Medical Imaging in Patients with Cystic Fibrosis

Judith Greif, RN, MS, APNC


*Family Nurse Practitioner, East Brunswick, New Jersey.
Address correspondence to: Judith Greif, RN, MS, APNC, Family Nurse Practitioner, 50 Central Avenue, East Brunswick, NJ 08816. E-mail: grifcommedical@aol.com.

Disclosure Statement: Ms Greif reports having no significant financial or advisory relationships with corporate organizations related to this activity.

ABSTRACT

Cystic fibrosis (CF) is the most common autosomal recessive genetic disorder among the Caucasian population, affecting approximately 30 000 children and adults in the United States and 70 000 individuals worldwide. Although the median age for survival today is vastly improved from what it was merely a generation ago, patients with CF continue to face disease-related challenges and complications on a daily basis. Improving both life expectancy and the quality of life for patients with CF is contingent upon making an accurate diagnosis and being able to access disease status and response to therapy. Radiologic technologists play a key role in this process. This article reviews the underlying etiology and pathophysiology of CF. It discusses the various imaging modalities involved in identifying and tracking the pathologic changes caused by CF, including basic modalities, such as radiographs, and newer techniques, such as high-resolution computerized tomography, magnetic resonance imaging, and the latest in what currently remains to be a primarily research-based imaging method, positron emission tomography.

Introduction
Cystic fibrosis (CF) is the most common autosomal recessive genetic disorder among the Caucasian population, affecting approximately 30 000 children and adults in the United States and 70 000 individuals worldwide.1,2 Primarily identified during early childhood, approximately 1000 new cases of CF are diagnosed each year.2 Although CF was once almost universally fatal during infancy, the development of new diagnostic techniques and therapeutic regimens—especially over the past 20 years—has increased the predicted median age of survival to 37 years as of 2006. In fact, today more than 40% of the CF patient population is aged 18 or older.3 However, it remains the most common genetic disorder of the Caucasian population to result in premature death—with 95% of fatalities resulting from pulmonary complications.4

Cystic fibrosis is caused by 1 or more mutations involving the CF transmembrane conductance regulator (CFTR) gene located on chromosome 7.5 To date, 1550 mutations have been identified,6 although 70% of affected individuals have the ΔF508 defect, a deletion of 3 base pairs at position 508 on the CFTR protein that codes for the amino acid phenylalanine. (Other mutations are more common in non-Caucasian populations.)7 All these mutations generally affect ion transport within epithelia—primarily chloride and sodium transport. As a result, there is dehydration and production of thick secretions in many affected organs, most notably the lungs, but also including the sinuses, pancreas, intestines, hepatobiliary tree, and vas deferens. This pathologic process results in infection, inflammation, and obstruction of the airways, in addition to damage of vital structures within the respiratory, gastrointestinal (GI), and reproductive tracts. Specifically in the lung, the presence of highly viscous secretions from chronic infection and inflammation causes airway obstruction and subsequent vasoconstriction of the vessels in the microcirculation. This, in turn, causes perfusion defects, altering lung function and ultimately leads to a poor prognosis. In addition, patients with CF may suffer from metabolic disorders leading to diabetes mellitus and issues with bone density. The first step toward improving both life expectancy and the quality of life for patients with CF is to make a diagnosis. Radiologic technologists play a key role in this process. This article discusses various imaging modalities involved in identifying and tracking the pathologic changes caused by CF throughout the lives of its youngest to its most senior patients.

Pathophysiology of Pulmonary Manifestations
Most patients with CF experience the most significant morbidity and ultimately die from pulmonary complications. CF affects the structures of the lungs to varying degrees. The submucosa, a thick layer of connective tissue that lines portions of the respiratory tract, contains mucus glands and secretory ducts. Normally, along much of this tract, mucus bathes exposed surfaces, traps debris and pathogens, which are then eliminated by the beating action of cilia that sweeps the debris out of the body through the nasopharynx. Abnormally tenacious mucus is produced as a result of the instructions dictated by the defective CFTR gene. The gene carries instructions for a transmembrane protein responsible for the active transport of chloride ions. This protein is common to the exocrine cells that normally produce watery secretions. However, under the influence of the genetic defect that causes CF, the protein malfunctions, causing impairment of salt and water transport. The end result is thick and tenacious mucus incapable of functioning properly. The bronchi, which are the passages that connect the trachea or windpipe to each lung, accumulate this viscid mucus because it cannot be properly transported by the respiratory defense system, and there is blockage of smaller bronchi and bronchioles. Bronchiectasis, or chronic dilation of the bronchi, commonly ensues. Also as a result of impaired mucociliary clearance, there is a greater risk for pulmonary infections from both common and uncommon pathogens. Infection and resultant inflammation from microbes, such as Pseudomonas aeruginosa, Staphylococcus aureus, and Haemophilus influenzae, also cause bronchoconstriction, increasing resistance, and difficulty breathing—ultimately causing irreversible lung damage. CF primarily targets the bronchi and submucosal glands until its final stages when the interstitial tissue and alveoli of the lungs themselves may be impaired. (Other respiratory structures affected by CF include the paranasal sinuses, which are almost always completely opacified.)1,8 Interestingly, the lungs of children with CF appear normal at birth, but damage rapidly ensues, as evidenced by various diagnostic imaging techniques.

Respiratory Radiography
Chest X Rays
The current recommendation for routine monitoring of patients whose CF is well controlled is to obtain chest radiographs every 2 to 4 years. However, more frequent studies (at least annually) may be necessary for those individuals who suffer from frequent lung infections or other pulmonary complications.9 Conventional chest X rays will usually reveal the radiographic features needed to support the diagnosis of CF (although more sophisticated imaging modalities are frequently used and will be discussed later in this article). Abnormal findings can vary from patient to patient; however, many individuals will have radiographs that demonstrate the features of chronic bronchiectasis that accompany CF. These may include hyperinflation, bronchial thickening and dilatation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, an increase in interstitial markings, and scattered nodular densities. Complications of advanced CF notable on standard X rays include atelectasis, mucoid impaction, pneumothorax, pneumomediastinum, pulmonary hemorrhage, cardiomegaly, and enlargement of the pulmonary artery with cor pulmonale (Figure 1).10,11

Figure 1. Chest Radiograph of CF Diffuse Interstitial Disease

Frontal chest X ray in CF shows diffuse interstitial disease with bronchiectasis and nodular densities of mucoid impaction.
CF = cystic fibrosis.
Reprinted with permission from LearningRadiology.com. Case of the Week Archives—2003. Cystic Fibrosis. Available at: http://www.learningradiology.com/toc/tocsubsection/tocarchives2003.htm. Accessed January 28, 2008.11


Films are scored by radiologists using one of several scoring systems developed to track disease severity, progression, and prognosis. The most commonly used scoring systems include the Shwachman-Kulczycki score,12 the Chrispin-Norman score,13 the Brasfield score,14 the adjusted Chrispin-Norman score,15 the Wisconsin score,16,17 and the Northern score.18 The Shwachman-Kulczycki scoring system was the first CF scoring system developed and was published in 1958; however, some scoring systems are now believed to be outdated and of little clinical value.19 Despite this, standard chest radiographs continue to be valuable in the assessment of CF when evaluated with an appropriate scoring system (such as the modified Shwachman score by Doershuk)19 and used in conjunction with other studies (imaging and nonimaging diagnostic tools). Scoring systems may be used for a variety of purposes ranging from the evaluation of mild disease or acute changes in the short term all the way through the assessment of disease longitudinally to its final and severest stages. Scores may aid clinicians in determining treatment—including the appropriate selection of candidates for invasive interventions, such as lung transplantation—and the successful outcome of these various measures. Unfortunately, many scoring systems are not yet sufficiently fine-tuned to successfully accomplish all these goals.19 Despite this, studies have demonstrated that patients with CF should still be routinely monitored using traditional chest X rays, because this technique may be more sensitive than pulmonary function testing in some circumstances, such as in revealing early and progressive lung disease.7 (The standard for monitoring lung function in patients with CF has been pulmonary function testing, because a decrease in forced expiratory volume in the first second of expiration [or FEV1] has been demonstrated to be the best indicator of morbidity and mortality for these patients.)20 Of course, use of both chest radiograph and pulmonary function (spirometry) testing are superior to either modality used alone.

Sinus X Rays
When evaluated by standard radiographs alone, over 90% of children and adults have evidence of impairment in their sinuses, suggestive of chronic rhinosinusitis.21 However, plain films of the sinuses are inadequate to differentiate inflammatory from infectious paranasal sinus disease, because they delineate opacification, but fail to distinguish between mucosal thickening (inflammatory) and the presence of purulent material (infectious).22 This is critical in terms of determining prognosis and treatment. For example, one of the gray areas in CF pathophysiology is the question of whether the sinuses may serve as a bacterial reservoir for the acquisition of more serious lung infections. Therefore, radiologic technologists may be called on to perform computed tomography (CT) scans and/or magnetic resonance imaging (MRI) scans of the sinuses to determine whether true infection is present in order to determine proper management.21

In one study by Eggesbo et al of 62 patients with CF with ethmomaxillary sinus disease comparing CT scan to MRI, MRI was able to further differentiate the opacification noted on CT scan.22 Technologists used 2 different MRI procedures (coronal turbo spin-echo T1-weighted sequence and coronal fast short inversion time recovery sequence) with differing acquisition times depending on the age and health of the patients (ie, shorter acquisition times for young children and those patients with poor lung function). Three distinct patterns were noted on MRI: (1) air-filled with moderate-to-advanced mucosal thickening; (2) oval-shaped pus-filled sinus lumen with moderate-to-advanced mucosal thickening; and (3) streaky-shaped pus-filled sinus lumen with advanced mucosal thickening. MRI differentiated between opacification secondary to a thickened mucosa versus one containing purulent material. According to the authors, this has implications for surgeons, because MRI can help to guide them toward infectious areas requiring operative treatment (Figure 2).22

Figure 2. Comparison of CT vs MRI Scan for Sinus Disease in CF
Comparison of CT vs MRI Scan for Sinus Disease in CF
Air-filled maxillary sinuses with mucosal thickening in a 14-year-old girl with CF who had undergone FESS. A, Coronal CT shows air-filled sinus lumen with peripheral homogeneous opacification equal to thickened mucosa. B, Coronal MR T1-weighted sequence gives almost the same information as CT. C, Coronal MR STIR sequence reveals small circumscribed areas with no signal in the thickened mucosa interpreted as pus-filled loculaments.
CF = cystic fibrosis; CT = computed tomography; FESS = functional endoscopic sinus surgery; MRI = magnetic resonance imaging; STIR = short inversion time recovery.
Reprinted with permission from Eggesbo et al. Acta Radiol. 2001;42:144-150.22


Computed Tomography
Computed tomography, especially the high-resolution CT (HRCT) scan, has become the preferred imaging test to detect early pulmonary disease, which is evident with this examination before symptoms develop, spirometry measurements (eg, FEV1) are abnormal, or changes become noticeable on traditional chest X rays. It must be emphasized that, although pulmonary function tests have been the traditional and standard method for determining lung function in patients with CF, they are not reliable for young patients (<5 years old)—well past when other evidence suggests that lung disease may have gained a foothold and when treatment already should have been initiated.23

High-resolution CT is also capable of detecting and tracking a more rapid decline than FEV1 in pediatric and adult patients with already-established CF.24-27 The significance of this is in its usefulness to determine treatment effects and/or exacerbations.28,29 HRCT provides detailed information regarding the lung parenchyma and can delineate structures down to the level of the secondary pulmonary lobule. This is important because many characteristic changes of lung diseases, such as CF, are evident at this level of tissue. HRCT is differentiated from conventional CT scans by its use of a narrow slice width (0.5–1 or 2 mm vs conventional 10-mm slice width), minimal field of view (scans are obtained at 10- to 40-mm intervals), and a high spatial-resolution image reconstruction algorithm.30,31 HRCT can resolve an object of 0.5-mm diameter.30 Therefore, it is useful for diagnosing interstitial lung diseases, as well as bronchiectasis. In addition, for patients with CF who have undergone lung transplantation, HRCT can identify the major pulmonary complication of long-term immunosuppressive treatment, bronchiolitis obliterans.

Furthermore, some studies indicate that HRCT is not only best for assessing structural changes in the lungs, but also for assessing the patient functionally. In other words, certain abnormalities detected on a thin-section CT scan (eg, severity of bronchiectasis, air wall thickening, or the presence of abscesses) correspond to quality of life and the ability of the patient to carry out real-world activities of daily living, in addition to overall prognosis. In one study of 22 male and female patients by Dodd et al, the correlation between exercise limitation and HRCT was stronger than it was between pulmonary function testing or body mass index.32 This is important in that it allows clinicians caring for patients with CF to determine treatment (eg, the need for supplemental oxygen), the causes and extent of exercise limitations (which may be treatable), and the prognosis for the patient. HRCT may serve as a safe surrogate for exercise testing, which may not be appropriate for some patients.

It is preferable to use the prone position for HRCT scanning because the bases of the lungs are posterior in the chest and thus, may collapse to a small degree when a patient lies on his back. This may decrease the test's sensitivity in detecting early disease. In addition, the images are obtained during inspiration as well as expiration—particularly to be able to detect air trapping on expiration. Inspiratory images can be used to assess bronchiectasis, bronchial wall thickening, mucus plugging, and/or consolidation.31

Modern multidetector CT (MDCT) scanners allow greater flexibility in evaluating (diagnosing and monitoring) CF and offer greater safety due to their delivery of lower radiation doses than was necessary with previous machinery. With MDCT scanners, the technologist has the option of electing thin-slice HRCT imaging or spiral CT imaging of the entire chest (Figure 3).18,33 Data from the latter can be used to provide 3-dimensional reconstruction of the respiratory tract versus images solely available in the axial plane with HRCT.31 When using the HRCT technique, the CT scanner must stop and move to the next position for each slice, therefore, it is more time-consuming than spiral CT imaging; however, its major advantage is that it necessitates lower radiation exposure (0.3 mSv, which is close to the 0.1 mSv dose of radiation obtained during a traditional posteroanterior/lateral chest X ray).34 Although routine annual CT scanning seem to carry a low risk of radiation-induced mortality (from cancer), as patients with CF live longer, this becomes a consideration, and clinicians should be sure that the benefits outweigh the risks of cumulative exposure when ordering these examinations.35

Figure 3. High-Resolution CT and MRI Scans Demonstrating Lung Abnormalities in a Patient with CF

Comparison between (A) inspiratory multislice CT and (B) transversal half-Fourier single-shot turbo spin-echo sequence MRI for matched images in the middle and lower lobes of a 16-year-old patient who has CF. Note the severe mucus plugging in segment 4 of the left lung (white circles).
CF = cystic fibrosis; CT = computed tomography; MRI = magnetic resonance imaging.
Reprinted with permission from Robinson. Clin Chest Med. 2007;28:405-42118 and Puderbach et al. Eur Radiol. 2007;17:716-724.33


Spiral CT provides thinner slices (0.5–1.25 mm) in a shorter period of time. In fact, typically, the entire chest can be scanned in 5 to 10 seconds as compared to a 40-second HRCT scan. This technique allows better identification and measurement of airways and more accurate follow-up evaluation of issues, such as air trapping before and after treatments, including those provided and evaluated during clinical trials.31

Computed tomography scan results are influenced by lung volume, which is generally directed by instructions from the CT technologist to inspire, expire, and hold one's breath. In infants and young children, specialized techniques substituting for volitional breath holds include controlled ventilation CT scanning and spirometry-controlled CT scanning.

Similar to chest radiographs, several scoring systems have been developed for use with HRCT scans. Scores are based on the presence of bronchiectasis, peribronchial thickening, mucus plugging, and parenchymal thickening, among other pathologic indicators (such as air trapping).18,36 Various scoring systems have been evaluated for reproducibility, reliability, and correlation with pulmonary function test results, with favorable results. However, no one scoring system has been judged to be best. Ideally, the best scoring system would be fast, reproducible, and sensitive to early changes and disease progression.37 In addition, quantitative CT measurements using computer analysis are another means of providing data regarding the status of lung parenchyma (global lung hyperinflation and regional air trapping) and airway structures (airway wall thickness and lumen dilation/area), which appears at least comparable, if not superior, to expert radiologic evaluations (scoring).38,39

Magnetic Resonance Imaging
Magnetic resonance imaging is also being used in evaluation of patients with CF, not only for the lung, but also for the heart, sinuses, and GI tract. MRI provides the obvious advantage that there is no exposure to ionizing radiation, and this is particularly important in the pediatric population, which may require repeated diagnostic tests over a lifetime to assess severity of disease, disease progression, and/or response to treatment. However, beyond that, MRI provides functional assessment rather than merely depicting structural abnormalities of organs. Unlike pulmonary function tests or chest radiographs, which cannot detect the small airway disease that occurs early in the pathophysiology of CF, MRI can highlight these changes (Figure 4).4,40 It is able to differentiate soft tissue structures, such as lymph nodes, from blood vessels and to diagnosis conditions, such as pulmonary hypertension.18 Also, it may provide better data on issues, such as vascular abnormalities, ventilation, and perfusion, which up to now only have been accessible using perfusion scintigraphy, a test not routinely used for patients with CF.40 Thus MRI may present the best of both worlds in certain circumstances because it can assess functional lung defects (regional as opposed to the general information provided by spirometry) and indicate the structural abnormalities noted on CT scanning.40

Figure 4. Comparison of Images: Chest Radiograph vs MRI Scan for Asymptomatic Patient with CF


A,
A 6-year-old girl without symptoms, with minor scarring in the upper lobes. B, Corresponding coronal 3He ventilation image shows large ventilation defect in right upper lobe.
CF = cystic fibrosis; MRI = magnetic resonance imaging.
Reprinted with permission from van Beek et al. Eur Radiol. 2007;17:1018-1024.4


Despite these characteristics, traditional high-field MRI has not come to the forefront as the preferred imaging modality because it has lower spatial resolution, takes longer to perform, and requires more sedation in young patients than CT scanning. Furthermore, to obtain optimal images, contrast media (gadolinium diethylenetriamine pentaacetic acid) or polarized 3He gas must be used.18 Imaging difficulties occur because the lung parenchyma has low proton density and thus produces a low signal. Newer, low-field devices overcome this difficulty by creating thicker images with better signal strength. Hyperpolarizing helium magnetizes it and increases the signal-to-noise ratio by a factor of 100 000.41 Additionally, rapid short echo time gradient-echo sequences allow for depiction of both morphologic abnormalities and ventilation abnormalities.41,42 Three-dimensional MRI scans using gadolinium as a contrast medium are being used to determine lung perfusion, and hence to detect structural abnormalities that may be present in patients with CF and that are interfering with lung function. The extent of perfusion is indicated by how much of the lung parenchyma becomes enhanced with passage of the contrast agent through the pulmonary circulation.40 Using these techniques, some studies reveal good correlation with both HRCT and spirometry.40-42 With the updated devices, each imaging time is 3 to 4 seconds to reduce motion artifacts, and open MRI machines reduce fear and claustrophobia for young children. Because the newer machinery shortens total examination time to between 5 and 10 minutes, less sedation is required.

At the present time, the more costly and, particularly, the newer MRI technology seem to have a place in assessing patients—especially those with more advanced disease and those who have been exposed to repeated radiation over the years. Detecting early disease changes may remain the domain of the HRCT scan.18 In any case, more investigation into the use of MRI to supplement or replace traditional chest X ray, spirometry, or HRCT is necessary, because clinical trials thus far have used small patient populations, have had various limitations, and have produced mixed results.

Positron Emission Tomography
Another imaging modality that has the ability to detect regional lung inflammation is the positron emission tomography (PET) scan. PET scans are a powerful modality, because they are highly sensitive (the level of detection is approximately 10-11 M of tracer) and can detect abnormalities that extend beyond the body surface with the same level of accuracy regardless of tissue thickness.43 PET scans use 18F-fluorodeoxyglucose (18FDG), which is injected, and then its uptake is tracked. The rate of glucose uptake by lung tissue corresponds to inflammation and disease. PET is currently used in a variety of conditions, including the monitoring of tumor activity in patients with cancer. The PET scan may be used in conjunction with the CT scan, whereby the CT may be used to further elucidate the inflammation, for example, by specifying its density and precise location.44 In patients with CF, PET has the potential to be very useful in assessing disease status and tracking responses to therapies, including novel therapies under consideration in clinical trials. However, there are currently neither longitudinal studies nor serial studies for PET scan use among patients with CF; therefore, it is uncertain if its real-world usefulness will stand up to its theoretical usefulness as an imaging tool for these purposes.44 In addition, in the limited trials conducted thus far, it was not universally confirmed that glucose uptake was significantly different in patients with CF compared to normal subjects, and thus, this modality may lack the sensitivity needed to detect inflammatory changes.45,46 There are still no data available regarding the reproducibility of uptake measurements, and there is no evidence to show that it correlates with standard measurements of clinical status (eg, pulmonary function test results or the presence of neutrophils in sputum as a measure of inflammation).44

Another potential use for the PET scan in CF is monitoring lung ventilation. By inhaling nebulized 18FDG, patients have been assessed for deposition in various regions of the lungs as a function of aerosol droplet size, airway status, after treatment, and/or after methacholine challenge. (The administration of methacholine acts as an irritant to the lungs and provokes bronchoconstriction, which is then measured by spirometry). Studies of lung ventilation seem to reveal a difference in distribution of aerosol uptake between patients with CF and control subjects (Figure 5).44

Figure 5. PET Image of Patient with CF

PET images acquired after inhalation of 18FDG aerosol from a PARI LC Plus (Pari Respiratory Equipment, Inc, Midlothian, VA) nebulizer. The particle size of the aerosol (5.3-µm volume median diameter) is comparable to a therapeutic aerosol. The panel represents several transaxial slices from one subject with CF, FEV1 57% pred. In this subject, distribution of aerosol is nonuniform and preferentially distributed to the right lung.
18FDG = 18F-fluorodeoxyglucose; CF = cystic fibrosis; FEV1 = forced expiratory volume in the first second of expiration; PET = positron emission tomography.
Reprinted with permission from Dolovich and Schuster. Proc Am Thorac Soc. 2007;4:328-333.44


Although PET has potential as a future modality, drawbacks first must be overcome. For example, this test usually requires the patient to lie still on a narrow table for 45 to 60 minutes. In addition, there is exposure to radiation both when the PET scan is used alone and when it is used with the CT in an integrated scanner. In the pediatric population, these are not minor concerns.

Nonrespiratory Manifestations of CF
GI Disease: Pancreatic Insufficiency
Patients with CF frequently have GI complications, including pancreatic insufficiency, hepatobiliary, and intestinal disease (from plugging of the pancreatic ducts, biliary tree, and intestines with viscous secretions, respectively). Pancreatic exocrine insufficiency may be present from birth and is very common—affecting 85% to 90% of patients. Endocrine dysfunction also may occur, with between 33% and 50% of all patients with CF having glucose intolerance.47 Advanced pancreatic disease results in fat and protein malabsorption, deficiency of fat-soluble vitamins (eg, A, D, E, and K), and diabetes mellitus. Abnormalities of the pancreas are characterized by fat deposition and pancreatic fibrosis, in addition to the presence of cysts and calcifications within the organ.21,48

The least invasive and the least expensive of imaging techniques used for detecting pancreatic disease is transabdominal ultrasound. Ultrasound is also a useful imaging technique for detecting structural abnormalities (cysts and tumors) of the liver, gallbladder, and bile ducts. However, it is not as useful for detecting diffuse disease processes. These abnormalities may be best detected as changes in signal intensity on MRI scans. Specifically, pancreatic fat deposition increases signal intensity on T1-weighted images whereas pancreatic fibrosis decreases signal intensity on T1- and T2-weighted MRIs. Cysts are also notable using both MRI and magnetic resonance cholangiopancreatography (see next section), whereas calcification may be best viewed using plain radiographs.21

Hepatobiliary Disease
As patients with CF live longer because of advancements in the treatment of pulmonary manifestations, chronic liver disease has become more prevalent, affecting approximately 25% of adult patients with CF.47 Chronic cholestatic liver disease is perhaps the most serious GI complication, as thick, tenacious secretions obstruct intrahepatic bile ducts and cause progressive cholestasis and biliary fibrosis; approximately 5% of patients have cirrhosis and/or portal hypertension.47,49-51 Abnormal liver function (enzyme) tests and liver biopsy are not necessarily ideal diagnostic tests (results may be inaccurate) and may be an unnecessarily invasive means of attempting to identify hepatic damage. On the other hand, various imaging techniques (eg, ultrasound, CT scan, and MRI) afford opportunities to identify patients with early, possibly reversible, liver disease, in addition to the chance to stage its severity (Figure 6).47 Abdominal ultrasound reveals the size and shape of the liver, its texture, and also whether fluid (ascites) is present.49,52,53 It is capable of detecting dilated bile ducts secondary to obstruction. Furthermore, Doppler ultrasound is useful for demonstrating blood flow through the liver vasculature, specifically the portal vein, which brings blood from the intestines to the liver and indicates the presence of portal hypertension secondary to advanced CF complications. MRI may further delineate hepatomegaly with diffuse fatty infiltrates and may detect cirrhosis, as evidenced by fibrotic changes, regenerative nodules, and portal hypertension.21 CT scans provide information that overlaps both ultrasound and MRI. It can detect tumors, abscesses, and some diffuse disorders, such as fatty liver. CT scans are less costly and time-consuming than MRI, but at the "expense" of exposure to radiation.

Figure 6. Comparison of CT vs MRI Scan of Portal Structures: Patient with CF Liver Disease


Periportal fat deposition in a 31-year-old man with CF and chronic liver disease. A, US image shows increased echogenicity around the portal structures (arrows), a finding that was thought to represent periportal fibrosis. B, Corresponding T1-weighted FLASH (160/6.6; flip angle, 75°) MRI shows high signal intensity around the portal structures (arrows), a finding that is consistent with fat deposition. The left lobe of the liver is also enlarged, and there are multiple low–signal-intensity bands with linear fibrosis. Fat deposition was confirmed with a fat-saturated sequence.
CF = cystic fibrosis; CT = computed tomography; MRI = magnetic resonance imaging; US = ultrasound.
Reprinted with permission from King et al. Radiographics. 2000;20:767-777.47


Hepatobiliary scintigraphy or endoscopic retrograde cholangiopancreatography (ERCP) have also been used to diagnose hepatobiliary disease, especially cholecystitis and choledocholithiasis (gallstones)—again, more commonly found among patients with CF. Hepatobiliary scintigraphy detects the accumulation of a radioactive tracer in the hepatobiliary system through the use of a γ-ray camera and computer-generated image. If the cystic duct is blocked, there is acute inflammation of the gallbladder. ERCP uses an endoscope to deliver radiopaque dye injected through a thin catheter within the endoscope passed from the mouth down into the duodenum and biliary tree. Similarly, percutaneous transhepatic cholangiography involves insertion of dye injected under ultrasound guidance through the abdomen into the liver. However, studies indicate that ultrasound and MRI are less invasive techniques to make this diagnosis,21 and ERCP and percutaneous transhepatic cholangiography are not necessary when biopsy or treatment are not being performed during the procedures. Using a specialized MRI technique, magnetic resonance cholangiopancreatography provides images of the bile ducts and surrounding structures, avoiding the injection of dye into the biliary and pancreatic ducts.

Bowel Obstruction
In the intestines, bowel obstruction occurs (meconium ileus in newborns or distal ileal obstructive syndrome [DIOS]) in older children and adults—again due to plugging of the intestines with thick secretions. DIOS can be diagnosed on an abdominal X ray with the detection of stool in the right colon that is described as "bubbly" or granular. In addition, there may be air-fluid levels and dilation of the small intestine.54 Sometimes to differentiate DIOS from other conditions that may have a similar clinical presentation (abdominal pain and right-sided mass), clinicians may request abdominal ultrasound or CT scan. Water-soluble contrast enemas have also been used (polysorbate 80 [Tween-80; AppliChem GmbH, Darmstadt, Germany] and/or diatrizoate meglumine and diatrizoate sodium solution [gastrografin; Bracco Diagnostics Inc, Princeton, NJ]); if there is no contrast media in the terminal ileum, this is suggestive of DIOS. However, this test requires skilled radiologists to determine the correct dose and administration of contrast media, because there are risks associated with the technique, including potential hypovolemia, perforation, or ischemia of the bowel.55

Musculoskeletal Disorders (Osteoporosis and Hypertrophic Osteoarthropathy)
Although it is unclear how the genetic mutation that causes CF may be related, it has been noted that patients with CF have abnormal bone mineralization. Imaging studies (bone mineral density scans) reveal that these individuals average 20% lower bone density than their age- and gender-matched counterparts who do not have CF, and nearly 33% have clinically significant reductions in bone density, perhaps predisposing them to fractures.56-58 In addition, plain radiographs of patients with CF may reveal another musculoskeletal condition that affects approximately 5% of this population—hypertrophic osteoarthropathy. This causes abnormal periosteal new bone growth at the distal ends of extremities associated with clubbing.59

The Future of Imaging for CF
There have been significant advances in the diagnosis and treatment of CF, to the point that children who once would not have lived past infancy may now reach middle age and beyond in some cases. Similar to patients with other diseases (such as AIDS), which initially were fairly quickly fatal but now can be managed as chronic illnesses with individuals surviving for many productive years, patients with CF now face new challenges. For example, they may have GI, reproductive, or musculoskeletal conditions that must be identified and treated alongside the better-known pulmonary complications. For many of these conditions, radiologic technologists will be on the forefront of diagnosis—using ever-advancing imaging techniques to allow for earlier, more sensitive and more specific identification of various conditions. Although radiographs remain useful for baseline, basic studies, they are being supplemented or replaced by state-of-the-art techniques, such as HRCT scans and PET scans. However, concerns about radiation exposure increase as a patient ages and is subjected to repeated doses of radiation. Today and in the future, the emphasis will be on designing the least invasive methodologies with little or no radiation exposure (such as MRI scans). Costs are also a concern, in addition to the time it takes to perform certain imaging tests, such as PET scans, leading clinicians to question whether these negatives detract from the positives enough to make these methodologies impractical for patients with CF. Furthermore, standardized protocols are needed to assure that imaging tests (such as MRI, CT, and PET scans) are performed and scored uniformly and against well-established measurable clinical outcomes (eg, pulmonary function tests or inflammatory markers). Ever-advancing imaging machinery—perhaps combining various modalities, such as MRI, PET, and/or CT scans in one unit—will permit patients and clinicians a more sophisticated view of their condition and how they might be responding to new therapies. Finally, a new field of "molecular imaging" is developing that explores events on the cellular and subcellular level as opposed to the traditional examinations of structural/anatomic or even functional imaging. Molecular imaging is multidisciplinary and may be used to reveal processes, such as gene expression, inflammation, apoptosis, and cell trafficking—all of which may be relevant to understanding and treating CF.42 Molecular imaging techniques include radionucleotide-based methods, such as planar γ scintigraphy, single-photon emission CT, and PET scanning, in addition to optical imaging strategies that detect light emitted from organisms using bioluminescence and novel applications of the fairly well-established MRI.43 All in all, it is an exciting time in the field of imaging for CF as more sophisticated techniques are being developed. These techniques range from those that may have the potential to diagnose the disease in a child before it is born to those designed to detect abnormalities in older children and adults with CF, as they survive the pulmonary complications that once could have shortened their lives before other manifestations could gain a foothold.

References
1. Ratjen F, Doring G. Cystic fibrosis. Lancet. 2003;361:681-689.

2. Cystic Fibrosis Foundation. About Cystic Fibrosis. Available at: http://www.cff.org/AboutCF/. Accessed December 5, 2007.

3. Cystic Fibrosis Foundation Patient Registry. 2005 Annual Data Report to the Center Directors. Bethesda, MD: Cystic Fibrosis Foundation; 2006.

4. van Beek EJ, Hill C, Woodhouse N, et al. Assessment of lung disease in children with cystic fibrosis using hyperpolarized 3-helium MRI: comparison with Shwachman score, Chrispin-Norman score and spirometry. Eur Radiol. 2007;17:1018-1024.

5. Rommens JM, Iannuzzi MC, Kerem B, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989;245:1059-1065.

6. Cystic fibrosis genetic analysis consortium mutation database. Available at: http://www.genet.sickkids.on.ca/cftr/app. Accessed January 28, 2008.

7. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168:918-951.

8. Gharib R, Allen RP, Joos Ha, Bravo LR. Paranasal sinuses in cystic fibrosis. incidence of roentgen abnormalities. Am J Dis Child. 1964;108:499-502.

9. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Clinical Practice Guidelines 1997. Available at: http://www.cff.org. Accessed January 28, 2008.

10. Grum CM, Lynch JP 3rd. Chest radiographic findings in cystic fibrosis. Semin Respir Infect. 1992;7:193-209.

11. LearningRadiology.com. Case of the Week Archives—2003. Cystic Fibrosis. Available at: http://www.learningradiology.com/toc/tocsubsection/tocarchives2003.htm. Accessed January 28, 2008.

12. Shwachman H, Kulczycki LL. Long-term study of one hundred five patients with cystic fibrosis; studies made over a five- to fourteen-year period. AMA J Dis Child. 1958;96:6-15.

13. Chrispin AR, Norman AP. The systematic evaluation of the chest radiograph in cystic fibrosis. Pediatr Radiol. 1974;2:101-105.

14. Brasfield D, Hicks G, Soong S, Tiller RE. The chest roentgenogram in cystic fibrosis: a new scoring system. Pediatrics. 1979;63:24-29.

15. van der Put JM, Meradji M, Danoesastro D, Kerrebijn KF. Chest radiographs in cystic fibrosis. A follow-up study with application of a quantitative system. Pediatr Radiol. 1982;12:57-61.

16. Weatherly MR, Palmer CG, Peters ME, et al. Wisconsin cystic fibrosis chest radiograph scoring system. Pediatrics. 1993;91:488-495.

17. Conway SP, Pond MN, Bowler I, et al. The chest radiograph in cystic fibrosis: a new scoring system compared with the Chrispin-Norman and Brasfield scores. Thorax. 1994;49:860-862.

18. Robinson TE. Imaging of the chest in cystic fibrosis. Clin Chest Med. 2007;28:405-421.

19. Hafen GM, Ranganathan SC, Robertson CF, Robinson PJ. Clinical scoring systems in cystic fibrosis. Pediatr Pulmonol. 2006;41:602-617.

20. Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Engl J Med. 1992;326:1187-1191.

21. King VV. Upper respiratory disease, sinusitis, and polyposis. Clin Rev Allergy. 1991;9:143-157.

22. Eggesbo HB, Dolvik S, Stiris M, et al. Complementary role of MR imaging of ethmomaxillary sinus disease depicted at CT in cystic fibrosis. Acta Radiol. 2001;42:144-150.

23. Khan TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med. 1995;151:1075-1082.

24. Brody AS, Klein JS, Molina PL, et al. High-resolution computed tomography in young patients with cystic fibrosis: distribution of abnormalities and correlation with pulmonary function tests. J Pediatr. 2004;145:32-38.

25. de Jong PA, Nakano Y, Lequin MH, et al. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J. 2004;23:93-97.

26. de Jong PA, Lindblad A, Rubin L, et al. Progression of lung disease on computed tomography and pulmonary function tests in children and adults with cystic fibrosis. Thorax. 2006;61:80-85.

27. Judge EP, Dodd JD, Masterson JB, Gallagher CG. Pulmonary abnormalities on high-resolution CT demonstrate more rapid decline than FEV1 in adults with cystic fibrosis. Chest. 2006;130:1424-1432.

28. Brody AS, Sucharew H, Campbell JD, et al. Computed tomography correlates with pulmonary exacerbations in children with cystic fibrosis. Am J Respir Crit Care Med. 2005;172:1128-1132.

29. Robinson TE, Leung AN, Northway WH, et al. Spirometer-triggered high-resolution computed tomography and pulmonary function measurements during an acute exacerbation in patients with cystic fibrosis. J Pediatr. 2001;138:553-559.

30. Worthy S. High resolution computed tomography of the lungs. BMJ. 1995;310:616.

31. Robinson TE. Computed tomography scanning techniques for the evaluation of cystic fibrosis lung disease. Proc Am Thorac Soc. 2007;4:310-315.

32. Dodd JD, Barry SC, Barry RB, et al. Thin-section CT in patients with cystic fibrosis: correlation with peak exercise capacity and body mass index. Radiology. 2006;240:236-245.

33. Puderbach M, Eichinger M, Gahr J, et al. Proton MRI appearance of cystic fibrosis: comparison to CT. Eur Radiol. 2007;17:716-724.

34. Radiology Society of North America, Inc. Radiation Exposure in X-ray Examinations. Available at: http://www.radiologyinfo.org/en/safety/index.cfm?pg=sfty_xray. Accessed December 17, 2007.

35. de Jong PA, Mayo JR, Golmohammadi K, et al. Estimation of cancer mortality associated with repetitive computed tomography scanning. Am J Respir Crit Care Med. 2006;173:199-203.

36. Brody AS, Tiddens HA, Castile RG, et al. Computed tomography in the evaluation of cystic fibrosis lung disease. Am J Respir Crit Care Med. 2005;172:1246-1252.

37. de Jong PA, Ottink MD, Robben SG, et al. Pulmonary disease assessment in cystic fibrosis: comparison of CT scoring systems and value of bronchial and arterial dimension measurements. Radiology. 2004;231:434-439.

38. Montaudon M, Berger P, Cangini-Sacher A, et al. Bronchial measurement with three-dimensional quantitative thin-section CT in patients with cystic fibrosis. Radiology. 2007;242:573-581.

39. Zavaletta VA, Bartholmai BJ, Robb RA. High resolution multidetector CT-aided tissue analysis and quantification of lung fibrosis. Acad Radiol. 2007;14:772-787.

40. Eichinger M, Puderbach M, Fink C, et al. Contrast-enhanced 3D MRI of lung perfusion in children with cystic fibrosis-initial results. Eur Radiol. 2006;16:2147-2152.

41. McMahon CJ, Dodd JD, Hill C, et al. Hyperpolarized 3helium magnetic resonance ventilation imaging of the lung in cystic fibrosis: comparison with high resolution CT and spirometry. Eur Radiol. 2006;16:2483-2490.

42. Donnelly LF, MacFall JR, McAdams HP, et al. Cystic fibrosis: combined hyperpolarized 3He-enhanced and conventional proton MR imaging in the lung—preliminary observations. Radiology. 1999;212:885-889.

43. Richard JC, Chen DL, Ferkol T, Schuster DP. Molecular imaging for pediatric lung diseases. Pediatr Pulmonol. 2004;37:286-296.

44. Dolovich MB, Schuster DP. Positron emission tomography and computed tomography versus positron emission tomography computed tomography: Tools for imaging the lung. Proc Am Thorac Soc. 2007;4:328-333.

45. Chen DL, Ferkol TW, Mintun MA, et al. Quantifying pulmonary inflammation in cystic fibrosis with positron emission tomography. Am J Respir Crit Care Med. 2006;173:1363-1369.

46. Labiris NR, Nahmias C, Freitag AP, et al. Uptake of 18fluorodeoxyglucose in the cystic fibrosis lung: a measure of lung inflammation? Eur Respir J. 2003;21:848-854.

47. King LJ, Scurr ED, Murugan N, et al. Hepatobiliary and pancreatic manifestations of cystic fibrosis: MR imaging appearances. Radiographics. 2000;20:767-777.

48. Berrocal T, Pajares MP, Zubillaga AF. Pancreatic cystosis in children and young adults with cystic fibrosis: sonographic, CT, and MRI findings. AJR Am J Roentgenol. 2005;184:1305-1309.

49. Williams SG, Evanson JE, Barrett N, et al. An ultrasound scoring system for the diagnosis of liver disease in cystic fibrosis. J Hepatol. 1995;22:513-521.

50. Colombo C, Battezzati PM. Hepatobiliary manifestations of cystic fibrosis. Eur J Gastroenterol Hepatol. 1996;8:748-754.

51. O'Brien S, Keogan M, Casey M, et al. Biliary complications of cystic fibrosis. Gut. 1992;33:387-391.

52. Colombo C, Battezzati PM. Hepatobiliary manifestations of cystic fibrosis. Eur J Gastroenterol Hepatol. 1996;8:748-754.

53. Sokol RJ, Durie PR. Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr. 1999;28(suppl 1):S1-S13.

54. Khoshoo V, Udall JN Jr. Meconium ileus equivalent in children and adults. Am J Gastroenterol. 1994;89:153-157.

55. Katkin JP, Schultz K. Overview of gastrointestinal disease in children with cystic fibrosis. UpToDate. Available at: http://patients.uptodate.com/topic.asp?file=pedigast/10447. Accessed January 28, 2008.

56. Aris RM, Ontjes DA, Buell HE, et al. Abnormal bone turnover in cystic fibrosis adults. Osteoporos Int. 2002;13:151-157.

57. Henderson RC, Madsen CD. Bone mineral content and body composition in children and young adults with cystic fibrosis. Pediatr Pulmonol. 1999;27:80-84.

58. Haworth CS, Selby PL, Webb AK, et al. Low bone mineral density in adults with cystic fibrosis. Thorax. 1999;54:961-967.

59. Lipnick RN, Glass RB. Bone changes associated with cystic fibrosis. Skeletal Radiol. 1992;21:115-116.

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