Ep 133: A 45-Year-Old with Difficulty Climbing Stairs
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This is Katarina Heidhausen, Executive Editor of Harrison's Principles of Internal Medicine. Harrison's Pod Class is brought to you by McGraw-Hills Access Medicine, the online medical resource that delivers the latest content from the best minds in medicine. And now, on to the episode. Hi, everyone. Welcome back to Harrison's Pod Class. We're your co-hosts. I'm Dr. Kathy Handy. And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine.

Welcome to episode 133. Today's episode is about a 45-year-old with difficulty climbing stairs. Kathy, today you're seeing a 45-year-old man with a two-year history of worsening dyspnea on exertion and shortness of breath. He's always been active in sports, but over the last few years has limited his activity, and now what has really been noticeable was that he has even more difficulty climbing stairs. He has no significant past medical history, takes no medications, and has no bad habits.

He works at his family's furniture business. His family history is notable for his father and uncle with pulmonary fibrosis, though. The family history of pulmonary fibrosis, along with the dyspnea on exertion and the shortness of breath, certainly raised my suspicion for a primary pulmonary process or even potentially a muscular problem as the cause of his symptoms. Tell me about his physical examination, and has he had any evaluation so far?

Okay. At rest, his blood pressure, heart rate, and respirations are normal. His oxygen saturation at rest is 94%. His hair is gray, and he tells you that he went gray in his 30s, like many other members of his family. On lung exam, you hear basilar inspiratory crackles bilaterally. His JVP is normal, and there's no left or right heart abnormalities.

Pocus does not show a dilated left or right ventricle. When you walk him up a flight of stairs, his oxygen saturation drops to 86% and he reports shortness of breath. He has full and normal strength in his bilateral upper and lower extremities, both proximally and distally. So there are a couple of things to note in that, but first, what about PFTs and a CT chest and an echocardiogram?

Yes. Well, he's also had an echocardiogram that shows normal left ventricular function, normal left atrial size, no overt right ventricular dilation, but an estimated RV systolic pressure of 35. So that fits with the physical examination that showed no evidence of heart failure, but there is an elevation of the RV systolic pressure. What about the PFTs?

His PFT show a normal FEV1 to FVC ratio. His FVC and his TLC are both reduced to 60% predicted, and his diffusing capacity for carbon monoxide is 40% predicted or severely impaired. So no obstructive defect. He does have a moderate restrictive defect and a severe gas transfer defect. So that explains his desaturation with exercise. How about the chest CT?

His chest CT shows moderate lower lobe interstitial fibrosis, some subplural honeycombing, and scattered lower lobe brown glass opacities. Okay, he has a chronic interstitial lung disease and maybe some acute inflammation. With the honeycombing, I'm worried about idiopathic pulmonary fibrosis, but he's really young for that. And that's going to get us to today's question. The question asks, testing for which of the following is likely to provide an explanation for his interstitial lung disease?

And the options are A, alpha-1 antitrypsin level, B, chloride channel function, C, ciliary function, D, granulocyte macrophage colony stimulating factor antibodies, or E, telomere length. Okay, so the answer is E, telomere length. Okay, well, I'm going to need a refresher on telomeres.

Remember, telomeres are the physical termini of linear chromosomes and function to protect the chromosome ends against recognition as damaged or infectious DNA by the DNA repair machinery. As cells divide by mitosis, chromosome erosion is inevitable, but the non-coding telomeric long repetitive structure buffers loss of genetic information.

At birth, telomeres are relatively long, but they shorten with chronological aging. In an individual cell, critically short telomere length triggers the p53 pathway, usually leading to proliferative arrest, senescence, and apoptosis. Telomere loss is the molecular basis for the Hayflick phenomenon, the limit to cell division and thus to cell proliferation in tissue culture.

So I assume from what you're saying that disease involving the telomeres are genetic in Orangin? Yes, as far as we know now, telomere diseases, which are also called telomeropathies or telomere spectrum disorders, are characterized by organ dysfunction caused by loss of the ends of chromosomes or accelerated telomere attrition.

Affected tissues show defective organ regeneration, fibrosis or replacement by fat, and a proclivity for cancer. A variety of disorders affecting, especially the bone marrow, lungs, liver, and skin, all share telomere dysfunction and accelerated loss as their common molecular mechanism. So I'm assuming that lung fibrosis is one of the telomere spectrum disorders.

Approximately 10 to 15% of patients with idiopathic pulmonary fibrosis or familial pulmonary fibrosis have an etiologic telomerase gene mutation. And remember, our patient had a positive family history. How telomere erosion causes pulmonary fibrosis is unclear, but it might prevent adequate proliferation and regeneration of type 2 pneumocytes. So how do these patients typically present?

Well, our patient is pretty typical. Idiopathic pulmonary fibrosis due to a telomere disease usually manifests after the fourth decade of life. There's a restrictive pattern on pulmonary function testing, a decreased DLCO, and a diffuse honeycomb appearance on CT. Histopathology of biopsied lung most commonly shows usual interstitial pneumonia.

The pulmonary clinical presentation in telomere disease is indistinguishable from idiopathic pulmonary fibrosis, except that those with an underlying telomere defect may have cryptic hepatic cirrhosis, macrocytosis, cytopenias, and a family history of lung, liver, or bone marrow disease.

Pulmonary arteriovenous malformation leading to right to left shunting is observed in patients with pulmonary fibrosis due to pulmonary disease too. And as with our patient, they also have premature graying of the hair often. So the diagnostic test is a telomere length?

Yes, patients with idiopathic pulmonary fibrosis, particularly at a young age or familial pulmonary fibrosis, should have leukocyte telomere length assayed, and if telomeres are short, undergo screening for mutations in telomere-associated genes. Okay, well, before we close, let's run through the other options just for completeness. Reduced alpha-1 antitrypsin levels are associated with the premature development of panacinara emphysema.

Chloride channel dysfunction is a hallmark of cystic fibrosis. Ciliary dysfunction is a cause of Cartagena syndrome and may cause bronchiectasis that clinically looks like cystic fibrosis, as well as dextrocardia. And finally, granulocyte macrophage stimulating factor antibodies may cause pulmonary alveolar proteinosis.

Great. So today's teaching points are that diseases of the telomeres or telomereopathies may present in a variety of fashions, but one characteristic phenotype is the early development of idiopathic pulmonary fibrosis. This question and questions like it can be found in Harrison's self-review book and online, and you can read about this as well as other disorders associated with telomere dysfunction in the Harrison's chapter on telomere disease.

Visit the show notes for links to helpful resources, including related chapters and review questions from Harrisons. And thank you so much for listening. If you enjoyed this episode, please leave us a review so we can reach more listeners just like you.