Paul D. Thompson, MD

Hemochromatosis is caused by defects in the hemostatic iron regulator (HFE) gene (

.1 HFE binds to the transferrin receptor 2 (TRF-2). TRF-2 increases hepcidin production. Hepcidin inhibits elemental iron (Fe) uptake by binding to and downregulating the Fe exporter, ferroportin, which transports Fe from and between cells. So, genetic defects in 

, decrease HFE binding to TRF-2, decreasing hepcidin production, increasing ferroportin, and increasing Fe transport from the gut.

The most common gene mutation for hemochromatosis, 

probably originated in a single Celt or Viking in Northwestern Europe approximately 6000 years ago.

 It probably conveyed some survival advantage such as height

 mutation average 4.3 and 3.3 cm taller, respectively, than a reference Swiss population.

 variants demonstrate increased exercise performance and were 8% faster on a 10 km cycling time trial and had a 17% higher maximal oxygen uptake.

 The gene is highly prevalent in individuals of northern European origin and more than 6% of whites have at least one 

Ireland has the highest prevalence by country.

 Despite this prevalence, only 28% of homozygous men and 1.4% of homozygous women develop symptoms of hemochromatosis.

That’s because women lose iron with menstruation so present later in life, if at all. Also, alcohol enhances iron absorption and thereby affects the age of presentation. Hemochromatosis can present in mid-life with unexplained fatigue, joint pain, liver disease, diabetes, impotence due to hypogonadotrophic hypogonadism, bronzing of the skin (“bronze diabetes”)

Clinicians should consider the possibility of hemochromatosis in multiple disease states because of its prevalence in Northern Europeans and its effect on many organ systems. This is especially true for cardiologists because it can produce both dilated and restrictive cardiomyopathy, angina 

 CAD, pericarditis, atrial fibrillation, and more rarely, ventricular arrhythmias.

 Serum iron, transferrin saturation, and ferritin levels are usually all elevated. Genetic testing is recommended when the transferrin saturation value exceeds 45%.

Cardiac involvement is determined by cMRI with T2 imaging. The usual treatment is phlebotomy, but chelation therapy can be used for severe iron infiltration of the liver or heart because phlebotomy takes time to be effective.

 Both the hepatic and cardiac infiltration are reversible so clinicians and cardiologists should think of the disease because of its prevalence and its multiple systemic and cardiac manifestations.

Thakkar D, et. Al. HFE Genotype and Endurance Performance in Competitive Male Athletes. Med Sci Sports Exerc. 2021 Jul 1;53(7):1385-1390. PMID: 

Cippa PE, Krayenbuehl P-A. Increased height in HFE hemochromatosis. N Engl J. 2013 Aug 22;369(8):785-6. PMID: 23964954.

Stefanova, D, et.al. Endogenous hepcidin and its agonist mediate resistance to selected infections by clearing non-transferrin-bound iron. Blood. 2017 Jul 20;130(3):245-257. PMID: 28465342

Moore, AB et.al. Case 25-2021: A 48-Year-Old Man with Fatigue and Leg Swelling. N Engl J Med. 2021 Aug 19;385(8):745-754. PMID: 

Porter JL, Rawla P.2021 Jun 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. PMID: 28613612

Pietrangelo, A. Hereditary hemochromatosis--a new look at an old disease. Engl J Med. 2004 Jun 3;350(23):2383-97. PMID: 

Articles

Paul D. Thompson, MD, pens a column underlining the prevalence and impact of hemochromatosis on the health of patients based on current evidence. 

Don't Forget About Hemochromatosis, With Paul Thompson, MD

Pollution, greenhouse gases, and global warming are finally on everybody’s agenda, including the New England Journal of Medicine’s (NEJM) whose November 11, 2021, edition included an article entitled “Pollution and the Heart”.

 Pollution is defined as the release of unwanted materials into the environment by human activity. 

The article summarizes evidence linking air, metal, and chemical pollution to cardiovascular disease (CVD), primarily coronary artery disease (CAD). Both indoor and outdoor air pollution are a larger problem in less affluent countries because environmental regulation, such as the United States’ Clean Air Act of 1970, has reduced pollution in wealthier countries, and because indoor pollution is often a household problem and poorer homes cook and heat with polluting heat sources. 

The article also cites evidence linking metals including lead, mercury, arsenic, and cadmium to CVD. Lead is a known hypertension risk factor, but also appears to increase CAD even at low levels. Mercury enters environment from gold mining and burning coal. Mercury from burning coal precipitates into water, is consumed by fish, and enters the fish-to-man food chain. Arsenic is usually obtained from drinking water from international “hot spots” including the southwest US and northern New England. Arsenic in New England enters the water from the granite bedrock. Cadmium pollution comes from tobacco smoke and work exposure, as well as green leafy and tuberous vegetables grown in contaminated soil. 

The authors note the cadmium discussion that a randomized controlled clinical trial (RCCT), found that 

 using EDTA reduced the composite endpoint of total mortality, myocardial infarction, coronary revascularization, stroke, and hospitalization by 18% (95% CI, 1-31%, 

<.04) with a larger effect in patients with diabetes. I guess I should not have been so critical of my patients who asked about chelation therapy. Another RCCT of chelation therapy is underway to verify these results. The authors suggested that the benefit from chelation therapy might be due to removing toxic metals such as cadmium. The review also notes that chemical pollutants including halogenated hydrocarbons, perfluoroalkyl compounds, and chemicals associated with plastics have all been related to CVD.

But they forgot the beer. I was a medical student in the early 1970’s and not far removed from my fraternity house, undergraduate days when a lecturer mentioned that in 1965-6, there had been an outbreak of heart failure in Quebec, Canada linked to beer.

 I woke up immediately. A brewery in Quebec had added cobalt to their beer in order to stabilize the beer’s foam “head”.

 The added cobalt was determined to be the cause of the cardiomyopathy.

The cobalt cardiomyopathy was associated with elevated hemoglobin levels and pericardial effusions. A total of 48 habitual beer drinkers were affected in Quebec with a mortality rate of 46%. Similar epidemics related to beer consumption were subsequently reported from Omaha, NE; Minneapolis, MN; and Belgium. The dose of cobalt was not large and was below the dose of cobalt used at the time to treat anemia. This led to the hypothesis that it was the combination of cobalt and alcohol that lead to the cardiomyopathy. Concern about cobalt heart disease re-appeared with evidence that some patients developed heart failure from chromium leakage from failed hip replacements.

 This concern has abated, but not totally disappeared.

 It may require the combination of a failed hip replacement and excessive alcohol consumption.

In fairness to the pollution review, the chromium in the beer was not unwanted and was added intentionally, so should probably not have been included in a pollution review. In fairness to me, I only focused on the metal section of the NEJM article to make sure my beer was safe.

Rajagopalan S, Landrigan PJ. Pollution and the Heart.N Engl J Med. 2021 Nov 11;385(20):1881-1892. doi: 10.1056/NEJMra2030281.PMID: 34758254

Metal-on-Metal Total Hip Resurfacing Arthroplasty: An Evidence-Based Analysis. Medical Advisory Secretariat. Ont Health Technol Assess Ser. 2006;6(4):1-57. Epub 2006 Feb 1.

Bradberry SM, Wilkinson JM, Ferner RE. Systemic toxicity related to metal hip prostheses. Clin Toxicol (Phila). 2014 Sep-Oct;52(8):837-47.

Dr. Paul Thompson offers perspective on the recent "Pollution and the Heart" article published in NEJM and provides insight into the potential for metal pollution from beer on influencing risk of cardiovascular disease.

They Forgot the Beer? With Paul D. Thompson, MD

This article was originally published on 

 report of a trial comparing semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), versus tirzepatide, a drug that has both GLP-1a and glucose-dependent insulinotropic polypeptide activity.

 GLP-1 RA’s stimulate insulin secretion during hyperglycemia and decrease glucagon secretion during euglycemia and hypoglycemia.GLP-1 RA’s also decrease gastric emptying thereby decreasing appetite and body weight. Tirzepatide has GLP-1 RA activity, but also stimulates insulin release and decreases glucagon levels during euglycemia and hypoglycemia via its glucose-dependent insulinotropic activity. This dual-action has theoretical advantages. The study compared semaglutide 1 mg SQ weekly, versus tirzepatide 5, 10, or 15 mg SQ weekly. Tirzepatide has not yet been FDA approved.

All 3 tirzepatide doses decreased mean hemoglobin A1c (A1c) by 2.01 to 2.3% versus 1.86% for semaglutide. Bodyweight decreased 1.9 to 5.5 kg more with tirzepatide than with semaglutide over the 40-week study. But this was not a fair comparison because STEP 2 or the Semaglutide Treatment Effect in People with Obesity study used a semaglutide dose of 2.4 mg weekly,

 and higher semaglutide doses probably would have reduced hemoglobin A1c and body weight more.

But here’s the real question. Why is a cardiologist (me) studying an article on new diabetes treatments? I remember similar thoughts about why cardiologists were interested in lipid metabolism when lovastatin was FDA approved in November 1987. And look where cardiologists are now in managing lipids using statins, PCSK9 inhibitors, ezetimibe, and bempedoic acid. Cardiologists, like all clinicians, get interested in problems they can fix easily. Metformin, sodium-glucose transport type 2 inhibitors (SGLT2i), and GLP-1 RAs (as the oral semaglutide, Rybelsus) are now all available orally. Even when using GLP1a’s as injection is not difficult. They are easy to use because they rarely cause hypoglycemia unless administered with insulin or a sulfonylurea. This means they are “smart drugs” in that their glucose-lowering effect dissipates as the glucose levels fall. All reduce A1c and reduce body weight, and the latter effect can make you a hero to your patients!

I’ll bet that our experience with LDL management, that “even lower is even better”, will also ultimately be applied to A1c management. The Fourier Trial demonstrated a 2% absolute risk reduction in cardiovascular events after only 3 years when high-risk coronary patients reduced their median LDL-C from 92 to 30 mg/dl using the PCSK-9 inhibitor, evolucamab.

 I realize that available diabetes trials show no difference in outcomes with A1c’s above or below 7%, but these trials used insulin to achieve the A1c levels, and insulin causes hypoglycemia and has many atherogenic properties. Furthermore, someone with “borderline diabetes” has already lost 50% of his/her insulin-secreting capacity. The Diabetes Prevention Program demonstrated that treating patients with prediabetes, defined as an oral glucose tolerance 2-hour value above 140 mg/dl, but less than 200 mg/dl, decreased the onset of diabetes by 31%.

 Hyperglycemia not only glycosylates hemoglobin, but also glycosylates proteins in the LDL particle making LDL more inflammatory and atherogenic. In the Early ACS Trial, among 879 patients with non-ST segment elevation MIs (NSTEMI), 32.5% had known diabetes, 12.2% had undiagnosed diabetes but fasting glucose values at or above 126 mg/dL or an A1c greater than 6.5%, and 8% had prediabetes diagnosed by a glucose of 110 to 126 mg/dL. 5Only 44.4% had normal glucose metabolism. Prediabetes is dangerous. It leads to diabetes and causes cardiac events along the way.

Maybe it’s time for cardiologists to know more, do more, and be more aggressive about treating diabetes, borderline or otherwise.

Frias JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med 2021;385:503-15.

Davies M, Faerch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet 2021;397:971-84.

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713-22.

Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.

Giraldez RR, Clare RM, Lopes RD, et al. Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome. Am Heart J 2013;165:918,925.e2.

Editorial advisory board member Dr. Paul Thompson reflects on how advances in diabetes management have impacted cardiovascular medicine and why staying abreast of these advances is essential to being a cardiologist in 2021. 

Paul Thompson, MD: Why Cardiologists Need to Be Diabetologists

Somewhere during my medical school training, someone told me that if you really want to improve medical care, you should be a good teacher because being a good teacher magnifies your effect. Dr. Thomas Lee’s book on Eugene Braunwald

states that when Braunwald took over as Chief of Medicine at the Brigham, he considered getting the right residency director as one of his most important task.

His reasoning? Having a strong residency director would create a competitive residency that would attracted the best residents, who would provide better care.The best of the best residents could subsequently be recruited to join the faculty. Having a strong residency program also makes an institution more attractive to attendings who like to teach.

One of the most important effects of teaching, is that the teacher gets smarter. I always say that “Teaching Teaches the Teacher” or T4. Dr. Braunwald also knew that his trainees would go elsewhere across the country and if the residents were well-trained, they would enhance the Brigham’s reputation. It’s an upward spiral. Dr. Braunwald recruited Sheldon Wolff, who became a beloved leader of the Brigham residency program.

All of this makes me wonder if we reward clinical teachers well enough. Good teachers can make a place better. I am not referring only to teaching medical students and trainees. Constantly teaching nurses and other clinicians if done with respect and absolutely no condescension can improve clinical quality. A teaching environment also attracts job candidates to such an institution.

I once worked where we had lots of applicants for our advanced practice nurse practitioner (APRN) positions, despite not paying top dollar. I asked one of our APRN’s why she worked there when she could get more pay at just about any other hospital. She replied that her plan was to work there for a couple of years because the teaching/training was so good. She would then be more desirable at other places. I was disappointed when that APRN left, but had the satisfaction of knowing that what she learned from me would make someplace else, and its care, better.

We should use every opportunity to teach. It makes us and those we work with smarter. I start my clinical consult notes with, “Thank you for asking me to evaluate Mr. Jones. I made the following recommendations for the following reasons”.The goal is to make my consult notes educational, but does it work? I think so. When I first started the lipid management clinic at Hartford Hospital in 1997 approximately 5% of patients sent to me for hypercholesterolemia were hypothyroid. So, my first line would be: “I started Mr. Jones on thyroxine 25 mcg daily because his TSH is elevated indicating that he is hypothyroid. Hypothyroidism decreased LDL receptor activity, which reduces the clearance of LDL-cholesterol and increases LDL blood levels.” 

After 24 years of such letters, I almost never have a patient sent to me with hyperlipidemia who is hypothyroid. Are my notes totally responsible? I doubt it, but they may be partly responsible.

You do not have to practice at a teaching hospital to teach. Teaching the nurses and others around you is critically important. It makes their jobs more interesting, but also means that they can help you avoid oversights. Smart staff can also make suggestions to other doctors in the practice to help improve overall medical care.

Dr. Braunwald got it right, as he so often has. Being a good teacher and using every possible opportunity to teach creates an upward spiral for you, your clinical care and knowledge, and your institution. Good teachers should get more credit for the unmeasurable good they do to improve medical care.

1. Lee TH. Eugene Braunwald and the Rise of Modern Medicine.Harvard University Press, Cambridge, MA. 2013

Dr. Paul Thompson reflects on his experiences as a practicing cardiologist, including having the ability to impact early-career clinicians and what he gains when presented with the opportunity to teach other providers. 

Teaching Teaches the Teacher, Where Academia and Clinical Medicine Meet

Over the last 6 months, I have had two patients with more than a heart and lungs in their chest. The first was a retired teacher who developed dyspnea mowing his lawn. It sounded cardiac to me, but his echocardiogram and exercise stress test were normal. I ordered a chest x-ray because, years ago, I had a patient with similar symptoms who turned out to have a paralyzed right hemidiaphragm. 

I was embarrassed by missing that prior patient and, consequently, very proud of myself when the present patient’s chest x-ray showed an elevated right hemidiaphragm. I shipped the patient off to a pulmonologist, who did a radiographic cine sniff test that showed normally moving hemidiaphragms bilaterally, but a very large hiatal hernia. The patient is scheduled for closed hiatal hernia repair because the pulmonologist is convinced that this is the cause of the patient’s dyspnea.

I also recently saw a distance runner with palpitations. He had had palpitations (and gastro-esophageal reflux) for several years but a recent prolonged episode of palpitations sent him to the emergency department (ED). I ordered an event monitor that showed that 10% of his beats were PVCs. His echocardiogram and left ventricular function were normal, but his chest x-ray from the ED showed a large hiatal hernia. Large hiatal hernias have been associated with ventricular ectopy, which was cured by hernia repair.

 We did not pursue hernia repair in this patient because his left ventricular ejection fraction was normal, and he and his wife declined because the patient had early dementia.

So, what’s the point? Consider doing a chest x-ray when patients have dyspnea or frequent palpitations, but no history of lung disease, and a normal cardiac workup. Sometimes there is more in the chest than just a heart and lungs, like a paralyzed hemidiaphragm or most of their stomach.

Posterior cardiac compression from a large hiatal hernia-A novel cause of ventricular tachycardia.

HeartRhythm Case Rep. 2018 May 23;4(8):362-366.

In his most recent column, Dr. Paul Thompson offers perspective on why he feels clinicians should consider performing a chest x-ray in patients with dyspnea or frequent palpitations, but no history of lung disease and a normal cardiac work-up. 

More Than A Heart and Lungs in The Chest, with Paul Thompson, MD

Cardiac non-compaction (NC) can produce a form of cardiomyopathy (CM) typified by deep invaginations of the myocardium caused by an arrest of normal myocardial morphogenesis. NCCM was considered to be rare, but is increasingly diagnosed because of the widespread use of cardiac imaging. Patients with NCCM can present with syncope and systemic emboli believed to originate from clotting in the myocardial invaginations.

Sports cardiologists have suspected that athletes, especially black athletes, have an increased prevalence of imaging evidence of NCCM, but data confirming such a relationship were lacking. De la Chica and colleagues

 evaluated the relationship between physical activity (PA) and the imaging criteria for NCCM in 705 men and women in the Spanish Progression of Early Subclinical Atherosclerosis study (PESA). PA was measured using accelerometry, the gold standard for PA assessment. LV geometry was assessed using cardiac MR.

The diagnosis of NCCM was determined using the Petersen, Jacquier, Grothoff, and Stacey clinical scoring criteria. 1PA was divided into 6 activity groups from the least (0) to the most (5) active. Some of the subjects were very active, but the population was not a population of athletes. The prevalence of NCCM using the most permissive diagnostic criteria (Petersen) was significantly higher in the most active group (30 & 14% in PA group 5 vs 0, respectively).

The prevalence of NCCN was also significantly higher in the most active group using the middle 2 diagnostic criteria (Jacquier & Grothoff), but not different between groups using the most stringent criteria (Stacey). This confirms the clinical impression that more active subjects meet the imaging criteria for NCCM more frequently than the general population. These results should help prevent clinicians from diagnosing NCCM in athletes without supporting data such as a family history of cardiomyopathy, a reduced ejection fraction, or decreased exercise capacity. I have found that athletes can have the excrescences and pits suggestive of NCCM, but that the wall thickness is normal under the “non-compacted” area. In contrast, true NCCM often has wall thinning below the truly non-compacted segment.

Black athletes appear to have more highly trabeculated left ventricles making them more vulnerable to over-diagnosis

 and seem to have the appearance of non-compaction more frequently than whites. I have seen several athletes over my career who were diagnosed with NCCM based on imaging criteria alone and restricted from sports because of the diagnosis. This is never an easy decision, but clinicians should strongly consider the possibility that non-compaction in a healthy athlete, especially a healthy black athlete, is an abnormal image, but not necessarily a disease unless there is other supporting clinical evidence.

One of the most important tenets of medicine is “Do no harm”.An important corollary is “Do not over-diagnose” because it can cause harm. 

Sports participation in non-compaction cardiomyopathy: a systematic review.

 Br J Sports Med. 2014 Oct;48(20):1466-71. 

, et.al.Association Between Left Ventricular Noncompaction and Vigorous Physical Activity.J Am Coll Cardiol. 2020 Oct 13;76(15):1723-1733.

 J. A diagnostic dilemma in non-compaction, resulting in near expulsion from the Football World Cup. Case Reports - Eur J Echocardiogr . 2011 Feb;12(2):E8.

In his latest column, Dr. Paul Thompson offers perspective on the diagnosis and potential overdiagnosis of non-compaction cardiomyopathy in athletes.