Page 52 – Practical Gastro

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

December 2018 • Volume XLII, Issue 12

John Pohl

Editor: 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

Jonathan Schmidt,Shiqing Yan,Christopher Magiera

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

Michael Babich

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. 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. Gettle

Patients 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.

Dispatches From The Guild Conference, Series #18

Novel Therapies for Primary Sclerosing Cholangitis

Manan A. Jhaveri,

Kris V. Kowdley

Primary sclerosing cholangitis (PSC) is chronic, cholestatic liver disease that progresses to advanced liver disease and cirrhosis. PSC is strongly associated with inflammatory bowel disease (IBD). In this article we present new studies, clinical trials and novel therapies for the treatment PSC.

Manan A. Jhaveri MD, MPH Kris V. Kowdley MD, FACP, FAASLD Liver Care Network and Organ Care Research, Swedish Medical Center Seattle, WA

INTRODUCTION

Primary sclerosing cholangitis (PSC) is chronic, cholestatic liver disease that progresses to advanced liver disease and cirrhosis. It is characterized by inflammation and fibrosis of both intra and extra hepatic bile ducts leading to the formation of multiple bile duct strictures resulting into chronic cholestasis. This may eventually develop into cirrhosis with subsequent portal hypertension and hepatic decompensation.^1,2 The incidence and prevalence rates for PSC range from 0 to 1.3 per 100,000 people per year and 0 to 16.2 per 100,000 people, respectively. The estimated median survival from the time of PSC diagnosis until liver transplantation or mortality related to liver disease is 12 to 15 years.¹ Roughly 65% of PSC patients are male. PSC is strongly associated with inflammatory bowel disease (IBD), as the prevalence of IBD in PSC is 60-80%.³ The typical PSC patient is a male in their fourth or fifth decade of life presenting with a diagnosis of ulcerative colitis (UC) or Crohn’s colitis and abnormal liver biochemistries.^4,5 The IBD associated with PSC is unusual in that it is usually pancolitis with right sided predominance, backwash ileitis and rectal sparing.^6,7

PSC is associated with an increased risk of biliary and colorectal cancer; patients with concomitant UC and PSC have a much higher risk compared with patients with UC or PSC alone.^8,9 Surveillance colonoscopy, from the time of diagnosis of PSC, cannot be stressed enough. Patients with small duct PSC disease have an improved survival and lower risk of cholangiocarcinoma as comparted to patients with large duct PSC.^8,10 Patient who demonstrate a significant reduction in serum alkaline phosphatase (ALP) in a median time of two years following diagnosis have an improved transplant-free survival and reduced risk of cholangiocarcinoma.¹¹ PSC is also associated with increased frequencies of multiple gall bladder abnormalities including cholecystitis, cholelithiasis, benign lesions and malignancies.¹² Gallbladder lesions have been found in about 5% of patients with PSC, with half of these being malignant. Gallbladder polyps are significantly associated with high risk of malignancy, so cholecystectomy is recommended even if the lesion is less than 1 cm.^13,14

Pathogenesis

The exact pathogenesis of PSC is unknown. Multiple studies have supported an autoimmune etiology given the presence of concurrent autoimmune disease in up to 25% of PSC patients as well as strong linkage of PSC to human histocompatibility complex genes.⁴ The involvement of gut microbiota has been evaluated in PSC. Several in vitro studies have demonstrated that small bowel bacterial overgrowth may cause cholangitis and liver lesions similar to those seen in PSC. Subsequent antimicrobial therapy leads to an improvement in these lesions. The strong HLA associations suggest that adaptive innate responses are also involved in the pathogenesis of PSC. IgG4 (immunoglobulin-G4) related disease is a systemic disease characterized by extensive IgG4 plasma cells and T-lymphocyte infiltration of various organs including pancreas (autoimmune pancreatitis) and bile ducts (IgG associated cholangitis, IAC). It is important to distinguish between IAC and PSC with elevated IgG4 as cholangiographic changes of IAC may resolve completely after corticosteroids treatment. PSC patients with elevated IgG4 are less responsive to corticosteroids and also multiple studies have demonstrated that these patients may progress rapidly and have more severe liver disease.^15,16

Diagnosis

The diagnosis of PSC is made in patients with cholestatic liver test abnormalities and characteristic stricturing of the intrahepatic and/or extrahepatic bile ducts with segmental dilatation on cholangiography [e.g., magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERC) or percutaneous transhepatic cholangiography (PTC)] after excluding secondary causes of sclerosing cholangitis.^4,17 The preferable test for making a diagnosis of PSC is MRCP, which has acceptable sensitivity and specificity of 86% and 94% respectively. Small duct PSC is a disease variant characterized by cholestasis and histological features of PSC with normal bile ducts cholangiogram; liver biopsy is required for diagnosis in these cases.¹⁷ Secondary sclerosing cholangitis is characterized by multiple biliary strictures due to recognizable causes such as infection, inflammation and long-term biliary obstruction that leads to destruction of bile ducts. PSC overlap syndromes are conditions with features of PSC and other autoimmune liver diseases such as autoimmune hepatitis (AIH) and autoimmune pancreatitis. PSC-AIH overlap syndrome is characterized by clinical, biochemical, and histological features of AIH along with cholangiographic findings similar to PSC. However, current understanding is that rather than reflecting a separate entity, the observed features of autoimmune hepatitis in PSC, including elevated transaminases and IgG, may also be due to biliary disease. Autoimmune pancreatitis (AIP) is characterized by stricturing of pancreatic duct, raised IgG4 level, a lymphocytic infiltrate and response to corticosteroid therapy. AIP in association with stricturing of bile ducts similar to PSC is termed as autoimmune pancreatitis – sclerosing cholangitis (AIP-SC). It is important to note that alkaline phosphatase levels fluctuate in PSC patients and may be normal or only mildly elevated in a significant proportion of PSC patients.^4,8,9

Management

Managing patients with PSC is complicated, as it requires management of primary disease and also coexisting conditions and complications from end stage liver disease. Currently there is no medical therapy that will halt the progression of liver disease in PSC patients, despite numerous clinical trials over the past two decades. This is due to uncertainty regarding the pathophysiology of PSC and also lack of reliable diagnostic markers.

Ursodeoxycholic Acid

Multiple clinical trials have studied the efficacy and safety of ursodeoxycholic acid (UDCA) in PSC patients. UDCA is the most commonly prescribed drug for PSC, as it is effective in other cholestatic liver diseases, specifically primary biliary cholangitis (PBC). However, the role of UDCA in clinical improvement is questionable. UDCA reduces hydrophobicity of bile acid and also affects adaptive immunity by inhibiting dendritic cell response.^18,19 The initial placebo controlled clinical trials of low dose UDCA conducted in early 1990s demonstrated improvement in clinical symptoms, liver biochemistries and histological features. However, its clinical significance was limited due to small sample size.^20,21 A large, placebo-controlled clinical trial of low dose UDCA (13-15 mg/kg/day) in PSC demonstrated improvement in serum liver biochemistries but no effect on patient’s clinical symptoms or time to liver transplantation. ²² A large, multicenter, randomized, placebo-controlled trial treated 219 PSC patients with moderate doses of UDCA (17-23 mg/kg/day) and followed them for five years. Improvement in liver biochemistries with UDCA treatment was seen, but there was no statistically significant effect on survival, time to liver transplantation or prevention of cholangiocarcinoma.²³ Pilot clinical trials with a higher dose of UDCA (28-30 mg/kg/day) demonstrated clinical improvement in liver biochemistries as well as Mayo risk score.^24,25 However, the largest clinical trial of high dose UDCA26 was terminated at five years due to an increased risk of progression to liver transplantation, cirrhosis, gastric or esophageal varices and cholangiocarcinoma compared to placebo.²⁶ It has been demonstrated that an increased serum lithocholic acid concentration, a potent hydrophobic bile acid in patients receiving high dose of UDCA, may be responsible for these adverse outcomes.²⁷ A meta-analysis of nine randomized control trials (RCTs)²⁸ concluded that UDCA at any dose showed no significant improvement in symptoms, histological progression, mortality or cholangiocarcinoma. Similarly, a systematic review of eight RCTs ²⁹ showed improvement in liver biochemistries but no significant reduction in the relative risk of death, varices, ascites or encephalopathy. Due to variable doses of UDCA, different treatment time course, follow up and end points, the treatment guidelines for UDCA in PSC are conflicting. The two major United States (US) societies including the AASLD (American Society for the Study of Liver Diseases)17 and the ACG (American College of Gastroenterology)³⁰ do not support the use of ursodeoxycholic acid; however the EASL (European Association for the Study of the Liver)³¹ recommends the use of low dose UDCA (13-15 mg / kg / day).

Novel Treatment in PSC
Farnesoid X Receptor Ligands

The Farnesoid X receptor (FXR) plays an important role in bile acid homeostasis. The natural ligands for FXR are bile salts. The key role of FXR is to down regulate the cytochrome P4507A1, the rate limiting enzymes in bile acid synthesis.³² Obeticholic acid (OCA), a semisynthetic analogue of chenodeoxycholic acid and an FXR agonist with anti-fibrotic properties has been approved by the US Food and Drug Administration for the treatment of primary biliary cholangitis (PBC).³³ A clinical trial of obeticholic acid in patients with primary sclerosing cholangitis is underway (clinicaltrials.gov identifier, NCT02177136). The results from a phase 2 randomized, double blind, placebo controlled trial (AESOP) evaluating the safety and efficacy of OCA compared to placebo in 77 patients with PSC were presented at the annual meeting of the AASLD in 2017. Patients were randomized to placebo, OCA 1.5 – 3 mg, and OCA 5 – 10 mg (with dose titration occurring at the 12 week midpoint). By 24 weeks, ALP increased by 1% in placebo group and decreased by 22% in both OCA 1.5 – 3 and OCA 5 – 10 mg groups. In AESOP, about 46 – 48% of patients in each group were receiving UDCA at baseline. Results from a post-hoc analysis showed that improvement in serum ALP were observed with OCA regardless of treatment with UDCA. Pruritus is the common symptom of PSC and was the most common adverse event observed, occurring in 46%, 60% and 67% of patients in the placebo, OCA 1.5 – 3 mg and OCA 5 – 10 mg groups, respectively.³⁴

Role of Antibiotics in PSC

Multiple in-vitro studies demonstrated a link between the intestinal microbiota and biliary inflammation in PSC. The use of vancomycin in PSC showed improvement in liver biochemistries, however the long-term outcome is still unclear. The safety and efficacy of oral vancomycin and metronidazole were evaluated as well. Patients in the vancomycin arm achieved the primary end point (a decrease in alkaline phosphatase at 12 weeks) with less adverse effects.³⁵

Simtuzumab

Lysyl oxidase homolog 2 (LOKL2) catalyzes the first step in the formation of cross links in collagen and elastin and is associated with progression of liver disease. Pre-clinical models (e.g., MDR2 knock out mice), inhibition of LOKL2 improves fibrosis. In addition, serum and tissue LOXL2 levels are elevated in PSC and correlated with fibrosis stage. A clinical trial evaluating the safety and efficacy of simtuzumab (SIM, a humanized IgG4 monoclonal antibody against LOXL2) in PSC was conducted. In a phase 2b clinical trial (results were presented at the EASL International Liver Congress 2017, Amsterdam), 234 patients with PSC were randomized to receive weekly subcutaneous injections of SIM 75 mg, SIM 125 mg or placebo for 96 weeks. The authors concluded that neither dose of SIM lead to significant reduction in mean hepatic collagen content, change in Ishak fibrosis stage, serum alkaline phosphatase concentration or progression of cirrhosis.³⁶

Norursodeoxycholic Acid

24-Norursodeoxycholic acid is a synthetic bile acid and C23 homolog of ursodexoycholic acid. It reduces inflammation and improves fibrosis as well as liver function tests in rodent model of sclerosing cholangitis. Results from a phase 2 clinical trial evaluating the safety and efficacy of norursodeoxycholic in patients with PSC were presented at the EASL ILC in 2016;³⁷ 59 PSC patients were randomized to 500, 1000, and 1500 mg of norursodeoxycholic for 12 weeks. The authors concluded that PSC patients treated with norursodeoxycholic demonstrated significant reduction in serum ALP levels within 12 weeks of treatment in all groups (12.3%, 17.3% and 26%, respectively). A long term clinical trial will determine the effect of norursodeoxycholic acid on clinical outcomes of PSC such progression of disease to cirrhosis, time to liver transplantation and liver related mortality.³⁷

ASBT Inhibitor

Interruption of intestinal bile acid circulation might have therapeutic benefit in PSC. The active absorption of bile acids in the terminal ileum is mediated by Apical Sodium Dependent Bile Acid Transporter (ASBT). ASBT inhibition reduced cholestatic liver injury and fibrosis by increasing fecal excretion of bile acids, lowering hydrophobic biliary bile acid concentrations. Lopixabat, an ASBT inhibitor is currently being evaluated in patients with PSC.³⁸

Cenicriviroc

Cenicriviroc, a dual chemokine receptor (CCR) 5 and CCR2 antagonist is currently being studied for PSC. CCR5 and CCR2 are involved in the inflammatory and fibrogenic pathways that cause fibrosis and often lead to cirrhosis and liver cancer.³⁹

NGM282

NGM282 is a variant of the human hormone FGF19 that reduces liver fat content, reverses fibrosis and improves liver function. Results from a phase 2 clinical trial evaluating the safety and efficacy of NGM282 in patients with PSC were recently presented at the EASL ILC 2018; 62 PSC patients with elevated ALP were randomized to receive daily subcutaneous injection of NGM282 1mg or 3 mg or placebo. The primary end point was the change in ALP from baseline to week 12. The study did not meet the primary end point. However, significant reductions in serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) were observed in 3 mg cohort at week 12. Also markers of fibrosis and bile acid synthesis were significantly reduced in both NGM282 cohorts at week 12 as compared to placebo group.⁴⁰

CONCLUSION

PSC, a disease with complex pathophysiology, results in morbidity and mortality due to liver disease. No therapy thus far has been effective to slow the progression of disease and complications from cirrhosis in PSC. UDCA has been evaluated in depth in PSC, but even though it improves liver biochemistries, there is no significant improvement in clinical outcomes of PSC such as cirrhosis, time to liver transplantation and mortality from liver disease. Multiple novel therapeutic agents beyond UDCA are now targeting bile acid homeostasis and are currently being evaluated in patients with PSC.

Frontiers In Endoscopy, Series #47

Current Management of Ascending Cholangitis

Dan McEntire,

Douglas G. Adler

If not recognized and treated appropriately, ascending cholangitis can pose significant morbidity to affected patients. Accurate diagnosis and assessment of disease severity is essential to guide selection of antimicrobials, timing of biliary decompression, and selection of a decompression technique. This article reviews the current literature related to ascending cholangitis management, in conjunction with current international guidelines.

Dan McEntire MD, Douglas G. Adler MD, University of Utah School of Medicine, Gastroenterology and Hepatology, Salt Lake City, UT

INTRODUCTION

Ascending cholangitis (AC) is an infection of the biliary tract. The normal biliary tree is near-sterile secondary to constant drainage, bacteriostatic bile salts, and mucosal immune mechanisms. Biliary obstruction disrupts these processes and causes elevated intraductal pressure with increased bile duct permeability, which permits endotoxin and bacterial translocation into lymphatic and portosystemic circulation.¹ Biliary obstruction is most frequently caused by biliary stones, though there are many causes including mass effect of malignancy, benign and malignant strictures, parasites (e.g., Ascaris), and iatrogenic causes (e.g., biliary stenting, surgery).¹ (Figures 1 and 2)

The organisms implicated in AC originate from enteric flora, and cultures are usually polymicrobial.² The most frequently isolated Gram-negative organisms are E. coli and K. pneumoniae, with Enterococcus species being the most common Gram-positive organism.^3,4 Anaerobes, primarily Bacteroides and Clostridium, are relatively infrequently isolated.^3,4

Accurate diagnosis and assessment of severity are fundamental to guide appropriate therapy. In additional to clinical support and resuscitation, antibiotic administration and biliary decompression represent the central components of AC management. This article presents current data pertinent to these areas.

Diagnosis of Ascending Cholangitis

The classic clinical characteristics of AC are fever, right-upper-quadrant (RUQ) abdominal pain, and jaundice (Charcot’s triad). More severe cases may present with hypotension and altered mental status (Reynold’s pentad). However, because few cases present with all of these features, standardized criteria were recently developed.^5,6

The current Tokyo Guidelines 2018 (TG18) diagnostic criteria for AC are based on evidence of systemic inflammation, cholestasis, and biliary obstruction. The presence of systemic inflammation is defined as fever >38°C, shaking chills, leukocyte count <4,000/µL or >10,000/µL, or C-reactive protein (CRP) ≥1 mg/dL. Cholestasis is defined as clinical jaundice, total bilirubin ≥ 2 mg/dL, or alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, or gamma-glutamyltransferase >1.5 times the upper limit of normal. The presence of biliary dilatation, or evidence of the etiology (e.g., stone, stricture), indicates obstruction. A definitive diagnosis is made when at least one criterion is met in each of the three categories. A suspected diagnosis is made when one criterion is met in the systemic inflammation category, plus one item in either the cholestasis or imaging categories. One study found that the diagnostic criteria successfully identified 90% (73.1% definitive, 16.9% suspected) of cases.⁷ The remaining undiagnosed 10% were mild cases that lacked systemic inflammation. This suggests reasonable performance of criteria, especially for moderate to severe disease.

Imaging is necessary to make a definitive diagnosis of cholangitis (though clinical suspicion may be high in known cases of preexisting pancreaticobiliary disease). Abdominal ultrasound (US) is the suggested first step due to its wide availability, noninvasive nature, and low cost. US is well suited to visualize the proximal common bile duct (CBD) and common hepatic duct, but visualization of the distal CBD is typically limited. Computed tomography (CT) and magnetic resonance imaging/magnetic resonance cholangiopancreatography (MRI/MRCP) can be performed. MRI/MRCP is favored given the high-resolution imaging of the common bile duct that is possible. Invasive endoscopic or percutaneous imaging options, discussed below, can be both diagnostic and therapeutic.

Severity Grading of Ascending Cholangitis

TG18 includes a severity grading system that has prognostic value and may help to guide appropriate intervention timing.⁵ Grade III (severe) cholangitis is manifested by evidence of organ dysfunction. Organ dysfunction is defined as the presence of cardiovascular dysfunction requiring intravenous dopamine >5µg/kg/min or any dose of norepinephrine, neurologic dysfunction (i.e., disturbance of consciousness), respiratory dysfunction (PaO2/FiO2 <300), renal dysfunction (oliguria or serum creatinine >2mg/dL), hepatic dysfunction (INR >1.5), or hematologic dysfunction (platelet count <100,000/µL). Grade II (moderate) cholangitis is defined by the presence of high fever (>39°C), leukocyte count <4,000/µL or >12,000/µL, advanced age (>75 years), or hypoalbuminemia (<70% lower limit of normal). Grade I (mild) cholangitis lacks the aforementioned criteria. A large study that stratified patients by severity grade found 5.1%, 2.6%, and 1.2% 30-day mortality in patients with Grade III, II, and I disease, respectively.⁷

Antibiotics

Initiation of antibiotics should occur within one hour in cases of sepsis, or within six hours for all other cases.^4,8 Prescribing adequate empiric coverage is becoming increasingly difficult due to antibiotic resistance patterns.^2,9 Appropriate selection of empiric coverage is also made with consideration given to comorbidity, allergy, or other factors.

General recommendations for empiric coverage include intravenous treatment with a third-generation cephalosporin or a penicillin derivative/beta-lactamase inhibitor combination.⁴ TG18 and the Surgical Infection Society/Infectious Disease Society of America (SIS/IDSA) guidelines recommend to consult local antibiograms and administer alternative medications if community pathogen resistance exceeds 10-20%.4,10 Ampicillin-sulbactam and fluoroquinolones are not recommended for empiric use due to widespread E. coli resistance, but are frequently used in clinical practice.^2,4,9,10 Antipseudomonal agents can be reserved for severe cases and healthcare-associated infection.^3,4 Coverage of Enterococcus species with vancomycin is recommended in severe or healthcare-associated disease, or in immunocompromised patients.4,10 Anaerobic coverage with metronidazole is recommended in patients with a surgical history of biliary enteric anastomosis or for general prophylaxis.^4,10 This is due to a relative scarcity of anaerobe isolation in AC, and reports that anaerobic coverage for other indications does not improve outcomes.^2,3,11,12,13

Antibiotic treatment can be adjusted based on patient response and pathogen susceptibility data. TG18 and SIS/IDSA guidelines recommend a total of 4-7 days of therapy after source control is obtained, obstruction removed, and assuming absence of local complications (e.g., liver abscess).^4,10 In the presence of Gram-positive bacteremia, 2 weeks of therapy is recommended.⁴

Timing of Biliary Decompression

Several studies, mostly related to ERCP, have assessed clinical outcomes in AC patients with regards to time-to-intervention but a clear consensus has not been well defined. Based on findings of improved mortality in patients with Grade II (moderate) disease that received biliary drainage within 48 hours, TG18 generally recommends decompression within 48 hours in patients.^5,7 In practice, however, sometimes patients are too unstable to undergo a drainage procedure and require more time before biliary decompression. The recommendation for 48 hours as a general cutoff is supported by investigators who found worse outcomes (persistent organ failure, longer hospitalization, relapse, or mortality) in patients with further delayed decompression.^{14, 15, 16, 17, 18} In contrast, other accounts favor decompression within 24 hours, mostly on the basis of shorter hospitalization.^{16,17,19,20,21} A recent study describes outpatient management of AC after endoscopic drainage, suggesting that early intervention in mild to moderate disease can prevent hospitalization altogether.²² Patients with septic shock or critical illness appear to warrant early decompression after appropriate resuscitation, with significantly improved mortality reported when decompressed before 12 or 24 hours, respectively.^23,24

Biliary Drainage Techniques

Biliary drainage is recommended for all cases of AC, irrespective of severity.²⁵ Techniques for biliary decompression are broadly categorized into endoscopic, percutaneous, and surgical.

Endoscopic Biliary Drainage

ERCP biliary decompression by direct cannulation of the major duodenal papilla is the gold standard for acute cholangitis.^25,26 This is due to high success rates, minimally invasive nature, and fewer adverse events compared to percutaneous or surgical procedures.^26,27,28,29 Disadvantages, however, include need for sedation.³⁰ Endoscopic duct clearance by sphincterotomy, balloon extraction, and/or endoscopic stenting for strictures is performed as needed. Patients in whom stone extraction cannot be performed can simply undergo stent placement. An additional adjunctive technique is direct cholangioscopy with lithotripsy. Nasobiliary drains are rarely used in modern practice.^26,27,31 Balloon-assisted enteroscopy ERCP (BE-ERCP) is recommended in cases of altered postoperative anatomy.²⁵ Endoscopic ultrasound biliary drainage (EUS-BD) is a relatively new and developing technique, though current data are largely related to obstructive jaundice generally, and not specific to cholangitis. Several studies indicate that EUS-BD, in the hands of experienced endoscopists, is an effective alternative after failed ERCP and may outperform percutaneous drainage.^{32,33,34,35,36,37,38} EUS-BD may also represent a feasible approach in patients with surgically altered anatomy.³⁹ Research into the optimal tools and techniques to perform EUS-BD is ongoing.

Percutaneous Biliary Drainage

Percutaneous techniques include percutaneous transhepatic biliary drainage (PTBD) and percutaneous cholecystostomy (PC). PTBD is currently the recommended alternative to traditional ERCP drainage and may be required when endoscopy is unavailable or contraindicated (e.g., unusual anatomy) or after failed ERCP.25 PTBD usually involves local anesthesia, puncture of an intrahepatic duct with a fine needle under US or fluoroscopy, and placement of a drain. Successful needle placement requires ample intrahepatic ductal dilatation.⁴⁰ PTBD is second-line to ERCP due to invasiveness, common requirement for additional procedures, and higher rate of adverse events.25,29,37 PTBD is primarily used to provide biliary drainage, whereas stone removal is much less commonly performed via this route. Patients with stones and AC often require ERCP at a later time to remove the stones from the biliary tree, usually via sphincterotomy and balloon/basket extraction. PC, though rarely used for this indication, can be a useful alternative to PTBD, especially if intrahepatic duct dilation is insufficient to allow a successful transhepatic approach.^41,42

Surgical Biliary Drainage

Surgical drainage of the biliary ducts is generally thought of as the last option after unsuccessful endoscopic or percutaneous intervention.²⁵ This is primarily due to high success rates of less invasive techniques and observations of higher mortality compared to other less invasive methods.^1,25,28

CONCLUSION

Ascending cholangitis is a treatable illness with practice guidelines in place to assist in guiding diagnosis, severity grading, antibiotic selection, and therapeutic intervention. Use of the diagnostic and severity grading criteria reliably identifies patients and provides prognostic information. Antimicrobial selection is based on community isolate resistance patterns. ERCP remains the most common procedure selected for biliary drainage. PTBD is an acceptable alternative, with EUS-BD gaining acceptance as experience broadens.

A Case Report

Single Cause, Dual Presentation: Inferior Pancreatico-Duodenal Artery Pseudoaneurysm as a Cause of Acute Gastrointestinal Bleeding and Obstructive Jaundice

October 2018 • Volume XLII, Issue 10

Mir Adil Shamim,Rupinder Mann,Steven Lichtenstein

Pseudoaneurysms of the inferior pancreaticoduodenal artery are rare. We report a case of chronic pancreatitis-related inferior pancreaticoduodenal artery pseudoaneurysm that resulted in obstructive jaundice and life-threatening bleeding. This case highlights both of these complications, and it also reflects on the importance of a multidisciplinary and multimodal approach to diagnosis and management. Anticipating potential complications and intervening at the right time can prevent fatal consequences in such patients.

INTRODUCTION

Inferior pancreaticoduodenal artery pseudoaneurysms are rare. The most common causes include abdominal trauma, acute or chronic pancreatitis, septic emboli and laparoscopic cholecystectomy. This is in contrast to true aneurysms which are caused by arteriosclerosis, congenital disease or stenosis of celiac trunk.¹ Pseudoaneurysm rupture is more likely to cause gastrointestinal (GI) bleeding whereas true aneurysm rupture mostly causes a retroperitoneal bleed.¹ We present a case of a life-threatening GI bleed from a pseudoaneurysm of the inferior pancreaticoduodenal artery, also causing obstructive jaundice by virtue of its size and location. Case

A 45-year-old male with past medical history of chronic pancreatitis from alcohol use presented with severe right upper quadrant abdominal pain. On exam, he had exquisite right upper quadrant abdominal tenderness and scleral icterus. Vitals signs were stable on initial presentation (Blood pressure: 144/68mmHg, Pulse: 74/min, Resp: 18/min, O2 sat: 100% on room air). Labs revealed microcytic hypochromic anemia (Hb: 6.1, Hct: 20.3, RDW: 25.2), and abnormal liver enzymes with a cholestatic pattern (alkaline phosphatase 416 [reference range {RR} 45-115 U/L], gamma glutamyl transferase (GGT) 230 (RR 10-66)U/L, aspartate aminotransferase (AST) 76 (RR 8-40)U/L , alanine aminotransferase (ALT) 132 (RR 7-60)U/L, total serum bilirubin 4.4 (RR 0.2-1.2)mg/dL, direct bilirubin 3.4 (RR 0-0.3) mg/dL.

Computed tomography (CT) scan of the abdomen with intravenous contrast (Image 1a and 1b) showed a pseudoaneurysm measuring 65 x 41 mm arising from the inferior pancreaticoduodenal artery. In addition to evidence of acute on chronic pancreatitis, there was obstruction of the biliary tree due to mass effect from pseudoaneurysm, new marked intra and extrahepatic biliary dilation (common bile duct measuring up to 17 mm) and gallbladder distension. Mesenteric angiography (Image 2) also revealed the aneurysm but was felt not to be amenable to embolization. Overnight, the patient became hypotensive and his abdominal pain worsened. Stat CT angiography of the abdomen showed an increase in size of the pseudoaneurysm to approximately 67 x 43 mm. Hyperdense material was noted within a moderately distended stomach and dilated small bowel loops, new from the most recent previous CT, concerning for GI hemorrhage. After initial stabilization, the patient underwent exploratory laparotomy with distal gastrectomy along with duodenotomy with suturing of the pseudoaneurysm with anterior abdominal closure.

Following the procedure, his liver enzymes trended to normal. The course was complicated by delirium, multi-organ failure, pneumonia, prolonged ventilator dependent respiratory failure, severe protein-calorie malnutrition requiring total parenteral nutrition and tube feedings via jejunostomy tube. The patient was eventually discharged to a long-term acute care facility.

DISCUSSION

A bleeding pseudoaneurysm is a rare and potentially life threatening complication of chronic pancreatitis.² As a complication of chronic pancreatitis, pseudoaneurysms most commonly occur in the splenic artery, followed by the gastroduodenal, pancreaticoduodenal and hepatic arteries.⁹ Given the history of chronic pancreatitis with multiple severe acute exacerbations, it is the most likely cause of the pseudoaneurysm (of inferior pancreaticoduodenal artery) in our patient. Once formed, they can cause direct pressure over the pancreaticobiliary ducts, leading to recurrent bouts of acute pancreatitis and jaundice.

Some proposed mechanisms for pseudoaneurysmformation due to pancreatitis include: severe inflammation contributing to local spread of proteolytic enzymes causing auto digestion of pancreatic or peripancreatic arterial tissue, weakening of the vessel wall, producing arterial disruption and erosion of a long standing pseudocyst directly into a visceral artery potentiated by virtue of the enzymatic content of fluid especially if there is communication with the pancreatic ductal system.^2,3,4 Risk factors include necrotizing pancreatitis, sepsis, multi-organ failure, previous history of procedures such as necrosectomy, Whipple procedure or underlying vasculitis.⁸ Pseudoaneurysm formation after a surgical procedure is a late complication, mostly occurring days to weeks after the procedure.⁸

Abdominal computed tomography (CT) is the most commonly used noninvasive test for diagnosing pseudoaneurysms with a sensitivity of 80-100%. It can detect partial thrombosis or the effect on adjacent viscera, however, carries risks of exposure to ionizing radiation and intravenous iodinated contrast. Abdominal ultrasound (US) has limited ability to detect aneurysms.10 Mesenteric angiography is the gold standard diagnostic test that precisely identifies the feeding artery.^1,5,8 It has a sensitivity of 100% in detecting arterial bleeding due to pseudoaneurysms.^8,6 Smaller lesions which could be missed on other imaging modalities can also be identified.⁸ A fatal complication of pseudoaneurysms is acute hemorrhage. The mortality is 90-100% in untreated patients and remains 12-50% even with aggressive treatment.⁵ Pseudoaneurysms may bleed into the gastrointestinal tract, retroperitoneum, biliary tree (hemobilia), pancreatic ducts (hemosuccus pancreaticus), peritoneal cavity and pseudocysts, resulting in massive hemorrhage.⁸ Clinically, ruptured pseudoaneurysms present as abdominal pain, anemia or gastrointestinal (GI) bleeding. Bleeding can be chronic or acute leading to hemorrhagic shock.^5,6,7 Local inflammation or mechanical compression by virtue of the size of the aneurysm may lead to biliary and/or pancreatic duct compression resulting in obstructive jaundice and/or acute pancreatitis. Similarly, compression of the adjacent portal system may lead to variceal formation and eventual hemorrhage.⁸ Our patient had developed common bile duct obstruction and features of obstructive jaundice from the recent increase in the size of the aneurysm.

Two major treatment modalities (radiologic and surgical) are available, based on the location of pseudoaneurysm and hemodynamic stability. These include angiographic embolization and surgical treatment. Angiographic therapy has been reported to have a high success rate, ranging from 79-100% and has been associated with shorter lengths of stay as compared to surgery.⁸ Real time ultrasound guided thrombin injections have been reported to be of value, however, the efficacy is not well established. Surgical ligation of the feeding vessel can be attempted, however, if this fails, pancreatectomy may be required. A Whipple procedure may be needed for pseudoaneurysms near the pancreatic head.⁸ In general, this potentially lethal complication of chronic pancreatitis should be treated as an urgent situation, and a multidisciplinary approach covering diagnostic and therapeutic interventions including angiography, surgery and endoscopy may be needed to manage it optimally.

Liver Disorders, Series #8

Approach to Liver Disease in Pregnancy

October 2018 • Volume XLII, Issue 10

Hamza Arif,

Helen Lee,

Cristina Strahotin

Liver disease in pregnancy is a rare phenomenon, but its presence represents a challenging scenario as it can have harmful effects on both the mother and the fetus. Certain liver diseases are unique to pregnancy only, including hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, preeclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and acute fatty liver of pregnancy. In this article we discuss the management of these disorders as imperative to avoid development of maternal and fetal complications.

Hamza Arif, MD¹ Helen Lee, MD² Cristina Strahotin, MD³ ¹Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA ²Division of Gastroenterology, University of Pennsylvania, Philadelphia, PA ³Division of Gastroenterology, Hepatology and Nutrition, Allegheny Health Network, Pittsburgh, PA

INTRODUCTION

Liver disease in pregnancy is a rare phenomenon, occurring in 2-3% of pregnancies.¹ The presence of liver disease, however, can represent a challenging scenario as it can have harmful effects on both the mother and the fetus.² Certain liver diseases are unique to pregnancy only; these include hyperemesis gravidarum (HG), intrahepatic cholestasis of pregnancy (ICP), preeclampsia, acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. Concurrently, pregnant patients remain susceptible to acquiring liver disorders that may be encountered in general population including viral hepatitis or gallstones, whereas some diseases may predate pregnancy such as autoimmune hepatitis or Wilson disease.

Normal Physiology

Heart rate and cardiac output increase in pregnancy but systemic vascular resistance is reduced. Overall, these physiological changes lead to lowering of systemic blood pressure and a hemodynamic state mimicking decompensated liver disease.³ Elevation of alkaline phosphatase due to additional production from placenta may be observed as a normal change in liver enzymes in pregnancy. Conversely, increase levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and bilirubin may suggest a pathological process.⁴

Liver Diseases Unique to Pregnancy

Liver diseases unique to pregnancy can be divided by their predominance in a particular trimester. It must be noted that although some of these liver disorders may be specific to a one trimester, most overlap between trimesters and may even be present post-partum.

First Trimester
Hyperemesis Gravidarum (HG)

Hyperemesis gravidarum (HG) usually presents in the first half of pregnancy and typically resolves within 4-6 weeks of the second trimester. It has an incidence of 0.3-2% and with predisposition in pregnant females with increased body-mass index, molar pregnancy, multiple pregnancies and patients with co-morbid conditions such as diabetes.⁵ Clinical features include intractable vomiting that can result in dehydration and ketosis.

Mild elevation of serum bilirubin and aminotransferases is common while other biochemical abnormalities, likely related to the underlying symptoms, may also be observed including hypokalemia, hypomagnesemia and elevation of serum creatinine. Vomiting may be severe enough to cause weight loss along with ketonuria that is a diagnostic finding. Viral hepatitis should be ruled out during the workup as it may also present with similar clinical features.

HG is associated with premature delivery, low birth weight and small for gestational age babies but is not linked with perinatal death.⁶ Management is supportive with anti-emetics and intravenous (IV) fluids. Thiamine supplementation is necessary to prevent Wernicke’s encephalopathy.⁷ Recurrence of HG is common, with a risk of 15% in the second pregnancy compared to 0.7% without a prior history of hyperemesis.⁸

Second and Third Trimester
Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disease unique to pregnancy. It is more common in multiple gestation pregnancies, with prevalence of 0.4 – 5%.^9,10 ICP typically presents in the second half of pregnancy but can even occur in the first trimester. Patients present with pruritus, usually involving the palms and the soles of the feet, which may be worse at night. Jaundice can also occur but is not as common as pruritus. ICP is characterized by elevation of serum aminotransferases, up to 10 to 25 times upper limit of normal (rising to >1,000 U/L), and bile acids. Fat-soluble vitamin deficiencies may also be observed, which can lead to reduction of vitamin K-dependent coagulation factors and subsequent elevation of prothrombin time. Bile acid levels of >10 µmol/l is diagnostic of ICP but levels of >40 µmol/l are associated with adverse outcomes in pregnancy and fetal complications such as spontaneous preterm deliveries, asphyxia events and meconium staining of amniotic fluid, placenta and membranes.¹¹

Management focuses on both controlling the symptoms and preventing complications along with close monitoring of the fetus. First-line treatment is ursodeoxycholic acid (UDCA), given at 10-15mg/kg maternal body weight. UDCA not only improves pruritis, but also improves bile acid levels and serum aminotransferases. Most importantly, this decrease in bile acid levels can lead to reduction in adverse fetal outcomes such as prematurity and fetal distress.¹² S-adenosyl methionine (SAMe), a glutathione precursor that results in excretion of biliary salts by methylation of hormone metabolites, has also been used as a treatment modality.¹³ However, a meta-analysis revealed that SAMe alone was not as effective as UDCA in improvement of pruritus, serum ALT levels or total bile acids.¹⁴ Dexamethasone may improve lung maturity in the fetus but does not have a significant role in treatment of ICP. Delivery at 37 weeks is recommended to avoid the risk of intra-uterine death.¹⁵ Adequate nutritional status maintenance is important, particularly in patients with severe steatorrhea.

Pruritus usually resolves within a few days of delivery followed by normalization of elevated liver enzymes and bile acids. These tests may be repeated 6-8 weeks after delivery. Elevated bilirubin levels at the time of diagnosis or failure of resolution of cholestasis should prompt further investigation into alternative causes. Rarely, such as in familial cases, ICP will lead to chronic liver disease after delivery with cirrhosis and fibrosis.¹⁴ Therefore, patient follow-up after delivery should be continued in the outpatient setting. Recurrence of ICP is common, in up to 60-70% of subsequent pregnancies.

Preeclampsia

Hypertension in pregnancy, defined as blood pressure of ≥140/90 mmHg, has been associated with adverse outcomes in both the pregnant mother and the fetus. Preeclampsia is now described by International Society for the Study of Hypertension in Pregnancy (ISSHP) as de-novo hypertension present after 20 weeks gestation combined with proteinuria (≥300 mg/24h), other maternal organ dysfunction, including liver involvement, renal insufficiency, neurological or hematological complications, uteroplacental dysfunction, or fetal growth restriction.¹⁶ Complications of the liver include hepatocellular injury, hepatomegaly and hepatic rupture.

Risk factors for this disorder include extremes of age (less than 16 years old or greater than 45 years old), nulliparity, prior history of hypertension, previous preeclampsia episode or positive family history of preeclampsia.³ Although clinical presentation is variable, patients are mostly asymptomatic, but they may present with right-sided abdominal pain, nausea and vomiting along with headaches and visual disturbances. Liver enzymes may be deranged with elevation of serum aminotransferases predominantly.

Although hypertension control is important, delivery is the definitive treatment. This should be urgent if diagnosis is made at >34 weeks to prevent further complications such as eclampsia or hepatic rupture.¹⁷ For a fetus of less than 34 weeks, corticosteroids may be indicated to improve the maturity of fetal lung followed by delivery.

The United States Preventive Services Task Force (USPSTF) recommends using low-dose aspirin (81 mg/d) after 12 weeks of gestation in women who are at high risk for preeclampsia as a preventive medication (grade B recommendation).¹⁸ They define high risk factors as hypertensive disease during prior pregnancy, chronic kidney disease, autoimmune disease, type 1 or type 2 diabetes, chronic hypertension or multiple pregnancies. Of note, however, the American College of Gastroenterology (ACG) and American Association for the Study of Liver Diseases (AASLD) currently do not endorse this recommendation.

Abnormal liver enzymes tend to resolve within a couple of weeks after delivery. Patients should be followed-up regularly with yearly observation of their blood pressure as well as blood glucose and lipid profile.

Hemolysis, Elevated Liver Enzymes and Low Platelets (HELLP) Syndrome

Hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome characterizes severe features of preeclampsia. It manifests in 0.1 – 0.9% of pregnancies but may lead to complications in up to 20% of patients with preeclampsia.¹⁹ HELLP syndrome typically occurs after 20 weeks of gestation and but nearly one third of cases can occur post-partum.²⁰ Risk factors for HELLP syndrome are comparable to preeclampsia including nulliparity, prior history of hypertension or previous episode of HELLP syndrome. Clinical features of HELLP syndrome may also be similar to preeclampsia. Patients may have epigastric or right upper quadrant abdominal pain, nausea and vomiting as well as occasional headaches and visual disturbances. Hypertension may be present but HELLP syndrome can also occur in normotensive patients.

Complications of HELLP syndrome include development of renal failure, pulmonary edema, disseminated intravascular coagulation (DIC), and maternal death.^20,21 Subcapsular liver hematomas may be present in 0.9% of patients with HELLP syndrome.²⁰ Hepatic rupture can occur in 1-in-45,000 to 1-in-225,000 deliveries with associated maternal mortality rates of 60-86%.²² Perinatal mortality due to maternal complications and prematurity has also been reported in up to 70% of cases.¹⁹ The diagnosis of HELLP syndrome is established when a patient has hemolytic anemia, with lactate dehydrogenase (LDH) of > 600 U/L, elevation of liver enzymes including serum aminotransferase and reduced platelet counts of <100 k/mcL.^23,24 Increase in serum bilirubin levels may also be present. DIC should be considered in the presence of elevated prothrombin time and low fibrinogen levels. Hepatic imaging using computed tomography (CT) or magnetic resonance imaging (MRI) is preferred over ultrasonography to detect hepatic hematoma, infarction or rupture.²⁵ Imaging should be performed in all patients with HELLP syndrome that present with abdominal, neck or shoulder pain or elevation of aminotransferase of > 1,000 U/l to rule out hepatic complications.²³

Patients with HELLP syndrome need to be closely monitored. The plan should include stabilizing the mother while assessing for fetal distress and determining if urgent delivery is indicated. Just as with preeclampsia, in a pregnancy with >34 weeks of gestation, the decisive treatment is delivery. A fetus of <34 weeks of gestation, in the absence of complications, may benefit from glucocorticoids to improve fetal lung maturity after the mother has been stabilized, but delivery should not be delayed beyond 48 hours of presentation. Small or contained hematomas may be managed with supportive treatment but in patients with hepatic rupture who are hemodynamically stable, percutaneous embolization of hepatic artery may be preferred.^25,26 Surgery is reserved for hemodynamically unstable patients or those with persistent bleeding.

Patients with HELLP syndrome tend to improve after delivery but a small risk of recurrence persists in subsequent pregnancies. Liver enzymes tend to normalize 48 hours postpartum.

Acute Fatty Liver of Pregnancy (AFLP)

Acuter fatty liver of pregnancy (AFLP) is a rare but lethal phenomenon that generally presents in the third trimester, occurring in 1 in 10,000 pregnancies.²⁷ Risk factors for AFLP include multiple gestations and underweight women.²⁸

AFLP has been linked to an inherited defect in mitochondrial beta-oxidation. This fetal mitochondrial beta-oxidation defect, specifically, in the enzyme long-chain 3-hydroxyacyl coenzyme A dehydrogenase (LCHAD), results in the accumulation of fatty acids in hepatocytes and maternal circulation.^29,30 This eventually leads to hepatic failure and encephalopathy.

Patients may have complaints of epigastric pain, nausea and vomiting. However, they could also present with serious complications of AFLP such as pulmonary edema, renal or liver failure, proteinuria or DIC. Laboratory work may reveal hypoglycemia as well as elevated serum aminotransferases, bilirubin, ammonia and serum creatinine. Liver biopsy, although not usually performed, may show microvesicular fatty infiltration. The Swansea Criteria has been validated for diagnosis of AFLP. It requires six or more positive clinical or laboratory findings in the absence of another cause (Table 2). It has a positive predictive value of 85% and negative predictive value of 100%.³¹

AFLP is associated with fatal outcomes for the fetus and the mother, and maternal mortality rates of 12.5% have been reported.2,27 Like HELLP, treatment of AFLP requires stabilization of the mother, including resuscitation, as well as immediate delivery. Symptoms and laboratory abnormalities usually improve thereafter, but the patient may require monitoring in the postpartum period. Fulminant liver failure from AFLP may necessitate the need for liver transplant.³² Infants born to mothers with AFLP should undergo testing for LCHAD deficiency mutation. Recurrence of AFLP can manifest in future pregnancies if a patient has a mutation for LCAHD deficiency, but it may also occur in those patients without this specific mutation.³³

Liver Diseases Not Unique to Pregnancy
Cirrhosis and Portal Hypertension

Pregnancy is less common in patients with cirrhosis because of decreased fertility due to derangements in metabolic and hormonal balances that may result in anovulation. Gonadotrophin release is reduced in cirrhosis secondary to hypothalamic-pituitary dysfunction. This, combined with increased serum estradiol and testosterone levels in portosystemic shunts, can result in low fertility.³⁴

A pregnant cirrhotic mother presents a unique challenge as these patients are at a higher risk of developing complications that can affect both the mother and the fetus. These patients remain at risk for liver decompensation, including variceal bleeding, encephalopathy and ascites. There is also an increased risk of preterm labor and spontaneous loss of pregnancy.³⁵ Maternal mortality rates remain elevated at 18-50% from gastrointestinal bleeding.³⁶ These numbers have improved recently due to more urgent management of variceal bleeding and liver failure.³⁵

As the plasma volume expands in pregnancy, patients with portal hypertension may develop variceal bleeding, observed in nearly 30% of pregnant cirrhotic patients.37 Although no formal guidelines exist for screening prior to pregnancy, it is reasonable to perform pre-conception screening for varices just like for other cirrhotic patients.^38,39 Patients should also undergo repeat screening in the second trimester if varices were not observed on preconception screening esophagogastroduodenoscopy (EGD) given the increased variceal bleeding risk in pregnancy.⁴⁰ Varices observed on EGD should be treated with endoscopic variceal ligation. Non-selective beta-blockers, such as propranolol, are also indicated in management of esophageal varices in pregnancy despite potential adverse effects such as hypoglycemia, retardation of intrauterine growth and neonatal bradycardia.

Treatment of an acute variceal bleed is similar in both pregnant and non-pregnant females. Patients should receive IV fluids resuscitation and appropriate transfusion of blood products, antibiotic prophylaxis, octreotide and endoscopic therapy to achieve hemostasis. TIPS and liver transplant have also been described in patients with severe variceal bleeding, but this is not commonly practiced. As prolonged vaginal delivery is also associated with an increased risk of variceal bleeding, a short second stage of labor in vaginal delivery is preferable.⁴⁰ Cesarean section may also be considered but it is associated with increased bleeding risk. Further studies are still needed to determine the safest mode of delivery. Other complications of cirrhosis, including ascites and hepatic encephalopathy may also be observed in pregnancy but they are managed the same as in non-pregnant patients.³⁸

Viral Hepatitis

Viral hepatitis in a pregnant patient may be acute or chronic. These viral infections may account for up to 40% of jaundice in pregnant patients.⁴¹ The presence of hepatitis B virus (HBV) poses no risk to mother unless cirrhosis is present. However, the number of at-risk infants is increasing with an estimated 25,000 infants at risk for vertical transmission of HBV in the United States.⁴² The American College of Obstetricians and

Gynecologists (ACOG) recommends screening all pregnant women for hepatitis B at the first pre-natal visit.⁴³ Management with antivirals is avoided in women of childbearing age or in the first trimester of pregnancy as exposure to the medical treatment can result in adverse effects on organogenesis in the fetus. If the pregnant patient is known to have cirrhosis or fibrosis, however, the treatment may be initiated or continued. AASLD and ACG guidelines recommend antivirals in the third trimester of pregnancy if patients have positive hepatitis B surface antigen (HBsAg) and subsequent HBV DNA >200,000 IU/mL.^40,44 The treatment should continue until birth or three months postpartum. Perinatal transmission of hepatitis B when HBV DNA < 200,000 IU/mL has not been reported. Although positive hepatitis B e antigen (HBeAg) has also been linked to increased rate of transmission, the presence of HBV DNA is the most important predictor of persistent infection in the infant.⁴⁵ Tenofovir and telbivudine are first-line therapies for HBV infection. A high-risk pregnant patient with negative hepatitis B surface antibody (HBsAb) may be vaccinated safely during pregnancy. Infants born to HBV-infected mothers should receive both hepatitis B immune globulin (HBIG) and the hepatitis B vaccination series, which provide passive and active immunization respectively. The first dose of the vaccine should be delivered within 12 hours of delivery while the additional two doses are administered within 6-12 months. These interventions appear to have reduced the rate of transmission from more than 90% to less than 10% presently.⁴⁴ Current guidelines do not favor one mode of delivery over the other; therefore, elective cesarean section and vaginal delivery both remain an option. Breastfeeding is supported regardless of the mother’s treatment status.

Hepatitis C virus (HCV) infection, similarly to HBV, does not pose a risk to the mother unless she is cirrhotic. However, HCV was associated with a higher risk for preterm births in a meta-analysis.⁴⁶ Unlike HBV, current guidelines recommend screening for HCV in only those pregnant women with risk factors for HCV. Overall, mother-to-child transmission rates of up to 5% have been reported in HCV positive mothers but some co-morbidities are associated with an increase the rate of transmission.⁴⁷ Vertical transmission of HCV virus is enhanced to 19.4% if human immunodeficiency virus (HIV) co-infection exists, whereas intravenous drug use increases the rate of transmission to 8.6%.⁴⁷ Other risk factors that have been associated with increased risk of transmission include a viral load of more than 2.6 million and invasive procedures in pregnancy. Treatment of HCV is generally not pursued, as it usually does not require urgent therapy. Additionally, ribavirin is teratogenic and the new antivirals have not been well studied in pregnant patients thus far. Cesarean section and vaginal delivery both are an option for the patient as there are no guidelines favoring one mode of delivery to another. Breastfeeding is not discouraged if there is no skin breakdown or cracked nipples.

Acute hepatitis A virus (HAV) infections occur at the same frequency in pregnant and non-pregnant patients. HAV infection may increase gestational complications, including preterm labor, but overall, no differences in maternal and fetal outcomes has been observed.⁴⁸ Treatment is supportive, but it is recommended that a neonate receive HAV immunoglobulin if the mother has HAV infection within two weeks of delivery.⁴⁰

Acute hepatitis E virus (HEV) infection is the most common viral cause of acute liver failure in pregnancy.⁴⁹ Maternal and fetal mortality, as well as obstetrics complications, are significantly elevated in the presence of HEV infection. Fulminant liver failure has a reported mortality of 10-25% in pregnant women with HEV.⁵⁰ Therefore, all pregnant females presenting with acute hepatitis should have HEV-IgM levels checked. Management is supportive, although a successful liver transplant has been reported in a patient with acute liver failure from HEV infection.⁵¹

Herpes simplex virus (HSV) infection is a rare cause of liver failure in pregnancy even though pregnant females are at an increased risk of developing serious infections.⁹ Mortality has been reported to be as high as 74% in patients with HSV hepatitis,⁵² which should be suspected in patients who present with fever and elevated LFTs in the absence of jaundice. Pathognomonic mucocutaneous lesions are seen in <50% of the patients making the diagnosis challenging. HSV PCR is recommended to diagnose HSV infection due to the poor sensitivity and specificity of HSV-IgM testing. Nonetheless, as the results of HSV PCR may not be known immediately, if HSV infection is suspected, treatment with acyclovir should be promptly initiated. Acyclovir appears to be safe in pregnancy without an increased risk of birth defects in patients who have received this medication.⁵³

Gallstones

There is an increased risk for gallstone formation in pregnancy due to supersaturation of cholesterol, particularly in the second and third trimester of pregnancy. Decreased motility of the gallbladder in pregnancy and stasis of bile also promote lithogenicity. Gallstones can result in biliary colic, acute cholecystitis, or acute gallstone pancreatitis. Ultrasonography is a safe imaging modality that can be used to detect acute cholecystitis with a sensitivity of 85-95% and specificity of 95%.⁵⁴ In the past, conservative management with intravenous (IV) fluids, antibiotics and bed rest was the standard of care for pregnant patients with acute cholecystitis. Surgery was reserved for only those patients that failed conservative management. However, currently, it is recommended to perform laparoscopic cholecystectomy for symptomatic cholecystitis as this appears to be a safe procedure in pregnant patients.⁵⁵ Surgical interventions are also necessary in patients with intractable biliary colic and acute gallstone pancreatitis. As pregnant mothers with symptomatic cholelithiasis are at an increased risk of recurrent gallstones later in pregnancy, patients with episodes associated with severe complications should also undergo cholecystectomy.⁵⁶

Endoscopic retrograde cholangiopancreatography (ERCP) may be indicated for treatment of symptomatic choledocholithiasis, cholangitis, or biliary pancreatitis.48, 57 It is a safe procedure to perform in pregnancy, especially if exposure of fluoroscopy is minimized.⁵⁷ Complications of ERCP during pregnancy include post-ERCP pancreatitis, post-ERCP bleeding and pre-term births.^58,59

Autoimmune Hepatitis

Autoimmune hepatitis (AIH) may worsen in pregnancy or in the postpartum period.⁶⁰ Completion of pregnancy is possible if a patient’s disease is well managed but poor control of AIH is associated with prematurity.⁶¹ If a patient has a history of AIH, their maintenance medications should be continued during pregnancy. Azathioprine has the best safety data when compared to other immunosuppressants. While congenital malformations have been described in pregnant mice from azathioprine, it is associated with favorable outcomes in pregnancy in humans.⁶² Flares of the disease during pregnancy are usually treated with corticosteroid monotherapy,⁴⁰ but these flares can lead to hepatic decompensation and need for liver transplant or even death.

Wilson Disease

Wilson disease (WD) is an autosomal recessive disorder that affects biliary copper excretion resulting in deposition of copper in the brain, liver and kidneys. Patients typically present with elevated serum aminotransferases, hyperbilirubinemia and hemolytic anemia. Alkaline phosphatase levels may be low. Treatment should be maintained during pregnancy as interruptions can lead to liver failure.⁶³ Management of WD in pregnancy usually consists of zinc sulfate or chelating agents, penicillamine and trientine. AASLD recommends continuing zinc sulfate at the same dosage but the chelating agents should be dose-reduced by 25-50% to promote wound healing if cesarean section becomes necessary.⁶⁴ Patients on D-penicillamine are discouraged from breastfeeding due to concern for potential harm to the infant. Spontaneous abortions have been attributed to WD, particularly if it is poorly controlled.⁶⁵

Liver Transplant

Most patients with liver transplant have fertility restored within 6-12 months post-transplant, but higher rates of preeclampsia, preterm births and cesarean sections have been observed in these patients.⁶⁶ With the use of immunosuppressive medications including azathioprine, cyclosporine, tacrolimus and steroids, pregnant patients with history of a liver transplant can have a good quality of life.⁶⁷ Mycophenolic acid is avoided in pregnancy due to its association with congenital malformations and embryopathy.⁶⁸ Pregnancy should be avoided for at least one year following transplant to optimize graft function and subsequently, permit the use of a lower dose of immunosuppressive medications.³

Thrombosis

Pregnant women are at an increased risk for venous thromboembolism with an estimated incidence of 0.76 to 1.72 per 1000 pregnancies.⁶⁹ Pregnancy is associated with an increase in fibrinogen and clotting factors levels.⁷⁰ When thrombosis is observed, it is imperative to search for additional causes of hypercoagulable states due to a high recurrence risk.⁷⁰

Budd-Chiari syndrome (BCS) can be triggered by pregnancy. It is characterized by obstruction of hepatic venous outflow. Patients may complain of right upper quadrant pain, abdominal distention and jaundice. Ascites and icterus may be evident on examination. Although hepatic failure and portal hypertension are both common complications of BCS,⁷¹ anticoagulation therapy has improved fetal and maternal mortality.

Patients with a prior history of thrombosis should continue anticoagulation. Women on warfarin should be switched to low molecular weight heparin (LMWH) prior to conception due to the teratogenic effects of warfarin. Direct oral anti-coagulants (DOACs) are also teratogenic; therefore, these medications should be discontinued in pregnancy in favor of LMWH.⁷²

Medications and Pregnancy

Previously, medications used in pregnancy were assigned a risk category defined by the Food and Drug Administration (FDA) as A, B, C, D and X based on limited research data on their safety derived from animal and human studies. As this classification system was not able to completely elicit the risks versus the benefits of medical therapy and provided limited information on the medication’s effects in labor or lactation, the FDA introduced a new labeling system in June 2015. The new pregnancy and lactation labeling system includes narratives with general pregnancy information, fetal risk summary, clinical considerations and data on human and animal studies.⁷³

CONCLUSION

Pregnancy is associated with various physiological changes, affecting many organs, including the liver. It is important to differentiate between physiological and pathological processes in pregnancy to ensure timely diagnosis and management, particularly for the diseases unique to pregnancy. However, chronic liver diseases may present differently in pregnancy and that can pose a diagnostic and therapeutic dilemma.