1137CHAPTER 94 Gastrointestinal Structure and Function malnutrition, chronic liver disease, cachexia, or cytokines Alter natively, increased losses from proteinuria, protein losing enter opathy, burns[.]
CHAPTER 94 Gastrointestinal Structure and Function malnutrition, chronic liver disease, cachexia, or cytokines Alternatively, increased losses from proteinuria, protein-losing enteropathy, burns, or other iatrogenic losses—including paracentesis or chest tube losses—may cause hypoalbuminemia and hypogammaglobulinemia Prealbumin, also known as transthyretin, is a visceral protein with a short half-life of approximately 1.9 days Because hepatic synthesis is exquisitely sensitive to both the adequacy and levels of protein and energy intakes, it may be used as a nutritional marker and for monitoring short-term response to nutritional intervention.45 a1-Antitrypsin is an important antiprotease with regulatory activity for elastase and other plasma proteases a1-Antitrypsin is important in regulating elastase-induced tissue injury in certain lung diseases; its absence leads to uncontrolled proteolytic activity in the lung.46 Patients with a1-antitrypsin deficiency have an increased burden of portal hypertension.47 Since a1antitrypsin is an endogenous protein that is relatively resistant to hydrolysis by enteric bacteria, it is a useful marker of proteinlosing enteropathy.48 Transferrin facilitates iron transport in the plasma by binding two molecules of iron Ferritin is the primary storage molecule of iron, with each molecule storing up to 4500 atoms of iron Multiple coagulation factors are synthesized in the liver, including plasminogen, fibrinogen, and factors II, V, VII, IX, X, XI, XII, and XIII Factors II, VII, IX, and X are the so-called vitamin K–dependent factors that require vitamin K for synthesis and secretion in active form.49 In addition, the anticlotting proteins antithrombin III, protein C, and protein S are synthesized largely in the liver and may be vitamin K dependent Several additional common plasma proteins are synthesized by the liver, including haptoglobin, ceruloplasmin, lipoproteins, a-fetoprotein, and the C3 component of complement Alterations in plasma proteins frequently occur during acute and chronic liver disease Although the levels of many of these proteins may rise (acute-phase reactants) as part of the systemic inflammatory response syndrome, plasma levels are generally reduced during chronic liver disease depending on the duration of hepatic insufficiency and the half-lives of the specific proteins Thus, a decrease in albumin generally represents a chronic disease state, whereas a prolonged prothrombin time may be seen within hours of acute hepatic failure because of the short half-life of factor VII (6 hours).50 1137 as prehepatic if production is increased beyond the ability to clear or cholestatic if the conjugated bilirubin cannot be excreted Enterohepatic Circulation Bile acids represent a family of steroid molecules derived from cholesterol They eliminate cholesterol from the body and solubilize dietary fats through a detergent-like action Enterohepatic circulation conserves bile acids since a minimum concentration of bile acids is required for micelle formation Bile salts are secreted into the duodenum with 97% reuptake in the terminal ileum by the apical bile salt transporter, undergoing recycling to 12 times per day The distal and terminal ilea have specialized transport mechanisms for absorption of bile salts and vitamin B12, which are adversely affected by terminal ileal resection, jejunostomy, inflammatory bowel disease, or other acquired lesions in this anatomic region (e.g., necrotizing enterocolitis) Functional loss of the distal and terminal ilea results in malabsorption of vitamin B12, bile salt deficiency, and impaired digestion and absorption of fat-soluble vitamins and long-chain fats Furthermore, unresorbed bile acids entering the colon play a major role in secretory diarrhea Hepatic insufficiency, either from immaturity or as a result of disease, affects the elimination of many drugs A large number of commonly used drugs of all classes—including aminophylline preparations, narcotics, barbiturates, H2-blockers, vasodilators, antiarrhythmics, and others—demonstrate significant hepatic elimination The hepatic P450 (CYP) system plays a central role in many of the mixed-function oxidative reactions responsible for converting lipophilic compounds into more water-soluble ones.52,53 The liver may conjugate drug metabolites to form hydrophilic products that can be eliminated in bile or through the kidney The half-life of many drugs may be prolonged during hepatic insufficiency as a result of a decrease in the total number of functioning hepatocytes In addition, the half-life of many drugs may be prolonged through competitive inhibition by the presence of other drugs depending on P450 metabolism or may be shortened by induction of rate-limiting elimination pathways For example, phenobarbital decreases the half-life of opiates and xanthines and may increase the toxicity of acetaminophen Adjustment of medication dosage and schedule must be considered for those drugs with significant hepatic elimination when impaired liver function exists Degradation and Elimination by the Liver Hepatic Regulatory Function Detoxification and catabolism of ammonia, bilirubin, and xenobiotics is essential to life Ammonia arises through bacterial degradation of nitrogenous compounds in the intestine as well as from other physiologic sources, including the kidneys and peripheral tissues, such as skeletal muscle and the brain Ammonia is transported to the liver via the portal vein in high concentrations Ammonia is quickly degraded in the liver to urea High levels of ammonia are incompatible with life; during hepatic failure, hyperammonemia represents a life-threatening aspect of liver disease.51 Bilirubin is derived mainly from hemoglobin degradation; its elimination is a critical excretory function of the liver Smaller amounts are made through the breakdown of cytochromes and myoglobin Heme is broken down into bilirubin in the reticuloendothelial system Hepatic metabolism of bilirubin involves transport to the hepatocyte and cellular uptake, cytosolic transport within the hepatocyte, conjugation, active cellular export, and elimination through stool Impairment at any step results in hyperbilirubinemia and, ultimately, clinical jaundice It may be defined The liver provides major counter-regulation through (1) interconversion of amino acids to maintain physiologic plasma levels, (2) gluconeogenesis to maintain adequate serum levels for glucosedependent tissues, and (3) regulation of numerous plasma hormones The direct secretion of insulin and glucagon into the portal circulation exposes the liver to concentrations up to tenfold greater than peripheral tissues This relationship amplifies the hepatic influence over carbohydrate metabolism Approximately 50% of secreted insulin and a large portion of glucagon is degraded on a first-pass basis by the liver Both of these hormones are known to have hepatotrophic effects and are thought to be important for differentiation and regeneration of hepatocytes Intensive insulin therapy in the critical care setting is believed to have a beneficial effect on liver function.54 Storage Function The last category of hepatic function involves storage of glycogen, triglycerides, folic acid, vitamin B12, and vitamins A and D The 1138 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition liver uses glycogenolysis to mobilize hepatic glycogen stores and provide an almost immediate source of glucose to maintain serum levels The liver glycogen stores provide a 2-day supply of glucose, although these can be depleted rapidly by young infants who become ill and have a decrease in oral nutrition Synthesis of vitamin D3 (cholecalciferol) occurs in the skin with subsequent accumulation of vitamin D3 in the liver Hydroxylation in the 25-position that occurs in the liver results in a large pool of circulating 25-hydroxyvitamin D [25-(OH)D3], the precursor of the active 1,25 dihydroxyvitamin D [1,25-(di OH)D3] Defective storage and absorption of dietary vitamin D and 25-hydroxylation may be present in chronic liver failure.55,56 Host-Defense Mechanisms of the Gut: Immunology and Microbiology Both the intestine and hepatic-based macrophages can serve as a major source of nitric oxide following injury or stimulation and contribute to the GI tract’s role in systemic responses.4,57 The frequent association of hepatic dysfunction with acute respiratory distress syndrome has led to intensive investigation of the lungliver axis during critical illness.58 A major unifying theme in these organ interactions is the regional activation of macrophages and platelets and damage to the endothelium after injury, leading to both localized and remote organ function disturbance The gut has become one of the important focuses in our evolving understanding of the syndrome of multiple-organ dysfunction syndrome (see Chapter 112).2–4 The GI tract is the largest immunologic organ in the body, where 80% of the body’s entire immune system resides.59 As such, the gut is in a constant state of “controlled inflammation,” serving essentially three immunologic functions: (1) to achieve tolerance to commensal microbiota and dietary proteins, (2) to induce destruction and/or elimination of pathogenic organisms and antigens, and (3) to suppress the tendency toward dysplasia in this chronically controlled inflammatory environment While these processes develop from birth to adulthood, the gut also undergoes developmental changes in the microbiome.60 Based on multiple studies, it is clear that the components of the microbiome have effects on the health and disease of the gut immune system as well as the rest of the body61,62 (see also Chapter 107) Gut epithelial apoptosis, intestinal hyperpermeability, and perturbations in the intestinal mucosal layer have all been associated with critical illness.4,57 Immunologic Processing in the Gut When an antigen is presented to the gut, it must survive exposure to several nonimmune protective measures (referred to as innate immunity), including salivary and pancreatic enzymes, low gastric pH, the detergent effect of bile acids, the “housecleaning” function of intestinal peristalsis that sweeps intestinal bacteria through the intestines, and the protective effects of the mucus layer above the epithelium Once antigen reaches the epithelium, dendritic cells “sample” the antigen, process it, and then a response occurs involving either destruction/elimination of the antigen or tolerance of the antigen The cells of the gut-associated lymphoid tissue (GALT) involved in this process are diffusely scattered through the lamina propria, within the epithelium itself, and organized into lymphoid follicles called Peyer patches These lymphoid cells have evolved to form both innate and adaptive immune responses The cellular basis of immunity in the gut depends on the production of mucus by goblet cells, of a-defensins by Paneth cells, and tight junctions preventing penetration by large peptides once gut “closure” occurs.14 Immunoglobulin A (IgA) is produced in response to gut flora binding to bacteria and sweeping them out in the feces Lymphocytes play a central role in the balanced inflammatory response within the intestine and recapitulate patterns of control common to specialized lymphocyte population elsewhere in the body.63,64 In the infant, lymphocytes and antibodies such as IgA in fresh breast milk can confer the mother’s immunologic memory to the naïve infant’s immune system Similarly, intact protein can permeate the epithelium and lead to sensitization to foreign proteins, as is seen in cow’s milk protein sensitivity The intestinal lymphocytes depend on vitamins A and D as well as zinc for generation of T lymphocytes, suggesting the importance of micronutrients in intestinal immune function The intestinal flora, or microbiota, are extremely important for systemic health and are frequently disrupted by the broad-spectrum antibiotics used in critically ill patients.4 A broad array of metabolic reactions is performed by intestinal flora; thus, they are important for a number of hemostasis functions within the GI tract Small bowel bacterial overgrowth is usually caused by disorders that alter the small bowel motility Clinical manifestations include diarrhea, steatorrhea, weight loss, and protein and carbohydrate malabsorption Small bowel bacterial overgrowth is a well-recognized source of chronic diarrhea and morbidity in children.10,65,66 Dysbiosis is a known factor in several common diseases seen in the PICU, including Clostridium difficile colitis, Crohn disease, ulcerative colitis, and necrotizing enterocolitis Use of probiotics has been suggested to augment the intestinal microbiome with some beneficial effects on host immunity and antigen tolerance The continual cross-talk between the GALT and intestinal contents provides a critical feedback mechanism for counter-regulation of the lymphocyte pools.63,67 This area of intestinal immunology is under active investigation, although the importance of the intestinal flora in restoring and maintaining health is now beyond question Evidence for this effect comes from the 90% cure rate for C difficile colitis and improvement in inflammatory bowel disease achieved in the last several years through fecal material transplantation.68,69 In addition, the role of the intestinal bacteria in drug and bile salt metabolism has only become appreciated in recent years.70 The concept of the gut-brain axis as an interaction between the gut and brain has been described as recent studies have shown the effects of the intestinal microbiome with behavioral and psychological conditions such as depression and autism.1 Its implications for the intensivist are less clear than the data on restoring healthy gut flora but may impact a range of issues dealt with in the ICU, including delirium and muscle wasting Bacterial translocation is defined as the migration of bacteria or bacterial products from the intestinal lumen to mesenteric lymph nodes or other extraintestinal organs, representing a disruption of the normal host flora equilibrium that leads to a selfperpetuating inflammatory response and, ultimately, to infection This process is increasingly being recognized as a potential source of pathogens producing bacteremia and sepsis in a variety of premorbid disease conditions, such as cirrhosis and prematurity.71 Translocation may occur directly through the M cells that cover the Peyer patches, or it may occur by ingestion of viable pathogenic material by the mobile phagocytic system with transport into the host, bypassing the previously outlined barrier mechanisms Alteration in intestinal microbiome, host immune defenses, and damage to the microcirculation, such as that seen CHAPTER 94 Gastrointestinal Structure and Function in short bowel syndrome,72 predispose to bacterial translocation Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae appear to be more commonly associated with translocation from the GI tract Kupffer cells in the liver, which account for the largest pool of mononuclear phagocytes with direct access to the blood, play a major role in clearing portal bacteria In addition, Kupffer cells are key participants in the response to tissue injury or organ invasion through the elaboration of cytokine mediators such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) and the release of nitric oxide, leading to many of the systemic responses seen in sepsis Through their intimate proximity to the hepatocyte, Kupffer cells interact directly with hepatocytes by means of cellcell and paracrine interactions In response to TNF and IL-1, well-documented alterations in hepatic function—known as the acute phase reaction—occur, including the inhibition of albumin synthesis, gluconeogenesis, and P450–mediated detoxification Gastrointestinal and Hepatobiliary Testing in the Intensive Care Unit Diagnostic testing in the ICU permits the identification of organ system injury and dysfunction It also assists in monitoring the course of a disease and its response to therapies Laboratory testing is helpful in detecting and monitoring hepatocellular injury and dysfunction In the ICU setting, impaired synthetic function is the hallmark of liver failure This is of more immediate concern than hepatocellular injury alone Decreased synthesis of the liverdependent clotting factors I (fibrinogen), II (prothrombin), V, VII, IX, and X results in a prolonged prothrombin time In the absence of vitamin K deficiency or related inhibitors, this represents liver failure Since factor VII has the shortest half-life (2–6 hours) compared with the other factors, it acts as the ratelimiting step for conversion of prothrombin to thrombin The use of recombinant activated factor VII in acute liver failure remains under debate.73 Other less specific measures of liver dysfunction include increased bilirubin, decreased serum albumin, and decreased prealbumin Liver failure may also be associated with life-threatening hypoglycemia due to decreased hepatic synthesis and release of glucose, hyperinsulinemia from impaired hepatic degradation, and increased glucose utilization secondary to anaerobic metabolism Plasma ammonia is frequently elevated resulting from urea cycle defects, portal systemic shunting, and events such as GI bleeding that lead to increased ammonia production by enteric bacteria Liver disease can be broadly categorized into hepatocellular, cholestatic, and infiltrative processes The biochemical tests commonly used to detect cholestasis, which is impaired bile flow, and hepatocellular injury are serum bilirubin and aminotransferase activities (alanine transaminase [ALT], aspartate transaminase [AST]; see eTable 94.2) Cholestasis, reduced bile excretion or transport, and biliary obstruction in the bile canaliculi or large ducts are represented by elevations in serum conjugated bilirubin, bile acids, alkaline phosphatase (ALK), g-glutamyltransferase (GGT), or 59-nucleotidase (5-NT) The van den Bergh reaction assesses conjugated (direct) bilirubin levels The unconjugated (indirect) fraction represents the difference between the total bilirubin and direct fraction Elevated levels of indirect bilirubin result from (1) increased bilirubin load to the liver (e.g., hemolysis), (2) diminished uptake and intracellular transport, and (3) reduced conjugation (e.g., immaturity, fulminant necrosis) 1139 In children, elevations in ALK may be seen with rickets or during periods of rapid skeletal growth Isoenzymes of ALK may distinguish between liver or bony sources Alanine transaminase (ALT or SGPT) and aspartate transaminase (AST or SGOT) are hepatic cytosolic enzymes that catalyze the reversible transfer of the a-amino group of the amino acids alanine and aspartic acid to the a-keto group of a-ketoglutaric acid producing pyruvic and oxaloacetic acids, respectively, plus glutamate Elevations in serum activities of ALT and AST suggest hepatocellular injury (see eTable 94.2) AST is also present in myocardial tissue, skeletal muscle, the kidney, the pancreas, and erythrocytes Therefore, increased AST is not specific for hepatocellular injury ALT is present in only relatively low concentrations in tissues other than liver, providing greater specificity for hepatocellular injury than AST Falling levels of AST and ALT in the setting of rising levels of conjugated bilirubin and ammonia represent increased destruction of hepatocytes rather than recovery Elevated serum lactate dehydrogenase (LDH) activity lacks specificity and may be seen in association with hepatocellular injury, hemolysis, and myopathy However, when in association with elevated serum creatine phosphokinase (CPK) or aldolase, elevated LDH indicates myopathy or a rhabdomyolysis Imaging of the hepatobiliary system has become easier, safer, and more reliable in the last decade Ultrasonography is particularly useful in the ICU and allows rapid, safe bedside evaluation of (1) hepatic vascular structures and patterns of blood flow; (2) structural abnormalities, such as tumors, abscess, hematoma, or dilated intrahepatic bile ducts; (3) the gallbladder, extrahepatic, pancreatic, and common biliary system; (4) the pancreas; (5) the genitourinary system; and (6) the abdomen and retroperitoneum In addition, ultrasound can provide guidance for therapeutic interventions such as drainage of abscesses CT scanning with and without contrast has become the diagnostic procedure of choice for evaluating the abdomen following trauma and in the ICU MRI provides an additional method for evaluating the abdominal and retroperitoneal organs for masses, abscesses, and fluid collections as well as vascular structures when contrast is administered A downside to both modalities is that they usually require a prolonged period away from the ICU, although rapid-sequence CT and MRI procedures have reduced acquisition time for unstable patients Many of the radioisotope studies can be performed in the ICU when a portable scintillation camera is available Technetium99m (99mTc) iminodiacetic acid (IDA) compounds are handled by the hepatobiliary system much like bilirubin, providing a qualitative and semiquantitative image of function and structure These compounds may be used diagnostically to evaluate infants with persistent jaundice Of the available biochemical markers of pancreatic disease, serum amylase and lipase determinations are the most widely available Serum lipase is elevated in about 87% of patients with acute pancreatitis and demonstrates fewer false-positive results than amylase testing Transient hypocalcemia (,8.0 mg/dL) occurs in about 30% of patients with pancreatitis Mild to moderate hyperglycemia as a result of islet cell damage is seen in up to 25% of cases, often necessitating the administration of exogenous insulin Hematologic evaluation of the alimentary tract consists of examining gastric aspirates and stool samples for gross bleeding or occult blood with the guaiac test (Hemoccult) A positive result mandates further evaluation and surveillance to determine the source and severity of GI tract blood loss Nasogastric lavage may be used to distinguish a source of bleeding as being proximal or 1140 S E C T I O N X Pediatric Critical Care: Gastroenterology and Nutrition distal to the pylorus CT angiography, 99mTc sulfur colloid or red blood cells labeled with 99mTc may provide information regarding the site of active mucosal bleeding and are less invasive than arteriography Esophageal pH monitoring is useful for evaluating the efficacy of antisecretory therapy It may be useful to correlate symptoms (e.g., cough, chest pain) with acid reflux episodes and to select those infants and children with wheezing or respiratory symptoms in whom gastroesophageal reflux (GER) is an aggravating factor The sensitivity, specificity, and clinical utility of pH monitoring for diagnosis and management of possible extraesophageal complications of GER are not well established.74 Imaging studies are of primary importance in acutely ill patients in a number of circumstances Plain radiographs can be reliably used to locate radio-opaque objects and to diagnose intestinal ileus, mechanical obstruction, and perforated viscus Contrast studies are required to diagnose organ and soft-tissue inflammation, including appendicitis, pancreatitis and its complications, mesenteric and retroperitoneal masses, abscesses/fluid collections, intussusceptions, and anatomic anomalies GI bleeding from sites distal to the ligament of Treitz and proximal to the terminal ileum are relatively inaccessible to video endoscopy Meckel diverticulum, vascular malformations, and altered anatomy following GI surgery are best assessed using radionuclide scans and angiography Because of the need to perform the more sophisticated imaging studies away from the controlled environment of the ICU, the studies must be tailored to the patient’s diagnostic needs according to the priorities of the initial stabilization of life-threatening illness and subsequent treatment of the underlying pathologic condition Common causes of bleeding in ICU patients can be due to hemorrhagic gastritis, gastric or duodenal ulcers, or vascular abnormalities such as Dieulafoy lesions GI endoscopy in the hands of specialists skilled in managing small children has found a place in ICU management to diagnose and treat the source of upper GI tract bleeding, to control bleeding varices, to place percutaneous gastrostomy tubes for feeding, and for the placement of stents to maintain patency of the distal biliary and pancreatic tract Deep enteroscopy via the single- or double-balloon method has demonstrated utility for evaluation of bleeding of the small intestine A summary of diagnostic approaches to hepatobiliary pathophysiology is provided in eTable 94.3 Key References Chan FK, Kyaw M, Tanigawa T, et al Similar efficacy of proton-pump inhibitors vs H2-receptor antagonists in reducing risk of upper gastrointestinal bleeding or ulcers in high-risk users of low-dose aspirin Gastroenterology 2017;152(1):105-110.e1 Lane ER, Hsu EK, Murray KF Management of ascites in children Expert Rev Gastroenterol Hepatol 2015;9(10):1281-1292 Rosen R, Vandenplas Y, Singendonk M, et al Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition J Pediatr Gastroenterol Nutr 2018; 66(3):516-554 Wahbeh G, Christie D Basic aspects of digestion and absorption In: Wyllie R, Hyams J, Kay M, eds Pediatric Gastrointestinal and Liver Disease Philadelphia: Elsevier; 2016:10-21 Wischmeyer PE, McDonald D, Knight R Role of the microbiome, probiotics, and ‘dysbiosis therapy’ in critical illness Curr Opin Crit Care 2016;22(4):347-353 The full reference list for this chapter is available at ExpertConsult.com 1140.e1 eTABLE Diagnosis of Selected Hepatobiliary Disorders 94.3 Form of Liver Injury Supportive History/Laboratory Data Predominantly Hepatocellular Viral hepatitis Viral serologies: Hepatitis A, B, C, E, EBV, CMV, VZV, HSV Drug-induced hepatitis History of toxic/excess ingestion, elevated eosinophil count Ischemia Shock, postcardiac surgery Autoimmune hepatitis Increased globulin ratio, antinuclear antibody, anti–smooth muscle antibody, anti–liver kidney microsomal antibody Wilson disease Serum ceruloplasmin, 24-hour urine copper a-Antitrypsin deficiency a1-antitrypsin phenotype Cholestatic Bacterial sepsis Proteus, Escherichia coli urinary tract infection Galactosemia Urine-reducing substances, E coli sepsis, red blood cell galactose1-phosphate uridyltransferase Tyrosinemia Urine succinylacetone Biliary atresia Intraoperative cholangiogram Anatomic anomalies: choledochal cysts, biliary stricture, cholelithiasis, congenital hepatic fibrosis, Caroli disease Ultrasonography, cholangiogram Alagille syndrome Butterfly vertebrae, posterior embryotoxin on eye examination, echocardiogram Cystic fibrosis Sweat test, genetic testing Graft-versus-host disease, veno-occlusive disease History of bone marrow transplant, high-dose busulfan Ischemia ECMO Infiltrative Hepatocellular carcinoma, hepatoblastoma a-fetoprotein Predominantly Coagulopathy Neonatal hematochromatosis Serum iron and ferritin CMV, Cytomegalovirus; EBV, Epstein Barr virus; ECMO, extracorporeal membrane oxygenation; HSV, herpes simplex virus; a1-antitrypsin phenotype; VZV, varicella zoster virus ... cells of the gut-associated lymphoid tissue (GALT) involved in this process are diffusely scattered through the lamina propria, within the epithelium itself, and organized into lymphoid follicles... pools.63,67 This area of intestinal immunology is under active investigation, although the importance of the intestinal flora in restoring and maintaining health is now beyond question Evidence for this... sweeping them out in the feces Lymphocytes play a central role in the balanced inflammatory response within the intestine and recapitulate patterns of control common to specialized lymphocyte population