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Basic Sciences: Answers
99
Figure 1. Pressure-volume loops.
Pressure-volume loops can be used to analyze various physiologic situations.
Increased
afterload (Figure 1B) moves the end-systolic pressure-volume point
slightly upward and to
the right. If stroke volume is maintained, end-diastolic
volume must increase. Thus, although
contractility is unchanged,
ejection fraction is slightly decreased. Figure 1C shows
the effect
of a decrease in ventricular compliance (increased
end-diastolic pressure-volume relationship
[EDPVR]) such as may result from hypertrophy, fibrosis, or cardiac
tamponade. Systolic
Shahzad G. Raja
100
function is maintained (E
ES
and V
0
are unchanged),
and stroke volume and ejection fraction
can be maintained but
require an increased end-diastolic pressure. The positive inotropic
(increased
E
ES
) and lusitropic (decreased EDPVR) effects of adrenergic
stimulation (Figure
1D), at constant stroke volume, shift the pressure-volume
loop to the left and increase the
ejection fraction. In the
hypertrophied heart (Figure 1E), in contrast to Figure 1C,
diastolic
compliance is decreased, and systolic contractility
is increased. A constant stroke volume
leads to an increase
in end-diastolic filling pressure and decreased end-diastolic
volume. The
pressure-volume loop shifts to the left with an
increase in ejection fraction. The ability of the
hypertrophied
heart to increase stroke volume is limited. Acute ischemia (Figure 1F)
decreases
diastolic compliance (increased EDPVR) and contractility. The
pressure-volume
loop shifts to the right and up to maintain
stroke volume, consistent with the clinical
observation of an
acute decrease in ejection fraction and increase in left ventricular
filling
pressure. In the dilated heart of chronic congestive
heart failure (Figure 1G), the pressure-
volume loop is shifted
to the right. Note that the slope of the end-diastolic pressure-volume
curve (EDPVR) changes little; rather, the curve shifts to the
right. The end-diastolic pressure
is not increased owing to a
change in compliance; instead, to maintain stroke volume, the
pressure-volume loop has moved upward on the compliance curve.
Contrast this with the
fibrotic process. The
effect of afterload reduction on the chronically failing heart
from Figure
1G is demonstrated in Figure 1H. Note that the end-systolic pressure-volume relationship
(ESPVR),
EDPVR, and stroke volume are unchanged. The pressure-volume loop
has moved
back to the left, decreasing the degree of chamber dilatation,
the end-diastolic pressure, and
the ejection fraction. A positive
inotropic agent would shift the ESPVR line to the left (toward
the dashed line), the degree of dilatation would be reduced, and
both stroke volume and
ejection fraction would be increased.
It is important to remember that these relationships are
idealized
and may not reflect true clinical responses.
References
Savage EB, et al. Cardiac surgical physiology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:51-76.
Villars PS, Hamlin SK, Shaw AD, Kanusky JT. Role of diastole in left ventricular function, I:
Biochemical and biomechanical events. Am J Crit Care. 2004;13:394-403.
1.23 Answer: D
Resting coronary blood flow is slightly less than 1 mL/g of
heart muscle per minute. This
blood flow is delivered to the
heart through large epicardial conductance vessels and then
into
the myocardium by penetrating arteries leading to a plexus
of capillaries. The bulk of the
resistance to coronary flow
is in the penetrating arterioles (20 to 120 µm in size).
Because the
heart is metabolically very active, there is a high
density of capillaries such that there is
approximately one
capillary for every myocyte, with an intercapillary distance
at rest of
approximately 17 µm. Capillary density is greater
in subendocardial myocardium than in
subepicardial tissue. When
there is an increased myocardial oxygen demand (e.g., with
exercise), myocardial
blood flow can increase to three or four times normal (coronary flow
reserve). This increased blood flow is accomplished by vasodilation of
the resistance vessels
and by recruitment of additional capillaries (many
of which are closed in the resting state).
This capillary recruitment is
important in decreasing the intercapillary distance and thereby
decreasing
the distance that oxygen and nutrients must diffuse through the
myocardium. The
Basic Sciences: Answers
101
blood flow pattern from a coronary artery perfusing the
left ventricle, measured by flow
probe, is phasic in nature,
with greater blood flow occurring in diastole than in systole.
The
cyclic contraction and relaxation of the left ventricle
produce this phasic blood flow pattern
by extravascular compression
of the arteries and intramyocardial microvessels during systole.
There is a gradient in these systolic extravascular compressive
forces, being greater or equal
to intracavitary pressure in
the subendocardial tissue and decreasing toward the subepicardial
tissue.
Measurement of transmural blood flow distribution during systole shows
that
subepicardial vessels are perfused preferentially, whereas subendocardial
vessels are
hypoperfused significantly. Toward the end of systole,
blood flow actually reverses in the
epicardial surface vessels.
Hence the subendocardial myocardium is perfused primarily during
diastole, whereas the subepicardial myocardium is perfused during
both systole and diastole.
A greater capillary density per square
millimeter in the subendocardium than in the
subepicardial tissue
facilitates the distribution of blood flow to the inner layer
of myocardium,
and myocardial blood flow normally is greater
in the subendocardial tissue than in the
subepicardial tissue.
This places the subendocardium at greater risk of dysfunction,
tissue
injury, and necrosis during any reduction in perfusion.
This is related to (1) the greater
systolic compressive forces,
(2) the smaller flow reserve owing to a greater degree of
vasodilation,
and (3) the greater regional oxygen demands owing to wall tension
and
segmental shortening. If end-diastolic pressure is elevated
to 25, 30, or 35 mm Hg, then there
is diastolic as well as systolic
compression of the subendocardial vasculature. Flow to the
subepicardium
is effectively autoregulated as long as the pressure in the
distal coronary artery
is above approximately 40 mm Hg. Flow
to the subendocardium, however, is effectively
autoregulated only
down to a mean distal coronary artery pressure of approximately 60
to 70
mm Hg. Below this level, local coronary flow reserve in
the subendocardium is exhausted,
and local blood flow decreases
linearly with decreases in distal coronary artery pressure.
Subendocardial perfusion is further compromised by pathologic
processes that increase wall
thickness and systolic and diastolic
wall tension. Aortic regurgitation in particular threatens
the
subendocardium because systemic diastolic arterial pressure
is reduced and
intraventricular systolic and diastolic pressures
are elevated.
In contrast to the phasic nature of blood flow in the left coronary artery,
blood flow in the
right coronary artery is relatively constant during
the cardiac cycle. The constancy of blood
flow is related to the
lower intramural pressures and near absence of extravascular
compressive forces in the right ventricle compared with the
left ventricle.
References
Savage EB, et al. Cardiac surgical physiology. Cohn LH, ed. Cardiac Surgery in the Adult.
New York: McGraw-Hill, 2008:51-76.
Beyar R. Myocardial mechanics and coronary flow dynamics. Sideman S, Beyar R, eds.
Interactive Phenomena in the Cardiac System. New York: Plenum Press, 1993:125.
1.24 Answer: B
Disseminated intravascular coagulation (DIC), also called consumptive coagulopathy, is
a pathological process in the body where the blood starts to coagulate throughout the whole
body. This depletes the body of its platelets and coagulation factors, and there is a
paradoxically increased risk of haemorrhage. It occurs in critically ill patients, especially
those with Gram-negative sepsis and acute promyelocytic leukaemia.
Shahzad G. Raja
102
There are a variety of causes of DIC, all usually causing the release of chemicals into the
blood that instigates the coagulation.
Sepsis, particularly with Gram-negative bacteria.
Obstetric complications (most common cause), with chemicals from the uterus being
released into the blood, or from amniotic fluid embolism, and eclampsia can be
causes. Another obstetric condition which can cause DIC is abruptio placentae.
Tissue trauma such as burns, accidents, surgery or shock.
Liver disease
Incompatible blood transfusion reactions or massive blood transfusion (more than the
total circulatory volume)
Malignant cancers, or hypersensitivity reactions all can produce the chemicals
leading to a DIC.
Acute promyelocytic leukaemia
Viral haemorrhagic fevers bring about their frank effects, paradoxically, by causing
DIC.
Envenomation by some species of venomous snakes, such as those belonging to the
genus Echis (saw-scaled vipers)
Under homeostatic conditions, the body is maintained in a finely tuned balance of
coagulation and fibrinolysis. The activation of the coagulation cascade yields thrombin that
converts fibrinogen to fibrin; the stable fibrin clot being the final product of hemostasis. The
fibrinolytic system then functions to break down fibrinogen and fibrin. Activation of the
fibrinolytic system generates plasmin (in the presence of thrombin), which is responsible for
the lysis of fibrin clots. The breakdown of fibrinogen and fibrin results in polypeptides called
fibrin degradation products (FDPs) or fibrin split products (FSPs). In a state of homeostasis,
the presence of thrombin is critical, as it is the central proteolytic enzyme of coagulation and
is also necessary for the breakdown of clots, or fibrinolysis.
In DIC, the processes of coagulation and fibrinolysis lose control, and the result is
widespread clotting with resultant bleeding. Regardless of the triggering event of DIC, once
initiated, the pathophysiology of DIC is similar in all conditions. One critical mediator of DIC
is the release of a transmembrane glycoprotein called tissue factor (TF). TF is present on the
surface of many cell types (including endothelial cells, macrophages, and monocytes) and is
not normally in contact with the general circulation, but is exposed to the circulation after
vascular damage. For example, TF is released in response to exposure to cytokines
(particularly interleukin), tumour necrosis factor, and endotoxin. This plays a major role in
the development of DIC in septic conditions. TF is also abundant in tissues of the lungs,
brain, and placenta. This helps to explain why DIC readily develops in patients with extensive
trauma. Upon activation, TF binds with coagulation factors that then trigger both the intrinsic
and the extrinsic pathways of coagulation.
Excess circulating thrombin results from the excess activation of the coagulation cascade.
The excess thrombin cleaves fibrinogen, which ultimately leaves behind multiple fibrin clots
in the circulation. These excess clots trap platelets to become larger clots, which leads to
microvascular and macrovascular thrombosis. This lodging of clots in the microcirculation, in
Basic Sciences: Answers
103
the large vessels, and in the organs is what leads to the ischemia, impaired organ perfusion,
and end-organ damage that occurs with DIC.
Coagulation inhibitors are also consumed in this process. Decreased inhibitor levels will
permit more clotting so that a feedback system develops in which increased clotting leads to
more clotting. At the same time, thrombocytopenia occurs because of the entrapment of
platelets. Clotting factors are consumed in the development of multiple clots, which
contributes to the bleeding seen with DIC.
Simultaneously, excess circulating thrombin assists in the conversion of plasminogen to
plasmin, resulting in fibrinolysis. The breakdown of clots results in excess amounts of FDPs,
which have powerful anticoagulant properties, contributing to hemorrhage. The excess
plasmin also activates the complement and kinin systems. Activation of these systems leads
to many of the clinical symptoms that patients experiencing DIC exhibit, such as shock,
hypotension, and increased vascular permeability. The acute form of DIC is considered an
extreme expression of the intravascular coagulation process with a complete breakdown of
the normal homeostatic boundaries. DIC is associated with a poor prognosis and a high
mortality rate.
Although numerous blood tests are often performed on patients prone to DIC, the
important measures are: full blood count (especially the platelet count), fibrin degradation
products or D-dimer tests (markers of fibrinolysis), bleeding time and fibrinogen levels levels.
Decreased platelets, elevated FDPs or D-dimers, prolonged bleeding time and decreased
fibrinogen are markers of DIC.
References
Wilde JT. Hematological consequences of profound hypothermic circulatory arrest and aortic
dissection. J Card Surg. 1997;12(2 Suppl):201-6.
Dalainas I. Pathogenesis, diagnosis, and management of disseminated intravascular
coagulation: a literature review. Eur Rev Med Pharmacol Sci. 2008;12:19-31.
1.25 Answer: C
Warfarin necrosis is acquired protein C deficiency due to treatment with the vitamin K
inhibitor anticoagulant warfarin. It is a feared (but rare) complication of warfarin treatment.
This rare reaction occurs usually between the third and tenth days of therapy with warfarin
derivatives, usually in women. Lesions are sharply demarcated, erythematous, indurated, and
purpuric and may resolve or progress to form large, irregular, haemorrhagic bullae with
eventual necrosis and slow-healing eschar formation. Development of the syndrome is
unrelated to drug dose or underlying condition. Favored sites are breasts, thighs, and buttocks.
The course is not altered by discontinuation of the drug after onset of the eruption. In initial
stages of action, inhibition of protein C may be stronger than inhibition of the vitamin K-
dependent coagulation factors (II, VII, IX and X), leading to paradoxical activation of
coagulation and necrosis of skin areas. It occurs mainly in patients with a deficiency of
protein C. Protein C is an innate anticoagulant, and as warfarin further decreases protein C
levels by inhibiting vitamin K, it can lead to massive thrombosis with necrosis and gangrene
of limbs.
Shahzad G. Raja
104
References
Nazarian RM, Van Cott EM, Zembowicz A, Duncan LM. Warfarin-induced skin necrosis. J
Am Acad Dermatol. 2009;61:325-32.
Chan YC, Valenti D, Mansfield AO, Stansby G. Warfarin induced skin necrosis. Br J Surg.
2000;87:266-72.
1.26 Answer: C
Long-term survival of cardiac transplant recipients is primarily
limited by the
development of allograft coronary artery disease
(ACAD), the leading cause of death after the
first posttransplantation
year. Angiographically detectable ACAD is reported
in approximately
50% of patients by 5 years after transplantation.
The etiology of this allograft vasculopathy is
multifactorial
and involves both immunologic and nonimmunologic components.
Recently, it
has been shown that immune-related risk factors
appear to be more significant in the
development of ACAD.
Likewise, many nonimmune-associated related risks have been
implicated in ACAD including increased donor age, hyperlipidaemia,
and cytomegalovirus
(CMV) infection. These immune and nonimmune risk
factors lead to unique coronary
pathology characterised by diffuse,
concentric intimal proliferation with infiltration by smooth
muscle cells and macrophages leading to narrowing along the
entire length of the vessel.
Furthermore, collateral
vessels are notably absent. ACAD may begin within several weeks
posttransplantation and insidiously progress at an accelerated
rate to complete obliteration of
the coronary lumen with allograft
failure secondary to ischaemia.
References
Lee MS, Finch W, Weisz G, Kirtane AJ. Cardiac allograft vasculopathy. Rev Cardiovasc
Med. 2011;12:143-52.
Zimmer RJ, Lee MS. Transplant coronary artery disease. JACC Cardiovasc Interv.
2010;3:367-77.
1.27 Answer: E
Infective endocarditis (IE), one of the most serious of all infections, is characterised by
colonisation or invasion of the heart valves or the mural endocardium by a microbe, leading
to the formation of bulky, friable vegetations composed of thrombotic debris and organisms,
often associated with destruction of the underlying cardiac tissues. The aorta, aneurysmal
sacs, other blood vessels, and prosthetic devices can also become infected. Although fungi,
rickettsiae (Q fever), and chlamydiae have at one time or another been responsible for these
infections, most cases are bacterial (bacterial endocarditis). Prompt diagnosis and effective
treatment of IE can significantly alter the outlook for the patient.
IE may develop on previously normal valves, but a variety of cardiac and vascular
abnormalities predispose to this form of infection. In years past, rheumatic heart disease was
the major antecedent disorder, but more common now are myxomatous mitral valve,
degenerative calcific valvular stenosis, bicuspid aortic valve (whether calcified or not), and
artificial (prosthetic) valves. Host factors such as neutropenia, immunodeficiency,
malignancy, therapeutic immunosuppression, diabetes mellitus, and alcohol or intravenous
drug abuse are predisposing influences. Sterile platelet-fibrin deposits that accumulate at sites
of impingement of jet streams caused by pre-existing cardiac disease or indwelling vascular
catheters may also be important in the development of endocarditis.
Basic Sciences: Answers
105
The causative organisms differ somewhat in the major high-risk groups. Endocarditis of
native but previously damaged or otherwise abnormal valves is caused most commonly (50%
to 60% of cases) by Streptococcus viridans; this is not the organism responsible for rheumatic
disease. In contrast, the more virulent S. aureus organisms commonly found on the skin can
attack either healthy or deformed valves and are responsible for 10% to 20% of cases overall;
S. aureus is the major offender in intravenous drug abusers. The roster of the remaining
bacteria includes enterococci and the so-called HACEK group (Haemophilus, Actinobacillus,
Cardiobacterium, Eikenella, and Kingella), all commensals in the oral cavity. Prosthetic valve
endocarditis is caused most commonly by coagulase-negative staphylococci (e.g., S.
epidermidis). Other agents causing endocarditis include gram-negative bacilli and fungi. In
about 10% of all cases of endocarditis, no organism can be isolated from the blood ("culture-
negative" endocarditis) because of prior antibiotic therapy, difficulties in isolating the
offending agent, or because deeply embedded organisms within the enlarging vegetation are
not released into the blood.
References
Tornos P, Gonzalez-Alujas T, Thuny F, Habib G. Infective endocarditis: the European
viewpoint. Curr Probl Cardiol. 2011;36:175-222.
Que YA, Moreillon P. Infective endocarditis. Nat Rev Cardiol. 2011;8:322-36.
1.28 Answer: E
Thromboangiitis obliterans is a segmental non-atherosclerotic inflammatory disorder that
primarily involves the small- and medium-sized arteries, veins, and nerves of the extremities.
Von Winiwarter provided the first description of a patient with thromboangiitis obliterans in
1879. Thromboangiitis obliterans is also known as Buerger's disease, after Leo Buerger who
published a detailed description of the pathological findings of amputated limbs in patients
with the disease in 1908.
The annual incidence of thromboangiitis obliterans is reported to be 12.6 per 100,000 in
the United States. Although it is observed worldwide, thromboangiitis obliterans is more
prevalent in the Middle East and Far East. The disease typically presents in patients younger
than 45 years of age. While young men are more frequently affected, thromboangiitis
obliterans also occurs in women.
Exposure to tobacco is central to the initiation, maintenance, and progression of
thromboangiitis obliterans. Although smoking tobacco is by far the most common risk factor,
thromboangiitis obliterans may also develop as a result of chewing tobacco or marijuana use.
Nearly two-thirds of patients with thromboangiitis obliterans have severe periodontal disease
and chronic anaerobic periodontal infection may represent an additional risk factor for the
development of the disease. Polymerase chain reaction analysis demonstrated DNA fragments
from anaerobic bacteria in both arterial lesions and oral cavities of patients with
thromboangiitis obliterans but not in arterial samples from healthy controls.
Thromboangiitis obliterans is a vasculitis characterized by a highly cellular inflammatory
thrombus with relative sparing of the vessel wall. Although acute phase reactants, such as
erythrocyte sedimentation rate and C-reactive protein, and commonly measured
autoantibodies are typically normal, abnormalities in immunoreactivity are believed to drive
the inflammatory process. Patients with thromboangiitis obliterans have been shown to have
increased cellular immunity to types I and III collagen when compared with those who have
Shahzad G. Raja
106
atherosclerosis. In addition, high titers of anti-endothelial cell antibodies have been detected
in patients with this disorder.
References
Piazza G, Creager MA. Thromboangiitis obliterans. Circulation. 2010;121:1858-61.
Aqel MB, Olin JW. Thromboangiitis obliterans (Buerger's disease). Vasc Med. 1997;2:61-6.
1.29 Answer: C
In this clinical vignette the clinical features are suggestive of a valvular lesion which can
best be assessed by echocardiography. Echocardiography uses ultrasound waves to produce
an image of the heart and great vessels. It helps assess heart wall thickness (e.g., in
hypertrophy or atrophy) and motion and provides information about ischaemia and infarction
and valvular function and structure. It can be used to assess diastolic filling patterns of the left
ventricle, which can help in the diagnosis of left ventricular hypertrophy, hypertrophic or
restrictive cardiomyopathy, severe heart failure, constrictive pericarditis, and severe aortic
regurgitation.
References
Khasawneh FA, Smalligan RD. Focused transthoracic echocardiography. Postgrad Med.
2010;122:230-7.
Marwick TH. Echocardiography in the era of multimodality imaging. Echocardiography in
the era of multimodality imaging. Heart Lung Circ. 2010;19:175-84.
1.30 Answer: D
Persistent truncus arteriosus (or truncus arteriosus) is a rare form of congenital heart
disease that presents at birth. It derives its name from the embryological structure also known
as the truncus arteriosus. In the condition, the vessel never properly divides into the
pulmonary artery and aorta.
Most of the time, this defect occurs spontaneously. Genetic disorders, and teratogens
(viruses, metabolic imbalance, and industrial or pharmacological agents) have been associated
as possible causes. Up to 50% (varies in studies) of cases are associated with chromosome
22q11 deletions. The neural crest, specifically a population known as the cardiac neural crest,
directly contributes to the aorticopulmonary septum. Microablation of the cardiac neural crest
in developing chick embryos and genetic anomalies affecting this population of cells in
rodents results in persistent truncus arteriosus. Numerous perturbations affecting the cardiac
neural crest have been associated with persistent truncus arteriosus, some of which include
growth factors (fibroblast growth factor 8 and bone mophogenetic protein), transcription
factors (T-box, Pax, Nkx2-5, GATA-6,and Forkhead), and gap junction proteins
(Connexin).The cardiac neural crest also contributes to the smooth muscle of the great
arteries.
References
Rodefeld MD, Hanley FL. Neonatal truncus arteriosus repair: surgical techniques and clinical
management. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu. 2002;5:212-7.
Jacobs ML. Congenital Heart Surgery Nomenclature and Database Project: truncus arteriosus.
Ann Thorac Surg. 2000;69(4 Suppl):S50-5.
Basic Sciences: Answers
107
1.31 Answer: E
Eisenmenger's syndrome or Eisenmenger's reaction is defined as the process in which a
left-to-right shunt in the heart causes increased flow through the pulmonary vasculature,
causing pulmonary hypertension, which in turn, causes increased pressures in the right side of
the heart and reversal of the shunt into a right-to-left shunt.
Conditions needed for a person to be diagnosed with Eisenmenger's syndrome are:
an underlying heart defect that allows blood to pass between the left and right sides
of the heart
pulmonary hypertension, or elevated blood pressure in the lungs
polycythaemia, an increase in the number of red blood cells
the reversal of the shunt
The left side of the heart supplies to the whole body, and as a result has higher pressures
than the right side, which supplies only deoxygenated blood to the lungs. If a large anatomic
defect exists between the sides of the heart, blood will flow from the left side to the right side.
This results in high blood flow and pressure travelling through the lungs. The increased
pressure causes damage to delicate capillaries, which then are replaced with scar tissue. Scar
tissue does not contribute to oxygen transfer, therefore decreasing the useful volume of the
pulmonary vasculature. The scar tissue also provides less flexibility than normal lung tissue,
causing further increases in blood pressure, and the heart must pump harder to continue
supplying the lungs, leading to damage of more capillaries.
The reduction in oxygen transfer reduces oxygen saturation in the blood, leading to
increased production of red blood cells in an attempt to bring the oxygen saturation up. The
excess of red blood cells is called polycythaemia. Desperate for enough circulating oxygen,
the body begins to dump immature red cells into the blood stream. Immature red cells are not
as efficient at carrying oxygen as mature red cells, and they are less flexible, less able to
easily squeeze through tiny capillaries in the lungs, and so contribute to death of pulmonary
capillary beds. The increase in red blood cells also causes hyperviscosity syndrome.
A person with Eisenmenger's syndrome is paradoxically subject to the possibility of both
uncontrolled bleeding due to damaged capillaries and high pressure, and random clots due to
hyperviscosity and stasis of blood. The rough places in the heart lining at the site of the septal
defects/shunts tend to gather platelets and keep them out of circulation, and may be the source
of random clots.
Eventually, due to increased resistance, pulmonary pressures may increase sufficiently to
cause a reversal of blood flow, so blood begins to travel from the right side of the heart to the
left side, and the body is supplied with deoxygenated blood, leading to cyanosis and resultant
organ damage.
References
Kumar RK, Sandoval J. Advanced pulmonary vascular disease: the Eisenmenger syndrome.
Cardiol Young. 2009;19:622-6.
Moons P, Canobbio MM, Budts W. Eisenmenger syndrome: A clinical review. Eur J
Cardiovasc Nurs. 2009;8:237-45.
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1.32 Answer: B
Cystic fibrosis is one of the most common life-shortening, childhood-onset inherited
diseases. In the United States, incidence is 1 in 1000. In Victoria, Australia, incidence is 1 in
3600. In northern Italy, incidence is 1 in 4300. It is most common among Europeans and
Ashkenazi jews; one in twenty-two people of European descent carry one gene for CF,
making it the most common genetic disease among them.
Individuals with cystic fibrosis can be diagnosed prior to birth by genetic testing or in
early childhood by a sweat test. Newborn screening tests are increasingly common and
effective. There is no cure for CF, and most individuals with cystic fibrosis die young —
many in their 20s and 30s from respiratory failure although with many new treatments being
introduced the life expectancy of persons with CF is increasing. Ultimately, lung
transplantation is often necessary as CF worsens.
CF is caused by a mutation in a gene called the cystic fibrosis transmembrane
conductance regulator (CFTR). The product of this gene helps create sweat, digestive juices
juices, and mucus. Although most people without CF have two working copies of the CFTR
gene, only one is needed to prevent cystic fibrosis. CF develops when neither gene works
normally. Therefore, CF is considered an autososmal recessive disease. The name cystic
fibrosis refers to the characteristic 'fibrosis' and cyst formation within the pancreas, first
recognized in the 1930s.
Cystic fibrosis affects the entire body and impacts growth, breathing, digestion, and
reproduction. The newborn period may be marked by poor weight gain and intestinal
blockage caused by thick faeces. Other symptoms of CF appear during the remainder of
childhood and early adulthood. These include continued problems with growth, the onset of
lung disease, and increasing difficulties with poor absorption of vitamins and nutrients by the
gastrointestinal tract. In addition, difficulties with fertility may become apparent when
reproduction is attempted.
Lung disease in cystic fibrosis results from clogging of airways due to inflammation.
Inflammation and infection cause injury to the lungs and structural changes that lead to a
variety of symptoms. In the early stages, incessant coughing, copious phlegm production, and
decreased ability to exercise are common. Many of these symptoms occur when bacteria that
normally inhabit the thick mucus grow out of control and cause pneumonia. In later stages of
CF, changes in the architecture of the lung further exacerbate chronic difficulties in breathing.
Bronchiectasis defined as a chronic dilation of bronchi or bronchioles as a sequel of
inflammatory disease or obstruction is a debilitating complication of cystic fibrosis. Infection
is the mechanism by which the bronchiectasis progresses. The disease, left untreated, will
continue to damage lung tissue and airways and cause emphysema and severe breathing
difficulties.
Dilation of the bronchial walls results in airflow obstruction and impaired clearance of
secretions because the dilated areas interrupt normal air pressure of the bronchial tubes,
causing sputum to pool inside the dilated areas instead of being pushed upward. The pooled
sputum provides an environment conducive to the growth of infectious pathogens, and these
areas of the lungs are thus very vulnerable to infection. The more the lungs experience
infections, the more lung tissue and alveoli are damaged, and the more inelastic and dilated
the bronchial tubes become, perpetuating the cycle of the disease.