Stefan Fischli

Glucagon-like peptide-1 receptor imaging for the localisation of insulinomas: a prospective multicentre imaging study

BACKGROUND Small benign insulinomas are hard to localise, leading to difficulties in planning of surgical interventions. We aimed to prospectively assess the insulinoma detection rate of single-photon emission CT in combination with CT (SPECT/CT) with a glucagon-like peptide-1 receptor avid radiotracer, and compare detection rates with conventional CT/MRI techniques. METHODS In our prospective imaging study, we enrolled adults aged 25-81 years at centres in Germany, Switzerland, and the UK. Eligible patients had proven clinical and biochemical endogenous hyperinsulinaemic hypoglycaemia and no evidence for metastatic disease on conventional imaging. CT/MRI imaging was done at referring centres according to standard protocols. At three tertiary nuclear medicine centres, we used whole body planar images and SPECT/CT of the abdomen up to 168 h after injection of (111)In-[Lys40(Ahx-DTPA-(111)In)NH2]-exendin-4 ((111)In-DTPA-exendin-4) to identify insulinomas. Consenting patients underwent surgery and imaging findings were confirmed histologically. FINDINGS Between Oct 1, 2008, and Dec 31, 2011, we recruited 30 patients. All patients underwent (111)In-DTPA-exendin-4 imaging, 25 patients underwent surgery (with histological analysis), and 27 patients were assessed with CT/MRI. (111)In-DTPA-exendin-4 SPECT/CT correctly detected 19 insulinomas and four additional positive lesions (two islet-cell hyperplasia and two uncharacterised lesions) resulting in a positive predictive value of 83% (95% CI 62-94). One true negative (islet-cell hyperplasia) and one false negative (malignant insulinoma) result was identified in separate patients by (111)In-DTPA-exendin-4 SPECT/CT. Seven patients (23%) were referred to surgery on the basis of (111)In-DTPA-exendin-4 imaging alone. For 23 assessable patients, (111)In-DTPA-exendin-4 SPECT/CT had a higher sensitivity (95% [95% CI 74-100]) than did CT/MRI (47% [27-68]; p=0.011). INTERPRETATION (111)In-DTPA-exendin-4 SPECT/CT could provide a good second-line imaging strategy for patients with negative results on initial imaging with CT/MRI. FUNDING Oncosuisse, the Swiss National Science Foundation, and UK Department of Health.

Assessment of quality of life in patients with uncontrolled vs. controlled acromegaly using the Acromegaly Quality of Life Questionnaire (AcroQoL)

Objective Acromegaly is a chronic disease with an important impact on quality of life. An acromegaly disease‐generated quality of life questionnaire (AcroQoL) has recently been developed. We aimed to confirm reliability, construct validity and disease‐specificity of the AcroQoL questionnaire. Second, we investigated the effect of remission status on health‐related quality of life (HRQoL) in patients with acromegaly.

Glucocorticoid Replacement and Mortality in Patients with Nonfunctioning Pituitary Adenoma

CONTEXT Current treatment guidelines generally suggest using lower and weight-adjusted glucocorticoid replacement doses in patients with insufficiency of the hypothalamic-pituitary-adrenal (HPA) axis. Although data in patients with acromegaly revealed a positive association between glucocorticoid dose and mortality, no comparable results exist in patients with nonfunctioning pituitary adenomas (NFPA). OBJECTIVE Our objective was to assess whether higher glucocorticoid replacement doses are associated with increased mortality in patients with NFPA and HPA axis insufficiency. DESIGN, PARTICIPANTS, AND INTERVENTION We included 105 patients receiving glucocorticoid replacement after pituitary surgery due to NFPA and concomitant HPA axis insufficiency. Patients were grouped according weight-adapted and absolute hydrocortisone (HC) replacement doses. Mortality was assessed using Kaplan-Meier methodology as well as multivariable Cox regression models. SETTING This was a retrospective analysis conducted at a tertiary referral center. MAIN OUTCOME We evaluated overall mortality based on HC replacement doses. RESULTS Average age at inclusion was 58.9±14.8 yr, and mean follow-up was 12.7±9.4 yr. The groups did not differ according to age, follow-up time, pattern of hypopituitarism, and comorbidities. Kaplan-Meier survival probabilities differed significantly when comparing individuals with differing weight-adjusted HC dose (P=0.001) as well as absolute HC dose (5-19, 20-29, and ≥30 mg, P=0.009). Hazard ratios for mortality increased from 1 (0.05-0.24 mg/kg) to 2.62 (0.25-0.34 mg/kg) to 4.56 (≥0.35 mg/kg, P for trend=0.006) and from 1 (5-19 mg) to 2.03 (20-29 mg) to 4 (≥30 mg, P for trend=0.029), respectively. CONCLUSION Higher glucocorticoid replacement doses are associated with increased overall mortality in patients with NFPA and insufficiency of HPA axis. This further substantiates the importance of a balanced and adjusted glucocorticoid replacement therapy in these patients.

A combined presentation of Graves' disease and Miller-Fisher syndrome.

In April, 2007, a 42-year-old woman was admitted to hospital with periorbital swelling, double vision, hyper osmia, and dizziness. Recent history included a gastro intest inal in fection (February, 2007), bilateral ear pain, and a sore throat. Systolic blood pressure was 150 mm Hg, heart rate was 80 beats per min, and temperature was 37∙4°C. Laboratory tests showed a low concentration of thyroidstimulating hormone (0∙04 mU/L, normal value 0∙27–4∙2 mU/L) and raised values of free T3 (12∙1 pmol/L; 3∙1–6∙8 pmol/L) and free T4 (36∙1 pmol/L; 12∙0–22∙0 pmol/L). TSH-receptor antibodies (1∙9 U/L; normal 15 000 U)— suggesting the presence of Miller-Fisher syndrome. Our patient continued treatment with carbimazole and prednisolone; her Miller-Fisher syndrome was managed supportively. 4 months later all her symptoms had disappeared. Carbimazole and prednisolone were gradually reduced and then stopped completely. Miller-Fisher syndrome is a rare variant of the GuillainBarre syndrome and is characterised by combined ophthalmoplegia, ataxia, and hyporefl exia. Antibodies to GQ1b, which are present in 85–90% of patients, are highly sensitive for this syndrome, indicating that peripheral nerve myelin is the target of an immune attack. The binding of anti bodies to oculomotor nerves causes ophthalmoplegia. The diff erential diagnosis encompasses Guillain-Barre syn drome, acute ophthalmoplegia without ataxia, and Bickerstaff ’s brainstem encephalitis, but not other neuropathic disorders. Molecular mimicry may have a signifi cant role in the onset of the Miller-Fisher syndrome, since the GQ1b epitope has been found in lipopoly sac charides of Campylobacter jejuni. Therapeutic regimens for the Miller-Fisher syndrome include treatment with intravenous immuno globulin and plasmapheresis to remove the anti bodies to GQ1b, although the rate of spon tan eous recovery is high. Our patient had a mild form of Graves’ disease—the thickened eye muscles visible on MRI were compatible with the presence of an endocrine ophthalmopathy, but the pattern of limited eye movement was atypical and is better explained by the coinciding presence of Miller-Fisher syndrome.

Is Graves’ disease a primary immunodeficiency? New immunological perspectives on an endocrine disease

BackgroundUncertainty about factors influencing the susceptibility and triggers for Graves’ disease persists, along with a wide variation in the response to anti-thyroid drugs, currently at approximately 50% of non-responders. The aim of this narrative review is to summarize immunological concepts, with a combined endocrine and immunological perspective, to highlight potential new areas of research.Main textRelevant studies were identified through a systematic literature search using the PubMed and EMBASE databases in March 2016. No cut-offs regarding dates were imposed. We used the terms “Graves’ Disease” or “Basedow” or “thyrotoxicosis” together with the terms “etiology”, “pathophysiology”, “immunodeficiency”, “causality”, and “autoimmunity”. The terms “orbitopathy”, “ophthalmopathy”, and “amiodarone” were excluded. Articles in English, French, German, Croatian, Spanish, and Italian were eligible for inclusion.ConclusionsWhile concepts such as the impact of iodine, smoking, human leucocyte antigen, infections, and ethnicity are established, new ideas have emerged. Pertaining evidence suggests the involvement of autoimmunity and immunodeficiency in the pathophysiology of Graves’ disease. Recent studies point to specific immunological mechanisms triggering the onset of disease, which may also serve as targets for more specific therapies.

Catecholamine Metabolism in Paraganglioma and Pheochromocytoma: Similar Tumors in Different Sites?

Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.

The Significance of 18F-Fluorocholine-PET/CT as Localizing Imaging Technique in Patients with Primary Hyperparathyroidism and Negative Conventional Imaging

Objective The essential prerequisite for focused parathyroidectomy in patients with primary hyperparathyroidism (pHPT) is proper localization of all autonomic tissue. Sensitivity of conventional imaging modalities (ultrasound, 99mTc-sestamibi scintigraphy/SPECT/CT) is influenced by different factors (i.e., size/weight and position of autonomic tissue) and decreases in the presence of a multinodular goiter. Therefore, a considerable percentage of pHPT patients have negative or equivocal localization studies before surgery. The aim of this study is to evaluate the utility of FCH-PET/CT for preoperative localization in patients with pHPT and negative/equivocal 99mTc-sestamibi scintigraphy/SPECT/CT and/or ultrasound. Methods and measurements Between 2014 and 2017, a total of 39 patients with pHPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In the analysis, we included those (n = 23) who had surgery and a histopathologic workup of the lesions. Results 19 of 23 patients demonstrated no tracer uptake with 99mTc-sestamibi scintigraphy/SPECT/CT, 6 patients had an equivocal sonographic lesion, and multinodular goiter was present in 43% (10/23). In 21 of 23 patients, hyperfunctioning parathyroid tissue was identified correctly by FCH-PET/CT [21 true positive, 1 false negative, and 1 false positive; per-patient sensitivity 95.5% (95% confidence interval {CI}, 77.2–99.9)]. 29 lesions were resected [21 true positives, 3 false negatives, 1 false positive, and 4 true negatives; per-lesion sensitivity 87.5% (95% CI, 67.6–97.3)]. All patients were classified as having surgical success according to a decrease of intraoperative parathyroid hormone of ≥50% and normalization of postoperative serum calcium levels. Conclusion Despite a high prevalence of multinodular goiter, diagnostic accuracy of FCH-PET/CT in our patient group was excellent. Therefore, FCH-PET/CT is a promising new imaging tool in patients with pHPT and negative/equivocal results by conventional imaging techniques.

Iron metabolism in patients with Graves’ hyperthyroidism

Graves’ hyperthyroidism (GH) interferes with iron metabolism and elevates ferritin. The precise mechanisms remain unclear. The influence of thyroid hormones on the synthesis/regulation of hepcidin, an important regulator of iron metabolism, remains uncharacterized.

Aktuelles zur Therapie mit GLP-1-Rezeptoragonisten bei Patienten mit Diabetes mellitus Typ 2

Zusammenfassung. GLP-1-Rezeptoragonisten (GLP-1-RA) sind eine neuere Therapieoption zur Behandlung des Diabetes mellitus Typ 2. Diese Substanzen besitzen eine analoge Struktur zum menschlichen glukagon-like peptide 1 (GLP-1), einem fur die Glukosehomoostase zentralen Inkretin, das unter anderem fur die postprandiale Insulinsekretion verantwortlich ist. GLP-1-RA fuhren glukoseabhangig zur Stimulation der Insulin- und Hemmung der Glukagon-Sekretion. Sie besitzen kein intrinsisches Hypoglykamierisiko und bewirken eine Gewichtsabnahme. In kardiovaskularen Endpunktstudien konnte fur mehrere Substanzen (Liraglutid, Semaglutid) eine Reduktion der kardiovaskularen Endpunkte gezeigt werden. Die haufigsten Nebenwirkungen der GLP-1-RA sind gastrointestinaler Natur (Nausea, Erbrechen und Diarrho) und Ausdruck der Wirkung an zentralem Nervensystem und Gastrointestinaltrakt. GLP-1-RA sind die teuersten Diabetesmedikamente, die Applikation erfolgt subkutan und es existieren zum jetzigen Zeitpunkt noch ungenugende Daten ...

A rare cause of cardiogenic shock with psychotic symptoms

HISTORY AND FINDINGS A 40-year-old man was admitted to the emergency department with psychotic symptoms and marked hypothermia. He was known to have had a macroadenoma of the pituitary gland which had been excised 10 years before. No information about his current medication was available. Several hours after admission the patient developed signs of acute cardiac failure and cardiogenic shock. He was admitted to the intensive care unit, intubated and treated with vasoactive drugs. Later investigations revealed that the patient had stopped his hormonal therapy (hydrocortisone and thyroxine) at least 3 months previously. INVESTIGATIONS Transthoracic electrocardiography revealed diffuse myocardial contractile abnormalities with an ejection fraction of 30%. Acute ischemic damage was ruled out by serial troponin-T test and electrocardiography. Severe hypothyroidism and hypocortisolism were confirmed by laboratory tests. DIAGNOSIS, THERAPY AND COURSE The diagnosis of acute pituitary insufficiency with myxedema coma and hypocortisolism was suspected and the patient was treated with parenteral cortisone and L-thyroxine. The response was favorable and the patient was extubated after 5 days. Cardiac contractility and ejection fraction normalized. CONCLUSIONS Myxedema coma can be a predominant finding of acute anterior pituitary insufficiency. There are important effects on the cardiovascular system and cerebral functions (altered mentation). Immediate diagnosis and therapy are crucial to reduce the otherwise high mortality.