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Red Flags Part II

Part of Weitzman Webinar 2021 Genetics Series

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Red Flags Part II

  1. 1. Lab Testing in Metabolic Disease: Spotting the Red Flags, Part II Mark Korson, MD VMP Genetics, LLC
  2. 2. Disclosures MARK KORSON does not have anything to disclose.
  3. 3. 1. Review how simple biochemical tests indicate important pathophysiologic scenarios. 2. Describe patterns of routine biochemical testing that can increase suspicion about an underlying metabolic disease 3. Recognize the uncommon physiological significance of certain chemistry tests OBJECTIVES © Copyright 2020. VMP Genetics. All rights reserved
  4. 4. © Copyright 2019 VMP Genetics. All rights reserved Urinalysis - blood
  5. 5. An otherwise healthy athletic teenager complains of his muscles aching after football work-outs. He says that his arms and shoulders feel less strong than they did during last year’s season. After one strenuous practice (a lot of tackling), he develops intense pain in his shoulders and upper arms and thighs. CASE #1
  6. 6. Two hours later, he voids a painless “bloody” urine. Upon direct questioning, the color is more cola-colored than red blood. A urinalysis shows large blood and protein. Case 1
  7. 7. • Think RENAL BLOOD ON A URINALYSIS © Copyright 2020. VMP Genetics. All rights reserved U/A – blood Micro - RBCs
  8. 8. • Think RENAL BLOOD ON A URINALYSIS U/A – blood Micro - RBCs U/A – blood Micro – no RBCs Think… A. Heart B. Muscle C. Liver D. Bladder © Copyright 2020. VMP Genetics. All rights reserved
  9. 9. • Think RENAL BLOOD ON A URINALYSIS U/A – blood Micro - RBCs U/A – blood Micro – no RBCs Think… A. Heart B. Muscle C. Liver D. Bladder © Copyright 2020. VMP Genetics. All rights reserved
  10. 10. Two hours later, he voids a painless “bloody” urine. Upon direct questioning, the color is more cola-colored than red blood. A urinalysis shows large blood and protein. Diagnosis – carnitine palmitoyltransferase (CPT) II deficiency, a defect in fatty acid oxidation Case 1
  11. 11. CARNITINE PALMITOYLTRANSFERASE (CPT) II DEF’Y • Muscles convert fat to energy during prolonged exercise Physiology © Copyright 2020. VMP Genetics. All rights reserved • With exercise: • Muscle pain, weakness • Myoglobinuria • Cardiomyopathy Symptoms
  12. 12. SUMMARY POINT • Blood on a dipstick should be confirmed by checking for RBCs in a microscopic examination • If none are seen, it is not “blood” • Think myoglobin, not hemoglobin © Copyright 2020. VMP Genetics. All rights reserved
  13. 13. © Copyright 2019 VMP Genetics. All rights reserved Transaminases (AST, ALT)
  14. 14. Lab tests: • CBC: Hgb=13.3, WBC=10.5, Plts=238 • Lytes: Na=139, K=4.5, Cl=92, HCO3=29 • BUN=10.6, creatinine=8.8 • AST=4580 (NL=5-40), ALT=1200 (NL=5-40) • Bilirubin: Total=0.9, direct=0.1 • Alkaline phosphatase=140 (NL=44-147) Cairns AP, et al.Nephrol Dial Transpl.2000.
  15. 15. Lab tests: • CBC: Hgb=13.3, WBC=10.5, Plts=238 • Lytes: Na=139, K=4.5, Cl=92, HCO3=29 • BUN=10.6, creatinine=8.8 • AST=4580 (NL=5-40), ALT=1200 (NL=5-40) • Bilirubin: Total=0.9, direct=0.1 • Alkaline phosphatase=140 (NL=44-147) Cairns AP, et al.Nephrol Dial Transpl.2000. Based on these lab data, which organ system worries you the most? A. Liver B. Kidneys C. Bone D. Heart E. Muscle
  16. 16. Lab tests: • CBC: Hgb=13.3, WBC=10.5, Plts=238 • Lytes: Na=139, K=4.5, Cl=92, HCO3=29 • BUN=10.6, creatinine=8.8 • AST=4580 (NL=5-40), ALT=1200 (NL=5-40) • Bilirubin: Total=0.9, direct=0.1 • Alkaline phosphatase=140 (NL=44-147) Cairns AP, et al.Nephrol Dial Transpl.2000. Based on these lab data, which organ system worries you the most? A. Liver? B. Kidneys C. Bone D. Heart E. Muscle
  17. 17. A 41 year old man experiences dark urine for three days, associated with extreme fatigue, pain and heaviness in his legs. The symptoms were triggered after a significant amount of heavy work while moving house the previous week. There is a history of similar symptoms following moderate exercise during the previous 20 years. CASE #2 Cairns AP, et al.Nephrol Dial Transpl.2000.
  18. 18. Past medical history significant for two acute episodes of gout. On no medications. Ex-smoker (5 years). Drank ~10 units of alcohol per week. Examination: • HR=80/min, BP=160/82 • Normal muscle tone, power. Normal sensation. Normal reflexes. Cairns AP, et al.Nephrol Dial Transpl.2000. Case 2
  19. 19. Lab tests: • CBC: Hgb=13.3, WBC=10.5, Plts=238 • Lytes: Na=139, K=4.5, Cl=92, HCO3=29 • BUN=10.6, creatinine=8.8 • AST=4580 (NL=5-40), ALT=1200 (NL=5-40) • Bilirubin: Total=0.9, direct=0.1 • Alkaline phosphatase=140 (NL=44-147) Cairns AP, et al.Nephrol Dial Transpl.2000. Case 2
  20. 20. Lab tests: • CBC: Hgb=13.3, WBC=10.5, Plts=238 • Lytes: Na=139, K=4.5, Cl=92, HCO3=29 • BUN=10.6, creatinine=8.8 • AST=4580 (NL=5-40), ALT=1200 (NL=5-40) • Bilirubin: Total=0.9, direct=0.1 • Alkaline phosphatase=140 (NL=44-147) • CK=600 (NL=25-180) • Aldolase=22.2 (NL=1.2-7.6) Cairns AP, et al.Nephrol Dial Transpl.2000. Case 2
  21. 21. Diagnosis: • Very long chain acyl CoA dehydrogenase (VLCAD) deficiency Cairns AP, et al.Nephrol Dial Transpl.2000. Case 2
  22. 22. VERY LONG CHAIN ACYL CoA DEHYDROGENASE (VLCAD) DEF’Y • A defect in fatty acid oxidation (conversion of fat to ketones) VLCAD def’y © Copyright 2020. VMP Genetics. All rights reserved • The liver converts fat to ketones during fasting or poor calorie intake • Muscles convert fat to energy during prolonged exercise Physiology
  23. 23. VERY LONG CHAIN ACYL CoA DEHYDROGENASE (VLCAD) DEF’Y • Reduced fasting tolerance • Hypoglycemia, altered mental status with prolonged fasting/poor fat intake • With exercise: • Muscle pain, weakness • Myoglobinuria • Cardiomyopathy Symptoms © Copyright 2020. VMP Genetics. All rights reserved
  24. 24. TRANSAMINASES • Indicators of hepatocyte integrity • If abNL, may reflect hepatoxicity • Abnormal in many (metabolic) diseases Significance © Copyright 2020. VMP Genetics. All rights reserved
  25. 25. TRANSAMINASES • Indicators of hepatocyte integrity • If abNL, may reflect hepatoxicity • Abnormal in many (metabolic) diseases Significance • Concentrated in the liver but are also found in: • Skeletal muscle • Myocardium • Kidney Not necessarily liver-specific © Copyright 2020. VMP Genetics. All rights reserved
  26. 26. A neonate is admitted to the NICU on day 3 of life in severe congestive heart failure. On examination, he is non-dysmorphic and lethargic. Weight=2.2 kg. Echocardiogram identifies a dilated cardiomyopathy with an ejection fraction of 20%. CASE #3 Courtesy SIMD-NAMA 2019
  27. 27. Lab findings: • Venous gas: pH=7.2, HCO3=17 • Glucose=25 • AST=230, ALT=200 • CK>500 Metabolic testing – VLCAD deficiency (a defect in long chain fatty acid oxidation) Courtesy SIMD-NAMA 2019 Case 3
  28. 28. A newborn is born at term to consanguineous parents. Apgar score: 91 and 105. Weight=2.93 kg. On day 2, he developed lethargy and apathy. Katz.MolecGeneticsMetabolism.2017 Lab findings: • Glucose=normal • AST=240, ALT=58 • CK=13,445 CASE #4
  29. 29. He later developed left ventricular hypertrophy and a pericardial effusion. Metabolic testing – VLCAD deficiency Katz.MolecGeneticsMetabolism.2017 Case 4
  30. 30. SUMMARY POINT • When AST and ALT are high, look carefully at other markers of liver disease. • If AST and ALT are the only ones elevated, and/or if there are concerns about muscle symptoms, order a CK © Copyright 2020. VMP Genetics. All rights reserved
  31. 31. © Copyright 2019 VMP Genetics. All rights reserved Bilirubin
  32. 32. CASE #5 A female is born to consanguineous parents (first cousins) at term following an unremarkable pregnancy. Normal Apgar scores. Birth weight=3300 gm. Develops jaundice on day 2 and starts having feeding problems. Admitted to hospital on day 3 because of fever and jaundice. On examination, she is lethargic and has a weak suck. Kundak.Turk J Hemat.2012
  33. 33. Lab tests: • CBC: Hgb=15.7, WBC=10.3, Plts=233 • Electrolytes: Na=147, K=4.5 • Total bilirubin=15.6, direct=1.0 • AST=1367, ALT=504 Kundak.Turk J Hemat.2012 Case 5
  34. 34. Lab tests: • CBC: Hgb=15.7, WBC=10.3, Plts=233 • Electrolytes: Na=147, K=4.5 • Total bilirubin=15.6, direct=1.0 • AST=1367, ALT=504 Kundak.Turk J Hemat.2012 Case 5 Based on the nature of the hyperbilirubinemia, this baby is not likely to have galactosemia. A. True B. False
  35. 35. Lab tests: • CBC: Hgb=15.7, WBC=10.3, Plts=233 • Electrolytes: Na=147, K=4.5 • Total bilirubin=15.6, direct=1.0 • AST=1367, ALT=504 Kundak.Turk J Hemat.2012 Case 5 Based on the nature of the hyperbilirubinemia, this baby is not likely to have galactosemia. A. True B. False
  36. 36. …causes a direct hyperbilirubinemia” “Metabolic liver disease… ASSESSMENT OF LIVER DISEASE / DYSFUNCTION
  37. 37. • …causes a direct hyperbilirubinemia” “Metabolic liver disease… ASSESSMENT OF LIVER DISEASE / DYSFUNCTION • True but it starts as an unconjugated hyperbilirubinemia © Copyright 2020. VMP Genetics. All rights reserved
  38. 38. Age (days of life) Direct/ Total Bilirubin Ratio 0 4 102 8 0.2 0.4 0.6 0.8 1.0 Galactosemia: Direct / Total Bilirubin (n=27)
  39. 39. Lab tests: • CBC: Hgb=15.7, WBC=10.3, Plts=233 • Electrolytes: Na=147, K=4.5 • Total bilirubin=15.6, direct=1.0 • AST=1367, ALT=504 • Urine reducing substances positive Confirmation – Galactose-1-phosphate uridyltransferase low Diagnosis - galactosemia Kundak.Turk J Hemat.2012 Case 5
  40. 40. SUMMARY POINT • Don’t rule out a metabolic disease just because the patient presents with primarily an unconjugated hyperbilirubinemia… © Copyright 2020. VMP Genetics. All rights reserved
  41. 41. GALACTOSEMIA • A defect in metabolizing galactose, a component of milk sugar (lactose) GALT def’y © Copyright 2020. VMP Genetics. All rights reserved • Poor feeding, failure to thrive • Liver disease  failure • Cataracts • Sepsis risk in the newborn period Symptoms
  42. 42. There is a concern for a diagnosis of galactosemia. Cow’s milk feedings are held. Which ONE of the following actions would be your next move? A. Molecular DNA testing to confirm the diagnosis B. Complete sepsis work-up C. Eye examination for cataracts D. Assess for coagulopathy CASE #6 © Copyright 2020. VMP Genetics. All rights reserved
  43. 43. There is a concern for a diagnosis of galactosemia. Cow’s milk feedings are held. Which ONE of the following actions would be your next move? A. Molecular DNA testing to confirm the diagnosis B. Complete sepsis work-up C. Eye examination for cataracts D. Assess for coagulopathy © Copyright 2020. VMP Genetics. All rights reserved Case 6
  44. 44. Lab tests: • CBC: Hgb=15.7, WBC=10.3, Plts=233 • Electrolytes: Na=147, K=4.5 • Total bilirubin=15.6, direct=1.0 • AST=1367, ALT=504 • Urine reducing substances positive • PT>60 sec; INR>6; aPTT=88 sec Diagnosis – classical galactosemia Kundak.Turk J Hemat.2012 Case 6
  45. 45. COAGULATION MEASUREMENTS • An important indicator of hepatic synthetic function Significance • Transaminase and bilirubin levels do not predict and do not correlate with PT, INR, PTT Caution! © Copyright 2020. VMP Genetics. All rights reserved
  46. 46. A male infant presents with lethargy. His belly is distended due to ascites and his liver edge is irregular and firm at 5 cm below the right costal margin. • AST=65 • Bilirubin: total=2.1, direct=0.99 • PT=26.8 sec, INR=61.1 sec Case #7 - TYROSINEMIA TYPE I Rashad.SudJPediatr.2011
  47. 47. REMINDER • When assessing a patient for possible metabolic liver disease, always assess all aspects of liver function. © Copyright 2020. VMP Genetics. All rights reserved
  48. 48. • AST, ALT • Alkaline phosphatase (5’-nucleotidase and GGTP) • Bilirubin, total and direct • PT, INR, PTT • Albumin Tests ASSESSMENT OF LIVER DISEASE / DYSFUNCTION © Copyright 2020. VMP Genetics. All rights reserved
  49. 49. • AST, ALT • Alkaline phosphatase (5’-nucleotidase and GGTP) • Bilirubin, total and direct • PT, INR, PTT • Albumin • ⍺-fetoprotein • Glucose, NH3 Tests ASSESSMENT OF LIVER DISEASE / DYSFUNCTION © Copyright 2020. VMP Genetics. All rights reserved
  50. 50. © Copyright 2019 VMP Genetics. All rights reserved The anion gap (electrolytes) Urinalysis - pH
  51. 51. What is the most common cause of a metabolic acidosis? © Copyright 2020. VMP Genetics. All rights reserved
  52. 52. PRIMARY METABOLIC ACIDOSIS INCREASED ANION GAP NORMAL ANION GAP - GI disease © Copyright 2020. VMP Genetics. All rights reserved
  53. 53. PRIMARY METABOLIC ACIDOSIS INCREASED ANION GAP NORMAL ANION GAP - GI disease - Renal disease - Metabolic disease © Copyright 2020. VMP Genetics. All rights reserved
  54. 54. PRIMARY METABOLIC ACIDOSIS INCREASED ANION GAP NORMAL ANION GAP - GI disease - Renal disease - Metabolic disease - Shock, dehydration - Starvation - Poisons, toxins - Metabolic disease © Copyright 2020. VMP Genetics. All rights reserved
  55. 55. PRIMARY METABOLIC ACIDOSIS INCREASED ANION GAPINCREASED ANION GAP - Shock, dehydration - Starvation - Poisons, toxins - Metabolic disease ORGANIC ACIDEMIAS CONGENITAL LACTIC ACIDEMIAS © Copyright 2020. VMP Genetics. All rights reserved
  56. 56. PRIMARY METABOLIC ACIDOSIS NORMAL ANION GAP - GI disease - Renal disease - Metabolic disease METABOLIC LIVER DISEASE MITOCHONDRIAL DISEASE CYSTINOSIS © Copyright 2020. VMP Genetics. All rights reserved
  57. 57. THE “ANION GAP” There is no “anion gap” really… © Copyright 2020. VMP Genetics. All rights reserved
  58. 58. THE ANION GAP • Difference between measured anions and cations in the blood Definition Calculation • Anion gap = Na - (Cl + HCO3) • Anion gap = 140 - (105 + 25) • Anion gap = 10 • Normal anion gap = 10-15 © Copyright 2020. VMP Genetics. All rights reserved
  59. 59. THE NON-ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (115 + 10) Anion gap = 15 HIGH NORMAL LOW  Bicarbonate loss (urine or stool) © Copyright 2020. VMP Genetics. All rights reserved
  60. 60. THE ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 10) Anion gap = 25 NORMAL HIGH LOW  Anion accumulation © Copyright 2020. VMP Genetics. All rights reserved
  61. 61. THE ANION GAP ACIDOSIS Anion gap = Na - (Cl + HCO3) Anion gap = 140 - (105 + 10) Anion gap = 25  Anion accumulation (lactate, ketones, organic acids, toxins…) NORMAL HIGH LOW © Copyright 2020. VMP Genetics. All rights reserved
  62. 62. A 6 month old infant male, product of a healthy pregnancy/labor/delivery, is found to have a distended belly at 3 months. By that time, he has lost 1 kg of weight and is failing to thrive. He continues to feed every 3-4 hours day and night. At 5 months of age, the liver is noted to be enlarged. He is evaluated in the ED shortly after that for fever and upper respiratory symptoms. He presents to the ED, looking ill. Last feeding ~3 hours prior to arrival. CASE #8 © Copyright 2020. VMP Genetics. All rights reserved
  63. 63. Lab tests: • Glucose=39 mg/dL • Electrolytes: Na=141, K=3.7, Cl=112, HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 © Copyright 2020. VMP Genetics. All rights reserved Case 8
  64. 64. Lab tests: • Glucose=39 mg/dL • Electrolytes: Na=141, K=3.7, Cl=112, HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 © Copyright 2020. VMP Genetics. All rights reserved Anion gap = 14 (NL) Case 8
  65. 65. Lab tests: • Glucose=39 mg/dL • Electrolytes: Na=141, K=3.7, Cl=112, HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Eyes D. Heart E. Muscle © Copyright 2020. VMP Genetics. All rights reserved Case 8
  66. 66. Lab tests: • Glucose=39 mg/dL • Electrolytes: Na=141, K=3.7, Cl=112, HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Eyes D. Heart E. Muscle © Copyright 2020. VMP Genetics. All rights reserved Case 8
  67. 67. Lab tests: • Glucose=39 mg/dL • Electrolytes: Na=141, K=3.7, Cl=112, HCO3=15 • ALT=118, AST=274 • Other liver functions normal • Lactate=3.6 mmol/L (NL<2.2) • Urinalysis: pH=6.5 Diagnosis – glycogen storage disease type I Based on these clinical/lab data, this patient has liver disease. Which other organ are you worried about? A. Brain B. Kidneys C. Eyes D. Heart E. Muscle © Copyright 2020. VMP Genetics. All rights reserved Case 8
  68. 68. © Copyright 2019 VMP Genetics. All rights reserved Glucose + Ketones
  69. 69. Three glucose-ketone scenarios: A. The septic newborn: • Blood glucose=32 mg/dL • Urine ketones=trace B. The 3 month old child with gastroenteritis and dehydration: • Blood glucose=40 mg/dL • Urine ketones=1+ C. The septic newborn: • Blood glucose=32 mg/dL • Urine ketones=4+ CASE #9 © Copyright 2020. VMP Genetics. All rights reserved All are abnormal clinical situations but which of the glucose-ketone relationships are pathological? A. A, B, C B. A, B C. B, C D. A, C E. A
  70. 70. HYPOKETOTIC HYPOGLYCEMIA © Copyright 2020. VMP Genetics. All rights reserved
  71. 71. HYPOKETOTIC HYPOGLYCEMIA HIGH Insulin State LOW Insulin State © Copyright 2020. VMP Genetics. All rights reserved
  72. 72. HYPOKETOTIC HYPOGLYCEMIA HIGH Insulin State FAT FATTY ACIDS KETONES © Copyright 2020. VMP Genetics. All rights reserved
  73. 73. HYPOKETOTIC HYPOGLYCEMIA HIGH Insulin State • Insulin tumor • Infant of DM mother • Beckwith-Wiedemann syndrome • Iatrogenic © Copyright 2020. VMP Genetics. All rights reserved
  74. 74. HYPOKETOTIC HYPOGLYCEMIA FAT FATTY ACIDS KETONES LOW Insulin State © Copyright 2020. VMP Genetics. All rights reserved
  75. 75. HYPOKETOTIC HYPOGLYCEMIA LOW Insulin State • Fatty acid oxidation defects • Glycogen storage disease type I © Copyright 2020. VMP Genetics. All rights reserved
  76. 76. • Immaturity in fatty acid oxidation  reduced production • Rapid metabolic rates  increased consumption/uptake • …hypoketotic hypoglycemia is normal In neonates… WHAT’S THE STORY WITH NEONATAL KETOGENESIS? © Copyright 2020. VMP Genetics. All rights reserved
  77. 77. • Hypoketosis is normal • Significant ketosis is not normal • Absent or inadequate ketosis is never normal in a very catabolic or hypoglycemic child In neonates… KETONES – “THE RULES” Beyond 2-3 months of age… © Copyright 2020. VMP Genetics. All rights reserved
  78. 78. Three glucose-ketone scenarios: A. The septic newborn: • Blood glucose=32 mg/dL • Urine ketones=trace B. The 3 month old child with gastroenteritis and dehydration: • Blood glucose=40 mg/dL • Urine ketones=1+ C. The septic newborn: • Blood glucose=32 mg/dL • Urine ketones=4+ CASE #9 © Copyright 2020. VMP Genetics. All rights reserved All are abnormal clinical situations but which of the glucose-ketone relationships are pathological? A. A, B, C B. A, B C. B, C D. A, C E. A
  79. 79. Three glucose-ketone scenarios: A. The septic newborn: • Blood glucose=32 mg/dL • Urine ketones=trace B. The 3 month old child with gastroenteritis and dehydration: • Blood glucose=40 mg/dL • Urine ketones=1+ C. The septic newborn: • Blood glucose=32 mg/dL • Urine ketones=4+ CASE #9 © Copyright 2020. VMP Genetics. All rights reserved All are abnormal clinical situations but which of the glucose-ketone relationships are pathological? A. A, B, C B. A, B C. B, C D. A, C E. A
  80. 80. Questions? Call Genetics! We like answering your questions! THANK YOU FOR PARTICIPATING TODAY.

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