Apha One Anti trypsin deficiency

[GreenGully]

Anyone out there with any knowledge of this condition? I have it, and have few symptoms (and no signs of emphysema at 28). It isn't actually an autoimmune disease, but it does affect the immune system.
As a side note I have tested positive for antinuclear antibodies and there is a history of Lupus, Rheumatoid arthritis (that is the autoimmune one right?) and Scleroderma in my family. I am unsure what being ANA positive actually means, my specialist seems to think in the absence of other symptoms that it shouldn't be a problem, though I wonder if it is ever a precursor to developing something later in life.

[Momtezuma Tuatara]

Can you tell us what you know already, about it please?

[GreenGully]

lol, sure, that'd be a good start!
My history first. I was diagnosed as an infant via liver biopsy, after I developed severe liver scarring/inflamation. My phenotype is ZZ null, which is very rare. I have seen various gastroenterologists (sp) sporadically throughout my life, though I have started having yearly check ups in recent years and hopefully I will be able to continue seeing the new one I have (they keep moving hospitals). My liver function has been fine since I was around 15 I think. My new specialist ordered a million blood tests last year for all sorts of things (not that I understand what most of them were - but mostly related to the liver and related diseases I think) and that was when the ANA was picked up. My understanding of the condition is pretty much what is written here (http://en.wikipedia.org/wiki/A1AD).

The thing I am most interested in, is whether there is a real case for ABs to be used in the case of lung infestions. I know that in the US that ABs are taken preventatively by some patients, a concept I find quite scary.

[deesalie]

I wonder how the TCM herb Cordeyceps would work in a situation like this? It's excellent support for lung function. Obviously, best to check with a TCM practitioner though.

[Momtezuma Tuatara]

Have they worked out your percentage function?

Where do you fit on this scale of things?


In individuals with PiSS, PiMZ and PiSZ phenotypes (http://en.wikipedia.org/wiki/Phenotype), blood levels of A1AT are reduced to between 40 and 60% of normal levels. This is sufficient to protect the lungs from the effects of elastase (http://en.wikipedia.org/wiki/Elastase) in people who do not smoke (http://en.wikipedia.org/wiki/Tobacco_smoking). However, in individuals with the PiZZ phenotype, A1AT levels are less than 15% of normal, and patients are likely to develop emphysema (http://en.wikipedia.org/wiki/Emphysema) at a young age; 50% of these patients will develop liver cirrhosis (http://en.wikipedia.org/wiki/Cirrhosis), because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy (http://en.wikipedia.org/wiki/Liver_biopsy) in such cases will reveal PAS (http://en.wikipedia.org/wiki/Periodic_acid-Shiff)-positive, diastase (http://en.wikipedia.org/wiki/Diastase)-negative granules.
Cigarette (http://en.wikipedia.org/wiki/Cigarette) smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory (http://en.wikipedia.org/wiki/Inflammation) reaction in the airways (http://en.wikipedia.org/wiki/Airway), cigarette (http://en.wikipedia.org/wiki/Cigarette) smoke directly inactivates alpha 1-antitrypsin (http://en.wikipedia.org/wiki/Alpha_1-antitrypsin) by oxidizing (http://en.wikipedia.org/wiki/Oxidation) essential methionine (http://en.wikipedia.org/wiki/Methionine) residues to sulfoxide (http://en.wikipedia.org/wiki/Sulfoxide) forms, decreasing the enzyme (http://en.wikipedia.org/wiki/Enzyme) activity by a factor of 2000.

[Momtezuma Tuatara]

Hmmmm it seems that this is one occasion when paracetamol is likely to help, BUT this is the first time I've seen an admission that paracetamol suppresses the immune system:



As α1-antitrypsin is an acute phase reactant (http://en.wikipedia.org/wiki/Acute_phase_reaction), its transcription (http://en.wikipedia.org/wiki/Transcription_(genetics)) is markedly increased during inflammation (http://en.wikipedia.org/wiki/Inflammation) elsewhere in response to increased interleukin (http://en.wikipedia.org/wiki/Interleukin)-1 and 6 and TNFα (http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha) production. Any treatment that blunts this response, specifically paracetamol (http://en.wikipedia.org/wiki/Paracetamol) (acetaminophen), can delay the accumulation of A1AT polymers in the liver and (hence) cirrhosis (http://en.wikipedia.org/wiki/Cirrhosis). A1AD patients are therefore encouraged to use paracetamol when slightly to moderately ill, even if they would otherwise not have used antipyretics (http://en.wikipedia.org/wiki/Antipyretic).

funny what they say, under "abnormal" circumstances, innit?

[Momtezuma Tuatara]

Okay, so ZZ-null is very rare, so are you in uncharted waters? I've read the others up, http://www.alphaone.org/alphas/?c=01-What-is-Alpha-1-Alphas and you appear to be unique :D so on this basis below (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2441617), what are you?


An issue further supported by the observation that individuals with SZ and SS genotype (although significantly less clinical information is available about SS type patients), who on average have higher levels of alpha-1-antitrypsin than the Null and Z genotype, are less prone to the development of emphysema [20 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2441617#B20)].

Now this is interesting:
The Alpha1 International Registry (AIR) database contains patients over age 40 with a smoking history of more than 10 packyears and Z genotype who have a completely normal lung function, including normal forced expiratory volume in the first second (FEV1) and normal gas transfer [22 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2441617#B22)]. This suggests that protective factors may exist, an issue that is currently under intense investigation.

so it's not at all cut and dried, is it?

[Momtezuma Tuatara]

This is interesting http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2441617

[Momtezuma Tuatara]

I would say that any baby born with this should never receive the Hepatitis B vaccine at birth... okay... what is your "clinical status"?

In otherwords, how does it affect you day to day?

[GreenGully]

0% is my production level according to my childhood medical notes. I am apparently rare - there was talk of me going to the US to be a part of studies when I was a child, but that didn't eventuate. Apparently there are no people documented with the null phenotype with liver disease (because there is no mutant/dysfuctional protein building up in the liver) but I did as an infant, so I wonder if it is a reference to adult liver disease only. It would explain my happy liver today - at 12 I was told to expect to need a liver transplant in the next 5 years (my liver was enlarged at the time) but I just didn't get sick. I did have my phenotype rechecked by my new specialist - he said yes, just as we thought, ZZ, but he didn't mention the null component (which is in my notes and I recall being dicussed by my specialist when I was a child so I assumed he meant that too) so I will clarify that at my next appointment (May this year).

Thank you for finding those articles for me. Very interesting about the paracetamol, you'd think you would be best avoiding it with a liver disease.

Ok, right now I am well and have been since I was a teenager (which generally confuses the drs when they realise how ill I was as an infant). My most recent ultrasound showed that my spleen was just inside the range of normal - almost enlarged, which was unusual for me as it is normally perfect. So something may be going on with my liver, despite the fact it is seeming to function properly. The only symptoms I get are less specific things like insomnia and irritability (which could be unrelated afterall).

I suppose I have mostly been able to ignore the fact that I have the condition because I don't ever recall being sick. But I am am getting closer to 30, when the risk of developing problems with my lungs increases. I have never ever smoked (thank goodness) and I stopped getting the recommended flu vax when I was 18 (and not had influenza since). I really want to find ways to protect my lungs especially (and if I do indeed have the null phenotype this is particularly important to me) that don't involve abs and vaccinations. I do take vit C, echinacea and OLE when I get sick and use some homeopathics if I feel I need. I don't often get fevers (and I don't check temps anyway) and I would normally let one run its course and do what its job, however I wonder if this is really the best thing (for me) having read the above links. Lots to think on, thank you Hilary for taking the tiem to respond and read up on this!

[GreenGully]

I should add that I have recently moved to live near my father (who is SZ) for the first time in my life and he has both cirrhosis and emphysema. He isn't exactly a wealth of knowledge (he knows less than me about the condition and isn't interested in making life changes to improve his chances of living longer), but he is demonstrating for me what could happen. It is hard to ignore when it is in your face all the time, which isn't neccessarily a bad thing cos it is prompting me to try to research NOW before it is too late etc etc. I certainly care for my body much more than my father (he is an alcolholic and ex smoker) so I think I am slightly ahead there.

[Momtezuma Tuatara]

[/URL]

My brain is going ten to the dozen on this one, because if this "disorder" is so common, and causes liver cirrhosis, then why do doctors "always" blame Hepatitis B virus alone? Questions need to be asked as to whether the people who get liver cirrhosis after hepatitis B have AAT, and THAT is actually the trigger, because the majority of people who get hepatitis B as an infection never progress to carriage, liver cirrhosis or cancer.

This whole issue raises a lot of unanswered questions in my mind.

First, the issue of paracetamol surprises me, but it shouldn't, since doctors have always suggested a lot of strange things. Sometimes suggestions are empirical, as in, "Well, we know paracetamol suppresses the immune system (but we wont tell mothers that) and if that reduces anything with Il6 etc, theoretically that could reduce the damage done in the lungs."

When they talk about antibiotics they don't KNOW that antibiotics will help. They are speculating that theoretically, they could. Where are the studies which prove that? Look at page 2 here (http://www.medicinesformankind.eu/upload/pdf/E_antitrysp.pdf) .

Look at this atrocious admission here


Research groups are studying the development of small molecule inhibitors to block the polymerisation of Z AAT. These advances in the understanding of the basic mechanisms of inflammation will allow the development of novel anti-inflammatory therapies for a variety of lung diseases. how does drug application inhibiting polymerisation of Z AAt advance the understanding of basic inflammation mechanisms? Shouldn't they actually KNOW the basic mechanisms of inflammation? After all, if you DON'T know those basics, anything else you do is simply a stab in the dark. Called "science"....

[URL]http://emedicine.medscape.com/article/295686-overview

the very fact that a lot of people with this disease do not progress to COPD, tells me that "epigenetics" is a major factor.

What is it, that is different for children, than adults? There is some "switch" that results on someone suddenly developing problems.

If I was in your position, I wouldn't take paracetamol, because I know what else it does to the liver besides, causing hormonal upsets, which can result in migraines and rebound migraines, so it wouldn't be an option.

I'd be looking at the role of free radicals and a whole lot of other stuff.

Your history already gives cause for considerable optimism, as you continue to prove their predictions wrong.

[Momtezuma Tuatara]

Thank you for bringing it up. I'm putting up a list of things on my notice board that I want to look at with regard to it, and I will add them to this thread as I find them. Because AAT ranks along with Down's and Cystic Fibrosis, I think it needs close scrutiny. There's a lot of hypothesis in what I've read this morning, and I'm not happy with all their assumptions.

[GreenGully]

Yes, this is what frustrates me the most, none of the known treatments, including ABs and plasma transfusions of the protein ( which are not available in Australia as far as I am aware) have been proved to actually help at all.

And yes, I certainly have blasted the predictions out of the water as I was initially given 2 weeks to live when I was born.

thank you again!

[Momtezuma Tuatara]

You know, oxidation could be the key, which might be why cigarette smokers can get sick so fast. This article which I put above, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2441617 says,


Here is where the most important amino acid is present, a methionine in position 358, an aminoacid susceptible to conversion to methionine sulfoxide by oxidants from cigarette smoke, rendering it much less potent as an inhibitor of neutrophil elastase



I note they also mention alcohol which is a massive free radical producer.


Theoretically, that might be one key. What can you do to make sure that you have as high levels of anti-oxidants as possible?


Obviously fruit and vegetables are very important, but I'm wondering if something like www.moxxor.com (http://www.moxxor.com) which is supposedly the world's most potent anti-oxidant, might be worth considering, though obviously the 83% of those mentioned below, probably did nothing much at all.

But it is theoretically possible that people who really look after their nutrition etc will, as the end of the article says,



Patients who have never smoked and who are detected by screening of affected family members turn out to have a normal life expectancy. Most of these AATD individuals (83%) are clinically healthy throughout adulthood and most will have liver enzyme abnormalities in early life.




So, it could be that if you get the basics right, you can shrug your shoulders and say, "So what?"

[Momtezuma Tuatara]

none of the known treatments, including ABs and plasma transfusions of the protein ( which are not available in Australia as far as I am aware) have been proved to actually help at all.

Yet there is always the assumption that doing something, is better than doing nothing, even if 83% of those identified through testing after a family member is diagnosed, do just fine. :giggle:

[Momtezuma Tuatara]

There are 23 studies being done http://clinicaltrials.gov/ct2/results?term=Alpha+1-Antitrypsin+Deficiency . This one below, is only one...

http://clinicaltrials.gov/ct2/show/NCT00571272?cond=%22Alpha+1-Antitrypsin+Deficiency%22&rank=20

[Momtezuma Tuatara]

1: Swiss Med Wkly. (javascript:AL_get(this, 'jour', 'Swiss Med Wkly.');) 2008 Apr 5;138(13-14):191-6.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.smw.ch-docs-images-pubmed-smw_link_pdf.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3671&itool=AbstractPlus-def&uid=18389391&db=pubmed&url=http://www.smw.ch/dfe/set_archiv.asp?target=2008/13/smw-11991) Links (javascript:PopUpMenu2_Set(Menu18389391);)

Alpha-1 antitrypsin: now available, but do we need it?

Russi EW (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Russi%20EW%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Pulmonary Division, Department of Internal Medicine, University Hospital, Zurich, Switzerland. erich.russi@usz.ch
Severe alpha1-antitrypsin (AAT) deficiency is the best characterised genetic risk factor for the development of emphysema. AAT has a wide spectrum of antiprotease activity and its primary function is inhibition of neutrophil elastase in the lung. Smokers with this genetic defect develop severe impairment in their fifth to sixth decade of life. Intravenous administration of human AAT is well tolerated and has been shown to increase the levels of AAT in the alveolar lining fluid of individuals with this deficiency. In contrast to the proof of the biochemical effectiveness of augmentation treatment, the favourable clinical effect of AAT on pulmonary function, emphysema progression, morbidity and survival has not been persuasively demonstrated by prospective controlled clinical trials and remains controversial.
PMID: 18389391 [PubMed - indexed for MEDLINE]

Related Articles


ReviewEmphysema in alpha1-antitrypsin deficiency: does replacement therapy affect outcome? (http://www.ncbi.nlm.nih.gov/pubmed/15725045?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedreviews&logdbfrom=pubmed) [Treat Respir Med. 2005]
ReviewAlpha 1-antitrypsin deficiency: memorandum from a WHO meeting. (http://www.ncbi.nlm.nih.gov/pubmed/9447774?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedreviews&logdbfrom=pubmed) [Bull World Health Organ. 1997]
ReviewAugmentation therapy in alpha-1 antitrypsin deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/18352854?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedreviews&logdbfrom=pubmed) [Expert Opin Biol Ther. 2008]
ReviewAralast: an alpha 1-protease inhibitor for the treatment of alpha-antitrypsin deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/17931094?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedreviews&logdbfrom=pubmed) [Expert Opin Pharmacother. 2007]
Strategies for aerosol therapy of alpha 1-antitrypsin deficiency by the aerosol route. (http://www.ncbi.nlm.nih.gov/pubmed/2117165?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed) [Lung. 1990]

» See Reviews... (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed_reviews&LinkReadableName=Related Reviews&IdsFromResult=18389391&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&log$=relatedreviews&logdbfrom=pubmed) | » See All... (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&LinkReadableName=Related Articles&IdsFromResult=18389391&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&log$=relatedarticles&logdbfrom=pubmed)

[Momtezuma Tuatara]

Expert Opin Biol Ther. (javascript:AL_get(this, 'jour', 'Expert Opin Biol Ther.');) 2008 Apr;8(4):515-26.http://www.ncbi.nlm.nih.gov/corehtml/query/egifs/http:--www.expertopin.com-templates-jsp-_midtier-_ashley-images-Ashley100x25.gif (http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3204&itool=AbstractPlus-def&uid=18352854&db=pubmed&url=http://www.expertopin.com/doi/abs/10.1517/14712598.8.4.515) Links (javascript:PopUpMenu2_Set(Menu18352854);)

Augmentation therapy in alpha-1 antitrypsin deficiency.

Heresi GA (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Heresi%20GA%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Stoller JK (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Stoller%20JK%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).
Respiratory Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
BACKGROUND: Alpha-1 antitrypsin deficiency is a genetic disorder that leads to early-onset emphysema. Recently, exogenous supplementation of the enzyme has become a therapeutic alternative. OBJECTIVE: To review the role of so-called augmentation therapy with pooled human plasma alpha-1 antitrypsin as a specific treatment for emphysema caused by alpha-1 antitrypsin deficiency. METHODS: The authors performed a Medline (1966 - 2007) search with the keywords 'alpha-1 antitrypsin deficiency' and 'therapy'. The authors focused on articles regarding biochemical and clinical efficacy. RESULTS/CONCLUSION: Augmentation therapy has been shown to raise antiprotease serum and epithelial lining fluid levels above the 'protective threshold' value. Evidence suggests that this approach slows the decline in lung function, could reduce infection rates, might enhance survival, and is well tolerated. Questions about the cost-effectiveness of this therapy remain.
PMID: 18352854 [PubMed - indexed for MEDLINE]

Related Articles


ReviewEmphysema in alpha1-antitrypsin deficiency: does replacement therapy affect outcome? (http://www.ncbi.nlm.nih.gov/pubmed/15725045?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=1&log$=relatedreviews&logdbfrom=pubmed) [Treat Respir Med. 2005]
ReviewLung disease due to alpha 1-antitrypsin deficiency. (http://www.ncbi.nlm.nih.gov/pubmed/9363132?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=2&log$=relatedreviews&logdbfrom=pubmed) [Curr Opin Pulm Med. 1996]
ReviewAlpha-1 antitrypsin: now available, but do we need it? (http://www.ncbi.nlm.nih.gov/pubmed/18389391?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=3&log$=relatedreviews&logdbfrom=pubmed) [Swiss Med Wkly. 2008]
Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. (http://www.ncbi.nlm.nih.gov/pubmed/11243951?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=4&log$=relatedarticles&logdbfrom=pubmed) [Chest. 2001]
Biochemical efficacy and safety of a new pooled human plasma alpha(1)-antitrypsin, Respitin. (http://www.ncbi.nlm.nih.gov/pubmed/12114340?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&linkpos=5&log$=relatedarticles&logdbfrom=pubmed) [Chest. 2002]

» See Reviews... (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed_reviews&LinkReadableName=Related Reviews&IdsFromResult=18352854&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&log$=relatedreviews&logdbfrom=pubmed) | » See All... (http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&DbFrom=pubmed&Cmd=Link&LinkName=pubmed_pubmed&LinkReadableName=Related Articles&IdsFromResult=18352854&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsP anel.Pubmed_DiscoveryPanel.Pubmed_Discovery_RA&log$=relatedarticles&logdbfrom=pubmed)

[Momtezuma Tuatara]

Here is an interesting article. http://ajrccm.atsjournals.org/cgi/content/full/173/10/1072

So tell me what this means :lol

Over the centuries of evolution and in the preantibiotic era, the largest threat to man has been infectious disease; pneumonia, tuberculosis, influenza, and gastroenteritis accounted for 40% of all deaths in the United States in 1900. Thus, more inflammation would lead to a more rapid clearance of infection and a higher chance of recovery. The risk of death from liver disease in childhood, even in a Z http://ajrccm.atsjournals.org/math/alpha.gif1-antitrypsin homozygote, is relatively small (1–2%) and so would not itself cause a significant depletion in allele frequency given that infant mortality in the United States and Europe in 1900 was 100–140/1,000 live births. Moreover, the average life expectancy in the middle of the 19th century was 43 years (www.prb.org (http://www.prb.org/)), and so the risk of emphysema at ages 50 to 60 years was not sufficient to negate the protective advantage against infectious disease. Finally, the most significant factor in driving lung inflammation, tobacco smoking, was not widely adopted until this century (51 (http://ajrccm.atsjournals.org/cgi/content/full/173/10/1072#BIB51)). Thus, the proinflammatory response of the Z http://ajrccm.atsjournals.org/math/alpha.gif1-antitrypsin allele (most probably driven by polymers) was likely to be hugely advantageous to a population living with malnutrition, poor housing, overcrowding, poor sanitation, and the high risk of infectious disease that for many characterized the preantibiotic era. Only since the advent of improved living standards, antibiotics, increased longevity, and smoking has this previously protective allele become a disadvantage.

[GreenGully]

Very interesting! Thank you!