Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis.

Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations.

High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis.

BACKGROUND: Indolent systemic mastocytosis (ISM) is a rare disease characterized by accumulation of abnormal mast cells in various tissues, including bone marrow. Symptoms are usually related to release of mast cell mediators. The aims are to establish the prevalence of osteoporotic fractures in ISM and to investigate the association with serum tryptase and the urinary histamine metabolites, methylhistamine (MH), and methylimidazole acetic acid. METHODS: The fracture prevalence in 157 patients (65 men; 92 women), mean age 54 ± 12 years, was assessed by vertebral morphometry and data from patient records, supplemented by a questionnaire. Bone mineral density (BMD) of lumbar spine and femoral neck was measured, and tryptase and histamine metabolites were analysed. RESULTS: We registered 235 lifetime fractures in 154 patients, including 140 osteoporotic (low-energy trauma) fractures, of which 62% were vertebral, 1% hip and 36% other nonvertebral fractures. Osteoporotic fractures and osteoporosis were found in 37% and 28% of the patients, respectively. In men, the prevalence of these osteoporotic manifestations (46% <50 years; 73% ≥50 years) was much higher compared with women (18% <50 years; 58% ≥50 years). Older age, male gender, and higher urinary MH were independently related to the osteoporotic manifestations. CONCLUSIONS: This first publication about prevalence of fractures and osteoporosis in patients with ISM shows that the risk of osteoporotic fractures is high, especially in men. Higher urinary MH levels are associated with a higher risk of osteoporotic manifestations. Routine measurements of BMD and vertebral morphometry are warranted in these patients for early detection of osteoporosis.

Tryptase and histamine metabolites as diagnostic indicators of indolent systemic mastocytosis without skin lesions.

BACKGROUND: Risk indicators of indolent systemic mastocytosis (ISM) in adults with clinical suspicion of ISM without accompanying skin lesions [urticaria pigmentosa (UP)] are lacking. This study aimed at creating a decision tree using clinical characteristics, serum tryptase, and the urinary histamine metabolites methylimidazole acetic acid (MIMA) and methylhistamine (MH) to select patients for bone marrow investigations to diagnose ISM. METHODS: Retrospective data analysis of all adults, in whom bone marrow investigations were performed to diagnose ISM, was carried out. RESULTS: In total, 142 patients were included. SM was absent in all 44 patients with tryptase <10 µg/l, in 45 of 98 (46%) patients with tryptase ≥10 µg/l and in 18 of 52 patients (35%) with tryptase >20 µg/l. Above 43 µg/l, all patients had ISM (n = 11). Male gender, insect venom anaphylaxis as presenting symptom, tryptase, MIMA, and MH were independent ISM predictors. If tryptase was ≥10 µg/l, the diagnostic accuracy of MIMA and MH was high (areas under the ROC curve 0.92). CONCLUSIONS: In suspected patients without UP, the ISM risk is very low (if present at all) if tryptase is <10 µg/l. If tryptase is ≥10 µg/l, this risk depends on MIMA and MH, being low if these are normal, but high if these are elevated. Male gender and insect venom anaphylaxis are additional risk indicators. We recommend refraining from bone marrow examinations in suspected patients without UP if tryptase is <10 µg/l. Our results question the reliability of the minor diagnostic World Health Organization criterion of tryptase >20 µg/l.

Gene expression profile, pathways, and transcriptional system regulation in indolent systemic mastocytosis.

BACKGROUND: Mastocytosis is an uncommon disease resulting from proliferation of abnormal mast cells infiltrating skin, bone marrow, liver, and other tissues. The aim of this study was to find differences in gene expression in peripheral blood cells of patients with indolent systemic mastocytosis compared to healthy controls. The second aim was to define a specific gene expression profile in patients with mastocytosis. METHODS: Twenty-two patients with indolent systemic mastocytosis and 43 healthy controls were studied. Whole genome gene expression analysis was performed on RNA samples isolated from the peripheral blood. For amplification and labelling of the RNA, the Illumina TotalPrep 96 RNA Amplification Kit was used. Human HT-12_V3_expression arrays were processed. Data analysis was performed using GeneSpring, Genecodis, and Transcriptional System Regulators. RESULTS: Comparison of gene expression between patients and controls revealed a significant difference (P < 0.05 corrected for multiple testing) and the fold change difference >2 in gene expression in 2303 of the 48.794 analysed transcripts. Functional annotation indicated that the main pathways in which the differently expressed genes were involved are ubiquitin-mediated proteolysis, MAPK signalling pathway, pathways in cancer, and Jak-STAT signalling. The expression distributions for both groups did not overlap at all, indicating that many genes are highly differentially expressed in both groups. CONCLUSION: We were able to find abnormalities in gene expression in peripheral blood cells of patients with indolent systemic mastocytosis and to construct a gene expression profile which may be useful in clinical practice to predict the presence of mastocytosis and in further research of novel drugs.

Gene expression analysis predicts insect venom anaphylaxis in indolent systemic mastocytosis.

BACKGROUND: Anaphylaxis to insect venom (Hymenoptera) is most severe in patients with mastocytosis and may even lead to death. However, not all patients with mastocytosis suffer from anaphylaxis. The aim of the study was to analyze differences in gene expression between patients with indolent systemic mastocytosis (ISM) and a history of insect venom anaphylaxis (IVA) compared to those patients without a history of anaphylaxis, and to determine the predictive use of gene expression profiling. METHODS: Whole-genome gene expression analysis was performed in peripheral blood cells. RESULTS: Twenty-two adults with ISM were included: 12 with a history of IVA and 10 without a history of anaphylaxis of any kind. Significant differences in single gene expression corrected for multiple testing were found for 104 transcripts (P < 0.05). Gene ontology analysis revealed that the differentially expressed genes were involved in pathways responsible for the development of cancer and focal and cell adhesion suggesting that the expression of genes related to the differentiation state of cells is higher in patients with a history of anaphylaxis. Based on the gene expression profiles, a naïve Bayes prediction model was built identifying patients with IVA. CONCLUSIONS: In ISM, gene expression profiles are different between patients with a history of IVA and those without. These findings might reflect a more pronounced mast cells dysfunction in patients without a history of anaphylaxis. Gene expression profiling might be a useful tool to predict the risk of anaphylaxis on insect venom in patients with ISM. Prospective studies are needed to substantiate any conclusions.

Mastocytosis and insect venom allergy: diagnosis, safety and efficacy of venom immunotherapy.

The most important causative factor for anaphylaxis in mastocytosis are insect stings. The purpose of this review is to analyse the available data concerning prevalence, diagnosis, safety and effectiveness of venom immunotherapy (VIT) in mastocytosis patients. If data were unclear, authors were contacted personally for further information. Quality of evidence (A: high, B: moderate, C: low and D: very low) and strength of recommendation (strong 1 and weak 2) concerning VIT in mastocytosis patients are assessed according to the Grading of Recommendations Assessment, Development and Evaluation and are marked in square brackets. Results of VIT were described in 117 patients to date. The mean rate of side-effects during treatment in studies published so far is 23.9% (7.6% requiring adrenaline) with an overall protection rate of 72%. Based on the review we conclude that (1) mastocytosis patients have a high risk of severe sting reactions in particular to yellow jacket, (2) VIT could be suggested [2] in mastocytosis, (3) probably should be done life long [2], (4) VIT in mastocytosis is accompanied by a higher frequency of side-effects, so (5) special precautions should be taken into account notably during the built up phase of the therapy [2], (6) VIT is able to reduce systemic reactions, but to a lesser extent compared to the general insect venom allergic population [2], so (7) patients should be warned that the efficacy of VIT might be less than optimal and they should continue carrying two adrenaline auto injectors [2].

[Lifestyle intervention for the prevention of cardiovascular disease]. / Leefstijlinterventie ter preventie van hart- en vaatziekten.

The high cardiovascular disease prevalence in western countries is largely attributable to the contemporary lifestyle. Interventions in the area of nutrition and physical activity have been shown to be effective in the prevention of cardiovascular disease. Successful implementation of lifestyle intervention programmes may be just as effective as drug treatment. In combination with drug treatment, intervention in the area of nutrition and physical activity is the recommended treatment for patients at a high risk of cardiovascular disease. Addition of new drugs to those presently available is associated with low absolute risk reductions and high costs, particularly in the presence of successful lifestyle interventions.

[Clinical reasoning and decision-making in practice. A 31-year-old woman with transient monocular blindness and polycythaemia]. / Klinisch denken en beslissen in de praktijk. Een 31-jarige vrouw met voorbijgaande visusklachten en polycytemie.

A 31-year-old woman presented with recurrent transient monocular blindness. As transient ischaemic attacks were suspected further investigations were targeted at evaluation of premature atherosclerotic lesions in the internal carotid artery. Initially laboratory tests were not performed. After referral to a cardiovascular-disease prevention outpatient clinic, laboratory evaluation disclosed a marked isolated polycythaemia that turned out to be secondary to right-left shunting through multiple pulmonary arteriovenous malformations. The ultimate diagnosis was hereditary haemorrhagic telangiectasia. Later on, physical signs such as telangiectasia and central cyanosis were noticed. In the clinical decision-making process, laboratory tests associated with causes of transient monocular visual loss were not carried out and therefore clues important for the ultimate diagnosis were not obtained. In only a minority of young patients with transient monocular visual loss can this be ascribed to premature atherosclerosis. For these reasons, a proper physical examination and laboratory tests directed towards other causes must be part of the initial diagnostic work-up in young patients with visual disturbances and suspected transient ischaemic attacks.

Long-term effects of protein-restricted diet on albuminuria and renal function in IDDM patients without clinical nephropathy and hypertension.

OBJECTIVE: To determine the long-term effects of an LPD on albuminuria and renal hemodynamics in IDDM patients without nephropathy. RESEARCH DESIGN AND METHODS: We selected 31 patients with overnight albuminuria between 10 and 200 g/min and without hypertension from a referral-based diabetic clinic. One participant dropped out. A 2-yr randomized prospective study was conducted on 14 patients assigned to an LPD (0.6 g.kg-1.day-1) and 16 patients assigned to continue their UPD. Protein intake was assessed by using urinary urea excretion. Albuminuria (three overnight collections) was measured at baseline and on seven occasions thereafter. GFR and ERPF were measured annually using [125I]iothalamate and [131I]hippuran, respectively. RESULTS: In the LPD group, protein intake decreased from 1.05 +/- 0.32 to 0.79 +/- 0.16 g.kg-1.day-1 (P < 0.005), but only seven participants consumed < 0.8 g.kg-1.day-1. Protein intake was unaltered in the UPD group (P < 0.001 vs. LPD). Baseline albuminuria and renal hemodynamics were not different in the groups. In the LPD group albuminuria decreased from 36 (95% CI, 16-83) to 30 micrograms/min (95% CI, 14-67) (P < 0.05). After adjustment for MAP and diabetes duration, the decrease in albuminuria in the LPD group was 26% (95% CI, 13-36) (P < 0.001), which was significantly different from the 5% (95% CI, -10-22) change in the UPD group (P < 0.005 vs. LPD). Multiple regression analysis showed the actual decrease in protein intake lessened (P < 0.005), whereas prevailing MAP accelerated albuminuria (P < 0.001). Low-protein intake independently reduced ERPF (P = 0.009) and GFR (indirectly via ERPF, P < 0.001) after 1 yr. Only minor changes in renal hemodynamics occurred in the second yr. CONCLUSIONS: This study suggests that long-term dietary protein restriction beneficially reduces albuminuria and renal hemodynamics in IDDM patients with mildly elevated albuminuria. Systemic BP counteracts these effects even in the absence of hypertension. Suboptimal compliance limits diet efficacy.

Milk of patients with tightly controlled insulin-dependent diabetes mellitus has normal macronutrient and fatty acid composition.

The composition of macro- and micronutrients in milk from six patients with tightly controlled insulin-dependent diabetes mellitus [median glycosylated hemoglobin concentrations at parturition of 5.2% (range 4.9-5.3%, reference range 4.9-6.6%) and 6 wk thereafter of 6.1% (range 5.0-6.3%, reference range 5.0-6.4%) was compared with that from five control subjects. Milk samples were collected halfway through a single breast-feeding at days 3-5 (colostrum); 7, 9, and 10 (transitional milk); and 12, 15, 17, 21, 25, 29, and 35 (mature milk). We found no abnormalities in macronutrient (triglycerides, lactose, and protein), cholesterol, glucose, and myoinositol concentrations or fatty acid composition. Two of three longitudinally studied patients showed rather constant ratios between glucose concentrations in milk and capillary blood. The present data suggest that tight control corrects a multitude of milk abnormalities associated with moderate and poor control.

Effects of initial and long-term lipid-lowering therapy on vascular wall characteristics.

Several studies have demonstrated the beneficial effects of 3 hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on vascular properties, but little is known about treatment intensification. We compared patients in whom statins were started (INITIAL, n=30) for hypercholesterolaemia (>6.5 mmol l(-1)) with a matched patient group of long-time statin users, with similar baseline characteristics for lipids, intima-media thickness (IMT), and pulse wave velocity, in whom treatment with statins was intensified (LONG-TERM, n=54). At baseline and after 1 year, lipid profile, IMT of the carotid and femoral arteries, aortic distensibility using pulse-wave velocity and various properties of the peripheral vascular bed using a recently developed bio-impedance method were measured. After 1 year the relative changes in lipid profile were significantly better in the INITIAL compared with the LONG-TERM-group. The relative changes in IMT of the mean internal carotid and common femoral arteries significantly differed between the INITIAL and LONG-TERM-group (-8 and +11%, -11 and +22%, respectively). After 1 year, in both groups, most other vascular wall characteristics were unaltered compared with baseline. In conclusion, the beneficial structural alterations of the vascular wall were greater after starting than after intensifying already existing lipid-lowering treatment. This suggests that other effects of HMG-CoA reductase inhibitors than lipid-lowering alone must be involved in vascular changes.

Hypothyroidism leads to more small-sized platelets in circulation.

The effect of induced hypothyroidism on platelet count and platelet volume distribution was studied in twelve athyreotic patients. After a two weeks withdrawal of triiodothyronine supplementation, platelet count and the ratio between platelet and red cell count were increased in all patients. Furthermore, mean platelet volume was declined and platelet distribution width was risen. Thus, hypothyroidism appears to increase the number of circulating platelets, especially the smaller ones.

AECA and ANCA in patients with premature atherosclerosis.

UNLABELLED: Autoimmunity is suggested to play a pathogenetic role in premature atherosclerosis. Since atherosclerosis and vasculitis seem pathogenetically related, we hypothesized that ANCA, an important antibody in vasculitis, plays a role in atherosclerosis as well. We therefore investigated the prevalence of ANCA in patients with premature atherosclerosis and related the presence of these antibodies to levels of AECA and markers of inflammation. METHODS & RESULTS: In a cohort of 286 patients with premature atherosclerosis the prevalence of ANCA was 5.6% (16/286). All had perinuclear ANCA. More females were ANCA-positive (8M/8F vs. 200M/70F, p = 0.03). In a nested case-control study, comparing the 16 ANCA-positive patients with 32 controls, levels of AECA were higher in the first (7.32 +/- 0.91U vs. 5.52 +/- 0.41U, p < 0.05). CONCLUSION: ANCA does not seem to play a major role in premature atherosclerosis. Whether elevated levels of AECA in ANCA-positive patients with premature atherosclerosis reflect more extended vascular disease remains to be determined.

Clinical experience with simvastatin compared with cholestyramine.

Simvastatin (MK733), derived from lovastatin by substituting CH3 for H at the 2' position, is a potent hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor. Its cholesterol-lowering effect in 40 patients with heterozygous familial hypercholesterolaemia was more pronounced (an LDL-cholesterol reduction of 43%) than that of cholestyramine monotherapy in a matched group of 20 patients (30% reduction). The combination of the 2 drugs for 50 patients who tolerated cholestyramine was even more effective (a 54% reduction of LDL-cholesterol). The other changes were as follows: total cholesterol (simvastatin [S] -36%, cholestyramine [C] -23%, both drugs in combination [S + C] -45%); HDL-cholesterol (S +16%, C +9%, S + C +20%); triglyceride (S -21%, C +11%, S + C -17%); and the apolipoprotein B/apolipoprotein A ratio (S -51%, C -39%, S + C -67%). Cholestyramine caused more gastrointestinal adverse effects (12 of 20 patients), whereas a transaminase increase was seen both with cholestyramine (2 of 20 patients) and simvastatin (3 of 40 patients) and with the combination (6 of 50 patients). Treatment with simvastatin decreases the atherogenic potential of plasma more than cholestyramine monotherapy and causes fewer adverse effects. For those patients who tolerate cholestyramine, the combination of the drugs is even more potent.

Rapid changes in serum, plasma and erythrocyte lipid compositions, and serum transaminase levels during continuous enteral hyperalimentation by carbohydrates alone.

Twelve normal men received twice their estimated basal energy requirement by a carbohydrate solution via a nasogastric catheter during 48 hours, followed by a seven-hour fast. Subsequently, in nine of them 0.5 mg epinephrine was given subcutaneously under ongoing fasting. During hyperalimentation, serum triglycerides, phospholipids, total and free cholesterol, phospholipids/free cholesterol ratio, and plasma free fatty acids decreased, whereas the percentage of free cholesterol increased. During fasting and subsequent epinephrine administration triglycerides and free fatty acids rose without reaching basal levels. Plasma and red blood cell (RBC) fatty acid composition already changed from two hours after the start of the feeding. Most markedly, a steady decrease in RBC 18:2c, omega 6, amounting to more than 17% of the basal value at the end of the observation period was found. Neither in plasma, nor in RBC a concomitant appearance of 20:3c, omega 9 was seen. In RBC, the relative amounts of the saturated fatty acids increased, whereas those of monounsaturated and polyunsaturated fatty acids decreased. RBC content of total fatty acids decreased and that of cholesterol increased. The ratios 16:1c, omega 7/16:0 and 18:3c, omega 6/18:2c, omega 6 in plasma, and 20:3c, omega 6/18:2c, omega 6 in plasma and RBC increased, whereas those of 18:1c, omega 7/16:1c, omega 7 and 20:3c, omega 6/18:3c, omega 6 in plasma decreased. After 48 hours feeding serum glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels were moderately increased and rose further during fasting. Thus, continuous enteral hyperalimentation by carbohydrates alone rapidly induces profound changes in serum-, plasma-, and RBC lipid compositions and serum parameters of hepatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Method-dependent increase in lipoprotein(a) in insulin-dependent diabetes mellitus during pregnancy.

The current prevalent view is that plasma lipoprotein(a) [Lp(a)] concentrations are under strong genetic control. Most dietary and drug interventions seem to have little or no effect on plasma Lp(a) levels. However, evidence for a possible regulatory rol e of hormones is accumulating, for instance, fluctuations of Lp(a) levels during pregnancy have been reported. Also, in insulin-dependent diabetes mellitus (IDDM) patients, elevated Lp(a) levels have been reported. In the present longitudinal study, plasma lipid concentrations, including Lp(a), were determined in IDDM women before pregnancy, during pregnancy, and 3 months postpartum. In our study population, Lp(a) concentration was not significantly correlated with either hemoglobin A1c (HbA1c) levels of apolipoprotein(a) [apo(a)] phenotype. Changes in other lipid parameters observed during pregnancy in our IDDM population were similar to those reported during normal pregnancy. Lp(a) concentrations were quantified using two different immunochemical methods that possess different sensitivities and specificities: an immunoradiometric assay (IRMA) using two different anti-apo(a) antibodies, and an enzyme-linked immunosorbent assay (ELISA) using an anti-apo(a) and an anti-apo B antibody. Median prepregnancy Lp(a) concentrations were 118 mg/L (range, 15 to 672) as determined with the IRMA and 107 mg/L (range, 21 to 451) as determined with the ELISA. Women with IDDM showed, in general, no significant change in Lp(a) concentration during pregnancy when it was assayed with the IRMA, although a tendency to increased values was observed. When Lp(a) concentrations were determined with the ELISA, a strong and significant increase in Lp(a) from weeks 17 to 24 of pregnancy onward was found. The latter results confirm the prevalent view that during pregnancy Lp(a) levels are increased. However, the present results and those of others and Lp(a) in normal pregnancy strongly emphasize the importance of method selection when determining Lp(a) concentrations.

Gamma-linolenic acid does not augment long-chain polyunsaturated fatty acid omega-3 status.

Augmentation of long chain polyunsaturated omega3 fatty acid (LCPUFA omega3) status can be reached by consumption of fish oil or by improvement of the conversion of alpha-linolenic acid (ALA) to LCPUFA omega3. Since gamma-linolenic acid (GLA) might activate the rate-limiting delta-6 desaturation, we investigated whether GLA augments LCPUFA omega3 status. Eight adults received 1.4 g GLA for 4 weeks and subsequently 2.2 g ALA+1.4 g GLA daily during another 4 weeks. Another seven adults received a daily oral dose of 2.2 g ALA for 4 weeks, and subsequently 2.2 g ALA+1.4 g GLA during another 4 weeks. ALA, or ALA+GLA, did not significantly augment EPA and DHA contents. We conclude that the LCPUFA omega3 status can not be improved by supplementation of low dose GLA, neither by co-supplementation of ALA. Poor conversion of ALA to LCPUFA omega3 may be caused by preferential beta-oxidation of ALA, negative feedback of arachidonic acid from the omnivorous diet, or by the low dietary ALA/LA ratio.

Cytogenetic study of a nodular hyperplasia of the thyroid after irradiation for Hodgkin's disease.

We describe cytogenetics of a case of nodular hyperplasia of the thyroid with papillary microcarcinoma following radiotherapy for Hodgkin's disease. The chromosomal pattern found was very heterogeneous with a clonal abnormality of chromosome 10, among others. Together with some recent data from the literature, this finding may point to an important role of chromosome 10 abnormalities in the pathogenesis of benign and malignant thyroid neoplasms.

Chromosomal aberrations in follicular thyroid carcinoma. Case report of a primary tumor and its metastasis.

We present the result of a cytogenetic study of a case of follicular carcinoma of the thyroid and its metastasis. Both tumors have a low number of chromosomes. The primary tumor is characterized by a idic(22;22)(p11;p11). The skeletal metastasis has also structural abnormalities of chromosome 22.