eric niederhoffer siu-som making basic science clinically relevant for learners: the biochemistry...
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Eric Niederhoffer
SIU-SOM
Making basic science clinically relevant for learners: the
biochemistry example
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Considerations• Wants and needs
Curriculum design, objectives, goals; USMLE
• Biochemistry as a foreign languageWeb lessons, resource pages, animations
• Resource sessionsComplement self-directed learningApplied to patient caseStart simple, discuss difficultBig picture, relevant detailsOverlap and redundancyBuild upon previous knowledge
• Clinical probes for content and conceptsSelf-assessment questions, examinations
• Glucose metabolism as an example
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RBC Structure - size, spectrin, channels
Metabolism - glycolysis (2,3-BPG), pentose phosphate pathway (G6PDH, NADPH), glutathione
Hemoglobin - Genes, heme, Mb/Hb (normal), O2 binding, HbS (defect), fibers (sickling and inflammation)
Red Blood Cell BiochemistryA 4-year-old African boy presents with a 2-day history
of painful extremities.
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Red Blood Cell Biochemistry
Eric Niederhoffer
SIU-SOM
RBC Structure - size, spectrin, channels
Metabolism - glycolysis (2,3-BPG), pentosephosphate pathway (G6PDH, NADPH),
glutathione
Hemoglobin - Genes, heme, Mb/Hb (normal), O2 binding,HbS (defect), fibers (sickling and inflammation)
Devlin, T. M. (ed.). 2006. Textbook of biochemistry with clinical correlations, 6th ed. John Wiley & Sons, Inc., New York. This is very good for most of what you need.
Mehta, A. B., and A. V. Hoffbrand. 2000. Haematology at a glance, Blackwell Science, Malden, Mass.
Salway, J. G. 2006. Medical biochemistry at a glance, 2nd ed. Blackwell Science, Malden, Mass. This is very good for general principles and topics, and metabolic pathways and regulation. Good focused clinical correlations.
Students’ Notes
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RBC Metabolic Pathways
2,3-BPG
BPG mutase
2,3-BPG phosphatase
PPP
NADPH
6PG
3-7 C metabolites(R5P, F6P, G3P)
G6PDHlactonase6PGDH
CO2
NADP+ + H+
GSH
GSSGGR
GP
H2O2 H2O
Glc
Pyr
G6P
1,3-BPG
3PG
HK
PGI
PK
F6P
G3P
PFK
aldolaseF16BP
DHAP
2PG
PEP
PGK
PGM
enolase
G3PDH
Glycolysis
LactateNo O2
LDH
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RBC Metabolic Pathways
2,3-BPG
BPG mutase
2,3-BPG phosphatase
PPP
NADPH
6PG
3-7 C metabolites(R5P, F6P, G3P)
G6PDHlactonase6PGDH
CO2
NADP+ + H+
GSH
GSSGGR
GP
H2O2 H2O
Glc
Pyr
G6P
1,3-BPG
3PG
HK
PGI
PK
F6P
G3P
PFK
aldolaseF16BP
DHAP
2PG
PEP
PGK
PGM
enolase
G3PDH
Glycolysis
LactateNo O2
LDH
Glc: glucose HK: hexokinase G6P: glucose-6-phosphate G6PDH: glucose-6-phosphate dehydrogenase
PGI: phosphoglucose isomerase PFK: phosphofructokinase DHAP: dihydroxyacetonephosphate
BPG: bisphophoglycerate PEP: phosphoenolpyruvate Pyr: pyruvate PK: pyruvate kinase (2 genes, 4 isozymes)
NADP+/NADPH: nicotinamide adenine dinucleotide R5P: ribulose-5-phosphate F6P: fructose-6-phosphate
G3P: glyceraldehyde-3-phosphate GSH: reduced glutathione (GSH = Glu-Cys-Gly) GSSH: oxidized glutathione
LDH: lactate dehydrogenase PPP: pentose phosphate pathway 6PGDH: 6-phosphogluconate dehydrogenase
GR: glutathione reductase GP: glutathione peroxidase 3PG: 3-phosphoglycerate 6PG: 6-phosphogluconate
Defect in HK, PGI, aldolase, or BPG mutase/2,3-BPG phosphatase decreased [2,3-BPG]; defect in PK increased [2,3-BPG]
BPG mutase(or synthase)/2,3-BPG phosphatase is a bifunctional enzyme (one protein, two activities), regulated by hypoxia and T3
MIultiple inositol polyphosphate phosphatase acts on 2,3-BPG to give 2-PG
Fetal Hb - lower affinity for 2,3-BPG compared with adult Hb; 2,3-BPG binds to and stabilizes deoxyHb; it is easily displaced from oxyHb
Common deficiencies: G6PDH - X-linked PGI - autosomal recessive PK - autosomal recessive
Sodium fluoride inhibits enolase, used to preserve blood samples for glucose determinations.
Students’ Notes
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Hemoglobin Structure Changes
http://www.mfi.ku.dk/PPaulev/chapter8/images/8-3.jpg
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Factors Affecting Binding of O2
Depends on pH ([H+]), CO2, BPG (DPG), Temp
pH BPG or T ; right shift
pH BPG or T ; left shift
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Review Questions
• What metabolic pathways are used in erythrocytes?
• What clinical observations would you make concerning patients with SCD?
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Metabolism in Skeletal Muscle and Nervous Tissue
• Metabolism in skeletal muscle
• Pathways overview
• Regulation in skeletal muscle
• Metabolism in nervous tissue
• Pathways overview
• Clinical aspects
• Clinical aspects
• Clinical/laboratory findings
• GSD, PDHCD
• Glycogen storage disease type VII
• Pyruvate dehydrogenase complex deficiency
• Inborn errors of metabolism
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• Glycolysis
• Glycogenolysis
-oxidation (ketone bodies)
• Krebs (tricarboxylic acid) cycle
• Branched-chain amino acids
• Electron transport chain
• Calcium regulation
• Key enzyme regulation
Metabolism in Skeletal MuscleA 21-year-old woman comes to the physician with pain in her right mid-arm.
A 5-year-old boy is brought to the physician to have sutures removed.
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Pathways Overview
Acetyl-CoALactateNo O2
Production of ATP
G6P
GlucoseGlycolysis
Pyruvate
BCAAIle, Leu, Val
Krebscycle
ElectronTransport
Chain
GlycogenGlycogenolysis
Ca2+
PKa Ca2+
PDH
Ca2+
ISDH, KGDH
Fatty acids
-Oxidation
Ketone bodies
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Regulation in Skeletal MuscleGlc Glycolysis
GlycogenGlycogenolysis
PDH
PK
PFK-1
cAMP
Acetyl-CoAPyr
F6P
F16BP
PEP
G6PPKA
ACATP
EpAR
PiIMPAMP
Ca2+
PKa PP
Ca2+
PDHPPDHK
PDHP
PDH
NH4+
AMPPi
PFK-2
F26BP
ATPCitrate
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Metabolism in Nervous Tissue
• Glycolysis
• Glycogenolysis (stress)
-oxidation (ketone bodies)
• Krebs (tricarboxylic acid) cycle
• Branched-chain amino acids
• Electron transport chain
A 21-year-old woman comes to the physician with pain in her right mid-arm.A 19-year-old man is brought to the emergency department after a diving accident.
A 63-year-old woman is brought to the physician for her “parkinsonism.”
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Pathways Overview
Acetyl-CoA
Lactate(glial)
Production of ATP
Glycolysis
G6P
Glucose
Pyruvate
BCAAIle, Leu, Val
Krebscycle
ElectronTransport
Chain
Glycogen
Glycogenolysis
LactateNo O2
Fatty acids
-oxidation
Ketone bodies
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Clinical Aspects for Inborn Errors of Metabolism in Muscles
Toxic accumulation disorders
• Protein metabolism disorders (amino acidopathies, organic acidopathies, urea
cycle defects)
• Carbohydrate/intolerance disorders
• Lysosomal storage disorders
Energy production/utilization disorders
• Fatty acid oxidation defects
• Carbohydrate utilization, production disorders (glycogen storage,
gluconeogenesis, and glycogenolysis disorders)
• Mitochondrial disorders
• Peroxisomal disorders
• Metabolic acidosis (elevated anion gap)
• Hypoglycemia
• Hyperammonemia
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Clinical Aspects for Inborn Errors of Metabolism in Nervous Tissue
Evidence of familial coincidence
Progressive decline in nervous functioning
Appearance and progression of unmistakable neurologic signs
General symptoms
• State of consciousness, awareness, reaction to stimuli
• Tone of limbs, trunk (postural mechanisms)
• Certain motor automatisms
• Myotatic and cutaneous reflexes
• Spontaneous ocular movements, fixation, pursuit; visual function
• Respiration and circulation
• Appetite
• Seizures
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Clinical/Laboratory FindingsClinical findings AA OA UCD CD GSD FAD LSD PD MD
Episodic decompensation X + ++ + X + - - X
Poor feeding, vomiting, failure to thrive
X + ++ + X X + + +
Dysmorphic features and/or skeletal or organ malformations
X X - - X X + X X
Abnormal hair and/or dermatitis - X X - - - - - -
Cardiomegaly and/or arrhythmias - X - - X X + - X
Hepatosplenomegaly and/or splenomegaly
X + + + + + + X X
Developmental delay +/- neuroregression
+ + + X X X ++ + +
Lethargy or coma X ++ ++ + X ++ - - X
Seizures X X + X X X + + X
Hypotonia or hypertonia + + + + X + X + X
Ataxia - X + X - X X - -
Abnormal odor X + X - - - - - -
Laboratory Findings*
Primary metabolic acidosis X ++ + + X + - - X
Primary respiratory alkalosis - - + - - - - - -
Hyperammonemia X + ++ X - + - - X
Hypoglycemia X X - + X + - - X
Liver dysfunction X X X + X + X X X
Reducing substances X - - + - - - - -
Ketones A H A A L/A L A A H/A
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Glycogen Storage DiseasePyruvate Dehydrogenase Complex Deficiency
Krebscycle
G6P
Glucose
GlycolysisGlycogenGlycogenolysisGlycogenesis F6P
F16BPPFK
Tarui diseaseGlycogen Storage Disease Type VII
Acetyl-CoAPyruvatePDH
PDH complex deficiency
R5P nucleotides
Pentose Phosphate Pathway
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Glycogen Storage Disease Type VII (Tarui Disease)
Classic, infantile onset, Late onset
Exercise intolerance, fatigue, myoglobinuria
Phosphofructokinase• Tetramer of three subunits (M, L, P)
• Muscle/heart/brain - M4; liver/kidneys - L4; erythrocytes - M4, L4, ML3, M2L2, M3L
General symptoms of classic form• Muscle weakness, pronounced following exercise
• Fixed limb weakness
• Muscle contractures
• Jaundice
• Joint pain
Laboratory studies• Increased serum creatine kinase levels
• No increase in lactic acid levels after exercise
• Bilirubin levels may increase
• Increased reticulocyte count and reticulocyte distribution width
• Myoglobinuria after exercise
• Ischemic forearm test - no lactate increase with ammonia increase
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Neonatal, infantile, childhood onset
Abnormal lactate buildup (mitochondrial disease)
Pyruvate dehydrogenase complex
• E1 - (thiamine dependent) and subunits, 22 tetramer
• E2 - monomer (lipoate dependent)
• E3 - dimer (riboflavin dependent) common to KGDH and BCAKDH
• X protein - lipoate dependent
• Pyruvate dehydrogenase phosphatase
Nonspecific symptoms (especially with stress, illness, high carbohydrate intake)• Severe lethargy, poor feeding, tachypnea
• Key feature is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem (Leigh syndrome)
• Infants with less than 15% PDH activity generally die
Developmental nonspecific signs• Mental delays
• Psychomotor delays
• Growth retardation
Laboratory studies• High blood and cerebrospinal fluid lactate and pyruvate levels
• Elevated serum and urine alanine levels
• If E2 deficient, elevated serum AAs and hyperammonemia
• If E3 deficient, elevated BCAA in serum, KG in serum and urine
Pyruvate Dehydrogenase Complex Deficiency
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Inborn Errors of Metabolism
Carbohydrates (Glycogen storage diseases)
Amino acids (Maple syrup urine disease)
Organic acids (Alkaptonuria)
Mitochondrial function (Pyruvate dehydrogenase deficiency)
Purines and pyrimidines (Lesch-Nyhan disease)
Lipids (Familial hypercholesterolemia)
Porphyrins (Crigler-Najjar syndromes)
Metals (Hereditary hemochromatosis)
Peroxisomes (X-linked adrenoleukodystrophy)
Lysosomes (GM2 gangliosidoses - Tay Sachs disease)
Hormones (hyperthyroidism)
Blood (Sickle cell disease)
Connective tissue (Marfan syndrome)
Kidney (Alport syndrome)
Lung (1-antitrypsin deficiency)
Skin (Albinism)
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Review Questions• How does muscle produce ATP (carbohydrates, fatty
acids, ketone bodies, branched-chain amino acids)?• How is skeletal muscle phosphofructokinase-1 regulated?• What are the key Ca2+ regulated steps?• How does nervous tissue (neurons and glial cells)
produce ATP (carbohydrates, fatty acids, ketone bodies, branched-chain amino acids)?
• How do glial cells (astrocytes) assist neurons?• What are some key clinical features (history, physical,
laboratory test results) associated with defects in metabolism that affect muscles and nervous tissue?
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Carbohydrate Metabolism in Diabetes
• For the third example taken from the ERG Unit, what would you choose for the resource session?
A 59-year-old man is brought to the emergency department for evaluation of his semiconsciousness and minimal responsiveness
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Carbohydrate Metabolism in Diabetes
• Regulation of glycolysis, glycogenesis, glycogenolysis, gluconeogenesis by insulin/glucagonPFK-2 (PKA, AMP-dependent PK)PK (PKA)PDHGS (PKA, PPK, GSK-3, PP-1)GP (PKA, PPK, PP)PEPCK (glucagon)G6Pase (glucagon)
• Regulatory differences among tissuesLiverMuscleCardiac muscle
• Key clinical features (history, physical, laboratory test results) associated with carbohydrate metabolism that occur in diabetes
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Summary
• Remember curriculum wants and needs• Practice new language skills• Use resource sessions effectively
Complement self-directed learningApplied to patient caseStart simple, discuss difficultBig picture, relevant detailsOverlap and redundancyBuild upon previous knowledge
• Clinical probes for content and concepts