Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.

OBJECTIVES: Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum. METHODS: All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects. RESULTS: Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms. CONCLUSIONS: Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.

Moderate weight reduction in an outpatient obesity intervention program significantly reduces insulin resistance and risk factors for cardiovascular disease in severely obese adolescents.

Background. Metabolic risk factors like insulin resistance and dyslipidemia are frequently observed in severly obese children. We investigated the hypothesis that moderate weight reduction by a low-threshold intervention is already able to reduce insulin resistance and cardiovascular risk factors in severely obese children. Methods. A group of 58 severely obese children and adolescents between 8 and 17 years participating in a six-month-long outpatient program was studied before and after treatment. The program included behavioral treatment, dietary education and specific physical training. Metabolic parameters were measured in the fasting state, insulin resistance was evaluated in an oral glucose tolerance test. Results. Mean standard deviation score of the body mass index (SDS-BMI) in the study group dropped significantly from +2.5 ± 0.5 to 2.3 ± 0.6 (P < 0.0001) after participation in the program. A significant decrease was observed in HOMA (6.3 ± 4.2 versus 4.9 ± 2.4, P < 0.03, and in peak insulin levels (232.7 ± 132.4 versus 179.2 ± 73.3 µU/mL, P < 0.006). Significant reductions were also observed in mean levels of hemoglobin A(1c), total cholesterol and LDL cholesterol. Conclusions. These data demonstrate that already moderate weight reduction is able to decrease insulin resistance and dyslipidemia in severely obese children and adolescents.

Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters.

Objectives Isolated methylmalonic acidurias (MMAurias) are caused by deficiency of methylmalonyl-CoA mutase or by defects in the synthesis of its cofactor 5'-deoxyadenosylcobalamin. The aim of this study was to evaluate which parameters best predicted the long-term outcome. Methods Standardized questionnaires were sent to 20 European metabolic centres asking for age at diagnosis, birth decade, diagnostic work-up, cobalamin responsiveness, enzymatic subgroup (mut(0), mut(-), cblA, cblB) and different aspects of long-term outcome. Results 273 patients were included. Neonatal onset of the disease was associated with increased mortality rate, high frequency of developmental delay, and severe handicap. Cobalamin non-responsive patients with neonatal onset born in the 1970s and 1980s had a particularly poor outcome. A more favourable outcome was found in patients with late onset of symptoms, especially when cobalamin responsive or classified as mut(-). Prevention of neonatal crises in pre-symptomatically diagnosed newborns was identified as a protective factor concerning handicap. Chronic renal failure manifested earlier in mut(0) patients than in other enzymatic subgroups. Conclusion Outcome in MMAurias is best predicted by the enzymatic subgroup, cobalamin responsiveness, age at onset and birth decade. The prognosis is still unfavourable in patients with neonatal metabolic crises and non-responsiveness to cobalamin, in particular mut(0) patients.

Coenzyme Q(10) is decreased in fibroblasts of patients with methylmalonic aciduria but not in mevalonic aciduria.

The content of coenzyme Q(10) (CoQ(10)) was examined in skin fibroblasts of 10 patients with mevalonic aciduria (MVA) and of 22 patients with methylmalonic aciduria (MMA). Patients with these inborn errors of metabolism are thought to be at risk for CoQ(10) depletion either by direct inhibition of the proximal pathway of CoQ(10) synthesis (MVA) or indirectly by inhibition of mitochondrial energy metabolism (MMA). We demonstrated that CoQ(10) concentrations were not significantly different from controls in MVA patients, suggesting that there may be upregulatory effects. On the other hand the CoQ(10) content in fibroblasts of patients with MMA was significantly reduced.

Aromatic L-amino acid decarboxylase deficiency: clinical features, drug therapy and follow-up.

BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) deficiency is a disorder of biogenic amine metabolism resulting in generalized combined deficiency of serotonin, dopamine and catecholamines. Main clinical features are developmental delay, muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Response to therapy has been variable and unsatisfactory; the overall prognosis is guarded. METHODS: To gain more insight into this rare disorder we collected clinical and laboratory data of nine German patients. All patients were clinically examined by one investigator, and their responses to different drug regimes were evaluated by the patients' charts. RESULTS: Symptoms were obvious from early infancy. Later, main neurological features were truncal muscular hypotonia, hypokinesia, oculogyric crises and rigor. Three patients had single seizures. All patients presented distinct extraneurological symptoms, such as hypersalivation, hyperhidrosis, nasal congestion, sleep disturbances and hypoglycaemia. In CSF all patients revealed the pattern typical of AADC with decreased concentrations of homovanillic and 5-hydroxyindoleacetic acid and elevated concentration of 3-ortho-methyldopa. Diagnosis was confirmed by measurement of AADC activity in plasma in all patients. Drug regimes consisted of vitamin B6, dopamine agonists, MAO inhibitors and anticholinergics in different combinations. No patient achieved a complete recovery from neurological symptoms, but partial improvement of mobility and mood could be achieved in some. CONCLUSION: AADC deficiency is a severe neurometabolic disorder, characterized by muscular hypotonia, dystonia, oculogyric crises and additional extraneurological symptoms. Medical treatment is challenging, but a systematic trial of the different drugs is worthwhile.

Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres.

The long-term outcome of patients with methylmalonic aciduria (MMA) is still uncertain due to a high frequency of complications such as chronic renal failure and metabolic stroke. The understanding of this disease is hampered by a huge variation in the management of these patients. The major aim of this study was to evaluate the current practice in different European metabolic centres. A standardized questionnaire was sent to 20 metabolic centres asking for standard procedures for confirmation of diagnosis, testing cobalamin responsiveness, dietary treatment, pharmacotherapy, and biochemical and clinical monitoring. Sixteen of 20 metabolic centres (80%) returned questionnaires on 183 patients: 89 of the patients were classified as mut(0), 36 as mut(-), 13 as cblA, 7 as cblB, and 38 as cblA/B. (1) Confirmation of diagnosis: All centres investigate enzyme activity by propionate fixation in fibroblasts; six centres also perform mutation analysis. (2) Cobalamin response: Ten centres follow standardized protocols showing large variations. A reliable exclusion of nonspecific effects has not yet been achieved by these protocols. (3) Long-term treatment: In cobalamin-responsive patients, most centres use hydroxocobalamin (1-14 mg/week i.m. or 5-20 mg/week orally), while two centres use cyanocobalamin. All cobalamin-nonresponsive patients and most cobalamin-responsive patients are supplemented with L: -carnitine (50-100 mg/kg per day). Fourteen centres use intestinal decontamination by antibiotic therapy. Most centres follow D-A-CH (n = 6) or Dewey (n = 4) recommendations for protein requirements. Fourteen centres regularly use precursor-free amino acid supplements. Standardized monitoring protocols are available in seven centres, again showing high variability.

Looking beyond the basal ganglia: the spectrum of MRI changes in methylmalonic acidaemia.

We report imaging abnormalities from 5 brain MR examinations in 4 children with methylmalonic acidaemia between the ages of 20 days and 31 months. In addition to bilateral basal ganglia lesions (pallidum) observed in 3 of 4 children, we found signs of delayed brain maturation (myelination delay, immature gyral pattern, incomplete opercularization) in all children and signs of a white matter disorder in the 3 older children. Unexpectedly, brainstem and cerebellar changes were present in all children. Reviewing the brain imaging changes reported for methylmalonic acidaemia, we discuss the findings and patterns observed in our patients. We postulate that delayed myelination and signs of a white matter disorder as well as brainstem and cerebellar involvement are common findings and may be due to a chronic neurotoxic effect on the developing and ageing brain.

Neurodegeneration and chronic renal failure in methylmalonic aciduria--a pathophysiological approach.

In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called 'toxic metabolite' hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites ('trapping' hypothesis') is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

A novel mutation causing DEND syndrome: a treatable channelopathy of pancreas and brain.

OBJECTIVES: Activating mutations in the human KCNJ11 gene, encoding the pore-forming subunit (Kir6.2) of the ATP-sensitive potassium (K(ATP)) channel, are one cause of neonatal diabetes mellitus. In a few patients, KCNJ11 mutations cause a triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). The aim of this study was to determine the clinical effects, functional cause, and sensitivity to sulfonylurea treatment of a novel KCNJ11 mutation producing DEND syndrome. METHODS: We screened the DNA of a 3-year-old patient with neonatal diabetes, severe developmental delay, and therapy-resistant epilepsy for mutations in KCNJ11. We carried out electrophysiologic analysis of wild-type and mutant K(ATP) channels heterologously expressed in Xenopus oocytes. RESULTS: We identified a novel Kir6.2 mutation (I167L) causing DEND syndrome. Functional analysis showed both homomeric and heterozygous mutant channels were less inhibited by MgATP leading to an increase in whole-cell K(ATP) currents. This effect was due to an increase in the intrinsic open probability. Heterozygous channels were strongly inhibited by the sulfonylurea tolbutamide. Treatment of the patient with the sulfonylurea glibenclamide not only enabled insulin therapy to be stopped, but also resulted in improvement in epilepsy and psychomotor abilities. CONCLUSIONS: We report a case of developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome that shows neurologic improvement with sulfonylurea therapy. Early recognition of patients with DEND syndrome may have considerable therapeutic benefit for the patient.

Disorders of intermediary metabolism: toxic leukoencephalopathies.

Myelination starts in the latter half of gestation. It is initiated by oligodendrocyte progenitor cells. Three sequential steps can be distinguished: (1) initial ensheathment of axons by premyelin sheaths generated by oligodendrocyte progenitor cells; (2) initial insertion of myelin basic protein (MBP) into transitional sheaths; and (3) generation of mature MBP-rich myelin. Different inborn errors of metabolism can interfere with different stages of these physiological processes, causing white-matter diseases, i.e. toxic leukoencephalopathies. Some inborn errors of metabolism disturb the formation of myelin by being toxic to oligodendrocytes or by interference with the biosynthesis of cholesterol and lipids, e.g. globoid cell leukodystrophy and phenylketonuria. Remethylation defects, e.g. methylenetetrahydrofolate reductase deficiency, cobalamin C, D, E, F and G defects, interfere with the expression, processing and insertion of MBP. The concept of excitotoxicity, which has been developed in neurons, has recently been modified and has been extended to the oligodendroglial lineage. Mitochondriopathies and cerebral organic acid disorders may cause secondary excitotoxicity resulting in toxic encephalopathies, which may affect both neurons and oligodendrocytes. This review aims to present relevant diseases, summarizing recent knowledge on mechanisms and formulating testable hypotheses of pathophysiology leading to new and improved treatment strategies.

Excitotoxicity and bioenergetics in glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase deficiency is an inherited organic acid disorder with predominantly neurological presentation. The biochemical hallmark of this disease is an accumulation and enhanced urinary excretion of two key organic acids, glutaric acid and 3-hydroxyglutaric acid. If untreated, acute striatal damage is often precipitated by febrile illnesses during a vulnerable period of brain development in infancy or early childhood, resulting in a dystonic dyskinetic movement disorder. 3-hydroxyglutaric and glutaric acids are structurally similar to glutamate, the main excitatory amino acid of the human brain, and are considered to play an important role in the pathophysiology of this disease. 3-hydroxyglutaric acid induces excitotoxic cell damage specifically via activation of N-methyl-D-aspartate receptors. It has also been suggested that secondary amplification loops potentiate the neurotoxic properties of these organic acids. Probable mechanisms for this effect include cytokine-stimulated NO production, a decrease in energy metabolism, and reduction of cellular creatine phosphate levels. Finally, maturation-dependent changes in the expression of neuronal glutamate receptors may affect the vulnerability of the immature brain to excitotoxic cell damage in this disease.

3-Ureidopropionate contributes to the neuropathology of 3-ureidopropionase deficiency and severe propionic aciduria: a hypothesis.

3-Ureidopropionate (3-UPA) is a physiologic metabolite in pyrimidine degradation. Pathological accumulation of 3-UPA in body fluids is found in 3-ureidopropionase deficiency and severe forms of propionic aciduria. Both diseases clinically present with a severe neuropathology involving gray and white matter as well as with a dystonic dyskinetic movement disorder. To date nothing is known about the toxic nature of this metabolite. The aim of the present study was to elucidate whether 3-UPA may act as endogenous neurotoxin. Exposure of cultured chick neurons to 3-UPA induced a concentration- and time-dependent neurodegeneration. Neuronal damage was reduced by the antioxidant alpha-tocopherol and the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. In contrast, the non-NMDA receptor antagonist CNQX, the metabotropic glutamate receptor antagonist L-AP3, and succinate showed no protective effect. Furthermore, 3-UPA elicited an increased production of reactive oxygen species followed by a delayed increase in intracellular calcium concentrations. Activity measurement of single respiratory chain complexes I-V revealed an inhibition of complex V activity, but not of the electron-transferring complexes I-IV by 3-UPA. In contrast, 3-UPA did not affect the mitochondrial beta-oxidation of fatty acids. In conclusion, our results provide strong evidence that 3-UPA acts as endogenous neurotoxin via inhibition of mitochondrial energy metabolism, resulting in the initiation of secondary, energy-dependent excitotoxic mechanisms.

Follow up of thyroid hormone parameters in chronically ill geriatric patients: screening for thyroid disorders at hospital admission justified.

UNLABELLED: The objective of this study was to investigate if screening of chronically ill geriatric patients for thyroid dysfunction is justified just upon hospital admission. TSH was measured in 124 patients at hospital admission and 11-86 (Median 37) days afterwards. FT4 was measured in cases with subnormal, suppressed or elevated TSH (43 cases). Out of 81 patients with normal (0.5-3.6 mU/l) TSH, the control value was subnormal (0.1-<0.5 mU/l) in 6 and elevated (>3.6 mU/l) in one case, but in none of the patients became suppressed (<0.1 mU/l). In 13/30 patients with subnormal TSH the control value was normal but in none of the patients suppressed or elevated. On the contrary, all cases with suppressed (N=9) or elevated (N=4) TSH remained in the same ranges at follow up. Low (<13 pmol/l, N=3) or elevated (>27 pmol/l, N=5) initial FT4 levels did not change in the follow up as well. Out of 35 patients with normal FT4, one became low and another elevated. Improvement or worsening of the clinical state in the follow up did not correlate to changes of TSH. The prevalence of unsuspected thyroid dysfunctions were 11.3% (hyperthyroidism clinical: 4, subclinical: 5, hypothyroidism clinical: 3, subclinical: 2 cases). All cases except one with subclinical hypothyroidism were detected by the initial screening. Only one patient with clinical hyperthyroidism was initial misinterpreted as having subclinical disease. CONCLUSIONS: In chronically ill geriatric patients investigated at hospital admission, a measurable TSH practically excludes hyperthyroidism in the follow up. Suppressed TSH levels remain suppressed but subnormal levels should be controlled because their normalization frequently occur in the follow up. Screening upon hospital admission is sensitive enough to detect cases of thyroid dysfunction and justified by their high prevalence.

Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome.

The deleterious effects of ethanol on the developing human brain are poorly understood. Here it is reported that ethanol, acting by a dual mechanism [blockade of N-methyl-D-aspartate (NMDA) glutamate receptors and excessive activation of GABA(A) receptors], triggers widespread apoptotic neurodegeneration in the developing rat forebrain. Vulnerability coincides with the period of synaptogenesis, which in humans extends from the sixth month of gestation to several years after birth. During this period, transient ethanol exposure can delete millions of neurons from the developing brain. This can explain the reduced brain mass and neurobehavioral disturbances associated with human fetal alcohol syndrome.

[Therapy of endemic goiter with iodide or l-thyroxine in older patients]. / Therapie der endemischen Struma mit Jodid oder L-Thyroxin bei älteren Patienten.

OBJECTIVE: To compare the efficacy of iodide (300 micrograms daily) with that of levothyroxine (1.5 micrograms/kg daily) in the treatment of endemic goitre in middle-aged and elderly persons. The possible occurrence of antibodies against thyroid peroxidase and thyroglobulin was also tested. PATIENTS AND METHODS: 67 patients (54 women, 13 men; aged over 40 years, average 53.5 years) with endemic goitre, excluding toxic goitre, were randomly treated with either iodine or thyroxine. Every 3 months for one year their thyroid volume was obtained by ultrasound and the activities of thyroid hormone (TH) and thyroid stimulating hormone (TSH) and the concentration of antibodies against peroxidase and thyroglobulin were measured. RESULTS: In patients on levothyroxine the thyroid volume had already markedly decreased after 3 months (P < 0.0001), diminishing by 15.4% at 12 months. Volume reduction in the group on iodine was 16.2% at one year. There was no significant difference between the two medications and no case of antibody production in the iodine group. CONCLUSIONS: Treatment of endemic goitre with iodine alone is efficacious even in middle-aged or elderly patients, toxic goitre having been excluded. There was no evidence of antibody production against thyroid antigens at the stated iodine dosage.

Thyroid autoantibodies in hospitalized chronic geriatric patients: prevalence, effects of age, nonthyroidal clinical state, and thyroid function.

OBJECTIVE: To investigate the effect of age, clinical condition, and thyroid function on the prevalence of thyroid autoantibody positivity in hospitalized chronic geriatric patients. DESIGN: A screening study of hospitalized chronic geriatric patients. PARTICIPANTS: 249 non-selected, hospitalized, chronic geriatric patients more than 60 years of age and 81 20 to 40-year-old healthy persons. MEASUREMENTS: Thyrotropin (TSH); thyroxine (T4) and free thyroxine (FT4); and triiodothyronine (T3), thyroglobulin (Tg), antibodies against thyroid peroxidase (AbTPO) and antibodies against thyroglobulin (AbTg) estimation in a screening study. RESULTS: AbTPO positivity (AbTPO+) was found more often than AbTg positivity (AbTg+) (15.3% vs 9.2%, P = .04), one being positive (Ab+) in 19.3%. The occurrence was higher in females than males (Ab+:27.1% vs 7.1%, P < .001; AbTPO+:21.9% vs 5.1%, P < .001; AbTg+:13.2% vs 3.1%, P = .0052). Among the Ab+ patients, AbTPO was more often positive than AbTg (40/48 vs 21/48, P < .001). The sensitivity, specificity, and positive predictive value of Ab positivity to detect a thyroid disorder were 0.35, 0.85 and 0.38, respectively. Within the population of euthyroid geriatric patients, the occurrence of AbTg+ (chi 2(2) = 8.65, P = .013) and Ab+ (chi 2(2) = 8.02, P = .018) correlated positively with the age of the patients, and there was also a female predominance (AbTPO+ 18% vs 3.7% in the males; AbTg+ 13% vs 2.4%; Ab+ 25.8% vs 6.1%). When compared with 20 to 40-year-old subjects, only the euthyroid > or = 80-year-old patients showed a significantly higher occurrence of Ab+ (26.2% vs 9.9% chi 2(1) = 5.64, P = .017). In the euthyroid > or = 80-year-old females, AbTPO+ was 25%, AbTg:22.2%, and Ab+: 36.1%!. The nonthyroidal clinical state of the euthyroid patients did not correlate with the antibody prevalence. CONCLUSIONS: In hospitalized chronic geriatric patients, AbTg and especially AbTPO positivity is frequent, even in euthyroid patients without goiter. This aspecific Ab positivity in the euthyroid state correlates to the age, but not to the severity of the nonthyroidal clinical condition of the patients and explains why the Ab positivity is not predictive enough for thyroid dysfunction in this subpopulation. Thus, in hospitalized chronic geriatric patients the AbTg and AbTPO titers should be examined only in cases where thyroid screening (TSH) reveals abnormal results.

[Rational diagnosis of disorders of thyroid function]. / Rationelle Diagnostik von Schilddrüsenfunktionsstörungen.

A. A dysfunction of the thyroid gland can be safely excluded when the local finding of the thyroid gland, perhaps including an ultrasound, is normal and the TSH-levels are unchanged (between 0.4 and 4.0 microE/ml). B. A hyperthyreosis can be proven in 98% when TSH is suppressed (possibly a negative TSH-test) and the T3 levels and the FT3 levels, respectively, are elevated. Following examinations are necessary for the further diagnostics: When a Base-dow hyperthyreosis is suspected, T4, TR and TPO antibodies should be measured and an ultrasound obtained. When a focal or disseminated autonomy is suspected, a scintigraphy and suppression scintigraphy, respectively as well as an ultrasound should be undertaken. C. A hypothyreosis can be proven in 98% when TSH is elevated (possibly an overshooting TSH test), and the T4 levels are low. For further diagnostics, ultrasound and maybe scintigraphy should be undertaken in case of a congenital hypothyreosis. In case of an acquired hypothyreosis, TR and TPO antibodies should be measured, an ultrasound obtained, and a cytology might be taken to exclude a thyreoiditis De Quervain or a Hashimoto thyreoiditis.

[Pathogenesis, diagnosis and therapy of hyperthyroidism]. / Pathogenese, Diagnose und Therapie der Hyperthyreose.

Different forms of hyperthyreosis have to be distinguished: Frequent forms: Basedow's disease (Graves' disease, autoimmunogenic hyperthyreosis), Plummer's disease (focal or disseminated functional autonomy). Rare forms: Hyperthyreosis with thyreoiditis. This 'morphologic' hyperthyreosis is due to a destruction caused by an infection combined with a release of the thyroid hormones. This transitory hyperthyreosis can be observed particularly in the beginning of a thyreoiditis De Quervain. The treatment of the inflammation eliminates the hyperthyreosis. Sometimes, a hyperthyreosis may also be observed during a Hashimoto-thyreoiditis which, however, will turn into a hypothyreosis. An increased TSH stimulation (secondary hyperthyreosis) is a rare disease which, i.e., may be due to a genetically caused hormone resistance in the periphery followed by an overproduction of TSH. The even more rare hyperthyreosis caused by a TSH producing tumor of the pituitary gland should also be mentioned. A hyperthyreosis during struma ovarii, trophoblast tumors and recently during interferon treatment are similarly rare. A 'hyperthyreosis factitia' in correlation with a permanent application of an overdose of thyroid hormones is observed only rarely in Germany. However, a hyperthyreosis caused by physicians is more frequent: The application of contrast mediums or other substances containing iodine during a hidden functional autonomy of the thyroid gland is taken into account for the diagnosis and treatment of the Plummer's disease.

Serum thyroglobulin in hospitalized chronic geriatric patients: its relationship to age, non-thyroidal illness, goitre and thyroid dysfunction in a follow-up study.

The objectives were to determine whether the serum thyroglobulin (TG) level is influenced by age or by non-thyroidal illness (NTI) of the aged, to investigate the constancy of the TG level after 1- and 2-month intervals and to investigate if the TG level could help to differentiate whether a subnormal thyrotrophin (TSH) level in a geriatric patient is caused by autonomous thyroid function, by age or by NTI. Two-hundred and twenty-six non-selected, chronic hospitalized patients over 60 years old and 82 healthy adults (20-40 years) participated in the study, and TSH, thyroxine, free thyroxine, triiodothyronine and TG were estimated. In 122 euthyroid geriatric patients with normal TSH the mean TG was normal (12.18 micrograms/l), but elevated (> 45 micrograms/l) TG values occurred more often than in healthy control persons (15/122 vs 3/82; chi 2(1) = 4.54, p = 0.03). The severity of the clinical state of the euthyroid patients had no influence on the TG values. If TG was measured after 1 and/or 2 months, in only 3/123 non-selected geriatric patients was there a fluctuation between the normal and abnormal range (versus fluctuation of the corresponding TSH values in 19/123 cases; chi 2(1) = 12.78, p = 0.0012). In 28 patients with subnormal TSH, a normal TG value had a predictive value of 0.6 to exclude autonomous thyroid function. Age and NTI of the geriatric patients have no significant influence on their mean TG level but high TG levels occur more often, even in euthyroid patients. The predictive value of TG is not sufficiently high to allow a clear differentiation of whether a subnormal TSH is caused by autonomous thyroid function or by the age process or by NTI. Nevertheless, the advantage of TG estimation to be more constant than TSH could be of benefit in screening studies.