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THE PHYSIOLOGY OF FASTING AND
FATTY ACID OXIDATION DEFECTS
Mark Korson, M.D.Tufts-New England Medical Center
Boston, MA
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Time after eating
Sour
ce o
f glu
cose
/ en
ergy glycogen
gluconeogenesis, muscle
gluconeogenesis, other
fatty acid oxidation
food
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FED STATE
• The body uses glucose and nutrients from the last meal.
• The body/brain relies on glucose as the prime source of energy.
• The body synthesizes fat.
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FED STATE to FASTING STATE:Step One
• When eaten food is no longer a source of glucose or energy, stored glycogen in the liver gets broken down to form glucose.
• As the body’s stores of glycogen are used up, the body starts to make “new” sugar from various sources including lactate and amino acids (from muscle).
• The body/brain continues to rely on sugar as the prime source of energy.
• The body synthesizes fat.
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FED STATE to FASTING STATE:Step Two
• Some glucose is still formed by the body (gluconeogenesis), but not from amino acids (muscle).
• Fat is oxidized to form ketones.• During prolonged fasting, the body
relies on fat conversion to ketones as the prime source of energy.
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Time after eating
Sour
ce o
f glu
cose
/ en
ergy glycogen
gluconeogenesis, muscle
gluconeogenesis, other
fatty acid oxidation
food
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Glycogen Storage Disease
• Stored sugar or glycogen cannot be accessed.
• Infants cannot go for longer than 3-4 hours without feeding.
• After 3-4 hours, hypoglycemia occurs.• Glycogen cannot be broken down but
just accumulates in the liver, causing liver enlargement.
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Time after eating
Sour
ce o
f glu
cose
/ en
ergy glycogen
gluconeogenesis, muscle
gluconeogenesis, other
fatty acid oxidation
food
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Disorders of Gluconeogenesis
• Glucose cannot be synthesized from certain substrates.
• Patients with severe disease are very affected neurologically – low muscle tone or spastic, seizures, developmentally delayed, failure to thrive.
• Lactic acid is usually elevated chronically.• Symptoms, lactic acid become worse with
fasting; hypoglycemia may occur at that time.
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Time after eating
Sour
ce o
f glu
cose
/ en
ergy glycogen
gluconeogenesis, muscle
gluconeogenesis, other
fatty acid oxidation
food
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Fatty Acid Oxidation Disorders
• When eating well, and while otherwise healthy, patients may show no symptoms.
• When food intake is inadequate and/or the patient is sick and food intake cannot keep up with demand, symptoms may occur.
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Fatty Acid Oxidation Disorders
• Nausea and vomiting• Encephalopathy – lethargy, coma,
seizures• Liver enlargement, dysfunction• Muscle and heart muscle dysfunction• +/- Hypoglycemia
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Encephalopathy: Causes
• Fatty acid oxidation disorders are disorders of energy metabolism in which the brain “runs out of energy”:– glucose stores are exhausted.– ketone production is diminished.
• The accumulating metabolites are toxic to the brain, causing brain swelling and coma.
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FATTY ACIDS
FATTY ACYL CoA
CoA
�-OXIDATION
ACETYL CoA
KETONES
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FATTY ACIDS
FATTY ACYL CoA
CoA
�-OXIDATION
ACETYL CoA
KETONES
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Encephalopathy: Causes
• The low concentrations of CoA and the accumulation of fatty acyl CoAmolecules interfere with normal energy production in the Krebs cycle.
• Inadequate amounts of acetyl CoAimpair gluconeogenesis or production of glucose in the body.
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CLINICAL APPLICATIONS
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CLINICAL APPLICATIONS
• Fasting avoidance is the cornerstone of therapy
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Fasting Avoidance
• If you rely on glucose and avoid relying on fat, symptoms are minimized.
• Exception: in long chain fatty acid oxidation defects, heart muscle and skeletal muscle depend on both glucose and fat.
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CLINICAL APPLICATIONS
• Fasting avoidance is the cornerstone of therapy
• Is fat restriction necessary? Fat synthesis is not impaired (under healthy conditions).
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TR’s Story
• TR was born following a normal pregnancy, labor and delivery. Developed hypoglycemia (12 mg/dL) on day 2 with associated lethargy and mottling.
• At four months, she became sweaty with feedings and often choked.
• At five months, she became irritable and less responsive and had staring spells.
• Examination revealed a gallop and murmur.• Testing revealed cardiomyopathy & heart
failure.
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TR’s Story (continued…)
• Metabolic testing revealed a diagnosis of VLCAD (very long chain acyl CoAdehydrogenase) deficiency. Enzyme testing confirmed the diagnosis.
• TR’s diet: 30-35% of calories from fat -– 90% of fat from medium chain triglycerides– 10% of fat from long chain fat
• Carnitine given to maintain normal levels.• Night-time feeds ended at 30 months; given
corn starch instead with MCT during the day.
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TR’s Story (continued…)
• Heart size normalized over 24 months.• Ventricular hypertrophy resolved by four
years.• Intercurrent illnesses associated with
elevated liver enzymes and CPK; resolve with intravenous fluids.
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Fat Restriction
• When sick, energy demands rise and food intake diminishes; the body will use dietary fat to make ketones.
• The diet during times of illness should be high in carbohydrate and low in fat.
• Fat restriction may not be so important when the patient is otherwise healthy.
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CLINICAL APPLICATIONS
• Fasting avoidance is the cornerstone of therapy
• Is fat restriction necessary?• Medium chain fat supplementation (for
long chain fatty acid oxidation disorders).
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DIETARY FAT AND
BODY FAT STORES
ARE LONG CHAIN IN LENGTH
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LONG CHAIN FATTY ACYL CoA
Mitochondrial
Membrane
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LONG CHAIN FATTY ACYL CoA
Mitochondrial
Membrane
CARNITINE
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LONG CHAIN FATTY ACYL CoA
Mitochondrial
Membrane
CARNITINE
LONG CHAIN FATTY ACYL CoA
CARNITINE
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
CARNITINE
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
LONG CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
NEW KETONE BODY
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
LONG CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
NEW KETONE BODY
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Mitochondrial
Membrane
LONG CHAIN FATTY ACYL CoA
LONG CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
MEDIUM CHAIN FATTY ACYL CoA
NEW KETONE BODY
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Mitochondrial
Membrane
MEDIUM CHAIN FATTY ACYL CoA
MEDIUM CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
MEDIUM CHAIN FATTY ACYL CoA
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Mitochondrial
Membrane
MEDIUM CHAIN FATTY ACYL CoA
MEDIUM CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
SHORT CHAIN FATTY ACYL CoA
SHORT CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
SHORT CHAIN FATTY ACYL CoA
SHORT CHAIN �-OXIDATION
ENZYMES
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Mitochondrial
Membrane
SHORT CHAIN FATTY ACYL CoA
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MEDIUM CHAIN FATTY ACYL CoA
Mitochondrial
Membrane
CARNITINE
MEDIUM CHAIN FATTY ACYL CoA
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Mitochondrial
Membrane
MEDIUM CHAIN FATTY ACYL CoA
MEDIUM CHAIN �-OXIDATION
ENZYMES
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Medium Chain Triglycerides
• MCT does not require carnitine, often deficient in any sick person, to be transported into the liver.
• MCT does not require oxidation by those enzymes that break down long chain fat; it bypasses them, and is broken down to form ketones using other, working enzymes.
• Important for long chain fatty acid defects
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TR’s Story (continued…)
• TR continued to avoid prolonged fasting and watched her fat intake but stopped taking daily MCT supplement.
• Complained of muscle cramping after exercising, increased muscle fatigue, jaw cramping in the morning.
• CPK levels ran 4000-5000 (normal<300).• Once MCT supplementation restarted,
symptoms diminished significantly, and CPK levels normalized.
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CLINICAL APPLICATIONS
• Fasting avoidance is the cornerstone of therapy
• Is fat restriction necessary? • Medium chain fat supplementation (in long
chain fatty acid oxidation disorders).• The role of carnitine.
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The Role of Carnitine
• Carnitine binds to the fatty acid oxidation intermediate molecules and facilitates their excretion for the body.
• Its benefit during periods of health are unclear; often levels are normal at these times. Deficiencies should be corrected.
• The benefit is more obvious when the patient is sick and producing large amounts of fatty acid intermediates.
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Potentially ToxicLONG CHAIN
FATTY ACYL CoA
CARNITINE
LONG CHAIN FATTY
ACYLCARNITINE
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CLINICAL APPLICATIONS
• Fasting avoidance is the cornerstone of therapy
• Is fat restriction necessary? • Medium chain fat supplementation (in long
chain fatty acid oxidation disorders).• The role of carnitine.• Glucose monitoring.
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Free
Fat
ty A
cids
, Ket
ones
,mM
Hours of Fasting
Glu
cose
, mg/
dL
8 12 16 20 24 28 32
20
40
60
80
100
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Glucose
Ketones
Stanley et al, 1990
Free Fatty Acids
MCAD Deficiency
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Glucose Monitoring
• Problem: Lethargy and coma can occur in the absence of a low blood sugar.
• Glucometer readings (if not hypoglycemic) may offer a false sense of security.
• The patient should be evaluated and treated if symptoms of concern are present whether or not hypoglycemia is present.
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CLINICAL APPLICATIONS
• Fasting avoidance is the cornerstone of therapy
• Is fat restriction necessary? • Medium chain fat supplementation (in long
chain fatty acid oxidation disorders).• The role of carnitine.• Glucose monitoring.• When sick, give 10% dextrose at >1.25
maintenance rate.
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Why 10% Dextrose When Sick?
• “Catabolism”, including glycogen breakdown, and eventually gluconeogenesis and fatty acid oxidation, occurs when the amount of dietary or IV glucose falls below the basal glucose production rate in liver.
• Bier et al, 1977, determined this rate: y=0.0014 x3 – 0.214 x2 + 10.411 x – 9.084y=glucose production rate (mg/min) x=body weight (kg)
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Example: 10 kg child
• y=0.0014 x3 – 0.214 x2 + 10.411 x – 9.084y=glucose production rate (mg/min) x=body weight (kg)
• Basal glucose production rate = 75.03 mg/min of glucose (or 7.5 mg/kg/min)
• 10% dextrose at maintenance provides 70 mg/min (or 7.0 mg/kg/min)
• 10% dextrose at 1.25 maintenance provides 87 mg/min (or 8.7 mg/kg/min)
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PREVENTIONis the best approach
Newborn screening….• Allows pre-symptomatic monitoring.• Allows early intervention when
symptoms arise.• Allows prevention of complications that
occur during metabolic crises.
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NEWBORN SCREENING
• PRO:– Allows prevention of serious morbidity
and mortality
• CON:– In some identified patients, it is difficult to
prove whether or not they have clinically-significant disease.
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Approach to Confirming a Diagnosis
• Blood and urine testing (especially when sick)
• Skin fibroblast fatty acid oxidation testing
• Skin fibroblast enzyme testing• ?Liver enzyme testing• DNA testing
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Approach to Confirming a Diagnosis
• Monitored fasting study, to evaluate the patient’s physiologic response to fasting
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Approach to Confirming a Diagnosis
• Monitored fasting study –– Admit when healthy.– Fast for a prolonged period of time.– Monitor the physiologic response to
fasting (e.g., fatty acids, ketones).– Monitor glucose.– When glucose drops or patient’s mental
status changes – draw final tests, then administer glucose and allow to eat.
– Allows a “bottom-line” conclusion.
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DG’s Story
• Well until 7 months of age; developed viral illness.
• Became lethargic, seen by pediatrician who diagnosed hypoglycemia with inappropriately low ketones in the urine.
• Urine sent for organic acid analysis: showed inappropriately low ketones and pattern suggestive of medium chain ketoacyl CoAthiolase deficiency.
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DG’s Story (continued…)
• Repeat blood and urine tests not informative.• Skin biopsy did not show an abnormality in
oxidation.• The parents consented to a fasting study to
evaluate DG’s physiologic response to fasting; she was 26 months old.
• At 17 hours of fasting, glucose dropped <50 mg/dL. “Critical specimens” obtained.
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DG’s Story (continued…)
• DG showed a normal free fatty acid and ketone response.
• Other testing (acylcarnitines, acylglycines) all normal.
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< sigh >
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THERE’S SO MUCH MORE TO LEARN.
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Thanks for listening.
Now go eat something.