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[nobimbo]

The topic of fatty liver/elevated liver enzymes comes up a lot here, so I thought I'd post an interesting article I ran across. It discusses a study that points to a link between fatty liver and insulin resistance, and suggests insulin resistance itself, apart from obesity, as a cause for fatty liver. Later in the article, it suggests that insulin-sensitizing agents such as Metformin may actually be helpful in treating the condition of NAFLD (Non-Alcoholic Fatty Liver Disease). By the way, this condition is also associated with iron overload, and I read on another site that women with PCOS are especially vulnerable to this and that we should be careful not to take supplements containing iron (unless one is diagnosed with iron deficiency):

http://www.medforum.nl/idm/fatty_liv...istance___.htm

Fatty liver, hepatic insulin resistance and the metabolic syndrome
Original article:
Nonalcoholic fatty liver disease. A feature of the
metabolic syndrome. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Diabetes 2001; 50: 1844–50.

Summary
In order to test the hypothesis that non-alcoholic fatty liver disease (NAFLD) might represent another feature of the metabolic syndrome, with decreased insulin sensitivity being the common factor, Marchesini and colleagues measured insulin sensitivity by means of the euglycaemic clamp technique in a group of 30 patients with NAFLD, and compared the results with values obtained in 10 patients with type 2 diabetes under good metabolic control and 10 healthy subjects used as controls.
Of those subjects with NAFLD, nine had pure fatty liver and 21 had evidence of steatohepatitis. Most patients with NAFLD had central fat accumulation, increased triglyceride and uric acid levels, and low HDL cholesterol concentrations, irrespective of BMI.
Glucose disposal during the clamp was reduced by nearly 50% in NAFLD patients, to an extent similar to that of type 2 diabetic patients (Fig. 1A).


Fig. 1: (A) Glucose disposal during the euglycaemic clamp and (B) hepatic glucose production in control subjects (n = 5), patients with type 2 diabetes (n = 5) and NAFLD subjects (n = 10); and (C) plasma FFA concentrations in control subjects (n = 10), patients with type 2 diabetes (n = 10) and NAFLD subjects (n = 30). Data are presented as means and 95% CI.

Postabsorptive hepatic glucose production (HGP), measured by [6,6-2H2]glucose, was normal. However, in response to insulin infusion, HGP decreased by only 63% of basal values in NAFLD vs. 84% in control subjects (p = 0.002), an impairment similar to that seen in type 2 diabetic patients (Fig. 1B). In NAFLD patients, basal free fatty acid (FFA) levels were increased, whereas insulin-mediated suppression of lipolysis was less effective (-69% in NAFLD vs. -84% in control subjects; p = 0.003). Again, the latter abnormalities were similar in NAFLD subjects and diabetic patients (Fig. 1C). There was laboratory evidence of iron overload in many NAFLD patients, but clinical, histological and biochemical data (including insulin sensitivity) were not correlated with iron status.
The authors concluded that NAFLD, even in the presence of normoglycaemia and normal or moderately increased body weight, is characterized by clinical and laboratory data similar to those found in diabetes and obesity. NAFLD may be considered an additional feature of the metabolic syndrome, with specific hepatic insulin resistance.

Comment
The presence of fatty liver in patients with obesity and type 2 diabetes has long been reported. Patients with fatty liver and hepatitis are identified as having non-alcoholic steatohepatitis (NASH), a condition which has been found to be associated with clinical and biological markers of the metabolic syndrome [1, 2]. Interestingly, several studies have demonstrated that weight loss is associated with a parallel regression of biological markers of NASH (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) and biological markers of the insulin resistance syndrome (hyperinsulinaemia, high triglyceride levels, low HDL cholesterol concentrations and hyperuricaemia) [3].
The present study confirms that NAFLD is characterized by a remarkable reduction in insulin sensitivity, with decreased insulin effects on both glucose and lipid metabolism. Such a defect is not exclusively associated with abnormal glucose regulation and/or overweight as is frequently observed in NAFLD, but also extends to subjects with normal glucose tolerance and normal weight. Indeed, to rule out diabetes as a primary cause of insulin resistance, only NAFLD subjects with normal fasting glucose and glucose tolerance were selected for the present study. In addition, although total fat mass and intra-abdominal fat were not quantitatively measured, one-third of NAFLD patients had normal body weight, and there was no significant difference in glucose disposal during the clamp between normal-weight and overweight NAFLD subjects, a finding which rules out the possibility that obesity plays a significant role in the present study. Taken together, these data suggest that insulin resistance in NAFLD might be a primary phenomenon, sometimes in addition to obesity- and diabetes-associated insulin resistance.
In NAFLD patients, HGP was normal or high-normal in the fasting state, despite basal hyperinsulinaemia, and liver did not switch off glucose production in response to insulin infusion, indicating the presence of liver insulin resistance. Comparing NAFLD with type 2 diabetes, it appears that the two conditions are very similar in the presence of different fasting glucose levels and overall glucose metabolism. Liver insulin resistance in NAFLD might theoretically derive from liver damage itself, as is commonly observed in patients with cirrhosis, but this is not the case in the present study. It might also result from hypertriglyceridaemia and high FFA levels: a striking lipid abnormality in NAFLD patients was the higher basal FFA concentrations and the lower-than-normal decrease in plasma FFA levels in response to insulin infusion, a finding which may be associated with
relatively increased visceral adiposity found in most NAFLD patients even in the presence of normal body weight. Finally, hepatic insulin resistance might be related to iron overload. The present study confirmed that serum indices of iron overload (increased ferritin, low unsaturated transferrin and higher-than-normal transferrin saturation) are present in most patients with NAFLD. In addition, an appreciable proportion of these patients (4 out of 30) was heterozygous for mutation His63Asp of the hemochromatosis gene HFE. However, iron status did not classify patients according to the histological severity of their liver disease, and serum indices of iron overload did not correlate with measures of insulin sensitivity. Accordingly, hepatic iron might be one but not the only agent causing hepatic insulin resistance and ongoing fatty liver disease in these patients.
The possible relevance of impaired insulin sensitivity in the pathogenesis of NAFLD has potential therapeutic implications that must be tested in clinical studies. In obese subjects, a weight-reducing intervention programme is likely to reduce the obesity-related insulin resistance, which might be partly responsible for liver fat deposition. A parallel reversibility of biological markers of the metabolic syndrome and histological findings of liver steatosis was observed after gastroplasty-induced weight loss in severe obesity [3]. Alternatively, insulin sensitizer agents, such as metformin and thiazolidinediones, might break the vicious circle linking hyperinsulinaemia and insulin resistance to elevated triglyceride and FFA concentrations, and NAFLD, including progressive steatosis, inflammatory reactions (NASH), ultrastructural mitochondrial lesions in the hepatocytes, and ultimately hepatocyte death. A pilot study demonstrated an early and significant response by ALT and AST measurements in 10 NASH patients treated with the first available thiazolidinedione, troglitazone [4]. However, this was associated with only mild improvement in necroinflammatory grade, and all of the biochemical responders showed persistent steatohepatitis in the follow-up liver biopsies. Considering the well-known hepatotoxicity related to troglitazone (which resulted in the withdrawal of the drug from the market), and even if this liver complication does not appear to be shared by rosiglitazone and pioglitazone [5], such pharmacological intervention with glitazones in NAFLD should be considered with caution and must first be validated in large, prospective, controlled clinical trials.

Linda

[Raiderette]

Thank You for posting this. I have been on a mini quest trying to find a reason for my eleveted liver levels .

This posting was very helpful. Something to show my Dr.

[nobimbo]

Maybe once more docs are aware of this, they won't panic when liver enzymes come out elevated and immediately take a woman off Met. Met can take a long time to work it's wonders, so the elevated enzymes may just be a part of the insulin resistance syndrome, not a result of taking the Met.

Linda

[JezzabellNY]

Thanks for posting this! My RE doesn't want to put me on metformin because of my liver test came back elevated. My reg doc did tests to see make sure there was no other reason... but concluded it's a fatty liver. I told my RE this but it doesn't seem to make a difference. I am currently ttc and feel metformin would help! I'm so frustrated!

[christyz]

Thanks for this excellent article, Linda. In my reading on the subject I have found a lot of factors can contribute to elevated liver enzymes: Common medications such as non-steroidal anti-inflammatory drugs (Acetaminophen/Tylenol) , antibiotics (tetracycline), anti-epileptic drugs, cholesterol medications and anti-tuberculosis drugs. Gallbladder issues can also be refelected in high enzymes. So it's something that always needs thorough investigation.

http://www.medhelp.org/forums/gastro...es/35523a.html

[Dixie Lee]

thanks I too had high liver enzymes and was concluded I had a fatty liver. He backed me off 1500mg of gluc and put me back to 1000mg until they become lower, I am scared he will pull me off my gluch for good.

[aasunshine]

Do any of you with a fatty liver experience pain along with it? I have been experiencing alot of pain in my right upper abdomen area and at first the Dr's thought it was my gall bladder but every test came back normal. So now they think it is my liver. Is there anyone else out there with this problem?

[JD8]

When I was in college, I donated blood and found out that I had the Hep C antibody in my blood. I'm one of those people who have no idea how they got it. I never took, let alone shared, IV drugs; never had a blood transfusion; I hadn't even had sex with anyone yet. Anyway, that's not important to my story...

I've never actually had Hep C. I just have the antibody. I get tested every year, but my doc thinks it just passed through my body somehow, leaving only the antibody. I prefer to be very careful about what medications I put in my body.

I went to an OB/GYN who specializes in PCOS. He put me on met and when I inquired about effects on the liver, he told me that met doesn't pass through the liver. He told me that it is broken down in the kidneys. He is the only one who has ever said this to me, and, trust me, I do plenty of research. Just to be safe, I made an appointment with another doctor (endocrinologist) to get her/his opinion. Do any of you ladies know (for a fact) how met affects the liver?

Jenny

[sanctuary1999]

My gyno, a reproductive endo


Put me on 2000 gluc xr!

I trust him! Funny every year at my primary, I say...
here we go again, let's do the liver test!!



However, I have been highly irregular in taking my meds!

[nobimbo]

Doctors have been warned repeatedly to not prescribe Met to patients who have kidney or liver disease, because of the increased risk in those patients of lactic acidosis. The study at the beginning of this thread seems to show that Met can actually improve fatty liver disease. The results are preliminary and more research is needed. Here is blurb in another article about this study:

"Although these studies are preliminary, our data justify cautious evaluation of metformin as a treatment for fatty liver disease," says Diehl. "And although one of the side effects of this drug is lactic acidosis, a build up of lactic acid, which is more serious in people with liver disease, we found no evidence of toxicity in the mice we studied." The researchers next plan to test the drug in other animal models

http://www.hopkinsmedicine.org/press...UST/000829.HTM

There is no evidence that Metformin causes damage to the liver or kidneys. It does increase the risk of lactic acidosis if a patient has severe kidney disease. The liver helps to filter out lactic acid from the bloodstream, which is why it is suggested that the liver be functioning normally when taking Met. So it seems to me that if the kidneys are functioning normally, liver function is not as important a consideration. However, doctors are still being adivsed to use Met with caution in patients with liver disease because of this theoretical risk.

Linda

[Jllrdh]

For me, I was tested at first and my liver numbers were abnormal, they did all the tests and thought it was just a fatty liver, but then with one more test, the numbers suggested that I had mono in the past. I never knew it, but since they had that data they started me on 1000 mg of met, and within 6 months I had my liver enzymes done again, and they were within normal limits. Now they have increased me to 2000 mg. they should give met a chance, because there could be other reasons for abnormal levels.

Jenny

[Scatterbunny]

women with PCOS are especially vulnerable to this and that we should be careful not to take supplements containing iron

I have always been sensitive to too much iron, my prenatal vitamins made me sick. So should I not pick a multivitamin that includes iron?

[nobimbo]

I have read that unless your blood tests indicate low iron, you shouldn't take it; you might want to ask your doc to test you to be sure.

Linda

[LaurieAnne83]

I've heard that you should take a multivitamin without iron unless you have lowish iron that you've been tested for... but the only vitamin not hard on my stomach are the chewable childrens kind, and they only have them with iron here...anyway I've been taking that for years, and when I got blood tests I stil have low iron, so now I'm taking that plus an extra iron supplement..they say women who bleed a lot due to heavy or excessive periods often get low iron..just in case you are that person. Yeah but you should get tested, especiallyyyy if your taking something with more than 100%...but there ar eseveral vitamins that are iron-free...especially the 'senior' ones.

[Scatterbunny]

Thanks, I'll have to ask for an iron test, I have an appointment on February 2nd.