Carol Rees Parrish M.S. R.D. Series Editor Protein Losing .
NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #162Carol Rees Parrish, M.S., R.D., Series EditorProtein Losing Enteropathy:Diagnosis and ManagementAndrew P. CoplandJohn K. DiBaiseProtein losing enteropathy (PLE) is an uncommon etiology of hypoproteinemia. It is caused by proteinloss from compromised gastrointestinal (GI) mucosa as a result of GI mucosal diseases, GI tractinfections, as well as from disruptions of venous and lymphatic outflow. The prevalence of PLE ispoorly understood given the wide variety of causes of both hypoalbuminemia and PLE, and due to alack of systematic screening. The evaluation of a potential PLE patient includes a careful assessmentfor alternative causes of hypoalbuminemia and a measurement of GI tract protein loss. This reviewprovides the clinician with diagnostic criteria, as well as management and nutrition support options.INTRODUCTIONProtein-losing enteropathy (PLE), sometimesreferred to as protein-losing gastroenteropathy,is an unusual cause of hypoproteinemia and ischaracterized by the shedding of large quantities ofprotein from the gastrointestinal (GI) mucosa. PLE mayresult from a wide variety of etiologies and can be botha diagnostic and therapeutic challenge to the practicinggastroenterologist. The clinical presentation of PLEmay also be complicated by micronutrient deficienciesrelated to the underlying etiology of the PLE. In somecases, we have noted significant vitamin deficienciesand deficiency of essential fatty acids complicatingAndrew P. Copland, MD1 John K. DiBaise, MD21Division of Gastroenterology and Hepatology,University of Virginia Health System, Charlottesville,VA 2Division of Gastroenterology and Hepatology,Mayo Clinic in Arizona, Scottsdale, AZ22the care of these patients. Through the use of a caseillustration, we will explore a practical approach to theevaluation and management of PLE.In early 2016, a 51 year-old woman presented to theGI clinic upon referral by a hematologist because of thedevelopment of progressive hypoalbuminemia (albumin2.6 g/dL) which had been identified approximately 1year earlier. She described one normal appearing stoolper day, denied any GI complaints, and her physicalexamination was entirely normal.PLE is generally considered to be a rare condition;however, given a lack of systematic screening and a widevariety of causes of hypoalbuminemia, its prevalence ispoorly understood. There are robust data describing anincidence of up to 18% among survivors of the Fontanprocedure, used as treatment of the univentricularcongenital heart; however, data are much more limited(continued on page 24)PRACTICAL GASTROENTEROLOGY APRIL 2017
Protein Losing Enteropathy: Diagnosis and ManagementNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #162(continued from page 22)for other causes of PLE.1 A 2-3% prevalence of PLEhas been reported among Asian patients with systemiclupus erythematosus (SLE).2 In a study of 24 patientswith ileal Crohn’s disease in clinical remission, allhad laboratory evidence of PLE (although none hadclinical signs), suggesting that the prevalence of PLEmay be significantly underrecognized.3 Similarly, ina study from 1975, 22% of 55 patients with primarylymphedema who were screened for PLE were foundto have evidence of protein wasting from the GI tract.4Despite the poor understanding of its prevalence,PLE should be a consideration in the evaluation of patientswho present with moderate to severe hypoalbuminemia(serum albumin 3.0 g/dL), particularly those whopresent with edema. Although some patients with PLEpresent with severe GI symptoms such as diarrhea,which can take on a secretory character, it is importantto recognize that not all patients suffering from PLEwill exhibit overt GI symptoms. In fact, the key clinicalcharacteristic of PLE is symptomatic hypoalbuminemiawhich manifests most commonly as edema. Otherclinical manifestations generally reflect the underlyingdisease responsible for PLE.PathophysiologyThe protein loss in the bowel typically results in serumalbumin levels 3.0 g/dL, and frequently 2.0 g/dL. Inthe normal GI tract, only 1-2% of total daily protein islost through active intestinal secretions and mucosalturnover.5 This is significantly different from thedramatic protein losses from the GI tract seen in PLE,which can result in daily loss of as much as 60% ofthe total serum protein. 6 Because albumin contributesabout 80% of the total colloidal osmotic effect of humanserum due to its oncotic effect and affinity for sodiumions, loss of serum albumin results in third-spacing offluid and generally manifests clinically as peripheraledema, ascites, and pleural effusions.7 In addition tosymptomatic hypoalbuminemia, patients presentingwith PLE may be at increased risk of infection andthrombosis due to concomitant stool loss of serumimmunoglobulins and key anticoagulant proteinsrespectively, although neither occurs commonly.In the context of increased serum protein loss, thebody will attempt to compensate by increasing proteinsynthesis. As such, serum levels of rapid turnoverproteins including prealbumin, immunoglobulin E(IgE), and insulin may remain normal.8 In contrast,24 Table 1. Causes of Hypoalbuminemia Other Than PLE Impaired Synthesiso Chronic liver disease Increased Losso Nephrotic syndrome Dilutiono Volume overload in context of heartfailure Inflammationo Acute inflammatory response (negative phase reactant)o Chronic inflammatory responseinsufficient compensatory protein production and lowserum level is more often seen with slower turnoverproteins such as albumin, ceruloplasmin, fibrinogen,transferrin, and immunoglobulins (other than IgE), asthe body has a less robust capacity to increase dailyproduction.5 Albumin in particular is a slow turnoverprotein with a half-life of about 25 days; there is alsoevidence that the liver is unable to fully compensatefor sustained albumin losses.7 Decreased serum levelsof lipids and trace elements have also been reported inPLE, as has the presence of lymphopenia, particularlyin the setting of lymphatic obstruction or malnutrition.The reduction of serum proteins other than albuminseldom causes clinically significant problems.Her past medical history was notable for remotepeptic ulcer disease, hyperlipidemia, seasonal allergiesand persistent unexplained peripheral eosinophilia firstdiscovered in 2010. In 1989, she underwent a vagotomyand pyloroplasty for gastric outlet obstruction dueto peptic ulcer disease. Extensive evaluations of theeosinophilia by specialists in infectious diseases,hematology, allergy, immunology, and rheumatologywere unsuccessful in identifying an etiology.Alternative causes of hypoalbuminemiaOther causes of hypoalbuminemia are diverseand warrant careful thought when evaluating thehypoalbuminemic patient. In particular, fluid overload(e.g., congestive heart failure), reduced protein synthesis(e.g., chronic liver disease), and other sources of serumprotein losses (e.g., nephrotic syndrome) are importantPRACTICAL GASTROENTEROLOGY APRIL 2017
Protein Losing Enteropathy: Diagnosis and ManagementNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #162to consider. This evaluation should include a carefulhistory and physical examination, as well as standardevaluations of other causes of hypoalbuminemia notedin Table 1.A diagnostic evaluation revealed no evidence ofchronic liver disease, nephrotic syndrome or congestiveheart failure. Alpha-1-antritrypsin clearance wasfound to be 341 mL/24 hours (normal, 27 mL/24hr), consistent with PLE.Testing to Confirm a Diagnosis of PLEThe primary diagnostic test for PLE is stool testingfor the presence of alpha-1-antritrypsin (A1AT) (Table2). A1AT is a protein that suffers minimal degradationor active secretion in the GI tract and is of similarmolecular weight as albumin. By measuring A1ATlevels in both serum and a 24-hour stool collection,A1AT clearance can be calculated as follows:A1AT clearance [(mL Stool) x (stool A1AT mg/dL)] / [serum A1AT mg/dL]An elevated A1AT clearance 27 mL/day reflectsa general state of GI protein loss and has a sensitivityof approximately 80%.7 Diarrhea from any cause,however, results in some obligate A1AT loss and, thus,a higher threshold ( 56 mL/day) may be required forthe diagnosis of PLE in this situation.9,10 A1AT is alsosensitive to degradation by acid so, in the setting of ahypersecretory state, this test is optimally performedwhile the patient is receiving acid suppression.11Finally, A1AT testing of a spot stool specimen mayalso show elevated levels in PLE, but this is a lesssensitive approach and is not recommended in theinitial diagnosis.10 Use of a random stool A1AT levelcoupled with serum A1AT level, however, may serveas a convenient surveillance method for patients withknown PLE undergoing treatment or in remission.There are a number of other methods to searchfor protein loss in the GI tract, albeit none as widelyavailable or as safe as the A1AT clearance. Historically,the gold standard test for PLE has been the fecalexcretion of 51Cr labelled albumin, which requirescollection of stool for a minimum of 4 days.7 It is notonly challenging for patients to complete a 4-day stoolcollection but it exposes them to radiation and it is notwidely available. The 51Cr-albumin clearance may beuseful when there is a high clinical suspicion in thecontext of a negative A1AT clearance given its highersensitivity. An alternative is technetium 99m-labelledhuman serum albumin (HSA) scintigraphy. This testPRACTICAL GASTROENTEROLOGY APRIL 2017 Figure 1.has demonstrated superior sensitivity and negativepredictive value compared to A1AT clearance for thediagnosis of PLE and has the added benefit of notrequiring a prolonged stool collection.12 These testsmay also be used to monitor response to treatment.Upper endoscopy was subsequently performedand was notable for patchy gastric erythema with anatrophic appearance to the stomach. Biopsies from thesecond portion of the duodenum demonstrated patchyeosinophilia while biopsies from the duodenal bulb werenormal. Random biopsies from the stomach showedmarked eosinophilia without other abnormalities(Figure 1). Based on the peripheral eosinophilia andpresence of eosinophils on the biopsy, the patientwas suspected to have eosinophilic gastroenteritis.Interestingly, in 2010, she had undergone upperendoscopy and colonoscopy to evaluate iron deficiencyanemia. While both examinations were grosslynormal, random biopsies from the stomach revealeda similar intense eosinophilic inflammatory infiltratethroughout the mucosa and submucosa. Biopsies fromthe duodenum, terminal ileum and colon were normal.Evaluating Confirmed PLEWhen a diagnosis of PLE has been determined,additional testing is necessary in order to identify theunderlying cause and help direct treatment. PLE isassociated with a diverse set of diseases often affectingmultiple organ systems and can be divided into GI andnon-GI causes (Table 3). GI sources can be furtherdivided into erosive and nonerosive diseases of thebowel that result in protein loss across the mucosalmembrane of the intestine and are detailed in Table 3.(continued on page 28)25
Protein Losing Enteropathy: Diagnosis and ManagementNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #162(continued from page 25)Circulatory dysfunction from cardiac pathologysuch as congestive heart failure (CHF), constrictivepericarditis, and congenital heart disease can lead toPLE. The most common cardiac cause of PLE occurs inadults with congenital heart disease, a functional singleventricle, treated as a child with a palliative Fontanoperation.1 Post-Fontan patients make up the largestcohort of patients with PLE described in the literature.PLE is associated with a significant morbidity andmortality depending upon the underlying cause. Thefive-year mortality after diagnosis of PLE in the settingof a Fontan procedure approaches 50%; however, recentdata suggest that advances in our understanding of thedisease may have improved this rather dismal outlook.13While data on morbidity and mortality associatedwith PLE related to other causes are more limited,malnutrition, volume overload, thrombophilia, andsecondary immunodeficiency, likely have a significantimpact on long-term outcomes.Because the management of PLE is closelytied to treating the underlying disease, when PLE isidentified, a thorough evaluation should be undertakento better characterize the state of the GI tract mucosa,lymphatic system, and cardiovascular system. Thisis best approached through upper and lower GIendoscopy with mucosal biopsies as well as infectiousstudies (focusing on chronic intestinal infections). Ifconventional endoscopy does not yield a diagnosis,video capsule endoscopy or small bowel enteroscopyhave been shown to be useful in patients with knownPLE.14 Cross-sectional imaging of the abdomen andpelvis, echocardiogram, lymphatic/hematologic testsand, sometimes, diagnostic laparoscopy may also beuseful depending on the clinical presentation.Mechanisms Causing PLEAs our understanding of PLE has improved, it hasbecome increasingly clear that a common link betweenthe various etiologies of the disease involves injury to,or breakdown of, the GI epithelium causing increasedpermeability. Conceptually, this pathology is clearwhen considering PLE caused by mucosal diseasessuch as inflammatory bowel disease, eosinophilicgastroenteritis, and microscopic colitis, for example.Poor lymphatic drainage from congenital defects orfrom significant lymphatic obstruction may causeloss of lymphatic fluid into the GI tract throughdirect hydrostatic forces.15 Although the mechanism28 responsible for PLE in systemic autoimmune diseaseis unclear, it has been hypothesized that it results frommucosal or capillary inflammation caused by:1. l ocal vascular injury mediated by complementor vasculitis2. l ymphatic damage through mesentericinflammation, or3. i ncreased endothelial permeability throughthe effect of inflammatory cytokines.16The cause of PLE associated with cardiovasculardiseases such as CHF and the Fontan procedure isgenerally considered to be increased hydrostaticpressure from venous hypertension which, at leastin part, results in loss of protein into the GI tract.1Interestingly, these patients do not have significantlyelevated venous hypertension relative to similar patientswithout PLE making the exact pathophysiologic processless clear.1 Some of these patients seem to respond totreatments based at the level of the mucosal membrane,implying that perhaps mucosal injury is again a primaryroot cause. Some hypothesize that hemodynamicchanges associated with the Fontan procedure resultin increased mesenteric vascular resistance as acompensatory mechanism to poor cardiac output.17 Thismay in turn damage the mucosal epithelium, increasepermeability and engorge intestinal lymphatics withan appearance histologically similar to congenitalintestinal lymphangiectasia. There are also data tosuggest that patients with univentricular-type congenitalheart disease may have increased protein loss in theGI tract prior to the Fontan procedure; this may reflecteither a response to the initial circulatory dysfunctionof the congenital heart disease or concurrent congenitalmalformation of some component of the GI tract itself.18Others have attempted to strengthen the argument formucosal injury by demonstrating that patients who haveundergone a Fontan procedure typically have elevatedinflammatory markers.19The patient was placed on prednisone for suspectedeosinophilic gastroenteritis with rapid normalization ofher serum albumin and eosinophils and more gradualnormalization of the A1AT clearance. With weaning ofthe prednisone, an increase in peripheral eosinophilsand decrease in albumin occurred prompting initiationof oral cromolyn and budesonide. Thereafter, shewas able to eliminate prednisone use. Repeat upper(continued on page 30)PRACTICAL GASTROENTEROLOGY APRIL 2017
Protein Losing Enteropathy: Diagnosis and ManagementNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #162(continued from page 28)endoscopy approximately one year later was normalincluding duodenal and gastric biopsies. Interestingly,biopsies from the upper esophagus demonstratedmarked eosinophilia consistent with eosinophilicesophagitis. Notably, she denied dysphagia or any otheresophageal symptoms.Management of PLEBecause PLE is a rare disease with a variety ofseemingly disparate causes, there are limited data onits optimal treatment. As such, no single treatmentreliably improves PLE in all patients. A core principleis to treat the underlying disease which, if successful,should generally result in improvement in the PLE.Fortunately, most causes of PLE can be readily diagnosedand treated. Examples might include optimization ofthe management of eosinophilic gastroenteritis asdemonstrated in our case illustration, or fenestrationof the Fontan heart to improve cardiac output.20A number of PLE-specific strategies have beendescribed and include dietary, pharmacological orsurgical interventions. No controlled studies, however,have been performed to demonstrate the utility of theseapproaches. It is also important to recognize that thereis often a substantial delay in clinical response totreatment of PLE, which may take months to displaya measurable response. Nutritional strategies focusingon protein deficiency are important. A high proteindiet is recommended in patients with PLE and mayrequire significantly greater protein intake (2.0-3.0 g/kg/day) than normal (0.6-0.8 g/kg/day) to remain in apositive nitrogen balance.6 In patients with associatedfat malabsorption, primary or secondary intestinallymphangiectasia or other lymphatic disorders causingPLE, a lowering of fat intake may decrease pressure onthe lymphatics and limit protein leakage.15 To replacethese lost fats, medium-chain triglycerides can be triedas these provide a source of energy rich fats and areabsorbed largely via the portal vein rather than thelymphatics.15 However if a very low fat diet is used 3weeks, a source of essential fatty acids will be necessaryand fat soluble vitamins may need to be monitored.21If oral intake is inadequate, enteral feedings should beconsidered. If fat malabsorption has been demonstratedbased on a quantitative fecal fat collection with fatingested or infused enterally, then a semi-elemental orelemental product should be used. If the patient failsenteral, then parenteral will be necessary.Although dietary modification may not produceobvious benefit in terms of symptoms or degree ofprotein wasting, the optimization of the PLE patient’snutritional status is important to the success of othertherapies and the patient’s overall outcome.Table 2. Testing in PLE Test of Choice: A1AT clearanceo 27 mL/day reflects a general state of GI protein loss 80% sensitiveo Diarrhea results in obligate A1AT loss, use a higher threshold ( 56 mL/day)o A1AT is sensitive to acid degradation; use acid suppression in hypersecretory stateo Spot A1AT testing of stool specimen is less sensitive and not recommended for diagnosiso A random stool A1AT level with serum A1AT level may be a convenient surveillancemethod for known PLE patients under treatment or in remission Alternatives to A1AT clearance:o May be useful when there is a high clinical suspicion in the context of a negative A1ATclearance given its higher sensitivityo Technetium 99m-labelled human serum albumin (HSA) scintigraphy§ Involves radiationNo prolonged stool collection51oCr-albumin clearance§ Involves radiationRequires collection of stool for a minimum of 4 days30 PRACTICAL GASTROENTEROLOGY APRIL 2017
Protein Losing Enteropathy: Diagnosis and ManagementNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #162Table 3. Etiologies of PLEErosive Gastrointestinal Disease······Inflammatory bowel disease – primarily Crohn’s 23NSAID enteropathy 14Gut malignanciesGraft vs Host diseaseSarcoidosis 24Ulcerative jejunoileitisNonerosive Gastrointestina
Protein Losing Enteropathy: Diagnosis and Management for other causes of PLE.1 A 2-3% prevalence of PLE has been reported among Asian patients with systemic lupus erythematosus (SLE).2 In a study of 24 patients with ileal Crohn’s disease in clinical remissi
Revenge of the Cyst –Part II NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #55 Joe Krenitsky, MS, RD, Nutrition Support Specialist; Diklar Makola, MD, MPH, PhD, Gastroen-terology Fellow; Carol Rees Parrish MS, RD, Nutrition Support Specialist all at Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA.
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WEST COAST HOTEL CO. v. PARRISH. 379 Syllabus. WEST COAST ttOTEL CO. v. PARRISH ET AL. APPEAL FROM THE SUPREME COURT OF WASHINGTON. No. 293. Argued December 16, 17, 1936.-Decided March 29, 1937. 1. Deprivation of liberty to contract is forbidden by the Constitution if without due process of law; but restraint or regulation of this .
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