Minireviews
Copyright ©The Author(s) 2021.
World J Hepatol. Nov 27, 2021; 13(11): 1727-1742
Published online Nov 27, 2021. doi: 10.4254/wjh.v13.i11.1727
Table 1 Spectrum of cystic fibrosis liver disease in children
Spectrum of cystic fibrosis liver disease in children
Liver
Neonatal cholestasis
Pre-clinical
Elevated aminotransferases
Increased GGT
Steatosis
Portal hypertension including non-cirrhotic portal hypertension
Cirrhosis
Focal biliary
Multi-lobular
Gallbladder and biliary system
Cholelithiasis
Abnormal size/function
Intra and extrahepatic biliary strictures (sclerosing cholangitis)
Table 2 Causes of acute or chronic liver disease in cystic fibrosis patients showing hepatic abnormalities
Condition
Investigation
Acute/chronic viral hepatitisSerology for HAV, HBV, HCV, EBV, CMV, adenovirus, HHV 6, parvovirus
α1 antitrypsin deficiencySerum α1 antitrypsin level, including phenotype
Autoimmune hepatitisNon-organ specific autoantibodies (SMA, anti-LKM1, LC1)
Celiac diseaseTotal IgA, IgA anti-tissue transglutaminase
Wilson diseaseCeruloplasmin, serum copper, 24 h urinary copper
Drug induced liver injuryAntibiotics (cyclines, macrolides, amoxicillin-based, and cephalosporins) & antifungals (azoles and polyenes)
Genetic hemochromatosis (adults)Iron, Ferritin, Transferrin binding capacity
Other causes of steatosisMalnutrition, diabetes, obesity
Table 3 Examples of noninvasive monitoring of liver fibrosis in pediatric cystic fibrosis liver disease
Non-invasive marker
Ref.
Outcome measured
AUC
Sensitivity
Specificity
Comments
Indirect markers of liver fibrosis
APRILeung et al[37]CFLD diagnosis and severe CFLD0.8173%70%APRI score cut-off > 0.264; Predict CFLD and significant fibrosis in CFLD with a high degree of accuracy
FIB-4Leung et al[37]Portal hypertension0.9178%93%FIB-4 cutoff 0.358
Direct markers of liver fibrosis
TIMP-1Pereira et al[38]CFLD diagnosis0.7664%83%Significantly increased in CFLD vs no-CFLD
Prolyl hydroxylasePereira et al[38]CFLD 60%91%Negative correlation between serum TIMP-1 levels and the stage of histological fibrosis; Prolyl hydroxylase useful in distinguishing CFLD patients with early fibrogenesis vs extensive fibrosis; Not able to differentiate CFLD versus no-CFLD
diagnosis
TIMP-2Rath et al[38]CFLD diagnosis0.69--
m-RNA’sCook et al[39] CFLD diagnosis0.7847%94%Able to differentiate between CFLD versus no-CFLD but quantify not fibrosis stage; Pathological significance not yet certain, more studies needed
Imaging methods
Transient elastographyWitters et al[40]Liver stiffness0.8663%87%Less inter and intra-observer variability; Easy to learn and perform; Regular measurements for serial follow-up feasible
Rath et al[34]Liver stiffness0.68--Few centres have access to technology
MR elastographyPalermo et al[41]Liver stiffness-100%100%Small study, paucity of data; Shear stiffness significantly elevated in CF patients with cirrhosis; Costly with limited availability
Table 4 Diagnostic criteria of cystic fibrosis liver disease
Debray et al[25]
CF foundation classification[24]
Hepatomegaly and/or splenomegaly- increased liver span at midclavicular line and spleen size in longitudinal coronal plane for age and sex, confirmed by ultrasonographyCF related liver disease with cirrhosis/portal hypertension (based on clinical exam/imaging, histology, laparoscopy)
Abnormalities of liver function tests-elevated AST and ALT and GGT levels above the upper limit of normal with at least at 3 consecutive determinations over 12 months after excluding other causes of liver diseasesLiver involvement without cirrhosis/portal hypertension consisting of at least one of the following: (1) Persistent AST, ALT, GGT > 2 times upper limit of normal; (2) Intermittent elevations of the above laboratory values; (3) Steatosis (histologic determination); (4) Fibrosis (histologic determination); (5) Cholangiopathy (based on ultrasound, MRI, CT, ERCP); and (6) Ultrasound abnormalities not consistent with cirrhosis
Ultrasonographic evidence of coarseness, nodularity, increased echogenicity, or portal hypertensionPreclinical: No evidence of liver disease on clinical examination, imaging or laboratory values
Liver biopsy showing cirrhosis
Table 5 Indications and contraindications for liver transplantation in cystic fibrosis liver disease (Modified from Freeman et al[43])
Indications and contraindications
Indications
Strong(1) Progressive hepatic dysfunction with hypoalbuminemia and coagulopathy (Coagulopathy not corrected by vitamin K, cholestasis not attributed to other causes); (2) Complications of portal hypertension (Intractable/recurrent variceal bleeding which is not controlled by medical or endoscopic management); (3) Hepatopulmonary and porto-pulmonary syndrome; (4) Overt hepatic encephalopathy; and (5) Hepatorenal syndrome
Controversial (1) Deteriorating pulmonary function (FEV1/FVC <50%) with increased frequency and severity of pulmonary infective episodes requiring hospitalization; and (2) Severe malnutrition, unresponsive to intensive nutritional support
Contraindications
Absolute(1) Extrahepatic malignancies not amenable to curative therapy; (2) Multiorgan disease for which transplant would not be considered life-sustaining; (3) Uncontrolled systemic or pulmonary infection, active exacerbation, or veno-arterial extracorporeal membrane oxygenation; and (4) Severe porto-pulmonary hypertension nonresponsive to medical management
Relative(1) Hepatocellular carcinoma; (2) Noncompliance or psychosocial concerns unamenable to transplant; (3) Uncontrollable CF-related diabetes; (4) Substance abuse; (5) Severe cardiopulmonary disease; and (6) Infection/colonization with multi-resistant organism (e.g., Burkholderia cenocepacia and Mycobacterium abscessus)
Table 6 Liver transplantation in cystic fibrosis liver disease - data from few published series
Ref.
Type
Number of pediatric recipients
Type of transplants
Males
Mean age at isolated liver transplantation (yr)
Lung function after Liver transplantation
5-year survival
Milkiewicz et al[45], 2002Single center9Liver; Liver- lung -heartNot available15ImprovedNot available
Fridell et al[21], 2003Single center12Liver 83%10 ± 4.5 Improved or remained unchanged75%
Molmenti et al[47], 2003Single center10Liver90%9.7 (1.23–19)Not available60%
Mendizabal et al[44], 2011Analysis of United Network for Organ Sharing database148Liver; Liver- lung (3.4%)62%11 ± 4.7 Not available86%
Miguel et al[48], 2011Single center11Liver67%12 (5.4–17)Worsened or remained unchanged> 85%
Dowman et al[49], 2012Single center19LiverNot available11.8 (9.5–16.5)Stable/improved initially, deteriorated > 5 years after transplant> 60%
Table 7 Pre and post-transplant protocol for prevention and treatment of distal intestinal obstructive syndrome
Pre and post-transplant protocol
Low risk(1) 600 mg N-acetyl-cysteine in 120 mL water orally/nasogastric tube twice/day. Senna twice daily; (2) 2 liters of Klean prep per day post-transplant; (3) Consider early nasogastric tube in patients with delayed gastric emptying studies pre-operatively; (4) All patients in intensive care unit should only receive only elemental feed via nasogastric tube as this does not require pancreatic enzyme replacement. Once transferred to ward, can be restarted on regular feeding and pancreatic enzyme supplements; (5) Try and reduce opiates early during hospital stay; and (6) Treat all patients with proton pump inhibitors.
High risk(1) As per low risk management; and (2) High risk of developing DIOS and subsequent surgical gut decompression is associated with a high mortality. So these patients should receive a prophylactic loop ileostomy.
Treatment of DIOS(1) Stop feeding, nasogastric tube on free drainage and intravenous fluids; (2) 100 mL gastrografin in 400 mL water enterally and repeat after 6 h; (3) Subsequent management is with Klean prep in 1 L water over 1 h via oral/nasogastric tube and can be repeated up to 4 times every 24 h until bowel movement is achieved; and (4) If no improvement after 48 h, then it is unlikely to resolve without surgery to decompress the gut and also consider total parenteral nutrition.
Table 8 Cystic fibrosis transmembrane conductance regulator modulators
Type of modulator
Mechanism of action
Mutation class in which drug is effective
Example
Clinical effects/present status of modulator
PotentiatorsRestore or even enhance the channel open probability, thus allowing for CFTR-dependent anion conductanceClasses III and IVIvacaftorImprovement in lung function, pancreatic function and body mass index
CorrectorsRescue folding, processing and trafficking to the plasma membrane of a CFTR mutant. Enhance protein conformational stability during the endoplasmic reticulum folding processClass IILumacaftor; Tezacaftor; Posenacaftor; ElexacaftorSignificant improvement in lung function when used with Ivacaftor
StabilizersAnchor CFTR at the plasma membrane, thus preventing its removal and degradation by lysosomesClass VICavosonstat First CFTR stabilizer studied in clinical trials- studies terminated because of lack of clinical efficacy
Read-through agents Induce ribosomal over-reading of premature termination codon, enabling the incorporation of a foreign amino acid in place and continued translation to the normal end of the transcriptClass IAtaluren (PTC124)Clinical trials terminated
AmplifiersIncrease expression of CFTR mRNA and thus biosynthesis of the CFTR proteinClass VNesolicaftor (PTI-428)Clinical trial planned