Incidence of myocardial infarction and stroke in acromegaly patients: results from the German Acromegaly Registry.

PURPOSE: Acromegaly is a rare disease generally brought about by a benign tumour in the pituitary and characterized by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) excess. Increased mortality has been related to cardiovascular events that could be linked to these hormones and patients suffer from high rates of diabetes and hypertension. In this study, we examine if the incidence of myocardial infarction (MI) and stroke differ from that of the general population. METHODS: Data from the German Acromegaly Registry in seven specialized endocrine centres were analysed (n = 479, 56% female, 46 years old at diagnosis, 5549 person-years from diagnosis). Standardized incidence ratios (SIR) were calculated as compared to the general population. RESULTS: MI and stroke incidences were very close to those of the general population with an SIR (95% CI) of 0.89 (0.47-1.52, p = 0.80) for MI and 1.17 (0.66-1.93, p = 0.61) for stroke. Acromegaly was uncontrolled in 16% of patients with MI or stroke versus 21% in those without (p = 0.56). Prevalence of hypertension at the initial visit was much higher in those with MI or stroke than those without (94 vs. 43%, p < 0.001). No association was seen between radiation therapy and stroke. CONCLUSIONS: For acromegaly patients being treated at specialized centres, the incidence of MIs and strokes does not seem to differ from the general population. Certainty regarding such statements requires large, prospective studies however.

The Incidence of Cancer Among Acromegaly Patients: Results From the German Acromegaly Registry.

CONTEXT: Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected. OBJECTIVE: The objective was to determine whether the overall and site-specific incidence of cancer is comparable to that of the general population. DESIGN AND SETTING: Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed. MAIN OUTCOME MEASURE: Standard incidence ratios (SIRs) were calculated as compared to the general population. RESULTS: Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P = .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges <1, 1-2.5, and ≥ 2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P = .94). There was not a significant dependence on normal vs elevated IGF-1 (P = .87), radiation therapy (P = .45), disease duration (P = .96), age at diagnosis (P = .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P = .41). CONCLUSIONS: Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer.

Failure to achieve disease control in acromegaly: cause analysis by a registry-based survey.

CONTEXT: Disease control is a prime target in acromegaly treatment. This should be achievable in the vast majority of patients by available treatment options. For unknown reasons, however, a significant number of patients do not achieve disease control. OBJECTIVE: To investigate reasons for failure to achieve disease control in long-standing acromegaly. DESIGN AND METHODS: Survey based on the German Acromegaly Registry database (1755 patients in 57 centres). Questionnaires were sent to 47 centres treating 178 patients with elevated disease markers (IGF1 and GH) at the last documented database visit out of 1528 patients with a diagnosis dated back ≥2 years. Thirty-three centres returned anonymised information for 120 patients (recall rate 67.4%). RESULTS: Median age of the 120 patients (58 females) was 57 years (range 17-84). Ninety-four patients had at least one operation, 29 had received radiotherapy and 71 had been previously treated medically. Comorbidities were reported in 67 patients. In 61 patients, disease activity had been controlled since the last documented database visit, while 59 patients still had biochemically active disease. Reasons were patients' denial to escalate therapy (23.3%), non-compliance (20.6%), fluctuating insulin-like growth factor 1 (IGF-1) and growth hormone (GH) levels with normal values at previous visits (23.3%) and modifications in pharmacotherapy (15.1%). Therapy resistance (9.6%), drug side effects (4.1%) and economic considerations (4.1%) were rare reasons. CONCLUSIONS: Main reasons for long-standing active acromegaly were patients' lack of motivation to agree to therapeutic recommendations and non-compliance with medical therapy. Development of patient education programmes could improve long-term control and thus prognosis of acromegalic patients.

Frequency of AIP gene mutations in young patients with acromegaly: a registry-based study.

CONTEXT: Familial and sporadic GH-secreting pituitary adenomas are associated with mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. Patients with an AIP mutation (AIPmut) tend to have more aggressive tumors occurring at a younger age. OBJECTIVE: The objective of the study was to investigate the frequency of AIPmut in patients diagnosed at 30 years of age or younger. DESIGN: The German Acromegaly Registry database (1795 patients in 58 centers) was screened for patients diagnosed with acromegaly at 30 years of age or younger (329 patients). Sixteen centers participated and 91 patients consented to AIPmut analysis. INTERVENTION: DNA was analyzed by direct sequencing and multiplex ligation dependent probe amplification Main outcome Measures: The number of patients with AIPmut was measured. RESULTS: Five patients had either a mutation (c.490C>T, c.844C>T, and c.911G>A, three males) or gross deletions of exons 1 and 2 of the AIP gene (n = 2, one female). The overall frequency of an AIPmut was 5.5%, and 2.3% or 2.4% in patients with an apparently sporadic adenoma or macroadenoma, respectively. By contrast, three of four patients (75%) with a positive family history were tested positive for an AIPmut. Except for a positive family history, there were no significant differences between patients with and without an AIPmut. CONCLUSIONS: The frequency of AIPmut in this registry-based cohort of young patients with acromegaly is lower than previously reported. Patients with a positive family history should be tested for an AIPmut, whereas young patients without an apparent family history should be screened, depending on the individual cost to benefit ratio.

Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register.

BACKGROUND: Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under 'real life' conditions are scarce. OBJECTIVE: To describe biochemical long-term outcome of acromegaly patients in Germany. DESIGN AND METHODS: Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0-52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range. RESULTS: Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25-443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0-44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy. CONCLUSION: The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.

[Role of TSH receptor autoantibodies for the diagnosis of Graves' disease and for the prediction of the course of hyperthyroidism and ophthalmopathy. Recommendations of the Thyroid Section of the German Society of Endocrinology]. / Bedeutung der TSH-Rezeptor-Antikörper für die Diagnose des Morbus Basedow sowie die Prognoseabschätzung der Schilddrüsenüberfunktion und der endokrinen Orbitopathie. Stellungnahme der Sektion Schilddrüse der DGE.

Graves' disease (GD) is the only autoimmune disease where autoantibodies stimulate the target organs. Among the most common clinical manifestations are hyperthyroidism and orbitopathy (GO). To ensure the diagnosis of autoimmune hyperthyroidism, activity of TSH receptor autoantibodies (TRAb) should be determined. Because of their significantly improved sensitivity and equal specificity, second-generation TRAb assays (activity given in IU/l) should be preferred over first-generation assays (activity given in U/l). During follow-up of antithyroid drug therapy it is possible to predict outcome for some patients with high chances if TRAb levels are high. On this basis, thyreoablative treatment (operation or radioiodine) can already be indicated before the 1st year of antithyroid drug treatment has passed. If TRAb antibody titers are > 10 IU/l, it is possible to predict outcome as early as 6 months after initiation of antithyroid drug therapy. Below a certain threshold, depending on the time point of measurement, no representative risk analyses are available for TRAbs. TRAb measurement is also helpful to determine the course of GO. This may guide the physician through crucial treatment decisions, especially if the patient is at risk of deterioration.

[The LISA trial-a- randomized, double-blind, placebo-controlled four-arm study of 1,000 patients with nodular goiter in Germany. Study Design and first results of feasibility]. / Die LISA-Studie--eine randomisierte, doppelblinde, vierarmige, plazebokontrollierte, multizentrische Studie an 1 000 Patienten über die medikamentöse Therapie der Struma in Deutschland. Studiendesign und erste Ergebnisse zur Machbarkeit.

BACKGROUND: Although levothyroxine is the mostly prescribed medicament in Germany, its therapeutic effectiveness in nodular goiter was never studied in a randomized, double-blind trial with sufficient power. Thus, in May 2004 a TSH-adapted (TSH: thyroid-stimulating hormone), randomized, doubleblind, placebo-controlled four-arm (placebo [P] vs. levothyroxine [T] vs. iodine [I] vs. levothyroxine + iodine [TI]) multicenter study was started in Germany (LISA study). PATIENTS AND METHODS: Based on former retrospective and prospective studies, it was calculated that a sufficient statistical power (> 80%) would be achieved with 250 patients in each arm. The primary endpoint of the trial is the 1-year change of ultrasonographically measured total volume of all nodules. Secondary criteria are volume of goiter, number of nodules, and echogenic structure of nodules. While the study is kept strictly double-blind, the dose of levothyroxine in the T and TI groups is adapted once according to 3-month TSH measurements (target range 0.2-0.8 mU/l). RESULTS: Up to now (1 year after beginning), 305 patients have been included. TSH adaptation could be performed without compromising the double-blind character of the study with good results: about 90% of the patients reached the TSH target range. CONCLUSION: Unblinded results are to be expected in 2007.

[Bioequivalence of L-thyroxine tablets and a liquid L-thyroxine solution in the treatment of hypothyroid patients]. / Bioäquivalenz von L-Thyroxin-Tabletten und L-Thyroxin-Tropfen bei der Behandlung der Hypothyreose in der täglichen Praxis.

BACKGROUND AND PURPOSE: The therapeutic equivalence of L-thyroxine (T(4)) tablets and a new liquid T(4) solution was investigated in patients with hypothyroidism. PATIENTS AND METHODS: The study was unblinded, multicentric and prospective: 136 patients (with autoimmune thyroiditis, after thyroid surgery and/or after therapy with radioiodine), who had been treated with T(4) tablets, were switched to a treatment with a liquid T(4) solution (containing 5 microg T(4) per drop) in the same dosage. Thyrotropin (TSH) was measured after 1, 2, 3, and 6 months; the dose of the T4 solution was adapted to obtain a midnormal TSH level. RESULTS: The T(4) dose remained constant during the 6 months. Dose adaptations were necessary in 19-23% of patients at the different timepoints, with dose reductions and increases, respectively, becoming equally frequently necessary. The mean TSH level was 0.79 mU/l at the beginning and 0.81 mU/l after 6 months; similarly, the mean levels of free triiodothyronine (fT(3)) and free thyroxine (fT(4)) were equivalent. The liquid T(4) solution was well tolerated: adverse events were noted in three patients (1.8%); one serious adverse event (thyroid carcinoma) showed no correlation to the treatment. CONCLUSION: T(4) tablets and liquid T(4) solution have been proven to be therapeutically equivalent; the use of liquid T(4) solutions will have advantages in the treatment of hypothyroid infants or elderly patients with disturbed swallowing, patients who need a differentiated titration of the T(4) dose, as well as patients with an allergy against inactive ingredients of L-thyroxine tablets.