Cystic fibrosis associated liver disease in children

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)

GGT: Gamma glutamyl transferase.

Table 2 Causes of acute or chronic liver disease in cystic fibrosis patients showing hepatic abnormalities

Condition	Investigation
Acute/chronic viral hepatitis	Serology for HAV, HBV, HCV, EBV, CMV, adenovirus, HHV 6, parvovirus
α1 antitrypsin deficiency	Serum α1 antitrypsin level, including phenotype
Autoimmune hepatitis	Non-organ specific autoantibodies (SMA, anti-LKM1, LC1)
Celiac disease	Total IgA, IgA anti-tissue transglutaminase
Wilson disease	Ceruloplasmin, serum copper, 24 h urinary copper
Drug induced liver injury	Antibiotics (cyclines, macrolides, amoxicillin-based, and cephalosporins) & antifungals (azoles and polyenes)
Genetic hemochromatosis (adults)	Iron, Ferritin, Transferrin binding capacity
Other causes of steatosis	Malnutrition, diabetes, obesity

This table is modified from Debray et al[25]. HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; CMV: Cytomegalovirus; EBV: Epstein-Barr virus; HHV6: Herpes hominis virus type 6; SMA: Smooth muscle antibody; LKM1: Liver kidney microsomal type 1; LC: Liver cytosol type 1; IgA: Immunoglobulin A.

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
APRI	Leung et al[37]	CFLD diagnosis and severe CFLD	0.81	73%	70%	APRI score cut-off > 0.264; Predict CFLD and significant fibrosis in CFLD with a high degree of accuracy
FIB-4	Leung et al[37]	Portal hypertension	0.91	78%	93%	FIB-4 cutoff 0.358
Direct markers of liver fibrosis
TIMP-1	Pereira et al[38]	CFLD diagnosis	0.76	64%	83%	Significantly increased in CFLD vs no-CFLD
Prolyl hydroxylase	Pereira 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-2	Rath et al[38]	CFLD diagnosis	0.69	-	-
m-RNA’s	Cook et al[39]	CFLD diagnosis	0.78	47%	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 elastography	Witters et al[40]	Liver stiffness	0.86	63%	87%	Less inter and intra-observer variability; Easy to learn and perform; Regular measurements for serial follow-up feasible
	Rath et al[34]	Liver stiffness	0.68	-	-	Few centres have access to technology
MR elastography	Palermo 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

AUC: Area under the curve; APRI: Aspartate aminotransferase to platelet ratio index; CFLD: Cystic fibrosis associated liver disease; Fib-4: Fibrosis-4; TIMP: Tissue inhibitor of metalloproteinase; m-RNA: Messenger ribonucleic acid; MR: Magnetic resonance.

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 ultrasonography	CF 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 diseases	Liver 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 hypertension	Preclinical: No evidence of liver disease on clinical examination, imaging or laboratory values
Liver biopsy showing cirrhosis

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; GGT: Gamma glutamyl transpeptidase; CF: Cystic fibrosis; MRI: Magnetic resonance imaging; CT: Computed tomography; ERCP: Endoscopic retrograde cholangiopancreatography.

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)

FEV1: Forced expiratory volume in one second; FVC: Forced vital capacity.

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], 2002	Single center	9	Liver; Liver- lung -heart	Not available	15	Improved	Not available
Fridell et al[21], 2003	Single center	12	Liver	83%	10 ± 4.5	Improved or remained unchanged	75%
Molmenti et al[47], 2003	Single center	10	Liver	90%	9.7 (1.23–19)	Not available	60%
Mendizabal et al[44], 2011	Analysis of United Network for Organ Sharing database	148	Liver; Liver- lung (3.4%)	62%	11 ± 4.7	Not available	86%
Miguel et al[48], 2011	Single center	11	Liver	67%	12 (5.4–17)	Worsened or remained unchanged	> 85%
Dowman et al[49], 2012	Single center	19	Liver	Not available	11.8 (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.

DIOS: Distal intestinal obstructive syndrome.

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
Potentiators	Restore or even enhance the channel open probability, thus allowing for CFTR-dependent anion conductance	Classes III and IV	Ivacaftor	Improvement in lung function, pancreatic function and body mass index
Correctors	Rescue folding, processing and trafficking to the plasma membrane of a CFTR mutant. Enhance protein conformational stability during the endoplasmic reticulum folding process	Class II	Lumacaftor; Tezacaftor; Posenacaftor; Elexacaftor	Significant improvement in lung function when used with Ivacaftor
Stabilizers	Anchor CFTR at the plasma membrane, thus preventing its removal and degradation by lysosomes	Class VI	Cavosonstat	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 transcript	Class I	Ataluren (PTC124)	Clinical trials terminated
Amplifiers	Increase expression of CFTR mRNA and thus biosynthesis of the CFTR protein	Class V	Nesolicaftor (PTI-428)	Clinical trial planned

CFTR: Cystic fibrosis transmembrane conductance regulator; mRNA: Messenger RNA.