ENDOCRINOLOGY UPDATEENDOCRINOLOGY NEWS FROM MAYO CLINIC

volume 1 number 3 2006

Ts, Zs, and LSCs—Understanding Bone Mineral Density ReportsIn the absence of established skeletal fragility,assessment of bone mineral density (BMD) bydual-energy x-ray absorptiometry (DXA) is thebasis for the diagnosis of osteoporosis. The verylow radiation exposure associated with DXA,coupled with extensive epidemiologic data andvalidation in clinical trials, has made it thestandard clinical tool for the assessment of BMD.However, proper interpretation of the resultsfrom DXA requires a good understanding of thelimitations of this technology.

Caveats When Using DXA for the Diagnosis of OsteoporosisModern DXA systems compare the results in apatient with a number of normal databases. KurtA. Kennel, MD, of the Division of Endocrinology,Diabetes, Metabolism, and Nutrition at MayoClinic in Rochester, notes: “The T-score comparesthe patient’s BMD with that of a young adultpopulation, while the Z-score compares it with anage-matched population. In both cases, the scorereflects how much the patient’s BMD differs fromthe mean value for that database (in units ofstandard deviations). For the diagnosis ofosteoporosis and assessment of fracture risk, theT-score should be used only in postmenopausalwomen (World Health Organization recom-mendation, found on the WHO Web site listed inthe Table) and men older than 50 years. Thediagnosis of osteoporosis in healthy premeno-pausal women or healthy men younger than 50years should not be made on the basis of the BMDresult alone. These patients should be comparedwith age- and sex-matched databases to derive Z-scores. Osteoporosis may be diagnosed if there islow BMD in the appropriate clinical setting (forexample, glucocorticoid therapy, hypogonadism,fragility fracture, hyperparathyroidism).”

Technical Issues Important to Clinical InterpretationSerial BMD measurements can be helpful in

monitoring the response to therapy and in thedetection of secondary causes of osteoporosis.Hence, an understanding of the validity andinterpretation of serial measurement data isessential to avoid making unsupported clinicaldecisions.

Michael K. O’Connor, PhD, of the Depart-ment of Nuclear Medicine at Mayo Clinic inRochester, says: “One of the most importantnumbers in a BMD report is the least significantchange (LSC). This is defined as the smallestchange that can occur in BMD that we are 95%sure is due to changes in the patient’s BMD andnot to machine or patient factors. The LSC varieswith the type of machine, operator experience,the patient’s position, the region of the body,and the patient’s BMD. Because softwareupgrades by manufacturers may incorporatedifferent reference populations to generate T-and Z-scores, only the LSC in absolute BMD(reported as grams per square centimeter)should be used for serial comparisons.

“At Mayo Clinic in Rochester, the average of 2scans is determined during each assessment toreduce the LSC. Furthermore, an average LSCfor all technicians and densitometers is used inthe DXA laboratory to eliminate the need for

Kurt A. Kennel, MD, and Michael K. O’Connor, PhD

Inside This Issue

Thyroid Nodules: ASystematic and Cost-effective Approach . . . . . . . 3

Intensive Diabetes Self-management Programs atMayo Clinic . . . . . . . . . . . . . . 5

Hypoglycemia—A Role forArterial Stimulation Venous Sampling . . . . . . . . 6

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patients to be scanned on the samemachine by the same technician whenserial assessments are performed. TheLSC at each site and range of BMD isreported. Absolute changes in BMDgreater than the LSC at the site ofinterest likely represent a real change inBMD at that site. Values less than theLSC should not be considered as smallchanges or ‘trends.’ ”

Clinicians should ask themselves thefollowing questions: • What is the precision error (LSC) of

the local DXA laboratory? • Is the precision error (LSC) clearly

stated in the DXA report whereserial changes in BMD are beingreported?

Degenerative changes resulting inperiarticular osteosclerosis or exo-phytic bone and undetected compres-sion in the lumbar spine may spur-iously elevate the BMD measurement.However, a low T-score at 2 or morevertebrae, despite the presence of somedegenerative joint disease, may still beof use to the c l in i c ian who canconclude the lumbar spine BMD is thesame or worse than the measured value.However, LSC values are usually quotedfor the entire spine, and the fewervertebrae used in the analysis, the

poorer the accuracy of serial measurements. Ifonly 1 evaluable vertebra remains after excludingother vertebrae, diagnosis should be based on adifferent valid skeletal site (International Societyfor Clinical Densitometry 2005 recommen-dations, reached via the Web site listed in theTable).

DXA Does Not Stand Alone in Assessing Fracture Risk

The diagnostic threshold for osteoporosis

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MAYO CLINIC ENDOCRINOLOGY UPDATE 2

DXA: Online Resources forClinicians and Patients

Patient educationmaterial regarding BMDby DXA: http://www.mayoclinic.com/health/bone-density-tests/WO00024

WHO Technical Reporton Prevention andManage-ment ofOsteoporosis 2003:http://whqlibdoc.who.int/trs/WHO_TRS_921.pdf

US Surgeon General’sReport on Bone Healthand Osteoporosis 2004:http://www.surgeongeneral.gov/library/bonehealth/

Official positions on theuse of DXA for thediagnosis and manage-ment of osteoporosis atthe International Societyfor Clinical DensitometryWeb site, www.iscd.org

2006 Graduating ClinicalEndocrinology Fellows Left to right (and their upcoming appointments): NeenaNatt, MD (program director); Lisa S. Chow, MD(University of Minnesota, Minneapolis); HelenKarakelides, MD (Mayo Clinic Rochester); Julie E.Hallanger-Johnson, MD (MeritCare, Fargo, NorthDakota).

Example of a Mayo Clinic BMD report clearly statingleast significant change (LSC). This patient hadosteomalacia (low T-scores do not always indicateosteoporosis) due to vitamin D deficiency, which wasdiagnosed and treated in 2005.

Serial Comparisons

Lumbar spine L2-L4 results:

11/26/2001 BMD: 0.775 g/cm2, T-score: �3.0

11/18/2004 BMD: 0.709 g/cm2, T-score: �3.5

04/07/2006 BMD: 0.813 g/cm2, T-score: �2.7

Change – baseline: 4.9%/previous: 14.7%.

The LSC in BMD for the spine is 0.041 g/cm2.

The absolute BMD change from previous,0.104 g/cm2, is greater than the LSC.

The absolute BMD change from baseline,0.038g/cm2, is less than the LSC.

(T-score ≤�2 .5 ) us ing BMD by DXA inpostmenopausal women was chosen to identifywomen with a high risk for hip fracture. DrKennel cautions: “Just as the risk of a cardio-vascular event is not determined by serumcholesterol alone, fracture risk assessment shouldbe based on several clinical risk factors inaddition to BMD. Notable examples include age,prior fragility fracture, parental history of hipfracture, history of smoking, chronic glucocort-icoid use, history of falls, and low body weight (seeserial comparison BMD report below).” Whileclinicians can look forward to a World HealthOrganization absolute fracture risk assessmentmethod that may clarify this approach, it isessential to consider current DXA BMD measure-ments in the context of other risk factors whenassessing the benefits and risks of interventionsto reduce the possibility of fracture.

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Thyroid nodules are commonly encountered inclinical practice. In the United States,approximately 300,000 new nodules are diag-nosed each year. Their prevalence ranges from4% by palpation to more than 60% by ultra-sonography (US). Thyroid “incidentalomas,”found in up to 40% of patients undergoing USevaluation for suspected parathyroid and carotidartery disease, add another level of complexityfor the clinician.

M. Regina Castro, MD, of the Division ofEndocrinology, Diabetes, Metabolism, andNutrition at Mayo Clinic in Rochester, notes:“Although most thyroid nodules are benign,approximately 5% of all nodules may be malig-nant. Thus, a systematic evaluation is crucialboth to reassure the majority of patients withbenign disease who do not require surgery andto refer for surgical treatment the small minorityof patients with malignant, suspicious, or largesymptomatic nodules who will benefit fromsurgical excision.”

Fine-needle aspiration (FNA) biopsy is a cost-effective and safe outpatient procedure with adiagnostic accuracy that approaches 95%.“Thyroid FNA has resulted in up to 75%reduction in the number of patients requiringsurgery, while at least doubling the rate ofmalignancy found at the time of thyroidectomy,”says Hossein Gharib, MD, of the Division ofEndocrinology, Diabetes, Metabolism, andNutrition at Mayo Clinic in Rochester. However,the yield and accuracy of thyroid FNA dependon several factors, including whether the nodule

sampled is, for example, apapillary carcinoma or afollicular neoplasm, theexperience of the individualperforming the procedure, andthe cytopathologist inter-preting the results. At MayoClinic in Rochester, approxi-mately 1,000 thyroid FNAbiopsies are performed eachyear. Obtaining an adequatespecimen with enough cell-ularity to give a conclusiveresult is important, althoughthe detection of malignancyfollowing a nondiagnosticFNA is not much greater thanthat of a negative FNA (1.4%

and 0.7%, respectively, at Mayo Clinic inRochester). Nondiagnostic specimen rates in theliterature average about 15% and may be greatlyreduced by performing the FNA biopsy underUS guidance. Dr Castro notes: “US guidance isvaluable for small nodules (<1.5 cm) andessential for all nonpalpable nodules, helping toensure proper needle placement for precisesampling and avoiding cystic areas in complexnodules which often yield inadequate specimens(Figure 1). In patients with multinodular goiters,US guidance is also helpful to select for biopsythose nodules more likely to be malignant(hypoechoic nodules with microcalcifications,irregular borders, increased vascular flow,greater height than width, or rapid growth).Nodule size, in the absence of other worrisomefeatures, is not a good predictor of malignancy.”

Nodules classified on FNA as nondiagnosticshould be reaspirated, preferably under USguidance. Nodules repeatedly inadequate forcytologic evaluation may be followed closely, butsurgical excision should be considered if USdemonstrates worrisome features, if considerableinterim growth is documented, or if the patient isat high risk for developing malignancy. It isimportant to consider the clinical findings of athyroid nodule classified as nondiagnostic whendetermining the most appropriate form ofmanagement in a given patient, since somestudies have shown that up to 10% of patientsundergoing surgery for repeatedly nondiagnosticaspirates were found to have malignant nodules.

Dr Gharib highlights: “One of the mostdifficult management dilemmas for the endo-

Figure 1. Ultrasound-guided FNA, showingneedle tip (arrow) in the solid componentof this complex nodule.

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Thomas J. Sebo, MD, M. Regina Castro, MD, and HosseinGharib, MD

Thyroid Nodules: A Systematicand Cost-effective Approach

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MAYO CLINIC ENDOCRINOLOGY UPDATE 4

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crinologist is evaluatinga patient with a thyroidnodule classified on FNAcytology as ‘suspicious.’”This occurs in approx-imately 10% of all FNAsand includes specimenswith features suggestiveof, but not conclusive for,malignancy, such as folli-cular and Hürthle cellneoplasms, and sampleswith features worrisomefor papillary and med-ullary carcinoma. ThomasJ. Sebo, MD, of the Depart-ment of Laboratory Medi-cine and Pathology atMayo Clinic in Rochester,says: “In follicular neo-plasms, the smears aretypically cellular with thepresence of microfollicles(Figure 2). In these cases,the determination ofmal ignancy requiresidentification of capsularor vascular invasion inthe surgical specimen.There are no cytologicfeatures to help distin-g u i s h f o l l i c u l a r o r

Hürthle cell adenomas from their malignantcounterparts.” Thus, surgery is typically recom-mended to firmly establish the biologicalbehavior of folliculogenic tumors. Only about15% of smears considered suspicious forfollicular and Hürthle cell neoplasms areidentified as carcinomas at surgery (Table). DrSebo notes: “Many ancillary biomarkers, eval-uated using methods such as immunoperoxidasetechniques, flow cytometry, digital image analysis,and, most recently, reverse transcriptase–polymerase chain reaction analysis have beenused in an attempt to further define a ‘suspicious’folliculogenic lesion as malignant, but the resultshave been equivocal.” Hence, at present, noduleswith a suspicious cytologic appearance arereferred for surgical excision. Other indicationsfor surgery besides a “suspicious” or “positivefor malignancy” cytology include rapid nodulegrowth, development of pressure symptoms(such as dysphagia), and, for some patients,cosmetic concerns.

Figure 2. A, Benign thyroid nodule. Follicular cells are in relatively large sheetswithout microfollicle formation. Abundant colloid in the background (Papanicolaoustain,�50). B, Nondiagnostic specimen shows foamy macrophages, both scatteredand in clusters, reflective of cystic degeneration, likely in a benign thyroid nodule. Thelack of follicular cells precludes classifying the aspirate as diagnostic and negativefor malignancy (Papanicolaou stain, �100). C, This specimen, suspicious for afollicular neoplasm, shows follicular cells increased in cellularity with a lack ofcohesion. Many of the cells are in microfollicles, and colloid is reduced or absent. Theconstellation of findings suggests classifying the aspirate as suspicious (Pap-anicolaou stain, �50). D and E, In these specimens, positive for malignancy(papillary thyroid carcinoma), the presence of well-defined papillary structures (D) andcells with nuclear enlargement, crowding, and sharp longitudinal grooves (E)earmarks this aspirate as definitely coming from a nodule of papillary thyroidcarcinoma (Papanicolaou stain, �100 [D] and �400 [E]).

Reproduced with permission from Castro MR, Gharib H. Continuing controversiesin the management of thyroid nodules. Ann Intern Med. 2005;142:926-931.* Specimen labeled by a cytopathologist as “suspicious for” follicular neoplasm,Hürthle cell neoplasm, or papillary thyroid carcinoma.

Cytology * Histology,no.

Malignant, no. (%)

Follicular neoplasm 561 83 (15)

Hürthle cellneoplasm

548 77 (14)

Papillary carcinoma 489 318 (65)

Total 1,598 478 (29)

Suspicious FNA Results in 2,175 Smears With 73% Tissue Examination at Mayo Clinic,

1980-2001

A B

C D E

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The primary goal of intensive diabetesmanagement is to keep the blood glucose as nearnormal as possible without causing severehypoglycemia. The key to achieving this goal iseffective diabetes self-management. The Divisionof Endocrinology, Diabetes, Metabolism, andNutrition at Mayo Clinic in Rochester played apioneering role in describing glucose profiles anddevising complex insulin programs for patientswith diabetes.

Yogish C. Kudva, MD, an endocrinologist atMayo Clinic in Rochester, notes: “Our centercontributed the largest cohort of patients to theDiabetes Control and Complications Trial, thelandmark study that established the effectivenessof tight glycemic control in preventingmicrovascular and neurologic complications oftype 1 diabetes. Over the years, the program hasexpanded to incorporate advances in diabetesmanagement, particularly utilization oftechnology.” Services currently offered includethe following: • A 3-day outpatient program in intensive

diabetes management (called the “DiabetesUnit”)

• Fast-track instruction in intensive diabetesmanagement

• Insulin pump initiation program• Upgrading an insulin pump program• Insulin pump clinic

Diabetes Unit“The Diabetes Unit is an intensive diabeteseducation and management program establishedin 1983 at Saint Marys Hospital as an inpatientprogram. The unit is now an outpatient programlocated on the 19th floor of the Mayo Building,”according to Nancy M. Klobassa, a registerednurse and certified diabetes educator. Theprogram has undergone some changes throughthe years, but the principles are largelyunchanged.

The Diabetes Unit is a 3-day outpatientprogram held twice a month. The program meetsMonday through Wednesday from 7:15 AM to4:30 PM each day it is in session. Class size islimited to 5 patients, and family involvement isencouraged.

A team approach is used to help each patientwork with specific lifestyle issues. The healthcare team consists of an endocrinologist,endocrinology clinical fellow, certified diabetes

educator, dietitian, and behavioral medicinecounselor. Breakfast and lunch are served in aspecial nutrition dining room at the RochesterMethodist Hospital. Patients are able to makemeal choices under the direction of a dietitian.

The program includes the following topics:• Introduction to the intensive insulin program • Concepts of dose adjustment and correctional

bolus• Introduction to meal planning, food

exchanges, and carbohydrate counting• Intensive insulin program sick-day

management• Use of food labels and strategies for special

occasions• Stress management• Exercise guidelines• Medical management and follow-up as

appropriate (phone or return visits)

Fast-Track Instruction in Intensive Diabetes ManagementThe fast-track instruction is a 6-hour class, held 3times per month, specifically for individualsalready using an intensive insulin program. Theprimary focus of this class is to review theprinciples of intensive diabetes self-management.A certified diabetes nurse educator andregistered dietitian provide the instruction.

Insulin Pump Initiation ProgramThe full-day insulin pump initiation program isheld twice monthly. Appropriate candidates forthe external pump are patients who are testing

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The management of patients with diabetes at MayoClinic is a team effort and, in addition to the patient,includes physicians, certified diabetes nurse educators,and dietitians.

Intensive Diabetes Self-management Programs at Mayo Clinic

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The observation that intravenously administeredcalcium stimulates insulin release from insulin-oma, but not in normal subjects, prompted the lateDr John Doppman from the National Institutes ofHealth to adapt the Imamura test, which involvesvenous sampling for gastrin in response to thearterial injection of secretin, for the identificationof gastrinomas. Arterial stimulation venoussampling, when applied to the assessment ofpossible insulinoma, has been referred to also asthe selective arterial calcium stimulation test(SACST). F. John Service, MD, PhD, of theDivision of Endocrinology, Diabetes, Metabolism,and Nutrition at Mayo Clinic in Rochester, notes:“SACST is performed in patients with biochemicalevidence of hyperinsulinism but with inconclusivenoninvasive imaging (eg, abdominal CT,transabdominal ultrasound [US], and endoscopicUS). SACST is not necessary if an insulinoma isclearly identified on CT or US.”

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Figure 1. Graphic representation of the relationshipsamong the 3 major arteries (gastroduodenal, superiormesenteric, and splenic) and regions of the pancreassupplied (head, uncinate, and tail, respectively).

Hypoglycemia—A Role for Arterial Stimulation Venous Sampling

Splenic artery

Superior mesenteric arteryGastroduodenal artery

Right hepatic vein

Selective Arterial Calcium Stimulation Test

their blood glucose 4 times daily andwere previously instructed in intensivediabetes management. A prepumpassessment with the endocrinologistand nurse educator is advised. Thepatient and endocrinologist can thendecide if insulin pump therapy isappropriate. Nurse educators discusstherapy and provide hands-on insulinpump demonstrations. Highlights ofthis program include the following:• Insulin pump therapy and hypo-

glycemia• Insulin sensitivity factor and correc-

tion bolus• Adjustment of basal insulin and bol-

us insulin• Exercise and insulin pump therapy• Carbohydrate counting• Calculating the ratio of insulin to

carbo-hydrates • Phone call follow-up

Upgrading an Insulin Pump Nancy Klobassa notes: “Since insulin pumpmodels are continually being improved,instructions to upgrade insulin pumps are

offered on a 1-on-1 basis.” This is a 2-hourindividual education session with the diabetesnurse educator to learn the pump functions andinfusion set insertion of a new insulin pumpmodel.

Insulin Pump Clinic The insulin pump clinic is offered on 3 daysevery month. This is a team visit with a patient,an endocrinologist, and a certified diabeteseducator with expertise in pump management.Information from the pump and glucose meter isdownloaded and interpreted, and changes aremade to the pump program during the samevisit. This clinic is appropriate for patients whohave recently completed the insulin pump classor for patients who are currently on insulinpump therapy. Participation in this clinicincludes a visit at 2 to 4 weeks after startinginsulin pump therapy and every 3 monthsthereafter.

Dr Kudva concludes: “Medical care andtechnology utilization in the management ofdiabetes mellitus have improved substantially,and we are excited to offer an intensive diabetesmanagement program that is efficient, evidence-based, and responsive to patient needs.”

Nancy M. Klobassa, RN, CDE, andYogish C. Kudva, MD

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Technique“In brief, the femoral vein and artery arecannulated, and catheters are passed to the righthepatic vein for sampling for insulin andsequentially under fluoroscopic guidance into thesplenic, superior mesenteric, and gastroduodenalarteries,” says James C. Andrews, MD, of theDepartment of Radiology at Mayo Clinic inRochester (Figure 1). A baseline sample for insulinis obtained before injection of calcium gluconate,0.025 mEq/kg body weight, into each artery.Additional samples for insulin are obtained at 20,40, and 60 seconds after each injection. Alternatesites of injection are dictated by anomalies of thearterial circulation. Should a hepatic lesion besuspected as the source of hyperinsulinism, thehepatic artery should also be injected.

InterpretationDr Service notes: “A positive response to theinjection of calcium is defined as at least adoubling and, better yet, a tripling of the insulinlevel at more than 1 time point after the injectionand is indicative of hyperfunctioning � cells(either insulinoma or islet hypertrophy) in thevascular territory of the artery studied” (Figure 2).Although overlap across vascular territories canoccur, these can be identified from the angio-graphic findings. In general, the body and tail ofthe pancreas are within the splenic distribution,the head and secondarily the uncinate process arewithin the gastroduodenal distribution, and theuncinate process and secondarily the head arewithin the superior mesenteric distribution. Thistest serves not only as a means to regionalize (to 1or more arterial distributions) the site ofhyperfunctioning � cells, but also as a dynamictest to confirm the presence of hyperfunctioning �cells. In patients with clinical features of the

noninsulinoma pancreatogenous hypoglycemiasyndrome or who have postgastric bypasshypoglycemia, it is an essential procedure todocument and regionalize the hyperfunctioning �cells.

More than 100 SACSTs have been performedat Mayo Clinic in Rochester in the past decade. Inaddition to the preinjection venous sampling forinsulin, an arterial sample is also obtained beforeeach calcium injection. When the basal arterialinsulin concentration exceeds the hepatic venouslevel, the source of insulin may be extrapancreatic,ie, from another organ or by self-administration.In addition, the insulin responses to the calciuminjection are flat in persons with a nonpancreaticcause for hypoglycemia, eg, insulin autoimmunehypoglycemia, non–islet cell tumor hypoglycemia,and hypoglycemia from renal failure. Dr Andrewscautions: “Variations in arterial anatomy may leadto errors in interpretation. There is great patient-to-patient variation in the area of the pancreassupplied by the branches of the superiormesenteric artery, and it is critical that the hepaticvein insulin levels be interpreted along with acareful analysis of the diagnostic angiogram.”

4�

3�

2�

1�

Selective ArterialCalcium Stimulation Test

Rig

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epat

ic v

ein

insu

lin a

s a

mul

tipl

e of

bas

al in

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leve

l

Time, s20 40 60 20 40 60 20 40 60

SMA

GDA

Splenic artery

GDASMASplenic

Figure 2. Results from SACST show a less than 2-foldrise in right hepatic vein insulin levels when calcium isinfused into the gastroduodenal artery (GDA) andsuperior mesenteric artery (SMA). The more than 2-foldincrease in right hepatic vein insulin concentrationswhen calcium is infused into the splenic artery (datashown in orange) is diagnostic of an insulinoma in thetail of the pancreas.

James C. Andrews, MD F. John Service, MD, PhD

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Education OpportunitiesPlease call 800-323-2688 or visit www.mayo.edu/cme/endocrinology.html for more information about thiscourse or to register.

10th Mayo Clinic Endocrine Course

The 10th Mayo Clinic Endocrine Course will be heldMarch 18-23, 2007, on the Big Island of Hawaii. Thiscourse, created for endocrinologists and interestedinternists and surgeons, will present the latest materialon the diagnosis and treatment of endocrine disorders.This 5-day course (7:30 AM to 12:30 PM daily) will spanthe full spectrum of endocrinology through shortlectures, case-based debates, clinicopathologic sessions,clinical pearls sessions, and small group discussionswith experts. The digital audience response system willbe used extensively, and there will be many opportun-ities for interaction with the course faculty. An optionalsession on thyroid ultrasonography also will be offered.

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NON-PROFITORGANIZATION

U.S. POSTAGE PAIDROCHESTER, MN PERMIT NO. 259

To make anappointment fora patient throughthe ReferringPhysiciansService, usethese toll-freenumbers:

Mayo ClinicRochester800-533-1564

Mayo Clinic Arizona866-629-6362

Mayo ClinicJacksonville800-634-1417

©2006

MC5810-0306

Endocrinology Update

Produced by Mayo Clinic 200 1st Street SW Rochester, MN 55905

Medical Editor

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Endocrinology Update is written for physiciansand should be relied upon for medicaleducation purposes only. It does not providea complete overview of the topics coveredand should not replace the independentjudgment of a physician about theappropriateness or risks of a procedure for agiven patient.

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