Non-alcoholic steatohepatitis: effect of Roux-en-Y gastric bypass surgery

OBJECTIVE: Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent problem. Treatment options are still under investigation. The primary aim of the study was to determine whether weight loss, achieved through Roux-en-Y gastric bypass (RYGBP), improved histopathology in obese patients with biopsy proven NASH. METHODS: One hundred and forty-nine patients were identified from a surgical database as having RYGBP for obesity and concomitant intra-operative liver biopsies from October 2001 to September 2003. Thirty-five patients were found to have evidence of NASH at the time of surgery. Nineteen patients were contacted and underwent repeat percutaneous liver biopsies. Biopsies were evaluated and compared in blinded fashion by an experienced hepatopathologist. Fasting lipid panel, insulin and glucose, hemoglobin A1c (HgbA1c), and liver enzymes were obtained. RESULTS: Significant differences were noted in the following variables pre- and post-bypass surgery: body mass index 46.8-28.8 kg/m2 (p < 0.001); body weight in kilograms 132.1-79.7 (p < 0.001); glucose 102.9-94.1 mg/dL (p = 0.015); Hgb A1c 5.79-5.15% (p = 0.026); high density lipoprotein 45.7-64.4 mg/dL (p < 0.001); low density lipoprotein 112-88.6 mg/dL (p = 0.003); triglycerides 132.1-97 mg/dL (p = 0.013). Significant improvements in steatosis, lobular inflammation, portal, and lobular fibrosis were noted. Histopathologic criteria for NASH were no longer found in 17/19 patients (89%). CONCLUSIONS: Weight loss after gastric bypass surgery in obese patients with NASH results in significant improvement in glucose, HgbA1c. and lipid profiles. Furthermore, RYGBP results in significant improvement in the histological features of NASH with resolution of disease in a majority of these patients.     

Treatment of NASH with Gastric Bypass

Purpose of Review

Nonalcoholic steatohepatitis (NASH) is a spectrum of nonalcoholic fatty liver disease (NAFLD). It is defined as the presence of fatty liver along with inflammation and hepatocyte injury. To date, weight loss achieved via lifestyle intervention remains the mainstay of NASH treatment. However, given the known benefit of weight loss on NASH and the known effect of bariatric surgery on weight loss, several studies have explored the potential role of bariatric surgery on the treatment of NASH.

Recent Findings

This review article summarizes the evidence on the effect of Roux-en-Y gastric bypass (RYGB), a common bariatric surgery, on NASH therapy. Specifically, studies show that RYGB is associated with an improvement of all NASH histologic features at 1 year.

Summary

Compared to adjustable gastric band, RYGB appears to be superior at treating NASH. Randomized controlled trials and long-term studies are underway to better clarify the role of these procedures specifically for NASH therapy.

     

Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4-12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2-6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3-19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6-11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity.     

Effects of bariatric surgery on nonalcoholic fatty liver disease: preliminary findings after 2 years

Background and Aim: Although nonalcoholic fatty liver disease (NAFLD) is very common among morbidly obese patients, the effect of weight loss after bariatric surgery on inflammation and fibrosis related to NAFLD is still a matter of debate. The aim of this study was to evaluate the impact of Roux‐en‐Y gastric bypass (RYGB) surgery on NAFLD with a follow up of 2 years. Methods: Eighteen consecutive NAFLD patients with body mass index >40 kg/m² undergoing gastroplasty with RYGB were enrolled, and wedge liver biopsy was obtained at the operation. After 2 years, these patients underwent percutaneous liver biopsy. Results: At baseline, 67% of patients had nonalcoholic steatohepatitis (NASH) and 33% had steatosis, according to the NASH Clinical Research Network Scoring System (NAS) for biopsy. Cirrhosis was present in 5.5% of the patients with NASH. After a mean excess weight loss of 60%, steatosis disappeared in 84% and fibrosis disappeared in 75% of the patients. Hepatocellular ballooning disappeared in 50%. A slight lobular inflammatory infiltrate remained in 81%, apparently unrelated to fatty degeneration. As liver biochemical variables had been found within normal limits in 92.3% of patients at initial biopsy, no difference was found 2 years later. Lipid profile and blood sugar plasma concentration were closer to normal in all patients after 2 years (P < 0.05). Conclusions: Aspects of NAFLD including steatohepatitis improved significantly with massive weight loss at 2 years after RYGB surgery. No patient in this series had progression of hepatic fibrosis.     

Intestinal and Gastric Bypass

Jejunal bacterial flora, bile acid deconjugation, and breath hydrogen and methane excretion were studied in nine patients with end-to-side and nine patients with end-to-end jejunoileostomy and in eight patients with gastric bypass. Bacterial numbers did not differ significantly between healthy controls and any of the patient groups. Production of fermentation gases in anaerobic cultures supplemented with carbohydrates did not occur with jejunal secretions from healthy controls but was found in all intestinal bypass patients and half the gastric bypass patients. Bacterial bile acid deconjugation activity was significantly higher in end-to-side compared with end-to-end jejunoileostomy patients. In gastric bypass patients bile acid deconjugation was not significantly affected. Breath hydrogen after glucose ingestion was abnormal in six patients with end-to-side and three with end-to-end jejunoileostomy and in six of the patients subjected to gastric bypass. The highest values were found in the latter group. Breath methane, which is found in one third of a healthy population, was absent in all 18 patients with intestinal bypass, and this may indicate that a change occurs even in the colonic microflora after this operation. Both intestinal and gastric bypass may change the small-bowel microflora, with the greatest changes occurring after end-to-side jejunoileostomy and the least changes after gastric bypass.     

A Synergy between Incretin Effect and Intestinal Gluconeogenesis Accounting for the Rapid Metabolic Benefits of Gastric Bypass Surgery

The early improvement of glucose control taking place shortly after gastric bypass surgery in obese diabetic patients has long been mysterious. A recent study in mice has highlighted some specific mechanisms underlying this phenomenon. The specificity of gastric bypass in obese diabetic mice relates to major changes in the sensations of hunger and to rapid improvement of glucose parameters. The induction of intestinal gluconeogenesis plays a major role in diminishing hunger, and in restoring insulin sensitivity of endogenous glucose production. In parallel, the restoration of the secretion of glucagon-like peptide 1 and insulin plays a key additional role, in this context of recovered insulin sensitivity, to improve postprandial glucose tolerance. Therefore, a synergy between an incretin effect and intestinal gluconeogenesis is a key feature accounting for the rapid improvement of glucose control in obese diabetic patients after bypass surgery.     

The impact of bariatric surgery on nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) is a stage of nonalcoholic fatty liver disease (NAFLD), and in most patients, is associated with obesity and the metabolic syndrome. The current best treatment of NAFLD and NASH is weight reduction with the current options being life style modifications, with or without pharmaceuticals, and bariatric surgery. Bariatric surgery is an effective treatment option for individuals who are severely obese (body mass index ≥ 35 kg/m(2)), and provides for long-term weight loss and resolution of obesity-associated diseases in most patients. Regression and/or histologic improvement of NASH have been documented after bariatric surgery. We review the available literature reporting on the impact of the various bariatric surgery techniques on NASH.     

Postoperative arrhythmias after coronary artery and cardiac valvular surgery detected by long-term electrocardiographic monitoring.

Twenty-four hour long-term electrocardiographic recordings were used to supplement routine perioperative monitoring to determine the frequency and significance of arrhythmias occurring after coronary artery bypass graft surgery and cardiac valve replacement. Patients underwent “ambulatory” electrocardiographic monitoring for 24 hours before surgery and on the first and fifth days after discharge from intensive care.New arrhythmias occurred in 26 of 50 patients (52 per cent) after coronary artery bypass graft surgery and in six of 15 patients (40 per cent) after valve replacement. This high frequency of arrhythmia detection was directly attributable to the use of long-term electrocardiography. New atrial arrhythmias were common after both valvular and coronary artery bypass graft surgery (44 per cent and 38 per cent of patients, respectively). Ventricular arrhythmias were uncommon preoperatively in both groups but occurred frequently after coronary artery bypass graft surgery (36 per cent). Arrhythmias contributed to morbidity but not to mortality in this series.These results suggest that new atrial arrhythmias occurring after coronary artery bypass graft or valvular surgery may be related more to the immediate intrathoracic sequelae of surgery than to a specific underlying cardiac lesion, in contrast to ventricular arrhythmias which may be more specific for patients with ischemia. Long-term electrocardiographic recording is a useful technique to supplement routine methods of perioperative electrocardiographic monitoring.     

Individualized treatment options for patients with non-cirrhotic and cirrhotic liver disease

The obesity pandemic has led to a significant increase in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). While dyslipidemia, type 2 diabetes mellitus and cardiovascular diseases guide treatment in patients without signs of liver fibrosis, liver related morbidity and mortality becomes relevant for MAFLD’s progressive form, non-alcoholic steatohepatitis (NASH), and upon development of liver fibrosis. Statins should be prescribed in patients without significant fibrosis despite concomitant liver diseases but are underutilized in the real-world setting. Bariatric surgery, especially Y-Roux bypass, has been proven to be superior to conservative and/or medical treatment for weight loss and resolution of obesity-associated diseases, but comes at a low but existent risk of surgical complications, reoperations and very rarely, paradoxical progression of NASH. Once end-stage liver disease develops, obese patients benefit from liver transplantation (LT), but may be at increased risk of perioperative infectious complications. After LT, metabolic comorbidities are commonly observed, irrespective of the underlying liver disease, but MAFLD/NASH patients are at even higher risk of disease recurrence. Few studies with low patient numbers evaluated if, and when, bariatric surgery may be an option to avoid disease recurrence but more high-quality studies are needed to establish clear recommendations. In this review, we summarize the most recent literature on treatment options for MAFLD and NASH and highlight important considerations to tailor therapy to individual patient’s needs in light of their risk profile.     

肠源性内毒素血症：非酒精性脂肪性肝炎的重要危险因素

非酒精性脂肪性肝病（NAFLD）是指除外酒精和其他明确损肝因素所致的、以肝细胞脂肪变性和脂质沉积为主要特征的临床病理综合征.非酒精性脂肪性肝炎（NASH）是NAFLD病程进展中的主要阶段.近年多项研究发现肠源性内毒素血症与NASH关系密切,本文就肠源性内毒素血症所致的肥胖和肝脏损伤对NASH发生的影响作一综述.     

Nonalcoholic Fatty Liver Disease Treated by Gastroplasty

Nonalcoholic steatohepatitis (NASH), which is the most severe histologic form of nonalcoholic fatty liver disease (NAFLD), is emerging as the most common clinically important form of liver disease in obese patients. The prevalence of NASH may increase with the rise in the rate of obesity and metabolic syndrome in affluent communities. The aim of this work is to describe clinical and histopathologic findings and correlate liver tissue damage to the length of duration of the obesity in the group of patients who underwent surgery as obesity treatment. Eighty-seven severely or morbidly obese patients underwent gastroplasty. Each patient was evaluated with complete clinical and laboratory medical assessment together with wedge liver biopsy taken from 59 unselected patients during the surgery. Patients were followed up for 41 months. Repeat liver biopsy was taken from 10 patients. Pathologic analysis recorded the presence and degree of steatosis, portal and lobular inflammation and fibrosis. Age, body mass index (BMI), and laboratory assessment correlated with pathologic data. Male patients showed more pronounced metabolic syndrome and fatty liver damage. Patients who become obese in childhood or as teenagers showed no differences in metabolic syndrome and NAFLD in mature age. There was statistically significant association between BMA, elevated transaminases, NAFLD, and fibrosis. Significant weight reduction was observed within first year after surgery, was slower in the second year, and stabilized within third year. Remarkable improvement followed in biological markers of metabolic syndrome. Ninety-six percent of initial liver biopsies had steatosis; 16% developed steatohepatitis and mild perivenular fibrosis. Significant improvement of the degenerative and inflammatory hepatic lesions in repeated biopsies and liver function readings was noted within 8 months after surgery. Obesity is a major and independent risk factor for the metabolic syndrome, NAFLD, NASH, and fibrosis. Surgical treatment improves metabolic abnormalities and hepatic lesions in long-term observations.     

Early assessment of coronary artery bypass graft patency by high-dose dipyridamole echocardiography

To assess the role of high-dose (up to 0.84 mg/kg during 10 minutes) dipyridamole echocardiographic testing in the evaluation of coronary artery bypass graft patency early after surgery, 18 consecutive patients with angina underwent dipyridamole echocardiography and coronary angiography before and 7 to 10 days after bypass surgery. Coronary angiography showed 2- or 3-vessel disease in 7 and 11 patients, respectively. A total of 53 bypass grafts were performed. Before bypass surgery 14 patients had a positive and 4 a negative test result. No complication occurred during the test performed early after surgery. Of the 14 patients with positive dipyridamole echocardiographic results before surgery, 10 had negative and 4 had positive results after surgery. All 4 patients had negative results before and after surgery. In the 4 patients with positive results after dipyridamole echocardiographic testing before and after bypass surgery, dipyridamole time increased from 5.8 +/- 5 to 9.3 +/- 0.9 minutes (p = 0.3) after the procedure and wall motion score index at peak dipyridamole changed from 1.55 +/- 0.2 to 1.28 +/- 0.3 (p = 0.05). Forty-nine of 53 grafts were patent as seen on angiography. Dipyridamole echocardiographic results were positive in 4 of 5 patients who had at least 1 obstructed graft or native vessel obstructed distal to bypass graft insertion. The remaining patient had diagnostic electrocardiographic changes during dipyridamole infusion without wall motion abnormalities. Dipyridamole echocardiographic results were negative in all 13 patients who had complete revascularization. In the 4 patients with positive test results, the procedure correctly identified the localization of the diseased bypass graft.(ABSTRACT TRUNCATED AT 250 WORDS)     

Surgical treatment for obesity and its impact on non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) in obese and severely obese populations is associated with the metabolic syndrome, with features of the syndrome predicting those who will have NASH rather than simple steatosis, a more benign form of non-alcoholic fatty liver disease. Substantial weight loss is proving the most effective therapy for obesity-related conditions. Improvements have seen the development of less invasive procedures. There is growing evidence that laparoscopic adjustable gastric banding and roux-en-Y gastric bypass provide effective therapy.     

Surgical Issues in NASH: Bariatric Surgery and Liver Transplantation

Purpose of Review

The rising prevalence of obesity in general and non-alcoholic steatohepatitis (NASH) specifically as an indication for liver transplantation has occurred in parallel with an increase in the consideration and performance of bariatric surgery before and after liver transplantation. We review the impact and relative merits of bariatric surgery before, during, and after liver transplantation.

Recent Findings

The sleeve gastrectomy approach has several practical advantages over other forms of weight loss surgery and has been shown to improve metabolic parameters. Bariatric surgical procedures inevitably affect immunosuppression pharmacokinetics, with the least impact being observed following sleeve gastrectomy. In the non-transplant setting, bariatric surgery has been shown to be an effective therapy for histological features of NASH.

Summary

When compared to lifestyle changes alone, bariatric surgery performed during or after liver transplantation results in sustained weight loss and improved metabolic parameters associated with liver disease, cardiovascular risk, and overall mortality. Further studies are needed to confirm which surgical procedures, timing, and NASH patients will receive most benefit.

     

腹腔镜下Roux-en-Y胃旁路手术对肥胖2型糖尿病患者胰岛素敏感性和单核细胞趋化蛋白影响的研究

目的探讨腹腔镜下Roux-en-Y胃旁路手术(LRYGB)对肥胖T2DM患者血清IS和单核细胞趋化蛋白1(MCP-1)的影响。方法选取40例肥胖T2DM患者行LRYGB,ELISA法测定患者术前、术后6个月血清MCP-1水平,应用高胰岛素正葡萄糖钳夹实验评估IS,分析LRYGB对肥胖T2DM患者MCP-1和IS的影响。结果40例肥胖T2DM患者均无术中并发症发生及中转开腹。患者术后6个月HbA₁c、FPG、TC、TG及MCP-1水平较术前降低(P<0.05),FIns、葡萄糖代谢率及胰岛素抵抗指数较术前显著改善(P<0.05)。结论LRYGB可改善肥胖T2DM患者IS和MCP-1介导的炎症状态。     

Origins of and Recognition of Micronutrient Deficiencies After Gastric Bypass Surgery

Roux-en-Y gastric bypass surgery remains the major surgical option for individuals with medically complicated obesity. The importance of preoperative evaluation to permit identification of micronutrient deficiencies is being re-evaluated. The risk of complications related to pregnancy after gastric bypass supports careful follow-up. Micronutrient deficiencies are common in postoperative gastric bypass patients, despite the suggested use of routine vitamin and mineral supplements after surgery. Copper deficiency must be considered as an origin for visual disorders after gastric bypass. Vitamin D deficiency with metabolic bone disease remains common after gastric bypass and the results suggest that the present postoperative supplements of calcium and vitamin D are inadequate. Major nutritional complications of bariatric surgery are occurring more than 20 years after surgery. There is no evidence for intestinal adaptation as there remains decreased intestinal absorption of iron up to 18 months after gastric bypass surgery. This article supports ongoing examination of nutritional complications after gastric bypass surgery and supports the notion that the daily doses of micronutrient supplements, such as vitamin D, may need to be revised.     

Establishment of a hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol

AIM: To determine the feasibility and safety of establishing a porcine hepatic cirrhosis and portal hypertension model by hepatic arterial perfusion with 80% alcohol.METHODS: Twenty-one healthy Guizhou miniature pigs were randomly divided into three experimental groups and three control groups. The pigs in the three experimental groups were subjected to hepatic arterial perfusion with 7, 12 and 17 mL of 80% alcohol, respectively, while those in the three control groups underwent hepatic arterial perfusion with 7, 12 and 17 mL of saline, respectively. Hepatic arteriography and direct portal phlebography were performed on all animals before and after perfusion, and the portal venous pressure and diameter were measured before perfusion, immediately after perfusion, and at 2, 4 and 6 wk after perfusion. The following procedures were performed at different time points: routine blood sampling, blood biochemistry, blood coagulation and blood ammonia tests before surgery, and at 2, 4 and 6 wk after surgery; hepatic biopsy before surgery, within 6 h after surgery, and at 1, 2, 3, 4 and 5 wk after surgery; abdominal enhanced computed tomography examination before surgery and at 6 wk after surgery; autopsy and multi-point sampling of various liver lobes for histological examination at 6 wk after surgery.RESULTS: In experimental group 1, different degrees of hepatic fibrosis were observed, and one pig developed hepatic cirrhosis. In experimental group 2, there were cases of hepatic cirrhosis, different degrees of increased portal venous pressure, and intrahepatic portal venous bypass, but neither extrahepatic portal-systemic bypass circulation nor death occurred. In experimental group 3, two animals died and three animals developed hepatic cirrhosis, and different degrees of increased portal venous pressure and intrahepatic portal venous bypass were also observed, but there was no extrahepatic portal-systemic bypass circulation.CONCLUSION: It is feasible to establish an animal model of hepatic cirrhosis and portal hypertension by hepatic arterial perfusion with 80% alcohol, however, the safety of this model depends on a suitable perfusion dose.     

Primary liver cancers with nonalcoholic steatohepatitis

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.     

Angiogenesis achieved by granulocyte colony-stimulating factor in combination with bypass surgery in 2 cases of critical limb ischemia

Patients demonstrating critical limb ischemia with a long-distance occlusion of the major arteries are sometimes poor candidates for bypass surgery, because tandem occlusion complicates distal anastomoses and poor run-off causes early occlusion of bypass grafts. In order to resolve these problems, angiogenesis therapy was attempted by subcutaneous injection of granulocyte colony-stimulating factor either before or after peripheral bypass surgery in 2 cases.     

体外循环心脏术后急性肝功能损害的危险因素分析

目的：通过分析体外循环心脏手术后肝功能损害的危险因素，认识心脏手术后肝功能损害的发生规律及特点。方法：对397例体外循环心脏手术后发生肝功能损害的相关因素进行单因素和多因素分析。结果：单因素分析显示：高龄、风湿性心脏病、慢性病毒性肝炎、术前右心衰、肝淤血、黄疸、腹水、术后严重感染、乳酸酸中毒、低心排血量及低氧血症等因素可能会导致术后急性肝功能损害的发生；多因素分析显示：术前就有肝功能损害、手术中体外循环时间长（超过2h）、手术出血多导致血制品输入量超过1000ml、术后低心排血量以及低氧血症是术后急性肝功能损害发生的独立危险因素。结论：体外循环心脏手术后肝功能损害是多种因素共同作用的结果，应提高对围术期肝功能损害危险因素的认识，正确指导临床治疗，从而避免术后急性肝功能衰竭的发生。