The histological assessment of liver fibrosis in grafts from extended criteria donors predicts the outcome after liver transplantation: A retrospective study

BackgroundThe use of extended criteria donors (ECD) in liver transplantation is increasing due to the organ shortage. Histological evaluation of the liver graft in the context of procurement is an important tool for extending the donor pool without affecting the quality of the transplanted organs. Macrovesicular steatosis is widely accepted as predictor of early allograft dysfunction (EAD), while other features, such as portal fibrosis, are poorly studied.AimTo identify morphological features, other than macrovesicular steatosis, that may affect recipients’ outcome.MethodsBetween 2014 and 2016, 132 donors with extended criteria underwent pre-transplant liver biopsy during procurement. Histological variables of the graft, donors’/recipients’ clinical data, EAD and patient/graft survival were registered.ResultsThe recipients who received a graft with histological-proven portal fibrosis had a significant lower patient and graft survival in comparison to patients without fibrosis (P = 0.044 and P = 0.039, respectively). Donors’ dyslipidemia was significantly associated with the occurrence of EAD (P = 0.021). When dyslipidemia was combined with histological liver fibrosis a 54.5% incidence of EAD was observed (P = 0.012).ConclusionsThe histological assessment of liver fibrosis in pre-transplant biopsy of ECD grafts, together with donor’s clinical data, provides important information on recipients’ outcome.     

Colorectal disease in liver allograft recipients -- a clinicopathological study with follow-up

OBJECTIVE : To determine the spectrum and outcome of colorectal diseases occurring in adult liver allograft recipients. DESIGN : A retrospective cohort analysis of clinical, microbiological and histopathological data regarding colorectal disease. PATIENTS : Forty three out of 302 adult primary liver allograft recipients were transplanted and followed up (at median 42 months) at a tertiary referral centre/teaching hospital. RESULTS : Out of 302 patients, 43 (14%) were investigated (by endoscopy and/or laparotomy) for symptoms of colorectal disease after orthotopic liver transplantation. The symptoms were: diarrhoea (n = 31); per-rectal bleeding (n = 5); and symptoms relating to pre-transplant ulcerative colitis (n = 7). Among the patients without known ulcerative colitis, per-rectal bleeding occurring early after orthotopic liver transplantation was most commonly caused by cytomegalovirus colitis and carried a poor prognosis. Excluding ulcerative colitis, the commonest causes of diarrhoea were Clostridium difficile, cytomegalovirus infection and medications, particularly during the first 2 months after orthotopic liver transplantation. No cases of colorectal graft-versus-host disease, cryptosporidiosis, amoebiasis, atypical mycobacterial infection or post-transplant lymphoproliferative disease were demonstrated. The activity of pre-transplant ulcerative colitis was unchanged or increased after orthotopic liver transplantation. Two further patients developed new-onset ulcerative colitis after orthotopic liver transplantation. CONCLUSIONS : Ulcerative colitis, C. difficile, cytomegalovirus infection and medications are the commonest colorectal causes of morbidity after orthotopic liver transplantation. Adult liver allograft recipients are, however, unlikely to show certain large bowel diseases encountered in other immunosuppressed groups. Amongst non-ulcerative colitis patients, those presenting with diarrhoea show a good outcome with appropriate management, whereas those with per-rectal bleeding have a more guarded prognosis.     

A novel prognostic model based on serum levels of total bilirubin and creatinine early after liver transplantation.

BACKGROUND/AIM: We aim to evaluate the impact of early renal dysfunction (ERD), early allograft dysfunction (EAD) on post-transplant mortality, and further explore a simple and accurate model to predict prognosis. PATIENTS: A total of 161 adult patients who underwent liver transplantation for benign end-stage liver diseases were enrolled in the retrospective study. Another 38 patients were used for model validation. RESULTS: Poor patient survival was associated with ERD or EAD. A post-transplant model for predicting mortality (PMPM) based on serum levels of total bilirubin and creatinine at 24-h post-transplantation was then established according to multivariate logistic regression. At 3 months, 6 months and 1 year, the area under receiver operating characteristic curves (AUC) of PMPM score at 24-h post-transplantation (0.876, 0.878 and 0.849, respectively) were significantly higher than those of pre-transplant model for end-stage liver diseases (MELD) score (0.673, 0.674 and 0.618, respectively) or the post-transplant MELD score at 24-h post-transplantation (0.787, 0.787 and 0.781, respectively) (P<0.05). Patients with PMPM score -1.4 (high-risk group, n=47) (P<0.001). The patients in the high-risk group showed a relatively good outcome if their PMPM scores decreased to 相似文献   

UCSF criteria by pre-transplant radiologic study can not assure similar post-transplant results of hepatocellular carcinoma within Milan criteria

The recurrence of hepatocellular carcinoma (HCC) after transplantation is the main limitation of liver transplantation. Therefore, several selection criteria for liver transplantation in HCC patients have been established. The objective of this study was to verify the clinical validity of selection criteria evaluated by pre-transplant radiologic imaging study. Sixty-nine participants were enrolled for this study between September 2005 and May 2007. We analyzed the post-transplant survival and recurrence rate using radiologic selection criteria and other clinical factors. Grouping by pretransplant criteria for liver transplantation, 16 recipients (23.2%) were above Milan criteria and 7 recipients (10.1%) were above UCSF criteria. Nine recipients (13.0%) were grouped as above Milan/below UCSF. The recipients who met Milan showed 85.8% 1-year survival rates, which was comparable to that of non-HCC (91.6%) (p = 0.767). During the post-transplant follow-up period (1-52 months, 14.81 +/- 12.0 months), 16 recurrences (23.2%) were diagnosed. The 1-year recurrence-free survival rate of recipients who met the Milan criteria was 78.6%, and those that did not meet these criteria was 22.7% (p < 0.0001). With regard to UCSF criteria, these percentages were 72.0% and 14.2%, respectively (p < 0.0001). According to a combined grouping, the 1-year recurrence-free survival rate was 25.4% in the above Milan/below UCSF group. There were significant differences among each of the groups (overall p < 0.0001). The application of UCSF criteria that are defined by pre-transplant radiologic findings as patient selection criteria for liver transplantation is limited.     

胆汁中趋化因子C-X3-C-基元受体1和可溶性CD40配体在肝移植术后肝损伤中的预测价值

目的探究胆汁中细胞因子联合临床指标对肝移植术后肝损伤程度的预测作用。方法选取2018年1月—12月青岛大学附属医院器官移植中心收治的16例肝移植患者。按术后第1天ALT水平分为轻度肝损伤(ALT<500 U/L,10例)和重度肝损伤(ALT>500 U/L,6例)。采集两组患者术后第1、3、5、7天的胆汁,应用MILLIPLEX高通量多因子检测技术测定17种细胞因子水平。运用R软件,对胆汁中细胞因子和临床指标进行主成分分析(PCA),并对胆汁中细胞因子进行GO富集分析。符合正态分布的计量资料两组间比较采用两独立样本t检验;非正态分布的计量资料两组间比较采用Mann-Whitney U检验。采用Spearman相关性分析对临床指标与胆汁中细胞因子的相关性进行分析。采用受试者工作特征曲线(ROC曲线)分析评估胆汁中细胞因子及临床相关指标对肝移植术后肝损伤的预测价值。结果与轻度肝损伤组相比,重度肝损伤组胆汁中趋化因子C-X3-C-基元受体1(Fractalkine)(Z=-2.828,P=0.003)、可溶性CD40配体(sCD40L)(Z=-2.850,P=0.008)、IL-4(Z=-2.398,P=0.017)、趋化因子CXCL10(Z=-2.475,P=0.023)和巨细胞炎性蛋白-1α(Z=-1.844,P=0.043)表达水平更高,差异均有统计学意义。相关性分析结果显示,肝移植术后第1天,AST、ALT和LDH与胆汁中多个细胞因子呈正相关(P值均<0.05)。Fractalkine、sCD40L、AST的ROC曲线下面积分别为0.933(0.812~1.000)、0.833(0.589~1.000)、0.917(0.779~1.000),提示术后第1天AST及胆汁中Fractalkine和sCD40L水平对肝移植术后肝损伤程度有明显预测价值。PCA分析结果显示,肝移植术后第1天胆汁中细胞因子结合临床指标可以将肝移植术后轻度与重度肝损伤患者较好地进行区分。GO分析结果显示,胆汁中细胞因子与外部刺激的正反馈调节、细胞趋化性、受体配体活性、细胞因子活性、细胞因子-细胞因子受体相互作用有关。结论胆汁中Fractalkine和sCD40L对肝移植术后肝损伤程度具有潜在的预测价值。     

Risk factors of metabolic syndrome after liver transplantation

BACKGROUND: Liver transplantation is a treatment of choice for both acute and chronic liver failure. Accompanied with the increase of long-term survival rates of recipients,metabolic syndrome and its individual components,including obesity,hyperglycemia,hypertension and hyperlipidemia,have become more frequent post liver transplantation. Here we reviewed the literature concerning the risk factors for the development of metabolic complications in liver recipients. DATA SOURCES: Pub Med was searched for English-language articles published from January 2000 to June 2015. The search criteria focused on risk factors for metabolic syndrome after liver transplantation. RESULT: The risk factors of metabolic syndrome in liver recipients include older age,obesity,pre-transplantation diabetes mellitus,hepatitis C virus infection,certain genetic polymorphisms and the use of immunosuppressive drugs. CONCLUSION: Active intervention of the risk factors will reduce the occurrence rate of metabolic syndrome after liver transplantation and improve the recipients' quality of life.     

The effect of statins and fibrates on interferon-gamma and interleukin-2 release in patients with primary type II dyslipidemia

The aim of the study was to assess the effect of two major groups of hypolipemic drugs, HMG-CoA reductase inhibitors (statins) and PPARalpha activators (fibrates), on the secretory function of T-lymphocytes in patients with primary type II dyslipidemia. Sixty-three patients with type IIa dyslipidemia were randomized to fluvastatin (40 mg daily; n = 33) or simvastatin (20mg daily; n = 30), while 68 type IIb dyslipidemic patients were treated with micronized ciprofibrate (100mg daily; n = 34) or micronized fenofibrate (200mg daily; n = 34). Lipid profile and cytokine (interferon-gamma and interleukin-2) release by phytohemagglutinin-stimulated lymphocytes were determined at the beginning of the study and after 30 and 90 days of treatment. Compared to healthy subjects (n = 59), both type IIa and IIb dyslipidemic patients exhibited higher baseline release of interferon-gamma and interleukin-2. Fluvastatin, simvastatin and, to a less extent, ciprofibrate and fenofibrate inhibited the release of both cytokines, but this effect did not correlate with their lipid-lowering potential. Hypolipemic agents also slightly reduced plasma interleukin-2 levels. Our study suggests that the beneficial effect of hypolipemic drugs involves their inhibitory action on the secretory function of T-lymphocytes. This lipid-independent action is stronger for statins than for fibrates and probably results from their "class" effect. The treatment-induced reduction in the release of both cytokines may contribute to the clinical effectiveness of statins and fibrates in the therapy of atherosclerosis and in the management of organ transplant recipients.     

Liver pathology and the metabolic syndrome X in severe obesity.

The metabolic syndrome X, characterized by insulin resistance, dyslipidemia, hypertension, and a male, visceral distribution of adipose tissue, is associated with increased morbidity and mortality from several prevalent diseases, such as diabetes, cancers, myocardial infarction, and stroke. Because the liver has a central role in carbohydrate, lipid, and steroid metabolism, we investigated the relationships between liver pathology and the metabolic syndrome. Blood chemistry, anthropometry (waist/hip circumference ratio), and intraoperative routine knife biopsies of the liver were obtained in 551 (112 men) severely obese patients (body mass index, 47 +/- 9; mean +/- SD) undergoing antiobesity surgery. Steatosis was found in 86%, fibrosis in 74%, mild inflammation or steatohepatitis in 24%, and unexpected cirrhosis in 2% (n = 11) of the patients. The risk of steatosis was 2.6 times greater in men than in women (P < 0.0001). With each addition of 1 of the 4 components of the metabolic syndrome, elevated waist/hip ratio, impaired glucose tolerance, hypertension, and dyslipidemia, the risk of steatosis increased exponentially from 1- to 99-fold (P < 0.001). Fibrosis correlated with steatosis (r = 0.56; P < 0.0001), whereas patients with diabetes or impaired glucose tolerance had a 7-fold increased risk of fibrosis (P < 0.0001). Diabetes, steatosis, and age were all significant indicators of cirrhosis, whereas inflammation was only associated with age. We conclude that the metabolic syndrome via impaired glucose tolerance is strongly correlated with steatosis, fibrosis, and cirrhosis of the liver.     

Clinical factors affecting rejection rates in liver transplantation

BACKGROUND: With improvements in survival, liver transplant recipients now suffer more morbidity from long-term immunosuppression. Considerations were given to develop individualized immunosuppression based on their risk of rejection. METHOD: We retrospectively analyzed the data of 788 liver transplants performed during the period from October 1991 to December 2011 to study the relationship between acute cellular rejection(ACR) and various clinical factors. RESULTS: Multivariate analysis showed that older age(P=0.04,OR=0.982), chronic hepatitis B virus infection(P=0.005, OR=0.574), living donor liver transplantation(P=0.02, OR=0.648) and use of interleukin-2 receptor antagonist on induction(P0.001, OR=0.401) were associated with fewer ACRs. Patients with fulminant liver failure(P=0.004, OR=4.05) were more likely to develop moderate to severe grade ACR. CONCLUSIONS: Liver transplant recipients with older age,chronic hepatitis B virus infection, living donor liver transplantation and use of interleukin-2 receptor antagonist on induction have fewer ACR. Patients transplanted for fulminant liver failure are at higher risk of moderate to severe grade ACR.These results provide theoretical framework for developing individualized immunosuppression.     

Obesity is an independent risk factor for pre-transplant portal vein thrombosis in liver recipients

ABSTRACT: BACKGROUND: Portal vein thrombosis is a frequent complication in end-stage cirrhosis with a considerable peri-operative risk for liver transplant candidates. We aimed to characterize the pre-transplant portal vein thrombosis in a cohort of liver transplant recipients, and to identify independent risk factors for this complication. METHODS: 380 consecutive primary orthotopic liver transplants were performed in the Digestive Surgery Department of "12 de Octubre" Hospital (Madrid, Spain), between January 2001 and December 2006. The main risk factors considered were smoking, obesity, metabolic disorders, previous immobility, surgery or trauma, nephrotic syndrome, associated tumor, inflammatory disease, neoplasm myeloprolipherative. Furthermore we have reported genetic thrombophilia results for 271 recipients. RESULTS: Sixty-two (16.3%) patients developed pre-transplant portal vein thrombosis and its presence had no impact in the overall survival of liver recipients. Obesity was the only independent risk factor for pre-transplant portal vein thrombosis. CONCLUSION: We recommend close control of cardiovascular factors in patients with liver cirrhosis in order to avoid associated thrombosis.     

Health-related quality of life in Egyptian patients after liver transplantation

Introduction-Aim. Health-Related Quality of Life (HRQOL) has become an important focus of patient care and clinical outcomes research with the improvement in patient and graft survival after liver transplantation (LT). The current study was designed to evaluate the post-transplant HRQOL profiles using the Liver Disease Quality of Life 1.0 (LDQOL 1.0) Questionnaire and demonstrate the possible effect of peri-transplant clinical covariates on these profiles.Material and methods. Participants included pre-transplant group (waiting-list patients n = 50) and post-transplant group (mean 5 ± 4 years after deceased or living donor LT n = 103) who were recruited from 3 specialized centers in Egypt. We applied the LDQOL 1.0 questionnaire; a 111-item containing the Short Form-36 version 2.0 (SF-36v2) as a generic component supplemented by 75 disease-specific items. The etiology of cirrhosis, co-morbidities, model for end-stage liver disease (MELD), Child-Pugh class and post-operative complications were analyzed.Results. All recipients had significant higher HRQOL scores than patients in waiting-list using both questionnaire components. Recipients with pre-LT MELD ≥ 15, Child-Pugh class C, history of hepatocellular carcinoma (HCC) demonstrated low HRQOL scores. Recipients without post-operative surgical complications had a statistically better HRQOL using the disease-specific, but not the SF-36v2 component. On the other hand, both components demonstrated non-significant lower scores in recipients with rejection episodes, cytomegalovirus (CMV) infection and hepatitis C recurrence had compared to those without medical complications.Conclusion. Generally HRQOL improves dramatically after LT as assessed by LDQOL questionnaire. Moreover, combined questionnaires can provide accurate information about the possible impaired HRQOL post-LT due to pre-transplant disease severity and post-operative complications.     

Indications for liver transplantation in British Columbia's Aboriginal population: a 10-year retrospective analysis.

OBJECTIVES: To study the indications for liver transplantation among British Columbia's First Nation population. MATERIALS AND METHODS: A retrospective analysis of the British Columbia Transplant Society's database of Aboriginal and non-Aboriginal liver transplant recipients from 1989 to 1998 was undertaken. For primary biliary cirrhosis (PBC), the transplant assessment database (patients with and without transplants) was analyzed using a binomial distribution and compared with published census data regarding British Columbia's proportion of Aboriginal people. RESULTS: Between 1989 and 1998, 203 transplantations were performed in 189 recipients. Fifteen recipients were Aboriginal (n=15; 7.9%). Among all recipients, the four most frequent indications for liver transplantation were hepatitis C virus (HCV) infection (n=57; 30.2%), PBC (n=34; 18.0%), alcohol (n=22; 11.6%) and autoimmune hepatitis (n=14; 7.4%). Indications for liver transplantation among Aboriginal people were PBC (n=8; 53.3%; P<0.001 compared with non-Aboriginal people), autoimmune hepatitis (n=4; 26.67%; P=0.017), acute failure (n=2; 13.3%) and HCV (n=1). Among all patients referred for liver transplantation with PBC (n=43), 29 (67.44%) were white and 11 (25.6%) were Aboriginal. A significant difference was found between the proportion of Aboriginal people referred for liver transplantation and the proportion of Aboriginal people in British Columbia (139,655 of 3,698,755 [3.8%]; 1996 Census, Statistics Canada) (P<0.001). CONCLUSIONS: Aboriginal people in British Columbia are more likely to be referred for liver transplantation with a diagnosis of PBC but are less likely to receive a liver transplant because of HCV or alcohol than are non-Aboriginal people.     

Cardiovascular risk,atherosclerosis and metabolic syndrome after liver transplantation: a mini review

Liver transplantation is the standard of care for acute and chronic end-stage liver disease. Advances in medical therapy and surgical techniques have transformed the long-term survival of liver-transplant (LT) recipients. The prevalence of post-transplant cardiovascular complications has been rising with increased life expectancy after liver transplantation. Currently, deaths related to cardiovascular complications are one of the main causes of long-term mortality in LT recipients, as cardiovascular disease is the reason of 19–42% of non-liver-related mortality after transplant. On the other hand, metabolic syndrome is common among LT recipients before and after transplantation. In fact, their components (abdominal obesity, diabetes mellitus, hypertension and dyslipidemia) are often exacerbated by transplant-specific factors, such as immunosuppression, inappropriate diet, smoking and a sedentary lifestyle, and add a significant risk of developing atherosclerosis. These aspects are discussed in this article.     

Effects of resveratrol therapy on glucose metabolism,insulin resistance,inflammation, and renal function in the elderly patients with type 2 diabetes mellitus: A randomized controlled clinical trial protocol

Background:Diabetes mellitus is a spectrum of metabolic disorders characterized by hyperglycemia and shows a growing global public health problem in the elderly. Resveratrol presents antiaging, anti-inflammatory, antitumor antioxidant, and cardioprotective activities. The purpose of this study was to investigate the ameliorative effects of resveratrol on blood glucose, insulin metabolism, lipid profile, renal function, inflammation, and nutrient sensing systems in the elderly patients with type 2 diabetes mellitus.Methods:The study is a single-blind, parallel-group, randomized controlled clinical trial consisting of a 6-month treatment period. A total of 472 elderly patients with type 2 diabetes mellitus were enrolled, and included participants will be randomized into 2 groups: resveratrol (n = 242) and placebo (n = 230). The clinical efficacy and changes in clinical parameters in each group will be measured at the indicated time. Clinical parameters included blood glucose, insulin resistance index, blood lipid index, proinflammatory cytokines, renal function, and nutrient sensing systems.Results:Resveratrol treatment greatly improved glucose metabolism, insulin tolerance, and insulin metabolism compared to placebo. Resveratrol relieved symptoms through enhancing nutrient sensing systems, which in turn reduced production and activity of glucose-6-phosphatase. Compared with placebo, resveratrol treatment significantly decreased proinflammatory cytokines glycated hemoglobin/hemoglobin A1c, interleukin-6, tumor necrosis factor-alpha, and interleukin-1beta in the elderly diabetes. Resveratrol treatment decreased blood glucose parameters, improved the lipid profile (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides), and renal function compared to placebo.Conclusion:In conclusion, resveratrol treatment improves inflammation, renal function, blood glucose parameters, inflammation, insulin resistance, and nutrient sensing systems in the elderly patients with type 2 diabetes mellitus, indicating resveratrol may be a potential therapeutic drug for the treatment of the elderly patients with type 2 diabetes mellitus.     

Advanced non-alcoholic steatohepatitis cirrhosis: A high-risk population for pre-liver transplant portal vein thrombosis

AIM To examine if liver transplant recipients with high-risk non-alcoholic steatohepatitis(NASH) are at increased risk for pre-transplant portal venous thrombosis.METHODS Data on all liver transplants in the United States from February 2002 through September 2014 were analyzed. Recipients were sorted into three distinct groups: High-risk(age 60, body mass index 30 kg/m2, hypertension and diabetes), low-risk and non-NASH cirrhosis. Multivariable logistic regression models were constructed.RESULTS Thirty-five thousand and seventy-two candidates underwent liver transplantation and of those organ recipients, 465 were transplanted for high-risk and 2775 for lowrisk NASH. Two thousand six hundred and twentysix(7.5%) recipients had pre-transplant portal vein thrombosis; 66(14.2%) of the high-risk NASH group had portal vein thrombosis vs 328(11.8%) of the lowrisk NASH group. In general, all NASH recipients were less likely to be male or African American and more likely to be obese. In adjusted multivariable regression analyses, high-risk recipients had the greatest risk ofpre-transplant portal vein thrombosis with OR = 2.11(95%CI: 1.60-2.76, P 0.001) when referenced to the non-NASH group.CONCLUSION Liver transplant candidates with high-risk NASH are at the greatest risk for portal vein thrombosis development prior to transplantation. These candidates may benefit from interventions to decrease their likelihood of clot formation and resultant downstream hepatic decompensating events. Prospective study is needed.     

Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.     

Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea

Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia (IH) during sleep. There is growing evidence from animal models of OSA that IH is independently associated with metabolic dysfunction, including dyslipidemia and insulin resistance. The precise mechanisms by which IH induces metabolic disturbances are not fully understood. Over the last decade, several groups of investigators developed a rodent model of IH, which emulates the oxyhemoglobin profile in human OSA. In the mouse model, IH induces dyslipidemia, insulin resistance and pancreatic endocrine dysfunction, similar to those observed in human OSA. Recent reports provided new insights in possible mechanisms by which IH affects lipid and glucose metabolism. IH may induce dyslipidemia by up-regulating lipid biosynthesis in the liver, increasing adipose tissue lipolysis with subsequent free fatty acid flux to the liver, and inhibiting lipoprotein clearance. IH may affect glucose metabolism by inducing sympathetic activation, increasing systemic inflammation, increasing counter-regulatory hormones and fatty acids, and causing direct pancreatic beta-cell injury. IH models of OSA have improved our understanding of the metabolic impact of OSA, but further studies are needed before we can translate recent basic research findings to clinical practice.     

Mechanisms Linking Nonalcoholic Fatty Liver Disease with Coronary Artery Disease

The most common cause of death in patients with nonalcoholic fatty liver disease (NAFLD) is coronary artery disease (CAD), not chronic liver disease. Fatty liver increases cardiovascular risk by classical (dyslipidemia, hypertension, diabetes) and by less conventional mechanisms. Common pathways involved in the pathogenesis of fatty liver and CAD includes hepatic insulin resistance and sub clinical inflammation. The hepatic insulin resistance state of fatty liver infiltration is characterized by increased FFA, which causes lipotoxicity and impairs endothelium-dependent vasodilatation, increases oxidative stress, and has a cardio toxic effect. Additional metabolic risk factors include leptin, adiponectin, pro inflammatory cytokines [such as IL-6, C-reactive protein and plasminogen activator inhibitor-1 (PAI-1)], which together lead to increased oxidative stress and endothelial dysfunction, finally promoting coronary artery disease (CAD). When classical risk factors are superimposed on fatty liver accumulation, they may further increase the new metabolic risk factors, exacerbating CAD. The clinical implication is that patients with NAFLD are at higher risk (steatohepatitis, diabetes, obesity, atherogenic dyslipidemia) and should undergo periodic cardiovascular risk assessment including the Framingham score, cardiac effort test, and measurement of intimae-media thickening of the carotids arteries. This may improve risk stratification for CAD.     

High prevalence of metabolic complications in patients with non-alcoholic fatty liver disease

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is considered to be the liver component of the metabolic syndrome and is frequently associated with obesity, dyslipidemia and type II diabetes mellitus (NIDDM). We aimed to determine the development of liver function tests (LFTs) and metabolic complications in patients previously diagnosed with NAFLD. METHODS: One-hundred-and-two patients with NAFLD diagnosed in the period 1994-2001 were identified. Eighty were brought in for new investigations, including LFTs, blood pressure, BMI, lipid profile, blood glucose and insulin. Original liver biopsy was re-evaluated. RESULTS: Sixty-two patients (77%) were males (median age 46 years; mean follow-up time 2.8 +/- 1.2 years). Fifty-four patients (68%) were light to moderately overweight with body mass index (BMI) 25-30 kg/m. Mean BMI (28.2) was the same at diagnosis and at follow-up (28.3). At the new examination, 18 patients (23%) had developed diabetes mellitus type II (n = 6) or had impaired fasting glucose (IFG) (n = 12), compared to only 2 patients at diagnosis. Hyperinsulinemia was observed in 19 patients (24%). Dyslipidemia, with elevated triglycerides and/or hypercholesterolemia, was now present in 65 patients (81%). Twenty-two patients (27%) had hypertension compared to 9 (11%) at diagnosis. Liver biopsy was performed in 24%, and 89% of those fulfilled the criteria for NASH. However, mild inflammation and fibrosis was observed, grade 1-2 (n = 17), stage I-II (n = 13) and none had cirrhosis. CONCLUSION: A significant proportion of patients with both clinical and histological diagnosis of NAFLD develop metabolic problems soon after diagnosis. These patients should be screened regularly for metabolic disorders.     

Prognostic analysis of pre-transplant peripheral T-cell levels in patients receiving an autologous hematopoietic progenitor-cell transplant

The purpose of this study was to evaluate pre-transplant T-cell status in autologous hematopoietic progenitor-cell transplantation (HPCT) recipients. Between 1999 and 2002 we prospectively enrolled 85 autologous HPCT recipients with solid tumors (N = 50) or hematological malignancies (n = 35). Patient diagnoses included breast cancer (N = 49), non-Hodgkin's lymphoma (N = 20), myeloma (N = 11), Hodgkin's disease (N = 3), germ-cell tumor (N = 1) and amyloidosis (N = 1). Levels of CD3, CD4, CD8, memory and na?ve CD4, and CD8 T-cell subsets were analyzed before autologous HPCT. Autologous HPCT recipients presented with lower pre-transplant counts of CD3, CD4, but not CD8 T cells, as compared to healthy controls. Pre-transplant CD4 T-cell levels correlated with progression-free survival (PFS) (P = 0.002) and overall survival (OS) (P = 0.05), in patients with hematologic malignancies (P = 0.02) and breast cancer (P = 0.04). Specifically, pre-transplant memory CD4 + CD45RA - CD62L - T-cell levels correlated with PFS (P = 0.01). The prognostic effects of pre-transplant CD4 and CD4 + CD45RA - CD62L - T cells were independent of tumor diagnosis, tumor stage, tumor sensitivity, and, for breast cancer patients, Her2 / neu status. Our results suggest that pre-transplant CD4 T-cell status, specifically CD4 + CD45RA - CD62L - memory T cells, correlates with the outcome of autologous HPCT recipients. These observations suggest the feasibility of prospective identification of those patients at higher risk of relapse, based on their immune status.