Discussion
The improved CF management in high income countries has led to an increased life expectancy in CF cases. Consequently, as pwCF get older, a substantial liver dysfunction emerges, which complicates the disease with incidence of 10-15%.10 The occurance of CF in a prospective study was found to be 2.5 per 100 patient-years during early life years, with an increase in the second decade.11Hepatobiliary involvement was reported in 4-10.9 percent of Middle Eastern CF cases.12,13 In a previous study of CF cases in Egypt, the CFLD rate was found to be more elevated compared to the US population.12 In the current study, the frequency of liver disease in CF patients was 38%, significantly higher than previously reported in the Middle Eastern population. This study revealed that the male sex is a significant risk factor associated with CFLD, which was reported previously in 2 case-control studies in several western countries.13,14
A large cohort study was done on 177 pwCF (aged between one month and 23 years) and found that liver disease occurred before puberty in all female patients, and the incidence increased up to 18% by the age of eleven years, but in male patients, the incidence increased from 25% by the age of eleven up to 42% by the age of eighteen.11That could be due to endocrine factors involved in CFLD development with the estrogen and its receptors substantially contributing to the modulation of secretory and proliferative activities of the intrahepatic biliary epithelium due to liver damage.11 This incidence was similar to what we found in our study and it was significantly higher than previously reported in other studies.
In a retrospective analysis of data from 561 pwCF in Canada, Stonebraker et al. found that mutations, as well as male gender related to severe phenotype, increased the progression of severe liver disease.15 This study had illustrated risk factors including male sex, and class I-III mutations, which is related to meconium ileus as well as pancreatic insufficiency at birth.15 In a prospective study, F508del was detected in 51-55 percent of CFLD cases.11 That was similar to what was found in our study where 64% of the patients with CFLD had F508del and that was statistically significant compared to patients that didn’t have CFLD (33%).
In addition, the young age at diagnosis and the longer duration of the disease, the more susceptibility to CFLD development. This is in agreement with a study, in which the median age of onset of CFLD was between 6-8 months.16 In a study regarding risk factors leading to CFLD in a large-scale cohort of patients in France concluded that male sex and long duration of illness are significant risk factors for developing CFLD, they also found that CFLD occurrence elevated by 1-2 percent every year from birth until the age of 25 years of age.17 Also, Fagundes et al. and Efrati et al. in a study including one hundred and fifty pwCF between 1975 and 2000 in the National Cystic Fibrosis Center in Israel revealed that the early onset of CF and long duration are significant risk factors for developing CFLD.18,19
CFLD often manifests during the two decades of life. The majority of CF children tend to develop a degree of steatosis. CF-related multi-lobular cirrhosis or focal biliary cirrhosis occur in children and adolescent, but major biliary involvement resembling sclerosing cholangitis is more common in adults. In severe CFLD, portal hypertension, particularly non-cirrhotic portal hypertension, might cause variceal bleeding.20
It has been reported that severe CFLD is life-threatening because it is associated with the progression of portal hypertension, and worsening of the respiratory status and liver transplantation might be indicated.21 In our CFLD patients, 89% of the patients had productive cough and 46% had dyspnea. Steatorrhea was present in 90% and CF-assocaited diabetes CFRD was present in 37% of patients. In addition to 68% of patients had hepatomegaly, 16% had splenomegaly, 57% had abdominal distention, 2 patients had gall bladder stones and 1 had ascites. None of the patients had portal hypertension, biliary dilation, or jaundice. In accordance with these findings, Colombo et al. observed hepatomegaly in 6–30% of cases,21 even though our patients had higher rate of hepatomegaly (68%).
In our patients with CFLD, abdominal ultrasound revealed hepatomegaly in 28%, hepatic steatosis in 24%, Cholelithiasis in 4% (males), ascites in 2%, and splenomegaly in 16%. That was similar to the finding in a study, which revealed hepatic steatosis in 20–60% and Cholelithiasis was in 1–10% of the studied patients in a study including a group of 124 children with an average age of 5.4 years in the United Kingdom.22 A retrospective review of sequential abdominal ultrasound reported that 11.9% of the patients had splenomegaly, seven cases (4.2%) had frank cirrhotic changes on ultrasound criteria, and eight cases (4.8%) experienced gall bladder stones with male predominance in this group (6/8).23
History of meconium ileus was reported in the CFLD cases representing 26.3% than the non-CFLD cases representing 6.5%. While Bock et al. revealed that meconium ileus was reported in 20% of the cases.24 Colombo et al. reported that cases with a history of meconium ileus were five times more prone to develop CFLD compared to cases without.11 The development of liver disease in intestinal obstruction cases could be due to inspissated bowel that leads to biliary secretion that plugs the bile ductule leading to liver damage. One-fourth of patients in this study developed liver disease.
This study showed that CFRD is a major risk factor associated with CFLD development as 37% of patients were diagnosed with CFRD. That was similar to a study that reported, that 32% of patients with CFLD had CFRD.25 In another study, CFRD was a considerable risk factor for CFLD development in Italian CF Registry.26In addition, this study showed that pancreatic insufficiency, meconium ileus history, and younger age at diagnosis, were all related to severe CFTR mutation classes, and were proven as risk factors for CFLD development.26 Another study reported that severe mutations (classes I, II, or III) manifesting with elevated mortality as well as morbidity are substantially related to younger age (<1 year), meconium ileus, as well as pancreatic insufficiency at diagnosis, and liver affection.27 Another study reported that mild CFTR mutations (class IV and class V) are uncommon in individuals with CFLD.28 Our study revealed that severe mutations including classes I and II was a significant risk factor associated with the development of CFLD. Furthermore, F508del is the most common mutation representing 64.3% of the studied patients. That was similar to previous reports, of correlation between CFLD and severe genetic mutations (class I and II) in retrospective studies to investigate potential risk factors for developing CFLD in the Netherlands.11,19,29
In this study, CFLD was associated with severe CF disease as per Shwachman score (63.2% of the CFLD group had severe CF disease compared to 16.1% in the non-CFLD group). Patients with CFLD had frequent hospital admissions and impaired growth and nutrition. Similarly, it was reported in some studies that, children with established CFLD suffer from impaired nutrition and growth, severe lung disease with worse pulmonary function, as well as altered body composition .26,30 In another study, similar findings were noted.13
Early liver disease diagnosis is a significant problem for the clinical management of those cases. Usually, liver-associated symptoms might be undetectable until cirrhosis and portal hypertension are developed.21 All our CFLD patients were treated with ursodeoxycholic acid. Nevertheless, Cochrane Reviews have shown that the effectiveness of ursodeoxycholic acid has not been proven clearly.31
As there is no efficient medication to treat or inhibit the development of cirrhosis, portal hypertension, or fibrosis in CFLD, its management should be carried out by a multidisciplinary team and is mostly supportive. Liver transplantation (LT) might be recommended for CFLD cases with intractable complications of portal hypertension or end-stage liver disease since it provides substantial survival advantages. However, LT does not always enhance long-term pulmonary prognosis. Therefore, subjects with liver disease, as well as combined lung disease,  may undergo combined lung and liver transplantation (CLLT).32
This study revealed in addition, that non-adherence to pancreatic enzyme replacement therapy represent 78.9% of the CFLD group while representing 38.7% of the non- CFLD group. In addition, non-adherence to fat-soluble vitamins represents 47.4% of CFLD group vs. 16.1% in the non-CFLD group. These findings could be factors in developing CFLD, as well.