PDF herunterladen
Semin Liver Dis 2020; 40(04): 385-391
DOI: 10.1055/s-0040-1713007
Review Article

Short Telomeres: Cause and Consequence in Liver Disease

Daniel D. Penrice
1   Department of Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota
,
Douglas A. Simonetto
2   Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, Rochester, Minnesota
› Institutsangaben
› Weitere Informationen
    Lizenzen und Reprints

Abstract

Short telomere syndrome is a genetically inherited syndrome resulting in premature telomere shortening. This premature shortening of telomeres can result in hematologic, pulmonary, vascular, gastrointestinal, and hepatic manifestations of disease. Identifying patients with short telomere syndrome can be a clinical challenge due to the multitude of potential manifestations and lack of widely available diagnostic tests. In this review, we will highlight hepatic manifestations of short telomere syndrome with a focus on diagnosis, testing, and potential treatments.

Keywords

telomere - cirrhosis - portal hypertension - telomerase

Financial Support and Disclosures

None.




Publikationsverlauf

Artikel online veröffentlicht:
11. Juni 2020

© 2020. Thieme. All rights reserved.

Thieme Medical Publishers
333 Seventh Avenue, New York, NY 10001, USA.

 

  • References

  • 1 Blackburn EH. Switching and signaling at the telomere. Cell 2001; 106 (06) 661-673
    CrossrefPubMedGoogle Scholar
  • 2 Palm W, de Lange T. How shelterin protects mammalian telomeres. Annu Rev Genet 2008; 42 (01) 301-334
    CrossrefPubMedGoogle Scholar
  • 3 Gilson E, Géli V. How telomeres are replicated. Nat Rev Mol Cell Biol 2007; 8 (10) 825-838
    CrossrefPubMedGoogle Scholar
  • 4 Barnard A, Moch A, Saab S. Relationship between telomere maintenance and liver disease. Gut Liver 2019; 13 (01) 11-15
    CrossrefPubMedGoogle Scholar
  • 5 Patnaik MM, Kamath PS, Simonetto DA. Hepatic manifestations of telomere biology disorders. J Hepatol 2018; 69 (03) 736-743
    CrossrefPubMedGoogle Scholar
  • 6 Aikata H, Takaishi H, Kawakami Y. et al. Telomere reduction in human liver tissues with age and chronic inflammation. Exp Cell Res 2000; 256 (02) 578-582
    CrossrefPubMedGoogle Scholar
  • 7 Laish I, Mari A, Mannasse B. et al. Telomere length, aggregates, and capture in cirrhosis. Isr Med Assoc J 2018; 20 (05) 295-299
    PubMedGoogle Scholar
  • 8 Aravinthan AD, Alexander GJ. Telomere, telomerase and liver disease. Liver Int 2018; 38 (01) 33-34
    CrossrefPubMedGoogle Scholar
  • 9 Heiss NS, Knight SW, Vulliamy TJ. et al. X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions. Nat Genet 1998; 19 (01) 32-38
    CrossrefPubMedGoogle Scholar
  • 10 Kelmenson DA, Hanley M. Dyskeratosis congenita. N Engl J Med 2017; 376 (15) 1460-1460
    CrossrefPubMedGoogle Scholar
  • 11 Ayas M, Ahmed SO. Dyskeratosis Congenita. In: Congenital and Acquired Bone Marrow Failure. Rochester, MN: Elsevier Inc.; 2017: 225-233
    CrossrefGoogle Scholar
  • 12 Alter BP, Giri N, Savage SA, Rosenberg PS. Cancer in dyskeratosis congenita. Blood 2009; 113 (26) 6549-6557
    CrossrefPubMedGoogle Scholar
  • 13 Fernández García MS, Teruya-Feldstein J. The diagnosis and treatment of dyskeratosis congenita: a review. J Blood Med 2014; 5: 157-167
    PubMedGoogle Scholar
  • 14 Mangaonkar AA, Patnaik MM. Short telomere syndromes in clinical practice: bridging bench and bedside. Mayo Clin Proc 2018; 93 (07) 904-916
    CrossrefPubMedGoogle Scholar
  • 15 Diaz de Leon A, Cronkhite JT, Yilmaz C. et al. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest 2011; 140 (03) 753-763
    CrossrefPubMedGoogle Scholar
  • 16 Koch DG, Fallon MB. Hepatopulmonary syndrome. Clin Liver Dis 2014; 18 (02) 407-420
    CrossrefPubMedGoogle Scholar
  • 17 Gorgy AI, Jonassaint NL, Stanley SE. et al. Hepatopulmonary syndrome is a frequent cause of dyspnea in the short telomere disorders. Chest 2015; 148 (04) 1019-1026
    CrossrefPubMedGoogle Scholar
  • 18 Higgs C, Crow YJ, Adams DM. et al; Clinical Care Consortium for Telomere-associated Ailments (CCCTAA). Understanding the evolving phenotype of vascular complications in telomere biology disorders. Angiogenesis 2019; 22 (01) 95-102
    CrossrefPubMedGoogle Scholar
  • 19 Jonassaint NL, Guo N, Califano JA, Montgomery EA, Armanios M. The gastrointestinal manifestations of telomere-mediated disease. Aging Cell 2013; 12 (02) 319-323
    CrossrefPubMedGoogle Scholar
  • 20 Hoare M, Das T, Alexander G. Ageing, telomeres, senescence, and liver injury. J Hepatol 2010; 53 (05) 950-961
    CrossrefPubMedGoogle Scholar
  • 21 Verma S, Tachtatzis P, Penrhyn-Lowe S. et al. Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver. Hepatology 2012; 56 (04) 1510-1520
    CrossrefPubMedGoogle Scholar
  • 22 Aravinthan A, Scarpini C, Tachtatzis P. et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. J Hepatol 2013; 58 (03) 549-556
    CrossrefPubMedGoogle Scholar
  • 23 Kim D, Li AA, Ahmed A. Leucocyte telomere shortening is associated with nonalcoholic fatty liver disease-related advanced fibrosis. Liver Int 2018; 38 (10) 1839-1848
    CrossrefPubMedGoogle Scholar
  • 24 Dixit S, Whooley MA, Vittinghoff E. et al. Alcohol consumption and leukocyte telomere length. Sci Rep 2019; 9 (01) 1404
    CrossrefPubMedGoogle Scholar
  • 25 Strandberg TE, Strandberg AY, Saijonmaa O, Tilvis RS, Pitkälä KH, Fyhrquist F. Association between alcohol consumption in healthy midlife and telomere length in older men. The Helsinki Businessmen Study. Eur J Epidemiol 2012; 27 (10) 815-822
    CrossrefPubMedGoogle Scholar
  • 26 Scaglione S, Kliethermes S, Cao G. et al. The epidemiology of cirrhosis in the United States a population-based study. J Clin Gastroenterol 2015; 49 (08) 690-696
    CrossrefPubMedGoogle Scholar
  • 27 Caldwell SH, Crespo DM. The spectrum expanded: cryptogenic cirrhosis and the natural history of non-alcoholic fatty liver disease. J Hepatol 2004; 40 (04) 578-584
    CrossrefPubMedGoogle Scholar
  • 28 Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003; 289 (22) 3000-3004
    CrossrefPubMedGoogle Scholar
  • 29 Greeve M, Ferrell L, Kim M. et al. Cirrhosis of undefined pathogenesis: absence of evidence for unknown viruses or autoimmune processes. Hepatology 1993; 17 (04) 593-598
    CrossrefPubMedGoogle Scholar
  • 30 Rudolph KL, Hartmann D, Opitz OG. Telomere dysfunction and DNA damage checkpoints in diseases and cancer of the gastrointestinal tract. Gastroenterology 2009; 137 (03) 754-762
    CrossrefPubMedGoogle Scholar
  • 31 Andert A, Alizai HP, Ulmer TF. et al. Influence of telomere length in hepatocytes on liver regeneration after partial hepatectomy in rats. Eur Surg Res 2018; 59 (1-2): 83-90
    CrossrefPubMedGoogle Scholar
  • 32 Rudolph KL, Chang S, Millard M, Schreiber-Agus N, DePinho RA. Inhibition of experimental liver cirrhosis in mice by telomerase gene delivery. Science 2000; 287 (5456): 1253-1258
    CrossrefPubMedGoogle Scholar
  • 33 Kapuria D, Ben-Yakov G, Ortolano R. et al. The spectrum of hepatic involvement in patients with telomere disease. Hepatology 2019; 69 (06) 2579-2585
    CrossrefPubMedGoogle Scholar
  • 34 Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 2014; 15 (07) 482-496
    CrossrefPubMedGoogle Scholar
  • 35 Calado RT, Young NS. Telomere diseases. N Engl J Med 2009; 361 (24) 2353-2365
    CrossrefPubMedGoogle Scholar
  • 36 Nault J-C, Ningarhari M, Rebouissou S, Zucman-Rossi J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol 2019; 16 (09) 544-558
    CrossrefPubMedGoogle Scholar
  • 37 Urabe Y, Nouso K, Higashi T. et al. Telomere length in human liver diseases. Liver 1996; 16 (05) 293-297
    CrossrefPubMedGoogle Scholar
  • 38 Wiemann SU, Satyanarayana A, Tsahuridu M. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 2002; 16 (09) 935-942
    CrossrefPubMedGoogle Scholar
  • 39 Papatheodoridi A, Chrysavgis L, Koutsilieris M, Chatzigeorgiou A. The role of senescence in the development of non-alcoholic fatty liver disease and progression to non-alcoholic steatohepatitis. Hepatology 2020; 71 (01) 363-374
    CrossrefPubMedGoogle Scholar
  • 40 Hartmann D, Srivastava U, Thaler M. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 2011; 53 (05) 1608-1617
    CrossrefPubMedGoogle Scholar
  • 41 Nault J-C. Pathogenesis of hepatocellular carcinoma according to aetiology. Best Pract Res Clin Gastroenterol 2014; 28 (05) 937-947
    CrossrefPubMedGoogle Scholar
  • 42 Hastie ND, Dempster M, Dunlop MG, Thompson AM, Green DK, Allshire RC. Telomere reduction in human colorectal carcinoma and with ageing. Nature 1990; 346 (6287): 866-868
    CrossrefPubMedGoogle Scholar
  • 43 de Lange T, Shiue L, Myers RM. et al. Structure and variability of human chromosome ends. Mol Cell Biol 1990; 10 (02) 518-527
    CrossrefPubMedGoogle Scholar
  • 44 Ohashi K, Tsutsumi M, Nakajima Y, Kobitsu K, Nakano H, Konishi Y. Telomere changes in human hepatocellular carcinomas and hepatitis virus infected noncancerous livers. Cancer 1996; 77 (08) 1747-1751
    CrossrefPubMedGoogle Scholar
  • 45 Satyanarayana A, Manns MP, Rudolph KL. Telomeres and telomerase: a dual role in hepatocarcinogenesis. Hepatology 2004; 40 (02) 276-283
    CrossrefPubMedGoogle Scholar
  • 46 Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990; 11 (05) 787-797
    CrossrefPubMedGoogle Scholar
  • 47 Hillaire S, Bonte E, Denninger M-H. et al. Idiopathic non-cirrhotic intrahepatic portal hypertension in the West: a re-evaluation in 28 patients. Gut 2002; 51 (02) 275-280
    CrossrefPubMedGoogle Scholar
  • 48 Kaymakoglu S, Kahraman T, Kudat H. et al. Hepatopulmonary syndrome in noncirrhotic portal hypertensive patients. Dig Dis Sci 2003; 48 (03) 556-560
    CrossrefPubMedGoogle Scholar
  • 49 Krasinskas AM, Eghtesad B, Kamath PS, Demetris AJ, Abraham SC. Liver transplantation for severe intrahepatic noncirrhotic portal hypertension. Liver Transpl 2005; 11 (06) 627-634 , discussion 610–611
    CrossrefPubMedGoogle Scholar
  • 50 Aubert G, Hills M, Lansdorp PM. Telomere length measurement-caveats and a critical assessment of the available technologies and tools. Mutat Res 2012; 730 (1-2): 59-67
    CrossrefPubMedGoogle Scholar
  • 51 Kimura M, Stone RC, Hunt SC. et al. Measurement of telomere length by the Southern blot analysis of terminal restriction fragment lengths. Nat Protoc 2010; 5 (09) 1596-1607
    CrossrefPubMedGoogle Scholar
  • 52 Wang F, Pan X, Kalmbach K. et al. Robust measurement of telomere length in single cells. Proc Natl Acad Sci U S A 2013; 110 (21) E1906-E1912
    CrossrefPubMedGoogle Scholar
  • 53 Baerlocher GM, Vulto I, de Jong G, Lansdorp PM. Flow cytometry and FISH to measure the average length of telomeres (flow FISH). Nat Protoc 2006; 1 (05) 2365-2376
    CrossrefPubMedGoogle Scholar
  • 54 Alder JK, Hanumanthu VS, Strong MA. et al. Diagnostic utility of telomere length testing in a hospital-based setting. Proc Natl Acad Sci U S A 2018; 115 (10) E2358-E2365
    CrossrefPubMedGoogle Scholar
  • 55 Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I. Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 2004; 36 (05) 447-449
    CrossrefPubMedGoogle Scholar
  • 56 Mitchell A, Adams LA, MacQuillan G, Tibballs J, vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 2008; 14 (02) 210-213
    CrossrefPubMedGoogle Scholar
  • 57 Bayne S, Liu JP. Hormones and growth factors regulate telomerase activity in ageing and cancer. Mol Cell Endocrinol 2005; 240 (1-2): 11-22
    CrossrefPubMedGoogle Scholar
  • 58 Townsley DM, Dumitriu B, Liu D. et al. Danazol treatment for telomere diseases. N Engl J Med 2016; 374 (20) 1922-1931
    CrossrefPubMedGoogle Scholar
  • 59 Khincha PP, Wentzensen IM, Giri N, Alter BP, Savage SA. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol 2014; 165 (03) 349-357
    CrossrefPubMedGoogle Scholar
  • 60 Theodoris CV, Mourkioti F, Huang Y. et al. Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency. J Clin Invest 2017; 127 (05) 1683-1688
    CrossrefPubMedGoogle Scholar
  • 61 Carulli L, Dei Cas A, Nascimbeni F. Synchronous cryptogenic liver cirrhosis and idiopathic pulmonary fibrosis: a clue to telomere involvement. Hepatology 2012; 56 (05) 2001-2003
    CrossrefPubMedGoogle Scholar
  • 62 Girard M, Amiel J, Fabre M, Pariente D, Lyonnet S, Jacquemin E. Adams-Oliver syndrome and hepatoportal sclerosis: occasional association or common mechanism?. Am J Med Genet A 2005; 135 (02) 186-189
    CrossrefPubMedGoogle Scholar