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Home , Essential fatty acid

Essential Deficiency

Kris M. Mogensen, MS, RD, LDN, CNSC Team Leader Dietitian Brigham and Women’s Hospital Instructor Boston University College of Health and Rehabilitation Sciences: Sargent College [email protected] November 13, 2015 Disclosures

• I will discuss “off label” use of a product • I will discuss “novel” emulsions Objectives

• Identify three patient populations at risk for essential fatty acid deficiency (EFAD) • Interpret biochemical measures of fatty acids to determine presence/absence of EFAD • Identify two interventions to prevent or treat EFAD Overview • Role of essential in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Overview • Role of essential fats in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Role of in the Body

• Major source of energy & energy storage • Cushioning/insulation • A means to absorb fat-soluble • Cell membranes • Inflammatory mediators/cell signaling systems • Creation of hormones Impact of Fatty Acid Exposure on Cell and Tissue Responses

From Calder PC. Functional roles of fatty acids and their effects on human health. JPEN 2015;39:18S-32S Essential Fatty Acids

• Cannot be synthesized in the body • Two major EFAs: – Alpha-linolenic acid (omega-3) – (omega-6)

Fatty Acids Created from EFA

*EFA

Hamilton C et al. Essential fatty acid deficiency in human adults during parenteral nutrition. Nutr Clin Pract. 2006;21:387- 394 Overview • Role of essential fats in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Risk Factors for EFAD

• Malabsorptive disorders – Crohn’s disease – Chronic pancreatitis – Cystic fibrosis – Short-bowel syndrome Sites of Absorption

From Krause, 12th edition Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders. Siguel EN and Lerman RG. . 1996;45:12-23 • 47 patients with chronic intestinal disease – 25 Crohn’s disease – 11 UC – 4 Celiac – 7 Short-bowel syndrome • 56 healthy controls • Blood samples analyzed for fatty acids and triene:tetraene ratio Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders. Siguel EN and Lerman RG. Metabolism. 1996;45:12-23 Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders. Siguel EN and Lerman RG. Metabolism. 1996;45:12-23 Essential fatty acid deficiency in patients with severe fat malabsorption. Jeppesen PB et al. AJCN. 1997;65:837-843 • 112 patients with GI disorders – 66 Crohn’s disease – 26 UC – 16 bowel resection for varying reasons – 2 celiac disease – 1 radiation enteritis – 1 cholestatic liver disease • All had fecal fat analyzed • Blood analyzed for fatty acids • Stratified by % of fat malabsorption

Essential fatty acid deficiency in patients with severe fat malabsorption. Jeppesen PB et al. AJCN. 1997;65:837-843

Degree of % with EFAD based Malabsorption on LA levels <10% 0% (n=52) 10-25% 5% (n=21) 25-50% 38% (n=24) >50% 67% (n=15) Risk Factors for EFAD

• deficiency – Necessary for metabolism of fat in the mitochondria – Required component for remodeling and • Part of cell membranes! – Reservoir for long-chain fatty acids that will eventually be incorporated into cell membranes Carnitine Shuttle

CPT-I, carnitine palmitoyltransferase-1; CPT-II, carnitine palmitoyltransferase-2; CACT, carnitine acylcarnitine translocase; CrAT, carnitine acetyl transferase; OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane. From Sharma & Black Drug Discov Today Dis Mech. 2009 From: Mogensen KM and Pfister DP. Carnitine supplementation: an update. Support Line. 2013;35:3-9 Risk Factors for EFAD

• Patients with limited fat intake/delivery – PN-dependent patients with hypertriglyceridemia – Allergy to intravenous fat emulsion – Ultra-low fat diets – Possibly extracorporeal membrane oxygenation (ECMO) patient receiving PN • Will you be allowed to give IVFE? – (that’s a whole ‘nother talk) Essential fatty acid deficiency in four adult patients during total parenteral nutrition. Richardson TJ and Sgoutas D. AJCN. 1975;28:258-263 Essential fatty acid deficiency during total parenteral nutrition. Barr LH et al. Ann Surg. 1981;193:304-311 Diet-induced essential fatty acid deficiency in ambulatory patient with type I diabetes mellitus. Piper CM et al. Diabetes Care. 1986;9:291-293

43 y.o. M who followed a 7% fat diet for 4 months. Developed lethargy, fatigue, and a dry, scaly rash… Risk Factors for EFAD

• National shortages of intravenous fat emulsion

Anybody have any to spare? Overview • Role of essential fats in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Drug Shortages • A major problem over the past 5 years – Intermittent shortages occurring for > 15 years • As of 2/28/2013 there were 324 medications in shortage – 70% were sterile injectables

Data from: http://www.nutritioncare.org/Professional_Resources/Drug_Shortages_Update/#Why_do_drug_shortages_occur accessed 9/28/2015 Nutrition Support Drug Shortages

• IV multivitamins, individual vitamins • IV multiple trace elements & individual trace elements • Individual electrolytes • Macronutrients (resolved…for now) – Intravenous fat emulsion – Various amino acid preparations IVFE Shortage

• Still in shortage when I was preparing this talk in 2014 • Things are better… From http://www.nutritioncare.org/public-policy/product-shortages/ accessed 9/28/2015 A.S.P.E.N. Guidelines

• Rationing guidelines include reserving IVFE for neonates and pediatric patients • For non-malnourished adults, or those with mild or moderate malnutrition, hold IV fat for the first two weeks of PN • Provision of 100g fat total/week after the first two weeks of PN • Also available at: http://www.nutritioncare.org/Professional_Resources/Drug_Short ages/PN_IV_Fat_Emulsions_Product/ Overview • Role of essential fats in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Physical Signs and Symptoms of EFAD • – Dry, scaly rash • Hair loss • Poor wound healing • Impaired growth in children Essential fatty acid deficiency in adults receiving total parenteral nutrition. Fleming CR et al. AJCN. 1976;29:976-983 Essential fatty acid deficiency in surgical patients. O’Neill JA et al. Ann Surg. 1977;185:535-541 Essential Fatty Acid Deficiency in a Severely Malnourished Patient Receiving Parenteral Nutrition. Duerksen D and McCurdy K. Diges Dis Sci 2005;12:2386-2388 Essential Fatty Acid Deficiency in a Child

http://images.medscape.com/pi/editorial/cmecircle/2002/1819/hansen/slide17.jpg accessed 2/16/06 Be careful of look-alikes! Physical Signs and Symptoms of EFAD • Correlate physical exam with clinical history – Limited fat intake only? – Other potential causes of a similar rash? • alone, or superimposed on EFAD? • Other causes of skin rash Other Signs and Symptoms of EFAD • Fatty liver • Elevated liver function tests • Hyperlipidemia • Hemolytic anemia • Thrombocytopenia • Reduced platelet aggregation • Increased susceptibility to infection Biochemical Evaluation • Evaluate the triene:tetraene ratio – Why? – Mead acid (triene acid) production is increased and linoleic and are decreased – Triene:tetraene ratio evaluates the mead:arachidonic acid ratio – If > 0.4 (some references suggest 0.2), the patient has EFAD Timeframe of EFAD Development

• Typical EFAD onset occurs after 4 weeks of fat-free PN • Other reports have shown earlier onset of 10-20 days • Most of EFAD is associated with linoleic acid deficiency; few reports of alpha-linolneic acid deficiency Overview • Role of essential fats in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Treating Deficiency

• Prevent when you can! – Provide at least 10% of energy from polyunsaturated fats – 2%-4% of total calories should be from linoleic acid Treating Deficiency

• For PN-Dependent patients – The main IVFE available is Intralipid – 50% of the fat content is linoleic acid – To give 10g linoleic acid, you must give 20g fat total Comparison of IV Fat Emulsions

Concentration 10% 20% 30% kcal/mL 1.1 2 2.9 Fat g/L (9.3 kcal/g) 100 200 300 Phospholipid g/L (6 kcal/g) 12 12 12 Glycerol g/mL (4.2 kcal/g) 22.5 22.5 17

Example: 250 mL 20% IVFE = 500 kcals, 50 g fat (25 g as linoleic acid), 3 g phospholipid, 5.625 g glycerol

Parenteral fat does NOT provide 10 kcal/gram! Treating Deficiency • For patients taking an oral diet, encourage high intake of rich in essential fats • Encourage fatty or omega-3 fatty acid supplements Linoleic acid (g/tbsp) Safflower 1.73 Canola 2.61 Sunflower 3.904 for mid-oleic (? up to 8.9) Soybean 6.857

http://ndb.nal.usda.gov/ndb/nutrients/report?nutrient1=675&nutrient2=&nutrient3=&fg=4&max=25&subset=0&offset=50&sort= f&totCount=76&measureby=m accessed 9/28/2015 Use of Topical Oils • There is some cutaneous absorption of essential fats • The question: is that absorption adequate?

Orphan baby elephants after coconut oil rubdown! https://www.sheldrickwildlifetrust.org/asp/gallery_zoom.asp?Name=/keepers_diary/3420117121- pic2.jpg&S=Keepers&Caption=Orphans%20after%20being%20rubbed%20down%20in%20coconut%20oil&id=9047 https://www.facebook.com/thedswt/photos/a.167086934888.112085.120805694888/10153636320399889/?type=3&theater Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. Prottey C. et al J Invest Dermatol 1975;64:228-234

• 3 patients with short bowel syndrome and known EFAD • 7 controls on an unrestricted diet • Intervention: – 250 mg oil applied to the R arm – 250 mg applied to the L arm • Measured – Various skin surface lipids – Day 4, 8, 15 of the intervention

Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. Prottey C. et al J Invest Dermatol 1975;64:228-234

• Results – Deficient patients had higher levels of linoleic acid in the epidermis of the sunflower seed oil arm – No change in the olive oil arm – Resolution of scaly lesions – Epidermal changes not seen in the control group Human essential fatty acid deficiency. Treatment by topical application of linoleic acid. Skolnik P et al. Arch Dermatol. 1977;113:939-941

• 19 y.o. M with short bowel syndrome from severe IBD • Receiving fat-free PN • Developed EFAD • 150 mg linoleic acid rubbed into R thigh once/day x 3 weeks • Changed to safflower oil after 3 weeks

Human essential fatty acid deficiency. Treatment by topical application of linoleic acid. Skolnik P et al. Arch Dermatol. 1977;113:939-941 Cutaneous application of safflower oil in preventing essential fatty acid deficiency in patients on home parenteral nutrition. Miller DG et al. AJCN. 1987;46:419-423

• Study of 5 HPN patients – 4 weeks no IVFE – 4-6 weeks of topical safflower oil (3 mg/kg/d to provide 2.3 mg/kg/d of linoleic acid) – 5 mL PO safflower oil once/day x 4 weeks

Cutaneous application of safflower oil in preventing essential fatty acid deficiency in patients on home parenteral nutrition. Miller DG et al. AJCN. 1987;46:419-423 Cutaneous application of safflower oil in preventing essential fatty acid deficiency in patients on home parenteral nutrition. Miller DG et al. AJCN. 1987;46:419-423 Failure of topical vegetable oils to prevent essential fatty acid deficiency in a critically ill patient receiving long-term parenteral nutrition. Sacks GS et al. JPEN. 1994;18:274-277

• Case report of a critically ill trauma patient requiring fat-free PN because of hypertriglyceridemia • Developed EFAD • Received topical safflower oil per Miller protocol • No resolution of EFAD with use of topical oils alone; resolved when IVFE could be resumed What About Novel Lipids?

Gramlich L et al. Essential fatty acid deficiency in 2015: the impact of novel intravenous lipid emulsions. JPEN 2015;39:61S-66S Novel Lipid Case Reports • 3 obese patients • Required PN for various complications related to GI surgery • All received PN for >200 days • All started on Intralipid, 2 transitioned to ClinOleic, one received ClinOleic, then SMOF

Gramlich L et al. Essential fatty acid deficiency in 2015: the impact of novel intravenous lipid emulsions. JPEN 2015;39:61S-66S Novel Lipid Case Reports

Case 1 Case 2 Case 3 BMI (kg/m2) 53.9 42 39 Pre-PN weight (kg) 163.2 110.8 104

Post-PN weight (kg) 124 79.5 Not reported

Energy delivery 75% MREE Hypocaloric MREE feeding x 2 months, then MREE Duration of PN (days) 215 205 186*

*71 days, then a 1 month break, then another 115 days

Gramlich L et al. Essential fatty acid deficiency in 2015: the impact of novel intravenous lipid emulsions. JPEN 2015;39:61S-66S Case 1

• 72g Intralipid/d x 1 month (36g LA) • 60g ClinOleic/d x 1month (12g LA) • Decreased to 72g 3x/wk (6.2g LA) x 137d • 81.6g ClinOleic x 1 day then 38.4g/d (7.7g LA) x 16 days Case 2 • 57.6g Intralipid (28.8g LA)/day x 19d • 48g Intralipid (24g LA)/day x 23 days • No lipid x 14 d • 8g Intralipid (4g LA) x 18d • 50.4g ClinOleic (10g LA)/day x unspecified time • Change to SMOF after for elevated LFTs Case 3 • Started with ClinOleic 62.4g (12.5g LA)/day • One month off for attempt at oral diet • Resumed with ClinOleic 43.2g (8.6g LA/day) for unclear timeframe • Changed to Intralipid 50.4g (25g LA)/day x 9 days • Changed to SMOF 50.4g (15g LA)/day Novel Lipid Case Reports

Case 1 Case 2 Case 3 PN cycled? “when able” “when able” “when able” Average LA 11.4 g/day 13 g/day 7.54 g/day delivery 4.7% total kcals 7% total kcals 3.7% total kcals EFAD? Low LA Normal LA Low LA Normal AA Normal AA Normal AA Normal mead acid Mildly elevated Mildly elevated T:T normal mead acid mead acid T:T normal T:T normal

Gramlich L et al. Essential fatty acid deficiency in 2015: the impact of novel intravenous lipid emulsions. JPEN 2015;39:61S-66S Novel Lipid Case Reports

Gramlich L et al. Essential fatty acid deficiency in 2015: the impact of novel intravenous lipid emulsions. JPEN 2015;39:61S-66S Considerations • These were obese patients • Two lost weight (the 3rd might have as well) – mobilized fat depot • If PN was cycled, also promotes fat mobilization • Your own fat is a source of essential fats!

Mascioli EA et al. Effect of total parenteral nutrition with cycling on essential fatty acid deficiency. JPEN 1979;3:171-173 Overview • Role of essential fats in the body • Risk factors for EFAD • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion IVFE Allergy Case • 79 y.o. F with multiple GI surgeries • Diverticulitis s/p sigmoid colectomy • Colostomy, ileostomy • Multiple SBOs, small bowel volvulus • Multiple small bowel resections • Presented with a high-output ECF

IVFE Allergy Case

• Plan for PN and bowel rest • If fistula didn’t close spontaneously, then OR • Pt was on PN in the past, had h/o anaphylaxis with IVFE • Fat-free PN was started IVFE Allergy Case

• Ideally, would have checked a fatty acid panel prior to starting PN • After one month of PN found: – Low linoleic acid – Low alpha-linolenic acid – Triene:tetraene ratio of 0.034 • Lab uses the more sensitive measure, so EFAD is > 0.02 in this case – Pt discharged home on PN, returned 11 months later IVFE Allergy Case

• Pt was seen by a home infusion provider – Recommended to take po: • 1 tbsp + 1 tbsp daily • Pt stopped fish oil many months prior to readmission because she was worried about the mercury content • She increased to 2 tbsp canola oil daily IVFE Allergy Case • Repeat fatty acid panel done

1 month 11 months Normal range fat free PN fat free PN Linoleic acid 1074 1627 2270-3850 nMol/mL Alpha-linolenic acid 13 13 50-130 nMol/mL Mead acid 12 39 7-30 nMol/mL Arachidonic acid 352 850 520-1490 nMol/mL Triene:tetraene ratio 0.034 0.046 0.010-0.038*

*EFAD diagnosis should be made at > 0.02-0.04 IVFE Allergy Case

• Pt went to the OR and had the fistula taken down • Diet advanced and pt went home on an unrestricted oral diet! IVFE Allergy Case

• What should we have done differently? – Pushed for an allergy consult – Counseled pt on appropriate fats to take po • Sunflower, soybean, or safflower would have been better choices – Counseled pt to try topical oils • At least her PN was cycled! Overview • Role of essential fats in the body • Risk factors for essential fatty acid deficiency • Drug shortages and EFAD • Clinical manifestations & evaluation process • Treatment • Case study • Conclusion Conclusion

• Identify high-risk patients • Look for signs/symptoms of EFAD • Evaluate biochemical measures • Prevent EFAD when you can • Employ treatment options – Appropriate IVFE dosing, when there isn’t a shortage – High intake of essential fats for patients taking an oral diet – Cycle the PN – Trial of topical oils rich in essential fats – Stay tuned for more info on “novel lipids” POP QUIZ!!!!!!! Test Your Knowledge #1

• True or false? • The only patients at risk for EFAD are those with malabsorptive disorders or on long-term PN. Test Your Knowledge #1 Answer • FALSE! • Patients with carnitine deficiency and limited fat intake for many reasons are at risk for EFAD. Test Your Knowledge #2

• True or false? • EFAD has a very distinctive rash that looks like no other deficiency state. Test Your Knowledge #2 Answer • FALSE • The dry scaly rash may also indicate zinc deficiency. Test Your Knowledge #3

• True or false? • Cycling PN may help prevent EFAD. Test Your Knowledge #3 Answer • TRUE • Cycling promotes mobilization of the body’s own linoleic acid stores. References • Hise M, Brown JC. Lipids. In: CM Mueller, DS Kovacevich, SA McClave, SJ Miller, DB Schwartz (eds.). The A.S.P.E.N. Adult Nutrition Support Core Curriculum. 2nd ed. American Society for Parenteral and Enteral Nutrition. Silver Spring, MD. 2012:63-82 • Calder PC. Functional roles of fatty acids and their effects on human health. JPEN. 2015;39:18S-39S. • Hamilton C, Austin T, Seidner DL. Essential fatty acid deficiency in human adults during parenteral nutrition. Nutr Clin Pract. 2006;21:387-394. • Siguel EN, Lerman RG. Prevalence of essential fatty acid deficiency in patients with chronic gastrointestinal disorders. Metabolism. 1996;45:12-23. • Jeppesen PB, Christensen MS, Hoy C-E, Mortensen PB. Essential fatty acid deficiency in patients with severe fat malabsorption. Am J Clin Nutr. 1997;65:837-843 • Mogensen KM, Pfister DP. Carnitine supplementation: an update. Support Line. 2013;35:3-9. • Richardson TJ, Sgoutas D. Essential fatty acid deficiency in four adult patients during total parenteral nutrition. Am J Clin Nutr. 1975;28:258-263. • Barr LH, Dunn GD, Brennan MF. Essential fatty acid deficiency during total parenteral nutrition. Ann Surg. 1981;193:304-311. • Piper CM, Carroll PB, Dunn FL. Diet-induced essential fatty acid deficiency in ambulatory patient with type I diabetes mellitus. Diabetes Care. 1986;9:291-293. • Vanek VW, Allen P, Harvey-Banchik LP, Bistrian B, Collier S, Driscoll DF, Gura K, Houston DR, Miles J, Mirtallo J, Mogensen KM, Seidner D. Parenteral nutrition intravenous fat emulsion product shortage considerations. Nutr Clin Pract. 2013;28:528-529. • Fleming CR, Smith LM, Hodges RE. Essential fatty acid deficiency in adults receiving parenteral nutrition. Am J Clin Nutr. 1976;29:976-983. References

• O’Neill JA, Caldwell MD, Meng HC. Essential fatty acid deficiency in surgical patients. Ann Surg. 1977;185:535-541. • Duerksen D, McCurdy K. Essential fatty acid deficiency in a severely malnourished patient receiving parenteral nutrition. Digest Dis Sci. 2005;50:2386-2358. • Prottey C, Hartop PJ, Press M. Correction of the cutaneous manifestations of essential fatty acid deficiency in man by application of sunflower-seed oil to the skin. J Invest Dermatol. 1975;64:228-234. • Skolnik P, Eaglstein WH, Ziboh VA. Human essential fatty acid deficiency. Treatment by topical application of linoleic acid. Arch Dermatol. 1977;113:939-941. • Miller DG, Williams SK, Palombo JD, Griffin RE, Bistrian BR, Blackburn GL. Cutaneous application of safflower oil in preventing essential fatty acid deficiency in patients on home parenteral nutrition. Am J Clin Nutr. 1987;46:419-423. • Sacks GS, Brown RO, Collier P, Kudsk KA. Failure of topical vegetable oils to prevent essential fatty acid deficiency in a critically ill patient receiving long-term parenteral nutrition. JPEN J Parenter Enteral Nutr. 1994;18:274-277 • Marccason W. Can cutaneous application of vegetable oil prevent an essential fatty acid deficiency? J Am Diet Assoc. 2007;107:1262. • Gramlich L et al. Essential fatty acid deficiency in 2015: the impact of novel intravenous lipid emulsions. JPEN J Parenter Enteral Nutr. 2015;39:61S-66S • Mascioli EA, Smith MF, Trerice MS, Meng HC, Blackburn GL. Effect of total parenteral nutrition with cycling on essential fatty acid deficiency. JPEN J Parenter Enteral Nutr. 1979;3:171-173 Thank you!