By Dr. Geoffrey Modest
A recent Cuban study looked at the effects of weight loss through lifestyle modification and biopsy-proven changes in nonalcoholic steatohepatitis (See Gastroenterology 2015;149:367–378).
Background:
- NAFLD (non-alcoholic fatty liver disease) is probably the most common cause of abnormal liver chemistries throughout the world, with purported incidence of 15-40% (16% in the recent NHANES III data) and increasing dramatically over time (paralleling the increases in obesity and diabetes); NAFLD is often associated with obesity, metabolic syndrome, diabetes, dyslipidemia. NAFLD is definitely more common than hepatitis C at our health center, where we certainly see a lot of hepatitis C.
- NASH (non-alcoholic steatohepatitis), a biopsy diagnosis, is the most advanced/aggressive form of NAFLD, and has the highest likelihood within NAFLD to progress to cirrhosis, liver transplant, and hepatoma. The risk of hepatoma varies in studies, e.g. from 2.4% over five years in one study and 12.8% over 3 years in another.
Details of study:
- Prospective study of 293 patients with histologically proven NASH. Mean age 48.5, 41% male, weight 83.4 kg and BMI 31.3, 61% hypertensive, 52% hyperlipidemic, 33% diabetes, 33% prediabetes, ALT 52.4 U/L
- Baseline histology: steatosis 33-66% in 48%, >66% in 23%; NAS score (NASH disease activity score) >4 in 60%; lobular inflammation in >1 focus in 41%; “many” ballooning cells in 58%; fibrosis stage 0 in 61%, 1 in 8%, 2 in 20% and 3 in 11%
- All patients were encouraged to adopt lifestyle changes to decrease their weight over 52 weeks, during the time period of 2009-2013, consisting of dietary recommendations — low-fat diets with 750 kcal/d less than their daily energy needs (CHO 64%, fat 22% and <10% sat fats, protein 14%) and encouragement to walk 200 minutes/week. There were individual behavioral sessions to promote adherence to this every 8 weeks.
- Paired liver biopsies were available for 261 patients, all of whom had fatty liver on imaging studies, persistent increase in ALT (for at least 2 consecutive visits), or risk factors for advanced disease (metabolic syndrome, >45 yo, obesity and diabetes). Men drinking >20g/d and women >10g/d alcohol for the previous 2 years were excluded, as well as those with evidence of other causes of liver disease. Diabetics had to have A1C<9%. Other exclusions include using meds felt to be insulin sensitizers (e.g. glitazones, vitamin E), prior use of hypolipidemic drugs (though they did use meds in those who continued to be hyperlipidemic after 3 months of lifestyle changes)
Results:
- At 52 weeks, 30% lost >= 5% of their weight (10% lost >10% of their weight, 9% lost between 7-10%, 12% lost between 5-7%). Mean weight loss of 4.6 kg, corresponding to 413 kcal reduction in daily consumption, with 12.9% reduction in CHO intake and 14% reduction in fats. Physical activity score increased minimally (and there were no relationships found between physical activity and either weight loss or in liver histology changes). No difference in outcomes for weight loss by initial BMI or if diabetic or not
- 25% achieved biopsy-proven resolution of their NASH
- 47% had reductions in their NAS score by at least 2 points
- 19% had regression of their fibrosis/65% were stable, 39% had improvement in ballooning score, 50% had improvement in lobular inflammation, 27% had improvement in portal inflammation
- Degree of weight loss was independently associated with improvement of all NASH-related histologic parameters
- Comparing those who lost >=5% of their weight to those <5%: 58% had NASH resolution and 82% had a 2-point decrease in their NAS (p<0.001). And all patients without baseline fibrosis who lost >5% of their weight remained fibrosis-free.
- Those losing >=10% of their weight: 90% has resolution of NASH, 45% had regression of fibrosis and all had reductions of NAS
- In females with BMI>35, fasting glucose >5.5 mmol/L (100 mg/dl), and many ballooned cells on biopsy, NAS scores decreased significantly with weight reduction >10% [I’m not sure why they singled out this group — I have never seen anything suggesting that females have a higher likelihood of progression of NASH. The major predictor of progression is the initial biopsy showing fibrosis or inflammation]
So, there was a graded decrease in NASH as weight loss increased, the maximal benefit in those able to loss >10%, and most of the patients with worsening fibrosis had little or no (<5%) weight reduction. this study was significant (to me) in that they achieved impressive weight loss overall in a real-world setting (i.e., without those irreproducible, aggressive study environments). This study did show that lifestyle-induced weight loss of >7% was associated with significant decreases in NASH activity, showing that achievable weight losses work and people do not have to get down to their ideal body weight to have dramatic effects. And, this study adds to the literature finding weight loss leads to decreases in NAFLD (see https://stg-blogs.bmj.com/bmjebmspotlight/2013/10/16/primary-care-corner-with-geoffrey-modest-diet-exercise-can-lead-to-fatty-liver-disease-nafld-remission/ , for example, which looked at a noninvasive assessment of liver fat and found a graded effect of hepatic fat resolution with increased weight loss.) Also, there was a companion study in the same Gastroenterology journal as the Cuban study which assessed the effect of bariatric surgery, finding a year later that NASH resolved in 85% and fibrosis was reduced in 34% (see Gastroenterology 2015; 149: 379–388). Another implication of this study (as in other studies of hepatic fibrosis) is that fibrosis is not the fixed, irreversible scarring that we had learned in medical school (at least for those of us trained in the foregone dusky ages, if not the dark ones)