To compare the incidence of hospitalization for upper gastrointestinal bleeding in patients using individual anticoagulants with and without PPI cotherapy and to determine variation according to underlying gastrointestinal bleeding risk, a retrospective cohort study in Medicare beneficiaries was carried out between January 1, 2011 and September 30, 2015. The agents studied included apixaban, dabigatran, rivaroxaban, or warfarin, with or without PPI cotherapy.
Misoprostol and Aspirin-Induced Small Bowel Bleeding
A double-blind, randomized, placebo-controlled trial was carried out to determine whether misoprostol can heal small bowel ulcers in patients with small bowel bleeding who require continuous aspirin therapy. The study was prospective among 84 aspirin users who required continued aspirin therapy in Hong Kong and Japan.
Antibiotic Resistance in H. Pylori Infection
A systematic review and meta-analysis was carried out to assess the distribution of H. pylori resistance to commonly used antibiotics and to measure the association between antibiotic resistance and treatment failure.
Diverticular Hemorrhage and Anticoagulants
To analyze the incidence of and risk factors for recurrent diverticular hemorrhage and to determine whether discontinuing anticoagulation after diverticular hemorrhage is associated with ischemic stroke, a retrospective cohort study of patients enrolled in the OptumInsight Clinformatics database from 2000 to 2016 was carried out. Incidence rate for initial and recurrent diverticular hemorrhage was calculated by identifying patients who had hospitalizations with a primary discharge diagnosis consistent with diverticular hemorrhage.
BMI, Diabetes, and Cholangiocarcinoma Risk
Obesity and diabetes are associated with an increased liver cancer risk. To evaluate their relationship with intrahepatic cholangiocarcinoma (ICC), the second most common cause of liver cancer, a pooled analysis was conducted with a systemic review/meta-analysis of the literature. The liver cancer pooling project was a consortium of 13 U.S. based, prospective cohort studies with data from 1,541,143 individuals (ICC cases, N = 414). In this systematic review, 14 additional studies were identified and a meta-analysis was carried out, combining the results from LCCP with the results from the 5 prospective studies identified through September 2017.
Pattern of Alcoholic Consumption and Liver Fibrosis
To determine whether quantity, binge pattern consumption or type of alcohol was associated with liver fibrosis in patients with NAFLD, previous and current alcohol consumption was assessed in NAFLD patients undergoing liver biopsy. All subjects currently consumed less than 210 grams per week (male), or less than 140 grams per week (female). Binge consumption was defined as greater than 4 standard drinks (female), or greater than five standard drinks (male), in one sitting. Liver biopsies were scored according to the NASH CRN system with F3/4 fibrosis defined as advanced.
Among the 187 patients (24% with advanced fibrosis), the median weekly alcohol consumption was 20 (2.3-60)g over an average of 18 years. Modest consumption (1-70 g per week), was associated with lower mean fibrosis stage compared to lifetime abstainers and a decreased risk of advanced fibrosis (OR 0.33). The association with reduced fibrosis was not seen in subjects drinking in a binge-type fashion. Exclusive wine drinkers, but not exclusive beer drinkers, had lower mean fibrosis stage and lower odds of advanced fibrosis (OR 0.20), compared to lifetime abstinent subjects. No interaction between gender and alcohol quantity, type, or binge consumption on fibrosis was observed.
It was concluded that modest alcohol consumption, particularly wine in a non-binge pattern is associated with lower fibrosis in patients with NAFLD. Prospective longitudinal studies into fibrosis progression, cardiovascular outcomes and mortality are required before clinical recommendation can be made.
Mitchell, C., Jeffrey, G., Boer, B., et al. “Type and Pattern of Alcohol Consumption Liver Fibrosis in Patients with Non-Alcoholic Fatty Liver Disease.” American Journal of Gastroenterology; Vol. 113, pp. 1484-1493
Digestive Disease Interventions, 1st Edition
John PohlEditor: Baljendra S. Kapoor and Jonathan M. Lorenz
Publisher: Thieme Medical Publishers, 2018
ISBN-13: 978-1626233744
Hardcover Price: $82.99 (also available in eBook) Pages: 322
Digestive Disease Interventions, 1st Edition, edited by Kapoor and Lorenz, is co-authored by a diverse group of experts in interventional radiology (IR), gastroenterology, and surgery whose aim is to provide a comprehensive review of the management and treatment of gastrointestinal disorders with an emphasis on image-guided gastrointestinal interventions.
This book is divided into 30 chapters. An introductory chapter discusses the application of cutting-edge technology, such as cone-beam CT (CBCT), to revolutionize the delivery of transarterial liver-directed therapy. The remaining chapters cover a wide array of gastrointestinal diseases and their interventions including portal hypertension managed by transjugular intrahepatic portosystemic shunt (TIPS) and balloon retrograde transvenous obliteration (BRTO), nonvariceal upper and lower gastrointestinal hemorrhage, mesenteric ischemia, biliary strictures, malignant obstructive jaundice, acute cholecystitis, cholelithiasis, choledocholithiasis, liver and pancreatic cancer, islet cell transplantation, bariatric embolization, and pediatric gastrointestinal interventions.
The structure of each chapter is straightforward with logical progression. Chapters focus on a specific pathology such as portal hypertension, typically beginning with foundational knowledge on anatomy and pathophysiology followed by discussion on clinical patient evaluation including risk factors, complications, and treatment options associated with a disease. Chapters detailing specific interventions, such as TIPS, cover pertinent aspects from a procedural standpoint— the indications, contraindications, procedural steps, and complications. Each chapter ends with a summary of the material followed by a list of references. Supplemental material is appropriately inserted within the text of each chapter. Charts, figures, and graphs provide a consolidated overview of the text and highlight treatment algorithms and any landmark trials or current studies of significant impact. Images are vast, ranging from cartoon renditions of anatomy to diagnostic procedural X-ray, magnetic resonance, and computed tomography images.
This text is thorough and written with great detail. The comprehensive nature of each chapter could not be applauded enough and will benefit IR trainees greatly. The book provides readers with a global picture of how to diagnose, manage, and treat patients with a particular gastrointestinal disorder. Further, the text does a nice job detailing the key knowledge base necessary for understanding and performing image-guided gastrointestinal interventions. Thinking ahead to subsequent editions of this book, a section highlighting key points within each chapter may benefit readers. In addition, a supplemental book that provides clinical scenarios and practice questions may complement this book greatly, allowing trainees to apply the comprehensive understanding of the content.
In summary, this book covers a broad range of topics and affords a detailed review of a wide array of gastrointestinal pathology, ranging from common everyday encounters to more complex, rare pathologies. It brings light to a rapidly expanding and promising sector of medicine whereby IR play a major role. With the paradigm shift transitioning IR physicians from consult proceduralists to clinical specialists, this book fosters this notion by providing IR trainees with a wide clinical knowledge base specifically relevant to gastrointestinal diseases. Practitioners outside the realm of IR may also benefit from this book by understanding how interventionalists work in concert with their colleagues to manage and treat patients with a broad range of complex gastrointestinal disorders.
Jeff Wang, B.S. Chicago Medical School at Rosalind Franklin University North Chicago, Illinois
Ravi N. Srinivasa, M.D. Associate Professor of Clinical Radiology Ronald Reagan UCLA Medical Center Los Angeles, CA
John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology
A Case Report
Spontaneous Pancreaticoduodenal Fistula:An Uncommon Case of Severe GI Bleeding
Spontaneous upper gastrointestinal (GI) tract fistulas are an uncommon occurrence that may present with fever, nausea, and vomiting. We describe a spontaneous pancreaticoduodenal fistula presenting with large-volume hematemesis requiring transfusions and emergency esophagogastroduodenoscopy (EGD) in a patient with acute on chronic pancreatitis in the setting of alcoholism and cirrhosis. Computed tomography (CT) imaging and endoscopic retrograde cholangiopancreatography (ERCP) demonstrated pseudocyst decompression and vascular compromise secondary to the formation of the fistula. Conservative management, rather than surgical ligation of the fistula, allowed full recovery.
1Jonathan Schmidt, BS 1,2Shiqing Yan, MD2 Christopher Magiera, MD 1Indiana University School of Medicine, Indianapolis, IN 2IU Health Arnett Hospital Lafayette, IN
INTRODUCTION
Pancreatic fistulas are a well-described phenomenon, particularly following surgical procedures involving disruption of the pancreatic parenchyma.1 However, spontaneous pancreatic fistulas are rare, occurring most commonly in the setting of pseudocyst formation secondary to necrotizing pancreatitis in patients with alcoholism. When spontaneous fistulization occurs, pain is typically partially relieved, though upper gastrointestinal (GI) fistula can be associated with new onset vomiting, diarrhea, and fever.2,3,4
Typical management of upper GI fistula formation is conservative, with medical therapy resulting in closure of approximately 80% of fistulas. Octreotide therapy has been shown to reduce fistula output resulting in accelerated closure of the aberrant connection in some cases. When intervention is required, endoscopic retrograde cholangiopancreatography (ERCP) can be used to stent the sphincter of Oddi providing an alternative, low-resistance pathway and facilitating fistula closure.5 Surgical ligation of the fistula is an acceptable intervention in refractory cases.
In addition to fistula formation, a number of vascular adverse events have been observed in the setting of chronic pancreatitis, with an incidence of 7-10% and mortality as high as 34-52%. Direct vascular injuries, while uncommon, can result in rapid blood loss and clinical decline. Pseudoaneurysm and arterial rupture can occur secondary to the leakage of exocrine pancreatic secretions, which weaken the vessel wall. This vascular compromise may result in any combination of hematoma or intraperitoneal, retroperitoneal, or intraluminal bleeding. Treatment involves establishing vascular control via endovascular, endoscopic, or surgical modalities, and the treatment option depends on hemodynamic stability, coagulation status, and vascular accessibility.6
Case Report
A 53 year-old man with a history of acute on chronic pancreatitis, cirrhosis, alcoholism, gallstones, and a 40 pack-year smoking history presented with acute abdominal pain in the epigastric region radiating to the back. While he experienced chronic epigastric pain that varied in intensity, he noted that this pain was substantially more severe than usual. He described four episodes of large-volume hematemesis and one episode of bright red blood per rectum occurring within 12 hours preceding presentation to the ED. He had no history of prior abdominal surgery. Physical exam findings included pallor and fatigue.
At admission, vital signs showed temperature of 36.9 °C, blood pressure of 99/68, heart rate of 117, respiratory rate of 18 br/min, and oxygen saturation of 100%. He was found to have prominent leukocytosis (18.4 k/cumm) and a hemoglobin of 9.7 g/dL, decreased from 14.8 g/dL two months earlier. Lipase levels were elevated at 139 units/L. BUN was elevated at 36 mg/dL. Analgesics, intravenous (IV) octreotide, and an IV proton pump inhibitor (PPI) were administered.
CT scan demonstrated interval decompression of a primary cystic lesion (Figure 1), now 2.4 cm in diameter (3.5 cm two months prior), in the head of the pancreas exerting a mass effect on the second portion of the duodenum (Figure 2). The clinical impression was that of a pancreatic pseudocyst.
Due to continued anemia (Hgb 6.8 g/dL), the patient received two units of packed red blood cells (RBCs) and emergent esophagogastroduodenoscopy (EGD). The EGD revealed no evidence of esophageal or gastric varices, peptic ulcers or blood in the stomach. A large fistula was noted in the first portion of the duodenum (Figure 3). An ulcerated lesion involving a compromised blood vessel was observed on the border of the fistula, and two clips were successfully applied. The remainder of the duodenum was normal. An additional unit of packed RBCs was required to stabilize the patient.Subsequent physical examinations following the procedure demonstrated severe epigastric pain that slowly abated over the course of hospitalization. No additional hematemesis or frank hematochezia was documented, and the patient’s hemoglobin stabilized at 9.4 g/dL. Repeat abdominal CT four days later demonstrated no significant change in the pseudocyst diameter. Once the patient’s diet was advanced, he was discharged after resolution of his acute pain.
Discussion and Conclusion
This case represents both an unusual pathology and presentation of pancreatoenteric fistula, a rare disease occurring in less than 5% of patients with acute pancreatitis.2 Spontaneous fistulization into the duodenum has been reported by several authors, though symptoms have more commonly included pain, fever, nausea, and vomiting rather than bright red hematemesis.2,3,4 Colonic fistulization resulting in hematemesis has also been reported, and its proclivity for severe hemorrhage documented, though these cases are often associated with hematochezia and melena rather than large-volume, bright red hematemesis.2,3A broad differential diagnosis should be considered when evaluating patients with inflammatory abdominal disease. EGD may have therapeutic value in some instances, notably for the debridement of necrotic tissue and stent placement in other instances of pancreatoenteric fistulas.2 Most importantly, the case raises a dilemma regarding management, as this patient presented with a large-volume bleeding and hemodynamic instability analogous to the vascular compromise typically seen in colonic fistulization. Management of duodenal fistulas is traditionally conservative, while colonic fistulas often require surgical intervention.2,3 After application of Resolution clips to achieve hemostasis, conservative management was employed with careful monitoring of symptoms and hemoglobin levels. This facilitated symptomatic relief via continued drainage of the pancreatic fluid collection and allowed for the avoidance of an invasive procedure in a patient with multiple surgical risk factors.
In summary, this patient presented with an episode of pain consistent with acute on chronic pancreatitis in the setting of gallstones, liver disease, alcoholism, and tobacco use. However, this pain was complicated by the presence of large-volume hematemesis. A combination of CT and EGD images strongly suggested fistula formation, which not only resulted in pseudocyst drainage, but, in addition, also resulted in significant upper gastrointestinal hemorrhage due to vascular involvement. This case reaffirms the versatility of EGD in diagnostic and therapeutic interventions for pancreatitis, and demonstrates how conservative management of pancreaticoduodenal fistulas may be appropriate even in the setting of significant vascular compromise.
Liver Disorders, Series #9
Analysis and Interpretation of Classic Liver Enzymes
Archana Kulkarni
Mrinal Garg
Rad M. Agrawal
Michael BabichSymptoms and signs of liver disease are often seen late in the disease. As a result laboratory testing helps in identifying and characterizing liver disease. For the purposes of this article, the liver chemistries that will be focused on will be bilirubin, alkaline phosphatase, aminotransferases and gamma-glutamyl transferase. In addition, albumin and prothrombin time will be discussed briefly. Following discussion of these tests, this article will focus on different patterns of abnormalities that relate to different disease processes.
Archana Kulkarni, MD1 Mrinal Garg, MD2 Rad M. Agrawal, MD3 Michael Babich, MD4 1Department of Internal Medicine 2Division of Gastroenterology, Department of Internal Medicine 3Professor Emeritus, Division of Gastroenterology, Department of Internal Medicine 4Associate Professor of Medicine, Division of Gastroenterology, Department of Internal Medicine, Allegheny General Hospital, Pittsburgh, PA
INTRODUCTION
Accessibility, ease of collection, and relatively low cost give serum chemistries an integral initial role in medical diagnosis. With the liver being a critical organ in the metabolism of carbohydrates, lipids and proteins as well as in first pass metabolism of exogenous medications, a great deal can be learned about hepatobiliary processes by having an appropriate grasp of specific liver chemistry tests. Liver enzymes are also commonly ordered for evaluation of other non-hepatic diagnoses and as part of health screening, which makes it imperative for all primary care physicians and specialists to have an accurate understanding of their normal values and an ability to interpret abnormal levels. Symptoms and signs of liver disease are often seen late in the disease. As a result laboratory testing helps in identifying and characterizing liver disease.
The term “liver function tests” is a misnomer, as many of these tests do not naturally reflect hepatobiliary function and are rather used as a determinant of liver injury. Furthermore, the origin of these tests may not be specific to the liver and, as such, abnormal results may be related to alternative organ injury. It is vital to use these test results in the context of patient history and physical examination in order to form an accurate diagnosis. For the purposes of this article, the liver chemistries that will be focused on will be bilirubin, alkaline phosphatase, aminotransferases and gamma-glutamyl transferase. In addition, albumin and prothrombin time will be discussed briefly. It will also provide a reference of normal laboratory values for an average adult male of individual tests based on information provided by the Mayo Clinic. Furthermore, as clinicians will be ordering these tests on a routine basis, the cost is relevant and Medicare pricing guidelines will be provided for each laboratory test. Following discussion of these tests individually, this article will focus on different patterns of abnormalities that relate to different disease processes.
Bilirubin
Bilirubin is a product of the digestion of hemoglobin. During the catabolism of erythrocytes, an initial unconjugated or “indirect” form of bilirubin is released into the reticuloendothelial system. As unconjugated bilirubin is water insoluble, it binds with albumin and is transported to the liver. Unconjugated bilirubin exists in majority as a component of total bilirubin when compared to direct bilirubin. In the liver, the unconjugated bilirubin enters the hepatocyte and is conjugated with glucuronic acid by the enzyme UDP-glucuronyltransferase (UGT), rendering it water soluble.1 This conversion process, from the unconjugated form to “direct”, or conjugated, form allows bilirubin to be transported through the canalicular membrane, mix with other components of bile within the biliary tree, and flow into the duodenum.2,3,4 In the duodenum, part of the direct bilirubin is reabsorbed while the rest is converted to urobilinogen by intestinal flora and excreted in the urine and stool. In addition, there is also a delta bilirubin, which can also be referred to as biliprotein, which is produced by reaction of conjugated bilirubin with albumin.5 It is important to note that the half-life of this product is about 17-20 days (the same as albumin) accounting for prolonged jaundice in patients recovering from hepatitis or obstruction.6 The total bilirubin, which is a measure of both direct and indirect forms, has a normal reference range of 0.1-1.0 mg/dL.
Historically, in order to determine the serum levels of the two types of bilirubin, laboratories utilized the technique developed through the van den Bergh diazo reaction,7 which was able to separate water soluble conjugated bilirubin from unconjugated bilirubin for individual measurement. The accuracy of the direct bilirubin levels increased as the total bilirubin rose. The direct, or conjugated, bilirubin reference range is 0.0-0.3 mg/dL in a normal individual and should be no more than 20% of the total bilirubin when the total bilirubin is elevated due to non-hepatic causes, such as hemolysis or congestive heart failure. The indirect or unconjugated bilirubin is obtained by subtracting the direct bilirubin level from the total bilirubin.
Identifying the subtype of bilirubin, which is elevated, allows for accurate diagnosis when analyzing bilirubin levels. Isolated elevation of unconjugated bilirubin occurs mainly secondary to increased bilirubin production, decreased hepatic uptake and decreased bilirubin conjugation. Elevated levels of unsuccessful erythrocyte production, hemolysis, or reabsorption of large hematomas may lead to increased unconjugated bilirubin levels. Fulminant Wilson’s disease can cause isolated elevation in unconjugated bilirubin secondary to the release of copper in the blood resulting in cellular lysis 8 Unsuccessful erythrocyte production exists in the setting of rapid heme and hemoglobin turnover in the bone marrow due to premature destruction of red blood cells. There exists evidence that in these conditions there is also presence of erythroid hyperplasia of bone marrow, reticulocytosis, increased iron turnover with diminished red blood cell incorporation, and hemosiderosis of hepatic parenchymal cells and Kupffer cells. However, why this occurs in the bone marrow is not known.8
Isolated elevation of unconjugated bilirubin also may be due to genetically inadequate UGT production preventing conjugation in disease processes such as Gilbert’s syndrome and Crigler-Najjar disease.9 Gilbert’s syndrome is a commonly seen disorder, which is relatively benign. The hyperbilirubinemia in Gilbert’s syndrome is exacerbated with fasting.10 Elevated conjugated bilirubin can be caused secondary to inherited or acquired conditions. Genetic disease processes such as Dubin-Johnson and Rotor syndrome cause an impaired hepatocellular secretion of bilirubin into the bile canaliculus causing elevated conjugated bilirubin.11,12 As the anatomy suggests, elevations in conjugated bilirubin can occur secondary to hepatocellular dysfunction and cholestatic processes, which impair bile, flow. It has been found that despite the loss of liver function in hepatocellular disease processes, such as cirrhosis, UGT is produced at an increased rate in the remaining functioning hepatocytes forming conjugated bilirubin, such that increase in total bilirubin may not occur until late in the course of disease.13,14 Cholestasis can occur either because of impaired secretion into a bile canaliculus or impaired transit through the biliary tree and into the duodenum. Some of the causes of intra hepatic cholestasis are drug toxicity, primary biliary cirrhosis, primary sclerosing cholangitis, viral hepatitis, cholestasis of pregnancy, benign postoperative cholestasis, infiltrative liver diseases, sepsis and total parenteral nutrition. Certain causes of extra hepatic cholestasis are choledolithiasis, malignant obstruction secondary to a mass in the pancreas, bile duct, gall bladder or ampulla, primary sclerosing cholangitis with an extra hepatic bile duct stricture, chronic pancreatitis and AIDS cholangiopathy.
Alkaline Phosphatase and gamma-glutamyltansferase
Alkaline phosphatase (ALP) is a zinc metalloenzyme and can be found in many different tissues, with most clinical relevance due to production in the bone, intestine, kidney or liver, and with more than 80% of serum ALP originating from bone or liver.15 The average serum level of ALP in a normal adult male is 45 to 115 U/L. There are certain physiological causes that lead to increased alkaline phosphatase, examples being the during the third trimester of pregnancy secondary to the influx of alkaline phosphatate from the placenta, in adolescents secondary to increase in bone turnover, or some individuals with an increased production of intestinal alkaline phosphatase which is familial and benign.10 Although it is generally ordered as part of routine liver chemistry, ALP abnormalities should be evaluated within the framework of hepatobiliary vs non-hepatobiliary diseases. In the liver, ALP is present in the hepatocytes on the cannalicular membrane, but is localized to the microvilli of the bile canaliculus, and elevated levels typically reflect a cholestatic disease process. The half life of ALP is one week and, as a result, even after the cholestatic process has resolved, the normalization of the ALP level may lag. In order to distinguish whether an isolated elevation of ALP is of hepatic origin, one could order ALP isozymes, which fractionate the total ALP into its tissues of origin. Alternatively, confirmation via a gamma-glutamyltransferase (GGT) level can be performed since GGT is more concentrated in hepatic tissue1 and is not present in bone. A concurrent elevation of ALP and GGT excludes a boney origin of the enzyme. It is important to note that initially the only notable abnormality that may be seen in infiltrative diseases such as primary biliary cirrhosis, sarcoidosis, primary sclerosing cholangitis, etc. is isolated elevations in ALP.1 Elevation in ALP is typically seen for duration of more than six months in these conditions. These cases normally require follow up with imaging or liver biopsy. ALP can also interestingly be raised in various neoplasms, which do not involve the bone or liver directly. This occurs secondary to an isozyme of ALP called the ‘Regan isoenzyme’.17
GGT is an enzyme primarily located in hepatocytes, epithelial lining of biliary ducts, pancreas, renal tubules and the intestine. The normal GGT level in adult male ranges from 9 to 48 U/L. GGT levels may be elevated in a large variety of common diseases such as diabetes, hyperthyroidism, pancreatitis, alcoholism, COPD and rheumatoid arthritis and also as a result of various medications like coumadin, carbamazepine, phenytoin, and barbiturates. Hence the specificity for liver disease is poor. Isolated GGT elevation may be seen in alcohol abuse. Note, however, the degree of GGT elevation does not directly correlate with the amount of alcohol consumed.11
Aminotransferases – Alanine aminotransferase (ALT) & Aspartate aminotransferase (AST)
In 1955, serum AST and ALT elevations were first noted in patients with known viral hepatitis and other hepatic specific diseases.18 Aminotransferases are so named as their enzymatic function is to transfer amino groups to form pyruvate via AST and form oxaloacetate via ALT. While present in several tissues including skeletal and cardiac muscle and erythrocytes, clinically relevant elevations are usually reflective of liver disease, especially with respect to ALT elevations, isolated elevations of which should be assumed to reflect liver disease until proven otherwise. Their location within the hepatocyte is imperative to understanding the elevation patterns seen in various liver diseases. AST has two isoenzyme forms, with 80% operating as a mitochondrial isoenzyme; however, most of the circulating serum AST is derived from the cytoplasmic isoenzyme.19 Conversely, ALT is found only in the cytosol and is more specific to liver tissue. This makes an elevated ALT more specific for hepatocellular injury than AST. Elevated ALT levels however have also been noted in myopathic diseases.20
When determining a laboratory range for aminotransferases, important characteristics must be considered. Interestingly, as body mass index (BMI) increases, so does ALT; ALT is also higher in males relative to females. It is worth noting as well that AST levels may be 215% higher in African-American males.21 As ALT has more specificity for hepatocellular injury, cutoff values are important to ensure proper inclusion of patients with liver disease and elevated aminotransferases without unnecessary evaluation of patients with potentially normal levels.22 For the purposes of this article, we use a reference range for ALT as 7 to 55 U/L and AST as 8 to 48 U/L, with an understanding that a wide upper limit variability exists across different laboratories likely related to different reference standards.23 The magnitude of transaminase elevation relative to the upper limit of normal may help to narrow down the differential diagnosis for the cause of hepatocellular injury. Specifically, aminotransferase levels that are 15x or more the upper limit of normal deserve to be considered separately from mild or moderate elevations.13 Also to further classify pathologies, it is important to consider the ratio of ALT to AST.
Albumin
Albumin is a plasma protein produced solely in the liver, with a half-life of three weeks.24 As a result, a decrease in the albumin level compared to normal (<3.5 g/L) signifies a liver disease which has been occurring for greater than three weeks. Albumin level can be influenced by other factors such as the nutritional status, catabolism, hormonal factors, and urinary and gastrointestinal losses. As a result, these factors should be taken into consideration when interpreting albumin levels. In conclusion albumin is useful to interpret chronic and progressive liver disease and is also used to predict the prognosis of liver disease.
Prothrombin Time (PT)
All coagulation factors are produced in the liver. Factor VIII is produced in endothelial cells outside the liver in addition to being produced by the sinusoidal cells in the liver. The rate of conversion of prothrombin to thrombin requiring factors II, V, VII, X and fibrinogen is the measurement of prothrombin time (PT), thus a function of the liver. Prothrombin time can be prolonged even in a severe liver disease of < 24 hours secondary to the half life of most factors being equal to or less than 24 hours.2 It should also be noted that vitamin K is required in the production of factors II, VII IX and X. As a result, vitamin K deficiency can also cause prolonged prothrombin time. Some other factors that should be considered in cases of prolonged prothrombin time are warfarin therapy, disseminated intravascular coagulation (DIC), hypothermia and steatorrhea.
International Normalized Ratio (INR)
In order to avoid variability in laboratory values, international normalized ratio (INR) is more commonly tested instead of or in place of PT. The results are interpreted in the same way as PT would be interpreted. It is calculated according to a formula as follows: International normalized ratio = [patient PT/mean control PT] ISI (ISI = international sensitivity index).
Patterns Of The Liver Function Tests
Once a general understanding of each individual liver enzyme has been achieved, clinicians can then use the liver enzyme panel to begin recognizing patterns. Each test is important to understand; however the elevation of each in relation to the other parts of the panel is what is most useful in interpreting disease processes. In this section we will describe the different liver enzyme patterns and their associated disease processes.
The liver enzyme panel abnormalities can be broken down into two main subgroups, which will be discussed individually. These subgroups are a cholestatic pattern and a hepatocellular pattern. These subgroups will then be broken down further into respective categories. The R ratio has been described to assess whether the pattern of liver injury is hepatocellular, cholestatic, or mixed and may be applied in drug-induced liver injury.26 The R ratio is calculated by the formula R = (ALT value ÷ ALT ULN) ÷ (alkaline phosphatase value ÷ alkaline phosphatase ULN). An R ratio of >5 is defined as hepatocellular, <2 is cholestatic, and 2-5 is a mixed pattern. This paper will describe hepatocellar and cholestatic patterns.
Hepatocellular Disease Pattern
Hepatocellular pattern is diagnosed with a disproportionate elevation in AST and ALT relative to alkaline phosphatase. For the purpose of this paper we will use the following definitions to describe the magnitude of elevations of AST and ALT (Table 1).
It is important to identify acute liver failure or fulminant liver failure as diagnosed by hepatic encephalopathy and coagulopathy in a patient with no prior history of liver disease. For acute liver failure, it is not imperative to describe the magnitude of rise in ALT or AST. Rapid involvement of the consultancy groups and evaluation of liver transplant should be begun early on.
Causes of Aminotransferase Elevation Massive Elevation
(More than 10,000 times the upper limit) There is an overlap for the causes of elevation in AST and ALT between the groups of severe and massive elevation in AST and ALT. Ischemic liver disease, toxin and viruses related injuries can cause a massive elevation in AST and ALT. They are described further in the section below. It is also important to note that massive AST elevations can be seen in heat stroke and rhabdomyolysis.
Severe (15 times or greater than the upper limit of normal)
The severe elevations of serum aminotransferase levels are mainly found in the setting of excessive hepatocellular injury or necrosis in an acute setting. Although highly elevated aminotransferases can suggest an acute injury, the actual quantification of hepatocyte necrosis cannot be inferred. Furthermore, extremely elevated aminotransferases do not indicate prognosis.10 The differential is limited and generally includes a drug or toxin induced hepatotoxicity, acute viral hepatitis, or ischemic hepatitis. Toxin-related hepatitis and acute viral hepatitis can increase the AST and ALT levels to >25 times the upper limit of normal, while ischemic hepatopathy can increase the levels to >50 times.
Many medications and toxins can cause liver injury. Some of the commonly seen medications are non-steroidal anti-inflammatory drugs, antibiotics, statins, antiepileptic drugs, and antituberculous drugs. It is also pertinent to note that certain herbal remedies and illicit drugs can cause liver injury.10 In the United States (USA), the leading cause of acute liver failure is acetaminophen poisoning, accounting for 46% of cases.27 Hepatotoxicity occurs when sulfate and glucuronide metabolic pathways become saturated, pushing more acetaminophen metabolism towards the cytochrome P450 pathway that results in the formation of the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQ1). Chronic alcohol abusers can be more prone to acute liver failure in the setting of acetaminophen use and caution should be taken when treating these patients.28 Cytochrome P-450, principally cytochrome CYP2E1, metabolizes acetaminophen into a toxic metabolite, which is detoxified by glutathione under normal circumstances. CYP2E1 also detoxifies ethanol. Thus in chronic alcohol abusers, there is increase in CYP2E1 which increases the metabolism of acetaminophen into its toxic metabolites.29 Careful attention to occupational history should be given to patients with excessive aminotransferase elevation. Occupations that could lead to aminotransferase elevation include mushroom picking (Amanita phalloides) and those involved in the chemical industry (vinyl chloride).30
Acute hepatitis can also be caused by infection with any of the primary hepatitis viruses (A-E). Hepatitis B and hepatitis C are most prevalent in the USA, with hepatitis B being the leading cause of acute viral hepatitis in the USA. Viral serological tests are important to differentiate acute from chronic hepatitis. Hepatitis A is transmitted by the fecal oral route. It is a RNA virus, which has an
incubation period of a few weeks. The IgM antibodies to hepatitis A remain in the body for a period of three to six months after the infection.31
Hepatitis B is mainly spread through unsafe sexual practice, parental drug use or vertical transmission. Hepatitis B surface antigen (HBSAg) is positive in either acute or chronic hepatitis B infection, while HBV core IgM antibody generally specifies the acute state. Checking for HBVsAg and HBVDNA would indicate whether there is an active infection and infectivity of the virus. In addition, checking for hepatitis B surface antibody would indicate immunity to hepatitis B either secondary to resolution of a prior infection or vaccination.
Hepatitis C is transmitted through parental drug use, cocaine inhalation, blood transfusion prior to 1992, tattoos or body piercings, needle stick injury and unsafe sexual practices. Hepatitis C antibody testing is sensitive. Presence of HCV viremia should be confirmed in the setting of a positive antibody with the HCV RNA PCR assay, which has high sensitivity and specificity. Hepatology should be consulted for patients positive for hepatitis C for evaluation of treatment, education on hepatitis C, and screening for cirrhosis and hepatocellular carcinoma.
Hepatitis D is an RNA virus that is only seen in the presence of hepatitis B surface antigen positivity. Suspicion for hepatitis D should arise when hepatitis B presents with fulminant hepatitis. Acute co-infection with hepatitis D is diagnosed when HBSAg, IgM anti-HBc, and total anti- HDV are present.
Another cause of acute hepatitis is hepatitis E virus. It is an enterically transmitted RNA virus. Another method of transmission of hepatitis E is through vertical transmission. Anti-HEV immunoglobulin IgM and IgG are used to detect hepatitis E. HEV RNA is used to confirm the presence of hepatitis E.
Occasionally, in the setting of acute hepatitis with excessively elevated AST and ALT levels, history and serology may not uncover a toxic or viral cause, and in these cases ischemic hepatitis should be considered. In ischemic hepatitis, the AST and ALT levels have the potential to increase to >50x the upper limit of normal. Several mechanisms can result in massive AST and ALT elevation, including decreased blood flow in instances such as hypotension, sepsis, hemorrhage, and myocardial infarctions.13 Concurrent elevation of lactate dehydrogenase (LDH) may suggest the diagnosis of ischemic hepatitis.32 These examples highlight the importance of a thorough history and physical examination to help stratify differential diagnoses in the setting of severe aminotransferase elevation.
Mild to Moderate (5-15 times the upper limit of normal)
Borderline and mild elevation in AST and ALT are seen in a variety of diseases. Moderate increase in AST and ALT often coincides with causes of mild and severe elevations. The two most commonly identified non-viral entities, alcoholic liver disease and non-alcoholic fatty liver disease, will be briefly described below.
Alcoholic Liver Disease
Alcohol ingestion can cause elevation in liver chemistries. Alcohol ingestion can be an independendant cause or can attenuate transaminitis concurrent with other chronic liver diseases. Alcohol can cause a wide spectrum of liver disease from fatty liver to alcoholic hepatitis to alcoholic cirrhosis. These conditions can also be present all at once in an individual. Liver biopsy is useful to identify the stage and severity of liver disease since the liver chemistries do not always correlate with these.33,34 The definition of significant alcohol consumption has been suggested as >210 g of alcohol per week in men and >140 g per week in women.35 In practice, an AST:ALT ratio of 2-3:1 raises the suspicion for alcoholic liver disease. It has been demonstrated that alcohol consumption leads to decrease in plasma pyridoxal 5′-phosphate.36 This decrease in levels results in a decrease in ALT activity. The decrease in plasma pyridoxal 5′-phosphate does not have an effect on AST leading to the ratio of AST:ALT being 3:1. Once alcohol abstinence is observed with appropriate nutritional uptake, plasma pyridoxal 5′-phosphate normalizes causing a normal ALT level.36,37,38 When alcohol use is felt to cause liver disease, it is strongly recommended to quit alcohol use, and appropriate counseling should be given.
Non-Alcoholic Fatty Liver Disease and Nonalcoholic Steato-Hepatitis
Nonalcoholic fatty liver disease (NAFLD) is defined as (a) there is evidence of hepatic steatosis, either by imaging or by histology and (b) absence of causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of medication that could cause fatty liver injury, or hereditary disorders. NAFLD is commonly seen in individuals with the metabolic syndrome, characterized by obesity, diabetes mellitus, and dyslipidemia. Histologically, NAFLD can be characterized as non-alcoholic liver (NAFL) or non alcoholic steato-hepatitis (NASH). Differentiation of NAFL from NASH is characterized by the presence of inflammation and hepatocellular injury, in the form of ballooning of the hepatocytes, with or without fibrosis, in the setting of NASH. It is concluded that patients with NAFL have a rather benign, slow progression (if any) histologically, while NASH can rapidly progress to the cirrhotic stage.39,40 Steatohepatitis and fibrosis as seen in NAFLD cannot be assessed accurately with serum transaminases, emphasizing the importance of further evaluation with imaging studies such as ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) and magnetic resonance elastrography (MRE) or with liver biopsy. MRE has proven to be a non-invasive, feasible and accurate modality to identify hepatic steatosis and fibrosis. MRE quantifies the extent of hepatic fibrosis with great accuracy. As compared to ultrasound, MRE is beneficial secondary to being non-technician dependant and being able to identify small amount of fibrosis. However liver biopsy continues to be the preferred modality to differentiate NAFL and NASH. The procedure related morbidity and mortality, cost and sampling error of liver biopsy has lead to interest is identifying non invasive biomarkers to identify steatohepatitis and fibrosis in NAFLD. The NAFLD fibrosis score, enhanced liver fibrosis (ELF) panel and transient elastography are identified as non-invasive methods to identify the spectrum and stage of NAFLD. The NAFLD fibrosis score is comprised of six variables (age, BMI, hyperglycemia, platelet count, albumin, AST/ALT ratio) and it is calculated using the published formula (http://nafldscore.com). Cytokeratin-18 (CK18) fragments have been investigated extensively as novel biomarkers for the presence of steatohepatitis in patients with NAFLD.41,42 Weight loss in the form of decreased caloric intake and exercise is recommended as the primary treatment. Vitamin E (a-tocopherol) administered at daily doses of 800 IU/day improves liver histology in many non-diabetic adults with biopsy-proven NASH and therefore it should be considered as a first-line pharmacotherapy for this patient population.43,44
AST/ALT Ratio
AST/ALT ratios are of great diagnostic aid. An AST:ALT ratio of 2-3:1 raises the suspicion for alcoholic liver disease as discussed previously under the section of alcoholic liver disease. ALT has a longer half life compared to AST. The half life of ALT is 47 +/- 10 hours and that of AST is 17+/- 5 hours. In cholecystitis secondary to gallstone impaction in the distal cystic duct or choledocholithiasis, there is as increase in the AST:ALT ratio initially. However once disimpaction of the stone either spontaneously or iatrogenically is achieved, there is a reversal of this ratio secondary to ALT having a longer half life as compared to AST. It is also important to note that in chronic hepatitis the AST:ALT ratio may be increased up to 1. In advanced hepatic fibrosis, there is a reversal in the AST:ALT ratio in chronic as compared to acute hepatitis. Studies have shown that this is mainly caused by to the increased catabolism of ALT. Earlier it was thought to be secondary to increased production of AST and decreased production of ALT, which has now proven to not be the cause of the ratio reversal.45,46
Cholestatic Liver Disease Pattern
Cholestatic injury is defined as disproportionate elevation in alkaline phosphatase level as compared with AST and ALT levels. Anatomic obstructions to bile flow (extrahepatic cholestasis) or inability to form bile by the hepatocytes (intra-hepatic cholestasis) can cause a cholestatic injury pattern.
Once the origin of alkaline phosphatase has been identified as the liver, it is recommended to evaluate with an ultrasound or other form of liver imaging to identify whether the source is intra-hepatic or extra-hepatic. An MRI/MRCP (magnetic resonance cholangiopancreatography), endoscopic retrograde cholangiopancreatography and/or endoscopic ultrasound can be ordered to better examine the bile duct morphology. In the presence of biliary dilation, the source of a cholestatic pattern is most likely extra hepatic, while the absence would indicate an intra hepatic source. Causes of cholestatic liver disease as outlined in Figure 1.
For intrahepatic cholestasis, autoimmune markers including antimitochondrial antibody, antinuclear antibody, and smooth muscle antibody should be checked to assess for PBC or auto- immune cholangiopathy. Finally, pregnancy testing in women of childbearing age should be done to assess for intrahepatic cholestasis of pregnancy. Other infiltrative disorders may raise the alkaline phosphatase and cause intrahepatic cholestasis, including sarcoidosis, atypical fungal infection, or malignancies. In these instances of infiltrative diseases, a liver biopsy may be considered to assess for primary biliary cirrhosis or other infiltrative diseases.
Nutrition Issues In Gastroenterology, Series #181
Pancreatic Exocrine Insufficiency and Enteral Feeding: A Practical Guide with Case Studies
Mary E. Phillips
Amy Berry
Lucy S. GettlePatients with pancreatic disease can develop severe malnutrition. Pancreatic enzyme replacement therapies (PERT) are predominantly designed for oral administration, but this can be challenging in patients requiring enteral nutrition (EN). This review explores the use of PERT in complex patients who are on EN. Case studies will be utilized to demonstrate different methods available in order to provide practical guidance on administration, both in the United States (U.S.) and the United Kingdom (U.K.).
Mary E. Phillips BSc (Hons) RD DipADP Advanced Specialist Dietitian (Hepato-pancreatico-biliary Surgery), Royal Surrey County Hospital NHS Foundation Trust, Egerton Road, Guildford, Surrey, UK Amy Berry MS, RD, CNSC Nutrition Support Specialist (GI Surgery at the Emily Couric Cancer Center), University of Virginia Medical Center, Charlottesville VA Lucy S. Gettle, RDN CNSC Clinical Dietitian Specialist (Adult Cystic Fibrosis), University of Virginia Medical Center, Charlottesville VA
INTRODUCTION
Patients with pancreatic disease, pancreatic resection, and cystic fibrosis often develop significant malnutrition as a result of the numerous gastrointestinal (GI) complications preventing adequate oral intake. Malabsorption, as well as side effects of medications such as antibiotics and opiates, adds an additional challenge to meeting nutritional requirements. In patients requiring EN, standard elemental formulas may not be tolerated or absorbed. Semi-elemental (or peptide-based) formulas are often utilized, providing less long-chain triglycerides and more medium-chain triglycerides, thereby decreasing the dependence of pancreatic lipase for absorption. However, some patients will continue to malasborb, even with semi-elemental products, worsening the malnutrition present.
Traditional signs and symptoms of malabsorption include the presence of pale stools (often described as yellow or clay colored), floating or oily stools, stools with an unusually foul and offensive odor, abdominal bloating, cramping or gas, urgency and/or frequent stools.1 The use of gut slowing medications, such as opiates, or the use of low fat enteral feedings may result in reduction of obvious clinical signs and mask ongoing malabsorption. In these patients, constipated or infrequent stools (vs. diarrhea) may be reported, as well as abnormal color, unusually large volume stools, abnormal cramping and/or gas etc. The addition of antibiotics or prokinetics, can further confuse the clinical picture. Hence, sometimes it is the presence of more subtle signs of malnutrition such as difficulty with wound healing, worsening functional status, ongoing weight loss, or recurrent hypoglycemia/reduction in insulin requirement despite adequate caloric intake, that should trigger the consideration to consider an empiric trial of PERT. 2,3
EN and PERT products vary internationally. The aim of this paper is to provide a guide in the management of this complex patient group, combining the experience of dietitians specializing in patients with PEI, both in the U.S. and the U.K. We will also provide practical guidance in implementing the various modalities that can be utilized when it is determined that a patient is malabsorbing on their current EN regimen, as direction provided in the literature is sparse.4-10
CASE #1
A 62 year old female with pancreatic cancer and poorly controlled diabetes (HbA1c = 8.3%) completed a neo-adjuvant course of chemo-radiation prior to surgery. She reported a recent reduction in her insulin dose due to multiple episodes of severe hypoglycemia. Her oncologist also recently started her on enteric coated PERT due to reported yellow, oily stools and continued weight loss. She underwent a classic Whipple procedure, combined with a percutaneous gastro-jejunostomy (PEG-J) tube placement. Semi-elemental EN (Perative®, Abbott, U.S.) was chosen due to the presence of malabsorption preoperatively. Her recovery was complicated by delayed gastric emptying requiring NPO (nil per os) status, and she was treated with a prokinetic and high dose proton pump inhibitor (PPI) given via her J-port. Her gastric port was vented as needed for gastric decompression. She was experiencing diarrhea, but was receiving enteral electrolyte replacement therapy (including magnesium oxide) and a prokinetic. On discharge, she was tolerating G-tube clamping around the clock. She transitioned to a nocturnal feeding regimen that met her nutritional needs and was kept NPO.
Once home, her diarrhea increased. Her prokinetic dose was successfully weaned, with no worsening of her nausea. The patient reported improvement in her diarrhea, yet, eventually frequent loose stools associated with cramps and urgency were again reported. Her glycemic control was erratic; she began holding her long acting insulin due to episodes of hypoglycemia.
Two weeks post discharge her weight was down 5 pounds (2.25 kg), and an area of her midline wound opened, which required packing. At this time, it was determined an EN change was required. The elemental formula Vivonex® (Nestle, U.S.) was considered for its very low fat profile, however the patient was quite volume sensitive and would not have tolerated the rate increase needed. She was to be tried on a non-enteric coated PERT (Viokace®; Aptalis Pharma, U.S.), that could be crushed and added directly to her EN, but her insurance denied coverage for this product. We were hesitant to attempt enteric coated granules to mix with EN (described elsewhere6,7) for fear of tube clogging, as the patient was completely dependent on her jejunal EN. Fortunately, she advanced to oral intake. Full liquids were tolerated and she was able to take medications by mouth. She began to take her enteric coated PERT (2 capsules of Zenpep® 25,000 USP; Aptalis Pharma, U.S.) by mouth at the start of feedings, ~3 hours into her feeding cycle, and again before turning her EN off in the morning. Her stools firmed and improved; however, she still reported urgency and pale stools in the middle of the night. We increased her oral PERT administration to four times during her nocturnal cycle (she reported being awake and ambulatory at night, and agreeable to medication at this time), with one loperamide at the start of EN. This finally resulted in normalization of stooling and weight maintenance. She also resumed her intermediate acting insulin due to rising blood glucose with improved absorption; her blood glucoses now remaining in the 80-200mg/dL range. Over the next 2 months she increased her weight by 12 pounds (5.5 kg) and her abdominal wound began to heal.
CASE #2
A 26 year old male with cystic fibrosis (CF) related PEI was struggling to gain weight and adhere to his EN regimen. He had been taking oral enteric coated PERT with his meals since being diagnosed with PEI at a young age, and was automatically started on PERT with a polymeric EN formula via G-tube. His original EN regimen consisted of a 2.0 kcal/mL formula (TwoCalHN®, Abbott, U.S.) with enteric coated PERT taken by mouth at the beginning and end of an 8-hour nocturnal EN schedule. He continually endorsed abdominal discomfort and stool urgency in the middle of the night during his EN. Though taking oral enzymes at the beginning and end of an EN cycle tends to be the easiest regimen for CF patients, this method does not provide enzymatic coverage for the entire duration of nocturnal EN. Due to continued malabsorptive symptoms and failure to gain weight, a non-enteric coated PERT product (Viokace®) was crushed and mixed with his EN prior to administration. This helped relieve some of the abdominal discomfort, but he continued to have difficulty consuming breakfast due to post-feeding appetite suppression. This patient also struggled with EN adherence due to the reported burden of effort to crush and mix PERT into the EN formula. Furthermore, the patient did not have a consistent living situation and did not always have EN supplies with him. We then trialed an in-line digestive enzyme cartridge (Relizorb®, Alcresta, U.S.), as this would greatly reduce the burden of EN preparation, and discontinued Viokace®. Due to poor fat hydrolysis data of TwoCal HN® using Relizorb®, his EN was changed to the highest caloric density compatible formula available at our facility (Osmolite 1.5®, Abbott, U.S.). The patient had a dramatic improvement in tolerance and adherence to his EN regimen. His abdominal discomfort was much improved and he was able to consume a large breakfast due to reduced post-EN appetite suppression (consistent with results of a recent study10). He gained 10 pounds (4.5 kg) in the first three months after this therapy change, but was not able to maintain the rate of weight gain. In order to increase caloric provision, his outpatient EN was changed to Nutren 2.0® (Nestle, U.S.). He continued to tolerate the new EN regimen with 2 cartridges of Relizorb® nightly and gained 22 pounds (10 kg; 17.5% body weight) over the following year. It should be noted that the patient’s appetite and oral intake also improved, contributing to weight gain.
CASE #3
A 54 year old male with chronic pancreatitis suffered a splenic bleed which resulted in extensive ischaemia of the bowel. A total gastrectomy, hemi-hepatectomy, total colectomy with end ileostomy, and feeding jejunostomy was performed; high stool output followed. The oesophagus was left disconnected (with a drain in situ, or “spit fistula”) for 18 months prior to reconstruction. Short bowel syndrome was presumed, as there had been concern over the perfusion of his small bowel, and we utilized a full range of trials with peptide-based EN. In addition, loperamide up to 16mg QID and 60mg of codeine TID was administered. An electrolyte mix was used to flush his jejunostomy instead of water. Additional sodium (50mL 30%NaCl solution which provides 50mmol sodium, increasing the total sodium to 90-100mmol/l) was added to the EN to optimize water absorption. His stoma output remained >2000mL per day, and he continued to require supplemental parenteral nutrition (PN) to prevent weight loss. As this management was ineffective, his ongoing high stoma output was presumed to be not only due to loss of compensatory mechanisms (saliva and gastric secretions; colonic fermentation of malabsorbed carbohydrate, intestinal hurry), but also to severe PEI.
PERT was administered as 2g Pancrex V® powder (Essential Pharmaceuticals, U.K.) dissolved in 50mL sterile water and flushed by the nursing staff every 2 hours through his 24 hour EN. No benefit was observed and the decision was made to administer PERT to the EN directly. The 4 g Pancrex V® powder (100,000 units lipase) was added directly to 400 mL of Vital 1.5® (Abbott, U.K.), the mixture was shaken well and run at 100mL/hr over 4 hours. UK guidelines limit hang time for EN with any additives to 4 hours.11 This was repeated 4 times during the day, and provided a total of 2400 calories. His stoma output reduced to less than 600mL per day, and he was weaned off PN and began to gain weight. This method of EN was continued until he underwent reconstructive surgery and was able to recommence oral intake.
CASE #4
A 64 year old man status post chemotherapy, radiation, and distal pancreatectomy/splenectomy for pancreatic cancer suffered many post-operative complications including a chyle leak, GI bleed, recurrent abscesses, bacteremia, and delayed gastric emptying requiring placement of a PEG-J. He required multiple readmissions and continued to struggle with nausea, vomiting, abdominal pain and weight loss. He eventually requested a second opinion and was admitted to our facility. His esophagogastroduodenoscopy (EGD), upper GI series and computed tomography (CT) scan showed gastric stenosis that would require surgical revision. Due to his malnourished state, nutritional optimization prior to surgery was necessary. He came to us receiving 6 cans of Vital 1.5® (Abbott, U.S.). Each can of Vital 1.5 was mixed with 2 capsules of Creon 24,000® (AbbVie, U.S.), which were opened and mixed with 2 tabs of sodium bicarbonate (650 mg) crushed and mixed with 60mL of water and sat as a slurry for 30 minutes prior to administration. This slurry was flushed via his feeding tube every 4 hours. He had lost 21% of his usual body weight over the last year, and presented to us with a weight of 130 pounds (59 kg). He was 5 feet, 6 inches (168cm); preoperative weight goal was 140-145 pounds (63-65 kg). He was switched to 8 cans of Vivonex®, allowing him to stop the PERT slurry flushes. However, after 2-3 weeks, he had not gained any weight. His EN regimen was then changed to a mixture of 1 can of Vital 1.5® mixed with 3 cans of Vivonex® twice daily for a total of 8 cans per day. This provided increased calories while keeping fat content low, avoiding the use of enzymes. However, his lack of weight gain persisted and the patient reported a decline in quality of life due to the continuous EN infusion regimen. At this time his EN was adjusted to 7 cans of Vital 1.5®, and PERT slurries were restarted every 4 hours. Over the next 4 weeks EN was increased to 8 cans, then 9 cans of Vital 1.5®. One month after his 9th can was added, he reached his goal weight of 142 pounds (64.5 kg) and was able to undergo a surgical gastro-jejunostomy with eventual progression to an oral diet.
CASE #5
A 68 year old male underwent a pancreatico-duodenectomy for adenocarcinoma of the pancreas with subsequent completion pancreatectomy following the development of a high volume pancreatic fistula. A nasojejunal (NJ) feeding tube was inserted intra-operatively and he was initially fed with a semi-elemental EN (Peptisorb®, Nutricia Clinical Care, U.K.). He had a protracted length of stay and ongoing delayed gastric emptying, thus he remained dependent on NJ feedings for his nutrition. He had normal bowel function, yet continued to lose weight, developed a hospital acquired pneumonia and an abdominal wound breakdown requiring the use of a vacuum wound management system.
His glycemic control was erratic despite continuous EN, with frequent episodes of hypoglycemia. Given his complete pancreatectomy, malabsorption was presumed, and 4g of Pancrex V® powder (100,000 units lipase) was added to each bottle of his peptide EN, which was changed to a 1.5kcal/mL product (400mL Vital 1.5®) to allow a rest period for physiotherapy. This was repeated 4 times a day, to provide 2400 calories. Within a week, his insulin requirements increased and he no longer experienced hypoglycemic episodes. Over the next few weeks his grip strength and weight started to increase. There was no change in his bowel habits, and he continued with brown formed stools every 24-36 hours. His wound began to heal, and he began to eat and drink. On day 92 he discontinued NJ feedings and was discharged home on day 94 on an oral diet, PERT and insulin. Table 1 provides an overview of all 5 cases including nutritional parameters, PERT, and outcomes. Not Everyone Needs PERT
The cases above highlight the need to identify patients with PEI who would benefit from the use of PERT. However, it is worth noting that not all patients with pancreatic disease and frequent stooling require PERT. The use of antibiotics, prokinetics, diagnosis of Clostridium difficile, and occurrence of dumping syndrome among other causative factors should be considered prior to adjusting EN or initiating PERT for suspected malabsorption from PEI.
A 76 year old patient post Whipple procedure for ampullary adenocarcinoma was readmitted with severe diarrhea, nausea, vomiting, dehydration and failure to thrive. He was also on a prokinetic due to symptoms of delayed gastric emptying, and receiving enteral electrolytes, both of which could potentially affect stool output. In attempts to rule out malabsorption, the surgical team ordered a fecal elastase, which came back low; the watery stool sample as well as recent pancreatic surgery invalidated the low result.12 A fecal fat check (qualitative) was obtained, however, he had little to no enteral nutrition (hence fat) for days. As a result, the fecal fat came back negative, adding little to the clinical assessment. His CT scan showed colitis (stool sample was negative for Clostridium difficile). The team ordered PERT, with no change in stool output. Eventually the enzymes were stopped. Ultimately, the patient required a PEG-J, tolerating standard EN, and his stools improved over time as his colitis resolved based on his repeat CT scan.
DISCUSSION
Assessment of nutritional adequacy and feeding tolerance is complex in patients who have pancreatic disease. There are no standard guidelines in the administration of PERT with EN, and clinical practice differs internationally as a result of the differences in EN and PERT products. Consequently, methods for adding PERT to EN also differ.
The use of a fecal fat stool collection or fecal elastase may help to support the diagnosis of ongoing malabsorption in certain circumstances; however, limitations exist (see Table 2). Assessment of residual pancreatic function, signs and symptoms, in concert with clinical judgment, is needed to establish if the patient is malabsorbing. Ongoing reassessment to ensure adequate response to therapy is also important (see Table 3). In the U.K., peptide/semi-elemental formulas are used as first line EN in patients with pancreatic disease as per European Society for Enteral and Parenteral Nutrition (E.S.P.E.N) guidelines;13 it is also standard practice to use PERT routinely in patients after pancreatic head resection2 and inoperable pancreatic cancer.14 In the U.S. practices vary, but at UVA, we consider standard EN as first line therapy when initiating EN and readjust as signs or symptoms of malabsorption develop or PEI is confirmed. If a patient fails on standard EN, a semi-elemental feeding will be tried, followed by a strict elemental product or initiation of PERT. Initiation of PERT is carefully considered on an individual basis as circumstances dictate. If a clinician determines PERT with EN is the best approach, they then must also decide on the best method of administration. Figure 1 provides methods that may be employed when providing PERT with EN.
In the U.S., another major hurdle when utilizing PERT with EN (or orally) is obtaining insurance coverage. Certain enzyme formulations may not be covered, or the patient may not have met their out-of-pocket premiums for their particular insurance plan (see Table 4 for an overview of Medicare Part D drug coverage).
CONCLUSION
Patients with pancreatic disease are often complex and present many nutritional challenges. There are significant variations in absorptive capacity between patients with cystic fibrosis, acute and chronic pancreatitis, pancreatic resection, pancreatic cancer, and other conditions that may lead to PEI. Therefore, it is crucial that clinicians have a range of management options to optimize the nutritional care of these vulnerable patients. This is a ‘how to’ guide for the addition of PERT to EN, and highlights the variation in practice and patient management internationally.