|
Draft Genetic Test Review Cystic
Fibrosis CLINICAL
UTILITY
Question 26: What is the natural history of the disorder?
|
Summary
|
Respiratory
morbidity is the most frequent cause of death among individuals with
cystic fibrosis. The highly
viscous mucus secretions in the respiratory tract cannot be adequately
cleared. This provides an
ideal habitat for bacterial colonization and subsequent lung infection.
This, in turn, results in chronic bronchial and lung
inflammation. Bacterial
infections associated with a marked inflammatory response occur
frequently in untreated infants under three months of age (Armstrong et
al., 1995; Khan et al.,
1995). Some
primary lung changes may precede postnatal lung infection (Ornoy et
al., 1987). Occasionally,
inflammatory responses have been seen even in the absence of positive
bacterial cultures, suggesting that some intrinsic factor, such as the
biochemical defect itself, may act as a trigger (Khan et
al., 1995). The
severe inflammatory response is responsible for progressive tissue
damage which eventually results in destruction of the bronchial passages
and, together with plugging of the airways, leads to respiratory
failure. Airway
obstruction, caused by abnormal secretion, inflammatory exudate and
epithelial debris, results in further hyperinflation or collapse.
Chronic hypoxia is a major factor causing pulmonary hypertension
and cor pulmonale. Pneumothorax
and hemoptysis are common complications in those with advanced disease.
Cystic fibrosis
related liver disease is the second most common cause of mortality after
lung disease. The incidence
increases with age from about 0.3 percent before the age of 5 years to a
peak of 8.7 percent in those aged 16-20 years (Scott-Jupp et
al., 1991). The exact
pathogenesis of the disease is unknown; however, recent evidence
suggests that defective CFTR chloride channel function may cause
abnormal biliary secretions resulting in mucus plugging of intrahepatic
bile ducts (Grubman et al., 1995). This, in
combination with other factors such as increased levels of toxic bile
acids and inflammatory cytokines, has been implicated in the development
of portal hypertension and associated cirrhosis (Maurage et al., 1989; Tanner, 1992).
Severe
gastrointestinal disease in the form of intestinal obstruction caused by
meconium ileus is the first clinical manifestation in 10-18 percent of
newborns with cystic fibrosis (Rescorla et
al., 1989; Littlewood 1992). Meconium
ileus is frequently associated with peritonitis, volvulus and atresia.
Because of the severity of these complications, mortality in the
first month of life is higher when meconium ileus is present.
Thereafter, the clinical course is similar whether or not
meconium ileus was present (Coutts et
al., 1997), although those with meconium ileus may have a higher
risk of developing liver complications (Padoan et
al., 1997).
Many of the
subsequent clinical manifestations related to the gastrointestinal tract
are due to malabsorption, the main cause of which is insufficient
pancreatic enzyme and bicarbonate activity.
In the absence of pancreatic enzyme secretion, protein and fat
malabsorption occurs, leading to bulky, frequent malodorous stools with
an abnormally high fat (steatorrhea) and nutrient content (Murphy et
al., 1991). Approximately
60 percent of neonates diagnosed with cystic fibrosis through neonatal
screening already suffer from pancreatic insufficiency and require
dietary pancreatic enzyme supplements (Waters et
al., 1990). By 12
months, the frequency of pancreatic insufficiency has risen to 92
percent (Bronstein et al.,
1992). Most of those who develop pancreatic insufficiency will do so
before the age of 10 years (Cooper et
al., 1992). The
prevalence of pancreatic insufficiency in adults with cystic fibrosis
exceeds 85 percent (Gaskin et al., 1982) and is probably closer to 95 percent.
Further complications of pancreatic dysfunction include impaired
glucose tolerance, leading to diabetes mellitus.
As adults, cystic fibrosis patients are approximately six times
more likely than unaffected individuals to develop digestive tract
cancers (Neglia et al., 1995;
Schöni et al., 1996).
As with digestive tract cancer, the prevalence of diabetes is
increasing in cystic fibrosis patients because of improved survival.
In a recent study performed over a 5-year period, the average
annual incidence was 3.8 percent, and prevalence increased from 11
percent to 24 percent, overall. In
those aged over 20 years, the annual incidence was 9.3 percent, and the
prevalence rose from 25 percent to 53 percent (Lanng et
al., 1994). Reports of
microvascular complications such as retinopathy, nephropathy and
neuropathy among cystic fibrosis patients with diabetes are also
increasing.
Esophageal problems
include frequent gastroesophageal reflux, peptic esophagitis or
esophageal varices. Approximately
25 percent of cystic fibrosis patients aged 5 years or more have
gastroesophageal reflux (Malfoot et
al., 1991). In the
small intestine, viscous mucin leads to obstruction of the goblet cells,
Brunner cells and even the lumen. Clinical
problems include rectal prolapse, distal intestinal obstruction
syndrome, intussusception and volvulus.
More recently, fibrosing colonopathy leading to colonic
strictures has been observed as a rare complication of high lipase
pancreatic enzyme treatment.
Lung
transplantation was introduced as a therapeutic modality for cystic
fibrosis in 1988; three of those procedures were performed for that
reason in 1988, and the number rose steadily on an annual basis until
1995, when 136 transplantations were carried out.
The number leveled off, thereafter (Cystic Fibrosis Foundation,
2000). In the year 2000, 161 lung transplants of various types were
carried out (bilateral 134, heart-lung 1, lobar-cadaveric 10,
lobar-living related donor 11, lobar-unrelated donor 5).
In addition, 18 liver transplants and 6 "other"
transplants were performed. Patients
with cystic fibrosis now account for an important portion of lung
transplants done annually in the United States. Kurland and Orenstein
[2001] wrote a commentary explaining the difficulties encountered by
families in this situation. This
article highlighted the psychological, social, medical and financial
costs faced by patients, families, and caregivers, over and above the
traditional stresses associated with managing this chronic, progressive
disorder. Even in the
absence of transplantation, patients with cystic fibrosis often face
increasing psychosocial, as well as medical, difficulties as they reach
adulthood. One young woman
with cystic fibrosis recently described her day-to-day struggles (Hillyard,
2001). One important hope
for the future is gene therapy, and research currently focuses on how
this treatment might be effectively delivered to the lungs of affected
individuals (McCray, 2001). Although
promising, this treatment modality has not yet proven successful.
Armstrong DS, Grimwood K, Carzino R, Carlin J, Olinsky A,
Phelan PD. 1995.
Lower respiratory tract infection and inflammation in infants
with newly diagnosed cystic fibrosis.
BMJ
310:1570-1572.
Bronstein MN, Sokol RJ, Abman SH, Chatfield BA, Hammond
KB, Hornbridge KM, et al.
1992. Pancreatic
insufficiency, growth and nutrition in infants identified by newborn
screening as having cystic fibrosis.
J Pediatr
120:533-540.
Coutts JAP, Docherty JG, Carachi R, Evans TJ.
1997. Clinical
course of patients with cystic fibrosis presenting with meconium ileus.
Br J Surg 84:555.
Gaskin KJ, Gurwitz D, Durie P, Corey M, Levison H,
Forstner G. 1982.
Improved respiratory prognosis in patients with cystic fibrosis
and normal fat absorption. J Pediatr
100:857-862.
Grubman SA, Fang SL, Mulberg AE, Perrone RD, Rogers LC,
Lee DW, et al.
1995. Correction of
the cystic fibrosis defect by gene complementation in human intrahepatic
biliary epithelial cell lines. Gastroenterology
108:584-592.
Khan TZ, Wagener JS, Bost T, Martinez J, Accurso FJ,
Riches DWH. 1995.
Early pulmonary inflammation in infants with cystic fibrosis.
Am J Respir Crit Care Med 151:1075-1082.
Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiøtz,
Koch C. 1994.
Diabetes mellitus in Danish cystic fibrosis patients: prevalence
and late diabetic complications. Acta Paediatr
83:72-77.
Littlewood JM. 1992.
Gastrointestinal complications in cystic fibrosis.
J R Soc Med
85 (suppl
18):13-19.
Malfoot A, Dab I. 1991.
New insights on gastro-oesophageal reflux in cystic fibrosis by
longitudinal follow-up. Arch
Dis Child 66:1339-1345.
Maurage C, Lenaerts C, Weber AM, Brochu P, Yousef I, Roy
CC. 1989. Meconium ileus and its equivalent as a risk factor for the
development of cirrhosis: an autopsy study in cystic fibrosis.
J Pediatr Gastroenterol
Nutr 9:17-20.
Murphy JL, Wooton SA, Bond SA, Jackson AA.
1991. Energy content
of stools in healthy normal controls and patients with cystic fibrosis.
Arch Dis Child 66:495-500.
Neglia JP, FitzSimmons SC, Maisonneuve P, Schöni MH, Schöni-Affloter
F, Corey M, et al.
1995. The risk of
cancer among patients with cystic-fibrosis.
N Engl J Med
332:494-499.
Ornoy A, Arnon J, Katznelson D, Granat M, Caspi B, Chemke
A. 1987.
Pathological confirmation of cystic fibrosis in the fetus
following prenatal diagnosis. Am
J Med Genet 28:935-947.
Padoan R, Marzano MT, Colombo C, Genoni S, Corbetta C,
Seia M, et al.
1997. Genotype
prognosis and clinical follow-up of cystic fibrosis patients with
meconium ileus or neonatal intestinal obstruction [abstract].
Proceedings 21st European Cystic Fibrosis Conference (EWGCF),
157.
Rescorla FJ, Grosfield JL, West KJ, Vane DW.
1989. Changing
pattern of treatment and survival of neonates with meconium ileus.
Arch Surg 51:34-48.
Schöni MH, Mainsonneuve P, Schöni-Affloter F, Lowenfels
AB. 1996. Cancer risk in patients with cystic fibrosis: The European
data. J R Soc Med 89
(suppl 27):38-43.
Scott-Jupp R, Lama M, Tanner MS.
1991. Prevalence of
liver disease in cystic fibrosis. Arch
Dis Child 66:698-701.
Waters DL, Dorney SFA, Gaskin KJ, Grauca MA, O’Halloran
M, Wilken B. 1990.
Pancreatic function in infants identified as cystic fibrosis in a
neonatal screening program. N Engl J Med
322:303-308.
SummaryWhen both partners have an identifiable mutation, genetic counseling is provided to advise the couple of the risk that the fetus is affected (1 in 4) and possible options When one partner has an identifiable mutation but the other does not there are two possibilities depending on the screening model employed
When the first, or both, partners have a negative test, the couple receives a negative test result and no further testing is recommended. |
Screening models
The initial impact of prenatal screening for cystic
fibrosis on patient care depends upon which of three published models is
being used.
The two-step (sequential) model,
the pregnant woman's sample is collected and analyzed.
If a mutation is identified, the woman is made aware of this
finding, counseled, and her cooperation sought in obtaining a sample
from her partner for DNA analysis.
Approximately 1 in 30 screened non-Hispanic Caucasian women will
require counseling in this model. When
the partner is also identified as having a mutation, the couple will
then be provided with more intensive counseling, given the 1 in 4 risk
that the fetus will be affected by cystic fibrosis.
Approximately 1 in 900 screened pregnancies will fall into this
category. The uptake of diagnostic testing and decision-making about
termination of affected fetuses found in pilot trials is summarized in
Question 33, Table 4-3.
The one-step model, samples are collected from both the pregnant
woman and her partner at the outset.
DNA analysis is then performed on the woman's sample, but the
partner's sample is tested only if a mutation is identified in the
woman. Notification of a
positive screening result is made only when both partners are found to
carry a mutation (unless the woman specifically requests a report of her
carrier status). In this
model, more effort is required initially to obtain samples from both
partners, but the need for counseling is reduced; being restricted to
the 1 in 900 couples who will need to make decisions about diagnostic
testing.
The modified one-step model,
has been recommended by the American College of Medical Genetics (Grody et al., 2001). It calls
for samples to be collected at the outset from both partners (as in the
one-step model, above). DNA
testing is then performed on all of the samples from both partners. Notification is made when a mutation is found in either
partner, and counseling is provided.
If all couples with positive screening results for
cystic fibrosis were to choose diagnostic testing, this would lead to
one additional amniocentesis (or CVS) for every 900 couples screened.
The impact on prenatal diagnostic testing services is relatively
small, in comparison to demands incurred by other prenatal screening
tests. For example, if a
woman's age of 35 is used as a screening test for Down syndrome, 100
amniocenteses would be performed for every 1,000 women screened.
Even with more efficient serum screening tests for Down syndrome,
between 30 and 50 amniocenteses would be indicated for every 1,000
screened women.
Other
data indicate that during the two-step process, the women identified as
being carriers of a CF mutation usually experience some anxiety while
awaiting the partner’s results. However,
this worry usually resolves when the partner is found not to carry and
identifiable mutation (Miedzybrodzka et
al., 1995; Mennie et al.,
1992; Grody et al., 1997). In both
the two-step and modified one-step process, couples will be identified
where one partner is a carrier and the other is not.
These couples are at a higher risk than background (Question 23),
but no definitive testing is available to provide diagnostic testing for
their fetus.
References
Grody WW, Cutting GR, Klinger KW, Richards CS, Watson MS, Desnick RJ. 2001. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med 3:149-154.
Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I, Whyte DA, Brock DJH. 1992. Prenatal screening for cystic fibrosis. Lancet 340:214-216.
CLINICAL
UTILITY
Question 28: If applicable, are
diagnostic tests available?
The purpose of prenatal screening for cystic fibrosis
is to determine whether or not that disorder is present in the fetus.
The diagnostic test is DNA testing for cystic fibrosis mutations
in fetally derived cells obtained via amniocentesis, or chorion villus
sampling (CVS). If two disease-causing mutations are identified, the couple
is counseled that the fetus will have the disorder.
CLINICAL
UTILITY
Question
29: Is there an effective
remedy, acceptable action, or other measurable benefit?
There is no effective treatment in utero for cystic fibrosis identified in the fetus. However, the pregnant woman and her partner can choose to terminate the pregnancy and thus avoid the birth of an affected child. For couples who choose to terminate an affected pregnancy, there is an assumption of benefit, although little research exists on the psychological sequelae of this decision. The couple might also choose to continue the pregnancy and plan for initiating treatment immediately after birth. There is little information about the psychological sequelae of this decision, either. The couple might want to consider alternatives for future reproductive planning, including adoption and preimplantation genetic testing. Some couples identified as carriers might be unwilling to undergo further testing in their current pregnancy but might, nevertheless, alter their reproductive behavior in future pregnancies. There are some studies that suggest that carriers misunderstand the implications of carrier status for their own health and for the health of their children.
Marteau T,
Dundas R, Axworthy D. 1997.
Long-term cognitive and emotional impact of genetic testing for
carriers of cystic fibrosis: the effects of test result and gender.
Health Psych 16:51-62.
Pregnancy termination before the third trimester
is legal through federal statute, but access is limited by two factors.
First, there are areas of the country where health care
practitioners providing this service are scarce.
Secondly, there are many states in which pregnancy termination is
not a reimbursable service; this affects access by women with limited
economic resources. For
couples choosing to continue the pregnancy, resources for treating the
infant and child exist throughout the United States.
Pregnant
women are considered a medically vulnerable population, and a case can
be made for their being psychosocially vulnerable, as well.
There is often a time-related urgency involved in medical
decisions during pregnancy, which can foreshorten time to carefully
consider options. In
addition, data have shown that women’s motivation to do whatever they
can to protect the health of their fetus can lead to overestimates or
misunderstandings of the benefits of prenatal testing.
Offering screening for cystic fibrosis early in pregnancy (at the
first prenatal visit between 8 and 12 weeks’ gestation) allows for
more time to consider further testing if both members of the couple are
found to be carriers. Carefully
constructed and validated patient informational materials will also be
important (Question 38). It
may be helpful to develop strategies for educating the public about this
testing to alleviate the burden of ‘learning’ at the time of
pregnancy.
Updated on August 13, 2004