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Cystic fibrosis-associated liver disease
Best Practice & Research Clinical Gastroenterology 24 (2010) 585–592
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Best Practice & Research Clinical Gastroenterology
5
Cystic fibrosis-associated liver disease Ulrike Herrmann a, Gerd Dockter, Professor b, Frank Lammert, Professor, Head of Department a, * a b
Department of Medicine II, Saarland University Hospital, Saarland University, Kirrberger Str. 1, 66421 Homburg, Germany Department of Paediatrics, Saarland University Hospital, Saarland University, Homburg, Germany
Keywords: Biliary fibrosis Cystic fibrosis transmembrane conductance regulator fibrosing cholangiopathy Microgallbladder Mucoviscidosis Ursodeoxycholic acid
Liver disease is increasingly common in cystic fibrosis (CF). As new therapeutic options emerge, life expectancy increases and common hepatobiliary manifestations impact on quality of life and survival of CF patients. Hepatobiliary abnormalities in CF vary in nature and range from defects attributable to the underlying CFTR gene defect to those related to systemic disease and malnutrition. Today complications of liver disease represent the third most frequent cause of disease-related death in patients with CF. Here we review molecular and clinical genetics of CF, including genetic modifiers of CF-associated liver disease, and provide practical recommendations for genetic testing, diagnosis and treatment of hepatobiliary manifestations in CF. Ó 2010 Elsevier Ltd. All rights reserved.
Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disorder with an incidence of 1 in 3000. Although lung disease is the main cause of morbidity and mortality, advances in patient care and medical have altered CF course and led to a striking increase of life expectancy, with children born today expected to reach 50 years. Hence, other organ manifestations become clinically more relevant. No more than one-third of CF patients present with clinically significant liver disease, but hepatobiliary disease is the third leading cause of death in CF (following pulmonary disease and transplant complications), accounting for 2.5% of the overall mortality of CF patients [1]. Pathophysiology The CFTR (cystic fibrosis transmembrane conductance regulator) gene defect was discovered in 1989 [2]. Located on chromosome 7, the gene encodes a large protein (1480 amino acids), which
* Corresponding author. Tel.: þ49 6841 1623201; fax: þ49 6841 1623267. E-mail address: [email protected] (F. Lammert). 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.08.003
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includes two membrane-spanning domains, two nucleotide-binding domains and a regulatory domain that functions as a cAMP-dependent Cl channel. Hence, CTFR belongs to the family of ATP-binding cassette (ABC) transporters (subfamily C, member 7; ABCC7). The transporter localises to the apical membrane of secretory and absorptive epithelial cells within lungs, pancreas, liver, intestine, sweat glands and Vas deferens. Binding of secreting to basolateral receptors increases intracellular cAMP levels and activates CFTR. Subsequent Cl secretion through CFTR imposes a negative luminal potential and an osmotic gradient that triggers secretion of Naþ and H2O and facilitates bile salt-mediated Cl/ HCO 3 exchange, thus maintaining an alkaline pH and diluting fluid secretion [3]. The absence of functional CFTR protein presumably initiates a cascade of abnormal Cl and HCO 3 secretion, decreased flow and plugging by abnormally thick mucus [4]. Table 1 summarises the wide variety of specific hepatobiliary complications that can be ascribed to the underlying CFTR gene defect. Of note, fatty liver (steatosis) is another common hepatobiliary complication of CF (23–75%) [5]. However, the pathogenesis is not directly related to the gene defect but has been attributed to malnutrition, essential fatty acid deficiency, carnitine or choline deficiency, or insulin resistance [5]. The CFTR protein localises to the apical membrane of cholangiocytes in bile ducts and gallbladder epithelium, where it regulates the fluid and electrolyte content of bile. Focal biliary cirrhosis (FBC) and multilobular cirrhosis (MBC) are caused by blockage of biliary ductules with thick eosinophilic, periodic acid-Schiff (PAS) positive material, resulting in periductal inflammation, bile duct proliferation, and periportal fibrosis. Hepatic stellate cells (major drivers of hepatic fibrogenesis) become activated to produce collagen and stimulate the bile duct epithelium to produce profibrogenic cytokines such as TGFb (see Weber & Wasmuth, this issue). The progression from FBC to MBC and portal hypertension, which occurs in up to 8% of patients, may take years to decades, and should be viewed as a continuum [6]. Freudenberg et al. [7] showed that in DF508 mutant mice increased faecal bile acid loss leads to more hydrophobic bile salts in hepatic bile and to hyperbilirubinbilia, a major contributor in augmenting the bile salt-to-phospholipids ratio and, following hydrolysis, precipitation of divalent metal salts of unconjugated bilirubin. These alterations were found to be associated with damage to intrahepatic bile ducts, allowing increased permeability of unconjugated bilirubin into cholangiocytes. In addition, lower gallbladder bile pH values and elevated calcium bilirubinate ion products in bile of CF mice raise the likelihood of supersaturating bile and forming black pigment gallstones [8]. In fact, gallstones are frequent in CF patients and generally are ‘black’ pigment, i.e. composed of calcium bilirubinate with an appreciable cholesterol admixture, [8,9] but rarely cause symptoms. Minagawa et al. [10] suggested that CFTR regulates the release of ATP into the bile duct lumen, which regulates cholangiocyte secretion via the activation of purinergic (P2Y) receptors. Accordingly, Fiorotto et al. [11] demonstrate that the choleretic effect of ursodeoxycholic acid (UDCA) is mediated via CFTR-dependent ATP secretion. The decreased bile flow in models of CFTR dysfunction could also be associated with alterations in mechanosensitive pathways, which exacerbate abnormalities in Cl secretion and bile formation.
Genetic testing To date, >1700 mutations of the CFTR gene have been described (http://www.genet.sickkids.on.ca/ cftr/app/). The most common mutation results in deletion of phenylalanine at amino acid position 508. Table 1 Specific CFTR-related hepatobiliary manifestations of CF. Condition
Frequency (%)
Focal biliary cirrhosis (FBC) Multilobular biliary cirrhosis (MBC) Portal hypertension Microgallbladder Cholelithiasis Neonatal cholestasis Sclerosing cholangitis Cholangiocarcinoma
20–30 5–15 2–5 15–45 3–25 Rare Rare Rare
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Fig. 1. The CFTR mutations have been divided into five classes based on their impact on transporter molecule or regulation. A number of corrective agents are in or approaching clinical trials; however, only gene transfer represents potential cure (illustration by Katrin Hochrath and Armin Schneider).
One copy of the DF508 mutation is present in 60–70% of CF patients and is the predominant mutation in Europe and North America. Given the complex genotype–phenotype relationships in CF, a recent consensus statement was issued to aid clinicians in genetic testing for CF [12]. Hepatobiliary manifestations occur almost exclusively in CF patients with severe class I–III mutations [13] affecting CFTR synthesis, processing or regulation (Fig. 1, Table 2), but there are no clear phenotype relationships with specific CFTR mutations. Therefore, genetic testing should not be used to predict which patients are most likely to develop hepatobiliary manifestations. It remains unclear why only a minority of patients with the same severe CFTR mutations develops CF-associated liver disease. Several factors have been found to be associated with hepatobiliary manifestations, including age at diagnosis of CF, male gender, history of meconium ileus, and pancreatic insufficiency [5]. Table 3 summarises potential ‘genetic modifiers’ such as variants of genes that up-regulate inflammation, fibrosis or oxidative stress, which have been tested previously. However in two large populations with 260 patients with liver disease in CF, only the a1-antitrypsin Z allele (p.G342L; see Bals, this issue) was consistently associated with CF-associated liver disease. Patients who carry this allele are at high risk (OR ¼ 4.2) of developing portal hypertension, [14] and the population attributable fraction for this allele is 6.7%. Table 2 Mortality rates (including transplantation as deaths) by CFTR mutation class [13]. b
Class
Patients (n)
Person-years
Deaths
Crude mortality ratea
Standardised mortality ratea (95% CI)
p value
I II III IV V Unclassified
1670 9820 667 349 296 5051
9499 54 060 3688 1713 1398 26 517
181 1059 65 26 22 548
19.1 19.6 17.6 15.2 15.7 20.6
20.4 21.2 16.0 7.8 9.1 19.1
0.615 – 0.013 <0.0001 <0.0001 0.039
(17.4–23.4) (20.0–22.5) (12.1–20.2) (4.2–11.4) (4.8–13.5) (17.4–20.7)
Abbreviation: CI, confidence interval. a Per 1000 person-years. b Calculated by comparison of standarised mortality rates for all functional classes with that for class II.
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Table 3 Potential modifier genes of CF-related liver disease: prevalence of polymorphic genotypes in CF patients with and without severe liver disease [12]. Gene
Variant
P value
Angiotension converting enzyme (ACE) a1-antitrypsin (SERPINA1)
del D/I p. G264V (PiS) p. G342L (PiZ) p. V105I O XA/O 509C>T p. C29T p. G74C
0.45 0.16 9.9 109 0.32 0.92 0.50 0.01* 0.96 0.71
Glutathione S-transferase P1 (GSTP1) Mannose-binding lectin 2 (MBL2) TGF-b1 (TGFB1)
Frequency of risk genotype (%) Liver disease
No liver disease
8.8
2.3
OR (95% CI)
4.17 (2.46–7.05)
*nominal P-value, not replicated. Abbreviations: CI, confidence interval; del, Deletion; OR, odds ratio; p, protein; PI, proteinase inhibitor.
Of note, the common UGT1A1 promoter mutation associated with Gilbert syndrome (see Strassburg, this issue) represents a lithogenic risk factor for gallstone formation in CF [9]. Patients with CF and gallstones are significantly more likely to carry at least one Gilbert UGT1A1 allele compared with stone-free patients (OR ¼ 7.3; P ¼ 0.042). This association supports the current concept for gallstone formation in CF and suggests that genetic and exogenous sources contributing to hyperbilirubinbilia are lithogenic in CF. Clinical course Neonatal cholestasis – a direct consequence of the basic CFTR defect resulting in obstruction of extrahepatic bile ducts (‘inspissated bile syndrome’) – can be the first hepatic manifestation of CF. It may mimic biliary atresia (from which it may be distinguished by a positive endoscopic retrograde cholangiogram), but generally resolves within the first-three months and does not progress. Children with meconium ileus are at greater risk. Usually clinically apparent CF-associated liver disease develops during or before puberty with a prevalence of 13–17%, with no significant increase after mid-adolescence, and displays a slowly progressive course [5]. A recent study on CF patients >40 years of age revealed portal hypertension in up to 7.9%, [15] yet during a median follow-up 7 years only 28% of these develop variceal bleeding or ascites [16]. Liver failure is a late event. Additionally, a case-control study evaluating the prognostic implications of variceal bleeding found that the median age at which haemorrhage occurred was 20 years, with a median survival after the first episode of 8.4 years [17]. Therefore, although liver disease is a relatively common complication of CF, morbidity and mortality associated with portal hypertension are low. However, CF patients with end-stage liver disease are at risk of severe malnutrition and hepatic osteodystrophy. Table 4 lists the most important triggers of hepatic encephalopathy in CF. Diagnosis Since evidence of liver disease in CF is often subclinical, it is frequently underdiagnosed. Although recent consensus guidelines for CF diagnosis [18] and management of liver and biliary tract disease in CF [19] have been published, early diagnosis of CF-associated liver disease remains a challenge and a combination of diagnostic modalities is to be used. A sweat test to exclude CF is indicated in every newborn with cholestasis of unknown origin. The majority of CF patients have non-significant elevations of alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) activities in serum up to 2.5 the upper limits of normal (ULN), but these biochemical markers do not identify patients with significant liver disease such as MBC. Serum liver tests have been recommended at yearly intervals in CF patients [20]. Elevations >1.5 ULN should induce controls after 3–6 months, [20] and when persisting should prompt further investigations to more closely evaluate liver damage (prothrombin time, albumin) and exclude other causes of liver disease (e.g. drugs, toxins, infections, biliary atresia, gallstones, a1-antitrypsin deficiency, autoimmune hepatitis, primary sclerosing cholangitis, or other
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Table 4 Triggers of hepatic encephalopathy in CF.
Bacterial sepsis Pneumonia Gastrointestinal bleeding Distal intestinal obstruction syndrome (DIOS) Diarrhoea, vomiting Electrolyte imbalance, acidosis Forced diuresis Liver failure
causes of bile duct obstruction). Table 5 summarises the diagnostic criteria established by Colombo et al. [21] which were met by 9.7% of CF patients [16]. Liver biopsy is controversially discussed due to the focal nature of fibrosis and cirrhosis in many cases. Beyond biochemical and histological assessment, imaging modalities such as ultrasound, magnetic resonance and computed tomography are used. Isolated hepatomegaly occurs in 6–30% of CF patients but is rarely associated with advanced liver disease [1]. Ultrasound criteria for diagnosis of liver disease in CF include coarseness of the liver parenchyma, nodularity of the liver edge, and increased periportal echogenicity indicating periportal fibrosis [22]. More recently, an alternative scoring system was proposed that evaluates many different components of liver disease but is yet to be validated [23]. Duplex sonography facilitates the assessment of portal hypertension and portosystemic collaterals. Magnetic resonance cholangiography is very helpful for evaluation of the extra- and intrahepatic biliary tree, abnormalities of which are detected in all patients with liver disease (in particular common-bile duct stenosis) and in half of those without clinically apparent liver disease [24]. Upper gastrointestinal endoscopy is performed for grading of oesophageal and gastric varices. Therapy No therapy of proven benefit for the long-term prognosis of CF-associated liver disease exists. Optimisation of nutritional state to avoid vitamin deficiency and malnutrition is recommended, but not with proven efficacy. UDCA UDCA (20–30 mg/kg/day) has been shown to improve serum liver tests and histopathological alterations (over 2 years) as well as nutritional status, [19,25,26] but no effect on survival has been documented [27]. UDCA dose is higher than for other cholestatic liver diseases, [19] probably due to poor intestinal absorption in CF patients. There are several postulated mechanisms of action, including stimulation of hepato- and cholangicellular secretion, antiapoptotic effects as well as decrease of bile cytotoxicity (reviewed in [28]). UDCA acts as a posttranscriptional secretagogue: UDCA-induced stimulation of biliary HCO 3 secretion may include purinergic signalling and targeting of basolateral transporters including CFTR [3]. A retrospective study of 278 adult patients with CF identified 27 (9.7%) with liver disease; UDCA taken by 22 patients was associated with improvement in hepatobiliary symptoms in half of them and significant reductions of serum ALT, GGT and alkaline phosphatase (AP) activities [16]. The additional supplementation of the amino acid taurine (20–40 mg/kg/day) might have beneficial effects on bile salt pool composition and fat absorption in individual patients. Elevated endogenous Table 5 Diagnostic criteria for liver disease in CF according to Colombo et al. [26]. Positive liver histology (FBC, MBC) or At least two of the following conditions on at least two consecutive examinations spanning a one-year period: o o o
Hepatomegaly (liver span >2 cm below the costal margin on the midclavicular line) confirmed by ultrasound Two abnormal serum liver enzyme levels (ALT, aspartate aminotransferase or GGT >ULN) Ultrasound abnormalities other than hepatomegaly (increased, heterogeneous echogenicity, nodularity, irregular margins, splenomegaly)
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UDCA in children with CF without hepatobiliary manifestations as compared to those with liver disease suggests a protective role of UDCA against liver injury [29]. Given that UDCA is well tolerated and without major side effects, there may even be a role for UDCA in the prevention of liver disease. However, UDCA is not indicated for the treatment of gallstones in CF but might be considered for prevention of intrahepatic sludge and stones. Transjugular intrahepatic portosystemic stent-shunt (TIPS) and surgery In contrast to symptomatic gallbladder stones, microgallbladder is no indication for cholecystectomy. In general, treatment of complications of cirrhosis in CF does not differ from other liver diseases. Medical treatment of portal hypertension with b-blockers (limited by the potential for bronchoconstriction) and endoscopic treatment of varices have not been adequately evaluated in CF, whereas elective shunt surgery in portal hypertensive patients has allowed long-term survival in case series [30]. Symptomatic portal hypertension has been successfully treated with TIPS in long-term follow-up (70 months) without clinical signs of hepatic encephalopathy [31]. Splenic artery embolisation or (partial) splenectomy in children with portal hypertension and splenomegaly can stabilise lung function and delay progression of portal hypertension [32]. Liver cirrhosis can adversely affect respiratory function secondary to organomegaly, ascites and hepatopulmonary syndrome (intrapulmonary shunts). For this reason, the traditional approach in children with CF has been to consider orthotopic liver transplantation (OLT) early prior to deterioration of lung function. Although there are several studies on prolonged survival and improved quality of life in patients with CF-associated liver disease after OLT, there is just as much evidence to suggest that there is no benefit [33]. Long-term survival is frequent in CF patients who presented with variceal bleeding, and age at death is comparable to the general CF population [17]. A pooled analysis from European CF and transplant registries showed that the decision to transplant is based on various factors generally before the development of end-stage liver disease [34]. Outcome data indicate that the 1-year patient survival rate following OLT ranges from 75% to100% [35]. According to a recent study on outcomes after combined lung and liver transplantation, overall survival rates at one and five years were 69% and 49%, respectively [36]. Given the improved therapeutic options for complications of portal hypertension, OLT may be reserved for CF patients with features of liver decompensation or growth failure in addition to portal hypertension [17]. Novel therapies Several new CF medications are in phase I–III clinical trials [37]. These include salt modulators that modulate other chloride or sodium channels as well as drugs designed to repair the damaged CFTR protein (Fig. 1). A novel agent that passed a phase II clinical trial is ataluren (PTC124), an orally bioavailable small molecule designed to induce ribosomes to selectively read through premature stop codons during mRNA translation to produce functional CFTR [38]. As nonsense mutations account for only 10% of CFTR mutations, this is an example of ‘personalized medicine’, in which patients with specific gene mutations are targeted for therapy.
Practice points Liver diseases affect one-third of patients with CF during long-term follow-up and may be disclosed by detection of hepatomegaly, annual performance of serum liver tests, and ultrasound of the liver. UDCA improves serum liver tests and histological parameters in CF-associated liver disease. However, no medical therapy of proven long-term benefit exists. Liver transplantation is the treatment of choice in end-stage liver disease, but recent studies indicate that OLT may not improve survival in CF patients with portal hypertension but without hepatocellular failure.
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Research agenda Future studies should define the role of CFTR during cholestasis and understand the potential regulatory roles of alternate secretory pathways. Further identification of ‘genetic modifiers’ could facilitate the identification of patients at risk for CF-associated liver disease and help tailoring prophylactic and therapeutic strategies. Confirmation of the concept of a ‘biliary HCO 3 umbrella’ might contribute to unravelling the pathophysiology of chronic fibrosing cholangiopathy and developing novel therapeutic strategies. The optimal dose of UDCA and its impact on survival in CF remain to be established. New pharmacologic agents targeting the underlying CFTR defect are to be assessed in randomised clinical trials.
Summary CF is associated with liver disease in almost 30% of all patients. The spectrum includes neonatal cholestasis, hepatic steatosis, focal or multilobular cirrhosis. The latter represent the pathophysiological sequelae of loss-of-function of the CFTR transporter, which disturbs Cl and HCO3 secretion of cholangiocytes and leads to ‘inspissated’ bile ducts. Defined CFTR genotype–phenotype correlations do not exist, but heterozygosity for the pathogenic a1-antitrypsin variant PiZ represents a ‘genetic modifier’ that contributes to severe liver phenotypes. Further diagnostic assessment is based on ultrasound and magnetic resonance cholangiography. In general, CF-associated liver disease develops during the first decades of life and does not progress rapidly. Liver transplantation is restricted to patients with complications of portal hypertension, chronic liver failure and malnutrition, but outcome is better prior to deterioration of lung function. Acknowledgements We thank Dr. Hiltrud Dohmen (Aachen) and Prof. Dr. Michael Barker (Berlin) for taking care of CF patients included in clinical studies. This work has been supported, in part, by Deutsche Forschungsgemeinschaft (SFB/TRR 57, TP01). Conflict of interest None. References [1] Moyer K, Balistreri W. Hepatobiliary disease in patients with cystic fibrosis. Curr Opin Gastroenterol 2009;25:272–8. [2] Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–73. [3] Beuers U, Hohenester S, Maillette de Buy Wenniger L, Kremer AE, Jansen PL, Elferink RP. The biliary HCO 3 umbrella. Hepatology 2010; e-pub. [4] Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 2008;372:415–7. [5] Lindblad A, Glaumann H, Strandvik B. Natural history of liver disease in cystic fibrosis. Hepatology 1999;30:1151–8. [6] Colombo C, Botto Poala S, Motta V, Zazzeron L. Liver disease in cystic fibrosis. In: Blum HE, Cox DW, Häussinger D, Jansen PL, Kullak-Ublick GA, editors. Genetics in liver diseases. Proceedings of the Falk Symposium, vol. 156. Dordrecht: Springer; 2007. p. 102–18. [7] Freudenberg F, Broderick AL, Yu BB, Leonard MR, Glickman JN, Carey MC. Pathophysiological basis of liver disease in cystic fibrosis employing a DeltaF508 mouse model. Am J Physiol Gastrointest Liver Physiol 2008;294:G1411–20. [8] Freudenberg F, Leonard MR, Liu SA, Glickman JN, Carey MC. Pathophysiological preconditions promoting mixed “black” pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis. Am J Physiol Gastrointest Liver Physiol 2010;299:G205–14. [9] Wasmuth HE, Keppeler H, Herrmann U, Schirin-Sokhan R, Barker M, Lammert F. Coinheritance of Gilbert syndromeassociated UGT1A1 mutation increases gallstone risk in cystic fibrosis. Hepatology 2006;43:738–41. [10] Minagawa N, Nagata J, Shibao K, Masvuk Al, Gomes DA, Rodriques MA, et al. Cyclic AMP regulates bicarbonate secretion in cholangiocytes through release of ATP into bile. Gastroenterology 2007;133:1592–602.
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Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
5
Cystic fibrosis-associated liver disease Ulrike Herrmann a, Gerd Dockter, Professor b, Frank Lammert, Professor, Head of Department a, * a b
Department of Medicine II, Saarland University Hospital, Saarland University, Kirrberger Str. 1, 66421 Homburg, Germany Department of Paediatrics, Saarland University Hospital, Saarland University, Homburg, Germany
Keywords: Biliary fibrosis Cystic fibrosis transmembrane conductance regulator fibrosing cholangiopathy Microgallbladder Mucoviscidosis Ursodeoxycholic acid
Liver disease is increasingly common in cystic fibrosis (CF). As new therapeutic options emerge, life expectancy increases and common hepatobiliary manifestations impact on quality of life and survival of CF patients. Hepatobiliary abnormalities in CF vary in nature and range from defects attributable to the underlying CFTR gene defect to those related to systemic disease and malnutrition. Today complications of liver disease represent the third most frequent cause of disease-related death in patients with CF. Here we review molecular and clinical genetics of CF, including genetic modifiers of CF-associated liver disease, and provide practical recommendations for genetic testing, diagnosis and treatment of hepatobiliary manifestations in CF. Ó 2010 Elsevier Ltd. All rights reserved.
Cystic fibrosis (CF) is the most common life-threatening autosomal recessive disorder with an incidence of 1 in 3000. Although lung disease is the main cause of morbidity and mortality, advances in patient care and medical have altered CF course and led to a striking increase of life expectancy, with children born today expected to reach 50 years. Hence, other organ manifestations become clinically more relevant. No more than one-third of CF patients present with clinically significant liver disease, but hepatobiliary disease is the third leading cause of death in CF (following pulmonary disease and transplant complications), accounting for 2.5% of the overall mortality of CF patients [1]. Pathophysiology The CFTR (cystic fibrosis transmembrane conductance regulator) gene defect was discovered in 1989 [2]. Located on chromosome 7, the gene encodes a large protein (1480 amino acids), which
* Corresponding author. Tel.: þ49 6841 1623201; fax: þ49 6841 1623267. E-mail address: [email protected] (F. Lammert). 1521-6918/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2010.08.003
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includes two membrane-spanning domains, two nucleotide-binding domains and a regulatory domain that functions as a cAMP-dependent Cl channel. Hence, CTFR belongs to the family of ATP-binding cassette (ABC) transporters (subfamily C, member 7; ABCC7). The transporter localises to the apical membrane of secretory and absorptive epithelial cells within lungs, pancreas, liver, intestine, sweat glands and Vas deferens. Binding of secreting to basolateral receptors increases intracellular cAMP levels and activates CFTR. Subsequent Cl secretion through CFTR imposes a negative luminal potential and an osmotic gradient that triggers secretion of Naþ and H2O and facilitates bile salt-mediated Cl/ HCO 3 exchange, thus maintaining an alkaline pH and diluting fluid secretion [3]. The absence of functional CFTR protein presumably initiates a cascade of abnormal Cl and HCO 3 secretion, decreased flow and plugging by abnormally thick mucus [4]. Table 1 summarises the wide variety of specific hepatobiliary complications that can be ascribed to the underlying CFTR gene defect. Of note, fatty liver (steatosis) is another common hepatobiliary complication of CF (23–75%) [5]. However, the pathogenesis is not directly related to the gene defect but has been attributed to malnutrition, essential fatty acid deficiency, carnitine or choline deficiency, or insulin resistance [5]. The CFTR protein localises to the apical membrane of cholangiocytes in bile ducts and gallbladder epithelium, where it regulates the fluid and electrolyte content of bile. Focal biliary cirrhosis (FBC) and multilobular cirrhosis (MBC) are caused by blockage of biliary ductules with thick eosinophilic, periodic acid-Schiff (PAS) positive material, resulting in periductal inflammation, bile duct proliferation, and periportal fibrosis. Hepatic stellate cells (major drivers of hepatic fibrogenesis) become activated to produce collagen and stimulate the bile duct epithelium to produce profibrogenic cytokines such as TGFb (see Weber & Wasmuth, this issue). The progression from FBC to MBC and portal hypertension, which occurs in up to 8% of patients, may take years to decades, and should be viewed as a continuum [6]. Freudenberg et al. [7] showed that in DF508 mutant mice increased faecal bile acid loss leads to more hydrophobic bile salts in hepatic bile and to hyperbilirubinbilia, a major contributor in augmenting the bile salt-to-phospholipids ratio and, following hydrolysis, precipitation of divalent metal salts of unconjugated bilirubin. These alterations were found to be associated with damage to intrahepatic bile ducts, allowing increased permeability of unconjugated bilirubin into cholangiocytes. In addition, lower gallbladder bile pH values and elevated calcium bilirubinate ion products in bile of CF mice raise the likelihood of supersaturating bile and forming black pigment gallstones [8]. In fact, gallstones are frequent in CF patients and generally are ‘black’ pigment, i.e. composed of calcium bilirubinate with an appreciable cholesterol admixture, [8,9] but rarely cause symptoms. Minagawa et al. [10] suggested that CFTR regulates the release of ATP into the bile duct lumen, which regulates cholangiocyte secretion via the activation of purinergic (P2Y) receptors. Accordingly, Fiorotto et al. [11] demonstrate that the choleretic effect of ursodeoxycholic acid (UDCA) is mediated via CFTR-dependent ATP secretion. The decreased bile flow in models of CFTR dysfunction could also be associated with alterations in mechanosensitive pathways, which exacerbate abnormalities in Cl secretion and bile formation.
Genetic testing To date, >1700 mutations of the CFTR gene have been described (http://www.genet.sickkids.on.ca/ cftr/app/). The most common mutation results in deletion of phenylalanine at amino acid position 508. Table 1 Specific CFTR-related hepatobiliary manifestations of CF. Condition
Frequency (%)
Focal biliary cirrhosis (FBC) Multilobular biliary cirrhosis (MBC) Portal hypertension Microgallbladder Cholelithiasis Neonatal cholestasis Sclerosing cholangitis Cholangiocarcinoma
20–30 5–15 2–5 15–45 3–25 Rare Rare Rare
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Fig. 1. The CFTR mutations have been divided into five classes based on their impact on transporter molecule or regulation. A number of corrective agents are in or approaching clinical trials; however, only gene transfer represents potential cure (illustration by Katrin Hochrath and Armin Schneider).
One copy of the DF508 mutation is present in 60–70% of CF patients and is the predominant mutation in Europe and North America. Given the complex genotype–phenotype relationships in CF, a recent consensus statement was issued to aid clinicians in genetic testing for CF [12]. Hepatobiliary manifestations occur almost exclusively in CF patients with severe class I–III mutations [13] affecting CFTR synthesis, processing or regulation (Fig. 1, Table 2), but there are no clear phenotype relationships with specific CFTR mutations. Therefore, genetic testing should not be used to predict which patients are most likely to develop hepatobiliary manifestations. It remains unclear why only a minority of patients with the same severe CFTR mutations develops CF-associated liver disease. Several factors have been found to be associated with hepatobiliary manifestations, including age at diagnosis of CF, male gender, history of meconium ileus, and pancreatic insufficiency [5]. Table 3 summarises potential ‘genetic modifiers’ such as variants of genes that up-regulate inflammation, fibrosis or oxidative stress, which have been tested previously. However in two large populations with 260 patients with liver disease in CF, only the a1-antitrypsin Z allele (p.G342L; see Bals, this issue) was consistently associated with CF-associated liver disease. Patients who carry this allele are at high risk (OR ¼ 4.2) of developing portal hypertension, [14] and the population attributable fraction for this allele is 6.7%. Table 2 Mortality rates (including transplantation as deaths) by CFTR mutation class [13]. b
Class
Patients (n)
Person-years
Deaths
Crude mortality ratea
Standardised mortality ratea (95% CI)
p value
I II III IV V Unclassified
1670 9820 667 349 296 5051
9499 54 060 3688 1713 1398 26 517
181 1059 65 26 22 548
19.1 19.6 17.6 15.2 15.7 20.6
20.4 21.2 16.0 7.8 9.1 19.1
0.615 – 0.013 <0.0001 <0.0001 0.039
(17.4–23.4) (20.0–22.5) (12.1–20.2) (4.2–11.4) (4.8–13.5) (17.4–20.7)
Abbreviation: CI, confidence interval. a Per 1000 person-years. b Calculated by comparison of standarised mortality rates for all functional classes with that for class II.
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Table 3 Potential modifier genes of CF-related liver disease: prevalence of polymorphic genotypes in CF patients with and without severe liver disease [12]. Gene
Variant
P value
Angiotension converting enzyme (ACE) a1-antitrypsin (SERPINA1)
del D/I p. G264V (PiS) p. G342L (PiZ) p. V105I O XA/O 509C>T p. C29T p. G74C
0.45 0.16 9.9 109 0.32 0.92 0.50 0.01* 0.96 0.71
Glutathione S-transferase P1 (GSTP1) Mannose-binding lectin 2 (MBL2) TGF-b1 (TGFB1)
Frequency of risk genotype (%) Liver disease
No liver disease
8.8
2.3
OR (95% CI)
4.17 (2.46–7.05)
*nominal P-value, not replicated. Abbreviations: CI, confidence interval; del, Deletion; OR, odds ratio; p, protein; PI, proteinase inhibitor.
Of note, the common UGT1A1 promoter mutation associated with Gilbert syndrome (see Strassburg, this issue) represents a lithogenic risk factor for gallstone formation in CF [9]. Patients with CF and gallstones are significantly more likely to carry at least one Gilbert UGT1A1 allele compared with stone-free patients (OR ¼ 7.3; P ¼ 0.042). This association supports the current concept for gallstone formation in CF and suggests that genetic and exogenous sources contributing to hyperbilirubinbilia are lithogenic in CF. Clinical course Neonatal cholestasis – a direct consequence of the basic CFTR defect resulting in obstruction of extrahepatic bile ducts (‘inspissated bile syndrome’) – can be the first hepatic manifestation of CF. It may mimic biliary atresia (from which it may be distinguished by a positive endoscopic retrograde cholangiogram), but generally resolves within the first-three months and does not progress. Children with meconium ileus are at greater risk. Usually clinically apparent CF-associated liver disease develops during or before puberty with a prevalence of 13–17%, with no significant increase after mid-adolescence, and displays a slowly progressive course [5]. A recent study on CF patients >40 years of age revealed portal hypertension in up to 7.9%, [15] yet during a median follow-up 7 years only 28% of these develop variceal bleeding or ascites [16]. Liver failure is a late event. Additionally, a case-control study evaluating the prognostic implications of variceal bleeding found that the median age at which haemorrhage occurred was 20 years, with a median survival after the first episode of 8.4 years [17]. Therefore, although liver disease is a relatively common complication of CF, morbidity and mortality associated with portal hypertension are low. However, CF patients with end-stage liver disease are at risk of severe malnutrition and hepatic osteodystrophy. Table 4 lists the most important triggers of hepatic encephalopathy in CF. Diagnosis Since evidence of liver disease in CF is often subclinical, it is frequently underdiagnosed. Although recent consensus guidelines for CF diagnosis [18] and management of liver and biliary tract disease in CF [19] have been published, early diagnosis of CF-associated liver disease remains a challenge and a combination of diagnostic modalities is to be used. A sweat test to exclude CF is indicated in every newborn with cholestasis of unknown origin. The majority of CF patients have non-significant elevations of alanine aminotransferase (ALT) or gamma-glutamyl transferase (GGT) activities in serum up to 2.5 the upper limits of normal (ULN), but these biochemical markers do not identify patients with significant liver disease such as MBC. Serum liver tests have been recommended at yearly intervals in CF patients [20]. Elevations >1.5 ULN should induce controls after 3–6 months, [20] and when persisting should prompt further investigations to more closely evaluate liver damage (prothrombin time, albumin) and exclude other causes of liver disease (e.g. drugs, toxins, infections, biliary atresia, gallstones, a1-antitrypsin deficiency, autoimmune hepatitis, primary sclerosing cholangitis, or other
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Table 4 Triggers of hepatic encephalopathy in CF.
Bacterial sepsis Pneumonia Gastrointestinal bleeding Distal intestinal obstruction syndrome (DIOS) Diarrhoea, vomiting Electrolyte imbalance, acidosis Forced diuresis Liver failure
causes of bile duct obstruction). Table 5 summarises the diagnostic criteria established by Colombo et al. [21] which were met by 9.7% of CF patients [16]. Liver biopsy is controversially discussed due to the focal nature of fibrosis and cirrhosis in many cases. Beyond biochemical and histological assessment, imaging modalities such as ultrasound, magnetic resonance and computed tomography are used. Isolated hepatomegaly occurs in 6–30% of CF patients but is rarely associated with advanced liver disease [1]. Ultrasound criteria for diagnosis of liver disease in CF include coarseness of the liver parenchyma, nodularity of the liver edge, and increased periportal echogenicity indicating periportal fibrosis [22]. More recently, an alternative scoring system was proposed that evaluates many different components of liver disease but is yet to be validated [23]. Duplex sonography facilitates the assessment of portal hypertension and portosystemic collaterals. Magnetic resonance cholangiography is very helpful for evaluation of the extra- and intrahepatic biliary tree, abnormalities of which are detected in all patients with liver disease (in particular common-bile duct stenosis) and in half of those without clinically apparent liver disease [24]. Upper gastrointestinal endoscopy is performed for grading of oesophageal and gastric varices. Therapy No therapy of proven benefit for the long-term prognosis of CF-associated liver disease exists. Optimisation of nutritional state to avoid vitamin deficiency and malnutrition is recommended, but not with proven efficacy. UDCA UDCA (20–30 mg/kg/day) has been shown to improve serum liver tests and histopathological alterations (over 2 years) as well as nutritional status, [19,25,26] but no effect on survival has been documented [27]. UDCA dose is higher than for other cholestatic liver diseases, [19] probably due to poor intestinal absorption in CF patients. There are several postulated mechanisms of action, including stimulation of hepato- and cholangicellular secretion, antiapoptotic effects as well as decrease of bile cytotoxicity (reviewed in [28]). UDCA acts as a posttranscriptional secretagogue: UDCA-induced stimulation of biliary HCO 3 secretion may include purinergic signalling and targeting of basolateral transporters including CFTR [3]. A retrospective study of 278 adult patients with CF identified 27 (9.7%) with liver disease; UDCA taken by 22 patients was associated with improvement in hepatobiliary symptoms in half of them and significant reductions of serum ALT, GGT and alkaline phosphatase (AP) activities [16]. The additional supplementation of the amino acid taurine (20–40 mg/kg/day) might have beneficial effects on bile salt pool composition and fat absorption in individual patients. Elevated endogenous Table 5 Diagnostic criteria for liver disease in CF according to Colombo et al. [26]. Positive liver histology (FBC, MBC) or At least two of the following conditions on at least two consecutive examinations spanning a one-year period: o o o
Hepatomegaly (liver span >2 cm below the costal margin on the midclavicular line) confirmed by ultrasound Two abnormal serum liver enzyme levels (ALT, aspartate aminotransferase or GGT >ULN) Ultrasound abnormalities other than hepatomegaly (increased, heterogeneous echogenicity, nodularity, irregular margins, splenomegaly)
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UDCA in children with CF without hepatobiliary manifestations as compared to those with liver disease suggests a protective role of UDCA against liver injury [29]. Given that UDCA is well tolerated and without major side effects, there may even be a role for UDCA in the prevention of liver disease. However, UDCA is not indicated for the treatment of gallstones in CF but might be considered for prevention of intrahepatic sludge and stones. Transjugular intrahepatic portosystemic stent-shunt (TIPS) and surgery In contrast to symptomatic gallbladder stones, microgallbladder is no indication for cholecystectomy. In general, treatment of complications of cirrhosis in CF does not differ from other liver diseases. Medical treatment of portal hypertension with b-blockers (limited by the potential for bronchoconstriction) and endoscopic treatment of varices have not been adequately evaluated in CF, whereas elective shunt surgery in portal hypertensive patients has allowed long-term survival in case series [30]. Symptomatic portal hypertension has been successfully treated with TIPS in long-term follow-up (70 months) without clinical signs of hepatic encephalopathy [31]. Splenic artery embolisation or (partial) splenectomy in children with portal hypertension and splenomegaly can stabilise lung function and delay progression of portal hypertension [32]. Liver cirrhosis can adversely affect respiratory function secondary to organomegaly, ascites and hepatopulmonary syndrome (intrapulmonary shunts). For this reason, the traditional approach in children with CF has been to consider orthotopic liver transplantation (OLT) early prior to deterioration of lung function. Although there are several studies on prolonged survival and improved quality of life in patients with CF-associated liver disease after OLT, there is just as much evidence to suggest that there is no benefit [33]. Long-term survival is frequent in CF patients who presented with variceal bleeding, and age at death is comparable to the general CF population [17]. A pooled analysis from European CF and transplant registries showed that the decision to transplant is based on various factors generally before the development of end-stage liver disease [34]. Outcome data indicate that the 1-year patient survival rate following OLT ranges from 75% to100% [35]. According to a recent study on outcomes after combined lung and liver transplantation, overall survival rates at one and five years were 69% and 49%, respectively [36]. Given the improved therapeutic options for complications of portal hypertension, OLT may be reserved for CF patients with features of liver decompensation or growth failure in addition to portal hypertension [17]. Novel therapies Several new CF medications are in phase I–III clinical trials [37]. These include salt modulators that modulate other chloride or sodium channels as well as drugs designed to repair the damaged CFTR protein (Fig. 1). A novel agent that passed a phase II clinical trial is ataluren (PTC124), an orally bioavailable small molecule designed to induce ribosomes to selectively read through premature stop codons during mRNA translation to produce functional CFTR [38]. As nonsense mutations account for only 10% of CFTR mutations, this is an example of ‘personalized medicine’, in which patients with specific gene mutations are targeted for therapy.
Practice points Liver diseases affect one-third of patients with CF during long-term follow-up and may be disclosed by detection of hepatomegaly, annual performance of serum liver tests, and ultrasound of the liver. UDCA improves serum liver tests and histological parameters in CF-associated liver disease. However, no medical therapy of proven long-term benefit exists. Liver transplantation is the treatment of choice in end-stage liver disease, but recent studies indicate that OLT may not improve survival in CF patients with portal hypertension but without hepatocellular failure.
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Research agenda Future studies should define the role of CFTR during cholestasis and understand the potential regulatory roles of alternate secretory pathways. Further identification of ‘genetic modifiers’ could facilitate the identification of patients at risk for CF-associated liver disease and help tailoring prophylactic and therapeutic strategies. Confirmation of the concept of a ‘biliary HCO 3 umbrella’ might contribute to unravelling the pathophysiology of chronic fibrosing cholangiopathy and developing novel therapeutic strategies. The optimal dose of UDCA and its impact on survival in CF remain to be established. New pharmacologic agents targeting the underlying CFTR defect are to be assessed in randomised clinical trials.
Summary CF is associated with liver disease in almost 30% of all patients. The spectrum includes neonatal cholestasis, hepatic steatosis, focal or multilobular cirrhosis. The latter represent the pathophysiological sequelae of loss-of-function of the CFTR transporter, which disturbs Cl and HCO3 secretion of cholangiocytes and leads to ‘inspissated’ bile ducts. Defined CFTR genotype–phenotype correlations do not exist, but heterozygosity for the pathogenic a1-antitrypsin variant PiZ represents a ‘genetic modifier’ that contributes to severe liver phenotypes. Further diagnostic assessment is based on ultrasound and magnetic resonance cholangiography. In general, CF-associated liver disease develops during the first decades of life and does not progress rapidly. Liver transplantation is restricted to patients with complications of portal hypertension, chronic liver failure and malnutrition, but outcome is better prior to deterioration of lung function. Acknowledgements We thank Dr. Hiltrud Dohmen (Aachen) and Prof. Dr. Michael Barker (Berlin) for taking care of CF patients included in clinical studies. This work has been supported, in part, by Deutsche Forschungsgemeinschaft (SFB/TRR 57, TP01). Conflict of interest None. References [1] Moyer K, Balistreri W. Hepatobiliary disease in patients with cystic fibrosis. Curr Opin Gastroenterol 2009;25:272–8. [2] Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989;245:1066–73. [3] Beuers U, Hohenester S, Maillette de Buy Wenniger L, Kremer AE, Jansen PL, Elferink RP. The biliary HCO 3 umbrella. Hepatology 2010; e-pub. [4] Quinton PM. Cystic fibrosis: impaired bicarbonate secretion and mucoviscidosis. Lancet 2008;372:415–7. [5] Lindblad A, Glaumann H, Strandvik B. Natural history of liver disease in cystic fibrosis. Hepatology 1999;30:1151–8. [6] Colombo C, Botto Poala S, Motta V, Zazzeron L. Liver disease in cystic fibrosis. In: Blum HE, Cox DW, Häussinger D, Jansen PL, Kullak-Ublick GA, editors. Genetics in liver diseases. Proceedings of the Falk Symposium, vol. 156. Dordrecht: Springer; 2007. p. 102–18. [7] Freudenberg F, Broderick AL, Yu BB, Leonard MR, Glickman JN, Carey MC. Pathophysiological basis of liver disease in cystic fibrosis employing a DeltaF508 mouse model. Am J Physiol Gastrointest Liver Physiol 2008;294:G1411–20. [8] Freudenberg F, Leonard MR, Liu SA, Glickman JN, Carey MC. Pathophysiological preconditions promoting mixed “black” pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis. Am J Physiol Gastrointest Liver Physiol 2010;299:G205–14. [9] Wasmuth HE, Keppeler H, Herrmann U, Schirin-Sokhan R, Barker M, Lammert F. Coinheritance of Gilbert syndromeassociated UGT1A1 mutation increases gallstone risk in cystic fibrosis. Hepatology 2006;43:738–41. [10] Minagawa N, Nagata J, Shibao K, Masvuk Al, Gomes DA, Rodriques MA, et al. Cyclic AMP regulates bicarbonate secretion in cholangiocytes through release of ATP into bile. Gastroenterology 2007;133:1592–602.
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