Mechanisms of intestinal failure in Crohn's disease

PURPOSE: The purpose of this study was to determine the mechanisms by which patients with Crohn's disease develop intestinal failure and, in particular, to assess the relative importance of severe primary disease, repeated uncomplicated elective small intestine resection, and resection performed as a consequence of intra-abdominal septic surgical complications. METHODS: This was a retrospective analysis of 41 patients with Crohn's disease referred to a specialized intestinal failure unit between January 1987 and September 1998 for permanent home parenteral nutrition. To compare the surgical activity in patient groups, a resection index was calculated by dividing the number of intestinal resections by the interval in years between the first resection for Crohn's disease and referral for management of intestinal failure. RESULTS: Extensive primary Crohn's disease was responsible for intestinal failure in 7 cases (17 percent). The remainder (n=34, 83 percent) developed intestinal failure after intestinal resection. Nine of the surgical Crohn's patients developed intestinal failure after uncomplicated sequential resection, (median small-bowel length 65 (range, 60–120) cm) after a median of 3 (range, 2–8) operations over a median of 17 (range, 3–27) years. By contrast, the other 25 surgical Crohn's patients developed intestinal failure after multiple unplanned laparotomies for intra-abdominal sepsis (median small-bowel length 70 (range, 60–200) cm), with a median of 4 (range, 2–7) laparotomies performed over a median of 0.5 (range, 0.1 to 1.5) years (P<0.001). The resection index for the 25 Crohn's patients undergoing laparotomies for intra-abdominal sepsis was significantly greater than that of the 9 patients who had planned sequential resections (2.1 (0.27–25)vs. 0.23 (0.1–1.0);P < 0.002, Mann-WhitneyU test). CONCLUSION: Intestinal failure develops in Crohn's disease primarily as a result of complications of surgical treatment. The largest group of patients at risk consists of those who are undergoing multiple unplanned laparotomies to control intra-abdominal sepsis.     

Survival rate and prognostic factors in patients with intestinal failure

BACKGROUND: Intestinal failure impairs nutritional status and survival expectance. Though intestinal adaptation and enteral independence may be achieved, artificial nutrition is needed in about half of the patients. AIMS: This study is aimed at assessing the causes of death, survival rate, enteral independence in time, and factors affecting the clinical outcome in a group of patients with intestinal insufficiency. PATIENTS: Sixty-eight patients with intestinal insufficiency, due to major intestinal resection in 60 cases (short bowel syndrome) (remnant intestine length 101-150 cm in 31 cases, 50-100 cm in 23 cases, <50 cm in 6 cases), and due to chronic idiopathic pseudo-obstruction in 8 cases, were enrolled and followed-up for (median) 36 months (25th and 75th percentile in 12 and 60 months, respectively). In 60 short bowel syndrome patients, the main conditions that led to intestinal failure were ischemic bowel (28), major surgery complications or severe adhesions (17), radiation enteritis (10), Chron's disease, intestinal tuberculosis, small bowel lymphoma and trauma (others). METHODS: Seventeen variables age, underlying disorders, length of remnant bowel, type of surgery, hospital stay, type of nutrition (hospital and home) and its variations in time, causes of death, survival rate and time were considered. Statistical analysis was carried out by Mann-Whitney U-test, Pearson chi2, Spearman correlation test, Kaplan-Meyer method and Cox's proportion hazards regression model. RESULTS: At the time of admission to the hospital, none of the patients had nutritional independence, 54 (79.4%) were on parenteral nutrition and 14 (20.6%) were on enteral nutrition. At the time of discharge, 23 (33.8%) patients showed enteral independence, 39 were on home parenteral nutrition, 3 on enteral nutrition + i.v. feeding, 1 on enteral nutrition, and 2 needed oral supplementation with hydroelectrolyte solutions only. After a median value of 36 months, 30 and 2 patients were on home parenteral nutrition and enteral nutrition + i.v. feeding, respectively, 2 on enteral nutrition, 2 on oral supplementation with hydroelectrolyte solutions, and 26 cases reached enteral independence. A significant relationship was detected between the length of remnant bowel and types of nutrition at both admission (r = 0.38; P = 0.001) and discharge (r = 0.48; P = 0.001), parenteral nutrition being more frequent in patients with very short bowel. Twenty-two patients (32.4%) died (4 from newly occurring malignancies), 40 (58.8%) survived, and 6 (8.8%) were lost to the follow-up. Eleven of 22 patients died from conditions related to intestinal failure (8 cases) and/or home parenteral nutrition complications (3 cases). At 12, 24, 36, 48, 60 and 72 months, survival rates were 95.4, 93.3, 88.1, 78.6, 78.6 and 65.5%, respectively, but it was significantly lower for patients with <50 cm of remnant bowel than those with longer residual intestine (P < 0.05), and in patients who started home parenteral nutrition above the age of 45 years (P < 0.02). Survival rate was higher in patients with enteral independence than those with enteral dependence (P < 0.05). Better survival rates were registered in patients with chronic obstructive intestinal pseudo-obstruction and major surgery complications, whereas ischemic bowel and even more radiation enteritis were associated with a lower survival expectance. CONCLUSIONS: Actuarial survival rate of patients with intestinal failure quotes 88 and 78% at 3 and 5 years, respectively. It is influenced by the length of remnant intestine, age at the start of home parenteral nutrition, enteral independence and, to some extent at least, by the primary disorder. Enteral independence can be achieved in time by about 40% of the patients with intestinal insufficiency, but for home parenteral nutrition-dependent cases, intravenous feeding can be stopped in less than one out of five patients during a median 3-year period.     

Chronic intestinal failure and short bowel syndrome in Crohn’s disease

Chronic intestinal failure (CIF) is a rare but feared complication of Crohn’s disease. Depending on the remaining length of the small intestine, the affected intestinal segment, and the residual bowel function, CIF can result in a wide spectrum of symptoms, from single micronutrient malabsorption to complete intestinal failure. Management of CIF has improved significantly in recent years. Advances in home-based parenteral nutrition, in particular, have translated into increased survival and improved quality of life. Nevertheless, 60% of patients are permanently reliant on parenteral nutrition. Encouraging results with new drugs such as teduglutide have added a new dimension to CIF therapy. The outcomes of patients with CIF could be greatly improved by more effective prevention, understanding, and treatment. In complex cases, the care of patients with CIF requires a multidisciplinary approach involving not only physicians but also dietitians and nurses to provide optimal intestinal rehabilitation, nutritional support, and an improved quality of life. Here, we summarize current literature on CIF and short bowel syndrome, encompassing epidemiology, pathophysiology, and advances in surgical and medical management, and elucidate advances in the understanding and therapy of CIF-related complications such as catheter-related bloodstream infections and intestinal failure-associated liver disease.     

Definitions of intestinal failure and the short bowel syndrome

The European Society for Clinical Nutrition and Metabolism defined intestinal failure (IF) as “the reduction of gut function below the minimum necessary for the absorption of macronutrients and/or water and electrolytes, such that intravenous supplementation is required to maintain health and/or growth”. IF is classified as type 1-acute, type 2-prolonged acute and type 3-chronic IF. A short bowel syndrome (SBS) due to the intestinal malabsorption associated with a functional small intestine length of less than 200 cm is the most frequent mechanism of IF. SBS is a difficult and multifaced disease. Complications due to SBS itself and to treatments, such as long term home parenteral nutrition, can adversely affect the patient outcome. The care of SBS requires complex technologies and multidisciplinary and multiprofessional activity and expertise. Patient outcome is strongly dependent on care and support from an expert specialist team. This paper focuses on the aspects of the pathophysiology and on the complications of SBS, which are most relevant in the clinical practice, such as intestinal failure associated liver disease, renal failure, biliary and renal stones, dehydration and electrolyte depletion, magnesium deficiency and d-lactic acidosis.     

Implementation of a multidisciplinary team approach and fish oil emulsion administration in the management of infants with short bowel syndrome and parenteral nutrition-associated liver disease

OBJECTIVE:

To describe the authors’ experience with the implementation of a multidisciplinary approach and use of fish oil emulsion (FOE) in the management of infants with short bowel syndrome (SBS) and parenteral nutrition-associated liver disease (PNALD).

METHODS:

Between August 2006 and June 2009, four cases of SBS and severe PNALD were managed by the team using specifically developed protocols. The FOE was initiated if serum direct bilirubin levels were ≥100 μmol/L. To quantify the degree of exposure to high serum direct bilirubin levels over time, the area under the curve (AUC) for each patient was calculated before and after initiation of FOE. Linear regression analyses were performed to evaluate correlations between the AUC, duration of cholestasis and initiation of FOE.

RESULTS:

All patients survived and no complications were observed during the study period. After the first patient, FOE was initiated progressively earlier, but poor correlation between the AUC before and after its introduction was observed (r²=0.41924). However, there was strong correlation between the duration of PNALD before FOE initiation and time to resolution (r²=0.72133): the earlier the FOE was initiated, the shorter the time to resolution.

CONCLUSION:

The authors report a positive experience with the implementation of a multidisciplinary approach and the use of FOE in infants with SBS and severe PNALD. The earlier the FOE was initiated during the cholestatic process, the shorter the time to resolution. The present study is a hypothesis generator, raising the question of whether an earlier introduction of this particular therapy can effectively shorten the cholestasis process in these patients.     

内毒素在酒精性肝病肠损伤中的作用

目的探讨内毒素在酒精性肝病肠损伤中的作用。方法选择酒精性肝病患者15例和健康不饮酒者15例。采用ELISA法测定血清内毒素;采用分光光度法测定血清丙二醛。另将20只小鼠随机分为对照组和模型组,每组10只,分别喂饲Lieber-Decarli无酒精和含酒精液体饲料。10周后处死小鼠,检测血清内毒素,并进行肝脏和肠组织形态学观察。结果酒精性肝病组和对照组血清内毒素水平分别为0.52±0.54 Eu/L和0.47±0.34 Eu/L（P〈0.05）;酒精性肝病组和对照组血清丙二醛水平分别为5.6±5.0nmol/ml和3.7±3.4nmol/m（lP〉0.05）;模型组和对照组小鼠血清内毒素水平分别为0.38±0.05 Eu/L和0.13±0.02 Eu/L（P〈0.01）;模型组肝细胞明显脂肪变,结肠组织损伤病理学评分为10.3±1.3分,较对照组明显升高（4.8±1.2分,P=0.01）。结论酒精性肝病伴发了肠粘膜损伤,内毒素可能参与了发病过程。     

Outcome of liver disease in children with Alagille syndrome: a study of 163 patients

BACKGROUND AND AIMS: Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS). PATIENTS AND METHODS: We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit. RESULTS: At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%, respectively. Neonatal cholestatic jaundice was associated with poorer survival with native liver (p=0.0004). CONCLUSIONS: The prognosis of liver disease in AGS is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease, demanding follow up throughout life.     

Gut hormones, and short bowel role of glucagon-like peptide-2 in adaptation syndrome： The enigmatic the regulation of intestinal

Short bowel syndrome (SBS) refers to the malabsorption of nutrients, water, and essential vitamins as a result of disease or surgical removal of parts of the small intestine. The most common reasons for removing part of the small intestine are due to surgical intervention for the treatment of either Crohn's disease or necrotizing enterocolitis. Intestinal adaptation following resection may take weeks to months to be achieved, thus nutritional support requires a variety of therapeutic measures, which include parenterai nutrition. Improper nutrition management can leave the SBS patient malnourished and/or dehydrated, which can be life threatening. The development of therapeutic strategies that reduce both the complications and medical costs associated with SBS/long-term parenterai nutrition while enhancing the intestinal adaptive response would be valuable. Currently, therapeutic options available for the treatment of SBS are limited. There are many potential stimulators of intestinal adaptation including peptide hormones, growth factors, and neuronally-derived components. Glucagon-like peptide-2 (GLP-2) is one potential treatment for gastrointestinal disorders associated with insufficient mucosal function. A significant body of evidence demonstrates that GLP-2 is a trophic hormone that plays an important role in controlling intestinal adaptation. Recent data from clinical trials demonstrate that GLP-2 is safe, well-tolerated, and promotes intestinal growth in SBS patients. However, the mechanism of action and the localization of the glucagon-like peptide-2 receptor (GLP-2R) remains an enigma. This review summarizes the role of a number of mucosal-derived factors that might be involved with intestinal adaptation processes; however, this discussion primarily examines the physiology, mechanism of action, and utility of GLP-2 in the regulation of intestinal mucosal growth.     

Non-alcoholic fatty liver disease in patients with intestinal,pulmonary or skin diseases: Inflammatory cross-talk that needs a multidisciplinary approach

Non-alcoholic fatty liver disease (NAFLD) is currently considered the most common cause of liver disease. Its prevalence is increasing in parallel with the obesity and type 2 diabetes mellitus (DM2) epidemics in developed countries. Several recent studies have suggested that NAFLD may be the hepatic manifestation of a systemic inflammatory metabolic disease that also affects other organs, such as intestine, lungs, skin and vascular endothelium. It appears that local and systemic proinflammatory/anti-inflammatory cytokine imbalance, together with insulin resistance and changes in the intestinal microbiota, are pathogenic mechanisms shared by NAFLD and other comorbidities. NAFLD is more common in patients with extrahepatic diseases such as inflammatory bowel disease (IBD), obstructive syndrome apnea (OSA) and psoriasis than in the general population. Furthermore, there is evidence that this association has a negative impact on the severity of liver lesions. Specific risk characteristics for NAFLD have been identified in populations with IBD (i.e. age, obesity, DM2, previous bowel surgery, IBD evolution time, methotrexate treatment), OSA (i.e. obesity, DM2, OSA severity, increased transaminases) and psoriasis (i.e. age, metabolic factors, severe psoriasis, arthropathy, elevated transaminases, methotrexate treatment). These specific phenotypes might be used by gastroenterologists, pneumologists and dermatologists to create screening algorithms for NAFLD. Such algorithms should include non-invasive markers of fibrosis used in NAFLD to select subjects for referral to the hepatologist. Prospective, controlled studies in NAFLD patients with extrahepatic comorbidities are required to demonstrate a causal relationship and also that appropriate multidisciplinary management improves these patients’ prognosis and survival.     

IGF-1在酒精性肝病伴发肠粘膜损伤中的作用探讨

目的探讨IGF-1在酒精性肝病伴发肠粘膜损伤中的作用,并观察谷氨酰胺对肠粘膜IGF-1表达的影响。方法将30只小鼠随机分为对照组、模型组和治疗组,每组10只。对照组饲喂Lieber-Decarli无酒精液体饲料,模型组和治疗组饲喂含4%乙醇Lieber-Decarli液体饲料建立酒精性肝病模型,治疗组同时给予谷氨酰胺灌胃。12周后处死小鼠,心脏采血检测血清内毒素;取肠组织进行肠形态学检查,采用免疫组织化学法检测IGF-1表达。结果模型组血清内毒素较对照组明显升高(0.38±0.05 Eu/L对0.13±0.02 Eu/L,P<0.05),治疗组较模型组血清内毒素水平下降;模型组结肠损伤病理学评分较对照组明显升高(10.3±1.3分对4.8±1.2分,P<0.05),治疗组结肠损伤病理学评分较模型组降低;模型组肠粘膜IGF-1表达明显高于对照组(2.3±0.2分对0.9±0.2分),治疗组表达也相应的减少。结论酒精性肝病时伴有肠粘膜损伤。IGF-1在酒精性肝病伴发肠粘膜损伤中起到了修复作用。谷氨酰胺可保护肠粘膜,而且可能与IGF-1的表达有关。     

Obesity,fatty liver disease and intestinal microbiota

Nonalcoholic fatty liver disease(NAFLD) is a chronic liver disorder that is increasing in prevalence with the worldwide epidemic of obesity. NAFLD is the hepatic manifestation of the metabolic syndrome. The term NAFLD describes a spectrum of liver pathology ranges from simple steatosis to steatosis with inflammation nonalcoholic steatohepatitis and even cirrhosis. Metabolic syndrome and NAFLD also predict hepatocellular carcinoma. Many genetic and environmental factors have been suggested to contribute to the development of obesity and NAFLD, but the exact mechanisms are not known. Intestinal ecosystem contains trillions of microorganisms including bacteria, Archaea, yeasts and viruses. Several studies support the relationship between the intestinal microbial changes and obesity and also its complications, including insulin resistance and NAFLD. Given that the gut and liver are connected by the portal venous system, it makes the liver more vulnerable to translocation of bacteria, bacterial products, endotoxins or secreted cytokines. Altered intestinal microbiota(dysbiosis) may stimulate hepatic fat deposition through several mechanisms: regulation of gut permeability, increasing low-grade inflammation, modulation of dietary choline metabolism, regulation of bile acid metabolism and producing endogenous ethanol. Regulation of intestinal microbial ecosystem by diet modifications or by using probiotics and prebiotics as a treatment for obesity and its complications might be the issue of further investigations.     

Glucagon-like peptide-2 analogues for Crohn’s disease patients with short bowel syndrome and intestinal failure

Short bowel syndrome (SBS) with intestinal failure (IF) is a rare but severe complication of Crohn’s disease (CD), which is the most frequent benign condition that leads to SBS after repeated surgical resections, even in the era of biologics and small molecules. Glucagon-like peptide-2 analogues have been deeply studied recently for the treatment of SBS-IF. These drugs have a significant intestinotrophic effect and the potential to reduce the chronic dependence of SBS-IF patients on parenteral support or nutrition. Teduglutide has been approved for the treatment of SBS-IF, and apraglutide is currently in clinical development. The use of these drugs was examined with a focus on their use in CD patients.     

Metabolic associated fatty liver disease: Addressing a new era in liver transplantation

Metabolic associated fatty liver disease (MAFLD), previously termed non-alcoholic fatty liver disease, is the leading global cause of liver disease and is fast becoming the most common indication for liver transplantation. The recent change in nomenclature to MAFLD refocuses the conceptualisation of this disease entity to its metabolic underpinnings and may help to spur a paradigm shift in the approach to its management, including in the setting of liver transplantation. Patients with MAFLD present significant challenges in the pre-, peri- and post-transplant settings, largely due to the presence of medical comorbidities that include obesity, metabolic syndrome and cardiovascular risk factors. As the community prevalence of MAFLD increases concurrently with the obesity epidemic, donor liver steatosis is also a current and future concern. This review outlines current epidemiology, nomenclature, management issues and outcomes of liver transplantation in patients with MAFLD.     

代谢相关性脂肪性肝病患者发生明显肝纤维化的危险因素研究

目的分析经肝活检确诊的代谢相关性脂肪性肝病(metabolic associated fatty liver disease, MAFLD)患者发生明显肝纤维化的危险因素。方法回顾性分析193例经肝活检确诊的MAFLD患者发生明显肝纤维化的危险因素。结果与MAFLD伴无/轻微肝纤维化(F0~1)患者比较,MAFLD伴明显肝纤维化(F2~4)患者中女性比例更高、年龄更大、肥胖更多见、伴高血压病者更多(P均<0.05);与MAFLD伴无/轻微肝纤维化(F0~1)患者比较,MAFLD伴明显肝纤维化(F2~4)患者外周血中血红蛋白水平及血小板计数更低(P<0.05),血清中白蛋白及尿酸水平更低(P<0.05),而TBA及空腹血糖水平更高(P<0.05)。单因素回归分析发现,女性(OR=2.277, 95%CI:1.181~4.390)、高血压病(OR=3.305, 95%CI:1.606~6.801)、BMI(OR=1.083, 95%CI:1.006~1.167)、年龄(OR=1.030,95%CI:1.006~1.055)、血红蛋白(OR=0.978,95%CI:0.958~0.997)及血小板计数(OR=0.998,95%CI:0.989~1.000)是MAFLD患者发生明显肝纤维化的危险因素,而多因素回归分析发现,高血压病(OR=2.662,95%CI:1.092~6.489)、BMI(OR=1.163,95%CI:1.062~1.275)及血小板计数(OR=0.993,95%CI:0.987~0.999)是MAFLD患者发生明显肝纤维化的独立危险因素。结论高血压、BMI及血小板计数是肝活检确诊的MAFLD患者发生明显肝纤维化的独立危险因素。     

肠道菌群对终末期肝病患者营养和代谢的作用

<正>人体肠道内存在数量庞大、结构复杂的菌群,彼此之间相互作用,相互制约,处于动态平衡状态,直接参与人体的消化、营养吸收、能量供应等诸多方面,对宿主的健康和营养起重要的作用。目前,关于肠道菌群与肥胖的关系研究较多,而关于肠道菌群与营养不良的研究相对较少。在终末期肝病患者往往存在营养不良,而易引起严重的后果。本文阐述肠道菌群对于终末期肝病患者营养状况的影响和可采取的干预措施。1肠道菌群对宿主营养和能量代谢的影响     

Role of γδT cells in liver diseases and its relationship with intestinal microbiota

γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity. Based on the composition of T cell receptor and the cytokines produced, γδT cells can be divided into diverse subsets that may be present at different locations, including the liver, epithelial layer of the gut, the dermis and so on. Many of these cells perform specific functions in liver diseases, such as viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease, liver cirrhosis and liver cancers. In this review, we discuss the distribution, subsets, functions of γδT cells and the relationship between the microbiota and γδT cells in common hepatic diseases. As γδT cells have been used to cure hematological and solid tumors, we are interested in γδT cell-based immunotherapies to treat liver diseases.