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.

Download the Nonalcoholic Steatohepatitis teaching module at www.professorebm.com.

Experimenting on the Unconscious

Those of you who read the last post about the RAMPART study, comparing IM midazolam to IV lorazepam in status epilepticus, may have wondered: How did the investigators obtain informed consent from the patients?  The answer is, they didn't.  At least, not until after the patient had already received the study medication.


There is no way to get prospective consent from an unconscious patient.  Even if a family member is present, time is of the essence when treating status.  The paramedics don't have the time to discuss the risks and benefits of the study, and families can't be expected to make a snap decision under duress.


This doesn't mean, though, that researchers are allowed to experiment willy-nilly on unconscious or confused patients.  The U.S. Food and Drug Administration allows exceptions to informed consent requirements under the following conditions (among others):

• Life-threatening condition requiring urgent intervention
• Unproven or unsatisfactory treatments
• Obtained informed consent is not feasible
• No reasonable way to prospectively identify individuals who may become eligible
• Possible direct benefit to study participants

Examples of patients who might be eligible for such a study include trauma or cardiac arrest victims.


Although the FDA tries to set clear criteria for what kinds of studies qualify for this exception, they leave room for interpretation.  For example, you can't really say that the standard treatment of status epilepticus is "unproven" or "unsatisfactory."  The majority of patients will respond to anticonvulsants, though some may require aggressive ICU support.  In addition, while a study may hold the promise of benefit to study participants, there is no guarantee against possible harm.


Perhaps the most notorious trial to meet the exemption from informed consent was the PolyHeme study, which randomized trauma patients to synthetic hemoglobin or crystalloid solution in the field.  While there was no overall difference in mortality, those in the PolyHeme group had significantly more adverse events, including myocardial infarction.


Even touchier, studies that qualify for the exemption from informed consent are bound to enroll more racial minorities, because of their higher rates of trauma or use of emergency medical services.  For example, one study found that blacks represented 41% of patients on a U.S. trauma registry, even though they comprised only 20% of the population in those areas. Moreover, the majority of trauma patients enrolled in a hypertonic saline trial, which waived prior informed consent, were black.  On a reassuring note, blacks who met the study eligibility criteria were not enrolled disproportionately more than other racial groups.  As for RAMPART, the authors noted in their results that "the overall number of subjects who were black reflected the proportion of blacks in the subject population from which the sample was drawn."  Whether this is enough to allay the suspicions of a community that has suffered from unethical experimentation in the past remains to be seen.


There is one way that patients can refuse to participate in such a trial.  In RAMPART, paramedics did not enroll patients who wore a medical-alert tag that read "RAMPART declined" -- but how would a patient know to wear such a tag in the first place?  The investigators are responsible for publicizing the trial, for example, in YouTube videos or newspaper ads.  Given that only about 400 patients have viewed RAMPART's video at the time of this posting, my guess is that most people, even those with seizure disorders, were unaware of the study or the fact that they could opt out.  It also seems unfair to place the burden on patients to wear these bracelets 24-7 just to avoid possible, unwanted experimentation.  And what if you want to avoid participating in all the emergency trials taking place in your area - must you don multiple tags or bracelets?

Despite these concerns, I still think RAMPART was an ethical study, and here's the reason why:  Even before the commencement of this trial, IM midazolam, the experimental treatment, was fast becoming the drug of choice among many EMS providers, due to its ease of storage and administration.  Surely performing a randomized trial of this drug in unconscious patients is more ethical than continuing to give those same patients a medication of uncertain efficacy.