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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.