[Cardiogenic shock following yew needle poisoning : Digoxin immune fab, va-ECMO and albumin dialysis for the treatment of a suicidal yew leaf poisoning]. / Kardiogener Schock nach Eibennadelintoxikation : Digitalisantidot, va-ECMO und Albumindialyse in der Therapie der suizidalen Eibennadelintoxikation.

We present the case of a 46-year-old male who developed refractory bradycardia with cardiogenic shock after attempting suicide by ingestion of yew leaves. Due to delayed availability of the Digoxin immune fab, a va-ECMO was established to maintain sufficient circulation. Administration of the digoxin fab resulted in recovery of spontaneous circulation. Continuous venovenous hemodiafiltration with hemoadsorption and albumin dialysis were initiated with the intention to remove immune fab-toxin complexes and as organ support in acute kidney and liver failure. Within 5 days the patient was successfully weaned from ECMO, liver support and renal replacement and discharged without physical sequelae.

[Necrotizing esophagitis by stress-cardiomyopathy with right ventricular insufficiency]. / Nekrotisierende Ösophagitis bei Stresskardiomyopathie mit Rechtsherzversagen.

Acute necrotizing esophagitis ("black esophagus") is defined as complete necrosis of the esophageal mucosa, which typically affects the entire circumference. We report a case of a healthy 62-year-old woman, who became hemodynamically unstable due to stress cardiomyopathy with acute right heart failure. Transfusion-dependent anemia occurred 24 h later and an upper gastrointestinal endoscopy revealed a black discoloured mucosa of the distal esophagus. After hemodynamic stabilization and treatment with proton pump inhibitors and sucralfate, complete healing of the esophageal mucosa was achieved.

Novel use of endogenous GH-measurement directly after transsphenoidal microsurgery in acromegaly treated with pegvisomant.

OBJECTIVE: The GH receptor antagonist pegvisomant is increasingly used as therapy in acromegaly. Pituitary surgery might be indicated on pegvisomant treatment, due to side effects, adenoma growth or intention to cure after primary treatment. This study was initiated to clarify if, and when, GH measurement could be useful postoperatively with an assay specific for endogenous GH that does not cross-react with pegvisomant. METHODS: This study was designed as a prospective study in 2006 with the German Pituitary Working Group. Only 2 cases with potentially resectable adenomas from the German Pegvisomant Observational Study (GPOS) had been operated. Now with a post-operative follow-up of more than 5 years in these 2 cases, the usefulness of immediate pre-operative GH measurement shortly after pegvisomant treatment was evaluated. RESULTS: In both patients a steep decline of endogenous GH after transnasal microsurgery could be proven by using the special GH assay after near radical or radical removal, of the GH secreting adenomas respectively. Conventional GH assays showed no effect. GH half-life was more than 20 min in the patient with a small invasive residual adenoma and less than 20 min in the cured patient. Endogenous GH-levels declined to less than 1 ng/ml in the days after surgery in the patient with long-term cure. CONCLUSION: Measurement of endogenous GH in this special subgroup of patients under pegvisomant therapy can be used to decide upon early reoperation. Thus the beneficial effect of pegvisomant on acromegalic symptoms can be kept without interfering with post-operative monitoring of GH levels.

[An uncommon cause of recurrent abdominal pain in a 63-year-old obese woman]. / Ungewöhnlicher Grund für rezidivierende Bauchschmerzen bei einer adipösen 63-jährigen Patientin.

HISTORY AND CLINICAL FINDINGS: A 63-year-old woman was admitted because of abdominal pain for 12 months, associated with an increasing abdominal distension. One month before a gastroscopy had revealed mild gastritis. The taking of proton pump inhibitors did not improve her symptoms. There was no relevant neurological or psychiatric past history. INVESTIGATIONS: Ultrasound and laboratory tests demonstrated a fatty liver and increased serum levels of lipoproteins. Magnetic resonance imaging revealed an increase in subcutaneous and intraperitoneal adipose tissue. Endoscopy did not show any additional significant findings. DIAGNOSIS AND TREATMENT: The patient had adiposis dolorosa. Initially she was given daily a combination of mexiletine 400 mg and 75 mg Amitriptyline. After a few days the ailment decreased and had disappeared completely after one week. Three months later the dosage was reduced to 100 mg mexiletine and 25 mg Amitriptyline daily. After another two months all medication was discontinued. At follow-up after 12 months the symptoms had not recurred. CONCLUSION: This case demonstrates that abdominal pain is not always caused by diseases of the visceral hollow organs. It must also be borne in mind that abdominal pain may be associated with adipose tissue, as is the case in adiposis dolorosa. The disease can be successfully treated, as in this case, using a combination of mexiletine and Amitriptyline.

[Anti-phospholipid antibody syndrome: a case report (interview by Dr. Erik Heintz)]. / Wiederholte Aborte, Thrombosen und Thrombozytopenie: Bringen Sie diese Symptome auf einen gemeinsamen Nenner?

In a 29-year old patient with a triad of symptoms arising from an abortion in conjunction with a thrombosis and thrombocytopenia, the suspicion of an anti-phospholipid antibody syndrome (APS) was confirmed through the detection of increased levels of antiphospholipid antibody. Because of the continued wish to have children, the patient received oral methyl prednisolone and therapeutic doses of low molecular weight heparin.

[Chronic upper abdominal pain without improvement after using proton pump inhibitors]. / Langjährige Oberbauchschmerzen ohne Besserung durch Protonenpumpeninhibitoren.

HISTORY AND CLINICAL FINDINGS: A 57-year-old woman was admitted to our hospital because of relapsing, therapy-resistant pain, predominantly in the upper abdomen. The symptoms began 6 years previously, after a resection of parts of the small intestine for an ileus of unclear cause. Subsequently 11 (!) gastroscopies showed repeatedly gastritis and Helicobacter pylori- negative gastric and/or small intestinal ulcers which were treated with proton pump inhibitors. This led to no significant improvement of the complaints and produced no healing. DIAGNOSTIC FINDINGS AND THERAPY: Gastroscopy showed, at the transition of the gastric fundus to the corpus, an area with multiple, fibrin coated ulcers. Histologically an active, chronic gastric ulcer was seen, with perifocally dense inflammatory infiltration by predominantly eosinophils. In the colon these histological findings, although clearly less pronouncedly, were also seen i.e. an eosinophilic gastroenteropathy. This was initially treated with 60 mg/day prednisone. Under this treatment she became completely symptom-free. After a dose reduction to 5 mg prednisone daily the symptoms occurred again. Thereupon long-term immunosuppressive therapy with 100 mg azathioprine daily was introduced. Regular clinical and endoscopic monitoring showed a complete remission of the ulcers and no complaints after 1.5 years. CONCLUSION: Our case report shows that in patients with uncharacteristic abdominal pain and gastric ulcers, which improve inadequately under the usual medication such as proton pump inhibitors, less common illnesses must be considered. Despite the rarity of eosinophilic gastroenteropathy the exact (histological) diagnosis plays an important role, because a specific therapy with corticosteroids and/or azathioprine can induce improvement of the symptoms.

[An older female patient with refractory anemia and hemochromatosis]. / Eine ältere Patientin mit refraktärer Anämie und Hämochromatose.

CASE HISTORY AND CLINICAL FINDINGS: A 69-year-old woman was admitted because of a normocytic anemia. One year before an acute B19 parvovirus infection had been diagnosed, but the anemia was attributed to intestinal bleeding caused by a dysplastic colonic polyp. However, anemia persisted despite polypectomy. There was an excessive elevation of serum ferritin. ADDITIONAL EXAMINATIONS: A bone marrow biopsy and aspirate led to the diagnosis of a myelodysplastic syndrome (pure sideroblastic anemia). Ultrasound demonstrated advanced fibrosis of the liver. Fibrosis in association with severe parenchymatous siderosis was also demonstrated by histology. Analysis of the hemochromatosis gene (B-HFE, nt 845, G/A) was negative. DIAGNOSIS, THERAPY AND CLINICAL COURSE: The patient had secondary hemochromatosis due to a myelodysplastic syndrome. An acute infection with parvovirus B19 had been noted at the time of the first admission, one year before MDS was diagnosed. At that time, hemochromatosis had already caused fibrosis of the liver. However, complete regression of organ siderosis was achieved by deferoxamine administration. The myelodysplastic syndrome itself did not show any progression even 7 years after the diagnosis was established. CONCLUSION: Our case demonstrates the uncommon association between sideroblastic anemia and secondary hemochromatosis. Acute parvovirus infection may induce severe anemia in myelodysplastic syndromes. In acute B19 parvovirus infections an underlying hematologic disease should be excluded.

Overexpression and overactivation of Akt in thyroid carcinoma.

Enhanced activation of Akt occurs in Cowden's disease, an inherited syndrome of follicular thyroid, breast, colon, and skin tumors, via inactivation of its regulatory protein, PTEN. Whereas PTEN inactivation is uncommon in sporadic thyroid cancer, activation of growth factor pathways that signal through Akt is frequently identified. We hypothesized that Akt overactivation could be a common finding in sporadic thyroid cancer and might be important in thyroid cancer biology. We examined thyroid cancer cells lines and benign and malignant thyroid tissue for total Akt activation and isoform-specific Akt expression. In thyroid cancer cells, Akt 1, 2, and 3 proteins were expressed, total Akt was activated by insulin phosphatidylinositol 3'-kinase, and inhibition of phosphatidylinositol 3'-kinase reduced cell viability. In human thyroid tissue, increased levels of phosphorylated total Akt were identified in follicular but not papillary cancers compared with normal tissue. Levels of Akt 1 and 2 proteins and Akt 2 RNA were elevated only in the follicular cancers. In paired samples, Akt 1, 2, 3, and phospho-Akt levels were higher in five of six cancers, including three of three follicular cancers. These data suggest that Akt activation may play a role in the pathogenesis or progression of sporadic thyroid cancer.

[A young man with adynamia, subepicardial ischemia and sleep apnea]. / Ein junger Mann mit Adynamie, Aussenschichtischämie und nächtlicher Apnoe.

HISTORY AND CLINICAL FINDINGS: A 44-year-old manager presented himself for the assessment of nocturnal apnoea. He reported increasing lack of drive and nightly angina pectoris. INVESTIGATIONS: Polysomnography indicated obstructive apnoea and hypopnoea with a respiratory disturbance index of 29.1, while the ECG showed T wave inversion in all leads. There was severe hypothyroidism with atrophic thyroid tissue. DIAGNOSIS, TREATMENT AND COURSE: The patient had an obstructive sleep apnoea syndrome (OSAS), hypothyroidism with myxoedema, hypopnoea and myocardial ischaemia. He was treated with negative peak airway pressure (nCPAP) ventilation, administration of L-thyroxine and initiation of anti-anginal medication, which relieved his symptoms. The severe hypothyroidism was thought to be the most important cause of his respiratory disorder and angina. CONCLUSION: This case illustrates the connection between hypothyroidism and OSAS. Hypothyroidism must be excluded in patients with OSAS, regardless of the patient's age.

Graves' disease: a host defense mechanism gone awry.

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.

[A young woman with neurofibromatosis 1 (Recklinghausen disease), abdominal tumor and hypertension]. / Eine junge Patientin mit Neurofibromatose Typ 1 (Morbus Recklinghausen), Unterbauchtumor und Hypertonus.

HISTORY AND ADMISSION FINDINGS: A 38-year-old woman, known to have type 1 neurofibromatosis (NF1; von Recklinghausen's disease) and recurrence of a malignant haemangiopericytoma in the lower abdomen developed hypertension. She also had headaches and marked perspiration. Physical examination revealed tachycardia and paleness of the distal digits, in addition to multiple neurofibromas and café-au-lait spots. INVESTIGATIONS: A tumour was found in the region of the right adrenal gland, in addition to the known haemangiopericytoma. The levels of epinephrine and dopamine were elevated, suggesting an orthotopic phaeochromocytoma as the cause of the hypertension. Mutation analysis confirmed the neurofibromatosis by demonstrating a splice mutation of the NF1 gene in exon 8. She also was found to have emphysema of the right upper and middle lobes of the lung. TREATMENT AND COURSE: Because of the extensive local changes the recurrent haemangiopericytoma was only partially resected. At the same time a right adrenalectomy was performed without complication. However, the patient's postoperative recovery was slow, but she was now normotensive. Planned radiotherapy was omitted because of her poor general state. Instead she was given weekly palliative chemotherapy with adriamycin, with little improvement. She died several weeks later from the malignancy. CONCLUSION: This case emphasizes that in a patient with NF1 a phaeochromocytoma must be considered as a possible cause of hypertension. It is likely that the patient's emphysema was associated with the NF1, while the haemangiopericytoma was presumably unconnected with the NF1.

A study on the genetics of obesity: influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors.

Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IRS-1) have been implicated in the pathogenesis of obesity and in obesity related increase in insulin resistance which is associated with, among other diseases, dyslipidemia and type 2 diabetes mellitus. We studied 210 white female Caucasian obese subjects, who underwent a formal weight loss program (Optifast). We examined the association between mutations of the IRS-1 gene at codon 972, mutations of the beta-3-AR gene at codon 64, and the combination of both mutations with the degree of weight loss, waist to hip ratio and the prevalence of hypertension, dyslipidemia and type 2 diabetes mellitus. Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation, 23 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were polymorph for both alleles. No patient displayed a homozygous polymorphism. Similar frequencies of these polymorphisms were observed when the 100 non-obese control women were tested (14.0, 15.0, 3.0, respectively). After 13 weeks of weight loss the group with multiple polymorph alleles had lost less of their weight than the obese controls without mutation (Delta BMI 5.32+/-0.18 versus 6.12+/-0.2 kg/m2, p<0.05). In this group, the frequency of type 2 diabetes (66.7%) was significantly higher than in the obese control group without mutations (16.7%, p=0.008). Our findings suggest there is a synergy between the polymorphisms of Trp64Arg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. This seems to be accompanied with an increased frequency of type 2 diabetes.

Increased major histocompatibility complex (MHC) expression in nontoxic goiters is associated with iodide depletion, enhanced ability of the follicular thyroglobulin to increase MHC gene expression, and thyroid autoantibodies.

Recent studies suggest that thyroglobulin (TG) accumulated in the follicular lumen of colloid nodular goiters can increase major histocompatibility complex (MHC) class I gene expression in FRTL-5 thyrocytes. Iodide deficiency, also present in these patients, was separately suggested to enhance thyroidal MHC class I and class II gene expression in vivo and in vitro. To test the clinical relevance of these observations, we examined 41 nontoxic goiters surgically removed from patients who had compression problems. Northern analysis revealed that there was a mean 3.9-fold increase in MHC class I expression and a 8.3-fold increase in class II expression by comparison to 9 normal glands. In situ hybridization showed that thyrocytes were the main source of class I and class II transcripts; histological examination revealed that lymphocytic infiltration was minimal to non-existent. The iodine content of the 41 nontoxic goiters was significantly lower than in normal glands, consistent with increased MHC class I and class II. There is also a profound accumulation of TG in the follicles of the nontoxic goiters, and TG purified from the follicles of these glands increased MHC class I gene expression in FRTL-5 thyroid cells significantly more than TG from normal glands per mg protein. Nearly all patients with nontoxic goiter had low, but significantly elevated, levels of antibodies against thyroid peroxidase and/or against TG in their sera compared with those in normal individuals. Moreover, there was a positive correlation between the titer of the serum antibodies against thyroid peroxidase and against TG and MHC class I and class II expression in the thyroid. The data support the possibility that the TG accumulated in the follicular lumen of nontoxic goiters together with relative iodine deficiency contributes to increased MHC expression in thyroid cells in vivo and that increased MHC gene expression contributes to the ability of thyroid antigens to trigger an autoimmune reaction.

[A patient with an ACTH-producing pituitary tumor with liver metastasis]. / Eine Patientin mit ACTH-produzierendem Hypophysentumor und Lebermetastasen.

HISTORY AND FINDINGS: A 57-year-old woman had an ACTH-producing pituitary adenoma twice resected, followed by bilateral adrenalectomy for recurrent hypercortisolism. She subsequently developed a secondary postadrenalectomy syndrome (Nelson's tumour) which required further surgery and radiotherapy. The patient now presented for elucidation of a space-occupying lesion in the liver, found incidentally on abdominal ultrasonography. INVESTIGATIONS: Immunocytochemistry of the liver biopsy revealed ACTH-producing cells that were structurally identical to the cells found in the specimen resected at the previous operation. Changes were also found in the lower thoracic vertebrae, suspicious of metastases, thus suggesting a metastasizing hypophyseal carcinoma. RESULTS AND COURSE: Resection of the primary tumour and subsequent radiotherapy had arrested the corticotropic, thyrotropic, and gonadotropic functions of the pituitary, which had been adequately treated by administration of the corresponding hormones. Ocreotide, bromocriptin or cytostatics were not given because of their reported doubtful efficacy. At the time of diagnosis of the malignancy a curative operation on the liver or palliative embolization of the liver metastases were not possible because of their number and size. The bone metastases were managed palliatively by radiotherapy. CONCLUSION: No curative treatment has been found for the 66 cases of hypophyseal carcinoma reported so far. Screening investigations in patients with operated pituitary adenoma with the aim of eliciting an early diagnosis of possible malignancy cannot, therefore, be recommended, particularly since renewed tumour growth and local invasiveness do not constitute criteria for the diagnosis of pituitary carcinoma.

Analysis of mutations in exon 1 of the human thyrotropin receptor gene: high frequency of the D36H and P52T polymorphic variants.

The aim of the present study was to investigate the N-terminal part (the translated part of exon 1) of the human thyrotropin receptor (TSHR) for the presence of mutations. Patients with Graves' disease (n = 160) and healthy controls (blood donors; n = 140) were screened using single-stranded conformational polymorphism (SSCP) in combination with restriction enzyme digestion for the two previously known mutations in this part of the receptor, viz. D36H and P52T TSHR-variants. We did not find any novel mutation in this region. However, D36H and P52T variants were found both in the TSHR of Graves' patients and in the healthy controls. The overall frequency of the D36H-receptor variant was 5.0% (15/300) and of the P52T-receptor, 7.3% (22/300). There was no major difference in the frequency for either of the TSHR alleles between the 2 groups. Thus, these 2 polymorphic variants of the TSHR seem to occur in a relatively high frequency in the population.