Unfolded Protein Response and A Possible Treatment for CFS

[skwag]

Here's an interesting case of liver injury due to copper overload in dogs

Must Read: Copper Storage

The short story is that dog food had been supplemented with too much copper, which likely lead to the deaths of a number of dogs. Further down the thread (post #10), we find that someone has given their dog TUDCA with good results.

Sorry to bring up old post but I wanted to share some info to those who have babies suffering from liver problems. After a biopsy showed CAH and his liver enzymes continued to climb to over 800 in June, he started taking the usual antioxidants liver support drugs.. SAM-E, Silybin (way better than milk thistle), NAC, Vit E, Zinc therapy, and swithed to Honest Kitchen Verve (3.85 mg/kg copper hydrated) in August his levels came back 324. Still high. Vet recommened Ursodiol (UDCA). After doing extensive research on this expensive drug I found a cheaper alternative that seems to work BETTER and is OTC. TUDCA which is taurine conjugate of UDCA. His liver tests were just done ... ALT is 67 I noticed a difference in his energy, mood, and appetite from day 3 of taking it. He is up 4 lbs (he's always been a little too thin) I just wan to throw this out there and help out as many people as I can. I started him on 2 pills a day for 2 weeks then 1 pill a day. It can be found on ebay search for TUDCA.

I've spent countless hours the past 7 months researching this disease, fighting to keep my boy alive and healthy. I know the journey is still in the beginning stages, but I will fight till the end to keep him healthy and alive.

For those that believe liver injury is a component, or even basis, of our disease, it is natural to ask exactly how did the liver injury occur. There's a long list of possibilities, including this one: copper overload.

 

[ahmo]

Yes, I take all these as single mineral supps.
Zinc 50mg
Se 200mcg
Molybd 450 mcg AM/PM
Mg 600mg AM/PM (malate)
Mang 15mg; on stressed days, x2

 

[mariovitali]

@skwag

I've spoken with a lot of people and there seems to be a pattern. Some of them say that they've "been living life to the max with drugs and a lot of drinking". Others here talk about EBV (a typical liver stressor). Others took Accutane or got Lyme disease.

I was using Finasteride but the problem was not only that : I also took Ketoconazole which is a potent P450 Inhibitor to a liver which also has a problematic Phase I (as confirmed from my SNPs).

Looking back, i created the "perfect storm" for my Liver.


A random search for "CFS" Causes has led me to this page :

https://umm.edu/health/medical/reports/articles/chronic-fatigue-syndrome

Looking at the causes i ended up reading about Cytomegalovirus. I then search for it and this virus creates Liver problems :

• CMV mononucleosis. This syndrome resembles infectious mononucleosis, but the Epstein-Barr virus (EBV) causes classic mononucleosis. If you have signs and symptoms that resemble mononucleosis — a sore throat, swollen glands and tonsils, fatigue, and nausea — your doctor will test you for the antibody your body makes to fight off EBV. If it's absent, there's a chance CMV is causing your symptoms.
• Intestinal complications. CMV infection in your intestines can result in diarrhea, fever and abdominal pain; inflammation of your colon; and blood in your stool.
• Liver complications. CMV can cause abnormal functioning of your liver and an unexplained fever.
• Nervous system complications. A variety of neurological complications have been reported as a result of CMV infection in the nervous system. These may include inflammation of your brain (encephalitis).
• Lung complications. CMV can cause inflammation of your lung tissue (pneumonitis).

See more : http://www.mayoclinic.org/diseases-conditions/cmv/basics/complications/con-20029514

Remember : You may have Liver Injury but the tests may be perfectly normal. However a Liver Injury coupled with specific SNPs (My Theory) could trigger a vicious cycle of Oxidative/Er Stress and further Liver Injury

Edit : Using "Liver Injury" is most probably not the correct term.


@ahmo

OK Great. So how are you feeling?

 

[ahmo]

@mariovitali Today I'm great. A few days ago I poisoned myself by doubling my dose of FMN. So I found out that not only did plain B2 poison me, but excess FMN did, to. Including serotonin crash, ready to quit. Not only that, but I've just uncovered the reason I've been sliding downhill, w/ less cognitive and physical energy: I've been starving myself.

Starting on an Alternate Day Fasting program, and switching from animal fat to coconut oil, put me into a position where I've been under adrenal stress, which also makes losing weight unlikely. I can't tell you how much better I feel from having now eaten 3 days in a row. Live and learn.

As far as the minerals, this feels like a good equilibrium. At times I used a lot more molybdenum to overcome ammonia issues, but this dose seems to be right for me.

 

[skwag]

Hi @mariovitali,

Are you in contact with any other people, not on this thread, that have tried your regimen? I'm curious to know if it is working for others, and under what circumstances it works or doesn't.

 

[ahmo]

You're too quick mario. I came back to add, the upshot of starving myself is that I was inducing oxidative stress, which a significant amount of my intake was trying to remedy. Truly vicious circle.And I wasn't actually starving at all, the fast days still include 400 calories. But I was lacking protein and animal fat.

 

[mariovitali]

@skwag

I am in contact with other people from solvepfs. com : Here is from a conversation about the SNPs for Biliary Cirrhosis

Unfortunately many people either already have a regimen, take Testosterone (which messes things up) or have some other reason (such as no DNA Data).

I still have no answer from many people telling me that "they gave to the regimen a good try" and evaluate and disclose how they feel from following it.


Here is an E-Mail from a Guy from solvepfs who recently started the full Regimen :

Of course there was also another Guy who had startup symptoms from taking Methylation supplements and he wasn't very happy... This is the reason for particularly adding to the document that i do not know many things about Methylation support.


@ahmo

Sorry to hear that..Let me know if we can setup a Skype call to discuss

 

[skwag]

I still have no answer from many people that gave the regimen a "good try" and evaluate and disclose how they feel.

This is unfortunate.

 

[mariovitali]

This is unfortunate.



I feel guilty for laughing! But I've already taken my licks.

Yes i agree this is unfortunate. So all i am trying to say here is :

1. Give this Regimen a good try for a couple of months.
2. Evaluate.
3. Let -all of- us know what happened

Note also that as time passes by, more pieces are added to the puzzle

 

[mariovitali]

@ahmo

Perhaps water fasting is not a good idea. I do not know how intense your fasting was but i am sending this FYI :

WATER FASTING AND DETOXIFICATION

Water fasting can be detrimental to the body's ability to support detoxification. Fasting and alcohol both overinduce the CYP450E family of enzymes, leading to unbalanced detoxification.26 In addition, fasting results in catabolism of
muscle over fat, which is not beneficial to health. Fasting also results in a decreased intake of necessary cofactors, which leads to a decrease in sulfation, glutathione, and glucuronidation conjugation cofactors. In animal models, fasting causes decreased glutathione levels and enhanced susceptibility to toxicity after toxin exposure.33 Thus, the Phase II reactions are decreased and reactive intermediates remain in the body

http://www.metagenics.com/sites/def..._metabolic_detoxification_research_review.pdf

OTOH caloric restriction may have positive effects.

 

[mariovitali]

From the CDC Center regarding CFS :

http://www.cdc.gov/cfs/general/index.html

Various types of infections have been studied to determine if they might cause or trigger CFS:

• Epstein-Barr virus infection, also known as mononucleosis
• Human herpesvirus 6 infection, a virus that can cause problems for people with impaired immune systems, such as AIDS patients or organ transplant recipients taking immune-suppressant drugs
• Enterovirus infection, a type of virus that enters through the gastrointestinal track and can have no symptoms, mild flu-like symptoms, or rarely severe and even deadly symptoms
• Rubella, a viral infection also known as German measles
• Candida albicans, a fungus that causes yeast infections
• Bornaviruses, which cause borna disease, an infectious neurological syndrome
• Mycoplasma, a cause of atypical pneumonia
• Ross River virus, which causes Ross River Fever, a mosquito-borne tropical disease
• Coxiella burnetti, the agent that causes Q fever
• Human retrovirus infection, such as HIV, the virus that causes AIDS, or xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus

So is there Liver involvement ? :

-About EBV we know that there is Liver involvement


Ross River Virus
http://www.members.westnet.com.au/prohealth/rrv.htm (although no studies were found for this one)


Human Herpes Virus 6
http://www.ncbi.nlm.nih.gov/pubmed/12923440


Rubella
http://www.ncbi.nlm.nih.gov/pubmed/25023706


Mycoplasma
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC165294/


Enterovirus
http://www.ncbi.nlm.nih.gov/pubmed/15056237



Coxiella Burnetti
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264321/


I couldn't find anything on XMRV.

 

[Gondwanaland]

Do we know the effect of TUDCA on bilirubin? My husband has Gilbert's.

 

[mariovitali]

Do we know the effect of TUDCA on bilirubin? My husband has Gilbert's.

I haven't found anything related. Please let me research about this more. It is possible that bilirubin acts also as an antioxidant in the case of your Husband (however this comes at a cost)

Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration.
Oveson BC1, Iwase T, Hackett SF, Lee SY, Usui S, Sedlak TW, Snyder SH, Campochiaro PA, Sung JU.
Author information

Abstract
Two constituents of bile, bilirubin and tauroursodeoxycholic acid (TUDCA), have antioxidant activity. However, bilirubin can also cause damage to some neurons and glial cells, particularly immature neurons. In this study, we tested the effects of bilirubin and TUDCA in two models in which oxidative stress contributes to photoreceptor cell death, prolonged light exposure and rd10+/+ mice. In albino BALB/c mice, intraperitoneal injection of 5 mg/kg of bilirubin or 500 mg/kg of TUDCA prior to exposure to 5000 lux of white light for 8 h significantly reduced loss of rod and cone function assessed by electroretinograms. Both treatments also reduced light-induced accumulation of superoxide radicals in the outer retina, rod cell death assessed by outer nuclear layer thickness, and disruption of cone inner and outer segments. In rd10+/+ mice, intraperitoneal injections of 5 or 50 mg/kg of bilirubin or 500 mg/kg of TUDCA every 3 days starting at postnatal day (P) 6, caused significant preservation of cone cell number and cone function at P50. Rods were not protected at P50, but both bilirubin and TUDCA provided modest preservation of outer nuclear layer thickness and rod function at P30. These data suggest that correlation of serum bilirubin levels with rate of vision loss in patients with retinitis pigmentosa could provide a useful strategy to test the hypothesis that cones die from oxidative damage in patients with retinitis pigmentosa. If proof-of-concept is established, manipulation of bilirubin levels and administration of TUDCA could be tested in interventional trials.

Let me do some more search about Gilbert's. Did you already knew or you just found out?


See also here :

http://quixoticmeblog.blogspot.gr/2011/12/connection-between-me-and-gilberts.html

 

[Gondwanaland]

Did you already knew or you just found out?

Just found out. Back in June our dr asked for bilirubin testing and it's the only time he tested it in his life. I didn't know that high bilirubin was a specific condition, just found out about it yesterday and I looked up on his Promethease report and he is +/-.

Thanks for the links, Mario!

Edit -- BTW I suppose that this is why part of his family has no heart problems. OTOH he has a rare SNP on CYP that has been causing severe diseases in the same side of the family.
Edit2-- he is +/+ UGT1A10 rs6742078(T;T) 8% frequency +16% bilirubin levels increased risk of gallstones

 

[Gondwanaland]

UGT1A10 rs6742078(T;T) 8% frequency, +16% bilirubin levels increased risk of gallstones
UGT1A10 rs4124874(C;C) 21.2% frequency, The (C;C) genotype is linked to reduced UGT1A1 activity, and increased Bilirubin, except in people of African origin for whom the T allele is a risk factor for breast cancer.
UGT1A10 rs4148323(G;G), normal
He is also normal for the other Gilbert's markers.

 

[ahmo]

@mario thanks for the offer. I wasn't water fasting. I was doing a modified 5:2 diet, which means 400cal on the fasting days. I'm now looking forward to learning a lot more about the physiology of fat loss and gain, from the upcoming summit.

 

[mariovitali]

@Gondwanaland

I just started the execution of the software. It will take close to 10 hours to complete.


I will let you know what comes regarding Gilbert's. For now, to the already existing Topics these are the matchings :

(Look some of the Topics i put in Bold. It appears that Gilbert's has to do with impaired Glucuronidation)

gilberts.csv : 99.02 %
udpgluc.csv : 3.09 %
glucuronidation.csv : 1.40 %
bilirubin.csv : 1.18 %
caloric_restriction.csv : 0.21 %
niacin.csv : 0.19 %
conjugation.csv : 0.15 %
isotretinoin.csv : 0.13 %
n-acetyltransferase.csv : 0.10 %
enterohepatic_circulation.csv : 0.09 %
cholestasis.csv : 0.08 %
liver_disease.csv : 0.08 %
bile_acid.csv : 0.08 %
biliary_cirrhosis.csv : 0.06 %
detoxification.csv : 0.06 %
redox_homeostasis.csv : 0.05 %
cyp2d6.csv : 0.05 %
hepatotoxicity.csv : 0.05 %
exercise_intolerance.csv : 0.05 %
protease_inhibitor.csv : 0.04 %
intestinal_motility.csv : 0.04 %
liver_injury.csv : 0.04 %
acetylation.csv : 0.03 %
hyperammonemia.csv : 0.03 %
steatohepatitis.csv : 0.03 %
cyp3a4.csv : 0.03 %
cfs.csv : 0.03 %
oxidative_stress_protection.csv : 0.03 %
nafld.csv : 0.03 %
oxidation.csv : 0.02 %
gut.csv : 0.02 %
cyp2e1.csv : 0.02 %
zinc_supplementation.csv : 0.02 %
cyp1a2.csv : 0.02 %
sulfation.csv : 0.02 %
oxidative_stress_markers.csv : 0.02 %
hepatocytes.csv : 0.02 %
mthfr.csv : 0.02 %
hgh.csv : 0.02 %
p450.csv : 0.02 %
ggt.csv : 0.02 %
n-acetylglucosamine.csv : 0.02 %
limbic_system.csv : 0.02 %
cyp1a1.csv : 0.01 %
hydrolysis.csv : 0.01 %
mitochondrial_dysfunction.csv : 0.01 %
glutathione_stransferase.csv : 0.01 %
uric_acid.csv : 0.01 %
xanthine_oxidase.csv : 0.01 %
cimetidine.csv : 0.01 %
reduced_glutathione.csv : 0.01 %
nad.csv : 0.01 %
ebv.csv : 0.01 %
social_anxiety.csv : 0.01 %
crohns_disease.csv : 0.01 %
nac.csv : 0.01 %
taurine.csv : 0.01 %
vitamin_k.csv : 0.01 %
serotonin_levels.csv : 0.01 %

Please visit the following link and see how you can boost Phase II for your Husband :

https://books.google.gr/books?id=zzDE_fraj8IC&pg=PA147&lpg=PA147&dq=glucuronidation gilbert's&source=bl&ots=kN_JQWVxfr&sig=tCI2urMce2nUiz_13YX0qiENY_c&hl=en&sa=X&ved=0CEoQ6AEwB2oVChMIic2XupSJyQIVgdssCh0WcQv2#v=onepage&q=glucuronidation gilbert's&f=false

 

[Gondwanaland]

Thank you so much, Mario! I just found a small section about Gilbert's in the liver document linked in my signature. I am also reading the pages you linked, thanks

 

[skwag]

Biliary Cirrhosis

Autonomic dysfunction in primary biliary cirrhosis correlates with fatigue severity
......

CONCLUSION:
The prevalence of autonomic dysfunction in primary biliary cirrhosis patients is significantly higher than has previously been thought to be the case. Indeed, when sensitive detection modalities are used, it is found to be almost universal at all stages of the disease process. Fatigue in primary biliary cirrhosis is associated with abnormalities of autonomic function.

I would guess orthostatic intolerance and primary biliary cirrhosis are connected through the same autoimmune process.

 

[jump44]

So would bilary problems be treatable with TUDCA mainly?
Also @Gondwanaland I too have Gilberts syndrome like your husband.
From my reading online it seems theres lots of people who have
CFS type symptoms with this supposedly "harmless"
condition. Every doctor whos told me I have it basically smiles and says its
no big deal.