Future studies need to be at least 1 to 2 years in duration.”
“Any therapy shown to be effective [against NASH] will need
to be lifelong, making careful assessment of the risk-benefit ratio
paramount,” McCullough adds.
McCullough, who has financial ties to Takeda, is a principal
investigator in a newly begun placebo-controlled trial of pioglitazone. The 2-year study, which aims to include 240 patients, is also
testing vitamin E against the disease (see sidebar).
That study is supported by the National Institute of Diabetes and
Digestive and Kidney Diseases in Bethesda, Md., and conducted
by the NASH Clinical Research Network, which includes
researchers at eight medical institutions.
Some researchers are considering a related insulin-sensitizing
compound called rosiglitazone (Avandia). In a preliminary, man-ufacturer-funded study published in 2003, liver specialist Brent
Tetri of Saint Louis University Hospital and his colleagues found
that 48 weeks of rosiglitazone treatment for 25 NASH patients produced improvements in insulin sensitivity and reduced liver fat,
inflammation, and fibrosis. Here, too, weight gain was a problem—
two-thirds of the volunteers gained weight while taking the drug.
Utzschneider, too, is conducting a trial of rosiglitazone. Her
6-month, placebo-controlled test of 48 people who have NASH
will also examine a cholesterol-lowering drug.
AIMING AT INSULIN Metformin is the most widely used therapy for type 2 diabetes, and the American Diabetes Association recommends it as the first-line treatment for the disease. It’s generally less expensive than rosiglitazone and
pioglitazone, which scientists classify as
peroxisome proliferators–activated
receptor (PPAR)-gamma ligands. Those
compounds bind to receptors in cell
nuclei, altering the activity of metabo-lism-related genes.
On the other hand, metformin reduces
the liver’s production of glucose, which
in turn lowers insulin production, says
gastroenterologist John W. Haukeland
of Aker University Hospital in Oslo. Since
insulin boosts cell metabolism of sugar
and signals the liver to synthesize fat, a
drop in insulin production could be therapeutic for fatty liver disease.
Several studies have tested metformin
against NASH. In the largest, 55 people
took the drug daily for nearly a year, while
a similar number of volunteers received either daily vitamin E or
dietary counseling. During the study, metformin-treated volunteers
experienced the greatest improvements in insulin sensitivity and
liver-enzyme concentrations, a group of Italian researchers reported
in 2005.
At least some patients who received metformin in that trial also
lost liver fat. But that finding is tentative because only 17 volunteers’ livers were evaluated by biopsy at the study’s end.
Haukeland is conducting a 6-month trial in which he aims to
give either metformin or a placebo to 90 people who have fatty
liver or NASH and either diabetes or prediabetes. In this trial, all
volunteers will undergo liver biopsy at the beginning and end of
treatment.
“The metformin studies that I’ve seen have not been very impressive,” says Tetri. “It might have a role in conjunction with rosiglitazone or pioglitazone, just as it does in diabetes.”
“No medications have been shown to be clearly effective [against
NASH],” Haukeland says. “We have no established therapy, except
for weight loss.”
But if the trials under way prove that any of the drugs are effective in stopping NASH, he adds, it will be an important coup for
preventive medicine. ■
STATS
45
million
Estimated
number of
U.S. adults
with fatty liver
disease—
most of whom
don’t have
symptoms
Weighing All Options
Potential liver treatments abound
An array of potential therapies besides the insulin-sensitizing
drugs is being tested against fatty liver disease. They range
from surgery to bonus bacteria and include some that have
shown promise in people in at least one clinical trial.
WEIGHT-LOSS Researchers are evaluating the effect of gastric-bypass surgery on fatty liver disease. That procedure shrinks
the stomach and leads to reduced calorie intake and weight
loss, which is known to reverse the liver condition. The weight-loss medication orlistat (Xenical), which blocks intestinal fat
absorption, has also decreased volunteers’ liver fat in pilot trials. However, excessively rapid weight loss that the surgery or
orlistat might cause could paradoxically aggravate fatty liver.
HERBS AND SPICES Chinese and Japanese scientists have collaborated to test several traditional Asian herbal remedies in
rats that are predisposed to fatty liver. Last October at a meeting of the American College of Gastroenterology in Las Vegas,
researchers led by Hisao Takayama of Tottori University in
Japan reported that a diet composed of 6 percent cinnamon
by weight decreased the fat in the animals’ livers.
VITAMIN ANTIOXIDANTS Studies suggest they might prevent
inflammation and therefore reduce formation of scar tissue in
the liver. A 2003 trial of 45 people found that a combination of
the antioxidant vitamins E and C reduced liver scar tissue
over a 6-month period. Researchers, however, observed no
change in inflammation. Now, some volunteers in trials of
pioglitazone or metformin are receiving vitamin E in addition
to one of the drugs.
GOOD FATS In a yearlong Italian study of 56 people, liver fat
declined in those who each day took a capsule containing 1 gram
of polyunsaturated fatty acids. The report appeared in the April
15, 2006 Alimentary Pharmacology & Therapeutics. Animal data
from other studies suggest that these healthful fatty acids act as
pioglitazone and rosiglitazone do.
IRON-DEPLETION THERAPY Doctors conducting a small U.S.
study are bleeding patients—although, unlike medieval physicians, they’re extracting blood with sterilized needles rather
than leeches or lacerations. The rationale behind the study,
which is sponsored by the National Institutes of Health in
Bethesda, Md., is that removing excess iron from the body by
withdrawing blood may improve insulin activity.
BENEFICIAL BACTERIA Preliminary studies hint that disturbances in naturally occurring bacteria in the gut may contribute to fatty liver disease. Last year, for example,
researchers at Imperial College London and the University of
Oxford in England found that unidentified intestinal microbes
tend to use up the dietary supply of the nutrient choline in a
strain of mice that’s susceptible to fatty liver. Choline deficiency has been linked to fatty liver in lab animals, so the bacteria may contribute to that strain’s high rates of fatty liver disease. However, researchers at Johns Hopkins University in
Baltimore recently conducted a trial that tested a probiotic
bacterium—a harmless bug that might control harmful ones—
in people who have fatty liver disease. The researchers found
no benefit from the bacterial strain that they used. —B.H.
