NON-ALCOHOLIC FATTY LIVER DISEASE AND
- Non-Alcoholic Fatty Liver Disease ("NAFLD")
- Abnormal deposition of fat in the liver in the absence of alcohol
- Natural history
- In a case series of 173 patients with biopsy-proven NAFLD,
followed for minimum of 5y (42% had NASH; see below), there was no
sig. diff. in overall mortality between NASH and non-NASH pts, but
NASH pts had higher liver-related mortality (17.5% vs. 2.7%) (Clin.
Gastroent. Hepatol. 7:234, 2009--JW)
- In a study in 173 pts 8-17yo with biopsy-confirmed NAFLD
randomized to vitamine E 800IU QD, metformin 1000mg QD, or placebo,
x 96wks, incidence of (sustained reduction in ALT by 50% or moreor
40 U/l or more) was not sig. diff. in either of the active-treatment
groups vs. placebo, though among the pts who had NASH (see below), a
sig. higher proportion resolved at 96wks with vitamin E vs. placebo
(58% vs. 28%; no sig. diff. between metformin and placebo) (JAMA
- Non-Alcoholic Steatohepatitis ("NASH")
- Definition = liver biopsy changes consistent with alcoholic hepatitis in
absence of excessive alcohol intake (fatty changes and hepatocyte
injury, with or w/o fibrosis; may see cirrhotic changes).
- A subset of
Non-Alcoholic Fatty Liver Disease (NASH represents the more severe end of the
spectrum of NAFLD)
- 9% of liver biopsies meet this definition
- Risk factors:
- Diabetes Mellitus
- Clinical Features and Natural History
- Usually asymptomatic though modest aminotransferase elevations and
hepatomegaly are common
- Progression, when present, is usually indolent.
- In an observational study in 129 pts with biopsy-proven non-alcoholic fatty liver disease and elevated transaminase levels, compared with an age- and sex-matched reference population, over mean 13.7y f/u, the subgroup with nonalcoholic steatohepatitis had sig. lower survival rates than reference population (70% vs. 80%); no sig. dif. between those with simple steatosis vs. reference group.
(Hepatol. 44:865, 2006--JW)
- cirrhosis occurs in a small number of patient--Risk factors:
- Type 2 DM
Age > 45yo
- BMI > 30
- AST/ALT ratio > 1
- Liver biopsy (unlike other two, allows determination of severity)
- Elevated "caspase activity" as measured by plasma levels of
cytokeratin-18 fragments, may be an independent predictor of the
existence of NASH on liver biopsy (FP News, 5/15/06)
- Clinical features and Natural History
- Treatment of underlying risk factors (see above)
- In a study in 55pts with nonalcoholic steatohepatitis (configurmed
histologically) and either impaired glucose tolerance or type 2 DM
randomized to pioglitazone vs. placebo, at 6mos, pioglitazone recipients
had sig. reductions in serum transaminase levels and sig. greater
histologic improvements (NEJM 355:2297, 2006--JW)
- Gemfibrozil and metformin have been shown to reduce transaminase
- In a study in 110 nondiabetic patients
with non-alcoholic fatty liver disease randomized to metformin 2g/d vs.
vitamin E 800IU/d vs. weight-loss dietary counseling x 12mos, metforming
group had sig. greater ALT reductions and incidence of ALT normalization
(56% vs. 18% for the combination of the other 2 groups); this association
persisted after adjustment for weight loss during the trial period (Am. J.
Gastroent. 100:1082, 2005--abst)
- Liver transplantation for end-stage cirrhosis
- 49 pts with biopsy-proven NASH randomized
to vitamin E 100IU QD + vit. C 1000mg QD vs. placebo x 6mos. Improvement
in disease activity scores on liver biopsies at 6mos were sig.
greater in vitamin-treated group. (Am. J. Gastroent. 98:2485, 2003--abst)
- 166 pts with bx-proven NASH randomized to
13-15mg/kg/d of ursodeoxycholic acid vs. placebo; over 2y f/u, no sig. diff.
in bx findings between the groups (Hepatology 39:770, 2004--abst)
- In a nonrandomized trial in 18 pts with
histologically-proven NASH and persistently elevated ALT (> 1.5 x
normal), treated with pentoxifylline 400mg TID x 6mos, mean serum ALT and
AST were sig. reduced (Am. J. Gastroent. 99:1946, 2004--abst)
- Vitamin E
- In a study in 247 pts with
biopsy-proven NASH randomized to vitamin E 800 mg/d vs.
pioglitazone 30mg/d vs. placebo x 96wks, vitamin E (but
not pioglizatone) was associated
with lower nonalcoholic fatty liver disease activity scores c/w
placebo (Study by Arun Sanyal presented at conference of
American Association for the Study of Liver Diseases 2009-FP
- See also above under
- In a study in 63 pts with biopsy-proven NASH (32% with DM)
randomized to (rosiglitazone 4mg/d x 1mo then 8mg/d x 11mos) vs.
placebo, at 12mos, the rosiglitazone group ahd sig. higher
likelihood of having normal hepatic transaminases (38% vs. 75%)
and at least a 30% reduction in steatosis (47% vs. 16%) (Gastroent.
- In a study in 61 pts with biopsy-proven NASH (none with DM)
randomized to pioglitazone 30mg/d vs. placebo, at 12mos, the
pioglitazone group had no sig. diff. from the placebo group in
improvement in steatosis, but had sig. greater improvements in
hepatocyte injury and fibrosis (Gastroent. 135:1176, 2008-JW)
(Sources include Mayo Clin. Proc. 75:733, 2000--AFP; NEJM 346:1221,
2002--AFP, and others as cited)