Necessity for long-term follow-up of patients with head and neck paraganglioma and mutation in the succinate dehydrogenase genes: an index case report and literature review.

OBJECTIVE: To describe a patient with hereditary head and neck paraganglioma (HNPGL) and to review the literature on these rare tumors. METHODS: We review the English-language literature regarding SDH mutations, HNPGL, hereditary paraganglioma-pheochromocytoma syndrome, and the role of functional imaging in the follow-up of these tumors. We also describe the clinical findings, imaging results, and follow-up of a man who initially presented with HNPGL and subsequently developed metastatic pheochromocytoma 20 years later. RESULTS: A 66-year-old man presented with a history of hypertension, palpitations, sweating, and elevated urinary norepinephrine. Iodine-123-metaiodobenzylguanidine (123I-MIBG) scan demonstrated a left suprarenal mass and multiple avid lesions in the abdomen, chest, and posterior cranial fossa. Histologic examination confirmed a metastatic pheochromocytoma, and molecular genetic testing revealed a mutation in the SDHD gene. The patient had had surgery 20 years earlier for HNPGL. Although most HNPGLs arise sporadically, susceptibility genes have been identified in approximately one-third of cases. Optimal follow-up remains controversial. We reiterate a need for long-term follow-up of patients with a mutation in an SDH gene. 123I-MIBG, highly specific for identifying ectopic neuroendocrine tissue, may have a role in long-term follow-up. CONCLUSIONS: Although HNPGLs rarely metastasize, their malignant potential is difficult to predict. Routine surveillance for at-risk patients is recommended. Patients with a mutation in an SDH gene should therefore undergo regular surveillance.

Hereditary fibrinogen A alpha-chain amyloidosis: phenotypic characterization of a systemic disease and the role of liver transplantation.

Variants of fibrinogen A alpha-chain (AFib) cause the most common type of hereditary renal amyloidosis in Europe and, possibly, the United States as well. Variant fibrinogen is produced in the liver, and solitary renal allografts fail within 1 to 7 years with recurrent amyloidosis. We assessed 22 AFib patients for combined liver and kidney transplantation (LKT) and report the clinical features and outcome. Twenty-one had E526V and 1, the R554L variant. Coronary atherosclerosis was identified in 68% and systemic atheromatosis in 55%. Vascular atheroma excised at endarterectomy and endomyocardial biopsies contained purely variant fibrinogen amyloid. Half had autonomic neuropathy. Six of 9 patients who underwent LKT are alive (67%), with good allograft function and no amyloidosis at median 67 months (range, 33-155 months) of follow-up. Serial technetium-99m-labeled dimercaptosuccinic acid ((99m)Tc-DMSA) renal scintigraphy in 2 cases of preemptive LKT demonstrated preserved native kidney residual function at 5 years. Four explanted livers were used successfully for domino transplantation. Fibrinogen amyloidosis is a systemic amyloid disease with visceral, vascular, cardiac, and neurologic involvement. LKT is curative; however, cardiovascular amyloidosis may preclude this option. Our data encourage evaluation of preemptive solitary liver transplantation early in the course of amyloid nephropathy to prevent hemodialysis and kidney transplantation.

Development and intra-institutional and inter-institutional validation of a comprehensive new hepatobiliary software: Part 1--Liver and gallbladder function.

OBJECTIVE: To develop a software tool for quantification of liver and gallbladder function, and to assess the repeatability and reproducibility of measurements made with it. MATERIALS AND METHODS: The software tool developed with the JAVA programming language uses the JAVA2 Standard Edition framework. After manual selection of the regions of interest on a 99mTc hepatic iminodiacetic acid study, the program calculates differential hepatic bile flow, basal duodeno-gastric bile reflux (B-DGBR), hepatic extraction fraction (HEF) of both the lobes with deconvolutional analysis and excretion half-time with nonlinear least squares fit. Gallbladder ejection fraction, ejection period (EP), ejection rate (ER), and postcholecystokinin (CCK) DGBR are calculated after stimulation with CCK-8. To assess intra-observer repeatability and intra-observer reproducibility, measurements from 10 normal participants were analyzed twice by three nuclear medicine technologists at the primary center. To assess inter-site reproducibility, measurements from a superset of 24 normal participants were also assessed once by three observers at the primary center and single observer at three other sites. RESULTS: For the 24 control participants, mean+/-SD of hepatic bile flow into gallbladder was 63.87+/-28.7%, HEF of the right lobe 100+/-0%, left lobe 99.43+2.63%, excretion half-time of the right lobe 21.50+6.98 min, left lobe 28.3+/-11.3 min. Basal DGBR was 1.2+/-1.0%. Gallbladder ejection fraction was 80+/-11%, EP 15.0+/-3.0 min, ER 5.8+/-1.6%/min, and DGBR-CCK 1.3+/-2.3%. Left and right lobe HEF was virtually identical across readers. All measures showed high repeatability except for gallbladder bile flow, basal DGBR, and EP, which exhibited marginal repeatability. Ejection fraction exhibited high reproducibility. There was high concordance among the three primary center observers except for basal DGBR, EP, and ER. Concordance between the primary site and one of the other sites was high, one was fair, and one was poor. CONCLUSION: New United States Food and Drug Administration-approved personal computer-based Krishnamurthy Hepato-Biliary Software for quantification of the liver and gallbladder function shows promise for consistently repeatable and reproducible results both within and between institutions, and may help to promote universal standardization of data acquisition and analysis in nuclear hepatology.

Hepatobiliary scintigraphy after Kasai procedure for biliary atresia: clinical correlation and prognostic value.

BACKGROUND/PURPOSE: Kasai portoenterostomy (KP) is regarded as first-line treatment for biliary atresia, although its postoperative course is often unpredictable. Hepatobiliary scintigraphy using technetium-labeled iminodiacetic acid derivatives offers a dynamic, objective assessment both of parenchymal liver function and restored biliary excretion. The value of postoperative radionuclide scans was assessed prospectively in a large population of post-KP infants. METHODS: Radionuclide scans consisted of an intravenous dose of 20 MBq of 99mTc mebrofenin iminodiacetic acid and subsequent gamma camera imaging. Four scan variables were evaluated: the hepatic extraction fraction (HEF; ie, initial liver uptake divided by the peak vascular uptake), the half-life of tracer excretion (TEX), the shape of the excretion curve, and the presence of activity in the Roux loop at 4 hours postinjection. All infants had type 3 biliary atresia with a median age at KP of 59 days (24-120 days). To assess predictive value, outcome (clearance of jaundice and need for transplant) was assessed at 6 months (for 1-week scan) and 2 years (for 6-month scan). RESULTS: Eighty-seven infants underwent a radionuclide scan at 1 week post-KP. The median HEF was 34% (10%-90%). No relationship could be identified between HEF (P = .2) or excretion curve shape (P = .9) and outcome (at 6 months), and there were too few examples of a measurable TEX to allow meaningful comparison. The only predictive element at this time point was Roux loop activity (positive predictive value, 79%; negative predictive value, 53%; for "good" isotope bowel activity). Forty-four infants completed a second scan at 6 months. Median HEF increased from a baseline of 37% (11%-90%) to 64% (8%-100%) (P < .0001), although there was no significant intercorrelation (P = .12). The most predictive variables (of outcome at 2 years) were curve shape (positive predictive value, = 95%, negative predictive value, 82%) and TEX, and the least predictive was now Roux loop activity. CONCLUSIONS: Early (at 7 days) hepatic scintigraphy is not predictive of poor outcome in general, although Roux loop activity does indicate later success. Later hepatic scintigraphy (at 6 months) allows a detailed assessment of dynamic liver function with biliary excretion variables predictive of outcome in the medium term.

A Monte Carlo analysis technique applied to cerebral perfusion SPECT scans.

OBJECTIVE: Voxel-based techniques are used to provide objective analyses of SPECT scans. The aim of this study was to develop a voxel-based analysis technique that uses a Monte Carlo method of statistical inference and assess this analysis technique for application to cerebral perfusion SPECT scans. METHODS: Assessment of the validity of this non-parametric, Monte Carlo method of statistical inference has been performed for a range of study designs, image characteristics and analysis parameters using phantom SPECT and Gaussian images. The Monte Carlo method of statistical inference and the voxel-based analysis technique were clinically evaluated for the analysis of individual cerebral perfusion SPECT scans using control subject data. In addition, a comparison has been performed with an existing analysis package that uses a theoretical parametric method of statistical inference (statistical parametric mapping). RESULTS: The Monte Carlo method was found to provide accurate statistical inference for phantom SPECT and Gaussian images independent of degrees of freedom, acquired counts, image smoothness and voxel significance level threshold. The clinical evaluation of the analysis of individual cerebral perfusion SPECT scans demonstrated satisfactory statistical inference and characterization of perfusion deficits. CONCLUSION: An analysis method incorporating a Monte Carlo method of statistical inference has been successfully applied for the analysis of cerebral perfusion SPECT scans.

Cystatin C, an easy and reliable marker for assessment of renal dysfunction in children with liver disease and after liver transplantation.

Renal dysfunction of variable severity is being increasingly recognized as a major complication of calcineurin inhibitors (CI), in some patients even necessitating renal transplantation. Close and effective monitoring of the renal function is indicated. Current methods for this monitoring are calculation of the glomerular filtration rate (GFR) based on creatinine or exogenous substances like 51Cr-EDTA. The first method is unreliable in children and the second is expensive and cumbersome. Cystatin C has been shown to be an accurate marker of glomerular filtration but has not been evaluated in a large cohort of pediatric patients before and after liver transplantation (LT). We evaluated the accuracy of cystatin C in 62 children (30 male) with LT, who had their 51Cr-EDTA measured on 40 occasions prior to LT and on 47 occasions after LT. The reciprocal of cystatin C correlated better with 51Cr-EDTA GFR (r = .78) than the reciprocal of creatinine (r = .40). Diagnostic accuracy in the identification of reduced GFR was assessed by ROC analysis. Cystatin C yielded the highest area under the ROC curve (AUC) in all groups assessed. From these data a cutoff level of cystatin C predicting 51Cr-EDTA GFR < 80 ml/min/1.73 m2 was calculated. A level of 1.06 mg/L was found to have a sensitivity of 91% and a specificity of 81%. Applying this cutoff level in our patient group would have avoided 51Cr-EDTA GFR estimation in 43 of the 87 estimations. In conclusion, the use of this simple test could be recommended as screening of renal dysfunction in children with liver disease and after LT.

Bilateral orbital metastases from a neuroendocrine tumor.

When neuroendocrine tumors metastasize to the orbit, they usually do so as solitary lesions, sometimes involving an extraocular muscle. A 70-year-old woman with a known neuroendocrine tumor had bilateral painful proptosis, orbital soft tissue swelling, and ophthalmoplegia. Imaging showed masses within all the extraocular muscles. Orbital biopsy disclosed metastatic neuroendocrine tumor cells within the connective tissue.

Diurnal, week-to-week, and long-term variation in urine deoxypyridinoline cross-link excretion in healthy older women.

OBJECTIVES: To establish a reference range for morning and afternoon excretion of urinary deoxypyridinoline (DPD) in apparently healthy older women selected from a volunteer database. To assess the extent of diurnal variation and short and long-term within-subject longitudinal variation. DESIGN: Prospective, observational, cohort study. SETTING: Clinical Age Research Unit, King's College School of Medicine, London, United Kingdom. PARTICIPANTS: Forty-two women aged 68 to 89 (median age 75) selected from a volunteer database. METHODS: Subjects completed an osteoporosis risk factor questionnaire and a physical examination and had a measurement of the broadband ultrasound attenuation and speed of sound of their right heel. Subjects provided six urine samples: morning and afternoon at baseline and 1 week and 60 weeks later for measurement of DPD. RESULTS: The mean baseline values for DPD of morning and afternoon samples were 7.2 nM/mM and 6.0 nM/mM creatinine, respectively. The majority of subjects showed diurnal variation, with mean afternoon values 15% lower than morning values (P <.0001 for afternoon vs morning values). The mean difference in DPD after 60 weeks was 1.67 nM/mM for morning and 1.34 nM/mM for afternoon creatinine. This difference was not significant. Some individuals displayed marked changes in DPD excretion with no change in health status or treatment. DPD excretion in a nonfasting afternoon sample showed similar characteristics to morning void samples in terms of scatter, week-to-week variation, and long-term reproducibility. CONCLUSIONS: The study was set up to provide background data to assist the development of a clinical osteoporosis service for older women. Further studies are needed to determine whether these measurements predict fracture risk and respond to treatment changes in this age group.

Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation.

BACKGROUND: Osteodystrophy is a well-described complication of chronic liver disease. Previous reports in adults and children undergoing liver transplantation (LT) were discordant, with the former showing no improvement of bone disease in the first year after transplantation and the latter demonstrating remarkable benefit from it. Our aim was to perform a pilot study on osteodystrophy in children undergoing LT and evaluate the contribution of growth on bone mineral density (BMD) changes. METHODS: We studied six patients (two male), with a median age at transplantation of 8.8 (range 3.8-16.6) years. Indications for transplantation were biliary atresia and progressive familial intrahepatic cholestasis (three patients each). BMD was studied with dual-energy x-ray absorptiometry and biochemical markers of liver and bone function in patients before and at 3, 6, and 12 months after LT. RESULTS: Median L2-L4 spinal BMD was 0.54 g/cm2 (range 0.29-0.87) before LT, and 0.58 g/cm2 (0.27-0.86) at 3 months, 0.66 g/cm2 (0.36-1.00) at 6 months, and 0.76 g/cm2 (0.44-1.02) at 12 months after LT (P=0.005). Median height was 133 (range 93-167) cm before LT, and 134 (93-167) at 3 months, 136 (97-167) at 6 months, and 139 (102-167) at 12 months after LT. There was direct correlation between height gain and total body BMD improvement (r=0.929, P=0.007). CONCLUSION: BMD in children with chronic cholestatic liver disease improves remarkably by 12 months after LT. Catch-up growth in children can account for the different effect of LT on bone density between adult and pediatric populations in the first year after surgery.