The gut-liver axis.

PURPOSE OF REVIEW: The liver adaptively responds to extra-intestinal and intestinal inflammation. In recent years, the role of the autonomic nervous system, intestinal failure and gut microbiota has been investigated in the development of hepatic, intestinal and extra-intestinal disease. RECENT FINDINGS: The autonomic nervous system can be stimulated via enteral fat leading to cholecystokinin release, stimulating receptors in the gut and in the brain. This promotes bowel integrity, dampening the inflammatory response to food antigens. Consensus exists that intravenously administered long-chain fatty acids can cause liver damage but randomized-controlled trials are lacking. Disruption of the enterohepatic circulation of bile salts can give rise to cholestasis and nonalcoholic fatty liver disease, which may progress to fibrosis and cirrhosis. Reduced intestinal availability of bile salts reduces stimulation of the farnesoid X receptor. This may induce hepatic bile salt overload and associated hepatotoxicity through reduced action of intestinal fibroblast growth factor 19. Evidence is put forward to suggest that the intestinal microbiota is associated with liver abnormalities. SUMMARY: Enteral lipids reduce inflammation and liver damage during stress or systemic inflammation, whereas parenteral lipid is associated with liver damage. Maintaining the enterohepatic circulation of bile salts limits hepatic cholestasis through an farnesoid X receptor feedback pathway. Changes in gut microbiota composition may induce liver disease.

Adaptive reciprocity of lipid and glucose metabolism in human short-term starvation.

The human organism has tools to cope with metabolic challenges like starvation that are crucial for survival. Lipolysis, lipid oxidation, ketone body synthesis, tailored endogenous glucose production and uptake, and decreased glucose oxidation serve to protect against excessive erosion of protein mass, which is the predominant supplier of carbon chains for synthesis of newly formed glucose. The starvation response shows that the adaptation to energy deficit is very effective and coordinated with different adaptations in different organs. From an evolutionary perspective, this lipid-induced effect on glucose oxidation and uptake is very strong and may therefore help to understand why insulin resistance in obesity and type 2 diabetes mellitus is difficult to treat. The importance of reciprocity in lipid and glucose metabolism during human starvation should be taken into account when studying lipid and glucose metabolism in general and in pathophysiological conditions in particular.

Guided treatment improves outcome of patients with enterocutaneous fistulas.

BACKGROUND: The present study was designed to evaluate the effects of guided treatment of patients with an enterocutaneous fistula and to evaluate the effect of prolonged period of convalescence on outcome. METHODS: All consecutive patients with an enterocutaneous fistula treated between 2006 and 2010 were included in this study. Patient information was gathered prospectively. Treatment of patients focused on sepsis control, optimization of nutritional status, wound care, establishing the anatomy of the fistula, timing of surgery, and surgical principles. Outcome included spontaneous and surgical closure, mortality, and postoperative recurrence. The relationship between period of convalescence and recurrence rate was determined by combining the present prospective cohort with a historical cohort from our group. RESULTS: Between 2006 and 2010, 79 patients underwent focused treatment for enterocutaneous fistula. Cox regression analysis showed that period of convalescence related significantly with recurrence of the fistula (hazard ratio 0.99; 95 % confidence interval 0.98-0.999; p = 0.04). Spontaneous closure occurred in 23 (29 %) patients after a median period of convalescence of 39 (range 7-163) days. Forty-nine patients underwent operative repair after median period of 101 (range 7-374) days and achieved closure in 47 (96 %). Overall, eight patients (10 %) died. CONCLUSIONS: Prolonging period of convalescence for patients with enterocutaneous fistulas improves spontaneous closure and reduces recurrence rate.

Laparoscopic fistula excision and omentoplasty for high rectovaginal fistulas: a prospective study of 40 patients.

AIM: The aim of this study is to prospectively evaluate 40 patients with a high rectovaginal fistula treated by a laparoscopic fistula division and closure, followed by an omentoplasty. PATIENTS AND METHODS: Forty patients with a rectovaginal fistula, between the middle third of the rectum and the posterior vaginal fornix, resulting from different causes (IBD, iatrogenic and birth trauma) were treated by a laparoscopic excision of the fistula and insertion of an omentoplasty in the rectovaginal septum. The patients completed the gastrointestinal quality of life index questionnaire (GIQLI) and the Cleveland Clinic incontinence score (CCIS). All tests were performed at regular intervals after treatment. RESULTS: In 38 (95%) patients with a median age of 53 years (range 33-72), the surgical procedure was feasible. In two patients, the fistula was closed without an omentoplasty, and a diverting stoma was performed. The median follow-up was 28 months (range 10-35). Two patients (5%) developed a recurrent fistula. In one patient, the interposed omentum became necrotic and was successfully treated laparoscopically. In another patient, an abscess developed, which needed drainage procedures. The mean CCIS was 9 (range 7-10) before treatment and 10 (range 7-13) after treatment (p = 0.5 Wilcoxon). The median GIQLI score was 85 (range 34-129) before treatment and 120 (range75-142) after treatment (p = 0.0001, Wilcoxon). CONCLUSIONS: Laparoscopic fistula excision combined with omentoplasty is a good treatment modality with a high healing rate for high rectovaginal fistulas and an acceptable complication rate.

The role of ectopic adipose tissue: benefit or deleterious overflow?

Ectopic adipose tissues (EAT) are present adjacent to many organs and have predominantly been described in overweight and obesity. They have been suggested to be related to fatty acid overflow and to have harmful effects. The objective of this semi-comprehensive review is to explore whether EAT may play a supportive role rather than interfering with its function, when the adjacent organ is challenged metabolically and functionally. EAT are present adhered to different tissues or organs, including lymph nodes, heart, kidney, ovaries and joints. In this review, we only focused on epicardial, perinodal, and peritumoral fat since these locations have been studied in more detail. Evidence was found that EAT volume significantly increased, associated with chronic metabolic challenges of the corresponding tissue. In vitro evidence revealed transfer of fatty acids from peritumoral and perinodal fat to the adjacent tissue. Cytokine expression in these EAT is upregulated when the adjacent tissue is challenged. In these tissues, glycolysis is enhanced, whereas fatty acid oxidation is increased. Together with more direct evidence, this shows that glucose is oxidized to a lesser degree, but used to support anabolic metabolism of the adjacent tissue. In these situations, browning occurs, resulting from upregulation of anabolic metabolism, stimulated by uncoupling proteins 1 and 2 and possibly 3. In conclusion, the evidence found is fragmented but the available data support the view that accumulation and browning of adipocytes adjacent to the investigated organs or tissues may be a normal physiological response promoting healing and (patho)physiological growth.

The anabolic role of the Warburg, Cori-cycle and Crabtree effects in health and disease.

In evolution, genes survived that could code for metabolic pathways, promoting long term survival during famines or fasting when suffering from trauma, disease or during physiological growth. This requires utilization of substrates, already present in some form in the body. Carbohydrate stores are limited and to survive long, their utilization is restricted to survival pathways, by inhibiting glucose oxidation and glycogen synthesis. This leads to insulin resistance and spares muscle protein, because being the main supplier of carbon for new glucose production. In these survival pathways, part of the glucose is degraded in glycolysis in peripheral (muscle) tissues to pyruvate and lactate (Warburg effect), which are partly reutilized for glucose formation in liver and kidney, completing the Cori-cycle. Another part of the glucose taken up by muscle contributes, together with muscle derived amino acids, to the production of substrates consisting of a complete amino acid mix but extra non-essential amino acids like glutamine, alanine, glycine and proline. These support cell proliferation, matrix deposition and redox regulation in tissues, specifically active in host response and during growth. In these tissues, also glucose is taken up delivering glycolytic intermediates, that branch off and act as building blocks and produce reducing equivalents. Lactate is also produced and released in the circulation, adding to the lactate released by muscle in the Cori-cycle and completing secondary glucose cycles. Increased fluxes through these cycles lead to modest hyperglycemia and hyperlactatemia in states of healthy growth and disease and are often misinterpreted as induced by hypoxia.

Rationale for albumin infusions.

PURPOSE OF REVIEW: To describe the metabolism and function of albumin, and to scrutinize the evidence that infusion of albumin may be beneficial in disease. To explain why albumin infusion does not improve clinical outcome in most disease states, studied. RECENT FINDINGS: Albumin acts as a binding protein and an oncotic agent. However, albumin may also act as an extracellular scavenger, which leads to oxidation of albumin. It is likely that this compromises its function and it is possible that this drives its degradation. In disease, these useful processes are accelerated leading to rapid ageing of the molecule.Albumin infusion does not improve clinical outcome despite increasing oncotic pressure in chronic disease. It is not superior to nonprotein colloids or electrolyte solutions in acute hypovolemia with one or two exceptions (liver failure, possibly cerebral infarction). One potential explanation is that pharmaceutical albumin does not have the oxidative qualities that freshly synthesized albumin has. SUMMARY: Albumin infusion has not proven to achieve clinical benefit in many acute and chronic disease states with a few exceptions in acute hypovolemia (e.g. postparacentesis). Future studies should reveal whether infusion of freshly synthesized nonoxidized albumin is of greater clinical benefit.

Advances in understanding and assessing malnutrition.

PURPOSE OF REVIEW: To describe the varying views on the pathophysiology of malnutrition in different populations and the definitions that result from these views. To propose an umbrella definition for different malnutrition syndromes and principles of assessment of nutritional state. RECENT FINDINGS: At present, tacitly or openly inflammatory activity is considered to contribute to the malnourished state. The malnourished state, therefore, arises from a combination of inflammation and a disturbed nutrient balance (undernutrition or overnutrition). The undernourished category of malnutrition leads to loss of body cell mass, which, together with inflammation diminish host response and quality of life. On the basis of these findings, malnutrition may be assessed by estimating nutrient balance but, subsequently, to measure body composition (muscle mass), inflammatory activity (plasma albumin and C-reactive protein) and muscle endurance and force. Changes in muscle function in patients with chronic obstructive pulmonary disease are associated with changes in fiber composition. Few data exist in other malnourished states. SUMMARY: There is an increasing acknowledgement of the fact that malnutrition is caused by disturbances in nutrient balance and inflammatory activity. This leads to changes in body composition and diminished function. An umbrella definition has been proposed including the pathogenetic factors, underlying the different malnutrition syndromes and dictating the methods to assess malnutrition.

Hypoalbuminemia: Pathogenesis and Clinical Significance.

Hypoalbuminemia is associated with inflammation. Despite being addressed repeatedly in the literature, there is still confusion regarding its pathogenesis and clinical significance. Inflammation increases capillary permeability and escape of serum albumin, leading to expansion of interstitial space and increasing the distribution volume of albumin. The half-life of albumin has been shown to shorten, decreasing total albumin mass. These 2 factors lead to hypoalbuminemia despite increased fractional synthesis rates in plasma. Hypoalbuminemia, therefore, results from and reflects the inflammatory state, which interferes with adequate responses to events like surgery or chemotherapy, and is associated with poor quality of life and reduced longevity. Increasing or decreasing serum albumin levels are adequate indicators, respectively, of improvement or deterioration of the clinical state. In the interstitium, albumin acts as the main extracellular scavenger, antioxidative agent, and as supplier of amino acids for cell and matrix synthesis. Albumin infusion has not been shown to diminish fluid requirements, infection rates, and mortality in the intensive care unit, which may imply that there is no body deficit or that the quality of albumin "from the shelf" is unsuitable to play scavenging and antioxidative roles. Management of hypoalbuminaemia should be based on correcting the causes of ongoing inflammation rather than infusion of albumin. After the age of 30 years, muscle mass and function slowly decrease, but this loss is accelerated by comorbidity and associated with decreasing serum albumin levels. Nutrition support cannot fully prevent, but slows down, this chain of events, especially when combined with physical exercise.

Disease or adaptation: another look at the practice of medicine.

The practice of medicine has changed considerably over the past few decades and is now focusing more and more on early intervention strategies. As a result, we tend to consider pre-symptomatic abnormalities, however small, already as a potential target for treatment. In this viewpoint, we argue that we should put more emphasis on pathophysiological thinking as many of the so-called early abnormalities may, in fact, reflect adaptive mechanisms rather than disease. This view should influence medical care and education, emphasizing the importance of knowledge of pathophysiology.

Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism.

BACKGROUND: The liver plays a central role in amino acid metabolism. However, because of limited accessibility of the portal vein, human data on this subject are scarce. OBJECTIVE: We studied hepatic amino acid metabolism in noncirrhotic fasting patients undergoing liver surgery. DESIGN: Twenty patients undergoing hepatectomy for colorectal metastases in a normal liver were studied. Before resection, blood was sampled from a radial artery, portal vein, hepatic vein, and renal vein. Organ blood flow was measured by duplex ultrasound scan. RESULTS: The intestine consumed glutamine and released citrulline. Citrulline was taken up by the kidney. This was accompanied by renal arginine release, which supports the view that glutamine is a precursor for arginine synthesis through an intestinal-renal pathway. The liver was found to extract citrulline from this pathway at a rate that was dependent on intestinal citrulline release (P < 0.0001) and hepatic citrulline influx (P = 0.03). Fractional hepatic extractions of citrulline (8.4%) and arginine (11.5%) were not significantly different. Eighty-eight percent of arginine reaching the liver passed it unchanged. Splanchnic citrulline release could account for one-third of renal citrulline uptake. CONCLUSIONS: This is the first study of hepatic and interorgan amino acid metabolism in humans with a normal liver. The data indicate that glutamine is a precursor of ornithine, which can be converted to citrulline by the intestine; citrulline is transformed in the kidneys to arginine. Hepatic citrulline uptake limits the amount of gut-derived citrulline reaching the kidney. These findings may have implications for interventions aimed at increasing systemic arginine concentrations.

SGA and measures for muscle mass and strength in surgical Vietnamese patients.

OBJECTIVE: This study compared the outcome of the Subjective Global Assessment (SGA) in preoperative surgical patients with objective measurements of muscle mass and strength and with biochemical data. A secondary aim was to test the influence of inflammatory activity on muscle strength. METHODS: Two hundred seventy-four consecutive patients who were admitted for elective major abdominal surgery were assessed using the SGA, anthropometry, muscle strength, and laboratory measurements (hemoglobin, protein, albumin, C-reactive protein, and lymphocytes). Normal values for midarm muscle circumference (MAMC) and handgrip strength were obtained in a healthy control group. For all other variables, normal values available for the Vietnamese population were used. RESULTS: Of 274 patients (151 men, 123 women) assessed, 61 (22.3%) were classified as SGA class A (well nourished), 97 patients (35.4%) as class B (moderately malnourished), and 116 patients (42.3%) as class C (severely malnourished). There were significant differences in age, body weight, percentage of weight loss, triceps skinfold thickness, MAMC, and serum albumin across the three SGA classes. Almost all patients rated class A had normal MAMC and handgrip strength. However, a large proportion of patients rated as B or C also had normal MAMC and handgrip strength (38% of men, 50% of women). Handgrip strength per square meter correlated with serum albumin (r = 0.278, P < 0.001) and this correlation persisted when handgrip strength was controlled for MAMC (r = 0.296, P < 0.001 in men; r = 0.237, P < 0.01 in women). CONCLUSION: The SGA correctly identifies patients with normal muscle mass and strength but a substantial number of patients rated SGA B or C have normal muscle mass and strength. Muscle strength is not only positively associated with muscle mass but also negatively with inflammatory activity.

Nutritional and metabolic abnormalities in pre-AIDS HIV infection.

Since the earliest reports of human immunodeficiency virus (HIV) disease, undernutrition has been associated with HIV infection, typically with the late stages of the disease (namely acquired immunodeficiency syndrome), and may advance to severe wasting and cachexia. Specific micronutrient deficiencies are also recognized to occur with HIV infection, but their actual effect on the clinical course of the disease is hard to assess. The studies reviewed provide more insight into the complex interface between undernutrition and, in some cases, obesity and HIV/acquired immunodeficiency syndrome and highlight the possibility of alleviating or curing undernutrition by means of simple and comparatively inexpensive dietary adjustments.

Macronutrient Metabolism in Starvation and Stress.

In starvation and to a lesser extent in stress starvation, the loss of protein mass is spared as much as possible. This metabolic arrangement must have developed under the influence of evolutionary pressure in view of the importance of protein mass for function and longevity. Peripheral adipose tissue mass is only limiting when its mass is extremely small. Protein is the predominant precursor of glucose in (stress) starvation and glucose is an essential substrate for the synthesis and maintenance of cells and matrix and for the control of the redox state. To spare protein, glucose should be used efficiently only for those purposes that cannot be achieved by fat. It is suggested that this is achieved by limiting full glucose oxidation and increasing fatty acid and ketone body oxidation, which most likely can also largely cover energy needs of the central nervous system. In stress states, net negative nitrogen balance (catabolism) largely results from net losses of peripheral protein mass, predominantly muscles, whereas central organs (e.g. the liver), the immune system and wound healing are anabolic. A number of factors are responsible for a net negative nitrogen balance which may ultimately lead to death if stress persists. In stress, the amino acid mix derived from peripheral (predominantly muscle) tissues is modified in interplay with the liver and to a minor extent the kidney. This mix is different in nonstressed conditions, containing substantially increased amounts of the nonessential amino acids glutamine, alanine, glycine and (hydroxy)proline. Part of the amino acid skeletons released by muscles are substrates to produce glucose in the liver and kidney. Glucose and the amino acids produced especially serve as substrates for cell proliferation and matrix deposition. The catabolic processes in peripheral tissues cannot be countered completely by adequate nutritional support as long as stress persists. This metabolic arrangement dictates a nutritional mix containing liberal amounts of protein and carbohydrates and addition of lipids to cover energy requirements.

The Biological Value of Protein.

The biological value of a protein extends beyond its amino-acid composition and digestibility, and can be influenced by additional factors in a tissue-specific manner. In healthy individuals, the slow appearance of dietary amino acids in the portal vein and subsequently in the systemic circulation in response to bolus protein ingestion improves nitrogen retention and decreases urea production. This is promoted by slow absorption when only protein is ingested (e.g. casein). When a full meal is ingested, whey achieves slightly better nitrogen retention than soy or casein, which is very likely achieved by its high content of essential amino acids (especially leucine). Elderly people exhibit 'anabolic resistance' implying that more protein is required to reach maximal rates of muscle protein synthesis compared to young individuals. Protein utilization in inflammatory or traumatic conditions increases substantially in the splanchnic tissues containing most of the immune system, and in wounds and growing tissues. This happens especially in the elderly, which often suffer from chronic inflammatory activity due to disease, physical inactivity and/or the aging process itself. Consequently, the proportion of protein absorbed in the gut and utilized for muscle protein synthesis decreases in these situations. This compromises dietary-protein-induced stimulation of muscle protein synthesis and ultimately results in increased requirements of protein (∼1.2 g/kg body weight/day) to limit gradual muscle loss with age. To optimally preserve muscle mass, physical exercise is required. Exercise has both direct effects on muscle mass and health, and indirect effects by increasing the utilization of dietary protein (especially whey) to enhance rates of muscle protein synthesis.

Routes for early enteral nutrition after esophagectomy. A systematic review.

BACKGROUND: Early enteral feeding following surgery can be given orally, via a jejunostomy or via a nasojejunal tube. However, the best feeding route following esophagectomy is unclear. OBJECTIVES: To determine the best route for enteral nutrition following esophagectomy regarding anastomotic leakage, pneumonia, percentage meeting the nutritional requirements, weight loss, complications of tube feeding, mortality, patient satisfaction and length of hospital stay. DESIGN: A systematic literature review following PRISMA and MOOSE guidelines. RESULTS: There were 17 eligible studies on early oral intake, jejunostomy or nasojejunal tube feeding. Only one nonrandomized study (N = 133) investigated early oral feeding specifically following esophagectomy. Early oral feeding was associated with a reduced length of stay with delayed oral feeding, without increased complication rates. Postoperative nasojejunal tube feeding was not significantly different from jejunostomy tube feeding regarding complications or catheter efficacy in the only randomised trial on this subject (N = 150). Jejunostomy tube feeding outcome was reported in 12 non-comparative studies (N = 3293). It was effective in meeting short-term nutritional requirements, but major tube-related complications necessitated relaparotomy in 0-2.9% of patients. In three non-comparative studies (N = 135) on nasojejunal tube feeding only minor complications were reported, data on nutritional outcome was lacking. Data on patient satisfaction and long-term nutritional outcome were not found for any of the feeding routes investigated. CONCLUSION: It is unclear what the best route for early enteral nutrition is after esophagectomy. Especially data regarding early oral intake are scarce, and phase 2 trials are needed for further investigation. REGISTRATION: International prospective register of systematic reviews, CRD42013004032.