Propylthiouracil: clinical overview of its efficacy and its side effects more than 50 years after the introduction of its use in thyrostatic treatment.

This minireview gives a clinical overview of the efficacy and of the side effects of the thyrostatic drug propylthiouracil, which is in use for the treatment of Graves' disease for more than 5 decades. It is the aim of this minireview to give convincing evidence of the value of propythiouracil in the treatment of thyrotoxic patients with Graves' disease: The modalities of treatment are given. The advantages in comparison to methimazole are mentioned: Especially for thyrotoxic nursing mothers it represents the only thyrostatic drug approved by the American Academy of Pediatrics. Patients who experience side effects with methimazole usually can be switched successfully to propylthiouracil and vice versa. Its use for the treatment of thyrotoxicosis in pregnant women is recommended by many centres because of the comparatively little placental transfer of the drug, although the effect for the newborn does not seem to differ from that of methimazole. The minireview should remind the medical community of the value of propylthiouracil as a very valuable thyrostatic drug representing a good alternative to methimazole. It should attract interest in the drug, in spite of the fact that after 5 decades in the market there is probably only little financial profit left in selling it.

Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) in patients with MALT lymphoma.

BACKGROUND: Autoimmune diseases have been implicated in the genesis of MALT lymphoma of various localizations. The development of thyroidal MALT lymphoma has been described as an adverse event in patients suffering from long-standing chronic autoimmune thyroiditis (CAT, Hashimoto's thyroiditis). The percentage and possible association between CAT and extrathyroidal MALT lymphoma, however, have not been assessed so far. PATIENTS AND METHODS: A retrospective analysis of 80 patients with MALT lymphoma diagnosed and treated at our institution identified a total of 13 patients (16%) with MALT lymphoma suffering from an underlying CAT. Patient characteristics including site of disease, stage, genetic changes and clinical course were assessed and evaluated. RESULTS: In total, 10 patients were female and 3 male, with the median age being 57 years (range: 31-80). Four patients suffered from thyroidal lymphoma and nine patients had extrathyroidal lymphoma (four gastric, two orbital, one small intestinal and two salivary gland lymphomas). Three patients had a long-standing history of CAT at diagnosis of MALT lymphoma, while CAT was discovered during staging and clinical work-up of MALT lymphoma in the remaining 10 patients. All 13 patients had localized disease, i.e. stage I or II. Only one of the four patients with gastric MALT lymphoma responded to antibiotic treatment against Helicobacter pylori infection. Genetic aberrations were detected in four patients, two of whom had a t(11;18)(q21;q21) translocation, one patient had trisomies 3 and 18 and one had trisomy 18. CONCLUSION: Our findings suggest that CAT is found in patients with not only thyroidal but also nonthyroidal MALT lymphoma. While the nature of our data does not allow for delineation of a direct association between CAT and development of extrathyroidal MALT lymphoma, further prospective studies on this issue are warranted.

Heat shock protein 70 (Hsp70) subtype expression in neuroendocrine tissue and identification of a neuroendocrine tumour-specific Hsp70 truncation.

In order to identify neuroendocrine tumour-specific protein expression, we generated monoclonal antibodies (mAbs) with a tumour-related reaction pattern using a human insulinoma as immunogen. One of the generated mAbs (mAb 1D4) exhibited striking immunoreactivity against various neuroendocrine tumours without staining pancreatic islets of Langerhans. Furthermore, mAb 1D4 immunostained a characteristic subtype of hypothalamic neurones. Using two-dimensional (2-D) gel electrophoresis, mAb 1D4 immunoblotting and mass spectrometry, heat shock protein 70 (Hsp70) isoforms were identified as the mAb 1D4-specific antigen. In hypothalamic tissue, the presence of two different Hsp70 isoforms (Hsp70-8 and Hsp70-1) was revealed by 2-D gel immunoblots and consecutive mass spectrometric peptide analysis. In contrast, insulinoma and other neuroendocrine tumours displayed solely Hsp70-8 expression. Moreover, the tumour-specific presence of an additional mAb 1D4 immunoreactive protein of 40 kDa was observed in eight out of eight tested neuroendocrine tumours. For this variant, exclusively, peptides derived from the C terminus excluding the 299 amino-terminal residues were detected. In cultured tumour-derived fibroblasts, expression of the truncated Hsp70-8 subtype was not present. In conclusion, we have demonstrated a neuroendocrine tumour-specific expression pattern of Hsp70 isoforms and identified an as yet unknown N-terminally truncated Hsp70-8 variant.

Legal augmentation of iodine content in table salt from 10 to 20 mg KI/kg: documented effects a decade later.

In this brief review I have tried to gather all relevant data that have been published, concerning the long-term effects of the statutory requirement by Austrian authorities in 1990 to augment the iodine content of table salt from 10 mg KI/kg table salt to 20 mg KI/kg. Most of the available studies have a selection bias, studying persons referred to hospital for different reasons. Only studies on school children investigate more random samples of the population. However, in spite of the fact that iodine deficiency does not seem to be eradicated completely by this measure, some tendencies have become apparent. The positive tendencies are: (1) thyroid volume in school children has shrunk in comparison to (historical) data before 1990--leading to lack of goitre in this age group; (2) the expected rise in the incidence of thyrotoxicosis was only transient and not very pronounced--indeed thyrotoxicosis seems to have become rarer now than before; (3) the phenotype of thyroid cancer has changed towards the more benign variants. Negative trends described since 1990 are (1) a small increase in the overall incidence of thyroid cancer (possibly due to better diagnostic tools), and (2) a relative rise of autoimmune thyroid disease. All these tendencies await their substantiation by a nationwide survey that is based on strong epidemiological criteria.

Autoimmune diseases in vitiligo: do anti-nuclear antibodies decrease thyroid volume?

An increased prevalence of autoimmune thyroiditis (AT) in vitiligo patients is well known. The aim of this study was firstly, to evaluate the clinical course of patients with both vitiligo and AT and secondly, to identify additional autoimmune disorders affecting the thyroid gland in a large cohort of vitiligo patients. We analysed a study group of 106 vitiligo patients and 38 controls. A detailed thyroid examination including sonography was performed in all study participants. In addition, the study participants were HLA typed and screened for various autoimmune disorders. AT was significantly more frequent in vitiligo patients than in controls (21%versus 3%; P < 0.01). In 12 of the 22 patients with AT, vitiligo was the initial disease preceding AT by 4-35 years. In the other 10 patients with AT, both vitiligo and AT were diagnosed within one year. There were two individuals with diabetes mellitus type 1 and a single patient with Addison's disease. Anti-nuclear antibody (ANA), anti-smooth muscle cell antibody, and parietal cell antibody levels occurred with a similar frequency in patients and controls. In all vitiligo patients with both elevated ANA levels and AT (n = 6), the atrophic but not the goitrous variant was diagnosed. These vitiligo patients with both AT and elevated ANA levels had a significantly smaller thyroid volume compared to the vitiligo patients with AT whose ANA levels were normal (6.7 +/- 4.5 ml versus 13.4 +/- 9.1 ml, respectively; P < 0.05). The same was found in the entire study group: Thyroid volume of all vitiligo patients (with or without concomitant AT) was significantly smaller in the presence of ANA (6.9 +/- 5.3 versus 10.5 +/- 5.9 ml, respectively; P < 0.05). However, this phenomenon was not observed in the control group. There was a trend for a decreased frequency of HLA-DR3 (6.7%versus 23%) in our study group, but after correction for the number of comparisons, no HLA-allele was statistically significant associated neither with vitiligo nor with multiple autoimmune diseases in our patient sample. Our findings suggest that AT is the most frequent autoimmune disease associated with vitiligo. In our patients, AT presented simultaneously or after the onset of vitiligo but not before. Elevated ANA levels were associated with the atrophic variant of AT and may affect the volume of the thyroid gland, and there was no statistically significant association with the HLA system.

[Possible consequences of subclinical hypothyroidism]. / Mögliche Konsequenzen der subklinischen Hypothyreose.

Subclinical hypothyroidism is defined as elevated TSH in the presence of normal free T4 and T3 levels. This review discusses the following questions concerning subclinical hypothyroidism that have not been solved yet: 1) does elevated TSH always mean failure of the thyroid gland? 2) Do patients with subclinical hypothyroidism always develop overt hypothyroidism? 3) Are they symptomatic? 4) Does treatment with L-Thyroxine cure these symptoms,--if they exist? Summarizing the results of the literature one can give the following answers: 1) Elevated TSH with normal free T4 can but does not necessarily mean thyroid failure. 2) Patients with positive thyroid antibodies and especially with TSH levels above 10 mU/l are at high risk to develop overt hypothyroidism. 3) Typical symptoms (thyroid-specific, cardiovascular, neurological and psychiatric and finally alterations of risk factors for atherosclerosis) seem to occur in a greatly varying percentage of patients--some of the described symptoms are of questionable clinical importance. 4) Some of the symptoms, especially the cardiovascular, seem to be treatable by L-T4, whereas others like most of the changes in lipid metabolism can not be influenced by normalization of the TSH levels. In conclusion, screening for TSH and free T4 seems to be justified in elderly women, where the prevalence of the disease is approximately 20%. However, treatment of "symptoms" of subclinical hypothyroidism like elevated cholesterol levels or depression should be done only in patients with a TSH > 10 mU/l and there only with great caution in order to avoid unnecessary overdosage with the danger of eliciting atrial fibrillation.

[Diagnosis and therapy of Graves' ophthalmopathy--consensus guidelines]. / Diagnostik und Therapie der endokrinen Orbitopathie--Konsensusrichtlinien.

On 22-09-2001 the VIth Grazer Hormonsymposion took place. Diagnosis and therapy of Graves' Ophthalmopathy was discussed in an interdisciplinary way by endocrinologists, surgeons and ophthalmologists. The results of the round-table discussion and the consensus talk are presented.

[Conservative therapy in endocrine orbitopathy: "State of the art"]. / Konservative Therapie bei endokriner Orbitopathie: "State of the Art".

This review describes the state of the art of the conservative therapeutical approach of thyroid associated eye disease. Radiotherapy, surgery and ablative therapy of thyroid ophthalmopathy are discussed elsewhere in this issue of Acta Med Austriaca. All forms of therapy have to be adjusted to the severeness of the eye disease. The assessment of the severeness of this ailment can be difficult. Therefore, the impact of scoring systems like the "Clinical Activity Score" is pointed out. Treatment of thyroid dysfunction is the widely accepted first therapeutic measure. Additional supportive local therapy is usually sufficient in patients with only mild activity of endocrine ophthalmopathy. Glucocorticoids applied via different routes in various dose regimens are the therapy of first choice in (moderately) severe forms of the disease. Reported response rates for the oral form of therapy are about 63%, for the intravenously applied very high doses (given only in very severe forms of the disease) nearly 77%. Cyclosporin has been shown to be more efficient in combination with oral glucocorticoids in patients with moderately severe eye disease than glucocorticoids alone. Patients need a close follow up since both drugs have considerable side effects. An alternative treatment with high-dose intravenous immunoglobulins seems to have less side effects, but has the disadvantage of bearing the danger of serious infections as all plasma derived products and of being extremely expensive. Finally, preliminary data of new treatment modalities with the immunomodulators pentoxifylline and methotrexat are presented. These drugs have been tested so far with good success in patients with severe endocrine ophthalmopathy and unresponsive to other forms of treatment.

[Hyperthyroidism and heart]. / Hyperthyreose und Herz.

This review discusses the clinically relevant effects of thyroid hormone excess on the heart. Tachycardia and atrial fibrillation are usually reversible after euthyroidism is restored. Atrial fibrillation may, however, take several months to return to sinus rhythm. The increase in contractility leads to an increase of cardiac output. The development of a relative myocardial hypertrophy following long-term high-dose therapy with thyroid hormones is controversial. Cardiac failure at stress in spite of an increased cardiac output at rest is a phenomenon typical for thyrotoxicosis. Reports of dilated cardiomyopathy associated with Graves' disease and evidence for TSH-receptors in the human myocardium suggest a relationship between these two diseases. Endomyocardial biopsy studies have, however, failed to prove this hypothesis. Mitral valve prolapse is more frequent in hyperthyroid patients than in normals. Thyroid hormone excess as well as the autoimmune origin of the disease are suggested as etiology for this phenomenon. The frequently observed angina pectoris seems to be a consequence of the increase in consumption of oxygen in the presence of an unchanged oxygen supply rather than of obstruction of coronary circulation. Well documented cases of myocardial infarction patients with thyroid hormone excess and normal coronary arteries in angiography substantiate this theory. Finally diagnostic and therapeutic options of the two forms of thyrotoxicosis induced by the antiarrhythmic drug amiodarone are presented.

Emergency angioplasty and stent deployment for acute occlusion of an anomalous single coronary artery (all three coronary arteries from one ostium in the right sinus of Valsalva).

A single coronary ostium is traditionally considered to be of little clinical significance. We report a case of a single ostium in the right sinus of Valsalva, giving rise to the right coronary artery, from which the left main coronary artery originated. Sudden death occurred seven days after acute gastrointestinal bleeding and subsequent interruption of aspirin therapy. Acute coronary angiography following successful resuscitation revealed an ascending thrombus in the right coronary artery. The patient underwent a complex percutaneous coronary angioplasty with stent deployment. We conclude that coronary artery disease may lead to severe ischemia with a large area at risk and major complications in patients with coronary anomalies. Patients with acute stent implantation might benefit from platelet aggregation even in cases of recent intestinal bleeding.

Clinical significance of autoimmune thyroid disease in myasthenia gravis.

We investigated thyroid function and autoimmunity in 74 (61% females) consecutive patients with MG. 30 of these patients were tested twice: the time between the investigations ranging from 1 to 4 years. MG was diagnosed on the basis of typical clinical symptoms, a positive tensilone-test, and/or detectable acetylcholine antibodies and/or repetetive stimulation tests. Eye involvement was present in 86%, concurrent thymomas in 56%. The following parameters were measured in the serum of these patients by commercially available kits: free and total T4, TSH, TSH-Receptor-Antibodies ("TRAB"), antibodies against thyroglobulin (Tg-Ab), against thyroid microsomes (M-Ab) and against acetyl-choline-receptors . An age matched group of 50 patients (54% females) with no known thyroid disease from a cardiological ward and from the neurological outpatient department served as control. There was only 1 MG patient with overt thyroid dysfunction (iodine induced thyrotoxicosis in a patient with autonomous adenoma and no circulating thyroid autoantibodies detected at the second investigation). There were, moreover, 1 euthyroid MG-patient on L-thyroxine therapy with a history of Hashimoto's disease and positive thyroid autoantibodies and 1 other MG-patient with mildly elevated TSH without elevated thyroid antibodies, who has had subtotal thyroidectomy without substitution therapy years before for unknown reasons. Tg-Ab were positive (>360 IU/ml) in 5%, M-Ab were positive (>154 IU/ml) in 15% of the MG patients. The control group had 4% Tg-Ab and 6% M-Ab. TRAB levels were normal in all patients and controls. The relative increase in M-Ab frequency was not statistically significant (x-square test). We conclude from our results, that autoimmune thyroid disease may be associated with MG but that the occurrence of thyroid dysfunction induced by autoimmunity is a very rare phenomenon in MG.

Dermatitis herpetiformis is associated with atrophic but not with goitrous variant of Hashimoto's thyroiditis.

BACKGROUND: Dermatitis herpetiformis (DH) is a gluten-sensitive skin disease that is associated with a variety of autoimmune disorders. Several investigations demonstrated an association between DH and autoimmune thyroid disease. However, it has not been shown if DH is associated with atrophic or goitrous variant of Hashimoto's thyroiditis. MATERIALS AND METHODS: We investigated a cohort of 41 DH patients (18 male, 23 female) and a control group (11 male, 19 female; sex and age matched healthy volunteers) to find out which variant of Hashimoto's thyroiditis is associated with DH. All patients had thyroid hormones and antibodies measured. In addition to that, thyroid sonography as well as detailed history-taking of previous thyroid disease were performed. RESULTS: In the control group no individual with elevated levels of thyroid antibodies nor abnormal thyroid hormones nor thyroid atrophy was found. Median thyroid volume in the control group was 11 mL (range 4.8-24.7 mL). However, in nine DH patients (22%) elevated levels of antithyroid microsomal (TM) antibodies were seen (P < 0.01). Three of them had abnormal thyroid hormones (7%). In the group of DH patients a significantly smaller thyroid volume was found (median 8 mL, range 1. 6-25.2 mL; P < 0001). Thyroid atrophy (volume < 4.4 mL) was found in 10 DH patients (24%) of whom 9 were females. All patients with elevated levels of TM antibodies or abnormal thyroid hormones and all patients with a history of previous hypothyroidism had a thyroid volume < 7 mL. Goitrous variant of Hashimoto's thyroiditis was not seen in any of the DH patients. CONCLUSIONS: Our findings demonstrate that DH is associated with atrophic but not with goitrous variant of Hashimoto's thyroiditis.

[Spontaneous healing of retroperitonea fibroasis after successful therapy of sigmoid carcinoma]. / Spontanheilung einer Retroperitonealfibrose nach erfolgreicher Therapie eines Sigmakarzinoms.

In a 64 year old man sigma cancer was diagnosed unexpectedly during an operation for retroperitoneal fibrosis (histologically benign fibrosis), that had caused unilateral hydronephrosis. In the following hemicolectomy this tumor of the colon turned out to be a medium high grade adenocarcinoma (tumor staging pT2, pN1, DUKES C). Chemotherapy with 450 mg/m2 5-FU once a week and a concomitant therapy with laevamisol was added for 6 months. Computer-tomography revealed a significant reduction of the retroperitoneal masses already before induction of chemotherapy. One year after termination of chemotherapy retroperitoneal fibrosis was no longer detectable. The course of events makes us assume that the retroperitoneal fibrosis of our patient was paraneoplastic and therefore completely reversible by successful removal of the underlying tumor.

[Administration of thyroid hormones in therapy of psychiatric illnesses]. / Einsatz von Schilddrüsenhormonen in der Therapie psychiatrischer Erkrankungen.

This review tries to give the state of the art of the therapeutic use of thyroid hormones in psychiatric disorders, mainly in depression. Four hypotheses suggest an effect in these ailments: 1) a local relative T4 excess present (or better postulated to be present) in the brain of depressed patients is lowered by triiodothyronine (T3), by lowering serum levels of thyroxine (T4), 2) the effect of a depression-mediated cerebral lack of catecholamines is compensated by the T3/T4 induced activation of beta-receptors, 3) a postulated depression-induced local cerebral hypothyroidism can be counteracted by T3 and T4. 4) thyroid hormones increase the cerebral content of serotonin. This may be beneficial in depression, where shortage of serotonin in the brain is accused to be etiologically important. Thyroid hormones have been used so far in the following ways: 1) as T3 monotherapy in depression; 2) initial additive T3 for acceleration of the response to treatment with tricyclic antidepressants (TCA); 3) additive T3 for augmentation of the response to TCA in therapy-resistant patients with depression, 4) as high-dose (250-500 micrograms/die) T4-treatment of "rapid cycling bipolar disorder". Low dose (5-50 mg/die) T3 "augmentation therapy" is the best documented form of treatment with thyroid hormones in depression. The results suggest a convincing benefit for a varying percentage of non responders to therapy with TCA. For the other forms of treatment placebo-controlled double blind studies are not yet available or give conflicting results.

[Thyrotoxic hypokalemic periodic paralysis in a male Kurd]. / Thyreotoxische hypokaliämische periodische Paralyse bei einem männlichen Kurden.

Thyrotoxic hypokalemic periodic paralysis has been described to occur quite frequently in male Asiatic patients. The syndrome is, however, very rare in patients of Caucasian origin. To our knowledge it has never been described in Austria so far. This is the reason why we present the following case: A 22-year old male patient of Kurdish origin suffered from two periods of typical flaccid paralysis of the extremities after strenuous physical exertion, that were 4 months apart. The periods of paralysis were quickly reversed by substitution with potassium. Graves' disease was retrospectively diagnosed to have existed already during the first period. The patient was treated with an ablative dose of 131-I (25 mCi) and can perform strenuous exercise without symptoms since. This case and the review of the literature clearly illustrates the advantage of screening for thyroid dysfunction in patients with flaccid paralysis: unnecessary further periods of paralysis can be avoided by the correct treatment of thyrotoxicosis in such patients.

Culture of human insulinoma cells: development of a neuroendocrine tumor cell- and human pancreatic islet cell-specific monoclonal antibody.

We report on the culture of human insulinoma cells derived from a 32-year-old male patient with hyperinsulinism due to an insulinoma of the pancreas. A single-cell suspension was made by passing insulinoma fragments through a fine-gauge stainless-steel mesh. Cluster-forming insulinoma cells resembling pancreatic islets grew in the presence of fibroblasts. The insulinoma cell clusters could be differentiated from fibroblasts by using in situ pan optic staining and specific immunocytochemical staining (anti-human insulin and anti-human insulinoma monoclonal antibody (mAb) D24). mAb D24 was generated using insulinoma cells as antigen for immunization of a Balb/C mouse and cell fusion by the hybridoma cell technique. The anti-insulinoma cell mAb recognized a 32 kDa protein on immunoblot analysis of neuroendocrine tumor cells. D24 mAb also reacted immunohistochemically with normal pancreatic beta-cells and tumors such as vipoma, gastrinoma and carcinoid. Insulinoma cell clusters separated from fibroblasts by micromanipulation and plated into multiwell culture dishes exhibited an insulin-secretion rate of approximately 30 U/100 cells per 24 h with no insulin-secretory response to elevated glucose concentration. Purified insulinoma cells incubated with 1 ng/ml human nerve growth factor expressed neurofilament and neurite extension. These findings together with earlier observations in animal models suggest that human pancreatic beta-cells share some properties with neurons and are related to other neuroendocrine cells in the gastrointestinal tract.

[Post partum thyroiditis: is early detection of risk patients during pregnancy worthwhile?]. / Post-partum-Thyreoiditis: Ist eine Früherfassung von Risikopersonen während der Schwangerschaft sinnvoll?

This short review summarizes the arguments for and against a screening for post-partum thyroiditis in early pregnancy: Measurement of circulating TPO (thyro-peroxydase) antibodies in early pregnancy seems a valid screening method for detecting persons at risk. TPO positive mothers seem to have, moreover, an increased risk to develop post-partial depression or symptoms of thyroid disease even without alteration of thyroid function. In addition, a higher frequency of miscarriages has been described in such patients. In contrast to these arguments in favour of performing such a screening is the fact that post-partum thyroiditis usually has only mild clinical symptoms and is a self-limiting disease.