*1.1.1 Pathophysiological changes to the bile acids in the course of cystic fibrosis*

The important roles played by the pathophysiological changes of the bile duct include changes to the components of the bile (abnormal water and electrolyte contents and change to the pH of the bile) and changes to the profile of bile acids—to hydrophobic, abnormal transport of the bile, retention of toxic bile acids (taurocholic acid), and induction of pro-inflammatory chemokines which influence on biliary fibrogenesis. Factors contributing to the processes of precipitation of bile acids in the bile ducts include decreased synthesis of the salts of the bile acids, decreased absorption of bile acids from the lumen of the small intestine, and narrowing of the bile ducts impairing the outflow of the bile from the liver to the lumen of the duodenum [5, 8, 10].

#### *1.1.2 Genetic factors*

So far, no specific mutation relating solely to liver damage in the course of cystic fibrosis has been discovered. Most commonly, these are the so-called "serious mutations" of the CFTR gene (delta F508,G524X, N1303K, CFTRdel21kB, 1811 + 1G- > C). The delta F508 mutation plays a particular role in the development of hepatic lesions in the course of cystic fibrosis due to its stimulation of an increased loss of bile acids with stools and the fact that it leads to the formation of more hydrophobic bile acids. Hepatic lesions co- occurring with cystic fibrosis in patients with the 3849 + 10kB C- > T mutation have not yet been the subject of interest. However, the clinical course in patients with diagnosed cystic fibrosis and the same mutation of the CFTR gene tends to vary. There is no strict phenotype–genotype corelation. The role of the SERPINE1 mutation: it occurs in about 2% of the patients with cystic fibrosis and in about 5% of the patients with cystic fibrosis and co-occurring hepatic lesions. Responsible for the synthesis of the inhibitor of serine protease. The protein connected to allele Z is concentrated within the endoplasmic reticulum of hepatocytes leading to their damage, inflammation, and cirrhosis. In about 10% of allele Z homozygotes, the accumulation of the SERPINA gene protein leads to neonatal hepatitis and in 2–3% of cases to fibrosis and cirrhosis. In pathogenesis some genes were suspected as a factor inducing pathological processes in the liver and bile duct in patients with cystic fibrosis (gene of plasminogen activator inhibitor type 1, genes relating to metalloproteinases, P1 glutation s-transferase gene, transforming growth factor beta gene, uridylyltransferase gene (UGT1A1). But the role is not strictly confirmed [12–17].

#### *1.1.3 Immunological factors*

Chemokines play a role as an activator of stellate cells (source: hepatic macrophages, endothelial cells, bile duct epithelial cells, lymphocytes, blood platelets, and hepatocytes). The main chemokines are monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1 beta (MIP1B), TGF-beta, TNF-alpha, platelet-derived growth factor (PDGF), and interleukins IL-1, IL-6, and IL-10 [11, 18–23].

**Pathogenesis of hepatic lesions the course of cystic fibrosis according to Colombo** [1, 2, 8]**.**

 Abnormalities of cholangiocytes. ↓ Mucous plugs in bile ducts. ↓ Inflammatory and proliferative processes. ↓ Focal biliary fibrosis (25–30%). ↓ Multilobular biliary cirrhosis (10%). ↓ Portal hypertension. ↓ Hepatic insufficiency.

**81**

*Liver Changes in the Course of Cystic Fibrosis DOI: http://dx.doi.org/10.5772/intechopen.89306*

*1.2.1 Nutritional factors*

and cholelithiasis.

*1.2.2 The role of medications*

mide, lorazepam, and ibuprofen [30–32].

*1.2.3 Defects of the gall bladder and bile ducts*

**1.2 Organ lesions contributing to the manifestation of CFLD**

biliary cirrhosis develops into multilobular cirrhosis [25].

In the examination of Wilchanski et al., the presence of hepatic lesions (cystic fibrosis liver damage (CFLD)) was concluded in 28% (80/288) of CF patients. All patients with hepatic lesions were diagnosed with pancreatic insufficiency. No correlation between the occurrence of hepatic lesions and pulmonary lesions, respiratory insufficiency, the level of malnutrition, meconium ileus, and/or distal intestinal obstruction syndrome (DIOS) was concluded [24]. Lindblad observed meconium ileus in only 12% of CF patients, out of whom only 6/15 patients with meconium ileus had the symptoms of liver damage [6]. Siano did not prove the correlation between the occurrence of hepatic lesions in the course of cystic fibrosis and the pancreatic efficiency and the level of nutrition. In 2–5% of patients, focal

Malnutrition influences on liver function in children with cystic fibrosis. Children

with diagnosed cystic fibrosis and liver damage have lower body mass, height, circumference of the upper arm, and BMI. Patients with cystic fibrosis also have significantly lower levels of linoleic (LA), docosahexaenoic (DHA), and docosapentaenoic (DPA) acids. The influence of parenteral nutrition and antioxidant and vitamin deficiency is confirmed [26–29]. Sometimes in children with cystic fibrosis especially with meconium ileus, total parenteral nutrition is necessary. Total parenteral nutrition (TPN) therapy is a well-recognized cause of liver injury. The histologic changes attributed to TPN in the literature vary widely. Total parenteral nutritioninduced liver disease develops in 40–60% of infants who require long-term TPN. The clinical spectrum includes cholestasis, cholelithiasis, hepatic fibrosis with progression to biliary cirrhosis, and the development of portal hypertension and liver failure in a significant number of children who are totally parenterally fed. The pathogenesis is multifactorial and is related to prematurity, low birth weight, and duration of TPN. The degree and severity of the liver disease are related to the recurrent sepsis including catheter sepsis, bacterial translocation, and cholangitis. The lack of enteral feeding leading to reduced gut hormone secretion, reduction of bile flow, and biliary stasis may be important mechanisms in the development of cholestasis, biliary sludge,

In patients with cystic fibrosis, abnormal functions of oxidases and P450, CYP2C8, CYP2C9, and CYP3A4 cytochromes are observed. The dose of beta-lactam should be reduced by 20%. The doses of aminoglycosides should be decided upon depending on the level of the medication in the blood serum. Increased microsomal metabolism relating to theophylline and methylxanthine through the affected first phase of the biotransformation of the medications. Increased hepatic clearance of the second phase, which may be reflected in the abnormal metabolism of furose-

In about 30% of patients with cystic fibrosis, atrophic gall bladder, or the lack thereof, also its defects and/or of bile ducts is reported. No correlation between cirrhosis and abnormalities in the gall bladder and/or bile ducts has been observed. Gallbladder hydrops and lithiasis are more commonly observed in patients with

*Cystic Fibrosis - Heterogeneity and Personalized Treatment*

lumen of the duodenum [5, 8, 10].

*1.1.2 Genetic factors*

firmed [12–17].

*1.1.3 Immunological factors*

and IL-10 [11, 18–23].

**Colombo** [1, 2, 8]**.**

narrowing of the bile ducts impairing the outflow of the bile from the liver to the

So far, no specific mutation relating solely to liver damage in the course of cystic fibrosis has been discovered. Most commonly, these are the so-called "serious mutations" of the CFTR gene (delta F508,G524X, N1303K, CFTRdel21kB, 1811 + 1G- > C). The delta F508 mutation plays a particular role in the development of hepatic lesions in the course of cystic fibrosis due to its stimulation of an increased loss of bile acids with stools and the fact that it leads to the formation of more hydrophobic bile acids. Hepatic lesions co- occurring with cystic fibrosis in patients with the 3849 + 10kB C- > T mutation have not yet been the subject of interest. However, the clinical course in patients with diagnosed cystic fibrosis and the same mutation of the CFTR gene tends to vary. There is no strict phenotype–genotype corelation. The role of the SERPINE1 mutation: it occurs in about 2% of the patients with cystic fibrosis and in about 5% of the patients with cystic fibrosis and co-occurring hepatic lesions. Responsible for the synthesis of the inhibitor of serine protease. The protein connected to allele Z is concentrated within the endoplasmic reticulum of hepatocytes leading to their damage, inflammation, and cirrhosis. In about 10% of allele Z homozygotes, the accumulation of the SERPINA gene protein leads to neonatal hepatitis and in 2–3% of cases to fibrosis and cirrhosis. In pathogenesis some genes were suspected as a factor inducing pathological processes in the liver and bile duct in patients with cystic fibrosis (gene of plasminogen activator inhibitor type 1, genes relating to metalloproteinases, P1 glutation s-transferase gene, transforming growth factor beta gene, uridylyltransferase gene (UGT1A1). But the role is not strictly con-

Chemokines play a role as an activator of stellate cells (source: hepatic macrophages, endothelial cells, bile duct epithelial cells, lymphocytes, blood platelets, and hepatocytes). The main chemokines are monocyte chemoattractant protein-1 (MCP1), macrophage inflammatory protein-1 beta (MIP1B), TGF-beta, TNF-alpha, platelet-derived growth factor (PDGF), and interleukins IL-1, IL-6,

**Pathogenesis of hepatic lesions the course of cystic fibrosis according to** 

Abnormalities of cholangiocytes.

Inflammatory and proliferative processes.

Focal biliary fibrosis (25–30%).

Multilobular biliary cirrhosis (10%).

Mucous plugs in bile ducts.

Portal hypertension.

Hepatic insufficiency.

↓

↓

↓

↓

↓

↓

**80**
