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Eric Niederhoffer SIU-SOM

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Eric Niederhoffer SIU-SOM

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    2. Alcoholic Ketoacidosis Ketone body processing overview Ketogenesis and ketone body utilization Clinical features

    3. Ketone Body Processing Overview TAG: triacylglycerol HSL: hormone sensitive lipase FA: fatty acid Ile: isoleucine Leu: leucine; prominent source Lys: lysine Phe: phenylalanine Trp: tryptophan Tyr: tyrosine AT: aminotransferase aKA: a-ketoacid Ketogenic amino acids: Ile, Leu, Lys, Phe, Trp, Tyr FA are bound to serum albumin and are transported through capillariesTAG: triacylglycerol HSL: hormone sensitive lipase FA: fatty acid Ile: isoleucine Leu: leucine; prominent source Lys: lysine Phe: phenylalanine Trp: tryptophan Tyr: tyrosine AT: aminotransferase aKA: a-ketoacid Ketogenic amino acids: Ile, Leu, Lys, Phe, Trp, Tyr FA are bound to serum albumin and are transported through capillaries

    4. Ketogenesis and Ketone Body Utilization TAG: triacylglycerol Acetyl CoA: acetyl coenzyme A Ile: isoleucine AACoAT: acetoacetyl coenzyme A thiolase AACoA: acetoacetyl coenzyme A Lys: lysine Trp: tryptophan HMGCoAS: 3-hydroxy-3-methylglutaryl coenzyme A synthase HMGCoA: 3-hydroxy-3-methylglutaryl coenzyme A Leu: leucine AA: acetoacetate Tyr: tyrosine Phe: phenylalanine 3HBDH: 3-hydroxybutyrate dehydrogenase 3HB: 3-hydroxybutyrate 3KACoAT: 3-ketoacyl coenzyme A transferase Inborn errors in HMGCoA synthase and HMGCoA lyase (increased [HMGCoA) Alcoholic ketoacidosis can result from abrupt halt in EtOH consumption leading to high 3HB:AA ratio (NADH is required). Clinical assay only looks for AA, so underestimates ketone bodies. ß-oxidation is inhibited by high [NADH]/[NAD+], so ketogenesis is most likely through ketogenic amino acids. Utilization of ketone bodies spares the muscle wasting associated with gluconeogenesis from muscle amino acids.TAG: triacylglycerol Acetyl CoA: acetyl coenzyme A Ile: isoleucine AACoAT: acetoacetyl coenzyme A thiolase AACoA: acetoacetyl coenzyme A Lys: lysine Trp: tryptophan HMGCoAS: 3-hydroxy-3-methylglutaryl coenzyme A synthase HMGCoA: 3-hydroxy-3-methylglutaryl coenzyme A Leu: leucine AA: acetoacetate Tyr: tyrosine Phe: phenylalanine 3HBDH: 3-hydroxybutyrate dehydrogenase 3HB: 3-hydroxybutyrate 3KACoAT: 3-ketoacyl coenzyme A transferase Inborn errors in HMGCoA synthase and HMGCoA lyase (increased [HMGCoA) Alcoholic ketoacidosis can result from abrupt halt in EtOH consumption leading to high 3HB:AA ratio (NADH is required). Clinical assay only looks for AA, so underestimates ketone bodies. ß-oxidation is inhibited by high [NADH]/[NAD+], so ketogenesis is most likely through ketogenic amino acids. Utilization of ketone bodies spares the muscle wasting associated with gluconeogenesis from muscle amino acids.

    5. Clinical Features (H&P) History (Typical symptoms reflect poor nutritional status from long-term alcohol abuse) Nausea, vomiting, and abdominal pain (each found in 60-75% of patients) Dyspnea, tremulousness, and/or dizziness (10-20% each) Muscle pain, diarrhea, syncope, and seizure (1-8% each) Physical examination Tachycardia, tachypnea, and/or abdominal tenderness (30-40% each) Hypotension, hypothermia, fever, abdominal distention, rebound tenderness, hepatomegaly, ascites, and/or heme-positive stools (1-15% each.)

    6. Clinical Features (Laboratory Studies) Arterial blood gas Look for MAC, may have mixed acid-base disorder (MAC from ketone formation, MAL from vomiting/volume depletion, RAL secondary to hyperventilation) Serum ketones Order specific test of 3HB (3HB/AA > 5) Glucose and electrolytes Low, normal, or high Glc (in DKA, Glc high) Elevated anion gap Elevated lactate Elevated BUN and creatinine Complete blood count Looking for anemia, intravascular volume depletion Liver and pancreatic function tests Total bilirubin, ALT, AST, LDH, AP, PA, PL Alcohol levels Patient may have decreased drinking; generally does not change approach MAC: metabolic acidosis MAL: metabolic alkalosis RAL: respiratory alkalosis 3HB: 3-hydroxybutyrate AA: acetoacetate Glc: glucose DKA: diabetic ketoacidosis BUN: blood urea nitrogen ALT: alanine aminotransferase AST: aspartate aminotransferase LDH: lactate dehydrogenase AP: alkaline phosphatase PA: pancreatic amylase PL: pancreatic lipaseMAC: metabolic acidosis MAL: metabolic alkalosis RAL: respiratory alkalosis 3HB: 3-hydroxybutyrate AA: acetoacetate Glc: glucose DKA: diabetic ketoacidosis BUN: blood urea nitrogen ALT: alanine aminotransferase AST: aspartate aminotransferase LDH: lactate dehydrogenase AP: alkaline phosphatase PA: pancreatic amylase PL: pancreatic lipase

    7. Review Questions What are ketone bodies? Which amino acids are ketogenic? How are ketone bodies generated (substrates, enzymes, pathways, location)? How are ketone bodies metabolized (enzymes, pathways, location)? What is the effect of NADH levels on ketone bodies? How does the metabolism of ketone bodies correlate with clinical findings?

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