Armin E. Heufelder

Leptin Serum Levels Are Not Correlated With Disease Activity in Patients With Rheumatoid Arthritis

Leptin, the ob gene product, has been proposed as a mediator of inflammatory cytokine-dependent decreased food intake and cachexia in rodents. In humans, leptin serum levels increase after administration of tumor necrosis factor-alpha (TNF-alpha) or interleukin-2 or during septicemia. However, the effect of human chronic inflammatory disease on serum leptin is unknown. We therefore determined the serum leptin level (radioimmunoassay), body mass index (BMI), percent body fat ([%BF] bioelectrical impedance analysis), and disease activity (Disease Activity Score [DAS]) in 58 patients with rheumatoid arthritis (RA) and 16 controls. The BMI, %BF, serum leptin, and ratio of leptin to %BF (leptin/%BF) did not differ significantly in 25 patients with moderate RA activity (DAS, 3.6 +/- 0.5), 33 patients with low RA activity (DAS, 1.8 +/- 0.5), and controls. A positive correlation for serum leptin and %BF was detected in all groups. Our data indicate that in RA, a human chronic cytokine-mediated inflammatory disease, the serum leptin level is directly related to %BF but not to disease activity.

Detection and characterization of RANK ligand and osteoprotegerin in the thyroid gland

Receptor activator of NF‐κB (RANK) ligand (RANKL) and osteoprotegerin (OPG) play essential roles in bone metabolism and immune responses. RANKL activates RANK, which is expressed by osteoclasts and dendritic cells (DC), whereas OPG acts as its decoy receptor. The role of RANKL and OPG in thyroid physiology is unclear. Northern analysis revealed pronounced OPG mRNA levels in normal human thyroid. By contrast, RANKL mRNA levels were most abundant in lymph node and appendix, and low in the thyroid. In the human thyroid follicular cell line XTC and in primary human thyroid follicular cells, OPG mRNA levels and protein secretion were upregulated by interleukin (IL)‐1β ?(33‐fold), tumor necrosis factor (TNF)‐α (eightfold), and thyrotropin (TSH) (threefold). RANKL mRNA was stimulated in XTC by IL‐1β? and TNF‐α, but inhibited by TSH. Conditioned medium harvested from IL‐1β‐treated XTC (containing high concentrations of OPG) inhibited RANKL‐induced CD40 upregulation and cluster formation of DC. OPG mRNA levels were three times more abundant in surgical thyroid specimens of Graves disease as compared to other thyroid diseases. Our data suggest that RANKL and OPG are produced in the thyroid gland by thyroid follicular cells, are regulated by cytokines and TSH, and are capable of modulating dendritic cell functions. Thus, these cytokines may represent important local immunoregulatory factors involved in the pathogenesis of autoimmune thyroid diseases. J. Cell. Biochem. 86: 642–650, 2002.

Retro-orbital autoimmunity

What causes Graves ophthalmopathy is still a mystery, but the disease process results from a complex interplay of genetic and environmental factors. Genes such as those encoding for human leukocyte antigens, cytokines or putative target antigens may determine a patients susceptibility to the disease and the disease severity, but environmental factors may determine its course. During the last 5 years, significant progress has been made towards a more in-depth understanding of the initiating events of the orbital immune process which occur in the context of autoimmune thyroid disease. Once established, the chronic inflammatory process within the orbital tissues appears to take on a momentum of its own. The work of many investigators has recently helped to extend our knowledge about the effector and target cells, and their reciprocal interaction, in the evolution and perpetuation of the orbital immune process. This chapters focus is on the more recent aspects of retro-orbital autoimmunity, discussing new developments concerning orbital T-cell repertoires, candidate orbital antigens, potential target and effector cells, and their role in the extrathyroidal manifestations of autoimmune thyroid disease.

Extracervical fibrosclerosis causing obstruction of a ventriculo-peritoneal shunt in a patient with hydrocephalus and invasive fibrous thyroiditis (Riedel's struma)

The association of invasive fibrous thyroiditis (IFT) with foci of extracervical fibrosclerosis is well recognized. Affected sites include the retroperitoneum, the mediastinum, the biliary tract, and the orbit. The development of subcutaneous fibrosclerosis, however, is extremely rare. We report a patient with known invasive fibrous thyroiditis and hypoparathyroidism who presented with localized subcutaneous fibrosclerosis of the anterior chest wall resulting in compression of his ventriculoperitoneal shunt. The aetiology of IFT has remained unclear. Several histological and serological features, including the presence of mononuclear cells within the fibrosclerotic process, the occurrence of microscopic vasculitis, and the detection of autoantibodies directed against thyroid‐specific antigens in a large proportion of patients with IFT, currently support the notion of autoimmune mechanisms playing a role in the pathogenesis of this rare disease.

Sakkadenmessung bei endokriner Orbitopathie

Zur Diagnose und Verlaufskontrolle der endokrinen Orbitopathie stehen eine Vielzahl klinischer Untersuchungen sowie morphometrische Befunde zur Verfügung. Die Veränderungen der Augenmuskeln können auch zu Alterationen der Sakkaden führen. Wir haben uns die Frage gestellt, ob sich aus der Analyse von Sakkaden funktionelle Parameter zur Beurteilung einer endokrinen Orbitopathie ergeben. Mit dem auf Infrarottechnik basierenden Registriergerät für Augenbewegungen (Ober-2-Gerät) wurden horizontale und vertikale Sakkaden von 10° Amplitude bei 20 Normalpersonen und 30 Patienten mit endokriner Orbitopathie aufgezeichnet. Bei den Patienten zeigten sich qualitative Veränderungen des Sakkadenablaufs, u. a. das Auftreten von Glissaden und zusätzlichen Korrektursakkaden. Außerdem wurden quantitative Änderungen von Sakkadenparametern gemessen, u. a. ein Anstieg der Maximalgeschwindigkeit und eine Verlängerung der Latenzzeit. Diese Befunde sind Folgen der Augenmuskelveränderungen der endokrinen Orbitopathie. Ob sie sich bestimmten Erkrankungsstadien zuordnen lassen und ob sich die Sakkadenanalyse zur Früherkennung und zur Verlaufsbeurteilung einer endokrinen Orbitopathie eignet, müssen weiterführende Untersuchungen zeigen.Thyroid-associated ophthalmopathy (TAO) is evaluated mainly by orthoptic examination and morphometric parameters such as ultrasound, CT scanning or magnetic resonance imaging. Inflammatory changes of the extraocular muscles lead to an impairment of eye movement. Recent evidence suggests that saccades are altered by changes to the extraocular muscles. Although of potential interest, this phenomenon has so far received little attention. To determine the role of saccades as a potential diagnostic tool for assessing the function of the affeced muscles, we have begun to analyze saccadic parameters in patients with TAO. Preliminary results of this study are reported in the present paper. For registration of both horizontal and vertical eye movements, we used the ``Ober-2-Apparatus, which uses the infrared technique. Horizontal and vertical saccades with an amplitude of 10° were analyzed in 20 healthy persons and 30 patients suffering from TAO. Patients showed changes in the quality of saccades, such as the appearance of glissades and additional correctional saccades as well as quantitative changes, such as an increase in the maximum speed and latency. Our current data suggest the presence of saccadic alterations in TAO. Our ongoing studies are designed to evaluate whether characteristic changes can be assigned to certain stages of the disease and whether assessment of saccadic changes in a promising tool for early detection and functional follow-up in patients with TAO.

Mediastinal Parathyroid Tumor: Giant Adenoma or Carcinoma?

A 71-yr-old woman presented with progressive weakness, bone pain, polydipsia, and epigastric pain. Laboratory studies established the diagnosis of primary hyperparathyroidism with excessively elevated levels of parathyroid hormone (PTH) complicated by renal failure and anemia. Preoperative imaging using99mtechnetium hexakis 2-methoxy-isobutylisonitrile (MIBI) demonstrated an area of intense uptake in the mediastinum, which on T2-weighted magnetic resonance imaging revealed the presence of a hyper-intense mediastinal mass of 25 mm in diameter adjacent to the ascending aorta. Surgical exploration and resection of the mass were performed, and histological examination of the tumor revealed solid masses of epithelial cells growing in a trabecular pattern, hyaline bands, and low mitotic activity. Immunohistochemical staining of the tumor specimens using monoclonal mouse antihuman antibodies revealed markedly positive immunoreactivity of tumor cells for p53 protein and absence of nuclear immunoreactivity for the retinoblastoma tumor-suppressor protein, findings consistent with parathyroid carcinoma. Improved imaging techniques and advances in molecular pathology of parathyroid disorders may help to improve clinical management of patients with parathyroid neoplasia.

Endokrinologische und metabolische Komplikationen des Alagille-Syndroms

Zusammenfassung□ HintergrundPatienten mit angeborenen oder in früher Kindheit erworbenen gastrointestinalen und hepatobiliären Erkrankungen haben ein hohes Risiko für diverse endokrinologische und metabolische Störungen.□ FalldarstellungEine 27jährige Frau mit bekanntem Alagille-Syndrom stellte sich mit nach einer Operation und der Einnahme oraler Kontrazeptiva progredientem Ikterus und zunehmenden Gangstörungen vor. Bei der körperlichen Untersuchung fielen zudem ein Minderwuchs, faziale Dysmorphiezeichen sowie neuromuskuläre Symptome (Polyneuropathie, spinozerebelläre Ataxie) auf. Die Serumkonzentrationen des. Gesamtbilirubins (54 mg/dl) und der alkalischen Phosphatase waren deutlich erhöht, die Serumspiegel für Haptoglobin, Zink, Vitamin D und E erniedrigt. Trotz der wahrscheinlicheren prä- brw. intrahepatischen Ursachen für den Ikterusschub wurden aufgrund des prolongierten Verlaufs posthepatische Störungen mittels Sonographie und ERCP ausgeschlossen. Die Patientin wurde unter der Verdachtsdiagnose einer medikamentös bedingten akuten Cholestase hochdosiert mit fettlöslichen Vitaminen und Ursodesoxycholsäure behandelt, worunter sich die pathologischen Laborbefunde normalisierten und die neurologische Symptomatik sich deutlich besserte.□ SchlußfolgerungAm Beispiel einer Patientin mit dem seltenen Alagille-Syndrom zeigt diese Kasuistik die metabolischen und endokrinen Komplikationen bei chronischer Cholestase und deren Therapie.Summary□ BackgroundPatients with gastrointestinal and hepatobiliary disorders, either congenital or acquired early in childhood, are at high risk for various endocrine and metabolic abnormalities.□ Case reportA 27-year-old woman with Alagille’s syndrome presented with progressive jaundice and gait disturbances following surgery and ingestion of oral contraceptives. On physical examination, short stature, facial dysmorphism and neuromuscular symptoms such as polyneuropathy and spinocerebellar ataxia were noted. Serum concentrations of total bilirubin (54 mg/dl) and alkaline phosphatase were markedly increased, whereas serum levels of haptoglobin, zinc, vitamin D and E were decreased. Although prehepatic or intrahepatic etiologies were ruled out by abdominal ultrasound and endoscopic retrograde etiologies of jaundice were more likely in this patient, posthepagrade cholandgio-pancreaticography. Based on a working diagnosis of acute drug-induced cholestasis, treatment with high doses of lipid-soluble vitamins and ursodeoxycholic acid was initiated. In response to therapy, her abnormal laboratory results normalized and her neurologic symptoms markedly improved.□ ConclusionThis clinicopathological conference of a patient with Alagille’s syndrome illustrates the clinical presentation and therapy of metabolic and endocrine complications in chronic cholestasis.

Leptin — Neue Erkenntnisse zur Pathogenese der Adipositas

Cloning of the ob-gene and characterization of its gene product leptin has led to the identification of a satiety factor, which signals the amount of peripheral fat stores to the central nervous system and regulates further feeding behaviour, thus playing a central role in the regulation of body weight. Soon after cloning of the ob-gene, a leptin-binding receptor has been identified in the central nervous system as well as in various peripheral organs. A feedback loop between peripheral fat stores and leptin receptors in the central nervous system appears to play an important role in normal body weight regulation. In contrast to human obesity, which associated with leptin resistance of uncertain etiology, the obesity syndromes associated with several animal models are now known to result from the interruption of the feedback loop at different points. Moreover, leptin may play a role in manifestation of insulin resistance and type II diabetes. Since the identification of leptin, a vast number of studies have been conducted to assess the molecular mechanisms and signal transduction pathways that are involved in the development and manifestation of obesity. From the large body of data generated to date, novel concepts of the regulation of energy balance and target strategies to control human obesity should soon be forthcoming.Zusammenfassung□ Die Entdeckung des ob-Gens und seines Genproduktes Leptin führte zur Identifizierung eines schon seit Jahrzehnten postulierten «Sättigungsfaktors», der im Rahmen der Körpergewichtsregulation das Gehim über die peripheren Fettspeicher informiert und die weitere Nahrungsaufnahme reguliert. Schon bald wurde ein leptinbindender Rezeptor sowohl im Zentralnervensystem als auch in zahlreichen peripheren Organen identifiziert. Ein geschlossener Regelkreis zwischen peripheren Fettspeichern und zentralnervösem Leptinrezeptor scheint die Grundlage einer intakten Körpergewichtsregulation zu sein. Während die Adipositas des Menschen mit einer Resistenz gegenüber körpereigenem Leptin assoziiert ist, deren Ursachen noch weitgehend unbekannt sind, beruht die Adipositas verschiedener Tiermodelle auf der Unterbrechung dieses Regelkreises an unterschiedlichen Stellen. Auch bei der Manifestation von Insulinresistenz und Diabetes mellitus Typ II scheint Leptin eine mögliche Rolle zu spielen.□ Nach Jahren der Stagnation in der Grundlagenforschung zur Adipositas konnten seit der Entdeckung von Leptin zahlreiche neue Erkenntnisse über die an der Adipositas beteiligten molekularen Mechanismen und Signaltransduktionswege gewonnen werden. Hieraus dürften sich neue, kausal orientierte Strategien zur Therapie der Adipositas ergeben.Abstract□ Cloning of the ob-gene and characterization of its gene product leptin has led to the identification of a satiety factor, which signals the amount of peripheral fat stores to the central nervous system and regulates further feeding behaviour, thus playing a central role in the regulation of body weight. Soon after cloning of the ob-gene, a leptin-binding receptor has been identified in the central nervous system as well as in various peripheral organs. A feedback loop between peripheral fat stores and leptin receptors in the central nervous system appears to play an important role in normal body weight regulation. In contrast to human obesity, which associated with leptin resistance of uncertain etiology, the obesity syndromes associated with several animal models are now known to result from the interruption of the feedback loop at different points. Moreover, leptin may play a role in manifestation of insulin resistance and type II diabetes.□ Since the identification of leptin, a vast number of studies have been conducted to assess the molecular mechanisms and signal transduction pathways that are involved in the development and manifestation of obesity. From the large body of data generated to date, novel concepts of the regulation of energy balance and target strategies to control human obesity should soon be forthcoming.

Funktionelle Augenmuskelveränderungen bei endokriner Orbitopathie

Fragestellung: Ziel der Studie war es, die Funktionsänderung der äußeren Augenmuskeln bei Patienten mit endokriner Orbitopathie zu beurteilen.Patienten und Methode: Horizontale Sakkaden mit einer Amplitude von 20° für die Dauer von 2 min wurden untersucht. Acht Patienten mit akuter und 5 Patienten mit chronischer endokriner Orbitopathie wurden 10 gesunden Normalpersonen gegenübergestellt. Die Registrierung der Augenbewegungen erfolgte mit dem auf Infrarottechnik basierenden Ober 2-Gerät. Zur Ermittlung des Ermüdungseffekts wurden die Parameter der ersten 5 Sakkaden denen der letzten 5 Sakkaden gegenübergestellt.Ergebnisse: Vor und nach Ermüdung unterschieden sich jeweils 4 bzw. 5 von 9 untersuchten Sakkadenparametern der Patienten signifikant von denen der Normalpersonen, darunter auch die maximale Geschwindigkeit (vmax). Gegenüber den Normalpersonen wiesen die Patienten mit chronischer endokriner Orbitopathie nach Ermüdung eine geringfügig stärker ausgeprägte Reduktion von vmax auf. Patienten mit akuter endokriner Orbitopathie zeigten abhängig von der Aktion des am stärksten betroffenen Muskels ein unterschiedliches Verhalten. Bei einer aktiven Kontraktion des M. rectus medialis (Adduktionssakkaden) war vmax nach Ermüdung nicht signifikant erniedrigt. Bei passiver Dehnung des M. rectus medialis (Abduktionssakkaden) hingegen war vmax initial stark reduziert und stieg nach Ermüdung signifikant an.Schlußfolgerung: Mit Hilfe der Sakkadenanalyse lassen sich Muskelfunktionsänderungen bei Patienten mit endokriner Orbitopathie nachweisen. Die inverse Geschwindigkeitsänderung nach Ermüdung bei akut Erkrankten läßt auf eine Zunahme der Muskelelastizität im Testverlauf schließen und bestätigt die Annahme, daß die frühe Motilitätseinschränkung im akuten Stadium der endokrinen Orbitopathie auf einer Kontraktur der Myofibrillen beruht. Die Analyse des Ermüdungseffekts kann dadurch eine Differenzierung in akutes oder chronisches Geschehen ermöglichen.Background: To determine the functional changes in the extraocular muscles in patients with thyroid-associated ophthalmopathy (TAO).Patients and methods: Horizontal saccades with an amplitude of 20° were carried out over a period of 2 min. Eight patients with acute TAO and five patients with chronic TAO were compared with ten age-matched healthy individuals. Ocular movements were recorded using the Ober 2 system based on infrared technology. For evaluation of fatigue effects, the parameters of the first five and the last five saccades were analysed.Results: A significant difference of four and five, respectively, out of nine tested saccadic variables including maximum velocity (Vmax) was found both before and after fatigue. In comparison to normal subjects, patients with chronic TAO revealed mildly increased reduction of Vmax after fatigue. Results in patients with acute TAO were related to the action of the most severely affected muscle. On active contraction of the medial rectus muscle (adducting saccades), Vmax was not significantly decreased after fatigue. On passive elongation of the medial rectus muscle (abducting saccades), however, Vmax was initially markedly decreased and increased significantly after fatigue.Conclusions: Functional changes of extraocular muscles in patients with TAO can be demonstrated by saccadic analysis. The inverse change in velocity after fatigue in acute disease indicates an improvement of muscle elasticity during exertion and strongly supports the concept that early impairment of bulbar motility in active TAO results from contracture of myofilaments. Thus, analysis of the fatigue effect may help to differentiate between acute and chronic disease.

Pathogenesis of Graves' ophthalmopathy

Ophthalmopathy is a potentially disfiguring and sight-threatening component of Graves disease. It is clinically evident in 25 to 50 percent of patients with Graves hyperthyroidism and occurs occasionally in patients with Hashimotos thyroiditis and in those with Graves disease but no evident thyroid disease1. At present, ophthalmopathy is not preventable, and treatment options for established, symptomatic disease are limited. To develop new strategies for the treatment and prevention of Graves ophthalmopathy, a better understanding of its pathogenesis is necessary. In this paper we review studies aimed at identifying the pathogenic mechanisms that lead to Graves ophthalmopathy. Clinical Features Patients .xa0.xa0.