My stepfather was the quintessential short telomere syndrome patient. His hair turned gray in high school, his father died of idiopathic pulmonary fibrosis, his sister died of idiopathic pulmonary fibrosis, and then he too died of idiopathic pulmonary fibrosis, complicated by bone marrow failure from myelodysplasia. Last month, I attended an international conference on telomeres in lung transplant and the information from that conference has profound implications for treating our patients with these conditions.

Telomeres are repeating sequences of the DNA nucleotides, TTAGGG, that are on the ends of our chromosomes and serve to protect the genes inside those chromosomes from damage, kind of like how the plastic caps on your shoelace protect the shoelace from unraveling and becoming damaged.

We are all born with fairly long telomere segments at the end of our chromosomes but then as we age, our telomeres shorten, presumably making the genes underneath these chromosomes more more fragile and subject to damage. Thus, our telomeres start off about 11 kilobases when we are born but by age 80, they have shortened by two-thirds, to 4 kilobases.

The reason that we lose these repeating TTAGGG sequences is that when our chromosomes divide, about 50-100 base pairs of telomere DNA is lost from the end of one of the two chromosomes because of the way that a chromosome divides and then re-builds new twin strands of DNA to form the 2 new chromosomes.

Our cells can restore these lost telomeres by using a protein complex called “telomerase” that adds TTAGGG nucleotide groups to the ends of our chromosomes. But if there is a genetic abnormality in one of this group of proteins, then telomerase does not work properly and cannot fully restore the telomeres to their previous length. Thus, with each chromosomal division of mitosis, the telomeres get a little shorter. Telomeres are akin to a “molecular clock” in our cells and some people have postulated that if we can maintain normal telomere lengths, that we may be able to avoid the scourge of aging, in other words, create a Fountain of Youth. Although it is not clear if this is possible, it does appear prematurely shortened telomeres due to an abnormal telomerase protein gene results in the opposite, in other words, a “Fountain of Age”.

A patient with one of these abnormal genes will have telomeres that are shorter than normal people of their same age. This results in “short telomere syndromes”. In adults, the main short telomere syndromes are:

1. Familial idiopathic pulmonary fibrosis
2. Cirrhosis
3. Aplastic anemia
4. Myelodysplasia
5. Prematurely gray hair

There are two ways to measure telomere length: a polymerase chain reaction (PCR) method and a fluorescent in situ hybridization (flow-FISH) method. The flow-FISH method is considerably more accurate than the PCR method. People can get a take-home telomere PCR test done essentially over-the-counter for about $100 through internet DNA companies. The flow-FISH method is only available at a few university laboratories, requires a physician order, and costs $400-800. I send my patients’ blood to be tested at one of these labs that use the flow-FISH method. The length of telomeres that indicates a short telomere syndrome is unknown but when the length is less than the lowest 1st percentile, I consider it highly likely. Since my clinical practice is primarily patients with interstitial lung diseases (including idiopathic pulmonary fibrosis), I end up seeing a number of these patients. Here is a telomere length test result on one of my patients with familial idiopathic pulmonary fibrosis, cirrhosis, and pancytopenia from a hypocellular bone marrow:

Idiopathic pulmonary fibrosis patients with short telomeres are different

There are some important differences in patients with familial idiopathic pulmonary fibrosis and short telomeres compared to everyone else with idiopathic pulmonary fibrosis. First, they do poorly with immunosuppressives. In the past, we used to use medications that suppressed the immune system to treat idiopathic pulmonary fibrosis, thinking (incorrectly) that inflammation was the genesis of the lung scarring that characterizes the disease. A number of years ago, there was a study sponsored by the National Institutes of Health comparing a treatment with the immunosuppressive medications azathioprine and prednisone with placebo. It turned out that the patients who got azathioprine or prednisone did a lot worse than those getting placebo. Recently, researchers went back and looked at stored blood samples of the patients who were in this study and it turns out that only those patients with short telomeres did poorly with immunosuppressive medications – patients with normal telomeres had the same outcome whether they received immunosuppressive medications or placebo.

Second, these patients do poorly after lung transplant. They are more prone to developing low white blood cell counts, presumably from being more susceptible to side effects of immunosuppressive medications. Also, they are more prone to getting devastating infections with cytomegalovirus (CMV) and aspergillus. Patients with short telomeres who get lung transplants can develop myelodysplasia or cirrhosis after lung transplant and those with liver transplants can develop myelodysplasia or pulmonary fibrosis after liver transplant.

More Questions Than Answers

Our understanding of short telomere syndromes and how to best medically manage these patients is still in its infancy. There is much that we do not yet know. For example:

1. Which patients with idiopathic pulmonary fibrosis should undergo telomere length testing? Currently, I limit testing to those patients with a family history of idiopathic pulmonary fibrosis who also have a personal or family history of premature graying of the hair, unexplained cirrhosis, myelodysplasia, or unexplained cytopenia. Telomere length testing is not widely available and not always covered by insurance. If it only cost $25 and insurance covered it, I would probably order it on all of my patients with idiopathic pulmonary fibrosis. In addition, there may be other lung diseases associated with short telomeres. For example, pleuropulmonary fibroelastosis appears to be associated with short telomeres.
2. Which patients with cirrhosis should undergo telomere length testing? NASH (non-alcoholic steato-hepatitis, aka fatty liver) is the most rapidly growing cause of cirrhosis due to the epidemic of obesity and diabetes in the United States. It seems like whenever there is no obvious cause of cirrhosis (such as hepatitis C or alpha-1-antitrypsin deficiency), then patients get labeled as having NASH cirrhosis by default. Many patients who carry a diagnosis of NASH cirrhosis likely have liver disease due to short telomeres.
3. Should every patient with short telomeres be referred for genetic testing? Genetic testing is usually done in conjunction with genetic counseling by trained genetic counselors. Unfortunately, these counselors are in short supply and are mainly associated with pediatric hospitals and cancer hospitals. Furthermore, genetic testing is not cheap and typically costs around $800; most insurance companies will not cover it or will only cover it after a lot of physician effort doing denial appeals. The results of genetic testing in short telomere syndromes can be difficult to interpret – these syndromes can be associated with abnormal genes such as TERT and TERC but these genetic abnormalities can also be seen in some otherwise normal people.
4. Should telomere length testing be done in all patients prior to transplant? One of the basic tenets of transplantation is to offer it to those patients who will most benefit by transplant. Since some studies indicate that patients with short telomeres have worse outcomes after transplant, should this affect their transplant eligibility? Could short telomeres be a relative contraindication to transplant?
5. Should transplant patients with short telomeres get different immunosuppression regimens? Since it appears that patients with short telomeres do poorly with immunosuppressive medications, it may be that they need to have reduced doses of these medications when used to prevent transplant rejection. Or perhaps there are some immunosuppression regimens that are safer than others in patients with short telomeres. Once again, at this time, we just do not know.
6. Should patients with short telomeres get combined lung and liver transplants? These patients are prone to getting both pulmonary fibrosis and cirrhosis and not infrequently does cirrhosis become apparent only after lung transplant for pulmonary fibrosis and vice versa. At the least, patients with known short telomeres undergoing liver transplant should probably be screened for interstitial lung disease and those undergoing lung transplant should be screened for cirrhosis. Most combined lung/liver transplants in the United States are done in patients with cystic fibrosis. Many centers have found that combined lung/liver transplant in other patients has a high mortality rate. One has to wonder whether a lot of these non-cystic fibrosis patients who have had combined lung/liver transplant actually had undiagnosed short telomere syndromes.
7. Should patients with short telomeres undergoing transplant get a bone marrow biopsy? This is not part of the normal work-up for patients undergoing either lung or liver transplant. But the development of myelodysplasia or it malignant cousin, acute myelogenous leukemia, can be devastating in the post-transplant period. Clues to subclinical myelodysplasia can include unexplained macrocytosis (increased MCHC), leukopenia, or thrombocytopenia. No transplant physician likes a hematologic surprise after transplant.

One of the simultaneously frustrating and exciting things about medicine is that just when we think that we know everything, we realize that we don’t. Short telomere syndromes epitomize this axiom – clearly, we have much more to learn.

October 2, 2019