Cystic fibrosis: Hepatobiliary disease

INTRODUCTION — Liver involvement in cystic fibrosis (CF) is common, occurring in 30 to 50 percent of individuals with CF. CF-related liver disease (CFLD) is a broad term that has been used to define a spectrum of liver involvement in CF. The recognition of CFLD is increasing due to early diagnosis of CF, improved life expectancy, and greater awareness among clinicians, which leads to screening and monitoring for CFLD. Advanced CFLD (aCFLD) is the most clinically significant form of CFLD with portal hypertension due to cirrhosis and noncirrhotic causes. Patients with aCFLD due to cirrhosis present almost exclusively during childhood with evidence of portal hypertension by the first decade of life and associated complications [1]. Patients with noncirrhotic portal hypertension present across all ages [2-4]. It is unclear if milder forms of CFLD can identify individuals who will eventually progress to aCFLD; however, noninvasive biomarkers (both serum and imaging based) are emerging as potential predictors of aCFLD. Early identification of progressive CFLD prior to the development of complications of portal hypertension allows prospective monitoring for and treatment of complications, which include malnutrition, ascites, splenomegaly, variceal bleeding, and, rarely, liver failure. Other hepatobiliary complications of CF include transient or persistent hepatitis, cholelithiasis (gallstones), cholecystitis, and microgallbladder.

The clinical manifestations, diagnosis, and management of CFLD will be discussed in this topic review, and associated disorders of the gallbladder will be discussed briefly. Other aspects of CF are discussed separately.

Gastrointestinal and nutritional issues:

●(See "Cystic fibrosis: Overview of gastrointestinal disease".)

●(See "Cystic fibrosis: Nutritional issues".)

●(See "Cystic fibrosis: Assessment and management of pancreatic insufficiency".)

●(See "Cystic fibrosis-related diabetes mellitus".)

Pulmonary issues:

●(See "Cystic fibrosis: Clinical manifestations of pulmonary disease".)

●(See "Cystic fibrosis: Overview of the treatment of lung disease".)

●(See "Cystic fibrosis: Treatment with CFTR modulators".)

●(See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection".)

●(See "Cystic fibrosis: Management of pulmonary exacerbations".)

●(See "Cystic fibrosis: Antibiotic therapy for pulmonary exacerbations".)

●(See "Cystic fibrosis: Management of advanced lung disease".)

EPIDEMIOLOGY AND NATURAL HISTORY — The term CF-related liver disease (CFLD) has been used to describe a wide range of manifestations, from common but inconsequential elevations of transaminases to advanced CFLD (aCFLD) with portal hypertension with or without cirrhosis. Cirrhotic aCFLD primarily presents between 5 and 15 years of age and tends to progress to clinically significant portal hypertension by adolescence [5]. Noncirrhotic portal hypertension can present at any age and is thought to be due to obliterative portal venopathy, often with nodular regenerative hyperplasia at a microscopic level [2-4].

CFLD has historically been defined as the presence of at least two of the following findings: hepatomegaly, abnormalities of liver biochemistries, characteristic abnormalities on liver ultrasound, and abnormal liver biopsy [6,7]. (See 'Diagnosis' below.)

However, it may be useful to consider classification of liver disease using a more phenotypic description that differentiates between aCFLD and other forms (table 1) [8,9]. The prevalence of the most common forms of liver involvement in CF is shown in this table (table 2).

●Early signs of CFLD – Mild forms of CFLD are common and are generally asymptomatic. During the first two years of life, up to 50 percent of individuals with CF have elevations of aminotransferase activity that may be transient [6,10,11]. In two series of pediatric patients with CF who underwent rigorous screening, 30 to 40 percent exhibited elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), or gamma-glutamyl transpeptidase (GGT), with most cases presenting within the first 12 years of life [12,13]. In a prospective study of children identified by newborn screen and followed for up to 20 years, 95 percent had at least one abnormal liver enzyme value and persistently elevated AST, ALT, or GGT occurred in up to 40 percent of individuals [11]. In children and adults with CF who have more frequent monitoring of liver enzymes, abnormalities are very common [14]. Two studies have suggested that early and persistent levels of GGT at or above the upper limit of normal (ULN; ie, 35 to 45 international units/L) are associated with an increased risk for the subsequent development of advanced liver disease [11,15]. The frequency of ultrasound imaging abnormalities is approximately 20 percent, with a spectrum of abnormalities described [16,17]. In autopsy studies from nearly five decades ago (ie, performed before the modern era of CF management), focal biliary cirrhosis and fibrosis were reported in 10 to 20 percent of patients with CF by one year of age and up to 80 percent in adults; in many of these patients, the liver involvement is focal [18-20].

●aCFLD – aCFLD (portal hypertension with or without cirrhosis) is the most clinically important manifestation of CF liver involvement and is closely associated with poor outcome. Most people with aCFLD do not become cholestatic or jaundiced, and hepatic synthetic function usually is preserved.

aCFLD occurs in 7 to 10 percent of individuals with CF, as reported by CF registries [21]. In the modern era, approximately 5 percent of children <13 years of age with CF have imaging findings demonstrating nodularity, suggestive of cirrhosis or noncirrhotic portal hypertension [16]. Other clinical clues to aCFLD include low or normal but declining platelet count and splenomegaly. Virtually all patients with aCFLD have severe pathogenic variants (class I to III) in the CFTR gene (CF transmembrane conductance regulator), such as the F508del variant, and are pancreatic insufficient. However, only a minority of patients with these variants develop aCFLD. Additional risk factors for aCFLD include male sex, Hispanic ethnicity, heterozygosity for the PiZ allele of alpha-1 antitrypsin [22,23], and a patchy or heterogenous pattern on research liver ultrasound. Patients with aCFLD have a fourfold risk of death or liver transplant (12/51 [23.5 percent]) compared with CF patients without liver disease (25/526 [4.8 percent]) [24].

Among patients with aCFLD and presumed cirrhosis, variceal bleeding develops in approximately 7 percent of individuals within 10 years of being diagnosed with aCFLD and is the presenting feature in approximately one-half of those cases [25]. Although the bleeding can be life-threatening, all-cause mortality is similar in individuals with CF cirrhosis with or without bleeding. In a multicenter follow-up study of CF patients with nodular liver on ultrasound (n = 54), the cumulative incidence of esophageal varices within 10 years was 20 percent, whereas no CF patients with normal ultrasound experienced liver-related events [26].

aCFLD is also associated with CF-related diabetes, and both of these disorders are predictors of mortality, independent of pulmonary function [27,28]. In a pilot study (n = 20) of youth with and without CFLD, those with aCFLD were more likely to have dysglycemia, with impaired insulin secretion, sensitivity, and clearance [29].

While children or adults with aCFLD continue to have preserved synthetic liver function for many years (compensated cirrhosis), some may decompensate early in life. The majority of liver transplants for this disorder are performed in children. As an example, in the United States between 1987 and 2009, 210 children or adolescents underwent liver or liver-lung transplantation for CFLD, compared with 84 adults [30].

●Noncirrhotic portal hypertension – Noncirrhotic portal hypertension associated with focal nodular hyperplasia is a distinct phenotype of aCFLD. It can be very difficult to distinguish from cirrhosis. It was previously thought to occur primarily in adults with CF. However, case reports have identified histologic portal vein abnormalities and nodular regenerative hyperplasia in liver biopsies or explants of children as young as eight years old (picture 1) [2-4]. This disease process appears to be distinct from the progressive CF-related biliary cirrhosis that is often seen in children. In an analysis of explants from nine adults transplanted for portal hypertension, noncirrhotic portal hypertension (obliterative portal venopathy) was the predominant form of chronic liver disease. Interestingly, in this small series, none of the nine explants demonstrated cirrhosis [31].

PATHOGENESIS — In the liver, CF transmembrane conductance regulator (CFTR) is located on the apical membrane of the biliary epithelium, not in the hepatocyte. CFTR controls water and solute movement through chloride and bicarbonate secretion, thus promoting bile flow and alkalinization of bile. One theory of the pathogenesis of liver disease in CF is that the dysfunctional CFTR leads to thick and tenacious bile with lower bicarbonate concentrations, leading to microscopic biliary obstruction in the ductules that causes inflammation and biliary fibrosis. Other factors that may contribute to the development of liver disease in CF include impaired secretion of mucins from the submucosal glands and increased glycine-conjugated bile acids. Another proposed mechanism of liver disease in CF is the gut-liver axis theory, in which an altered gut microbiome and intestinal inflammation associated with CF contribute to the development of liver disease [32]. This mechanism has been shown to impact the progression of nonalcoholic fatty liver disease, and a pilot study in CF suggests that the factors necessary (increased intestinal permeability, intestinal mucosal inflammation, and altered microbiome) exist in CF [33]. Intestinal inflammation is common in children and adults with CF [34]. The progression to cirrhosis may be rapid or may take years to decades [35].

The distinct phenotype of noncirrhotic portal hypertension (characterized by nodular regenerative hyperplasia and obliterative portal venopathy) in both children and adults with CF and portal hypertension suggests a vascular pathogenesis that has not yet been mechanistically characterized [4,31,36].

Other factors that may contribute to CFLD include malnutrition, essential fatty acid deficiency [37], drug-induced liver injury, ethanol ingestion in older patients, and, occasionally, obesity. Each of these factors can be associated with hepatic steatosis (the accumulation of fat in the liver), which may cause elevation in liver transaminases. However, it has not been shown that hepatic steatosis associated with CF progresses to cirrhosis. In CF infants with meconium ileus (MI), exposure to prolonged parenteral nutrition or a history of abdominal surgery may contribute to the development of cholestasis, which typically resolves when feedings are resumed.

CLINICAL MANIFESTATIONS — There are multiple presentations of liver involvement in CF (table 2). The most clinically important form is portal hypertension with or without cirrhosis, which is slowly progressive and can lead to sarcopenia and nutritional issues. More common but less clinically important manifestations of liver disease include asymptomatic elevation in aminotransferases (up to 45 percent of individuals with CF), imaging abnormalities, and hepatic steatosis (up to 60 percent of individuals with CF) [6].

Progression to cirrhosis — Approximately 40 percent of individuals with CF develop clinically detectable CF-related liver disease (CFLD) during childhood or adolescence (characterized by persistently elevated aminotransferase levels, hepatomegaly, and/or ultrasonographic abnormalities), and approximately 20 percent of these (5 to 10 percent of individuals with CF) go on to develop a nodular liver, a marker of aCFLD [13]. Several case series that used universal screening procedures demonstrated that CF cirrhosis usually develops during childhood or adolescence, with no incident cases beyond the age of 18 years [6,13]. Similarly, the Cystic Fibrosis Foundation data registry reports approximately equal percentages of patients with CF cirrhosis (and specific manifestations thereof, such as varices) in the <18 and >18 age groups, suggesting that most cases present before age 18 [21]. Noncirrhotic portal hypertension and intrahepatic cholangiopathies are disorders primarily described in adults with CF [2,3,38,39].

Liver involvement usually comes to clinical attention when routine screening in an asymptomatic patient reveals abnormal liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and/or alkaline phosphatase, or by abnormalities on physical examination (hepatomegaly or splenomegaly). Some individuals have evidence of portal hypertension at presentation or as the disease progresses, characterized by massive splenomegaly, which results in splenic sequestration and decreased platelet count in the peripheral blood as well as prominent abdominal vasculature and abdominal girth. Serum bilirubin levels are generally not elevated until late in the disease course, as is typical for cirrhosis. Screening for and diagnosis of progressive CFLD are discussed below. (See 'Evaluation' below.)

Patients with cirrhosis and portal hypertension have associated risks for variceal hemorrhage [40,41]. A large registry study reported that patients with CF cirrhosis have a 10-year cumulative risk of variceal hemorrhage of 6.7 percent [25]. Most patients with cirrhosis remain in a state of compensated cirrhosis for years or decades. Eventually, some progress to decompensated cirrhosis, heralded by ascites, liver failure with synthetic dysfunction (coagulopathy and hypoalbuminemia), or hepatic encephalopathy. Cutaneous manifestations such as jaundice, palmar erythema, and spider hemangiomata develop late in the disease course.

Histologically, CFLD is typically characterized by proliferation of the bile ducts and portal fibrosis, with accumulation of amorphous pink material within the bile ducts when stained with periodic acid-Schiff (PAS) stain (picture 2). In the earlier phases, the lesions may have a patchy distribution, which has been termed "focal biliary cirrhosis" in autopsy studies. With disease progression, cirrhosis develops, characterized (as in other forms of cirrhosis) by the development of collagenous bridges between nearly all portal and central venous areas, encircling nodules of varying sizes (picture 3) [6,12,13].

Nodular regenerative hyperplasia with portal hypertension is a distinct phenotype of CFLD and may mimic cirrhosis radiographically. Nodular regenerative hyperplasia and cirrhosis both demonstrate significant nodularity on imaging. Liver biopsy may be needed to distinguish between these entities by staging the fibrosis and assessing for portal venopathy. In patients with the nodular regenerative hyperplasia form of CFLD, studies have characterized either absence or obliteration of the portal veins by smooth muscle or calcifications at a microscopic level (picture 1) [4].

Other manifestations of liver disease

Neonatal cholestasis — Fewer than 10 percent of infants with CF develop cholestatic liver disease during the neonatal period. The majority of infants with cholestasis also have meconium ileus (MI). Those who do present in infancy present with prolonged conjugated hyperbilirubinemia. Rarely, biliary obstruction can be very severe during infancy, mimicking biliary atresia (picture 4) [42,43] (see "Causes of cholestasis in neonates and young infants"). The hepatomegaly and cholestasis tend to regress during the first few months of life with improvements in nutrition, and this presentation does not predict subsequent aCFLD [44,45]. Similarly, isolated elevations in aminotransferase activity prior to two years of age are often transient and generally do not predict aCFLD [6,10]. However, early and persistent elevations in liver enzymes were associated with an increased risk for advanced CFLD (aCFLD) in one study [11].

Hepatic steatosis — Hepatic steatosis is the most commonly observed pathologic abnormality in CFLD (picture 5) and can be found in up to 60 percent of individuals with CF, with a wide range in prevalence depending on the patient population and methods used to determine steatosis [6,46,47]. The sonographic or histologic finding of steatosis is sometimes related to iatrogenic or environmental factors, particularly malnutrition, overconsumption of fat calories, and essential fatty acid deficiency [37] (see 'Pathogenesis' above). However, in most individuals with CF, no nutritional cause is identified [48]. The relationship between hepatic steatosis and the development of cirrhosis in CF is unclear. Steatosis is thought to be a benign finding among children with CF. Even in severe cases, in which the steatosis becomes panacinar or more widespread, inflammation and other features of steatohepatitis generally are absent [49,50].

EVALUATION — The goal of the evaluation is to confirm that abnormalities are due to liver involvement associated with CF and to detect advanced CF-related liver disease (aCFLD) and distinguish it from other liver abnormalities that are relatively benign (eg, steatosis and/or mild elevations of aminotransferases).

Screening — Annual screening for CFLD is recommended for all individuals with CF [6,35]:

●Physical examination – Examine the patient for hepatomegaly and new-onset splenomegaly, noting contour, liver span, and texture by both palpation and percussion. It is important to note that hepatomegaly may be asymmetric (due to regenerative nodules), producing subxiphoid hepatomegaly. If splenomegaly is massive, the tip may only be palpable in the lower abdomen and pelvis.

●Laboratory testing – Measure and trend platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and alkaline phosphatase at least annually. Abnormalities in AST, ALT, and GGT are common in CF and have low specificity and sensitivity for CFLD. A decline in platelet count over time (eg, decline of >30 percent relative to baseline) should be vigilantly followed up, even if does not meet laboratory criteria for thrombocytopenia, because this finding may be a harbinger of portal hypertension. Low albumin, particularly if paired with coagulopathy, is a sign of synthetic compromise and can signal decompensated cirrhosis. (See 'Further evaluation' below.)

The following indices can be used as biomarkers of liver fibrosis in CFLD (table 3):

•APRI – The AST to platelet ratio index (APRI) is a reasonably good surrogate marker for hepatic fibrosis in CFLD, as validated by liver biopsy [51]. Some experts have suggested calculating the APRI as part of the routine annual evaluation [52].

-If the results of liver aminotransferases alone are abnormal, but the patient has no hepatosplenomegaly or other symptoms and APRI is normal, it is reasonable to observe and repeat the screen 6 to 12 months later.

-If APRI is ≥0.4, or if GGT is persistently elevated (>21), further evaluation is warranted (eg, imaging) [15].

-If APRI is >1.0, further investigation for aCFLD is warranted (imaging, potentially biopsy) [1,51].

The combination of APRI and spleen size-for-age Z-score is also correlated with nodularity on ultrasound examination [53]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'AST to platelet ratio index'.)

•GGT-to-platelet ratio (GPR) – The GPR is another useful predictor of CFLD. A GPR 0.2 to 0.32 is associated with a higher rate of moderate hepatic fibrosis, and a GPR >0.6 is associated with more advanced fibrosis [54,55]. A combination of GPR >0.68 and a heterogeneous liver ultrasound was able to predict a very high risk for the development of aCFLD [52].

Note that interpretation of APRI and GPR, including the cutoffs derived from the above studies, depend on the upper limit of normal (ULN) used for AST and GGT, which are not well standardized and vary among laboratories. Data suggest using CALIPER upper limits for these calculations; however, these may differ from local laboratory ULNs [56].

●Ultrasound – If the above measures are persistently abnormal, then the next step is complete abdominal ultrasonography. Ultrasonography can detect abnormalities, which include coarseness of liver parenchyma, nodularity of the liver edge, and increased periportal echogenicity, and can exclude gallstones as a cause of intermittently elevated GGT. In a prospective, case-controlled study, research-based ultrasound (in which ultrasound findings were graded by a consensus of radiologists who underwent specialized training) identified a subset of children with CF at high risk (>9-fold) for developing a nodular liver indicative of aCFLD [22,57]. If a nodular liver is identified, Doppler measurements of hepatic blood flow can assess portal venous flow or detect a recanalized umbilical vein, which may be seen in both cirrhotic and noncirrhotic portal hypertension. Evidence of aCFLD includes splenomegaly, large collateral veins, or ascites [6,35,58]. Although uncommon, patients with right heart failure due to pulmonary disease (cor pulmonale) may have additional sonographic findings of hepatic congestion and dilated hepatic veins.

●Elastography – For patients with clinical features suggesting cirrhosis or portal hypertension (eg, splenomegaly, decline in platelet count, or firm, enlarged liver on physical examination), other advanced imaging modalities may be useful to assess for fibrosis. Elastography is a technique that can measure liver stiffness reflective of liver fibrosis, inflammation, or congestion using ultrasound-based techniques or magnetic resonance elastography (MRE). The techniques and their use in other forms of liver disease are discussed separately. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

•Vibration-controlled transient elastography (VCTE) is an ultrasound-based technique that can be performed in the clinic and permits accurate liver stiffness measurements (LSMs) in a short period of time (often <5 minutes) with good reproducibility. VCTE provides no anatomic imaging or Doppler evaluation of blood flow, and its accuracy is limited in patients with obesity, steatosis, or ascites. The most commonly used device in clinical practice is FibroScan. In a study of 160 children with CF, a VCTE cutoff value of 8.7 kilopascals (kPa) was a good predictor of finding bridging fibrosis and/or cirrhosis (Metavir fibrosis stage F3-F4) on liver biopsy [59]. Correlation between VCTE and ultrasound findings was shown in another study, in which children with nodular liver on research ultrasound had a higher median LSM (9.1 kPa) on VCTE compared with those with normal ultrasound (5.1 kPa), homogeneous ultrasound (5.9 kPa), and heterogeneous ultrasound (6.1 kPa) [60]. VCTE technology also has the capability to concurrently quantify liver fat or steatosis using controlled attenuation parameter (CAP). In a study of adolescents and young adults with CF, while degree of steatosis did not correlate with clinical markers of liver disease, higher CAP was reported in those with CFLD (n = 44) than those with evidence of cirrhosis and portal hypertension (n = 15), suggesting that steatosis may be replaced in more advanced CFLD [61].

•Shear-wave elastography (SWE) is an ultrasound-based technique that provides additional information compared with a traditional ultrasound [62]. Liver stiffness determined by SWE demonstrated good diagnostic accuracy (area under the curve [AUC] 0.79) in detecting CFLD in children with CF versus healthy controls using a threshold of 6.85 kPa [63]. By combining APRI, the accuracy improved even more (AUC 0.84) and, using a higher LSM threshold of 9.05 kPa, SWE accurately distinguished aCFLD (AUC 0.95). Neither are proficient in morbidly obese patients or those with ascites [64]. With SWE, the operator can still examine the region of interest in detail (eg, examine texture of the liver, exclude lesions, evaluate patency of large blood vessels and bile ducts) while capturing elastographic measurements. Limitations of SWE include reliance on operator experience and variation in cutoffs among different vendors [65].

•MRE is another modality to assess liver stiffness. It differs from the ultrasound-based techniques in that it utilizes a mechanical driver to create a heat map of the entire liver using low-frequency mechanical waves rather than a small area of the liver. In postprocessing, cooler colors correspond with less stiffness, while warm colors correlate with increasing liver stiffness. MRE can also quantify fibrosis and differentiate it from fat [66], while providing anatomic assessments within and outside the liver. However, cost and the potential need for sedation may pose barriers and its use in CF has been limited.

In a cross-modality comparison study, VCTE, SWE, and MRE were performed on 55 children with CF [67]. Each of these modalities performed well for diagnosing fibrosis in CFLD. VCTE, SWE, and MRE data on liver stiffness cannot be directly compared, since the physics and frequencies captured are distinct for each modality [68].

Diagnosis — Several sets of criteria have been proposed for the diagnosis of CFLD. The most commonly used criteria utilized clinical findings: A diagnosis of CFLD is made if two or more of the following findings are present, as suggested by both a European panel [6] and the joint Cystic Fibrosis Foundation/National Institutes of Health CFLD Clinical Research Workshop [7,8]. A study in adults has suggested that elastography abnormalities should be added to the criteria for adults [36].

●Hepatomegaly (liver span greater than the ULN for age [69]) and/or splenomegaly, confirmed by ultrasonography

●Abnormalities of ALT, AST, and GGT >1.5 to 2 times the laboratory ULNs for >6 months, after excluding other causes of liver disease

●Ultrasonographic evidence of coarseness, nodularity, increased echogenicity, or portal hypertension, as described above

●Liver biopsy showing focal biliary cirrhosis or multilobular cirrhosis (if performed)

Further evaluation — Patients suspected of having CFLD based upon the clinical features described above should undergo further evaluation to assess for severity and exclude other causes of liver disease. The intensity of the evaluation should be guided by the clinical presentation. In patients with persistent aminotransferase elevations, the evaluation should include a history, asking specifically about the neonatal course, history of jaundice, change in activity level, abdominal pain or nausea, weight loss, medication intake including over-the-counter medications and supplements, history of blood transfusions, and family history of liver disease. The physical examination includes evaluation for hepatosplenomegaly and for manifestations of chronic liver disease such as jaundice, spider angiomata, palmar erythema, and ascites, although these are uncommon in CFLD. Signs or symptoms of nutritional deficiencies should also be noted.

Additional laboratory evaluation for CFLD may include markers of liver synthetic function such as albumin and prothrombin time with international normalized ratio (INR). A complete blood count, specifically platelet count, is useful to screen for hypersplenism, which is associated with portal hypertension. Screening for other causes of liver disease should be performed, including infectious hepatitis (eg, hepatitis B and C), Wilson disease, celiac disease, alpha-1 antitrypsin deficiency, hemochromatosis, drug toxicity, and autoimmune disease. Appropriate laboratory tests should be performed when indicated. (See "Approach to the patient with abnormal liver biochemical and function tests".)

Liver biopsy is not routinely needed to assess the severity of the liver disease, because the findings rarely affect decisions about clinical interventions, such as endoscopic variceal banding/sclerosis or liver transplantation. Moreover, liver biopsy may underestimate the severity of disease because the lesions of CFLD tend to be patchy or heterogeneous [6]. Liver biopsy may be useful if there is a suspicion of a concomitant liver disease (ie, hepatitis C, drug toxicity, or autoimmune hepatitis) or in patients with suspected noncirrhotic portal hypertension without liver dysfunction. If noncirrhotic portal hypertension is confirmed, the patient may be a candidate for transjugular intrahepatic portosystemic shunt (TIPS) or distal splenorenal shunt as an alternative to liver transplant [70,71].

MANAGEMENT

Nutrition — For all patients with established CF-related liver disease (CFLD) (see 'Diagnosis' above), it is important to optimize nutrition, including ensuring a high energy intake, typically targeting 150 percent of the recommended daily allowance [6]. Malabsorption of fats is common in CFLD because of insufficient or abnormal bile acids in the intestinal lumen, in addition to the underlying pancreatic insufficiency. Because patients with CF may have insulin deficiency (with or without overt CF-related diabetes), supplemental energy should be supplied primarily by fats rather than carbohydrates. Fat-soluble vitamins should be monitored and vigorously supplemented (even at massive doses) as needed [6]. Patients with CFLD often require higher doses of fat-soluble vitamin supplements compared with other patients with CF. (See "Cystic fibrosis: Nutritional issues", section on 'Fat-soluble vitamins'.)

Risk reduction — Full immunization against hepatitis A and hepatitis B is recommended for all children but is especially important for individuals with CFLD. For those with progressive liver disease, we also suggest:

●Avoid alcohol and medications with hepatotoxic side effects, including certain herbal remedies. (See "Drug-induced liver injury".)

●Individuals with aCFLD should be advised to avoid using nonsteroidal antiinflammatory drugs (NSAIDs) and salicylic acid to minimize risks of bleeding from portal hypertensive gastropathy, or from gastric or esophageal varices, if present [6].

Ursodeoxycholic acid — The role of ursodeoxycholic acid (UDCA) in CFLD has not been established and is controversial. Limited clinical evidence suggests that UDCA at moderate doses may improve biochemical parameters in patients with CFLD. In two large studies, there was no impact of UDCA on the development of advanced CFLD (aCFLD; portal hypertension) [72,73]. In view of these uncertainties, expert opinion differs as to whether UDCA should be used for all patients with CFLD or only those with significant cholestasis and fibrosis [6,35,74].

Our practice is to give UDCA to children who have established cholestasis (eg, conjugated bilirubin >1 mg/dL [17.1 micromol/L]), particularly those on or recently weaned off of total parenteral nutrition. We use a dose of 10 to 20 mg/kg body weight per day in two divided doses and continue for two months beyond resolution of hyperbilirubinemia. We do not use UDCA for children with subclinical or milder forms of CFLD. However, more liberal use of UDCA has been advocated in the past by an expert panel, including its use for children with early or mild CFLD (eg, persistently elevated aminotransferases), and escalating the dose if there is no improvement in aminotransferase concentrations after three months of treatment [6].

UDCA is a nontoxic bile acid, is naturally occurring in humans, and is thought to reduce liver injury in cholestatic liver disease by replacing cytotoxic bile acids. It also may increase bicarbonate secretion and may have a direct cytoprotective and antiinflammatory effect [40,75]. Despite these theoretical benefits, the clinical evidence supporting the use of UDCA is weak and consists of low-quality or indirect clinical evidence [76], as outlined below:

●Several observational studies and two small randomized trials suggest that UDCA may delay the progression of CFLD [77-79]. One of the randomized trials included 55 children and adults with CFLD and reported that those treated with UDCA for one year experienced improvements in gamma-glutamyl transpeptidase (GGT) and in a global measure of CF severity, as compared with placebo [78]. A separate trial in children who presented with meconium ileus (MI) at birth (and who were therefore at increased risk for developing CFLD) reported that treatment with UDCA reduced the likelihood of developing chronic liver disease by nine years of age [80]. However, a large retrospective study in France concluded that the early use of UDCA did not alter the incidence of severe CFLD in the last 20 years [73]. Similarly, a large study in Russia and Italy found no difference in the incidence of severe CFLD between centers that routinely used UDCA and centers that did not [72].

●A Cochrane review found insufficient evidence to determine whether UDCA is effective for treatment or prevention of CFLD [76].

Gallstones in CF are not responsive to therapy with UDCA, because their main component is not cholesterol [35,46,81]. (See 'Gallbladder disease' below.)

Management of specific complications

Portal hypertension — In patients with clinical or radiographic signs of portal hypertension, we suggest consideration of screening upper gastrointestinal endoscopy to evaluate for esophageal varices and risk for gastrointestinal bleeding [6]. Endoscopic band ligation should be performed for patients who have experienced prior variceal bleeding (secondary prophylaxis), particularly those who have varices with characteristics that suggest a high risk for bleeding (eg, red wale or overlying ulcer), although specific data are lacking in the CF patient population. Multiple courses of band ligation may be needed after a first variceal bleed and tend to have a lower risk of bleeding than sclerotherapy. Whether primary prophylaxis (band ligation before the first variceal bleed) is indicated is controversial in children. Accordingly, many centers do not perform surveillance endoscopy with band ligation for primary prophylaxis in children [82]. It is clearly indicated in adults due to high mortality associated with first variceal hemorrhage. (See "Methods to achieve hemostasis in patients with acute variceal hemorrhage" and "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis" and "Primary prevention of bleeding from esophageal varices in patients with cirrhosis".)

Although esophageal varices in adult patients without CF are often treated with nonselective beta-adrenergic blockers, these agents are generally avoided in patients with CF because of their potential to cause bronchoconstriction. Moreover, beta-adrenergic blockers usually are avoided in children with portal hypertension because children rely on reflex tachycardia to compensate for acute variceal bleeding. In an acute variceal bleed, octreotide may be used to decrease splanchnic flow, thus decreasing the tension on gastroesophageal varices.

Placement of a transjugular intrahepatic portosystemic shunt (TIPS) is an appropriate option for patients with recurrent or refractory variceal bleeding for whom endoscopic band ligation is not possible or not effective. Use of TIPS has been effective for CF patients with portal hypertension as a bridge until liver transplantation; TIPS also may be used as a primary management strategy for well-selected patients with cirrhotic portal hypertension and perhaps those with noncirrhotic portal hypertension [71,83-85]. Improvement in body mass index and lung function after TIPS has been well documented. TIPS and any other portosystemic shunt may be complicated by encephalopathy or thrombus, though the use of new conduit material may decrease the incidence of occlusion. (See "Prevention of recurrent bleeding from esophageal varices in patients with cirrhosis", section on 'Options if initial strategy fails'.)

Hepatopulmonary syndrome — Patients with CFLD and portal hypertension also may develop hepatopulmonary syndrome. This is caused by dilation of the pulmonary capillary bed, leading to a functional right-to-left shunt and hypoxemia [86]. One clinical feature of hepatopulmonary syndrome is "orthodeoxia," which refers to a decrease in oxygenation in the upright as compared with recumbent position. Patients with portal hypertension should be evaluated for orthodeoxia by measuring oxygen saturation (using pulse oximetry) in the supine and upright positions. A significant decrease in oxygen saturation (5 percentage points) when moving into the upright position suggests hepatopulmonary syndrome and should be further evaluated [6]. Because hepatopulmonary syndrome can be rapidly progressive, producing profound hypoxemia, CF patients with hepatopulmonary syndrome should be considered for liver transplantation and are eligible for higher priority based on this diagnosis. (See 'Liver transplantation' below and "Hepatopulmonary syndrome in adults: Prevalence, causes, clinical manifestations, and diagnosis".)

Portopulmonary hypertension — Portopulmonary hypertension (or portopulmonary syndrome) refers to pulmonary arterial hypertension that is associated with portal hypertension and is a well-recognized complication of chronic liver disease including CFLD [86]. A provisional diagnosis can be made with echocardiography. CF patients with portopulmonary hypertension should be considered for liver transplantation. They are candidates for pulmonary hypertension pharmacotherapy to reduce operative risks in the event of future liver transplantation. On occasion, the portopulmonary hypertension can be severe enough to indicate lung-liver transplantation. They may receive priority on the transplant waiting list, as do patients with hepatopulmonary syndrome. (See 'Liver transplantation' below and "Portopulmonary hypertension".)

Liver failure — Patients with liver failure (which is rare in CF) or end-stage liver disease should be considered for liver transplantation. Patients should be referred promptly for a transplant evaluation because wait time for a liver may exceed one year. Whether liver transplantation may stabilize lung function is unclear [6,35,87]. Evidence of progressive hepatic dysfunction includes hypoalbuminemia (<3 g/dL and falling) and/or increasing coagulopathy that is not corrected by administration of vitamin K. Many experts consider the development of ascites as an ominous sign in aCFLD that should also prompt referral for evaluation for liver transplantation. (See 'Liver transplantation' below.)

Liver transplantation — The optimal timing of liver transplantation in CFLD and the use of combined liver-lung or liver-pancreas transplant is often complicated by nutritional problems and progressive pulmonary disease. Recommended indications for consideration of liver transplantation in patients with CFLD include [6]:

●Intractable variceal bleeding that is not adequately controlled by other means.

●Ascites and jaundice.

●Progressive hepatic dysfunction (hypoalbuminemia and coagulopathy).

●Hepatopulmonary syndrome.

●Portopulmonary hypertension. If portopulmonary hypertension is present, eligibility for transplantation must be evaluated on a case-by-case basis because high pulmonary vascular resistance may be a relative or absolute contraindication to liver transplantation. Medical pharmacotherapy should be maximized first.

●Deteriorating pulmonary function, if this is thought to be a consequence of the liver disease (hepatopulmonary syndrome), because this may improve after liver transplantation. Similarly, a patient with worsening hemoptysis that is attributable to portal hypertension (due to thrombocytopenia or coagulopathy) may benefit from liver transplantation.

●Severe malnutrition, unresponsive to intensive nutritional support and treatment for CF-related diabetes, if present.

CF patients with advanced lung and liver disease are candidates for liver-lung transplantation, but the combined procedure is uncommon, particularly in the pediatric age group [88-90]. In the United States between 2006 and 2016, combined liver-lung transplantation was performed in 52 individuals, 30 of whom had CF [90]. The frequency of combined liver-lung transplantation varies among institutions. Given the association of CF-related diabetes and aCFLD combined, liver-pancreas transplantation has been suggested as an option. This is infrequently performed but should be considered in the appropriate setting [91,92].

Overall outcomes of patients with CF after liver transplant are close to those with other forms of liver disease, with a one-year survival of approximately 85 percent and a five-year survival of 75 percent [18,35,40,93]. For liver-lung transplantation, mean survival rates in the United States are 83, 69, and 56 percent at 1, 5, and 10 years, respectively [90]. A review of data from the United Network for Organ Sharing (UNOS) for children and adults with CF between 1987 and 2013 reported an increased risk of death in CF patients undergoing liver or liver-lung transplant compared with non-CF patients, but this was not true for liver graft survival, suggesting that this was related to non-liver issues [94]. A prior study of the UNOS data from 1987 to 2008 suggested that there were no differences in outcome for CF patients undergoing liver transplant as compared with those undergoing liver-lung transplant [89]. Thus, either isolated liver transplant or liver-lung transplant are viable options for CF patients with end-stage liver disease. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)

CONSIDERATIONS RELATED TO CFTR MODULATOR THERAPY

CFTR modulator-induced liver injury — CF transmembrane conductance regulator (CFTR) modulator and corrector therapy (elexacaftor-tezacaftor-ivacaftor [ETI] and others) have low rates of liver-related adverse effects, but a minority of patients experience drug-induced liver enzyme elevations and a few case reports describe severe acute hepatitis. (See "Cystic fibrosis: Treatment with CFTR modulators".)

●Prevalence – During treatment with a CFTR modulator, between 5 and 10 percent of patients develop liver enzyme elevations above three to five times the ULN, but, in most cases, this does not require interruption of therapy [95]. In the initial clinical trials of ETI, elevations in serum aspartate or alanine aminotransferase (>3 × ULN) occurred in 8 percent of participants taking ETI, compared with 5 percent of those taking placebo [96]. Less than 3 percent had serum aminotransferase values >5 × ULN, and none had concurrent elevated serum bilirubin. Generally similar findings were reported in trials of other CFTR modulators (tezacaftor-ivacaftor [97], lumacaftor-ivacaftor [98], and ivacaftor alone [99]). In the trial of lumacaftor-ivacaftor, a few participants (3 of 738) had elevations of serum bilirubin (>2 × ULN) in addition to aminotransferases; among seven participants with cirrhosis, one developed elevated bilirubin and hepatic encephalopathy within five days of initiating treatment that resolved following cessation of lumacaftor-ivacaftor [98]. Postmarketing follow-up includes a report of ETI drug-induced severe acute hepatitis in a patient with aCFLD, suggesting a need for caution in these patients [95,100].

●Monitoring – Liver enzymes should be measured prior to beginning CFTR therapy, then every three months for the first year of therapy, and then at least annually thereafter. Interruption of CFTR modulator therapy is recommended if the ALT or AST is >5 × ULN or if ALT or AST is >3 × ULN with bilirubin >2 × ULN [101].

For patients whose CFTR modulator therapy is interrupted because of such liver enzyme elevations, clinical experience suggest that some can successfully restart therapy, but it remains unclear if there are predictors for recurrence of injury with repeat exposure. This is an evolving area of interest that will likely have changes in recommendations as more data become available. It should also be noted that 11 percent of patients with aCFLD would not be eligible for either triple combination therapy or ivacaftor based on their CFTR genotype [102].

Use of CFTR modulators post-liver transplant — Use of CFTR modulator therapy after liver transplantation is controversial because of the potential for drug interactions, CFTR modulator-induced liver injury, and unclear benefit. However, small case series suggest that most patients tolerate ETI and have symptomatic and quality-of-life improvement, increased body mass index, and maintained or improved lung function [103,104].

Drug interactions are common because each of the components in ETI are substrates of CYP3A4/5. Tacrolimus, the primary antirejection immunosuppressant used in pediatric liver transplantation, is a substrate of CYP3A4/5 as well as CYP3A. Accordingly, ETI tends to increase tacrolimus levels, which may require adjustment of the tacrolimus dose. Conversely, tacrolimus tends to increase ETI concentrations, which could increase the risk for CFTR modulator-induced liver disease. ETI also can increase antifungal (azole) levels. For details and guidance on drug interactions and dose reductions, refer to the manufacturer's prescribing information or the Lexicomp drug interactions database [101].

If the decision is made to continue or initiate ETI after liver transplantation, the optimal initial dose of ETI is uncertain. In a case series of 10 patients treated with ETI after liver transplant, most patients were started on standard dosing of ETI; a few were started on a reduced dose and then advanced to a full dose if tolerated [103]. A majority of patients (7 of 10) also required reduction of the tacrolimus dose. Two patients discontinued ETI therapy (one for ETI-related liver injury and another for tacrolimus toxicity).

Regardless of the starting ETI dose, liver biochemistries and tacrolimus trough concentration should be monitored frequently (eg, at one and two weeks after initiating ETI and then monthly thereafter). If aminotransferases are elevated, further evaluation may be needed to distinguish the effects of the CFTR modulator from rejection.

Some of these considerations also apply to people undergoing lung transplant; the experience is described separately. (See "Cystic fibrosis: Treatment with CFTR modulators", section on 'Post-transplant'.)

GALLBLADDER DISEASE — CF is associated with microgallbladder, cholelithiasis (gallstones), and cholecystitis [18,35].

●Microgallbladder is defined as a gallbladder measuring <35 mm in the longest axis in adults and occurs in 25 to 30 percent of patients with CF [6,105]. The pathogenesis is unclear. One theory is that it is caused by a developmental abnormality of the fetal gallbladder, which has high expression of the CFTR gene [35].

●Cholelithiasis has been reported in up to 12 percent of patients and may result from excessive loss of bile acids in the stool with consequent production of lithogenic bile [40,41]. Asymptomatic cholelithiasis generally does not require treatment, although prophylactic cholecystectomy may be performed in such patients prior to lung transplantation in some centers. Evaluation may include ultrasonography or magnetic resonance cholangiopancreatography (MRCP). Recurrent or severe biliary colic may warrant cholecystectomy. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management".)

●Cholecystitis is triggered by biliary obstruction due to sludge or gallstones. Evaluation and management is similar to that for patients without CF. (See "Acute calculous cholecystitis: Clinical features and diagnosis".)

SCLEROSING CHOLANGITIS AND HEPATOLITHIASIS IN CYSTIC FIBROSIS — CF is associated with intrahepatic biliary ductular disease that can have the appearance of sclerosing cholangitis or hepatolithiasis. The most common presentation is abdominal pain with or without jaundice and intrahepatic ductal calculi that can be single or multiple [106]. The involvement in the liver is often segmental and may evolve into recurrent pyogenic cholangitis with hepatolithiasis and biliary strictures. Screening with abdominal ultrasound followed by magnetic resonance cholangiography is recommended. Treatment options have not been subjected to randomized studies due to the rarity of the condition. They can include medical therapy with ursodeoxycholic acid (UDCA) and antibiotics, therapeutic endoscopic retrograde cholangiopancreatography (ERCP), and segmental liver resection. Multidisciplinary treatment approaches have demonstrated the best outcomes [39].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cystic fibrosis" and "Society guideline links: Portal hypertension and ascites".)

SUMMARY AND RECOMMENDATIONS

●Cystic fibrosis-related liver disease (CFLD)

•Clinical manifestations – CFLD typically presents with nonspecific liver enzyme or imaging abnormalities (table 2). Rarer presentations include neonatal cholestasis, hepatic steatosis, biliary cirrhosis, and portal venopathy. Among these, biliary cirrhosis and portal venopathy with portal hypertension are associated with progressive liver disease and associated complications and mortality. (See 'Clinical manifestations' above.)

Cirrhosis or noncirrhotic portal hypertension develop in approximately 10 percent of individuals with CF. The disease usually develops during childhood and in its most severe form progresses to portal hypertension. Most such patients remain in a state of compensated cirrhosis for years or decades. Eventually, some progress to decompensated cirrhosis, heralded by gastrointestinal bleeding, ascites, liver failure with synthetic dysfunction (coagulopathy and hypoalbuminemia), or hepatic encephalopathy. (See 'Progression to cirrhosis' above.)

•Monitoring – All patients with CF should be evaluated annually for CFLD by examining for hepatosplenomegaly and laboratory testing, including platelet count, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (GGT), followed by abdominal ultrasonography, if needed. (See 'Evaluation' above.)

•Management

-Supportive care – Patients with CFLD require rigorous nutritional management with close monitoring and supplementation of energy and fat-soluble vitamins. Those with cirrhosis should avoid nonsteroidal antiinflammatory medications (NSAIDs) to minimize risks of gastrointestinal bleeding and take measures to minimize infectious and toxic insults to the liver. (See 'Nutrition' above and 'Risk reduction' above.)

-Ursodeoxycholic acid (UCDA) – UCDA is commonly used in the management of CFLD but has not been adequately studied, particularly regarding whether it has a role in the treatment of subclinical or other early forms of CFLD. Limited clinical evidence suggests that UDCA at moderate doses may improve biochemical parameters in patients with CFLD. However, there is no good evidence that it improves other outcomes.

For children who have established cholestasis due to CFLD (eg, serum conjugated bilirubin >1 mg/dL [17.1 micromol/L]), we suggest treatment with UDCA (Grade 2C), with doses of 20 mg/kg/day. Many clinicians do not use UDCA for children with subclinical or milder forms of CFLD, but practice varies for this group of patients; there is no specific evidence that it is harmful in CF. (See 'Ursodeoxycholic acid' above.)

-Portal hypertension – Patients who develop portal hypertension are at risk for complications including hemorrhage from esophageal varices, ascites, malnutrition, hepatopulmonary syndrome, and portopulmonary hypertension; these complications may be indications for portosystemic shunt or liver transplantation. Liver transplantation is indicated for patients with progressive hepatic dysfunction, which is suggested by falling albumin, hepatic encephalopathy, and coagulopathy. (See 'Management of specific complications' above and 'Liver transplantation' above.)

●CF transmembrane conductance regulator (CFTR) modulator-induced liver injury – CFTR modulator therapy (elexacaftor-tezacaftor-ivacaftor [ETI] and others) has low rates of liver-related adverse effects. A minority of patients experience drug-induced liver enzyme elevations, and a few case reports describe severe acute hepatitis. Laboratory monitoring and vigilance for drug-drug interactions are advised. (See 'Considerations related to CFTR modulator therapy' above and "Cystic fibrosis: Treatment with CFTR modulators".)

●Gallbladder disease – Gallbladder disease associated with CF includes microgallbladder, cholelithiasis (gallstones), and cholecystitis. Evaluation and management are similar to that for patients without CF. (See 'Gallbladder disease' above.)

ACKNOWLEDGMENT — The authors and UpToDate editorial staff are grateful to Deborah Schady, MD, for providing the histologic images for this topic review.