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Exp Clin Endocrinol Diabetes 2001; 109(5): 250-260
DOI: 10.1055/s-2001-16344
Review

© Johann Ambrosius Barth

Nodular goiter and goiter nodules: Where iodine deficiency falls short of explaining the facts[*]

M. Derwahl 1 , H. Studer 2
  • 1 Department of Medicine, St. Hedwig Hospital and Humboldt University Berlin, Germany
  • 2 Professor emeritus, Bern, Switzerland
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Publication History

Publication Date:
31 December 2001 (online)

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Summary:

While the concept of iodine deficiency (ID) still dominates most discussions about the pathogenesis of multinodular goiter (MNG), the present review focuses on those mechanisms that may cause MNG in the absence of ID. Among the many facets of MNG that cannot simply be explained by ID, are the frequent occurrence of the disease in patients not exposed to ID, the autonomous growth of goiters - often accompanied by subclinical or even overt thyrotoxicosis -, the inverse relationship between goiter size and serum TSH, the multifocal, heterogeneous and nodular growth pattern, the heterogeneity of function with the familiar patchy iodine metabolism on scintiscans, the growth of clonal and polyclonal nodules, the prominent genetic predisposition. Even the notoriously low intrathyroidal iodine concentration - common to endemic as well as to sporadic goiter - is a secondary, rather than a primary event. Thus, the fundamental process of goitrogenesis, is independent from ID but operates through mechanisms innate to the hereditary and acquired heterogeneity among the thyrocytes themselves. In this view, goiter nodules and nodular goiters are true benign neoplasias arising by mechanisms common to all benign endocrine and nonendocrine neoplasms. However, superimposed iodine shortage greatly enhances the incidence of MNG and shifts its clinical appearance toward younger ages by adding one more growth factor - presumably enhanced TSH secretion - to an intrinsically activated growth regulating network.

Key words:

Nodular goiter - neoplasia - pathogenesis - iodine deficiency - sporadic goiter - heterogeneity - molecular aspects

1 * Supported in part by Dr. Mildred Scheel Foundation for Cancer Research and by E. Merck, Darmstadt and Biomedic e.V., Berlin.

References[*]

  • 1 Abuye C, Omwega A M, Imungi J K. Familial tendency and dietary association of goitre in Gamo-Gofa, Ethiopia.  East Afr Med J. 76 447-551 1999; 
    PubMedGoogle Scholar
  • 2 Aeschimann S, Buergi U, Wagner H E, Kaempf J, Lauber K, Studer H. Low intrathyroidal iodine concentration in non endemic human goiters: A consequence rather than a cause of autonomous goiter growth.  J Endocrinol. 140 155-164 1994; 
    PubMedGoogle Scholar
  • 3 Aeschimann S, Gerber H, von Grünigen Ch, Oestreicher M, Studer H. The degree of inhibition of follicular cell proliferation by iodide is a highly individual characteristic of each cell and differs profoundly in vitro and in vivo.  Europ J Endocrinol. 130 595-600 1994; 
    PubMedGoogle Scholar
  • 4 Aeschimann S, Kopp P A, Kimura E T, Zbaeren J, Tobler A, Fey M F, Studer H. Morphological and functional polymorphism within clonal thyroid nodules.  J Clin Endocrinol Metab. 77 846-851 1993; 
    PubMedGoogle Scholar
  • 5 Artavanis-Tsakonas S, Rand M D, Lake R J. Notch signaling: Cell fate control and signal integration in development.  Science. 284 770-776 1999; 
    CrossrefPubMedGoogle Scholar
  • 6 Asmis L M, Kaempf J, von Grünigen C, Kimura E T, Wagner H E, Studer H. Acquired and naturally occurring resistance of thyroid follicular cells to the growth inhibitory action of transforming growth factor β1(TGF β1).  J Endocrinol. 149 485-496 1996; 
    CrossrefPubMedGoogle Scholar
  • 7 Bidey S P, Hill D J, Eggo M C. Growth factors and goitrogenesis.  J Endocrinol. 160 321-332 1999; 
    CrossrefPubMedGoogle Scholar
  • 8 Bignell G R, Canzian F, Shayeghi M, Stark M, Shughart Y Y, Biggs P, Mangion J, Hamoudi R, Rosenblatt J, Buu P, Sun S, Stoffer S S, Goldgar D E, Romeo G, Houlston R S, Narod S A, Stratton M R, Foulkes W D. Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer.  Am J Hum Genet. 61 1123-1130 1997; 
    CrossrefPubMedGoogle Scholar
  • 9 Bishop J M. Molecular themes in oncogenesis.  Cell. 64 235-248 1991; 
    CrossrefPubMedGoogle Scholar
  • 10 Brix T H, Kyvik K O, Hegedüs L. Major role of genes in the etiology of simple goiter in females: a population based twin study.  J Clin Endocrinol Metab. 84 3071-3075 1999; 
    CrossrefPubMedGoogle Scholar
  • 11 Bröcker M, de Buhr I, Papageorgiou G, Schatz H, Derwahl M. Expression of apoptosis-related proteins in thyroid tumors and thyroid carcinoma cell lines.  Exp Clin Endocrinol Diabetes. 104 20-23 1996; 
    PubMedGoogle Scholar
  • 12 Burikhanov R, Coulonval K, Pirson I, Lamy F, Dumont J E, Roger P P. Thyrotropin via cyclic AMP induces insulin receptor expression and insulin co-stimulation of growth and amplifies insulin and insulin-like growth factor signaling pathways in dog thyroid epithelial cells.  J Biol Chem. 271 29400-29406 1996; 
    CrossrefPubMedGoogle Scholar
  • 13 Chow M, Rubin H. Irreversibility of cellular aging and neoplastic transformation: a clonal analysis.  Proc Natl Acad Sci USA. 93 9793-9798 1996; 
    CrossrefPubMedGoogle Scholar
  • 14 Clark O H, Gerend P L, Davis M, Goretzki P E, Hoffman P G. Estrogen and thyroid-stimulating hormone (TSH) receptors in neoplastic and nonneoplastic human thyroid tissue.  J Surg Res. 38 89-96 1985; 
    CrossrefPubMedGoogle Scholar
  • 15 Delange F, Ermans A M. Iodine deficiency. In: Braverman LE, Utiger RD (eds.) The Thyroid, Sixth Edition. Lippincott, Philadelphia, New York, London 368-390 1991
    Google Scholar
  • 16 Delange F. Neonatal thyroid screening as a tool for the control of iodine deficiency.  Acta Paediatr 88 (00(Suppl 432)) 21-24 1999; 
    CrossrefPubMedGoogle Scholar
  • 17 Deleu S, Allory Y, Radulesco A, Pirson I, Carrasco N, Corvilain B, Salmon I, Franc B, Dumont J E, van Sande J, Maenhaut C. Characterization of autonomous thyroid adenoma: Metabolism, gene expression, and pathology.  Thyroid. 10 131-140 2000; 
    PubMedGoogle Scholar
  • 18 Derwahl M. Editorial: TSH receptor and Gs-alpha gene mutations in the pathogenesis of toxic thyroid adenomas: a note of caution.  J Clin Endocrinol Metab. 81 1-3 1996; 
    CrossrefPubMedGoogle Scholar
  • 19 Derwahl M, Broecker M, Kraiem Z. Clinical review 101: Thyrotropin may not be the dominant growth factor in benign and malignant thyroid tumors.  J Clin Endocrinol Metab. 84 829-834 1999; 
    CrossrefPubMedGoogle Scholar
  • 20 Derwahl M, Hamacher Ch, Russo D, Bröcker M, Manole M, Schatz H, Kopp P, Filetti S. Constitutive activation of the Gsα-protein-adenylate cyclase pathway may not be sufficient to generate toxic thyroid adenomas.  J Clin Endocrinol Metab. 81 1898-1904 1996; 
    CrossrefPubMedGoogle Scholar
  • 21 Derwahl M, Studer H, Huber G, Gerber H, Peter H J. Intercellular propagation of individually programmed growth bursts in FRTL-5 cells. Implications for interpreting growth factor actions.  Endocrinology. 127 2104-2110 1990; 
    PubMedGoogle Scholar
  • 22 Derwahl M, Studer H. Pathogenesis and treatment of multinodular goiter. In: Fagin JA (ed.) Thyroid Cancer. Kluwer Academic Publisher, Boston 155-186 1998
    Google Scholar
  • 23 Di Carlo A, Mariano A, Pisano G, Parmeggiani U, Beguinot L, Macchia V. Epidermal growth factor and thyrotropin response in human thyroid tissues.  J Endocrinol Invest. 13 293-299 1990; 
    PubMedGoogle Scholar
  • 24 Dumont J E, Lamy F, Roger P, Maenhaut C. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors.  Physiol Rev. 72 667-679 1992; 
    CrossrefPubMedGoogle Scholar
  • 25 Eggo M C, King W J, Black E G, Sheppard M C. Functional human thyroid cells and their insulin-like growth factor-binding proteins: regulation by thyrotropin, cyclic 3′,5′ adenosine monophosphate and growth factors.  J Clin Endocrinol Metab. 81 3056-3062 1996; 
    CrossrefPubMedGoogle Scholar
  • 26 Fagin J A. Molecular pathogenesis of tumors of thyroid follicular cells. In: Fagin JA (ed.) Thyroid cancer. Kluwer Academic Publisher, Boston 59-83 1998
    Google Scholar
  • 27 Fenzi G F, Ceccarelli C, Macchia E, Monzani F, Bartalena L, Giani C, Ceccarelli P, Lippi F, Baschieri L, Pinchera A. Reciprocal changes of serum thyroglobulin and TSH in residents of a moderate endemic goitre area.  Clin Endocrinol (Oxf). 23 115-122 1985; 
    PubMedGoogle Scholar
  • 28 Gabriel E M, Bergert E R, Grant C S, van Heerden J A, Thompson G B, Morris J C. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter.  J Clin Endocrinol Metab. 84 3328-3335 1999; 
    CrossrefPubMedGoogle Scholar
  • 29 Gärtner R, Veitenhansl M, Atkas J, Schophol D. Role of basis fibroblast growth factor in the pathogenesis of nodular goiter.  Exp Clin Endocrinol Diabetes. 104 36-38 1996; 
    PubMedGoogle Scholar
  • 30 Gebel F, Ramelli F, Burgi U, Ingold U, Studer H, Winand R. The site of leakage of intrafollicular thyroglobulin into the blood stream in simple human goiter.  J Clin Endocrinol Metab. 57 915-919 1983; 
    PubMedGoogle Scholar
  • 31 Gemsenjäger E, Staub J J, Girard J, Heitz P H. Preclinical hyperthyroidism in multinodular goiter.  J Clin Endocrinol Metab. 43 810-816 1967; 
    PubMedGoogle Scholar
  • 32 Gerber H, Zbaeren J, Kopp P, Aeschimann S, Maciel R, Studer H. Human nodular goiters grow by episodic replication of disseminated cell cohorts expressing several growth factors at the same time.  J Endocr Invest 15 (00(Suppl 2)) Abstract 95 1992; 
    PubMedGoogle Scholar
  • 33 Hamacher Ch, Studer H, Zbaeren J, Schatz H, Derwahl M. Expression of functional stimulatory guanine nucleotide binding protein in nonfunctioning thyroid adenomas is not correlated to adenylate cyclase activity and growth of these tumors.  J Clin Endocrinol Metab. 80 1724-1732 1995; 
    CrossrefPubMedGoogle Scholar
  • 34 Harrer P, Broecker M, Zint A, Schatz H, Zumtobel V, Derwahl M. Thyroid nodules in recurrent multinodular goiters are predominantly polyclonal.  J Endocrinol Invest. 21 380-385 1998; 
    CrossrefPubMedGoogle Scholar
  • 35 Henderson B E, Ross R K, Pike M C, Casagrande J T. Endogenous hormones as a major factor in human cancer.  Cancer Res. 42 3232-3239 1982; 
    PubMedGoogle Scholar
  • 36 Holzapfel H P, Fuhrer D, Wonerow P, Weinland G, Scherbaum W A, Paschke R. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters.  J Clin Endocrinol Metab. 82 4229-4233 1997; 
    CrossrefPubMedGoogle Scholar
  • 37 Inoue H, Oshimo K, Miki H, Kawano M, Monden Y. Immunohistochemical study of estrogen receptors and the responsiveness to estrogen in papillary thyroid carcinoma.  Cancer. 72 1364-1368 1993; 
    PubMedGoogle Scholar
  • 38 Jhiang S, Cho J Y, Ryu K Y, DeYoung B R, Smanik P A, McGaughy V R, Fischer A H, Mazzaferri E L. An immunohistochemical study of the Na+/I- symporter in human thyroid tissues and salivary gland tissues.  Endocrinology. 139 4416-4419 1998; 
    CrossrefPubMedGoogle Scholar
  • 39 Kimura E D, Kopp P, Zbaeren J, Asmis L, Ruchti Ch, Maciel R, Studer H. Expression of transforming growth factor β 1, β 2 and β 3 in multinodular goiters and differentiated thyroid carcinomas: A comparative study.  Thyroid. 9 119-125 1999; 
    PubMedGoogle Scholar
  • 40 Kopp P, Aeschimann S, Asmis L, Tobler A, Fey M F, Studer H. Polyclonal and clonal nodules may coexist within multinodular goiters.  J Clin Endocrinol Metab. 79 134-139 1994; 
    CrossrefPubMedGoogle Scholar
  • 41 Langer P, Tajtáková M, Bohov P, Klimes I. Possible role of genetic factors in thyroid growth rate and in the assessment of upper limit of normal thyroid volume in iodine-replete adolescents.  Thyroid. 9 557-562 1999; 
    PubMedGoogle Scholar
  • 42 Manole D, Gosnell B, Harland J, Duentsch U, Derwahl M. Synergistic and antagonistic effects of sex hormones in the regulation of thyroid tumor growth.  Exp Cin Endocrinol Diabetes 109 (00(Suppl. 1)) Abstract 013 2001a; 
    PubMedGoogle Scholar
  • 43 Manole D, Schildknecht B, Gosnell B, Adams E, Derwahl M. Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms.  J Clin Endocrinol Metab. 86 1072-1077 2001b; 
    CrossrefPubMedGoogle Scholar
  • 44 McTiernan A M, Weiss N S, Daling J R. Incidence of thyroid cancer in women in relation to previous exposure to radiation therapy and history of thyroid disease.  J Natl Cancer Inst. 73 575-581 1984; 
    PubMedGoogle Scholar
  • 45 Minuto F, Barreca A, Del Monte P, Cariola G, Torre G C, Giordano G. Immunoreactive insulin-like growth factor I (IGF-1) and IGF-binding protein content in human thyroid tissue.  J Clin Endocrinol Metab. 68 621-626 1989; 
    PubMedGoogle Scholar
  • 46 Morosini P P, Taccaliti A, Montironi R, Scarpelli M, Diamanti L, Simonella G, Mancini V, Petrelli M D, Mantero F. TGF-beta 1 immunohistochemistry in goiter: Comparison of patients with recurrence or no recurrence.  Thyroid. 6 417-422 1996; 
    PubMedGoogle Scholar
  • 47 Namba H, Gutman R A, Matsuo K, Alvarez A, Fagin J A. H-ras protooncogene mutations in human thyroid neoplasms.  J Clin Endocrinol Metab. 71 223-229 1990; 
    PubMedGoogle Scholar
  • 48 Neumann S, Willgerodt H, Ackermann F, Reske A, Jung M, Reis A, Paschke R. Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter.  J Clin Endocrinol Metab. 84 3750-3756 1999; 
    CrossrefPubMedGoogle Scholar
  • 49 Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy: Long-term follow-up of a Swedish cohort.  Int J Cancer. 67 327-332 1996; 
    CrossrefPubMedGoogle Scholar
  • 50 Peter H J, Gerber H, Studer H, Groscurth P, Zakarija M. Comparison of FRTL-5 cell growth in vitro with that of xenotransplanted cells and the thyroid of the recipient mouse.  Endocrinology. 128 211-219 1991; 
    PubMedGoogle Scholar
  • 51 Peter H J, Gerber H, Studer H, Smeds S. Pathogenesis of heterogeneity in human nodular goiter.  J Clin Invest. 76 1992-2002 1985; 
    PubMedGoogle Scholar
  • 52 Peter H J, Studer H,  Forster ,  Gerber . The pathogenesis of hot and cold follicles in multinodular goiters.  J Clin Endocrinol Metab. 55 941-946 1982; 
    PubMedGoogle Scholar
  • 53 Preston-Martin S, Bernstein L, Pike M C, Maldonado A A, Henderson B E. Thyroid cancer among young women related to prior thyroid disease and pregnancy history.  Br J Cancer. 55 191-195 1987; 
    PubMedGoogle Scholar
  • 54 Rentsch H P, Studer H, Frauchiger B, Siebenhüner L. Topographical heterogeneity of basal and thyrotropin-stimulated adenosine 3′,5′-monophosphate in human nodular goiter.  J Clin Endocrinol Metab. 53 514-521 1981; 
    PubMedGoogle Scholar
  • 55 Rubin H, Chow M, Yao A. Cellular aging, destabilization, and cancer.  Proc Natl Acad Sci USA. 93 1825-1830 1996; 
    CrossrefPubMedGoogle Scholar
  • 56 Roger P P, Baptist M, Dumont J E. A mechanism generating heterogeneity in thyroid epithelial cells: suppression of the thyrotropin/cAMP-dependent pathway after cell division induced by cAMP independent factors.  J Cell Biol. 117 383-393 1992; 
    CrossrefPubMedGoogle Scholar
  • 57 Ron E, Kleinerman R A, Boice J D, LiVolsi V A, Flannery J T, Fraumeni J F. A population-based case-control study of thyroid cancer.  J Natl Cancer Inst. 79 1-12 1987; 
    PubMedGoogle Scholar
  • 58 Rossi R, Zatelli M C, Franceschetti P, Maestri I, Magri E, Aguiari G, Cavazzini P, degli Uberti E C, del Senno L. Inhibitory effect of dihydrotestosterone on human thyroid cell growth.  J Endocrinol. 151 185-194 1996; 
    CrossrefPubMedGoogle Scholar
  • 59 Royaux I E, Suzuki K, Mori A, Katoh R, Everett L A, Kohn L D, Green E D. Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells.  Endocrinology. 141 839-845 2000; 
    CrossrefPubMedGoogle Scholar
  • 60 Rubin H, Chow M, Yao A. Cellular aging, destabilization and cancer.  Proc Nat Acad Sci USA. 93 1825-1830 1996; 
    CrossrefPubMedGoogle Scholar
  • 61 Russo D, Arturi F, Schlumberger M, Caillou B, Monier R, Filetti S, Suarez H G. Activating mutations of the TSH receptor in differentiated thyroid carcinomas.  Oncogene. 11 1907-1911 1995; 
    PubMedGoogle Scholar
  • 62 Schuerch M, Peter H J, Gerber H, Studer H. Cold follicles in a multinodular human goiter arise partly from a failing iodide pump and partly from deficient iodine organification.  J Clin Endocrinol Metab. 71 1224-1229 1990; 
    PubMedGoogle Scholar
  • 63 Schwartzman R A, Cidlowski J A. Apoptosis: the biochemistry and molecular biology of programmed cell death.  Endocr Rev. 14 133-151 1993; 
    CrossrefPubMedGoogle Scholar
  • 64 Skipper M, Lewis J. Getting to the guts of enteroendocrine differentiation.  Nature Genet. 24 3-4 2000; 
    CrossrefPubMedGoogle Scholar
  • 65 Studer H, Derwahl M. Mechanisms of nonneoplastic endocrine hyperplasia - A changing concept: A review focused on the thyroid gland.  Endocr Rev. 16 411-426 1995; 
    CrossrefPubMedGoogle Scholar
  • 66 Studer H, Gerber H, Zbaeren J, Peter H J. Histomorphological and immunohistochemical evidence that human nodular goiters grow by episodic replication of multiple clusters of thyroid follicular cells.  J Clin Endocrinol Metab. 75 1151-1158 1992; 
    CrossrefPubMedGoogle Scholar
  • 67 Studer H, Peter H J, Gerber H. Natural heterogeneity of thyroid cells: The basis for understanding thyroid function and nodular goiter growth.  Endocr Rev. 10 125-135 1989; 
    PubMedGoogle Scholar
  • 68 Stuebner D, Gaertner R, Greil W, Gropper K, Brabant G, Permanetter W, Horn K, Pickardt C R. Hypertrophy and hyperplasia during growth and involution in rats - separate bioeffects of TSH and iodine.  Acta endocrinologica (Kbh). 116 537-548 1987; 
    PubMedGoogle Scholar
  • 69 Suarez H G, du Villard J A, Caillou B, Schlumberger M, Parmentier C, Monier R. Gsp mutations in human thyroid tumours.  Oncogene. 6 677-679 1991; 
    PubMedGoogle Scholar
  • 70 Tonaccherra M, Vitti P, Agretti P, Giulianetti B, Mazzi B, Cavaliere R, Ceccarini G, Fiore E, Viacava P, Naccarato A, Pinchera A, Chiovato L. Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter.  Thyroid. 8 559-564 1998; 
    PubMedGoogle Scholar
  • 71 Tonacchera M, Agretti P, Chiovato L, Rossellini V, Ceccarini G, Perri A, Viacava P, Naccarata A, Miccoli P, Pinchera A, Vitti P. Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiters.  J Clin Endocrinol Metab. 85 2270-2274 2000; 
    CrossrefPubMedGoogle Scholar
  • 72 Vanelli G B, Barni T, Modigliani U, Paulin I, Serio M, Maggi M, Fiorelli G, Balboni G C. Insulin-like growth factor-I receptors in nonfunctioning thyroid nodules.  J Clin Endocrinol Metab. 71 1175-1182 1990; 
    PubMedGoogle Scholar
  • 73 Westermark K, Lundqvist M, Wallin G, Dahlman T, Hacker G W, Heldin N E, Grimelius L. EGF-receptors in human normal and pathological thyroid tissue.  Histopathology. 28 221-227 1996; 
    CrossrefPubMedGoogle Scholar
  • 74 Williams D W, Williams E D, Wynford-Thomas D. Loss of independence on IGF-I or proliferation of human thyroid adenoma cells:.  Br J Cancer. 57 535-359 1988; 
    PubMedGoogle Scholar
  • 75 Williams D W, Williams E D, Wynford-Thomas D. Evidence for autocrine production of IGF-1 in human thyroid adenomas.  Mol Cell Endocrinol. 61 139-143 1989; 
    CrossrefPubMedGoogle Scholar
  • 76 Wollman S H, Breitman T R. Changes in DNA and weight of thyroid glands during hyperplasia and involution.  Endocrinology. 86 322-327 1970; 
    PubMedGoogle Scholar
  • 77 Yane K, Kitahori Y, Konishi N, Naito H, Okaichi K, Onishi T, Miyahara H, Matsunaga H, Hiasa Y. Expression of the estrogen receptor in human thyroid neoplasms.  Cancer Lett. 84 59-66 1994; 
    CrossrefPubMedGoogle Scholar

1 * Supported in part by Dr. Mildred Scheel Foundation for Cancer Research and by E. Merck, Darmstadt and Biomedic e.V., Berlin.

2 1 A different process - not considered here - is autoimmune destruction of thyroid tissue followed by nodular outgrowth of the follicle clusters left intact within the network formed by the destructed parenchyma.

3 A considerably more detailed reference list is provided in the 3 following overviews: Derwahl and Studer, 1998 Studer and Derwahl, 1995 Studer et al., 1989

Professor Dr. M. Derwahl

Department of Medicine

St. Hedwig Hospital

Grosse Hamburger Str. 5-11

D-10115 Berlin

Germany

Phone: +49 30 2311 2504

Fax: +49 30 2311 2324

Email: M.Derwahl@alexius.de

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