DEFINITION
Cystic fibrosis (also known as CF or mucoviscidosis) is a hereditary disease whose effects are clinically evident in the exocrine (mucus) glands of the lungs, liver, pancreas, and intestines, causing progressive disability due to multisystem failure.
CF is caused by a mutation in a gene called the cystic fibrosis transmembrane conductance regulator (CFTR).
CF is an autosomal recessive disease
EPIDEMIOLOGY
Cystic fibrosis is the most common life-limiting autosomal recessive disease among people of European heritage. In the United States, approximately 30,000 individuals have CF; most are diagnosed by six months of age. Canada has approximately 3,000 citizens with CF. Approximately 1 in 25 people of European descent is a carrier of a cystic fibrosis mutation. Although CF is less common in these groups, approximately 1 in 46 Hispanics, 1 in 65 Africans and 1 in 90 Asians carry at least one abnormal CFTR gene.[66]
Although technically a rare disease, cystic fibrosis is ranked as one of the most widespread life-shortening genetic diseases. It is most common among nations in the Western world. An exception is Finland, where only one in 80 people carry a CF mutation. In the United States, 1 in 4,000 children are born with CF. In 1997, about 1 in 3,300 caucasian children in the United States was born with cystic fibrosis. In contrast, only 1 in 15,000 African American children suffered from cystic fibrosis, and in Asian Americans the rate was even lower at 1 in 32,000.
Cystic fibrosis is diagnosed in males and females equally. For unclear reasons, males tend to have a longer life expectancy than females[71] although recent studies suggest this gender gap may no longer exist in younger patients with access to excellent health care facilities.[73]
The distribution of CF alleles varies among populations. The frequency of ΔF508 carriers has been estimated to be 1:200 in northern Sweden, 1:143 in Lithuanians, and 1:38 in Denmark. No ΔF508 carriers were found among 171 Finns and 151 Saami people. ΔF508 does occur in Finland, but it is a minority allele there. Cystic fibrosis is known to occur in only 20 families (pedigrees) in Finland, and within these families ΔF508 occurs in 45% of chromosomes carrying a cystic fibrosis
Cystic fibrosis may be diagnosed by many different categories of testing including those such as, newborn screening, sweat testing, or genetic testing. As of 2006 in the United States, 10 percent of cases are diagnosed shortly after birth as part of newborn screening programs. The newborn screen initially measures for raised blood concentration of immunoreactive trypsinogen. Infants with an abnormal newborn screen need a sweat test in order to confirm the CF diagnosis. Trypsinogen levels can be increased in individuals who have a single mutated copy of the CFTR gene (carriers) or, in rare instances, even in individuals with two normal copies of the CFTR gene. Due to these false positives, CF screening in newborns is somewhat controversial.[34] Most states and countries do not screen for CF routinely at birth. Therefore, most individuals are diagnosed after symptoms prompt an evaluation for cystic fibrosis. The most commonly used form of testing is the sweat test. Sweat-testing involves application of a medication that stimulates sweating (pilocarpine) to one electrode of an apparatus and running electric current to a separate electrode on the skin. This process, called iontophoresis, causes sweating; the sweat is then collected on filter paper or in a capillary tube and analyzed for abnormal amounts of sodium and chloride. People with CF have increased amounts of sodium and chloride in their sweat. In opposite, people with CF have less thiocyanate and hypothiocyanite in their saliva (Minarowski et al) and mucus (Banfi et al). CF can also be diagnosed by identification of mutations in the CFTR gene.
In the worldwide populations studied to date, the most frequent mutations are:
| Mutation | % |
| DF508 | 66% |
| G542X | 2.4% |
| G551D | 1.6% |
| N1303K | 1.3% |
| W1282X | 1.2% |
from Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil. 2005 ref. 5-13.
SYMPTOMS
Symptoms depends on the CFTR role in different tissues.
- Pancreas
- Lung
- Macrophages
DIAGNOSIS
A multitude of tests are used to identify complications of CF and to monitor disease progression. X-rays and CAT scans are used to examine the lungs for signs of damage or infection. The examination of the sputum is required to isolate organisms which may be causing an infection or colonising the lower respiratory tract so that effective antimicrobial therapy can be provided. Culture for organisms such as Burkholderia (previously Pseudomonas) cepacia is required for candidates of Lung transplantation as persisant bacterial colonisation reduces the chances of survival.
Pulmonary function tests measure how well the lungs are functioning, and are used to measure the need for and response to antibiotic therapy. Blood tests can identify liver abnormalities, vitamin deficiencies, and the onset of diabetes. DEXA scans can screen for osteoporosis and testing for fecal elastase can help diagnose insufficient digestive enzymes.
People with CF may be listed in a disease registry that allows researchers and doctors to track health results and identify candidates for clinical trials.
histopathology
radiology
NMR
laboratory tests
PATHOGENESIS
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Hormonal
Genetic
Acquired
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
COMPLICATIONS
CORRELAZIONE CELIACHIA E FIBROSI CISTICA
La malattia celiaca è un’enteropatia autoimmune scatenata dall’ingestione di cereali che contengono glutine. La gliadina del glutine e proteine similari presenti in altri cereali sono i fattori ambientali responsabili dello sviluppo del danno a carico del piccolo intestino con atrofia dei villi e iperplasia delle cripte. Il complesso genico HLA è molto importante per la suscettibilità genetica in questa malattia; soprattutto per quanto riguarda l’eterodimero DQ i cui singoli geni si trovano in linkare disequilibrium con alcuni aplotipi DR, marcatori dell’effetto dei geni DQ.
La prima segnalazione in letteratura di associazione tra fibrosi cistica e celiachia risale al 1969 ad opera di Hidd e Barman. Da allora l’associazione è stata spesso segnalata ma solo in casi di reports.
Nel 1973 Taylor e Sokol descrivono due casi di morbo celiaco in 175 soggetti con fibrosi cistica; più recentemente Valletta e Mastella in uno studio trasversale fatto su ampia casistica riportano una prevalenza di malattia celiaca di 1:220.
Probabilmente però la patologia è sottostimata perché in tutti i casi riportati la malattia celiaca è stato sospettata in soggetti con fibrosi cistica in base a classici sintomi gastrointestinali mentre oggi si sa che esistono forme atipiche identificabili solo tramite sierologia. Non si sa però a oggi se l’associazione tra le due patologie sia un evento casuale o se la presenza di una possa predisporre allo sviluppo o al manifestarsi dell’altra.
L’esistenza di un linkage genetico sarebbe in grado di spiegare un’eventuale associazione non casuale fra le due patologie.
A sostegno di tale ipotesi ci sarebbe:
- La presenza di HLA tipici della malattia celiaca in soggetti con fibrosi cistica (DQ2 e DQ8).
- Il vantaggio degli eterozigoti per fibrosi cistica per le diarree secretorie.
In Europa fino a 20 anni fa le diarree acute erano la principale causa di decesso in età infantile. Il tasso maggiore si rilevava tra i bambini celiaci ma nonostante la bassa probabilità di sopravvivenza dei bambini la malattia celiaca non scomparve. E’ possibile che i soggetti celiaci eterozigoti per fibrosi cistica abbiano avuto maggiori probabilità di sopravvivenza rispetto ai celiaci che non avevano mutazione per il CFTR.
Infatti da studi fatti da Gabriel nel 1994 usando modelli murini correlati strettamente con il fenotipo della fibrosi cistica per il tratto intestinale è stato dimostrato infatti che i topi eterozigoti per il CFTR mutato hanno una secrezione in risposta alla tossina colerica del 50% inferiore rispetto ai topi normali; nessuna risposta è stata riscontrata in topi con CFTR mutato allo stato omozigote.
Nell’uomo eterozigote un più basso livello di CFTR funzionante a livello intestinale eviterebbe la disidratazione in risposta alla tossina colerica.
Grazie a questo effetto protettivo i geni della malattia celiaca si sarebbero mantenuti nella popolazione insieme a quelli della fibrosi cistica rendendo più probabile e non casuale l’associazione tra le due malattie.
Sono stati poi fatti nuovi studi che però ancora non sono riusciti pienamente a dimostrare le basi biologiche di legame tra queste patologie anche per la mancanza di significatività statistica dei dati vista l’esiguità dei soggetti esaminati, la mancanza della tipizzazione del DQ8 e l’impossibilità di verificare un link fra loci genetici (HLA e CFTR) che mappano su cromosomi differenti.
Useful Links
Fibrosi cistica: l’importanza della diagnosi precoce e la prevenzione delle complicanze Bambin Gesù
THERAPY
Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation. 2010
A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro.
