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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 contrast-enhanced 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. A case of CC and IPF associated with a novel mutation in hTERT. (A) High-resolution chest CT scan shows diffuse infiltrative lung disease with peripheral bilateral reticular opacities and honeycombing, with predilection toward the upper lobes. (B) Point mutation in hTERT: chromatogram showing the nucleotide change 5619 C>A on heterozygous state in exon 2 that results in a leucine to methionine substitution in residue 153. (C) Schematic representation of the functional domains of hTERT with the position of the mutation. hTERT contains three major domains: the N-terminal region, the reverse transcriptase motif, and the C-terminal region, all containing evolutionarily conserved motifs. (Figure adapted from Podlevsky et al.7) (D) Alignment of the hTERT sequences of human, Mus musculus (mouse), Canis familiaris (dog), Bos taurus (cow), and Gallus gallus (chicken). The L153M mutation lies within Motif GQ, which is conserved among telomerase proteins. (E) The scatterplot graph shows leukocyte telomere length (LTL) distribution in relation to age of controls and family members with or without hTERT L153M mutation. The proband's LTL is indicated by the arrow. LTL resulted in significantly shorter in family members compared to age-matched healthy controls (0.94 ± 0.45 versus 1.37 ± 0.63; P = 0.007). LTL was evaluated with a quantitative polymerase chain reaction (q-PCR)-based assay. Telomere DNA was amplified using primers provided by Cawthon.8 The relative telomeres/single copy gene ratio (T/S-ratio value) was calculated as an expression of the relative average LTL in genomic DNA samples. CC, cryptogenic liver cirrhosis; CT, computed tomography; IPF, idiopathic pulmonary fibrosis; LTL, leukocyte telomere length; NASH, nonalcoholic steatohepatitis. 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). Telomerase mutations and disease phenotypes in the pedigree of the proband. Pedigree showing telomerase mutations and disease phenotypes in this family. The number in the box indicates the age of the subject at death or at presentation. 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.1 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.2 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.3 Recently, a growing body of evidence suggests a possible role of telomerase mutations and accelerated telomeres shortening also in liver disease progression.4, 5 Interestingly, Alder et al.6 identified CC in 3% of patients with IPF that had shortened telomeres but without detectable telomerase mutations. Several epidemiological studies have shown that CC shares common risk factors with nonalcoholic steatohepatitis (NASH), suggesting that the majority of CC could derive from progression of previously unrecognized NASH. However, the mechanisms underlying NASH development and progression are to be further elucidated. It is intriguing to suggest that in our patient shortened telomeres resulting from genetic dysfunctional telomeres repair (hTERT L153M mutation) and acquired increased cell turnover (chronic inflammation and tissue damage secondary to smoking habits and diabetes) may have contributed, on the one hand, to lung fibrosis development and, on the other hand, to progression to liver cirrhosis of an unrecognized NASH. The fact that telomerase mutation did not track with liver diseases in the family (Fig. 2) raises two important issues. First, telomeropathies encompass a large spectrum of phenotypes (from no clinical manifestations to multiorgan failure and fibrosis) whose development requires the interaction of both genetic and environmental factors. Second, chronic hepatopathies are multifactorial diseases; telomere involvement could shed some light on their complex biological underlying mechanisms, but many other factors need to be investigated. In conclusion, this is the first description of the coexistence of CC and IPF in a middle-aged woman, active smoker with type 2 diabetes, and not in the setting of dyskeratosis congenita. Genetic analysis revealed a novel telomerase mutation associated with extremely short telomeres. This case report not only confirms the association between IPF and telomere dysfunction, but, more interestingly, gives further evidence of telomere involvement in liver disease progression and suggests a possible link between NASH and CC through telomere shortening. We thank Maria Rosaria Odoardi, Claudia Anzivino, Enrica Baldelli, Valentina Spigoni, and Erica Meschiari for dedicated work in the laboratory; Prof. Paola Loria and Prof. Marco Bertolotti for their contribution and support.
Carulli et al. (Mon,) studied this question.