从系统方法看肝脏病机五行传变模式

以系统科学方法的整体性、动态性、模式化、最佳化四大特点,剖析肝脏有病可传心、肺、脾、肾四脏,四脏有病可波及肝脏的母子相传,乘侮传变等模式,并辅以相关佐证,旨在整合中医脏腑病机,从而为五行辨证提供最佳思维方法。

Interleukin-10 and chronic liver disease

Interleukin （IL）-10 is an important immunoregulatory cytokine produced by many cell populations. Numerous investigations suggest that IL-10 plays a major role in chronic liver diseases. IL-10 gene polymorphisms are possibly assodated with liver disease susceptibility or se-verity. Recombinant human IL-10 has been produced and is currently tested in clinical trials. These trials may give new insights into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.

Functional evaluation of a new bioartificial liver system in vivo and in vivo

AIM:To evaluate the functions of a new bioartificial liver(BAL)system in vitro and in vitro.MEHTODS:The BAL system was configurated byinoculating porcine hepatocyte spheroids into the cellcircuit of a hollow fiber bioreactor.In the experiments ofBAL in vitro,the levels of alanine aminotransferase(ALT),total bilirubin(TB),and albumin(ALB)in the circulatinghepatocyte suspension and RPMI-1640 medium weredetermined during 6 h of circulation in the BAL device.In the experiments of BAL in vitro,acute liver failure(ALF)model in canine was induced by an end-side portocavalshunt combined with common bile duct ligation andtransaction.Blood ALT,TB and ammonia levels ofALF in canines were determined before and after BALtreatment.RESULTS:During 6 h of circulation in vitro,therewas no significant change of ALT,whereas the TB andALB levels gradually increased with time both in thehepatocyte suspension and in RPMI-1640 medium.Inthe BAL treatment group,blood ALT,TB and ammonialevels of ALF in canines decreased significantly.CONCLUSION:The new BAL system has the ability toperform liver functions and can be used to treat ALF.

Pathological mechanisms of alcohol-induced hepatic portal hypertension in early stage fibrosis rat model

AIM： To study the role of hepatic sinusoidal capillarization and perisinusoidal fibrosis in rats with alcohol-induced portal hypertension and to discuss the pathological mechanisms of alcohol-induced hepatic portal hypertension. METHODS： Fifty SD rats were divided into control group （n=20） and model group （n=30）. Alcoholic liver fibrosis rat model was induced by intragastric infusion of a mixture containing alcohol, corn oil and pyrazole （1 000：250：3）. Fifteen rats in each group were killed at wk 16. The diameter and pressure of portal vein were measured. Plasma hyaluronic acid （HA）, type IV collagen （COW） and laminin （LN） were determined by radioimmunoassay. Liver tissue was fixed in formalin （10%） and 6-μm thick sections were routinely stained with Mallory and Sirius Red. Liver tissue was treated with rabbit polydonal antibody against LN and ColⅣ. Hepatic non-parenchymal cells were isolated, total protein was extracted and separated by SDS-PAGE. MMP-2 and TIMP-1 protein expression was estimated by Western blotting. RESULTS： The diameter （2.207 ± 0.096 vs 1.528±0.054 mm, P〈0.01） and pressure （11.014±0.395 vs 8.533±0.274 mmHg, P〈0.01） of portal vein were significantly higher in model group than those in the control group. Plasma HA （129.97±16.10 vs 73.09±2.38 ng/mL, P〈0.01）, ColⅣ （210.49±4.36 vs 89.65±4.42 ng/mL, P〈0.01） and LN （105.00±7.29 vs 55.70±4.32 ng/mL, P〈0.01） were upregulated in model group. Abundant collagen deposited around the central vein of Iobules, hepatic sinusoids and hepatocytes in model group. ColⅠ and ColⅢ increased remarkably and perisinusoids were almost surrounded by ColⅢ. Immunohistochemical staining showed that ColⅣ protein level （0.130±0.007 vs 0.032±0.004, P〈0.01） and LN protein level （0.152±0.005 vs 0.029±0.005, P〈0.01） were up-regulated remarkably in model group. MMP-2 protein expression （2.306±1.089 vs 0.612±0.081, P〈0.01） and TIMP-1 protein expression （3.015±1.364 vs 0.446±0.009, P〈0.01） in freshly isolated hepatic nonparenchymal cells were up-regulated in model group and TIMP-1 protein expression was evidently higher than MMP-2 protein expression （2.669±0.170 vs 1.695±0.008, P〈0.05）. CONCLUSION： Hepatic sinusoidal capillarization and peri-sinusoidal fibrosis are responsible for alcoholinduced portal hypertension in rats,

Biochemical mechanisms in drug-induced liver injury:Certainties and doubts

Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local 02 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca^2＋-dependent ATPase, reduced capability to sequester Ca^2＋ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

Role of lipid rafts in liver health and disease

Liver diseases are an increasingly common cause of morbidity and mortality; new approaches for investigation of mechanisms of liver diseases and identification of therapeutic targets are emergent. Lipid rafts (LRs) are specialized domains of cellular membranes that are enriched in saturated lipids; they are small, mobile, and are key components of cellular architecture, protein partition to cellular membranes, and signaling events. LRs have been identified in the membranes of all liver cells, parenchymal and non-parenchymal; more importantly, LRs are active participants in multiple physiological and pathological conditions in individual types of liver cells. This article aims to review experimental-based evidence with regard to LRs in the liver, from the perspective of the liver as a whole organ composed of a multitude of cell types. We have gathered up-to-date information related to the role of LRs in individual types of liver cells, in liver health and diseases, and identified the possibilities of LR-dependent therapeutic targets in liver diseases.

Liver hemangioma and vascular liver diseases in patients with systemic lupus erythematosus

AIM:To investigate whether systemic lupus erythematosus (SLE) is associated with benign focal liver lesions and vascular liver diseases, since these have been occasionally reported in SLE patients. METHODS:Thirty-five consecutive adult patients with SLE and 35 age-and sex-matched healthy controls were evaluated. Hepatic and portal vein patency and presence of focal liver lesions were studied by colour-Doppler ultrasound, computerized tomography and magnetic resonance were used to refine the diagnosis, clinical data of SLE patients were reviewed. RESULTS:Benign hepatic lesions were common in SLE patients (54% vs 14% controls, P < 0.0001), withhemangioma being the most commonly observed lesion in the two groups. SLE was associated with the presence of single hemangioma [odds ratios (OR) 5.05; 95% confidence interval (CI) 1.91-13.38] and multiple hemangiomas (OR 4.13; 95% CI 1.03-16.55). Multiple hemangiomas were associated with a longer duration of SLE (9.9 ± 6.5 vs 5.5 ± 6.4 years; P = 0.04). Imaging prior to SLE onset was available in 9 patients with SLE and hemangioma, showing absence of lesions in 7/9. The clinical data of our patients suggest that SLE pos- sibly plays a role in the development of hemangioma. In addition, a Budd-Chiari syndrome associated with nodular regenerative hyperplasia (NRH), and a NRH associated with hepatic hemangioma were observed, both in patients hospitalized for abdominal symptoms, suggesting that vascular liver diseases should be specifically investigated in this population. CONCLUSION:SLE is associated with 5-fold increased odds of liver hemangiomas, suggesting that these might be considered among the hepatic manifestations of SLE.

How albumin administration for cirrhosis impacts on hospital albumin consumption and expenditure

AIM:To assess the impact of guidelines for albumin prescription in an academic hospital,which is a referral center for liver diseases.METHODS:Although randomized trials and guidelines support albumin administration for some complications of cirrhosis,the high cost of albumin greatly limits its use in clinical practice.In 2003,a multidisciplinary panel at Sant'Orsola-Malpighi University Hospital(Bologna,Italy)used a literature-based consensus method to list all the acute and chronic conditions for which albumin is indicated as first-or second-line treatment.Indications in hepatology included prevention of post-paracentesis circulatory dysfunction and renal failure induced by spontaneous bacterial peritonitis,and treatment of hepatorenal syndrome and refractory ascites.Although still debated,albumin administration in refractory ascites is accepted by the Italian health care system.We analyzedalbumin prescription and related costs before and after implementation of the new guidelines.RESULTS:While albumin consumption and costs doubled from 1998 to 2002,they dropped 20%after 2003,and remained stable for the following 6 years.Complications of cirrhosis,namely refractory ascites and paracentesis,represented the predominant indications,followed by major surgery,shock,enteric diseases,and plasmapheresis.Albumin consumption increased significantly after guideline implementation in the liver units,whereas it declined elsewhere in the hospital.Lastly,extra-protocol albumin prescription was estimated as<10%.CONCLUSION:Albumin administration in cirrhosis according to international guidelines does not increase total hospital albumin consumption if its use in settings without evidence of efficacy is avoided.

Sonographic fatty liver, overweight and ischemic heart disease

AIM: To demonstrate the prevalence of sonographic fatty liver, overweight and ischemic heart disease (IHD) among the male workers in Taiwan, and to investigate the possible association of these three factors.METHODS: From July to September 2003, a total of 2 088 male aircraft-maintenance workers aged from 22to 65 years (mean 40.5) underwent an annual health examination, including anthropometrical evaluation, blood pressure measurement, personal medical history assessment,biochemical blood analysis, abdominal ultrasonographic examination and digital electrocardiography (ECG). The Student's t-test, x2 test and multivariate logistic regression analysis were utilized to evaluate the relationship between IHD and salient risk factors.RESULTS: The all-over prevalence of overweight was 41.4%, and that of fatty liver was 29.5% (mild, moderate and severe fatty liver being 14.5%, 11.3%, and 3.7%,respectively); while the prevalence of ischemic changes on ECG was 17.1% in this study. The abnormal rates for conventional IHD risk factors including hypertension,dyslipidemia, hyperglycemia and overweight increased in accordance with the severity of fatty liver. Overweight and severity of fatty liver were independently associated with increased risks for developing IHD. Overweight subjects had a 1.32-fold (95%CI: 1.01-1.73) increased IHD risk. Participants with mild, moderate, and severe fatty liver had a 1.88-fold (95%CI: 1.37-2.6), 2.37-fold (95%CI: 1.66-3.37) and 2.76-fold (95%CI: 1.62-4.72)increased risk for developing IHD. The prevalence of ischemic ECG for the fatty liver-affected subjects with or without overweight was 30.1% and 19.1%, while that of overweight subjects free from fatty liver was 14.4%.Compared to the subjects without fatty liver nor overweight,IHD risk for the three subgroups above was as follows:OR: 2.95 (95%CI:2.31-4.09), OR: 1.60 (95%CI: 1.07-2.39)and OR: 1.11 (95%CI: 0.78-1.56), respectively.CONCLUSION: The presence of fatty liver and its severity should be carefully considered as independent risk factors for IHD. Results of the study suggest the synergistic effect between fatty liver and overweight for developing IHD.Abdominal sonographic examination may provide valuable information for IHD risk assessment in addition to limited report about liver status, especially for overweight males.

Treatment for liver metastases from breast cancer: Results and prognostic factors

AIM: Liver metastases from breast cancer (BCLM) are associated with poor prognosis. Cytotoxic chemotherapy can result in regression of tumor lesions and a decrease in symptoms. Available data, in the literature, also suggest a subgroup of patients may benefit from surgery, but few talked about transcatheter arterial chemoembolization (TACE). We report the results of TACE and systemic chemotherapy for patients with liver metastases from breast cancer and evaluate the prognostic factors. METHODS: Forty-eight patients with liver metastases, from proved breast primary cancer were treated with TACE or systemic chemotherapy between January 1995 and December 2000. Treatment results were assessed according to WHO criteria, along with analysis of prognostic factors for survival using Cox regression model. RESULTS: The median follow-up was 28 mo (1-72 mo). Response rates were calculated for the TACE group and chemotherapy group, being 35.7% and 7.1%, respectively. The difference was significant. The one-, two- and three-year Survival rates for the TACE group were 63.04%, 30.35%, and 13.01%, and those for the systemic chemotherapy group were 33.88%, 11.29%, and 0%. According to univariate analysis, variables significantly associated with survival were the lymph node status of the primary cancer, the clinical stage of liver metastases, the Child-Pugh grade, loss of weight. Other factors such as age, the intervals between the primary to the metastases, the maximal diameter of the liver metastases, the number of liver metastases, extrahepatic metastasis showed no prognostic significances. These factors mentioned above such as the lymph node status of the primary cancer, the clinical stage of liver metastases, the Child-Pugh grade, loss of weight were also independent factors in multivariate analysis. CONCLUSION: TACE treatment of liver metastases from breast cancer may prolong survival in certain patients. This approach offers new promise for the curative treatment of the patients with metastatic breast cancer.

CT perfusion at early stage of hepatic diffuse disease

AIM: To determine the validity of the non-invasive method of CT perfusion (CTP) in rat model of hepatic diffuse disease. METHODS: Twenty-eight Wistar rats were divided into two groups. Liver diffuse lesions were induced by diethyln-itrosamine in 14 rats of test group. Rats in control group were bred with pure water. From the 1st to 12th wk after the test group was intervened, both groups were studied every week with CTP. CTP parameters of liver parenchyma in different periods and pathologic changes in two groups were compared and analyzed. RESULTS: The process of hepatic diffuse lesions in test groups was classified into three stages or periods according to the pathologic alterations, namely hepatitis, hepatic fibrosis, and cirrhosis. During this period, hepatic artery flow (HAF) of control group declined slightly, mean transit time (MTT), blood flow (BF) and volume (BV) increased, but there were no significant differences between different periods. In test group, HAF tended to increase gradually, MTT prolonged obviously, BV and BF decreased at the same time. The results of statistical analysis revealed that the difference in the HAF ratio of test group to control group was significant. The ratio of BV and BF in test group to control group in stage of hepatitis and hepatic cirrhosis, hepatic fibrosis and early stage of hepatic cirrhosis was significantly different, but there was no significant difference between hepatitis and hepatic fibrosis. The main pathological changes in stage of hepatitis were swelling of hepatic cells, while sinusoid capillarization and deposition of collagen aggravated gradually in the extravascular Disse's spaces in stage of fibrosis and early stage of cirrhosis. CONCLUSION: The technique could reflect some early changes of hepatic blood perfusion in rat with liver diffuse disease and is valuable for their early diagnosis.

Prevention and treatment of hepatic encephalopathy: Focusing on gut microbiota

The gut flora plays an important role in the pathogenesis of the complications of cirrhosis. Hepatic encephalopathy (HE) represents a broad continuum of neuropsychological dysfunction in patients with acute or chronic liver disease and/or porto-systemic shunting of blood flow and it manifests with progressive deterioration of the superior neurological functions. The pathophysiology of this disease is complex, as it involves overproduction and reduced metabolism of various neurotoxins, particularly ammonia. Management of HE is diversified and requires several steps: elimination of precipitating factors, removal of toxins, proper nutritional support, modulation of resident fecal flora and downregulation of systemic and gut-derived inflammation. This review will provide an overview of gut barrier function and the influence of gut-derived factors on HE, focusing on the role of gut microbiota in the pathogenesis of HE and the recent literature findings on its therapeutic manipulation.

Alcohol and liver

Liver is a primary site of ethanol metabolism, which makes this organ susceptible to alcohol-induced damage. Alcoholic liver disease （ALD） has many manifestations and complicated pathogenesis. In this Topic Highlight, we included the key reviews that characterize new findings about the mechanisms of ALD development and might be of strong interest for clinicians and researchers involved in liver alcohol studies.

Mild hypothermia protects liver against ischemia and reperfusion injury

AIM: To determine whether mild hypothermia could protect liver against ischemia and reperfusion injury in pigs. METHODS: Twenty-four healthy pigs were randomly divided into normothermia, mild hypothermia and normal control groups. The experimental procedure consisted of temporary interruption of blood flow to total hepatic lobe for different lengths of time and subsequent reperfusion. Hepatic tissue oxygen pressure (PtiO2) and aspartate aminotransferase (AST) values were evaluated, and ultrastructural analysis was carried out for all samples. RESULTS: Serum AST was significantly lower, and hepatic PtiO2 values were significantly higher in the mild hypothermia group than in the normothermia group during liver ischemia-reperfusion periods (P= 0.032, P= 0.028). Meanwhile, the histopathologic injury of liver induced by ischemia-reperfusion was significantly improved in the mild hypothermia group, compared with that in the normothermia group. CONCLUSION: Mild hypothermia can protect the liver from ischemia-reperfusion injury in pigs.

Drug-induced liver injury:Is it somehow foreseeable?

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neosubstances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

Mechanisms of alcohol-mediated hepatotoxicity in human-immunodeficiency-virus-infected patients

Clinical observations have demonstrated that excessive chronic alcohol use negatively affects human immuno- deficiency virus (HIV) infection and contributes to the liver manifestations of the disease, even in HIV mono- infection. HIV/hepatitis C virus (HCV) co-infection is as- sociated with increased progression of HVC liver disease compared to HCV infection alone, and both of these are negatively affected by alcohol use. Recent data suggest that alcohol use and HIV infection have common targets that contribute to progression of liver disease. Both HIV infection and chronic alcohol use are associated with increased gut permeability and elevated plasma levels of lipopolysaccharide; a central activator of inflammatory responses. Both alcoholic liver disease and HIV infec tionresult in non-specific activation of innate immunity, proinflammatory cytokine cascade upregulation, as well as impaired antigen presenting cell and dendritic cell functions. Finally, alcohol, HIV and antiretroviral therapyaffect hepatocyte functions, which contributes to liver damage. The common targets of alcohol and HIV infection in liver disease are discussed in this minireview.

Hepatoma with cardiac metastasis: An advanced cancer requiring advanced treatment

AIM: To investigate the clinical and pathologic fi ndings, and to discuss the pathophysiology of hepatocellular carcinoma with cardiac metastasis. METHODS: Eight hepatoma patients with cardiac metastasis, who were treated by surgical excision from 1993 to 2006, were retrospectively studied. Detailed clinical parameters were analyzed. RESULTS: Of those eight patients, two (25%) were women and six (75%) were men, with the mean age of 50 years (range, 40-70 years). The presentations included: asymptomatic (75%), heart failure (25%), and pulmonary embolism (12.5%). All lesions involved the right atrium, and extended to the lung (12.5%), inferior vena cava (25%), and left atrium (12.5%). The level of tumor marker, alpha-fetal protein, was not correlated with the severity of metastasis or disease prognosis. Moreover, the availably estimated doubling time was less than 3 mo. The pathological fi ndings included variablehemorrhage and necrosis. The survival time following surgery also varied from one month to more than 30 mo. CONCLUSION: Hepatoma metastasis to the heart was detected in all eight patients. This study demonstrates that surgery might help the outcome in such cases.

Role of SPECT/CT in diagnosis of hepatic hemangiomas

AIM: To investigate the role of SPECT/CT in the diagnosis of hepatic hemangiomas whose anatomical positions are not ideal, situated adjacent to the heart, the inferior cava,hepatic vessels or abdominal aorta, etc.METHODS: The hepatic perfusion, blood pool, and fusion imaging were carried out using SPECT/CT in 54 patients,who were suspected for hepatic hemangiomas. When the anatomical positions were not ideal, the diagnosis was difficult by SPECT only. So the information of computed tomography (CT) was applied to help in diagnosing. The results were recorded as hemangiomas or not.RESULTS: Of the 54 patients, 31 patients were diagnosed as suffering from hepatic hemangiomas. The anatomical positions of eight patients' hepatic hemangiomas (25.81%)were not ideal. Among these lesions of the eight patients,three patients' hepatic lesions were located near to the abdominal aorta, one to the heart, and four to the inferior cava. In addition, six abnormal radioactivity accumulation regions, adjacent to the heart and inferior cava, with the help of CT, were confirmed to be the imaging of inferior cava other than hepatic hemangiomas.CONCLUSION: When the anatomical positions of hepatic hemangiomas are not good enough for diagnosis, the fusion imaging of SPECT/CT is a simple and efficient method for differential diagnosis.