Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment spproaches using vitamin E, magnesium, and betaine - Fatty Liver

Alternative Medicine Review, August, 2002 by Lyn Patrick

SAMe is considered the most important methyl donor in human biochemical reactions and is necessary in the production of carnitine, coenzyme Q, creatine, methylcobalamin, and phosphatidylcholine. (88) SAMe is also considered important in gene regulation, since a large number of genes are dependent on SAMe methyltransferase enzymes. As much as 85 percent of methylation reactions and 48 percent of methionine metabolism occurs in the liver. Hepatic function is dependent to a large extent on methionine metabolism. It has been proposed that SAMe acts as an "intracellular control switch" with the ability to regulate hepatic cellular regeneration, differentiation and susceptibility to injury by oxidative stress, and hepatotoxin exposure. (89) Lowered SAMe levels are suspected to lead to steatosis and steatohepatitis. (90) The transsulfuration pathway (Figure 3) has been shown to be impaired in cirrhosis, potentially contributing to hepatic glutathione deficiency seen in both alcoholic and nonalcoholic liver disease. Oral SAMe (1.2 g/day for six months) led to significant increases in hepatic glutathione in a small controlled trial of patients with alcoholic and nonalcoholic liver disease. (91) The ALT levels in the nonalcoholic liver disease patients decreased significantly as did the AST levels in the alcoholic liver disease patients during SAMe therapy, although they did not reach normal levels. Considering that three of the seven NAFLD patients had cirrhosis and three had chronic active hepatitis, a significant lowering of the specific liver enzymes in alcohol and non-alcohol-related liver disease is worthy of attention. This study provides evidence that the production of glutathione levels in hepatic tissue could be significantly up-regulated by SAMe, and that up-regulation would have a measurable outcome in terms of hepatic function.

Conclusion

Current trends in the prevalence of obesity indicate that 40 percent of the U.S. population will be obese by the year 2025. (37) The incidence of diabetes mellitus is predicted to extend to 7.2 percent of the population (29 million Americans) by 2050. (22) Given these trends, particularly in children and adolescents, the prevalence of NAFLD may increase significantly in the next 25 years. The identification and treatment of NASH is critical, since 20-30 percent of these patients may progress to cirrhosis. (4) Large-scale clinical trials of vitamin E and betaine are warranted. If NASH is clearly another symptom of insulin resistance, the use of magnesium as an insulin-sensitizing nutrient in a pilot study would be worth investigating.

Table 1. Predictors of Fibrosis
in NASH (2,18)

Body Mass Index over 30
45 or more years of age
AST:ALT ratio greater than 1
Type 2 diabetes mellitus
In those with BMI over 35
ALT>40
Hypertension
Insulin resistance
Table 2. Diagnostic Criteria for Insulin Resistance Syndrome (30)

Clinical Feature                    Definition

1. Diabetes mellitus, glucose
intolerance, or hyperinsulinemia
and two or more of the following:

2. Hypertension                     140/90 or current documented use of
                                    anti hypertensive medication

3. Elevated triglycerides, and/or   >1.7 mmol/L
decreased HDL lipoprotein           <0.9mmol/L for men, <1.0 mmol/L for
cholesterol levels                  women

4. Central (truncal obesity)        Waist/hip ratio >0.9 for men and
                                    >0.85 for women or a BMI >30kg/
                                    [m.sup.3]

5. Microalbuminuria                 Urinary albumin/creatinine ratio of
                                    20 mg/g or urinary albumin
                                    excretion rate of 20 mcg/min.
Table 3. Signs and Symptoms of Metabolic Syndrome
(Syndrome X) in "Healthy" NAFLD Patients (21)

Sign or Symptom                                 Prevalence in Study

Overweight (BMI between 25-29.9 kg/[m.sup.3])   67%

Central obesity (waist >102 cm for men and      47%
>88 cm for women)

Impaired glucose metabolism:
Elevated fasting insulin (>100 pmol/l)          57%
Postload hyperinsulinemia (>1000pmol/l)         27%
First-degree relative with diabetes             47%

Elevated triglycerides (>2 mmol/l)              47%

Hyperuricemia (>400 micromol/l)                 27%

Hypertension
(>160/95 or currently on medication)            17%
First-degree relative with hypertension         57%

Cardiovascular disease
Previous acute MI or angina                     0
First-degree relative less than 55 years if     27%
male and 60 years if female
Table 4. Medications
Known to Cause Fatty
Liver (5)

Glucocorticoids
Synthetic estrogens
Aspirin
Calcium-channel blockers
Tamoxifen
Methotrexate
Tetracycline
Valproic Acid (Depakote)
Cocaine
Zidovudine (AZT)
Didianosine (ddl)
Table 5. NASH and NAFLD Patients' Lab Data Before and After Diet and
Vitamin E. (74)

                            Before
                            Treatment

                 Normal
                 Value           NASH                NAFLD

Body wt. (kg)               73 [  or -] 5        75 [  or -] 4

Triglycerides    30-150     225 [  or -] 8      229 [  or -] 17
(mg/dL)

AST (IU/L)       8-35       121 [  or -] 8     59 [  or -] 3 ***
ALT (IU/L)       6-37       171 [  or -] 4      167 [  or -] 8

                           After
                           Diet

                 Normal
                 Value           NASH                NAFLD

Body wt. (kg)               67 [  or -] 3 *     69 [  or -] 4 *

Triglycerides    30-150    100 [  or -] 5 *    102 [  or -] 6 *
(mg/dL)

AST (IU/L)       8-35       100 [  or -] 11     27 [  or -] 3 *
ALT (IU/L)       6-37       161 [  or -] 14     43 [  or -] 3 *

                            After
                            Vitamin E

                 Normal
                 Value           NASH                NAFLD

Body wt. (kg)                65 [  or -] 4       70 [  or -] 4

Triglycerides    30-150     110 [  or -] 6      127 [  or -] 10
(mg/dL)

AST (IU/L)       8-35      36 [  or -] 4 **      28 [  or -] 2
ALT (IU/L)       6-37      37 [  or -] 4 **      41 [  or -] 3

ALT (alanine transaminase); AST (aspartate transaminase)

* p < 0.01 compared with before treatment

** p < 0.01 compared with after diet therapy

*** p < 0.01 compared with NASH