Liver involvement in cystic fibrosis in children

Introduction

Liver involvement is the second leading cause of death in cystic fibrosis, accounting for 2.3%⁽¹⁾.

Cystic fibrosis (CF) is the most common potentially lethal genetic disease in the Caucasian population, and mutation of the CFTR gene (encoding a cAMP pathway-activated chloride channel located in the apical membrane of secretory epithelia) is the genetic substrate of the disease. The gene has been extensively studied, and pathogenic variants (over 2000 known mutations) are correlated with multiple and complex phenotypes.

Hepatomegaly and steatosis-like liver damage occur in 30% of cases, with liver failure cited in 9% of patients. This is due to obstruction of intra- and extrahepatic tracts by thick bile or pancreatic compression. Biliary cirrhosis, as an adverse event in the course of these patients, was reported in 2-5% of cases⁽²⁾.

In the liver, CFTR is located in biliary epithelial cells (cholangiocytes) and in the gallbladder epithelium, where it appears to play a role in normal bile formation.

Approximately 5-10% of CF patients develop multilobular cirrhosis in the first decade of life. Most patients show signs of portal hypertension and its complications (variceal bleeding). Liver failure usually occurs after pediatric age, so annual screening is recommended for the early detection of liver damage and the initiation of ursodeoxycholic acid (UDCA) therapy, which may slow disease progression.

Improved life expectancy has led to greater recognition of hepatobiliary complications in the disease (37.4 years in the USA and Germany and 48.1 years in Canada)⁽³⁾.

Biliary tract involvement is usually clinically obvious, while liver involvement may be silent, manifesting clinically as end-stage and portal hypertension (PH). Compared to pancreatic involvement in CF, in this case there does not seem to be a genotype-phenotype correlation in the expression of hepatopathy, suggesting the presence of a “genetic modifier” that would influence disease expression.

History

In 1938, D. Anderson described the first cases of hepatobiliary damage as a complication, possibly causing death; in turn, Farber and Bodian described focal biliary cirrhosis (FBC) in cases of cystic fibrosis.

Di Sant Agnese and Blanc reported progression to multilobular biliary cirrhosis (MBC), a much more severe complication; Gaskin (1988) stated that 95% of CF cases had liver disease and strictures of the common bile duct.

In 1990, Bilton described common bile duct strictures, and 11 years later, Gabolde pointed out the higher frequency of cirrhosis⁽⁴⁾.

In a study of 241 cases, Thierry Lamireau stated that liver disease occurred in 18%, 29% and 41% in two, five and 12 years, thus the average cirrhosis at 10 years was 8%⁽⁵⁾.

Prevalence

The prevalence is still unclear due to the absence of sensitive markers and the difficulty of defining clinically significant liver disease in cystic fibrosis. On average, 20-25% of CF patients develop liver damage, but only 6-8% of cases will develop cirrhosis, and there is currently no consensus for incidence and prevalence.

However, there are more recent data showing that the incidence of CBM complicated with portal hypertension (PH) is 5-15%, with a mean age at diagnosis of 9 years old, that 39% of esophageal varices are diagnosed at 6-10 years old, and 37% at 10-15 years; the decline of the disease occurs in the third decade of life. Unexplained steatohepatitis occurs in about 60% of cases, the relationship to cirrhosis being unknown.

CBF is “quieter” clinically and biochemically, with post-mortem prevalence increasing with age, so that more than 19% of cases are infants who die within the first 3 months of life. There is no relationship with neonatal obstructive jaundice; 27-50% are young children who die at more than 12 months of life, and 72% are adults⁽⁶⁾.

Clinically manifest CFLD does not appear until pubertal age, with a prevalence of 13-17%, although isolated hepatomegaly is present in 6-30% of patients. The incidence declines rapidly after the age of 10 years old, with a slowly progressive course over time⁽⁷⁾.

Pathogenesis of hepatobiliary dysfunction (CFLD-cystic fibrosis liver disease)

The cystic fibrosis transmembrane regulator (CFTR) mutation results in the following: abnormal chloride secretion, increased sodium reabsorption, bile dilution in the intrahepatic bile ducts (IHC), increased concentration of conjugated bile acids, biliary obstruction with direct bile duct injury, cytokine and activated stellate cell intervention that will promote collagen hypersynthesis and biliary fibrosis⁽⁸⁾.

The viscosity of biliary secretion is not always evident in patients with CFLD which has led to the idea that other pathogenic mechanisms are responsible for CFLD. The gut-phagocyte axis and the influences of gut microflora on liver inflammatory status are currently discussed in focus and in other liver pathologies (steatosis, steatohepatitis, fibrogenic evolution outside the existence of mucoviscidosis). Increased intestinal permeability associated with pathogenic bacterial strains, which are also the result of altered microbiota, leads to bacterial translocation or bacterial products, including pathogen-associated molecular patterns (PAMPs). Furthermore, altered microbiota leads to the disruption of bile acid homeostasis by disrupting the farnesoid X receptor (FXR) – fibroblast growth factor 19 (FGF19) activation pathway⁽⁹⁾.

A vicious circle of infection and inflammation thus develops in CF, making it even more difficult to disentangle the dynamic sequences involved. Events such as cell death and debris clearance, which generate inflammatory syndrome – all of these follow one another, creating and sustaining chronic inflammation, leading to irreversible parenchymal degradation. It cannot be judged whether activated immune or secondary necrotic cells are mainly responsible for perpetuating the inflammatory process. The only available methods to assess immune responses are ex vivo, by determining inflammatory cells in biological products, and the local dynamics of these processes can only be surmised.

Determining influences

There are no specific changes in CFTR that are associated with the presence and/or severity of liver disease. The liver phenotype is variable, suggesting that CF progression may be influenced by environmental factors or gene modifiers. Of the genes suspected to be related to CF liver phenotype (SERPINA1, ACE, TGFB1, MBL2, GSTP1), only the Z allele of SERPINA1 has been associated with CFLD and portal hypertension⁽¹⁰⁾.

Hepatobiliary manifestations

The most important manifestations in the gallbladder are hypoplasia, distention, cystic duct atresia and cholelithiasis. In the bile ducts, lithiasis, extrinsic compression stenosis, sclerosing cholangitis (SC) or cholangiocarcinoma dominate. The liver suffers from steatohepatitis, focal biliary cirrhosis (FBC) or multilobular cirrhosis (MBC)⁽¹¹⁾.

Steatosis

Steatosis is considered to be benign in cystic fibrosis, unrelated to the subsequent development of cirrhosis, and is the most common early lesion in children. It is unexplained in 20-60% of cases and does not correlate with prognosis. However, current discussions on the NASH- cirrhosis link require reconsideration of this entity in CF patients.

Mild steatosis is the most common, being associated with selective nutritional deficiencies (essential fatty acids, altered phospholipid metabolism).

Massive steatosis is rare due to early diagnosis and available nutritional therapy.

Neonatal cholestasis

It occurs in less than 2% of neonates with CF and is associated with meconium ileus (MI) in half of cases or total parenteral nutrition. Increased direct bilirubin of unknown origin in the newborn implies testing for CF. Increased TGP, TGO, sometimes isolated GGT or FA or PTTK are common in infants with ileus and pancreatic insufficiency. They may persist chronically without developing liver disease⁽¹²⁾.

Vesicular lithiasis

Cholelithiasis is represented by cholesterol stones (24%) and may be the only symptom in cystic fibrosis. It has a higher prevalence in CF patients compared to the normal population. Approximately 15-25% of adults with CF have vesicular lithiasis, regardless of pancreatic damage.

Absence of functional CTFR in bile duct epithelial cells results in reduced chloride secretion and reduced passive transport of water and chloride, which in turn results in increased bile viscosity (mucin hypersecretion, impaired secretion and absorption of bile acids)⁽¹³⁾.

Focal biliary cirrhosis (FBC)

FBC occurs in 10.6-15.6% of infants up to 12 months of age, in 19-50% of children and adolescents, and in more than 72% of adults. It is a difficult diagnosis in isolated hepatomegaly (hard, painless liver, nodular border), sometimes the disease is asymptomatic or begins with recurrent abdominal pain. Its progression is to CBM with PTH expressed by esophageal and gastric varices, the complications being represented by hematoma or melena (one third of cases with varices) or just iron deficiency anemia, ascites, hypersplenism, portosystemic encephalopathy (PSE), marked fatigue or coagulopathies.

Multilobular biliary cirrhosis (MBC)

MBC occurs in less than 1% of young children, but it has a higher prevalence in adults (24%). It is manifested by abdominal distention, vascular stellate, ascites, sometimes normal TGP when associated with PTH. Liver biopsy may be normal, and liver failure occurs late, with no parallelism with lung involvement⁽¹⁴⁾.

Screening for liver disease in cystic fibrosis

First of all, a careful physical examination is necessary at each medical visit, with a preference for palpation of the spleen and liver.

Paraclinically, TGO, TGP, alkaline phosphatase, GGT and bilirubin are monitored. When their values exceed 1.5 times the upper limit of normal, repeating at 3-6 months and abdominal ultrasound are recommended. Persistent biochemical abnormalities over six months without other explanation probably indicate liver disease, requiring systematic ultrasound and liver biopsy puncture, this indicating the presence of eosinophilic granules in portal ducts, proliferation of bile ducts, chronic portal infiltrates, variable fibrosis or focal distribution of lesions.

“Silent” PH is the most serious complication of the liver disease, manifested by upper gastrointestinal bleeding (ruptured esophageal varices at onset), rarely with abnormal TGP (D. Debray followed 44 cases for 36 years, of whom 39% had PTH with esophageal varices and 36% liver failure). Early diagnosis requires suspicion, as the stage of the disease dictates the therapeutic decision. Hepatomegaly at 2 cm below the costal margin with or without confirmatory ultrasound and liver cytolysis enzymes raised to twice normal are two conditions required at least twice a year.

The reported echographic abnormalities are nodularity, irregular liver border and splenomegaly. Steatosis is not a diagnostic criterion. However, there are no clear predictive criteria for liver disease, but frequent evaluation allows early diagnosis.

Advanced cystic fibrosis-associated liver disease (aCFLD), manifested by hepatic nodularity with or without portal hypertension, occurs in approximately 7% of patients with cystic fibrosis⁽¹⁵⁾. The cyrogenic form of aCFLD occurs mainly in children and adolescents, with a mean age at diagnosis of 10 years old⁽¹⁶⁾, whereas the non-cyrogenic form of aCFLD occurs in all age groups and is more common in children than previously recognized⁽¹⁷⁾. The risk factors for the development of aCFLD in children and adolescents include male sex and class I-III mutations of the cystic fibrosis transmembrane regulator (CFTR)⁽¹⁸⁾. Bartlett et al. identified that heterozygous Z alpha 1 anti­trypsin status is associated with a seven-fold increased risk for the development of aCFLD. A higher level of gamma glutamyl transpeptidase (GGTP) at younger ages is also associated with an increased risk for developing aCFLD^(19,20).

Abdominal ultrasound

Some studies have attempted a correlation between echographic findings and laboratory tests. Patriquin et al. demonstrated in 1999 that, out of 195 children, 21% had normal echograms but the biochemical tests were altered, and 33% of patients with echographic abnormalities had normal blood tests.

In 2002, Williams showed in a nine-year study that in 24% of cases there were discrepancies between ultrasonographic changes and TGP values. Thus, ultrasound can select a subgroup of patients with focal liver lesions but normal blood tests, who usually respond very well to bile acid ther­apy. In some cases, the gallbladder is hypoplastic, associated or not with other changes (irregular liver margin).

Doppler studies of the portal vein, which detect dilatation of the portal shaft, can be performed to better assess portal hypertension. Portal hypertension is suggested by decreased venous flow velocity or reversal of flow in the portal vein (hepatofugal flow).

Other imaging methods

Computer tomography (CT) shows increased vascular structures or multifocal hypoattenuation.

MRI cholangiography (MRCP) differentiates between primary sclerosing cholangitis and ductular involvement from cystic fibrosis.

Other methods include transient elastography (TE) and Acoustic Radiation Force Impulse Elastography (ARFI) with the following cut-off values by degree of fibrosis: F0 1.13 m/s, F1 1.17 m/s, F2 1.37 m/s, F3 1.64 m/s, and F4 1.99 m/s.

Treatment of liver damage in cystic fibrosis

The treatment aims to improve bile excretion and bile composition. Bile acids, especially ursodeoxycholic acid (UDCA) in doses of 10-15-20 mg/ kg/day, are known to improve clinical and biochemical parameters altered in liver disease (cholestasis) by decreasing bile viscosity. UDCA increases resistance of hepatocytes and cholangiocytes to cytotoxins, stops progression of early multifocal lesions (antifibrotic effect), is hydrophilic, non-toxic, choleretic and hepatoprotective. It is likely to affect the natural history of hepatopathy in cystic fibrosis.

Coenzyme Q10 has antioxidant and vitamin E-preserving effects. It is recommended in doses of 60-100 mg/day.

Taurine leads to increased pre-albumin and fat absorption. It is recommended in severe liver failure and poor nutritional status at a dose of 30 mg/kg/day.

Flavonoids prevent the release of proteases, and glutathione may also be useful in some cases.

Treatment of portal hypertension

The current treatment of portal hypertension is oriented towards therapeutic directions, having as objective a prolonged decrease in portal pressure, aiming, on the one hand, at reducing portal blood flow and, on the other, at decreasing intrahepatic resistance. The major therapeutic directions in portal hypertension are pharmacological therapy, endoscopic therapy, interventional radiological therapy and surgical therapy.

The treatment of portal hypertension is mainly directed towards the management of its most dramatic clinical manifestation, gastrointestinal bleeding, especially variceal bleeding. The therapeutic modalities are diverse and the choice of optimal therapy is made at the progressive stage of varicose veins, depending on the presence or absence of varicose veins, the risk of bleeding or digestive hemorrhage. Current effective therapies in the prevention of primary variceal bleeding are the use of non-selective beta-blockers and endoscopic ligation of varicose veins.

CFTR modulator therapy in cystic
fibrosis-associated liver disease

CFTR modulator therapies are now available for people with cystic fibrosis, and the eligibility for such treatment is based on CFTR genotype. Eligibility for CFTR modulator therapy also implies adequate liver function, as transaminases are known to increase after initiation of CFTR modulator therapy, and their increase should be closely monitored. Increases of more than five times the upper normal value for AST and ALT require stopping the treatment, and increases of up to three times the upper normal value may occur in the first weeks after introduction. Hepatocytolysis has been observed to occur more frequently in patients who have previously had these biological changes⁽²¹⁾.

It therefore remains at the discretion of the clinician to introduce modulators if all other criteria for inclusion in treatment are met. Thus, if CFTR modulators are proven beneficial on the occurrence and progression of CFLD, the increasing international use of CFTR modulators may prevent the majority of cases of severe liver disease from developing⁽⁹⁾.

Conflict of interest: none declared

Financial support: none declared

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