metformin, it can reverse liver disease and IR

[merryBe]

I'm having a real dilemna here, and I would really like to see more discussion of this topic.

here is a great synopsis I just found:


http://www.nature.com/nm/journal/v6/n9/full/nm0900_998.html

WOW, that was a mouthful!!

in light of the findings from all those studies listed I would think this needs much closer examination.

In light of the fact that I am currently UND and have no virus, the reversal of fatty liver and less necrosis and less HCC all sounds very appealing, not to mention any reduction in IR would mean ones own Interferon response would be better post tx. and this alone may increase ones chances of an SVR even if begun at the end of an SOC regime.
Perhaps now, more than any other time it could help insure one will recognize any lingering HCV and seek and destroy as designed.
As long as one kept the dose low, monitored the liver, and watched for lactic acidosis, what would be the harm in trying?

arguments in favor or opposed please weigh in, if obese women went from 20% to 60% SVR that should tell us something??

mb

[bajawoman]

HOLA  I have been really learning a lot from Co she has taught me so much ; my computers being super taxed with all the info I am collecting and passing on to my GI

"OK remember in the Rodriguez-Torres study where it talks about the rations of mitochondrial dna dropping from 200-1 down to 30-1 with certains antivirals and PI therapies?? "

A decrease in the ratio of mitochondrial to nuclear DNA from its normal 100-to-1 (NOT 200-1) to approximately 30-to-1 leads to clinical mitochondrial toxicity.
(oxidative stress also causes mitochondrial DNA depletion).


"Wouldn't this then mean that since the mitochondrial is "the powerplant that drives the cell" that this would creat a marked drop in ability to metabolize any and all drugs?"

But the mitochondria is not only in the liver....and drugs are absorbed differently in different tissue and organs.

Mitochondrial toxicity in the liver may promote lactic acidosis. Mitochondrial toxicity in adipose tissue might promote body composition change....lipodystrophy (which of course is associated with IR). Mitochondrial dysfunction in peripheral nerves is suspected to cause neuropathy.

Mitochondrial dysfunction caused by Ribavirin, can also be related to development of pancreatitis....which can raise your blood sugar >>>IR : )


"So your explaination of CYP2E1 means that tx componds the whole issue as one is having a tremendous drain of RNA/DNA brought on chiefly by the riba, or telprevir.."

Some drugs can cause more mitochondrial toxicity than others. For example, some of the PI's used by HIV patients (or co-infected) can cause mitochondrial damage in the liver, which can cause lactic acidosis....so for them it is riskier to take Metformin which can also cause lactic acidosis.

But for an HCV patient, the risk of lactic acidosis is rare and usually happen as a secondary event caused by things like trauma. So for them, the risk of lactic acidosis is not the same as for co-infected patients.


I just wonder what you think of the metformin in light of this. Would preloading be safest, and continuing as long as stage/grade and enxymes indicated tolerance was good?

Tx should be started when you're sensitive to insulin to give you the best chance for SVR. It shouldn't be, let's predose for a month or three months, but when you're sensitive to insulin.


"7 very small meals is better than 3 large ones in terms of how overtaxed the liver gets, especially when disease has reduced its size and function.
So how much of a role would you say this plays in say, for instance whether one should be on any drug therapy in addition to SOC. "

Depends what you're eating. Are you eating charbroiled foods 7 times a day? Because that will induce CYP1A2. Do you skip breakfast? Because fasting induces CYP2E1. Are you drinking grape juice or pomegranate juice? Because they'll inhibit CYP3A.


"I know you know but for those who do not...the study I'm referencing"

The entire link didn't post. You're missing the end of it. Here you go....I clicked it with my magic IR wand and got you the part that's missing ; )

/SIDE_EFFECTS.pdf

[merryBe]

update on my situation.

My AC1 has risen to 5.5 my fasting glucose to 144. This in spite of all the dietary changes AND in even with the lower HGB of 10, which could be making my reading inordinately LOWER than they really are (thanks for telling me Co).

Ergo my endocrinologist confirmed what Cowriter has been saying.
He also looked over the studies I brought him on TZD's pioglozone and metforming as well as the Nash studies at the top of this thread.

Then too we considered this study

http://qjmed.oxfordjournals.org/cgi/content/full/96/4/315-b

Bottom line, one watches for hypoglycemia, obviously, one monitors liver, obviously,
lactidacidosis is a 1 in 300,000 occurance that should not dissuade the majority, people with NO virus may benefit from lowering their IR in that their interferon will work better, and their Nash can reverse. People with virus in early stage grade may also benefit.

Ergo, In light of the fact that I do not currently have the virsu, and my ALT/AST and other liver numbers have all returned to normal, it has been decided that a short course
of metformin CX (Time released)  500 mg. should be tried for the several benefits it may solicit.

If any of my liver numbers or BS's indicate problems we will discontinue, but presently this tx seems a reasonable solution to at least try. My diebetes may resolve itself in a few months once the INF is permanently lower, he said, since INF may be sriving part of the high BS, but we'll have to wait and see if improvement occurs there before deciding whether to cut back the HGH as well, or just resign ourselves to some sort of IR intervention permanently.

So that's it for now.
I know Bill thinks it's preposterous, but was unaware of my medical history or how long this struggle had been ongoing, or how borderline diebetic I have been for years.

I was actually not surprised by the higher numbers, In fact, I fasted 12 hrs. before my last draw.......but somehow knew my numbers wouldn't be as good as they had been.......
as I started having changes in my feet a few months back....
numbness on the top of all toes...
so I knew something was changing,
even though my monthly fasting glucoses weren't showing it...
again, COwriter you were right there too.
I wish I had known sooner about all this, and that the anemia I've had all year was hiding my true higher numbers...but at least now I do know.

FYI, part of the bad rap metformin has gotten was based on things like the lactic acidosis scare.....but since we can see by the study that the occurence is 1 in 300,000...I think that is something doctors need to review and get past. That is a very low risk considering the potential benefits rate and it should not carry the weight it currently still does.
MY endo was also one who did not think metformin was good for liver patients, but has reevaluated that in light of the most recent findings, and especially for those whose livers are now UND he thinks it does make sense to keep the IR down and try to reverse any fatty liver.  SO he has changed his mind.  
We had an hour appt. so he was able to sit and read the studies...
I don't think he would go along with this if he did not think it could improve my diebetes
(which he says I do have) and improve my NASH, and improve my chances of permanent SVR just because I say so. He's been an endocrinologist for 30 years and did not think the proposal preposterous at all.....

One more thing, I spoke to him about my intent to begin walking again as soon as the HGB got up a couple pts.
He said yes, to walk......BUT TO NOT eat any carbs after my walk. Carbs will cancel out any of the lower IR resistance that walking would achieve. And that lasts about 12 hrs.  So after a walk, high protein snacks only for best control of IR.

mb

[merryBe]

here is the long and short of it courtest of COWriter, to whom all the credit goes.

I was having trouble getting my mind around P450 metabolism and she took the time to  explain it better than any place I had looked, so she get's real kudos here.

Only one thing isn't mentioned here and I'll have to ask her now that I thought of it...
but I think I'll start a new thread for it.



Cytochrome P450  is a group of enzymes. "Cyto", means cell.  "Chrome" means color.   Cytochromes are colored with iron.  Cytochrome P450  is located on the inner membrane of the mitochondria of liver cells (the mitochondria is the powerplant of the cell...it stores oxygen to power the cell).  CYP450, is a target of the hepatitis C virus.  The virus gets help from CYP450.

Why does HCV target the mitochondria?  Because the mitochondria is the location of the interferon response mechanism. By damaging the mitochondria, the Hep C virus stops the interferon response.

So the CYP450 group of enzymes are implicated with liver destruction by Hepatitis C.   So it is possible that inhibiting CYP450, might give you more time to wait for a cure, might help slow down or reverse liver damage, and it may help other drugs clear the virus.  

CYP450 has other family members called isoforms.......

CYP2E1  - Causes mitochondrial damage and oxidative stress on the liver cell.  This is liver enzymes worst enemy.  Alcohol is a CYP2E1 substrate. Even in people who don't drink, CYP2E1 is implicated in non-alcoholic steatohepatitis (NASH)...fatty liver.  What inhibits CYP2E1?  Antabuse....the drug that helps you stop drinking alcohol by making you violently ill if you do drink.  The way it makes you sick is by inhibiting alcohol's metabolizer.  Whenever you inhibit a metabolizer, you raise the level of that drug in your bloodstream and liver....and it makes you sick.

CYP3A4   - Allows HCV to move from cell to cell.  Cell migration is one of the ways in which HCV keeps itself alive and multiplying.  It has to keep moving to new cells.  So inhibiting CYP3A4 will lower your viral load.

A recent study showed that grapefruit juice lowered viral load, because there's a bioflavanoid in grapefruit juice that inhibits CYP3A4.  

HOWEVER, the problem with inhibiting CYP450 enzymes is that many prescription drugs are metabolized by these enzymes..... and by inhibiting them, that can raise the level of the drug in your blood and it can cause an overdose.  (taking Tylenol and alcohol together can cause the level of Tylenol to be toxic.  That's why we always tell people that Tylenol by itself is not really a problem but never to take it with alcohol).

So for example, if you take a blood pressure medication that is metabolized by CYP3A4, inhibiting this enzyme with grapefruit juice may  raise the levels of the blood pressure med in your blood and IN YOUR LIVER....and it can cause an overdose (and your blood pressure to go down too low).

So if you want to lower your viral load by drinking grapefruit juice, you'll need to make sure that you're not taking any meds that are metabolized by CYP450.

(WARNING: Do not drink grapefruit juice during HCV treatment since it can cause oxidative stress and impact treatment success.  Also, be aware that the effect from a small amount of grapefruit juice can last all day).


Another enzyme, CYP1A2, is also implicated in liver damage (and tobacco related cancer)....and SMOKING INCREASES THE ACTIVITY OF THIS ENZYME THREEFOLD!!!!!  You know what else induces this enzyme?  Caffeine.....and Marijuana.....and exposure to polycyclic aromatic hydrocarbons, such as those found in charbroiled foods.:

It's all very complicated.....and some people are more sensitive than others ......and this info is very new.

You also have to be careful using supplements.....St. John's Wort, an over-the-counter anti-depressant, targets CytochromeP450....and interferon (and PI's) inhibits CYP450.  So basically, St John's Wort interferes with the interferon.


Something else that's important.....

HYPERINSULINEMIA  INCREASES CYP1A and CYP2E1  (fasting also induces CYP2E1).

Interferon is a CYP450 1A2 INHIBITOR....a WEAK inhibitor.  And insulin is a CYP450 1A2 INDUCER.  That's how I found out that it was the insulin that made interferon ineffective.  I had been looking for the causal connection between insulin resistance and interferon resistance......and it turned out to be insulin.  Hyperinsulinemia caused by insulin resistance.

(Hey....did you notice how well I stuck insulin resistance in the conversation?  I'm a master at it.....LOL)

Co
P.S,  Sorry.....I wrote you a book....LOL


And just in case you post this somewhere and they ask you for sources....

"CYP1A2 can be induced by exposure to polycyclic aromatic hydrocarbons, such as those found in charbroiled foods and cigarette smoke. This is the only CYP450 isoform affected by tobacco. Cigarette smoking can result in an increase of as much as threefold in CYP1A2 activity."

http://www.aafp.org/afp/980101ap/cupp.html


Hyperinsulinemia causes a preferential increase in hepatic P450 1A2 activity.
"administration of insulin ........also enhances P450 1A2 activity, presumably as a result of hyperinsulinemia."

http://www.ncbi.nlm.nih.gov/pubmed/1562279?dopt=Abstract


Star fruit is a better inhibitor of CYP3A than grapefruit juice.... POTENT INHIBITION BY STAR FRUIT OF HUMAN CYTOCHROME P450 3A (CYP3A) ACTIVITY

http://dmd.aspetjournals.org/cgi/content/abstract/32/6/581?ijkey=3142833449ed0472aa65ca659aaecdd53316e051&keytype2=tf_ipsecsha


Inhibitory effect of fruit juices on CYP3A activity.
"The inhibitory potential of human CYP3A was in the order: grapefruit > black mulberry > wild grape >pomegranate > black raspberry."

http://dmd.aspetjournals.org/cgi/content/abstract/34/4/521?ijkey=8fc3bc688dccea368d29077e08e6a92230856feb&keytype2=tf_ipsecsha


Effects of different spices (ginger) on CYP3A4

http://dmd.aspetjournals.org/cgi/content/abstract/36/7/1283

[merryBe]

as I understand it, and correct me if I'm wrong anyone, the way the oral drugs in metforims class work it to help the cell overcome it's resistance to the insulin present.
The insulin is present BUT the cell is shut down, and not recognizing that the insulin is knock on the door...first insulin must open the door, then it and the food (blood sugars) can get in and feed the cell. So if there is a key to the door it's insulin, but if there is a grease to make the key turn in the lock, it's metformin and the like.

That said, there comes a time, even when on oral meds for a while, that the IR is no longer the only problem, the other problem becomes that the pancreas is kaput and simply stops making enough insulin to go round. You see because it was made to overproduce insulin for years, by not treating the IR with diet, excersise and meds as need be, now you have a gland unable to produce enough, so even if you are correcting for the IR with the metformin, you may still have to add some insulin.

Willing discussed this above as potentially a better outcome for some...again this would be dependant on what was going on with the gland.

Sometimes just correcting the IR can last a lifetime, but if diet isn't corrected, weight is not reduced, the odds are the person will progress from IR to full blown diebetes, and as Cowriter pointed out, that curve, untreated takes about 7 years.

Going from type 2 to type 1 diebetes is not unheard of, nor is having both at the same time. The shut down of the pancreas is caused by overwork and/or autoimmune conditions. What happens there is the insulin producing cells begin to disappear. They are called the isles of langerhans...they are protected by things like enough vitamin D (which may be part of Cocksparrows reason for including that.)
One can also develop pancreatitis...the pancreas makes several digestive aides besides insulin. Calcium is amongst them, but when these juices back up in the gland the gland can digest itself or be destroyed that way.....which is why passing a gall stone can be dangerous...if it gets stuck it the common bile duct...it will chew up your pancreas.

that's about all I know...oh except for I've asked 3 doctors....before this latest ASSLD came out, if I should be on metformin  and they all said no...not best for liver patients.
However, I have a theory now that it may have a lot to do with what dose you need.
It has to do with how things work in the liver...how hard the liver works to detox them.
It has to do with the P450....I'll post something cowriter wrote aabout that.
If you weren't overtaxing with too many other drugs..it might be OK..the kicker is....while on tx there's hardly such a thing as being on too little drugs.
Quite a dilemna if I do say so.

However, think this one through...we just saw a post on African doing 30% worse on tx.
Now if research came out they could improve that by 20-30% and docs ignored it, they holler genocide! (well Rev. Wright would anyway)...Same with HIV...if suddenly they found a way to improve or cure 10% more HIV patients do you not think they would holler from the rafters that it was discrimination to suppress those findings....even if it was ONLY in a subgroup...like fatties...who happen to have the highest rates of IR...HELLO...which is why they are fat, because of IR, in most case....how the heck can we not pay attention and try to do all we can.
It's not as if everyone in here has a 90% cure rate....many are at 50 at the high end, and 20% if they are IR........so OF COURSE we are looking for answers here!

mb

[geterdone]

Thanks MerryBe, I’ll take those twenty pats on the back. Yes, I thought the taper was right on mark also, but few have followed through with it thus far. I can only see the benefits of the taper because I don’t know what the risks would have been if not. The Riba taper… humm… well when colonel sander divulges the recipe then you’ll know. The interesting thing is I have not found ANY research of the negatives on the lasting effects of our beloved meds with any credence and evidence to substantiate why there is no long last effects, why is that? Because there is none? I am a believer in that if you have any unseen or hidden predisposed illness it will surface during the course of treatment.

jasper

[JennyPenny]

Hi there, Jim. We do think a lot a like. I certainly appreciate your always balanced approach. I, too, have learned a ton of stuff on some message boards, but it is always prudent to check it out with your favorite hep doc.

Have a great weekend.