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Pulmonary, Critical Care, and Sleep Pearls |

A 49-Year-Old Man With Cirrhosis and Pulmonary Fibrosis FREE TO VIEW

Priyanka Rajaram, MD; Brent Little, MD; J.P. Norvell, MD; Morgan McLemore, MD; Srihari Veeraraghavan, MD, FCCP
Author and Funding Information

CORRESPONDENCE TO: Priyanka Rajaram, MD, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University School of Medicine, 615 Michael St, Ste 205, Atlanta, GA 30322


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(2):e57-e60. doi:10.1016/j.chest.2015.06.010
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A 49-year-old man with a history of cryptogenic cirrhosis was referred to pulmonary clinic for evaluation prior to liver transplantation. Chest imaging obtained as part of the transplant workup had shown evidence of interstitial abnormalities. The patient noted shortness of breath on moderate exertion that was worsening over the past 2 to 3 years and associated with a nonproductive cough. He denied chest pain, chills, or fevers. His past medical history was significant for hypothyroidism. He did not have a history of alcohol consumption, smoking, or occupational exposures. He noted a family history of lung disease in his father and evidence of prominent clubbing in his sister and nephew. Workup for liver failure included a liver biopsy, which showed cirrhosis without evidence of autoimmune hepatitis.

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On physical examination, the patient was afebrile, with a heart rate of 70 beats/min, BP 118/67 mm Hg, respiratory rate of 16 breaths/min, and oxygen saturation of 100% on room air. Neck examination revealed no lymphadenopathy or thyromegaly. Cardiac examination revealed normal heart sounds. Bibasilar Velcro-type crackles were heard on lung auscultation in the bases. On abdominal examination, there was no palpable organomegaly or evidence of free fluid. Significant clubbing of his fingers and trace lower extremity swelling were present.

Pertinent laboratory findings showed microcytic anemia (hemoglobin, 7.6 g/dL), leukopenia (WBC = 1.6 × 109/L), and thrombocytopenia (platelets = 34 × 109/L). Pulmonary function test results showed an FEV1/FVC ratio of 85 with a moderately reduced total lung capacity (61%) and severely reduced diffusion capacity (34%, corrected for hemoglobin).

Posteroanterior chest radiograph showed moderately low lung volumes. Minimal reticular opacities were present at the lung bases, suggesting an interstitial abnormality. Undulating opacities along the paraspinal regions and left-side heart border corresponded to multiple varices (Fig 1).

Figure 1
Figure Jump LinkFigure 1 Posteroanterior chest radiograph showing moderately low lung volumes. Minimal reticular opacities were present at the lung bases, suggesting an interstitial abnormality. Undulating opacities along the paraspinal regions and left-side heart border corresponded to multiple varices.Grahic Jump Location

High-resolution chest CT images showed reticular opacities at the basal lung periphery with interlobular and intralobular septal thickening. Although no macroscopic honeycombing was present, traction bronchiolectasis, mild posterior bowing, and distortion of the major fissures suggested fibrosis (Fig 2).

Figure 2
Figure Jump LinkFigure 2 A, B, High-resolution chest CT images showing reticular opacities at the basal lung periphery with interlobular and intralobular septal thickening.Grahic Jump Location

What is the diagnosis?

What is the next diagnostic step?

Diagnosis: Syndrome of telomere shortening with pulmonary fibrosis, cirrhosis, and bone marrow failure

Next diagnostic step: Telomere length measurement

Idiopathic pulmonary fibrosis (IPF) is an adult-onset, progressive fibrotic disease of the lungs resulting in respiratory failure. Although the exact cause is unknown, both environmental and genetic factors have been implicated as risk factors for the disease. About 2% to 20% of patients report a family history of the disease, which has been described to have an autosomal-dominant inheritance with variable penetrance. Familial IPF can be indistinguishable in terms of clinical features from its sporadic counterpart. However, the age of onset tends to be earlier (55 years vs 67 years) in familial IPF compared with sporadic IPF. Mutations in the telomerase components have been observed in 8% to 15% of the patients with a family history of IPF and 1% to 3% of sporadic cases.

Telomeres are DNA-protein structures made up of TTAGGG nucleotide repeats that protect the ends of each chromosome. Telomerase is an enzyme that synthesizes new telomeres to maintain sufficient length, thereby preventing apoptosis and cellular senescence. A critical reduction in telomere length due to defective telomerases can trigger senescence or cell death. Telomerase reverse transcriptase and telomerase RNA, the catalytic component and template for telomere addition, respectively, are essential to this process. Mutations in these components lead to haploinsufficiency, which is a decrease in telomere repeats. This results in shortened telomeres, which can manifest as a wide array of clinical disorders.

Dyskeratosis congenita, a rare x-linked hereditary disease with mutations in the DKC1 gene, is one of the earliest manifestations of shortened telomeres. This presents in childhood as a triad of mucocutaneous features, including oral leukoplakia, skin hyperpigmentation, and nail dystrophy associated with premature aging. About 10% of patients with dyskeratosis congenita do not have classic physical findings suggestive of the disease. The high mortality rate of this disorder is due to bone marrow failure, presenting as aplastic anemia. Twenty percent of the patients manifest features of pulmonary fibrosis, which is the second leading cause of death. Mutations in telomerase reverse transcriptase and telomerase RNA can lead to diverse phenotypes of disease presentations outside of the bone marrow, with an autosomal-dominant inheritance and genetic anticipation, leading to earlier and more severe forms of disease in successive generations.

Familial IPF is one of most common manifestations of the syndrome of telomere shortening. The age of onset and severity of disease is determined by the length of the telomeres rather than specific mutations. Cross-sectional studies have shown that in individuals with the shortest telomeres, the risk of developing IPF is increased. This is further supported by the increasing incidence of cryptogenic cirrhosis, another feature of telomere shortening, in patients with familial IPF and some cases of sporadic IPF. Lung biopsies of patients with familial IPF show patterns consistent with histologic usual interstitial pneumonia (UIP) including peripheral interstitial fibrosis with fibroblastic foci, honeycombing, and traction bronchiectasis.

A typical (“definite”) UIP pattern of fibrosis on chest CT scan has been described in up to 74% of patients with familial pulmonary fibrosis. Basilar predominant reticular opacities, honeycombing, and traction bronchiectasis/bronchiolectasis are usually present. Less commonly, a “possible UIP” pattern of disease is observed, with patchy reticulation in a basilar predominance without detectable honeycombing (as in this patient). A final subset of patients present with certain CT scan features inconsistent with UIP, such as an upper lobe or peribronchovascular predominance.

The combination of early-onset IPF, cryptogenic cirrhosis, and evidence of bone marrow failure should raise the suspicion for the syndrome of telomere shortening. In most cases, organ failure is deemed to be idiopathic and may be mistaken for an autoimmune etiology. In the right clinical setting, telomere length measurement on peripheral blood will aid in confirming the diagnosis. The majority of individuals with the syndrome of telomere shortening will have telomere lengths below the 10th percentile in lymphocytes and granulocytes.

Familial IPF, similar to other forms of IPF, does not respond to immunosuppression. This has been observed in patients with aplastic anemia related to the syndrome of telomere shortening as well. In patients with end-stage organ failure related to this syndrome, organ transplant remains the definitive mode of treatment. Lung transplantation is feasible in patients with IPF related to telomerase mutations. However, these patients are susceptible to higher rates of drug-related, hematologic and renal complications compared with other lung transplant recipients. An exhaustive family history is of utmost importance in these individuals to provide appropriate genetic counseling and identify affected family members.

Clinical Course

A diagnosis of pulmonary fibrosis was made based on the patient’s clinical and radiologic presentation. He underwent bone marrow biopsy for the pancytopenia that showed evidence of hypoplasia with reactive plasmacytosis. Given the constellation of cryptogenic cirrhosis, pancytopenia, and IPF, telomere length measurement was obtained. The telomere length in his peripheral blood lymphocytes and granulocytes was less than the first percentile for age, consistent with a diagnosis of the syndrome of telomere shortening. We were unable to evaluate his family members.

  • 1.

    IPF, pancytopenia, and cryptogenic cirrhosis are the key findings associated with the syndrome of telomere shortening.

  • 2.

    In patients suspected of having the syndrome of telomere shortening, a diagnosis can be established by telomere length measurement from a peripheral blood sample.

  • 3.

    The age of symptom onset and severity of disease is determined by the telomere length and not by specific mutations.

  • 4.

    The definitive treatment of organ failure (lung, liver, or bone marrow) in the syndrome of telomere shortening is organ transplantation.

Financial/Nonfinancial disclosures: None declared.

Other contributions:CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met. All work for this project was completed at Emory University.


Figures

Figure Jump LinkFigure 1 Posteroanterior chest radiograph showing moderately low lung volumes. Minimal reticular opacities were present at the lung bases, suggesting an interstitial abnormality. Undulating opacities along the paraspinal regions and left-side heart border corresponded to multiple varices.Grahic Jump Location
Figure Jump LinkFigure 2 A, B, High-resolution chest CT images showing reticular opacities at the basal lung periphery with interlobular and intralobular septal thickening.Grahic Jump Location

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