The pathology of cystic fibrosis - M. N. Sheppard and A. G. Nicholson
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Current Diagnostic Pathology (2002) 8, 50d59
^ 2002 Elsevier Science Ltd
doi:10.1054/cdip.2001.0088, available online at http://www.idealibrary.com on
REVIEW
The pathology of cystic fibrosis
M. N. Sheppard and A. G. Nicholson
Royal Brompton Hospital, Sydney St. London SW3 6NP, UK
KEYWORDS Summary Cystic fibrosis (CF) is one of the commonest lethal inherited conditions
cystic fibrosis, pathology, among Caucasians. It affects multiple organ systems and exhibits a range of clinical
gene therapy problems of varying severity. Life expectancy has improved in recent years as treatment
regimes have become more intensive, but current treatments are expensive, often time
consuming and may affect quality of life. New treatments for the pulmonary disease are
under clinical trial and include antiproteases, amiloride, a sodium channel blocker, DNase
and gene therapy. The gene for cystic fibrosis was identified in 1989 and this together with
the emerging technology of gene therapy heralded a new dawn for the treatment of
genetic disease. The lung is considered an ideal organ to target due to ease of access, but
subsequent research has shown that the airway surface provides an efficient barrier to
topically applied gene transfer agents. A number of Phase I clinical safety trials were
carried out through the 1990s and provided proof of concept evidence that delivery of
DNA by either viral or non-viral means was safe though not clinically efficacious. Current
research is now focusing more on the barriers faced by delivery agents, with the aim that
more efficient gene delivery will lead to a gene therapy for cystic fibrosis. The histopathol-
ogist is rarely called upon to make the initial diagnosis as cystic fibrosis is usually diagnosed
clinically, being characterized by chronic bronchopulmonary infection, malabsorption due
to pancreatic insufficiency and a high sweat-sodium concentration on sweat testing. Most
information concerning both macroscopic and microscopic findings in cystic fibrosis has
come from autopsy studies, so the pathological features are often extreme. However,
with increasing survival of patients with cystic fibrosis, we are seeing more subtle changes
in other organs and in addition, more aggressive drug therapy, gene therapy and lung
transplantation are bringing with them new disease entities and complications. ^ 2002
Elsevier Science Ltd
INTRODUCTION in the accumulation of sticky tenacious mucus in rela-
tion to epithelial surfaces in many organs, including the
Cystic fibrosis (CF), an autosomal recessive disorder, is lungs, sinuses, pancreas, gastrointestinal tract, and
the most common genetic disease of Caucasians. One in hepatobiliary system, sweat glands and reproductive
25 Caucasians are carriers of the gene, although this is tract.
rarer in other races. There are over 230 different alleles
of the gene, located on the long arm of chromosome 7.
The gene encodes for a membrane protein, the cystic GENETICS
fibrosis transmembrane conductance regulator (CFTR),
which functions as an ion channel. CF is caused by More than 900 mutations in the CFTR gene have been
mutations in this gene. The mutations affect CFTR reported but diagnosis is based on the occurrence of two
through a variety of molecular mechanisms, which leads mutations and on assays that measure the basic defect of
to little or no functional CFTR at the apical membrane in abnormal chloride transport in the affected organs. This
epithelial cells. The basic defect in ion transport results gene encodes a protein expressed in the apical
membrane of exocrine epithelial cells, which functions
principally as a cAMP-induced chloride channel but also
Correspondence to: MNS. E-mail: m.sheppard@rbh.nthames.nhs.uk appears capable of regulating other ion channels. The
THE PATHOLOGY OF CYSTIC FIBROSIS 51
commonest mutation is a deletion of phenylalanine at associated with CFTR mutations uncharacteristic
position 508 (deltaF508), which accounts for 70% of for CF. The composition, frequency and type of
cases.1 However, genetic tests can lead to confusion. CFTR mutations/variants parallel the spectrum of CFTR-
Genetic analysis has shown that a symptomatic patient associated phenotypes, from classic CF to mild
can be a heterozygote, indicating that one lesion in the monosymptomatic presentations, and this expansion of
CFTR gene may be sufficient to cause CF-like lung the spectrum of disease associated with the CFTR
disease.2 Asymptomatic normal patients with two mutant mutant genes perhaps creates a need for revision of
alleles, deltaF508 and R117H, have also been reported. diagnostic criteria and a dilemma for setting nosological
Although genotype analysis can be a useful adjunct, it boundaries between CF and other diseases with CFTR
should not be the sole diagnostic criterion for CF.3 aetiology.7
Assessment of molecular genotypes has shown
correlation with the severity of pancreatic insufficiency
but generally not with the severity of pulmonary disease,4 RESPIRATORY TRACT
the exception being the A455E CFTR mutant which is
associated with mild lung disease.5 The poor correlation Upper respiratory tract
between CFTR genotype and severity of lung disease
The upper airway is often involved in cystic fibrosis with
strongly suggests an influence of environmental and
nasal polyps found at all ages, their incidence in children
secondary genetic factors (the so-called CF modifiers)
ranging from 6.7% to 20%.8 Nasal polyps are very rare in
and several candidate genes related to innate and
normal children, so their presence strongly points
adaptive immune response, have been implicated. In
towards the diagnosis in this age group. Histologically,
addition, the presence of a genetic CF modifier for
they contain mucous cysts and hyperplastic mucous
meconium ileus has been demonstrated on human
glands. The polyps are often multiple and may cause nasal
chromosome 19q13.2.
obstruction with depression and widening of the nasal
It is now clear that the pathophysiology of CF airways
bridge. In adults up to 40% of patients develop polyps,
disease is far more complex than can be solely attributed
a considerably higher incidence than in children. The
to altered chloride transport. For example, in addition to
presence of nasal polyps bears no relation to the severity
functioning as a chloride channel, CFTR has also been
of pulmonary involvement in either children or adults.
implicated in the regulation of other apical membrane
conductance pathways through interactions with the
amiloride-sensitive epithelial sodium channel (ENaC) and Lower respiratory tract
the outwardly rectifying chloride channel (ORCC).
Superimposed on this functional diversity of CFTR is The majority of patients die of pulmonary disease. The
a highly regulated pattern of CFTR expression in the abnormal chloride transfer across epithelial membranes
lung. This heterogeneity occurs at both the level of CFTR causes an excessively viscid mucus lining of the airways,
protein expression within different cell types in the and bacterial infection, particularly with Staphylococcus
airway and the anatomical location of these cells in the aureus, Haemophilus influenzae and Pseudomonas
lung. aeruginosa, stimulates a vigorous and excessive primarily
Evolution of lung damage is highly variable in CF even neutrophil-driven inflammatory response, which
in patients with the same CFTR mutations, and it is eventually damages host tissue. The airways typically
likely that human leukocyte antigen (HLA) class II become chronically colonized with bacteria that cannot
polymorphism contributes to CF-associated pulmonary be eradicated, leading to bronchitis, bronchiectasis, and
inflammation. Among 98 adult CF patients tested, the finally, pulmonary fibrosis with respiratory failure. All
genotypic frequencies of DR4 and DR7 alleles (serologic these pathologies may be complicated by massive
group DR53) and DR7/DQA*0201 haplotype were haemoptysis and pneumothorax.9
higher than in 39 selected control subjects without
atopy, although these did not significantly relate to
Bacterial infection
specific CFTR genotypes. In the CF patients, the DR7
allele was significantly associated with an increase in The main infective agents are bacteria, with
total IgE and with chronic Pseudomonas aeruginosa Staphylococcus aureus, Haemophilus influenzae and
colonization.6 Pseudomonas aeruginosa being the chief pathogens.
The phenotypic spectrum associated with mutations S. aureus is associated with infection in the first few years
in the CFTR gene extends beyond the classically de- of life. It can be seen in almost 40% of infants within the
fined cases of CF. For example, there are large numbers first 3 months of life.10 Chronic S. aureus infection usually
of the so-called monosymptomatic diseases, such as precedes P. aeruginosa infection, and a deterioration in
various forms of obstructive azoospermia, idiopathic lung function with chronic S. aureus infection before
pancreatitis and disseminated bronchiectasis, that are colonization by P. aeruginosa indicates that it is the
52 CURRENT DIAGNOSTIC PATHOLOGY
S. aureus infection that often initiates lung injury.11 or no granuloma formation. Therefore, special stains for
However, it is chronic P. aeruginosa infection that is fungi should be done routinely in any study of cystic
associated with chronic lung injury and reduced fibrosis pathology in the lung.20
survival,12 with P. aeruginosa being rarely eradicated.
Burkholderia cepacia, formerly known as Pseudomonas
Viral infection
cepacia, has been isolated in older cystic fibrosis patients
and its isolation has been causally associated with a rapid The place of viral infection in initiating or promoting lung
decline in pulmonary function.13 The role of non- damage remains controversial. Viral infections can
tuberculous mycobacteria in causing infection and damage mucociliary clearance and encourage secondary
damage in the lungs of patients with cystic fibrosis has bacterial infection, but their role in cystic fibrosis is not
also recently been highlighted,14 as has chlamydial firmly established.
infection.15
Bronchi and bronchioles
Fungal infection
Several authors have shown that the lungs are normal at
Between 50% and 60% of patients have fungi, usually birth,21 although one study in fetal lungs during the
Aspergillus fumigatus, in their sputum and an equal second trimester of pregnancy showed accumulation of
proportion may develop fungal precipitating antibodies mucin in the tracheobronchial glands as compared with
in their serum.16 Patients with cystic fibrosis are controls.22 Even before infection becomes clinically de-
predisposed to pulmonary fungal colonization because of tected, there is submucosal gland hypertrophy, duct ob-
extensive lung damage and long-term antibiotic therapy, struction and mucous cell hyperplasia of the trachea and
usually within airways but occasionally as intra-cavity major bronchi with mucus hypersecretion. The bronchial
fungal balls.17 seromucous glands are increased in volume with an
Allergic bronchopulmonary aspergillosis (ABPA) was elevated gland-to-wall ratio and dilated ducts filled with
first associated with cystic fibrosis in 1965. Asthma, inspissated secretions.
mucoid impaction, bronchiectasis, bronchocentric granu- Once infection sets in, the airways are filled with thick
lomatosis and eosinophilic pneumonia have all been mucopurulent material containing bacterial colonies,
described as part of the spectrum of ABPA.18 neutrophils and thick mucus, and there is often papillary
Microscopically, there may be eosinophilic infiltration proliferation of the overlying epithelium (Fig. 1). Repeat-
of the bronchial wall, desquamation of epithelium, ed pulmonary infections cause acute bronchitis, and this
thickening of the basement membrane and plugging with is found at autopsy in patients with cystic fibrosis dying
mucus, containing large numbers of eosinophils and at more than 1 month of age.23 The bronchitis and
CharcotdLeyden crystals. As an allergic response to bronchiolitis are associated with a mixed cellular infil-
inhaled Aspergillus spores, fungal elements may be sparse trate of acute and chronic inflammatory cells including
in the mucus plugs. These plugs can have a characteristic neutrophils, histiocytes, lymphocytes and plasma cells
appearance. Bands of agglutinated eosinophils alternate with no difference in the lesions produced by different
with layers of mucus. In cases with co-existent bacteria. Prominent follicular hyperplasia is also
bronchiectasis, there are the characteristic plugs as well frequently seen.
as inflammation and destruction of the bronchial walls
with a prominent eosinophilic infiltrate. Bronchocentric
granulomatosis represents a more profound hyper-
sensitivity reaction with palisading epitheloid cells,
Langhans giant cells and many eosinophils surrounding
and infiltrating bronchi. When the inflammatory
pattern extends into the small airways and alveoli it gives
a similar pattern to eosinophilic pneumonia. The
increasing use of immuno-suppressive strategies and
aggressive antipseudomonal therapy in CF has led to an
increase in Aspergillus lung disease, including invasive
aspergillosis.19
Autopsy reports on 156 patients with cystic fibrosis
from 1964 to 1982 disclosed only one with disseminated
fungal infection, but a more recent study in the 1980s
showed an increased incidence (21%) of invasive Figure 1 Bronchial wall showing inspissated mucus in the
disease.20 It should be noted that the cellular reaction to lumen with papillary proliferation of the surface epithelium and
fungal infection in cystic fibrosis may be acute, with little dense underlying chronic inflammation in cystic fibrosis.
THE PATHOLOGY OF CYSTIC FIBROSIS 53
pneumonia, with clinical improvement with cortico-
steroid therapy has been reported.25
Cysts can occur within the lung, which may be
separate from the bronchial tree or communicate via
a small channel. Four types are described. The first
and most common is bronchiectatic with direct
communication with bronchi. The second is interstitial
with a cystic space located in the visceral pleura or
interlobular septae lined by fibrous tissue, which is
associated with pneumothoraces. The third is the
pneumocoele already described and the fourth and least
common is the emphysematous type.23
Pulmonary vasculature
Pulmonary hypertension leads to medial hypertrophy
Figure 2 Cystic fibrosis postmortem lung with bronchiectasis and intimal fibrosis of the pulmonary arterial branches.
in the upper lobe. Note dilated thickened bronchi, which extend Haemoptysis is common and is the result of rupture of
to the periphery of the lung and contain pus. dilated bronchial arteries or veins in the walls of airways
or bronchiectatic cavities, as well as direct injury to
vessels by infection, an increase in bronchopulmonary
arterial anastomoses and loss of elasticity of vessels due
Bronchiectasis increases in severity with age. to pulmonary hypertension.26 Massive haemoptysis is the
Bedrossian et al.23 showed that bronchial changes and terminal event in many patients (Fig. 3).
bronchiectasis could be seen from birth and became
more common with advancing age and universal by the
Complication of improved survival in the lungs
time the patients reached their twenties. This process
affects the proximal airways and the distribution is The survival of cystic fibrosis patients has been gradually
usually most marked in the upper lobes, right middle increasing, with a mean survival in 2001 of 35 years.
lobe, lingula and superior segments of the lower lobes Patient survival rates have increased because of antibiotic
(Fig. 2). Parenchymal changes with pneumonia were also therapy and improved nutrition with pancreatic enzyme
seen from birth and were present in up to 82% of cases replacements. The severity of the lung disease increases
by age 24. Formation of endobronchial abscesses with age with eventual respiratory failure. Haemoptysis
produces saccular spaces within the lung parenchyma. with fatal outcome, emphysema and pneumothorax
Collapse can result from mucus plugging and by enlarged become more common.27 Pulmonary hypertension and
lymph nodes impinging on the bronchi and is very cor pulmonale develops. Pulmonary amyloidosis can also
common in infants.24 Emphysema is much less common, present with a diffuse interstitial pattern in long-term
being present only from 2 years upwards and reaching survivors.28
41% in the 10d24-year age group.
As with the bronchi, bronchiolitis is almost universal in
infants with florid mucosal and luminal inflammation and
ulceration. Follicular bronchiolitis with hyperplasia of the
mucosa-associated lymphoid tissue is also common.
Lung parenchyma
Pneumonia is seen at all stages in the evolution of the
disease23 with alveoli filled with neutrophils and/or foci
of organization. Although these changes can revert to
normal, parenchymal destruction often occurs with
repeated infection, and S. aureus infection is particularly
associated with pneumatocoeles resulting from
pulmonary parenchymal necrosis. There is often a
chronic inflammatory interstitial infiltrate with lympho-
cytes, plasma cells and fibrosis of the interstitium. Figure 3 Cystic fibrosis postmortem lung with the bronchiec-
Histologically proven bronchiolitis obliterans organizing tatic cavities filled with fresh blood.
54 CURRENT DIAGNOSTIC PATHOLOGY
Complications of lung transplantation GASTROINTESTINAL TRACT
Heart}lung transplantation is now well established in the On occasion the pathologist may make a diagnosis of
management of end-stage respiratory disease in both cystic fibrosis in fetal autopsy material, the most obvious
children and adults with cystic fibrosis.29 Children with changes being found in the gastrointestinal tract where
cystic fibrosis have an increased incidence of lung thick meconium plugs can be present from as early as 17
rejection compared with cystic fibrosis adults. There is weeks gestation.34 Their presence is highly suggestive of
also a higher incidence of tracheal stenosis in children, cystic fibrosis in the fetus and can occur in the absence of
which could be explained by a less well-developed changes in the lung, pancreas or liver. It is a combination
collateral circulation. Bilateral (sequential) cadaver of reduction in water content, increase in mucoprotein,
donor transplantation is the usual procedure of choice. absence of proteolytic enzymes and increase in albumin
The 4-year survival rate for adult, all-disease, double- that accounts for the increased viscosity. The plugging
bilateral lung transplantation has improved to 53%. Issues can progress to meconium ileus in which there is
of diabetes mellitus, mechanical ventilation, osteo- mechanical obstruction of the distal ileum, which affects
porosis, malnutrition, fungi and drug-resistant bacteria, 17% of patients with cystic fibrosis at birth.35 This shows
pleural fibrosis and sinusitis in relation to transplantation dense meconium adherent to the intestinal mucosa, with
can adversely affect outcome.30 However, due to lack of dilatation and obstruction of the lumen. Microscopically,
organ donation, over 50% of patients die on the waiting there is extensive goblet cell hyperplasia and strongly
list for transplantation. The lungs after transplantation alcianophilic mucinous material. Obstruction may lead to
are also prone to infection with common bacterial ischaemic necrosis of the ileal wall with perforation and the
pathogens and pulmonary infection often co-existing with development of meconium peritonitis.36 Other associated
rejection. P. aeruginosa is the most common isolate.31 intestinal abnormalities include volvulus and ileal atresias.
Postnatally, pathology can be found throughout the GI
PLEURA tract. In adults, lesions in the salivary and labial glands can
be found, with eosinophilic plugs in ducts causing
With increased survival, pneumothorax has emerged as enlargement.37 Upper gastrointestinal problems include
an increasingly common complication. This is related to reflux and oesophagitis with peptic ulceration. There is
the spontaneous rupture of apical bullae (subpleural cysts also an increased incidence of Barrett’s oesophagus.
'1 cm in diameter), pneumatocoeles or subpleural Oesophageal varices associated with portal hypertension
abscesses. There is little pathological difference between occur with cirrhosis. Patients with cystic fibrosis are at
the pleural changes in pneumothorax of non-cystic increased risk of developing gastrointestinal adeno-
fibrosis and cystic fibrosis cases. CF is associated with carcinoma.38
varying degrees of pleural inflammatory reaction, and the In the small bowel, the characteristic findings of
extent of pleural reaction may be associated with surgical meconium ileus can be one of the earliest features of
difficulties at the time of lung transplantation. cystic fibrosis.39 Some infants present with the ‘meconium
plug syndrome’ in which a hard plug of meconium is
HEART present in the colon with abdominal distension. The
infant then passes the plug and resumes normal bowel
Most changes are secondary to respiratory failure and function. Intussusception can also develop in up to 1% of
pulmonary hypertension. As patients survive longer, cor patients with cystic fibrosis.40 Older patients with cystic
pulmonale frequently occurs late in the course of the fibrosis may develop ‘meconium ileus equivalent’ or
disease and carries a poor prognosis.32 Myocardial ‘distal intestinal obstruction syndrome’, especially if oral
necrosis and fibrosis can cause sudden and unexpected intake of fluids is inadequate or patients fail to take
death in infancy due to cardiac arrest. Eighteen reported pancreatic enzyme preparations. Appendiceal abscess
CF patients with this complication had varied clinical should also be considered as a rare complication of CF.41
features including mild pulmonary involvement, early Colonic strictures, after the use of high-dose
onset severe pancreatic insufficiency and profound pancreatic enzymes, are being increasingly reported,
electrocardiogram (ECG) changes. In this group of especially in children. The main histological feature of
patients, five were deltaF508 homozygotes, one was delta- ‘fibrosing colonopathy’ is dense fibrosis of the submucosa
F508/N1303K and one was a deltaF508/M compound involving long segments. The pathogenesis is uncertain,
heterozygote. The co-existence of a genetic predisposition but a direct toxic effect of the enzymes, a low fibre cystic
to myocardial lesions, resulting most probably from fibrosis diet, malabsorbed fat, poor blood supply,
severe cystic fibrosis transmembrane (CFTR) geno- abnormal motility and use of laxatives and gastrografin
types (such as deltaF508/deltaF508, deltaF508/N1303K) have all been implicated. The affected colon has
and deficiency of certain trophic factors necessary for a cobblestone appearance and, on microscopy, there is
metabolism of the myocardium, has been postulated.33 thickening of the muscularis propria, submucosal fibrosis,
THE PATHOLOGY OF CYSTIC FIBROSIS 55 widespread interruption of the muscularis mucosae and chronic mucosal inflammation, with active cryptitis. Moderate to severe infiltration by eosinophils, with increase in the number of mast cells, may be seen.42 Rectal prolapse of mucosa can occur in up to 22% of patients with cystic fibrosis43 and may be the first manifestation of the disease. It often recurs in the first 5 years of life but resolves following treatment for pancreatic insufficiency. PANCREAS Pathological changes in the pancreas were amongst the first to be recognized, the disease initially being called Figure 4 Cystic fibrosis pancreas showing dilated ducts filled ‘cystic fibrosis of the pancreas’, and from as early as with gelatinous material. There is fibrosis and fatty change in the 20 weeks gestation an accumulation of eosinophilic parenchyma. secretions with dilatation of ductules may be seen.44 In the postnatal exocrine pancreas, there is tissue damage due to acinar release of lytic enzymes with loss of acini, fibrosis and fatty replacement. Four histological grades LIVER AND BILE DUCTS of severity are described.45 Grade I is accumulation of secretion, grade II exocrine atrophy, grade III atrophy Obstructive biliary disease occurs in 15d20% of affected with lipomatosis and grade IV fibrosis with total patients. Inspissated secretions can be seen in bile ducts obliteration of the exocrine glands and ducts with prior to birth, along with bile duct proliferation, focal scattered islets of Langerhans. Pancreatic insufficiency chronic inflammation and fibrosis.34 Due to the presence may result and this often causes the prominent clinical of these inspissated secretions, prolonged jaundice with symptoms of cystic fibrosis in infancy and early cholestasis may be seen in neonates.50 This accumulation childhood. About 85% of patients have such severe loss of mucus leads to the formation of intrahepatic and of pancreatic tissue that inadequate secretion of digestive extrahepatic biliary stones which can lead to clinical enzymes leads to malabsorption, which adversely affects obstruction. Gallbladder calculi occur in about 12% of CF survival. Pancreatitis can also occur, with the thick patients due to the production of thick lithogenic bile51 secretions blocking ducts and subsequent autodigestion and gallbladder complications are becoming more by pancreatic enzymes,46 and a recent study has shown frequent with increasing survival. that some cases of idiopathic chronic pancreatitis are Within the liver, bile stasis with proliferation of bile associated with mutations in the CFTR gene. The ducts and periportal inflammation with fibrosis occurs.52 abnormal CFTR genotypes in these patients with These lesions have been called ‘focal biliary fibrosis’ and pancreatitis resemble those associated with male are typical of cystic fibrosis hepatic involvement, seen infertility.47 Patients with pancreatic sufficiency have in up to 25% of patients,53 although they may be a better prognosis and do not usually develop the asymptomatic and have little clinical significance. Bile duct hepatobiliary disease and distal intestinal obstruction. stenosis with development of sclerosing cholangitis is The pancreas at autopsy is typically fibrosed and fatty, also common and there is eventual progression to with residual dilated ducts filled with secretions (Fig. 4). cirrhosis with the formation of multiple regenerating In the endocrine pancreas, progressive pancreatic nodules within the liver (Fig. 5). This occurs in a minority fibrosis ultimately disrupts pancreatic islet function with of patients (2d5%) and seems to increase with age.54 a decrease in cells and an increase in non- cells. This extensive liver pathology is responsible for the Adenocarcinoma of the pancreas has been reported in development of portal hypertension with oesophageal cystic fibrosis.48 Data on 141 cases of CF-related diabetes varices and hypersplenism, seen with similar frequency to (CFRD) patients show DeltaF508 as the most frequent cirrhosis from other causes.55 Fatty infiltration of the mutation and N1303K as the second most frequent liver is common in patients with cystic fibrosis.56 Liver as mutation, but without significant difference as compared well as heartdlung transplantation has been successful in with CF patients without diabetes. W1282X is the third cystic fibrosis.57 Five sets of cystic fibrosis siblings bearing most frequent mutation in CFRD patients, more a strongly discordant liver phenotype, suggests that frequent than in CF patients without diabetes. There is modifier genes, inherited independently of the cystic a significant correlation between the W1282X mutation fibrosis transmembrane regulator gene, could modulate and CFRD.49 the liver expression in cystic fibrosis patients.58
56 CURRENT DIAGNOSTIC PATHOLOGY
Figure 5 Cystic fibrosis liver with macronodular cirrhosis.
GENITOURINARY TRACT Figure 6 Cystic fibrosis testis with no identifiable epididymis.
Loose fatty tissue is identified. No vas deferens is present.
Kidneys
the genital tract in nearly all males with CF. The vasa
In the past, glomerular changes were considered to be
deferentia are atretic or completely absent,66 with the
secondary to diabetes mellitus and hypertension.
body and tail of the epididymes and seminal vesicles
However, there is an increase in urinary oxalate
abnormally dilated or absent (Fig. 6).67 These
excretion, which is linked to malabsorption, the patients
abnormalities cannot be explained simply by obstruction
developing urolithiasis.59 Renal amyloidosis and immune
or infection alone, and a primarily genital phenotype has
complex glomerulonephritis as well as IgA nephropathy
been described in otherwise healthy males who have
have also been reported in CF,60 as has microscopic
congenital absence of the vas deferens and are
nephrocalcinosis. A primary defect of calcium meta-
heterozygous for deltaF508 CFTR mutation.68 It has been
bolism in the kidney has been postulated.61
suggested that the CFTR gene plays a role beyond the
normal development of the vas deferens, perhaps being
Female genital tract related to spermatogenesis as well. Forty-two different
CFTR mutations have been identified. The prevalence of
Anatomically the female genital tract is normal, but the cryptorchidism and inguinal hernia is increased in
cervical mucus has reduced water content and may not patients with absence of the vas deferens, as well as nasal
undergo the normal viscosity change in midcycle that pathology and frequent respiratory infections.69
favours sperm penetration,62 one factor contributing to
infertility. Chronic pulmonary sepsis may delay menarche
and cause menstrual irregularities, but pregnancy can MUSCLE, BONE AND JOINT
occur with normal delivery of an infant, a more frequent
finding with improved pulmonary function into
CHANGES
adulthood. Cervicitis, cervical erosions and mucus gland Many patients suffer malnutrition because of their
hyperplasia are common pathological findings in the gastrointestinal pathology with poor weight gain, short
cervix and vaginitis occurs.63 Multiple follicular cysts can stature and muscle wasting. Clubbing and hypertrophic
be found in the ovaries.64 Postpubertal breasts have pulmonary osteoarthropathy with proliferation of
normal development with varying degrees of fibrosis vascular connective tissue beneath the periosteum
affecting lobular units and ducts, but proliferative lesions occurs.70 Osteoporosis, low bone mass and fractures are
and carcinoma can occur.65 increasingly recognized in children and adults with cystic
fibrosis and, compared with a normal control population,
Male genital tract CF patients have significantly reduced bone density at the
lumbar spine, hip and femoral neck. Despite oral
Like females, males enter puberty and develop all the supplements, vitamin D deficiency is also common and is
secondary sexual characteristics and sexual function is associated with more severe demineralization at the
normal. However, there is an anatomical abnormality of lumbar spine and hip.71THE PATHOLOGY OF CYSTIC FIBROSIS 57
SKIN PRACTICE POINTS
E Cystic fibrosis is the most common genetic disease
Eccrine glands in Caucasians
E It affects lungs, gastrointestinal tract, pancreas,
The eccrine sweat glands, while providing the invaluable
diagnostic clue of excess sodium and chloride concen- liver, genitourinary system with variable severity
E Mutation in the cystic fibrosis gene is also seen in
trations, are usually normal by light microscopy.
patients with isolated pancreatitis and absence of
the vas deferens
E Patients are at increased risk of gastrointestinal and
Apocrine glands
pancreatic adenocarcinomas
Dilatation with retained secretions are found in up to E Patient survival is increasing
33% of postmortem cases. The changes are more severe E With survival to adulthood females can be fertile
in children over the age of 7 years.72 but males are infertile due to absence of vas
deferens
E New therapeutic options include gene therapy
Other skin lesions
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