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.