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Skin Autofluorescence, a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products, Predicts Mortality in Hemodialysis Patients

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.

Extra-intestinal manifestations of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care—common for other disorders—is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase.We present a clinical overview of extra-intestinal manifestations, including management and treatment options for the FAP syndrome. Furthermore, we provide recommendations for surveillance of FAP complications based on available literature.

Symptom scoring systems to diagnose distal polyneuropathy in diabetes : the Diabetic Neuropathy Symptom score

Aims To provide one of the diagnostic categories for distal diabetic polyneuro‐pathy,several symptom scoring systems are available, which are often extensive andlack in validation. We validated a new four‐item Diabetic Neuropathy Symptom (DNS) scorefor diagnosing distal diabetic polyneuropathy.

Simple Noninvasive Measurement of Skin Autofluorescence

Abstract: Accumulation of advanced glycation end products (AGEs) is thought to play a role in the pathogenesis of chronic complications of diabetes mellitus and renal failure. Several studies indicate that AGE accumulation in tissue may reflect the cumulative effect of hyperglycemia and oxidative stress over many years. Simple quantitation of AGE accumulation in tissue could provide a tool for assessing the risk of long‐term complications. Because several AGEs exhibit autofluorescence, we developed a noninvasive autofluorescence reader (AFR). Skin autofluorescence measured with the AFR correlates with collagen‐linked fluorescence and specific skin AGE levels from skin biopsy samples. Furthermore, skin autofluorescence correlates with long‐term glycemic control and renal function, and preliminary results show correlations with the presence of long‐term complications in diabetes. The AFR may be useful as a clinical tool for rapid assessment of risk for AGE‐related long‐term complications in diabetes and in other conditions associated with AGE accumulation.

Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy

Aims/hypothesisThe accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader (AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy.Materials and methodsSkin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP+), 23 diabetic patients without clinical neuropathy (NP−) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity (BRS) were measured by Finapres to assess autonomic nervous function.ResultsAutofluorescence was increased in NP− compared with control subjects. In NP+ patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP+ and NP− groups. Autofluorescence correlated with age, diabetes duration, mean HbA1c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy.Conclusions/interpretationSkin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long-term diabetic complications.

Impact of 18F-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography (FDG-PET) in Patients with Biochemical Evidence of Recurrent or Residual Medullary Thyroid Cancer

AbstractBackground: Conventional imaging such as with 99mTc(V)dimercaptosunnic acid (DMSA), 111In-octreotide scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) rarely localizes occult medullary thyroid cancer (MTC). The role of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is not well defined. The aim of this study was to examine the usefulness of postoperative FDG-PET in localizing MTC metastases. Methods: FDG-PET was performed in 26 patients with elevated serum tumor markers after total thyroidectomy with central compartment dissection and additional neck dissection on indication. Patient- and lesion-based results were compared with the findings of conventional nuclear imaging and validated by morphological imaging (CT, MRI, ultrasonography), including bone scintigraphy and pathology when possible. Clinical impact was evaluated. Results: FDG-PET detected foci in 50% of patients with lesion-based sensitivity of 96%. 111In-octreotide detected foci in 19% with sensitivity of 41%, and 99mTc(V)DMSA scintigraphy and morphological imaging detected foci in 21% and 40%, respectively, with sensitivity of 57% and 87%. No lesions were found in 11 patients (42%). Positive FDG-PET findings led to surgical intervention in nine patients (35%). They all underwent surgery for removal of residual tumor or metastases. One patient achieved disease-free status. In all patients who underwent surgery, serum calcitonin levels were reduced by an average of 58 ± 31%. Conclusions: For detection of occult MTC lesions, FDG-PET is superior to conventional nuclear imaging and is the best detection method yet available. FDG-PET in postoperative follow-up has clinical value and may be used for guiding reoperation and additional morphological imaging preoperatively.

Imatinib induces hypothyroidism in patients receiving levothyroxine

Interactions of imatinib with other drugs have been scarcely reported. We report a previously unknown effect of imatinib on levothyroxine therapy. Eleven patients (1 with gastrointestinal stromal tumor and 10 with medullary thyroid carcinoma) received imatinib. Eight had undergone thyroidectomy and used levothyroxine, and 3 had the thyroid in situ. Thyroid function was measured before, during, and within 2 weeks after any change in either imatinib or levothyroxine dosage. We observed symptoms of hypothyroidism in all patients who had undergone thyroidectomy, whereas patients with the thyroid in situ remained clinically and biochemically euthyroid. On average, thyrotropin (INN, thyrotrophin) levels increased to 384% ± 228% of the upper limit in patients after thyroidectomy, whereas free thyroxine (fT4) and free tri‐iodothyronine (fT3) values remained within the reference range (59% ± 17% of the upper limit for fT4 and 63% ± 4% of the upper limit for fT3). Clinicians should be aware that hypothyroid subjects receiving imatinib have a high likelihood for increased levothyroxine replacement and should be closely monitored for elevations in thyrotropin indicating worsening hypothyroidism.

Quality of life in patients with diabetic foot ulcers

PURPOSE To compare Quality of Life (QoL) between diabetic patients with (former or present) and without foot ulcers. METHODS Two patient groups of comparable age, sex distribution, type distribution and duration of diabetes were studied. Fourteen patients with former or present, but clinically stable diabetic foot ulcers (DFUs) were studied. The control group was 24 unknown patients with DFUs. None of the participants had other diabetic complications or conditions that would potentially affect QoL. A diabetic foot risk score and QoL were assessed. QoL was scored with the RAND-36, the Barthel Score (ADL) and the Walking and Walking Stairs Questionnaire (WSQ). RESULTS Marked and significant differences were found in physical functioning (p < 0.001), social functioning (p < 0.05), physical role (p < 0.001) and health experience (p < 0.05) between the two groups with the RAND-36 and the four subscales of the WSQ (all p < 0.001). On all these scales, QoL was significantly poorer in the study group. A correlation was found between the risk scores and QoL (physical functioning and physical role Spearmans r: -0.66, -0.56 and WSQ -0.63, -0.64, -0.67 and 0.71, respectively). CONCLUSION Presence or history of DFUs has a large impact on physical role, physical functioning and mobility. Physical impairments especially influenced QoL. Probably, QoL can be increased by providing attention that will enhance mobility and by giving advice about adaptations and special equipment.Purpose: To compare Quality of Life (QoL) between diabetic patients with (former or present) and without foot ulcers. Methods: Two patient groups of comparable age, sex distribution, type distribution and duration of diabetes were studied. Fourteen patients with former or present, but clinically stable diabetic foot ulcers (DFUs) were studied. The control group was 24 unknown patients with DFUs. None of the participants had other diabetic complications or conditions that would potentially affect QoL. A diabetic foot risk score and QoL were assessed. QoL was scored with the RAND-36, the Barthel Score (ADL) and the Walking and Walking Stairs Questionnaire (WSQ). Results: Marked and significant differences were found in physical functioning (p < 0.001), social functioning (p < 0.05), physical role (p < 0.001) and health experience (p < 0.05) between the two groups with the RAND-36 and the four sub scales of the WSQ (all p 0.001). On all these scales, QoL was significantly poorer in the study group. A correlation was found between the risk scores and QoL (physical functioning and physical role Spearmans r: 0.66, 0.56 and WSQ 0.63, 0.64, 0.67 and 0.71, respectively). Conclusion: Presence or history of DFUs has a large impact on physical role, physical functioning and mobility. Physical impairments especially influenced QoL. Probably, QoL can be increased by providing attention that will enhance mobility and by giving advice about adaptations and special equipment.

6-[F-18]Fluoro-l-Dihydroxyphenylalanine Positron Emission Tomography Is Superior to Conventional Imaging with 123I-Metaiodobenzylguanidine Scintigraphy, Computer Tomography, and Magnetic Resonance Imaging in Localizing Tumors Causing Catecholamine Excess

CONTEXT Catecholamine excess is rare, but symptoms may be life threatening. OBJECTIVE The objective of the study was to investigate the sensitivity of 6-[F-18]fluoro-l-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA PET), compared with (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy and computer tomography (CT)/magnetic resonance imaging (MRI) for tumor localization in patients with catecholamine excess. DESIGN AND SETTING All consecutive patients with catecholamine excess visiting the University Medical Center Groningen, Groningen, The Netherlands, between March 2003 and January 2008 were eligible. PATIENTS Forty-eight patients were included. The final diagnosis was pheochromocytoma in 40, adrenal hyperplasia in two, paraganglioma in two, ganglioneuroma in one, and unknown in three. MAIN OUTCOME MEASURES Sensitivities and discordancy between (18)F-DOPA PET, (123)I-MIBG, and CT or MRI were analyzed for individual patients and lesions. Metanephrines and 3-methoxytyramine in plasma and urine and uptake of (18)F-DOPA with PET were measured to determine the whole-body metabolic burden and correlated with biochemical tumor activity. The gold standard was a composite reference standard. RESULTS (18)F-DOPA PET showed lesions in 43 patients, (123)I-MIBG in 31, and CT/MRI in 32. Patient-based sensitivity for (18)F-DOPA PET, (123)I-MIBG, and CT/MRI was 90, 65, and 67% (P < 0.01 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 1.0 (123)I-MIBG vs. CT/MRI). Lesion-based sensitivities were 73, 48, and 44% (P < 0.001 for (18)F-DOPA PET vs. both (123)I-MIBG and CT/MRI, P = 0.51 (123)I-MIBG vs. CT/MRI). The combination of (18)F-DOPA PET with CT/MRI was superior to (123)I-MIBG with CT/MRI (93 vs. 76%, P < 0.001). Whole-body metabolic burden measured with (18)F-DOPA PET correlated with plasma normetanephrine (r = 0.82), urinary normetanephrine (r = 0.84), and metanephrine (r = 0.57). CONCLUSION To localize tumors causing catecholamine excess, (18)F-DOPA PET is superior to (123)I-MIBG scintigraphy and CT/MRI.

18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation.

Curative treatment for recurrent medullary thyroid cancer (MTC), diagnosed by rising serum calcitonin, is surgery, but tumor localization is difficult. Therefore, the value of 18F-dihydroxyphenylanaline PET (18F-DOPA PET), 18F-FDG PET, 99mTc-V-di-mercaptosulfuricacid (DMSA-V) scintigraphy, and MRI or CT was studied. Methods: Twenty-one patients with biochemical recurrent or residual MTC underwent 18F-DOPA PET, 18F-FDG PET, DMSA-V scintigraphy, and MRI or CT. Patient- and lesion-based sensitivities were calculated using a composite reference consisting of all imaging modalities. Results: In 76% of all patients with MTC, one or more imaging modalities was positive for MTC lesions. In 6 of 8 patients with a calcitonin level of <500 ng/L, imaging results were negative. In 15 patients with positive imaging results, 18F-DOPA PET detected 13 (sensitivity, 62%; with 4.6 lesions per patient [lpp]). Morphologic imaging (n = 19) was positive in 7 (sensitivity, 37%; 4.7 lpp), DMSA-V (n = 18) in 5 (sensitivity, 28%; 1.1 lpp), and 18F-FDG PET (n = 17) in 4 (sensitivity, 24%; 1.6 lpp). In a lesion-based analysis, 18F-DOPA PET detected 95 of 134 lesions (sensitivity, 71%), morphologic imaging detected 80 of 126 (sensitivity, 64%), DMSA-V detected 20 of 108 (sensitivity, 19%), and 18F-FDG PET detected 48 of 102 (sensitivity, 30%). In 2 of 3 patients with a calcitonin/carcinoembryonic antigen (CEA) doubling time of ≤12 mo, 18F-FDG PET performed better than 18FDOPA PET; in the third patient, 18F-FDG PET was not performed. Conclusion: MTC lesions are best detectable when serum calcitonin was >500 ng/L. 18F-DOPA PET is superior to 18F-FDG PET, DMSA-V, and morphologic imaging. With short calcitonin doubling times (≤12 mo), 18F-FDG PET may be superior.