胆胃关系探析

脏腑相关论治是中医学基本理论框架的重要内容之一。胆胃同为六腑,二者关系十分密切,生理上相互影响,病理上互为因果。明确其生理、病理关系对于理论研究和指导临床具有重大的意义。胆胃同病,多以口苦或呕苦、咽干为主要临床表现,胆胃同治就是要利胆和胃,佐以清热消导。

先天性胆总管囊肿壁MMP-2、TIMP-2的表达研究

目的通过观察先天性胆总管囊肿壁明胶酶MMP-2及其组织抑制因子TIMP-2的表达,结合组织形态学观察,探讨其与CCC发病机制的关系。方法收集53例先天性胆总管囊肿患儿的临床资料以及组织标本,其中男21例,女32例,平均年龄6.5岁(4个月～17岁)。取正常胆囊组织28例作为对照组。采用免疫组化方法检测MMP-2、TIMP-2蛋白,通过图像分析技术进行定量分析。结果MMP-2、TIMP-2蛋白见于胆总管囊肿壁粘膜上皮细胞、基质细胞及炎性细胞胞浆、胞膜;胆总管囊肿胆囊粘膜上皮细胞内也见不同程度表达。对照组胆囊表达阴性或弱阳性。定量分析显示胆总管囊肿壁MMP-2蛋白表达强度明显高于胆总管囊肿胆囊及对照组胆囊(P<0.01),胆总管囊肿胆囊与对照组胆囊组织比较,差异无统计学意义(P>0.05);胆总管囊肿壁及胆囊组织间TIMP-2的表达强度比较,差异无统计学意义(P>0.05),但均明显高于对照组(P<0.01)。结论MMP-2/TIMP-2的平衡失调和MMP-2的高表达参与了胆总管壁基质的降解,可能与胆总管囊肿的形成有关。

L-12P35,P40和IFN-γ在胆道闭锁小鼠模型肝脏组织中的表达

目的检测小鼠胆道闭锁(biliary atresia,BA)模型肝脏IL-12p35,p40,IFN-γmRNA的表达情况,探索其在BA发病中的作用。方法采用腹腔注射RRV病毒建立Balb/c新生小鼠BA模型,其中胆道闭锁组(BA组)45只,对照组24只(腹腔注射病毒培养液)。应用RT-PCR方法检测小鼠模型肝脏中IL-12p35,p40,IFN-γmRNA的表达。结果与对照组相比,BA组肝内IL-12p35,p40,IFN-γmRNA的表达水平均明显高于对照组,P<0.01,在第9天时IFN-γ表达水平达峰值(13.340±0.539),IL-12p35,IL-12p40也同时达峰值,分别为(47.629±2.041)和(45.987±2.06),之后,IL-12p35和IFN-γ表达均下降,但IL-12p40表达仍维持在较高水平。结论IL-12P35,P40及IFN-γmRNA表达水平在BA发病过程中明显升高,IL-12P35,P40在BA发病机制中可能与调节gamma干扰素(IFN-γ)的分泌相关。

CD68和MMP-9在小儿先天性胆总管囊肿中的表达及意义

目的 通过观察先天性胆总管囊肿（congenital choledochocgst，CCC）囊壁CD68和MMP-9的表达，探讨其与CCC发病机制的关系。方法 收集48例先天性胆总管囊肿患儿的临床资料以及组织标本，为观察组，取正常胆囊组织11例作为对照组。采用免疫组化方法检测CD68和MMP-9。结果 观察组CD68和MMP-9均有较高阳性表达，与对照组比较，差异有统计学意义（P≤0．05），其中MMP-9在囊性型囊肿和梭状型囊肿囊壁组织中的表达差异有统计学意义（P≤0．05）。结论 CD68和MMP-9的高表达，提示炎性因素可能参与了胆总管囊肿的形成过程。

超声检查对胆道下段恶性肿瘤的诊断价值

目的:探讨超声检查对胆道下段恶性肿瘤诊断价值,提高超声诊断符合率。方法:对87例恶性肿瘤(胰头癌、壶腹癌、胆管癌)患者进行超声检查,并对检查结果与临床和(或)手术病理结果进行比较,观察肿瘤位置、大小形态、包膜边界、内部结构、胆总管梗阻的程度与形态、胰管增宽情况及手术治疗方式。结果:87例恶性肿瘤中胰头癌39例,壶腹癌31例,胆管癌17例;手术治疗胰头癌29例(74.4%),壶腹癌23例(74.2%),胆管癌11例(64.7%)。胰头癌术前超声诊断与术后病理诊断符合率为94.9%;胆管癌术前超声诊断与术后病理诊断符合率为82.4%。结论:引起肝外胆管低位梗阻之恶性肿瘤超声诊断特征不同,超声诊断对临床治疗方案的制定和预后评价有重要意义。

Management of hilar cholangiocarcinoma in the North of England: Pathology, treatment, and outcome

AIM: To assess the management and outcome of hilar cholangiocarcinoma (Klatskin tumor) in a single tertiary referral center.METHODS: The notes of all patients with a diagnosis of hilar cholangiocarcinoma referred to our unit for over an 8-year period were identified and retrospectively reviewed. Presentation, management and outcome were assessed.RESULTS: Seventy-five patients were identified. The median age was 64 years (range 34-84 years). Male to female ratio was 1:1. Eighty-nine percent of patients presented with jaundice. Most patients referred were under Bismuth classification 3a, 3b or 4. Seventy patients required biliary drainage, 65 patients required 152percutaneous drainage procedures, and 25 had other complications. Forty-one patients had 51 endoscopic drainage procedures performed (15 failed). Of these,36 subsequently required percutaneous drainage. The median number of drainage procedures for all patients was three, 18 patients underwent resection (24%), nine had major complications and three died post-operatively.The 5-year survival rate was 4.2% for all patients, 21%for resected patients and 0% for those who did not undergo resection (P = 0.0021). The median number of admissions after diagnosis in resected patients was two and three in non-resected patients (P＜0.05).Twelve patients had external-beam radiotherapy, seven brachytherapy, and eight chemotherapy. There was no significant benefit in terms of survival (P = 0.46) or hospital admissions.CONCLUSION: Resection increases survival but carries the risk of significant morbidity and mortality.Percutaneous biliary drainage is almost always necessary and endoscopic drainage should be avoided if possible.

Estrogens and the pathophysiology of the biliary tree

The scientific framework concerning estrogen effects on different tissues has expanded enormously during the last decades, when estrogen receptor （ER） subtypes were identified. Estrogens are not only essential for the female reproductive system, but they also control fundamental functions in other tissues including the cardiovascular system, bone, brain and liver. Recently, estrogens have been shown to target the biliary tree, where they modulate the proliferative and secretory activities of cholangiocytes, the epithelial cells lining bile ducts. By acting on both estrogen receptors （ER-α） and （ER-β） subtypes, and by activating either genomic or non-genomic pathways, estrogens play a key role in the complex loop of growth factors and cytokines, which modulates the proliferative response of cholangiocytes to damage. Specifically, estrogens activate intracellular signalling cascades JERK1/2 （extracellular regulated kinases 1/2, PI3-kinase/AKT （phosphatidylinositol-3＇ kinase/AKT）] typical of growth factors such as insulin like growth factor （IGF1）, nerve growth factor （NGF） and vascular endothelial growth factor （VEGF）, thus potentiating their action. In addition, estrogens stimulate the secretion of different growth factors in proliferating cholangiocytes. This review specifically deals with the recent advances related to the role and mechanisms by which estrogens modulate cholangiocyte functions in normal and pathological conditions.

Bile acids:Chemistry,physiology,and pathophysiology

The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics.They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving finetuning by the levels of certain bile acid species.Although their best-known role is their participation in the digestion and absorption of fat,they also play an important role in several other physiological processes.Thus,genetic abnormalities accounting for alterations in their synthesis,biotransformation and/or transport may result in severe alterations,even leading to lethal situations for which the sole therapeutic option may be liver transplantation.Moreover,the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis,resulting in damage to the liver parenchyma and,eventually,extrahepatic tissues.When this occurs during pregnancy,the outcome of gestation may be challenged.In contrast,the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.

Medical treatment of cholestatic liver diseases:From pathobiology to pharmacological targets

Bile secretion is dependent on the coordinated functions of a number of hepatobiliary transport systems. Cholestasis may be caused by an impairment of bile secretion, an obstruction of bile flow or a combination of the two. The common consequence of all forms of cholestasis is retention of bile acids and other potentially toxic compounds in the hepatooltes leading to apoptosis or necrosis of hepatocytes and eventually to chronic cholestatic liver disease. In certain cholestatic disorders there is also leakage of bile acids into the peribiliary space causing portal inflammation and fibrosis. The following pharmacological targets for treatment of intrahepatic cholestasis can be identified： stimulation of orthograde biliary secretion and retrograde secretion of bile acids and other toxic cholephils into the systemic circulation for excretion via the kidneys to reduce their retention in the hepatocytes; stimulation of the metabolism of hydrophobic bile acids and other toxic compounds to more hydrophilic, less toxic metabolites; protection of injured cholangiocytes against toxic effects of bile; inhibition of apoptosis caused by elevated levels of cytotoxic bile acids; inhibition of fibrosis caused by leakage of bile acids into the peribiliary space. The clinical results of ursodeoxcholic acid therapy of primary biliary cirrhosis may be regarded as the first success of this strategy.

Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis

Cholangiocytes, the epithelial cells lining the biliary ducts, are the target cells in several liver diseases. Cholangiopathies and cholangiocarcinoma generate interest in many scientists since the genesis. The developing mechanisms, and the therapeutic tools of these diseases are still undefined. Several studies demonstrate that many hormones, neuropeptides and neurotransmitters regulate malignant and non-malignant cholangiocyte pathophysiology in the course of chronic biliary diseases. The aim of this review is to present the findings of several studies published in the recent years that contributed to clarifying the role of nervous and neuroendocrine regulation of the pathophysiologic events associated with cholestasis and cholangiocarcinoma development. This manuscript is organized into two parts. The first part offers an overview of the innervation of the liver and the origin of neuroendocrine hormones, neurotransmitters and neuropeptides affecting cholangiocyte function and metabolism. The first section also reviews the effects played by several neuroendocrine hormones and nervous system on cholangiocyte growth, survival and functional activity in the course of cholestasis. In the second section, we summarize the results of some studies describing the role of nervous system and neuroendocrine hormones in the regulation of malignant cholangiocyte growth.

Early bile duct cancer

Bile duct cancers are frequently diagnosed as advanced diseases. Over half of patients with advanced bile duct cancer present with unresectable malignancies and their prognosis has been very poor even after curative resections. Although there has been a need to diagnose bile duct cancer at its eady stage, it has been a difficult goal to achieve due to our lack of knowledge regarding this disease entity. Early bile duct cancer may be defined as a carcinoma whose invasion is confined within the fibromuscular layer of the extrahepatic bile duct or intrahepatic large bile duct without distant metastasis irrespective of lymph node involvement. Approximately 3%-10% of resected bile duct cancers have been reported to be early cancers in the literature. The clinicopathological features of patients with early bile duct cancer differ from those of patients with advanced bile duct cancer, with more frequent asymptomatic presentation, characteristic histopathological findings, and excellent prognosis. This manuscript is organized to emphasize the need for convening an international consensus to develop the concept of early bile duct cancer.

Intestinal bile acid physiology and pathophysiology

Bile acids (BAs) have a long established role in fat digestion in the intestine by acting as tensioactives, due to their amphipatic characteristics. BAs are reabsorbed very efficiently by the intestinal epithelium and recycled back to the liver via transport mechanisms that have been largely elucidated. The transport and synthesis of BAs are tightly regulated in part by specific plasma membrane receptors and nuclear receptors. In addition to their primary effect, BAs have been claimed to play a role in gastrointestinal cancer, intestinal inflammation and intestinal ionic transport. BAs are not equivalent in any of these biological activities, and structural requirements have been generally identified. In particular, some BAs may be useful for cancer chemoprevention and perhaps in inflammatory bowel disease, although further research is necessary in this field. This review covers the most recent developments in these aspects of BA intestinal biology.

Reassessment of functional dyspepsia:A topic review

Dyspepsia itself is not a diagnosis but stands for a constellation of symptoms referable to the upper gastrointestinal tract. It consists of a variable combination of symptoms including abdominal pain or discomfort, postprandial fullness, abdominal bloating, early satiety, nausea, vomiting, heartburn and acid regurgitation. Patients with heartburn and acid regurgitation invariably have gastroesophageal reflux disease and should be distinguished from those with dyspepsia. There is a substantial group of patients who do not have a definite structural or biochemical cause for their symptoms and are considered to be suffering from functional dyspepsia （FD）. Gastrointestinal motor abnormalities, altered visceral sensation, dysfunctional central nervous system-enteral nervous system （CNS- ENS） integration and psychosocial factors have all being identified as important pathophysiological correlates. It can be considered as a biopsychosocial disorder with dysregulation of the brain-gut axis being central in origin of disease. FD can be categorizeo into different subgroups based on the predominant single symptom identified by the patient. This subgroup classification can assist us in deciding the appropriate symptomatic treatment for the patient.

Imaging findings of biliary hamartomas

AIM： To evaluate the imaging findings of biliary hamartomas （yon Meyenburg complexes, VMCs） and discuss the differential diagnosis with other related diseases. METHODS： Imaging findings of biliary hamartomas on ultrasonography （US）, computed tomography （C-T）, magnetic resonance imaging （MRI）, MR cholangiopancreatography （MRCP）and hepatobiliary scintigraphy were retrospectively analyzed in six patients. RESULTS： On ultrasound images, five of the six cases showed multiple small hyper- and hypo-echoic lesions with comet-tail echoes, especially when magnified by US with the usage of zoom function. In all the six cases, multiple tiny hypodense lesions less than 10 mm in diameter were revealed as scattered throughout the liver with no enhancement on CT. These tiny lesions were demonstrated to be hyper- and hypo-intensity on T2- and TI-weighed images, respectively, in three patients who underwent MRI examinations. MRCP was performed in two patients, and clearly showed multiple tiny irregular- and round-shaped hyper-intensity lesions. MRCP and hepatobiliary scintigraphy showed normal appearances of intra- and extra-hepatic bile ducts in two and one patients, respectively. CONCLUSION： Imaging modalities are useful in the diagnosis and differential diagnosis of VMCs. A correct diagnosis might be obtained when typical imaging findings are present even without a histological confirmation.

Chronic acalculous cholecystitis:correlation of clinical assessment,laboratory data and final histopathology

Objective:To summarize and analyze the clinical and histopathological features of chronic acalculous cholecystitis (CAC) and to investigate the diagnosis and surgical treatment of chronic acalculous cholecystit.Methods:The study subjects were 39 patients with chronic biliary symptoms but no evidence of stones in the gallbladder by B ultrasonography and magnetic resonance cholopancreatography (MRCP) (CAC group).The CCC group consisted of 66 patients taken randomly from concurrent all patients of chronic calculous cholecystitis (CCC).All patients accepted fibergastroscopy,B ultrasonography,MRCP,laboratory examination preoperatively.We retrospectively analyzed the clinical features,B ultrasonography and MRCP findings,histopathological results and clinical outcomes between the two groups.Results:All the 39 patients were diagnosed by clinical symptoms,B ultrasonography,fatty meal gallbladder contractability studies under ultrasound,fibergastroscopy and magnetic resonance cholangiopancreatography (MRCP),what's more,they were pathologically verified postoperatively.In all patients,there was a complete absence of gallbladder wall contractability.Mucosa epithelial defect was found in 21 patients in CAC group (53.8%) and 16 patients in CCC group (24.2%) respectively (P<0.005).Thickened arteriole wall was found in 29 patients in CAC group (74.4%) and none patient in CCC group (P<0.0001).Thickened gallbladder wall (4 mm or more in thickness) was found in 33 patients in CAC group (84.6%) and 28 patients in CCC group (42.4%) respectively (P<0.005).Bile stasis was found in 23 patients in CAC group (59.0%) and 14 patients in CCC group (21.2%) respectively by ultrasonography preoperatively and confirmed in operation (P<0.005).The outcomes of cholecystectomy,expressed as total or near total relief,was similar in the two groups.No statistically significant differences were observed between patients with CAC (90%) and CCC (80%),the P-value >0.05.Conclusion:Chronic acalculous cholecystitis could be diagnosed by symptoms,ultrasound,fatty meal gallbladder contractability studies under untrasoundand MRCP.The optimal treatment of chronic acalculous cholecystitis characterized by thickened arteriole wall and mucosa epithelial defect is cholecystectomy.

Sclerosing cholangitis following severe trauma: Description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms

MM： Persistent cholestasis is a rare complication of severe trauma or infections. Little is known about the possible pathomechanisms and the clinical course.METHODS： Secondary sclerosing cholangitis was diagnosed in five patients with persistent jaundice after severe trauma （one burn injury, three accidents, one power current injury）. Medical charts were retrospectively reviewed with regard to possible trigger mechanisms for cholestasis, and the clinical course was recorded.RESULTS： Diagnosis of secondary sclerosing cholangitis was based in all patients on the primary sclerosing cholangitis （PSC）-Iike destruction of the intrahepatic bile ducts at cholangiography after exclusion of PSC. In four patients, arterial hypotension with subsequent ischemia may have caused the bile duct damage, whereas in the case of power current injury direct thermal damage was assumed to be the trigger mechanism. The course of secondary liver fibrosis was rapidly progressive and proceeded to liver cirrhosis in all four patients with a follow-up 〉2 years. Therapeutic possibilities were limited.CONCLUSION： Posttraumatic sderosing cholangitis is a rare but rapidly progressive disease, probably caused by ischemia of the intrahepatic bile ducts via the peribiliary capillary plexus due to arterial hypotension.Gastroenterologists should be aware of this disease in patients with persistent cholestasis after severe trauma.

Prevalence of cholelithiasis in patients with chronic inflammatory bowel disease

AIM： To investigate the effect of chronic inflammatory bowel disease （CIBD） specific risk factors for cholecystolithiasis, as duration and involvement pattern of the disease and prior surgery in patients with Crohn＇s disease （CD） and ulcerative colitis （UC）. METHODS： A total of 222 patients with CD （135 females, 87 males, average age, 35.8±11.8 years; range 17-81 years） and 88 patients with UC （39 females, 49 males; average age, 37.2±13.6 years; range 16-81 years） underwent clinical and ultrasound examinations. Besides age, sex and degree of obesity, patients＇ CIBD specific parameters, including duration and extent of disease and prior operations were documented and evaluated statistically using logistic regression. RESLTLTS： The overall prevalence of gallbladder stone disease in patients with CD was 13% （n = 30）. Only age could be shown to be an independent risk factor （P = 0.014）. Compared to a collective representative for the general population in the same geographic region, the prevalence of cholecystolithiasis was higher in all corresponding age groups. Patients with UC showed an overall prevalence of gallbladder stone disease of only 4.6%. CONCLUSION：Only age but not disease-specific factors such as duration and extent of disease, and prior surgery are independent risk factors for the development of cholecystolithiasis in patients with CIBD.