Liver Disorders, Series #7

Metabolic Diseases of The Liver – A Review

September 2017 • Volume XLI, Issue 9
Long Le,Duminda Suraweera,Gaurav Singhvi

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Inherited metabolic liver diseases are a group of disorders caused by the pathologic accumulation of metals or misfolded proteins from disrupted normal metabolic pathways. The common diseases are hemochromatosis, Wilson disease (WD), alpha-1-antitrypsin deficiency (AAT) and glycogen storage diseases (GSD). New pathophysiologic understanding at the molecular level has changed clinical practice and research in recent years. This review article focuses on pathophysiology, clinical presentations, current management strategies and future directions.

Long Le, Duminda Suraweera, Gaurav Singhvi Olive View-UCLA Medical Center, Sylmar, CA

INTRODUCTION

Inherited metabolic liver diseases are a group of disorders caused by the pathologic accumulation of metals or misfolded proteins from disrupted normal metabolic pathways. The common diseases are hemochromatosis, Wilson disease (WD), alpha- 1-antitrypsin deficiency (AAT) and glycogen storage diseases (GSD). New pathophysiologic understanding at the molecular level has changed clinical practice and research in recent years. This review article focuses on pathophysiology, clinical presentations, current management strategies and future directions.

HEMOCHROMATOSIS
Pathogenesis

Hemochromatosis is a well-defined syndrome characterized by toxic accumulation of iron in the parenchymal cells of the liver, heart and endocrine glands. In normal homeostasis, iron load will trigger an interaction between various signaling proteins including HFE, transferrin receptor 2 (TfR2) and hemojuvelin (HJV) leading to the expression of hepcidin, an important hormone in iron homeostasis. Hepcidin binds to and causes the degradation of ferroportin (FPN) on the surface of duodenal enterocyte and macrophages.1 When ferroportin is down regulated, iron will not be released from enterocytes and macrophages into the plasma thus keeping plasma iron levels low. Hepcidin also inhibits enterocyte iron absorption from the gut. If one or more components of this pathway fails, hepcidin will not be expressed in sufficient quantity and plasma iron will rise leading to hemochromatosis.2 A defect to FPN will lead to hepcidin resistance and can result in hemochromatosis as well. In humans, hepcidin deficiency has been associated with HFE-associated, TfR2-associated and HJV associated hemochromatosis. Table 1.

The most well-known and most common form of hereditary hemochromatosis (HH) is HFE related hemochromatosis. This variant of the disease is associated with the homozygous polymorphic variant of the C282Y allele of the HFE gene. C282Y allele frequency is about 6%, and its prevalence of homozygosity among Caucasian is 1:2000 to 1:3000. A low penetrance of about 2% means disease manifestation is rare.

Clinical Presentation

The clinical presentation of hemochromatosis can vary widely depending on which organs are involved and the severity of iron overload. Symptoms range from simple laboratory abnormalities (elevated serum aminotransferase levels) to severe end organ damage (cirrhosis, liver fibrosis, hepatocellular carcinoma (HCC), restrictive cardiomyopathy, congestive heart failure, arrhythmia, gonadal dysfunction, glucose intolerance, diabetes). Environmental factors that could increase the risk of end organ damage includes excess alcohol consumption, pre-existing hepatic steatosis and coexisting viral hepatitis.3 However, the classic presentation of diabetes, skin pigmentation and cirrhosis has become increasingly uncommon given more sensitive lab tests and increased awareness of the disease. Typical symptoms include malaise, fatigue, decreased libido, arthralgia and hepatomegaly. The majority of the cases of hemochromatosis are diagnosed after detecting elevated serum transferrin-iron saturation (TS) and serum ferritin (SF) levels. In general, males usually have worse manifestation of the disease. Their ferritin levels are usually higher (>200 ug/L for females and > 300 ug/L for male); excess tissue iron (>25 umol/g liver tissue) is more common in males.

Diagnosis

The diagnosis of hemochromatosis should be considered in patients with the above non-specific symptoms and abnormal liver tests. Middle age men of Caucasian origin are especially susceptible. TS is almost always increased in affected patients. As the disease progresses, serum ferritin begins to rise indicating the accumulation of iron in tissue. If either test is abnormal (TS > 45% or ferritin above the upper limit of normal), then HFE mutation analysis should be performed. Serum ferritin can also be elevated in other conditions such as infection, alcoholic liver disease, chronic hepatitis B and C and nonalcoholic fatty liver disease. If the HFE mutation analysis shows C282Y heterozygosity or non-C282Y mutation, one should exclude other liver/hematologic diseases and consider liver biopsy. Figure 1.

Management

Once the diagnosis has been confirmed with genetic testing, the next step is to determine if liver biopsy is warranted. A ferritin level of > 1000 ug/L is associated with 20%-45% risk of having cirrhosis, therefore liver biopsy is recommended. Once the diagnosis has been confirmed, all first degree relatives should also be screened with gene testing.3

Despite the lack of randomized controlled trial of phlebotomy versus no phlebotomy, there is substantial evidence that early intervention will reduce morbidity and mortality of HH.4 In a survey of 2500 patients, “86% of patients reported some or all symptom improvement with phlebotomy and 65% of patients agreed that benefits of treatment outweighed the difficulties”.5 Treatment should be initiated in: 1) symptomatic patients and 2) asymptomatic patients with homozygous C282Y and markers of iron overload or increased level of hepatic iron.6 The removal of iron will relieve malaise, fatigue, skin pigmentation, abdominal pain, abnormal liver enzymes and even insulin requirements for diabetics.6 However, certain features of the disease are irreversible such as arthropathy, hypogonadism and advanced cirrhosis. Patients with cirrhosis should be screened for HCC.

Phlebotomy should be performed as follows: one unit (500cc) of blood should be removed weekly or biweekly with hemoglobin and hematocrit (H/H) check prior to avoid H/H from falling > 20% of the starting value. Ferritin should be checked every 10 phlebotomy sessions with a goal level of 50-100 ug/L. Most patients require maintenance phlebotomy to stay at goal. The frequency of maintenance therapy varies among patients. Dietary adjustments are not necessary in the treatment of hemochromatosis.3,6

WILSON DISEASE
Pathogenesis

Wilson disease is an autosomal recessive disease in which copper homeostasis is disrupted, leading to end organ damage from copper accumulation in tissues. Copper plays an important role in many cellular processes and serves as a co-factor for many enzymes such as cytochrome c oxidase (mitochrondial oxidation) and dopamine beta – hydroxylase (catecholamine production).7 In its free form, copper has high redox potential, and it can degrade cellular structures if left unescorted by its chaperone proteins.

Central to copper homeostasis is the ATP7B gene which codes for a copper-transporting P type ATPase. The ATP7B protein is expressed most abundantly in the liver cells and has been localized to the trans-Golgi network within a cell. The ATP7B protein functions to incorporate free copper to apoceruloplasmin to form a 6 copper binding structure known as ceruloplasmin. Ceruloplasmin carries up to 90% of copper in the plasma and also stores copper in peripheral tissues.8 Mutations to the gene can change the protein structure and functions that will lead to toxic accumulation of copper in the liver and brain. Wilson disease may present with hepatic, neurologic or psychiatric manifestations.

Clinical Presentation

Similar to hemochromatosis, Wilson disease’s clinical course is highly variable. In general, there are two forms of the disease; the predominantly hepatic form and the predominantly neurologic form. The hepatic form onset is usually earlier than that of neurologic form by several years, but most patients eventually develop both.7

The predominantly hepatic form affects about 40% of patients, and symptoms can vary from asymptomatic elevated liver enzymes, chronic hepatitis to liver cirrhosis and liver failure. It is often associated with a coombs-negative hemolytic anemia, acute renal failure and coagulopathy.9 Initial presentation could be as subtle as transient episodes of jaundice due to hemolysis.

In the predominantly neurologic form, initial symptoms may be mild and nonspecific. Characteristics symptoms include asymmetric tremors that can involve the trunk and head. Dystonia is another common symptom which presents in 10 to 60% of patients and is characterized by the abnormal posture of various body segments (involuntary head rotation, shoulder elevation, forceful eye closure, etc.). Memory decline, change in hand writing and lack of coordination have also been documented.7,9

Up to 10% patients exhibit non-specific psychiatric symptoms including attention deficit, depression, mood swings and even psychosis. Fortunately these symptoms may resolve with adequate therapy.7

Diagnosis

The diagnosis of Wilson disease is challenging given the non-specific symptoms and variable clinical course. Clinicians should suspect Wilson disease in patients with liver abnormalities with or without typical neurologic symptoms. See Figure 2 for diagnostic algorithm. A liver ultrasound is needed to assess for signs of cirrhosis.7

Management

All patients require lifelong drug therapy with liver transplant being the curative treatment in specific patient populations. Available treatments include chelators such as trientine and D-penicillamine or copper absorption inhibitors such as zinc salt.

D-penicillamine acts as copper chelating moiety. It also promotes urinary excretion of copper and induces production of metallothionein, an endogenous copper chelator. Trientine is another chelator that works by forming a stable complex with copper and promotes its urinary excretion. Zinc salt inhibits intestinal copper absorption by stimulating an endogenous copper chelator called metallothioneine.

Initial treatment focuses on having a negative copper balance with either of the chelators mentioned above. Treatment for this initial phase could last up to 6-12 months while aiming for a 24 hour urinary copper level of 800-1000 ug per day.10 The maintenance phase of therapy is done with either low dose chelators (compared to initial treatment) or zinc salts with the aim of 24 hour urinary copper secretion being approximately 200-500 ug per day. First degree relatives of any new patient must also be screened for Wilson disease.10 Zinc is also recommended in the presymptomatic stage of Wilson disease given its favorable side effect profile.

Liver transplantation is the only curative treatment and it should be considered in patients with fulminant hepatic failure or end-stage cirrhosis. The effect of a low copper diet remains unknown. Gene therapy and stem cell research showed some early promise in animal studies but needs further study.7,9

ALPHA 1 ANTITRYPSIN DEFICIENCY
Pathogenesis

Alpha-1-antitrypsin (AAT) is a glycoprotein synthesized in liver cells and other tissues. It inhibits a wide range of proteases including pancreatic trypsin, cathepsin G and neutrophil elastase, which plays an important role in host defense.11

AAT deficiency is an autosomal co-dominant condition. AAT is encoded by the SERPINA1 gene (also known as Pi for protease inhibitor). AAT can be deficient either qualitatively or quantitatively. There are many Pi mutations both heterozygous and homozygous, that can lead to low level, non-functional or complete absence of AAT. The terminology Pi MM (protease inhibitor, genotype MM, Pi MZ, Pi ZZ) is used. AAT deficiency primarily affects the lungs and liver by two different mechanisms: polymerizations in the liver and elastase over activity in the lungs.12

In the lungs, Z or null mutation results in ineffective and low level of AAT leading to elastase over activity which causes emphysema. In the liver, the Z variant causes conformational changes in the AAT protein leading to their polymerizations and subsequent accumulation in hepatocyte endoplasmic reticulum. This accumulation of misfolded protein is thought to lead to apoptosis and cirrhosis, though the exact mechanism remains unclear. The proposed pathophysiology has been supported in animal models where the over expression of Z allele is associated with cirrhosis.13 Table 2.

Clinical Presentation

In the lungs, the most common presentation of AAT deficiency is early onset emphysema usually in the 4th or 5th decades of life, notably in patients without a significant smoking history. Emphysema from AAT deficiency disproportionately affects the lung bases and is usually panacinar in pathology.12

In the liver, the disease follows a bimodal distribution of neonatal hepatitis and cholestatic jaundice in infants and chronic liver disease in adult. In infants, clinical symptoms include jaundice which can be easily mistaken for physiologic jaundice, bleeding diathesis, and change in urine color due to conjugated hyperbilirubinemia. Jaundice lasts for about 3 months on average. Other non-specific symptoms include slow weight gain, irritability and lethargy. Fortunately only 2-3% of PiZZ infants develop cirrhosis or fibrosis in childhood.14 The jaundice eventually clears in the majority of these infants however some will continue to have abnormal liver enzymes, hepatomegaly or splenomegaly.15,16

In adults, AAT deficiency can present as asymptomatic abnormal liver function tests, cirrhosis (seen in up to one-third of adult PiZZ patients) or hepatocellular carcinoma.

Diagnosis

The diagnosis of AAT deficiency can be confirmed by laboratory testing in three ways: AAT plasma or serum level, AAT phenotype, or AAT genotype. AAT deficiency testing should be performed in all patients with unexplained liver diseases.12,17

Serum AAT level can be measured accurately and is an acceptable initial test but has limitations. Heterozygous patients may have normal levels. AAT is also an acute phase reactant which can be elevated in inflammatory states. The gold standard of diagnostic testing is via phenotypic analysis, although there are drawbacks. Phenotyping is time consuming, not readily available and cannot distinguish between heterozygous and homozygous. Genotyping is generally more expensive but offers more information about the likelihood of clinical consequences.12 Liver biopsy is not required for the diagnosis except in uncertain cases and when other conditions need to be ruled out. In older adult patients, once the diagnosis is confirmed, annual liver enzyme testing is recommended for monitoring. All first degree relatives should also be screened.17

Management

AAT deficiency management depends on the severity and the organs involved. A major component of therapy consists of early detection and prevention of complications by reducing modifiable risk factors.

Lung Diseases

In patients with COPD, management includes standard treatment with bronchodilators, inhaled corticosteroids, pneumococcal vaccine, influenza vaccine and smoking cessation. Surgical treatment with lung volume reduction and transplant are available but clinical improvement remains inconsistent and controversial for the AAT deficient patients.12,17

Currently there are four different AAT augmentation therapies being investigated for the treatment of CODP: (1) intravenously human plasma derived augmentation, (2) augmentation by inhalation, (3) recombinant augmentation and (4) synthetic elastase inhibition.12

Injection of purified AAT protein has been shown to increase AAT level in the lungs of AAT deficient patients. However, only a modest reduction in FEV1 decline with weekly infusion was observed in a small, randomized trial18. Overall evidence for significant clinical improvement remains lacking.

Liver Diseases

Besides the standard management for liver failure and associated complications, there is no specific therapy for AAT deficient patients. Effective preventive measures include: hepatitis A and B vaccination with avoidance of hepatotoxins such as alcohol. AAT augmentation therapy is not effective in AAT deficiency related liver diseases. To date, liver transplant remains the only curative treatment for AAT deficiency liver disease. AAT deficiency continues to be a leading indication for liver transplant in pediatric patients with 5 year survival rate up to 90%.19 Liver transplant in adults occur less frequently but has a similar prognosis compared to liver transplant for other indications.12,19,20

The concept of chemical chaperones, where a synthetic compound would bind to the mis-folded AAT proteins to aid their secretion and avoid polymerization, have been explored. However the efforts were limited by the massive amount of drugs that would require for one to one binding. Currently, AAT liver gene silencing in animal models have been reported to be successful in suppressing liver damage and phase II trials have been announced.20

Glycogen Storage Disease
Pathophysiology

Glycogen storage disease (GSD) is a group of inherited heterogeneous disorders characterized by abnormal accumulation of glycogen in various tissues with an incidence of approximately 1 in 20,000 infants. Since glycogen usually serves as dynamic energy storage for muscle and liver, the disorders can be divided roughly into those that predominantly affecting the liver and those affecting muscle. These glycogen disorders are numbered in the order they were discovered and their severity with type I being the one discovered first and also the most severe variant. Based on prevalence, severity and liver involvement, this article will only discuss types I and III. The other two types, type IV and VI, also affect the liver but they are not as common and less severe.21,22

GSD Type I

There are two subtypes of type I glycogen storage disease (GSD I), type Ia and Ib, both having autosomal recessive transmission.23 Type I GSD typically presents early in infancy and was first discovered by von Gierke in 1929. The final step of gluconeogenesis and glycogen break down involves the translocation of glucose 6 phosphate (G6P) from the cytoplasm into the endoplasmic reticulum (ER) lumen where it is hydrolyzed into glucose and phosphate by glucose 6 phosphatase. GSD Ia is the true enzyme defect whereas GSD Ib is the transport defect.24 Both processes lead to build up of G-6-P and hypoglycemia.

GSD Type III

Similar to GSD I, GSD III is also an autosomal recessive condition with two subtypes, IIIa and IIIb, with an incidence of 1:100,000. The primary defect is a mutation in the AGL gene that leads to deficiency of the glycogen debranching enzyme (GDE). GDE participates in one of the last steps in converting glycogen to glucose-1- phosphate.

Clinical Presentation and Diagnosis
GSD Type I

Patients commonly present at 3-4 months of age with symptoms that include hepatomegaly, doll-like facies (fat deposit in the cheeks), growth failure and enlarged kidneys. Laboratory examination often reveals fasting lactic acidosis, hypertriglyceridemia, mild elevated LFTs and symptomatic hypoglycemia occuring 2-3 hours after meals.25 Both types have abnormal platelet aggregation and there may be excessive bleeding. GSD Ib is moderately associated with inflammatory bowel disease and recurrent bacterial infections such as otitis media and pneumonia due to neutropenia and neutrophil dysfunction. The diagnosis is usually suspected clinically and confirmed with gene analysis. Liver biopsy is no longer required for diagnosis.24 Long term complications include liver adenomas and renal disease. Progression to cirrhosis is rare though there has been case reports of liver cirrhosis in GSD Ib.26

GSD Type III

The median age of first clinical symptoms is about 8 months. Early symptoms are very similar to GSD I; including hepatomegaly, hypoglycemia, failure to thrive and recurrent illness/infections. Kidneys are typically not enlarged. GSD IIIa affects both muscle and the liver while only the liver is affected in GSD IIIb. Unlike GSD I, progressive liver cirrhosis and failure may occur. Hepatic complication incidence of 11% has been reported in a study of 175 patients.27 In the same study, cardiac complications occurred in 58% of patients with ventricular hypertrophy being the most common. GSD IIIa patients often have minimal muscle weakness in childhood that can later progress to distal muscle wasting.21 Diagnosis can be made via clinical symptoms and laboratory exam demonstrating deficient GDE in skin fibroblasts or lymphocytes.24 Gene analysis can confirm the diagnosis and identify the subtype.

Management
GSD Type I

Management focuses on maintaining euglycemia through dietary therapy which includes a combination of continuous nasogastric tube feeding (CNTF), uncooked cornstarch (CS) and regular oral feeds high in complex carbohydrates evenly distributed over 24 hours. The management frequently requires a specialist dietician. Frequent blood glucose monitoring is crucial for well controlled GSD. Fructose and galactose are usually restricted since they cannot be converted into free sugar. CNTF should be started at the time of diagnosis with the aim of providing 8-10mg/kg/min of glucose in an infant and 5-7mg/kg/min in an older child. Traditionally, CS is ingested at bedtime and a trial of CS therapy is often introduced between 6mo and 1 year of age.28 However consumption of cooked pasta, a more palatable alternative to CS and MCS, has been shown achieve adequate nighttime glucose control in older patients.29 Common complications of the disease such as hyperlipidemia, high uric acid level, and microalbuminuria can be treated with HMG-CoA reductase inhibitor, allopurinol and ACE inhibitors respectively. In type Ib patients, granulocyte stimulating factor is added to treat neutropenia and neutrophil dysfunction. Liver and bone marrow transplantation can be considered in patients with extremely low fasting glucose tolerance and severe immune compromise.

GSD Type III

Similar to GSD type I, the main stay of management is dietary. The regimen includes carbohydrates rich meals and nocturnal uncooked cornstarch. Unlike GSD type I, fructose and galactose do not need to be restricted. Some studies suggest that a high protein diet can help improve muscle strength and exercise tolerance besides and serve as substrate for gluconeogenesis.30 In those studies, relative daily protein intake was increased from 18% to 25%.31

CONCLUSION

Historically, metabolic diseases commonly presented with end organ damage, but with increased knowledge of these conditions and a high degree of suspicion patients can be diagnosed earlier. Various diagnostic criteria and screening methods, including sensitive blood tests and genetic testing, allow early treatment that can alter disease outcomes. As there may be a delay before these patients see a specialist, primary care physicians need to be familiar with the clinical presentations in order to send off the appropriate screening tests. The key is identifying abnormal liver tests in combination with non-hepatic disease presentations. These include endocrine and cardiac presentations with hereditary hemochromatosis, neuro-psychological with Wilson disease, and pulmonary with alpha-1-antitrypsin. We continue to make progress in our understanding at the molecular level in order to identify new potential targets of therapy. Finding curative treatments for many of these disorders remain challenging but gene therapy offers promise in glycogen storage disease, Wilson disease and alpha-1-antitrypsin.9,20,32

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Nutrition Issues In Gastroenterology, Series #166

Parenteral Nutrition Lipid Emulsions and Potential Complications

August 2017 • Volume XLI, Issue 8
Manpreet S. Mundi,Bradley R. Salonen,Sara L. Bonnes,Ryan T. Hurt

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Intravenous lipid emulsions (ILE) have become a crucial component of parenteral nutrition providing a source of essential fatty acids as well as non-protein calories. However, their long-term use has been associated with significant complications. This has led to the quest to identify a lipid emulsion that decreases complications and provides beneficial physiologic effects. Multiple plant and fish based sources of ILE have been identified and are in use throughout the world. In this review, we focus on the benefits and adverse effects associated with soybean oil (SO) ILE and subsequent generations of ILE.

Manpreet S. Mundi, MD1 Bradley R. Salonen, MD2 Sara L. Bonnes, MD2 Ryan T. Hurt, MD, PhD1,2 1Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic, Rochester, MN 1Division of General Internal Medicine, Mayo Clinic, Rochester, MN

INTRODUCTION

Intravenous lipid emulsions (ILE) are a key component of parenteral nutrition (PN), providing a source of essential fatty acids (EFA) as well as non-protein calories. Development of a stable ILE took decades of work by leaders in the field before the introduction of the first stable ILE (Lipomul®; 15% cotton seed, 4% soy phospholipids, 0.3% ploxamer).1,2 Unfortunately, due to adverse effects felt to be from the emulsifying agent, as well as a non-extractable toxic substance in cottonseed oil, Lipomul® was removed from the market.3 Subsequently, work by Wretlind and Schuberth led to the introduction of a soybean oil (SO) based ILE as a 10% SO solution.4 Since that initial introduction, significant modifications have taken place in subsequent generations of ILE, largely in an effort to reduce omega-6 fatty acid (FA) concentrations.

Soybean Oil Based ILE (Generation 1)

SO ILE are composed of SO triglycerides enveloped by a phospholipid emulsifier allowing the triglyceride core to remain soluble in an aqueous PN mixture, similar to a chylomicron-like particle.2 The emulsifiers are typically provided in excess amounts to ensure that particles maintain a size of 200-600 nanometers (nm), thus allowing them to pass through the smallest capillaries.5 Due to this, a typical composition of first generation ILE is 10-30% SO, 1.2% egg yolk phospholipids, and 2.25% glycerin with calorie content ranging from 10- 11 kcal/g depending on concentration.2,6 Therefore ILE provide an excellent source of calories allowing for a reduction in the amount of dextrose used in PN. This distribution of calories is important because, after the technique of “hyperalimentation” in the US with a solution of glucose, fibrin hydrolysate, vitamins, and minerals was introduced by Drs. Wilmore and Dudrick, reports began linking the high dextrose, fat-free PN to hyperosmolar, hyperglycemic, non-ketotic diabetic coma, hypoglycemia, hepatic enzyme elevations, fatty liver, and essential fatty acid deficiency (EFAD).6-8 Meguid et al. subsequently performed a pivotal study showing that providing one-third of daily calories as SO ILE (10% Liposyn®) was associated with lower metabolic complications in 23 men, leading to a gradual change in the U.S. to include ILE in PN.8

In addition to serving as a calorie source, SO ILE also contain robust amounts of essential fatty acids, linoleic acid (18:2n-6) and a-linolenic acid (18:3n-3), all of which play a key role in structural stability of membranes, as well as in generation of cellular signaling molecules.9 Humans lack the ability to synthesize these fatty acids and must obtain them from plant sources such as seed oils.10 Minimal PN requirements of linoleic acid to prevent EFAD have been estimated to be at least 1% of total calories, with optimal levels being 3-4%, whereas a-linolenic acid requirements are even less at 0.2-0.5% of total calories.9,11 Given that Intralipid® contains 20% SO, with 52% of the fat as linoleic acid, only 2.9-8.7g/day of lipid or 29-87 mL of Intralipid® would be required to meet the essential fatty acid needs of a 60 kg individual receiving 25 kcal/kg/day.9

Despite these benefits, the high ratio of n-6 to n-3 polyunsaturated fatty acids (PUFA) in SO ILE can have adverse effects. These 18-carbon fatty acids are used to make 20- and 22-carbon derivatives including arachidonic acid (AA, 20:4n-6) and eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic (DHA, 22:6n- 3).2,11 AA can be further metabolized to give rise to pro-inflammatory eicosanoids (2-series prostaglandins and thromboxanes, and 4-series leukotrienes).6,10,12,13 On the other hand, EPA, which originates from n-3 PUFAs, tends to generate less pro-inflammatory 3-series prostaglandins and thromboxanes, as well as the 5-series leukotrienes. In addition to these pro- inflammatory metabolites, SO ILE have also been noted to lead to reduced clearance of the reticuloendothelial system (RES), a key player in the phagocytosis of microorganisms, tissue debris, and particulate matter.14 With provision of SO ILE at a rate of 0.13 g/kg/hr over 10 hrs daily for 3 days, RES clearance fell by an average of 40%.14 In a 60kg individual, this would amount to 39 mL/hr of 20% lipid emulsion, which typically has 50g per 250 ml.

SO ILE can also lead to increased LDL and triglyceride levels as well as a decrease in HDL levels. This is due to the liposomes created from excess phospholipid emulsifier acquiring cholesterol and apolipoproteins from HDL in exchange for phospholipids.15,16 The capacity of HDL to handle this phospholipid influx is saturable, and if infusion rates exceed this capacity, liposomes begin to accumulate in plasma where they can continue to be enriched in cholesterol and begin to show characteristics of lipoprotein-X (Lp-X).17 It is important to note that 20% ILE tend to have lower phospholipid to triglyceride ratios compared to 10% ILE, resulting in faster phospholipid clearance. Twenty percent ILE are predominantly used in clinical practice.18

Another common complication of PN is intestinal failure associated liver disease (IFALD) affecting 30-60% of children and 15-40% of adults requiring long-term SO ILE.2 IFALD tends to vary in clinical presentation and can include hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis.19 Although, the etiology of IFALD seems multifactorial, some studies have revealed a correlation between parenteral lipid intake of ≥1 g/ kg/day with higher phytosterol levels.20 Additionally, elevated levels of phytosterols from SO ILE may be another contributing factor as higher phytosterol levels correlate with severity of IFALD.21 Typically, only a small percentage (5-10%) of dietary phytosterols are absorbed and play a beneficial role by inhibiting enteral absorption of cholesterol. Unfortunately, with parenteral administration, increased levels of phytosterols enter the circulation leading to higher concentrations as they cannot be converted to bile acids.22

Soybean Oil and Medium Chain Triglycerides (SO:MCT 50:50) (Generation 2)

The search for improved sources of ILE following widespread use of SO lipids first led to the use of medium chain triglycerides (MCT). Similar to other triglycerides, MCTs have a glycerol backbone with fatty acids attached, typically composed of between 6 (caprioc) and 12 (lauric) carbon atoms compared to the 13-21 carbon chains of long chain triglycerides (LCTs).23 In addition to being hydrolyzed faster by pancreatic lipases, MCTs are not incorporated into chylomicrons, and are thus rapidly delivered directly to the liver via portal circulation.23 In contrast to LCTs, once delivered to the cell, MCTs are able to passively cross the mitochondrial membrane due to their water- soluble properties and proceed directly for oxidation.

Based largely on these theoretical advantages of MCTs demonstrated primarily in animal models, ILE formulations have included combination MCT/LCT for the past 30 years in Europe. A number of small short- term studies have shown MCT ILE to be beneficial compared to SO ILE in terms of liver function tests, phospholipid to triglyceride ratio, and recovery of RES, although some studies reveal minimal benefit.24-27 Additionally, a larger prospective RCT showed that MCT/LCT use resulted in phospholipid profiles similar to healthy controls at the end of 4 weeks compared to 100% LCT.28 Due to the limited data on MCT (in any PN formulations – MCT/ LCT or pure MCT), there is a need for longer-term studies to evaluate the safety and efficacy of these ILE formulations.

Olive Oil (OO) Containing ILE (Generation 3)

In the third generation of ILEs, OO was introduced as an alternative lipid source. OO was seen as a potential substitute for SO because it contains higher amounts of monounsaturated fatty acids (MUFA) and less n-6 PUFAs.29 During the 1990s, ClinOleic®20% became available and was comprised of 80% OO and 20% SO.30 Since 18.5% of the fat is linoleic acid, 81-240ml per day would be needed to meet daily EFA needs. Concerns were raised that patients may not get these doses and may develop EFAD.31 Despite data showing a significant reduction in a-linolenic acid and higher Mead acid levels, there was no clinical evidence of EFAD and triene:tetraene ratios remained normal.31 Studies comparing OO/SO ILE to SO ILE have noted less deterioration of liver enzymes, better phospholipid profile, and improvement in some clinical variables such as ventilator days.32-34

Fish-Oil (FO) Containing ILE (Generation 4)

The latest generation of ILE have reduced the SO content by either completely switching to fish oil (FO) alone (Omegaven®; Fresenius Kabi) or using FO in combination with other sources of triglycerides (Smoflipid®; 30% SO, 30% MCT, 25% OO, and 15% FO or Lipoplus; 50% MCT, 40% SO, and 10% FO). FO is an ideal choice for use in ILE given its high content of n-3 PUFA, a-tocopherol, and minimal amounts of plant phytosterols.35 Omegaven® is currently the only ILE composed entirely of FO, but is not approved for routine use or commercially available in the U.S., and instead is available under study protocols or under a compassionate-use allowance through the FDA for treatment of IFALD.35 Smoflipid®, on the other hand has recently been approved by the FDA and is now commercially available in the U.S.

Numerous studies have shown significant improvement or reversal of IFALD with the use of FO ILE in the pediatric and adult population.36,37 Heller et al. studied the impact of combining FO (0.2 g/kg/day Omegaven®) with SO (0.8g/kg/day of 10% Lipovenoes®) versus SO alone (10% Lipovenoes®) in 44 post abdominal surgery patients and noted that the combination of FO with SO resulted in significant decrease in liver enzymes and bilirubin levels.38 Klek et al. conducted a 4 week-long trial randomizing 73 patients with stable intestinal failure to either Smoflipid® or SO ILE (Intralipid®) and noted that mean ALT, AST, and total bilirubin concentrations were significantly lower in the Smoflipid® group.42

All 3 FO ILE tend to have higher levels of a-tocopherol (∼200mg/L) raising plasma concentrations compared to SO ILE.42-43 .-tocopherol is an antioxidant from the Vitamin E family that is capable of scavenging free radicals that form from peroxidation of lipids, especially PUFAs and can result in cell damage.44 In addition to raising a-tocopherol concentrations, patients receiving FO ILEs also tend to have lower n-6 PUFA and higher n-3 PUFA concentrations, producing a less pro-inflammatory profile.43 Metry et al. noted a significantly lower IL-6 level in surgical ICU patients randomized to Smoflipid® compared to Intralipid® on both day 4 and 7 of the trial.45

Beyond these liver and anti-inflammatory benefits, studies have also revealed metabolic benefit as patients randomized to Lipoplus® had a greater reduction in free-fatty acids, smaller rise in triglyceride levels, and less reduction in HDL after ∼7 days of use compared to the Lipofundin® group.47 Wu et al. also noted lower triglyceride levels on day 6 in patients randomized to Smoflipid® versus Lipovenoes®.48

Of note, most of these trials are very short term and further studies on the long-term impact of FO ILE needs to be evaluated. One area of concern is the development of EFAD given the lower ratio of n-6 PUFAs. Fortunately, clinical trials thus far have revealed that although triene:tetraene ratios do rise, they did not exceed threshold for EFAD if the dose of ILE is ≥1g/kg/day.49,50 Mead acid levels also remained low again confirming that the rise in Mead acid levels may be largely due to the composition of ILE. An important contributor to the lack of EFAD with fish oil ILE may be their higher content of AA, which is typically derived from linoleic acid.51

CONCLUSION

In summary, significant advances have been made since the initial development and administration of ILE. We have progressed from searching for ILE that are non-toxic, to development of ILE that have beneficial properties other than being a source of non-protein, non-carbohydrate calories. Moving forward, additional research is necessary to expand our knowledge regarding the use of later generation of ILE in disease specific situations. The benefits with long-term use also need to be delineated, as much of current research has focused on short-term trials in small cohorts. In order to continue to provide the best care possible to our patients, we need to continue work in this field to not only reduce the risk of harm, but also continue to find ILE that will improve outcomes.

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Dispatches From The Guild Conference, Series #7

Hepatitis C Resistance Testing – When, Why and How to Do it

August 2017 • Volume XLI, Issue 8
Jordan J. Feld

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Hepatitis C virus (HCV) therapy has evolved dramatically in recent years with the development of highly effective and well-tolerated direct-acting antivirals (DAAs). Although it was initially felt that DAA resistance would be a challenge, the cure rates in most patient populations are extremely high. Fortunately, new therapies in development will likely make the need for resistance testing less and less relevant. In this review, the principles of resistance development are reviewed and the role of resistance testing in clinical practice is discussed, with specific recommendations on when to do testing, how to interpret the results and how to modify therapy appropriately based on the results.

Jordan J. Feld MD MPH, Toronto Centre for Liver Disease, Toronto General Hospital, University Health Network, Sandra Rotman Centre for Global Health, University of Toronto Financial Disclosure: JJF has received consulting and/or research support from Abbvie, Abbott, Gilead, Janssen and Merck

Treatment for hepatitis C virus (HCV) infection has been revolutionized with the development of highly effective and extremely well tolerated direct-acting antivirals (DAAs). With these new therapies, cure rates well above 90% are now reliably achieved in almost all patient populations. With such remarkable success rates, patients, providers and payers have come to expect cure when a course of antiviral therapy is undertaken. With the cost of therapy and restrictions on retreatment, getting it right the first time, or certainly the second time, must be the priority for all clinicians. At least for the time being, maximizing the chance of success requires resistance testing in certain clinical scenarios. Fortunately, this is likely a temporary situation. New salvage regimens that work across all genotypes and against many resistant variants will likely significantly limit the need for resistance testing in the future, but until then, resistance testing has an important role.

Why is Resistance an Issue?

Like all RNA viruses, in a given patient, HCV circulates as a swarm of closely related but non-identical virions known as quasispecies. The virus has an error-prone polymerase that leads to approximately one error or substitution in the viral sequence with every round of replication. With upwards of 1012 new virions made per day, a virus with a substitution at every single site in the genome is generated every single day, just by chance.1 Most of these substitutions will have a detrimental effect on the ability of the virus to replicate and they will thus be selected against and disappear from the viral population. However, some substitutions, just by chance, will affect how a given drug, or a class of drugs, inhibits HCV replication. During therapy, these substitutions provide a major survival advantage and virions containing them will outgrow any drug- susceptible viruses. DAAs do not create resistance, they just select for it.

Not all Resistance is Created Equal

If all resistance-associated substitutions are generated every day, it is perhaps surprising that DAA therapy works at all. A number of factors limit the effect of resistant variants (Table 1).2,3 The first is the genetic barrier to resistance. For some DAAs, a single point mutation will lead to high-level resistance. However for others, 2 or more substitutions are required. The more substitutions required, the greater the genetic barrier to resistance and the less likely resistance is to occur. In addition to the genetic barrier, the replicative fitness of the resistant variant is also relevant. If the substitution leading to drug resistance also markedly impairs the ability of the virus to replicate, variants with this substitution will replicate extremely poorly making them hard to detect and they will quickly be outgrown by wild-type virus in the absence of drug treatment.

The best example of this scenario is the substitution that leads to sofosbuvir resistance (S282T). This substitution in the viral polymerase prevents sofosbuvir from binding to HCV but it also almost completely incapacitates the virus’ ability to replicate. As a result, even though variants with the S282T substitution are created as frequently as any other single substitution, they grow so poorly that they are effectively never found in patients before receiving sofosbuvir and remarkably have rarely even been identified and quickly disappear even in patients who have relapsed after a course of sofosbuvir treatment.4,5 It is the marked fitness impairment of the S282T variant that has made sofosbuvir and any agents of this class (nucleotide polymerase inhibitors) ‘special’ in the sense that resistance is not really an issue and patients can be retreated with sofosbuvir or another member of this class (none yet approved) after failing a previous course of therapy with this agent.

Fitness of resistant variants varies markedly by DAA class. Variants resistant to non-structural 5a (NS5A) inhibitors are highly fit and can effectively compete with wild-type virus. This has two important consequences. Firstly, variants resistant to these agents are more frequently found at baseline, even in patients who have never been treated before, and secondly, if they emerge after a failed attempt at treatment, they will persist long-term, affecting options for future therapy.The other classes of DAAs fall in between the extremes of the highly fit NS5A inhibitor-resistant variants and the extremely unfit sofosbuvir-resistant variants. Variants resistant to non-nucleotide protease inhibitors (NNI) are generally fit and more similar to NS5A-resistant variants, while polymerase inhibitor- (PI)-resistant variants are relatively unfit and are thus uncommon at baseline and do not persist long-term when they emerge after treatment.6

Beyond genetic barrier and fitness, the degree and the prevalence of resistance also affect the impact of detected variants. Certain substitutions can lead to high- level resistance, making the virus 100 or even 1000-fold less susceptible, while others may only lead to 2 to 5-fold reduced susceptibility. In addition, resistant variants may be very rare within the quasispecies population or very frequent. Most studies suggest that unless a variant is present in at least 15% of the quasispecies population, it is unlikely to be clinically significant.7 It is important to be aware of these details because the impact of resistance can easily be manipulated through selective reporting.

Terminology

There has been some debate in the literature about the preferred term to describe resistance. The original term proposed was resistance-associated variant or RAV. However, the appropriateness of this term has been challenged because a variant is either resistant or it is not (i.e. it replicates better than wild-type virus in the presence of drug or it does not). It is the substitution in the sequence that is associated with resistance and as such, the term resistance-associated substitution or RAS has largely supplanted RAV. Other terms including resistance-associated polymorphism (RAP) or resistance-associated mutation (RAM) have also been proposed.3 This is largely a semantic argument and for clinical purposes, the terms are interchangeable.

When is Resistance Testing Useful?

In order for any test to be clinically useful, outcomes should differ based on the result. If the outcome is the same whether the test is positive or negative, there is no point in doing the test. For most clinical scenarios, baseline HCV resistance testing is not useful because it has no meaningful impact on management. In such cases, it is best not to do the testing, as it only leads to confusion.

In fact, based on data available to date, baseline resistance testing is only relevant for certain patients with genotype 1a infection and for patients with genotype 3 infection and cirrhosis (Table 2). For all other patients, existing data do not support resistance testing.

Elbasvir/Grazoprevir

The importance of detection of substitutions associated with elbasvir-resistance in patients receiving elbasvir/ grazoprevir in different contexts highlights why the details matter. For example, the SVR12 rate in patients with genotype 1b infection treated with elbasvir/ grazoprevir is 98% in those with baseline substitutions associated with elbasvir resistance compared to 100% in those without any substitutions.8 Clearly, patients with genotype 1b respond very well to this regimen irrespective of the presence of elbasvir resistance and as such, no testing is warranted. In contrast, in those with genotype 1a infection treated with the same regimen, SVR12 rates drop to 58% in those with elbasvir-specific resistance-associated substitutions compared to 98% in those without baseline resistance. Clearly there is a large impact of resistance in genotype 1a and thus baseline testing is warranted. Furthermore, simple alterations in the treatment regimen can overcome the effect of resistance. Although the numbers are small, available data suggest that with extension of therapy from 12 to 16 weeks and the addition of ribavirin, SVR12 rates increased from 53% to 100% in genotype 1a patients with elbasvir-resistance at baseline.9

Sofosbuvir-Ledipasvir

Data regarding the importance of baseline resistance on outcomes with sofosbuvir/ledipasvir therapy are very illustrative of how the details matter for correct interpretation. Initial reports claimed that the presence of baseline resistance-associated substitutions had no effect on the response to sofosbuvir/ledipasvir in clinical trials. This conclusion was based on the observation that among genotype 1 patients, 25% had baseline substitutions associated with NS5A resistance, however the SVR12 rate was 95% in this group of patients, similar to the 98.5% in those without baseline resistance. However, as illustrated in Figure 1, the importance of baseline resistance increases markedly as relevant sub-populations are considered and low-level or low-frequency variants that dilute the apparent effect are removed from consideration. Similar to elbasvir/ grazoprevir, with sofosbuvir/ledipasvir, resistance has minimal or no effect on genotype 1b meaning that resistance should be reported by subtype, not for genotype 1 as a whole. In addition, only ledipasvir- specific substitutions and not all NS5A substitutions, and only those with at least 15% prevalence in the quasispecies population, should be reported. Among treatment-experienced patients with genotype 1a infection, only 6.5% harboured ledipasvir-specific resistance-associated substitutions at the 15% threshold, but only 76% of these patients achieved SVR12, compared to 98% among those without detectable resistance[10]. Based on a careful review of the data, baseline resistance testing is warranted in patients who previously failed interferon-based therapy and have genotype 1a infection with a plan to add ribavirin in those in whom resistance is found to be present. It may also be helpful in treatment-naïve patients with cirrhosis who will receive this regimen, as the difference in outcome is smaller but the consequences of failure are potentially greater.

Other Regimens for Genotype 1

With only 2 virological failures out of 624 patients in the ASTRAL 1 study of sofosbuvir/velpatasvir, resistance does not appear to have an effect and testing is not required before using this regimen for patients with genotype 1.11

Data suggest that resistance-associated substitutions may affect outcomes with paritaprevir/r/ombitasvir plus dasabuvir, but again only in patients with genotype 1a infection. However, for genotype 1a infection, ribavirin is recommended with this regimen for all patients and with this approach, SVR12 rates do not differ by the presence of resistance-associated substitutions. Whether a population with genotype 1a infection with no baseline resistance who does not require ribavirin could be identified, remains to be seen.12

A frequent polymorphism at position 80 (Q80K) is associated with treatment-failure with simeprevir. The effect was quite significant when simeprevir was combined with peginterferon and ribavirin. When simeprevir was combined with sofosbuvir, the effect of Q80K was only notable in patients with cirrhosis. As such, patients with cirrhosis and genotype 1a infection scheduled to receive this regimen should have Q80K testing done and if positive, should consider an alternative therapy.7

Genotype 3 Cirrhosis

The preferred therapy for patients with genotype 3 infection and cirrhosis is sofosbuvir/velpatasvir for 12 weeks. Although the results with this regimen are much improved over previous options, in patients with cirrhosis, SVR rates were 91%, compared to 97% in this without cirrhosis.13 Closer inspection revealed that SVR rates were down to 88% in patients with baseline NS5A inhibitor resistance-associated substitutions compared to 97% in those without these baseline substitutions. A similar effect was not seen in the sofosbuvir/velpatasvir arm of the recent POLARIS 3 study, with no obvious explanation for the differences between the two studies. Currently, international guidelines recommend NS5A inhibitor resistance testing for patients with genotype 3 and cirrhosis.7,14 If resistance is found, the addition of ribavirin is recommended based on extrapolation from the ASTRAL 4 study of patients with decompensated cirrhosis in whom those who received ribavirin had the highest SVR rates.15

Resistance Testing After Treatment Failure

The AASLD guidelines recommend resistance testing in all patients prior to retreatment after a failed course of DAAs.7 Importantly they also caution that the strategies to overcome resistance with current regimens have not been validated in the retreatment setting. However, numerous ‘salvage’ regimens that have shown proven efficacy for retreatment are in late- stage development.16 Although the detailed resistance data from these salvage studies have not yet been made publically available, the very high SVR rates despite a very high frequency of detectable resistance-associated substitutions at baseline suggest that most patients will not need baseline resistance testing prior to their use. However, it will be important to scrutinize the data carefully to avoid drawing incorrect conclusions about the value of resistance testing, as was originally done with sofosbuvir/ledipasvir. If specific substitutions are shown to be associated with failure, testing may be warranted. Fortunately, retreatment of HCV is rarely an emergency. As such, most patients would likely be better to wait for one of the coming therapies than to be retreated with one of the existing approved regimens.

The Counter-Argument to Testing

Some argue that baseline resistance testing is not necessary even for the specific populations mentioned because the number of patients with baseline resistance- associated substitutions who will not respond represents a relatively small percentage of the overall population and testing may be a barrier to treatment access or uptake. Other arguments against testing include cost, limited access in some regions and hard to interpret reports.3 While the effect may not be huge at the population level, for the individual patient, the presence of baseline resistance may have a major effect on the chance of SVR. The cost of resistance testing is generally fairly low, particularly if centralized at a reference center. Given the high cost of the therapies, even infrequent improvements in treatment approach or a small absolute effect on SVR would still pay for the cost of most, if not all testing.

Ideally resistance reports should be improved. Currently most HCV resistance reports follow the approach used for antibiotic and/or HIV resistance. However, unlike in other disease areas, DAAs for HCV cannot be easily mixed and matched. HCV regimens are studied as combinations and particularly with the increasing use of fixed dose combination pills; it is difficult, if not impossible, for example, to use a protease inhibitor from one company with the NS5A inhibitor from another. As such, resistance reports should give guidance on how to use an overall regimen in the context of the resistance profile observed e.g. extend to 16 weeks and add ribavirin for a detected elbasvir resistance-associated substitution. Improved reports would make it much easier for clinicians with limited virological experience to enter the HCV field and would reduce the reluctance of experienced clinicians to order resistance testing.

CONCLUSION

Resistance has added a layer of complexity to HCV management. If properly interpreted, baseline resistance data can add significant clinical value for specific patient populations. Hopefully standardized reporting in the literature will more clearly define the importance of resistance in studies and improved clinical reports will make resistance testing easier to use clinically. Fortunately, this is likely a temporary situation. Future regimens are unlikely to require baseline resistance testing and may not even require testing before retreatment. Until these new regimens arrive, resistance testing has a relatively small but potentially important role.

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Inflammatory Bowel Disease: A Practical Approach, Series #102

Fecal Microbiota Transplantation in the Elderly – A Need for Early Consideration in Select Cases of Clostridium difficile Infection

August 2017 • Volume XLI, Issue 8
Yao-Wen Cheng,Monika Fischer

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Fecal microbiota transplantation (FMT) is recommended treatment for recurrent Clostridium difficile infection (CDI). There is also increasing evidence that FMT is effective in severe and severe-complicated CDI and in averting CDI-related complications such as colectomy and mortality. In this article, we explore the role of FMT in elderly patients with CDI and other gastrointestinal diseases. It may be reasonable to offer FMT earlier in the CDI disease course in older individuals, possibly after just the second recurrence and/or for the first episode of severe CDI to halt disease progression and prevent development of associated complications.

Yao-Wen Cheng1 Monika Fischer2 1Resident, Department of Medicine, Indiana University School of Medicine 2Associate Professor, Division of Gastroenterology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

INTRODUCTION

Elderly patients (age ≥65 years) are considered a unique treatment population due to decreased physiological, immunologic, and cognitive reserve, while also shouldering a greater number of comorbidities and medications compared to their younger counterparts.1,2 These factors make elderly patients not only more susceptible to disease, but also less tolerant to aggressive therapies. Additional considerations such as age-related impairments in hepatic metabolism and renal clearance of medications,3 the Beers Criteria of medication contraindications in nursing home residents,4 and the heterogenous spectrum of elderly health status ranging from fit to frail,5 introduce multiple levels of complexity when treating disease in this unique population.

Over the past decade, the gut microbiome has risen to prominence after researchers realized its role in pathogen resistance, immunomodulation, epithelial cell propagation and nutrient metabolism.6 In parallel, researchers have pursued the allure of manipulating the gut microbiome via fecal microbiota transplantation (FMT), a procedure in which healthy fecal material is transferred into the diseased gut. The intent of FMT is to restore healthy microbial communities, thereby alleviating disease that may have resulted from a dysbiotic gut microbiota.

The purpose of this article is to explore current literature supporting the use of FMT for treatment of various diseases with a particular emphasis on its role in elderly patients.

Clostridium difficile Infection

Clostridium difficile infection (CDI) disproportionately effects the elderly population, causing greater incidence of first-time and recurrent CDI compared to their younger counterparts7,8 as well as an elevated risk of progression to severe and/or complicated CDI.9 The combination of these factors culminates in particularly poor outcomes for elderly patients, who represented 93% of CDI-associated deaths in 2008,10 92% of CDI- related US hospital admissions in 2009,11 and higher odds of CDI-related colectomy (OR 1.9)12 compared to patients <65 years of age.

There are likely multiple components contributing to elderly morbidity and mortality when afflicted with CDI. They may be more prone to Clostridium difficile colonization due to greater fluctuation in gut microbiome composition due to immunosenescence and alterations in gut transit time.13,14 Furthermore, elderly patients have higher rates of exposure to CDI risk factors such as antibiotics, healthcare facilities, chronic kidney disease, and multiple co-morbidities.15 Risk of healthcare-associated CDI increases by 2% for each year of age.16

Recurrent CDI

The use of FMT is best described as treatment for Clostridium difficile infection. Healthy colonies of bacteria such as bacteroides and firmicutes are transferred via FMT into the diseased gut and re- establish the microbiome diversity, thereby suppressing colonization by Clostridium difficile.17,18 A single FMT is effective at treating recurrent CDI (RCDI) at a rate approaching 90%,19 and is currently recommended by the American College of Gastroenterology (ACG).20 More importantly, FMT is superior to traditional antimicrobials at inducing durable cure. Subsequent CDI recurrence after treatment with FMT is lower (5- 15%)21,22 compared to the traditional antimicrobials vancomycin (35-65%)23 and fidaxomicin (25%).24

In studies focusing solely on elderly patients, rates of successful RCDI treatment with FMT have been quite comparable to those conducted in the general population. One review article found an 89.6% cure rate among 115 cases of RCDI treated with FMT in the elderly.25 In another systematic review, patients ≥65 were compared to patients <65 years of age and found to have inferior response rates to FMT; 26 primary cure for RCDI was 87% versus 99.4%, while CDI recurrence within 90 days was 4.9% vs 0.1%, respectively. The results suggest that the post-FMT clinical course of elderly patients should be followed closely for signs of recurrence. A significant fraction of patients may require repeat FMT or subsequent medical therapy for adequate treatment.

Severe and Severe-Complicated CDI

Beyond RCDI, there remains a need to introduce new and effective modalities for the treatment of severe and/ or complicated CDI (SCCDI). Colectomy is currently standard therapy, particularly for refractory cases of SCCDI. However, post-surgical mortality has remained close to 50% over the last decade despite new surgical techniques and prediction models for poor surgical outcomes.27-30 There have been several convincing studies suggesting that FMT may adequately treat SCCDI31-34 and also decrease rates of colectomy.35

Only one study, published by Agrawal and colleagues, has focused on elderly patients.31 In their cohort of 146 patients, 30.8% had severe CDI, 8.2% had severe CDI, and the remainder had RCDI. Overall primary cure rate was 82.9% (91% severe and 66% severe-complicated CDI), which improved to 95.9% after subsequent vancomycin or repeat FMT infusion. Only six patients in the study reported a serious adverse event, which consisted almost exclusively of recurrent diarrhea requiring repeat intervention or hospitalization. Notably, 69.2% of patients reported an improvement in their functional status after FMT.

Since 2013, our center has utilized a sequential FMT protocol with selective use of vancomycin.33 Compared to the 66% cure rate after a single FMT,31 our sequential FMT protocol has a cure rate of 87% for the treatment of severe-complicated CDI.34 Furthermore, since inception of our inpatient sequential FMT program, our center has seen a decrease in CDI-related mortality from 10.2% to 4.5% (p=0.021) among patients with SCCDI, and from 43.2% to 12.1% (p<0.001) in a subgroup of SCCDI patients who did not respond to 5 days of optimal medical therapy (medically refractory). CDI- related colectomy has also decreased from 6.8% to 2.7% (P=0.042) in SCCDI and 31.8% to 7.6% (P=0.001) in the medically refractory subgroup [unpublished data].

FMT has an emerging role in the treatment of SCCDI. Its acceptance as a therapeutic modality in elderly patients is particularly important because it can avert the need for colectomy. Furthermore, it can serve as an alternative for patients that are regarded as non- surgical candidates due to age-related frailty and/or co-morbidities. In instances where FMT is only partially effective, it can also serve as adjunct medical therapy to stabilize patients before surgery, which has been shown to be associated with better surgical outcomes.29

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is similar to CDI in that both diseases are characterized by a dysbiotic microbiome.36 However, it is unclear whether dysbiosis is the result of an inappropriate host immune response to normal gut flora or a proper response to an abnormal microbiome. Almost 15% of inflammatory bowel disease (IBD) cases arise in patients ≥65 years of age, coinciding with the secondary peak of IBD incidence in the general population.37 Cases of ulcerative colitis (UC) tend to be more severe at time of diagnosis for elderly patients.38,39 However, for both UC and Crohn’s disease (CD), the clinical course in elderly patients tends to be less aggressive compared to younger patients,40-43 with fewer relapses and hospitalizations particularly in UC.40,44 Though the overall disease course of IBD may be favorable in elderly patients, outcomes during IBD-related hospitalizations are not. Higher rates of gastrointestinal bleed, anemia, hypovolemia, electrolyte disturbance, and malnutrition among the elderly lead to greater in-hospital mortality (OR 3.91) and post- colectomy length of stay (1.73 days) compared to patients <65 years.45

Poor outcomes among elderly patients with IBD may partially be explained by practical differences in therapy used for IBD suppression. Underutilization of biologic therapy and immunomodulators is well- described, likely driven by the perception that elderly patients are at higher risk of infection, malignancy,46 as well as drug interactions from polypharmacy.47,48

The role of FMT as a “natural” means of restoring the normal balance of gut microbiota in patients with IBD has thus piqued the interest of researchers, particularly with elderly patients in mind. Unfortunately, cohort studies of FMT for CD treatment have conflicting results,49,50 while several randomized controlled trials (RCT) involving UC patients of all ages have not been convincing. In two RCTs, UC patients who underwent FMT with stool sourced from a healthy donor responded better than those that received placebo, with 25-27% achieving remission.51,52 A third RCT did not generate significance between groups of UC patients receiving FMT with healthy versus autologous stool.53

The role of FMT in the treatment of IBD is unclear at this time. Additionally, the rigorous treatment regimens utilized by the aforementioned studies (daily self-administered FMT enemas for multiple weeks) would not be feasible for many of our elderly patients.

Clostridium difficile infection in IBD patients

CDI in patients with underlying IBD (CDI-IBD) is another noteworthy group that could benefit from treatment with FMT. Among all age groups, the likelihood of IBD patients contracting CDI is 2.5 to 8-fold higher than the general population.54-56 Moreover, mortality and colectomy rates are much higher for hospitalized CDI-IBD patients compared to patients with solely IBD or CDI.57-59

Successful treatment of CDI with FMT in IBD patients is close to 90%, similar to that of non-IBD patients.60-62 However, there is concern that patients can have an unpredictable IBD clinical course post-FMT. Fischer and colleagues found that 17.9% of patients had worsening IBD activity after treatment of CDI. 12% of this study group also experienced a serious adverse event, though not directly related to the FMT itself.62

The literature is currently devoid of studies on this topic, but it would not be unreasonable to expect worse outcomes among elderly patients with CDI-IBD. Previous comparisons to younger patients demonstrated worse rates of colectomy and mortality when elderly patients are hospitalized with IBD or CDI alone. Early intervention with FMT could attenuate progression to severe-complicated CDI thereby improving outcomes. However, a possible IBD flare after FMT could itself lead to colectomy and/or mortality. In elderly patients with CDI-IBD, aggressive anti-CDI medical therapy should be balanced with selective use of FMT after a thorough discussion with the patient about risks and benefits.

FMT Applications on the Horizon

The impact of the gut microbiome on host metabolism, immunogenicity, and neuro-hormonal responses has opened multiple avenues of research for the application of FMT.63,64 Larger case series have identified a potential for FMT in the treatment of pouchitis65-67 and irritable bowel syndrome.68,69 Further targets of treatment via FMT have only progressed to the level of case reports: hepatic encephalopathy,70 acute graft-versus- host disease,71 multiple sclerosis,72 and chronic fatigue syndrome.73

As it pertains to the elderly population, researchers have theorized that the gut microbiome may have a role in the development of Alzheimer’s disease. Disturbances to the elderly microbiome caused by immunosenescence or external factors such as antibiotics allows for colonization of fungi and bacteria capable of secreting amyloids and lipopolysaccharides into their environment,74-76 which induces host inflammation and gut permeability.77,78 Researchers hypothesize that the leaky gut could allow amyloids to reach the level of the brain where they could polymerize into the beta- pleated sheets characteristic of Alzheimer’s disease.74 Alternatively, proinflammatory bacterial colonizers may also induce cytokines and reactive oxygen species contributing to neurodegeneration.78-80 Further studies are needed to validate these theories.

Safety and Delivery of FMT

FMT is delivered in various methods including nasoduodenal/jejunal tube, esophagogastroduodenoscopy, pill, and enema, though colonoscopy is the most widely practiced. There are multiple benefits of colonoscopy including targeted delivery of fecal material, direct visualization of the colonic mucosa, and ability to rule out alternate etiologies such as IBD, ischemia, microscopic colitis, or malignancy.81 Importantly, there is strong evidence that treatment of CDI is superior when FMT is delivered via lower rather than upper GI modalities. In a cohort of over 2000 patients who received FMT for recurrent, severe, and/or refractory CDI, cure was 85.8% via colonoscopy versus 74.1% with an upper GI route (p<0.01).82

Previous studies have found increased risk of perforation in elderly patients after diagnostic colonoscopies. In one study, the incidence of perforation increased by age group: 0.026% for age 50-64, 0.087% for 65-79, and 0.317% for ≥80 years.83 Another study placed the odds of perforation at 1.33 when patients >65 were compared to those <65 years.84

Endoscopic injury and sedation-related aspiration events appear to be negligible after FMT, though no direct comparison to diagnostic colonoscopies or among age groups has been published. One review found that among 1,555 FMTs only 4 resulted in a direct procedural complication (mucosal tear or perforation) and 3 were associated with death that could not be directly attributed to the FMT itself.85 Another review comprised of 1,089 FMTs described adverse events in 17.7% of lower GI versus 43.6% upper GI FMTs. Severe adverse events, or procedural complications leading to death or hospitalization was found in 6.1% of lower GI versus 2.0% upper GI FMTs.86 In most cases, side effects from FMT were described as mild, self-limited, and confined to the gastrointestinal tract. In a study comprised exclusively of 146 elderly patients, the treatment of recurrent, severe, and/or complicated CDI with FMT resulted in only 6 serious adverse events, most of which were severe, recurrent diarrhea requiring hospital admission.31 The authors suggest that elderly age may be a relative contraindication to upper GI delivery of FMT due to risk of aspiration and small intestinal bacterial overgrowth.

CONCLUSION

The adage of “start low and go slow” for initiation of therapeutics in the elderly may not apply to FMT for the treatment of CDI, where rates of cure and CDI relapse are superior compared to traditional antimicrobials. Elderly patients may also appreciate the benefits of avoiding colectomy or having alternative therapy when they are non-surgical candidates due to age or co- morbidities. It may be reasonable to offer FMT earlier in the CDI disease course, possibly after just the second recurrence and/or the first episode of severe CDI to decrease progression of CDI severity and development of associated complications.

There is insufficient evidence to suggest that FMT for the sole purpose of treating IBD is beneficial. However, when elderly patients have CDI-IBD, clinicians will need to balance the benefit of FMT for treating CDI and its potential to induce an IBD flare.

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A Case Report

Internal Biliary Fistula Secondary to Cushing’s Ulcer in a Child

July 2017 • Volume XLI, Issue 7
Allison Ta,Suchitra Hourigan,Otto Louis-Jacques

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Allison Ta, MD1 Suchitra Hourigan, MD2 Otto Louis-Jacques, MD2 1Inova Fairfax Children’s Hospital, Falls Church, VA 2Pediatric Specialists of Virginia, Fairfax, VA

INTRODUCTION

Internal biliary fistulas are abnormal communications between the extrahepatic biliary tree and another organ. These fistulas are rare disorders, typically affecting elderly patients as complications of biliary disease or, less commonly, peptic ulcer disease or cancer requiring surgical intervention. We present the case of a cholecystoduodenal fistula (CDF) secondary to a perforated duodenal ulcer in a pediatric patient with posterior fossa tumor. We discuss the success of medically treating this patient with proton pump inhibitors and subsequent resolution of the fistula.

Case Report

A 10 year-old female presented to the hospital with complaints of headache, vomiting, abnormal gait and upper extremity weakness for approximately eight months. She utilized ibuprofen or acetaminophen several times a week for her symptoms. Her past medical history was significant only for hypothyroidism.

A magnetic resonance imaging (MRI) of her brain showed a large posterior fossa tumor (measuring 8x4x3 cm). The patient was admitted to the pediatric intensive care unit (PICU) for stabilization and pre-operative planning. Dexamethasone was started on hospital day (HD) 1 and weaned post-operatively. On HD 4, she underwent surgical debulking of the tumor. On HD 8, she was started on nasoduodenal feeds and famotidine. The patient complained intermittently of epigastric pain, but otherwise had an uncomplicated initial postoperative course.

On HD 11, she became acutely hypotensive and her hemoglobin dropped from 10 to 5.1g/dL. Nasogastric (NG) tube lavage revealed brown colored fluid. She was resuscitated with packed red blood cells and fluids. Urgent esophagogastroduodenoscopy (EGD) discovered a large, non-bleeding duodenal ulcer. An orifice was seen medially within the ulcer bed (Figure 1). Biopsies taken at the time of EGD confirmed ulceration and ruled out Helicobacter infection. An abdominal computed tomography (CT) scan revealed air and contrast in a normal-appearing gallbladder, with a small communication between gallbladder and duodenum, consistent with a cholecystoduodenal fistula (Figure 2). Pediatric surgery was consulted and recommended medical management.

The patient was started on intravenous pantoprazole at 120 mg daily (roughly 1.6mg/kg/day), total parenteral nutrition and a NG tube was placed for gastric decompression. An EGD was repeated on hospital day 20 due to persistent melena. It showed the fistula surrounded by ulcerated tissue with a small amount of blood and bile flowing out of fistula. Attempts to place a clip on the edges of the ulcer bed were unsuccessful. Her proton pump inhibitor (PPI) was switched to continuous drip after which the bleeding resolved. Repeat EGD and abdominal CT on HD 36 showed a healed ulcer and closure of the fistula. The patient was transitioned to oral PPI and NG feeds were resumed. She had no further complications before transfer to a rehabilitation facility. At clinic follow-up more than three months later, there was no recurrence of bleeding.

Discussion

Internal biliary fistulas (IBF) are abnormal communications that develop between the epithelial- lined biliary tract and another organ, most commonly the gastrointestinal tract or part of the biliary tree.1 IBF represent complications of cholelithiasis in >90% of cases.1 Far less frequently, peptic ulcer disease, malignancy, inflammatory bowel disease or prior surgery can cause the fistula.1 Morbidity associated with IBF is related to recurrent underlying disease, cholangitis if common bile duct is involved and/or acute gastrointestinal bleeding.2

The presentation of an IBF is often non-specific making its diagnosis difficult. Patients may complain of right lower quadrant pain or epigastric pain in setting of biliary disease and/or dyspepsia related to peptic ulcer disease.3 Fever and jaundice are seen in cases of cholangitis resulting from choledochoduodenal fistulas.2,3 Radiologic findings of pneumobilia and/or contrast in the biliary tree on plain abdominal X-ray or contrast studies (upper GI series, abdominal CT or magnetic cholangiopancreatography [MRCP]) are suggestive of the diagnosis.4,5

The etiology of the IBF and the stability of the patient are important in guiding management. In adults, biliary disease is commonly the cause of IBF. Definitive treatment requires cholecystectomy which allows the fistula to heal as recurrence can occur with gallstones formation.1,5 Proton pump inhibitors are key in closure of the fistula if it is secondary to peptic ulcer disease.3,5,6 Patients with smaller choledochoduodenal fistulas (orifice <0.5 cm) can be successfully treated medically, however surgical intervention may be necessary in case of complications from the ulcer, including uncontrolled bleeding or perforation.5

Given the lower incidence of gallstones and the rarity of peptic ulcer disease in children, it is not surprising that there are very few reports of IBF in children. In one case, a 6 year-old child presented with recurrent cholangitis.2 MRCP revealed a choledochoduodenal fistula for which she underwent cholecystectomy, common bile duct excision and Roux- en-Y hepaticojejunostomy. The only previous report of a child with a choledochoduodenal fistula secondary to peptic ulcer disease is a 10 year-old male with a three month history of abdominal pain and non-bilious vomiting.4 An EGD revealed a scarred ulcer in first part of duodenum causing obstruction which was treated surgically.

This is, to our knowledge, the first report of a pediatric patient with a CDF caused by a penetrating duodenal ulcer who was successfully treated medically. Our patient had multiple risk factors that predisposed her to developing an ulcer and subsequent bleeding including prolonged use of non-steroidal anti- inflammatory drugs (NSAIDs), the peri-operative use of systemic steroids and the stress of PICU hospitalization all in the setting of a posterior fossa tumor. An important aspect of our patient’s case is the development of a peptic ulcer in the setting of a posterior fossa tumor which has been described as a Cushing’s ulcer. Harvey Cushing’s initial work in 1932 described an association between intracranial tumors or injury and the development of ulceration in the upper gastrointestinal tract.7 He theorized that these intracranial masses caused stimulation of the vagal nerve leading to increased gastrin predisposing patients to develop an ulcer in the esophagus, stomach or duodenum. This suggests prophylactic acid suppressant medication may be necessary.7,8

CONCLUSION

This case highlights the successful use of acid suppressants to heal a CDF caused by a perforated duodenal Cushing’s ulcer, a complication rarely seen in children. In pediatrics, some patients are predisposed to develop peptic ulcer disease (NSAID use, steroids, posterior fossa tumors, to name a few) and should have prophylactic acid suppressant started. Hemorrhage from an ulcer can have high morbidity and aggressive treatment, including the use of continuous PPI infusion, should be initiated until bleeding is controlled.

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Dispatches From The Guild Conference, Series #6

Antiviral Therapy for Patients with Immune Active Hepatitis B – What, When and is Forever?

July 2017 • Volume XLI, Issue 7
Tatyana Kushner,Norah Terrault

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Hepatitis B is the most common chronic viral infection in the world and leads to significant complications. Antiviral therapies currently available are highly effective in achieving viral suppression, however if and when providers can consider discontinuation of antiviral therapy continue to evolve. Increasingly, there is emphasis on treating until HBsAg loss occurs, but this means many patients will be on life-long therapy. A finite duration of therapy is attractive to patients and providers but one must consider the potential risks when stopping treatment. New data continue to inform this question and are reflected in this review.

Tatyana Kushner, MD, MSCE, Norah Terrault, MD, MPH, Department of Gastroenterology/Hepatology, University of California, San Francisco, CA

INTRODUCTION

An estimated 240 million persons are affected by chronic hepatitis B infection, making HBV the most common chronic viral infection worldwide. Forty percent of chronic hepatitis B (CHB) patients will progress to liver complications of decompensated cirrhosis and hepatocellular carcinoma (HCC), leading to 1 million deaths/year.1 Given this tremendous disease burden, the WHO and CDC have made hepatitis B part of the viral hepatitis “elimination by 2030 initiative.

In the United States, approximately 2.2 million persons have chronic HBV, and this may be an underestimate since prevalence studies may under- sample immigrant and other high-risk populations. Over the past 35 years, it has become evident that up to 75% of persons with chronic HBV in the United States are foreign-born, and therefore despite implementation of universal vaccination in the United States, chronic hepatitis B is an ongoing public health problem in our country.2

With current therapies, hepatitis B cannot be cured, as hepatitis B virus exists as cccDNA in the hepatocyte and this serves as a reservoir, unaffected by the nucleoside analogues used to treat CHB. However, hepatitis B can be controlled with clinical benefits. Intermediate endpoints that reflect adequate disease control include sustained suppression of HBV DNA, HBeAg seroconversion in patients who are HBeAg positive at the time of initiation of treatment, reversal of hepatic fibrosis, and HBsAg loss (or appearance of hepatitis B surface antibody), the latter being the best marker of lasting immune control. Sustained viral suppression has been associated with reduced rates of cirrhosis, hepatic failure, liver cancer, and liver-related deaths.5

Recently updated guidelines from the American Association for the Study of Liver Diseases (AASLD) were published, supported by multiple systematic reviews of the literature.3 Who to treat, how to treat and when to stop were addressed in the guidelines. Importantly, the goal of HBsAg loss as an endpoint of therapy was highlighted but with discontinuation of therapy prior to HBsAg loss a possible option after careful consideration of provider and patient preferences/goals. Defining those patients in whom discontinuation of therapy is best suited is an active area of research.

Indications for Treatment in Chronic Hepatitis B

The dynamic natural history of chronic hepatitis B requires careful monitoring of patients with CHB throughout their lives. Patients who are not candidates for treatment on initial evaluation may become treatment candidates in future. Phases of infection (see Figure 1) include the HBeAg positive immune tolerant phase where there is no significant necroinflammatory activity and ALT is normal despite marked HBV DNA elevation, and the immune clearance phase characterized by active HBeAg positive hepatitis B defined by HBV DNA > 20,000 IU/mL and ALT elevated at ≥2 times the upper limit of normal (ULN). Once HBeAg is cleared, the immune control phase is characterized by inactive CHB with suppressed HBV DNA and normal ALT, although CHB reactivation can occur, and is defined by elevated HBV DNA and ALT despite HBeAg negative status. The presence of precore and basal core promoter mutations often characterizes this phase and can lead to marked elevations of HBV DNA with abnormal ALT values. In a small number of patients clearance of HBsAg occurs, although this is not common.1 HBeAg negative immune active phases, characterized by elevated HBV DNA and ALT levels, is recommended as these phases of infection place patients at the highest risk of liver-related complications (see Figure 2). The viral load threshold advised by AASLD guidelines is HBV DNA levels of ≥ 2000 IU/mL if HBeAg negative and HBV DNA ≥ 20,000 IU/mL if HBeAg is positive, along with elevated ALT ≥2 times ULN. 3 For patients with HBV DNA near but not quite at the treatment thresholds or ALT levels at 1-2 ULN, a liver biopsy may be useful in determining whether there is sufficient necroinflammation and/or fibrosis to warrant initiation of therapy.

Treatment Options for Immune Active Hepatitis B

Providers can choose between peg-interferon alfa-2a, entecavir (ETV), tenofovir dipovoxil fumarate (TDF), and the recently approved tenofovir alafenamide (TAF) (Table 1). Antiviral agents such as lamivudine and adefovir, which have been previously recommended, are no longer indicated given significantly higher risks of resistance. Although peg-interferon has no risk of resistance and achieves the highest rates of HBsAg loss with finite duration of treatment of 12 months, its use is limited by the higher frequency of side effects and more limited applicability (its use is contraindicated in those with cirrhosis, significant psychiatric disease or cardiopulmonary disease, for example). The oral antiviral agents, ETV, TDF and TAF all have high potency and very low rates of resistance in treatment naïve patients. For nucleoside analogue experienced patients, TAF and TDF are preferred drugs (Table 1).

As mentioned, the oral antiviral drugs are generally very well tolerated. However, prolonged use of TDF has been associated with kidney and bone toxicity (specifically Fanconi’s syndrome), and therefore monitoring of renal function (and phosphate level and urine studies) as well as bone scans need to be performed annually. The recently approved drug, TAF, which has been found to be non-inferior to TDF in efficacy,6,7 minimizes these toxicities, and therefore offers a better safety profile long-term. Entecavir is not associated with significant side affects other than rare reports of lactic acidosis in patients with decompensated cirrhosis. Thus, TAF and ETV are offer similarly high efficacy and excellent safety without the need for monitoring for toxicities.

Antiviral Treatment Discontinuation

Considerations for discontinuation of nucleos(t)ide analogue therapy differ for patients with immune active HBeAg positive versus HBeAg negative CHB.3 For patients with HBeAg positive immune active disease treated with ETV or TDF, about 20% of patients will undergo HBeAg seroconversion to HBeAb after 1 year of therapy and this percentage increases to ∼35% after 5 years of treatment. Given that HBeAg seroconversion is a key event in CHB natural history which signals an improved level of immune control and decreased risk of cirrhosis, HCC and liver-related death, the AASLD guideline recommends that persons with HBeAg-positive disease who achieve seroconversion to anti-HBe, may discontinue treatment after a period of treatment consolidation for at least 12 months. This recommendation does not apply to patients with cirrhosis, given ongoing high risk of clinical decompensation with discontinuation of antiviral therapy.

Although antiviral therapy may be discontinued, the durability of response is often not sustained, and treatment may have to be re-initiated. In patients who stop treatment with HBeAg seroconversion, studies have demonstrated virological relapse defined by HBV DNA>2000 IU/mL in up to 80% of patients.8 Furthermore, seroreversion back to HBeAg positive status occurs in up to 44% of patients.9 Thus, it is important to identify which patients are more likely to sustain virologic control. The factors most consistently associated with a durable response off treatment are younger age (<40 years) and longer duration of treatment consolidation after seroconversion (>12-15 months).10 Thus, adults under the age of 40 years with 18 months of consolidation therapy may be the best candidates for treatment discontinuation. Due to the risk of relapse and HBV flare, recommendations are to continue close monitoring of HBV DNA and ALT for at least a year after treatment withdrawal.

The AASLD guideline recommends that HBeAg negative immune active patients receive indefinite antiviral therapy, but adds that treatment discontinuation can be considered after HBsAg loss has occurred. The rationale for indefinite therapy stems from studies of treatment withdrawal that show that HBV DNA becomes elevated again in more than 90% of patients.11 Clinical relapse occurs in up to 53% of patients, with the rate dependent upon how relapse is defined. Hepatitis flares and even hepatic decompensation occurred, with those with cirrhosis at highest risk.12

Predictors of relapse have been investigated, and similarly to HBeAg positive patients, a prolonged period of HBV DNA undetectability and low HBsAg titer are most consistently associated with less hepatitis flares and clinical relapses. A recent study showed that sustained suppression of HBV DNA for over 3 years compared to 1 year was associated with lower rates of disease relapse.13 Even after treatment consolidation, once treatment is discontinued, patients should be monitored closely for recurrent viremia, flares, and clinical decompensation. HBeAg-negative patients with cirrhosis are not recommended for withdrawal of antiviral therapy due to concerns of HBV flare leading to liver decompensation.

Thus in order to determine whether to discontinue antiviral therapy, the patient and provider preferences need to be weighed against clinical considerations such as the risk of resistance and liver outcomes. In a survey of patient preferences, more than 80% of patients preferred a finite duration of therapy, when asked if they were willing to have lifelong treatment, more than 40% of patients agreed.13 Thus, patient preferences in discussion with their provider may help to inform the duration of treatment.

CONCLUSIONS

With currently available treatment options, CHB is controlled and not cured. Thus, a long-term treatment plan is needed in those with active disease. Tenofovir (TDF and TAF), ETV, and peg-IFN are the preferred treatment agents, as they have been shown to decrease progression of disease and disease-related complications. The endpoints of treatment are evolving, and although HBsAg loss is desirable, it is infrequently obtained with current therapies. Thus, discontinuation of therapy requires careful weighing of the risks and benefits of health outcomes, as well as patient/provider preference, with close monitoring after treatment discontinuation. Ongoing and future studies will help to define those patients with immune active disease who are best suited for discontinuation of antiviral treatment prior to achievement of HBsAg loss. Encouragingly, many new drug classes are being evaluated for CHB, and the hope is that future drug combinations will more frequently achieve HBsAg seroconversion (functional cure) with a finite treatment course.

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Nutrition Issues In Gastroenterology, Series #165

Reinfusion of Gastrointestinal Secretions – The Bedside Experience

July 2017 • Volume XLI, Issue 7
Amy Berry

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Both pancreatic enzymes and bile salts are necessary for complete absorption of dietary fat. While pancreatic enzymes are available to replace insufficient pancreatic secretion, there is no replacement for bile salts. Unabated external loss of upper intestinal secretions can result in dehydration, acid/base imbalance, electrolyte abnormalities as well as malabsorption. This article describes the reinfusion of GI secretions, various methods of reinfusion, as well as potential and significant pitfalls when embarking on this form of treatment.

Amy J. Berry, MS, RD, CNSC University of Virginia Health System, Surgical Nutrition Support Charlottesville, VA

INTRODUCTION

Successful digestion and absorption of long chain fat and fat soluble vitamins require coordinated release of adequate pancreato-biliary secretions, along with ingested nutrients. Bile, produced in the liver, flows into the right and left hepatic ducts before joining the common bile duct, where it finally enters the duodenum via the sphincter of Oddi (Figure 1).1 Between meals, bile is shunted into the gallbladder for storage. After fat ingestion, secretin stimulates bile release from the liver, while cholecystokinin (CCK) stimulates gallbladder contraction as well as relaxation of the sphincter of Oddi. Pancreatic enzyme release is dependent on both secretin and CCK.2

Approximately 1 liter each of bile and pancreatic fluid, as well as 2-3 liters of gastric secretions are produced daily.3 However, some conditions may prevent these digestive secretions from ever reaching the small intestine, leading to malabsorption, dehydration, and electrolyte disarray (Table 1). Reinfusion of these secretions may be a viable option in select populations, e.g., those with prolonged hospitalization, high volume upper GI losses with persistent fluid and electrolyte imbalance, and imperfect absorption. To date, only case reports have been published on this practice.4 Bile reinfusion can be complex; for example:

  • 1. When might a clinician consider this option?
  • 2. How is it actually executed on in-patient units?
  • 3. How does this work when transitioning the patient to home or a facility?

Case A
Pancreatitis with gastric outlet obstruction

PG, a 59-year-old male was transferred from an outside hospital to our service for continued management of severe gallstone pancreatitis after cholecystectomy. He was 5′ 11″ with a pre-illness weight of 88 kg (admit weight of 102 kg). He reported normal oral intake up until the time of admission for pancreatitis, however he had been NPO for 7 days prior to transfer. He was briefly placed on parenteral nutrition (PN) due to gastric outlet obstruction with prolonged NPO status, catabolic state, and lack of appropriate enteral access.

Two days after admission, a 24 Fr percutaneous endoscopic gastrostomy tube was placed with a 12 Fr jejunal extension tube (PEG/J) (Wilson-Cook; Cook Medical). Standard enteral nutrition (EN) was initiated through his j-tube, followed by PN discontinuation. The PEG was left to gravity drainage to decompress his gastric contents while continuing to feed his jejunum. PG’s gastric output was ∼1.5L over 24 hours with reported nausea and emesis. He was currently receiving 15mg of a proton pump inhibitor (PPI) suspension twice daily, via his j-tube, which was increased to 30mg twice daily. The surgical team allowed sips of clear liquids for comfort; however, his gastric output increased to 3-4 L/day. He was having difficulty tolerating the 150mL water flush through his j-tube, causing nausea and hiccups leading to emesis over his vented secretions. His gastric pH was checked to ensure PPI efficacy and confirmed to be >6. Due to the high gastric volume loss, the surgical team started replacement fluids through his j-tube using lactated ringers as 1/2 mL for each 1 mL of output from his gastric tube, run continuously. He complained of frequent “orange colored” stools, which coincided with the increase of his EN rate.

Two days after the standard EN reached goal rate, it was changed to a semi-elemental formula (Perative; Abbott Nutrition). The rationale for this change was the presumption that the external loss of pancreato-biliary secretions from gastric venting, known pancreatic damage, and his orange colored stools suggesting malabsorption. Due to his current complexity of care, with simpler methods available to stabilize fluid and electrolytes, it was deemed not the time in his course to consider GI reinfusion. After the change to the semi- elemental feeding, the patient reported firmer and color normalization of his stools.

PG required a negative pressure wound therapy vac due to dehiscence at his proximal surgical midline incision necessitating discharge to a facility for wound management, as well as ongoing dependence on intravenous volume replacement. He was changed to a nocturnal EN regimen in anticipation of discharge. His gastric output had decreased to 1-1.5L /day with small sips of clear liquids for pleasure. For volume replacement, he discharged with intravenous Lactated Ringer’s (1:1 replacement of gastric output), as well as water flushes via the j-tube. Weight on discharge was 97 kg.

Five days later, PG was readmitted with failure to thrive (FTT) and acute kidney injury (AKI) (Table 2); lipase was elevated to 6700. PG’s PPI had been stopped upon arrival at the outside facility and a standard, fiber containing formula had been substituted for the semi- elemental formula he was previously receiving. His fluid replacement was unknown, and the patient reported persistent and severe nausea/vomiting. PG required 10L of resuscitation, the PPI and semi-elemental EN were resumed. Due to his metabolic disarray and dehydration, the decision was made to start GI reinfusion through his j-tube. PG’s gastric pH was rechecked (7.9), therefore appropriate for reinfusion into the small bowel (goal gastric pH = ≥ 6 to mimic normal pH). The patient was stabilized and ready for discharge. The day prior to discharge, tubing was fashioned to shunt gastric output directly from his G-tube into his j-tube. This direct connection of gastric output to jejunal input was to occur during the day when EN was off; at night when j-tube was used for feeding, the G-tube would be left to gravity and those contents bolused into the jejunum in the morning; which varied between 400-600mL. He initially tolerated this change, and PG was discharged to the transitional care facility weighing 95 kg.

While at the transitional care facility, PG did not tolerate his G-tube being hooked directly up to his j-tube, reporting increased nausea/emesis. He also reported not seeing any fluid moving from his G-tube to his j-tube during the day. Intolerance of the large jejunal bolus of GI secretions collected overnight was now occurring. The facility was having difficulty reinfusing all of his upper GI losses. A follow up computed tomography (CT) scan showed a new peri-pancreatic fluid collection, in which a drain was placed. Over the next week, his stools became more watery and profuse and he was found to be C. Diff positive. Additionally, his glycemic control became erratic.

After 33 days, and exhibiting signs of sepsis, with increased nausea and vomiting, PG was readmitted to the hospital. Despite documentation reporting PG was receiving the majority of his goal EN on a consistent basis, he was down to 82 kg. This was presumed due to dehydration as well as his recent poor glycemic control altering his inability to fully utilize his EN. A CT scan demonstrated a recurrent retroperitoneal abscess. At this time, surgery was deemed necessary due to his persistent pancreatic fluid collection, associated fevers, and leukocytosis. Therefore, 2 months after PG’s first admission to our facility, he underwent an open necrosectomy for pancreatic abscess debridement, and 2 additional drains placed in the abscess cavity.

PG’s semi-elemental feeding was started post- operative day (POD) 1 at 20mL/hr, but he suffered from abdominal distention and discomfort when the rate was advanced. PG remained NPO at this time. Therefore, trophic EN continued for 3 days, after which slow advancement by 20mL/day commenced until goal rate was reached. PN was discussed with the surgical team during this time, but they preferred to avoid PN and continue to work on slow enteral advancement given his infectious risk and hyperglycemia. His PEG remained open to gravity, putting out 2-3L/day, with continued nausea. GI reinfusion was resumed as a bolus infusion. Unfortunately, due to his high volume losses and imprecise instruction to the nursing staff, jejunal boluses of >500mL were administered, causing the patient increased nausea and vomiting. EN advancement was further delayed as was adequate EN delivery.

At this time, one of the nurses devised a method for gravity feeding the patient’s gastric output through the j-tube using an enema bag. Biliary secretions were collected (over 4-6 hours), poured into the enema bag, hung alongside the EN, and then simply Y’d in utilizing the gravity method (Figure 2 A-D). The nurse and patient reported good tolerance to this method and patient was able to tolerate 100% reinfusion. Nocturnal EN was reattempted, but was met with intolerance. Therefore, he was discharged back to the transitional care hospital on continuous EN with gravity infusion of GI secretions. Three weeks later, the patient was able to tolerate G-tube clamping for 24 hours; one week later a clear liquid diet was restarted. Two weeks after this, his PPI was stopped. He was discharged home at 87kg. Two weeks later he followed up in surgical clinic, reporting he had stopped his nocturnal EN and was taking solid food. He had no signs or symptoms of malabsorption and weight had been stable since discharge. His feeding tube was removed in clinic.

Case B Surgical Leak

SL, a 41-year-old male, transferred to our facility for management of post-op complications. His history prior to transfer included: long term NSAID use, perforated duodenal ulcer requiring Billroth II/gastrojejunostomy and duodenal stump patch (Figure 3). On POD4 he required an exploratory laparotomy for drain dislodgement, and an additional drain placement. POD7, blood was noted in his drains. CT angiography was negative for bleeding; however, esophagogastroduodenoscopy (EGD) revealed a friable anastomosis with ulceration. POD13, he underwent an exploratory laparotomy: his anastomosis remained intact, but bile staining was found at the duodenal stump. It was at this time SL was transferred to our facility with AKI requiring continuous renal replacement therapy (CRRT), an open abdomen and ABThera wound vac. PN was started at the outside facility and was continued on admission. SL was 5′ 8″ and weighed 97.7kg.

  • Drainage of multiple fluid collections
  • Ligation of the gastroduodenal artery
  • Closure of a dehisced duodenal stump
  • Cholecystectomy
  • 2 intraluminal drains placed to divert bile drainage
  • J-tube placement
  • Abdomen remained open

An elemental formula (Vivonex, Nestle Health Science) was started POD 1 due to loss of pancreato- biliary secretions via external drains (Figure 4 A-B) as follows:

  • Drain #1 (most proximal) in the hepatobiliary limb put out ∼1L/day of pancreato-biliary secretions (Figure 4 A).
  • Drain #2 (distal) put out ∼50mL/day (Figure 4 A-B).
  • The tip of drain #3 in the right upper quadrant terminated near the duodenal perf repair with minimal serosanguinous fluid (Figure 4 A)

The patient’s GI secretions (drain #1 and #2) continued to increase up to 3L/day; concurrently SL’s stool output also increased requiring a rectal management system. Prior to initiation of reinfusion, the duodenal drainage pH was confirmed to be 7.6. GI reinfusion was then initiated via j-tube on the following day by continuous pump method (continuous method of bile reinfusion required 2 feeding pumps) (Figure 5). In the case of SL, GI secretions were collected every 3 hours and transferred into an empty EN bag to be infused via pump. By utilizing a “Y” adapter, this volume was infused concurrent with EN formula into the jejunum. The combined rate of bile and EN infusion averaged between 300-400mL an hour. Although SL tolerated this volume without complaint, he was changed to a more calorie dense, semi-elemental formula (Vital 1.5, Abbott Nutrition) given his high duodenal and stool output to maximize absorption potential. Of note, it is likely he would have done well on a concentrated standard formula also.

A week after admission, SL returned to the OR for debridement of his abdominal wall and fascia, as well as abdominal closure. His AKI was resolving; he was now off CRRT. Stooling had decreased to once daily. Over the next few days, the volume of his most proximal biliary drain (#1), significantly dropped, and the secondary drain increased (determined to be a clog in drain #1). The patient continued to tolerate full GI reinfusion via pump of ∼1.5- 2L/day. A regular oral diet was started, but poor appetite and nausea prevented much intake. Discharge planning for home began, as he wanted to go home with family and not to a facility.

In preparation for the transition to home, the following simplifications were made to his EN and reinfusion regimen:

  • 1. Trial GI reinfusion from pump to bolus. Bile was collected every 4 hours, 24/7, with reinfusion of at least 250mL (> 250mL was discarded) at each of the q 4 hour intervals (6 x/day).
  • 2. Intravenous fluids were stopped; 100mL of 0.45% normal saline (NS) flushes before and after EN cycle was initiated with 50mL after any bile reinfusion.
  • 3. PPI transitioned from IV to liquid suspension via jejunal tube.

The patient tolerated the changes well, and the new regimen appeared to keep SL’s electrolytes and volume status in balance. His weight was 93 kg. SL and family were educated and provided extensive written instructions, including home EN regimen, GI reinfusion, and home reconstitution of 1/2NS. However, it was noted that during the education, the patient and family asked very few questions and did not seem engaged. SL was discharged home and followed up in surgery clinic 4 days later. He reported not tolerating home EN, having increased nausea and vomiting; he was only reinfusing his bile on average of 2x/day (down from 6x/day in the hospital). He reported no BM since discharge. His weight in clinic was 79.5 kg. It was recommended he be readmitted for IV hydration; the importance of GI reinfusion was stressed. The patient declined readmission promising improved compliance at home.

One week later, SL was readmitted with FTT, nausea/vomiting, dehydration, and metabolic disarray (Table 2). SL reported not using EN, and that bile output had vastly tapered off. He was completely unable to eat due to gastric discomfort/fullness; feeling like food was “just sitting there” when he ate. He had not stooled in days. Of note, patient was on narcotics at home and only on stool softeners to relieve his constipation. SL was rehydrated and restarted on appropriate medications:

  • >PPI via j-tube, maximum dose BID
    • Stool softeners and osmotic laxatives prn; goal = 1 stool at least every other day
  • >Oxycodone prn, for abdominal discomfort
  • >Reglan, before meals and HS to help with nausea
  • >50mL, 1/2 NS flush after anything administered via j-tube

His EN was changed back to continuous and bolusing of GI secretions into the j-tube every 4 hours was resumed. SL remained in the hospital 4 days tolerating regimen well. He reported less nausea; however, oral intake remained poor. His EN continued to meet his nutritional needs. EN was readjusted to a 16-hour nocturnal regimen with bolus of bile reinfused 6x/day as follows (ideally prior to any oral intake):

  • >250mL before and after 16 hour EN run (1800 & 1000)
  • >250mL ∼ 4 hours into EN infusion (before bed at 2000) and upon waking (0600)-(stop EN, infuse, resume EN)
  • >250mL while EN off during day (1200 & 1500)

For total of: 250mL 6x/day (1500mL); discard remaining. In addition:

  • Patient to use 1/2 normal saline (NS) flushes (made with 3/4 teaspoon table salt mixed with 1 liter of water- NOTE: would only have those patients prepare this mixture if you are sure they can measure correctly)
    • Give 1 syringe (60mL) after medications, EN infusion, or GI secretion bolus.
    • Patient to increase volume of 1/2NS bolus if oral intake of liquids decreased.

The patient and his family were much more interactive with education for home with a much higher level of interest in EN/reinfusion instructions- they wanted to go home and stay home.

Three days after discharge, patient’s family called reporting increase in stools, increase in nausea and decrease in bile output. He reported infusing all GI secretions, but reported the output had decreased to <1.5L/day. We reviewed exact EN and flush regimen over the phone; the patient had not quite received goal EN or flushes due to his abdominal discomfort. SL’s labs had been checked the day prior and were normal, showing no signs of dehydration. Due to his nausea and diarrhea, EN was changed back to a continuous regimen again. His medications were reviewed; upon discharge his PPI had been changed to an oral capsule vs. the suspension BID via jejunal tube and his antiemetic and prokinetic coverage were inadvertently left off his discharge medications; all of which were resumed.

SL was seen twice in surgery clinic over the next month; his weight maintained at 79.5 kg and he remained well hydrated with decreasing GI secretions from his drains. Three months after his first admission, his final surgical drain was removed. He was off EN, maintaining his weight, and his feeding tube was removed.

APPLICATION AND CONCLUSION

These two cases highlight clinical applications of successful GI reinfusion along with EN to provide nutrition, hydration, electrolyte balance, and improved absorption in patients with excessive loss of GI secretions, avoiding both PN/IV fluids and a central line. They also highlight the complexity of this process, as well as the potential number of mistakes and pitfalls that can easily occur along the way. A multidisciplinary team is clearly needed to achieve success. Once a patient is deemed a good candidate for GI reinfusion (Table 3 lists poor candidates), the best method needs to be determined (Table 4). In deciding on how to reinfuse, it may not only depend on whether the patient tolerates it, but whether the patient will be in a facility or at home. Ideally, GI secretions should be administered concurrent with EN for optimal pancreato-biliary secretion and nutrient mixing once a pH >6 has been verified. If it is not in the best interest for the patient to receive this therapy, there are other options for EN without reinfusion of endogenous secretions in order to maintain hydration and electrolyte balance (Table 5).

Thank you to the surgical nurses, residents and attendings who help conceptualize unique solutions for complex patients, and who are always willing to take the time to teach me. A special thanks to Joe Freeze, NP.

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A Case Report

Familial Multifocal Gastrointestinal Stromal Tumors – Critical Lessons in Identification of a Rare Disorder

June 2017 • Volume XLI, Issue 6
Paul Fitzmorris,Leona Council,Fred Weber

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Paul Fitzmorris1 Leona Council2 Fred Weber1 1Department of Gastroenterology and Hepatology, 2Department of Pathology, University of Alabama at Birmingham, AL

INTRODUCTION

A 50 year-old Caucasian gentleman presented with melena. Identification of multiple gastric submucosal masses and a family history of gastrointestinal stromal tumors had important clinical implications for both the patient and his asymptomatic children.

Case

A 50 year-old Caucasian gentleman with a history of gastroesophageal reflux, diabetes mellitus and basal cell carcinomas presented with melena over the past few weeks. He denied nausea, vomiting and abdominal pain.

His vitals and abdominal exam were unremarkable. Digital rectal exam revealed black, tarry stool. Hemoglobin on admission was 6.3 g/dL. Computed tomography (CT) scan revealed two infiltrating masses in the proximal stomach (Images 1 and 2).

After resuscitation, an upper endoscopy noted a large submucosal mass in the fundus and two smaller submucosal masses along the angularis. Subsequent endoscopic ultrasound described the masses as lacking a defined capsule and having irregular extension into the gastric wall with isoechoic and heterogenous areas. Fine needle aspiration revealed spindle cell tumors (CD117 positive/DOG1 negative/SMA negative cells with < 2 mitoses per 20 high powered field) (Images 3 and 4). Upon further questioning he reported that multiple first- and second-degree relatives have been diagnosed with gastrointestinal stromal tumors (GISTs).

His disease was thought to be locally advanced and he was started on neo-adjuvant imantinib. Total gastrectomy was performed several months later; small ileal and jejunal tumors, not previously seen by CT, were identified intraoperatively and resected. These additional lesions were GISTs as well, and he was placed on long-term maintenance imantinib.

A detailed family history revealed that his father, brother, paternal aunt and multiple cousins on the paternal side had previously been diagnosed with GISTs, the youngest at age 25 and the oldest at age 57. The patient underwent genetic testing, revealing him to be heterozygous for a three nucleotide deletion on exon 11 of KIT mRNA.

After his diagnosis with the germline KIT mutation, his two adult children (son and daughter) were tested and both were positive. His asymptomatic daughter was found to have a 3 cm jejunal mass on screening CT enterography and resection is planned. His son is scheduled for an EGD, colonoscopy and CT enterography.

Discussion

GISTs are rare tumors, most commonly due to sporadic mutations of the KIT gene. The annual incidence of GISTs is estimated at 10 – 20 per 1,000,000. The median age of diagnosis is 50 years of age and some literature suggests a male predisposition. Presentations may include gastrointestinal bleeding, abdominal pain and gastrointestinal outlet obstruction. GISTs may occur in the stomach (60 – 70%), small intestine (20 – 30%), colon/rectum (5%) and esophagus (<5%).1 GISTs usually present as solitary tumors with local or locally advanced disease. Only 10% of cases are metastatic upon initial diagnosis. Multifocal disease can also be due to multiple primary tumors. The occurrence of multiple primary GISTs in adults is rare but may be under appreciated. It is almost exclusively seen in familial GIST disorders or other specific syndromes, such as Carney’s triad or type 1 neurofibromatosis.2

Familial GISTs are part of a rare autosomal dominant disorder of unknown incidence. It is due to inherited germline mutations of the KIT gene in 80% of cases and mutations of the PDGFRA gene in 10% of cases. Given how rare familial GISTs are, guidelines do not discuss when to screen for germline mutations, nor how/when to evaluate asymptomatic family members with the mutation.3 Finally, case reports have described an association between familial GISTs and other manifestations of the KIT gene mutations, including gastrointestinal dysmotility, cutaneous hyperpigmentation, urticaria pigmentosa, systemic mastocytosis and melanoma. The link between these disorders may be explained by a common progenitor cell that requires KIT activation to differentiate into interstitial cells of Cajal, gastrointestinal smooth muscle, melanocytes and mast cells.4-8

CONCLUSIONS

  • When a patient is found to have multifocal GISTs or a family history of gastrointestinal stromal tumors in multiple family members, consider genetic testing for a familial GIST mutation.
  • For patients with a germline KIT mutations, periodic GI tract surveillance, including dedicated small bowel imaging, seems reasonable. Our patient’s asymptomatic daughter underwent a CT enterography that identified a GIST, allowing for pre-symptomatic surgical resection.
  • Furthermore, an annual dermatologic evaluation may be prudent. Our patient’s daughter was found to have a dysplastic nevus.

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Dispatches From The Guild Conference, Series #5

Postoperative Management of Crohn’s Disease

June 2017 • Volume XLI, Issue 6
Jana G. Hashash,Miguel Regueiro

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The majority of patients with Crohn’s disease will require an intestinal resection at some point in their life. Postoperatively, these patients are at risk for developing recurrent Crohn&rsquo;s disease and medications are often required to prevent recurrence. Here we discuss the importance of stratifying patients according to their risk of recurrence as it determines postoperative management.

Jana G. Hashash, MD, MSc, Assistant Professor of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA Miguel Regueiro, MD, AGAF, FACG, FACP, Professor of Medicine and Professor, Clinical and Translational Science, University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Senior Medical Lead of Specialty Medical Homes, University of Pittsburgh Medical Center, IBD Clinical Medical Director, Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh, PA

INTRODUCTION

Crohn’s disease is a chronic inflammatory condition that affects the GI tract anywhere between the mouth and the anal verge. Approximately 780,000 people in the United States carry the diagnosis of Crohn’s disease and the incidence and prevalence have been on the rise.1,2 The majority of patients with Crohn’s disease will require an intestinal resection, most commonly an ileocecal resection. The indication for surgery is usually for medically refractory disease or complications such as strictures, abscess, fistulae, or rarely malignancy.3,4 In a recent systematic review, it was reported that the 1 year cumulative risk of surgery for Crohn’s disease patients is estimated to be 16.3%, 33.3% at 5 years, and as high as 46.6% at 10 years.5

Natural Course of Postoperative Crohn’s Disease and Recurrence Rates

After a curative ileocecal resection, the prevention of Crohn’s disease recurrence remains a challenge. Recurrence in these patients usually occurs at the ileocolonic anastomosis and in the neo-terminal ileum.6 Studies have shown that histologic recurrence may occur as early as 1 week after surgery.7 Endoscopic recurrence of Crohn’s disease tends to follow with recurrence rates as high as 70-90% at 1 year after surgery in patients who do not receive postoperative Crohn’s disease medications.6,8-12 Crohn’s disease recurrence after resection is often silent and this accounts for the lag between endoscopic and clinical recurrence, with the latter occurring later.13 Clinical recurrence rates, as defined by the Crohn’s disease Activity Index (CDAI), were shown to occur in 20-40% of patients at 1 year from surgery, and 35-50% by 5 years postoperatively.6,9-11,14 It is not an uncommon scenario for patients to require yet another surgical resection once clinical symptoms ensue in the postoperative setting (i.e. clinical recurrence). A quarter (25%) of patients will require a second intestinal resection by 5 years after their initial surgery, and up to 35% of patients by 10 years.15 The indication for subsequent intestinal resection tends to be similar to the indication of the initial operation.16-19

Surveillance of Postoperative Crohn’s Disease

The most sensitive modality for detection of postoperative Crohn’s disease is via an ileocolonoscopy which allows for the evaluation of the neo-terminal ileum mucosa. Due to the high rates of early endoscopic recurrence, it has been recommended that ileocolonoscopy is performed 6-12 months postoperatively.13,17,20-22 This would allow for early detection and aggressive treatment of recurrent disease, if present.

Endoscopic Scoring of Postoperative Crohn’s Disease

The most widely used endoscopic scoring system was developed by Rutgeerts et al.11 Although it is not validated, this score is widely used and predicts a patient’s risk for future clinical and surgical recurrence. Based on the endoscopic appearance of the neo-terminal ileum, patients are categorized into one of 5 groups; i0, i1, i2, i3, or i4 (Table 1). Patients with a score of i0 (normal appearing neo-terminal ileum) and i1 (<5 small aphthous ulcers in the neo-terminal ileum) have a low likelihood of progression to clinical or surgical recurrence in the next 5 years and are considered to be in endoscopic remission. Specifically, 85% remain in clinical remission over a 2-year time period and are considered very low risk for requiring a second operation.11,23,24 Patients with scores of i2, i3, and i4 are at a high risk to require a second Crohn’s disease intestinal operation within the following 5 years and are designated as having endoscopic recurrence.11,23,24

Risk Factors for Postoperative Crohn’s Disease Recurrence

There are several risk factors that have been shown to contribute to the postoperative recurrence of Crohn’s disease. These factors are classified as (1) patient- related factors, (2) disease-related factors, and (3) surgery-related factors.25 The only modifiable risk factor is tobacco smoking.26-30 Not only does smoking tobacco increase endoscopic and clinical recurrence rates, surgical rates were seen to increase by 2.5 fold.31 Recurrence rates were higher in females and those who were smoking greater than 15 cigarettes per day.28,32 Fistulizing or penetrating Crohn’s disease and the need for prior Crohn’s disease related intestinal resection have also been shown to be strong risk factors for postoperative recurrence.33 Data on peri-operative steroid use as a risk factor for Crohn’s disease recurrence has been inconclusive. Recently, however, a multi-centre observational study by de Barcelos et al. showed that perioperative steroid use was the only significant risk factor for early postoperative endoscopic recurrence.34 A number of other disease-related risk factors have been studied as potential risk factors and these include young age at diagnosis of Crohns’ disease, young age at initial intestinal resection, and short duration of disease prior to the need for surgery.16,17,19,25,27,28,30,35-40 Surgical risk factors pertaining to the intestinal resection itself have been extensively studied, but all have been inconclusive in identifying strong factors for postoperative recurrence of Crohn’s disease. Variables that were explored include: length of resected bowel, width of surgical margins, type of anastomosis, perioperative complications, and presence of granulomas in the surgical specimen.4,24,25,28,36,39,41-44

Medications Studied for the Management of Postoperative Crohn’s Disease

There have been many studies on the early use of different medication classes for the prevention of postoperative Crohn’s disease after resective surgery. Table 2 displays the 1 year clinical and endoscopic recurrence rates that have been reported in various randomized controlled studies of patients after an ileocecal resection and the use of immunomodulators,45-47 nitroidimazole,48,49 budesonide,50,51 5-aminosalicylic acid52-55 and placebo. The lowest endoscopic recurrence rates were seen with immunomodulators (azathioprine and 6 mercaptopurine) at 42-44%. Postoperative recurrence rates were further decreased with the widespread use of anti-tumor necrosis factors (anti-TNF) medications. Table 3 summarizes the postoperative endoscopic rates reported with these medications.56-64 Most recently, data from the PREVENT trial65 showed that the clinical recurrence rates in patients on infliximab was less than the rates on placebo at week 76 or less, however this difference was not statistically significant (12.9% vs 20%; p=0.097). Endoscopic recurrence rates, however, were significantly lower in patients receiving infliximab compared to placebo (22.4% vs 51.3%; p<0.001). In the POCER trial, endoscopic recurrence rates at 18 months after surgery compared those who underwent an ileocolonoscopy at 6 months after an ileocecal resection (active care arm) and who subsequently received medication escalation if needed (endoscopic ileal score ≥i2), to those patients who did not get a 6 month ileocolonoscopy (standard care arm).66 All patients received metronidazole 400 mg by mouth twice daily for the first 3 months postoperatively. Additionally patients who were classified as high risk (smokers, penetrating disease, and/or prior intestinal resection) received azathioprine. Those who were intolerant of azathioprine were given adalimumab instead. At 18 month follow up, endoscopic recurrence rates were significantly lower amongst patients in the active care arm compared to those in the standard arm (60/122=49% vs 35/52=57%; p=0.03). It was also noted that within the high-risk active arm patients, those who received adalimumab had lower 6 month endoscopic recurrence rates when compared to those who received azathioprine (6/28=21% vs 33/73=45%).66

Management of Postoperative Crohn’s Disease – Technical Review and Guidelines

Recently, the American Gastroenterological Association (AGA) published a technical review on the management of postoperative Crohn’s disease.67 This review addressed clinical questions pertaining to the different management strategies for postoperative Crohn’s disease patients and their role in reducing recurrence. For instance, this review addressed if routine early pharmacologic prophylaxis was superior to endoscopy- guided treatment in reducing long-term recurrence in postoperative Crohn’s disease patients. Another question related to the comparative effectiveness of the different medications used amongst Crohn’s disease patients who are receiving early postoperative pharmacological prophylaxis. Similarly, comparative effectiveness of the different medications used to decrease endoscopic recurrence in patients who already developed postoperative asymptomatic endoscopic recurrence. Additionally, this review compared whether routine endoscopic monitoring at 6-12 months postoperatively is superior to no endoscopic monitoring.67 This technical review informed AGA Guidelines for the management of postoperative Crohn’s disease.68 (Table 4) The authors provide two approaches to patients with postoperative Crohn’s disease (Figures 1, 2). Based on individuals’ risk factors, patients are stratified in to groups to aid physicians in their further management. Some physicians prefer to practice the ‘watchful waiting’ approach, while other physicians are more proactive and initiate medications postoperatively for prophylaxis and secondary prevention of recurrent Crohn’s disease. Despite the published algorithms, deciding the best option for patients often remains a dilemma. It is the authors’ personal practice to initiate postoperative Crohn’s disease prophylaxis to prevent recurrence. Almost all patients receive a medication postoperatively, whether using an immunomodulator or combination therapy with a biologic agent and an immunomodulator. Depending on a patient’s risk factors, he/she is categorized in to a low-risk, moderate-risk, or high-risk group (Figure 1). All patients regardless of their group will receive an ileocolonoscopy for surveillance of endoscopic recurrence, 6-12 months postoperatively. The authors stratify patients into risk categories when approaching postoperative management. Low risk patients include those who are undergoing their first intestinal resection for a short stricture and those who have had long standing disease (>10 years). Patients in the low risk group are not administered medications, however, if there is evidence of recurrent Crohn’s disease (ileal score of ≥i2), treatment with an immunomodulator and/or anti-TNF is initiated. Otherwise, they would remain off of any medications, but should continue to have surveillance colonoscopies every 1-3 years. Patients who are in the moderate risk group are those who are undergoing their first intestinal resection for a long stricture (>10 cm) or for inflammatory Crohn’s disease and who have had disease for shorter than 10 years. Patients in this moderate risk group start thiopurines in the postoperative setting +/- metronidazole. While the authors still believe there is a role for immunomodulators in patients not previously receiving this type of medication, there has been a recent trend to only use thiopurines in combination with biologics rather than monotherapy. Nonetheless, we still use immunomodulators for this moderate risk group naïve to treatment, but escalate to an anti-TNF if there is evidence of subsequent recurrence. Patients in the high-risk group include those with penetrating disease, more than 2 intestinal resection surgeries, and who are smokers. In these high-risk patients, we recommend a combination of an immunomodulator with anti-TNF. Whether therapeutic drug monitoring of biologic therapy would allow for monotherapy anti- TNF (without an immunomodulator) for postoperative Postoperative Management of Crohn’s Disease Crohn’s disease management is unknown. Another approach to the management of postoperative Crohn’s disease is to stratify patients by risk of recurrence but utilize endoscopic recurrence to guide therapy (Figure 2).66 In this approach, patients are separated in to a high-risk group and a low risk group for recurrence where only patients in the high-risk group would receive Crohn’s disease medications. The medication of choice is a thiopurine agent, but in cases of thiopurine intolerance, anti-TNF medications are used instead. Again, similar to the algorithm in Figure 1, all patients would undergo an ileocolonoscopy at 6 months postoperatively, and depending on evidence of endoscopic recurrence, medication escalation is made. Of note, the authors of POCER have also reported the potential for fecal calprotectin as a surrogate marker for Crohn’s disease recurrence and may be a noninvasive method to measure recurrence.69

CONCLUSION

The majority of patients with Crohn’s disease will require an intestinal resection at some point in their lifetime. Postoperative management of these patients remains a challenge. It is important to identify high- risk patients who exhibit risk factors for recurrence and to aggressively treat these patients to prevent or ameliorate recurrence of their Crohn’s disease. All patients regardless of their risk should have an ileocolonoscopy 6-12 months postoperatively to initiate or adjust medications in cases of endoscopic recurrence (ileal score ≥i2). The authors provide the algorithm that they utilize in their practice when approaching postoperative Crohn’s disease patients (Figure 1).

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Nutrition Issues In Gastroenterology, Series #164

Essential Fatty Acid Deficiency

June 2017 • Volume XLI, Issue 6
Kris M. Mogensen

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Essential fatty acid deficiency (EFAD) may occur in both the inpatient and outpatient setting. Patients with malabsorptive disorders as a result of pancreatic insufficiency or massive bowel resection are at risk, and it is important to recognize that other patient populations may develop EFAD. A relatively new risk factor for EFAD is the shortage of intravenous fat emulsions in those requiring parenteral nutrition. This article provides a brief review of the role of essential fats, identifies those at risk, the clinical signs and symptoms associated with EFAD, as well as prevention and treatment recommendations.

Kris M. Mogensen MS, RD-AP, LDN, CNSC Team Leader Dietitian Specialist, Department of Nutrition, Brigham and Women’s Hospital, Boston, MA

INTRODUCTION

Essential fatty acid deficiency (EFAD) is rare in healthy adults and children who consume a varied diet with adequate intake of essential fatty acids, linoleic acid (LA) and alpha-linolenic acid (ALA). Clinicians should be aware of the risk of EFAD in specific populations that may suffer from malabsorption syndromes, or have other reasons that severely limit fat intake, absorption, or metabolism. A recent concerning trend in the United States (US) is the increasing incidence of parenteral nutrition (PN) product shortages, including vitamins and minerals, but also lipid injectable emulsion (ILE, formerly known as intravenous fat emulsion or IVFE).1 This has led to new populations at risk for EFAD, and clinicians must be aware of these shortages and the risks posed to patients dependent on PN.

Role of Fats

Fat is an essential component in the diet, whether it part of an oral diet, an enteral nutrition formula, or part of a PN admixture. The human body needs fat stores to cushion organs and provide insulation for temperature regulation. The fat depot can be used for energy during times of starvation, although it is important to recognize that some tissues in the body (brain and red blood cells) rely solely on glucose for energy as fat cannot be metabolized to create glucose. Dietary fat is not only an energy source through oxidation, it is also required to facilitate absorption of fat-soluble vitamins in the small bowel.2

Fat has important roles at the cellular level as it is an essential part of cell membranes. The cell membrane is composed of phospholipids, which are sensitive to chemical signaling. Consuming diverse types of fat (e.g., omega-3 fatty acids vs. omega-6 fatty acids) will allow incorporation of different types of fat into the cell membrane, modifying the response to a number of metabolic processes including inflammation, controlling gene expression in the cell, and cellular protein production. A recent review by Calder provides a more detailed discussion of these processes.3

Fats are composed of triglycerides, containing a glycerol backbone with three fatty acids that vary in length and number of double bonds. Fatty acids can be classified based on their length, with short chain fatty acids having 2-4 carbon atoms, medium chain fatty acids having 6-12 carbon atoms, and long-chain fatty acids having 12-24 carbon atoms. Fatty acids are further classified by the number of double bonds: saturated fats – 0, monounsaturated fats – 1, and polyunsaturated fats ≥ 2. Humans generally consume enough fat in the diet to meet all fatty acid requirements; the EFAs are those that cannot be synthesized as humans lack the enzymes required.2-5

Fat Digestion, Absorption, and Metabolism

Digestion and absorption is a complex process. Understanding normal digestion and absorption of fat helps to identify risk factors for EFAD in patients with gastrointestinal (GI) diseases. Digestion of fat starts in the mouth with salivary lipase; when food enters the stomach there is exposure to gastric lipase, although this primarily digests medium- and short-chain fatty acids. As chyme is released from the stomach into the duodenum, fat is emulsified by bile, while pancreatic lipase and colipase digests fat into free fatty acids and monoglycerides that are packaged into micelles (∼ 200 times smaller than emulsion droplets). The micelles transport the free fatty acids and monogylcerides to the brush border of the distal jejunum and ileum for absorption. Once inside the enterocyte, monoglycerides and fatty acids are resynthesized into triglycerides with cholesterol, fat-soluble vitamins, and phospholipids into chylomicrons. Chylomicrons are transported via the lymphatic system to the liver, adipose, and muscle for additional metabolism and/or storage.2,4

Within the cell, fatty acids are metabolized through desaturation and elongation. When considering the essential fatty acids, ALA (an omega-3 fatty acid) is metabolized preferentially over LA (an omega-6 fat); when either fat is not available or limited, oleic acid (an omega-9 fat) is metabolized.5 Interestingly, most reports of EFAD are of LA deficiency, with little comment of ALA deficiency.

Risk factors for EFAD

When fat intake, digestion, absorption, and/or metabolism are impaired, there is risk of EFAD.

Patients with GI disorders are at high risk for EFAD because of potential impairment of pancreatic enzyme secretion or diseased small bowel preventing normal absorption of fat (see Table 1). Siguel and Lerman evaluated 47 patients with chronic intestinal disease (25 Crohn’s disease, 11 with ulcerative colitis, 7 with short bowel syndrome, and 4 with celiac disease) and compared them to 57 healthy controls. Using biochemical measures of EFAD, the authors found that the patients with GI diseases had significantly lower levels of fatty acids and biochemical evidence of EFAD.6 Jeppesen and colleagues evaluated 112 patients with GI disorders (including Crohn’s disease, ulcerative colitis, bowel resection, celiac disease, radiation enteritis, and cholestatic liver disease) by conducting fecal fat analysis and serum levels of LA. The authors found that those with higher degrees of malabsorption had lower LA levels.7

Cystic fibrosis (CF) is a risk factor for EFAD. There are approximately 30,000 patients in the U.S. with CF and 70,000 worldwide.8 Although this is a small number of patients, they may be seen by nutrition support clinicians given the intensive nutritional needs of this population. Pancreatic insufficiency is present in varying degrees in most patients with CF.8 Strandvik et al evaluated 110 CF patients taking a normal diet; only 15 had no evidence of pancreatic insufficiency. Presence of EFAD was evaluated using biochemical measures. The authors found that serum concentrations of LA and docosahexaenoic acid were significantly lower in patients who had severe CF transmembrane conductance regulator mutations, suggesting that the deficiency was associated with abnormal EFA metabolism.9 Patients with other causes of pancreatic insufficiency or impairment are also at risk for EFAD. There is very little reported in the literature on prevalence of EFAD in patients with acute or chronic pancreatitis, but one must consider pancreatitis to be a risk factor if pancreatic insufficiency is present.

There are clinical conditions where fat delivery is restricted. For example, patients dependent on PN who have an allergy to ILE and cannot receive it will be at risk for EFAD. PN-dependent patients with significant hypertriglyceridemia (e.g., triglyceride levels > 400 mg/dL) also have ILE restricted to decrease the risk of pancreatitis. Patients who follow extremely low-fat diets may also be at risk for EFAD, including patients with chyle leaks, who must be maintained on very low fat diets for ≥ 3 weeks.10-12 A small study of patients undergoing Roux-en-Y gastric bypass versus patients who have undergone adjustable gastric banding showed transient signs of EFAD.13 Carnitine is important in fat metabolism; deficiency may contribute to development of EFAD.14 Ahmad and colleagues found that maintenance hemodialysis patients with signs of EFAD showed partial correction with L-carnitine supplementation alone.15 Shortages of ILE are a relatively new risk for EFAD. The American Society for Parenteral and Enteral Nutrition (ASPEN) has published patient care guidelines in the event of ILE shortage on the ASPEN Website on the Product Shortage page (http://www. nutritioncare.org/public-policy/product-shortages/).16

Clinical Manifestations of EFAD

Patients with EFAD may exhibit both physical and biochemical evidence of deficiency (see Table 2). For patients with known risk factors, clinicians need to monitor for evidence of EFAD.

As stated above, in the absence of adequate ALA and LA, oleic acid is metabolized to mead acid (also known as eicosatrieonic acid [triene]). There is also reduced production of arachidonic acid (also known as eicosatetraenoic acid [tetraene]). An elevated triene:tetraene ratio demonstrates that more mead acid than arachidonic acid is being produced, suggestive of EFAD. A ratio > 0.2 (some suggest > 0.4) is diagnostic of EFAD.5 An elevated triene:tetraene ratio will manifest before any other signs or symptoms of EFAD.

There are non-specific biochemical changes that should raise suspicion of EFAD in at-risk patients. Richardson and Sgoutas monitored four patients receiving PN and found elevations in serum aspartate transaminase (AST), alanine transaminase (ALT), and lactate dehydrogenase that paralleled a rise in triene:tetraene ratio with duration of fat-free PN. The authors noted the same pattern with serum triglyceride levels. All improved with the addition of ILE.17 Alterations in liver function tests have been attributed to mitochondrial dysfunction that occurs with EFAD.18 Press and colleagues noted that patients with EFAD had altered platelet aggregation.19

Physical manifestations of EFAD are often present in the skin. Close examination of the skin may reveal many nutritional deficiencies, including B vitamins, vitamin C, and zinc, as well as EFAD. Much of what is known about the physical manifestations of EFAD come from early case reports in the 1970s and 1980s.10,17,19-24 Patients who complain of a dry, scaly rash, who also have an underlying disease associated with fat malabsorption, should raise clinical concerns of EFAD and prompt further investigation. It is important to recognize that zinc deficiency can also present as a dry, scaly rash and patients with malabsorption and chronic diarrhea may present with both EFAD and zinc deficiency.

Prevention of EFAD

Adequate fat provision is the starting point to prevent EFAD. At least 10% of total energy delivery should come from polyunsaturated fat, and 2%-4% of calories from LA. Once high-risk patients are identified, an appropriate nutrition plan can be developed. Patients dependent on PN can develop EFAD in 10 days without appropriate fat provision, but most reports are after 4 weeks of fat-free PN.5 For patients receiving PN with a standard, soybean oil based ILE, the minimum amount of fat to prevent EFAD is 100g (500mL of 20% ILE) per week.24 ILE products comprised of only soybean oil contain 50% LA.18 Smoflipid® (Fresenius Kabi, Lake Zurich, IL) is an ILE that contains a blend of soybean oil, medium chain triglycerides, olive oil, and fish oil that was introduced to the US market in 2016. ClinOleic 20% (Baxter Corporation, Mississauga, ON; not available in the U.S.) is a blend of olive oil and soybean oil (see Table 3). With either of the new ILEs, clinicians need to calculate the amount of LA infused to ensure adequate provision of LA.25 Table 4 summarizes EFAD prevention strategies.

Cycling of PN may also be beneficial to meet fatty acid requirements. Since human adipose tissue is 10% LA, the fat depot may be a significant source of EFAs. When PN is cycled, insulin secretion and lipogenesis are reduced during the time when PN is off or when hypocalorically feeding, allowing for some mobilization of LA from the fat depot;18,26 adequate fat stores are needed for this to be effective.

With the advent of new ILE products, clinicians may have questions about the ability to use these products to meet EFA requirements. Gramlich and colleagues reported on three obese patients requiring prolonged PN because of complications of GI surgery.18 All three patients started with standard, soybean oil based ILE, then transitioned to ClinOleic 20% and/or Smoflipid® throughout their prolonged course of PN. All had PN cycled for at least part of their time on PN. Although two of the three patients had mildly elevated mead acid (triene) levels by the end of their PN courses, all had normal triene-tetraene ratios. Patients likely met EFA needs with their ILE, but cycling of PN and their own adipose tissue may have provided some EFAs as well. It will be important for clinicians to report outcomes with these new ILE products in underweight patients with little fat stores.

Treatment of EFAD

If EFAD is identified, the clinician must first consider the cause. For patients taking an oral diet, take a careful diet history and determine adequacy of EFA intake. Counsel patients with known fat malabsorption to consume foods rich in EFAs, including condiments made with oils that have high EFA content (Table 5), such as mayonnaise and margarine made with soybean oil, and spreads such as sunflower seed butter (see Table 5). For those with pancreatic insufficiency, evaluate adequacy of pancreatic enzyme replacement.

For PN-dependent patients, recalculate the fat content of the PN prescription and determine how much LA is being provided. Although 100g soybean oil based ILE per week should be adequate to prevent EFAD, patients may need more to treat pre-existing EFAD. Unfortunately, there are no dosing guidelines to help determine how much more ILE to administer. If the patient is receiving only 4% of calories from LA, the clinician could consider increasing to 6% of calories from LA for a defined period of time (e.g., 2-4 weeks) and then recheck the triene:tetraene ratio. PN-dependent patients may also be at risk for carnitine deficiency and should be evaluated and treated if deficient.

For PN-dependent patients who cannot reliably receive ILE (e.g., patients with severe hypertriglyceridemia), topical oils may be a source of essential fats (Table 6). Use of topical oils to treat EFAD may be worth trying, but clinicians must recognize that this method may not be effective. In some cases, provision of ILE (particularly for those patients who must follow an extremely low fat diet, for example, those with a chyle leak) is the best way to treat EFAD.

Monitoring

There are little data to guide monitoring of EFA status. Standard monitoring practices for long-term PN patients suggest checking a fatty acid panel at least once or twice per year. Clinicians may want to monitor at-risk patients more closely, for example every 3-4 months. Clinicians must maintain a high level of suspicion of EFAD for patients who are at risk and should monitor for physical signs of deficiency that may prompt biochemical evaluation. For patients who require prolonged fat restriction, first conduct a careful physical examination to evaluate for signs or symptoms of EFAD. Check a triene:tetraene ratio if there is concern for EFAD or if the patient is malnourished. If there is no concern for EFAD at the baseline clinical evaluation, check a triene:tetraene ratio after four weeks of extreme fat restriction.

CONCLUSIONS1

Although EFAD is rare in the US, there are patient populations at risk for developing this deficiency including malabsorption disorders, those following highly fat restrictive diets, PN-dependent patients with restricted fat delivery due to inability to tolerate ILE (e.g., allergy or hypertriglyceridemia), or ILE product shortage. New ILE products coming to the market may reduce the risk of product shortage, and may be tolerated by those patients with adverse reactions to standard ILE products. At risk patients should be monitored closely for signs and symptoms of EFAD as biochemical changes indicative of EFAD will occur before clinical signs and symptoms appear.

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