Thursday, March 8, 2012

Supersize Me (and My Liver)

Fatty liver of a 14-year-old.  Source:  AJR
What's the most common cause of newly diagnosed chronic liver disease in the U.S.?

It's not alcohol.  It's not hepatitis C.  It's nonalcoholic fatty liver disease, or NAFLD, which now accounts for 39% of new liver disease diagnoses.

You would think with the epidemic of NAFLD, along with the rising rates of obesity and metabolic syndrome, that there would be an explosion of drug development in this field.  In fact, there have been but a handful of small, randomized, controlled trials.  The NIH clinical trial registration site lists only 193 ongoing or completed trials in NAFLD or NASH (nonalcoholic steatohepatitis, the more inflammatory form of NAFLD), compared to 1370 trials in hepatitis C.

Perhaps part of the reluctance in conducting trials has to do with the fact that simple NAFLD, without NASH, has not been definitively linked to increased liver-related complications or mortality.  NASH can progress to cirrhosis, end-stage liver disease, hepatocellular carcinoma and death, but the only way to distinguish NAFLD from early NASH is by liver biopsy.  At present, most patients who otherwise fit the clinical characteristics of fatty liver disease (elevated transaminases; risk factors such as hyperlipidemia, obesity or type diabetes; and a fatty liver on ultrasound or CT) do not undergo biopsy.  Will that change with the publication of the 2010 PIVENS trial?

PIVENS is the largest well-designed treatment trial of NASH, comparing pioglitazone, vitamin E, or placebo in 247 patients.  Notably, this trial excluded diabetics.  Since insulin resistance and oxidant damage are thought to be involved in the pathophysiology of NASH, it makes sense to study an insulin sensitizer and an antioxidant.  Patients were randomized to one of the three treatment arms for 96 weeks, then re-biopsied.  The primary outcome was improvement in histologic features.

Both the pioglitazone and vitamin E groups had significant drops in their transaminase levels.  Only the vitamin E group, though, experienced a highly statistically significant histologic improvement -- 43% for vitamin E, compared to 19% for placebo, with a number needed to treat of about 4.  Pioglitazone showed a trend towards improved histologic changes, but it didn't make the cut-off for statistical significance.  The investigators were no doubt disappointed in this finding, because they then took pains to explain that the pioglitazone group had less hepatocellular ballooning (a marker of more active disease) at baseline.  An imbalance in baseline characteristics is a known hazard of small clinical trials, and many researchers would have simply smacked their heads with a "D'oh!" and called it a day.  Instead, the PIVENS group went back and performed some post hoc data massaging, and found that if they had used slightly different histological criteria, pioglitazone would have been superior to placebo.

Basing clinical decisions upon subgroup analysis, especially post hoc (i.e., after the fact) analysis, is fraught with danger.  But even if we took these results at face value, should we be prescribing pioglitazone or vitamin E to our NASH patients?

First, note that these were biopsy-proven NASH cases.  Extrapolating the results to patients with NAFLD would not be appropriate.  Even if these drugs were effective in this population, the number needed to treat would be much higher, since many patients with NAFLD never progress to a more inflammatory stage.  Also, note that PIVENS excluded those with diabetes -- patients to whom you might prescribe pioglitazone anyway.  Would you be willing to give pioglitazone indefinitely to a non-diabetic with NASH, especially without a proven histological benefit?  As for vitamin E, it may be tempting to throw this pill at all your fatty liver patients, since it's cheap and "only a vitamin."  Just note that anti-oxidants, at least in pill form, have failed to live up to their promise in most clinical trials, and one meta-analysis even found that vitamin E increases overall mortality.

Finally, there haven't been any studies large enough to detect a difference in clinically significant outcomes, such as complications of cirrhosis.  One trial in progress is randomizing 1500 patients with NASH to either a polypill containing aspirin, a statin, hydrochlorothiazide and enalaparil or no intervention, with a 5-year follow-up.  Even with that many subjects, it still doesn't have the power or the duration to detect a difference in liver-related morbidity. 

Oh, and one more catch:  If you want to sign your patient up for that study, he'll have to fly to Tehran.  What an irony that the Axis of Evil is working on something that may end up benefiting our citizens even more than their own.

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