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Cystic fibrosis-related liver disease: Clinical presentations, diagnostic and monitoring approaches in the era of CFTR modulator therapies

  • Jérémy Dana
    Correspondence
    Corresponding author. Address: Department of Radiology, Beaujon Hospital, Clichy, France; Tel.: +33 1 40 87 53 58.
    Affiliations
    Department of Radiology, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris, Clichy, France

    Université de Strasbourg, Strasbourg, France

    Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France

    IHU-Strasbourg (Institut Hospitalo-Universitaire), Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
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  • Dominique Debray
    Affiliations
    Department of Pediatric Hepatology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France

    Sorbonne Université, INSERM, Centre de recherche Saint-Antoine (CRSA), Institute of Cardiometabolism and Nutrition (ICAN), F-75012 Paris, France
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  • Aurélie Beaufrère
    Affiliations
    Department of Pathology, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris Clichy, France
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  • Sophie Hillaire
    Affiliations
    Department of Hepatology, Foch Hospital, Suresnes, France
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  • Monique Fabre
    Affiliations
    Department of Pathology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France
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  • Caroline Reinhold
    Affiliations
    Department of Diagnostic Radiology, McGill University, Montreal, Canada

    Augmented Intelligence & Precision Health Laboratory of the Research Institute of McGill University Health Centre, Montreal, Canada
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  • Thomas F. Baumert
    Affiliations
    Université de Strasbourg, Strasbourg, France

    Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France

    IHU-Strasbourg (Institut Hospitalo-Universitaire), Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
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  • Laureline Berteloot
    Affiliations
    Department of Pediatric Radiology, Necker-Enfants Malades Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France
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  • Valérie Vilgrain
    Affiliations
    Department of Radiology, Beaujon Hospital, Assistance Publique - Hôpitaux de Paris, Université de Paris, Clichy, France
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Published:October 19, 2021DOI:https://doi.org/10.1016/j.jhep.2021.09.042

      Summary

      Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. Cystic fibrosis-related liver disease (CFLD) is defined as the pathogenesis related to the underlying CFTR defect in biliary epithelial cells. CFLD needs to be distinguished from other liver manifestations that may not have any pathological significance. The clinical/histological presentation and severity of CFLD vary. The main histological presentation of CFLD is focal biliary fibrosis, which is usually asymptomatic. Portal hypertension develops in a minority of cases (about 10%) and may require specific management including liver transplantation for end-stage liver disease. Portal hypertension is usually the result of the progression of focal biliary fibrosis to multilobular cirrhosis during childhood. Nevertheless, non-cirrhotic portal hypertension as a result of porto-sinusoidal vascular disease is now identified increasingly more frequently, mainly in young adults. To evaluate the effect of new CFTR modulator therapies on the liver, the spectrum of hepatobiliary involvement must first be precisely classified. This paper discusses the phenotypic features of CFLD, its underlying physiopathology and relevant diagnostic and follow-up approaches, with a special focus on imaging.

      Keywords

      Introduction

      Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population. It is caused by pathogenic variants in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel expressed in epithelial cells. Liver involvement, which is reported in up to approximately 40% of patients with CF,
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      Epidemiology

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      Cystic fibrosis-related liver disease

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      • Colombo C.
      • Battezzati P.M.
      • Crosignani A.
      • Morabito A.
      • Costantini D.
      • Padoan R.
      • et al.
      Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.
      Furthermore, while the heterogeneity of the manifestations of CFLD in siblings suggest that factors in addition to CFTR play an important role, the major impact of environmental factors can also be excluded.
      • Terlizzi V.
      • Lucarelli M.
      • Salvatore D.
      • Angioni A.
      • Bisogno A.
      • Braggion C.
      • et al.
      Clinical expression of cystic fibrosis in a large cohort of Italian siblings.
      ,
      • Castaldo G.
      • Fuccio A.
      • Salvatore D.
      • Raia V.
      • Santostasi T.
      • Leonardi S.
      • et al.
      Liver expression in cystic fibrosis could be modulated by genetic factors different from the cystic fibrosis transmembrane regulator genotype.
      Thus, modulatory genetic (called "modifier genes") and/or extrinsic (therapeutic and iatrogenic) factors probably play a decisive role in the heterogeneity of the disease. SERPINA1, encoding the ɑ-1antitrypsin protein, is the only modifier gene identified to date.
      • Debray D.
      • Corvol H.
      • Housset C.
      Modifier genes in cystic fibrosis-related liver disease.
      Indeed, patients with CF carrying the SERPINA1 Z allele have a higher risk of developing CFLD and related complications than non-carriers.
      • Bartlett J.R.
      • Friedman K.J.
      • Ling S.C.
      • Pace R.G.
      • Bell S.C.
      • Bourke B.
      • et al.
      Genetic modifiers of liver disease in cystic fibrosis.
      ,
      • Boëlle P.-Y.
      • Debray D.
      • Guillot L.
      • Corvol H.
      French CF Modifier Gene Study Investigators
      SERPINA1 Z allele is associated with cystic fibrosis liver disease.
      The accumulation of the Z variant of α1-antitrypsin in cholangiocytes could induce stress in the endoplasmic reticulum and promote biliary damage from bacterial endotoxins and hydrophobic bile acids. Nevertheless, the much lower proportion of patients with CF carrying the Z allele (2.7%) compared to the proportion of patients who develop CFLD (30.5%), suggests that other modifier genes also play a role.
      • Debray D.
      • Corvol H.
      • Housset C.
      Modifier genes in cystic fibrosis-related liver disease.
      ,
      • Boëlle P.-Y.
      • Debray D.
      • Guillot L.
      • Corvol H.
      French CF Modifier Gene Study Investigators
      SERPINA1 Z allele is associated with cystic fibrosis liver disease.
      Finally, several studies have reported a higher incidence of CFLD in male patients.
      • Colombo C.
      • Battezzati P.M.
      • Crosignani A.
      • Morabito A.
      • Costantini D.
      • Padoan R.
      • et al.
      Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.
      ,
      • Stonebraker J.R.
      • Ooi C.Y.
      • Pace R.G.
      • Corvol H.
      • Knowles M.R.
      • Durie P.R.
      • et al.
      Features of severe liver disease with portal hypertension in patients with cystic fibrosis.
      ,
      • Debray D.
      • Lykavieris P.
      • Gauthier F.
      • Dousset B.
      • Sardet A.
      • Munck A.
      • et al.
      Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.
       This is also true for patients with a history of meconium ileus, although this remains controversial.
      • Lamireau T.
      • Monnereau S.
      • Martin S.
      • Marcotte J.-E.
      • Winnock M.
      • Alvarez F.
      Epidemiology of liver disease in cystic fibrosis: a longitudinal study.
      ,
      • Colombo C.
      • Battezzati P.M.
      • Crosignani A.
      • Morabito A.
      • Costantini D.
      • Padoan R.
      • et al.
      Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.
      ,
      • Chryssostalis A.
      • Hubert D.
      • Coste J.
      • Kanaan R.
      • Burgel P.-R.
      • Desmazes-Dufeu N.
      • et al.
      Liver disease in adult patients with cystic fibrosis: a frequent and independent prognostic factor associated with death or lung transplantation.
      ,
      • Debray D.
      • Lykavieris P.
      • Gauthier F.
      • Dousset B.
      • Sardet A.
      • Munck A.
      • et al.
      Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.

      Diagnostic techniques

      Because liver disease progresses insidiously and is rarely symptomatic during the early stages, and portal hypertension can remain silent until the development of life-threatening complications, European guidelines recommend annual screening for liver involvement by clinical examination (hepatomegaly, splenomegaly), liver tests, and abdominal ultrasound (Fig. 1). However, the accuracy of liver tests and ultrasound is low for the diagnosis of liver fibrosis, especially in the early stages. Liver test abnormalities are found in more than 50% of infants with CF, which then normalise in most cases before the age of 2-3 years old.
      • Lindblad A.
      • Glaumann H.
      • Strandvik B.
      Natural history of liver disease in cystic fibrosis.
      Only persistently elevated gamma-glutamyltransferase has been associated with the development of cirrhosis.
      • Woodruff S.A.
      • Sontag M.K.
      • Accurso F.J.
      • Sokol R.J.
      • Narkewicz M.R.
      Prevalence of elevated liver enzymes in children with cystic fibrosis diagnosed by newborn screen.
      ,
      • Bodewes F.A.J.A.
      • van der Doef H.P.J.
      • Houwen R.H.J.
      • Verkade H.J.
      Increase of serum γ-glutamyltransferase associated with development of cirrhotic cystic fibrosis liver disease.
      Despite the significant intra- and inter-reader variability,
      • Mueller-Abt P.R.
      • Frawley K.J.
      • Greer R.M.
      • Lewindon P.J.
      Comparison of ultrasound and biopsy findings in children with cystic fibrosis related liver disease.
      liver ultrasound remains a key examination. It provides complete evaluation of the liver parenchyma (normal, homogeneous or heterogeneous hyperechogenicity, nodular) (Fig. 2), liver contours, gallbladder and biliary tree (i.e. focal dilatation, cholelithiasis, micro-gallbladder or gallbladder dyskinesia).
      • Siegel M.J.
      • Freeman A.J.
      • Ye W.
      • Palermo J.J.
      • Molleston J.P.
      • Paranjape S.M.
      • et al.
      Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease: interim results of a prospective observational case-controlled study.
      • Leung D.H.
      • Ye W.
      • Molleston J.P.
      • Weymann A.
      • Ling S.
      • Paranjape S.M.
      • et al.
      Baseline ultrasound and clinical correlates in children with cystic fibrosis.
      • Ling S.C.
      • Ye W.
      • Leung D.H.
      • Navarro O.M.
      • Weymann A.
      • Karnsakul W.
      • et al.
      Liver ultrasound patterns in children with cystic fibrosis correlate with noninvasive tests of liver disease.
      Portal hypertension may also be directly (portosystemic shunts, decreased or reversed portal flow, dilated portal vein) or indirectly (splenomegaly, ascites and, in children, increased thickness of the lesser omentum >1.5 times the diameter of the aorta) evaluated. Ultrasound patterns (normal, homogeneous or heterogeneous hyperechogenicity, nodular) seem to be correlated with the biomarkers of liver fibrosis (aspartate aminotransferase-to-platelet ratio index [APRI] and fibrosis-4 scores).
      • Ling S.C.
      • Ye W.
      • Leung D.H.
      • Navarro O.M.
      • Weymann A.
      • Karnsakul W.
      • et al.
      Liver ultrasound patterns in children with cystic fibrosis correlate with noninvasive tests of liver disease.
      A heterogeneous hyperechogenic pattern has also been associated with a risk of progression to a nodular pattern, suggesting the development of cirrhosis.
      • Siegel M.J.
      • Freeman A.J.
      • Ye W.
      • Palermo J.J.
      • Molleston J.P.
      • Paranjape S.M.
      • et al.
      Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease: interim results of a prospective observational case-controlled study.
      ,
      • Lenaerts C.
      • Lapierre C.
      • Patriquin H.
      • Bureau N.
      • Lepage G.
      • Harel F.
      • et al.
      Surveillance for cystic fibrosis-associated hepatobiliary disease: early ultrasound changes and predisposing factors.
      One long-term study with a 4-year follow-up reported a 9-fold increased risk of developing a nodular ultrasound pattern in patients with an initially heterogeneous pattern, compared to those with a normal pattern.
      • Siegel M.J.
      • Freeman A.J.
      • Ye W.
      • Palermo J.J.
      • Molleston J.P.
      • Paranjape S.M.
      • et al.
      Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease: interim results of a prospective observational case-controlled study.
      However, it should be noted that the progression to a nodular pattern was only found in 13/55 patients (23%). Moreover, a nodular pattern is not specific for cirrhosis but may also indicate nodular regenerative hyperplasia during porto-sinusoidal vascular disease. Finally, a heterogeneous pattern does not systematically indicate liver fibrosis, but may represent patchy steatosis.
      • Lewindon P.J.
      • Shepherd R.W.
      • Walsh M.J.
      • Greer R.M.
      • Williamson R.
      • Pereira T.N.
      • et al.
      Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy.
      Additional ultrasound tools, such as the attenuation coefficient (based on the ultrasound attenuation of the echo wave by the steatotic liver – like the controlled attenuation coefficient in transient elastography [TE]) and the hepatorenal B-mode ratio (defined as the ratio of the echogenicity of the liver parenchyma to the renal cortex) can help to identify steatosis, but must be validated in CF.
      • Dioguardi Burgio M.
      • Ronot M.
      • Reizine E.
      • Rautou P.-E.
      • Castera L.
      • Paradis V.
      • et al.
      Quantification of hepatic steatosis with ultrasound: promising role of attenuation imaging coefficient in a biopsy-proven cohort.
      ,
      • Moret A.
      • Boursier J.
      • Debry P.H.
      • Riou J.
      • Crouan A.
      • Dubois M.
      • et al.
      Evaluation of the hepatorenal B-mode ratio and the “controlled attenuation parameter” for the detection and grading of steatosis.
      Moreover, MRI enables non-invasive quantification of steatosis in the entire liver. One method called proton density fat fraction, defined as the fraction of mobile protons (H1) linked to the triglyceride relative to those of water, is achieved by application of multi-echo Dixon and compensates for multiple confounders including T2∗ relaxation effects and the spectral complexity of fat.
      • Tang A.
      • Tan J.
      • Sun M.
      • Hamilton G.
      • Bydder M.
      • Wolfson T.
      • et al.
      Nonalcoholic fatty liver disease: MR imaging of liver proton density fat fraction to assess hepatic steatosis.
      Ultrasound of the liver is a key test for the diagnosis and follow-up of this entity and can provide a complete evaluation of the liver parenchyma (normal, homogeneous or heterogeneous hyperechogenicity, nodular pattern) and portal hypertension.
      Figure thumbnail gr1
      Fig. 1Diagnostic approach to liver involvement and CFLD based on Debray et al.
      • Debray D.
      • Narkewicz M.R.
      • Bodewes F.A.J.A.
      • Colombo C.
      • Housset C.
      • de Jonge H.R.
      • et al.
      Cystic fibrosis-related liver disease: research challenges and future perspectives.
      CFLD is defined by the CFTR defect while liver involvement includes all hepatic manifestations including epiphenomena. In the presence of “red-flag” signs, porto-sinusoidal vascular disease should be investigated and liver biopsy and/or haemodynamic measurements of the hepatic venous pressure gradient should be considered. ALT, alanine aminotransferase; CFLD, cystic fibrosis-related liver disease; CFTR, cystic fibrosis transmembrane conductance regulator; GGT, gamma-glutamyltransferase; LSM, liver stiffness measurement; WBC, white blood cell.
      Figure thumbnail gr2
      Fig. 2Ultrasound patterns in patients with cystic fibrosis.
      (A) Normal. (B) Homogeneous hyperechogenicity. (C) Heterogeneous hyperechogenicity. (D) Nodular.
      Liver biopsy is a decisive examination that can reveal specific features of CFLD phenotypes. It is rarely performed in children with CF because it is invasive, there is a risk of under- or overestimating the lesions due to the focal nature of the fibrosis, and treatment options may be limited.
      • Lachaux A.
      • Le Gall C.
      • Chambon M.
      • Regnier F.
      • Loras-Duclaux I.
      • Bouvier R.
      • et al.
      Complications of percutaneous liver biopsy in infants and children.
      • Rowland M.
      • Bourke B.
      Liver disease in cystic fibrosis.
      • Regev A.
      • Berho M.
      • Jeffers L.J.
      • Milikowski C.
      • Molina E.G.
      • Pyrsopoulos N.T.
      • et al.
      Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection.
      The risk of under- or overestimation can be reduced by a dual-pass biopsy.
      • Lewindon P.J.
      • Shepherd R.W.
      • Walsh M.J.
      • Greer R.M.
      • Williamson R.
      • Pereira T.N.
      • et al.
      Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy.
      Liver biopsy can be performed by the transjugular route in association with haemodynamic measurements of the hepatic venous pressure gradient when porto-sinusoidal vascular disease is suspected, especially when evaluating the clinical consequences and therapeutic options of liver or lung transplantation.
      • Hillaire S.
      • Cazals-Hatem D.
      • Bruno O.
      • Miranda S de
      • Grenet D.
      • Poté N.
      • et al.
      Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.
      ,
      • Witters P.
      • Libbrecht L.
      • Roskams T.
      • De Boeck K.
      • Dupont L.
      • Proesmans M.
      • et al.
      Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.
      Liver stiffness, a biomarker based on the elasticity of the liver, has been found to be valuable for even early stage diagnosis, as well as for monitoring liver fibrosis in CF in children
      • Klotter V.
      • Gunchick C.
      • Siemers E.
      • Rath T.
      • Hudel H.
      • Naehrlich L.
      • et al.
      Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: results from a prospective longitudinal cohort study.
      and adults.
      • Sadler M.D.
      • Crotty P.
      • Fatovich L.
      • Wilson S.
      • Rabin H.R.
      • Myers R.P.
      Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.
      Different modalities are available including vibration-controlled TE or ultrasound-guided elastography, such as point shearwave elastography (pSWE) and 2D shearwave elastography (2D-SWE),
      • Sigrist R.M.S.
      • Liau J.
      • Kaffas A.E.
      • Chammas M.C.
      • Willmann J.K.
      Ultrasound elastography: review of techniques and clinical applications.
      as well as magnetic resonance elastography, but none have been shown to be better than the other methods to detect liver fibrosis in patients with CF. It is difficult to identify cut-off values because of the many different techniques. One-dimensional TE estimates liver stiffness by measuring the velocity of an elastic shear wave propagating through the liver parenchyma using pulsed echo ultrasound acquisitions. This technique appears to be as effective as 2D-SWE.
      • Sadler M.D.
      • Crotty P.
      • Fatovich L.
      • Wilson S.
      • Rabin H.R.
      • Myers R.P.
      Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.
      ,
      • Lewindon P.J.
      • Puertolas-Lopez M.V.
      • Ramm L.E.
      • Noble C.
      • Pereira T.N.
      • Wixey J.A.
      • et al.
      Accuracy of transient elastography data combined with APRI in detection and staging of liver disease in pediatric patients with cystic fibrosis.
      • Kitson M.T.
      • Kemp W.W.
      • Iser D.M.
      • Paul E.
      • Wilson J.W.
      • Roberts S.K.
      Utility of transient elastography in the non-invasive evaluation of cystic fibrosis liver disease.
      • Aqul A.
      • Jonas M.M.
      • Harney S.
      • Raza R.
      • Sawicki G.S.
      • Mitchell P.D.
      • et al.
      Correlation of transient elastography with severity of cystic fibrosis-related liver disease.
      Ultrasound-guided elastography techniques (pSWE and 2D-SWE) use ultrasound focused beams to generate shear waves. A quantitative estimation of tissue elasticity is obtained by measurement of shear wave velocity. These techniques are accurate and reproducible and targeted measurements can be obtained by guided B-mode ultrasound.
      • Calvopina D.A.
      • Noble C.
      • Weis A.
      • Hartel G.F.
      • Ramm L.E.
      • Balouch F.
      • et al.
      Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis.
      ,
      • Enaud R.
      • Frison E.
      • Missonnier S.
      • Fischer A.
      • de Ledinghen V.
      • Perez P.
      • et al.
      Cystic fibrosis and noninvasive liver fibrosis assessment methods in children.
      Unlike pSWE, which only provides focal measurement of liver stiffness, 2D-SWE provides real-time liver stiffness 2D colour mapping. TE and 2D-SWE can be performed easily in children. Magnetic resonance elastography is also a promising technique in children and has become the new non-invasive gold-standard for the assessment of liver stiffness in adults.
      • Hayes D.
      • Krishnamurthy R.
      • Hu H.H.
      Magnetic resonance elastography demonstrates elevated liver stiffness in cystic fibrosis patients.
      A complete map of liver stiffness is obtained using shear waves generated by an external acoustic driver that is especially useful in patients with focal fibrosis.
      • Dana J.
      • Girard M.
      • Debray D.
      Hepatic manifestations of cystic fibrosis.
      This technique can be performed in the presence of ascites, while steatosis does not affect liver stiffness measurements.
      • Venkatesh S.K.
      • Yin M.
      • Ehman R.L.
      Magnetic resonance elastography of liver: technique, analysis, and clinical applications.
      However, several challenges remain in children. First, spin-echo echo-planar imaging should be performed instead of gradient-recalled echo, as it only requires a single breath hold, which can be critical in patients with lung involvement.
      • Serai S.D.
      • Dillman J.R.
      • Trout A.T.
      Spin-echo echo-planar imaging MR elastography versus gradient-echo MR elastography for assessment of liver stiffness in children and young adults suspected of having liver disease.
      The focal nature of fibrosis may also require volumetric segmentation using regions of interest-based segmentation, thus reinforcing interest in 3D stiffness colour mapping.
      • Rezvani Habibabadi R.
      • Khoshpouri P.
      • Ghadimi M.
      • Shaghaghi M.
      • Ameli S.
      • Hazhirkarzar B.
      • et al.
      Comparison between ROI-based and volumetric measurements in quantifying heterogeneity of liver stiffness using MR elastography.
      The most commonly used techniques are TE, pSWE and 2D-SWE. They have been found to be reliable in longitudinal studies
      • Klotter V.
      • Gunchick C.
      • Siemers E.
      • Rath T.
      • Hudel H.
      • Naehrlich L.
      • et al.
      Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: results from a prospective longitudinal cohort study.
      ,
      • Sadler M.D.
      • Crotty P.
      • Fatovich L.
      • Wilson S.
      • Rabin H.R.
      • Myers R.P.
      Noninvasive methods, including transient elastography, for the detection of liver disease in adults with cystic fibrosis.
      ,
      • Lewindon P.J.
      • Puertolas-Lopez M.V.
      • Ramm L.E.
      • Noble C.
      • Pereira T.N.
      • Wixey J.A.
      • et al.
      Accuracy of transient elastography data combined with APRI in detection and staging of liver disease in pediatric patients with cystic fibrosis.
      ,
      • Enaud R.
      • Frison E.
      • Missonnier S.
      • Fischer A.
      • de Ledinghen V.
      • Perez P.
      • et al.
      Cystic fibrosis and noninvasive liver fibrosis assessment methods in children.
      ,
      • Van Biervliet S.
      • Verdievel H.
      • Vande Velde S.
      • De Bruyne R.
      • De Looze D.
      • Verhelst X.
      • et al.
      Longitudinal transient elastography measurements used in follow-up for patients with cystic fibrosis.
      but none of them have been shown to be effective for the longitudinal monitoring of the progression of liver fibrosis in patients with CF. The many different techniques, the absence of a precise definition of CFLD, and the absence of histological validation in several studies make it difficult to identify reliable cut-off values.
      Liver elastography is of interest to detect early-stage fibrosis and could play a role in long-term follow-up.
      Finally, portal hypertension should be carefully looked for and not underestimated because it may develop independently of cirrhosis (i.e. porto-sinusoidal vascular disease). In addition to ultrasound, upper gastrointestinal endoscopy and haemodynamic measurements of the hepatic venous pressure gradient may be indicated to accurately assess and characterise the cause of portal hypertension. Also, in the presence of discrepant diagnoses, spleen elastography has been shown to accurately predict portal hypertension and its complications, such as high-risk oesophageal varices, in other chronic liver diseases both in adults and children.
      • Elkrief L.
      • Ronot M.
      • Andrade F.
      • Dioguardi Burgio M.
      • Issoufaly T.
      • Zappa M.
      • et al.
      Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.
      ,
      • Tomita H.
      • Ohkuma K.
      • Masugi Y.
      • Hosoe N.
      • Hoshino K.
      • Fuchimoto Y.
      • et al.
      Diagnosing native liver fibrosis and esophageal varices using liver and spleen stiffness measurements in biliary atresia: a pilot study.
      The only study performed in children with CF reported higher spleen stiffness values than in healthy controls.
      • Cañas T.
      • Maciá A.
      • Muñoz-Codoceo R.A.
      • Fontanilla T.
      • González-Rios P.
      • Miralles M.
      • et al.
      Hepatic and splenic acoustic radiation force impulse shear wave velocity elastography in children with liver disease associated with cystic fibrosis.
      Thus, this approach has not yet been fully validated for the assessment of portal hypertension in CF. That said, like in other chronic liver diseases,
      • Elkrief L.
      • Ronot M.
      • Andrade F.
      • Dioguardi Burgio M.
      • Issoufaly T.
      • Zappa M.
      • et al.
      Non-invasive evaluation of portal hypertension using shear-wave elastography: analysis of two algorithms combining liver and spleen stiffness in 191 patients with cirrhosis.
      it has been suggested that liver elastography could be of added-value to predict clinically significant portal hypertension in CF.
      • Malbrunot-Wagner A.C.
      • Bridoux L.
      • Nousbaum J.B.
      • Riou C.
      • Dirou A.
      • Ginies J.L.
      • et al.
      Transient elastography and portal hypertension in pediatric patients with cystic fibrosis Transient elastography and cystic fibrosis.
      Portal hypertension, either as a direct complication of biliary cirrhosis or secondary to porto-sinusoidal vascular disease, should be carefully assessed because it may develop in the absence of cirrhosis and requires careful management, in some cases including liver transplantation for end-stage disease.

      Biliary fibrosis

      Historically, the hepatic histological feature in these cases is focal biliary fibrosis, characterised by heterogenous portal fibrosis that can gradually progress by forming bridges between the portal spaces, associated with bile duct proliferation and biliary plugs (Fig. 3).
      • Oppenheimer E.H.
      • Esterly J.R.
      Pathology of cystic fibrosis review of the literature and comparison with 146 autopsied cases.
      Figure thumbnail gr3
      Fig. 3Biliary cirrhosis with portal hypertension in an 8-year-old girl.
      Median liver stiffness measured by transient elastography, 2D shearwave elastography and magnetic resonance elastography was increased to 71 kPa, 75.1 kPa and 10.6 kPa, respectively. (A) Liver ultrasound and (B) axial fat-suppressed-T2 weighted MRI showed morphological changes, nodular contours and oesophageal varices (white arrowhead). Patient underwent liver transplantation. Explant liver pathology confirmed the diagnosis of biliary cirrhosis. (C) Macroscopic examination showed nodular contours. (D-F) Microscopic examination showed regenerative nodules on Masson’s trichrome staining (D), bile duct proliferation on cytokeratin 7 staining (E) and biliary plugs (black arrow) including a foamy and vacuolised plug (black arrowhead) on periodic acid schiff staining (F).
      Patients are asymptomatic and, in the absence of advanced fibrosis, there is usually no sign of portal hypertension. Increased heterogeneous echogenicity of the liver may be identified on ultrasound, suggesting focal fibrosis with or without associated steatosis, a frequent associated finding in patients with CF. Liver stiffness measurements may be particularly helpful in these cases to identify focal fibrosis over isolated patchy steatosis. Indeed, elastography can improve or clarify misleading ultrasound patterns by identifying liver fibrosis. Most studies on liver elastography have included children with CFLD defined by clinical, biological or ultrasound findings.
      • Colombo C.
      • Battezzati P.M.
      • Crosignani A.
      • Morabito A.
      • Costantini D.
      • Padoan R.
      • et al.
      Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.
      ,
      • Debray D.
      • Kelly D.
      • Houwen R.
      • Strandvik B.
      • Colombo C.
      Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.
      ,
      • Koh C.
      • Sakiani S.
      • Surana P.
      • Zhao X.
      • Eccleston J.
      • Kleiner D.E.
      • et al.
      Adult-onset cystic fibrosis liver disease: diagnosis and characterization of an underappreciated entity.
      Because of the high prevalence of biliary fibrosis in children with no evidence of portal hypertension, the following results can be safely applied to biliary fibrosis. These studies have proposed cut-off values from 5.5 to 7.1 kPa to predict CFLD using TE.
      • Klotter V.
      • Gunchick C.
      • Siemers E.
      • Rath T.
      • Hudel H.
      • Naehrlich L.
      • et al.
      Assessment of pathologic increase in liver stiffness enables earlier diagnosis of CFLD: results from a prospective longitudinal cohort study.
      ,
      • Kitson M.T.
      • Kemp W.W.
      • Iser D.M.
      • Paul E.
      • Wilson J.W.
      • Roberts S.K.
      Utility of transient elastography in the non-invasive evaluation of cystic fibrosis liver disease.
      ,
      • Friedrich-Rust M.
      • Schlueter N.
      • Smaczny C.
      • Eickmeier O.
      • Rosewich M.
      • Feifel K.
      • et al.
      Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis.
      The discrepancies may be related to different definitions of CFLD and rare pathological examinations.
      • Colombo C.
      • Battezzati P.M.
      • Crosignani A.
      • Morabito A.
      • Costantini D.
      • Padoan R.
      • et al.
      Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.
      ,
      • Debray D.
      • Kelly D.
      • Houwen R.
      • Strandvik B.
      • Colombo C.
      Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.
      ,
      • Koh C.
      • Sakiani S.
      • Surana P.
      • Zhao X.
      • Eccleston J.
      • Kleiner D.E.
      • et al.
      Adult-onset cystic fibrosis liver disease: diagnosis and characterization of an underappreciated entity.
      The only study including a pathological examination of the liver, by Lewindon et al., showed a good correlation between liver stiffness measurements and the METAVIR stages of fibrosis (Spearman rank = 0.67).
      • Lewindon P.J.
      • Puertolas-Lopez M.V.
      • Ramm L.E.
      • Noble C.
      • Pereira T.N.
      • Wixey J.A.
      • et al.
      Accuracy of transient elastography data combined with APRI in detection and staging of liver disease in pediatric patients with cystic fibrosis.
      The proposed cut-off value to predict fibrosis stage ≥F3 with TE was 8.7 kPa, which is comparable to chronic B and C viral hepatitis.
      • Ziol M.
      • Handra-Luca A.
      • Kettaneh A.
      • Christidis C.
      • Mal F.
      • Kazemi F.
      • et al.
      Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C.
      ,
      • Chon Y.E.
      • Choi E.H.
      • Song K.J.
      • Park J.Y.
      • Kim D.Y.
      • Han K.-H.
      • et al.
      Performance of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B: a meta-analysis.
      Two studies evaluated acoustic radiation-force impulse elastography with cut-off values of 1.28
      • Karlas T.
      • Neuschulz M.
      • Oltmanns A.
      • Güttler A.
      • Petroff D.
      • Wirtz H.
      • et al.
      Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.
      and 1.45 m/s to predict CFLD.
      • Friedrich-Rust M.
      • Schlueter N.
      • Smaczny C.
      • Eickmeier O.
      • Rosewich M.
      • Feifel K.
      • et al.
      Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis.
      In the study by Karlas et al.,
      • Karlas T.
      • Neuschulz M.
      • Oltmanns A.
      • Güttler A.
      • Petroff D.
      • Wirtz H.
      • et al.
      Non-invasive evaluation of cystic fibrosis related liver disease in adults with ARFI, transient elastography and different fibrosis scores.
      the diagnostic value was similar between acoustic radiation-force impulse and TE in the same population. 2D-SWE was evaluated by 1 study with a cut-off value of 6.85 kPa to predict CFLD, with a sensitivity and specificity of 75% and 71%, respectively.
      • Calvopina D.A.
      • Noble C.
      • Weis A.
      • Hartel G.F.
      • Ramm L.E.
      • Balouch F.
      • et al.
      Supersonic shear-wave elastography and APRI for the detection and staging of liver disease in pediatric cystic fibrosis.
      Once again, it is important to mention that the stiffness and cut-off values of these different elastography techniques are not comparable. Thus, liver stiffness should be monitored with the same elastography technique from the same manufacturer in the same patient. MRI can provide additional information, such as a patchy increased signal on T2-and diffusion-weighted imaging,
      • Poetter-Lang S.
      • Staufer K.
      • Baltzer P.
      • Tamandl D.
      • Muin D.
      • Bastati N.
      • et al.
      The Efficacy of MRI in the diagnostic workup of cystic fibrosis-associated liver disease: a clinical observational cohort study.
      which – together with elastography – can be used to identify focal increases in liver stiffness on a complete colour mapping of the liver (Fig. 4). Morphological changes (hypertrophy of the caudate lobe, atrophy of segment IV, hypertrophy of the left lobe and finally atrophy of the liver) and irregular contours suggest advanced fibrosis or cirrhosis.
      Figure thumbnail gr4
      Fig. 4Focal biliary fibrosis without portal hypertension in an 8-year-old boy.
      (A) Liver ultrasound shows a slightly heterogeneous hyperechogenic pattern with smooth liver contours and no signs of portal hypertension. (B) Liver stiffness on 2D shearwave elastography was normal (4.3 kPa). (C) Axial diffusion- (B=800) weighted MRI shows an abnormal increased signal in segment VII (arrowhead). (D) A focal increase in liver stiffness (arrowhead) on magnetic resonance elastography was consistent with the diagnosis of focal biliary fibrosis.

      Porto-sinusoidal vascular disease

      Porto-sinusoidal vascular disease, secondary to obliterative portal venopathy and/or nodular regenerative hyperplasia, is another presentation of CFLD. This entity has been more frequently reported in adults than in children.
      • Hillaire S.
      • Cazals-Hatem D.
      • Bruno O.
      • Miranda S de
      • Grenet D.
      • Poté N.
      • et al.
      Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.
      ,
      • Witters P.
      • Libbrecht L.
      • Roskams T.
      • De Boeck K.
      • Dupont L.
      • Proesmans M.
      • et al.
      Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.
      ,
      • Wu H.
      • Vu M.
      • Dhingra S.
      • Ackah R.
      • Goss J.A.
      • Rana A.
      • et al.
      Obliterative portal venopathy without cirrhosis is prevalent in pediatric cystic fibrosis liver disease with portal hypertension.
      Although the prevalence of non-cirrhotic portal hypertension in adults is important when deciding on the diagnostic approach, this should not exclude the presence of non-cirrhotic portal hypertension in children. In a single-centre series of 10 young adults who underwent liver transplantation for severe portal hypertension, 8 had features of non-cirrhotic portal hypertension with METAVIR stage 2 fibrosis in 3 livers and focal areas of stage 3 in 5 livers.
      • Hillaire S.
      • Cazals-Hatem D.
      • Bruno O.
      • Miranda S de
      • Grenet D.
      • Poté N.
      • et al.
      Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.
      Only one of these 8 patients had co-existing focal biliary fibrosis. The 2 remaining patients in this series had biliary cirrhosis. It is interesting to note that in a study by Pereira et al. in 15 children with CFLD and portal hypertension between 6.7 and 16 years old, only 4 (27%) had stage 4 fibrosis on pathological examination and 3 (20%) had stage 0 or 1 fibrosis.
      • Pereira T.N.
      • Lewindon P.J.
      • Greer R.M.
      • Hoskins A.C.
      • Williamson R.M.
      • Shepherd R.W.
      • et al.
      Transcriptional basis for hepatic fibrosis in cystic fibrosis–associated liver disease.
      However, this analysis was based on biopsy specimens, thus, there was a risk of under- or overestimating fibrosis. Specific characterisation of the CFLD phenotypes was not provided in this study. Another series including 40 children with suspected CFLD who underwent liver biopsy,
      • Lewindon P.J.
      • Shepherd R.W.
      • Walsh M.J.
      • Greer R.M.
      • Williamson R.
      • Pereira T.N.
      • et al.
      Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy.
      supported these results. Nine of them had portal hypertension but only 2 had stage 4 fibrosis (2 had stage 2 and 5 had stage 3 fibrosis). The diagnosis of porto-sinusoidal vascular disease is difficult on imaging and it can co-exist with biliary fibrosis (Fig. 5). Certain distinct imaging features should suggest this diagnosis. Liver biopsy and haemodynamic measurements of the hepatic venous pressure gradient may then be needed. These “red-flag” imaging features include the presence of portal hypertension associated with an absence of abnormalities in the hepatic parenchyma. The spleen is usually markedly enlarged
      • Chow K.U.
      • Luxembourg B.
      • Seifried E.
      • Bonig H.
      Spleen size is significantly influenced by body height and sex: establishment of normal values for spleen size at US with a cohort of 1200 healthy individuals.
      and portosystemic shunts are significant as seen in Fig. 6. In children, the thickness of the lesser omentum should be carefully evaluated compared to the aorta as a sign of portal hypertension. The calibre of the intrahepatic portal branches are reduced, while the portal vein is usually enlarged, but thrombosis and mural calcifications may also be present in both
      • Hillaire S.
      • Cazals-Hatem D.
      • Bruno O.
      • Miranda S de
      • Grenet D.
      • Poté N.
      • et al.
      Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.
      ,
      • Witters P.
      • Libbrecht L.
      • Roskams T.
      • De Boeck K.
      • Dupont L.
      • Proesmans M.
      • et al.
      Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.
      ,
      • Glatard A.-S.
      • Hillaire S.
      • d’Assignies G.
      • Cazals-Hatem D.
      • Plessier A.
      • Valla D.C.
      • et al.
      Obliterative portal venopathy: findings at CT imaging.
      (Fig. 6, Fig. 7). Peripheral perfusion disorders may be observed (Fig. 6) and the hepatic artery may also be enlarged.
      • Glatard A.-S.
      • Hillaire S.
      • d’Assignies G.
      • Cazals-Hatem D.
      • Plessier A.
      • Valla D.C.
      • et al.
      Obliterative portal venopathy: findings at CT imaging.
      Unlike biliary fibrosis, morphological changes characterised by hypertrophy of segment IV may indicate obliterative portal venopathy. Another “red-flag” finding is a coarse macronodular pattern of the liver. This is highly suggestive of nodular regenerative hyperplasia as shown in Fig. 7, Fig. 8.
      Figure thumbnail gr5
      Fig. 5Cirrhosis with portal hypertension on co-existing biliary and vascular injuries in a 16-year-old man.
      Liver stiffness on transient elastography, ultrasound-guided elastography and magnetic resonance elastography was consistent with advanced fibrosis (>F2 stage). (A) Liver ultrasound showed a heterogeneous hyperechogenic liver pattern with nodular contours and enlargement of the lesser omentum compared to the aorta. (B) Axial diffusion and (C) fat-supressed T2-weighted MRI showed morphological changes, nodular contours and a patchy increased signal. Large splenomegaly and portosystemic shunts (splenorenal - arrow) were consistent with portal hypertension. The patient underwent liver transplantation. (D) Macroscopic examination showed macronodular cirrhosis. Microscopic examination using H&E staining demonstrated (E) vascular lesions with obliterative portal venopathy and portal tract arterialisation and (F) biliary lesions with ductular proliferation (arrowheads) in the fibrous septa as well as certain ductules containing inspissated granular eosinophilic material (arrow).
      Figure thumbnail gr6
      Fig. 6Porto-sinusoidal vascular disease in a 21-year-old man.
      Liver stiffness on transient elastography was increased to 10.1 kPa. (A, B) Axial and (C) coronal portal-venous CT scan showed severe portal hypertension – rectal varices (arrowhead), portal vein dilation and inferior mesenteric vein dilation (star) – while the liver showed mild morphological changes with smooth contours and peripheral heterogeneous enhancement (arrow). The calibre of intrahepatic portal branches was reduced. Explant liver pathology confirmed the diagnosis of porto-sinusoidal vascular disease with obliterative portal venopathy and regenerative nodular hyperplasia. No biliary abnormalities were noted.
      Figure thumbnail gr7
      Fig. 7Macronodular cirrhosis with portal hypertension in the context of vascular lesions in a 30-year-old woman.
      (A) Macronodular cirrhosis on axial fat-suppressed T2-weighted MRI. The calibre of intrahepatic portal branches was reduced (white arrowhead). (B) Large splenomegaly and portosystemic shunts on coronal portal-venous phase CT scan were consistent with portal hypertension. The portal vein was enlarged (18 mm, star). (C) Macroscopic examination of the liver explant and (D) microscopic examination using picrosirius staining confirmed the macronodular aspect of cirrhosis. (E) H&E staining demonstrated residual portal tracts without the portal vein and with numerous arterial sections (arrowheads).
      Figure thumbnail gr8
      Fig. 8Macronodular cirrhosis with portal hypertension on co-existing vascular and biliary injuries in a 9-year-old girl.
      (A) Liver ultrasound showed morphological changes with a nodular pattern. (B, C) Axial fat-suppressed T2-and diffusion- (B=800) weighted MRI showed large liver nodules with a rim in increased T2 and diffusion signal, splenomegaly, and oesophageal varices (confirmed by gastroscopy). Microscopic examination of liver biopsy showed (D – H&E staining) regenerative nodules (arrowheads), (E – trichrome staining) biliary fibrosis (stars) with bile duct proliferation (arrowheads) and (F – actin staining) fibrous intimal thickening of the portal vein (arrowheads), consistent with a diagnosis of porto-sinusoidal vascular disease in association with biliary injury.
      Liver stiffness can play a key role in the diagnosis of porto-sinusoidal vascular disease. Indeed, in the presence of typical clinically significant cirrhotic portal hypertension, liver stiffness values are increased and higher than validated thresholds. In non-cirrhotic portal hypertension on porto-sinusoidal vascular disease, liver stiffness values are lower because of the absence of the cirrhotic process. In patients with porto-sinusoidal vascular disease, the discordance between liver stiffness values that are lower than those expected in cirrhotic portal hypertension is the third “red-flag” imaging feature. However, it should also be noted that liver stiffness values may still be increased because porto-sinusoidal vascular disease is often associated with grade 2 or 3 fibrosis.
      The results of liver biopsy will show signs of porto-sinusoidal vascular disease: obliterative portal venopathy (intrahepatic portal vein wall thickening, portal venule narrowing, disappearance, or sclerosis), nodular regenerative hyperplasia, incomplete septal fibrosis, portal tract abnormalities (arterialisation, periportal vessels, aberrant portal vessels), architectural disorganisation (irregular portal tracts and centrolobular vein distribution), non-zonal sinusoidal dilatation and mild perisinusoidal fibrosis.
      • Hillaire S.
      • Cazals-Hatem D.
      • Bruno O.
      • Miranda S de
      • Grenet D.
      • Poté N.
      • et al.
      Liver transplantation in adult cystic fibrosis: clinical, imaging, and pathological evidence of obliterative portal venopathy.
      ,
      • Guido M.
      • Alves V.A.F.
      • Balabaud C.
      • Bathal P.S.
      • Bioulac-Sage P.
      • Colombari R.
      • et al.
      Histology of portal vascular changes associated with idiopathic non-cirrhotic portal hypertension: nomenclature and definition.
      ,
      • De Gottardi A.
      • Rautou P.-E.
      • Schouten J.
      • Rubbia-Brandt L.
      • Leebeek F.
      • Trebicka J.
      • et al.
      Porto-sinusoidal vascular disease: proposal and description of a novel entity.
      However, the histological diagnosis of porto-sinusoidal vascular disease can be complex because the characteristic lesions may be unevenly distributed and not always concurrent. Reticulin staining and a systematic analysis of the microcirculation on liver biopsy, including vascular markers of sinusoids, portal venules and arteries, are essential for a diagnosis of porto-sinusoidal vascular disease.
      • Bakshi N.
      • Gulati N.
      • Rastogi A.
      • Chougule A.
      • Bihari C.
      • Jindal A.
      Nodular regenerative hyperplasia – an under-recognized vascular disorder of liver.
      Besides the pathological features of porto-sinusoidal vascular disease, bile duct dilation and mucosal biliary plugs are usually absent, except in the presence co-existent biliary fibrosis.
      Non-cirrhotic portal hypertension should be carefully investigated and may require liver biopsy and/or haemodynamic measurements of the hepatic venous pressure gradient in the presence of “red-flag” imaging features: i) the presence of portal hypertension as a primary feature with the absence of liver parenchyma abnormalities ii) liver stiffness values below the threshold for cirrhosis with clinically significant portal hypertension and, iii) a coarse macronodular pattern suggesting regenerative nodular hyperplasia.
      The hepatic venous pressure gradient often confirms the diagnosis of porto-sinusoidal vascular disease, because it is clearly below the threshold for clinically significant portal hypertension (10 mmHg in adults).
      • Witters P.
      • Libbrecht L.
      • Roskams T.
      • De Boeck K.
      • Dupont L.
      • Proesmans M.
      • et al.
      Liver disease in cystic fibrosis presents as non-cirrhotic portal hypertension.
      ,
      • de Franchis R.
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      Indeed, haemodynamic measurements of the hepatic venous pressure gradient only reflect hepatic sinusoidal pressure and not portal pressure. Because porto-sinusoidal vascular disease represents pre-sinusoidal involvement, the hepatic venous pressure gradient is falsely low which is highly suggestive of porto-sinusoidal vascular disease. This procedure is performed via the transjugular route, allowing for a liver biopsy during the same procedure.

      Biliary injury

      Biliary injury is thought to be a result of abnormal bile acidification. Neonatal cholestasis, caused by viscous and inspissated bile secretions, can sometimes be the first sign, mimicking biliary atresia.
      • Padoan R.
      • Cirilli N.
      • Falchetti D.
      • Cesana B.M.
      Risk factors for adverse outcome in infancy in meconium ileus cystic fibrosis infants: a multicentre Italian study.
      ,
      • Lykavieris P.
      • Bernard O.
      • Hadchouel M.
      Neonatal cholestasis as the presenting feature in cystic fibrosis.
      Biliary involvement can present as lesions from sclerosing cholangitis with single or multiple focal stenoses, micro-gallbladder, gallbladder dysfunction or pigmentary cholelithiasis.
      • Assis D.N.
      • Debray D.
      Gallbladder and bile duct disease in Cystic Fibrosis.
      Magnetic resonance cholangiography can identify irregularities of the intrahepatic bile ducts with alternating dilatations and strictures.
      • Assis D.N.
      • Debray D.
      Gallbladder and bile duct disease in Cystic Fibrosis.
      In a prospective study including 26 adult patients with CF, intrahepatic biliary injury was present in 18 (69%) including 10 (38%) with sclerosing cholangitis-like lesions. Eighteen of these patients had no signs of liver involvement.
      • Durieu I.
      • Pellet O.
      • Simonot L.
      • Durupt S.
      • Bellon G.
      • Durand D.V.
      • et al.
      Sclerosing cholangitis in adults with cystic fibrosis: a magnetic resonance cholangiographic prospective study.
      Micro-gallbladder, defined by a cut-off volume of 2 cm3, was reported in up to one-third of patients.
      • Santamaria F.
      • Vajro P.
      • Oggero V.
      • Greco L.
      • Angelillo M.
      • Carrillo F.
      • et al.
      Volume and emptying of the gallbladder in patients with cystic fibrosis.
      ,
      • Curry M.P.
      • Hegarty J.E.
      The gallbladder and biliary tract in cystic fibrosis.
      Gallbladder dysfunction is frequently reported, characterised by hypokinesia and resulting in impaired gallbladder emptying. However, Santamaria et al. did not find any difference in gallbladder emptying (gallbladder volume after an overnight fast and 30 minutes after a standardised meal) between 57 children with CF and 25 healthy controls.
      • Santamaria F.
      • Vajro P.
      • Oggero V.
      • Greco L.
      • Angelillo M.
      • Carrillo F.
      • et al.
      Volume and emptying of the gallbladder in patients with cystic fibrosis.
      Cholelithiasis is reported in 0.2% to 0.6% of cases (CF Foundation Registry).

      Cystic Fibrosis Foundation Registry - Annual Data Report n.d.

      Finally, a large cohort study over 20 years reported an increased risk of gallbladder carcinoma and cholangiocarcinoma (standardised incidence ratio = 11.4) in adult patients with CF, suggesting increased epithelial dysplasia due to the defective CFTR-mediated chronic inflammatory state.
      • Maisonneuve P.
      • Marshall B.C.
      • Knapp E.A.
      • Lowenfels A.B.
      Cancer risk in cystic fibrosis: a 20-year nationwide study from the United States.

      Steatosis

      Hepatic steatosis, most often moderate, is reported in up to 70% of cases in histological series.
      • Lewindon P.J.
      • Shepherd R.W.
      • Walsh M.J.
      • Greer R.M.
      • Williamson R.
      • Pereira T.N.
      • et al.
      Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy.
      ,
      • Craig J.
      • Haddad H.
      • Shwachman H.
      The pathological changes in the liver in cystic fibrosis of the pancreas.
      Steatosis is hypothesised not to be part of CFLD. There are numerous physiopathological explanations for this event, including nutritional (essential fatty acid deficiency,
      • Strandvik B.
      • Hultcrantz R.
      Liver function and morphology during long-term fatty acid supplementation in cystic fibrosis.
      ,
      • Werner A.
      • Havinga R.
      • Bos T.
      • Bloks V.W.
      • Kuipers F.
      • Verkade H.J.
      Essential fatty acid deficiency in mice is associated with hepatic steatosis and secretion of large VLDL particles.
      phospholipid metabolism abnormalities,
      • Kneeman J.M.
      • Misdraji J.
      • Corey K.E.
      Secondary causes of nonalcoholic fatty liver disease.
      malnutrition,
      • Craig J.
      • Haddad H.
      • Shwachman H.
      The pathological changes in the liver in cystic fibrosis of the pancreas.
      ,
      • Isenberg J.N.
      Cystic fibrosis: its influence on the liver, biliary tree, and bile salt metabolism.
      or obesity), pancreatic insufficiency, choline depletion,
      • Bernhard W.
      Choline in cystic fibrosis: relations to pancreas insufficiency, enterohepatic cycle, PEMT and intestinal microbiota.
      • Bernhard W.
      • Lange R.
      • Graepler-Mainka U.
      • Engel C.
      • Machann J.
      • Hund V.
      • et al.
      Choline supplementation in cystic fibrosis—the metabolic and clinical impact.
      • Chen A.H.
      • Innis S.M.
      • Davidson A.G.F.
      • James S.J.
      Phosphatidylcholine and lysophosphatidylcholine excretion is increased in children with cystic fibrosis and is associated with plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine.
      diabetes and prolonged antibiotic therapy. While malnutrition has long been a subject of debate,
      • Gobato A.O.
      • Vasques A.C.J.
      • Ribeiro A.F.
      • Yamada R.M.
      • Hessel G.
      Prevalence of hepatic steatosis among children and adolescents with cystic fibrosis and its association with nutritional status.
      this cannot be the only explanation, as patients with good nutritional status can present with steatosis.
      • Lindblad A.
      • Hultcrantz R.
      • Strandvik B.
      Bile-duct destruction and collagen deposition: a prominent ultrastructural feature of the liver in cystic fibrosis.
      On the other hand, the increasing prevalence of overweight and obese patients in the CF population (31.4% in 2019 vs. 12.8% in 1999
      Cystic Fibrosis Foundation
      2019 patient Registry annual data report.
      ) is of concern because of the association of this entity with metabolic dysfunction-associated fatty liver disease.
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • Anstee Q.M.
      • Targher G.
      • Romero-Gomez M.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      The progression to steatohepatitis and cirrhosis is still uncertain in CF.

      Differential diagnosis: non–CF–related liver involvement

      Although the detailed pathological mechanisms of CFLD must still be clarified, the previously discussed phenotypic involvements (biliary fibrosis, porto-sinusoidal vascular disease, and biliary injuries) have been shown to be induced by the CFTR mutation. Other hepatic manifestations may be epiphenomena or secondary to iatrogenic events (drug toxicity), extrahepatic events (hepatic congestion on heart failure and advanced lung damage), bacterial/viral infections or to associated non–CF–related liver diseases that should always be excluded, such as chronic hepatitis B or C, autoimmune hepatitis, alpha-1 antitrypsin deficiency, Wilson disease, coeliac disease or genetic haemochromatosis.
      • Debray D.
      • Kelly D.
      • Houwen R.
      • Strandvik B.
      • Colombo C.
      Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.
      Hepatic congestion on heart failure may result in dilation of the inferior vena cava and hepatic veins, loss of the normal triphasic flow pattern on doppler ultrasound or a mosaic parenchymal pattern on contrast-enhanced CT or MRI.

      Treatment

      Although ursodeoxycholic acid (UDCA) has long been the proposed treatment for patients with CF and liver involvement to prevent or halt the progression of fibrosis to cirrhosis,
      • Debray D.
      • Kelly D.
      • Houwen R.
      • Strandvik B.
      • Colombo C.
      Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease.
      its efficacy remains controversial. A Cochrane review, including 3 randomised controlled trials that compared the use of UDCA for at least 3 months to placebo or no additional treatment (n = 118), reported no benefit and did not recommend the routine use of UDCA in CF.
      • Cheng K.
      • Ashby D.
      • Smyth R.L.
      Ursodeoxycholic acid for cystic fibrosis-related liver disease.
      Colombo et al. also reported no evidence of any benefit on the occurrence of portal hypertension.
      • Colombo C.
      • Alicandro G.
      • Oliver M.
      • Lewindon P.J.
      • Ramm G.A.
      • Ooi C.Y.
      • et al.
      Ursodeoxycholic acid and liver disease associated with cystic fibrosis: a multicenter cohort study.
      On the other hand, a large longitudinal cohort study (n = 3,417) suggested that UDCA had a positive effect on survival in patients with mild CFLD.
      • Toledano M.B.
      • Mukherjee S.K.
      • Howell J.
      • Westaby D.
      • Khan S.A.
      • Bilton D.
      • et al.
      The emerging burden of liver disease in cystic fibrosis patients: a UK nationwide study.
      Recently, a synthetic side-chain-shortened derivative of UDCA, norursodeoxycholic acid (norUDCA), was developed and was shown to improve cholestasis in primary sclerosing cholangitis in a phase II clinical study.
      • Fickert P.
      • Hirschfield G.M.
      • Denk G.
      • Marschall H.-U.
      • Altorjay I.
      • Färkkilä M.
      • et al.
      norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis.
      Unlike UDCA, which increases bile acid secretion and the risk of cholangiocyte damage, norUDCA increases bile flow by stimulating bicarbonate secretion. In addition, by interfering with the NF-κB pathway, norUDCA has a direct anti-inflammatory effect.
      • Halilbasic E.
      • Steinacher D.
      • Trauner M.
      Nor-ursodeoxycholic acid as a novel therapeutic approach for cholestatic and metabolic liver diseases.
      However, there are no published reports on its use in patients with CF.
      Current management is based on symptomatic treatment, including nutritional support, management of the complications of portal hypertension with variceal band ligation and liver transplantation in patients who progress to end-stage liver disease.
      • Freeman A.J.
      • Sellers Z.M.
      • Mazariegos G.
      • Kelly A.
      • Saiman L.
      • Mallory G.
      • et al.
      A multidisciplinary approach to pretransplant and posttransplant management of cystic fibrosis–associated liver disease.
      Although the complications of portal hypertension and hepatocellular insufficiency are commonly accepted indications for liver transplantation in CF, there are no consensus guidelines because the natural history of CFLD has not been completely clarified and phenotypic characterisation is difficult. The survival rates associated with liver transplantation in children and adults are acceptable (5-year survival rate 85.8 and 72.7%, respectively, in a large series of 203 patients) and the long-term outcomes are influenced by the involvement of other organs.
      • Mendizabal M.
      • Reddy K.R.
      • Cassuto J.
      • Olthoff K.M.
      • Faust T.W.
      • Makar G.A.
      • et al.
      Liver transplantation in patients with cystic fibrosis: analysis of united network for organ sharing data.
      Portosystemic shunt procedures such as distal splenorenal or portocaval shunts in patients with symptomatic portal hypertension (recurrent bleeding or refractory ascites) can be considered as an alternative to liver transplantation,
      • Debray D.
      • Lykavieris P.
      • Gauthier F.
      • Dousset B.
      • Sardet A.
      • Munck A.
      • et al.
      Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.
      ,
      • Lemoine C.
      • Lokar J.
      • McColley S.A.
      • Alonso E.M.
      • Superina R.
      Cystic fibrosis and portal hypertension: distal splenorenal shunt can prevent the need for future liver transplant.
      while transjugular intrahepatic portosystemic shunts are a bridge to liver transplantation.
      • Lupi A.
      • Barbiero G.
      • Battistel M.
      • Ferrarese A.
      • Loy M.
      • Feltracco P.
      • et al.
      Transjugular intrahepatic portosystemic shunt in non-cirrhotic portal hypertension related to cystic fibrosis in a lung transplant patient.
      Portal hypertension on porto-sinusoidal vascular disease was the main indication for transplantation in a recent series of liver transplantation in patients with CF.
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      Conclusion

      Portal hypertension, either as a direct complication of biliary cirrhosis or secondary to porto-sinusoidal vascular disease, is the main complication of CFLD that influences patient management (and the need for liver transplantation). Screening for liver involvement and fibrosis should include an annual clinical examination, liver tests, and abdominal ultrasound. We also suggest liver stiffness measurements. Because characterisation of CFLD can be difficult on imaging, certain “red-flag” features should suggest the diagnosis of non-cirrhotic portal hypertension. In these cases, haemodynamic measurements of the hepatic venous pressure gradient and liver biopsy may be indicated to allow for evaluation of the liver parenchyma. To evaluate the efficacy of CFTR modulator therapies, precise characterisation of liver involvement is needed. Thus, the triptych of liver tests, ultrasound and elastography could be used for early detection of the response to treatment or the progression of CFLD.

      Abbreviations

      2D-SWE, 2D shearwave elastography; APRI, aspartate aminotransferase-to-platelet ratio index; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CFLD, CF liver-related disease; FXR, farnesoid X receptor; FGF, fibroblast growth factor; norUDCA, norursodeoxycholic acid; PAMPs, pathogen-associated molecular patterns; PPARγ, peroxisome proliferator-activated receptor γ; pSWE, point shearwave elastography; TGFβ, transforming growth factor-β; TLR4, Toll-like receptor 4; TE, transient elastography; UDCA, ursodeoxycholic acid.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      Jérémy Dana wrote the original draft of the article under the supervision of Valérie Vilgrain and Dominique Debray. Dominique Debray provided her expertise in pediatric hepatology and cystic fibrosis-related liver disease. Sophie Hillaire and Thomas Baumert provided their expertise in adult hepatology. Aurélie Beaufrère and Monique Fabre provided their expertise in adult and pediatric liver pathology, respectively. Caroline Reinhold and Valérie Vilgrain provided their expertise in adult liver imaging and Laureline Berteloot in pediatric liver imaging. All the authors reviewed, edited, and approved the manuscript.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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