Srp Arh Celok Lek. 2012 Mar-Apr;140(3-4):244-249 DOI: 10.

2298/SARH1204244R
244 ПРЕГЛЕД ЛИТЕРАТУРЕ / REVIEW ARTICLE

Cystic Fibrosis
Nedeljko Radlović1,2
1
School of Medicine, University of Belgrade, Belgrade, Serbia;
2
University Children’s Hospital, Belgrade, Serbia

SUMMARY
Cystic fibrosis (CF) is a multisystemic autosomal recessive disease caused by a defect in the expression of
CFTR protein, i.e. chloride channel present in the apical membrane of respiratory, digestive, reproductive
and sweat glands epithelium. It primarily occurs in the Caucasians, while being considerably or excep-
tionally rare in persons of other races. Absence, deficit or structural and functional abnormalities of CFTR
protein lead to mucosal hyperconcentration in the respiratory, digestive and reproductive systems and
malabsorption of chloride and sodium in the sweat glands. Thus, the clinical features of patients’ with
CF are predominated by respiratory, digestive and reproductive disorders, as well as the tendency to
dehydration in the condition of increased sweating. Beside genotype variations, the degree of disease
manifestation is also essentially influenced by various exogenous factors, such as the frequency and
severity of respiratory infections, the level of aero-pollution, quality of immunoprophylaxis, patients’
nutritional condition and other. Chloride concentration of over 60 mmol/L in sweat, a high level of
immunoreactive chymotrypsinogen in blood and the verification of homozygous mutation of CFTR
gene are the basic methods in the diagnostics of the disease. CF belongs to the group of severe and
complex chronic diseases, and therefore requires multidisciplinary therapeutic approach. Owing to the
improvement of healthcare provision, most patients with CF now survive into adulthood. In addition,
their quality of life is also considerably improved.
Keywords: cystic fibrosis; chloride channels; diagnostics; treatment

INTRODUCTION CFTR protein is a cAMP-dependent ion

channel located at the apical membrane of the
Cystic fibrosis (CF) or mucoviscidosis is a mul- respiratory, digestive, reproductive and sweat
tisystemic autosomal recessive disease caused epithelium [18]. It consists of 1480 amino acids
by a defect in the expression of chloride chan- distributed by a certain order into five basic
nels (cystic fibrosis transmembrane conduct- polypeptide segments – two intramembranous,
ance regulator – CFTR protein) present at the two nucleotide-binding and one regulatory
apical membrane of the respiratory, digestive, (Figure 1). The intramembranous segments
reproductive and sweat epithelium [1]. It pri- (IMD1 and IMD2) form a channel for the pas-
marily occurs in the population of the European sage of chloride ion, nucleotide-binding (NBD1
origin (1:2000-3200), while in the population and NBD2) which, in bondage with ATP, pro-
groups of other continents it is 3-4 times rarer vides energy for the CFTR protein function-
[2-7]. The frequency of heterozygous carriers ing, while the regulatory segment (R), after
of the pathologic gene in the Caucasians rates activation (phosophorylation) mediated by
1:25-30 [5, 8, 9]. Although involving most com- the specific cAMP-dependent protein-kinase
plex and severely ill patients, their prognosis A or C, triggers the process of the separation
today, owing to the improvement of healthcare of CFTR protein intramembranous segments
insurance, is far better than it used to be [4-7, and opening of the chloride channel [1, 19, 20].
10-13].

CFTR PROTEIN

In the basis of the disease is the defect of the

CFTR gene which provides the synthesis of the
CFRT protein responsible for the transport of
chloride ion at the cell membrane level [14]. The
CFTR gene was cloned by Riordan et al. in 1989
[15]. It is located on the long arm of the chromo-
some 7 (7q31.2). Its length is 250 kilobases and
Correspondence to: contains 27 exons. Owing to this knowledge,
Nedeljko RADLOVIĆ up-to-date DNA analysis represents a precious
University Children’s Hospital method in the prenatal and postnatal diagnos- Figure 1. Schematic presentation of CFTR protein
Tiršova 10, 11000 Belgrade tics of the disease, as well as in the disclosure of IMD – intramembranous domains; NBD – nucleotide-binding
Serbia domain; R – regulatory (domain); PKA – cAMP-dependent pro-
n.radlovic@beotel.net its heterogeneous carriers [4, 9, 16, 17]. tein kinase (according to ref. 19)
Srp Arh Celok Lek. 2012;140(3-4):244-249 245

Thus, CFRT protein function is carried out in the manner nation ΔF508 and non-ΔF508 gives exocrine pancreatic
that, under the influence of corresponding stimuli, it opens insufficiency in 72% cases, and two non-ΔF508 mutations
enabling transmembranous diffusion of chloride ions into in only 36% [30]. Also, in some mutations, among which
the direction of electrochemical gradient, which is of key 3849+10kbC→T, chloride concentration in sweat is normal
significance in the activity of secretory processes in the [16]. Beside genotype, in the fenotype expression of CF
respiratory, digestive and reproductive system, as well as essential participation is also displayed by various exog-
in the reabsorption of chloride and sodium in the sweat enous factors, such as the frequency and severity of respira-
glands [21]. Contrary to respiratory, digestive and repro- tory infections, level of aero-pollution, quality of vaccinal
ductive system, where both secretory and reabsorptive pro- protection, patients’ nutritive status and other [29, 31, 32,
cesses evolve simultaneously and in balance, in the sweat 33]. It is understood that the level of disease manifestation
glands distal tubules only reabsorptive processes take place is also essentially conditioned by the patient’s age.
[18, 22]. Chloride secretion is followed by the paracellular
transport of sodium and water, while the mechanisms of
their reabsorption or absorption are reversed, i.e. chloride CLINICAL FEATURES
ions and water molecules follow sodium transmembra-
nous (transcellular) transport [22]. Beside the exclusively Defect in the secretion of chloride, sodium and water fol-
reabsorptive characteristic, the difference in the epithe- lowed by the formation of hyperviscous mucus at the level
lium of the sweat glands distal segment, in relation to the of respiratory, digestive and reproductive systems repre-
respiratory, digestive and reproductive epithelium, is that sents a key problem in patients with CF, while the insuf-
the transport of both sodium and chloride evolve transcel- ficiency in the reabsorption of these ions at the level of
lularly [22]. sweat glands is of secondary significance [4, 5, 8, 16, 34].

PATHOGENETIC BASIS OF THE DISEASE

Phenotype expression of the CFTR gene in CF is followed

by the absence, insufficient amount or structural and
functional defect of the CFTR protein [18, 23]. Up-to-
now over 1500 genetic mutations have been discovered
that are responsible for the occurrence of this disease [16].
In 70-80% of patients CFTR gene mutation has been reg-
istered, followed by phenylalanine deletion at the posi-
tion 508 (ΔF508), with 50% in homozygous condition
and 25-30% in the combination with some other genetic
abnormalities [5, 24, 25].
Due to the defect in CFRT protein function, patients
with CF develop hyperconcentration of mucus in the
respiratory, digestive and reproductive system, as well as
malabsorption of chloride and sodium in the sweat glands
[18]. In the first case it is related to the insufficiency of the
intraluminal efflux of chloride, and in the second of the
inability of its reabsorption. Therefore, the clinical fea-
tures of patients with CF are predominated by respiratory
and digestive disorders, as well as a marked tendency of
dehydration in the state of increased sweating [26, 27].
The classical form of the disease is characterized by rather
typical clinical features already evident during the first
months after birth or somewhat later so that in 97-98%
of cases it is diagnosed before age 18 years, with about
70% until completed second year (Figure 2) [4, 28]. The
dependence of fenotype on the genotype is evident, but
not also absolute [28]. Regarding the question of exocrine
pancreatic insufficiency, it has been confirmed, which is
not the case with the respiratory, hepatobiliary and intes-
tinal component of the disease [29]. Thus, for example, in
the homozygous ΔF508 mutation (ΔF508/ΔF508) exocrine
pancreatic insufficiency is almost regularly present, while
in the combination R111H and 3849+10kbC→T mutation
it is preserved [16, 29, 30]. On the other side, the combi- Figure 2. A 12-year-old boy with classical cystic fibrosis

www.srp-arh.rs
246 Radlović N. Cystic Fibrosis

Respiratory problems are present in over 90% of patients liver changes are often associated with meconium ileus and
with CF [5]. They are usually manifested already in the first exocrine pancreatic insufficiency [16].
months after birth featuring pertussis-like cough, repeated The consequence of exocrine pancreatic insufficiency
episodes of bronchiolitis or obstructive bronchitis. Due and/or cholestasis, as a part of CF there is also the devel-
to difficulties with elimination of hyperviscous secretions opment of other manifestations, such as osteopenia and
and pulmonary hypoventilation, the disease is associated osteoporosis, hypoproteinemic oedema and discharges into
with the development of recurrent bronchopneumonia and free body cavities, hemorrhagic diathesis due to the deficit
pulmonary atelectasis that are sometimes also additionally of vitamin K-dependent coagulation factors (II, VII, IX
complicated by a pulmonary abscess and pneumothorax. and X), peripheral neuropathy and haemolytic anaemia
Recurrent otitis is often seen, followed by conductive deaf- caused by vitamin E deficiency and other [5, 16, 41]. Due
ness and in older children by purulent sinusitis and nasal to the associated deficit of proteins and minerals, rachitis
polyps. The most frequent causes of infective complica- is rare [16]. Because of chronic cough, malnutrition and
tions in CF are Pseudomonas aeruginosa, Staphylococcus abdominal distension, a significant number of CF patients
aureus, Haemophilus influenzae and Burkholderia cepacia has inguinal hernia, while 25% present with gastroesopha-
[5, 8, 16, 35]. In the later phase of the disease there is the geal reflux, among whom half of them have also gastroe-
development of bronchiectasis and progressive pulmonary sophageal reflux disease [16, 37].
fibrosis with emphysema and pulmonary hypertension. At As aforementioned, chloride malabsorption in the
this point there is usually the presence of club fingers as sweat glands does not feature so drastic clinical manifesta-
well. About 90% of patients with CF die due to cardiores- tions. Pathological concentration of chloride in sweat (>60
piratory failure [5, 36]. mmol/L) is disclosed in about 98-99% of patients with CF
Exocrine pancreatic insufficiency occurs in about 85% [4]. Chloride is eliminated with sodium and potassium,
of children with CF [6, 16]. It develops as the result of pan- so that such patients, under the condition of increased
creatic drainage tubes obstruction and secondary atrophy sweating, show a tendency to hyponatremic dehydration,
of acinar tissue. Due to the lack of pancreatic enzymes, hypokalemia and metabolic alkalosis [8, 10, 43]. Secondary
which play the major role in the digestive process, there hyperaldosteronism induced by hypovolemia and hipona-
is the development of the malabsorption of nutritive sub- tremia have essential participation in the development of
stances with global malnutrition. The child’s appetite is hypokalemia and metabolic alkalosis. Hypokalemia is also
often preserved, and sometimes even increased. Stools are contributed by metabolic alkalosis, which does not only shift
more frequent, abundant, fatty and putrid. In more severe potassium into the cell, but also favours its renal loss [44].
cases of the disease, particularly in children of the young-
est age, a prolapse of the rectal mucosa can be also seen
[37]. It is important to point out the fact that, owing to DIAGNOSIS
the compensatory effect of breast milk lipase and amylase,
malabsorption syndrome in infants on optimum natural Determination of chloride concentration in sweat (sweat
nutrition can be mild, and even unnoticeable [38]. test) is the first procedure in the diagnostics of CF. Chloride
In 10-20% of neonates with CF, particularly those with level in sweat of over 60 mmol/L is considered pathologi-
the ΔF508/ΔF508 genotype, meconium ileus is seen, some- cal and below 40 mmol/L normal, while 40-60 mmol/L
times associated with prenatal instestinal perforation and is border-line [5, 6, 16]. The sweat test does not have a
peritonitis [5, 16]. Episodes of bowel obstruction due to the diagnostic value in neonates aged below the first seven
thickened mucus, intussusception and intestinal volvulus days or of body weight less than 3000 gr, and neither in
are not rare even later [5, 6, 37]. There is also a possibility patients with oedema or eczema [6, 16]. When analyzing
of mucous impaction of the appendix with subcutaneous sweat test findings it should be kept in mind that border-
appendicitis and periappendicular abscess [16, 37]. line or slightly increased chloride rates in sweat can be also
Chronic pancreatitis is a rare complication of CF seen in found in other pathological conditions, such as untreated
patients with the ΔF508/ΔF508 genotype and a relatively adrenal insufficiency, ectodermal dysplasia, glycogenosis
preserved acinar tissue [16, 39]. Insulin-dependent diabetes type 1, hereditary nephrogenic diabetes insipidus, hypo-
mellitus caused by scarring destruction of the Langerhans thyreosis, hyperparathyroidism, mucopolysaccharidosis,
islets occurs in 1% of patients up to completed five years, fucosoidosis and severe malnutrition [16, 45]. Also, sweat
and in 12% among those aged 13-19 years [11, 12, 40]. test findings can be false in pyrexia, dehydration, high table
Cholestasis is found in 20-30% of patients, and is mainly salt consumption and during diuretic therapy.
of milder degree [5, 16]. Liver steatosis occurs in 15-30%, Today DNA analysis represents a modern method in the
focal biliary cirrhosis in 10%, and multilobular biliary cir- diagnostics of CF. However, most laboratories can detect
rhosis and portal hypertension in only 2-5% of patients only most frequent mutations, so that genetic verification of
with CF [5, 16]. Cholelithiasis is considerably more fre- rare variants of the disease are likely to go unnoticed [16].
quent in relation to the general population and mainly Others tests of diagnostic valued include a high level of
occurs in the second decade of life or later [16, 37]. In 40% immunoreactive serum trypsinogen, which is widely used
of patients with CF a dysfunctional or micro vesica fellea within the framework of neonatal screening on CF, then
can be seen [27]. Although being independent of genotype, a low level of pancreatic enzymes in the duodenal juice,

doi: 10.2298/SARH1204244R
Srp Arh Celok Lek. 2012;140(3-4):244-249 247

high content of fat in stool, pathological pancreozymin- based on protein hydrolysate. For a successful correction
secretion test, low fecal elastase level, increased potential of severe malnutrition, it is necessary to apply elementary
difference at the level of the nasal epithelium and other and sometimes also parenteral nutrition [6, 37, 46].
[6, 16, 34]. Due to the tendency of dehydration, patients with CF
require additional consumption of table salt [16, 48, 49].
This must be specially taken into account in the conditions
TREATMENT of increased sweating, such as in the summer period and
pyrexia. The correction of hypovolemia, hyponatremia,
Respiratory complaints represent the most severe prob- hypokalemia and hypochloremic metabolic alkalosis in
lem in the therapy of CF [5, 6, 16, 46, 47]. Pulmonary expressed hyponatremic dehydration is achieved by intra-
ventilation is improved with adequate hydration of the venous application of 10-20 ml/kg 0.9% NaCl in bolus or
patient, mucolytics, bronchodilatators and anti-inflamma- during 15-30 minutes [49].
tory drugs. Kinesytherapy and other forms of respiratory Certain disclosed complications in CF, such as intesti-
rehabilitation can be also useful. In infective complications nal obstruction or perforation, nasal polyposis and other,
antibiotics are indicated, and in cardiorespiratory failure require surgical treatment. Lung transplantation, per-
diuretics, cardiotonics and oxygenotherapy. formed in the condition of terminal respiratory failure,
Enzymic deficit compensation and adequate diet form yields modest results today [5].
the basis of the therapy of pancreatic exocrine insufficiency
[5, 6, 16, 48, 49]. Correction of malnutrition improves the
general condition, anti-infective resistance and respiratory PROGNOSIS
function of the patient. Due to a reduced level of nutri-
tive substances usage and increased metabolic require- Owing to modern therapeutic possibilities, as well as to
ments, the patient’s food must be easily digestible and up to the prevention of complications, particularly those which
20-50% richer in proteins and calories in relation to healthy additionally endanger the respiratory system, the progno-
children of identical body weight. Breast-feeding is of spe- sis of CF is increasingly better from year to year [13, 50].
cial significance in the first year after birth, and even after According to the US data, the average survival of patients
that period. Infants on artificial feeding, and particularly with CF was 10.6 years in 1966, 20 years in 1981, and 32
if malnourished, are indicated for milk formulas based years in 1998. [5].
on protein hydrolysate and a partial substitution of long-
chain with easily digestible and highly usable medium-
chain trigycerides. By additional intake of medium-chain CONCLUSION
instead of long-chain trigycerides later caloric needs are
also covered to a considerable level. The optimum of essen- CF represents a relatively rare multisytemic autosomal
tial fatty acids, linoleic and alpha-linolenic, is achieved by recessive disease. Beside genotype, the outcome of the
the daily nutritional addition of corn or sunflower oil in the disease is essentially influenced by numerous additional
quantity of 1 ml/kg. Liposoluble vitamins also require addi- factors, such as the quality of respiratory complications
tional intake, while the needs in hydrosolubile vitamins and prevention and treatment, the level of aero-pollution, nutri-
minerals are not essentially different from that of healthy tional status of the patient and other. Although, in most
children. Pancreatic enzyme preparations protected by an cases, this is a severe and potentially highly lethal disease,
acid-resistant protector are administered with each meal. owing to the advancement of healthcare and team-work
Their addition is also necessary for exclusively breastfeed- treatment, life perspective of such patients has been evi-
ing infants, as well as to those consuming infant formula dently improved over the last years.

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doi: 10.2298/SARH1204244R
Srp Arh Celok Lek. 2012;140(3-4):244-249 249

Цистична фиброза
Недељко Радловић1,2
1
Медицински факултет, Универзитет у Београду, Београд, Србија;
2
Универзитетска дечја клиника, Београд, Србија

КРАТАК САДРЖАЈ генотипских варијација, важан утицај на степен испољава-

Цистична фиброза је мултисистемско аутозомно рецесив- ња болести имају и различити егзогени фак тори, као што
но обољење изазвано поремећајем у експресији протеина су учесталост и тежина инфекција респираторног трак та,
CFTR, тј. хлорног канала који се налази на апикалној мембра- ниво аерозагађења, квалитет имунопрофилаксе, стање ис-
ни респираторног, дигестивног, репродук тивног и знојног храњености болесника и други. Концентрација хлора у зноју
епитела. Превасходно се јавља код припадника беле расе, већа од 60 mmol/l, висок ниво имунореак тивног химотрип-
док је код особа других раса знатно ређа или изузетно рет- синогена у крви и потврда хомозиготне му тације у CFTR ге-
ка. Услед изостанка протеина CFTR или његовог струк тур- ну основне су методе у дијагностиковању болести. Цистич-
ног и функционалног поремећаја долази до хиперконцен- на фиброза припада групи тешких и комплексних хронич-
трације мукуса у респираторном, дигестивном и репродук- них обољења, те изискује мултидисциплинарни терапијски
тивном систему и поремећене апсорпције хлора и натрију- приступ. Захваљујући унапређењу здравствене заштите, ве-
ма у знојним жлездама. Отуда у клиничкој слици болесни- ћина болесника са цистичном фиброзом данас доживи од-
ка с цистичном фиброзом доминирају сметње у респира- расло доба, а значајно им је побољшан и квалитет живота.
торним, дигестивним и репродук тивним органима, као и Кључне речи: цистична фиброза; хлорни канал; дијагно-
склоност дехидратацији у стању појачаног знојења. Поред стика; лечење

Примљен • Received: 23/12/2010 Прихваћен • Accepted: 09/11/2011

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