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Synchronous cryptogenic liver cirrhosis and idiopathic pulmonary fibrosis: A clue to telomere involvement

A 48-year-old woman, active smoker, formerly obese, with type 2 diabetes, was admitted to our unit after surgery for a bleeding duodenal ulcer. She presented with esophageal varices F1-2, postsurgical ascitic decompensation, and respiratory insufficiency. She denied alcohol and drug exposure; she had experienced premature menopause. On examination she presented digital clubbing, bibasilar Velcro crackles, and mild-moderate ascites; no classical mucocutaneous features of dyskeratosis congenita (dystrophic nails, patchy skin hyperpigmentation, or oral leukoplakia) were present. Laboratory tests showed liver enzymes alteration, posthemorrhagic normocytic anemia (corrected after blood transfusions), and leukothrombocytopenia attributed to portal hypertension; however, bone marrow failure could not be ruled out because bone marrow analysis was not performed. Viral hepatitis and autoimmune serologies were negative. Alpha1-antitrypsin and iron and copper status were normal. Abdominal ultrasound and contrastenhanced computed tomography (CT) scan revealed chronic hepatopathy, splenomegaly, and ascites. Chest x-ray, electrocardiogram, and echocardiogram with bubble-test were normal. Pulmonary-function testing revealed decreased diffusing capacity. High-resolution chest CT scan showed typical features of usual interstitial pneumonia (Fig. 1A). Diagnose of cryptogenic liver cirrhosis (CC) and idiopathic pulmonary fibrosis (IPF) were made. Both diseases had a rapid progression and after 18 months the patient died. The patient had a large family with a high prevalence of type 2 diabetes, chronic liver disease, different cancers, premature menopause, and osteoporosis (Fig. 2). Sequencing and mutation analysis of hTERT and hTR carried out in our patient and her relatives demonstrated the presence of a heterozygous hTERT mutation (L153M) and a heterozygous hTERT polymorphism (A305A). The patient was a carrier of both mutations and polymorphism, which were observed also in other family members (Fig. 2). The hTERT L153M variant is generated by substitution of cytosine with adenine in position 5619, resulting in a change of methionine for leucine at amino acid 153 (Fig. 1B). The protein region that carries the mutation (Fig. 1C) seems to be involved in the template RNA and telomeric DNA binding. To the best of our knowledge, the L153M variant has never been described. This leucine is highly conserved among different species (Fig. 1D). The relevance of this amino acid was strengthened by the prediction program PolyPhen that identified L153M substitution as probably damaging, with a score of 0.998. Furthermore, leukocyte telomere length was significantly shorter in family members compared to age-matched healthy controls (Fig. 1E). The hTERT A305A polymorphism is a known synonymous variant that has recently been associated with some cancer types. CC and IPF are chronic, progressive diseases with poor prognosis, which share inflammation and fibrosis of target organs as common pathogenetic mechanisms. Telomeres consist of TTAGGG repeats that serve to prevent chromosome erosion; telomerase is a ribonucleoprotein complex that ensures telomere length maintenance. Telomere shortening, deriving from genetic and environmental factors, determines cellular senescence and predisposes to multiorgan failure and fibrosis. It is well known that IPF is a disease of telomere maintenance. Recently, a growing body of evidence suggests a possible role of telomerase mutations and accelerated telomeres shortening also in liver disease progression. Interestingly, Alder et al. Abbreviations: CC, cryptogenic liver cirrhosis; CT, computed tomography; IPF, idiopathic pulmonary fibrosis; LTL, leukocyte telomere length; NASH, nonalcoholic steatohepatitis. From the Department of Internal Medicine, Endocrinology, Metabolism and Geriatrics, University of Modena and Reggio Emilia, Italy; Department of Internal Medicine and Biomedical Sciences, University of Parma, Italy Received August 24, 2012; accepted October 3, 2012. Partly supported by 6th Framework Program grant LSHM-CT-2006037498 and by COFIN-PRIN grant 2004067491. Address reprint requests to: Lucia Carulli, M.D., Ph.D., Dipartimento di Medicina, Endocrinologia, Metabolismo e Geriatria, Universit a degli Studi di Modena e Reggio Emilia, Nuovo Ospedale Civile, via Giardini 1355, 41126 Modena, Italy. E-mail: lucia.carulli@unimore.it; fax: þ39 059 3961335. CopyrightVC 2012 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26089 Potential conflict of interest: Nothing to report.