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1.  Measurement of fractionated plasma metanephrines for exclusion of pheochromocytoma: Can specificity be improved by adjustment for age? 
Background
Biochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age.
Methods
An age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma.
Results
The sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test).
Conclusion
An adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.
doi:10.1186/1472-6823-5-1
PMCID: PMC553971  PMID: 15737232
2.  Discriminating Pheochromocytomas from Other Adrenal Lesions: The Dilemma of Elevated Catecholamines 
Annals of surgical oncology  2013;20(12):3855-3861.
Introduction
Screening tests for pheochromocytoma involve measuring levels of catecholamines in the urine or plasma, which have significant false positive rates. We reviewed patients with adrenal masses and elevated levels of catecholamines to determine the value of different preoperative tests in diagnosing pheochromocytomas.
Methods
A retrospective chart review identified patients who underwent adrenalectomy between 1997 and 2011 with elevation of urine or serum catecholamines. A database of clinicopathologic factors was created including preoperative urine and plasma metanephrines, normetanephrines, vanillylmandelic acid, and fractionated catecholamines, and tumor dimensions on imaging and pathology.
Results
Seventy patients underwent adrenalectomy due to presence of an adrenal mass and elevation of catecholamines or normetanephrines or metanephrines. Forty-six had pathologically confirmed pheochromocytomas. To improve our ability to discriminate between pheochromocytoma and other pathology, we examined different combinations of clinicopathologic factors and catecholamine levels and found the best test was a scoring system. Points are awarded for a hierarchy of elevated NM, norepinephrine, metanephrines, with additional points received for age <50 and size on imaging >3.3 cm. A score of 2 is suggestive of pheochromocytoma, with a positive predictive value of 86–87%, while a score of 4 is diagnostic with positive predictive value of 100%.
Conclusion
We found that urine/serum normetanephrine levels were the most valuable screening tool, however a score examining the size of adrenal mass on preoperative CT, age, and either plasma or urine norepinephrine, metanephrine and normetanephrine values leads to a higher positive predictive value, making this scoring system superior to individual lab tests.
doi:10.1245/s10434-013-3142-z
PMCID: PMC4270467  PMID: 23884753
3.  Measurement of urinary metanephrines to screen for pheochromocytoma in an unselected hospital referral population 
Clinical chemistry  2006;52(11):2060-2064.
Background
Despite the rarity of pheochromocytoma, the dangers of uncontrolled severe hypertension and the very effective surgical treatment of this condition mean that diagnosis is important. Urinary or plasma catecholamines or catecholamine-derivatives are commonly used to screen for pheochromocytomas prior to imaging. This study investigates whether derived measures obtained from 24-hour urinary metanephrine results, patient age and sex can better predict tumors in populations with a low pre-test probability.
Methods
This study takes a pragmatic approach by retrospectively studying the outcomes of an unselected population referred for urinary metanephrine testing (1819 patients) to a tertiary hospital laboratory, and investigates the usefulness of some simple derivative measures for detecting pheochromocytoma. Urinary 24-hour excretion of metanephrine, normetanephrine and 3-methoxytyramine were normalized by dividing by an age- and sex- specific reference range. The ability of products of these normalized measures to predict pheochromocytomas was assessed, compared to a gold standard of biopsy-confirmed tumor.
Results
The normalized product of urinary metanephrine and normetanephrine excretion (nMAD.nNMT) proved to be a highly sensitive (100%) and specific (99.1%) measure yielding a positive predictive value 82%. Receiver-operator characteristic curves were not improved by including the normalized 3-methoxytyramine concentrations in the product. nMAD.nNMT gave higher sensitivity and specificity than either test alone.
Conclusion
We suggest that nMAD.nNMT is a useful measure for identifying pheochromocytoma in a population with a low pre-test probability.
doi:10.1373/clinchem.2006.070805
PMCID: PMC2640466  PMID: 16990424
Pheochromocytoma; urinary metanephrines
4.  PHEOCHROMOCYTOMA: A CATECHOLAMINE AND OXIDATIVE STRESS DISORDER 
Endocrine regulations  2011;45(2):65-90.
The WHO classification of endocrine tumors defines pheochromocytoma as a tumor arising from chromaffin cells in the adrenal medulla — an intra-adrenal paraganglioma. Closely related tumors of extra-adrenal sympathetic and parasympathetic paraganglia are classified as extra-adrenal paragangliomas. Almost all pheochromocytomas and paragangliomas produce catecholamines. The concentrations of catecholamines in pheochromocytoma tissues are enormous, potentially creating a volcano that can erupt at any time. Significant eruptions result in catecholamine storms called “attacks” or “spells”. Acute catecholamine crisis can strike unexpectedly, leaving traumatic memories of acute medical disaster that champions any intensive care unit. A very well-defined genotype-biochemical phenotype relationship exists, guiding proper and cost-effective genetic testing of patients with these tumors. Currently, the production of norepinephrine and epinephrine is optimally assessed by the measurement of their O-methylated metabolites, normetanephrine or metanephrine, respectively. Dopamine is a minor component, but some paragangliomas produce only this catecholamine or this together with norepinephrine. Methoxytyramine, the O-methylated metabolite of dopamine, is the best biochemical marker of these tumors. In those patients with equivocal biochemical results, a modified clonidine suppression test coupled with the measurement of plasma normetanephrine has recently been introduced. In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations.
Oxidative stress results from a significant imbalance between levels of prooxidants, generated during oxidative phosphorylation, and antioxidants. The gradual accumulation of prooxidants due to metabolic oxidative stress results in proto-oncogene activation, tumor suppressor gene inactivation, DNA damage, and genomic instability. Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development. In terms of cancer pathogenesis, pheochromocytomas and paragangliomas represent tumors where the oxidative phosphorylation defect due to the mutation of succinate dehydrogenase is the cause, not a consequence, of tumor development. Any succinate dehydrogenase pathogenic mutation results in the shift from oxidative phosphorylation to aerobic glycolysis in the cytoplasm (also called anaerobic glycolysis if hypoxia is the main cause of such a shift). This phenomenon, also called the Warburg effect, is well demonstrated by a positive [18F]-fluorodeoxyglycose positron emission tomography scan. Microarray studies, genome-wide association studies, proteomics and protein arrays, metabolomics, transcriptomics, and bioinformatics approaches will remain powerful tools to further uncover the pathogenesis of these tumors and their unique markers, with the ultimate goal to introduce new therapeutic options for those with metastatic or malignant pheochromocytoma and paraganglioma. Soon oxidative stress will be tightly linked to a multistep cancer process in which the mutation of various genes (perhaps in a logistic way) ultimately results in uncontrolled growth, proliferation, and metastatic potential of practically any cell. Targeting the mTORC, IGF-1, HIF and other pathways, topoisomerases, protein degradation by proteosomes, balancing the activity of protein kinases and phosphatases or even synchronizing the cell cycle before any exposure to any kind of therapy will soon become a reality. Facing such a reality today will favor our chances to “beat” this disease tomorrow.
PMCID: PMC3414427  PMID: 21615192
Pheochromocytoma; Paraganglioma; Catecholamines; Metanephrines; Mitochondria; Oxidative Phosphorylation; Glycolysis
5.  Characterization and Plasma Measurement of the WE-14 Peptide in Patients with Pheochromocytoma 
PLoS ONE  2014;9(2):e88698.
Granins and their derived peptides are valuable circulating biological markers of neuroendocrine tumors. The aim of the present study was to investigate the tumoral chromogranin A (CgA)-derived peptide WE-14 and the potential advantage to combine plasma WE-14 detection with the EM66 assay and the existing current CgA assay for the diagnosis of pheochromocytoma. Compared to healthy volunteers, plasma WE-14 levels were 5.4-fold higher in patients with pheochromocytoma, but returned to normal values after surgical resection of the tumor. Determination of plasma CgA and EM66 concentrations in the same group of patients revealed that the test assays for these markers had an overall 84% diagnostic sensitivity, which is identical to that determined for WE-14. However, we found that WE-14 measurement improved the diagnostic sensitivity when combined with the results of CgA or EM66 assays. By combining the results of the three assays, the sensitivity for the diagnosis of pheochromocytoma was increased to 95%. In fact, the combination of WE-14 with either CgA or EM66 test assays achieved 100% sensitivity for the diagnosis of paragangliomas and sporadic or malignant pheochromocytomas if taken separately to account for the heterogeneity of the tumor. These data indicate that WE-14 is produced in pheochromocytoma and secreted into the general circulation, and that elevated plasma WE-14 levels are correlated with the occurrence of this chromaffin cell tumor. In addition, in association with other biological markers, such as CgA and/or EM66, WE-14 measurement systematically improves the diagnostic sensitivity for pheochromocytoma. These findings support the notion that granin-processing products may represent complementary tools for the diagnosis of neuroendocrine tumors.
doi:10.1371/journal.pone.0088698
PMCID: PMC3921219  PMID: 24523932
6.  MIBG molecular imaging for evaluating response to chemotherapy in patients with malignant pheochromocytoma: preliminary results 
Cancer Imaging  2013;13(2):155-161.
Abstract
Malignant pheochromocytomas respond to chemotherapy with a reduction in tumor size and catecholamine secretion. We investigated the usefulness of molecular imaging with meta-iodobenzylguanidine (MIBG) for evaluating the effects of chemotherapy in patients with malignant pheochromocytoma. Six patients were studied before and after 6 ± 4 months of combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine. Urinary catecholamines, metanephrines, and vanillylmandelic acid (VMA) levels were measured before and after chemotherapy. [131I]MIBG uptake was calculated for each tumor lesion on images before and after chemotherapy. An intensity ratio (IR) of abnormal to normal tissue count density was used to evaluate the change in lesion activity with therapy. Urinary catecholamines, metanephrines, and VMA significantly decreased with chemotherapy. MIBG uptake decreased in most lesions and the reduction in overall IR correlated with the reduction in urinary VMA. However, the change in individual lesions was variable and MIBG IR did not change or increased in a number of lesions. In conclusion, MIBG imaging is useful in the evaluation of patients with malignant pheochromocytoma who are receiving chemotherapy. It can provide not only a measure of overall effectiveness of treatment but also allows a lesion-by-lesion evaluation of the heterogeneity of response to chemotherapy.
doi:10.1102/1470-7330.2013.0017
PMCID: PMC3629891  PMID: 23598367
Neuroendocrine tumor; treatment monitoring; molecular imaging
7.  Measurements of Plasma Methoxytyramine, Normetanephrine and Metanephrine as Discriminators of Different Hereditary forms of Pheochromocytoma 
Clinical chemistry  2011;57(3):411-420.
BACKGROUND
Pheochromocytomas are rare catecholamine–producing tumors derived in at least 30% of cases from mutations in 9 tumor-susceptibility genes identified to date. Testing of multiple genes at considerable expense is often undertaken before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine and methoxytyramine, the O-methylated metabolites of catecholamines, might help distinguish different hereditary forms of the tumor.
METHODS
Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome and 59 with mutations of succinate dehydrogenase (SDH) type B or D genes.
RESULTS
In contrast to patients with VHL and SDH mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDH mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL and SDH mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDH mutations from those with VHL mutations in a further 78% of cases.
CONCLUSIONS
The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily utilized tool to guide cost-effective genotyping of underlying disease-causing mutations.
doi:10.1373/clinchem.2010.153320
PMCID: PMC3164998  PMID: 21262951
pheochromocytoma; paraganglioma; norepinephrine; epinephrine; dopamine; normetanephrine; metanephrine; methoxytyramine; von Hippel-Lindau syndrome; neurofibromatosis type 1; multiple endocrine neoplasia type 2; succinate dehydrogenase
8.  Use of 6-[18F]-fluorodopamine positron emission tomography as first-line investigation for the diagnosis and localization of non-metastatic and metastatic pheochromocytoma 
Clinical endocrinology  2008;71(1):11-17.
Summary
Objective
Imaging modalities available for the localization of pheochromocytoma (PHEO) include computed tomography (CT), magnetic resonance imaging (MRI), [123I]-or [131I]-labeled metaiodobenzylguanidine (123/131I-MIBG) scintigraphy and 6-[18F]-fluorodopamine (18F-FDA) positron emission tomography (PET). Our aim was to investigate the yield of 18F-FDA PET versus biochemical testing and other imaging techniques to establish the diagnosis and location of PHEO.
Patients and measurements
The study included 99 consecutive patients (35 M, 64 F, mean±SD age 46.4±13.4 years), who underwent 18F-FDA PET, biochemical testing (plasma catecholamines and free metanephrines) and CT and/or MRI. The majority (78%) also underwent 123/131I-MIBG.
Results
26 patients had non-metastatic PHEO, 34 patients had metastatic PHEO, and PHEO was ruled out in 39 patients. Investigations to rule out or confirm PHEO yielded the following sensitivity/specificity: plasma metanephrines 97/95%, 18F-FDA 92/90%, 123I-MIBG 83/100%, 123/131I-MIBG 70/100%, CT 100/41%, MRI 98/60%. Sensitivities for localizing non-metastatic PHEO on a per-lesion base were: CT 97%, MRI 92%, 18F-FDA 78%, 123I-MIBG 78% and 123/131I-MIBG 76%. Sensitivities for detecting metastases on a per-patient base were: CT and MRI 100%, 18F-FDA 97%, 123I-MIBG 85%, and 123/131I-MIBG 65%.
Conclusion
For tumor localization, 18F-FDA PET and 123/131I-MIBG scintigraphy perform equally well in patients with non-metastatic PHEO, but metastases are better detected by 18FFDA PET than by 123/131I-MIBG.
doi:10.1111/j.1365-2265.2008.03496.x
PMCID: PMC2713382  PMID: 19138315
paraganglioma; positron emission tomography; imaging; fluorodopamine; metanephrines
9.  Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity 
PLoS ONE  2011;6(6):e21006.
Background
Recent studies have shown that adult human possess active brown adipose tissue (BAT), which might be important in controlling obesity. It is known that ß-adrenoceptor-UCP1 system regulates BAT in rodent, but its influence in adult humans remains to be shown. The present study is to determine whether BAT activity can be independently stimulated by elevated catecholamines levels in adult human, and whether it is associated with their adiposity.
Methodology/Principal Findings
We studied 14 patients with pheochromocytoma and 14 normal subjects who had performed both 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and plasma total metanephrine (TMN) measurements during 2007–2010. The BAT detection rate and the mean BAT activity were significantly higher in patients with elevated TMN levels (Group A: 6/8 and 6.7±2.1 SUVmean· g/ml) than patients with normal TMN concentrations (Group B: 0/6 and 0.4±0.04 SUVmean· g/ml) and normal subjects (Group C: 0/14 and 0.4±0.03 SUVmean·g/ml). BAT activities were positively correlated with TMN levels (R = 0.83, p<0.0001) and were inversely related to body mass index (R = −0.47, p = 0.010), visceral fat areas (R = −0.39, p = 0.044), visceral/total fat areas (R = −0.52, p = 0.0043) and waist circumferences (R = −0.43, p = 0.019). Robust regression revealed that TMN (R = 0.81, p<0.0001) and waist circumferences (R = −0.009, p = 0.009) were the two independent predictors of BAT activities.
Conclusions/Significance
Brown adipose tissue activity in adult human can be activated by elevated plasma TMN levels, such as in the case of patients with pheochromocytoma, and is negatively associated with central adiposity.
doi:10.1371/journal.pone.0021006
PMCID: PMC3118816  PMID: 21701596
10.  Pheochromocytoma: An Uncommon Presentation of an Asymptomatic and Biochemically Silent Adrenal Incidentaloma 
Pheochromocytomas are rare tumours originating from the chromaffin tissue. The clinical manifestations are variable and are not specific; as a result, pheochromocytomas often imitate other diseases. The diagnosis is usually established by biochemical studies, i.e., the measurement of catecholamines or their metabolites in urine or plasma, followed by radiographic and scintigraphic studies for localisation. Surgical removal of the tumour is the preferred treatment. We report a 30-year-old woman presenting with an adrenal incidentaloma that was 7.6 × 5.3 × 4.8 cm in size on an abdominal computed tomography scan. Investigations for adrenal hormones, including a low-dose dexamethasone suppression test, plasma aldosterone level, 24-hour urinary metanephrine and vanillylmandelic acid levels, and plasma metanephrine level were all within the normal ranges. During the surgical resection, the patient had a hypertensive spell. Surgery was postponed, and the blood pressure was adequately controlled with α blockers, followed by β blockers. After 2 weeks, the surgery was followed by a pathological biopsy that confirmed the pheochromocytoma diagnosis.
PMCID: PMC3431738  PMID: 22973143
adrenal incidentaloma; catecholamines; hypertension; pheochromocytoma; scintigraphy
11.  Plasma free versus deconjugated metanephrines for diagnosis of phaeochromocytoma 
Clinical endocrinology  2013;79(4):10.1111/cen.12191.
Summary
Background
Diagnosis of phaeochromocytoma is commonly performed by measurements of plasma free normetanephrine and metanephrine. Plasma deconjugated normetanephrine and metanephrine have been proposed as alternative equivalent, but easier to measure biomarkers.
Objective
The aim of this study was to compare the diagnostic performances of plasma free versus deconjugated normetanephrine and metanephrine in patients tested for phaeochromocytoma.
Methods
The study population included a reference group of 262 normotensive and hypertensive volunteers, 198 patients with phaeochromocytoma and 528 patients initially suspected of having the tumour, but with negative investigations after at least 2 years of follow up. Measurements were performed using liquid chromatography with electrochemical detection.
Results
Median plasma concentrations of free normetanephrine were 17-fold higher in patients with phaeochromocytoma than in the reference population, a 72% larger (p<0.001) difference than that for the 10-fold higher levels of plasma deconjugated normetanephrine. In contrast, relative increases of plasma concentrations of free and deconjugated metanephrine were similar. Using upper cut-offs established in the reference population, measurements of plasma free metabolites provided superior diagnostic performance than deconjugated metabolites according to measures of both sensitivity (97% vs 92%, p=0.002) and specificity (93 vs 89%, p=0.012). The area under the receiver operating characteristic curve for the free metabolites was larger than that for the deconjugated metabolites (0.986 vs 0.965, p<0.001).
Conclusion
Measurements of plasma free normetanephrine and metanephrine are superior to the deconjugated metabolites for diagnosis of phaeochromocytoma.
doi:10.1111/cen.12191
PMCID: PMC3762922  PMID: 23461656
Phaeochromocytoma; diagnostic tests; free metanephrines; deconjugated metanephrines; normetanephrine; metanephrine
12.  The role of urinary fractionated metanephrines in the diagnosis of phaeochromocytoma 
Background & objectives:
Plasma and urinary metanephrines are used as screening tests for the diagnosis of phaeochromocytoma. The recommended cut-off levels are not standardized. This study was conducted to identify a cut-off level for 24 h urinary fractionated metanephrines viz. metanephrine (uMN) and normetanephrine (uNMN) using enzyme immunoassay for the diagnosis of phaeochromocytoma.
Methods:
Consecutive patients suspected to have phaeochromocytoma were included in the study. uMN and uNMN in 24 h urinary sample were measured using a commercial ELISA kit.
Results:
Overall, 72 patients were included over a period of 18 months. Twenty patients had histopathologically confirmed phaeochromocytoma and in 52 patients phaeochromocytoma was ruled out. Using the upper limit of normal stated by the assay manufacturer as the cut-off, uMN >350 μg/day had a low sensitivity and uNMN >600 μg/day had a poor specificity. By increasing the cut-off value of uNMN to twice the upper limit, specificity increased significantly without much loss in sensitivity. Combining uMN and uNMN using a cut-off twice the upper limit improved the diagnostic performance - sensitivity (95%); specificity (92.3%); positive predictive value (PPV - 82.6%); negative predictive value (NPV - 98%). In subsets of patients with a variable pretest probability for phaeochromocytoma, the PPV correlates well with the occurred of these tumors decreased, while the NPV remained at 100 per cent.
Interpretation & conclusions:
ELISA is a simple and reliable method for measuring uMN and uNMN. The test has a good NPV and can be used as an initial screening test for ruling out phaeochromocytoma. Each hospital will have to define the cut-off value for the assay being used, choosing a proper control population.
PMCID: PMC3657855  PMID: 23563375
Adrenal tumour; catecholamines; ELISA; metanephrines; phaeochromocytoma
13.  Clinical Utility of Serologic Testing for Celiac Disease in Ontario 
Executive Summary
Objective of Analysis
The objective of this evidence-based evaluation is to assess the accuracy of serologic tests in the diagnosis of celiac disease in subjects with symptoms consistent with this disease. Furthermore the impact of these tests in the diagnostic pathway of the disease and decision making was also evaluated.
Celiac Disease
Celiac disease is an autoimmune disease that develops in genetically predisposed individuals. The immunological response is triggered by ingestion of gluten, a protein that is present in wheat, rye, and barley. The treatment consists of strict lifelong adherence to a gluten-free diet (GFD).
Patients with celiac disease may present with a myriad of symptoms such as diarrhea, abdominal pain, weight loss, iron deficiency anemia, dermatitis herpetiformis, among others.
Serologic Testing in the Diagnosis Celiac Disease
There are a number of serologic tests used in the diagnosis of celiac disease.
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibodies (DGP)
Serologic tests are automated with the exception of the EMA test, which is more time-consuming and operator-dependent than the other tests. For each serologic test, both immunoglobulin A (IgA) or G (IgG) can be measured, however, IgA measurement is the standard antibody measured in celiac disease.
Diagnosis of Celiac Disease
According to celiac disease guidelines, the diagnosis of celiac disease is established by small bowel biopsy. Serologic tests are used to initially detect and to support the diagnosis of celiac disease. A small bowel biopsy is indicated in individuals with a positive serologic test. In some cases an endoscopy and small bowel biopsy may be required even with a negative serologic test. The diagnosis of celiac disease must be performed on a gluten-containing diet since the small intestine abnormalities and the serologic antibody levels may resolve or improve on a GFD.
Since IgA measurement is the standard for the serologic celiac disease tests, false negatives may occur in IgA-deficient individuals.
Incidence and Prevalence of Celiac Disease
The incidence and prevalence of celiac disease in the general population and in subjects with symptoms consistent with or at higher risk of celiac disease based on systematic reviews published in 2004 and 2009 are summarized below.
Incidence of Celiac Disease in the General Population
Adults or mixed population: 1 to 17/100,000/year
Children: 2 to 51/100,000/year
In one of the studies, a stratified analysis showed that there was a higher incidence of celiac disease in younger children compared to older children, i.e., 51 cases/100,000/year in 0 to 2 year-olds, 33/100,000/year in 2 to 5 year-olds, and 10/100,000/year in children 5 to 15 years old.
Prevalence of Celiac Disease in the General Population
The prevalence of celiac disease reported in population-based studies identified in the 2004 systematic review varied between 0.14% and 1.87% (median: 0.47%, interquartile range: 0.25%, 0.71%). According to the authors of the review, the prevalence did not vary by age group, i.e., adults and children.
Prevalence of Celiac Disease in High Risk Subjects
Type 1 diabetes (adults and children): 1 to 11%
Autoimmune thyroid disease: 2.9 to 3.3%
First degree relatives of patients with celiac disease: 2 to 20%
Prevalence of Celiac Disease in Subjects with Symptoms Consistent with the Disease
The prevalence of celiac disease in subjects with symptoms consistent with the disease varied widely among studies, i.e., 1.5% to 50% in adult studies, and 1.1% to 17% in pediatric studies. Differences in prevalence may be related to the referral pattern as the authors of a systematic review noted that the prevalence tended to be higher in studies whose population originated from tertiary referral centres compared to general practice.
Research Questions
What is the sensitivity and specificity of serologic tests in the diagnosis celiac disease?
What is the clinical validity of serologic tests in the diagnosis of celiac disease? The clinical validity was defined as the ability of the test to change diagnosis.
What is the clinical utility of serologic tests in the diagnosis of celiac disease? The clinical utility was defined as the impact of the test on decision making.
What is the budget impact of serologic tests in the diagnosis of celiac disease?
What is the cost-effectiveness of serologic tests in the diagnosis of celiac disease?
Methods
Literature Search
A literature search was performed on November 13th, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1st 2003 and November 13th 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Studies that evaluated diagnostic accuracy, i.e., both sensitivity and specificity of serology tests in the diagnosis of celiac disease.
Study population consisted of untreated patients with symptoms consistent with celiac disease.
Studies in which both serologic celiac disease tests and small bowel biopsy (gold standard) were used in all subjects.
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, and retrospective cohort studies.
At least 20 subjects included in the celiac disease group.
English language.
Human studies.
Studies published from 2000 on.
Clearly defined cut-off value for the serology test. If more than one test was evaluated, only those tests for which a cut-off was provided were included.
Description of small bowel biopsy procedure clearly outlined (location, number of biopsies per patient), unless if specified that celiac disease diagnosis guidelines were followed.
Patients in the treatment group had untreated CD.
Studies on screening of the general asymptomatic population.
Studies that evaluated rapid diagnostic kits for use either at home or in physician’s offices.
Studies that evaluated diagnostic modalities other than serologic tests such as capsule endoscopy, push enteroscopy, or genetic testing.
Cut-off for serologic tests defined based on controls included in the study.
Study population defined based on positive serology or subjects pre-screened by serology tests.
Celiac disease status known before study enrolment.
Sensitivity or specificity estimates based on repeated testing for the same subject.
Non-peer-reviewed literature such as editorials and letters to the editor.
Population
The population consisted of adults and children with untreated, undiagnosed celiac disease with symptoms consistent with the disease.
Serologic Celiac Disease Tests Evaluated
Anti-gliadin antibody (AGA)
Anti-endomysial antibody (EMA)
Anti-tissue transglutaminase antibody (tTG)
Anti-deamidated gliadin peptides antibody (DGP)
Combinations of some of the serologic tests listed above were evaluated in some studies
Both IgA and IgG antibodies were evaluated for the serologic tests listed above.
Outcomes of Interest
Sensitivity
Specificity
Positive and negative likelihood ratios
Diagnostic odds ratio (OR)
Area under the sROC curve (AUC)
Small bowel biopsy was used as the gold standard in order to estimate the sensitivity and specificity of each serologic test.
Statistical Analysis
Pooled estimates of sensitivity, specificity and diagnostic odds ratios (DORs) for the different serologic tests were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance for differences in sensitivity and specificity between serologic tests was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. The bivariate regression analyses were performed using SAS version 9.2 (SAS Institute Inc.; Cary, NC, USA). Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced using Review Manager 5.0.22 (The Nordiac Cochrane Centre, The Cochrane Collaboration, 2008). The area under the sROC curve (AUC) was estimated by bivariate mixed-efects binary regression modeling framework. Model specification, estimation and prediction are carried out with xtmelogit in Stata release 10 (Statacorp, 2007). Statistical tests for the differences in AUC estimates could not be carried out.
The study results were stratified according to patient or disease characteristics such as age, severity of Marsh grade abnormalities, among others, if reported in the studies. The literature indicates that the diagnostic accuracy of serologic tests for celiac disease may be affected in patients with chronic liver disease, therefore, the studies identified through the systematic literature review that evaluated the diagnostic accuracy of serologic tests for celiac disease in patients with chronic liver disease were summarized. The effect of the GFD in patiens diagnosed with celiac disease was also summarized if reported in the studies eligible for the analysis.
Summary of Findings
Published Systematic Reviews
Five systematic reviews of studies that evaluated the diagnostic accuracy of serologic celiac disease tests were identified through our literature search. Seventeen individual studies identified in adults and children were eligible for this evaluation.
In general, the studies included evaluated the sensitivity and specificity of at least one serologic test in subjects with symptoms consistent with celiac disease. The gold standard used to confirm the celiac disease diagnosis was small bowel biopsy. Serologic tests evaluated included tTG, EMA, AGA, and DGP, using either IgA or IgG antibodies. Indirect immunoflurorescence was used for the EMA serologic tests whereas enzyme-linked immunosorbent assay (ELISA) was used for the other serologic tests.
Common symptoms described in the studies were chronic diarrhea, abdominal pain, bloating, unexplained weight loss, unexplained anemia, and dermatitis herpetiformis.
The main conclusions of the published systematic reviews are summarized below.
IgA tTG and/or IgA EMA have a high accuracy (pooled sensitivity: 90% to 98%, pooled specificity: 95% to 99% depending on the pooled analysis).
Most reviews found that AGA (IgA or IgG) are not as accurate as IgA tTG and/or EMA tests.
A 2009 systematic review concluded that DGP (IgA or IgG) seems to have a similar accuracy compared to tTG, however, since only 2 studies identified evaluated its accuracy, the authors believe that additional data is required to draw firm conclusions.
Two systematic reviews also concluded that combining two serologic celiac disease tests has little contribution to the accuracy of the diagnosis.
MAS Analysis
Sensitivity
The pooled analysis performed by MAS showed that IgA tTG has a sensitivity of 92.1% [95% confidence interval (CI) 88.0, 96.3], compared to 89.2% (83.3, 95.1, p=0.12) for IgA DGP, 85.1% (79.5, 94.4, p=0.07) for IgA EMA, and 74.9% (63.6, 86.2, p=0.0003) for IgA AGA. Among the IgG-based tests, the results suggest that IgG DGP has a sensitivity of 88.4% (95% CI: 82.1, 94.6), 44.7% (30.3, 59.2) for tTG, and 69.1% (56.0, 82.2) for AGA. The difference was significant when IgG DGP was compared to IgG tTG but not IgG AGA. Combining serologic celiac disease tests yielded a slightly higher sensitivity compared to individual IgA-based serologic tests.
IgA deficiency
The prevalence of total or severe IgA deficiency was low in the studies identified varying between 0 and 1.7% as reported in 3 studies in which IgA deficiency was not used as a referral indication for celiac disease serologic testing. The results of IgG-based serologic tests were positive in all patients with IgA deficiency in which celiac disease was confirmed by small bowel biopsy as reported in four studies.
Specificity
The MAS pooled analysis indicates a high specificity across the different serologic tests including the combination strategy, pooled estimates ranged from 90.1% to 98.7% depending on the test.
Likelihood Ratios
According to the likelihood ratio estimates, both IgA tTG and serologic test combinationa were considered very useful tests (positive likelihood ratio above ten and the negative likelihood ratio below 0.1).
Moderately useful tests included IgA EMA, IgA DGP, and IgG DGP (positive likelihood ratio between five and ten and the negative likelihood ratio between 0.1 and 0.2).
Somewhat useful tests: IgA AGA, IgG AGA, generating small but sometimes important changes from pre- to post-test probability (positive LR between 2 and 5 and negative LR between 0.2 and 0.5)
Not Useful: IgG tTG, altering pre- to post-test probability to a small and rarely important degree (positive LR between 1 and 2 and negative LR between 0.5 and 1).
Diagnostic Odds Ratios (DOR)
Among the individual serologic tests, IgA tTG had the highest DOR, 136.5 (95% CI: 51.9, 221.2). The statistical significance of the difference in DORs among tests was not calculated, however, considering the wide confidence intervals obtained, the differences may not be statistically significant.
Area Under the sROC Curve (AUC)
The sROC AUCs obtained ranged between 0.93 and 0.99 for most IgA-based tests with the exception of IgA AGA, with an AUC of 0.89.
Sensitivity and Specificity of Serologic Tests According to Age Groups
Serologic test accuracy did not seem to vary according to age (adults or children).
Sensitivity and Specificity of Serologic Tests According to Marsh Criteria
Four studies observed a trend towards a higher sensitivity of serologic celiac disease tests when Marsh 3c grade abnormalities were found in the small bowel biopsy compared to Marsh 3a or 3b (statistical significance not reported). The sensitivity of serologic tests was much lower when Marsh 1 grade abnormalities were found in small bowel biopsy compared to Marsh 3 grade abnormalities. The statistical significance of these findings were not reported in the studies.
Diagnostic Accuracy of Serologic Celiac Disease Tests in Subjects with Chronic Liver Disease
A total of 14 observational studies that evaluated the specificity of serologic celiac disease tests in subjects with chronic liver disease were identified. All studies evaluated the frequency of false positive results (1-specificity) of IgA tTG, however, IgA tTG test kits using different substrates were used, i.e., human recombinant, human, and guinea-pig substrates. The gold standard, small bowel biopsy, was used to confirm the result of the serologic tests in only 5 studies. The studies do not seem to have been designed or powered to compare the diagnostic accuracy among different serologic celiac disease tests.
The results of the studies identified in the systematic literature review suggest that there is a trend towards a lower frequency of false positive results if the IgA tTG test using human recombinant substrate is used compared to the guinea pig substrate in subjects with chronic liver disease. However, the statistical significance of the difference was not reported in the studies. When IgA tTG with human recombinant substrate was used, the number of false positives seems to be similar to what was estimated in the MAS pooled analysis for IgA-based serologic tests in a general population of patients. These results should be interpreted with caution since most studies did not use the gold standard, small bowel biopsy, to confirm or exclude the diagnosis of celiac disease, and since the studies were not designed to compare the diagnostic accuracy among different serologic tests. The sensitivity of the different serologic tests in patients with chronic liver disease was not evaluated in the studies identified.
Effects of a Gluten-Free Diet (GFD) in Patients Diagnosed with Celiac Disease
Six studies identified evaluated the effects of GFD on clinical, histological, or serologic improvement in patients diagnosed with celiac disease. Improvement was observed in 51% to 95% of the patients included in the studies.
Grading of Evidence
Overall, the quality of the evidence ranged from moderate to very low depending on the serologic celiac disease test. Reasons to downgrade the quality of the evidence included the use of a surrogate endpoint (diagnostic accuracy) since none of the studies evaluated clinical outcomes, inconsistencies among study results, imprecise estimates, and sparse data. The quality of the evidence was considered moderate for IgA tTg and IgA EMA, low for IgA DGP, and serologic test combinations, and very low for IgA AGA.
Clinical Validity and Clinical Utility of Serologic Testing in the Diagnosis of Celiac Disease
The clinical validity of serologic tests in the diagnosis of celiac disease was considered high in subjects with symptoms consistent with this disease due to
High accuracy of some serologic tests.
Serologic tests detect possible celiac disease cases and avoid unnecessary small bowel biopsy if the test result is negative, unless an endoscopy/ small bowel biopsy is necessary due to the clinical presentation.
Serologic tests support the results of small bowel biopsy.
The clinical utility of serologic tests for the diagnosis of celiac disease, as defined by its impact in decision making was also considered high in subjects with symptoms consistent with this disease given the considerations listed above and since celiac disease diagnosis leads to treatment with a gluten-free diet.
Economic Analysis
A decision analysis was constructed to compare costs and outcomes between the tests based on the sensitivity, specificity and prevalence summary estimates from the MAS Evidence-Based Analysis (EBA). A budget impact was then calculated by multiplying the expected costs and volumes in Ontario. The outcome of the analysis was expected costs and false negatives (FN). Costs were reported in 2010 CAD$. All analyses were performed using TreeAge Pro Suite 2009.
Four strategies made up the efficiency frontier; IgG tTG, IgA tTG, EMA and small bowel biopsy. All other strategies were dominated. IgG tTG was the least costly and least effective strategy ($178.95, FN avoided=0). Small bowel biopsy was the most costly and most effective strategy ($396.60, FN avoided =0.1553). The cost per FN avoided were $293, $369, $1,401 for EMA, IgATTG and small bowel biopsy respectively. One-way sensitivity analyses did not change the ranking of strategies.
All testing strategies with small bowel biopsy are cheaper than biopsy alone however they also result in more FNs. The most cost-effective strategy will depend on the decision makers’ willingness to pay. Findings suggest that IgA tTG was the most cost-effective and feasible strategy based on its Incremental Cost-Effectiveness Ratio (ICER) and convenience to conduct the test. The potential impact of IgA tTG test in the province of Ontario would be $10.4M, $11.0M and $11.7M respectively in the following three years based on past volumes and trends in the province and basecase expected costs.
The panel of tests is the commonly used strategy in the province of Ontario therefore the impact to the system would be $13.6M, $14.5M and $15.3M respectively in the next three years based on past volumes and trends in the province and basecase expected costs.
Conclusions
The clinical validity and clinical utility of serologic tests for celiac disease was considered high in subjects with symptoms consistent with this disease as they aid in the diagnosis of celiac disease and some tests present a high accuracy.
The study findings suggest that IgA tTG is the most accurate and the most cost-effective test.
AGA test (IgA) has a lower accuracy compared to other IgA-based tests
Serologic test combinations appear to be more costly with little gain in accuracy. In addition there may be problems with generalizability of the results of the studies included in this review if different test combinations are used in clinical practice.
IgA deficiency seems to be uncommon in patients diagnosed with celiac disease.
The generalizability of study results is contingent on performing both the serologic test and small bowel biopsy in subjects on a gluten-containing diet as was the case in the studies identified, since the avoidance of gluten may affect test results.
PMCID: PMC3377499  PMID: 23074399
14.  Loss of heterozygosity suggests multiple genetic alterations in pheochromocytomas and medullary thyroid carcinomas. 
Journal of Clinical Investigation  1991;87(5):1691-1699.
Loss of heterozygosity (LOH) at specific loci may help localize tumor suppressor genes involved in the formation of various familial and sporadic tumors. In addition, the genetic loci for a number of familial tumor syndromes have been mapped by linkage analysis. To explore the possible role of tumor suppressor genes in endocrine tumors, we tested 41 pheochromocytomas (34 sporadic and 7 familial) and 11 medullary thyroid cancers (MTC) (10 sporadic and 1 familial) for LOH near a variety of potentially important genetic loci: (a) the multiple endocrine neoplasia type 2A (MEN 2A) locus on chromosome 10; (b) the von Hippel-Lindau locus on 3p; and (c) the p53 and neurofibromatosis 1 loci on 17. We also examined chromosomes 1p and 22q because previous studies in a small number of pheochromocytomas and MTCs suggested LOH in these regions. Background rates for LOH were assessed using several "random" probes. Finally, we examined a number of clinical and histologic characteristics of these tumors for possible correlations with specific genetic alterations. LOH in the region of the MEN 2A locus was uncommon (0% for MTCs, 5% for pheochromocytomas). However, we found significant allelic losses in pheochromocytomas on chromosomes 1p (42%), 3p (16%), 17p (24%), and 22q (31%). We also noted a correlation between LOH on 1p and urinary excretion of metanephrine by these patients (P = 0.02). LOH on 1p, 3p, and 17p also appeared to be associated with increased tumor volume. Analysis of the smaller number of MTCs demonstrated allelic losses on chromosomes 1p and 22q. Our results suggest that tumor formation and/or progression in pheochromocytomas and MTCs involves multiple genes, analogous with the model proposed for colon carcinoma.
Images
PMCID: PMC295269  PMID: 2022740
15.  Pheochromocytomas and secreting paragangliomas 
Catecholamine-producing tumors may arise in the adrenal medulla (pheochromocytomas) or in extraadrenal chromaffin cells (secreting paragangliomas). Their prevalence is about 0.1% in patients with hypertension and 4% in patients with a fortuitously discovered adrenal mass. An increase in the production of catecholamines causes symptoms (mainly headaches, palpitations and excess sweating) and signs (mainly hypertension, weight loss and diabetes) reflecting the effects of epinephrine and norepinephrine on α- and β-adrenergic receptors. Catecholamine-producing tumors mimic paroxysmal conditions with hypertension and/or cardiac rhythm disorders, including panic attacks, in which sympathetic activation linked to anxiety reproduces the same signs and symptoms. These tumors may be sporadic or part of any of several genetic diseases: familial pheochromocytoma-paraganglioma syndromes, multiple endocrine neoplasia type 2, neurofibromatosis 1 and von Hippel-Lindau disease. Familial cases are diagnosed earlier and are more frequently bilateral and recurring than sporadic cases. The most specific and sensitive diagnostic test for the tumor is the determination of plasma or urinary metanephrines. The tumor can be located by computed tomography, magnetic resonance imaging and metaiodobenzylguanidine scintigraphy. Treatment requires resection of the tumor, generally by laparoscopic surgery. About 10% of tumors are malignant either at first operation or during follow-up, malignancy being diagnosed by the presence of lymph node, visceral or bone metastases. Recurrences and malignancy are more frequent in cases with large or extraadrenal tumors. Patients, especially those with familial or extraadrenal tumors, should be followed-up indefinitely.
doi:10.1186/1750-1172-1-49
PMCID: PMC1702343  PMID: 17156452
16.  Incidental pheochromocytoma presenting with sublaboratory findings in asymptomatic surrenal masses: a case report 
Cases Journal  2008;1:10.
Introduction
Adrenal incidentaloma can be described as adrenal lesions that are incidentally diagnosed during abdominal laparotomy or any abdominal screening without prior suspicion of adrenal disease. It is important to diagnose adrenal lesions to learn if they are hormonally active or malignant. The most common clinical sign of pheochromocytoma is sustained or paroxysmal hypertension, and the most common symptoms are headache, excessive truncal sweating, and palpitation. In some cases, the clinical symptoms are not clear. Roughly 70% of adrenal incidentalomas are non-functional. A small group of 5–7% of the functional ones (30%) may exist as pheochromocytoma. Ten percent of pheochromocytoma cases are diagnosed incidentally during computed tomography (CT) or magnetic resonance imaging (MRI) screenings for other reasons. The most frequent symptom of the pheochromocytoma is hypertension, and 90–100% of cases exhibit it. The literature indicates that incidental pheochromocytoma cases that are smaller than 1 cm have no clinical symptoms. Rarely, some large pheochromocytoma cases do not show any clinical symptoms, and it is difficult to diagnose very small ones.
Case presentation
A 45-year-old male patient experienced an epigastric ache and distended stomach for 7 years. The serum cortisol level was 19.2 ng/dL (normal range: 5–20 ng/dL), and urinary free cortisol excretion was 25.00 μg/24 h (normal range:10.00–100.00 μg/24 h). The serum basal level of adrenocorticotropic hormone (ACTH) was 21 pg/mL (normal range: 9 to 52 pg/mL). Plasma cortisol was under 1.00 μg/dL after low dose (1 mg) overnight dexamethasone suppression test. 24 hours urinary catecholamines level were vanil mandilic acid (VMA) 8.90 mg/day (normal range, 3 to 90 mg/day), metanefrin 330 μg/day (normal range, 52 to 341 μg/day), epinefrin 13 μg/day (normal range, 2 to 24 μg/day), norepinefrin 41 μg/day (normal range; 15 to 100 μg/day). During abdominal ultrasonography (USG), a tumor was diagnosed in the right perirenal space. A regular-shaped mass (dimension 36 × 35 × 35 mm) with a homogeneous and solid structure was diagnosed in CT. The density of the mass was 80 Hounsfield units (HU) in postcontrast CT. The patient was given a diagnosis of a non-functional adrenal incidental lesion, underwent a right adrenalectomy. Histopathological data correlated with pheochromocytoma as well
Conclusion
Pheochromocytoma can be diagnosed by establishing an increase in catecholamines and metabolites in the plasma and urine. The level of catecholamines and metabolites in the plasma and urine provide 95% of the evidence of the disease. Because the dimensions of the lesion were large and the HU was very clear, the patient was underwent surrenalectomy. During laboratory investigation, there was no evidence of abnormality; we, therefore, think that these cases can be named sublaboratory pheochromocytoma.
doi:10.1186/1757-1626-1-10
PMCID: PMC2438313  PMID: 18577248
17.  Prevalence of Germline Mutations in Patients with Pheochromocytoma or Abdominal Paraganglioma and Sporadic Presentation: A Population-Based Study in Western Sweden 
World Journal of Surgery  2012;36(6):1389-1394.
Background
Germline mutations in the susceptibility genes RET, SDHB, SDHD, and VHL have been reported in 7.5–24% of patients with pheochromocytoma (Pheo) or paraganglioma (PGL) and sporadic presentation. The purpose of the present study was to establish population-based data on the frequency of germline mutations in patients with apparently sporadic Pheo or abdominal PGL in Western Sweden.
Methods
From the Swedish National Cancer Registry, all patients with Pheo or PGL in Western Sweden (population 1.72 million) registered between 1958 and 2009 were identified (n = 256). Patients were characterized using register data, hospital records, and clinical interviews. All living patients with Pheo or abdominal PGL and sporadic presentation (n = 81) were invited to genetic screening; 71 patients accepted. Germline mutations were investigated by using direct sequencing for point mutations in RET, SDHB, SDHD, and VHL, and multiplex ligation-dependent probe amplification for gross deletions in SDHB, SDHC, SDHD, and VHL. Plasma or urinary metanephrines and/or urinary catecholamines were used for biochemical follow-up.
Results
The prevalence of germline mutations was 5.6%. Mutations were only seen in RET (n = 1) and SDHB (n = 3). Notably, in the patients with SDHB mutations, no malignant phenotype was observed during a mean follow-up of 23.3 years.
Conclusions
The frequency of germline mutations in patients with apparently sporadic Pheo and abdominal PGL in Western Sweden was lower than in previous studies. Variations in reported frequencies of germline mutations in patients with clinically sporadic Pheo/PGL may reflect geographical differences or patient selection.
doi:10.1007/s00268-012-1430-6
PMCID: PMC3348434  PMID: 22270996
18.  Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution 
Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.
doi:10.1055/s-0032-1304662
PMCID: PMC3501345  PMID: 22438210
pheochromocytoma; paraganglioma; von Hippel-Lindau syndrome; mutation testing; germline mutations; loss of heterozygosity
19.  Pheochromocytoma presenting with arterial and intracardiac thrombus in a 47-year-old woman: a case report 
Introduction
Pheochromocytoma is a rare cause of hypertension but it could have severe consequences if not recognized and treated appropriately. The association of pheochromocytoma and thrombosis is even rarer but significantly increases management complexity, morbidity and mortality. To the best of our knowledge, this is the first report of a patient with pheochromocytoma presenting with left axillary arterial and intracardiac thrombus.
Case presentation
A 47-year-old Caucasian woman with a past medical history of hypertension presented for medical attention with left arm numbness. Doppler ultrasound showed an obstructing thrombus in her left axillary artery. She had symptom resolution after stent placement in her left axillary artery. A subsequent echocardiogram demonstrated a large intracardiac mass and abdominal computed tomography revealed a 7 cm mass between her spleen and left kidney. Labile blood pressure was noted during admission and she had very high levels of plasma and 24-hour urine catecholamines and metanephrines tests. A (123)I- metaiodobenzylguanidine scan showed intense uptake in the left abdominal mass. After adequate alpha blockage with phenoxybenzamine, laparoscopic tumor resection was performed without complications. She had normal metanephrines and complete symptom resolution afterwards. The intracardiac mass also disappeared with anticoagulation. All other endocrine laboratory abnormalities returned to normal after surgery.
Conclusion
Arterial and ventricular thrombosis occurring in patients with pheochromocytoma is rare. A multi-disciplinary approach is necessary in caring for this type of patient. Catecholamines likely contributed to the development of thrombosis in our patient. Early recognition of pheochromocytoma is the key to improving outcome.
doi:10.1186/1752-1947-5-310
PMCID: PMC3152527  PMID: 21752274
20.  Updated and New Perspectives on Diagnosis, Prognosis, and Therapy of Malignant Pheochromocytoma/Paraganglioma 
Journal of Oncology  2012;2012:872713.
Malignant pheochromocytomas/paragangliomas are rare tumors with a poor prognosis. Malignancy is diagnosed by the development of metastases as evidenced by recurrences in sites normally devoid of chromaffin tissue. Histopathological, biochemical, molecular and genetic markers offer only information on potential risk of metastatic spread. Large size, extraadrenal location, dopamine secretion, SDHB mutations, a PASS score higher than 6, a high Ki-67 index are indexes for potential malignancy. Metastases can be present at first diagnosis or occur years after primary surgery. Measurement of plasma and/or urinary metanephrine, normetanephrine and metoxytyramine are recommended for biochemical diagnosis. Anatomical and functional imaging using different radionuclides are necessary for localization of tumor and metastases. Metastatic pheochromocytomas/paragangliomas is incurable. When possible, surgical debulking of primary tumor is recommended as well as surgical or radiosurgical removal of metastases. I-131-MIBG radiotherapy is the treatment of choice although results are limited. Chemotherapy is reserved to more advanced disease stages. Recent genetic studies have highlighted the main pathways involved in pheochromocytomas/paragangliomas pathogenesis thus suggesting the use of targeted therapy which, nevertheless, has still to be validated. Large cooperative studies on tissue specimens and clinical trials in large cohorts of patients are necessary to achieve better therapeutic tools and improve patient prognosis.
doi:10.1155/2012/872713
PMCID: PMC3407645  PMID: 22851969
21.  A CLINICAL OVERVIEW OF PHEOCHROMOCYTOMAS/PARAGANGLIOMAS AND CARCINOID TUMORS 
Nuclear medicine and biology  2008;35(Suppl 1):S27-S34.
Pheochromocytomas/paragangliomas are rare tumors, most are sporadic. Biochemical proof of disease is better with measurement of plasma metanephrines and less cumbersome than determinations in urine; its implementation is expanding. Anatomical imaging with computed tomography or magnetic resonance imaging should be followed by functional (nuclear medicine) imaging: chromaffin-tumor-specific methods are preferred. Treatment is surgical; for non-operable disease other options are available. Overall 5-year survival is 50%.
Carcinoid tumors derive from serotonin-producing enterochromaffin cells in the fore-, mid- or hindgut. Biochemical screening (and follow-up) is done with measurements of 5-hydroxyindoloacetic acid in urine. For most carcinoids functional imaging is better than other modalities in localizing primary tumors. Surgery is the treatment of choice; non-resectable tumors are treated with somatostatin analogs or chemotherapy. Overall 5-year survival for patients with carcinoids is 67%.
doi:10.1016/j.nucmedbio.2008.04.007
PMCID: PMC2597413  PMID: 18707631
Pheochromocytomas; paragangliomas; radionuclide imaging; carcinoid tumors
22.  False-Negative 123I-MIBG SPECT Is Most Commonly Found in SDHB-Related Pheochromocytoma or Paraganglioma with High Frequency to Develop Metastatic Disease 
Endocrine-related cancer  2012;19(1):83-93.
Objective
The purpose of this study was to present the characteristics and outcome of patients with proven pheochromocytoma or paraganglioma who had false-negative 123I-MIBG SPECT.
Methods
Twenty one patients with false-negative 123I-MIBG SPECT, (6 males, 15 females) aged 13–55 years (mean 40.9 years) were included. We classified them according to the stage of the disease as non-metastatic or metastatic at the time of false-negative 123I-MIBG SPECT study, the location and size of the tumor, plasma and urinary catecholamine and metanephrine levels, genetic mutations, and outcome in terms of occurrence and progression of metastases and death.
Results
Thirteen patients were evaluated for metastatic tumors while 8 others were seen for non-metastatic disease. All primary tumors and multiple metastatic foci did not show avid 123I-MIBG uptake regardless of the tumor diameter. The majority of patients had extra-adrenal tumors with hypersecretion of normetanephrine or norepinephrine. SDHB mutation was present in 52% (n=11) of cases, RET mutation in 4% (n=1), and the rest were apparently sporadic. Twenty four percent (n=5) had metastatic disease on initial presentation. Fourteen patients were followed-up for 3–7 years. From them, 71% (n=10) had metastatic disease and majority had SDHB mutation. Nine are still alive while 5 (4 were SDHB) died due to metastatic disease.
Conclusion
A false-negative 123I-MIBG SPECT is frequently related to metastatic tumors and usually due to SDHB mutations with unfavourable prognosis. We, therefore, recommend that patients with false-negative 123I-MIBG SPECT be tested for SDHB mutations and to undergo more regular and close follow-up.
doi:10.1530/ERC-11-0243
PMCID: PMC3420013  PMID: 22167067
123I-MIBG; pheochromocytoma; paraganglioma; succinate dehydrogenase subunit B; catecholamines; metanephrines
23.  A rare case of juvenile hypertension: coexistence of type 2 multiple endocrine neoplasia -related bilateral pheochromocytoma and reninoma in a young patient with ACE gene polymorphism 
Background
Pheochromocytoma and reninoma represent two rare diseases causing hypertension. We here reported a rare case of association between type 2 multiple endocrine neoplasia related bilateral pheochromocytoma and reninoma. Moreover, polymorphism of ACE gene, which is known to be related to an increase of cardiovascular risk, has been found in the same patient.
Case presentation
A 24 year old Caucasian man came to our attention for severe hypertension, resistant to anti-hypertensive polytherapy. At the age of twenty he had undergone total thyroidectomy with lymphadenectomy for medullary carcinoma. Genetic testing showed a RET mutation of codon 918 (exon 16) not documented in other family members. During the follow-up, a progressive increase of urinary metanephrines and catecholamines was recorded. Our evaluation confirmed the presence of severe hypertension (220/140 mmHg) and a severe increase of urinary catecholamines and metanephrines. Due to the presence of hypokalemia, other causes of hypertension were researched leading to the discovery of hyperreninemia (236 μUI/ml) with mild hyperaldosteronism, and a mild increase of the renal artery resistance at ultrasound. An abdominal MRI showed multiple adrenal masses and a right kidney nodular lesion of about 2 cm.
The patient underwent bilateral adrenalectomy and right nephrectomy, and histology confirmed the presence of bilateral pheochromocytoma and right reninoma. The post-surgery laboratory evaluation showed a rapid reduction of the urinary metanephrines while plasma renin level remained low in spite of the bilateral adrenalectomy without any mineralocorticoid supplementation. To further investigate these unusual feature, we performed genetic testing for the ACE gene, which revealed the presence of ACE I/D polymorphism.
Conclusion
This unique report describes the association between two rare causes of hypertension in the same patient. Furthermore, the absence of requirement of mineralocorticoid supplementation in spite of bilateral adrenalectomy, represent an uncommon and interest finding.
doi:10.1186/s12902-015-0022-5
PMCID: PMC4472263  PMID: 26084817
Pheochromocytoma; Reninoma; MEN2B; ACE polymorphism; Hypertension
24.  Pheochromocytoma in the Horse and Measurement of Norepinephrine Levels in Horses 
Ten cases of pheochromocytoma in horses were obtained from the literature and a computer search of medical records. The clinical, laboratory and pathological features of pheochromocytoma in horses were reviewed. Pheochromocytoma is a catecholamine secreting tumor which tends to occur in older horses without breed or sex predisposition. It is usually unilateral adrenal medullary in location and benign. Malignancy was present in one horse. The most common clinical signs were sweating, tachycardia, tachypnea, muscle tremor and anxiety; however the tumor may be asymptomatic. Clinical signs were nonspecific and could be confused with other diseases, especially abdominal pain. Hyperglycemia is a consistent finding. Venous norepinephrine levels were measured in normal horses. Norepinephrine measurements may prove to be a diagnostic aid in horses with pheochromocytoma.
PMCID: PMC1790512  PMID: 17422350
25.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
Objective
The objective was to update the 2001 systematic review conducted by the Institute For Clinical Evaluative Sciences (ICES) on the use of positron emission tomography (PET) in assessing myocardial viability. The update consisted of a review and analysis of the research evidence published since the 2001 ICES review to determine the effectiveness and cost-effectiveness of PET in detecting left ventricular (LV) viability and predicting patient outcomes after revascularization in comparison with other noninvasive techniques.
Background
Left Ventricular Viability
Heart failure is a complex syndrome that impairs the contractile ability of the heart to maintain adequate blood circulation, resulting in poor functional capacity and increased risk of morbidity and mortality. It is the leading cause of hospitalization in elderly Canadians. In more than two-thirds of cases, heart failure is secondary to coronary heart disease. It has been shown that dysfunctional myocardium resulting from coronary heart disease (CAD) may recover contractile function (i.e. considered viable). Dysfunctional but viable myocardium may have been stunned by a brief episode of ischemia, followed by restoration of perfusion, and may regain function spontaneously. It is believed that repetitive stunning results in hibernating myocardium that will only regain contractile function upon revascularization.
For people with CAD and severe LV dysfunction (left ventricular ejection fraction [LVEF] <35%) refractory to medical therapy, coronary artery bypass and heart transplantation are the only treatment options. The opportunity for a heart transplant is limited by scarcityof donor hearts. Coronary artery bypass in these patients is associated with high perioperative complications; however, there is evidence that revascularization in the presence of dysfunctional but viable myocardium is associated with survival benefits and lower rates of cardiac events. The assessment of left ventricular (LV) viability is, therefore, critical in deciding whether a patient with coronary artery disease and severe LV dysfunction should undergo revascularization, receive a heart transplant, or remain on medical therapy.
Assessment of Left Ventricular Viability
Techniques for assessing myocardial viability depend on the measurement of a specific characteristic of viable myocytes such as cell membrane integrity, preserved metabolism, mitochondria integrity, and preserved contractile reserve. In Ontario, single photon emission computed tomography (SPECT) using radioactive 201thallium is the most commonly used technique followed by dobutamine echocardiography. Newer techniques include SPECT using technetium tracers, cardiac magnetic resonance imaging, and PET, the subject of this review.
Positron Emission Tomography
PET is a nuclear imaging technique based on the metabolism of radioactive analogs of normal substrates such as glucose and water. The radiopharmaceutical used most frequently in myocardial viability assessment is F18 fluorodeoxyglucose (FDG), a glucose analog. The procedure involves the intravenous administration of FDG under controlled glycemic conditions, and imaging with a PET scanner. The images are reconstructed using computer software and analyzed visually or semi-quantitatively, often in conjunction with perfusion images. Dysfunctional but stunned myocardium is characterized by normal perfusion and normal FDG uptake; hibernating myocardium exhibits reduced perfusion and normal/enhanced FDG uptake (perfusion/metabolism mismatch), whereas scar tissue is characterized by reduction in both perfusion and FDG uptake (perfusion/metabolism match).
Review Strategy
The Medical Advisory Secretariat used a search strategy similar to that used in the 2001 ICES review to identify English language reports of health technology assessments and primary studies in selected databases, published from January 1, 2001 to April 20, 2005. Patients of interest were those with CAD and severe ventricular dysfunction being considered for revascularization that had undergone viability assessment using either PET and/or other noninvasive techniques. The outcomes of interest were diagnostic and predictive accuracy with respect to recovery of regional or global LV function, long-term survival and cardiac events, and quality of life. Other outcomes of interest were impact on treatment decision, adverse events, and cost-effectiveness ratios.
Of 456 citations, 8 systematic reviews/meta-analyses and 37 reports on primary studies met the selection criteria. The reports were categorized using the Medical Advisory Secretariat levels of evidence system, and the quality of the reports was assessed using the criteria of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) developed by the Centre for Dissemination of Research (National Health Service, United Kingdom). Analysis of sensitivity, specificity, predictive values and likelihood ratios were conducted for all data as well as stratified by mean left ventricular ejection fraction (LVEF). There were no randomized controlled trials. The included studies compared PET with one or more other noninvasive viability tests on the same group of patients or examined the long-term outcomes of PET viability assessments. The quality assessment showed that about 50% or more of the studies had selection bias, interpreted tests without blinding, excluded uninterpretable segments in the analysis, or did not have clearly stated selection criteria. Data from the above studies were integrated with data from the 2001 ICES review for analysis and interpretation.
Summary of Findings
The evidence was derived from populations with moderate to severe ischemic LV dysfunction with an overall quality that ranges from moderate to low.
PET appears to be a safe technique for assessing myocardial viability.
CAD patients with moderate to severe ischemic LV dysfunction and residual viable myocardium had significantly lower 2-year mortality rate (3.2%) and higher event-free survival rates (92% at 3 years) when treated with revascularization than those who were not revascularized but were treated medically (16% mortality at 2-years and 48% 3-year event-free survival).
A large meta-analysis and moderate quality studies of diagnostic accuracy consistently showed that compared to other noninvasive diagnostic tests such as thallium SPECT and echocardiography, FDG PET has:
Higher sensitivity (median 90%, range 71%–100%) and better negative likelihood ratio (median 0.16, range 0–0.38; ideal <0.1) for predicting regional myocardial function recovery after revascularization.
Specificity (median 73%, range 33%–91%) that is similar to other radionuclide imaging but lower than that of dobutamine echocardiography
Less useful positive likelihood ratio (median 3.1, range 1.4 –9.2; ideal>10) for predicting segmental function recovery.
Taking positive and negative likelihood ratios together suggests that FDG PET and dobutamine echocardiography may produce small but sometimes important changes in the probability of recovering regional wall motion after revascularization.
Given its higher sensitivity, PET is less likely to produce false positive results in myocardial viability. PET, therefore, has the potential to identify some patients who might benefit from revascularization, but who would not have been identified as suitable candidates for revascularization using thallium SPECT or dobutamine echocardiography.
PET appears to be superior to other nuclear imaging techniques including SPECT with 201thallium or technetium labelled tracers, although recent studies suggest that FDG SPECT may have comparable diagnostic accuracy as FDG PET for predicting regional and global LV function recovery.
No firm conclusion can be reached about the incremental value of PET over other noninvasive techniques for predicting global function improvement or long-term outcomes in the most important target population (patients with severe ischemic LV dysfunction) due to lack of direct comparison.
An Ontario-based economic analysis showed that in people with CAD and severe LV dysfunction and who were found to have no viable myocardium or indeterminate results by thallium SPECT, the use of PET as a follow-up assessment would likely result in lower cost and better 5-year survival compared to the use of thallium SPECT alone. The projected annual budget impact of adding PET under the above scenario was estimated to range from $1.5 million to $2.3 million.
Conclusion
In patients with severe LV dysfunction, that are deemed to have no viable myocardium or indeterminate results in assessments using other noninvasive tests, PET may have a role in further identifying patients who may benefit from revascularization. No firm conclusion can be drawn on the impact of PET viability assessment on long-term clinical outcomes in the most important target population (i.e. patients with severe LV dysfunction).
PMCID: PMC3385418  PMID: 23074467

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