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959
© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
nature publishing group 959
LIVER
EDITORIAL
Abstract: Pathogenesis of nonalcoholic fatty liver
(NAFLD) disease and gallbladder (GB) disease
secondary to cholesterol gallstones is complex, yet
both conditions share similar associated risk factors,
most of them related to the metabolic syndrome.
Cholecystectomy, the best treatment for GB disease,
is one of the most performed abdominal surgeries
worldwide. In this issue of the American Journal
of Gastroenterology , Ruhl and Everhart, using data
from the Third United States National Health and
Nutrition Examination Survey (1988 – 1994), show
that NAFLD is associated with cholecystectomy
(odds ratio (OR) = 2.4; 1.8 – 3.3), but not with gallstones
(OR = 1.1; 0.84 – 1.4). This fi nding suggests that
cholecystectomy may itself represent a risk factor
for NAFLD, which is in line with the recently
undisclosed role of the GB and bile acids in systemic
metabolic regulation. Thus, cholecystectomy may not
be innocuous and may have a major impact on public
health by contributing to NAFLD development.
Am J Gastroenterol 2013; 108:959 – 961; doi: 10.1038/ajg.2013.84
Nonalcoholic fatty liver disease (NAFLD) and gallbladder (GB)
disease secondary to cholesterol gallstones are signi cant health
problems. Both diseases have similar very high prevalence rates in
North and South America, and Europe, a ecting 10 – 50 % of the
adult population ( 1,2 ). e frequency of both conditions increases
with age. ey are more prevalent among Hispanics and Amerin-
dians ( 3,4 ), and in patients with metabolic (or insulin resistance)
syndrome associated disease conditions, including obesity, diabe-
tes type 2, and arteriosclerotic vascular diseases ( 5,6 ). Consistent
with shared risk factors and pathogenic links ( 7,8 ), NAFLD and
GB disease have been associated with an increased mortality from
chronic liver disease, cardiovascular disease, and cancer, com-
pared with the general population ( 9,10 ).
Although treatment of NAFLD is mainly based on promoting
lifestyle changes with relatively poor results owing to low levels of
patient adherence, the best and e ective treatment for GB disease
is cholecystectomy, which is one of the most frequently performed
surgical procedures worldwide. e frequency of cholecystec-
tomy determines high direct and indirect cost and represents a
very high consumption of resources for society, constituting a
major health burden. Symptoms are uncommon and transitory
a er cholecystectomy and, in general, GB removal is not associ-
ated with signi cant medical problems. Earlier studies have also
shown that cholecystectomy has no major adverse e ects on bile
acid (BA) metabolism ( 11 ) and does not a ect fat absorption ( 12 ).
Although BA pool size and synthesis remain unchanged, the BA
pool circulates faster, increasing the exposure of enterohepatic
organs and, eventually, of peripheral tissues to a higher ux of BA
as compared with normal individuals ( 11,13 ).
Almost all epidemiological studies of GB disease to date have
included in one homogeneous group patients with gallstones and
with previous cholecystectomy. is methodology was main-
tained during the 70s and 80s, because the paradigm of GB dis-
ease pathogenesis was primarily considered to be a result from a
defect in the regulation of hepatic lipid metabolism that persisted
in cholecystectomized subjects. However, a number of studies in
humans and in experimental animal models have shown that the
pathogenesis of gallstone formation is heterogeneous, with abnor-
mal regulation of hepatic lipid metabolism, biliary lipid secretion
and GB function having similar importance ( 6 ). us, it may be
useful to analyze gallstone and cholecystectomized patients sepa-
rately. In this issue of the American Journal of Gastroenterology ,
Ruhl and Everhart ( 14 ) use this strategy to interrogate the large
cross-sectional retrospective study conducted among US adults
in the ird National Health and Nutrition Examination Survey
(1988 – 1994) (NHANES III) ( 15 ). e aim was to test the hypoth-
esis that the prevalence of NAFLD is di erent among individuals
harboring gallstones in the GB as compared with cholecystect-
omized subjects ( 14 ). NAFLD and GB disease were assessed by
ultrasonography, and subjects with GB disease were grouped
into those with previous cholecystectomy and subjects harboring
gallstones. Odds ratios (OR) for the association of gallstones and
Cholecystectomy and NAFLD: Does Gallbladder
Removal Have Metabolic Consequences?
Flavio Nervi , MD 1 a n d M a r c o A r r e s e , M D 1
1 Departamento de Gastroenterolog í a, Facultad de Medicina, Pontifi cia Universidad Cat ó lica de Chile , Santiago , Chile . Correspondence: Flavio Nervi, MD ,
Departamento de Gastroenterolog í a, Pontifi cia Universidad Cat ó lica de Chile , Marcoleta 367, Santiago , Chile . E-mail: fnervi@med.puc.cl
Received 18 February 2013; accepted 26 February 2013
see related article on page 952
The American Journal of GASTROENTEROLOGY VOLUME 108 | JUNE 2013 www.amjgastro.com
LIVER
960 Nervi and Arrese
occurring within the enterohepatic circulation may be relevant
to understanding why cholecystectomy may induce metabolic
derangements. In this circuit, BAs downregulate their own synthe-
sis in the liver by inhibiting the expression of CYP7A1, the rate-
limiting enzyme of BA synthesis, through FXR-dependent and
FXR-independent mechanisms, the latter being BA-mediated by
the ileum-derived postprandial enterokine broblast growth factor
(FGF) 15 (human ortholog, FGF19) ( 24 ). is hormone also stim-
ulates GB relaxation and re lling with hepatic bile a er feeding
and has insulin-like e ects, promoting hepatic protein and glyco-
gen synthesis ( 25 ), and inhibiting hepatic fatty acid synthesis ( 26 ).
Pharmacological administration of FGF19 to mice attenuates diet-
induced obesity, lowers serum glucose and hepatic TG content,
and increases energy expenditure ( 27 ). ese metabolic e ects are
also observed in FGF19 transgenic mice ( 28 ). Moreover, human
GB mucosa has higher content of FGF19 than the ileal mucosa and
is secreted into bile, reaching high concentration levels ( 29 ).
Other relevant, BA-dependent signaling pathways within the
enterohepatic circulation are mediated by TGR5 ( 30 ). TGR5 acti-
vation by BA induces smooth muscle relaxation and stimulates
the lling of the GB with hepatic bile in a FGF15 / 19-independent
manner ( 31 ). Moreover, TGR5 activation in ileal enteroendocrine
L cells modulates glucose homeostasis through stimulation of the
incretin hormone glucagon-like peptide-1 ( 30 ). Finally, TGR5
activation by BA in extrahepatic tissues, such as brown adipose
tissue and skeletal muscle, increases energy expenditure and
prevents diet-induced obesity ( 32 ). Collectively, the above data
strongly support that GB is critical to controlling BA homeostasis
within the enterohepatic circulation, which may also be relevant
to whole-body metabolic homeostasis through potential changes
in serum levels of BA that, in turn, have a myriad of peripheral
actions in extrahepatic tissues. us, cholecystectomy may not be
inconsequential from a metabolic standpoint.
Recent data support the concept that cholecystectomy may be
associated with metabolic changes. Sonne et al. ( 33 ) recently dem-
onstrated a slight deterioration of postprandial glycemic control
a er GB removal, and even an increase in body weight has been
reported in cholecystectomized patients ( 34 ). Moreover, and in
line with current data from Ruhl and Everhard, recent studies in
cholecystectomized mice have shown an increase in hepatic and
serum TGs concentration, very-low-density lipoprotein synthesis
and production, and BA pool cycling ( 35 ).
Why ablation of the GB alters lipid metabolism favoring TGs
accumulation in the liver? Two mechanisms could be at play in
this setting. First, the increased cycling of the BA pool a er chole-
cystectomy could alter the BA-dependent signaling on several
enterohepatic and peripheral targets. And second, ablation of the
GB could induce suppression of hormonal factors (FGF15 / 19, glu-
cagon-like peptide-1, or others) that have important functions in
lipid metabolism and metabolic homeostasis. Both mechanisms
could potentially determine the occurrence of insulin resistance
and may render patients prone to developing NAFLD. Notewor-
thy, preliminary studies in humans showed that serum FGF19
concentration decreases a er cholecystectomy, which could have
an impact on metabolic regulation ( 36,37 ).
cholecystectomy with NAFLD were calculated by using logistic
regression analysis to adjust for all known associated risk factors,
common to both NAFLD and GB disease. e results showed,
by multivariate-adjusted analysis, that NAFLD was associated
with cholecystectomy (OR = 2.4; 1.8 – 3.3), but not with gallstones
(OR = 1.1; 0.84 – 1.4). When subjects with high alcohol intake
were included in the analysis, results remained unchanged. e
association of patients with cholecystectomy and NAFLD was
stronger in men than in women, and, remarkably, about two-
thirds of cholecystectomized men had NAFLD. e authors con-
cluded that the association of NAFLD with cholecystectomy, but
not with gallstones, indicates that cholecystectomy per se may be
a risk factor for NAFLD. Ruhl and Everhart ’ s report is of particu-
lar signi cance, as data were obtained from a well-designed and
unusually large population-based epidemiological study ( 14 ).
Moreover, NHANES III data collection avoids the ascertainment
bias that occurs in studies using selected patients and allows for
a better understanding of the relationships between gallstone dis-
ease, cholecystectomy, and NAFLD. An increased prevalence of
NAFLD in GB disease has been found in several previous studies
( 16 – 19 ), but only one of them grouped cholecystectomized sub-
jects separated from gallstone patients, showing a tendency for a
stronger association of NAFLD with cholecystectomized subjects
as compared with gallstone patients ( 19 ). In another study, chole-
cystectomy, but not cholelithiasis, was associated with cirrhosis
and elevated serum liver enzyme levels in a study based in the
cross-sectional NHANES III survey ( 20 ). ese last two observa-
tions are in line with the ndings of Ruhl and Everhart ( 14 ). us,
although current ndings warrant further epidemiological pro-
spective, clinical end experimental studies, Ruhl and Everhart ’ s
report is consistent with the hypothesis that cholecystectomy
increases the risk for NAFLD and other metabolic syndrome-
associated disease conditions.
Which could be the mechanisms underlying the link between
cholecystectomy and NAFLD? To address this question, an over-
view of the current understanding of GB physiology is in order.
GB function is integrated into the “ liver – GB – intestine axis, ” which
is responsible for maintaining the metabolic homeostasis of trig-
lycerides (TGs), nonesteri ed fatty acids, BAs and cholesterol of
the entire organism. In addition, the GB motor function regulates
the daily cycling of BA through the enterohepatic circulation dur-
ing the fed-fasting periods. During the last decade, a number of
studies have reported that BAs are signaling molecules that modu-
late complex enterohepatic and systemic metabolic functions, as
well as GB motility (reviewed in Lefebvre et al. ( 21 )]. BAs exercise
these functions in virtue of being ligands of the nuclear receptor
farnesoid X receptor (FXR), a ligand-activated transcription factor
that induces several metabolic and secretory pathways in the liver
and ileum (22), and the G-protein-coupled BA receptor TGR5,
which is expressed in the plasma cell membranes of several cell
types, including enteroendocrine L cells, cholangiocytes, and GB
epithelial cells, as well as in brown adipocytes and myocytes ( 23 ).
Both FXR and TGR5 regulate lipid, glucose, and energy metabo-
lism through complex and interrelated pathways, whose details
are beyond the scope of this editorial ( 23,24 ). However, events
© 2013 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY
LIVER
961
Editorial
In summary, Ruhl and Everhart ’ s epidemiological observa-
tion study and the recent experimental observations in men
and mice ( 33 – 35 ) suggest that cholecystectomy favors NAFLD
development. e emerging role of the GB as an endocrine organ
with potentially relevant metabolic functions is indeed behind
this connection, although pathophysiological details remain
unknown. Future prospective epidemiological and intervention
studies should help to address the actual cause – e ect relationship
between abnormalities of lipid metabolism, cholecystectomy, and
GB function. However, it may be time to consider that cholecys-
tectomy may not be innocuous from the standpoint of metabolic
homeostasis and could have a major impact on public health.
CONFLICT OF INTEREST
Guarantor of the article : Flavio Nervi, MD.
Speci c author contributions: Flavio Nervi and Marco Arrese
wrote the entire editorial.
Financial support : e authors were partially supported by grants
from the Fondo Nacional de Desarrollo Cient í co y Tecnol ó gico
(FONDECYT) number 1130146 (to FN) and number 110455
(to MA).
Potential competing interests : N o n e .
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