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Is the new professionalism and ACP's new ethics really just about following guidelines?

The Charter ( Medical Professionalism in the New Millennium.A Physician's Charter) did not deal with just the important relationship of ...

Friday, July 22, 2022

Soluble serum transferrin receptor increases acutely after exercise but is not an " acute phase reactant" ?

 At least two research projects in runners and rowers have demonstrated elevation of the soluble serum transferrin receptor after strenuous exercise. and in one of the articles the soluble receptor had returned to normal in 24 hours.

The point to be made is that both reticulocyte hemoglobin content and the soluble serum transferrin receptor are generally said to not be acute phase reactants but technically that is not correct in regard to the Soluble serum transferrin receptor .It does rise acutely but would likely be back to baseline by the time an athlete would be evaluated for anemia. So for almost all practical situations it is not   an  acute phase reactant as the value is likely to be back to baseline by 24 hours.Of course if an endurance athlete does their early morning work out and then goes to lab  that day for a blood draw the serum transferrin receptor level could be elevated misleading the doctor into thinking the test indicated iron deficiency anemia.

So both iron deficiency and acute strenuous exercise can elevate the serum transferrin receptor.With the significant perturbations in certain measures of body iron caused by strenuous exercise two tests have become the go-to tests to differentiate iron deficiency anemia from anemia of inflammation: the reticulocyte hemoglobin concentration and the soluble serum transferrin receptor.The National Kidney Foundation recommends the reticulocyte hemoglobin as the preferred test to detect iron deficiency in renal failure patients.  


1.Auersperger,L The effect of eight weeks of strenuous exercise


2.Skarpansa-Stejnborn A Effect of intense physical exercise on hepcidin  


Addendum:   7/22/22

A 2010 article provides contradictory data. Sim et al (senior author is Peter Peeling) 

In subjects who exercised at 75% of 02 max for 90 minutes were shown to have a decreased soluble serum transferrin receptor at 3 hrs and again at 24 hours. ( The effects of carbohydrate ingestion during endurance running on post exercise inflammation and hepcidin levels. Eur J app Physio nov 2010.

Tuesday, May 10, 2022

Left bundle branch block- new paradigm brewing- echo plus ekg

 Left bundle branch block (LBB) has been defined by various EKG criteria. The pattern of inter ventricular and intraventricular desynchrony cannot be predicted nor the response to CRT based on the EKG..

A patient with a EKG  pattern of LBBB may have a conduction block or delay within the His Bundle system ( intra Hissian block) or distal to the His bundle or some version of a diffuse intra-ventricular conducting defect (s) .

Various criteria have been proposed by the EKG diagnosis of LBBB but no criteria offers 100% predictive value regarding response to cardiac resynchronization therapy  (CRT )but some appear better than others.

CRT is the treatment for heart failure refractory to the usual medical treatment in patients with LBBB. CRT in the form of bi-ventricular pacing is a "work around" essentially replacing one pattern of ventricular dyssynchrony with another less damaging form of non physiological pacing, while His bundle pacing is capable of correcting the abnormal conduction.

The physiological purity of His pacing is undeniable but there are problems which include technical difficulty in placing the electrode in the right place  (the His bundle is small and surrounded by fibrous tissue),  variably high capture thresholds and a certain percentage of cases which later on develop an undesirable high capture threshold.

 Incentivized by the recognition that  although His pacing was beautifully physiologic it had definite problems,  innovatively adventurous EP cardiologists discovered they could advance the catheter further towards the cardiac apex and screw the lead deeply into the interventricular septum and then could pace the left bundle branch thus fixing the LBBB with the apparently minor physiological cost of inducing a right bundle branch block. Further there appeared to be more likelihood of success   as precise localization into the His bundle was replaced by the much less technically demanding job of getting the catheter  in the left bundle branch area, There was the concern and occasional occurrence of pushing too far and placing the lead tip into the left ventricular cavity .If recognized during the procedure the lead could be safely withdrawn.Besides EP cardiologists penetrate the  atrial septum routinely  performing ablations so  poking a small whole in a septum did not appear to be a deal breaker and a some centers Left bundle branch area pacing hasr replaced His pacing.

The term "true LBBB" has been used to indicate the conduction defect that responds well to CRT ( either Bi V or conducting system pacing ( His pacing or left bundle branch area  pacing). Further True LBBB is associated with right to left activation of the interventricular septum  and a  echocardiographic finding referred to as "septal flash"

An important question is which of the several EKG criteria of LBBB best predicts who has a true LBBB and therefore a greater likelihood of benefit from CRT

Calle et al compared the new,more stringent ESC criteria ( 2021) with the older 2013 ESC criteria.They suggest that certain other criteria should be considered;delayed R wave peak time,a septal flash,apcial rocking and a specific septal strain pattern.

Calle has published several papers on this general topic and seems to consider that the echo cardiographic finding of septal flash defines the " true electromechanical LBBB substrate and is predictive of complete reversible re-modeling.


1) Calle,S Defining left bundle branch block according to the new 2021 European Society of Cardiology Criteria.Neth Heart J. 03 May 2022  in their "point of view" section



Sunday, May 08, 2022

The coivid pandemic and one million U.S.deaths have waned my anti progressive,public health antibodies just a bit

 Many decades of reading libertarian and classical  liberal literature and at least semi serious reading of Austrian school economics mixed with mainline Econ101 had for the most fixed my thinking and planted some priors that seemed unlikely to be refuted.

I was disturbed by the movement in medical discourse toward something called population medicine and blogged about traditional medical ethics with a backbone of a fiduciary duty of the doctor to the patient was being challenged by a  mushy, vague admonition for the physician to be responsible not only to the patient but somehow also to be charged with a co-duty that including being responsible for the group.Some how the physician needed to treat his/her physician but to work to heal the village.

Although I  once displayed a certificate of board certification in preventive medicine- a field that includes public health,I had never felt aligned either by experience or philosophical leaning to be a member of the public health tribe. Noticing that it had become an often repeated mindless expression that Disease X,Y or r Z is a public health problem  I blogged that would make nearly everything a public health problem.I do not believe that everything is a public health problem; However, if there is spread of a potentially fatal respiratory illness than is spread by the small aerosol particle routes at times by asymptomatic persons and whose spread can significantly be mitigated by wearing masks then that is a public health problem if there ever was one and covid is one for the ages.

Claims by politicians that wearing masks is just  a personal decision because it only affects the wearer's health is clearly wrong,scientifically wrong and even wrong,IMO,from a libertarian point of view.Hat tip to Nassim Taleb who pointed out the obvious that the fundamental principle of libertarianism is the non-aggression axiom, ie. one does not have to right to initiate force against another human being. The fact that the CDC echoed the pretend conservative-libertarian thought that only the wearer is affected does not make it so and may have been the most shockingly  un public health advice even issued by a public health organization .The CDC began their battle against covid with a egregious technical error in test production and 2 years later topped that with a shape shifting moral error.

All of which brings me to admitting that I have convinced myself that not just out of a survival instinct that mandating masks and vaccines is necessary much as many abrogations of individual freedoms are necessary for a civilized society,

Mandatory vaccination and mandated masing have catalyzed a definite division in libertarian circles .One academic libertarian, Jessica Flanigan Phd has written a lengthy and I think persuasive commentary supporting the idea that mandatory vaccination  is consistent with basic libertarian views .My simplistic view of her argument is that she relies mainly on the nonaggression axiom without explicitly using those words.(Her essay can be found on the HEC forum, online, August 2013 edition. )

Reason is,and ought only to be, the slave of the passions.David Hume 





Tuesday, May 03, 2022

Hemolysis is part of strenuous exercise - it is not a disease

 The intravascular destruction of red blood cells (rbcs) is a normal part of strenuous exercise.It is a feature not a bug of strenuous exercise.A recent review by Lippi and Sanchis-Gomar describes hemolysis as being common place in running and characterizes the intravascular hemolysis as "paraphysiological"  and is "typically mild" with average variations of hemolysis  biomarkers( serum free hemoglobin and haptoglobin) perturbated    between 1.2 and 1.8 times and "self limiting"resolving within 24 to 8 hours.

All types of repeated  strenuous exercise are associated with hemolysis but  more notably so with running usually attributed to foot strike but non contact activities including rowing,swimming and cycling are all known to cause hemolysis.

Foot strike is thought to be a major contributor in running related hemolysis as was demonstrated in an excellent cross over study of hemolysis  in  running and cycling by Telford in 2003. Tri athletes ran and  cycled at 75% of their measured 02 max and serum free hemoglobin was elevated during both activities but  there was significant drop in haptoglobin only after the running session. Methemoglobin , an indicator of oxidative stress, was elevated to the same degree after each exercise.

Red blood cell survival is significantly shorter in runners versus sedentary controls. Chromium labelled RBCs survival is 74 days in runners  versus 115  days in a sedentary control group..

This shortened life span increases need for  RBC production with an associated increase in iron utilization. The 1 to 2 mg of iron absorption per day  normally is balanced against the normal 1-2 mg of iron loss. Endurance athletes will need a larger iron intake.Iron deficiency and iron deficiency anemia have been described not only in runners but cyclists,swimmers and rowers as well is in rugby,tennis and soccer players.

A possible mechanism for increased iron loss secondary to strenuous  exercise induced hemolysis (SEIH) is the following.Hepcidin is stimulated by the increased iron in the blood.Hepcidin decreases the release of iron from duodenal cells into the blood, trapping iron in the enterocytes. These cells live only about 3 days and then shed off which is probably one mechanism by which there increased GI blood loss in runners. Hepcidin also limits iron egress from macrophages and liver cells limiting the supply of iron to the bone marrow at a time when more iron is needed. The more running,the more hepcidin release ,the more iron tapped in the duodenal enterocytes the more iron loss in the stool. So runners and other endurance athletes  loose more iron and need more iron to increase RBC production and need a higher iron intake than a sedentary person.

Arguing against the role of hepcidin is the following: Although hepcidin is definitely elevated acutely several studies have demonstrated that after a period  of time ( 1-2 weeks) the hepcidin levels return to their baseline values.So hepcidin is only transiently elevated  and other studies have demonstrated that hepcidin levels are only elevated in those persons whose ferritin levels are above 30 suggesting that the red blood cell production imperative overrides the hemolysis induced hepcidin increase and any significant exercise related cytokine increase, 

Add to that metabolic supply chain issue a vegan diet in some athletes and menstrual  blood and there is no surprise that there is  iron deficiency and iron deficiency anemia is athletes who take part in repetitive strenuous exercise 

Hemoglobinemia and hemoglobinuria were first described medically in the early 1940s with studies of cross country runners and marathoners describing march hemoglobinuria  although observation of dark urine associated with strenuous exercise was described in the 1880s.

Iron deficiency in athletes is now so well recognized that athletes themselves and coaches and sport Medine doctors all utilize the measurement of blood ferritin levels to monitor iron levels. The 2019 Olympia Committe on Physical examination for athletes including measurement of iron status .One recent study reported that 70% of professional cyclists and competitive rowers had iron deficiency by the end of their seasons. 


"Runners anemia" is the prototype  of an iron deficiency anemia brought about by  the hemolysis associated with  multiple bouts of  strenuous exercise in an individual whose iron intake does not match the increased iron needed for the increased red blood cell production needed to compensate for the shortened average life span  and GIiron loss. Runner's anemia might be more  accurately described as the anemia of repeated strenuous exercise induced hemolysis in the face of inadequate iron intake to compensate for the associated increased iron needs. Or much simply-exertional hemolysis in a person with an iron poor diet. 

                                  



Friday, April 29, 2022

Epidemiologists are finding those thrown under the "we've had it with covid" bus

 

The strange transition of the CDC from a public health authority to a public voice of pseudo- libertarian thought was predicted to have consequences. Their abandonment of their long standing advocacy of protect the vulnerable was predicted to obviously have consequences on the vulnerable who in the context of covid are the  elderly and the immunocompromised and children under five years of age ( the later at least until a covid vaccine is approved for use in that group).

To be clear- the notion that mask wearing protects both the wearer and others was discarded in favor of the advice that mask wearing was an individual choice regarding the individual's assessment of his/her risk, This is strange advice indeed from a public health agency concerning a potentially fatal respiratory illness that may have asymptomatic spread and is spread by aerosol. 

There are now data indicating that some of the vulnerable (elderly even with boosters) are a increasing number of the deaths from omicron  making it not just a pandemic of the unvaccinated. Elderly vaccinated and boosted persons are not well advised to go maskless if they "consider their risk to be low". 


(14) Eric Topol on Twitter: "The headline: "Covid deaths no longer overwhelmingly among unvaccinated as toll on elderly grows" The reason: "The bulk of vaccinated deaths are among people who did not get a booster shot" https://t.co/6VEXi2eWgf by @FenitN @dtkeating" / Twitter

note the Washington Post article above is behind a pay wall so I cannot present the actual numbers.

Wednesday, April 27, 2022

Hepcidin is the major player in anemia of chronic disease but probably not so much in runner's anemia

 Dr. Thomas Ganz,in whose lab hepcidin and later a counter regulatory hormone erythroferrone were discovered,said in a commentary (1) written ten years after hepacin's discovery) that hepcidin maybe an important contributor in runner's anemia.

While at the time that seemed reasonable  based on the knowledge of the function of hepcidin and the finding of elevated hepcidin in runners, subsequently data has been published making hepcidin's role in runners anemia less ikely to be a key determinant 

The purposes of this posting are to  

1)present data showing that while early on perhaps in the first several weeks of an endurance exercise program hepcidin  is increased  after that initial period hepcidin returns to its the level present before imitation of the program. 

and

 2) to consider how mechanistically chronic hepcidin excess would not result in the iron profile pattern of runner's anemia but rather the iron profile  of the anemia of chronic inflammation.

First the stage needs to be set as regards 1) the hematologic physiology of prolonged strenuous exercise with running  as the prototype 2)the actions of hepcidin and 3) how iron travels into, out  of and through the body.

 1) Intravascular hemolysis,the breakdown of red blood cells within the blood circulation, has been repeatedly described in detail by numerous investigators  in runs of various distances and durations.This hemolysis is easily detected by measurement of serum free hemoglobin ( hemoglobulin not contained within  the red cells) and by the protein haptoglobin level which decreases in proportion to the red cell destruction. This is not a new observation , a study in 1943 from Boston demonstrated hemolysis and hemoglobinemia and hemoglobinuria in runners providing some scientific validation of observations made in the 19th century of dark urine following long marches.

 Hemolysis is commonplace in prolonged strenuous exercise of various types and has been well documented in running, cycling,distance swimming,rowing ,rigorous military training and in soccer,tennis and basketball players and in resistance exercise  and should be considered physiologic and a feature not a bug in the wisdom of the body's programming. Culling the older, less flexible and less well hemoglobinized RBCs should facilitate the increased need for more oxygen delivery during strenuous exertion.

Repeated episodes of this brief,self limited and relatively mild hemolysis results in  average life span  of RBC s in runner of about 74 days versus that of the sedentary subject which is 115-120 days. This increased turnover of RBCs requires an increase in iron supply and over time in a person with low oral iron intake can result in iron deficiency and ultimately iron deficiency anemia.Runner's anemia can be explained that simply.

2)Hepcidin is made by the liver and functions as a regulator of iron transport in the body. Hepcidin shuts down or at least slows down the delivery of iron to the bone marrow by blocking iron exit from the duodenal lining cells and from the macrophages, who routinely scavage iron from the hemoglobin of  the aged RBCs,and from the liver cells where iron is stored as feritin.Increased iron levels and inflammatory cytokines stimulate hepcidin release and anemia , hypoxia and increased red cell production decrease its production as do testosterone,increased RBC production ,Epo low iron levels and  the marrow derived hormone, erythroferrone.

3)Iron is absorbed in the duodenum and from there either released into the blood or stored briefly in these enterocytes  only to be sloughed off into the fecal matter as these cells survive only for 3 days.Iron absorption is limited to a few milligrams' per day which balance the daily loss and there is no mechanism by which excess body iron can be eliminated.

The anemia of chronic disease is thought to be a hepcidin excess conditions Inflammatory cytokines,mainly IL6, stimulate hepcidin production. Hepcidin  acting by disabling the ferroportin channels blocks down or markedly slows down the iron highway within the body.The iron egress is blocked from the duodenal cells,the macrophages and the liver cells restricting iron access to bone marrow. The anemia is characterized by low serum iron but elevated ferritin levels making it an anemia of iron restriction rather than iron deficiency. There is more than ample iron overall (the macrophages and liver cells have plenty) but the bone marrow is lacking.

Quoting Larsuphrom 2011 extensive review (2) " Judging from the prevailing evidence acute exercise seem to promote post exercise hepcidin elevation while long term exercise training might attenuate exercise induced increased hepcidin." If you measure urine or blood hepcidin after a long run hepcidin will be elevated. However, if you measure hepcidin on a runner several weeks into a training program the initial elevation of hepcidin returns to pre exercise levels. Research from Auersperger and from Moretti ( see reference no 2 for citations) indicate that hepcidin levels are not chronically elevated in endurance athletes. The baseline ferritin may be a key factor in the hepcidin respond to strenuous exercise. Peeling ( see ref 45 in my ref 2) found that increased hepcidin only occurs  in subjects whose baseline ferritin levels were greater than 30. This suggests that the biological systems that favor red blood cell  production may trump the hepcidin imperative to conserve iron .

An outliner to the above is the study authored by Dzerzej  et al  (4) in 2016 in which they presented data from hepcidin blood levels in professional basketball players before and then 2 days after a competitive season which showed levels were elevated at the end of the season implying a chronic elevation              of hepcidin.

Runner's anemia ( better named exertional anemia ) results from increased iron requirements due in  part ,( perhaps mainly to hemolysis) in a subject whose iron intake does not meet the increased need that occurs with prolonged and repeated strenuous exercise.It can be mechanistically explained without invoking a key role for hepcidin while admittedly the acute increase in hepcidin  (stimulated both by ILa 6 release during exercise and the hemolysis release of iron into the blood) and its effect to slow down release of absorbed iron into the blood could be contributory.See below for possible exceptions to tht generalization.

Incidence of iron deficiency is said to 30 to50% in endurance athletes.

Note- there is another runner's anemia also called pseudo anemia. This condition is a decreased hematocrit due to an increased plasma volume which is a regular adaptation to endurance exercise in excess of the overall increase in blood volume secondary to endurance exercise.It is typically associated with an increased MCV (mean red cell volume) likely due to an increased number of younger larger RBCS.

Serum iron levels, typically clinically measured as serum ferritin, is often the first thing an endurance athlete  or the coach or a sports medicine specialist  think about when exercise performance  does not meet expectations.

There is a subset of the anemia of repetitive strenuous exercise (ARSE) in which hepcidin may actually be contributory. If a person exercises repeatedly at a high  level of intensity with inadequate calorie intake to maintain body weight there may be chronic elevation of hepcidin,There is strong evidence that glycogen depletion stimulates hepcidin production and that subjects in this calorie deficient high exercise state may also poorly absorb iron.Recent extensive research by S R Hennigar and others on military personnel in simulated military maneuvers provides an example illustrating this concept.see ref 3). 

Also  James P McClung et al reported elevated hepcidin in military personnel after a 7 day training  event. The level of exercise and the reported food intake strongly suggested they were caolrie defecit and likely glycogen depleted. 

Further a report of chronically elevated hepcidin in runners who had twice a day workouts (I have misplaced the article but will add it evidence later)



1) Ganz,T Hepcidin and iron regulation 10 years later.Blood 2011 Aug 28 117 4425-4433

2)Larsuphrom,P Association of serum hepcidin levels with aerobic and resistance exercise.Nutrients 2021 jan 27 393

3)Hennigar,SR et al Energy deficit increases hepcidin and exacerbates  decline in dietary iron absorption Nutrition 113, Feb 20211 

4)Dzedej,A The effect of a competitive season inProfessional basketball on inflammation and iron metabolism. Biol of Sport 2016 May online


addendum . July 6 2022  The last paragraph added after learning about Hennigar's and similar

 publications.

Monday, March 14, 2022

Europe is surging again so will the U.S. "wall of immunity" prevent another spring surge.

 As of early March 2022 cases and hospitalization are increasing in several European countries.

Data from Great Britain indicate increases in cases in all age groups and in all parts of the country.See Eric Topol's wonderful twitter feed for detailed data on the European uptick in cases,etc

The hope of many is that in the US the "wall of immunity" is sufficiently robust to prevent further surges.The wall is built on immune protection from vaccines,boosters and infection which, it must be said are known to wane over time. The elderly were a group who received the vaccination and the boosters fairly early so now in England there is a plan for the 4th shot, not so for the US so far.

The US's waves of  alpha,delta,omercron were preceded by waves  in GB and Europe . Maybe now this is different but I struggle to find a reason why. The surges seem to be attributed to some combination of increase in the BA 2 variant,cessation of masking,etc and the waning of immunity all factors seemingly applicable to the US. Actually in one regard GB 's "wall" may be stronger since  90 % of their elderly has been triply vaxed versus 65  % in US.

The much talked about objective of "protect the vulnerable" has largely faded away but the numbers of the vulnerable have not.There are 100 million not vaccinated,seven million with various immunocompromised conditions and millions of kids currently too young for vaccination and the US lags behind Europe in the percent of the elderly who have received the booster shots. What could possibly go wrong?



EKG criteria for differentiation of non-selective His pacing from RV septal capture

 Dr. Marek Jastrzebski has written extensively on the differential diagnosis of  non selective His Bundle pacing (Ns HBP)  versus myocardial only capture.

In Ns HBP  not only is the His bundle captured but also  is a segment of the myocardium in the IV septum.The ORS morphology is influenced by the signal from the captured segment of myocardium  and the electricity traveling along the His Bundle  resulting in  a fusion beat.

His diagnostic algorithm is:

is there QRS notching in lead I v5 or v6 if yes then there is myocardial pacing

If no ,, then ask is the v6RWPT greater than 100 msec if yes then there is myocardial pacing.


However, there are false positives in the use of the notching rule wherein there may be QRS notching in cases of confirmed His Capture. particularly in cases of LBBB. A non corrected intra-hisian conduction defect resulting  in a prolonged HV interval may occasionally result in Lateral lead QRS notching.

 

1)Jastrzebski M, ECG Pacing criteria for differentiating conduction system pacing from myocardial pacing.Arrhythmia and Electrophysiology Review June 2021 p 172