Volume 5 No 3 Fall 99

Master List Volume 6 Number 1 Summer 2000

IN THIS ISSUE Molecular Imaging Development Laboratory Imaging Gene Transfer: A Collaboration with the Gene Therapy Center and Radiation Oncology

FAQS
Captopril renogram.
Breast Feeding: is intravenous iodinated contrast contraindicated?
Imaging Utilization Eudcation -
Radiologic Imaging in the Diagnosis of Sinusitis
Circle of Excellence Award
Who's New in Radiology

Figure 1. Dr. Tandra Chaudhuri is imaging gene transfer of the hSSTr2 reporter in cells growing in culture places.

Figure 2. Imaging adenoviral mediated gene transfer to tumors.

Molecular Imaging Development Laboratory Imaging Gene Transfer: A Collaboration with the Gene Therapy Center and Radiation Oncology

April 2000 marks the 5-year anniversary for Radiology's Molecular Imaging Development Laboratory. This research facility has a primary aim to develop Nuclear Medicine imaging modalities that can be eventually translated to human applications. The facility was established originally following a corporate grant to Dr. James Mountz to image animal models of autoimmune disease, as part of a program project headed by the Chairman of Medicine, Dr. William J. Koopman.

The imaging facility includes three Radiology faculty (Dr. James Mountz, Dr. Kurt Zinn, and Dr. Tandra Chaudhuri). These scientists have secured NIH RO1 grants that fund basic imaging research. Collaborative interactions also include the Unconventional Innovation Program (Dr. Curiel, PI), an "Imaging Core" as part of the Ovarian SPORE (Dr. Partridge, PI), and imaging autoreactive T-cells (Dr. John Mountz, PI).

Three gamma cameras are dedicated to nuclear medicine imaging in the laboratory. Techniques have been developed to image cells growing as monolayers, as shown in Figure 1. This capability allows high capacity screening of newly developed tracers, prior to conducting imaging studies in animal models.

An important focus of research is directed toward imaging gene transfer. The NCI award "An in vivo reporter system for imaging gene transfer" (Dr. Zinn PI, co-investigators Dr. James Mountz, Dr. Donald Buchsbaum, and Dr. Buck Rogers) has the goal of including a genetic reporter in gene therapy vectors. The reporter lead to expression of the somatostatin receptor (hSSTr2), the presence of which can be imaged following binding of a Tc-99m-labeled peptide with high affinity for hSSTr2.

An adenoviral vector encoding both the therapy gene (Thymidine Kinase, TK) and the hSSTr2 reporter gene was evaluated in nude mice bearing subcutaneous A427 tumors (non-small cell lung). The mice were injected with a Tc-99m-peptide specific for the hSSTr2 reporter, and I-131-FIAU, a substrate for TK. As shown in Figure 2, imaging detected expression of both genes. The Tc-99m-peptide was more sensitive, but correlated with expression of TK as well.

Two future gene therapy trials at UAB will include the hSSTr2 reporter system. Since NeoTectTM and OctreoscanTM are already approved for somatostatin receptor imaging in humans, immediate application of the approach will be possible.

The accomplishments in the Molecular Imaging Development Laboratory are directly related to the strong support from Dr. Robert Stanley, Chairman of Radiology. Under his leadership the Department recently broke into the national top 25 for research grant support in Radiology.

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Frequently asked questions about Captopril Renogram

Figure 1: Normal captopril renogram

Figure 2: Hemodynamically significant RAS in the right kidney

Renovascular disease includes renal artery stenosis (RAS), renovascular hypertension RVH) and ischemic nephropathy. Renovascular disease has been studied with radionuclides for a number of years. Although the renogram (time-activity curve) of an ischemic kidney was found to be abnormal, the sensitivity and specificity of this finding was not adequate for a screening test in a population with high prevalence of hypertension and very low prevalence of RVH. Prevalence of RVH in the general population is estimated to be 1-3%. It increases to 15-30% in patients with refractory hypertension referred to specialized clinics. In the latter group of patients, the diagnosis of RVH is very important since successful intervention (revascularization) results in a cure or improvement of hypertension.

What is the difference between RVH and RAS?

RAS is an anatomic finding - narrowing of the arterial lumen by arteriosclerotic process in older population or fibromuscular dysplasia in younger women. RVH is defined as an elevated blood pressure caused by hypoperfusion of the kidney usually caused by RAS with activation of reninangiotensin system. RAS is a very common finding in elderly non-hypertensive population. For this reason diagnosis of RAS on arteriogram or ultrasound does not indicate hemodynamic significance of this finding.

What is the mechanism of RVH?

Decreased blood flow to the kidney caused by RAS increases renin synthesis and secretion from the juxta-glomerular apparatus. Renin converts angiotensinogen (a tetradecapeptide) to inactive angiotensin I (a decapeptide), which during the passage through pulmonary vascular bed is cleaved by the action of converting enzyme (ACE) to a potent vasoactive angiotensin II (an octapeptide ). High level of angiotensin II and the stimulation of aldosterone release from adrenal cortex cause an increase in blood pressure. In the kidney vasoconstriction of the postglomerular efferent arteriole, results in an increased filtration pressure and preservation of glomerular filtration.

What is the action of Captopril and other angiotensin converting enzyme inhibitors (ACEI) on renal hemodynamics?

ACE inhibitors block the conversion of inactive angiotensin I to vasoactive angiotensin II. The results in lower filtration pressure and a consequential fall in glomerular filtration in the kidney with hemodynamically significant RAS. Therefore the goal of ACEI renography is to detect those patients who have RAS as the cause of hypertension and predict curability or amelioration of hypertension following intervention. ACE renography is a test for RVH, not for RAS. The reference test should be improvement after revascularization, not angiographic evidence of RAS.

Who should have Captopril renography?

ACEI renography is indicated in patients with moderate or high risk for RVH. Clues include sudden or severe hypertension resistant to medical therapy in a compliant patient, bruits in the abdomen or flank, unexplained azotemia or worsening renal function during therapy with ACEI inhibitors, occlusive disease in other vascular beds, grade 3 or 4 hypertensive retinopathy and onset of hypertension under age of 30 or over age of 55.

Is there a special preparation of the patient for the test?

Patients should be well hydrated prior to testing and should not eat solid meal within 4 hours of the test to assure complete absorption of the medication. For intravenous ACE inhibitors (enalaprilat) the hydration is performed by normal saline infusion. ACE inhibitors should be withheld for 2-5 days before the study depending on the half-life of the drug (captopril 2 days, enalapril 3 days, lisinopril 4 days). Angiotensin II receptor blockers should be also discontinued before the study. Chronic administration of diuretics may lead to volume depletion and loss of specificity. The effect of other antihypertensive drugs appears to be not significant.

Is there a risk to the test?

We have performed over 1400 ACEI studies without a single adverse reaction. 50 mg of captopril is given I hour before imaging and the blood pressure is monitored every 10-15 minutes until imaging. Hypotension has been reported in the literature, but supine position and intravenous fluids were able to correct the problem. The images are acquired on a nuclear medicine camera located under the imaging table after administration of a very small amount of radioactive renal tracer (5 mCi Tc-99m MAG3). The imaging lasts 30 minutes and a blood sample for renal function measurement is drawn at 45 minutes following the radiotracer injection.

What is a positive test?

Positive test demonstrates change in renal handling of the radiotracer after ACEI indicating hemodynamic nature of RAS. Theoretically there should be a baseline study for comparison. In practice we perform the ACEI phase first because a normal study excludes hemodynamically sigficant and therefore curable RAS (see image 1). An abnormal diagnostic study has characteristic findings (markedly prolonged tracer transit through the kidney cortex) and does not require a baseline for comparison (see image 2). If, however, the baseline is required, it can be obtained later.

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Breast Feeding: is intravenous iodinated contrast contraindicated?
Answer: No!

A frequently asked question is whether a woman who is breast feeding her infant should or should not receive intravenous iodinated contrast for a diagnostic study such as intravenous urography or computed tomography. Confusion seems to reign on this issue, with many radiologists themselves seeming uncertain, probably as a result of the scant literature on the subject.

Here are the facts regarding the pharmacokinetics of contrast. An injected dose of contrast is fully excreted within 24 hours by patients with normal renal function. Glomerular filtration and renal excretion account for 98%; the remainder is secreted in other body fluids such as bile, sweat, tears and, yes milk. One well done study demonstrated that 0.5% of the maternal dose of low osmolar contrast (the kind routinely used at UAB) was excreted in milk in the 24 hours following injection (1). This calculates to 0.2% of the dose one would administer if one were performing a contrasted diagnostic study on an infant.

The conclusion of experts in the field, including the authors of the cited paper, is that the amount of contrast, given its oral reception by the infant, is of no consequence, and an indicated contrast study on a breast feeding mother is not contraindicated. Should either the physician or mother continue to have concern, discontinuing breast feeding for 24-48 hours after maternal intravenous iodinated contrast eliminates any exposure of the infant.

1. Nielsen ST, Matheson I, Rasmussen JN et al. Excretion of Iohexol and metrizoate in human breast milk. Acta Radiologica 28 (1987) pp523-526

As a part of our Imaging Utilization education, a brief synopsis of a topic already discussed in an Imaging Utilization Conference will be distributed to appropriate clinicians throughout the hospital. Topics that are potentially helpful to our referring clinicians and are not controversial (i.e., we agree with the criteria) will be chosen. These are prepared residents and reviewed by the appropriate department section. They will be distributed by email to the appropriate primary care clinicians. The following is the first of such mailings. This will be sent to all residents and faculty of the Internal Medicine, Family Medicine, and Emergency Medicine Departments.

The American College of Radiology has been publishing Imaging Appropriateness Criteria for the past 5 years to assist the medical community in the choice of the most suitable imaging techniques for various clinical conditions. These criteria were derived by consensus of a panel of experts including radiologists and appropriate non-radiology clinicians. We thought that disseminating this information, after review by our own departmental faculty to make allowances for the local circumstances at UAB, availability of technology and local expertise, would be helpful and lead to more cost efficient use of radiological technology. We will disseminate this information periodically. The following is the first of such topics.

Radiologic Imaging in the Diagnosis of Sinusitis

Sinusitis is estimated to affect 30-35 million Americans (14% of the population) and account for 25 million office visits per year. The annual cost in 1992 was greater than $2.4 billion (excluding surgery). It has been called the most common chronic disease in the United States. Sinusitis is temporally divided into acute, subacute, and chronic forms.

In most cases, acute sinusitis is diagnosed by history and physical examination in patients with symptoms for less than 2 to 4 weeks. Conventional radiography is neither sensitive nor specific and should not be used in any setting where computed tomography (CT) is available. CT is very sensitive, but not highly specific. Up to 40% of asymptomatic patients and 87% of patients with viral upper respiratory infections will have CT abnormalities. Only 60% of patients with sinus related symptoms will have CT abnormalities. For this reason, the American College of Radiology suggests that no imaging is usually needed in patients with acute sinusitis, but this is at the discretion of the primary care physician.

Patients with recurrent or chronic sinusitis have failed courses of treatment and potentially have an underlying anatomical abnormality. These patients should be referred to an otolaryngologist for further work-up. Radiologic imaging in these patients is not used to diagnose sinusitis, but to define anatomy prior to Functional Endoscopic Sinus Surgery (FESS). Imaging should therefore be ordered by an otolaryngologist and not as a part of the diagnostic work-up in a primary care setting. Again, conventional radiography is not necessarily indicated. Computed tomography is the single best method to define bony anatomy prior to surgery.

In the setting of suspected intraorbital or intracranial spread of sinusitis, magnetic resonance imaging is the gold standard. MRI is superior to CT for evaluation of soft tissue abnormalities. In a patient with documented active sinus infection, MRI is appropriate to evaluate new orbital masses, acute onset of significant visual disturbance, acute onset of severe headache, or altered mental status.

To summarize:

Conventional radiographs of the sinuses have little if any role in the management of any form of sinusitis.

Usually, no imaging is necessary for patients with acute sinusitis

CT is the imaging modality of choice in the preoperative assessment for FESS, and best ordered by an otolaryngologist.

MRI is the technique of choice to diagnose and assess orbital and intracranial complications of sinusitis.

References:

American College of Radiology Appropriateness Criteria. Web address: http://www.acr.org/f-products.html

Bhattacharyya T, Piccirillo J, Wippold FJ. Relationship Between Patient-Based Descriptions of Sinusitis and Computed Tomographic Findings. Archives of Otolaryngology : Head and Neck Surgery 1997;123(11):1189-92

Hahnel S, Ertl-Wagner B, Tasman AJ, Forsting M, Jansen O. Relative Value of MR Imaging as Compared with CT in the Diagnosis of Inflammatory Paranasal Sinus Disease. Radiology 1999;210(1):171-6

McAlister WH, Kronemer K. Imaging of Sinusitis in Children. Pediatric Infectious Disease Journal 1999;18(11):1019-20

McAlister WH, Lusk R, Muntz HR. Comparison of Plain Radiographs and Coronal CT Scans in Infants and Children with Recurrent Sinusitis. American Journal of Roentgenology 1989;153(6):1259-64

Poole MD. A Focus on Acute Sinusitis in Adults: Changes in Disease Management. American Journal of Medicine 1999;106(5A):38S-47S

White PS, MacLennan AC, Connolly AA, Crowther J, Bingham BJ. Analysis of CT Scanning Referrals for Chronic Rhinosinusitis. Journal of Laryngology

Prepared by Dr. Todd D. Baker, endorsed by the Neuroradiology Section of the Department of Radiology.

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Congratulations to the Vascular Interventional Radiology Department Nursing Staff on their recent Circle of Excellence Award. They were recognized for their dedication to the Radiology patient population, co-workers, and the radiology department. The nursing staff consistently demonstrates teamwork, dedication and caring. Pictured Gretta McFarland, Cassandra Cooke, Cheryl Hollingsworth, Audrey Searcy, Jennifer Ward, Pat Clark, Nancy Payne, Candis Mapson, Cindy Holt, Lisa Wilson, and Donna Whitlock, Nursing Supervisor.

Who's new in Radiology...

Anna Kogan, MD
Pavel I. Krapiva, MD
Andrew E. Kreek, MD
Jonathan P. Coyle, MD
R. Douglas Hamiter, MD
Hugh Borak, MD
David Wu, MD
Buddhiwardhan Ojha, MD
Soumenda (Sam) Das, MD
Aakash B. Ahuja, MD
Kenneth S. Burton, MD
Andrew A. Finkbeiner, MD
James M. Groom, MD
Trevor A. Lundstrom, MD
Paul S. Colomb, MD
Scott Bartley, MD

Body Imaging Fellow
Neuroradiology Fellow
Neuroradiology Fellow
Vascular/Interventional Fellow
Vascular/Interventional Fellow
Musculoskeletal Imaging Fellow
Musculoskeletal Imaging Fellow
Nuclear Medicine Clinical PET Fellow
Neuro Nuclear Research Fellow
Resident
Resident
Resident
Resident
Resident
Resident
Resident

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UAB Radiology Home Page: www.rad.uab.edu
Visions In UAB Radiology is published quarterly by the University of Alabama Hospital, Department of Radiology. Professor and Chairman: Robert J. Stanley, MD; Vice-Chairman for Operations and Academic Affairs: Robert E. Koehler, MD; Vice-Chairman for Planning and Administration and Interim Director of Outpatient Services: Lincoln L. Berland, MD. Visions Staff: Managing Editor/Layout: Pat Moore; Editors: Lincoln L. Berland, MD; Robert Lopez, MD; Hrudaya Nath, MD; Rachel Oser, MD. Web Master: J. Kevin Smith, MD, PhD. Please direct questions, comments, and suggestions as follows: Attention: Pat Moore or Lincoln L. Berland, MD. Fax: (205) 975-7213; Address: JT N 348A; E-Mail lberland@uabmc.edu

IN THIS ISSUE	Molecular Imaging Development Laboratory	Imaging Gene Transfer: A Collaboration with the Gene Therapy Center and Radiation Oncology
FAQS Captopril renogram. Breast Feeding: is intravenous iodinated contrast contraindicated? Imaging Utilization Eudcation - Radiologic Imaging in the Diagnosis of Sinusitis		Circle of Excellence Award Who's New in Radiology


Figure 1. Dr. Tandra Chaudhuri is imaging gene transfer of the hSSTr2 reporter in cells growing in culture places.	Figure 2. Imaging adenoviral mediated gene transfer to tumors.

Figure 1: Normal captopril renogram
Figure 2: Hemodynamically significant RAS in the right kidney
Renovascular disease includes renal artery stenosis (RAS), renovascular hypertension RVH) and ischemic nephropathy. Renovascular disease has been studied with radionuclides for a number of years. Although the renogram (time-activity curve) of an ischemic kidney was found to be abnormal, the sensitivity and specificity of this finding was not adequate for a screening test in a population with high prevalence of hypertension and very low prevalence of RVH. Prevalence of RVH in the general population is estimated to be 1-3%. It increases to 15-30% in patients with refractory hypertension referred to specialized clinics. In the latter group of patients, the diagnosis of RVH is very important since successful intervention (revascularization) results in a cure or improvement of hypertension.
What is the difference between RVH and RAS?	RAS is an anatomic finding - narrowing of the arterial lumen by arteriosclerotic process in older population or fibromuscular dysplasia in younger women. RVH is defined as an elevated blood pressure caused by hypoperfusion of the kidney usually caused by RAS with activation of reninangiotensin system. RAS is a very common finding in elderly non-hypertensive population. For this reason diagnosis of RAS on arteriogram or ultrasound does not indicate hemodynamic significance of this finding.
What is the mechanism of RVH?	Decreased blood flow to the kidney caused by RAS increases renin synthesis and secretion from the juxta-glomerular apparatus. Renin converts angiotensinogen (a tetradecapeptide) to inactive angiotensin I (a decapeptide), which during the passage through pulmonary vascular bed is cleaved by the action of converting enzyme (ACE) to a potent vasoactive angiotensin II (an octapeptide ). High level of angiotensin II and the stimulation of aldosterone release from adrenal cortex cause an increase in blood pressure. In the kidney vasoconstriction of the postglomerular efferent arteriole, results in an increased filtration pressure and preservation of glomerular filtration.
What is the action of Captopril and other angiotensin converting enzyme inhibitors (ACEI) on renal hemodynamics?	ACE inhibitors block the conversion of inactive angiotensin I to vasoactive angiotensin II. The results in lower filtration pressure and a consequential fall in glomerular filtration in the kidney with hemodynamically significant RAS. Therefore the goal of ACEI renography is to detect those patients who have RAS as the cause of hypertension and predict curability or amelioration of hypertension following intervention. ACE renography is a test for RVH, not for RAS. The reference test should be improvement after revascularization, not angiographic evidence of RAS.
Who should have Captopril renography?	ACEI renography is indicated in patients with moderate or high risk for RVH. Clues include sudden or severe hypertension resistant to medical therapy in a compliant patient, bruits in the abdomen or flank, unexplained azotemia or worsening renal function during therapy with ACEI inhibitors, occlusive disease in other vascular beds, grade 3 or 4 hypertensive retinopathy and onset of hypertension under age of 30 or over age of 55.
Is there a special preparation of the patient for the test?	Patients should be well hydrated prior to testing and should not eat solid meal within 4 hours of the test to assure complete absorption of the medication. For intravenous ACE inhibitors (enalaprilat) the hydration is performed by normal saline infusion. ACE inhibitors should be withheld for 2-5 days before the study depending on the half-life of the drug (captopril 2 days, enalapril 3 days, lisinopril 4 days). Angiotensin II receptor blockers should be also discontinued before the study. Chronic administration of diuretics may lead to volume depletion and loss of specificity. The effect of other antihypertensive drugs appears to be not significant.
Is there a risk to the test?	We have performed over 1400 ACEI studies without a single adverse reaction. 50 mg of captopril is given I hour before imaging and the blood pressure is monitored every 10-15 minutes until imaging. Hypotension has been reported in the literature, but supine position and intravenous fluids were able to correct the problem. The images are acquired on a nuclear medicine camera located under the imaging table after administration of a very small amount of radioactive renal tracer (5 mCi Tc-99m MAG3). The imaging lasts 30 minutes and a blood sample for renal function measurement is drawn at 45 minutes following the radiotracer injection.
What is a positive test?	Positive test demonstrates change in renal handling of the radiotracer after ACEI indicating hemodynamic nature of RAS. Theoretically there should be a baseline study for comparison. In practice we perform the ACEI phase first because a normal study excludes hemodynamically sigficant and therefore curable RAS (see image 1). An abnormal diagnostic study has characteristic findings (markedly prolonged tracer transit through the kidney cortex) and does not require a baseline for comparison (see image 2). If, however, the baseline is required, it can be obtained later.