Unfolded Protein Response and A Possible Treatment for CFS

[mariovitali]

There are a number of SNPs which increase the risk of biliary cirrhosis:

rs7574865 (risk T)
rs6441286 (risk G)
rs7774434 (risk C)
rs9303277 (risk T)
rs3745516 (risk A)
rs10488631 (risk C)
rs4979462 (risk T)

From the above list, rs10488631 and rs7574865 are also associated with a host of autoimmune diseases.
I found these SNPs by searching in Promethease for "cirrhosis".

One homozygous, 3 heterozygous here.

 

[skwag]

I've got 4 homozygous from the list of 7.

 

[mariovitali]

I've got 4 homozygous from the list of 7.

Wow...

OK So the question is : How likely it is that someone has problems with the Liver while a Liver Panel (non-invasive) suggests otherwise.

It would be great if you can ask a Liver Specialist about this one, i will try the same.

 

[mariovitali]

I think we should all read this :


http://www.inl.asia/resources-main-navigation-bar/the-liver-a-detoxification-part-2

 

[ahmo]

2 homo, 2 hetero here. With autoimmune issues, but neither of the snps you correlate w/ autoimmune.

I discovered a couple years ago that coffee enemas are brilliant for my liver. Much of my healing in this time was due to using CEs to assist my liver in dealing w/ releasing toxins. Quite clearly, my adrenals also were greatly benefited from this. Overloaded liver led to adrenal distress and symptoms.

 

[skwag]

Wow...

OK So the question is : How likely it is that someone has problems with the Liver while a Liver Panel (non-invasive) suggests otherwise.

Very roughly speaking, each risk allele of the seven SNPs listed here

rs7574865 (risk T)
rs6441286 (risk G)
rs7774434 (risk C)
rs9303277 (risk T)
rs3745516 (risk A)
rs10488631 (risk C)
rs4979462 (risk T)

increases the risk of biliary cirrhosis by a factor of 1.5. Being homozygous for four of them, my total risk is approximately 25x. For @mariovitali 7.5x. And @ahmo, 11x.

Of course, to get a more accurate number you need to dive into the research, but this provides a first approximation.

I wish I knew the answer to your question mario, but my guess is it is quite common to have compromised liver function while blood tests come back ok.

Edit: I believe total risk should be calculated by multiplying the risk factors. So for me, with 8 risk alleles, total risk equals (1.5)^8. I managed to mess up this calculation a few times, but hopefully now I've got the idea right, at least.

 

[Valentijn]

@skwag - Here's the prevalence rates for these SNPs in the general population
rs7574865 (risk T) 6.5% TT, 38% GT - OR 1.35 per allele [1]
rs6441286 (risk G) 14% GG, 47% GT - No correlation [1] OR 1.54 per allele [3]
rs7774434 (risk C) 21% CC, 50% CT - OR 0.64 per T allele [1] (Reduced risk for the rarer T allele in the ethnic sample studied, but it's the more common allele elsewhere), OR 1.6 per C allele [4]
rs9303277 (risk T) 21% TT, 50% CT - OR 1.44 per allele [1]
rs3745516 (risk A) 31% AA, 50% AG - No correlation [1] OR 1.46 per allele [2]
rs10488631 (risk C) 0.35% CC, 11% CT - OR 1.63 per allele [2]
rs4979462 (risk T) 3.5% TT, 21% CT - OR 1.57 per allele [1]

[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3484650/ supplement
[2] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150510/
[3] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2857316/
[4] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071550/

rs6441286 and rs3745516 are suspect due to the largest and most ethnically diverse study/review contradicting the smaller ones. False positives are very common in these sorts of studies, and unless a correlation is holding up in other studies (like [1]), you can't read much into them.

 

[skwag]

rs6441286 and rs3745516 are suspect due to the largest and most ethnically diverse study/review contradicting the smaller ones. False positives are very common in these sorts of studies, and unless a correlation is holding up in other studies (like [1]), you can't read much into them.

Excellent. You've dropped my risk to either 4x or 10x, depending on how rs7774434 is interpreted. I can feel the bile flowing again.

Much appreciated.

 

[jump44]

Been on regimine about amonth now

250mg TUDCA
100mg resveratrol 3-4x per wk
choline/inositol 25omg each 3-4x per week
betaine digestive enzymes
fmn taking 1/4 pill 2-3x/wk
selenium 100mcg
also on LDN .7 mg./nite
ubiquinol 200mg
B12 3-4 x/week 1000mcg
folate 1-2x/wk 400-800mcg

So last week had a bit of a "crash", kidneys got sore(happens to me from time to time) I say kidneys but may be adrenals. My only problem when On a regimine like this is you cant really tell whats causing what.. I stopped Tudca for a few days and soreness went away..but then came back at beginning of this week. so added Tudca back in and its been gone again. I had a drinking session the previous weekend and also ate some very bad foods haha, so perhaps this was the cause. Anyways this weeks been much better. Last night on a whim I took some niacinamide before bed, and had taken some FMN earlier in evenign. Well today my mood is much improved and feel energized. @mariovitali, is there any connection w niacin/niacinamide with any of this? Its a supplement that I take from time to time and it provides a noticeable boost, but it seems to fade with consistent dosing.. Of course it could just be random and the ldn is starting to really kick in etc etc...who knows? haha but overall I feel improved Id say so far 20-30percent since I started. I have had setbacks but I think theyve been of my own doing,(hey have to live a little every now and again).

I see theres been some arguing. I think the genetic path is a good route to investigate and obviously understand the skepticism but I think w this illness unless you are willing to take certain risks and experiment a little you are essentially giving up. anyways just my 2 cents, and I think ultimately we all want the same thing-to be rid of this crap disease or at least have a better quality of life. Anyways so far marios treatment has helped me a lot more than almost all other things Ive tried. Ill keep updating.

 

[mariovitali]

@jump44

I believe that TUDCA 250 mg per day is too low of a dose. Could you up that to 500 mg per day? I also see that you take Folate 1-2 times per week? May be this is again too low of a dose. If possible try taking 800 mcg per day. The same applies for FMN (take 1/4 tablet per day). The same for Choline/Inositol.

I am currently looking also to Niacin (you will understand why later in this post).

In other words take these supplements on a daily basis and re-evaluate how you feel. Please have in mind that there will be "crashes" however they will become less frequent and less evident as time passes by.

@skwag @jump44 @Ema @Gondwanaland @Violeta

I will add one more Topic to the "mix" of this Thread which is Phase I and Phase II Detox Pathways. This information will be also added to the new document i sent earlier.


Please have a look at the following chart :

URL : http://www.bespokeclinic.ca/wp-content/uploads/2015/02/integrativefig_large31.jpg


Note how many supplements/vitamins are shown and which of them i am using or have used.

What i also believe should be looked at at the individual level are the Phases of Detox Pathways namely Phase I and Phase II.


1) Notice that Phase I consists of P450 Enzymes which exist on the Liver AND the Gut.
2) Notice that Methylation is a Phase II Reaction. But there are *so* many other reactions (Sulfation, Glucuronidation,Acetylation, etc). needless to say (Edit : My Theory) that Genes associated with these functions should be also looked at (e.g NAT2 => Acetylation, UGT1A9 => Glucuronidation etc)
3) Metabolites of Phase I are ROS which we know is not good to have too much of them around. If you have a slow Phase II which cannot keep up with metabolites of Phase I, you will have problems.
4) Recall that on the first page of this Thread P450 Inhibitors are mentioned (which slow down Phase I).
5) If you have a slow Phase I and Induce it (say with Indole-3 Carbinol) you may feel better but also you may feel much worse in the event that your Phase II is slow (The metabolites of Phase I will burden the sluggish Phase II)

So i believe that each one of us should identify how this system works. If for example you find out that your Phase II is slow, Phase II Inducers may make you feel much better. At the same time, you also must avoid anything that slows down Phase II Pathway.

A Nutrihacker or Detox profiling report may help you on that.

@jump44 Did you see Niacin been used as a Phase I vitamin?

As a final note, please see this link


http://forums.phoenixrising.me/index.php?threads/three-years-and-no-diagnosis-frustrated.36414/

and then this

http://forums.phoenixrising.me/index.php?threads/primary-billiary-cirrhosis.33429/#post-516730

Fortunately this particular member did not have a Primary Biliary Cirrhosis but NAFLD

Search the forum for Topics like NAFLD and increased Bilirubin and Liver-related problems.


From the same member :


http://forums.phoenixrising.me/inde...his-test-result-mean.36944/page-2#post-590982

So, Normal Liver values apart from GGT .

 

[ahmo]

I've been using FMN sublinguals. Can anyone verify that r5p is exactly the same? I've just begun applying it transdermally, instead of sublingual. Seems to be more effective, and seems to be demonstrating antioxidant properties. I'd like to get rid of the stickiness of these sublinguals, and would love it if this r5p is equivalent. Thx.

 

[skwag]

I've been using FMN sublinguals. Can anyone verify that r5p is exactly the same? I've just begun applying it transdermally, instead of sublingual. Seems to be more effective, and seems to be demonstrating antioxidant properties. I'd like to get rid of the stickiness of these sublinguals, and would love it if this r5p is equivalent. Thx.

The Wikipedia entry suggests FMN and R5P are identical.

The Thorne R5P contains R5P-sodium. I don't know whether this makes any difference, but I doubt it. I've tried the Douglas R5P and did not notice anything different from the Source Naturals. They both didn't do a whole lot for me. Hope you have better luck.

 

[mariovitali]

@skwag @ahmo

This is a run for FMN PubMed entries, note that both algorithms select "Pyridoxal 5 phosphate" (shown in red rectangle) as a Statistically Significant Phrase:

I then search for a possible association between FMN and P5P and i find this :


http://forums.phoenixrising.me/index.php?threads/enteric-coated-p5p.31531/#post-483880

Perhaps @skwag you could try taking FMN along with P5P.

 

[mariovitali]

Please find attached a new version of the document that summarizes this Thread.


Of course a lot more work has to be done but i included new genes and also sections for Phase I and Phase II Detox Pathways.

 

[ScottTriGuy]

Hi @mariovitali

From your OP:
"STAY AWAY From: P450 Inhibitors"

I am taking 3 ARVs, one of them is Nevirapine and from wiki:
"Nevirapine is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2B6"

Is an 'inducer' the opposite of an 'inhibitor'?

Could nevirapine be helpful within your theory?

 

[mariovitali]

Hi @mariovitali

From your OP:
"STAY AWAY From: P450 Inhibitors"

I am taking 3 ARVs, one of them is Nevirapine and from wiki:
"Nevirapine is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2B6"

Is an 'inducer' the opposite of an 'inhibitor'?

Could nevirapine be helpful within your theory?

It depends.

If your Phase II is sluggish and you induce (the opposite of "inhibit") Phase I, then you will have problems with increased Reactive Oxygen Species (ROS) that Phase I generates (and Phase II will not be able to keep up with as a consequence).

So you have to fix Phase II first (Methylation, AMino acid Conjugation, Glycation, Sylfation, etc,etc) and THEN induce Phase I.

Perhaps this was not clear to the document i just posted so i will put this information in.

 

[mariovitali]

I was looking at hyperammonemia because elevated ammonia is a finding of Liver disease :

Primary vs. secondary[edit]

• Primary hyperammonemia is caused by several inborn errors of metabolism that are characterised by reduced activity of any of the enzymes in the urea cycle.
• Secondary hyperammonemia is caused by inborn errors of intermediary metabolism characterised by reduced activity in enzymes that are not part of the urea cycle (e.g. .Propionic acidemia, Methylmalonic acidemia) or dysfunction of cells that make major contributions to metabolism (e.g., liver failure).

Acquired vs. congenital[edit]

• Acquired hyperammonemia is usually caused by liver diseases, such as viral hepatitis, or excessive alcohol consumption. Cirrhosis of the liver is formed, followed by a shunt of blood directly to the vena cava, resulting in decreased filtration of blood in the liver, which leads to hyperammonemia.
• Congential hyperammonemia is usually due to genetic defects in one of the enzymes of the urea cycle, which leads to lower production of urea from ammonia. The most common genetic defect is ornithine transcarbamylase deficiency, which is X-linked.

@Gondwanaland you mentioned Hyperammonemia at some point at previous posts.


So once again i run my software having Hyperammonemia as a Target :

See how hyperammonemia appears to be related with Choline, Sensorineural Hearing Loss, Tinnitus, DAO, Monosodium Glutamate, but also Pantothenic Acid.


I then change the Generality of the software and look at the new results for Hyperammonemia :

We see that Misfolded Proteins, Bile Acid, Phosphatidylcholine, Cholestasis but also Acetyl-Coa Carboxylase appear on the list. Recall that NQO1 and NRF2 have also appeared to previous runs.




Wikipedia entry for Pantothenic Acid :

Only the dextrorotatory (D) isomer of pantothenic acid possesses biologic activity.[10] The levorotatory (L) form may antagonize the effects of the dextrorotatory isomer.[11]

Pantothenic acid is used in the synthesis of coenzyme A (CoA). Coenzyme A may act as an acyl group carrier to form acetyl-CoA and other related compounds; this is a way to transport carbon atoms within the cell.[12] CoA is important in energy metabolism for pyruvate to enter the tricarboxylic acid cycle (TCA cycle) as acetyl-CoA, and for α-ketoglutarate to be transformed to succinyl-CoA in the cycle.[13] CoA is also important in the biosynthesis of many important compounds such as fatty acids, cholesterol, and acetylcholine.[13] CoA is incidentally also required in the formation of ACP,[14]which is also required for fatty acid synthesis in addition to CoA.[12]

Pantothenic acid in the form of CoA is also required for acylation and acetylation, which, for example, are involved in signal transduction and enzyme activation and deactivation, respectively.[15]

Since pantothenic acid participates in a wide array of key biological roles, it is essential to all forms of life.[16] As such, deficiencies in pantothenic acid may have numerous wide-ranging effects, as discussed below.

So we are taking care of Acetylation (Recall the Liver chart that i posted earlier) as well as an added Bonus.

@Violeta spot on!

http://forums.phoenixrising.me/inde...genomics-of-selenium.39405/page-2#post-633058


In other words it seems to me that we have to add **ALL** B-Complex vitamins. In our case the B-Complex Multis are not ideal because they contain Folate (and not 5-MTHF), Cobalamin (as opposed to Methylcobalamin or Dibencozide).

In order to support Phase I and Phase II Detox Pathways we will need :


B1 (Thiamine)
B2 (Riboflavin) as FMN
B3 (Biotin)
B5 (Pantothenic Acid)
B6 (as P5P)
B9 (as Metafolin / 5-MTHF)
B12 (as Dibencozide or Methylcobalamin)
K2
C


Minerals :


Manganese
Molybdenum
Zinc
Magnesium
Selenium

Vitamins A,D ( and also E) should -probably- be used with Caution. In my case, supplementing A+D was resulting to Tinnitus and increase of Symptoms. Perhaps Calcium homeostasis was impaired resulting to Excitotoxicity and ER Stress (?)

After seeing the above i become even more confident that Liver is the main culprit to our Condition.

 

[mariovitali]

Analysis of 59699 PUBMED Entries for "Liver Disease"


Note the words in Bold letters,as these co-occur with the term "Symptoms" and please use them to search the Forum to see how many hits you get here.

Another term i did not know was 'extrapyramidal' (and it is also discussed here).


Again, i do not imply causation here.

**********************************************************************************
Enter term : symptom
window size : 5
min freq : 10
17:42:56.250128
**********************************************************************************
('signs', 2243.2500615165854)
('patient', 2080.9958542410072)
('disease', 1427.3604569948645)
('depressive', 970.2396426856147)
('neuropsychiatric', 919.8697319690218)
('fatigue', 845.8005842494927)
('neurologic', 823.6674247713453)
('improve', 805.6996394204634)
('abdominal', 793.7043963360424)
('relief', 705.4423171312588)
('laboratory', 689.0285371397673)
('pain', 611.0976323221597)
('extrapyramidal', 579.4230456662259)
('treatment', 575.6117878268379)
('psychiatric', 550.2464065311034)
('pruritus', 525.2732059098532)
('liver', 515.9445065947012)
('resolved', 443.59533013938153)
('respiratory', 437.58932604315373)
('asymptomatic', 384.5656802152781)
('reflux', 383.6965369451183)
('debilitating', 373.36851625003476)
('resolution', 363.0914038171551)
('dyspeptic', 348.7746159076894)
('pld', 345.7673791038746)
('onset', 344.61301589417883)
('subjective', 331.7620675770607)
('fever', 325.44467952245043)
('suggestive', 304.1051509817471)
('anxiety', 298.2168297071803)
('diverticular', 285.41426964052437)
('relieve', 284.7381140153138)
('association', 278.63272388485746)
("patient's", 277.4860668166574)
('often', 274.46117281491536)
('rls', 270.62510329552265)
('present', 268.50538512811295)
('cutaneous', 267.12793381391884)
('gallbladder', 262.5215807732768)
('usually', 258.4261461405824)
('highly', 257.8073919866812)
('therapy', 252.7574237143701)
('psychological', 252.7293494987243)
('nausea', 251.18237651181755)
('cysts', 247.15428058243617)
('sicca', 246.20847504015398)
('diagnosis', 246.068883947088)
('gerd', 238.0250237664847)
('presentation', 226.20873081058565)
('experienced', 221.71263543241696)
('disabling', 221.47078810387828)
('uncomplicated', 221.07527603457692)
('depression', 219.54086381451336)
('cholelithiasis', 219.2232822393473)
('constitutional', 216.93275176313531)
('wide', 216.06911246901274)
('months', 215.53808177244474)
('complete', 213.9060046306019)
('diarrhea', 206.86876164380828)
('withdrawal', 204.77434035036595)
('physical', 201.36497484486148)
('severe', 201.14530848609888)
('clinical', 199.80712223329857)
('mild', 198.72848831783554)
('common', 195.5008778651445)
('hepatic', 195.2861262825378)
('gi', 193.4344171477841)
('cases', 191.96429998774155)
('pcld', 191.01378024265836)
('variety', 188.38243337301645)
('nonspecific', 188.17067715981483)
('constellation', 185.9916683282858)
('acute', 183.58615535448936)
('jaundice', 181.35400938775405)
('severity', 180.94963878880822)
('disappeared', 180.5581815119882)
('alleviate', 179.81557979791256)
('illness', 178.16318949842764)
('cognitive', 176.11389263160225)
('management', 172.10754301920213)
('recorded', 168.78837105058068)
('occurred', 167.3115879135662)
('compression', 166.0609017852093)
('related', 165.79209188177356)
('difficult', 165.49536905597293)
('reported', 165.0730863858887)
('pbc', 161.10740693510235)
('life', 161.03605000534205)
('case', 160.84563426859904)
('gastrointestinal', 158.47736726038008)
('appear', 157.82520243509754)
('emotional', 157.63480504555645)
('characterized', 156.6305094103202)
('dyspnea', 154.8457583901921)
('result', 153.60566713860894)
('early', 153.14500557530982)
('manifest', 152.7017442000711)
('solitary', 147.44539422546063)
('clinically', 143.88165886003043)
('wd', 142.78503140916666)
('vomiting', 141.3132869693858)
('neurological', 140.43904189129668)
('weeks', 138.4463321529321)
('cause', 137.56905472619601)
('main', 137.1489305107835)
('laparoscopic', 137.0164333550224)
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('attributable', 136.64241181740937)
('cholestatic', 135.30090437217626)
('distress', 133.75024863038294)
('joint', 133.35935747553407)
('attributed', 132.18210677104426)
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('spectrum', 131.04036617567374)
('disorder', 130.52259767571675)
('biliary', 128.3994683300378)
('frequently', 127.9740521692748)
("wilson's", 127.5546700698739)
('pulmonary', 126.52547247425558)
('autonomic', 125.62586782492451)
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('syndrome', 124.98798923244792)
('absent', 124.63191433212124)
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('cirrhosis', 124.26003341534354)
('commonest', 123.75942733324673)
('extrahepatic', 122.97864767121602)
('consistent', 122.61872056731441)
('ascites', 120.91827391154938)
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('biochemistry', 109.67622388780471)
('majority', 109.4834973268193)
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('weight', 92.50610609038172)
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('sex', 70.4737124888232)
('admission', 70.45691858192907)
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('minimal', 69.62580368136909)
('biochemical', 69.62570630359575)
('defined', 69.47685689926232)
('history', 68.99705646657111)
('late', 68.72090903448876)
('underwent', 67.23389030366683)
('pregnancy', 66.94340186484277)
('dysfunction', 66.91578679165787)
('finding', 66.46506133036446)
('toxicity', 66.13505534543222)
('recurrent', 66.11423513765457)
('number', 65.82033496174867)
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('especially', 64.89337036613296)
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17:46:32.011200
**********************************************************************************

 

[ahmo]

I've been using this Swanson's active B complex. I have to divide the capsules in half, using a capsule filler. But it's the only thing I've found that is low dose and the right forms. I can't remember which Fred has been using.

Amount Per Serving % Daily Value
Thiamin (vitamin B-1) (as benfotiamine) 25 mg 1,667%
Riboflavin (as riboflavin 5'-phosphate) 25 mg 1,471%
Niacin (as inositol hexanicotinate) 50 mg 250%
Vitamin B-6 (as pyridoxal 5-phosphate) 25 mg 1,250%
Folate (as Quatrefolic® [6S]-5-Methyltetrahydrofolic acid equivalent to 800 mcg of [6S]-5-Methyltetrahydrofolic acid, glucosamine salt) 400 mcg 100%
Vitamin B-12 (as methylcobalamin) 250 mcg 4,167%
Biotin 25 mcg 8%
Choline (as choline dihydrogen citrate) 25 mg *
PABA (para-aminobenzoic acid) 25 mg *
Pantethine (coenzyme A precursor)(from Pantesin® 55% pantethine) 25 mg *
Inositol (from inositol hexa

 

[mariovitali]

I've been using this Swanson's active B complex. I have to divide the capsules in half, using a capsule filler. But it's the only thing I've found that is low dose and the right forms. I can't remember which Fred has been using.

Amount Per Serving % Daily Value
Thiamin (vitamin B-1) (as benfotiamine) 25 mg 1,667%
Riboflavin (as riboflavin 5'-phosphate) 25 mg 1,471%
Niacin (as inositol hexanicotinate) 50 mg 250%
Vitamin B-6 (as pyridoxal 5-phosphate) 25 mg 1,250%
Folate (as Quatrefolic® [6S]-5-Methyltetrahydrofolic acid equivalent to 800 mcg of [6S]-5-Methyltetrahydrofolic acid, glucosamine salt) 400 mcg 100%
Vitamin B-12 (as methylcobalamin) 250 mcg 4,167%
Biotin 25 mcg 8%
Choline (as choline dihydrogen citrate) 25 mg *
PABA (para-aminobenzoic acid) 25 mg *
Pantethine (coenzyme A precursor)(from Pantesin® 55% pantethine) 25 mg *
Inositol (from inositol hexa

What about these minerals, are you taking them?


Manganese
Molybdenum
Zinc
Magnesium
Selenium