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Statins as potential treatment for cholesterol gallstones: An attempt to understand the underlying mechanism of actions
Expert Opinion on Pharmacotherapy
Abstract
Introduction:
Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decreases in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. Cholesterol gallstones are a common problem, resulting in hospital admission and surgery, throughout western healthcare systems.
Areas covered:
This review describes the mechanisms, and addresses the potential, for statins to be used as a treatment for gallstones. Medline was searched for the risk factors and treatment of cholesterol gallstones.
Expert opinion:
Obesity, metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), insulin resistance and high-fat diets (unsaturated fats) rich in cholesterol are all associated risk factors for cholesterol gallstones. In view of the high prevalence of cholesterol gallstones, there is an urgent need to understand whether pharmacological therapies can be harnessed for the treatment of cholesterol gallstones. Gallstones are shown to be associated with an increased risk, not only of mortality, but also of CVD. Statins, widely used in prevention of CVD and hypercholesteremia, have been shown to dissolve cholesterol gallstones in animal models and human studies, highlighting the potential for a pharmacological therapy for gallstones. More studies are required to understand the role of statins in the treatment of gallstones and for comparison with current treatment strategies.
... The most predominant impairments are abnormal bilirubin and lecithin levels. Ahmed et al. confirmed that serum bilirubin may bind with free metal ions, particularly calcium ions, thereby forming relevant bilirubinate [3]. Conversely, lecithin polymerizes the insoluble microparticles with bile acid during bile secretion [4]. ...
... In TCM, cholelithiasis is divided into the following five types according to the TCM syndromes: (1) Liver depression and qi stagnation (syndrome of stagnation of the liver and qi), (2) Wetness heat of liver and gallbladder (syndrome of dampness-heat of the liver and gallbladder), (3) Liver yin deficiency (liver yin deficiency syndrome), (4) Blood stasis stagnation (blood stasis syndrome), and (5) Heat-toxic stagnation. The newest guidelines for using CHCs are as follows: (1) good gallbladder function, (2) stone size < 10 mm in diameter, (3) absence of stricture at the bottom of the bile duct, and (4) applicability of CHCs for both extrahepatic and intrahepatic stones, as well as the residual stones following surgery [28]. Only few CHCs are approved by the China Food and Drug Administration (CFDA) for treating cholelithiasis. ...
Cholelithiasis is a major public health concern that necessitates highly effective, feasible, and recurrence-preventing therapies. Currently available surgical treatments and medications cannot effectively avoid the recurrence of cholelithiasis. Hence, several Chinese herbal compounds (CHCs) are considered for the treatment of cholelithiasis, considering that they can effectively discharge gallstones and prevent the recurrence of such condition. In the present narrative review, we aim to summarize the underlying mechanisms of currently used CHCs in the treatment of cholelithiasis and to describe the current situation of traditional Chinese medicine (TCM) use for cholelithiasis. Several commonly used CHCs were used to illustrate these issues. We found that the mechanisms underlying the CHC treatments rely on the amelioration of the biliary dynamics factors, maintenance and protection of the liver function, reduction of the cholesterol and bilirubin levels, and regulation of the inflammatory reactions. CHCs as treatments based on TCM can ameliorate the overall bodily function, thereby preventing the recurrence of cholelithiasis. Appropriate application of CHCs would be beneficial for patients and clinicians, although the safety and efficacy of CHCs need further verification.
... Our observed associations were modified by obesity, diabetes mellitus, and hypertension status, with perhaps counterintuitively stronger associations observed among the presumably healthier subsets of the population, ie, those without obesity, diabetes mellitus, and hypertension. In addition, because cholesterol is the main component of most gallstones and atherosclerotic plaques, and the use of statins seems to prevent gallstone formation, 25 we included hypercholesterolemia as a covariate in our statistical models and also conducted sensitivity analyses among the participants who had normal blood cholesterol levels, as well as among those not taking lipid-lowering medications, and yet the association of gallstone disease and CHD risk remained significant. Taken together, these observations may point to pathways independent of these important risk factors that link gallstone disease to CHD. ...
... Statins have been shown to dissolve cholesterol gallstones, suggesting their potential for a pharmacological therapy for gallstones beyond their well-known benefits on CHD prevention. 25 However, randomized clinical trials are warrant to test the effect of statins on gallstone disease to more clearly address this issue. 28 ...
Objective:
Gallstone disease has been related to cardiovascular risk factors; however, whether presence of gallstones predicts coronary heart disease (CHD) is not well established.
Approach and results:
We followed up 269 142 participants who were free of cancer and cardiovascular disease at baseline from 3 US cohorts: the Nurses' Health Study (112 520 women; 1980-2010), Nurses' Health Study II (112 919 women; 1989-2011), and the Health Professionals Follow-up Study (43 703 men; 1986-2010) and documented 21 265 incident CHD cases. After adjustment for potential confounders, the hazard ratio for the participants with a history of gallstone disease compared with those without was 1.15 (95% confidence interval, 1.10-1.21) in Nurses' Health Study, 1.33 (95% confidence interval, 1.17-1.51) in Nurses' Health Study II, and 1.11 (95% confidence interval, 1.04-1.20) in Health Professionals Follow-up Study. The associations seemed to be stronger in individuals who were not obese, not diabetic, or were normotensive, compared with their counterparts. We identified 4 published prospective studies by searching PUBMED and EMBASE up to October 2015, coupled with our 3 cohorts, involving 842 553 participants and 51 123 incident CHD cases. The results from meta-analysis revealed that a history of gallstone disease was associated with a 23% (15%-33%) increased CHD risk.
Conclusion:
Our findings support that a history of gallstone disease is associated with increased CHD risk, independently of traditional risk factors.
... 1 Moreover, the chronic use of some drugs (eg, octreotide, thiazide diuretics, and some oral contraceptives) may also increase the risk of developing GD. 1 In contrast, long-term statin use seems to prevent gallstone formation, possibly by decreasing biliary cholesterol secretion and saturation and inhibition of cholesterol crystal formation. 1,2 The rising pandemic of obesity and the metabolic syndrome is likely to lead to an increase in the prevalence of gallstones in many parts of the world in the foreseeable future. ...
... Gallstone Disease and IHD 2075 that long-term statin therapy in patients with GD might exert a beneficial effect not only on IHD prevention but also on the cholesterol gallstone formation, consequently decreasing the need for cholestectomy. 2 However, it is likely that new randomized clinical trials are needed to test the effect of statins on GD to address this issue. ...
Gallstone disease (GD) is a major health problem in developed societies, affecting up to 15% of the general
population.1 Although many risk factors for gallstone formation are not modifiable; obesity, diabetes,
metabolic syndrome, rapid weight loss and a sedentary lifestyle are risk factors for GD that can be
changed.1 Moreover, the chronic use of some drugs (e.g., octreotide, thiazide diuretics and some oral
contraceptives) may also increase the risk of developing GD.1 In contrast, long-term statin use seems to
prevent gallstone formation, possibly by decreasing biliary cholesterol secretion and saturation and
inhibition of cholesterol crystal formation.1,2 The rising pandemic of obesity and the metabolic syndrome is
likely to lead to an increase in the prevalence of gallstones in many parts of the world in the foreseeable
future.
... 1 Moreover, the chronic use of some drugs (eg, octreotide, thiazide diuretics, and some oral contraceptives) may also increase the risk of developing GD. 1 In contrast, long-term statin use seems to prevent gallstone formation, possibly by decreasing biliary cholesterol secretion and saturation and inhibition of cholesterol crystal formation. 1,2 The rising pandemic of obesity and the metabolic syndrome is likely to lead to an increase in the prevalence of gallstones in many parts of the world in the foreseeable future. ...
... Gallstone Disease and IHD 2075 that long-term statin therapy in patients with GD might exert a beneficial effect not only on IHD prevention but also on the cholesterol gallstone formation, consequently decreasing the need for cholestectomy. 2 However, it is likely that new randomized clinical trials are needed to test the effect of statins on GD to address this issue. ...
Gallstone disease (GD) is a major health problem in developed societies, affecting ≤15% of the general population.1 Although many risk factors for gallstone formation are not modifiable, obesity, diabetes mellitus, metabolic syndrome, rapid weight loss, and a sedentary lifestyle are risk factors for GD that can be changed.1 Moreover, the chronic use of some drugs (eg, octreotide, thiazide diuretics, and some oral contraceptives) may also increase the risk of developing GD.1 In contrast, long-term statin use seems to prevent gallstone formation, possibly by decreasing biliary cholesterol secretion and saturation and inhibition of cholesterol crystal formation.1,2 The rising pandemic of obesity and the metabolic syndrome is likely to lead to an increase in the prevalence of gallstones in many parts of the world in the foreseeable future.
See accompanying article on page 2232
Interestingly, in this issue of the journal, Lv et al3 examined the association between GD (as diagnosed by a standardized questionnaire) and the risk of incident ischemic heart disease (IHD) among 199 292 men and 288 081 women aged 30−79 years in the China Kadoorie Biobank study. Participants with a previous history of cancer, IHD, and stroke at baseline were excluded from the study. At baseline, 5.8% of 487 373 adult participants reported the presence of GD (men 3.7%; women 7.3%). During a median follow-up period of 7.2 years, there were 10 245 incident cases of IHD (≈90% nonfatal) in men and 14 714 (≈95% nonfatal) in women. The authors found that GD was associated with an increased incidence of IHD events (ie, a combined end point inclusive of fatal and nonfatal events), independently of multiple cardiovascular risk factors. As compared with those subjects without GD at baseline, the multivariate-adjusted hazard ratios for IHD were, respectively, 1.11 (95% confidence interval 1.02−1.22) …
... Numerous studies have confirmed that fatty liver is closely associated with gallstones. The incidence of gallstones was significantly higher in fatty liver patients than in the normal population, especially in those with nonalcoholic steatohepatitis [46,47] . An epidemiological survey of 14760 cases showed that in the Urumqi region of Xinjiang [48] , 17.33% of fatty liver patients had gallstones, compared with 9.21% of the non-fatty liver group. ...
... Liver function is thus damaged, leading to a reduction in the synthesis of bile acids and phospholipids in the liver, and in turn, a deficiency of cholinergic and non-saturated fatty acids. At the same time, the fatty liver combined with dyslipidaemia would promote the supersaturation of cholesterol in the bile, and these three factors would work together to accelerate the formation of gallstones [47,52,53] . ...
Aim:
To perform a single-centre survey of the prevalence of and possible risk factors for gallstones in Uighur and Han Chinese.
Methods:
Complete medical data for 9455 patients were collected from the medical centre of our hospital, and the overall prevalence of gallstones as well as the prevalence in different ethnic groups was studied. The risk factors for gallstones in different ethnic groups were identified in a univariate analysis, and variables with statistical significance were analysed by unconditional multiple logistic regression, to primarily explore the similarities and differences in gallstone risk factors between different ethnic groups.
Results:
The prevalence of gallstones was significantly higher in the Uighur population than in the Han population (22.87% vs 11.64%, P < 0.05). Further analysis of risk factors for gallstones based on the different ethnic areas revealed that age was a risk factor for gallstones in both groups; triglycerides, body-mass index (BMI) and high-density lipoprotein were risk factors for gallstones in the Han population, while total cholesterol (TC), gender and fatty liver were risk factors in the Uighur population. The Uighur patients were older than the Han patients, and had higher BMI, TC, low-density lipoprotein, female rate and fatty liver rate, while the incidence of hypertension was lower than that in the Han patients.
Conclusion:
The prevalence of and risk factors for gallstones differ between the Uighur and Han populations.
... Human studies have shown potential benefit of statins in treating cholesterol gallstones [2,3]. A summary of the mechanisms involved have been reviewed by Ahmed et al. [4]. ...
... Research to assess the impact of lipid-lowering medication on cholesterol gallstones is urgently needed due to various reasons, which include the association between cholesterol gallstones and cardiovascular disease [4]. The wide use of statins as treatment for cardiovascular disease may allow easy recruitment to studies looking at the effects of statins on cholesterol gallstones. ...
... Epidemiological studies have demonstrated that longterm oral therapy with statins reduces the risk of symptomatic gallstones disease [7,8] . Recent articles have proposed the therapeutic use of statins for the medical treatment of cholesterol gallstones [14]. The reported data about gallstones recurrence after oral biliary salts dissolution is 10% per year [1]. ...
... The reported data about gallstones recurrence after oral biliary salts dissolution is 10% per year [1]. The combination of statins and ursodeoxycholic acid has been more effective in cholesterol gallstone dissolution than ursodeoxycholic acid treatment alone [14]. Ezetimibe reduces cholesterol concentrations and can inhibit gall bladder stasis secondary to cholesterol-supersaturated bile [15]. ...
The prevalence of gallstones disease in Western countries is 10 - 15%. Gallstones can be one of two types - cholesterol or pigment - with cholesterol gallstones representing nearly the 80% of the total. Cholesterol and pigment gallstones have different predisposing factors: cholesterol gallstones are related to supersaturated bile in cholesterol, whereas black pigment gallstones are related to hyperbilirubinbilia factors (hemolysis, etc.); these are necessary, but not sufficient, factors to produce gallstones in vivo. Gall bladder mucosa factors (gall bladder secretion of mucin, local bile stasis and production of endogenous biliary β-glucuronidase) may coexist with the aforementioned factors and facilitate gallstone nucleation and growth. The gold-standard treatment for symptomatic gallstones is laparoscopic cholecystectomy. Several studies have reported a significant reduction in the onset of symptomatic gallstones disease in patients undergoing chronic therapy with statins, which can reduce bile cholesterol saturation. Aspirin, which has been shown to reduce the local production of gall bladder mucins (mucosal or parietal factors of gallstone formation) in animal experimental models, does not appear to reduce the risk of symptomatic gallstones disease when tested alone. The new horizon of oral therapy for the prevention of symptomatic gallstone disease needs to evaluate the long-term effect of statins and chronic aspirin administration in patients with dyslipidemia and/or atherosclerosis.
... The statins work by inhibiting HMG-CoA reductase, which catalyses the conversion of the substrate, HMG-CoA, to mevalonate; this reaction is an early and rate-limiting step in the biosynthesis of cholesterol. [49] At high doses, statins decrease triglyceride levels through the clearance of very low-density lipoprotein (VLDL) as well as by decreasing the production of lipoproteins [51] As oxidative alteration of low-density lipoprotein (LDL) appears to be an important mechanism mediating the uptake of lipoprotein cholesterol by macrophages, statins help to lower the susceptibility of lipoproteins to oxidation. [56] Certain statins work by preventing the intestine's brush border from absorbing cholesterol, which lowers the quantity of lipoprotein cholesterol that is transported to the liver. ...
... Statins are widely used anti-hyperlipidemic agents that act as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA-reductase) inhibitors [43]. Not only do statins lower cholesterol levels but they also have many pleiotropic effects including reduction of vascular inflammation, improvement of endothelial function, and inhibition of platelet aggregation [44]. ...
A global threat has emerged in 2019 due to the rapid spread of Coronavirus disease (COVID-19). As of
January 2021, the number of cases worldwide reached 103 million cases and 2.22 million deaths which
were confirmed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This global pandemic
galvanized the scientific community to study the causative virus (SARS-CoV2) pathogenesis,
transmission, and clinical symptoms. Remarkably, the most common complication associated with this
disease is the cytokine storm which is responsible for COVID-19 mortality. Thus, targeting the cytokine
storm with new medications is needed to hamper COVID-19 complications where the most prominent
strategy for the treatment is drug repurposing. Through this strategy, several steps are skipped especially
those required for testing drug safety and thus may help in reducing the dissemination of this
pandemic. Accordingly, the aim of this review is to outline the pathogenesis, clinical features, and
immune complications of SARS-CoV2 in addition to suggesting several repurposed drugs with their
plausible mechanism of action for possible management of severe COVID-19 cases.
... Various pathogenic mechanisms have been suggested as possible explanations for GD and CVD. Cholesterol accumulation is a major component in atherosclerotic CVD and GD (15,25). These disorders share common risk factors, including age, sex and obesity, as well as lipid and glucose metabolism disorders, which are also key components of metabolic syndrome (MS) (26,27). ...
Increasing evidence connects gallstone disease (GD) to cardio-cerebrovascular disease (CVD). The aim of the present systematic review and meta-analysis was to determine whether and to what extent an association between GD and CVD existed. PubMed, EMBASE and the Cochrane Library were systemically searched up to March 3rd, 2018. A total of 10 studies (1,272,177 participants; 13,833 records; 5 prospective cohorts and 5 retrospective cohorts) were included. It was demonstrated that GD was associated with an increased risk of incidence [hazard ratio=1.24, 95% (CI) confidence interval: 1.17–1.31] and prevalence (unadjusted odds ratio=1.23, 95% CI: 1.21–1.25) of CVD. In conclusion, the presence of GD was associated with an increased risk of CVD incidence and prevalence. The association may be influenced by age and sex. These findings suggest that individuals identified with cardio-cerebrovascular disease should be evaluated for GD.
... All other therapeutic options are currently not supported by strong scientific evidence or require further studies 40,94,105,169,200 . intestinal absorption of cholesterol such as ezetimibe 79,95,[201][202][203][204][205][206][207] ; nuclear receptor modulators 99,208-212 such as 6EUDCA, a synthetic derivative of UDCA acting as FXR modulator 99 , or piperine, an alkaloid able to inhibit ABCG5/8 and LXR expression in the liver reducing biliary cholesterol secretion 100 ; possible modulators of gut microbiota 112 ; dietary/lifestyle models 64,65,184,213 ; pharmacologic agents acting on gallbladder hypomotility 121,214,215 ; and inflammatory cytokine modulators 216-218 . ...
The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. From an epidemiologic point of view, the risk of gallstones has been associated with higher risk of incident ischemic heart disease, total mortality, and disease-specific mortality (including cancer) independently from the presence of traditional risk factors such as body weight, lifestyle, diabetes, and dyslipidemia. This evidence points to the existence of complex pathogenic pathways linking the occurrence of gallstones to altered systemic homeostasis involving multiple organs and dynamics. In fact, the formation of gallstones is secondary to local factors strictly dependent on the gallbladder (that is, impaired smooth muscle function, wall inflammation, and intraluminal mucin accumulation) and bile (that is, supersaturation in cholesterol and precipitation of solid crystals) but also to “extra-gallbladder” features such as gene polymorphism, epigenetic factors, expression and activity of nuclear receptors, hormonal factors (in particular, insulin resistance), multi-level alterations in cholesterol metabolism, altered intestinal motility, and variations in gut microbiota. Of note, the majority of these factors are potentially manageable. Thus, cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (surgery and, in a small subgroup of subjects, oral litholysis with bile acids), could be managed with tools oriented to primary prevention (changes in diet and lifestyle and pharmacologic prevention in subgroups at high risk), and there could be relevant implications in reducing both prevalence and health costs.
... Finally, the ATP-binding cassette (ABC) transporters ABCB4 [also known as multidrug resistance protein 2 (Mdr2)], ABCB11 [also known as bile salt export pump (Bsep)] and ABCG5/ABCG8 heterodimers serve essential roles in the biliary secretion of phospholipids, bile acids and cholesterol, respectively (6). Regulation of cholesterol metabolism is a therapeutic target, and statins are reported to be effective to treat gallstone disease (7) and to reduce the risk of cholecystectomy (8). However, the efficacy of statin treatment for gallstone diseases remains under debate (9). ...
Gallstone disease is one of the most prevalent and costly gastrointestinal disorders worldwide. Gallstones are formed in the biliary system by cholesterol secretions in bile, which result from excess cholesterol, a deficiency in bile salts or a combination of the two. The present study examined the effects of proteasome inhibition on gallstone formation using the proteasome inhibitors bortezomib (BT) and carfilzomib (CF). C57BL/6J mice were fed a lithogenic diet to generate gallstones and injected with BT or CF for 12 weeks. After 12 weeks of the lithogenic diet, 8 out of the 10 mice in the control group had developed gallstones, whereas none of the mice who received proteasome inhibitors had developed gallstones. Notably, the expression of genes associated with cholesterol synthesis (sterol regulatory element‑binding protein‑2 and 3‑hydroxy‑3‑methylglutaryl‑CoA reductase), cholesterol secretion [ATP‑binding cassette subfamily G member 5 (ABCG5) and ABCG8] and bile acid synthesis [cytochrome P450 family 7 subfamily A member 1 (Cyp7a1), Cyp7b1, Cyp27a1 and Cyp8b1] was reduced in the livers of mice injected with BT or CF. Cyp7a1 encodes cholesterol 7α‑hydroxylase, the rate‑limiting enzyme in the synthesis of bile acid from cholesterol. The present study therefore measured the expression levels of transcription factors that are known to inhibit Cyp7a1 expression, namely farnesoid X receptor (FXR), pregnane X receptor (PXR) and small heterodimer partner (SHP). Although FXR, PXR and SHP expression was predicted to increase in the presence of proteasome inhibitors, the expression levels were actually reduced; thus, it was concluded that they were not involved in the proteasome inhibition‑induced regulation of Cyp7a1. Further investigation of the mitogen‑activated protein kinase and protein kinase A (PKA) signaling pathways in human hepatoma cells revealed that proteasome inhibition‑induced c‑Jun N‑terminal kinase (JNK) phosphorylation reduced CYP7A1 and CYP27A1 expression. In addition, reduced PKA phosphorylation as a result of proteasome inhibition regulated ABCG5 and ABCG8 expression. In conclusion, these findings suggest that proteasome inhibition regulates cholesterol and biliary metabolism via the JNK and PKA pathways, and is a promising therapeutic strategy to prevent gallstone disease.
... С целью влияния на холестериновые желчные камни в качестве новой стратегии рассматривается применение гиполипидемических препаратов. По результатам нескольких исследований показано значительное снижение частоты симптомной ЖКБ у пациентов, принимающих статины, которые способны уменьшать насыщение желчи холестерином [14,22]. На фоне приема статинов значительно снижается вероятность холецистэктомии у женщин в США (в мультивариантном анализе относительный риск 0,88, 95%-й доверительный интервал 0,79-0,98, p < 0,05) [61]. ...
Summary
Investigating the relationship between gallstone disease and arterial hypertension in the epi-demiological study in the frame of WHO Programme «MONICA», performed in 1994-1995 years among representative sample from female population in Novosibirsk aged 25-64, it was shown that arterial hypertension was met more often (41,6%) in women with gallstone disease compared with women without gallstones (30,1%). Arterial hypertension was identified among 31,7% Pakistani patients with gallstone disease, but in the Chinese population in 1999 this association was not found. Decrease of high density lipoprotein blood level and hypertriglyceridemia are common risk factors for gallstone disease and arterial hypertension. However, the presence of arterial hyperten-sion in patients with gallstone disease, according to our epidemiological study, was not accompanied by changes in the blood lipid profile.
Key words: gallstone disease, arterial hypertension, dyslipidemia.
Распространенность желчнокаменной болезни (ЖКБ) в экономически развитых странах мира составляет от 10-15% до 30% населения [1]. ЖКБ находится на втором месте по частоте после язвенной болезни желудка и двенадцатиперстной кишки среди гастроэнтерологических заболеваний [5] и на третьем месте после сердечно-сосудистых заболеваний и сахарного диабета в структуре общетерапевтической патологии [7]. Среди хирургических пациентов с хроническими заболеваниями органов брюшной полости больные ЖКБ занима-ют первое место [9]. За последние 40 лет заболеваемость ЖКБ удваивалась каждые 10 лет [5]. Это связано не только с абсолютным учащением данной патологии, но и с возможностя-ми ранней (до развития хирургических осложнений) диагностики, в связи с массовостью и доступностью УЗИ органов брюшной полости [9].
Известно, что по составу около 75-80% всех желчных камней являются холестериновыми, остальные – билирубиновыми и смешанными [22]. В образовании пигментных камней имеют значение заболевания, сопровождающиеся хроническим гемолизом, а также алкогольный цирроз печени, инфекция желчевыводящих путей [5]. У женщин чаще выявляются холестериновые камни, а пигментные камни встречаются одинаково часто у женщин и муж-чин [19]. Эти данные коррелируют с большей – в 2-5 раз – распространенностью ЖКБ в жен-ской популяции по сравнению с мужской [3, 5]. В г. Новосибирске по данным эпидемиоло-гического обследования населения, проведенного в рамках программы ВОЗ «MONICA» в 1994-1995 годах, распространенность ЖКБ в женской и в мужской популяциях в возрасте 35-54 лет при УЗИ желчных путей составила 8,3 и 4,7%, соответственно, а среди женщин 25-64 лет – 10,5% [3]. Такая зависимость от пола, возможно, обусловлена гормональными причинами.
Во многих исследованиях подтверждена связь риска ЖКБ с наличием беременностей, количеством родов [26], заместительной эстрогенотерапией [3, 53]. Показано, что эстрогены повышают литогенность желчи за счет увеличения насыщения ее холестерином и снижения пула хенодезоксихолевой кислоты [32], снижают сократительную функцию желчного пузыря [3, 4, 62]. Некоторые авторы также связывают снижение скорости опорожнения желчного пузыря с повышением чувствительности рецепторов в стенке пузыря к прогестерону [3]. Кроме того, у беременных женщин, за счет частичного «переключения» энергетических прцессов с углеводных на липидные [11], может меняться липидный профиль: во втором триместре беременности отмечено повышение уровня общего холестерина (ОХС) на 50%, а уровня триглицеридов (ТГ) – на 150% [30]. Гендерные различия c преобладанием ЖКБ у женщин очевидны в молодом возрасте и постепенно нивелируются по мере взросления, особенно после менопаузы [39].
В восточно-азиатской популяции более распространенными являются коричневые пигментные камни, ассоциированные с билиарной инфекцией и паразитами [57]. Однако если еще 30-40 лет назад в Корее преобладали пигментные камни [40], то сегодня, вероятно, из-за вытеснения традиционного питания высококалорийными «западными диетами», все большее распространение получают холестериновые камни [69].
Предрасполагающими факторами к развитию холестериновых камней являются: воз-раст, избыточный вес, наследственный анамнез, этническая принадлежность, группа крови А (II) или 0 (I), чрезмерное употребление жирной пищи с высоким содержанием холестерина, животных жиров, белков, легкоусвояемых углеводов, редкий прием пищи, голодание, быстрая потеря веса, аномалии развития желчного пузыря, беременность, длительный прием некоторых медикаментов, способствующих литогенезу (клофибрат, диуретики, пероральные контрацептивы, никотиновая кислота, октреотид, циклоспорин А, цефтриаксон и др.), низкая физическая активность [3, 5, 57].
В связи с широкой распространенностью сердечно-сосудистых заболеваний (ССЗ) в популяции, в частности, артериальной гипертензии (АГ) – 22,9% лиц страдают АГ в развивающихся странах и 37,3% - в развитых [12], нам представляется актуальным изучение возможной связи этих двух заболеваний. Некоторые факторы риска ЖКБ и АГ являются общими: женский пол, возраст, ожирение, гипоальфахолестеринемия, гипертриглицеридемия, низкая физическая активность, сахарный диабет [3, 12].
В многочисленных исследованиях показана связь между ЖКБ и повышенным риском ССЗ. По данным Mendez-Sanchez N. с соавт. (2005), у больных ЖКБ повышена смертность от ССЗ, пациенты с ИБС, в свою очередь, имеют повышенный риск развития ЖКБ (OR 2.84, 95% CI: 1.33-6.07, p<0.007) [44]. В другом исследовании среди женщин обнаружено преоб-ладание случаев инфаркта миокарда у больных ЖКБ [67]. В более поздней работе Mendez-Sanchez N. с соавт. (2008) выяснили, что 38,7% больных ЖКБ имеют повышенную толщину слоя интима-медия в сонной артерии по сравнению с группой контроля (без ЖКБ) - 20%, а значит, по мнению авторов, повышенный риск инсультов и инфарктов миокарда [46]. По данным Григорьевой И.Н. с соавт. (2005), в эпидемиологическом исследовании обнаружена корреляция между ЖКБ и АГ, ЖКБ и ИБС у женщин при отсутствии такой зависимости у мужчин. При этом показано, что наличие АГ у больных с ЖКБ обоих полов не сопровождалось изменением липидного профиля [2].
Среди наиболее значимых факторов риска развития ЖКБ, наряду с окружностью талии, ИМТ, инсулинорезистентностью, указывается повышенное АД [44]. В работе Chavez-Tapia N.C. с соавт. (2012) было выявлено, что пациенты с ЖКБ, подвергшиеся холецистэктомии, по сравнению с группой контроля (без ЖКБ), имеют большее количество факторов риска ССЗ, независимо от возраста, пола и индекса массы тела, среди которых, помимо сахарного диабета (p<0,018), отмечены дислипидемия (p<0,004) и повышенное АД (p<0,001) [23]. Доказано, что 26% смертельных исходов холецистэктомии (открытым и лапароскопическим доступом) по поводу острого или хронического калькулезного холецистита обусловлено сердечно-сосудистой патологией [51].
При изучении китайской популяции в работе Chen C.Y. с соавт. (1999) сообщается об отсутствии ассоциации ЖКБ и повышенного АД [24], однако в исследовании Xu Q. с соавт. (2012) показана взаимосвязь развития желчных камней с АГ в анамнезе [68]. Согласно дан-ным Григорьевой И.Н. с соавт. (2005), среди женщин с ЖКБ АГ встречается достоверно ча-ще (41,6%) по сравнению с женщинами без ЖКБ (30,1%) [2]. В исследовании Muhammad N. с соавт. (2012) среди 410 пакистанских пациентов с ЖКБ АГ выявили в 31,7% случаев [49].
По мнению ряда авторов, ЖКБ, наряду с повышенным АД, относится к проявлениям метаболического синдрома [45]. Согласно исследованию Cojocaru C. с соавт. (2010), наличие 4 или 5 компонентов метаболического синдрома (окружность талии, ИМТ, гликемия натощак, инсулинемия и индекс инсулинорезистентности, АД > или = 130/85 мм рт. ст.) повышают риск развития ЖКБ в 3 раза (OR = 3.3, p < 0.001), при отсутствии статистически выраженного влияния дислипидемии [27].
До сих пор нет единого мнения по наличию ассоциации между холелитиазом и дислипидемией: одни авторы подтверждают гиперлипидемию у больных ЖКБ [3, 11, 70], другие не находят различий в липидном спектре у больных с и без ЖКБ [15, 17]. По мнению Thijs C. с соавт. (1990), неоднозначность результатов исследований можно объяснить тем, что липи-ды сыворотки крови, измеряемые в произвольный момент, не могут соответствовать истин-ной концентрации сывороточных липидов в критическое время образования желчных кам-ней [60].
Публикуются противоречивые данные по снижению гиперхолестеринемии после оперативного лечения ЖКБ. У лиц с конкрементами в желчном пузыре и у лиц, перенесших холецистэктомию по поводу ЖКБ, не обнаружено разницы между средними значениями липидов сыворотки крови, в том числе и между стандартизованными по возрасту показателями [2]. В исследовании Juvonen T. с соавт. (1995) показано достоверное снижение ОХС и ХС липопротеинов низкой плотности (ЛПНП) на третий день после холецистэктомии (p=0.0048 и p=0.0239), но возвращение этих показателей на предоперационный уровень в последующем, и увеличение концентрации липопротеинов очень низкой плотности (ЛПОНП) и липо-протеинов промежуточной плотности (ЛППП) аполипопротеина В через 3 года после опера-ции (p=0.0019 и p=0.0001) [37]. Согласно более поздней работе Malik A.A. с соавт. (2011), уровень ОХС, ЛПНП, ТГ снижаются после холецистэктомии на третий день и остаются сниженными через 6 месяцев после операции, что может иметь значение в снижении риска развития коронарной патологии. Значимого изменения уровня ЛПВП через 6 месяцев после операции не наблюдалось [43]. Ввиду того, что снижение концентрации ОХС в крови после удаления желчного пузыря по поводу ЖКБ может свидетельствовать о некотором позитив-ном влиянии холецистэктомии на риск ССЗ, необходимы дальнейшие исследования в этой области.
С целью влияния на холестериновые желчные камни в качестве новой стратегии рассматриавается применение гиполипидемических препаратов. По результатам нескольких исследований показано значительное снижение частоты симптомной ЖКБ у пациентов, при-нимающих статины, которые способны уменьшать насыщение желчи холестерином [14, 22]. На фоне приема статинов значительно снижается вероятность холецистэктомии у женщин в США (в мультивариантном анализе RR=0,88, 95% CI, 0,79-0,98, p<0,05) [61]. Обсуждается также включение в план терапии больных с холестериновыми желчными камнями блокатора кишечной абсорбции холестерина эзетимиба [3]. Однако данная тактика не относится к гиполипидемической терапии фибратами, которые, наоборот, увеличивают риск ЖКБ за счет гиперхолестеринбилии и снижения синтеза желчных кислот. Остается неясным влияние безафибрата на образование желчных камней ввиду его свойства улучшать моторику желчного пузыря [58].
Помимо клинико-лабораторных параметров, в мире активно изучают генетические факторы риска ЖКБ, дислипидемии и АГ, в частности, полиморфизм гена аполипопротеина Е (APOЕ). Аполипопротеин Е – это белок, который входит в состав липопротеинов очень низкой, промежуточной и высокой плотности, а также ремнантов хиломикронов, и играет ключевую роль в транспорте липидов в плазме крови. Наиболее часто встречающиеся аллели гена APOЕ – Е2, Е3 и Е4 [35].
Известно, что фенотип APOЕ4 ассоциирован с повышенной кишечной абсорбцией холестерина (ХС) [38], с пониженным содержанием дезоксихолевой кислоты в желчи [55], с повышенным содержанием ХС в гепатоцитах и, вследствие этого, увеличенным уровнем липопротеинов низкой плотности в сыворотке крови и гиперсекрецией ХС в желчь [38, 47]. Фенотип АРОЕ2, наоборот, ответственен за сниженную кишечную абсорбцию ХС [38], замедленное усвоение ХС печенью [65] и значительный рост синтеза желчных солей [16, 47]. Однако, полученные в разных странах результаты о связи ЖКБ и полиморфизма гена АРОЕ зачастую противоречивы: одни исследователи устанавливают положительную ассоциацию ЖКБ с наличием в генотипе аллеля Е4 [20, 31, 63], другие - обратную зависимость [21, 41], а третьи – отсутствие такой ассоциации [28, 29, 34, 36]. Portincasa P. с соавт. (1996) показали, что у пациентов с ЖКБ, носителей аллеля АРОЕ4, после ударно-волновой литотрипсии повышен риск повторного камнеобразования [54]. В другом исследовании такой зависимости не выявлено [64].
При изучении ассоциации полиморфизма гена АРОЕ с дислипидемией и риском ССЗ так же в одних исследованиях показана связь с наличием в генотипе аллеля Е4 [33, 59, 66], в других исследованиях – аллеля Е2 [18]. При изучении новосибирской популяции больных с холестериновыми желчными камнями не было выявлено различий в уровнях липидов между генотипами, содержащими аллели Е2, Е3 и Е4, хотя была отмечена некоторая тенденция к увеличению уровня ОХС у больных ЖКБ от аллеля Е2 к аллелю Е4 [2].
Ассоциация полиморфизма гена APOE с уровнем АД изучена мало. В исследовании Li X. с соавт. (2003) в китайской популяции обнаружена связь генотипов 3/4 и 4/4 с повышенным систолическим АД, по сравнению с генотипами 2/3 и 3/3 [42]. На основании данных Максимова В.Н. (2007), в российской популяции выявлена значимая ассоциация генотипа 4/4 с наличием АГ (р=0,022), а также с уровнем систолического АД (160 мм. рт. ст. и выше) (р=0,004) [6]. Вероятно, назрела необходимость обследования каждой конкретной популяции для поиска ассоциации полиморфизма генов, в частности АРОЕ, с ЖКБ, дислипидемией и АГ.
В некоторых работах изучают оперативную тактику в лечении ЖКБ в зависимости от ССЗ. Так, при выявлении у пациентов с хроническим течением ЖКБ сердечно-сосудистых факторов риска (наличие ИБС, СД и инсульта в анамнезе), с целью снижения интра- и послеоперационных осложнений, связанных с развитием острого холецистита, рекомендовано проведение ранней холецистэктомии [25].
Влияние патологии желчного пузыря на развитие ССЗ исследуют в эксперименте [50, 52]: показано, что кратковременное растяжение желчного пузыря приводит к рефлекторному повышению активности ренина плазмы с вовлечением афферентных вагусных путей и эфферентных симпатических механизмов, относящихся к бета-адренорецепторам, способствующих повышению частоты сердечных сокращений и АД, а также к коронарной, мезентериальной вазоконстрикции [48]. Однако авторы не изучали рефлекторные влияния при хрониче-ском растяжении желчного пузыря.
Исследователями изучается влияние антигипертензивной терапии на течение ЖКБ. Известно, что для хронической билиарной патологии, в т.ч. ЖКБ, характерна дисмоторика желчного пузыря, преимущественно гипокинетического типа, и вегетативная дисфункция с общей тенденцией к преобладанию активности эрготропных вегетативных механизмов (над-сегментарных структур и симпатического отдела вегегетативной нервной системы) [10, 13]. По данным исследования Николаевой А.Г. (2007), показано, что неселективные бета-адреноблокаторы (пропранолол) в качестве вегетотропной терапии имеют преимущества в коррекции дисмоторики желчного пузыря, главным образом, гипокинетического типа, по сравнению с рутинной фармакотерапией (миотропным спазмолитиком дротаверином и холе-ретиком аллохолом), которая эффективна при гиперкинетическом типе дискинезии [8]. В ра-боте другого автора выявлено, что альфа-адреноблокаторы (индорамин), несмотря на изу-ченный in vitro спазмолитический эффект на желчные пути, в исследовании in vivo обладают прокинетическим действием на желчный пузырь, что является профилактикой образования желчных камней, при этом бета-адреноблокаторы (пропранолол) этого действия не оказыва-ют [56].
Очевидно, что ЖКБ является мультифакториальным заболеванием, в генезе которого, по данным исследований, обсуждается участие сердечно-сосудистых заболеванй, в частности АГ, а также дислипидемии. В связи с этим нам представляется необходимым учитывать данные механизмы при определении тактики лечения больного с холестериновыми желчны-ми камнями.
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... Interestingly, both statins and ezetimibe administration are associated with significant improvement in NAFLD and cholesterol gallstones. Important reviews on the subject have recently been published by Ahmed et al. [40,41]. Future studies are urgently needed to determine the impact of the FDC of ezetimibe and atorvastatin on insulin sensitivity, NAFLD and cholesterol gallstones. ...
Introduction:
The combination of ezetimibe and atorvastatin (Liptruzet - referred to in this article as eze/ator), has recently been approved by the FDA for reducing low-density lipoprotein cholesterol (LDL-c) in patients with primary or mixed hyperlipidemia as in case of homozygous familial hypercholesterolemia. It helps block intestinal absorption of cholesterol and it inhibits the production of cholesterol in the liver.
Areas covered:
The safety and effectiveness of the eze/ator combination as treatment of hyperlipidemia. Medline was searched for atorvastatin and/or ezetimibe.
Expert opinion:
The combination of (eze/ator) is proven to be effective in lowering LDL-c. It is not only a safe and effective treatment of hyperlipidemia, but it also reduces inflammatory markers and atherosclerosis. It is not yet clear, however, whether the combination therapy can decrease the risk of diabetes associated with statin administration. Insulin sensitivity is improved by the single administration of ezetimibe, a finding that is documented by several clinical and animal studies. More specifically, ezetimibe has been shown to decrease insulin resistance associated with nonalcoholic fatty liver disease (NAFLD). The effects of combination therapy that have to be explored in future research and clinical trials include whether this combination can be used in the treatment of NAFLD, cholesterol gallstones and portal hypertension.
... Controlled clinical trials and clinical experience have shown the benefit of statins as treatment for CVD, familial hypercholesterolemia, and dyslipidemia with diabetes. 70 In addition, recent large clinical trials have further demonstrated the clinical benefits and safety of statins in patients with a wide range of high risks for CVD and safety of statins as monotherapy or in combination with other lipid-lowering medications. Interestingly, statins are safe and effective, and can improve liver tests and reduce cardiovascular morbidity in patients with NAFLD. ...
... Controlled clinical trials and clinical experience have shown the benefit of statins as treatment for CVD, familial hypercholesterolemia, and dyslipidemia with diabetes. 70 In addition, recent large clinical trials have further demonstrated the clinical benefits and safety of statins in patients with a wide range of high risks for CVD and safety of statins as monotherapy or in combination with other lipid-lowering medications. Interestingly, statins are safe and effective, and can improve liver tests and reduce cardiovascular morbidity in patients with NAFLD. ...
Human immunodeficiency virus (HIV) is a chronic disease associated with dyslipidemia and insulin resistance. In addition, the administration of combination antiretroviral therapy is associated with an increase in the incidence of metabolic risk factors (insulin resistance, lipoatrophy, dyslipidemia, and abnormalities of fat distribution in HIV patients). HIV dyslipidemia is a common problem, and associated with an increase in incidence of cardiovascular disease. Further challenges in the management of HIV dyslipidemia are the presence of diabetes and metabolic syndrome, nonalcoholic fatty liver disease, hypothyroidism, chronic kidney disease, the risk of diabetes associated with statin administration, age and ethnicity, and early menopause in females. Dyslipidemia in patients with HIV is different from the normal population, due to the fact that HIV increases insulin resistance and HIV treatment not only may induce dyslipidemia but also may interact with lipid-lowering medication. The use of all statins (apart from simvastatin and lovastatin) is safe and effective in HIV dyslipidemia, and the addition of ezetimibe, fenofibrate, fish oil, and niacin can be used in statin-unresponsive HIV dyslipidemia. The management of dyslipidemia and cardiovascular disease risks associated with HIV is complex, and a certain number of patients may require management in specialist clinics run by specialist physicians in lipid disorders. Future research is needed to address best strategies in the management of hyperlipidemia with HIV infection.
... Elevated serum HDL-C levels, with a larger proportion of cholesterol secreted in the form of bile acids [4], may reduce biliary cholesterol saturation [28] and decrease gallstone formation. There was no association between hypertriglyceridemia and GSD in this work and this may be due to excluding subjects using lipid-lowering medication, as these prescriptions are considered as potential treatments for NAFLD and GSD [29,30]. Diabetes mellitus was found to be a significant risk factor for GSD in this study. ...
Objective:
Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GSD) share some of the same risk factors. The association between NAFLD and GSD was inconsistent. Moreover, there are no studies on the association between GSD and the severity of NAFLD in the literature. The aim of this study was to determine the relationship between the severity of NAFLD and GSD in a Taiwanese population.
Materials and methods:
A total of 12,033 subjects were enrolled. The diagnoses of GSD and NAFLD were based on the finding of abdominal ultrasonography. The severity of NAFLD was divided into mild, moderate, and severe.
Results:
Compared with the non-GSD group, the GSD one was older and had a higher BMI, blood pressure, fasting plasma glucose, cholesterol, triglyceride, and higher prevalence of diabetes and hypertension, but they had a lower eGFR and HDL-C level and less prevalence of current smoking and alcohol drinking. There was a significant difference in the severity of NAFLD between subjects with and without GSD. Based on logistic regression, age ≥65 versus <40 years, 40-64.9 versus <40 years, female, current alcohol drinking, diabetes, hypertension, HDL-C level and moderate to severe NAFLD, but not mild NAFLD, were the independently associated risk factors of GSD.
Conclusion:
Moderate to severe, but not mild, NAFLD was associated with an increased risk of GSD, independent of the traditional cardio-metabolic risk factor. Age, female, diabetes, and hypertension were also related to a higher risk of GSD, but HDL-C level and moderate alcohol drinking showed a lower risk.
... The drugs used for the treatment of gallstones often have cholesterol-lowering properties (Lioudaki et al., 2011), but the only authorized drug is ursodeoxycholic acid. Statins and ezetimibe have properties for inhibiting the formation of gallstones, but their effects for the treatment are limited (Ahmed et al., 2011;Stein et al., 2012). Because of these limitations, the research of natural products is an alternative field that needs to be explored. ...
Cholesterol gallstones are a digestive disease of high prevalence that has many risk factors; for this reason, research has focused mainly on how to prevent it rather than how to treat it. Many molecules of the hepatic, bile and intestinal systems are involved in the pathophysiology of this disease, making it very difficult to find a therapeutic target. The pharmacological treatment is limited, so when gallstones generate symptoms, medical treatment indicates gallbladder removal. Ursodeoxycholic acid is used to dissolve cholesterol stones, and ezetimibe and statins are other drugs with possible applications in the treatment of this disease. Given the small number of drugs that have been developed for treating this disease, the research of natural products becomes of paramount importance. Resources such as black radish, glucosinolates, fenugreek, capsaicin, curcumin, garlic, and onion, have all shown significant effects in the prevention and treatment of cholesterol gallstones. In this review, we made a synthesis of the scientific reports that deal with these natural products and that can serve as antecedents for finding a way to treat the most common disease of the gallbladder.
The challenge of managing dyslipidemia in People Living with HIV (PLWHIV) is driven by the high prevalence of Human Immunodeficiency (HIV) and can be due to various coexisting factors such as diabetes, fatty liver, obesity, hypothyroidism, and high alcohol intake. Hyperlipidemia increases the risk of cardiovascular disease in PLWHIV. Importantly, HIV per se is a chronic inflammatory condition that may increase lipid profiles. Unfortunately, different types of antiretroviral therapies (ART) can also contribute to dyslipidemia. The treatment of HIV dyslipidemia is complex and requires a multidisciplinary approach where there is close collaboration between HIV physicians, metabolic medicine physicians, endocrinologists, HIV specialist nurses, and dieticians. Therefore, the HIV Metabolic Clinic must be an integral part of the HIV service. This is important, as management of the interactions between lipid-lowering agents such as statins and ARTs can be handled safely, and initiation of dietary intervention can be monitored by dieticians. In this regard, we have added to this chapter a section about our experience at the HIV Metabolic Clinic in Milton Keynes University Hospital, UK. It is important to note that the current calculators of cardiovascular disease (CVD) risk underestimate CVD risk in PLWHIV, and it is not yet established what is the goal of low-density lipoprotein cholesterol (LDL-C) levels. Future research is needed to establish: (i) whether PLWHIV can be treated with statin regardless of the level of the LDL-C; (ii) what is the best tool to calculate cardiovascular risks in PLWHIV; and (iii) whether the suggested interventions actually decrease morbidity and mortality of this disease.
Cholelithiasis is a common and frequent condition all over the world with a high prevalence rate in western countries. Individuals with cholesterol gallstone disease experience intense gastrointestinal symptoms and have a high risk of developing comorbidities like cholecystitis, Gall bladder (GB) cancer and pancreatitis. Multiple risk factors associated with cholesterol gallstones include but not limited to genetics, dietary habits, lifestyle changes, comorbid conditions and various drugs. These factors may lead to alteration in bile, cholesterol & phospholipids homeostasis in the GB, intestine and hepatocytes culminating in cholesterol gallstones formation. Surgical (cholecystectomy) and non-surgical (oral dissolution therapy) treatments are available for the disease, albeit with certain complications and high treatment cost. Thus, there is a need for interventions, complementary or alternative therapies for the treatment and prevention of cholesterol gallstones. Currently available drug therapies used for cholesterol gallstones include statins and ezetimibe. Many patients consider traditional herbal practitioners due to their promise of non-invasive and pain free management of gall stones. This present a positive shift towards generally acceptable safety and cost effectiveness of herbal treatment warranting extensive research for alternative or complementary choice such as herbal plants as an emerging area for their potential therapeutic effects. This review discusses current strategies, latest trends available in the disease pathogenesis, drug development for novel targets, risk management, newer anti-lithogenic drugs and herbal plants that target the different aspects of the disease.
The biliary tract system mainly transports bile secreted by hepatocytes and bile duct epithelial cells into the gut, and includes the intra-hepatic biliary tract and extra hepatic biliary tract. It starts from intra hepatic capillary biliary tract, and ends with pancreatic duct rendezvous with the Vater ampullary, opening into the duodenum nipple. The pancreas is the body’s second largest digestive gland secondary to the liver, and has exocrine and endocrine functions. Normally, the pancreas stimulated by food, etc. secretes mounts of characteristic pancreatic juice into the gut. Thus, biliary tract and pancreas infections are closely associated with intestinal bacterial translocation and microecology imbalance.
Two glucosinolates (glucoraphasatin and glucoraphanin) and their degradation products (raphasatin and sulforaphane) are secondary metabolites which have shown antioxidant properties and inhibitory properties against the hepatic cholesterol; these effects are very important for the prevention of cholesterol gallstones because in their pathophysiology there is an imbalance in the transport and secretion of cholesterol. These effects produce oxygen reactive species formation, which damages the hepatic and biliary tissues. Cholesterol gallstones are a public health problem; their pharmacological treatment is very limited and the invasive surgical treatment for symptomatic gallstones is the cholecystectomy. Current research focuses on the search for preventive treatments, as there are many risk factors associated with the development of gallstones; therefore, a natural therapeutic alternative may be the use of these glucosinolates and their degradation products.
BACKGROUND & AIMSThere is emerging evidence from animal and human studies that current statins can decrease the formation of gallbladder cholesterol gallstones and subsequently decrease the risk of gallstone disease, but consistent results have not been reported. We performed a meta-analysis to provide an overview of the relevant studies.METHODS
Relevant studies published between January 1980 and February 2014 were identified by searching Medline, Embase and The Cochrane Library. Studies were selected using a priori defined criteria. The strength of the relationship between statin use and risk of gallstone disease was assessed by adjusted Odds Ratio (ORs).RESULTSA total of 622,868 participants from six studies (four case-control studies, one cohort study and one cross-sectinal study) were identified in this meta-analysis. The studies provided adjusted overall ORs estimates for current statin use versus nonuse, leading to a pooled OR of 0.86 (95% confidence interval (CI), 0.77 -0.97; P <0.001). The overall ORs of population-base case control studies and cholecystectomy due to gallstone disease were 0.83 (95% CI, 0.73–0.95; P =0.0131) and 0.78 (95% CI, 0.74-0.82; P =0.615), respectively.CONCLUSIONS
There is evidence that current statin use lower the risk of gallstone disease compare with nonuse, especially for cholecystectomy due to gallstone disease. Low statin use (1-4 prescription) didn't decrease the risk of gallstone disease, but moderate and high statin use significantly decrease the risk. Further multicentres and better-controlled studies are need to confirm these findings.
Abstract Renal stone disease and gallstone disease are widely prevalent and costly disease across the globe. Both renal stone disease and gallstone disease are associated with a variety of diseases including obesity, metabolic syndrome, dyslipidemia, hypertension, insulin resistance diabetes and gout. Importantly, the presence of either renal stone disease or gallstone disease is associated with an increased risk of cardiovascular disease. In a recent study of the Atherosclerosis Risk in Communities (ARIC), individuals with a history of gallstones were 54% more likely to report a history of nephrolithiasis after adjusting for age, gender, body size and other factors. Furthermore, in three large cohorts including over 240,000 subjects: the Nurses' Health Studies (NHS) I and II and the Health Professionals Follow-up Study (HPFS), showed that gallstone disease is independently associated with nephrolithiasis. The mechanisms linking gallstone disease and renal stone disease are complex and not yet established. Insulin resistance, lithogenic diets, alterations of transporters in gallbladder and urinary system, and pH are possible potential mechanisms for future exploration. How the liver communicates with kidney in individuals with renal stone disease and gallstone disease is not well known and whether this communication is similar as in hepto-renal syndrome is subject for future research. Further research is needed to determine: (i) the underlying mechanisms of renal stone disease and gallstone disease; (ii) the potential treatment of renal stone disease and gallstone disease.
Abstract Nonalcoholic fatty liver disease (NAFLD) and gallstone disease (GD) are both highly prevalent in the general population and are associated with obesity, insulin resistance, dyslipidemia, and high dietary cholesterol intake. Insulin resistance is a key feature of both NAFLD and GD. Hepatic insulin resistance provides a crucial link between the metabolic syndrome, NAFLD, and increased cholesterol gallstone susceptibility. Hepatic insulin resistance is not only associated with accumulation of hepatic fat but also has a crucial role in supersaturation and excessive production of bile salts. It is not yet clear whether NAFLD is a precursor of GD or whether the presence of GD possibly indicates the presence of long-standing features of metabolic syndrome that accelerates the progression of NAFLD. Recent reports suggested the association between gallstones and nonalcoholic steatohepatitis and liver fibrosis. Importantly, both NAFLD and GD are both associated with high incidence of cardiovascular disease (CVD) and mortality. Emerging evidence suggests a potential benefit of statin therapy in NAFLD and GD. Further research is needed to determine (i) how the presence of NAFLD and GD is associated with CVD (ii) and whether the presence of GD in association with NAFLD increases the risk of liver fibrosis, and (iii) the impact of therapy of NAFLD in the incidence of GD.
Introduction:
Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decrease in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. HIV-dyslipidemia is a common problem with extensive use of combination antiretroviral therapy (CART), and is associated with an increase in incidence of cardiovascular disease (CVD), resulting in hospital admission and surgery throughout the western healthcare systems.
Areas covered:
This review describes the effectiveness and safety of statins in the treatment of HIV-dyslipidemia. Medline was searched for different statins as treatment for HIV-dyslipidemia.
Expert opinion:
Dyslipidemia in patients with HIV is different from the normal population, due to the fact that HIV treatment may not only cause dyslipidemia, but may also interact with lipid lowering medication. Statin-unresponsive HIV-dyslipidemia can be treated with the addition of ezetimibe, fenofibrate, fish oil and niacin. Current guidelines recommend the use of pravastatin and atorvastatin as first-line therapy, whereas European guidelines include rosuvastatin. There is an urgent need to confirm whether the use of statins in HIV-dyslipidemia is associated with an increase in the incidence of diabetes; this is significant because HIV patients are known to be insulin-resistant. HIV is also associated with Non-alcoholic Fatty Liver Disease (NAFLD), a condition known to be associated with insulin resistance. Further clinical trials are urgently needed to assess the impact of statins on CVD in HIV patients, and future challenges for researchers in this area are enormous.
Dear Editor, In a recent issue of Expert Opinion on Phamacotherapy, an interesting article on the use of statins in the oral treatment of cholesterol gallstones was published [1]. The authors speculated that the therapeutic use of statins in the treatment of cholesterol gallstones could decrease the annual number of cholecystectomies. Some considerations are necessary. In fact, the effects of statins on gallstones in humans has been controversial [2]. Actually, only in a case-control study the long-term use of statins was associated with a decreased risk of symptomatic gallstone [2], but the dissolution rates in case of multiple cholesterol gallstones are only 40-50% after one year of treatment and the recurrence rates after oral bile acid therapy is about 10% per year [2]. Several studies demonstrated that calcium salts (in particular calcium bilirubinate and calcium phosphate) are present in the pigmented center of the 88% of cholesterol gallstones [3]. Calcium ions and mixed mucin glycoproteins, that are secreted by gallbladder mucosa, are also present together in the center of gallstones [4] as showed by ultrastructural studies [5]. The efficacy of oral bile salts and statins in the dissolution of calcium bilirubinate or calcium phosphate, as well as in the elimination of the parietal (gallbladder mucosa) factors of gallstone formation have never been described or proved. In conclusion, the persistence of the parietal (gallbladder mucosa) factors of cholesterol gallstones heterogeneous nucleation and the persistence of the pig-mented center of cholesterol gallstones [5] seems to be the main important conditions related to the failure of oral dissolution therapy of cholesterol gallstones with statin and/or bile acids.
Statins have an established role in the treatment of hypercholesterolemia and the prophylactic treatment of patients with atherosclerotic disease, and have been found to prevent secondary cardiovascular events and thereby reduce morbidity and mortality. Nevertheless, the pathophysiologic effect of statins on inflammatory responses and local atherosclerotic plaque morphology in humans remains a matter of debate. In particular the question is unanswered whether statin-induced alterations in plaque composition can be ascribed to LDL lowering or an anti-inflammatory pleiotropic effect. We will discuss the results of a recent study by Puato et al. concerning the effect of two different atorvastatin dosages and a nonstatin lipid-lowering drug on atherosclerotic plaque morphology.
Obesity is associated with insulin resistance, non-alcoholic fatty liver disease (NAFLD) and gallstones.High fat diets (unsaturated fats) rich in cholesterol have been demonstrated to produce not only gallstones but also NAFLD and insulin resistance. Interestingly, a high incidence of gallstones is being reported in association with insulin resistance and NAFLD. Laparoscopic cholecystectomy is the best definitive therapy for symptomatic gallbladder disease. Ezetimibe is a drug that inhibits the absorption of both dietary and biliary cholesterol in the small intestine. Importantly, ezetimibe showed potential benefit not only in treating and preventing gallstones but also in insulin resistance and NAFLD. Further studies are required before the use of ezetimibe for the treatment of gallstones can be advocated.
Gallstone disease is a leading cause of morbidity in western countries and carries a high economic burden. Statins decrease hepatic cholesterol biosynthesis and may therefore lower the risk of cholesterol gallstones by reducing the cholesterol concentration in the bile. Data on this association in humans are scarce.
To study the association between the use of statins, fibrates, or other lipid-lowering agents and the risk of incident gallstone disease followed by cholecystectomy.
Case-control analysis using the UK-based General Practice Research Database. Incident patients between 1994 and 2008 and 4 controls per each patient were identified and matched on age, sex, general practice, calendar time, and years of history in the database. The study population was 76% women and the mean (SD) age was 53.4 (15.0) years at the index date. Conditional logistic regression was used to estimate the odds ratio (OR) of developing gallstones followed by cholecystectomy in relation to exposure to lipid-lowering agents, stratified by exposure timing and duration. The ORs and 95% confidence intervals (CIs) were adjusted for smoking, body mass index, ischemic heart disease, stroke, and estrogen use.
The adjusted OR (AOR) for developing gallstone disease followed by cholecystectomy in relation to exposure to lipid-lowering agents.
A total of 27,035 patients with cholecystectomy and 106,531 matched controls were identified, including 2396 patients and 8868 controls who had statin use. Compared with nonuse, current statin use (last prescription recorded within 90 days before the first-time diagnosis of the disease) was 1.0% for patients and 0.8% for controls (AOR, 1.10; 95% CI, 0.95-1.27) for 1 to 4 prescriptions; 2.6% vs 2.4% (AOR, 0.85; 95% CI, 0.77-0.93) for 5 to 19 prescriptions, and 3.2% vs 3.7% (AOR, 0.64; 95% CI, 0.59-0.70) for 20 or more prescriptions. The AORs for current use of statins defined as 20 or more prescriptions were similar (around 0.6) across age, sex, and body mass index categories, and across the statin class.
Long-term use of statins was associated with a decreased risk of gallstones followed by cholecystectomy.
The present investigation describes the influence of partial, pharmacologic interruption of bile acid enterohepatic circulation on cholesterol and bile acid synthesis in germfree rats. Seven rats received a basal, semisynthetic diet and five rats received the basal diet supplemented with 5% cholestyramine. After 6 weeks, feces were collected in one 3- and one 4-day pool for analysis of bile acids and cholesterol. When the sampling period was concluded, the rats were killed and the liver microsomal fractions were isolated. The activities of HMG CoA reductase and 7alpha-hydroxylase were determined. The main fecal bile acids in the untreated rats were cholic acid and beta-muricholic acid. During cholestyramine treatment cholic acid increased from 4.4 +/- 0.7 to 39.5 +/- 5.6 mg/kg body weight/day and beta-muricholic acid from 4.5 +/- 0.6 to 7.7 +/- 0.9 mg/kg body weight/day. Chenodeoxycholic acid became a major bile acid averaging 10.4 +/- 1.6 mg/kg body weight/day. The total amount of bile acids increased about 6-7 times and the percentage of cholic acid increased from 49.4 +/- 2.0 to 68.6 +/- 1.1%. The 7alpha-hydroxylase activity increased 4-5 times. During cholestyramine treatment the fecal excretion of cholesterol was increased from 12.0 +/- 1.4 to 68.0 +/- 5.0 mg/kg body weight/day. The endogenous formation of cholesterol was increased 6 times and the HMG CoA reductase activity was increased about 20 times. In conclusion, germfree rats, like conventional rats, have the ability to increase the endogenous formation of bile acids and cholesterol during interruption of the enterohepatic circulation of bile acids, which is also reflected in a stimulation of the activities of the rate-determining enzymes.
Interruption of the enterohepatic circulation of bile acids by cholestyramine or colestipol influences the hepatic metabolism of cholesterol in many ways. The synthesis of bile acids is increased, as reflected by a several-fold increase in the activity of the cholesterol 7 alpha hydroxylase, the rate-determining enzyme in bile acid synthesis. The increased metabolism of cholesterol to bile acids causes an enhanced demand of cholesterol in the hepatocytes which respond with both new synthesis of cholesterol, as reflected in a several-fold increase of the HMG-CoA reductase activity, and increased expression of LDL receptors. As a consequence, the plasma level of LDL-cholesterol is lowered. The hepatic secretion rate of VLDL particles is increased. Cholestyramine therapy does not affect the output of biliary lipids or the cholesterol saturation of bile, indicating that treatment with bile acid sequestrants should not be associated with any increased risk of gallstone formation.
We measured bile acid kinetics and bile lipids in 12 human subjects on a metabolic ward in four randomly allocated, 6-7 week periods: 1) lovastatin (40 mg b.i.d) + low cholesterol diet (mean 246 mg/day); 2) lovastatin+high cholesterol diet (mean 1071 mg/day); 3) low cholesterol diet alone; and 4) high cholesterol diet alone. Lovastatin did not significantly alter fractional turnover, synthesis, absorption, enterohepatic cycling, or pool sizes of bile acid measured by the Lindstedt method. The high cholesterol diet increased fractional turnover and synthesis rate of cholic acid, but not chenodeoxycholic acid, without altering pool size of either bile acid. The high cholesterol diet decreased bile acid absorption, but only during lovastatin treatment, suggesting the possibility of a "cholestyramine-like" effect of dietary cholesterol, appreciable at least when biliary cholesterol secretion is reduced by lovastatin. As in previous studies, lovastatin markedly lowered saturation index of gallbladder bile. Increased cholesterol consumption did not significantly alter cholesterol saturation index, suggesting that dietary cholesterol may not be a major factor in cholesterol gallstone pathogenesis.
The beneficial effects of statins on the reduction of cardiovascular events has been partly attributed to their anti-inflammatory properties. In the complex of the different pathogenetic events leading to atherosclerosis, recent data suggest a central role of monocyte chemotactic protein-1 (MCP-1), because mice knock-out for MCP-1 or its receptor CC-chemokine receptor 2 were considerably resistant to plaque formation. In this study we investigated the effect of different statins on in vitro and in vivo production of MCP-1. Lovastatin and simvastatin caused a dose-dependent inhibition of MCP-1 production in peripheral blood mononuclear cells exposed to lipopolysaccharide or inactivated Streptococcus hemoliticus and in human endothelial cells exposed to interleukin-1beta. The addition of mevalonate overrode the inhibitory effect of statins indicating that mevalonate-derived products are important for chemokine production. The in vivo anti-inflammatory effect of statins was investigated using the mouse air-pouch model of local inflammation. Lovastatin and pravastatin were orally administered to mice according to a treatment schedule that significantly inhibited the hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity without affecting total blood cholesterol. At the dose of 10 mg/kg, lovastatin and pravastatin reduced by approximately 50% the lipopolysaccharide-induced leukocytes recruitment and the exudate MCP-1 production. In conclusion, statins, by inhibiting mevalonate-derived products, reduced both in vitro and in vivo the production of chemokines involved in leukocyte migration, and this effect is unrelated to their cholesterol-lowering action.
Gallstones are common, affecting about one fourth of women and 10% to 15% of men over the age of 50. They are more prevalent in Amerindians and Mexican-Americans and less common in blacks. Principal risk factors are age, sex, and obesity. Lesser risk factors include childbearing, abstinence from alcohol, and some medications. The rate at which asymptomatic gallstones become symptomatic is low but significant, while patients with mildly symptomatic stones are at even greater risk for future pain and complications.
AIM: To evaluate gallstone incidence and risk factors in a large population-based study.
METHODS: Gallstone incidence and risk factors, were evaluated by structured questionnaire and physical examination, respectively, in 9611 of 11 109 (86.5%) subjects who were gallstone-free at the cross-sectional study.
RESULTS: Six centers throughout Italy enrolled 9611 subjects (5477 males, 4134 females, aged 30-79 years), 9517 of whom were included into analysis: 424 subjects (4.4%) had gallstones and 61 (0.6%) had been cholecystectomized yielding a cumulative incidence of 0.67% per year (0.66% in males, 0.81% in females). Increasing age, a high body mass index (BMI), a history of diabetes, peptic ulcer and angina, and low cholesterol and high triglyceride levels were identified as risk factors in men while, in females, the only risk factors were increasing age and a high BMI. Increasing age and pain in the right hypochondrium in men and increasing age in females were identified as predictors of gallstones. Pain in the epigastrium/right hypochondrium was the only symptom related to gallstones; furthermore, some characteristics of pain (forcing to rest, not relieved by bowel movements) were significantly associated with gallstones. No correlation was found between gallstone characteristics and clinical manifestations, while increasing age in men and increasing age and BMI in females were predictors of pain.
CONCLUSION: Increasing age and BMI represent true risk factors for gallstone disease (GD); pain in the right hypochondrium and/or epigastrium is confirmed as the only symptom related to gallstones.
Background: Gallstone disease is a major source of morbidity in the United States. Gallstones are twice as common in women as in men, but severe biliary events leading to surgery occur with equal frequency in the two sexes. Objective: To determine whether physical activity decreases risk for symptomatic gallstone disease in men. Design: Prospective cohort study. Setting: U.S. male health professionals. Patients: 45 813 men 40 to 75 years of age were followed from 1986 to 1994. Measurements: Questionnaires mailed in 1986, 1988, 1990, 1992, and 1994 asked about physical activity, incidence of gallstone disease, age, body weight, dietary and alcohol intake, smoking habits, use of medications, and occurrence of diagnosed medical conditions other than gallstone disease. Results: 828 men reported having newly symptomatic gallstones (diagnosed by ultrasonography or radiography) or undergoing cholecystectomy for recent symptoms. After adjustment for multiple confounders, increased physical activity was inversely related to risk for symptomatic gallstone disease. When extreme quintiles were compared, men younger than 65 years of age had a stronger inverse association (multivariate relative risk, 0.58 [95% Cl, 0.44 to 0.78]) with risk than did men 65 years of age or older (relative risk, 0.75 [Cl, 0.52 to 1.09]). In contrast, sedentary behavior was positively related to risk for symptomatic gallstone disease. Men who watched television more than 40 hours per week had a higher risk for symptomatic gallstones than men who watched less than 6 hours per week (relative risk for older men, 3.32 [CI, 1.51 to 7.27]; relative risk for younger men, 1.58 [Cl, 0.38 to 6.48]). Conclusions: Physical activity may play an important role in the prevention of symptomatic gallstone disease in men even beyond its benefit for control of body weight. The results of this study indicate that 34% of cases of symptomatic gallstone disease in men could be prevented by increasing exercise to 30 minutes of endurance-type training five times per week.
Fibrate derivatives and HMG-CoA reductase inhibitors modify homeostasis of cholesterol. The aim of this study was to assess in an unselected population whether these hypolipidemic drugs are risk factors for cholelithiasis or, conversely, are protective agents. Both sexes, all socioeconomic categories, pregnant women, and cholecystectomized subjects were included. Clinical data collection and gallbladder ultrasonography were both carried out in a double-blind fashion. Fibrate derivatives were predominantly fenofibrate, HMG-CoA reductase inhibitors were simvastatin and pravastatin. On univariate analysis, age (>50 years), sex, and use of fibrates were found to be significantly related to the presence of cholelithiasis. Age, sex, and fibrate treatment remained independently correlated with the presence of gallstones on multivariate analysis. With fibrates, the relative risk for lithiasis was 1.7 (P = 0.04). The HMG-CoA reductase inhibitors were not associated with a protective effect on univariate analysis. Of the lipid-lowering drugs, only fibrate derivatives were found to increase the risk of gallstone formation.
The rates of cholesterol 7α-hydroxylation (the first and rate-limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Twenty-three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7α-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7α position. Plasma bile acid composition, evaluated by gas-liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7α-hydroxylation increased in a dose-related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low-density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7α-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoproteincholesterol but exerted no change on 7α-hydroxylation rates. Our results support the existence of a feedback inhibition exerted on cholesterol 7α-hydroxylation (and consequently on bile acid synthesis) by hydrophobic bile acids returning to the liver through the enterohepatic circulation. The finding emphasizes the importance of the physicochemical properties of bile acids in the regulation of hepatic cholesterol balance. Under these experimental conditions, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and presumably reduced availability of newly synthesized cholesterol are not critical for bile acid synthesis. (HEPATOLOGY 1991;14:830–837).
The mechanisms for the hypocholesterolaemic action of niacin (nicotinic acid) were examined in rats administered niacin at a dose of 400 mg/kg body wt/day for either 2 or 4 weeks. Another group of rats were administered diosgenin, an inhibitor of acyl-CoAxholesterol acyltransferase, as a 1% (w/w) supplement in the diet for 7 days. Both agents produced small increases in bile flow rates (up to 40%) and mild hepatotoxicity evidenced by small increases in serum transaminase activities. Niacin treatment for 2 or 4 weeks lowered serum cholesterol concentrations by 13% or 29%, respectively, with the greatest decrease occurring in the low density lipoprotein fraction. This was accompanied by relatively large increases in biliary cholesterol output (114% and 130% after 2 and 4 weeks treatment, respectively) with smaller increases in the biliary output of phospholipid (18% and 45%) and bile acid (26% and 14%). Diosgenin treatment increased serum cholesterol by 29% and increased the biliary output of cholesterol, phospholipid and bile add by 800%, 10% and 45%, respectively. Thus, both agents increased the cholesterol saturation of bile (100% by niacin, 500% by diosgenin). Cholesterol and phospholipid in fistula bile from control rats were present in lamellar and micellar forms. Niacin treatment did not alter the physical form of biliary lipids whilst diosgenin caused the appearance of vesicular lipid in fistula bile. Thus, increased biliary secretion of cholesterol explains, at least in part, the hypocholesterolaemic action of niacin. In addition, since aggregation of biliary vesicles is involved in cholesterol gallstone formation in humans, the non-appearance of vesicular material in fistula bile from niacin-treated rats may be of some importance.
The aim of this study was to determine whether 12 months of therapy with Simvastatin, an HMG CoA reductase inhibitor, would dissolve gallstones. Twenty-seven subjects entered the study, all had a fasting oral cholecystogram, ultrasound examination, and fasting serum lipids prior to therapy. In addition, 22 subjects had their gallbladder ejection fraction, after CCK, determined by radionucleotide scanning. Eleven subjects had the cholesterol saturation index (CSI) of bile calculated before and at the end of 12 months of therapy. Of the 27 subjects, 26 completed 12 months of treatment with Simvastatin 20 mg daily. There was a significant fall in the total serum cholesterol (27%, P < 0.0001), LDL cholesterol (31%, P < 0.0001), triglyceride (34%, P < 0.0001) but no change in HDL after 12 months of therapy. Simvastatin treatment resulted in a 28% fall in the CSI of bile at the end of therapy (P < 0.01). The concentrations of individual bile acids did not change with therapy, and apart from a slight but significant increase in arachidonate, there were no other significant changes in the fatty acid composition of the biliary phospholipids. After 12 months of Simvastatin therapy there was a small decrease in the gallstone diameter but complete dissolution of gallstones was not achieved in any subjects. In conclusion 12 months of therapy with Simvastatin was effective in lowering the serum lipids and the CSI of bile but was not effective in dissolving gallstones.
Gallstone disease is a major source of morbidity in the United States. Gallstones are twice as common in women as in men, but severe biliary events leading to surgery occur with equal frequency in the two sexes.
To determine whether physical activity decreases risk for symptomatic gallstone disease in men.
Prospective cohort study.
U.S. male health professionals.
45,813 men 40 to 75 years of age were followed from 1986 to 1994.
Questionnaires mailed in 1986, 1988, 1990, 1992, and 1994 asked about physical activity, incidence of gallstone disease, age, body weight, dietary and alcohol intake, smoking habits, use of medications, and occurrence of diagnosed medical conditions other than gallstone disease.
828 men reported having newly symptomatic gallstones (diagnosed by ultrasonography or radiography) or undergoing cholecystectomy for recent symptoms. After adjustment for multiple confounders, increased physical activity was inversely related to risk for symptomatic gallstone disease. When extreme quintiles were compared, men younger than 65 years of age had a stronger inverse association (multivariate relative risk, 0.58 [95% CI, 0.44 to 0.78]) with risk than did men 65 years of age or older (relative risk, 0.75 [CI, 0.52 to 1.09]). In contrast, sedentary behavior was positively related to risk for symptomatic gallstone disease. Men who watched television more than 40 hours per week had a higher risk for symptomatic gallstones than men who watched less than 6 hours per week (relative risk for older men, 3.32 [CI, 1.51 to 7.27]; relative risk for younger men, 1.58 [CI, 0.38 to 6.48]).
Physical activity may play an important role in the prevention of symptomatic gallstone disease in men even beyond its benefit for control of body weight. The results of this study indicate that 34% of cases of symptomatic gallstone disease in men could be prevented by increasing exercise to 30 minutes of endurance-type training five times per week.
Most gallstones originate from cholesterol-supersaturated bile. Statins inhibit hepatic cholesterol biosynthesis and therefore may reduce the risk of gallstone disease. Population-based evidence, however, is sparse. Thus, the authors conducted a population-based case-control study using medical databases from northern Denmark (1.7 million inhabitants) to identify 32,494 cases of gallstones occurring between 1996 and 2008 and to identify age-, sex-, and county-matched population controls for each case. Cases and their matched controls who were exposed to lipid-lowering drugs were categorized as current users if their last prescription was redeemed ≤90 days before the case's diagnosis date; otherwise, they were categorized as former users. Conditional logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals for gallstone disease in patients treated with lipid-lowering drugs. In current users, the adjusted odds ratios associating statin use with the occurrence of gallstone disease were 1.17 (95% confidence interval (CI): 1.06, 1.30) for those who had 1-4 prescriptions, 0.89 (95% CI: 0.80, 0.97) for those who had 5-19 prescriptions, and 0.76 (95% CI: 0.69, 0.84) for those who had ≥20 total prescriptions. In former users, the corresponding adjusted odds ratios were 1.24 (95% CI: 1.11, 1.39), 0.97 (95% CI: 0.86, 1.10), and 0.79 (95% CI: 0.64, 0.97), respectively. The use of other lipid-lowering drugs showed no similar association.
Gallstone disease is common in Western countries. Statins reduce biliary cholesterol secretion and have anti-inflammatory effects, suggesting that they may play a role in reducing the incidence of surgically treated gallstone disease.
To examine a potential association between statin administration and risk of cholecystectomy.
We conducted a population-based case-control study of surgically treated gallstone disease using the database of Clalit Health Services (CHS). The study population consisted of all individuals age 40 - 85 enrolled with the central region of CHS during the period 1 January 2000 to 31 December 2006. We identified patients who underwent cholecystectomy between 1 January 2003 and 31 December 2006 (n = 1465). Controls (n = 5860) were individually matched on year of birth and sex in a 4:1 ratio. Multivariable conditional logistic regression models to compute the odds ratio of cholecystectomy associated with statin therapy were constructed to control for patients' clinical and socio-demographic characteristics.
Statin use with at least 80% adherence to treatment was associated with about 30% reduction in the risk of cholecystectomy (adjusted odds ratio 0.69; 95% CI 0.57 - 0.84).
The results of our large population-based study suggest that the use of statins reduces the risk of surgery for gallstone disease.
Epidemiologic investigations, clinical observations, and family and twin studies in humans, as well as gallstone prevalence investigations in inbred mouse models, support the concept that cholesterol cholelithiasis could result from a complex interaction of environmental factors and the effects of multiple undetermined genes. Quantitative trait locus (QTL) analysis is a powerful genetic method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes, and the subsequent positional cloning of such genes responsible for QTLs, followed by the use of manufactured mouse strains with "knockout" or "knockin" of the genes, could lead to the discovery of lithogenic actions of gallstone (LITH) genes. The combined use of genomic strategies and phenotypic studies in inbred strains of mice has successfully resulted in the identification of many candidate LITH genes. Because there is exceptionally close homology between mouse and human genomes, the orthologous human LITH genes can be identified from the mouse study. The discovery of LITH genes and more fundamental knowledge concerning the genetic determinants and molecular mechanisms underlying the formation of cholesterol gallstones in humans will pave the way for critical diagnostic and prelithogenic preventive measures for this exceptionally prevalent digestive disease.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of hepatic dysfunction encountered in general practice. A large proportion of individuals with type 2 diabetes and the metabolic syndrome develop NAFLD. NAFLD is associated with severe insulin resistance and increased risk of cardiovascular disease and can progress to non-alcoholic steato-hepatitis, liver cirrhosis and cancer. Currently the only known effective treatments for NAFLD are lifestyle changes including stable weight loss and a diet low in calories. General practitioners will increasingly play a key role in dealing with this evolving but serious epidemic of NAFLD and associated metabolic complications. However, success will depend on the appropriate systems and mechanisms being in place in primary care and the proper motivation, support and education of the patient. This review provides the primary care physician with: (a) a step-by step guide of how to identify NAFLD, (b) information to exclude common other causes of liver fat accumulation and (c) additional insight into relationships between NAFLD and other conditions such as obesity, cardiovascular disease and type 2 diabetes.
Statins can reduce biliary cholesterol secretion independently of their ability to inhibit cholesterol synthesis. Statins also prevent the formation of gallstones in animal studies, although the effect of statins on human gallstone disease has been controversial.
We examined the relationship between the use of statins and the risk of cholecystectomy in a cohort of US women. As part of the prospective Nurses' Health Study, participants biennially reported their history of gallstone disease and whether they had undergone cholecystectomy. Women also reported lifetime use of statins retrospectively in 2000. We conducted a retrospective analysis of statin using data collected in 2000, to define use from 1994 forward, and a prospective analysis for general lipid-lowering drugs from 1994 to 2004.
In the statin analysis we ascertained 2479 cases of cholecystectomy during 305,197 person-years of follow-up evaluation. The multivariate relative risk for current statin users, compared with nonusers, was 0.82 (95% confidence interval, 0.70-0.96). In the analysis of general cholesterol-lowering drugs, we ascertained 3420 cases of cholecystectomy during 511,411 person-years of follow-up evaluation. Compared with nonusers, the multivariate relative risk for current users of general cholesterol-lowering drugs, mostly statins in this cohort, was 0.88 (95% confidence interval, 0.79-0.98).
Statin use appears to reduce the risk of cholecystectomy in women.
Cholesterol gallstone formation is a complex process mediated by genetic and environmental factors. Until recently, the role of the immune system in the pathogenesis of cholesterol gallstones was not considered a valid topic of research interest. This review collates and interprets an extensive body of basic literature, some of which is not customarily considered to be related to cholelithogenesis, describing the multiple facets of the immune system that appear to be involved in cholesterol cholelithogenesis. A thorough understanding of the immune interactions with biliary lipids and cholecystocytes should modify current views of the pathogenesis of cholesterol gallstones, promote further research on the pathways involved, and lead to novel diagnostic tools, treatments, and preventive measures.
Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes (ACSs). The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a multicenter, randomized, double-blind, active-control trial designed to test the hypothesis that the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS.
The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS. Patients are randomized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg. Follow-up visits are at 1 and 4 months, and every 4 months thereafter. If consecutive measures of LDL-C are >79 mg/dL at follow-up visits, the simvastatin dose will be increased to 80 mg in a double-blind manner. The primary end point is the first occurrence of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke. Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point.
IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS. In addition, the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further.
Intestinal cholesterol absorption may influence gallstone formation and its modulation could be a useful therapeutic strategy for gallstone disease (GSD). Ezetimibe (EZET) is a cholesterol-lowering agent that specifically inhibits intestinal cholesterol absorption.
To test whether EZET can prevent gallstone formation in mice.
Gallstone-susceptible C57BL/6 inbred mice were fed control and lithogenic diets with or without simultaneous EZET administration. Lithogenic diet increased biliary cholesterol content and secretion, and induced sludge or gallstone formation in 100% of the animals. EZET administration reduced intestinal cholesterol absorption by 90% in control animals and by 35% in mice receiving the lithogenic diet. EZET prevented the appearance of cholesterol crystals and gallstones. In addition, mice fed the lithogenic diet plus EZET exhibited a 60% reduction in biliary cholesterol saturation index. Of note, EZET treatment caused a significant increase in bile flow (+50%, P<0.01) as well as bile salt, phospholipid and glutathione secretion rates (+60%, +44% and +100%, respectively, P<0.01), which was associated with a moderately increased expression of hepatic bile salt transporters. In addition, relative expression levels of Nieman-Pick C1 like 1 (NPC1L1) in the enterohepatic axis in humans were assessed. Expression levels of NPC1L1 were 15- to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of EZET on intestinal cholesterol absorption in humans.
In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.
Niemann-Pick C1-like 1 (NPC1L1) facilitates the uptake of sterols into the enterocyte and is the target of the novel cholesterol absorption inhibitor, ezetimibe. These studies used the Golden Syrian hamster as a model to delineate the changes in the relative mRNA expression of NPC1L1 and other proteins that regulate sterol homeostasis in the enterocyte during and following cessation of ezetimibe treatment and also to address the clinically important question of whether the marked inhibition of cholesterol absorption alters biliary lipid composition. In hamsters fed a low-cholesterol, low-fat basal diet, the abundance of mRNA for NPC1L1 in the small intestine far exceeded that in other regions of the gastrointestinal tract, liver, and gallbladder. In the first study, female hamsters were fed the basal diet containing ezetimibe at doses up to 2.0 mg.day(-1).kg body wt(-1). At this dose, cholesterol absorption fell by 82%, fecal neutral sterol excretion increased by 5.3-fold, and hepatic and intestinal cholesterol synthesis increased more than twofold, but there were no significant changes in either fecal bile acid excretion or biliary lipid composition. The ezetimibe-induced changes in intestinal cholesterol handling were reversed when treatment was withdrawn. In a second study, male hamsters were given a diet enriched in cholesterol and safflower oil without or with ezetimibe. The lipid-rich diet raised the absolute and relative cholesterol levels in bile more than fourfold. This increase was largely prevented by ezetimibe. These data are consistent with the recent finding that ezetimibe treatment significantly reduced biliary cholesterol saturation in patients with gallstones.
Human cholesterol gallstone disease has been a frequent and serious problem. A number of animal models have been reviewed for comparative study of cholesterol lithogenesis. These models in general have involved (1) decreasing bile salt excretion, (2) increasing dietary cholesterol, or (3) inducing gallbladder infection or stasis.
Because fatty acid composition of biliary phospholipids influences cholesterol secretion into bile, we investigated whether replacement of n-1 monounsaturated or n-6 polyunsaturated fatty acids with n-3 polyunsaturated fatty acids in biliary phosphatidylcholines reduces supersaturation with cholesterol and prevents precipitation of cholesterol crystals in bile of gallstone patients. Seven patients with radiolucent gallstones in functioning gallbladders were studied before (control) and after 5 wk of dietary supplementation with marine fish oil (11.3 gm/day = 3.75 gm n-3 polyunsaturated fatty acids/day). Duodenal bile was collected for analysis during intravenous infusion of cholecystokinin. Gallbladder emptying in response to cholecystokinin was comparable before and during intake of n-3 polyunsaturated fatty acids. Intake of n-3 polyunsaturated fatty acids increased (p less than 0.001) the fractions of eicosapentaenoic and docosahexaenoic acids and decreased the fractions of linoleic (p less than 0.001) and arachidonic acids (p less than 0.02) in biliary phospholipids. Concomitantly, the molar ratio of cholesterol to phospholipids decreased (-19%; p less than 0.05). As a consequence, the cholesterol saturation index was reduced by -25% (p = 0.01), from 1.60 +/- 0.44 to 1.24 +/- 0.38. However, in vitro nucleation time of duodenal bile was not prolonged. The decrease in cholesterol saturation was not sufficient to prevent nucleation of cholesterol crystals in bile of gallstone patients. In conclusion, our data suggest that cholesterol saturation can be influenced by the fatty acid composition of the phosphatidylcholines secreted in bile.
The effects of pravastatin on cholesterol gallstone formation were determined in prairie dogs. We fed 10 prairie dogs 1% cholesterol with or without 0.05% (w/w) pravastatin (n = 5, each) for 4 weeks. In addition, another 5 prairie dogs were fed a standard rodent chow as a control. Only the animals fed 1% cholesterol without pravastatin treatment formed cholesterol gallstones. Gallbladder bile from cholesterol-fed animals contained cholesterol monohydrate crystals, whereas those treated with pravastatin contained no crystal. Furthermore, marked increases in tissue cholesterol levels (serum, liver and bile), and in biliary mucous glycoprotein levels were evident in cholesterol-fed animals, whereas pravastatin treatment normalized these levels. These findings raise the possibility that such inhibitors might have a future role to play in the prevention of cholesterol gallstone formation and/or recurrence.
The efficacy of lovastatin, an inhibitor of hepatic cholesterol synthesis in the prevention of cholesterol gallstone formation, was evaluated in the prairie dog model. Two groups of animals were maintained on either nonlithogenic or 1.2% cholesterol-enriched chow for 21 days. Seven of the animals in each group received lovastatin, and the remaining six received only distilled water. All of the cholesterol-fed/water-treated animals had crystals and 83% had gallstones, but none of the cholesterol-fed/lovastatin-treated animals had gallstones and only three had microscopic crystals. These data indicate that lovastatin inhibits cholesterol gallstone formation in a diet-induced model of gallstone disease.
The rates of cholesterol 7 alpha-hydroxylation (the first and rate-limiting step of bile acid synthesis from cholesterol) were evaluated in vivo in patients administered bile acids with different structural properties, cholestyramine or simvastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Twenty-three subjects, with normal hepatic and intestinal functions, were studied in basal conditions and after one of the following treatment schedules, lasting 4 to 6 weeks: cholestyramine, 4 and 12 gm/day (four patients); ursodeoxycholic acid, 9 to 11 mg/kg/day (four patients); chenodeoxycholic acid, 12 to 15 mg/kg/day (five patients); deoxycholic acid, 8 to 10 mg/kg/day (four patients); and simvastatin, 40 mg/day (six patients). 7 alpha-Hydroxylation of cholesterol was assayed by measuring the increase in body water tritium after intravenous bolus of cholesterol tritiated at the 7 alpha position. Plasma bile acid composition, evaluated by gas-liquid chromatography, revealed a substantial enrichment of the recirculating pool by the administered bile acid, whereas treatment with cholestyramine decreased the content of dihydroxylated bile acids. Cholesterol 7 alpha-hydroxylation increased in a dose-related manner after cholestyramine, in parallel with a decrease of cholesterol in total plasma and low-density lipoproteins (1.006 to 1.063 gm/ml). Hydroxylation rates decreased by an average of 47% with chenodeoxycholic acid and by an average of 78% with deoxycholic acid; ursodeoxycholic acid treatment did not affect 7 alpha-hydroxylation significantly. Simvastatin markedly reduced plasma total and low-density lipoprotein-cholesterol but exerted no change on 7 alpha-hydroxylation rates.(ABSTRACT TRUNCATED AT 250 WORDS)
Owing to the presence of hyperlipoproteinemia IIa, twelve patients without gallstones were treated daily with 20 mg, 40 mg and 80 mg of Lovastatin, each dose being administered for 4 weeks. At the conclusion of each 4-week treatment phase, bile was obtained from the fasting patient following injection of 5 micrograms ceruletid i.v. with the aid of a duodenal tube. The long nucleation time of bile was not shortened by the therapy. The bile cholesterol saturation index showed a decline with Lovastatin, which was particularly obvious in patients with an initially oversaturated bile. In contrast to other lipid-reducing agents (e.g. fibrates), Lovastatin does not lead to increased lithogenesis of the bile, but may in certain circumstances have an prophylactic effect against the formation of gallstones.
This study was designed to clarify the effect of bile acid sequestrant treatment on the total biliary output rates of cholesterol, phospholipids and bile acids in man, and to correlate these changes with the alterations in plasma lipoprotein levels. For this purpose nine healthy, normolipidaemic men were treated with 16 g of cholestyramine daily over a period of 4 weeks, and the biliary secretion rates were measured by a duodenal perfusion technique. Resin therapy, which profoundly increases de novo synthesis of bile acids, resulted in a lowering of total plasma cholesterol levels, mainly due to a 35% reduction in low density lipoprotein (LDL) cholesterol, and in a 33% increase in plasma triglyceride levels, reflecting enhanced very low density lipoprotein (VLDL) triglyceride concentrations; high density lipoprotein (HDL) levels did not change. However, these lipoprotein changes did not correlate with any alterations in biliary lipid output. Total hepatic secretion rates of the biliary lipids remained generally unchanged during treatment, with a tendency towards lower cholesterol output, resulting in a lower molar percentage of cholesterol in hepatic bile, 3.4 +/- 0.4 vs. 2.9 +/- 0.2 mol %. This is probably due to an increased rate of conversion of cholesterol to bile acids in the hepatocyte. It is concluded that, in man, the liver may adapt well to changes in the enterohepatic circulation of bile acids, thereby maintaining output rates of biliary lipids at a relatively constant level.
Gallstones are common, affecting about one fourth of women and 10% to 15% of men over the age of 50. They are more prevalent in Amerindians and Mexican-Americans and less common in blacks. Principal risk factors are age, sex, and obesity. Lesser risk factors include childbearing, abstinence from alcohol, and some medications. The rate at which asymptomatic gallstones become symptomatic is low but significant, while patients with mildly symptomatic stones are at even greater risk for future pain and complications.
The effects of lovastatin and ursodeoxycholic acid on cholesterol saturation of gallbladder bile were examined, alone and in combination. Nine volunteers were studied before any treatment and after each of three treatment periods: lovastatin, 40 mg, twice a day; ursodeoxycholic acid, 10 mg/kg per day; and the combination of both drugs. Treatment periods were randomly ordered, lasted 4-5 wk, and each was preceded by a 3-wk washout period. Mean cholesterol saturation index decreased from a baseline value of 1.40-0.92 on lovastatin (p less than 0.008). Mean cholesterol saturation index on ursodeoxycholic acid was 0.87 and decreased to 0.70 with the addition of lovastatin (p less than 0.030). There was a strong correlation (r = 0.87, p less than 0.003) between saturation index on ursodeoxycholic acid and the further incremental reduction in saturation index with addition of lovastatin. These findings raise the possibility that addition of lovastatin to ursodeoxycholic acid treatment might improve the efficacy of this bile salt for dissolution of cholesterol gallstones, especially in patients with a suboptimal response to ursodeoxycholic acid.
We tested the possibility that simvastatin, a competitive inhibitor of HMG-CoA reductase related to mevinolin, might alter cholesterol saturation of gallbladder bile. Ten patients with Type IIa or IIb hypercholesterolemia underwent bile sampling before, and again after, treatment with 20 or 40 mg per day simvastatin for 7 to 13 weeks. Mean cholesterol saturation index of gallbladder bile fell from 1.01 to 0.77 during simvastatin treatment (p less than 0.01). This finding strongly suggests that treatment with HMG-CoA reductase inhibitors will not predispose to development of cholesterol gallstones. Indeed, it raises the possibility that such inhibitors might have a future role to play in treatment of gallstones.
A relationship between cholesterol gallstone disease and atherosclerosis or its sequellae has long been postulated but has never been adequately proven. Data for this investigation of the relationship of diagnosed cholesterol cholelithiasis to subsequent incident coronary heart disease were obtained from a review of the pre-existing prospectively collected medical records of the 5,209 individuals followed since 1952 as members of the original cohort of the Framingham Heart Study. Preliminary univariate examination of these data, making no correction for time ordering of the conditions or for shared risk factors, indicated a significant modest positive association in men but no relationship in women. Logistic multiple regression analyses, allowing for the effects of time ordering and for eight standard coronary disease risk factors, confirmed these findings. The authors speculate that the presence of cholesterol gallstones in male patients may be indicative of an unfavorable lipoprotein profile. These results have clinical implications in that male gallstone patients are at increased risk for subsequent coronary disease and should be monitored accordingly. This investigation marks the first time that a relationship between these conditions has been established using a longitudinal cohort study approach.
To study the pathogenesis of cholesterol gallstones, we fed 24 adult male prairie dogs a high cholesterol, egg yolk diet. 13 control animals received a cholesterol-free diet. All animals fed the egg yolk diet formed multiple gallstones in 2-6 months' time. These stones contained cholesterol, 77+/-14% by dry weight. No stones ocurred in the control group. The egg yolk-fed animals developed bile of altered chemical composition. The cholesterol concentration of hepatic and gallbladder bile increased significantly. The molar ratios of bile acid/cholesterol and phospholipid/cholesterol decreased in hepatic and gallbladder bile. The predominant bile acid shifted from cholic acid, 78% of the total bile acids, to chenodeoxycholic acid, 60% of the total. In common bile duct cannulated animals the high cholesterol diet produced increased secretion of cholesterol by the liver and increased bile flow. In animals fed the egg yolk diet for 2 months, cholesterol-4-(14)C was included in the daily diet for the next 4 months to establish an isotopic steady state. At autopsy the mean specific activity of cholesterol was similar in serum, liver, hepatic bile, gallbladder bile, and gallstones. Thus the cholesterol of gallstones apparently equilibrated constantly throughout the study and was not sequestrated as a static pool. The high cholesterol, egg yolk diet caused the secretion of an "abnormal bile" which led to precipitation of cholesterol from micellar solution. The increased bile cholesterol relative to bile acid and phospholipid favored stone formation. This dietary induction of cholesterol gallstones provided a unique animal model, in part but not completely analogous to human cholelithiasis.
There is no genetically susceptible, spontaneous and naturally occurring animal model for human cholesterol cholelithiasis. The disease has been reported to occur spontaneously only rarely in some primates. The human disease is probably multifactorial; therefore, the finding or development through inbreeding of a spontaneous genetic model is unlikely. The two most popular animals in use today as models are rodent species: hamster and prairie dog. Despite widely different means of dietary induction of the disease in the two, the feature common to both is cholesterol overload. In the case of the essential fatty acid-deficient hamster, the predominant defect is a unique endogenous overproduction through increased total body synthesis of cholesterol. In the prairie dog, the cholesterol overload is simply exogenous due to massive and rapid intestinal absorption. Neither model is remotely physiological. Although a number of useful aspects of the lithogenic process can be studied using these models, certain changes apparently associated with the formation of gallstones under these conditions may in part be a function of the unphysiological dietary requirements for induction of the disease.
Inhibitors of the HMG-CoA reductase have been shown to further reduce the biliary cholesterol saturation in patients treated with oral bile acids for cholesterol gallbladder stones. It was the aim of our study to evaluate the efficacy of simvastatin in addition to ursodeoxycholic acid in the dissolution of gallstone fragments after shock wave lithotripsy and adjuvant bile acid dissolution therapy. Eighteen patients with a single radiolucent gallbladder stone and a serum cholesterol of more than 250 mg/dl were randomly assigned to receive either ursodeoxycholic acid alone (750 mg per day, group A, n = 9) or in combination with simvastatin (20 mg per day, group B, n = 9) for the dissolution of the gallstone fragments generated by extracorporeal shock wave lithotripsy. The two groups were well matched regarding their baseline characteristics. At the primary end point of the study 6 months after lithotripsy, there was no difference between the groups in the rate of gallstone disappearance with 4 of 9 patients being stone free in each group. As evaluated by life table analysis, even further follow-up showed no significant difference between the groups (P = 0.8). In group B, serum cholesterol levels decreased by 22% at 3 months (P = 0.01 vs. baseline) and by 24% at six months (P = 0.02) during treatment while no significant change was observed in group A. With both regiments, no adverse effects were observed. While simvastatin added to ursodeoxycholic acid resulted in a decrease of elevated serum cholesterol levels in gallstone patients, it did not enhance stone disappearance after shock wave lithotripsy and adjuvant bile acid dissolution therapy.
Epidemiologic studies suggest that populations consuming a diet rich in fish oil have lower rates of both atherosclerotic heart disease and gallstones. The mechanisms underlying this inhibitory effect on cholesterol gallstone formation remain unclear. We therefore studied the effect of dietary fish oil on bile composition and cholesterol precipitation in an animal model of gallstone disease.
Adult male prairie dogs were fed a standard control diet (n = 12) or a lithogenic 1.2% cholesterol diet (n = 16). One half of the animals in each group had their diet supplemented with concentrated fish oil.
After 14 days animals receiving the cholesterol diet all developed biliary cholesterol monohydrate crystals and gallstones. When fish oil was added to this high cholesterol diet, solid cholesterol crystal precipitation and gallstone formation were completely inhibited. This inhibition of gallstone formation was accompanied by a significant decrease in biliary calcium and total protein concentration. Microscopic cholesterol liquid crystals were evident in the bile of all of the animals fed the cholesterol plus fish oil diet. Dietary fish oil also significantly prolonged cholesterol monohydrate crystal observation time in animals receiving the lithogenic diet.
These data suggest that dietary fish oil exerts a potent antilithogenic effect on cholesterol gallstone disease and may induce a stable liquid crystalline phase retarding nucleation.
Female non-insulin-dependent diabetics have a high prevalence of gallstones. Treatment of hyperlipidaemia in these patients may modify the risk. Seventeen female non-insulin-dependent diabetics (age 35-65) were treated with simvastatin (n = 10) or bezafibrate (n = 7) and had the cholesterol saturation index (CSI) of bile and gall-bladder emptying measured before and after 3 months therapy. In both groups, there was a significant reduction in serum cholesterol following treatment. The mean pretreatment cholesterol saturation indices of bile did not differ between the two groups but, after 3 months therapy, there was a highly significant difference in CSI between the bezafibrate group (2.0 +/- 0.33) and the simvastatin group (1.1 +/- 0.14) P < 0.002. Whereas the increase in the CSI (42%) observed with bezafibrate therapy was significant, the decrease in the simvastatin group (14%) was only significant in those whose pretreatment cholesterol saturation indices were elevated. Despite the differences in CSI observed between the two treatment groups, no changes in gall-bladder emptying were detected.
The mechanisms for the hypocholesterolaemic action of niacin (nicotinic acid) were examined in rats administered niacin at a dose of 400 mg/kg body wt/day for either 2 or 4 weeks. Another group of rats were administered diosgenin, an inhibitor of acyl-CoA:cholesterol acyltransferase, as a 1% (w/w) supplement in the diet for 7 days. Both agents produced small increases in bile flow rates (up to 40%) and mild hepatotoxicity evidenced by small increases in serum transaminase activities. Niacin treatment for 2 or 4 weeks lowered serum cholesterol concentrations by 13% or 29%, respectively, with the greatest decrease occurring in the low density lipoprotein fraction. This was accompanied by relatively large increases in biliary cholesterol output (114% and 130% after 2 and 4 weeks treatment, respectively) with smaller increases in the biliary output of phospholipid (18% and 45%) and bile acid (26% and 14%). Diosgenin treatment increased serum cholesterol by 29% and increased the biliary output of cholesterol, phospholipid and bile acid by 800%, 10% and 45%, respectively. Thus, both agents increased the cholesterol saturation of bile (100% by niacin, 500% by diosgenin). Cholesterol and phospholipid in fistula bile from control rats were present in lamellar and micellar forms. Niacin treatment did not alter the physical form of biliary lipids whilst diosgenin caused the appearance of vesicular lipid in fistula bile. Thus, increased biliary secretion of cholesterol explains, at least in part, the hypocholesterolaemic action of niacin. In addition, since aggregation of biliary vesicles is involved in cholesterol gallstone formation in humans, the non-appearance of vesicular material in fistula bile from niacin-treated rats may be of some importance.
Lovastatin, an agent that reduces both serum and biliary cholesterol in humans, also inhibits cholesterol gallstone formation in an animal model. The present study was designed to assess the efficacy of lovastatin in gallstone dissolution.
All prairie dogs were fed a 1.2% cholesterol-enriched diet during the entire study. Gallbladders from five animals were examined at 3 weeks, and four of five gallbladders contained gallstones. Remaining animals were maintained on the 1.2% cholesterol-enriched diet and randomized to receive either water (n = 7); lovastatin, 8 mg (n = 7); ursodeoxycholic acid, 50 mg (UR, n = 7); or both drugs (lovastatin and UR, n = 7) twice daily by way of orogastric tube for 4 additional weeks. Response to therapy was determined by blinded examination of gallbladders.
All three treatment groups had significant reductions in serum cholesterol, hepatic bile cholesterol, and hepatic cholesterol saturation index as compared to controls (water). Lovastatin induced a 28% response rate to dissolution therapy, which was equal to that achieved with UR, and the combination of lovastatin and UR produced a 56% response rate.
This preliminary study suggests that lovastatin, alone or in combination with UR, may be useful in dissolving gallstones in humans.
Hypolipidemic drugs like etofibrate and bezafibrate may induce lithogenic bile and increase the risk of gallstone formation. In this study, biliary lipids, lithogenic index and biliary drug concentrations were investigated in 6 hyperlipidemic patients after cholecystectomy. Patients were treated once daily for 5 days with either 500 mg/day etofibrate or 400 mg/day bezafibrate. Hepatic bile was collected for 6 days via T-drainage in 4 hourly aliquots. In the patients treated with etofibrate, the range of the lithogenic index remained stable with 0.89-1.69 before and 0.78-1.51 after 5 day drug therapy. In the bezafibrate group, the range of the lithogenic index rose from 0.81-1.40 to 1.26-1.66 mainly as a result of an increase of biliary cholesterol concentrations. Biliary drug concentrations were substantially higher under bezafibrate treatment than under etofibrate treatment. In conclusion, the fibrate drugs, etofibrate and bezafibrate, are different with regard to lithogenicity of bile and extent of biliary excretion. The safety profile of etofibrate may be preferably compared to other fibrate drugs.
HMG-CoA reductase inhibitors are now the therapy of choice in the treatment of hypercholesterolaemia. The effects of long-term treatment with these substances on plasma lipoproteins, cholesterol metabolism and biliary secretion of lipids have been extensively studied in humans. Much less is known about the effects of short-term treatment. The aim of this study was to determine the time course of the effects of HMG-CoA reductase inhibitors on plasma lipoprotein levels as well as cholesterol and bile acid synthesis in gallstone patients.
Thirty-six patients undergoing elective cholecystectomy were included in the study. Except for the gallstone disease, these patients were otherwise healthy. Four groups of subjects were treated with the HMG-CoA reductase inhibitor pravastatin (Pravachol), 20 mg twice daily for 12, 24, 48 and 72 h preoperatively. Plasma lipoproteins and plasma levels of lathosterol and 7 alpha-hydroxy-4-cholesten-3-one were determined before initiation of pravastatin treatment and on the morning of the day of the operation, lathosterol reflecting hepatic HMG-CoA reductase activity and 7 alpha-hydroxy-4-cholesten-3-one the activity of cholesterol 7 alpha-hydroxylase, the rate-determining enzyme in bile acid synthesis.
All treatment groups displayed a significant decrease in total cholesterol and low-density lipoprotein (LDL)-cholesterol, by about 12% and 17% respectively. Lathosterol was reduced by about 50% in all treatment groups. Of great interest was the finding that 7 alpha-hydroxy-4-cholesten-3-one was unaffected in all treatment groups.
The results show that short-term pravastatin treatment in gallstone patients rapidly inhibits cholesterol synthesis and lowers plasma LDL-cholesterol levels without effects on bile acid synthesis.
Inhibitors of 3-hydroxy,3-methylglutaryl coenzyme A (HMG-CoA) reductase have been reported to decrease the cholesterol saturation index (CSI) in duodenal bile in humans and to prevent formation of cholesterol gallstones in animal studies. We performed a prospective study to evaluate the role of HMG-CoA reductase inhibitors as gallstone-dissolving agents. Fifty patients with radiolucent gallstones in a gallbladder opacifying at drip infusion cholecystography were treated with either 10 mg/day simvastatin plus 600 mg/day ursodeoxycholic acid (group 1, n=26) or 600 mg/day ursodeoxycholic acid alone (group 2, n=24) for 12 months. The ratio of solitary to multiple gallstone cases was 21:29. Plasma lipid levels were assessed and ultrasonographic examination of the gallbladder was performed at baseline and at 3-month intervals during treatment. Duodenal bile sampling was performed in five patients in each group at baseline and after 12 months of treatment. Plasma cholesterol decreased significantly in group 1 but not in group 2. In solitary gallstone cases, no significant difference in dissolution rates was observed between groups 1 (3 of 9, 33%) and 2 (4 of 12, 33%). In contrast, the dissolution rate in multiple gallstone cases was significantly higher in group 1 (12 of 17, 71%) than in group 2 (3 of 12, 25%) (p < 0.01). Bile cholesterol saturation index was significantly decreased (p < 0.01) but did not significantly differ between the two groups. These results suggest that combination therapy with simvastatin and ursodeoxycholic acid is more effective for cholesterol gallstone dissolution than ursodeoxycholic acid monotherapy in patients with multiple gallstones.
Recent epidemiological studies have suggested that hyperinsulinaemia may be a central factor in the pathogenesis of cholesterol gallstones, explaining a probable link with physical inactivity as well as abdominal adiposity. There is also increasing evidence for the hypothesis that enrichment of bile with DCA. 'the colonic bile acid', leads to enrichment of bile with cholesterol. Biliary DCA can be raised and lowered by slowing down and speeding up colonic transit, respectively. Slow transit is characteristic of non-obese British women with gallstones and of non-obese peasants in a gallstone-prone mountain community. High biliary DCA predicts recurrence of gallstones and so does laxative usage, a pointer to constipation and therefore to slow transit. In some studies, at least, a high fibre intake is protective against gallstones. Much else besides fibre influences colonic function. Future studies of gallstone aetiology should include measurements of colonic function. Measures that speed up colonic transit should be tested for their ability to prevent gallstone formation in high-risk individuals.
To assess risk factors for gallstone recurrence following non-surgical treatment.
A prospective follow-up of a multicentre cohort of post-dissolution gallstone patients.
Six gastroenterology units in the UK and Italy.
One hundred and sixty-three patients with confirmed gallstone dissolution following non-surgical therapy (bile acids or lithotripsy plus bile acids), followed up by ultrasound scan and clinical assessment at 6-monthly intervals for up to 6 years (median, 25 months; range, 6-70 months).
Subject-related variables (sex, age, height, weight, body mass index), gallstone-related variables (number, diameter, presence of symptoms, months to complete stone clearance), treatment modalities (bile acid therapy, extracorporeal shock wave lithotripsy) and follow-up related variables (weight change, use of non-steroidal anti-inflammatory agents, statins, pregnancies and/or use of oestrogens) were assessed by univariate and multivariate analysis as putative risk factors for gallstone recurrence.
Forty-five gallstone recurrences were observed during the follow-up period. Multiple primary gallstones and length of time to achieve gallstone dissolution were the only variables associated with a significant increase in the recurrence rate. Appearance of biliary sludge during follow-up was also significantly related to development of gallstone recurrence. Use of statins or non-steroidal anti-inflammatory agents did not confer protection against recurrence.
Patients with primary single stones are the best candidates for non-surgical treatment of gallstones, because of a low risk of gallstone recurrence. The positive association of recurrence with biliary sludge formation and time to dissolution of primary stones may provide indirect confirmation for the role of impaired gallbladder motility in the pathogenesis of this condition.
There is limited information available on the effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on hepatic and biliary cholesterol metabolism in patients with gallstones. The aims of this study were to determine the effect of simvastatin on the regulatory elements of cholesterol metabolism that determine the concentrations of cholesterol in plasma and bile.
Thirty-one gallstone patients were enrolled in the study; 17 were treated with 20 mg simvastatin daily for 3 weeks prior to cholecystectomy and 14 served as controls. Samples of blood, liver, gall-bladder bile and bile from the common bile duct (CBD) were collected and analysed.
The plasma cholesterol (-30%), triacylglycerol (-23%) and low-density lipoprotein (LDL) cholesterol (-42%) concentrations were significantly lowered by simvastatin treatment, as was the plasma lathosterol: cholesterol (-70%), which reflects whole-body cholesterol synthesis. Despite these changes, the hepatic LDL receptor protein and LDL receptor activity in circulating mononuclear cells were similar in both groups. There were no differences in the plasma phytosterol: cholesterol, which reflects the intestinal cholesterol absorption capacity or in the activity of hepatic acyl-coenzyme A: cholesterol acyltransferase. There were however, lower cholesterol concentrations in CBD (-68%) and gall bladder (-41%) bile, and decreased lithogenic (-47%) and bile acid hydrophobicity (-22%) indices of CBD bile in the simvastatin group.
These data indicate that simvastatin reduced plasma and biliary cholesterol levels primarily by reducing cholesterol synthesis. The reduction in CBD bile lithogenicity and bile acid hydrophobicity by simvastatin suggests that this agent may be useful for people who have early stages of cholesterol gallstone development and in whom a choleretic effect is required.
Fibrate derivatives and HMG-CoA reductase inhibitors modify homeostasis of cholesterol. The aim of this study was to assess in an unselected population whether these hypolipidemic drugs are risk factors for cholelithiasis or, conversely, are protective agents. Both sexes, all socioeconomic categories, pregnant women, and cholecystectomized subjects were included. Clinical data collection and gallbladder ultrasonography were both carried out in a double-blind fashion. Fibrate derivatives were predominantly fenofibrate, HMG-CoA reductase inhibitors were simvastatin and pravastatin. On univariate analysis, age (>50 years), sex, and use of fibrates were found to be significantly related to the presence of cholelithiasis. Age, sex, and fibrate treatment remained independently correlated with the presence of gallstones on multivariate analysis. With fibrates, the relative risk for lithiasis was 1.7 (P = 0.04). The HMG-CoA reductase inhibitors were not associated with a protective effect on univariate analysis. Of the lipid-lowering drugs, only fibrate derivatives were found to increase the risk of gallstone formation.