing nutritional status of the patient. This should include a thorough evaluation by a nutritionist and institution of proper pancreatic enzyme supplementation; optimization of dietary intake of calories, protein, fat, and essential fatty acids; and fat-soluble vitamin supplementation. A quantification of fecal fat losses may be desirable during enzyme supplementation. Although steatosis has usually been associated with undernutrition in CF, it also may be present in a well-nourished patient. In these circumstances, deficiency of the above-mentioned nutrients should be investigated, history of ethanol ingestion and other drugs or toxins should be sought, and the possibility of diabetes mellitus should be evaluated by oral glucose tolerance testing.

Hepatic Congestion

This condition may lead to "cardiac cirrhosis" or may occur in conjunction with the other liver lesions that result in cirrhosis. It is signaled by clinical signs of cor pulmonale, dilated hepatic veins seen by ultrasound or other imaging studies, or liver biopsy findings. Thrombosis of hepatic veins or the inferior vena cava should be excluded by Doppler ultrasonographic or angiography. Treatment of hepatic congestion centers on therapy to optimize cardiopulmonary function and avoid hypoxia. Generally, AST and ALT are mildly elevated (less than two to three times the upper limit of normal) in hepatic congestion. Bilirubin may be mildly elevated, and prothrombin time may be prolonged up to 5 seconds ⁽⁵⁶⁾. Therefore, if AST or ALT is more than three times normal or if alkaline phosphatase or GGT is significantly elevated, the co-occurrence of focal biliary cirrhosis-multilobular cirrhosis is likely, and appropriate evaluation and therapy should be instituted (see later description). Because percutaneous liver biopsy can be dangerous in this setting, open surgical or transjugular approaches for liver biopsy should be considered if biopsy is indicated. Avoiding antioxidant deficiencies that are common in CF, such as α-tocopherol ⁽⁵⁷⁾ and β-carotene ⁽⁵⁸⁾, may be beneficial in reducing ischemia-reperfusion injury to the liver associated with hepatic congestion.

Cholestasis-Fibrosis-Cirrhosis Sequence

Occurrence of this sequence is suggested by elevated fasting serum bile acid, alkaline phosphatase, and GGT concentrations; abnormal scintigraphy; fat malabsorption and fat-soluble vitamin deficiencies in patients receiving adequate pancreatic enzyme supplements; firm or hard hepatomegaly; splenomegaly; complications of portal hypertension (ascites, upper gastrointestinal bleeding, spontaneous bacterial peritonitis or portosystemic encephalopathy); or hepatopulmonary syndrome. It and is confirmed by findings on histologic examination of liver tissue if deemed necessary.

These three liver lesions are part of a sequential progression that occurs over a variable period of time; therefore, certain aspects of treatment should be similar for these three lesions. The goal of therapy should be to minimize ongoing liver injury and the progression to cirrhosis, prevent complications of cholestasis, and manage complications of portal hypertension and cirrhosis. No therapy has yet been shown after the course of progression to cirrhosis in CF; however, treatment with the hydrophilic bile acid, UDCA, improves the biochemical indexes of liver injury and pruritus. Ursodeoxycholic acid improves bile flow in CF ⁽⁴⁸⁾, may displace toxic hydrophobic bile acids that accumulate in the cholestatic liver ⁽⁵⁹⁾, may have a cytoprotective effect ^(59,60,61), and may stimulate bicarbonate secretion into bile ⁽⁵⁹⁾. Several open clinical trials have shown that AST, ALT, and GGT are reduced when 15 to 20 mg/kg per day UDCA are administered over 3- to 12-month periods ^(59,62-68). There is no direct evidence yet that these reductions are accompanied by delay or reversal of progressive fibrosis or portal hypertension or by a change in the ultimate outcome in CF. In addition, in other studies, there was no improvement in quantitative tests of liver function ^(66,68) or in nutritional status ⁽⁶⁹⁾ after 6 to 12 months of UDCA therapy in patients with CF with chronic liver disease. However, the combined data from three studies involving adults with primary biliary cirrhosis (PBC) ⁽⁷⁰⁾ showed that UDCA therapy significantly retards the progression of this cholestatic liver disease, evidenced by improved survival free of liver transplantation. It should be noted that the PBC patients with the most advanced liver disease showed a more significant response, approximately a 30% reduction in deaths or need for liver transplant after 4 years of UDCA therapy. Although pathobiology of PBC and CF have major differences, the similar biochemical response to UDCA in these two cholestatic disorders and the improved clinical outcome in PBC suggest that UDCA may be of benefit in CF-associated liver disease. Therefore, although there is no conclusive evidence that UDCA alters the course and outcome of CF-related cirrhosis, it is prudent to treat patients with CF who have cholestasis-fibrosis-cirrhosis with 20 mg/kg per day UDCA divided into in two doses ^(65,71). There is currently no scientific justification for using UDCA in patients with CF who have little or no documented liver dysfunction or portal fibrosis.

It is recommended that patients who are candidates for UDCA treatment be entered into clinical trials, if possible, so that useful outcome data can be gathered. Side effects and toxicity of UDCA are unusual and minimal (increased pruritus, diarrhea), rarely causing discontinuation of treatment. Monitoring during therapy should include liver blood tests 3 months after initiating therapy and each 6 to 12 months thereafter and serial physical examinations. Obtaining another liver biopsy is generally not recommended (except in controlled clinical trials) because the focal nature of the liver lesion may make assessment of histologic change over time difficult in an individual patient. There are no other proven therapies that retard hepatic fibrogenesis, although maintaining adequate antioxidant status may be important.

Taurine has been suggested as an adjunctive therapy in liver disease, because patients with CF are commonly deficient in taurine as a result of bile acid malabsorption, treatment with unconjugated UDCA may increase taurine needed for bile acid conjugation, and taurine conjugates of bile acids are better micellar solubilizing agents than the glycine conjugates ⁽⁶³⁾. However, in a randomized, double-blind trial, Colombo et al. ⁽⁶³⁾ showed no significant effect of taurine supplementation (17-33 mg/kg per day) on liver blood test results or fecal fat excretion in patients with CF liver disease treated with UDCA or placebo. Therefore, taurine is not recommended for the treatment of CF-associated liver disease, although it may be of potential benefit in reducing severe steatorrhea in patients with CF.

All patients with CF liver disease should receive a complete immunization series for hepatitis A and hepatitis B virus, unless prior infection with these viruses has been documented.

Cholelithiasis

In CF, cholelithiasis is not responsive to UDCA therapy ⁽⁷²⁾. If, in the presence of gallstones, clinical symptoms of gallbladder dysfunction or pain are present or liver blood test results remain abnormal, a laparoscopic or surgical cholecystectomy should be performed, unless end-stage liver disease is present. Liver biopsy and intraoperative cholangiogram should always be obtained during any cholecystectomy procedure in a patient with CF.

Nutritional Therapy

An important component of the management of liver disease in CF is maintenance of a normal nutritional state. The emphasis is on preserving normal nutritional status and preventing deficiencies rather than on rehabilitating malnourished patients ⁽⁷³⁾. Patients with significant cholestasis (elevated serum direct bilirubin or serum bile acid concentrations, if measured) may need infant formulas containing medium-chain triglyceride (e.g., Pregestimil; Mead Johnson, Evansville, IN, U.S.A., or Alimentum; Ross Laboratories, Columbus, OH, U.S.A.) or supplements for older children containing medium-chain triglyceride oil, to promote intestinal absorption of dietary lipid. Protein intake should not be restricted unless decompensated hepatic failure with encephalopathy is present. Patients with CF may require energy intake that exceeds recommendations by 20% to 40%, depending on the degree of additional fat malabsorption caused by the cholestasis and the increased oxygen consumption associated with cholestasis and cirrhosis ⁽⁷⁴⁾.

Monitoring fat-soluble vitamin status every 6 to 12 months is even more important in the presence of liver disease ⁽³⁷⁾ than in the patient with CF who has pancreatic insufficiency alone ⁽⁷³⁾. All vitamin doses should be administered with a meal and with pancreatic enzyme supplements. Supplementation with the water-soluble form of vitamin E (D-α-tocopheryl polyethylene glycol-1000 succinate) at a dose of 15 to 25 IU/kg per day will correct or prevent vitamin E deficiency in this setting. Patients may also need large doses of vitamin D₂ or D₃ (800-1600 IU/day) or 2 to 4 µg/kg per day 25-hydroxyvitamin D (calcifediol) to normalize serum 25-hydroxyvitamin D concentrations. The optimal dose of vitamin A supplementation has not been determined; however, patients with low serum retinol (<15-20 µg/dl) should receive supplementation two to four times the recommended dietary allowance for age. Serum retinol and retinol-binding protein should be monitored to assure adequacy, as well as serum retinyl ester concentrations to assess for toxicity (elevated serum retinyl esters). Prothrombin time should be monitored to assess vitamin K status indirectly, and prolongation should be treated with 2.5-mg (infants) to 10-mg (adolescents and adults) doses of vitamin K supplements administered from twice per week to daily, depending on the response to therapy. One to 2 months after any change in vitamin dosage, further biochemical testing should be performed to assure nutritional adequacy.

Adolescent and adult patients with CF should be counseled about the risks of ethanol use and encouraged to avoid ethanol. Potentially hepatotoxic medications and herbal therapies should also be avoided.

Management of Portal Hypertension

The development of portal hypertension is a predictable complication of cirrhosis, although the magnitude of symptoms varies depending on how extensively intra-abdominal collateral vessels have developed. Esophageal varices may cause upper gastrointestinal hemorrhage or remain asymptomatic. If bleeding occurs, it should be managed as any other upper gastrointestinal hemorrhage, by nasogastric tube decompression and lavage, intravenous access, red blood cell transfusion, correction of coagulopathy or thrombocytopenia, intravenous octreotide or vasopressin, intravenous H2-blocker, and careful observation ⁽⁷⁵⁾ (see Table 3 for drug doses). Upper gastrointestinal endoscopy should be performed when the patient is stable, or if bleeding persists despite these measures, to determine the source of bleeding and ligate or sclerose esophageal varices if they are identified as the source of bleeding ⁽⁴⁹⁾. If varices are treated, serial sessions of ligation or sclerosis should be performed over several weeks or months until varices are eradicated, followed by periodic (yearly) endoscopy to screen for recurrence of esophageal varices and the need for sclerosis or ligation or the development of gastric varices. Portal hypertensive gastropathy is treated with gastric acid inhibitors, sucralfate, and possibly, β-blockers. Bleeding gastric varices may require placement of a transjugular intrahepatic portosystemic shunt ⁽⁷⁶⁾ or a surgical portosystemic shunting procedure (splenorenal or portacaval interposition shunts) ⁽⁷⁷⁾ if conservative measures (acid suppression and sucralfate therapy) are ineffective. β-Blocker therapy may be indicated to prevent rebleeding of gastric varices and should be used cautiously in patients with reactive airway disease. Patients with severe variceal disease may be considered for liver transplantation (see later discussion). Duodenal or gastric ulcers are treated with gastric acid inhibitors and antibacterial therapy for Helicobacter pylori, if present ⁽⁷⁸⁾.

TABLE 3: Drugs used in the treatment of cystic fibrosis-related liver disease

Chronic therapy with β-blockers has been established as a useful therapy in adults with cirrhosis with established varices to prevent the first variceal hemorrhage, resulting in a 10% reduction in risk of bleeding ^(50,51). Although one study showed a reduction in splenic pulp pressure in children with cirrhosis who were treated with propranolol, such a reduction was not found in those patients with decompensated cirrhosis ⁽⁷⁹⁾. Moreover, there have been no randomized, controlled clinical trials of β-blockers in infants with cirrhosis or in children with varices who have not bled. The value of this therapy as prophylaxis in children is therefore unknown. Theoretically, this therapy may not be of benefit because children with portal hypertension, compared with adults, may develop more extensive intra-abdominal collaterals as they grow; children depend more on increase in heart rate to maintain blood pressure during hypovolemia (e.g., during gastrointestinal hemorrhage) than do adults; and therapy would have to be life-long. In addition, the possible adverse effects of β-blockers on airway reactivity and the development of clinical depression in children with CF should be considered. In adults with CF and portal hypertension who have not had gastrointestinal bleeding, documentation of varices by endoscopy and treatment with β-blockers may be of benefit to prevent the first hemorrhage, although this has not been examined directly in CF. In patients with serious, chronic bleeding varices, β-blocker therapy should be considered as an adjunct to prevent further episodes of hemorrhage ⁽⁸⁰⁾.

Ascites is managed by sequential treatments as follows (see Table 3 for drug doses): careful salt restriction, diuretic therapy (initially spironolactone and then addition of furosemide), and transjugular intrahepatic portosystemic shunting, if severe and unresponsive. Hepatic encephalopathy is treated by dietary protein restriction, lactulose and/or oral antibiotics, prevention of gastrointestinal bleeding and constipation, and consideration of liver transplantation. Spontaneous bacterial peritonitis is treated with systemic antibiotics after appropriate cultures of peritoneal fluid and blood have been obtained.

Management of Liver Failure

Liver failure in patients with CF is rare; however, as the median survival time continues to increase, more patients with advanced liver disease will be encountered. Decompensated cirrhosis and hepatic synthetic failure are present when the patient has poorly controlled ascites, prolonged prothrombin time unresponsive to parenteral vitamin K, decreased levels of clotting factor V, elevated blood ammonia, fatigue, or encephalopathy ⁽⁸¹⁾. Referral to a center experienced in the care of chronic liver failure and liver transplantation should be made at this time. Liver transplantation should be considered, particularly if pulmonary function is relatively well preserved. Because the waiting time for a cadaveric liver may exceed 1 year, referral should be made before patients are desperately ill. Other measures may be taken to treat symptoms of liver failure, as outlined above. However, prognosis is poor when decompensated cirrhosis is present. Liver transplantation in CF results in a 1-year survival of approximately 75% to 80% ^(82,83).

Prophylactic Therapy

Although results in some studies suggest that it is possible to predict patients at high risk for the development of liver injury and cirrhosis in CF (e.g., infants with meconium ileus ^[4,38]), there is no set of criteria that identify most patients who will have significant liver disease. Thus, instituting any type of therapy to prevent the development of liver disease would require treating all infants and children unless a sensitive and specific biochemical, genetic, or clinical marker of early liver disease is identified. Optimally, prevention of liver disease in CF would be preferable to treating it when it is identified. However, there are no available data to support UDCA or any other therapy for prevention of CF liver disease in infants or children who show no evidence of liver disease. Properly controlled, long-term studies to determine whether early therapy would be of benefit are needed. Thus, beginning UDCA therapy is currently not recommended unless definite clinical, biochemical, or histologic evidence of liver dysfunction, cholestasis, or fibrosis is present. An abnormal finding in scintigraphy or sonography, in the absence of other features of liver disease, should not be an indication to initiate UDCA therapy. Measures discussed previously should be taken to prevent other causes of liver injury, such as vaccination against hepatitis A and B viruses and avoidance of ethanol intake.

Future Treatments

Improved ability to detect early liver involvement in CF and to predict which patients will experience development of significant liver disease will assist in future studies of earlier intervention with UDCA or other agents. Thus, clinical, biochemical or imaging markers of liver injury and fibrosis must be developed and validated. Controlled, prospective, multicenter studies must be conducted before prophylactic therapy with any agent can be recommended.

An exciting possible treatment of hepatobiliary disease in CF is the use of somatic gene transfer. Successful insertion of normal CFTR into normal and CF bile duct cells has been achieved in culture ⁽³⁾ and has been performed experimentally by retrograde infusion into the biliary tree of the rat ⁽⁸⁴⁾. It remains to be seen whether this approach can alter bile adequately to prevent the development of hepatobiliary lesions and cirrhosis. Strategies for clinically feasible approaches for gene transfer to the biliary tree must be developed before clinical application of this novel approach to therapy.

As understanding of the pathogenesis of hepatic injury and fibrogenesis continues to improve, new approaches to interfering with cellular injury, and the recruitment and activation of hepatic stellate cells may lead to prevention of fibrosis ⁽⁸⁵⁾. Current results of antioxidant treatment in experimental models of oxidative liver injury are promising ^(86,87); however, there is no direct clinical evidence to support this therapy. Further study of the long-term effects of UDCA and related bile acids on fibrogenesis and bile flow are needed before this therapy can be considered effective. Finally, a better understanding of the ion channels involved in bile secretion and their regulation should lead to new strategies of improving bile composition and flow through stimulation of alternate pathways of chloride and water secretion into bile.