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 of CFLD, which leads to screening and monitoring for CFLD. The most significant form of CFLD is portal hypertension, which is typically related to cirrhosis but also has noncirrhotic causes. Patients with portal hypertension and cirrhosis present almost exclusively during childhood with portal hypertension and associated complications [1]. Patients with noncirrhotic portal hypertension present in both childhood and adulthood [2-4]. It is unclear if milder forms of CFLD can identify individuals who will progress to advanced CFLD, and thus, available screening tests have targeted nonspecific markers of liver involvement. Early identification of progressive CFLD (and, certainly, prior to the development of complications of portal hypertension) allows prospective monitoring for and treatment of complications, which include malnutrition, variceal bleeding due to portal hypertension, and, occasionally, liver failure. Other hepatobiliary complications of CF include 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:

●(See "Cystic fibrosis: Clinical manifestations and diagnosis".)

●(See "Cystic fibrosis: Genetics and pathogenesis".)

●(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".)

●(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: Treatment of acute 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 portal hypertension with or without cirrhosis. CFLD with biliary cirrhosis and portal hypertension 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 at a microscopic level [2-4].

CFLD has traditionally 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 advanced CFLD 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 that were performed before the modern era of CF management and outcome, 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].

●Advanced CFLD – Advanced CFLD (cirrhosis with portal hypertension) is the most clinically important manifestation of CFLD and is closely associated with poor outcome. CF cirrhosis 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 suggestive of cirrhosis [16]. Other clinical clues to cirrhosis with portal hypertension include low or normal but declining platelet count and splenomegaly. Virtually all patients with advanced CFLD 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, not all patients with these variants develop advanced CFLD, even in the same family. Additional risk factors for advanced CFLD include male sex, Hispanic ethnicity, and heterozygosity for the PiZ allele of alpha-1 antitrypsin.

Among patients with cirrhosis, variceal bleeding develops in approximately 7 percent of individuals within 10 years of being diagnosed with cirrhosis and is the presenting feature in approximately one-half of those cases [22]. Although the bleeding can be life-threatening, all-cause mortality is similar in individuals with CF cirrhosis with or without bleeding. CF cirrhosis is also associated with CF-related diabetes, and both of these disorders are predictors of mortality, independent of pulmonary function [23,24]. While children or adults with CF cirrhosis may continue to have preserved synthetic liver function for many years (compensated cirrhosis), some will 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 [25].

●Noncirrhotic portal hypertension – Noncirrhotic portal hypertension associated with focal nodular hyperplasia is a distinct phenotype of CFLD. It was previously thought to occur primarily in adults with CF. However, case reports have identified biopsy-confirmed portal vein abnormalities in 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.

PATHOGENESIS — In the liver, CF transmembrane conductance regulator (CFTR) is located on the apical membrane of the biliary epithelium, not in the hepatocyte. CFTR is thought to control water and solute movement through chloride and bicarbonate secretion, thus promoting bile flow. When CFTR is dysfunctional, it causes thick and tenacious bile that has less bicarbonate and congests intrahepatic bile ducts. 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. Both of these factors are thought to contribute to the decreased flow and increased viscosity of the bile. Obstruction of the biliary ductules causes the release of proinflammatory agents and growth factors that induce the synthesis of collagen in the portal tracts, leading to progressive fibrosis and eventually cirrhosis. Another proposed mechanism of liver disease in CF is the gut-liver axis theory, in which an altered gut microbiome indirectly contributes to the development of liver disease [26]. 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 [27]. The progression to cirrhosis may be rapid or may take years to decades [28]. Interestingly, most patients with severe CF-related liver disease (CFLD) do not become cholestatic or jaundiced, and hepatic synthetic function usually is preserved.

The distinct phenotype of noncirrhotic portal hypertension (characterized by nodular regenerative hyperplasia) in both children and adults with CF suggests a vascular pathogenesis that has not yet been mechanistically characterized [4,29].

Abnormalities of the hepatobiliary system occur almost solely in patients with severe CFTR gene variants, which lead to the impaired synthesis, modification, or regulation of the CFTR protein [30]. However, patients with the same CFTR genotype are often discordant for CFLD phenotype, suggesting that variation in genes other than CFTR and other factors may be important determinants of susceptibility [5]. In particular, the SERPINA1 Z allele has been associated with an increased risk for advanced CFLD, although this accounts for only a small percentage of all patients with advanced CFLD. In addition, CF-related cirrhosis and portal hypertension may accelerate at an early age in the setting of pulmonary exacerbations, repeated infections, or malnutrition [12].

Other factors that may contribute to CFLD include malnutrition, essential fatty acid deficiency [31], and ethanol ingestion in older patients. 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 is unclear if hepatic steatosis progresses to cirrhosis in CFLD. 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 may resolve when feedings are resumed.

CLINICAL MANIFESTATIONS — There are multiple presentations of liver involvement in CF (table 2). The most clinically important form is biliary cirrhosis, which is slowly progressive and can lead to portal hypertension 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) 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 cirrhosis [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 [2,3,32,33].

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 splenomegaly, which results in splenic sequestration and decreased platelet count in the peripheral blood. 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 [34,35]. A large registry study reported that patients with CF cirrhosis have a 10-year cumulative risk of variceal hemorrhage of 6.7 percent [22]. 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 can have significant nodularity on imaging. Liver biopsy and portal venous pressure measurements may be needed to distinguish between the two entities. 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) [36,37] (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 later cirrhosis [38,39]. Similarly, isolated elevations in aminotransferase activity prior to two years of age are often transient and generally do not predict later CFLD [6,10]. However, early persistent elevations in liver enzymes were associated with an increased risk for advanced CFLD 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 [6,40,41]. The sonographic or histologic finding of steatosis is sometimes related to iatrogenic or environmental factors, particularly malnutrition and essential fatty acid deficiency [31] (see 'Pathogenesis' above). However, in most individuals with CF, no nutritional cause is identified [42]. 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 [43,44].

CFTR modulator/corrector drug-induced liver injury — With the advent of CFTR-directed modulator and corrector therapy (elexacaftor-tezacaftor-ivacaftor and others), there have been reports of drug-induced liver enzyme elevations and a case report of severe acute hepatitis [45]. The frequency of liver enzyme elevations above three to five times the upper limit of normal (ULN) is between 5 and 10 percent. Liver enzymes should be determined every three months for the first year of therapy and then at least annually. The manufacturer's prescribing information recommends interruption of therapy for ALT/AST >5× ULN or ALT/AST >3× ULN with bilirubin >2× ULN. (See "Cystic fibrosis: Treatment with CFTR modulators".)

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.

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 (CFLD) 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 [6,28]:

●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.

●Laboratory testing – Measure 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 AST to platelet ratio index (APRI) is a reasonably good surrogate marker for hepatic fibrosis, as validated by liver biopsy [46]. Some experts have suggested calculating the APRI as part of the routine annual evaluation [47]. If the results of liver transaminases 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 GGT is persistently elevated (>21), further evaluation is warranted [15]. The combination of APRI and spleen size-for-age Z-score is also correlated with nodularity on ultrasound examination [48]. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations", section on 'AST to platelet ratio index'.)

●Imaging – If the above measures are persistently abnormal, then the next step is complete abdominal ultrasonography, with or without Doppler measurements of hepatic blood flow. 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. Research-based ultrasound (in which ultrasound findings were graded by a consensus of radiologists who underwent specialized training) can identify a subset of children with CF at high risk for developing a nodular liver indicative of advanced CFLD [49]. Doppler can measure reversal of blood flow in the portal vein or a recanalized umbilical vein, which may be seen in both cirrhotic and noncirrhotic portal hypertension. Evidence of advanced CFLD includes splenomegaly, large collateral veins, or ascites [6,28,50]. 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.

For patients with clinical features suggesting cirrhosis or portal hypertension (eg, splenomegaly, decline in platelet count, or firm liver on physical examination), other imaging modalities may be useful to assess for fibrosis: Magnetic resonance elastography (MRE) may be the most helpful modality in assessing the extent of fibrosis in this very heterogeneous disease because it utilizes a mechanical driver to create a heat map of the entire liver rather than a small area of the liver. Cooler colors correspond with less stiffness, while warm colors correlate with increasing liver stiffness. MRE can also quantify fibrosis and differentiate it from fat [51]. Transient elastography, which uses ultrasound technology to measure liver stiffness, is more available and is used in some centers to screen for advanced liver disease. Several studies suggest that vibration-controlled or shear-wave transient elastography can identify CF cirrhosis with specific liver stiffness measurement cut-points [47,52,53]. Screening with ultrasound-based transient elastography is often preferred over MRE for screening due to cost and availability. (See "Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations".)

Diagnosis — 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 [29].

●Hepatomegaly (liver span greater than the upper limit of normal [ULN] for age [54]) and/or splenomegaly, confirmed by ultrasonography

●Abnormalities of ALT, AST, and GGT >1.5 to 2 times the laboratory upper limits of normal 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 careful 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 careful 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 [55,56].

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 advanced CFLD 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 UCDA on the development of advanced CFLD (portal hypertension) [57,58]. 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 [6,28,59].

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 [34,60]. Despite these theoretical benefits, the clinical evidence supporting the use of UDCA is weak and consists of low-quality or indirect clinical evidence [61], as outlined below:

●Several observational studies and two small randomized trials suggest that UDCA may delay the progression of CFLD [62-64]. 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 [63]. 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 [65]. However, a retrospective study in France concluded that the early use of UDCA did not alter the incidence of severe CFLD in the last 20 years [58]. A 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 [57].

●A Cochrane review found insufficient evidence to determine whether UDCA is effective for treatment or prevention of CFLD [61].

Gallstones in CF are not responsive to therapy with UDCA, because their main component is not cholesterol [28,40,66]. (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 [67]. 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 [56,68-70]. 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 [71]. 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 [71]. 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 [6,28,72]. 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 advanced CFLD 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 [73-75]. In the United States between 2006 and 2016, combined liver-lung transplantation was performed in 52 individuals, 30 of whom had CF [75]. The frequency of combined liver-lung transplantation varies among institutions. Given the association of CF-related diabetes and advanced CFLD combined, liver-pancreas transplantation has been suggested as an option. This is infrequently performed but should be considered in the appropriate setting [76,77].

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 [18,28,34,78]. For liver-lung transplantation, mean survival rates in the United States are 83, 69, and 56 percent at 1, 5, and 10 years, respectively [75]. 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 [79]. 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 [74]. 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".)

GALLBLADDER DISEASE — CF is associated with microgallbladder, cholelithiasis (gallstones), and cholecystitis [18,28].

●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 [6,80]. 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 (CF transmembrane conductance regulator) [28].

●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 [34,35]. 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 [81]. 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 [33].

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

●There are multiple presentations of cystic fibrosis-related liver disease (CFLD) including neonatal cholestasis, hepatic steatosis, and focal biliary cirrhosis (table 2). Among these, biliary cirrhosis is most likely to cause progressive liver disease, with associated complications and mortality. (See 'Clinical manifestations' above.)

●Cirrhosis develops in approximately 10 percent of individuals with cystic fibrosis (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.)

●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. This screening process is particularly important for patients with a severe CF genotype (eg, homozygous for the F508del variant). (See 'Evaluation' above.)

●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 (UDCA) 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, and indirect evidence from other cholestatic liver diseases suggest that high doses may be detrimental.

We suggest using UDCA for children who have established cholestasis due to CFLD (Grade 2C) (eg, serum conjugated bilirubin >1 mg/dL [17.1 micromol/L]), treating 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.)

●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.)

●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 editorial staff are grateful to Deborah Schady, MD, for providing the histologic images for this topic review.