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Liver disease in cystic fibrosis
SYMPOSIUM: HEPATOLOGY
Liver disease in cystic fibrosis
disease appears to have a very limited impact on the clinical manifestations of CF until the most advanced stages. Multilobular cirrhosis will develop in 5e10% of affected patients in those first 10 years of life with disease progression during the second decade characterized by the development of portal hypertension and oesophageal varices. Liver failure is a late event that occurs rarely in the paediatric population. CF liver disease is generally detected on routine screening although a very small number of patients will present with clinically significant hepatic disease. Whilst there has been no clear genotypeephenotype correlation established in relation to CFLD, other risk factors such as gender and modifier genes have been identified. However these are not entirely predictive.
Donna McShane
Abstract This review describes the spectrum of change associated with cystic fibrosis liver disease, and the treatments and interventions that are currently available. A description of the disease from simple fatty liver to multi-lobular cirrhosis, with associated with portal hypertension and oesophageal varices is given. Liver health in CF should be assessed annually by examination, biochemical studies and ultrasound, and ursodeoxycholic acid commenced if significant changes are found. Liver transplant should be considered in whom there is progressive hepatic decompensation.
Pathogenesis CF Liver Disease can be iatrogenic, or directly related to the primary defect (Table 1). Iatrogenic CFLD presents most commonly as fatty liver (hepatic steatosis) and this complication has been reported in up to 60% of CF patients. It appears to be of little clinical consequence with, as yet, no proven association to the subsequent development of cirrhosis. Extra-hepatic biliary disease such as micro- or undetectable gallbladder, or common bile duct stenosis, has also been described, with the former abnormalities being described in up to 30% of CF cases. CFLD secondary to the primary defect gives rise to a very characteristic hepatic lesion: focal biliary cirrhosis. CFTR is expressed on the apical surface of cholangiocytes within the intra-hepatic bile ducts. Abnormalities in chloride transport and hydration increase bile viscosity resulting in bile duct obstruction which is initially patchy, giving rise to a focal distribution of inflammation and eventually cirrhotic change. With increasing ductular obstruction, the process becomes more diffuse, and the picture of multi-lobular cirrhosis evolves. This process can occur over a variable length of time.
Keywords cirrhosis; cystic fibrosis; cystic fibrosis liver disease; oesophageal varices; portal hypertension
Introduction Cystic fibrosis (CF) is an autosomal recessive multi-organ disease characterized by progressive, non-reversible lung disease secondary to severe and recurrent lower respiratory tract infections. The incidence of CF is 1 in 3000 live births worldwide, with median life expectancy in the UK currently running at 42 years. The basic underlying gene defect affects the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is a large epithelial transmembrane protein which controls the flow of sodium, chloride and water across the apical cell surface. Disruption of this flow results in low volume, viscid secretions which ultimately results in obstruction. Aside from the pulmonary tree, the gastrointestinal system is frequently affected in CF with pancreatic insufficiency (PI) the most common complication. PI can affect the foetus in utero, presenting as meconium ileus in the newborn infant. Other affected organs in CF include the sweat glands, giving rise to the diagnostic high chloride sweat test, the Wolffian ducts in males causing obstructive azoospermia, and the liver, which can result in a wide spectrum of hepatobiliary disease, including most crucially, multi-lobular cirrhosis. Liver cirrhosis remains the single most common non-pulmonary cause of death in CF, causing 2.5% of overall CF mortality.
Risk factors CF liver disease affects a minority of CF patients and even within that group, there is a wide spectrum of disease. Both of these features are difficult to explain and a number of associated factors have been identified. Genetic Whilst attempts to match a specific CF genotype to a liver disease phenotype have failed, an association between the more severe mutations in which there is complete loss of CFTR function has been established. These mutations are of the class I, II and III type and include Delta F-508 (p. Phe508del), the most commonly inherited CFTR mutation being found on at least one allele in 70% of the CF population. In addition, evidence to support the role of modifier genes in the pathogenesis of CF liver disease is mounting. Modifier genes are inherited independently of the CFTR mutation. They may attenuate or exacerbate the CF phenotype by their influence on such factors as host defence and the inflammatory response. Polymorphisms within the mannosebinding lectin and a1-antitrypsin genes have been identified as independent risk factors for CF liver disease. Gender The male sex is associated with CFLD. Meconium Ileus
Incidence CF Liver Disease (CFLD) is a well recognized complication of this condition, generally presenting in the first decade of life with an incidence of 2.5 per 100 patient-years. In the vast majority, liver
Donna McShane MBChB MRCPCH is Paediatric CF Consultant with Cambridge University Hospitals NHS Foundation Trust, at Addenbrooke’s Hospital, Cambridge, UK. Conflicts of interest: none.
PAEDIATRICS AND CHILD HEALTH 23:12
526
Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HEPATOLOGY
cirrhosis and its associated complications of portal hypertension and oesophageal varices. Presentation of this stage of CF liver disease, although unusual, can be heralded by a significant variceal bleed. CF biliary cirrhosis progresses at a very slow rate, but decompensation characterised by ascites, jaundice and encephalopathy, can occur after a number of years. Such decompensation has been reported in 2e3% of patients, with oesophageal variceal bleeding reported in a further 1e2%. There is some evidence that CF liver disease has an adverse effect on prognosis, independent of these specific complications. CF liver disease can cause deterioration of pulmonary disease through diaphragmatic splinting, ventilation-perfusion mismatch and worsening malnutrition. Such patients may therefore die prematurely from rapidly progressing pulmonary disease.
CF hepatobiliary manifestations Lesion
Clinical findings
Frequency
Liver disease caused by the primary defect
Focal biliary cirrhosis Multi-lobular biliary cirrhosis Portal hypertension Neonatal cholestasis Sclerosing cholangitis Microgallbladder Gallstones Fatty liver
20e30% 10%
Iatrogenic
2e5% <10% Often silent 30% 15% 25e60%
Table 1
Investigations Liver function tests Standard laboratory liver function tests are frequently mildly or only intermittently deranged in CF. They have reasonable sensitivity but low specificity with regards to predicting CF liver disease, and abnormalities frequently do not correlate with histological change. It is not unusual for patients with multi-lobular cirrhosis to have normal liver function tests. Patients with persistently deranged liver function tests should have all other causes excluded before the diagnosis of CF liver disease is made (Table 2). Common abnormalities of the liver function tests include isolated elevation of the transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) which may suggest hepatic steatosis. Elevation of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) suggests cholestasis, particularly when sustained and of a factor of 3e4. Jaundice and impaired hepatic synthetic function tests are indicators of advanced liver disease, while isolated elevation of ALP in the growing child is completely normal. Liver function tests and coagulation studies should be performed annually on all CF patients to screen for CF liver disease.
Meconium ileus is a possible contributory factor to the development of CFLD although the link is weak. There is conflicting evidence to fully support an association between the two, and only a minority of patients with CFLD have a past medical history of meconium ileus. Other factors Existing liver injury may be exacerbated by poor nutrition, hepatotoxic drugs, sepsis, non-compliance or abdominal surgery.
Clinical features of CF liver disease CF liver disease is often asymptomatic, even when multi-lobular cirrhosis is present. Beyond the neonatal period, patients rarely describe jaundice or pruritus, and the diagnosis of CFLD in the older age group, is often incidental, identified on routine screening at annual review, or from the finding of hepatomegaly during a regular clinical examination. Liver function tests are frequently normal, even when the liver is clearly diseased. This broad range of clinical presentations is described below: Unconjugated hyperbilirubinaemia of the newborn CF is a rare cause of prolonged jaundice in the newborn period giving rise an unconjugated hyperbilirubinaemia. Inspissated bile causes common bile duct obstruction and deep cholestasis. This condition is self-limiting and resolves spontaneously, generally within the first month of life. It rarely results in significant liver disease. Hepatic steatosis (fatty liver) Fatty liver is an extremely common finding in CF. It is frequently identified on routine ultrasound and rarely progresses to cirrhosis. It is not due to the underlying primary defect, arising from extra-hepatic consequences of the disease such as malnutrition, insulin resistance and raised circulating inflammatory cytokines. It may occasionally cause hepatomegaly, but synthetic liver function tests are generally preserved. Biliary cirrhosis Focal biliary cirrhosis is the classic hepatic lesion of CF liver disease and rarely develops after the first decade of life. Clinically some patients with more advanced disease will display hepatosplenomegaly but this is an inconsistent finding. The irregular distribution of this fibrotic lesion and its variable rate of progression is not well understood. Only a minority of patients with focal biliary cirrhosis will go on to develop multi-lobular
PAEDIATRICS AND CHILD HEALTH 23:12
Differential diagnosis of CF Liver disease Disease
Investigations
Viral hepatitis (acute or chronic) a1-Antitrypsin deficiency Autoimmune hepatitis Coeliac disease Wilson disease Haemochromatosis
Viral serology (hepatitis A, B & C; EBV; CMV; HHV 6; adenovirus, parvovirus) Serum a1-antitrypsin level and phenotype Autoantibody screen (SMA; anti-LKM1) Total IgA, anti-tissue transglutaminase Ceruloplasmin, serum copper Iron, ferritin, transferring binding capacity
Abbreviations: EBV, EpsteineBarr Virus; CMV, cytomegalovirus; HHV, 6 human herpes virus 6; SMA, smooth muscle antibody; LKM1, liver kidney microsomal type 1.
Table 2
527
Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HEPATOLOGY
progressive synthetic hepatic dysfunction decompensated portal hypertension with ascites and/or variceal bleeding hepatopulmonary and portopulmonary syndromes severe malnutrition despite maximal support deteriorating lung function. Relative contraindications to liver transplant include: severely compromised lung function or frequent infective exacerbations of CF lung disease chronic infection with Burkholderia cepacia, or other multi-resistant organisms respiratory failure and severe pulmonary hypertension as indicated by carbon dioxide retention. Liver transplantation has been associated with an improvement in pulmonary health, and survival rates, up to 5 years following transplant, is similar to that in other groups of cirrhosis. Rather surprisingly, the immunosuppression has not been associated with significant infective exacerbations of CF lung disease. Oesophageal varices CF patients with evidence of portal hypertension may benefit from variceal screening and banding of high risk varices. Band ligation is the most effective therapeutic technique, and should be considered in those patients with varices of grade 2 or greater. All patients with varices should be commenced on a proton pump inhibitor. In the event of a bleed, the standard resuscitation protocol (basic and advanced life support) should be augmented with measures to protect airway health (commence prophylactic antibiotics and continue with airway clearance techniques). Vasoconstrictive drugs (vasopressin) should also be used to control variceal bleeding until variceal banding can be performed in a specialist centre. A
Ultrasound scan Transabdominal ultrasound provides a cheap, and noninvasive means of screening for CF liver disease. As a screening tool, it has proven more sensitive than clinical examination and biochemical abnormalities with abnormal echogenicity frequently preceding both. Once CF liver disease has been identified, it can be used to chart the progress of hepatobiliary change: the finding of splenomegaly, portal vein dilation and collateral blood vessels all heralding the development of portal hypertension. Annual transabdominal ultrasound is recommended and has been widely adopted for the routine screening of CF populations. Liver biopsy Liver biopsy is not useful in the routine clinic management of CF liver disease. The initial patchy distribution of early changes may result in considerable sampling error, even when ultrasound guidance is adopted to assist. The procedure itself carries a significant risk of pneumothorax, which could have serious consequences in the CF patient. As such liver biopsy is only deemed essential in those patients in whom an alternative cause of liver disease is being sought. Magnetic resonance imaging (MRI) MRI is extremely useful in the delineation of CF liver disease. This mode of imaging has been further refined in the techniques of magnetic resonance cholangiopancreatography (MRCP) and magnetic resonance angiography (MRA). MRCP is useful in the diagnosis of intra-or extra-hepatic biliary disease, while MRA can define the collateral circulation associated with portal hypertension. MRCP can be used in place of endoscopic retrograde cholangiography (ERCP) to define the cirrhotic liver. Endoscopic retrograde cholangiography (ERCP) The invasive nature of ERCP renders it unsuitable for screening and diagnostic purposes in the CF population. It is becoming increasingly redundant with the development of MRCP.
FURTHER READING Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosisrelated liver disease. Cochrane Database Syst Rev 2012. Issue 10 Art. No: CD000222. Debray Dominique, Kelly Deidre, Houwen Roderick, Strandvik Birgitta, Colombo Carla. Best practice guidance for the diagnosis and management of cystic fibrosis- associated liver disease. J Cyst Fibros 2011; 10(suppl 2): S29e36. Vicky Dondos, David Westaby. Liver, biliary and pancreatic disease. In: Margaret Hodson, Duncan Geddes, Andrew Bush, eds. Cystic fibrosis. 3rd edn. Hodder Arnold.
Management of CF liver disease Ursodeoxycholic acid (UDCA) Ursodeoxycholic acid (UDCA) is the mainstay of therapy. It is hoped that UDCA will delay disease progression, but despite its extensive use in the CF population, evidence from objective studies is sparse. A recent Cochrane review concluded that “Evidence of the effectiveness of UDCA is as yet inconclusive” and called for a large randomized controlled study to be undertaken to address this. Until this happens, and based on the small number of studies that are available, it is likely that the practise of prescribing this safe and well tolerated agent will continue. UDCA is a hydrophilic bile acid normally present in human bile, and is delivered as an oral preparation usually twice daily. The optimum dose is 15e20 mg/kg/day. There is no added benefit to combining it with taurine. Liver transplantation Liver transplant should be considered and referral to a liver transplant unit for assessment made, when there is:
PAEDIATRICS AND CHILD HEALTH 23:12
Acknowledgements Dr Gabi Noble-Jamieson, Associate Specialist in Paediatric Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital.
528
Ó 2013 Elsevier Ltd. All rights reserved.
Liver disease in cystic fibrosis
disease appears to have a very limited impact on the clinical manifestations of CF until the most advanced stages. Multilobular cirrhosis will develop in 5e10% of affected patients in those first 10 years of life with disease progression during the second decade characterized by the development of portal hypertension and oesophageal varices. Liver failure is a late event that occurs rarely in the paediatric population. CF liver disease is generally detected on routine screening although a very small number of patients will present with clinically significant hepatic disease. Whilst there has been no clear genotypeephenotype correlation established in relation to CFLD, other risk factors such as gender and modifier genes have been identified. However these are not entirely predictive.
Donna McShane
Abstract This review describes the spectrum of change associated with cystic fibrosis liver disease, and the treatments and interventions that are currently available. A description of the disease from simple fatty liver to multi-lobular cirrhosis, with associated with portal hypertension and oesophageal varices is given. Liver health in CF should be assessed annually by examination, biochemical studies and ultrasound, and ursodeoxycholic acid commenced if significant changes are found. Liver transplant should be considered in whom there is progressive hepatic decompensation.
Pathogenesis CF Liver Disease can be iatrogenic, or directly related to the primary defect (Table 1). Iatrogenic CFLD presents most commonly as fatty liver (hepatic steatosis) and this complication has been reported in up to 60% of CF patients. It appears to be of little clinical consequence with, as yet, no proven association to the subsequent development of cirrhosis. Extra-hepatic biliary disease such as micro- or undetectable gallbladder, or common bile duct stenosis, has also been described, with the former abnormalities being described in up to 30% of CF cases. CFLD secondary to the primary defect gives rise to a very characteristic hepatic lesion: focal biliary cirrhosis. CFTR is expressed on the apical surface of cholangiocytes within the intra-hepatic bile ducts. Abnormalities in chloride transport and hydration increase bile viscosity resulting in bile duct obstruction which is initially patchy, giving rise to a focal distribution of inflammation and eventually cirrhotic change. With increasing ductular obstruction, the process becomes more diffuse, and the picture of multi-lobular cirrhosis evolves. This process can occur over a variable length of time.
Keywords cirrhosis; cystic fibrosis; cystic fibrosis liver disease; oesophageal varices; portal hypertension
Introduction Cystic fibrosis (CF) is an autosomal recessive multi-organ disease characterized by progressive, non-reversible lung disease secondary to severe and recurrent lower respiratory tract infections. The incidence of CF is 1 in 3000 live births worldwide, with median life expectancy in the UK currently running at 42 years. The basic underlying gene defect affects the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR is a large epithelial transmembrane protein which controls the flow of sodium, chloride and water across the apical cell surface. Disruption of this flow results in low volume, viscid secretions which ultimately results in obstruction. Aside from the pulmonary tree, the gastrointestinal system is frequently affected in CF with pancreatic insufficiency (PI) the most common complication. PI can affect the foetus in utero, presenting as meconium ileus in the newborn infant. Other affected organs in CF include the sweat glands, giving rise to the diagnostic high chloride sweat test, the Wolffian ducts in males causing obstructive azoospermia, and the liver, which can result in a wide spectrum of hepatobiliary disease, including most crucially, multi-lobular cirrhosis. Liver cirrhosis remains the single most common non-pulmonary cause of death in CF, causing 2.5% of overall CF mortality.
Risk factors CF liver disease affects a minority of CF patients and even within that group, there is a wide spectrum of disease. Both of these features are difficult to explain and a number of associated factors have been identified. Genetic Whilst attempts to match a specific CF genotype to a liver disease phenotype have failed, an association between the more severe mutations in which there is complete loss of CFTR function has been established. These mutations are of the class I, II and III type and include Delta F-508 (p. Phe508del), the most commonly inherited CFTR mutation being found on at least one allele in 70% of the CF population. In addition, evidence to support the role of modifier genes in the pathogenesis of CF liver disease is mounting. Modifier genes are inherited independently of the CFTR mutation. They may attenuate or exacerbate the CF phenotype by their influence on such factors as host defence and the inflammatory response. Polymorphisms within the mannosebinding lectin and a1-antitrypsin genes have been identified as independent risk factors for CF liver disease. Gender The male sex is associated with CFLD. Meconium Ileus
Incidence CF Liver Disease (CFLD) is a well recognized complication of this condition, generally presenting in the first decade of life with an incidence of 2.5 per 100 patient-years. In the vast majority, liver
Donna McShane MBChB MRCPCH is Paediatric CF Consultant with Cambridge University Hospitals NHS Foundation Trust, at Addenbrooke’s Hospital, Cambridge, UK. Conflicts of interest: none.
PAEDIATRICS AND CHILD HEALTH 23:12
526
Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HEPATOLOGY
cirrhosis and its associated complications of portal hypertension and oesophageal varices. Presentation of this stage of CF liver disease, although unusual, can be heralded by a significant variceal bleed. CF biliary cirrhosis progresses at a very slow rate, but decompensation characterised by ascites, jaundice and encephalopathy, can occur after a number of years. Such decompensation has been reported in 2e3% of patients, with oesophageal variceal bleeding reported in a further 1e2%. There is some evidence that CF liver disease has an adverse effect on prognosis, independent of these specific complications. CF liver disease can cause deterioration of pulmonary disease through diaphragmatic splinting, ventilation-perfusion mismatch and worsening malnutrition. Such patients may therefore die prematurely from rapidly progressing pulmonary disease.
CF hepatobiliary manifestations Lesion
Clinical findings
Frequency
Liver disease caused by the primary defect
Focal biliary cirrhosis Multi-lobular biliary cirrhosis Portal hypertension Neonatal cholestasis Sclerosing cholangitis Microgallbladder Gallstones Fatty liver
20e30% 10%
Iatrogenic
2e5% <10% Often silent 30% 15% 25e60%
Table 1
Investigations Liver function tests Standard laboratory liver function tests are frequently mildly or only intermittently deranged in CF. They have reasonable sensitivity but low specificity with regards to predicting CF liver disease, and abnormalities frequently do not correlate with histological change. It is not unusual for patients with multi-lobular cirrhosis to have normal liver function tests. Patients with persistently deranged liver function tests should have all other causes excluded before the diagnosis of CF liver disease is made (Table 2). Common abnormalities of the liver function tests include isolated elevation of the transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) which may suggest hepatic steatosis. Elevation of alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) suggests cholestasis, particularly when sustained and of a factor of 3e4. Jaundice and impaired hepatic synthetic function tests are indicators of advanced liver disease, while isolated elevation of ALP in the growing child is completely normal. Liver function tests and coagulation studies should be performed annually on all CF patients to screen for CF liver disease.
Meconium ileus is a possible contributory factor to the development of CFLD although the link is weak. There is conflicting evidence to fully support an association between the two, and only a minority of patients with CFLD have a past medical history of meconium ileus. Other factors Existing liver injury may be exacerbated by poor nutrition, hepatotoxic drugs, sepsis, non-compliance or abdominal surgery.
Clinical features of CF liver disease CF liver disease is often asymptomatic, even when multi-lobular cirrhosis is present. Beyond the neonatal period, patients rarely describe jaundice or pruritus, and the diagnosis of CFLD in the older age group, is often incidental, identified on routine screening at annual review, or from the finding of hepatomegaly during a regular clinical examination. Liver function tests are frequently normal, even when the liver is clearly diseased. This broad range of clinical presentations is described below: Unconjugated hyperbilirubinaemia of the newborn CF is a rare cause of prolonged jaundice in the newborn period giving rise an unconjugated hyperbilirubinaemia. Inspissated bile causes common bile duct obstruction and deep cholestasis. This condition is self-limiting and resolves spontaneously, generally within the first month of life. It rarely results in significant liver disease. Hepatic steatosis (fatty liver) Fatty liver is an extremely common finding in CF. It is frequently identified on routine ultrasound and rarely progresses to cirrhosis. It is not due to the underlying primary defect, arising from extra-hepatic consequences of the disease such as malnutrition, insulin resistance and raised circulating inflammatory cytokines. It may occasionally cause hepatomegaly, but synthetic liver function tests are generally preserved. Biliary cirrhosis Focal biliary cirrhosis is the classic hepatic lesion of CF liver disease and rarely develops after the first decade of life. Clinically some patients with more advanced disease will display hepatosplenomegaly but this is an inconsistent finding. The irregular distribution of this fibrotic lesion and its variable rate of progression is not well understood. Only a minority of patients with focal biliary cirrhosis will go on to develop multi-lobular
PAEDIATRICS AND CHILD HEALTH 23:12
Differential diagnosis of CF Liver disease Disease
Investigations
Viral hepatitis (acute or chronic) a1-Antitrypsin deficiency Autoimmune hepatitis Coeliac disease Wilson disease Haemochromatosis
Viral serology (hepatitis A, B & C; EBV; CMV; HHV 6; adenovirus, parvovirus) Serum a1-antitrypsin level and phenotype Autoantibody screen (SMA; anti-LKM1) Total IgA, anti-tissue transglutaminase Ceruloplasmin, serum copper Iron, ferritin, transferring binding capacity
Abbreviations: EBV, EpsteineBarr Virus; CMV, cytomegalovirus; HHV, 6 human herpes virus 6; SMA, smooth muscle antibody; LKM1, liver kidney microsomal type 1.
Table 2
527
Ó 2013 Elsevier Ltd. All rights reserved.
SYMPOSIUM: HEPATOLOGY
progressive synthetic hepatic dysfunction decompensated portal hypertension with ascites and/or variceal bleeding hepatopulmonary and portopulmonary syndromes severe malnutrition despite maximal support deteriorating lung function. Relative contraindications to liver transplant include: severely compromised lung function or frequent infective exacerbations of CF lung disease chronic infection with Burkholderia cepacia, or other multi-resistant organisms respiratory failure and severe pulmonary hypertension as indicated by carbon dioxide retention. Liver transplantation has been associated with an improvement in pulmonary health, and survival rates, up to 5 years following transplant, is similar to that in other groups of cirrhosis. Rather surprisingly, the immunosuppression has not been associated with significant infective exacerbations of CF lung disease. Oesophageal varices CF patients with evidence of portal hypertension may benefit from variceal screening and banding of high risk varices. Band ligation is the most effective therapeutic technique, and should be considered in those patients with varices of grade 2 or greater. All patients with varices should be commenced on a proton pump inhibitor. In the event of a bleed, the standard resuscitation protocol (basic and advanced life support) should be augmented with measures to protect airway health (commence prophylactic antibiotics and continue with airway clearance techniques). Vasoconstrictive drugs (vasopressin) should also be used to control variceal bleeding until variceal banding can be performed in a specialist centre. A
Ultrasound scan Transabdominal ultrasound provides a cheap, and noninvasive means of screening for CF liver disease. As a screening tool, it has proven more sensitive than clinical examination and biochemical abnormalities with abnormal echogenicity frequently preceding both. Once CF liver disease has been identified, it can be used to chart the progress of hepatobiliary change: the finding of splenomegaly, portal vein dilation and collateral blood vessels all heralding the development of portal hypertension. Annual transabdominal ultrasound is recommended and has been widely adopted for the routine screening of CF populations. Liver biopsy Liver biopsy is not useful in the routine clinic management of CF liver disease. The initial patchy distribution of early changes may result in considerable sampling error, even when ultrasound guidance is adopted to assist. The procedure itself carries a significant risk of pneumothorax, which could have serious consequences in the CF patient. As such liver biopsy is only deemed essential in those patients in whom an alternative cause of liver disease is being sought. Magnetic resonance imaging (MRI) MRI is extremely useful in the delineation of CF liver disease. This mode of imaging has been further refined in the techniques of magnetic resonance cholangiopancreatography (MRCP) and magnetic resonance angiography (MRA). MRCP is useful in the diagnosis of intra-or extra-hepatic biliary disease, while MRA can define the collateral circulation associated with portal hypertension. MRCP can be used in place of endoscopic retrograde cholangiography (ERCP) to define the cirrhotic liver. Endoscopic retrograde cholangiography (ERCP) The invasive nature of ERCP renders it unsuitable for screening and diagnostic purposes in the CF population. It is becoming increasingly redundant with the development of MRCP.
FURTHER READING Cheng K, Ashby D, Smyth RL. Ursodeoxycholic acid for cystic fibrosisrelated liver disease. Cochrane Database Syst Rev 2012. Issue 10 Art. No: CD000222. Debray Dominique, Kelly Deidre, Houwen Roderick, Strandvik Birgitta, Colombo Carla. Best practice guidance for the diagnosis and management of cystic fibrosis- associated liver disease. J Cyst Fibros 2011; 10(suppl 2): S29e36. Vicky Dondos, David Westaby. Liver, biliary and pancreatic disease. In: Margaret Hodson, Duncan Geddes, Andrew Bush, eds. Cystic fibrosis. 3rd edn. Hodder Arnold.
Management of CF liver disease Ursodeoxycholic acid (UDCA) Ursodeoxycholic acid (UDCA) is the mainstay of therapy. It is hoped that UDCA will delay disease progression, but despite its extensive use in the CF population, evidence from objective studies is sparse. A recent Cochrane review concluded that “Evidence of the effectiveness of UDCA is as yet inconclusive” and called for a large randomized controlled study to be undertaken to address this. Until this happens, and based on the small number of studies that are available, it is likely that the practise of prescribing this safe and well tolerated agent will continue. UDCA is a hydrophilic bile acid normally present in human bile, and is delivered as an oral preparation usually twice daily. The optimum dose is 15e20 mg/kg/day. There is no added benefit to combining it with taurine. Liver transplantation Liver transplant should be considered and referral to a liver transplant unit for assessment made, when there is:
PAEDIATRICS AND CHILD HEALTH 23:12
Acknowledgements Dr Gabi Noble-Jamieson, Associate Specialist in Paediatric Gastroenterology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital.
528
Ó 2013 Elsevier Ltd. All rights reserved.