The Effect of Movement and Rest on Methylation …...Ketogenic Diets in Context Long history of use: •1797 first record of meat diet for diabetes •

Ketogenic DietsAssessment for Clinical Application

Troubleshooting

What We’ll Cover

Using a ketogenic diet in practice

• Suitability for a ketogenic diet

• Medication and supplement interactions

• Baseline and follow up evaluation

• Physiology of ketosis vs ketoacidosis

• Troubleshooting a ketogenic diet

• If we have time:• Calculating macros• Measuring ketosis• Exogenous ketone use

Introduction

• The ketogenic diet is a powerful (medical) dietary intervention

• It comes with its own controversies, contraindications, side effects and long-term risks

• Being adept at identifying and mitigating risks will help clinical decision making• Who is right for this diet

• When to discontinue the diet

• Many side effects and risks can be mitigated

My Goal

…is to make us and our patients/clients be more successful in our use of this important Functional Medicine tool

Ketogenic Diets in Context

Long history of use:

• 1797 first record of “meat diet” for diabetes

• <1921 Before ‘discovery’ of exogenous insulin, VLC diet was used for diabetes

• Nearly 100 years of use for pediatric epilepsy

Despite this, our scientific knowledge about ketogenic diets is still evolving.

Ketogenic Diets in Context

Ketogenic principles show up in several other diets

What Version of Keto Are You?

Egg and Avocado Salad

https://ketodietapp.com/Blog/post/2015/05/11/easy-avocado-and-egg-salad

P:C:F g = 17:6:36

Suitability for a Ketogenic Diet

Absolute Contraindications

Inborn errors of metabolism that affect the transport and metabolism of fatty acids, and production/utilization of ketones.

• Carnitine deficiency (primary)

• Carnitine palmitoyltransferase I or II deficiency

• Carnitine translocase deficiency

• Β-oxidation defects

• Short/Medium/Long-chain acyl dehydrogenase deficiency

Kossoff EH, et alEpilepsia2009; 50(2):304-317. Fukao, T.Orphanet2013: SCOT deficiency,

Laffel L.Diabetes Metab Res Rev.1999;15(6):412-426.

Absolute Contraindications

• Pyruvate carboxylase deficiency

• Medium/Long-chain 3-hydroxyacyl-coenzyme A deficiency

• SCOT deficiency (rate-limiting step in ketolysis)

• Beta-ketothiolase (T2) deficiency

• Methylmalonyl-CoA epimerase deficiency

Inborn errors of metabolism con’t.

Fukao, T.Orphanet2004 Beta-ketothiolase deficiency.

Waters PJ, et al.Mol. Genet. Metab. RepVol 9.; 2016.

Absolute Contraindications

Porphyria – an elevation of intermediates in the heme biosynthesis pathway.

• Glucose derived from carbohydrates has a disease-suppressing effect.

• May be diagnosed at birth or be uncovered when following low CHO diet.

• Ketogenic diet is contraindicated.

Sassa S, et al.Cell Mol Biol 2002;48(1):97-101.Tsai M-T, et al. Case Rep Emerg Med.2017:1-4Quiroz-Kendall E, et al.J Am Acad Dermatol.1983;8(1):46-49Bonkowsky HL, et al.Yale J Biol Med. 1979;52(1):13-37Porphyria.National Institute of Diabetes and Digestive and Kidney Diseases.2014

Heme biosynthesis pathway

http://epomedicine.com/medical-students/heme-synthesis/

Absolute Contraindications

Starvation-mimicking states – Active eating disorder or active alcoholics.

• Inability to enact a ketogenic diet.

• Prone to ketoacidosis (elevated anion gap).

• Prone to severe nutrient deficiency.

• Eating disorders –restriction of energy/macronutrient intake is not recommended.

George Ansstas,Medscape “Alcoholic Ketoacidosis: Background, Pathophysiology, Etiology.” 2017

• Insulin-dependent diabetes - type I diabetes or insulin-dependent type II diabetes, with episodes of hypoglycemia. Note that a ketogenic diet can still be an important therapeutic protocol in IDDM.

• Kidney dysfunction

a. Nutrient balance - carnitine

b. Electrolyte balance - sodium, potassium

c. Acid-base balance - hydrogen ions/bicarbonate (metabolic acidosis)

Proceed with Caution

Berry-Kravis E, et al.Epilepsia. 2001;42(11):1445-1451Tiwari S, et al.Am J Physiol Renal Physiol.2007;293(4):F974-84Nielsen JV, et al.Nutr Metab (Lond).2006;3:23.Mobbs CV, et alJ Child Neurol. 2013;28(8):1009-1014

Proceed with Caution

Urolithiasis – A ketogenic diet may increase the risk of precipitation of minerals in the kidneys

• Reported in 6% of children following a ketogenic diet

• Average time to present is 18 months but can happen after only 30 days

• High CHO/refined diets have the same effect

Barclay L. 2009MedScape PediatricsMasino SA.Ketogenic Diet and Metabolic Therapies.Oxford University Press; 2017Leslie S.MedScape “Hypercalciuria Treatment” 2017Agarwal MM, et al.Indian J Urol. 2011;27(3):310-319

Proceed with Caution

Liver disorders

• Long-term effects on liver are not yet fully understood

• Liver is where ketones are produced

• Liver makes glucose even during ketosis – fuel for tissues that can’t use ketones (e.g. RBCs)

• HepC: decreased expression of mitochondrial trifunctional protein needed for last steps in FA beta-oxidation

Schugar RC, et al.Curr Opin Clin Nutr Metab Care.2012;15(4):374-380.Rui L.Compr Physiol. 2014;4(1):177-197.Amako Y.J Virol. 2015;89(8):4092-4101

HF Diets and Fatty Liver –Untangling the Controversy

Studies in rodents show HF diet reliably induces metabolic dysregulation (obesity, IR) and fatty liver.

Leads many scientists to conclude that HF aren’t suitable for humans.

But…

• Overall lack of transparency of dietary components.

• Issues with lack of fiber, nutrients in HF purified rat diet, compared with standard chow.

• Deficiencies of methionine, choline, known to also induce fatty liver.

• Often contain sugar. Sugar+HF is most damaging.

HF Diets and Fatty Liver con’t

Schugar RC, et al.Curr Opin Clin Nutr Metab Care.2012;15(4):374-380.

Buettner R, et al.J Mol Endocrinol. 2006;36(3):485-501.

Yandell K. Inside a Lab Mouse’s High-Fat Diet. Sci. 2015

Borghjid and Feinman.Nutr Metab (Lond). 2012;9(1):69.

Yki-Järvinen H.Nutrients. 2015;7(11):9127-9138.

Stefanovic-Racic M, et al. AJP Endocrinol Metab. 2008;294(5):E969-E977.

Mazzotti A, et al.Dig Dis. 2016;34(Suppl 1):3-10.

Arslan N, et al. Seizure. 2016;43(June 2013):32-38.

“I think the main reason why mouse diet studies usually do not model human responses is that investigators use diets that do not correspond to human diets. So yes I agree most mouse diet studies demonize high fat diets, but human studies suggest they are healthy and effective.”

As a model of human obesity and insulin resistance, however, it suffers from the severe, if under-emphasized, limitation that high-fat diets do not generally cause these conditions in humans unless the diets are also high in carbohydrate. In fact, carbohydrate-restricted diets (CRDs), even with high fat, are the most effective therapy for diabetes and metabolic syndrome; the greater the replacement of carbohydrate with fat, the more effective the improvement (reviews: [5-11]).

Proceed with Caution

Hyperlipidemia

• Temporary rise in some serum lipids (LDL-C, total-C)

• Possibly due to release from adipose tissue

• In general, a keto diet had produced positive changes in lipid profile (particle size, HDL, serum triglycerides)

• Also shown to reverse all markers of MetS

• We take a cautious approach, monitor with advanced lipid profiles

• Note: statins can increase glucose levels

Proceed with Caution

Schoeler NE, et al. Epilepsy Behav. 2014;37:77-81.

Volek JS, Phinney SD. The Art and Science of Low Carbohydrate Living. 2011.

Volek JS, et al. J Nutr. 2005;135(6):1339-1342

Ivanova EA, et al. Oxid Med Cell Longev. 2017;1273042.

Gibas and Gibas.Diabetes Metab Syndr Clin Res Rev. March 2017.

Proceed with Caution

Gout

• Uric acid levels may rise during the first 4-6 weeks

• Uric acid competes with ketones for elimination in urine

• If you’re prone to gout, a keto diet may trigger an attack

• Suddenly stopping a keto diet may also trigger an attack

• Carb ‘cycling’ not recommended

Proceed with Caution

Fat maldigestion/malabsorption: Poor pancreatic exocrine or liver/gallbladder function.

• History of pancreatitis or gallbladder obstruction

• Cholecystectomy

• Gastric bypass

• Steatorrhea

Sawaya RA, et al.Curr Drug Metab. 2012;13(9):1345-1355.

Proceed with Caution

Underweight:

• Not usually suitable for underweight individuals

• Increase calories or delay until weight is normalized

• Initial weight loss is common. Typically will stabilize

• Consider carbohydrate cycling (provokes anabolic insulin) to help weight maintenance

• Discontinue if weight can’t be maintained

Tinsley and Willoughby.Int J Sport Nutr Exerc Metab. 2016;26(1):78-92.Heymsfield SB, et al.Obes Rev. 2014;15(4):310-321

Proceed with Caution

Bone density:

• Children who followed a keto diet for seizure control had marked negative effects on bone mineral metabolism

• These effects do not appear to occur in adults

• Possible cause is low grade metabolic acidosis and need for increased buffering

• Monitor mineral repletion, phytonutrient intake, and acid-alkaline balance

Hahn TJ, et al.Calcif Tissue Int. 1979;28(1):17-22.Bergqvist AC, et al.Am J Clin Nutr. 2008;88(6):1678-1684.Bertoli S, et al.Nutrition. 2014;30(6):726-728.

What Version of Keto Are You?

Broccoli and Leek Souphttps://www.myketokitchen.com/keto-recipes/low-carb-broccoli-and-leek-soup/P:C:F = 6:38:6 g

Proceed with Caution

Pregnancy and lactation:

• Physiological ketonemia and ketonuria appears to occur normally in pregnancy

• Pregnant women are more metabolically responsive, may tip into acidosis

• Ramadan-fasting mothers and controls had similar pregnancy outcomes

• Impact of low glucose and high ketone levels is still controversial and poorly studied

Proceed with Caution

Sacks DB, et al.Diabetes Care. 2011;34(6):e61-99.

Herrera E.Eur J Clin Nutr. 2000;54 Suppl 1:S47-51.

Metzger BE, et al.Lancet (London, England). 1982;1(8272):588-592.

Coetzee EJ, et al.Diabetes. 1980;29(3):177-181.

Malhotra A, et al.Br J Nutr. 1989;61(3):663-672.

Sussman D, et al.BMC Pregnancy Childbirth. 2013;13:109.

von Geijer and EkelundJ Med Case Rep. 2015;9:224.

Corrigan N, et al.Birth Defects Res Part A Clin Mol Teratol. 2009;85(6):523-530.

Pregnancy and lactation con’t.

Proceed with Caution

Childhood/adolescence:

• Long history of use in children for epilepsy

• Much of our understanding of side effects comes from this population

• Poor linear growth associated with protein or calorie intake <80% RDI

• More liberal protein/calorie allowance sometimes still associate with poor growth rates

• Some evidence of catch up growth after discontinuation of diet (worse catch up growth <3 years of age). Physical activity improves catch up growth

Proceed with Caution

Duchowny MS. Epilepsy Curr. 2005;5(4):152-154.

Evangeliou A, et al. J Child Neurol. 2003;18(2):113-118.

Nation J, et al. J Child Neurol. 2014;29(11):1496-1501.

Neal EG, et al. Pediatrics. 2008;122(2):e334-e340.

Spulber G, et al. Epilepsia. 2009;50(2):297-303.

Kim JT, et al. Clin Nutr. 2013;32(1):98-103.

Childhood/adolescence con’t.

Proceed with Caution

Cardiomyopathy:

• Selenium-deficiency cardiomyopathy (rare but seen in long-term use if not supplemented)

• Those with a history of cardiomyopathy should be evaluated prior to use

• Anyone using keto for long-term - have baseline selenium checked

• Supplements or dietary sources like Brazil nut (2-3/day)

Masino SA.Ketogenic Diet and Metabolic Therapies.Oxford University Press; 2017Sirikonda NS, et al.Pediatr Cardiol. 2012;33(5):834-838.Best TH, et al.Neurology. 2000;54(12):2328-2330.Bank IM, et al.Pediatr Neurol. 2008;39(6):429-431.

Decision Factors – Risk vs Benefit

• Health goals – what are the stakes?

• E.g. 15 lbs weight loss is different to cancer

• Most side effects can be mitigated/monitored

• Consider

• Trial period

• Short-term kd followed by more relaxed carbohydrate

intake or cyclical rotation

• Always: ongoing monitoring

Choe S, et al. Endocrine Society 2017.

What Version of Keto Are You?

Garlic Oregano Olive Tapenade https://paleoflourish.com/garlic-oregano-olive-tapenade-recipeP:C:F g = 1:5:18

Medication and Supplement Interactions

Categories of Interaction

Medications and nutrients that may:

• Increase risks and side effects of the diet:• Increase risk for metabolic acidosis• Induce hypoglycemia• Interfere with electrolyte balance

• Inhibit ketosis:• Induce hyperglycemia• Carbohydrate content

• Interfere with ketone test results:• False positive and false negative

Laffel L. Diabetes Metab Res Rev.1999;15(6):412-426Takeoka M, et al. Epilepsia. 2002;43(9):1072-1075.Liamis G, et al. Drug Saf. 2010;33(5):371-391Kreisberg and Wood. Clin Endocrinol Metab. 1983;12(2):391-411.Fralick M, et al.N Engl J Med. 2017;376(23):2300-2302.Hurd R, et al.drugs.com2014.Rashmi and Shilpy. Herb Med Open Access. 2016;2(1).Cefalu WT, et al. Diabetes and Herbal (Botanical) Medicine; 2011.Ansar H, et al. Saudi Med J. 2011;32(6):584-588.Rehman A, et al. Diabetes Spectr. 2011;24(4).Ganda OP.F1000 Research. 2016;5.McGHEE and KATYAL.J Am Diet Assoc. 2001;101(1):87-101.Free and Free. Lab Med. 1978;9(12):9-18.Anderson JC. Obesity. 2015;23(12):2327-2334.

Medication and Supplement Interactions.

Baseline Evaluation

Baseline Evaluation

• Review potential contraindications or conditions that require closer management

• Nutrition physical examination• Weight, height, BMI, waist circumference, hip

circumference and waist-to-hip ratio • Fat loss, muscle wasting, hydration

• Nutrition intake history• Food record• Dietary patterns (e.g. religious)• Food preferences/aversions • Allergies, sensitivities, intolerances

Continued…

Baseline Evaluation (cont.)

• Ability to enact a ketogenic diet• Medication and supplement review

• Feasibility, potential roadblocks

• Areas requiring additional education/support• Existing knowledge of low carbohydrate/ketogenic diets

• Cooking skills and environment

• Fat phobia

• Readiness to change

• Informed consent

Ling CHY, et al. Clin Nutr. 2011;30(5):610-615.Valenta R, et al. Gastroenterology. 2015;148(6):1120-31.e4.Boyce JA, et al. J Allergy Clin Immunol. 2010;126(6 Suppl):S1-58.Fitzgerald K.Institute for Functional Medicine Immune Advanced Practice Module.; 2016.

Laboratory Evaluation

• Baseline Assessment:• Complete blood count, with platelets

• Comprehensive metabolic panel

• Fasting insulin

• HbA1c

• Lipid panel

• Serum creatinine

• Carnitine panel

• Thyroid panel

• Vitamin D 25-OH-D

• RBC minerals (magnesium, selenium, zinc)

Laboratory Evaluation

• Possible other baseline considerations:• HOMO-IR, glycosylated serum proteins

• Urinalysis

• Urinary calcium/creatinine ratio

• Urinary adipate, suberate, ethylmalonate

• Renal ultrasound

• Serum amino acids

• Toxins

• Functional stool testing

• Serum beta-hydroxybutyrate

Berry-Kravis E, et al.Ann Neurol. 2001;49(1):98-103.Sorbi D, et al.Am J Gastroenterol. 1999;94(4):1018-1022.Phinney SD.Nutr Metab (Lond). 2004;1(1):2.Hawkes and Levine.J Clin Endocrinol Metab. 2014;99(5):1531-1536.Neal EG, et al.Epilepsy Res. 2012;100(3):267-271.

Matching Each Individual to the Right Type of Ketogenic Diet

Diet Pros Cons

Classic ketogenic diet 3:1 or 4:1

Most well-studied.Best clinical outcomes in research studies.Recommended for cancer.

Challenging to implement, poor palatability.Most side effects.Deficient in micronutrients

Modified ketogenic diet 2:1 or 1:1

May be sufficient for desired benefits.Easier to enact.Potentially useful as transition or maintenance diet.

May not achieve the same benefits.

Masino SA.Ketogenic Diet and Metabolic Therapies.Oxford University Press; 2017

Matching Each Individual to the Right Type of Ketogenic Diet

Diet Pros Cons

Modified Atkins Diet Unrestricted calories, more liberal protein.Easier to implement.May be easier to adhere to long-term

May not achieve the same benefits.Tendency to misinterpret as low in vegetables and phytonutrients.

MCT Diet Shown to be effective alternative for refractory epilepsy, may be useful for other conditions.

Bowel tolerance for MCT oil.May not achieve the same benefits.

Matching Each Individual to the Right Type of Ketogenic DietDiet Pros Cons

Low glycemic index treatment (LGIT)

Shown to have similar benefits for epilepsy.Easier to adhere to.Does not usually require full lab workup before initiation.

May not achieve the same benefits.

Intermittent fasting May be easier to adopt for some individuals.Does not usually require full lab workup before initiation.

Some individuals may not achieve ketosis.No chance for full metabolic adaptation.No appetite-suppressing effects – can make it hard to follow.

Hartman AL, et al. Epilepsia. 2010;51(8):1395-1402.Mattson MP, et al. Ageing Res Rev. 2017;39:46-58.

Ongoing Monitoring

During Diet Initiation

First 2-4 weeks: Close communication between practitioner/client

• Ability to implement the diet (food journals, macronutrient calculators)

• Ability to achieve ketosis (options for urine, breath, blood measures)

• Dietary tolerance

• Bowel function (goal = daily bowel movement)

• Review supplement/medication changes

• Troubleshooting as needed

Medium-Term Monitoring

Up to 6 months: Meet with practitioner every 1-3 months

• All of the previous slide PLUS

• Assessment of health outcomes

• Decide whether to continue, modify or stop the diet

• Follow up laboratory assessment

• Evaluation of nutrient intake and functional status

Long-Term Monitoring

> 6 months: Meet with practitioner every 3-6 months (except cancer clients – monthly)

• All of the previous short-term/medium-term PLUS

• Consider transition to maintenance plan

• Assessment for potential negative effects of a long-term ketogenic diet

Laboratory Evaluation

• Follow Up Assessment:• Complete blood count, with platelets• Comprehensive metabolic panel • Beta-hydroxybutyrate• Serum bicarbonate• Fasting insulin • HbA1c• Lipid panel• Serum creatinine• Carnitine panel• Thyroid panel • Vitamin D 25-OH-D• RBC minerals (magnesium, selenium, zinc)

Laboratory Evaluation

• Other follow up considerations:• Advanced lipid profiles with particle size

>6 months on diet:

• Renal evaluation for kidney stones (re-evaluate every 6-12 mo)

• Bone health – DEXA scan, bone resorption markers

• Cardiac evaluation

• Microbiome (PCR stool testing)

• Additional nutrients: RBC folate, serum B12, iron panel. Consider comprehensive Functional Medicine testing for nutrient status (including amino acids, organic acids)

Dietary Evaluation

• Any food choices not compatible with a ketogenic diet?

• Balance choice of fats• Balance of saturated (including medium-chain saturated

fats), monounsaturated and polyunsaturated fats

• Avoid refined vegetable oils and trans-fats

• Attention to fat quality: unrefined, cold-pressed, organic, as possible

Dietary Evaluation

• Variety of foods, as possible – important to support healthy micronutrient and phytonutrient intake

• Food quality – biggest concern may be fat-soluble, food-based toxins

• Avoid artificial sweeteners and food additives• Stevia, erythritol, xylitol OK until palate adjusts, if

tolerated

• Fiber: to nourish healthy gut flora and prevent constipation (use of ‘net carbs’ can help here)

Keto Version 1

Keto Version 2

What Version of Keto Are You?

Mexican Breakfast Hashhttps://ketodietapp.com/Blog/post/2017/04/18/keto-mexican-breakfast-hashP:C:F g = 22:8:35

Detoxification Support

• Mobilized fat stores can place extra demand on phase I/II detoxification

• Strategies:• Nutrients to support phase I/II

• Hydration

• Daily bowel movement

• Sauna, Epsom salt bath, dry brushing, etc.

Nutrient Intake Analysis

• Recommend track micronutrients the first few weeks and intermittently thereafter

• Several apps/software

• We use Cronometer• Be sure to select food from USDA and NCCBD only for

full micronutrient values

• High quality vitamin/mineral supplement (+ higher Ca, Mg)

Physiology of Ketosis vs Ketoacidosis

Physiology of Ketosis

• Most of the information we have comes from research on human fasting, starvation states and pathological ketoacidosis, NOT ketogenic diets

• Misunderstandings about physiological ketosis vs ketoacidosis

• Keto-adaptation appears to occur over time on a ketogenic diet, but is not yet well understood

Grabacka M, et al. Int J Mol Sci. 2016;17(12).Balasse and Féry. Diabetes Metab Rev. 1989;5(3):247-270.Schönfeld and Reiser. J Cereb Blood Flow Metab. 2013;33(10):1493-1499.

Physiology of Ketosis

• Ketones are always present in our blood

• Levels fluctuate depending on physiological state (fasting, pregnancy, exercise, low CHO)

• Endogenous ketone bodies include: • Beta-hydroxybutyrate 78%• Acetoacetate 20%• Acetone 2%

• Most cells can use ketones for fuel, except those without mitochondria (e.g. RBCs)

• Many tissues can also use fatty acids for fuel. One exception is brain – poor utilizer of fatty acids

Physiology of Ketosis

Grabacka et al. 2016 Int J Mol Sci. 17(12)

Physiology of Ketosis

• Physiological ketosis has negative feedback loops that prevent ketoacidosis• Ketones have weak insulin secretagogue effect, inhibit

lipolysis• Insulin has potent effects even at low levels – stalls FA

release, inhibits ketone formation, promotes glucose uptake• Tissue saturation of ketones occurs – amplifies inhibition of

ketone production

Physiology of Ketosis

• Ketoacidosis results from signaling breakdown• Lack of insulin is a key factor in “runaway” ketoacidosis

• Uncontrolled release of FFA

• Without inhibition, rate of ketogenesis can reach 3 mmol/min (vs 1.5-2.5 mmol/m in physiological ketosis)

• Poor ketone utilization in diabetic ketoacidosis

• Glucose AND ketones are high, pH drops

Physiology of Ketosis

Balasse and Féry.Diabetes Metab Rev. 1989;5(3):247-270.

Cotter DG, et al.Am J Physiol Heart Circ Physiol. 2013;304(8):H1060-76.

Paoli A, et al.Skin Pharmacol Physiol. 2012;25(3):111-117.

Macdonald MJ, et al.Biochim Biophys Acta. 2008;1780(7-8):966-972.

MacDonald MJ, et al. Am J Physiol - Cell Physiol. 2008;294(2).

McDonald L.The Ketogenic Diet : A Complete Guide for the Dieter and Practitioner. 1998.

Foster DW.J Clin Invest. 2012;122(6):1958-1959

Howard RD, Bokhari SRA.Alcoholic Ketoacidosis; 2017.

Targets for Physiological Ketosis

• Volek & Phinney: 0.5 to 5.0 mmol/L

• Thomas Seyfried: 3.0 - 6.0 mmol/L, combined with reduced blood glucose (cancer-specific)

• Patients with epilepsy - seizure control seems to be best when beta-hydroxybutyrate levels are maintained above 4.0 mmol/L.

Volek JS, Phinney SD. The Art and Science of Low Carbohydrate Living. 2011 Gilbert DL, et al. J Child Neurol.2000;15(12):787-790.

Don’t Lose Sight of the End Goal• Deeper ketosis isn’t necessarily better, or needed to achieve

health goals

• Example health biomarkers:• Cancer biomarkers, radiological scans• Fasting blood glucose, insulin, HbA1c• Weight, BMI, waist-hip ratio• CRP/hs-CRP, ESR, ferritin• Estrogen, estrogen-progesterone ratio• TG, TG/HDL ratio• Blood pressure

• Example health outcomes:• QOL indices• MSQ• Neurological improvement• Reduced migraines

Troubleshooting a Ketogenic Diet

Keto-Resistance

Failure to shift to fatty acid beta oxidation and ketogenesis

• Try testing blood ketones if using urine strips

• Any hidden sources of carbohydrates (medications, gum, oral care products?)

• Consider increasing intensity of diet (3:1 to 4:1)

Heldmaier and Seidl. J Comp Physiol B. 1985;155(6):679-684.Shephard RJ. Sports Med. 2(1):59-71.Tabeshpour J, et al. Iran J Basic Med Sci. 2017;20(5):557-568.

Keto-Resistance

Additional options

• Fasting 2-3 days, water or bone broth*

• 30-90 minutes moderate exercise on waking, before eating*

• Extended moderate exercise (3-6 hours, with intermittent rest periods)*

• Sauna or hot yoga*

• Cold water therapy (e.g. cold shower, cold-water bathing, exercise in cold temperatures)

• Supplemental berberine (lowers insulin and blood sugar)

• Supplemental ketogenic amino acids (leucine and lysine)

• Consider unidentified food sensitivities

• Stress management

• For dawn phenomenon (persistent spike in first morning blood glucose), add a late night high-fat, moderate protein snack such as macadamia nuts

• Supplemental MCT oil (2-6 tbsp per day, or to bowel tolerance)

*depending on tolerance

Electrolyte Depletion

• Early ketosis, before adaptation - sodium, potassium, magnesium and calcium can be imbalanced

• Can lead to dehydration, “keto flu”

• 2-3 grams of sodium per day, potassium-rich foods, and magnesium/calcium (if necessary)

Home Remedies for Electrolyte Imbalance

2-4 times a day:• 8 ounces of water• ¼ teaspoon sodium

bicarbonate• ¼ teaspoon Morton’s Lite salt • juice of ½ a lemon or lime.

OR: 8 ounces salted home-made bone stock

Hypoglycemia

• Symptoms are similar to those of electrolyte depletion:• Mild symptoms: lightheadedness, irritability, weakness,

shakiness, difficulty concentrating, and fatigue• Counsel patients/clients before initiating

• Next steps:• Check electrolyte intake first if symptoms are mild

• Use the home remedy drink above at the onset of mild symptoms

• If no resolution in 10-15 min, check blood sugar levels with home glucometer (if have)

• If blood sugar <60 mg/dL drink ¼ cup orange or apple juice. May repeat after another 10-15 min

• Seek medical attention if not resolved

Bergqvist AGC, et al. Epilepsia. 2005;46(11):1810-1819.

Mild acidosis

• May occur at beginning of diet: Nausea, vomiting. Can create a cycle that’s difficult to break.

• An oral buffering agent such as sodium bicarbonate (mixed with diluted orange or apple juice) can resolve mild cases.

• Severe acidosis is life-threatening.

• Caution with medications that can worsen acidosis.

Tapia Guerrero MJ, et alNutr Hosp. 25(5):864-866. Chen T-Y, et al. Lancet. 2006;367(9514):958.

Constipation

• Common, 65% of individuals

• Ways to help:• Increase water intake• Increase low carbohydrate, high fiber foods – e.g. raw celery,

avocado, spinach, flaxseeds• Calculate carbs as “net” encourage more fiber• Psyllium husk• Probiotics• Magnesium citrate

• Persistent constipation:• Miralax (polyethylene glycol)• Glycerin suppositories

Fat Intolerance

• Increase fat gradually

• Avoid over-feeding

• Supplemental lipase and/or bile salts with meals

• Try MCT oil

Undesired Weight Loss

• Increase fat intake first before removing CHO

• Track ability to maintain calorie intake

• Consider carb ‘cycling’

• Increase protein intake – from 0.8-1.2 g/kg/d

• BCAA and HMB (beta-hydroxymethylbutyrate) to preserve muscle mass

• Resistance training 2-3 times per week

• May need to stop diet (weight risk/benefit)

Carbone JW, et al. Adv Nutr An Int Rev J. 2012;3(2):119-126. Pasiakos SM, Margolis and Orr. FASEB J. 2015;29(4):1136-1142.Fitschen PJ, et al. Nutrition. 2013;29(1):29-36.

Vitamin and Mineral Deficiencies

• B vitamins, calcium, selenium and vitamin D are particular concern (as with many diets)

• Use a low/zero carbohydrate multivitamin and mineral supplement• Ensure sufficient Ca/Mg/Se

• Lab testing for monitoring long-term nutrient status

Medium - Long Term Concerns

• Carnitine sufficiency – deficiency is rare but dietary intake of carnitine is often reduced on a ketogenic diet while utilization increases• Some data show carnitine may normalize after 6 mo

naturally

• Kidney stones –Lemon water, potassium foods, Morton’s Lite salt. Maintain hydration. Consider oral potassium citrate, avoid excessive high oxalate foods and test at least 12+ mo or earlier if history of.

Berry-Kravis E, et al.Epilepsia. 2001;42(11):1445-1451Krajcovicová-Kudlácková et al,Physiol Res. 2000;49(3):399-402.Paterson R, et al.Can Urol Assoc J. 2010;4(6):375-379.

Thyroid Function

• Concern for reduction in Thyroid Hormone T3

• Some studies show this is temporary reduction, returning to normal after 1-2 weeks.

• Potential alterations in thyroid hormone levels should not be considered abnormal (as this may be a adaptive response to diet)

• Lower levels, however no clinical signs or symptoms of overt hypothyroidism

• Possible increased tissue sensitivity to T3

Thyroid Function

Sirikonda NS, et al.Pediatr Cardiol. 2012;33(5):834-838.

Ullrich IH, et al.J Am Coll Nutr. 1985;4(4):451-459.

DAVIDSON and CHOPRA.J Clin Endocrinol Metab. 1979;48(4):577-581.

Spaulding SW, et al.J Clin Endocrinol Metab. 1976;42(1):197-200.

Bisschop PH, et al.Clin Endocrinol (Oxf). 2001;54(1):75-80.

Danforth E, et al.J Clin Invest. 1979;64(5):1336-1347.

Pasquali R, et al.J Endocrinol Invest. 1982;5(1):47-52.

Schoeler and Cross.Pract Neurol. 2016;(16):208-214.

Chatzitomaris A, et al.Front Endocrinol (Lausanne). 2017;8:163.

Phinney SD.Does Your Thyroid Need Dietary Carbohydrates? 2017.

Fontana L, et al.J Clin Endocrinol Metab. 2006;91(8):3232-3235.

Bone Health

• Evaluate for vitamin D status, and intake of bone-relevant nutrients

• Supplement with bone-relevant nutrients

• Include weight training

• Reduce oxidative stress - Antioxidant phytonutrients

• Maintain healthy gut microbiome

• Methylation support

Reasons to Discontinuea Ketogenic Diet

• Health goals have been achieved, or are on track

• Poor/adverse response including unfavorable laboratory markers

• Risk/benefit ratio has changed

• Where next? Maintenance options:• Paleo, low carbohydrate, low glycemic, Mediterranean• Periods of cycling into ketosis• Intermittent fasting

Masino SA. Ketogenic Diet and Metabolic Therapies.Oxford University Press; 2017

Ketogenic DietsAssessment for Clinical Application

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