Cholecystectomy and risk of metabolic syndrome

Abstract

The gallbladder physiologically concentrates and stores bile during fasting and provides rhythmic bile secretion both during fasting and in the postprandial phase to solubilize dietary lipids and fat-soluble vitamins. Bile acids (BAs), major lipid components of bile, play a key role as signaling molecules in modulating gene expression related to cholesterol, BA, glucose and energy metabolism. Cholecystectomy is the most commonly performed surgical procedure worldwide in patients who develop symptoms and/or complications of cholelithiasis of any type. Cholecystectomy per se, however, might cause abnormal metabolic consequences, i.e., alterations in glucose, insulin (and insulin-resistance), lipid and lipoprotein levels, liver steatosis and the metabolic syndrome. Mechanisms are likely mediated by the abnormal transintestinal flow of BAs, producing metabolic signaling that acts without gallbladder rhythmic function and involves the BAs/farnesoid X receptor (FXR) and the BA/G protein-coupled BA receptor 1 (GPBAR-1) axes in the liver, intestine, brown adipose tissue and muscle. Alterations of intestinal microbiota leading to distorted homeostatic processes are also possible. According to this view, cholecystectomy, via BA-induced changes in the enterohepatic circulation, is a risk factor for the metabolic abnormalities and becomes another “fellow traveler” with, or another risk factor for the metabolic syndrome.

1. Introduction

Cholelithiasis encompasses a spectrum of conditions ranging from asymptomatic gallstones to uncomplicated symptomatic gallstone disease (biliary colic), to complicated gallstone disease (manifesting with acute cholecystitis, cholangitis, or gallstone pancreatitis) [1,2].

Cholecystectomy, the most commonly performed surgical procedure worldwide, is performed laparoscopically in > 90% of the cases and represents the “gold standard” for surgical treatment of gallstones [3,4]. The gallbladder removal can influence the enterohepatic circulation since the rhythmic functions of the gallbladder acting as a reservoir of bile and contractile pump are missing. Also, the adjusted BA metabolism and recirculation might influence homeostatic pathways involving the BAs/farnesoid X receptor (FXR) and the BA/G protein-coupled BA receptor 1 (GPBAR-1, also named TGR5) axes in the liver, intestine, brown adipose tissue and muscle [5,6]. These processes, in turn, might lead to negative metabolic consequences, including the metabolic syndrome [6,7], currently defined by the International Diabetes Federation as the coexistence of central obesity (in Europids as a waist circumference ≥ 94 cm and 80 cm in male and female, respectively) plus any two of the following traits: triglycerides ≥150 mg/dL or treatment, high-density lipoprotein (HDL) cholesterol < 40 mg/dL in men or < 50 mg/dL in women or treatment,systo-diastolic blood pressure ≥ 130 and ≥ 85 mm/Hg, respectively, or treatment, fasting plasma glucose ≥100 mg/dL (5.6 mmol/L) or previously diagnosed type 2 diabetes [8]. The metabolic syndrome represents a major public health problem with prevalence of about 25% of adults worldwide [8]) and is linked to increased risk of cardiovascular disease, type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma [9,10], hyperuricemia and gout [11], cholesterol cholelithiasis [12]. Thus, the aspects linking gallbladder removal with the metabolic syndrome deserve attention because of the high number of cholecystectomies being performed worldwide and affecting millions of patients.

Here, we will review the mechanisms through which cholecystectomy could be considered as additional risk factor for the development of the metabolic syndrome.

2. The feedback of BAs and gallbladder in the physiologic control of metabolic homeostasis

Bile contains organic molecules (mainly lipids), inorganic salts, electrolytes, and trace amounts of proteins in an aqueous solution. Following liver production and secretion, bile is stored and concentrated in the gallbladder during the interprandial (fasting) period, and released into the intestine during the gallbladder contraction, a step initiated by the meal-induced neurohormonal stimulus. Bile plays a key digestive role because it enhances the solubilization of dietary lipids (i.e., triglycerides, cholesterol) and fat-soluble vitamins. Bile is the main route for excreting excessive cholesterol from the body. Both BAs and phospholipids (> 95% lecithins) act as cholesterol carriers, starting at the canaliculus side of hepatocytes, by forming simple/mixed micelles and unilamellar/multilamellar vesicles according to their luminal concentrations [13]. BAs are the major component of biliary lipids. They are synthetized from cholesterol in the liver as “primary” BAs, i.e., cholic acid (CA) and chenodeoxycholic acid (CDCA) and subsequently conjugated to taurine or glycine, a step which increases their solubility while reducing their toxicity. BAs released with bile into the duodenum have a detergent effect and contribute to the digestion and absorption of lipids and fat-soluble vitamins [14]. BAs undergo continuous enterohepatic circulation due to active ileal transport and passive colonic diffusion, and return to the liver through the portal vein [5,15–17].Thus, hepatic BA synthesis is inhibited by a negative feedback regulatory mechanism. The small amounts of BAs that escape intestinal absorption enter the colon where they are further transformed by the resident gut microbiota into “secondary” BAs: deoxycholic acid (DCA) and lithocholic acid (LCA), and “tertiary” very hydrophilic BA ursodeoxycholic acid (UDCA) [5,18]. (Table 1).

Table 1.

Major physiological fluctuations of bile acids (BAs) in humans [5,13,142–144].

Hepatic synthesis	0.2–0.6 g/day
Ileal reabsorption (active)	≈85%
Colonic absorption (passive diffusion)	≈10–12%
Fecal loss	0.2–0.6 g/day (5%)
Pool	3 g (liver and intestine)
Recirculation: 4–12 cycles per day	Dynamic pool: 12–36 g/day.
Serum concentrations (fasting)	0.2–0.7 μM
Serum concentrations (postprandial)	4–5 μM

Besides their unique digestive functions, BAs are also critical regulators of the metabolism [5,15], since BAs are “hormonal” signaling molecules which interact with some important nuclear receptors: farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR), and G-protein coupled bile acid receptor-1 (GPBAR-1, also known as TGR5), and work on cell signaling pathways such as c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinases (ERKs). Thus, BAs could regulate energy, glucose, lipid metabolism, energy expenditure, inflammation, and gut microbiome configuration [14,19–22]. In contrast, abnormalities in BA metabolism and circulation might initiate, perpetuate or aggravate metabolic disorders [20] and liver diseases [14,23]. The nuclear receptor FXR is a BA-responsive ligand-activated transcription factor and the BAs/FXR axis plays a major role in metabolic functions. The liver regulates glucose homeostasis: FXR activation by BAs decreases the glycogenolysis and increases the glycogenesis, leading to a decrease in plasma glucose concentrations. The same signaling pathway also regulates lipid metabolism by activating nuclear receptors such as small heterodimer partner (SHP) and peroxisome proliferator-activated receptor α (PPARα), and upregulating expression of the VLDL receptor gene to decrease plasma VLDL levels and lipogenesis and to increase lipolysis. This step is associated with decreased accumulation of intrahepatic triglycerides and increased hepatic VLDL secretion [24]. Of note, BA homeostasis is regulated by the BA-FXR interaction through the modulation of expression of genes involved in hepatic synthesis, uptake, and secretion [25], as well as intestinal absorption of BAs [26]. Steps regulate intracellular BA concentrations and reduce liver injury due to BA accumulation and cytotoxicity [13,27,28]. In the L enteroendocrine cell of the intestine, BA activation of FXR increases the levels of enterokine fibroblast growth factor 19 (FGF19) in the portal circulation of humans. FGF19, in turn, activates its hepatic receptor FGFR4 and coreceptor β-klotho [29]. This step reduces BA synthesis by inhibiting expression of hepatic cholesterol 7α-hydroxylase gene [26,30]. The FGF19/FGFR4/β-klotho activation also inhibits the lipogenesis at different levels: a) suppression of insulin-mediated synthesis of fatty acids and insulin-induced expression of sterol regulatory element-binding protein-1c (SREBP-1c) that is a key transcriptional activator of lipogenic genes. This might increase activity of signal transducer and activator of transcription 3 (STAT3), the physiological inhibitor of SREBP-1c; b) decreased expression of peroxisome proliferator-activated receptor-γ coactivator (PGC)-1β that acts as an activator of SREBP-1c activity; and c) increased expression of SHP that works as a transcriptional repressor to inhibit activities of lipogenic enzymes via a SREBP-1c-independent mechanism [24,31]. Taken together, a lot of evidence links the BA function with important metabolic effects.

BAs, mainly LCA and DCA, also act as strong natural agonists of GPBAR-1 that is expressed in the gallbladder, hepatic Kupffer cells, [32,33] brown adipose tissue, skeletal muscle, [14,33] macrophages, monocytes, [14,33] and enteroendocrine cells of the intestine [34]. GPBAR-1 regulates energy and glucose homeostasis. In the ileum, GPBAR-1 activation by BAs increases the levels of the peptide YY (PYY) levels, leading to anorexigenic effects, i.e., appetite reduction [35,36]. GPBAR-1 activation also generates increasing levels of the glucagon-like peptide-1 (GLP-1), which, in turn, increases insulin secretion. This decreases the glycogenolysis and plasma glucose levels, and also improves insulin sensitivity [37–39]. In addition, GPBAR-1 activation also increases plasma levels of glucagon-like peptide-2 (GLP-2), a nutrient-responsive hormone active in the gastrointestinal tract via GLP-2 receptor (GLP-2R), which likely enhances epithelial cell survival and proliferation, mucosal blood flow, nutrient uptake, and inhibition of gastric motility and secretion [35,40]. GPBAR-1 activates iodothyronine deiodinase 2 enzyme, leading to a conversion of inactive T4 (thyroxine) to active T3 (3,5,3′-triiodothyronine) and increasing energy expenditure via fatty acid β-oxidation [14,33,41,42]. Indeed, GPBAR-1 knockout mice develop obesity in response to a high fat diet [42]. Such mechanisms might represent a way to counteract the weight gain due to excess caloric intake and a potential therapeutic target for treating obesity, but might also account for some of the metabolic alterations occurring after cholecystectomy.

The gallbladder, with its reservoir function, acts as the physiological pacemaker of the enterohepatic circulation of BAs. This function is mediated by distinct neuro-hormonal coordinate mechanisms involving the liver and intestine [43–45]. During fasting, vagal-motilin-mediated stimuli at the end of phase II of the migrating myoelectric complex induce low-intensity periodical gallbladder contractions, about 20% reduction of fasting volume [46,47]. In the postprandial phase, vagal-cholecystokinin (CCK)-mediated mechanisms induce about 60–80% reduction of fasting gallbladder volume after appropriate fat stimulation takes place in the upper small intestine [16,48,49]. The subsequent gallbladder refilling occurs when bile secreted by the liver flows through the cystic duct into the relaxing gallbladder. Gallbladder relaxation is promoted by the acid-stimulated release of duodenal vasointestinal peptide (VIP) and by the intraluminal concentration of BAs. BAs act as signaling agents of the GPBAR-1 which is abundantly present in the gallbladder epithelium and smooth muscle [15,50]. The rank order efficacy of BAs for stimulating GPBAR-1 is LCA > DCA > CDCA > CA [51]. The gallbladder smooth muscle relaxation is further promoted by the human FGF19 [52], which is found in the gallbladder epithelium, as well as in the cholangiocytes [53] and in the ileum. In humans, the gallbladder contains and secretes high levels of FGF19 into bile [54], with levels much higher in the gallbladder than in the ileum [54], and about 23-fold higher in bile than in serum [53]. Thus, BAs activate FXR (rank order of CDCA > LCA > DCA > CA) and promote the increase of FGF19, which, in turn, activates the FGFR4/coreceptor β-klotho pathway that is also responsible for smooth muscle relaxation [15]. After BAs reaching the terminal ileum are absorbed by the enterocytes, they stimulate FXR-mediated secretion of FGF19 into the portal circulation, which provides a further negative feedback to the gallbladder that refills before the next meal [16,52]. A diurnal rhythm of serum FGF19 levels is present, with peaks of FGF19 between 90 and 120 min following the postprandial release and trans-intestinal flow of BAs [55].

3. Cholesterol and pigment cholelithiasis

The prevalence of cholelithiasis is high in industrialized countries, and ranges from 10% to 15% [48,56,57].Types of gallstones are identified based on chemical composition: either pure or mixed cholesterol stones (~75% in the United States and Europe), or either black (~20%), brown (~4.5%), or rare (~0.5%) pigment stones [1,2,58].

Both cholesterol and pigment cholelithiasis put the populations at risk of developing gallstone-related symptoms and complications which ultimately might require cholecystectomy [48].

The pathogenesis of cholesterol gallstones is closely linked to metabolic disturbances and includes five key metabolic defects: 1) LITH genes and genetic factors; 2) hepatic hypersecretion of biliary cholesterol, resulting in sustained supersaturation of gallbladder bile with cholesterol; 3) enhanced absorption of biliary and dietary cholesterol in the small intestine; 4) accelerated phase transitions of cholesterol in bile, leading to rapid formation of cholesterol monohydrate crystals; and 5) prolonged gallbladder stasis due to impaired gallbladder motility, and immune-mediated gallbladder inflammation, as well as hypersecretion of mucins and accumulation of mucin gel in the gallbladder lumen [59]. Other risk factors for cholesterol gallstones include increasing age, female gender and pregnancy, rapid weight loss, physical inactivity, a diet high in cholesterol, estrogen and oral contraceptives, and low serum magnesium. Also, several factors within the metabolic syndrome such as insulin resistance, obesity, dyslipidemia, type 2 diabetes [60–63] also increase the risk of developing cholesterol gallstones because they share common pathogenic pathways [64]) Thus, cholesterol gallstone disease could be considered as another component of the metabolic syndrome [65]. According to the third National Health and Nutrition Examination Survey (NHANES III), 6.3 million men and 14.2 million women aged 20–74 suffer from gallbladder disease in the USA [56] and this condition represents a raising trend also for cholesterol cholelithiasis [66]. Moreover, combination of diverse factors is often found in patients with the metabolic syndrome [12,67], which strongly predispose to the formation of cholesterol gallstones [12,13,48,60–63,68–70], as confirmed by several epidemiological studies in South American, Middle East and Asian populations [65,71–74]. Epigenetic mechanisms modulate gene expression through complex gene-environment interactions [75,76] and insulin resistance [77].

The formation of pigment gallstones appear to be poorly related to major metabolic defects, although the gallbladder of patients with stones displays an intermediate form of hypomotility, compared to that in cholesterol gallstone patients [78–80]. The pathogenesis of pigment stones involves abnormalities in the bilirubin metabolism in the gut-liver axis, and risk factors include hemolytic anemias, liver cirrhosis, Crohn’s disease, cystic fibrosis, extended ileal resection, biliary infection (Escherichia coli, Clonorchis sinensis, roundworms), vitamin B-12/folic acid deficient diets, and aging. Genetic factors include UGT1A1 mutation [1,2].

4. May the metabolic syndrome be caused by cholecystectomy?

Cholecystectomy remains the main surgical approach for the treatment of gallstone disease of any type [1–3,13,66,81], with an optimal outcome in terms of morbidity and morbidity within the medium- and long-term period [66,82,83]. The indications for cholecystectomy include symptomatic gallstones (biliary colic) with or without complications, asymptomatic gallstones at increased risk for gallstone complications or gallbladder carcinoma, such as porcelain gallbladder and polyps > 1 cm or any size, if even small asymptomatic gallstones, biliary sludge, and acalcolous cholecystitis [1] Gastrointestinal symptoms (i.e., dyspepsia and vague abdominal non-colicky pain) may persist in about 40% of cases after surgery since they are not necessarily dependent on the physical presence of stone(s) [84].

Several pathophysiological and clinical changes are anticipated after cholecystectomy (Table 2, Figs. 1A, 1B), a procedure associated with loss of reservoir-concentrating function of the gallbladder [16,49,85]. The intestine will act as the major BA reservoir and BA synthesis will show a twofold increase [53], despite a significant reduction in serum FGF19 concentrations (mostly gallbladder-derived). Cholecystectomy prevents the expansion of the BA pool following cholesterol feeding [86–89], BA-induced inhibition of cytochrome P450 1A1 (CYP7A1, the rate limiting step enzyme of bile acid synthesis), and increase in biliary BA flux and in ileal apical sodium-dependent bile acid transporter (ASBT) expression [86]. Instead, gallbladder removal will increase the enterohepatic recirculation rates of BAs at least twice as often as normal [90], particularly during fasting [43,87,88,90–92] leading to accelerated intestinal recycling [89,93,94], increased secretion rates of BAs and cholesterol in bile [90] and preserved fat absorption [95]. This novel anatomical condition, by increasing bacterial deconjugation and dehydroxylation of BAs, leads to increased proportion of secondary BAs[90,92,96–99] within accelerated intestinal recycling and likely changes in the intestinal microbiota [96,100]. Such changes might induce osmotic diarrhea, secondary to accelerated colonic transit time [93].

Table 2.

Potential metabolic consequences of cholecystectomy.

Effect	Reference(s)
Lost reservoir-concentrating function of the gallbladder	[16,49,85]
Increased BA synthesis	[53]
Increased secretion rates of BAs and cholesterol in bile	[90]
Increased hepatic expression of enzymes catalyzing BA synthesis, including CYP7A1, the sodium taurocholate cotransporting polypeptide (Ntcp) in the liver, and ileal BA transporters (ASBT, IBABP)	[98]
Increased enterohepatic recirculation rates of BAs particularly during fasting	[43,87,88,90–92]
Increased intestinal availability of BAs and increased possibility for biosynthesis of more cytotoxic secondary BAs by gut microbiota	[89,90,92,96,97,145]
Increased colonic concentration of BAs deriving from increased recycling across the enterohepatic circulation	[89,93,94]
Altered glucose homeostasis	[39,73]
Increased risk for high blood pressure and cardiovascular disease	[102,106]
Increased risk of NAFLD	[88,104,106,110–113]
Increased risk of type 2 diabetes	[106]
Weight gain	[73,107]
Increments in serum insulin levels and increased risk for insulin resistance	[73,113]
Changes in serum lipids	[88,102,108,109]
Increased chance for liver damage due to secondary BAs	[98,99]

Abbreviations: ASBT, apical sodium-dependent bile acid transporter; BAs, bile acids; IBABP, ileal bile acid-binding protein; NAFLD, nonalcolic fatty liver disease.

Fig. 1A.

Potential mechanisms pointing to the links between cholecystectomy and metabolic disturbances.

1) Subjects living in industrialized countries tend to accumulate metabolic abnormalities, eventually leading to the metabolic syndrome and additional “fellow travellers” such as cholesterol cholelithiasis and liver steatosis (nonalcoholic fatty liver disease, NAFLD). 2) A subgroup of subjects (not necessarily metabolically unhealthy), may develop pigment gallstones. 3) At this stage, gallstone patients usually require cholecystectomy if asymptomatic cholelithiasisbecomes symptomatic, with or without complications. 4) The loss of multiple gallbladder functions leads to accelerated enterohepatic circulation of both hepatic primary (cholic acid, chenodeoxycholic acid), and intestinal secondary (deoxycholic acid, litocholic acid) and tertiary (ursodeoxycholic acid) bile acids (BAs).Under these circumstances, changes may occurr at the level of interaction between: a) intestinal BAs - farnesoid X receptor (FXR) and release of fibroblast growth factor 19 (FGF19); b) intestinal BAs - G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) and release of glucagon-like peptide-1 and 2 (GLP1/2) and peptide YY (PYY) with important metabolic effects on glucose, insulin metabolism and appetite; c) serum BAs and hepatocyte FXR and Kupffer cell GPBAR-1 with inhibition of BA synthesis as well as on brown adipose tissue and striated muscle GPBAR-1 with additional metabolic effects. See text for details. 5) A role for single nucleotide polymorphisms (SNP) is also emerging with influence on the nuclear receptor-mediated mechanisms leading to the development of metabolic syndrome and the level of risk in some individuals. LXR, liver X receptor; PXR, pregnane X receptor.

Fig. 1B.

Additional pathways linking cholecystectomy and metabolic disturbances, including liver steatosis.

After cholecystectomy, the dynamic reservoir function of the gallbladder controlled by neural mechanisms and entero-hormones (i.e. stimulatory fasting motilin and postprandial cholecystokinin and inhibitory myorelaxant vasoactive intestinal peptide, VIP) is lost. Also lost are the gallbladderreceptors fibroblast growth factor receptor 4 (FGFR4), targeted by FGF19 and G protein-coupled receptor (GPBAR-1) targeted by BAs both leading to gallbladder relaxation. Improved clinical conditions, increased caloric and fat intake might account for some of the metabolic changes associated with production of adypocyte-derived products and a chronic pro-inflammatory status. While the BA pool decreases and the intestine acts as the major bile acid reservoir, cholecystectomy increases the enterohepatic recirculation rates of BAs at least twice as often as normal especially during fasting, a step leading to accelerated intestinal recycling, increased secretion rates of BAs and cholesterol in bile with preserved fat absorption. Increased bacterial deconjugation and dehydroxylation of BAs will increase the proportion of secondary BAs due to accelerated intestinal recycling and likely changes of intestinal microbiota. Cholecystectomy is also associated to a twofold increase in BA acid synthesis, irrespective of a significant reduction in serum FGF19 concentrations which is mostly gallbladder-derived. Further metabolic effects of cholecystectomy are mediated by elevated serum BA concentrations, increased tissue exposure to BAs and increased basal metabolic rate. GPBAR-1 stimulation might decrease after cholecystectomy, but GPBAR-1-mediated metabolic effects include slight deterioration of postprandial glycemic, increased serum and hepatic triglyceride levels, and production of very low density lipoproteins. The changes occurr irrespective of gallstone disease per se and point to the steatogenic effect in the liver and propension to metabolic syndrome. Epigenetic changes might also play a role in the pro-steatogenic effect in the liver. Abbreviations: ChREBP, carbohydrate-responsive element-binding protein; DNL, de novo lipogenesis; IL, interleukin; PKCε protein kinase Cε; SREBP, sterol regulatory element-binding protein 1; TNF, tumor necrosis factor. Symbols: ↑ , increased; ↓, decreased; (−), inhibition.

The metabolic effects of cholecystectomy are mediated by elevated serum BA concentrations, increased tissue exposure to BAs and increased basal metabolic rate [101], likely GPBAR-1-mediated effect. The lack of the reservoir/concentrating function occurring after cholecystectomy might affect the homeostasis of glucose [73] and lipids, and may increase the risk for high blood pressure and cardiovascular disease [102].

Slightly deterioration of postprandial glycemic control can occurr after cholecystectomy [39]. Cholecystectomy is reported to increase serum and hepatic triglyceride levels, and the production of very low density lipoproteins, pointing to the steatogenic effect in the liver [88], propension to metabolic syndrome [73,102,103], irrespective of gallstone disease per se [103–105].

Cholecystectomized patients are exposed to disturbed glucose homeostasis with elevated postprandial glucose excursions and reduced postprandial concentrations of duodenal BAs. Serum levels of the incretin hormone, glucagon-like peptide-1 (GLP-1), remain unchanged [39]. A study in 881 cholecystectomized Chilean Hispanics reported anincreased prevalence of NAFLD, hypertension, and type 2 diabetes mellitus [106]. In a study of 103 patients in the UK, cholecystectomy was associated with a significant weight gain after six months from surgery, irrespective of gender [107]. Another Chinese study on 5672 patients showed relationships between cholecystectomy and weight gain, higher fasting blood glucose levels and overall metabolic syndrome [73]. A recent study in a group of 50 gallstone patients documented, one month after cholecystectomy, a significant improvement in serum lipid levels, with decrement in total cholesterol and triglycerides levels and increased high-density lipoproteins [108]. These changes, however, could be time-dependent. A Finnish study in cholecystectomized subjects found a short-term (3 days) transient decrement of total and HDL cholesterol concentrations and a long-term (three years after surgery) increase of very-low-density (VLDL) and intermediate-density apo-B lipoproteins (IDL-apoB), pointing to altered enterohepatic metabolism of cholesterol, linked to unbalanced lipoproteins [109].Similar results were confirmed in 798 Mexican patients, with cholecystectomized subjects having increased metabolic risk factors for cardiovascular disease, i.e., type 2 diabetes mellitus, hypertension, high levels of serum triglycerides, total and low-density lipoprotein (LDL) cholesterol levels, and lower HDL cholesterol levels [102]. Gallbladder removal can predispose to the development of liver steatosis [104]. In a Korean study on cholecystectomized patients, liver steatosis detected by ultrasonography increased during three months after surgery [110]. The NHANES III survey (12,232 US patients) also indicated cholecystectomy (but not gallstones) as a risk factor for the occurrence of NAFLD, the hepatic manifestation of the metabolic syndrome [111]), and a large study of 32,428 Chinese gallstone subjects showed an increased prevalence of NAFLD in cholecystectomized- (46.9%) vs. non-cholecystectomized (38.1%) patients [112]. Although, in this last study, adjusting for confounding variables did not confirm the association between cholecystectomy and ultrasonographically proven NAFLD, other metabolic parameters were abnormal in the cholecystectomized group. Conversely, another large Korean survey (17,612 gallstone patients) convincingly demonstrated a relationship between cholecystectomy (but not gallstones) and NAFLD, independently from confounders (metabolic risk factors) [104]. A prospective and case-control study in non-obese Hispanic gallstone patients undergoing elective cholecystectomy showed that two years after surgery, there were significant increments in serum insulin levels, HOMA-IR index, serum apoB levels, and hepatic fat content, as assessed by MRI [113].

5. Pathogenic pathways linking cholecystectomy to hepato-metabolic disturbances

The increased frequency of metabolic changes observed after cholecystectomy might involve distinct pathogenic pathways.

First, dietary consumption of fats and calories might increase when gallstone-related symptoms subside after cholecystectomy. This condition can generate novel metabolic alterations or could worsen previous metabolic abnormalities [107,114,115].

Second, several gallbladder functions are changed following cholecystectomy, including the reservoir and concentrating ability, the pacing enterohepatic circulation of concentrated BAs [110]. Rather, a dilute bile is constantly produced and secreted by the liver, quickly entering the intestine in the absence of the typical fluctuations secondary to fasting and postprandial gallbladder emptying [39,88] as a consequence of rhythmic neuro-hormonal gallbladder contraction and refilling episodes [78,79,116,117].

Third, the lack of the gallbladder can generate a derangement of a number of BA-mediated signaling pathways operating within the gallbladder [54,118] or systemically at other metabolically competent tissues through the involvement of the BAs/FXR and the BA/GPBAR-1 axes [26,33,119–123]. Cholecystectomy doubles BA synthesis, blunts the FGF19 diurnal rhythm, and reduces the FGF19 noon peak [53]. Cholecystectomy might also contrast some of the protective function of FGF19 in the liver, i.e., shifting the BA pool with more cytotoxic pro-inflammatory BAs, [110,124] and inhibiting the FGF19-(FGF4/β-klotho)-mediated negative feedback regulation on hepatic BA synthesis by down-regulating cholesterol 7α-hydroxylase [125,126].

The mechanisms that link cholecystectomy to NAFLD also are likely mediated by increasing hepatic secretion and recirculation kinetics of BAs and activating FXR and GPBAR-1 [121]. Low levels of serum FGF19 has been found in patients with NAFLD, [127] and this is also observed in cholecystectomized patients [53]. Thus, after cholecystectomy, reduction in serum levels of FGF19 might drive the excessive deposition of intrahepatic triglycerides, which is required for the development of NAFLD [103,128]. The mechanisms linking cholecystectomy to NAFLD might operate independently from insulin resistance [103,104,129]. NAFLD might represent a precursor of gallstone disease, but gallstone disease, as the fellow traveler with a long-standing metabolic syndrome, might represent a condition accelerating and aggravating the progression of liver steatosis to nonalcoholic steatohepatitis (NASH). The elucidations of environmental and genetic factors, diagnostic definition and severity of NAFLD require more longitudinal surveys to answer such fundamental questions.

The intestinal microbiota might also play a role in the development of NAFLD because this vast population of intestinal microbes contributes to host metabolism [130,131]. Obesity might be associated with changes of the intestinal microbiota, which include microbial diversity and function, i.e., BA dehydroxylation and peripheral insulin sensitivity highly dependent on Firmicutes phylum [132]. A recent study found that compared with controls, gallstone patients have higher concentrations of fecal BAs and a decreased microbial diversity with reduced beneficial genus Roseburia and increased Oscillospira, which correlated positively with secondary BAs. Thus, intestinal dysbiosis might be an important feature in gallstone patients [133].

Also, cholecystectomy, which changes bile flow to the intestine, could be followed by impaired interactions between BAs and the intestinal microbiota [134]. Evidence shows that surfactant protein D (SP-D), synthesized in the gallbladder and delivered in bile into the intestinal lumen, plays a critical role in maintaining symbiontic status of microbiota and their intestinal homeostasis. SP-D selectively binds to species of commensals bacteria, thereby interfering with their replication. Indeed, intestinal dysbiosis occurs in SP-D deficient mice [135]. Thus, the potential metabolic effect of cholecystectomy with respect to dysbiosis and BA metabolism requires further investigations. Both single nucleotide polymorphisms (SNPs) and epigenetic mechanisms affecting gene expression might also play a role. SNPs in genes encoding key regulators of adipocyte differentiation, fat storage and BA pathways could influence the mechanisms leading to the development of metabolic syndrome and the level of risk in some individuals. FXR SNPs have been involved in a number of diseases (including gallstone formation) and metabolic processes [136,137]. SNP in NR1H4 gene (encoding the nuclear receptors LXR and FXR, involved in BA synthesis and homeostasis) has been linked with obesity, since subjects with the AA or AG genotype for rs10860603 had a significant lower BMI and waist than those with the GG genotype [137]. SNP rs4764980 was linked with fasting glycaemia and with fasting and post-glucose load free fatty acid levels [138]. BA homeostasis and different metabolic pathways can an also be influenced by pregnane X receptor (PXR) SNPs linked with liver diseases (including NAFLD) and abnormal BA serum levels [139].

Lastly, epigenetic changes might derange gene expression. Epigenetic factors are involved in the homeostasis of metabolic processes, in particular, methylation of PGC-1α, transcription factor A, interleukin-1 beta, interleukin-6, and tumor necrosis factor-α promoters. Changes have been detected on day one after cholecystectomy in nonobese patients and in obese non-diabetic patients undergoing Roux-en-Y gastric bypass [140].

6. Summary and emerging fields

Cholecystectomy is largely performed worldwide, and remains the standard surgical procedure in symptomatic patients with gallstones of any type. However, recent evidence suggests that cholecystectomy is not a neutral event and could cause abnormal metabolic consequences. The mechanisms are likely mediated by the abnormal trans-intestinal flow of BAs that produce metabolic signaling and act without gallbladder rhythmic function in the fasting and the fed states. All of these involve the BA/FXR and the BA/GPBAR-1 axes in the liver, intestine, adipose tissue and muscle. Further homeostatic alterations might derive from changes in the intestinal microbiota, from SNPs and epigenetic changes altering the expression of genes involved in metabolic processes.

Thus, cholecystectomy may be an additional potential risk factor for the metabolic syndrome, independently of the original pathogenesis of gallstones, and even in the absence of major metabolic abnormalities prior to surgery (a possibility in pigment stone patients).

In patients with cholesterol gallstones, often harvesting already several metabolic disorders, cholecystectomy should be considered after careful selection of patients based on available clinical and epidemiological evidence, since gallbladder removal would act, at a systemic level, as a predisposing factor to the metabolic syndrome. Thus, current recommendations are further reinforced, i.e., cholecystectomy should be restricted to the subgroup of patients with symptomatic gallstones with colicky pain or complications of cholelithiasis or to the small group of patients requiring prophylactic cholecystectomy [1,4,48,66]. A further subgroup of patients with symptomatic uncomplicated cholelithiasis and small, cholesterol-enriched gallstones in a functioning gallbladder might benefit from oral litholysis with UDCA [4]. However, if cholecystectomy is unavoidable, all preventive measures including lifestyles and medical therapies should be considered to minimize additional metabolic risks.Nevertheless, both cohort surveys and experimental studies are strongly needed on this topic because of the high prevalence of cholecystectomy worldwide.

In patients at high risk, studies must address the role of SNPs and changes in gene expression secondary to epigenetic mechanisms [76,141], in order to identify tailored preventive and therapeutic strategies.

Abbreviations:

ASBT

apical sodium-dependent bile acid transporter

BAs

bile acids

CA

cholic acid

CDCA

chenodeoxycholic acid

DCA

deoxycholic acid

FGF

fibroblast growth factor

FXR

farnesoid X receptor

GPBAR-1

G-protein-coupled bile acid receptor-1 (also known as TGR5)

IBABP

ileal bile acid-binding protein

JNK

c-Jun N-terminal kinase

LCA

lithocholic acid

NAFLD

non-alcoholic fatty liver disease

UDCA

ursodeoxycholic acid