Carol Rees Parrish, M.S., R.D., Series Editor Nutritional

Nutritional Management of the Adult with Cystic Fibrosis – Part INUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #113Table 3: Food and Drug Administration Approved EnzymesProduct Name /ManufacturerLipase UnitsAmylase UnitsProtease UnitsDetailsCreon (Abbott) www.creon.com 800-633-9110Creon 3,0003,00015,0009,500Delayed release capsuleCreon 6,0006,00030,00019,000Delayed release capsuleCreon 12,00012,00060,00038,000Delayed release capsuleCreon 24,00024,000120,00076,000Delayed release capsulePancreaze (Janssen Pharmaceuticals) www.pancreaze.net 855-TEAM-PSTPancreaze 4,2004,20017,50010,000Delayed release capsulePancreaze 10,50010,50043,75025,000Delayed release capsulePancreaze 16,80016,80070,00040,000Delayed release capsulePancreaze 21,00021,00061,00037,000Delayed release capsulePertzye (Digestive Care, Inc) www.digestivecare.com 877-882-5950Pertzye 8,0008,00030,25028,750Bicarbonate bufferedPertzye 16,00016,00060,50057,500Bicarbonate bufferedUltresa (Aptalis Pharma) www.aptalispharma.com 800-950-8085Ultresa 13,80013,80027,60027,600Delayed release capsuleUltresa 20,70020,70041,40041,400Delayed release capsuleUltresa 23,00023,00046,00046,000Delayed release capsuleViokace (Aptalis Pharma) www.viokace.com 800-950-8085Viokace 10,44010,44039,15039,150Non enteric coatedViokace 22,88022,88078,30078,300Non enteric coatedZenpep (Aptalis Pharma) www.zenpep.com 800-950-8085Zenpep 3,0003,00016,00010,000Delayed release capsuleZenpep 5,0005,00027,00017,000Delayed release capsuleZenpep 10,00010,00055,00034,000Delayed release capsuleZenpep 15,00015,00082,00051,000Delayed release capsuleZenpep 20,00020,000109,00068,000Delayed release capsuleZenpep 25,00025,000136,00085,000Delayed release capsuleUsed with permission University of Virginia Health System, Nutrition Support Traineeship Syllabus; Charlottesville, VA, 2010PRACTICAL GASTROENTEROLOGY JANUARY 2013 15

Nutritional Management of the Adult with Cystic Fibrosis – Part INUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #1131,800 mutations associated with the CF diagnosis andthose with two “severe alleles” are nearly always PIwhile those with one “mild mutation” are more likelyPS.2,6 With advanced age, pancreas function can declineand those who are PS may eventually become PI asadults. Consequently, PS adults should routinely beasked about the frequency and composition of theirstools so that malabsorption can be addressed earlyin presentation. PI should be suspected in any patientwho is clearly getting adequate calories, but weightis dropping regardless of GI symptoms. Pancreaticexocrine function can be assessed by a 72-hour fecalfat study or by measuring fecal elastase-1 levels ina stool sample. The 72-hour fecal fat test is the goldstandard, but the fecal elastase-1 assay is easier tocollect, does not require interpretation of fat intake,and is not affected by exogenous pancreatic enzymes.6Those who are PI must take pancreatic enzymereplacement therapy (PERT) with all meals and snacksin order to properly absorb carbohydrate, protein, andmost importantly fat. Most PERT are enteric coated,preventing the enzymes from being degraded by theacidic environment of the stomach.7 The enteric coatingsubsequently dissolves once the pH exceeds 5 to 5.5,which ideally occurs within the duodenum.8 However,CFTR plays a role in both pancreatic and duodenalbicarbonate secretion meaning that many patients withCF do not produce enough bicarbonate to neutralize thegastric acid entering the duodenum.7 This means thatthe enteric coating may not dissolve until the PERTreaches the distal jejunum, having bypassed the majorabsorptive surface area of the duodenum and proximaljejunum.7 CF patients are often placed on proton pumpinhibitors (PPIs) or H2-receptor antagonists in an effortto decrease gastric acid secretion and therefore increasethe duodenal pH. There are limited studies to supportone therapy over another. Often the sample size in thesestudies is small and the majority of subjects are pediatric.One random cross-over trial of fifteen pediatric patientsdemonstrated decreased fat malabsorption when takingomeprazole versus placebo.9Dosing guidelines for PERT are based on the NorthAmerican CF Foundation consensus statement andthe Consensus Conference on Enzyme Therapy andFibrosing Colonopathy.10 General recommendations forinitiation and advancement of PERT therapy can be foundin Table 1. Although it is ideal to base dosage on unitsof lipase per gram of fat consumed, this information isoften not known at each meal so most recommendations16 are based on units of lipase per kilogram of body weight.Before increasing PERT dosage based on subjectivesymptoms of malabsorption, i.e. diarrhea, abdominalpain, or steatorrhea, it is important to review the list offactors that may contribute to poor response to PERT(Table 2). Excessive administration of PERT can causefibrosing colonopathy which may lead to colonicstrictures requiring surgical intervention.11 Therefore,finding the appropriate dose of PERT is imperative formaintaining nutritional status but without causing longterm complications.Although in regular use for many years, PERToriginally did not require Food and Drug Administration(FDA) approval. In 2004, the FDA mandated that allPERT gain new drug application approval by April2008.12 This deadline was later extended to April 2010and there are currently six FDA approved enzymebrands (Table 3).12 Of the six, four products come indelayed-release capsules. One product is non-entericcoated, meaning that it should be taken with a PPIwhen taken orally. One product is bicarbonate buffered.Vitamin SupplementationFat Soluble VitaminsIndividuals with CF, especially those with pancreaticinsufficiency, are at risk for fat-soluble vitamindeficiency. Through all stages of life, CF patients areprescribed vitamins that contain water-miscible versionsof the fat-soluble vitamins: A, D, E, and K. Over the lastseveral years, there has been a shift in the discussion ofvitamin status, pushing the focus away from definingpatients as “deficient” to appreciating broader termswith ranges such as “deficient, suboptimal, adequate,and optimal.” 13 General dosing guidelines for CFpatients for all fat-soluble vitamins can be found inTable 4.14 Check fat-soluble vitamins levels annuallyfor all adult CF patients. If levels are low, requiringrepletion, recheck levels every one to three monthsuntil optimal levels are reached.Vitamin AVitamin A and carotenoids are important for adequatevision, bone health, cell differentiation, and immunity.The human diet provides vitamin A in multiple formsincluding preformed vitamin A, which is metabolizedto retinol, and carotenoids, such as beta-carotene. Themajority of carotenoids are converted to retinol prior(continued on page 19)PRACTICAL GASTROENTEROLOGY JANUARY 2013

Nutritional Management of the Adult with Cystic Fibrosis – Part INUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #113(continued from page 16)to absorption, providing a means of regulation andpotentially decreasing the risk of hypervitaminosis A.13However, CF specific vitamins contain retinol, which isnot subject to this regulatory control and may increasethe risk of vitamin A toxicity. Current guidelinesrecommend 10,000 IU of vitamin A daily.Retinol esters are bound to retinol binding protein(RBP) and transthyretin (TTR) in a 1:1:1 ratio and thentransported from the liver to tissues.13 TTR is also knownas prealbumin. Serum retinol levels are one indicator ofvitamin A status, but in healthy individuals this serumconcentration does not drop until liver reserves aresignificantly depleted.15 Additionally, RBP is a negativeacute phase protein, meaning that concentrations ofRBP, and subsequently retinol, will decrease duringtimes of inflammation and infection. Evaluating serumvitamin A while taking into account RBP and TTRlevels may provide a more accurate reflection of vitaminA stores. A study of surgical patients who underwentliver biopsy and therefore had known hepatic vitaminA stores, found that a cutoff of 0.36 for RBP:TTRwas associated with marginal vitamin A deficiency.15,16Zinc deficiency can occur in states of malabsorption,such as CF. Adequate zinc status is necessary for thehepatic synthesis of RBP, meaning that those with zincdeficiency may not be able to mobilize retinol from theliver.17 A 2008 case report of a 23 year old female withCF reported that clinical vitamin A deficiency (nightblindness) was resolved by correcting zinc deficiencywith 220 mg of zinc sulfate daily for one week.18Subsequently, those with vitamin A deficiency that arenot responsive to increased vitamin A supplementationmay actually be zinc deficient and require additionalzinc supplementation.Vitamin DIt is widely accepted that suboptimal vitamin D status isfrequently present in the general population and this isespecially true in the CF population. Both vitamin D andcalcium are known to be important for the developmentand maintenance of healthy bones. The impact ofvitamin D on immune function and inflammation isstill being explored.13 The CF Foundation producedguidelines for vitamin D supplementation in 2002 andagain in 2005, but several studies of pediatric and adultpatients indicated that these recommendations were notsufficient.19-22 In September 2010, the CF Foundationassembled a committee to develop new guidelinesPRACTICAL GASTROENTEROLOGY JANUARY 2013 for the screening, diagnosis, supplementation, andtreatment of vitamin D insufficiency.19The inactive version of vitamin D comes in twoforms: vitamin D2 (ergocalciferol) and vitamin D3(cholecalciferol). Only vitamin D3 is produced by theskin after sun exposure while diet and supplements canprovide both vitamin D2 and D3.23 Both vitamin D2 andvitamin D3 are then transported to the liver where they areconverted to 25-hydroxyvitamin D (25OHD).23 VitaminD status is best assessed by measuring circulating levelsof 25OHD. The goal is to maintain serum levels of atleast 30 ng/ml.19 Since vitamin D levels can vary fromseason to season, it is ideal to check patient’s levels atthe end of winter, therefore catching their nadir levelto determine if their supplementation is adequate tomaintain optimal levels year round.19Studies evaluating the use of cholecalciferol versusergocalciferol for vitamin D repletion are limited,especially in the adult CF population. Furthermore,most of the trials evaluating osteoporosis and vitaminD use only cholecalciferol, limiting the data linkingergocalciferol to bone health. One randomized controlledtrial of 28 adult CF patients given either 50,000 IUof cholecalciferol or ergocalciferol weekly to correctlow vitamin D levels demonstrated that both formssignificantly raised 25OHD levels, but the response wasgreater for those receiving cholecalciferol (D3).24 Giventhe results of this study and that cholecalciferol is theendogenously produced version of vitamin D, the CFFoundation recommends that patients with suboptimalvitamin D status be treated with cholecalciferol.19 Therepletion dose can be given weekly, or the weekly dosecan be divided into a daily dose equivalent. Patients whofail to respond to high dose vitamin D therapy shouldbe referred to an endocrinologist who specializes invitamin D therapy. A stepwise approach was publishedin the current guidelines to treat vitamin D deficiency.19The Endocrine Society considers individuals with CFto be at risk for vitamin D deficiency and thereforerecommends a daily vitamin D requirement of 1500to 2000 IU, with an upper limit of 10,000 IU daily forthose greater than 18 years of age. Those with a 25OHDlevel 20 ng/mL, but 30 ng/mL should increase theirdaily dose by 1600 to 6000 IU of D3. Those with a25OHD level 20 ng/mL should increase their dailydose to the maximum of 10,000 IU per day of D3. Afterthree months of repletion doses, recheck the 25OHDlevel and treat accordingly.10 Additional studies arerequired to determine if these dosing guidelines will19

Nutritional Management of the Adult with Cystic Fibrosis – Part INUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #113be sufficient for repletion and maintenance of adequatevitamin D levels for CF adults. It is important to notethat once serum levels are replete, those patients willmost likely require ongoing vitamin D supplementationwith 800 to 2000 IU per day of D3 to prevent them fromreturning to suboptimal levels.Vitamin EVitamin E refers to a group of compounds includingtocopherols and tocotrienols which all containantioxidant properties. Signs of vitamin E deficiencyinclude hemolytic anemia, ataxia, muscle weakness,visual defects, dementia, and cardiac arrhythmias.25Adults with CF should take 200-400 IU of vitaminE daily. Vitamin E status is generally measured viaserum α-tocopherol and normal levels are 0.7 ml/dl.26However, since vitamin E is correlated with plasmalipid levels, low or high serum α-tocopherol levelsmay need to be viewed in the context of lipid status.The ideal, but difficult to obtain, method for assessingvitamin E status is the ratio of α-tocopherol:total lipid(cholesterol, triacyglcerol, and phospholipid) in which alevel 0.8 ml/dl indicates deficiency.13,26 An easier, butless ideal method is the ratio of α-tocopherol:cholesterolwhere a level of 2.47 mg/g indicates deficiency.26Vitamin KVitamin K is an important cofactor for the conversionof glutamyl residues to prothrombin and osteocalcinmaking it imperative for adequate blood coagulationand bone formation.13 Despite the production of vitaminK by bacterial flora in the intestine, patients with CFpresent with vitamin K deficiency without routinesupplementation.10, 27 Although the CF Foundationguidelines recommend 300-500 mcg per day of vitaminK, a recent study of children and young adults foundthat only those taking 1,000 mcg / day achievedoptimal vitamin K status.27 Elevated prothrombintime (PT) is an easy was to assess vitamin K status.However, this is a late marker of vitamin K deficiency,so even marginally high levels indicate the need foradditional supplementation. Protein-Induced in VitaminK Absence or Antagonist (PIVKA-II) is an early andsensitive marker of vitamin K status, but it is oftenan expensive lab that can only be evaluated at certainlaboratories. If PT is not correcting with vitamin Krepletion, PIVKA-II should be checked.Gastrointestinal Issues BeyondPancreatic InsufficiencyCystic Fibrosis Related Liver DiseaseFortunately, only about one third of CF patients developcystic fibrosis related liver disease (CFLD).28 As anearly complication of CF, the majority of cases arediagnosed by midadolescence.7, 28 Pathogenesis ofCFLD again leads back to a cellular defect. CFTR isnot expressed in hepatocytes, but in the epithelial cellsof the cholangiocytes and the gallbladder, causing adisruption in the fluid and electrolyte content of bile.28Table 4: General Vitamin Dosing Guidelines for Adults14DosingVitamin AVitamin DVitamin EVitamin KDaily10,000 IU800-2000 IU200-400 IU300-500 mcgRepletion120,000 IU1600-10000 IU800-12,000 IU5-10 mg/weekMultivitamins with Water-Miscible Versions of Fat-Soluble Vitamins2- SourceCF (Aptalis) www.sourceCF.com 888-419-8357- AquADEK (Aptalis) www.aptalispharma.com 800-950-8085- VITAMAX (Shear/Kershman Laboratories) www.cfservicespharmacy.com 800-541-49591. Recheck levels after 1 to 3 months of elevated dosage2. CF specific multivitamins contain water miscible versions of fat-soluble vitamins in additionto a full complement of the water-soluble vitamins plus zincUsed with permission University of Virginia Health System, Nutrition Support Traineeship Syllabus; Charlottesville, VA, 201020 PRACTICAL GASTROENTEROLOGY JANUARY 2013

Nutritional Management of the Adult with Cystic Fibrosis – Part INUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #113Increased bile viscosity creates mucous filled bile ductsand subsequent cholestasis.28 Bile acid retention maycause secondary hepatocyte injury, but the progressionfrom cholestasis to multilobular cirrhosis is often slow,taking decades to develop.28 Unfortunately, thosewho develop cirrhosis often quickly develop portalhypertension.28Diagnosis of CFLD is often based on clinicalexamination in combination with ultrasonography.Liver biochemistry should be done annually and thosewith abnormal laboratory results and/or physicalexamination findings should have an ultrasound.Those with CFLD are started on oral bile acid therapy,urosodiol or ursodeoxycholic acid, to improve bileviscosity and hopefully delay hepatocyte damage.28Nutritional consequences of CFLD include increasedfat malabsorption and alterations in resting energyexpenditure. Patients with CFLD are at increased riskfor fat-soluble vitamin deficiency and may requireaggressive supplementation to maintain normal levels.Since there is no bile acid replacer, a lower fat diet maybe helpful in this setting if the patient has a functionalbile salt deficiency.Small Bowel Bacterial OvergrowthAdults with CF are predisposed to small bowelbacterial overgrowth (SBBO) for a variety of reasons.Frequent use of antibiotics, chronic acid suppressionwith PPIs, and decreased gastrointestinal motility canincrease the incidence of SBBO. Symptoms of SBBOare similar to those of malabsorption; gas, bloating,diarrhea, steatorrhea, and abdominal pain. Similar to thegeneral population, diagnosis of SBBO in CF patientsis difficult. Small bowel aspiration can be used to detectSBBO, but the test is invasive and results are limitedto the specific area tested. Hydrogen breath tests havebeen used as a surrogate to diagnose SBBO as well, butcan result in false-positives. SBBO is often empiricallytreated with enteral antibiotics that cover both aerobicand anaerobic bacteria.29PancreatitisCF patients who are pancreatic sufficient are 900 timesmore likely than the general population to developrecurrent acute pancreatitis.30 Treatment of pancreatitiswith CF is similar to that of the general population andthose who experience recurrent episodes should becounseled to contact their CF team when symptomsarise. Patients will require adequate pain managementand likely intravenous fluids to maintain hydration.Jejunal tube feeding may be used for those who requirelong-term pancreatic rest and subsequently must remainnil per os (NPO or nothing by mouth) for an extendedperiod of time. Although patients may be technicallyTable 5: Risk Factors and Prevention of Distal Intestinal Obstruction SyndromeRisk Factors DehydrationImmobilitySBBOPrevious GI surgeryInadequate PERTNarcotic useRespiratory infectionBinge eating or grazingPrevention Ensure adequate hydration, especially during exercise, warm weather, and with respiratory infectionsEncourage regular physical activityAvoid inadequate or excessive pancreatic enzyme administrationDiscourage binge eating or frequent grazing which may limit PERT effectivenessStool softeners or osmotic laxatives (milk of magnesia, polyethylene glycol)Used with permission University of Virginia Health System, Nutrition Support Traineeship Syllabus; Charlottesville, VA, 2010PRACTICAL GASTROENTEROLOGY JANUARY 2013 21

Nutritional Management of the Adult with Cystic Fibrosis – Part INUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #113pancreatic sufficient, recurrent episodes of pancreatitismay induce fat malabsorption indicating the use ofpancreatic enzymes.Distal Intestinal Obstruction SyndromeDistal intestinal obstruction syndrome (DIOS) is acomplication unique to CF individuals and typicallyoccurs in adults or older children.7 The intestinalobstruction is often incomplete and occurs in theileo-cecal region of the small bowel extending intothe colon.7, 30 Slower transit time and a disruptedfluid environment in the small intestine

Jun 30, 2012 · Pancreas: Insufficient or Sufficient? Individuals with CF are classified as being pancreatic insufficient (PI) or pancreatic sufficient (PS) and more than 90% of patients with CF are PI.1 There appears to be a correlation between genotype and phenotype in regard to the exocrine function of the pancreas.6 There are over