B. Goichot

Oral cobalamin therapy for the treatment of patients with food-cobalamin malabsorption.

BACKGROUND The standard treatment for cobalamin (vitamin B(12)) deficiency involves regular intramuscular cobalamin injection. It has been suggested that oral cobalamin therapy may be effective for treating patients who have food-cobalamin malabsorption. SUBJECTS AND METHODS We prospectively studied 10 patients with cobalamin deficiency and well-established food-cobalamin malabsorption who received 3000 microg or 5000 microg of oral crystalline cyanocobalamin once a week for at least 3 months. Complete blood counts and serum cobalamin, homocysteine, and folate levels were determined at baseline and after 3 months of treatment. Patients were reexamined after 6 months. RESULTS After 3 months of treatment, all patients had increased hemoglobin levels (mean increase, 1.9 g/dL; 95% confidence interval: 0.9 to 3.9 g/dL;P <0.01 compared with baseline) and decreased erythrocyte cell volume (mean decrease, 7.8 fL; 95% confidence interval: 0.9 to 16.5 fL;P<0.001). However, 2 patients had only minor, if any, responses. Serum cobalamin levels were increased in all 8 patients in whom it was measured. CONCLUSION Our findings suggest that moderate doses of crystalline cyanocobalamin given orally may be an effective treatment for food-cobalamin malabsorption.

Anémies par carence en vitamine B12 chez le sujet âgé de plus de 75 ans : nouveaux concepts. À propos de 20 observations*

PURPOSE New hypotheses have recently been developed on vitamin B12 deficiency and the frequently observed occurrence in the elderly subject of food cobalamin malabsorption, i.e., the non-dissociation of B12 and its carrier protein (ND B12), and the possibility of rectifying this imbalance by oral crystalline B12 supplementation. The aim of this study was therefore to confirm these hypotheses in a series of patients aged over 75 years with anemia due to B12 deficiency. METHODS A retrospective study was carried out over a 5-year period on patients aged over 75 years presenting with megaloblastic anemia (hemoglobin [Hb] < 12 g/dL) and vitamin B12/cobalamin deficiency (B12 < 160 pg/mL). RESULTS Twenty cases were analyzed. The average age of the patient population was 82.5 +/- 6 years, and the F/M sex ratio was 1:2. Mean Hb levels were 7.9 +/- 2.4 g/dL, mean serum B12 levels were 83 +/- 24 pg/mL, and mean homocysteinemic levels were 35 +/- 27 mumol/L. The diagnosis was as follows: food cobalamin malabsorption/ND B12 (n = 10), Biermers disease/pernicious anemia (n = 5), malabsorption due to pancreatic insufficiency (n = 1), and low dietary B12 levels (n = 1). Disorders associated with ND B12 were: atrophic gastritis and Helicobacter pylori infection (n = 6), antacid or biguanide intake (n = 3), alcohol abuse (n = 2), or idiopathic syndrome (n = 2). In the patients who were followed up (n = 10), i.m. (n = 5) or oral (n = 5) administration of crystalline B12 resulted in the correction of hematological abnormalities. CONCLUSION In the elderly subject, food cobalamin/ND B12 malabsorption appears to be the main cause of B12 deficiency, and is frequently associated with atrophic gastritis. In these cases, administration of oral crystalline B12 may be an efficient means of treating this disorder.

Metabolome profiling by HRMAS NMR spectroscopy of pheochromocytomas and paragangliomas detects SDH deficiency: clinical and pathophysiological implications.

Succinate dehydrogenase gene (SDHx) mutations increase susceptibility to develop pheochromocytomas/paragangliomas (PHEOs/PGLs). In the present study, we evaluate the performance and clinical applications of 1H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy–based global metabolomic profiling in a large series of PHEOs/PGLs of different genetic backgrounds. Eighty-seven PHEOs/PGLs (48 sporadic/23 SDHx/7 von Hippel-Lindau/5 REarranged during Transfection/3 neurofibromatosis type 1/1 hypoxia-inducible factor 2α), one SDHD variant of unknown significance, and two Carney triad (CTr)–related tumors were analyzed by HRMAS-NMR spectroscopy. Compared to sporadic, SDHx-related PHEOs/PGLs exhibit a specific metabolic signature characterized by increased levels of succinate (P < .0001), methionine (P = .002), glutamine (P = .002), and myoinositol (P < .0007) and decreased levels of glutamate (P < .0007), regardless of their location and catecholamine levels. Uniquely, ATP/ascorbate/glutathione was found to be associated with the secretory phenotype of PHEOs/PGLs, regardless of their genotype (P < .0007). The use of succinate as a single screening test retained excellent accuracy in distinguishing SDHx versus non–SDHx-related tumors (sensitivity/specificity: 100/100%). Moreover, the quantification of succinate could be considered a diagnostic alternative for assessing SDHx-related mutations of unknown pathogenicity. We were also able, for the first time, to uncover an SDH-like pattern in the two CTr-related PGLs. The present study demonstrates that HRMAS-NMR provides important information for SDHx-related PHEO/PGL characterization. Besides the high succinate–low glutamate hallmark, SDHx tumors also exhibit high values of methionine, a finding consistent with the hypermethylation pattern of these tumors. We also found important levels of glutamine, suggesting that glutamine metabolism might be involved in the pathogenesis of SDHx-related PHEOs/PGLs.

Molecular Imaging of Gastroenteropancreatic Neuroendocrine Tumors: Current Status and Future Directions

Through diagnostic imaging and peptide receptor radionuclide therapy, nuclear medicine has earned a major role in gastroenteropancreatic neuroendocrine tumors (GEP NETs). GEP NETs are diagnosed fortuitously or on the basis of symptoms or hormonal syndrome. The functional tumor characteristics shown by radionuclide imaging allow for more accurate staging and treatment selection. Tumor grade helps determine which tracer should be selected. In the past, 111In-pentetreotide has been successful in well-differentiated (G1 and G2) tumors. However, PET/CT imaging with novel somatostatin analogs (e.g., 68Ga-DOTATOC, 68Ga-DOTATATE, 68Ga-DOTANOC, and 64Cu-DOTATATE) now offers improved sensitivity. 18F-fluorodihydroxyphenylalanine (18F-FDOPA) is another interesting radiopharmaceutical. 18F-FDOPA sensitivity is influenced by a tumor’s capacity to take up, decarboxylate, and store amine precursors. 18F-FDOPA sensitivities are highest in ileal NETs and may also be helpful in insulinomas. A high uptake of 18F-FDG with a low uptake of somatostatin analog usually indicates poorly differentiated tumors (G3). Starting from these principles, this article discusses theranostic approaches to GEP NETs, taking into account both primary and metastatic lesions.

Sympathovagal response to orthostatism in overt and in subclinical hyperthyroidism

Heart rate variability (HRV) is a measure of the physiological variation of R-R intervals, reflecting the sympathovagal balance. In both overt and subclinical hyperthyroidism, a relative increase in sympathetic activity has been demonstrated, mainly due to a decrease in vagal activity. The modifications of HRV during orthostatism in normal subjects resemble those seen in hyperthyroidism. We have studied the response of 19 patients with overt hyperthyroidism and 12 with subclinical hyperthyroidism during orthostatism using HRV and compared the results to those of 32 healthy controls. In the three groups, the R-R intervals decreased in the same proportion after orthostatism. The low frequency power (LF)/[LF + high frequency power (HF)] ratio, which reflects the sympathetic tone, also increased in the same proportion in the three groups. However, the mechanisms of the modulation of the sympathovagal balance during orthostatism were different among the three groups. In controls, the relative increase of sympathetic tone after orthostatism was due principally to a decrease in vagal tone (reflected by decreased power in the HF band), while in overt hyperthyroidism, where the power in the HF band was already minimal in the lying position, there was a clear increase in the LF band power during orthostatism. The results were intermediate in the subclinical hyperthyroidism group, reflecting a continuum of effects of the thyroid hormone excess on the autonomic nervous system. Our study shows that despite an apparent normal cardiovascular adaptation to orthostatism in hyperthyroidism, the modulation of the autonomic nervous system is profoundly modified.

Evaluation of Elecsys® free triiodothyronine assay: relevance of age-related reference ranges

OBJECTIVE This study aimed at evaluating Elecsys free triiodothyronine (FT3) assay performed on an Elecsys 2010 system, while paying special attention to age relationship in euthyroid subjects. DESIGN AND METHODS FT3 levels were measured in 149 euthyroid control subjects aged between 2 and 92 years old, 33 hyperthyroid and particular euthyroid patients: female in the last 3 months of pregnancy (n = 30), nonthyroidal ill hospitalized in medical (NTlm, n = 31), or intensive care units (NTlc, n = 31) and amiodarone-treated (n = 27). RESULTS FT3 was inversely related to age in controls (r = -0.67). Three reference ranges were used: below 20 years 4.5-9.0 pmol/L, between 20 and 60 years 3.9-7.2, and over 60 years 2.4-6.5. Compared to age-matched controls, FT3 decreased in pregnancy, NTlm, NTlc, and amiodarone groups. Use of age-related reference ranges improved the specificity markedly in amiodarone patients and to a lesser extent in NTlm and TClc patients. CONCLUSIONS The reliability of the Elecsys FT3 assay was found to be satisfactory for clinical use, when the age of patients was taken into account.

Metabolomic profile of the adrenal gland: from physiology to pathological conditions

In this study, we i) assessed the metabolic profile of the normal adrenal cortex and medulla of adult human subjects by means of (1)H-high-resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy; ii) compared the biochemical profile of adenoma (Ad), adrenal cortical carcinoma (ACC), and pheochromocytoma (PCC) samples with that of healthy adrenal tissue samples; and iii) investigated the metabolic differences between ACCs and Ads as well as between ACCs and PCCs. Sixty-six tissue samples (13 adrenal cortical tissue, eight medullary tissue, 13 Ad, 12 ACC, and 20 PCC samples) were analyzed. Adrenaline and noradrenaline were undetectable in cortical samples representing the metabolic signature of the tissue derived from neural crest. Similarity between the metabolic profile of Ads and that of the normal adrenal cortex was shown. Inversely, ACC samples clearly made up a detached group exhibiting the typical stigmata of neoplastic tissue such as choline-containing compounds, biochemical markers of anaerobic processes, and increased glycolysis. Significantly higher levels of lactate, acetate, and total choline-containing compounds played a major role in the differentiation of ACCs from Ads. Moreover, the high fatty acid content of ACCs contributed to the cluster identification of ACCs. Of the 14 sporadic PCC samples, 12 exhibited predominant or exclusive noradrenaline secretion. The noradrenaline:adrenaline ratio was inverted in the normal medullary tissue samples. Multiple endocrine neoplasia type 2- and NF1-related PCC samples exhibited both adrenaline and noradrenaline secretion. In the von Hippel-Lindau disease-related PCC samples, only noradrenaline secretion was detected by HRMAS NMR spectroscopy. This study is one of the first applications of metabolomics to adrenal pathophysiology and it is the largest study to report HRMAS NMR data related to the adrenal cortex and adrenal cortical tumors.

Évolution et pronostic à long terme des syndromes inflammatoires biologiques persistants inexpliqués

Purpose. – Unexplained inflammatory syndrome is a frequent and worrying condition in Internal Medicine. However, the long-term clinical outcome of these patients cannot be inferred from the literature. The aim of this study is to describe the long-term follow-up and the prognosis of a group of patients hospitalised for an inflammatory syndrome and discharged without causal diagnosis. Methods. – This retrospective study was carried out on 46 patients, 15 men and 31 women, aged 21 to 90 years, hospitalised between 1992 and 1999. Data concerning the hospital stay were obtained from the patients’ medical record. Follow-up was performed by consulting the treating physician. Results. – The prognosis of these patients is fairly good. In one third of the cases, the inflammatory syndrome resolved spontaneously (n = 13). In the second third, a definite diagnosis was established after discharge (n = 14) and consisted mainly of chronic inflammatory diseases (n = 9), cured with a specific treatment. In the remaining third (n = 12), the inflammatory syndrome persisted, in clinically asymptomatic patients. Conclusion. – These results suggest that the persistence of an inflammatory syndrome is not a poor prognostic factor. Thus we propose for patients discharged with an undiagnosed persistent inflammatory syndrome despite thorough investigations, a simple clinical and biological follow-up instead of repeated etiological investigations.

Métastases musculaires révélatrices d'un adénocarcinome

The authors report the case of a 67-year old man, with no particular medical history, presenting a large swelling of the left thigh. Investigations conclude to metastases located in muscles of the left thigh and of the pelvis, secondary to an adenocarcinoma of presumed pancreatic origin. With reference to this case, features of muscular metastases are reviewed. Muscular metastases seldom occur during the course of a cancer and are exceptionally the first manifestation of a neoplastic process. They are usually described as a painful mass, but symptoms can be misleading and delay diagnosis. Images obtained by ultrasonography, tomodensitometry and magnetic resonance imaging are not specific and histological examination is necessary to confirm the diagnosis.

Répercussions cardiaques des dysthyroïdies frustes: Données expérimentales, cliniques et épidémiologiques

Points essentiels ● Alors que les consequences cardiovasculaires des dysthyroidies dites averees sont largement connues et que leur traitement est globalement bien etabli, les dysthyroidies frustes demeurent a l’origine d’interrogations et de controverses concernant leur impact cardiovasculaire et leurs modalites de prise charge. ● L’hyperthyroidie fruste est une situation frequente chez le sujet âge, le plus souvent en rapport avec un goitre multinodulaire. ● Meme si plusieurs etudes epidemiologiques ont montre que l’hyperthyroidie fruste etait associee a une augmentation du risque de fibrillation auriculaire et a une mortalite cardiovasculaire accrue, il n’y a actuellement pas de donnees pratiques solides sur lesquelles fonder la prise en charge de ces patients. ● Concernant l’hypothyroidie fruste, le risque semble surtout vasculaire, mais son appreciation definitive necessite encore la realisation d’enquetes epidemiologiques rigoureuses.