1

Boards and Beyond: Biochemistry

1. Basic Pharmacology
2. Behavioral Science
3. Biochemistry
4. Biostatistics and Epidemiology
5. Cardiology
6. Cell Biology
7. Dermatology
8. Endocrinology
9. Gastroenterology
10. Genetics
11. Hematology
12. Immunology
13. Infectious Disease
14. Musculoskeletal
15. Neurology
16. Pathology
17. Psychiatry
18. Pulmonology
19. Renal
20. Reproductive
 2

- DNA
• Nucleotide: Base + Ribose Sugar + Phosphate
Cytidine, Thymidine, Uridine, Adenosine, Guanosine
Converted into triphosphate form before being incorporated into DNA
Human DNA is 70% methylated (silenced); methylation occurs on cytosine (CG islands)
• Nucleoside: base + Ribose Sugar
• Linked by 3,5-phosphodiester bond
• Histones:
High content of lysine, arginine (positively charges basic AAs; binds negative phosphate)
Core histones: H2A, H2B, H3, H4
Histone H1: Outside core; ties beads on string together
Anti-histone antibodies seen in drug-induced SLE
• Chromatin:
Heterochromatin: Condensed; non-transcribed; ↑ methylation
Euchromatin: Loose; transcriptionally active; ↑ histone acetylation
Deacetylation reverses the effect (densely packs chromatin; reduces transcription activity)

- Purine Synthesis
• Nitrogen Sources: Glutamine, Aspartate, Glycine
• Carbon Sources: CO2 + Tetrahydrofolate (single carbon donor)
• Step 1: Synthesize PRPP (derived from 5-ribose phosphate from HMP shunt)
• Step 2: Synthesize inosine monophosphate (IMP; contains hypoxanthine)
• Step 3: Synthesis of AMP + GMP
• Step 4: Ribonucleotide Reductase converts to deoxyribonucleotides (dADP + dGDP)

- Fate of Purines (adenine, guanine, xanthine)

• Degradation Free-floating purine bases
• Guanine and Hypoxanthine:
Both converted into
xanthine
Xanthine converted into uric acid by xanthine oxidase Excretion
• Adenine:
Adenine converts to adenosine Adenosine deaminase converts to inosine
Inosine converted to hypoxanthine Uric acid Excretion
SCID: Adenosine deaminase (ADA) deficiency
• Salvage Pathway: Reincorporates purine bases back into nucleotides
Requires PRPP to convert back into AMP, GMP, IMP
HGPRT: Enzyme required to convert hypoxanthine or guanine to IMP + GMP
APRT: Enzyme required to convert adenine to AMP

- Lesch-Nyhan Syndrome
• Secondary etiology of gout; juvenile gout
• X-linked recessive deletion of HGPRT (purine salvage pathway enzyme)
HGPRT normally converts hypoxanthine to IMP and guanine to
GMP
Loss of HGPRT Excess de novo purine synthesis (↑ PRPP, ↑ IMP) Hyperuricemia
• Findings:
Mentally retarded, self-mutilation, aggression, orange sand (sodium urate crystals) in diaper
Gout, dystonia, macrocytosis
 3

- 6-Mercaptopurine (6-MP)
• Purine analog; cancer therapy antimetabolite
• MOA:
Activated by hypoxanthine-guanine phosphoribosyltransferase (HGPRTase)
Added to PRPP (incorporates into DNA, because it is a structural analog of guanine)
Converted into toxic nucleotides Inhibits enzymes for purine synthesis
Reduces levels of IMP, AMP, GMP
• Clinical Uses:
AML, ALL, CML
Prevent organ rejection, RA, IBD, SLE
• Toxicity:
Myelosuppression, GI/hepatotoxicity (cholestasis, jaundice)
6-MP is metabolized by xanthine oxidase Inhibited by allopurinol/febuxostat
Levels of 6-MP boosted by allopurinol/febuxostat

- Azathioprine “Azathiopurine”
• MOA:
Prodrug that converts into 6-mercaptopurine (6-MP)
Inhibits lymphocyte proliferation by blocking purine nucleotide synthesis
• Uses: Autoimmune disease (RA, Crohn disease)
• Toxicity:
Pancytopenia (toxicity increased by xanthine oxidase inhibitors)
6-MP is metabolized by xanthine oxidase Inhibited by allopurinol/febuxostat

- Ribavirin
• Purine nucleoside analog; antiviral drug
• MOA: Competitively inhibits IMP dehydrogenase in viruses
Blocks conversion of IMP to GTP
Inhibits synthesis of guanine (purine)
Reduces levels of guanine for viral replication
Reduces intracellular pools of GTP
• Uses:
HCV (works well in combo with pegylated IFN-α)
Influenza, Parainfluenza, Arenavirus, RSV, HPV (condyloma acuminatum)
• Toxicity: Hemolytic anemia, teratogen

- Mycophenolate Mofetil
• MOA:
Reversibly inhibits IMP dehydrogenase in leukocytes
Inhibits de nova purine (GTP) synthesis of B/T cells Reduces DNA synthesis of
lymphocytes Adjunctive immunosuppressant actions Allows dose reductions of cyclosporine
• Uses: Lupus nephritis, organ transplants
• Toxicity:
GI distress, pancytopenia, HTN, hyperglycemia
Invasive CMV infection
 4

- Pyrimidine Synthesis
• Step 1: Synthesize carbamoyl phosphate via carbamoyl phosphate synthetase 2 (CPS2)
Glutamine and CO2 are reagents for the reaction
NOTE: CPS 1 is the RLS for urea cycle (unrelated!)
• Step 2: Synthesize orotic acid via addition of aspartate to carbamoyl phosphate
• Step 3: Synthesize UMP via UMP synthase (orotic acid + PRPP)
• Step 4: UMP converted to UDP
• Step 5: UDP converted to dUDP via ribonucleotide reductase
• Step 6: dUDP converted to dUMP
• Step 7: dUMP converted to dTMP via thymidylate synthase
Requires folate (N5, N10 Tetrahydrofolate)
Dietary folate DHF THF (via dihydrofolate reductase) N5, N10-THF

- Orotic Aciduria
• AR defect in UMP synthase; buildup of orotic acid Loss of pyrimidines
• Findings: Orotic acid in urine, megaloblastic anemia, growth retardation
SIMILAR to OTC deficiency; except it presents with hyperammonemia (encephalopathy)
• Treatment: Uridine (bypasses UMP synthase)

- Hydroxyurea
• Cancer antimetabolite
• MOA: Inhibits ribonucleotide reductase
Blocks formation of DNA (S-phase specific)
• Uses:
Myeloproliferative disorders (polycythemia vera, essential thrombocytosis)
Sickle cell anemia (↑ HbF)
• Toxicity: Severe myelosuppression, megaloblastic anemia

- Cytarabine
• Cancer antimetabolite; cytosine arabinoside (pyrimidine analog)
• MOA:
Activated (converted) to AraCTP
AraCTP inhibits DNA pol Inhibits DNA chain elongation DNA chain termination
• Uses: AML, ALL, CML
• Toxicity: Myelosuppression, megaloblastic anemia

- Fluorouracil (5-FU)
• Cancer antimetabolite (pyrimidine analog)
• MOA:
Activated (converted) to 5-FdUMP
Covalently complexes with thymidylate synthase and folate
Covalent complex inhibits thymidylate synthase “Thymineless death of cells”
Incorporation of FdUMP metabolite into DNA Inhibits DNA synthesis
Incorporation of FUTP metabolite into RNA Inhibits RNA processing
Leucovorin (folinic acid) enhance effects of 5-FU (extends half-life)
• Toxicity:
Myelosuppression, GI distress, alopecia
Palmar-plantar erythrodysesthesia (hand-foot syndrome)
 5

- Methotrexate
• Antimetabolite: Antagonist of folate; cytotoxic/immunosuppressant features
• MOA:
Competitively inhibits dihydrofolate reductase (DHFR)
Inhibits thymidylate synthase
Inhibits de nova purine synthesis
Polyglutamate derivative production Cytotoxic
• Uses: Cancers, ectopic pregnancy, RA, psoriasis, IBD, vasculitis
• Toxicity:
Myelosuppression (reversible with leucovorin rescue)
Hepatotoxicity, megaloblastic anemia, mucositis (mouth ulcers), pulmonary fibrosis
Teratogenic (folate deficiency NTD)

- Sulfonamide Antibiotics
• Sulfisoxazole, Sulfamethoxazole (SMX), Sulfadoxine
• Inhibit microbial enzymes involved in folate synthesis (folate is required for purine-synthesis)
• Weak Acid: Chemical nucleus resembles p-aminobenzoic acid (PABA)
• MOA: Competitive inhibitor of dihydropteroate synthase
PABA analog; acts as substrate for dihydropteroate synthase Produces nonfunctional
folate Selectively toxic for prokaryotes (eukaryotes cannot synthesize folate, only dietary)
 6

- Glucose Transporters
• Insulin-Independent Tissues:
GLUT-1: BBB (gets glucose into brain ECF), RBCs
GLUT-2 (Bidirectional; gluconeogenesis): Pancreatic ß-cells, liver, kidneys, intestines
GLUT-3: Neurons (glucose entry from ECF into neurons)
GLUT-5 (Fructose Transporter): Spermatocytes, GI tract
SGLT1 Na+-Glucose co-transporter: Enterocytes (small intestine)
SGLT2 (Na+-Glucose co-transporter: PCT
• Insulin-Dependent Tissues:
GLUT-4: Skeletal muscle, adipose
Exercise upregulates GLUT-4 (insulin-independent)

- Glucose Metabolic Pathways

• TCA Cycle, ETC Energy
• Pyruvate: Precursor for FAS Conversion to fats
• Lactate generation (anaerobic metabolism)
• HMP Shunt: Ribose, NADPH
• Glycogen storage

Red Arrow = Reversible

 7

- Oxidation of Glucose
• Aerobic: 30-32 ATP per glucose
Oxidation of Pyruvate = 12.5 ATP/ pyruvate (25/glucose)
Oxidation of NADH (Malate-Aspartate Shuttle) = 2.5 ATP/NADH (5/glucose)
Oxidation of NADH (G3P Shuttle) = 1.5 ATP/NADH (3/glucose)
• Anaerobic Oxidation of Glucose: 2 ATP per glucose

RLS of Glycolysis: Phosphofructokinase-1 (PFK-1)

Allosteric Activation (+) Allosteric Inhibition (-)
Low energy states; favors glycolysis High energy states; don’t need more ATP
AMP ATP
F-2,6-BP Citrate
 8

- Alanine Cycle
• Alanine inhibits pyruvate kinase (inhibits glycolysis)
• Alanine is the major byproduct of skeletal muscle breakdown via alanine transaminase (LFT)
Muscles degrade protein (ALT) Alanine enters blood Liver
Alanine inhibits pyruvate kinase (slows process of glycolysis)
↓ Liver glucose consumption Liver incorporates alanine into gluconeogenesis
Glucose sent to tissues that require energy

- Pyruvate Kinase Deficiency

• AR deficiency of pyruvate kinase
• Low ATP, rigid RBCs, extravascular hemolysis, burr cells (echinocytes)
• Increases levels of 2,3-BPG Lowers hemoglobin affinity for O2 (right-shift)
• Presentation: Hemolytic anemia with splenomegaly in newborn

- Gluconeogenesis
• Glucose Carbon Sources: Pyruvate, lactate, AAs, propionyl CoA (odd-chain FAs), glycerol
 9

- Gluconeogenesis and Glycolysis Balance

• ↑ ATP, ↑ Acetyl-CoA shuts down TCA cycle
Acetyl-CoA is an allosteric activator of pyruvate carboxylase (gluconeogenesis)
Pyruvate carboxylase has no activity unless there is ↑ acetyl-CoA

- Gluconeogenesis
• Mainly occurs in liver; maintains euglycemia during fasting
• Enzymes also present in kidneys and intestinal epithelium
• Gluconeogenesis is essentially the reverse pathway of glycolysis. However, it must use
special gluconeogenic enzymes to bypass the (3) irreversible steps of glycolysis:
1. Pyruvate carboxylase, PEPCK (phosphoenolpyruvate carboxykinase)
2. Fructose-1,6-bisphosphatase
3. Glucose-6-phosphatase

- Irreversible Step 1: Pyruvate Oxaloacetate Phosphoenolpyruvate

• Pyruvate Carboxylase: Activated by acetyl CoA; requires biotin, CO2, ATP; occurs in mitochondria
• PEPCK: Requires GTP; occurs in cytosol
 1

- Irreversible Step 2: Fructose 1,6 bisphosphate → Fructose 6 phosphate [RLS of gluconeogenesis]

• Fructose-1,6-bisphosphatase
Activation: ATP, Citrate
Inhibition: AMP, fructose-2,6-bisphosphate

- Irreversible Step 3: Glucose-6-Phosphate Glucose

• Glucose-6-phosphatase: Occurs in ER
 1

- Pyruvate Carboxylase Deficiency

• Very rare; presents with failure to thrive in infants
• HIGH pyruvate HIGH lactate Lactic acidosis

- Biotin (Vit B7)

• Cofactor for carboxylase enzymes; adds 1-carbon (transfers CO2 group)
• Deficiency: Long-term antibiotic use or overconsumption of raw eggs (avidin binds biotin)
Dermatitis, glossitis, enteritis, alopecia

- Glycogen Synthesis
• α1,4 glycosidic link: Straight polymer
• α1,6 glycosidic link: Branch-points of glycogen
• Steps:
1. Glucose-6P Glucose-1P
2. Glucose-1P UDP-glucose
3. UDP-glucose Unbranched glycogen (1,4)
4. Unbranched glycogen Branched glycogen (1,6)

- Glycogen Breakdown Enzymes

1. Glycogen Phosphorylase (stabilized by vitamin B6 pyridoxine)
Removes glucose molecules from glycogen polymer Glucose-1P
Stops when glycogen branches reduce to 2-4 linked glucoses (limit dextrans)
2. Debranching Enzyme: Cleaves limit dextrans
3. Glucose-6-Phosphatase: Converts to G-6P to glucose
4. α1,4-Glucosidase: Lysosomal enzyme; degrades glycogen into glucose
 12

- Glycogen Storage Disorders

• Rare, AR inborn errors of metabolism; defective glycogen breakdown Accumulation
• PAS Schiff Stain: Identifies glycogen (diagnostic tool)

- Von Gierke Disease (type 1)

• Enzyme Deficient: Glucose-6-phosphatase
• Accumulation: Liver
• Findings:
Severe fasting hypoglycemia in infants
Lethargy, seizures, lactic acidosis (↑ blood lactate due to Cori cycle)
Hepatomegaly (enlarged due to glycogen accumulation)
↑ TGs, ↑ uric acid (gout)
• Treatment: Frequent oral glucose; cornstarch between meals (glucose polymer)
Avoid sucrose, lactose, fructose, galactose

- Pompe Disease (type 2)

• Enzyme Deficient: Lysosomal acid α1,4-glucosidase (acid maltase)
• Accumulation: Lysosomes, muscle cells (ex. cardiac myocytes)
• Findings:
Cardiomegaly, hypertrophic cardiomyopathy (HCM), enlarged tongue
Hypotonia, muscle weakness, exercise intolerance, early death in infancy

- Cori Disease (type 3)

• Enzyme Deficient: Debranching enzyme
• Accumulation: Liver, muscle cells
• Findings:
Gluconeogenesis is still intact; mild fasting hypoglycemia
Similar to Von Gierke disease, but milder symptoms and normal blood lactate levels
Hepatomegaly, hypotonia, muscle weakness, cardiomyopathy risk

- McArdle Disease (type 5)

• Enzyme Deficient: Muscle glycogen phosphorylase (myophosphorylase)
• Findings:
Presents in adolescence or early adulthood
BGL unaffected (NO hypoglycemia)
Flat venous lactate curve with normal rise in ammonia levels during exercise
↑ Glycogen in muscle, but muscle cannot break it down Poor exercise endurance
Painful muscle cramps, myoglobinuria and ↑ CK with strenuous exercise, arrhythmias
Second-wind phenomenon during exercise (↑ blood flow to muscles)

- Hexose Monophosphate Shunt (Pentose Phosphate Pathway)

• Series of reactions that occur in cytosol; glucose-6P is shunted away from glycolysis
• Produces: NADPH, ribose-5P (nucleotide synthesis)
• NADPH: Used in reductive reactions
Cofactor in FAS, steroid synthesis
Phagocytosis (NADPH oxidase; ROS generation)
Protection from oxidative damage (RBC glutathione)
• Requires transketolase (transfers carbon unit; requires thiamine (B1) as cofactor)
 13

- Chronic Granulomatous Disease (CGD)

• NADPH oxidase deficiency (phagocyte oxidase)
• Deficient in the ability to produce ROS (superoxide)
↓ Respiratory burst in neutrophils Defective bacterial killing
Susceptible to intracellular/extracellular infection w/ granulomas
• Susceptible to infections of catalase (+) organisms
S. aureus, Pseudomonas, Serratia, Nocaria, Aspergillus fumigatis, Candida albicans
• Diagnosis:
Abnormal dihydrorhodamine (flow cytometry) test
Nitroblue tetrazolium dye reduction test Fails to turn blue (normally ROS makes it blue)

- Glucose-6-Phosphate Dehydrogenase Deficiency (G6PD)

• X-linked recessive hemolytic disorder
MC human enzyme disorder Deficiency of glutathione
Extravascular and intravascular hemolysis
• G6PD is involved in HMP-shunt Responsible for reducing NAPD to NADPH
NADPH reduces RBC glutathione Protection against RBC oxidative injury (ROS)
• Oxidant stress (ROS from infection (macrophages), drugs, fava beans
Protective against malaria infections
• Hemolysis in G6PD Deficiency:
Sulfa drugs, dapsone, antimalarial drugs (primaquine, quinidine), nitrofurantoin, INH
• Hemoglobin sulfhydryl cross-linking Protein denaturation
Recurrent hemolysis (dark urine) after exposure to trigger
Heinz Bodies: Precipitation of oxidized hemoglobin
Bite Cells: Phagocytic removal of RBCs by splenic macrophages
• Diagnosis: Fluorescent spot test (detects NADP generation)

- Thiamine (Vitamin B1) Deficiency

• Thiamine deficiency impairs glucose metabolism; low cell energy (wasting)
• Alcoholism is MCC of thiamine deficiency
Alcohol interferes conversion of thiamine to bioactive form
Alcohol reduces absorption of thiamine in gut brush border
Cirrhosis Inadequate hepatic storage for B1
• Wet Beriberi: Edema, ↓ TPR, ↑↑ CO, dilated cardiomyopathy
• Dry Beriberi: Muscle wasting, polyneuropathy
• Wernicke-Korsakoff Syndrome: BL mammillary body hemorrhage and necrosis
• Wernicke Encephalopathy:
Acute, reversible syndrome
Confusion, ophthalmoplegia, ataxia
• Korsakoff Psychosis:
Chronic, irreversible syndrome
Amnesia, confabulation (making up stories to fill in gaps of memory loss)
Irreversible memory loss, personality changes
• Thiamine Deficiency Treatment:
Most malnourished patients w/ B1 deficiency are also hypoglycemic Administer dextrose
Dextrose should NOT be administered BEFORE thiamine (give B1 first)
Must give thiamine first, because B1 is required for PDC If you administer dextrose first
then it will shunt to glycolysis Lactic acid production (exacerbates Wernicke-Korsakoff)
 14

- Carbohydrate GI Absorption
• SGLT-1: Glucose, Galactose
• GLUT-5: Fructose
• GLUT-2: Basolateral entry of all 3 monosaccharides into blood

- Fructose Metabolism
• MC acquired from sucrose (glucose + fructose)
• Fructose (Fructokinase) F-1P
• F-1P (Aldolase B) DHAP + Glyceraldehyde-3P Enters glycolysis
Faster metabolism than glucose/galactose due to bypass of PFK-1 (RLS of glycolysis)

- Essential Fructosuria
• Fructokinase (liver enzyme) deficiency
• Benign condition; fructose not taken up by hepatocytes Fructose spills into urine

- Hereditary Fructose Intolerance (HFI)

• Aldolase B deficiency; defective cleavage of F-1P into glycolytic intermediates
Buildup of F-1P in hepatocytes, depletion of ATP in liver
• Findings:
Hypoglycemia (defects in both glycogenolysis and gluconeogenesis)
Vomiting, diarrhea, hepatomegaly, hypoglycemia, renal tubular acidosis
Symptoms worsen after ingesting fructose (avoid fructose, sucrose, sorbitol)
• Presentation:
Baby just weaned from breast milk presents with failure to thrive; reducing sugars in urine
Hypoglycemia, seizures, hepatomegaly, liver failure

- Polyol Pathway
• Biochemical pathway from glucose to fructose
• Glucose (Aldose Reductase) Sorbitol
• Sorbitol (Sorbitol Dehydrogenase) Fructose

- Galactose Metabolism
• MC acquired from lactose (glucose + galactose)
• Galactose (Galactokinase) Galactose-1P
• Glucose-1P (Galactose 1-P Uridyltransferase) Glucose-6P

- Classic Galactosemia
• Galactose 1-phosphate uridyltransferase deficiency
• Findings: Symptoms begin when infant feeds (milk)
Accumulation of galactitol in lens (cataracts)
Failure to thrive, jaundice, hepatomegaly, intellectual disability
Predisposes to E. coli sepsis; must avoid lactose/galactose
 1

- Galactokinase Deficiency
• Milder form of galactosemia; galactose not taken up by cells
• Galactose accumulation in blood/urine Infantile cataracts
May present as failure to track objects on ophthalmic exam or to develop a social smile

- Pyruvate Dehydrogenase Complex (PDC)

• Mitochondrial enzyme; links glycolysis to TCA cycle; converts pyruvate into acetyl-CoA
• Activation: ↑ NAD+/NADH ratio, ↑ ADP, ↑ Ca2+
• 3 Enzymes:
1) E1: Pyruvate dehydrogenase
2) E2: Dihydrolipoyl transacetylase
3) E3: Dihydrolipoyl dehydrogenase
• 5 Cofactors:
1) Thiamine (vitamin B1)
2) Lipoate (inhibited by arsenic)
3) CoA (requires pantothenic acid, B5)
4) FAD (requires riboflavin, B2)
5) NAD+ (requires niacin, B3)

- PDC Deficiency
• Rare inborn error of metabolism; X-linked recessive
• Pyruvate shunted into alanine or lactate
• Findings:
Elevated serum alanine and lactate (lactic acidosis)
Poor feeding, growth failure, developmental delay
• Treatment:
Supplement with cofactors thiamine and lipoic acid
Ketogenic diet (ketogenic AAs lysine, leucine)
 1

Pyruvate

NAO
Pyruvate
dehydrogenase
ADH

Acetyl CoA

Ma/ate
dehydrogenase Oxaloacetate
Citrate synthase

Citra e
alate

Fumarate
lsoci rate
itochondrion
Succina.te
FAD
dehydrogenase
/socitrate
dehydrogenase
Succinate

NAO a-Ketoglutarate
Succinate thiokinase
(SuccinyJ-Co A synthetase)

a-Ketoglutarate
dehydrogenase complex

©UWor1d
 1

- TCA (Kreb’s Cycle)

• Occurs in mitochondrial matrix
• Mnemonic: Can I Keep Selling Substances For Money Officer?
1) Citrate (6 carbon)
2) Isocitrate
3) α-Ketoglutarate +2 NADH
4) Succinyl-CoA + 2 NADH
5) Succinate +2 GTP
6) Fumarate +2 FADH2
7) Malate +2 NADH
8) Oxaloacetate (4 carbon)
• RLS: Isocitrate dehydrogenase
• TCA Intermediate Pathways:
Citrate: Fatty acid synthesis
α-Ketoglutarate: AA synthesis, precursor for GABA
Succinyl CoA: Heme synthesis
Malate: Gluconeogenesis
Oxaloacetate: AA synthesis, gluconeogenesis

- Citrate
• Generated by: Citrate synthase (inhibited by ATP)
• Oxaloacetate (4C) + Acetyl CoA (2C) Citrate
• Citrate is an indicator of cell energy usage
Citrate inhibits PFK1
Citrate activates Acetyl CoA Carboxylase (FAS)

- Isocitrate
• Generated by: Aconitase (isomerization)
• Inhibited by fluoroacetate (rat poison)

- α-Ketoglutarate + 2 NADH
• Generated by: Isocitrate dehydrogenase (RLS of TCA)
Inhibited by ATP, NADH
Activated by ADP, Ca2+

- Succinyl CoA + 2 NADH

• Generated by: α-Ketoglutarate dehydrogenase complex (requires same 5 cofactors as PDC)
Inhibited by succinyl-CoA
Activated by Ca2+

- Succinate + 2 GTP
• Generated by: Succinyl-CoA synthetase

- Fumarate + 2 FADH2
• Generated by: Succinate dehydrogenase
Succinate dehydrogenase is imbedded in the inner mitochondrial membrane
Succinate dehydrogenase functions as complex 2 of the ETC
• Fumarate can also be produced by urea cycle, purine synthesis (IMP formation), and AA breakdown
 1

- Malate + 2 NADH
• Generated by: Malate dehydrogenase
• Malate:
Malate can cross mitochondrial membrane
NADH and oxaloacetate (OA) CANNOT cross
Malate transfers NADH into mitochondria (ETC)
Aspartate transfers out of mitochondria Converts back into OA (gluconeogenesis)
• Malate-Aspartate Shuttle: Mechanism to deliver NADH into mitochondria and regenerate OA
Malate enters mitochondria to deliver NADH
Malate is converted back to OA Aspartate
Aspartate exits mitochondria, and converts back into OA for use in gluconeogenesis

Energy Producing Steps of Cell Metabolism

Enzyme
G3PD
Phosphoglycerate kinase
Pyruvate kinase
Pyruvate dehydrogenase (PDC)
Isocitrate dehydrogenase
α-Ketoglutarate dehydrogenase α-Ketoglutarate Succinyl CoA
Succinyl CoA synthetase
Succinate dehydrogenase
Malate dehydrogenase
Reaction
Glyceraldehyde-3P 1,3-BPG
1,3-BPG 3-BPG
PEP Pyruvate
Pyruvate Acetyl CoA
Isocitrate α-Ketoglutarate
Succinyl CoA Succinate
Succinate Fumarate
Fumarate Malate
Products (per glucose)
2 NADH (2.5 ATP each)
2 ATP
2 ATP
2 NADH (2.5 ATP each)
2 NADH (2.5 ATP each)
2 NADH (2.5 ATP each)
2 GTP (2 ATP)
2 FADH2 (1.5 ATP each)
2 NADH (2.5 ATP each)

- Electron Transport Chain (ETC)

• Complex 1: NADH dehydrogenase (composed of flavin and iron sulfur compounds)
Transfers electrons from NADH to coenzyme Q (ubiquinone)
• Complex 2: Succinate dehydrogenase (TCA enzyme)
Transfers electrons from succinate FADH2 CoQ
• Complex 3: Cytochrome bc1 complex
Coenzyme Q shuttles electrons to complex 3
Complex 3 transfers electrons to cytochrome c
• Complex 4: Cytochrome c oxidase (contains copper)
Cytochrome c shuttles electrons to complex 4
Passes electrons onto O2 Creates water
 1

- ATP Synthase (Complex 5)

• Converts protons into electrochemical gradient (proton motive force) ATP
• Protons move down gradient (chemiosmosis)

ETC Inhibitors
Complex 1 (NADH Dehydrogenase) Rotenone (insecticide)
Complex 2 (Succinate Dehydrogenase) --
Complex 3 (Cytochrome bc1 Complex) Antimycin A
Complex 4 (Cytochrome c Oxidase) Carbon monoxide (CO)
Cyanide
Complex 5 (ATP Synthase) Oligomycin (macrolide)

- Cyanide Poisoning
• Tachypnea, tachycardia, HTN, HA, confusion, bright red venous blood (no O2 extracted)
• Almond breath, lactic acidosis (↑ anaerobic metabolism)
• Risk: Nitroprusside (HTN emergency drug)
• Treatment: Nitrites (amyl nitrite), hydroxocobalamin (B12), sodium thiosulfate
Nitrites convert Fe2+ to Fe3+ in hemoglobin (induces methemoglobin binds CN-)

- Uncoupling Agents
• Essentially “poke a hole” in the inner mitochondria to cause protons to leak out
• Drugs:
2,4-Dinitrophenol (DNP; research drug used illicitly for weight loss)
Aspirin OD Generates heat (fever)
• Brown Fat:
Contains thermogenin protein
ß3-adrenergic activation (SNS) Lipolysis Release of thermogenin
protein Generation of heat in hibernating animals and newborn humans

- Fatty Acid Metabolism

• Fatty Acid Synthesis (FAS):
Location: Cytosol of liver, mammary glands, adipose tissue
Conversion from excess carbohydrates and proteins
• Fatty Acid Storage: Stored as triglycerides in adipose tissue
• Fatty Acid Catabolism:
Location: Inner mitochondria (all cells except RBCs and CNS)
ß-oxidation (converts fatty acids into acetyl CoA TCA ATP)

- Fatty Acid Synthesis

• High-energy states (fed states) Lots of acetyl CoA and ATP
• ATP inhibits isocitrate dehydrogenase (TCA enzyme) Buildup of citrate
• High citrate levels
 2

- Fatty Acid Synthesis

• Step 1: Citrate Shuttle
Mechanism to get acetyl CoA (impermeable) across mitochondrial
membrane OA combines with acetyl CoA Forms citrate
Citrate is shuttled into cytosol
• Step 2: Citrate converted back into acetyl CoA via ATP citrate lyase
• Step 3: Acetyl CoA converted to malonyl CoA via acetyl-CoA carboxylase (requires biotin)
RLS of FAS
Activation: Insulin, citrate
Inhibition: Glucagon, epinephrine
• Step 4: Synthesis of palmitate (C16) from carbons of acetyl CoA and malonyl CoA
Requires NADPH (from HMP shunt)
Palmitate chain modified to other fatty acids for use in various tissues as needed
Fatty acids converted into triacylglycerols and stored in adipose tissues via LPL

- Hormone Sensitive Lipase (HSL)

• Removes fatty acids from TG in adipocytes
• Activated by glucagon/epinephrine
• Glycerol may be used as gluconeogenesis precursor
• Fatty acids must be transported via albumin

- ß-Oxidation of FAs
• Stepwise removal of 2-carbon units from FAs
Produces acetyl CoA Enters TCA
Produces NADH and FADH2 Enters ETC
• Step 1: Conversion of FA to fatty acyl CoA
Fatty acyl CoA synthetase + CoA + ATP
• Step 2: Carnitine Shuttle
Carnitine transports long-chain fatty acyl CoA from cytosol to mitochondria
Converted into acyl carnitines via carnitine palmitoyl transferase 1 (CPT1)
Acyl carnitine molecules move into mitochondrial matrix
Carnitine palmitoyl transferase 1 (CPT2) converts acyl carnitines back to fatty acyl CoA
• Step 3: Cycles of 2-C removal (ß-oxidation)
Acyl CoA dehydrogenase adds double bonds between α/ß carbons
Produces NADH and FADH2 Enters ETC
Even chain FAs can be broken down to enter ETC
Even chain FAs CANNOT be used for gluconeogenesis

- Odd-Chain FA Catabolism
• ß-oxidation proceeds until 3-carbons remain Proprionyl CoA
• Proprionyl CoA Methylmalonyl CoA (requires B12) Succinyl CoA
• Odd-chain FAs can be used for gluconeogenesis
 21

- Ketone Bodies
• Produced during fasting, low carbohydrate diets, starvation, prolonged exercise, alcohol, T1DM
• High levels of acetyl CoA are the major stimulus for ketone production
• ↓ pKa (release a lot of protons); ↓ blood pH; AG metabolic acidosis
• Combines 2 molecules of acetyl CoA Acetoacetyl CoA HMG CoA Acetoacetate
Acetoacetate can be cleaved into acetone (exhaled; not a fuel) and 3-hydroxybutyrate
• Tissue Usage: Muscle, heart, brain; liver CANNOT use ketones for energy
Ketone bodies allow use of fatty acids for energy use in the brain
 22

- Ethanol Metabolism
• Alcohol dehydrogenase (ADH) in liver oxidizes ethanol Acetaldehyde ↑ NADH shuts
Occurs in hepatocyte cytosol (↓Km for EtOH); zero order kinetics down TCA cycle
Generates NADH
• Acetaldehyde dehydrogenase (ALDH) converts acetaldehyde Acetate
Occurs in hepatocyte mitochondria (↓Km for acetate)
Generates NADH
• Acetate travels from liver into the blood Acetate travels into muscle
Acetyl-CoA Synthetase (muscle) converts acetate Acetyl CoA
Acetyl CoA enters TCA 7kcal/g (13ATP) per mole of EtOH

- Microsomal Ethanol Oxidizing System (MEOS)

• Secondary route for alcohol metabolism (~20%)
Proportion metabolized by MEOS increases substantially at high [ALC]
Large or chronic alcohol consumption Greater percentage travels into MEOS pathway
• CYP450 enzymes in ER CYP2E1
CYP2E1 has ↑ Km for EtOH, uses NADPH as electron donor, uses O2 as electron acceptor

- Acute Effects of Alcohol

• Rise in NADH (↑NADH/NAD+ ratio) results in:
Inhibition of fatty acid oxidation Accumulation of fatty acids (hyperlipidemia)
Stalled TCA cycle (↑ citrate) Activates acetyl CoA carboxylase (fatty acid synthesis)
Stalled TCA cycle (↑ malate) Malic enzyme generates NADPH NADPH used in FAS
Inhibition of gluconeogenesis (↑ ALC intake can cause hypoglycemia)
Ketogenesis (↑ ALC intake can cause alcohol-induced ketoacidosis) Kussmaul’s)
Lactic acidosis ↑ Lactate inhibits urate excretion in the nephron Gout

- Chronic Effects of Alcohol (Alcohol-Induced Liver Disease)

• Hepatic Steatosis (Fatty Liver) Zone 3 affected 1st
• Alcoholic Hepatitis AST>ALT, Zone 3 shows PMN infiltration with Mallory Bodies
• Alcoholic Cirrhosis Irreversible, portal HTN, liver fibrosis
 2

- Toxic Products of EtOH Metabolism

• Acetaldehyde and free radicals
Acetaldehyde forms adducts with proteins and compounds
Hydroxyethyl radical produced by MEOS Damage to the liver

- Anion Gap
• Formula = [Na+] - (Cl- + HCO -3)
• High anion gap Acidosis
Indicates presence of ketone bodies in context of ↑ ALC intake

- MEOS
• CYP2E1 oxidizes ethanol to acetaldehyde
NADPH and ethanol donate electrons for the oxidation Forms O2 + H2O
Cytochrome P450 reductase (FAD) and cytochrome P450 (Fe-heme) carry out the reaction

CYP2E
1
• ↑ Ethanol metabolism (greater EtOH tolerance)
• ↑ Rate of acetaldehyde formation
• ↑ Free radical formation
 2

- ALDH2 (Acetaldehyde Dehydrogenase) Mutations

• Flushing, nausea, palpitations in East Asian populations Protective against alcoholism
• Increased risk of esophageal CA

- Disulfiram
• Acetaldehyde dehydrogenase (ALDH) inhibitor used for alcoholics
• Blocks conversion of acetaldehyde Acetate
Results in accumulation of acetaldehyde Hangover effects

- Free Radical Damage

• MEOS pathway is capable of generating ROS
• Acetaldehyde-adduct formation Acetaldehyde binds to glutathione Loss of ROS protection
• Damages mitochondria ETC inhibited Uncoupling of OXPHOS
Release of free radicals by CYP2E1 Lipid peroxidation
↓ FA oxidation (↑ NADH) + Lipid peroxidation Accumulation of fats Fatty liver

- Thiamine Deficiency (Beriberi)

• Ethanol interferes with gut absorption of thiamine
• Thiamin (vitamin B1) is a required cofactor for oxidative decarboxylation reactions
Pyruvate DH, α-ketoglutarate DH, α-ketoacid DH (BCAA), transketolase (HMP shunt)

- Exercising Muscle
• Rapidly exercising muscles consume ATP and creatine phosphate
• Calcium release from muscles:
1) Calcium-calmodulin complex stimulates glycogen phosphokinase A Glycogen phosphorylase
2) Calcium activates isocitrate dehydrogenase + α-ketoglutarate dehydrogenase (TCA enzymes)
• Glucagon/Epinephrine:
Inhibit acetyl CoA carboxylase (RLS of FAS); ↓ malonyl CoA, ↑ ß-oxidation
Activate glycogen phosphorylase (breakdown)
• Muscle Cramps: ↑ NAD consumption (↑ NADH/NAD ratio); ↑ Lactate (↓ pH; muscle pain)

- Insulin Effects on Select Hormones

• Glucokinase: Transcription increased by insulin
Locks glucose in liver cells to favor glycolysis
• F-2,6-BP: Turns glycolysis ON, turns gluconeogenesis OFF; induced by insulin
• Glycogen Synthase: Activated by insulin
• Acetyl CoA Carboxylase (RLS of FAS): Activated by insulin
 2

- Kwashiorkor
• Inadequate protein intake; hypoalbuminemia leads to edema (swollen abdomen/feet)
• Fatty liver (↓ apolipoprotein synthesis), skin lesions (hyperkeratosis, depigmentation)

- Marasmus
• Inadequate total calories; muscle/fat wasting (NO edema)
• “Skin and bones”
 2

- Hypoketotic Hypoglycemia
• Carnitine Deficiency: No LCFA transport into mitochondria
↓ Carnitine, ↓ Acylcarnitine; dilated cardiomyopathy, muscle weakness/hypotonia
• MCAD Deficiency: Inability to adequately breakdown FAs into acetyl-CoA
↑ Acylcarnitine; vomiting, lethargy, seizures, liver dysfunction, hyperammonemia
May cause sudden death in infants; must avoid fasting

- Inborn Errors of Metabolism

• Defects in metabolic pathways; presents in infancy with failure to thrive, hypotonia, etc.
• Lab findings suggest either hypoglycemia, ketosis, hyperammonemia, lactic acidosis, etc.
• Hypoglycemia: Glycogen storage disorders, galactosemia, HFI, organic acidemias, FA disorders

- Organic Acidemia
• Organic acid accumulation due to enzyme deficiency; presents in infancy
Inhibits gluconeogenesis (hypoglycemia, ↑ ketoacids, ↑ AG metabolic acidosis)
Inhibits urea cycle (hyperammonemia)
• Findings: Poor feeding, vomiting, hypotonia, hepatomegaly, seizures

- Propionic Acidemia
• Deficiency: Propionyl CoA Carboxylase (requires biotin)
↑ propionyl CoA, ↓ methylmalonic acid

- Methylmalonic Acidemia
• Deficiency: Methylmalonyl CoA Mutase (requires Vitamin B12)
↑ methylmalonic acid, ↓ succinyl CoA

- Mitochondrial Disorders
• Pyruvate dehydrogenase deficiency
• Loss of ability to metabolize pyruvate to acetyl CoA
• Pyruvate Shunt: Severe lactic acidosis, ↑ alanine
 27

Catecholamine Synthesis

- Phenylketonuria (PKU)
• AR deficiency of phenylalanine hydroxylase or tetrahydrobiopterin (BH4)
BH4 Deficiency (rare): Dihydropteridine reductase deficiency
BH4 Deficiency: ↓ Catecholamine synthesis (↓ dopamine = ↑ PRL)
• Tyrosine becomes an essential AA; phenylalanine accumulates (phenyl ketones in urine)
Phenylalanine shunts into metabolic pathways that generate toxic phenylketones
Phenylacetate, phenyllactate, phenylpyruvate Toxic
• Findings:
Intellectual disability, growth retardation, seizures, eczema, pale skin (↓ TYR, ↓ melanin)
Musty body odor: Phenylalanine is aromatic (↑ aroma = musty smell)
• Treatment: ↓ Phenylalanine, ↑ tyrosine diet, supplement with BH4
Avoid artificial sweetener, which contains aspartame (↑ phenylalanine); ex. diet soda
• Screening occurs 2-3 days after birth

- Maternal PKU
• Pregnant women with PKU consume too much phenylalanine during pregnancy
• ↑ Phenylalanine acts as a teratogen (must monitor serum [F] during pregnancy!)
• Findings: Microcephaly, intellectual disability, growth retardation, congenital heart defects

- Metyrosine
• Antiadrenergic drug (old)
• MOA:
Inhibits tyrosine hydroxylase (blocks TYR Dopa)
Prevents NE synthesis
• Use: Pheochromocytoma
 28

- Levodopa (L-DOPA)
• MOA:
Dopamine CANNOT cross BBB; L-DOPA CAN cross
Enters BBB via L-amino acid transporter Converted to dopamine via dopa decarboxylase
Reduces mortality in Parkinson Disease
• ON/OFF Phenomena:
Responsiveness decreases over time Not a sustainable drug for long-term treatment
Apomorphine: Rescue therapy during intermittent hypomobility ("off" episodes)
COMT-Inhibitors: Also used to alleviate ON/OFF phenomena
• Carbidopa:
Dopa decarboxylase inhibitor co-administered w/ L-DOPA
Does NOT cross BBB Inhibits peripheral conversion of L-DOPA to dopamine
Decreases unwanted dopaminergic effects in peripheral tissues (nausea, vomiting)
• Toxicity:
GI distress (anorexia, nausea, vomiting), mydriasis (↑ IOP; glaucoma exacerbation)
Postural hypotension, may cause cardiotoxicity (tachycardia, asystole, cardiac arrhythmias)
Dyskinesias: Chorea, ballismus, myoclonus, tics, tremor
Psychiatric: Anxiety, depression, hallucinations (contraindicated w/ history of psychosis)

- Oculocutaneous Albinism
• AR disorder; deficiency of tyrosinase or tyrosine transporters
Chediak-Higashi: TYR transporter defect (lysosomal trafficking defect)
• Normal melanocyte number (↓ melanin synthesis)
• Risk of sunburn and skin CA

- Alkaptonuria
• AR disorder; homogentisate oxidase deficiency; defective TYR degradation
Unable to degrade TYR to fumarate
Homogentisic acid (pigment) accumulation in tissues; usually benign
• Findings:
Blue-black connective tissue, ear cartilage, sclerae (ochronosis)
Urine turns black after prolonged exposure to air
Arthritis (homogentisic acid is toxic to cartilage); black pigment found in joints
X-ray: Calcification of IVDs in spine
• Treatment: Dietary restriction of tyrosine/phenylalanine
 2

- Amino Acid Derivatives

• Tryptophan: Niacin, serotonin (5HT), melatonin
Carcinoid Tumors: Abnormal tryptophan metabolism; ↑ urinary 5-HIAA
Hartnup Disease: Absent AA transporter in PCT; loss of Trp in urine (↓ Trp causes pellagra)
• Histidine: Histamine
• Glycine: Heme
• Glutamate: GABA, glutathione
• Arginine: Creatine, urea, NO

- Branched Chain Amino Acids (BCAAs)

• Valine, Leucine, Isoleucine
Valine Succinyl CoA
Isoleucine Succinyl CoA + Acetyl CoA
Leucine Acetyl CoA + Acetoacetate (purely ketogenic)
• Metabolized by α-ketoacid dehydrogenase
(1) Transamination (2) Decarboxylation (3) Dehydrogenation

- Maple Syrup Urine Disease (MSUD)

• AR deficiency of α-ketoacid dehydrogenase; blocked degradation of BCAAs
↑ plasma BCAAs, ↑ urinary α-ketoacids
α-ketoacid of isoleucine gives urine a sweet smell
• Findings: Neurotoxic (↑ leucine), lethargy, cerebral edema, seizures, death
• Treatment: Dietary restriction of BCAAs, thiamine supplementation (↑ cofactor)

- Homocystinuria Lens Subluxation

• AR disorder; multiple etiologies, all forms lead to ↑ homocysteine Marfans: Up & Out
Cystathionine synthase deficiency Homocystinuria: Down &
Methionine synthase deficiency
Methylenetetrahydrofolate reductase (MTHFR) deficiency
• Findings:
Homocystinuria (↑ homocysteine in urine), marfanoid habitus (long limbs, pectus excavatum)
Lens dislocation (down/in), ↑ risk of atherosclerosis and thrombosis (stroke/MI)
Kyphosis, osteoporosis, intellectual disability, pale skin

SAM = Methionine + ATP

SAM loses methyl groupHomocysteine
 3

- Urea Cycle
• Ammonia Production:
Ammonia travels to the liver mainly via alanine and glutamine
Ammonia is produced by gut bacteria Travels to liver via portal vein
↑ Ammonia can deplete α-ketoglutarate
• Metabolism of toxic ammonia (NH +4) to nontoxic urea Excretion in urine
Urea is synthesized from ammonia, aspartate, and CO2
(1) nitrogen from aspartate, (1) nitrogen from ammonia (carbamoyl phosphate)
• Enzymes: Hydratases, transaminases, glutamate dehydrogenases, glutaminases, deaminases
Pyridoxal phosphate (PLP) cofactor Transaminase, deaminase, decarboxylation reactions

- Reaction #1
• Enzyme: Carbamoyl phosphate synthetase 1 (CPS1); RLS of urea cycle
• Location: Mitochondria
• Reactants: Ammonia (NH3) + CO2 + 2ATP
• Products: Carbamoyl phosphate
• Allosteric Activator of CPS1: N-acetylglutamate (regulator of urea cycle)
Carbamoyl phosphate synthetase will not function without N-acetylglutamate
↑ Protein (fed-state); Glutamate + Acetyl CoA N-acetylglutamate Activates urea cycle
CPS1 Deficiency: Inability to undergo urea cycle Severe
hyperammonemia Carbamoyl phosphate is an intermediate of pyrimidine
synthesis (via CPS2)

#1

- Reaction #2
• Enzyme: Ornithine transcarbamoylase (OTC)
• Location: Mitochondria
• Reactants: Carbamoyl phosphate + Ornithine
• Product: CitrullineCitrulline is transported into cytosol in exchange for ornithine
OTC Deficiency
#2 MC urea cycle defect
X-linked recessive
↑ Carbamoyl phosphate
↑ Ammonia
↑ Orotic acid
 31

- Reaction #3
• Enzyme: Argininosuccinate synthetase
Argininosuccinate Synthase Deficiency:
• Location: Cytosol
Citrullinemia, ↓ Arginine
• Reactants: Citrulline + Aspartate
Hyperammonemia
• Product: Argininosuccinate

- Reaction #4
• Enzyme: Argininosuccinate lyase
• Location: Cytosol
• Reactants: Argininosuccinate (cleavage)
• Product: Fumarate + Arginine

- Reaction #5
• Enzyme: Arginase
• Location: Cytosol
• Reactants: Arginine (cleavage)
• Product: Urea + Ornithine
Ornithine is regenerated Re-enters the mitochondria for next cycle

- Hyperammonemia
• Cerebral edema, tremor (asterixis), poor memory, slurred speech, vomiting, coma
• Treatment: Low protein diet, arginine supplements
Lactulose: Laxative; acidifies colon; traps NH4+ in colon to lower plasma NH4+
Antibiotics (eg, rifaximin, neomycin) to ↓ ammoniagenic bacteria
Benzoate, phenylacetate, or phenylbutyrate conjugate with glutamine Excreted in urine
 32

- Water Soluble B Vitamins

• B12 stored for ~3 years; B9 stored for ~3 months
All other B vitamins wash out fairly quick
• Deficiency mostly affects rapidly growing tissues
Dermatitis, glossitis, diarrhea, cheilitis, etc.

- Thiamine (B1)
• Converted to active thiamine pyrophosphate (TPP)
• Cofactor:
1) Pyruvate dehydrogenase
2) α-Ketoglutarate dehydrogenase
3) α-Ketoacid dehydrogenase
4) Transketolase
• Thiamine deficiency impairs glucose metabolism; low cell energy (wasting)
• Alcoholism is MCC of thiamine deficiency
Alcohol interferes conversion of thiamine to bioactive form
Alcohol reduces absorption of thiamine in gut brush border
Cirrhosis Inadequate hepatic storage for B1
• Wet Beriberi: Edema, ↓ TPR, ↑↑ CO, dilated cardiomyopathy
• Dry Beriberi: Muscle wasting, polyneuropathy
• Wernicke-Korsakoff Syndrome:
BL mammillary body hemorrhage and necrosis
Damage to medial dorsal nucleus (thalamus)
Abnormal transketolase may predispose
• Wernicke Encephalopathy:
Acute, reversible syndrome
Triad: Confusion + Ophthalmoplegia (blurry vision) + Ataxia
• Korsakoff Psychosis:
Chronic, irreversible syndrome
Amnesia, confabulation (making up stories to fill in gaps of memory loss)
Irreversible memory loss, personality changes
• Thiamine Deficiency Treatment:
Most malnourished patients w/ B1 deficiency are also hypoglycemic Administer dextrose
Dextrose should NOT be administered BEFORE thiamine (give B1 first)
Must give thiamine first, because B1 is required for PDC If you administer dextrose first
then it will shunt to glycolysis Lactic acid production (exacerbates Wernicke-Korsakoff)

- Riboflavin (B2)
• Involved in redox reactions
Generates flavin mononucleotide (FMN); found in complex 1 of ETC
Cofactor for succinate dehydrogenase (generates FADH2)
• Deficiency: Cheilosis (cracked corners of lips), corneal vascularization

- Niacin (B3)
• Used to create NADH/NADPH (NAD+ required for dehydrogenase enzymes)
• Synthesized from tryptophan (requires B6)
• Deficiency: Pellagra (diarrhea, dermatitis, dementia)
INH (↓ B6), Hartnup disease, carcinoid syndrome
 3

- Pantothenic Acid (B5)

• Component of CoA and fatty acid synthase
• Deficiency (very rare): Dermatitis, enteritis, alopecia, paresthesia, adrenal insufficiency

- Pyridoxine (B6)
• Converted to active pyridoxal phosphate (PLP)
• Involved in many reactions:
Transamination (aminotransferases; ALT, AST)
Decarboxylation reactions, glycogen phosphorylase
Synthesis of glutathione, cystathione, heme (δ-ALA), niacin, histamine
NT Synthesis: 5HT, NE, epinephrine, dopamine, GABA
• Deficiency:
Convulsions, peripheral neuropathy, sideroblastic anemia (impaired heme synthesis)
Drugs: INH (structural analog of vitamin B6), OCPs

- Biotin (B7)
• Cofactor for carboxylation reactions
1) Pyruvate carboxylase
2) Acetyl CoA carboxylase
3) Propionyl CoA carboxylase
• Deficiency: Overconsumption of raw egg whites

Vitamin 812 Also called coba lam in.
FU NCT ION C ofac tor for methion ine synthase (t ransfers
C H3 g rou ps as methylco balamin) and
me thylm alo nyl-C oA mutase. I mporta nt for
D A syn thesis.
DEFICIENC Y Mac rocytic , m ega loblastic anemia;
hypersegme nted PMNs; pare sthe sias
a nd suba cute com bined dege nera tion
(dege nera tion of do rsal colu m ns, later al
cor ticosp i nal t ract s, and spinoce rebella r tract s)
due to abnorm al m yeli n. Assoc ia ted with
t serum homocyste ine and methyl m alon ic
ac id levels, along with 2° folate deficiency.
Prolonged defic ie nc y -+ irre versible ne rve
damage.
3
Found in anim al produ cts.
Syn thes ize d only by m ic roorganism s. Very
large rese rve pool (severa l ye ars) stored prim ari
ly in the l ive r. D efic ie ncy ca used by
malabsorption (eg, sprue, enteritis,
Diphyllobothrium latum, ach lorhyd ria, bact
erial overg rowth, alcoh ol excess) , lack of int rinsic
factor (eg, pern icio us ane mia, gastric bypa ss
surge ry), abse nce of terminal ileu m (surg ic al
resec tion, eg , for Crohn disease), ce rtain drugs
(eg, metform in), or insufficie n t intake (eg,
veganis m).
Anti -intrins ic factor antibod ies diag nos tic for
per111c1ous ane mia.
Folate su pplement atio n can mask the
hem atologic sym ptoms of B12 de ficie ncy, but
not the neu rologic symptoms.

Macrocytic anemias MCV > 100 fL.

DESCRIPTION
FINDINGS
M egaloblastic anemia Impaired D A syn thesis -+ m atu ration of RBC mac rocytosis, hypers egm ented ne utroph ils
nucleus of precursor cells in bone ma rrow (a rrow in r.il), glossitis.
dela yed rel ative to mat uration of cytoplasm
.
Causes: vitamin B12 deficienc y, folate de ficienc y,
m ed ica tions (eg, hyd roxyur ea , phe nytoin,
metho trex ate, su lfa d ru gs).

El

Folate defic iency C auses: m alnu trition (eg, a lcohol ics ),
malabsor ption , d ru gs (eg, methot rex ate,
t rimethop ri m, phe nytoin), t require me nt (eg,
he molytic ane mia, pregna nc y).
Vitamin B12 C auses: pe rn ic ious anem ia, malabsorption
(cobalamin) (eg, Crohn disease), pancreatic insuf fic ienc y,
deficiency gas trecto my, insuffic ient intake (eg, veganism),
Diphyllobothrium latum (fish tapewor m).
t ho mocysteine , nor ma l me th ylm alonic ac id .
o n e urologic sym ptoms (vs B12 deficie ncy).
t homoc ysteine, t meth ylmalon ic ac id.
e u rolog ic sym ptom s: reve rsible dem entia,
sub acu te com bined degeneration (due to
invo lvem ent of B12 in fatty ac id pathways and
myelin synthes is): spinoce rebellar tract , lateral

Pernicious Anemia • Associated with sb.ic

adenocaninom.a.
• Chronic inflammation of gastric body
• More oommon among women
• Com, plex immunology
• Antibo mes again.st parietal cells
• Antibo mes again.st in.win.sic factor
• Type II hypersensffi:vity fearures
• Mso aiutoreactive CD4 T-cells
• Associated with HLA:-DR antigens
 3
co rtico spinal tract, dorsa l colu m n dysfu nction .
Folate sup plem entation in vitamin B12
de ficien cy can correct the anem ia, but worsens neu rologic
symptoms.
Historica lly diag nosed with the Sch illing tes t, a tes t that dete
rm ines if the cause is die tary ins ufficie ncy vs ma labsorption.
Anem ia 2° to insuf fic ient int ake may take several
yea rs to develop due to live r's abi lity to store B12
(as opposed to folate deficie ncy).
 active vitamin D! in 35
Need Antioxidant Vitam
s: ACE
functional 1-α-hydroxylase in kidneys to
- Fat Soluble Vitamins (ADEK)
• Form micelles in jejunum; diffuse into enterocytes, package inside
chylomicrons, enter lymph
• Deficiency: Absorption requires adequate bile and pancreatic lipase
CF, celiac sprue, Crohn’s disease, primary biliary cirrhosis, primary sclerosing cholangitis
Bowel resection

- Vitamin A
• Retinal, retinol, retinoic acid
ß-carotene: Dietary form of vitamin a (carrots)
• Retinoids: Vision; maintenance of differentiation of epithelial tissues
Rhodopsin: Light-sensitive protein receptor; contains 11, cis-retinal
• Excess: Risk of pseudotumor cerebri
• Deficiency:
Night blindness, xerophthalmia (keratinization of cornea)
Keratomalacia (retinoic acid regulates keratin growth)
• Therapy: Measles, APL

- Isotretinoin (Accutane)
• 13-cis-retinoic acid; used for acne
• Toxicity: Teratogenic (severe; must co-administer OCPs), hepatotoxic,

- Vitamin C (Ascorbic Acid)

• Roles:
1) Iron absorption (non-heme iron found in vegetables)
2) Collagen synthesis (hydroxylation of proline/lysine in the ER)
3) NE synthesis (dopamine NE; dopamine ß-hydroxylase enzyme requires vitamin C)
• Excess: Iron overload, risk of calcium oxalate kidney stones
• Deficiency: Scurvy
Sore bleeding gums, lose teeth, easy bleeding, corkscrew hairs, hemarthrosis,
• Therapy: Methemoglobinemia

- Vitamin D
• D2: Ergocalciferol: Obtained via plants
• D3: Cholecalciferol: Obtained via dairy (fortified milk) or UVB radiation (sunlight)
7-Dehydrocholesterol SUNLIGHT Vitamin D3
• 2-Step Activation:
25-hydroxylation at the liver Calcidiol (25-OH vitamin D)
1-hydroxylation at the PCT (regulated by PTH) Calcitriol (1,25-OH2 vitamin D)
Macrophages secrete 1α-hydroxylase in sarcoidosis Hypervitaminosis D (hypercalcemia)
• Function:
GI/Kidneys: ↑ Ca2+ and PO43- absorption
Bone: ↑ Ca2+ and PO43- resorption (paradoxical effects; only occur at ↑ vit D levels)
• Deficiency: Hypophosphatemia, hypocalcemia (tetany, seizures), Osteomalacia, Rickets
• Therapy:
Calcipotriene (calcitriol analog): Psoriasis
Calcitriol: Hypocalcemia in those with hypoparathyroidism
Calcitriol: Secondary hyperparathyroidism (↑ PTH) in patients with renal disease
 36

- Vitamin E (Tocopherol)
• Antioxidant; protects RBCs from free radical damage
• Deficiency:
Hemolytic anemia (↑ ROS damage), acantholysis, muscle weakness
Demyelination of posterior columns and spinocerebellar tract (↓ DCML, ataxia)
Presents like B12 deficiency but WITHOUT the megaloblastic anemia seen in ↓ B12
• Excess:
Risk of enterocolitis in infants
Inhibits metabolism of vitamin K (↑ anticoagulant effects of warfarin)
• Therapy: AZD

- Vitamin K
• Phytomenadione, phylloquinone, phtonadione,
menaquinone K1: Green, leafy vegetables
K2: Synthesized by gut bacteria
• Activated by vitamin K epoxide reductase (VKOR) Reduced form of vitamin K
Cofactor for γ-carboxylation of glutamate residues on vit-K dependent clotting factors
Vit-K dependent clotting factors: 2, 7, 9, 10, protein C/S
Vitamin K facilitates post-translational modification of clotting factors
• Deficiency:
Warfarin: Bleeding (↑ PT/INR, normal bleed time)
Newborns: ↓ Gut bacteria; risk of neonatal hemorrhage (babies given IM vit K at birth)

- Warfarin
• Oral, long-acting anticoagulant
• MOA:
Acts on liver Inhibits vitamin K epoxide reductase (VKOR)
Interferes synthesis (γ-carboxylation) of vit-K dependent clotting factors
Inhibits production of vit-K dependent factors 2, 7, 9, 10 and protein C/S
Affects extrinsic pathway (PT) Must monitor PT/INR (vit K levels differ in patients)
• Use: Chronic prophylaxis of coagulation (ex. A-Fib patient)
• Toxicity:
Initial risk of hypercoagulability (protein C deficiency is prothrombotic)
Skin necrosis (especially in protein C deficiency) Thrombosis of skin (dark purple lesions)
Teratogenic (heparin is safe for use in pregnancy)
OD Antidote: Vitamin K

- Zinc
• Deficiency:
Delayed wound healing, suppressed immunity, dysgeusia/anosmia (loss of taste/smell)
Impaired sexual development (male hypogonadism, ↓ armpit, facial, pubic hair)
Predisposes to alcoholic cirrhosis
• Acrodermatitis Enteropathica: AR defect in intestinal zinc absorption
Dermatitis (hyperpigmented in the perioral/perianal regions)

- Zinc Fingers
• Protein binding motif
• Bind specific DNA sequences; modify gene activity
 3

- Absorption of Dietary FAs

• Fatty acids TGs Packaged into chylomicrons
• Transported to lymph Empties into venous system

- Absorption of Cholesterol
• Cholesterol is converted into cholesteryl esters via acyl CoA cholesterol acyltransferase (ACAT)
• Cholesteryl esters packaged into chylomicrons (with TGs)

- Chylomicrons
• Lipoproteins synthesized by intestinal enterocytes
Only present when you eat a meal (that contains fats) Milky appearance of blood
Clear 1-5 hours after ingestion
• Course:
Package absorbed dietary TGs/cholesterol/ADEK from GI tract
Secreted from enterocyte via ApoB48 Enter lymph Enter venous
circuit Accept Apo C-2 and ApoE from HDL
Encounter LPL Apo C-2 activates LPL TG hydrolysis FA + glycerol enters
cells Loss of TG content Chylomicron remnant
Travel to liver Bind ApoE Absorption of chylomicron remnants via endocytosis
• ApoB48: Required for secretion of chylomicrons from enterocytes
ApoB48 is ONLY found on chylomicrons
• ApoE: Receptor found on chylomicrons; binds to liver receptors
ApoE is required for uptake of remnants of chylomicrons

- Lipoprotein Lipase (LPL)

• Extracellular enzyme anchored to capillary walls (adipose, muscle, heart; NOT found in liver)
• Hydrolyzes TGs (found in chylomicrons) into fatty acids and glycerol
Shrinks chylomicron size by draining them of TG content
• Apo C-2: Activates LPL (Apo C-2 found on chylomicrons, VLDL, IDL)

- Intrinsic Cholesterol Synthesis

• ONLY performed by the liver
• Acetyl CoA + Acetoacetyl CoA HMG CoA
• HMG CoA Reductase: Converts HMG CoA Mevalonate

- HDL
• Scavenger lipoprotein; reverse transport of cholesterol from periphery back to liver
• Components: Apo A-1, Apo C-2, ApoE
Donates Apo C-2 and ApoE to chylomicrons and VLDL
• Lecithin-Cholesterol Acyl Transferase (LCAT):
Activated by Apo A-1
Esterifies cholesterol in HDL; packs esters densely in core of HDL
• Cholesteryl Ester Transfer Protein (CETP):
Exchanges esters (in HDL) for TGs (in VLDL)
 NOTE: Document became corrupt after this page;
3
VLDL IDL luckily I printed beforehand
- VLDL
• Transports TGs and cholesterol (from liver) to tissues that require them
↑ TG content; responsible for majority of TG found on fasting blood test
• Nascent VLDL: Contains Apo B100
• ↑ TG content; reduces during circulation, forming IDL:
1) TG removal via LPL
2) TF removal via CETP (HDL)

- IDL
• Formed from VLDL
• IDL evolves into LDL:
1) HDL redeems Apo C-2 and ApoE from IDL
2) Encounter hepatic lipase (liver LPL)
Knockout mutation of
- LDL hepatic lipase shows that
• ↓ TG content; ↑ cholesterol content there is NO conversion of
High cholesterol content can be donated to vessel walls Atheroma formation
• Transfers cholesterol to cells with LDL receptors
LDL receptors bind Apo B100 (remains bound from VLDL to IDL to LDL)
 39

Apolipoprotein
Chylomicron
E Function
Chylornicron remnant
Mediates remnant uptake VLDL IDL LDL HDL
(everything except LDL)
A-I
Found only on alpha-
lipop roteins (HDL), activates
LCAT
C-11
Lipoprotein lipase cofactor that
catalyzes cleavage.
8-48
Mediates chylomicron
secretion into lymphatics
Only on particles originating
from lite i11lesli11cs
8-100
Binds LDL receptor
Only on particles originating
from the liver

llpoprotein functions
Lipop rotcin s are composed of ,·arying proportions of cholesterol, TCs,:ind phospholipids. LDL and
I IDL carry the most cholesterol.
Cholesterol is needed to maintain cell membrane integrit) and synthesize bile acids. steroids, and
vitamin D.
Chylomicron
Delivers dietar}' TCs to peripheml tissues. De,fh ers cholesterol to !her in the form of ch !omicron
remnants, which arc mostly depicted oftheirTCs. Secreted by intestinal epithelial cells.
VLDL Delivers hepatic TCs to peripheral tissue. Secreted by liver.
IDL Deli\'ers TCs and cholesterol to li,,er. formed from degradation of\'LDL.
LOL Delivers hepatic cholesterol to peripheml tissues. Fonned by hepatic lipase modilication of I DL in
th e li,·er and peripheral tissue. Taken up by target cells ,·ia receptor-mediated cndocytosis. LDL is
Let hal.
HDL :Vlediates re\'erse cholesterol transport from peripheral tissues to lh-er.. \cts as :i repositon· for
apolipoprotcins C and E (whic h are needed for clt}lonncron and VLDL metabolism). Secreted
from both li,·era nd intestine. Alcohol t sp1thesis. IIDL is Healthy.

Abetalipoproteinemia
• AR deficiency of microsomal TG transfer protein (MTP)
■ Inability to produce Apo848 Loss of ability to secrete chylomicrons
■ Inability to produce Apo 100 Loss of ability to secrete VLDL
• Findings: Steatorrhea (fatty stools), ADEK deficiency ('1,'1, Vit E), lipid-laden enterocytes
• Blood Smear: Acanthocyt osis (abnormal RBC membrane lipids)
• Lab:
■ VLDL/ IDL/ LDL: ABSENT
■ TG/Total Cholesterol: '1,
• Treatment: Restriction of LCFAs; vitamin E supplem ent (avoids ataxia, '1, DCML, hemolytic anemia)

Nephrotic syndrome (LDL) Alcoholism (TG) Pregnancy (TG>TC)

Be ta blockers (TG)
HCTZ (TC, LDL, TG)
 40

Symptoms of Hyperlipidemia
• Xanthomas: Yellowish plaques of lipid-laden histiocytes; bumps on eyelids
• Tendinous Xanthoma: Lipid deposits in tendons; MC in Achilles
• Corneal Arcus (arcus senilis): Ring shaped deposit of lipids surrounding cornea of eye
• Pancreatitis : Risk is high when TG >1000 (chylomicrons obstruct pancreatic capillaries)

Hyperchylomicronemia (Type 1 Familial Dyslipidemia)

• AR deficiency of LPL or Apo C-2
• Labs: 1' Chylomicrons, 1' TG, 1' cholesterol
• Findings: Recurrent pancreatitis, hepatosplenomegaly, xanthomas, creamy layer of supernatant

Familial Hypercholesterolemia (Type 2 Familial Dyslipidemia)

• AD mutation of LDL receptors or defective Apo 8100
• Labs: 1' LDL, 1' cholesterol
• Findings: Accelerated atherosclerosis (Ml in 20s), xanthomas, corneal arcu s
• Heterozygotes: Cholesterol >300mg/dL
• Homozygotes: Cholesterol >700mg/dL

Dysbetalipoproteinemia (Type 3 Familial Dyslipidemia)

• AR defect in ApoE ApoE2
• Labs: 1' Chylomicrons, 1' VLDL, 1' cholesterol Decreased risk of Alzheimer's
ApoE4
• Findings: Premature atherosclerosis, xanthomas Increasedrisk of Alzheimer's

Hypertriglyceridemia (Type 4 Familial Dyslipidemia)

• AD; overproduction of VLDL; associated with insulin resistance (T2DM, obesity)
• Labs: 1' VLDL, 1' TG
• Findings: Recurrent pancreatitis

'1
-
 - -:t1. --- 1111-' J ! .l , I l II

41
lipid Panel
• Total Cholesterol
• Normal: <200 Treating Hyperlipidemia
LDL-C It is rare to be treated for sJ., HDL or 1' TG
• 1' CV risk MC: Treatment of 1' LDL w/ statins
• <100 is very good
• >200 is high
•Treating 1' LDL reduces CV risk significantly
HDL-C Friedewald Formula
• Inversely associated w/ CV risk (1' HDL Lowerr is k ) LDL-C = TotChol - HDL-C - TG
• <45 is low
5
•Treating sJ., HDL offers very little improvement in CVr is k
TG (triglycerides)
• Normal: <150
• Levels >1000 can cause pancreatitis
• Treating sJ., HDL offers little improvement in CV risk
■ Main reason for treatment of isolated 1' TG is to avoid pancreatitis
Non-HDL Chole sterol = (Total Cholestero-l HDL)
Diet/ e xcrcise/ wc1ght loss= GREAT way to reduce
H- igh T. nglyce. ndes
and Acute Pancreatitis cholesterol levels and CV risk

• 1' Chylomicrons in plasma obstruct capillaries in pancreas

• When TG are >1000,chylomicrons are never cleared (always in pla sma circulat ing )
• Obstruction lschemia of pancreas Vessel damage Release of pancreatic lipases
■ TG breakdown Free fatty acids
• Acid Tissue injury to pancreas Acute pancreatitis

Statins
Lipophilic Statins : Atorvastatin, Simvastatin, Lovastatin
Hydrophilic Statins: Pravastatin, Fluvastatin, Rosuvastatin (crestor)
• Lower incidence of myalgias
MOA: Inhibit HMG-CoA reductase (liver)
■ Prevents formation of mevalonate (precursor for cholesterol synthesis)
• 1' LDL receptor expression in the liver Sequesters LDL in liver (lowers plasma LDL)
■ Moderately reduces TG
■ No appreciable effect on HDL
• Toxicity:
■ Hepatotoxicity (1' LFT)
■ Muscle toxicity (-.I, coenzyme Qin muscles) CoQ-10 supplements may reduce incidence
• Substrate for P450 (CYP inhibitors 1' statin levels Greater risk of hepatotoxicity/myalgias)
• Teratogenic Do NOT use during pregnancy
• Statin Muscle Toxicity:
■ Myalgias (weakness, soreness, normal CK)
■ Myositis (weakness, soreness, 1' CK)
■ Rhabdomyolysis: (weakness, soreness, muscle pain, dark urine, 1'1' CK, acute renal failure)
■ Statin + P450 Inhibitor Rhabdomyolysis
■ Statin + Gemfibrozil/Cyclosporine Rhabdomyolysis
 !FA !VLDL !HDL breakdown

l
mobilization

l J.LDL
l
tHDL
Niacin (Vitamin 83) J.TG
• M OA: Inhibits HSL (lipolysis) in adipose
tissue
• .J,, FA release, .J,, VLDL synthesis, .J,, HDL clearance
• .J,, LDL, 1'1' HDL (primary effect)
• Use: .J,, HDL
• Toxicity:
• Stimulates release of prostaglandins in skin Flushing (face is warm, red)

■
• Hepatotoxicity (1' LFT)
• Pruritus (itchy)

I
• Hyperglycemia (insulin resistance) Avoid in
diabetics

Fibrates
• Gemfibrozil, Clofibrate, Bezafibrate, Fenofibrate
• MOA: Activate PPAR-a
NSAIDs (PGE inhibitors)
• Modifies gene transcription Increases LPL activity
can help .J,, flushing
• 1' Liver fatty acid oxidation
Reduces VLDL
• .J,,.J,, TG (primary effect)
Flushing does not occur
• Use: 1' TG
after prolonged use
• Toxicity:
• Hepatotoxicity (1' LFT)
• Myositis (risk of rhabdomyolysis w/ gemfibrozil) Increased risk w/ statins
• Cholesterol gallstones (cholelithiasis)

Ezetimibe
• MOA: Absorption blocker
• Blocks dietary cholesterol absorption at the intestinal brush border
• 1' LDL receptor expression in the liver Sequesters LDL in liver {lowers plasma LDL)
• .J,, LDL (primary effect)
• Toxicity:
• Hepatotoxicity (1' LFT)
• Diarrhea (disrupts absorption in the intestines)

Bile Acid Resins

• Cholestyramine, Colestipol, Colesevelam
• MOA: Prevent intestinal reabsorption (enterohepatic circulation) of bile
• Increases bile excretion into stool
• .J,, LDL (primary effect)
• Toxicity:
• 1' TG
• Nausea, bloating, cramping, bad taste in mouth
• Impaired absorption of drugs and fat-soluble vitamins (ADEK)
• Cholesterol gallstones (cholelithiasis)

Omega-3 Fatty Acids (Fish Oil)

• MOA: .J,, VLDL synthesis, .J,, Apolipoprotein B synthesis
■ .J,, TG (primary effect), 1' HDL (modest effect)
• Toxicity: Nausea, diarrhea, fishy taste
.-- - - - - - -
- - - - - - - - -- · --r o+c » -1 1 : 11,.-, iJ , 1;; 1 Ill

43
PCSK9 Inhibitors
• Alirocumab, Evolocumab
• New drugs; FDA approval in 2015
• PCSK9 Enzyme: Degrades LDL receptors on hepatocytes
• MOA: Monoclonal antibodies inhibit PCSK9
• ,l, LDL receptor degradation More LDL receptors available in liver
• 1' LDL receptors in liver Sequesters LDL in liver (lowers plasma LDL)
• Toxicity:
• Skin reaction at injection site (mAb; must be administered SQ)
• Memory problems

Antihyperlipidemic medications
Drug Mechanism
Major lipid effects I Side effects
Statins • Inhibit HMG-CoA • ! ! LDL I■ Hepatotoxicity
reductase • ! Triglycerides • Muscle toxicity
• ! Intestinal
Ezetimibe cholesterol • t Hepatotoxicity if
• ! LDL
absorption given with statins

• Nausea,
• Prevent
Bfle acid bloating,
sequestrants
reabsorption of bile j• ! LDL cramping
acids in the • Impaired absorption
intestine of drug & fat-soluble
vitamin
LDL
Niacin • l Fatty acidre le. ase l 1t HDL • Flushing & pruritus
/•
• Hepatotoxicity
• ! VLDL synthesis •
• Hyperuricemia/gout
• ! HDL clearance
• Activate PPAR-a • l! Triglycerides
Fibrates • l VLDL synthesis • Muscle toxicity
• T HDL • Gallstones
• l VLDL synthesis
Fish oll/omega-3 • l Triglycerides
•! Apolipoprotein B • Fishy taste
fatty acids • T HDL
synthesis

Chronic Alcohol Ingestion

• t HDL
• t VLDL, t TG
Lipid-lowering agents
DatlG - -

LDL HDL --
HMG-CoA reductase u, T
TRIGLYCERIDES
l
MECHANISMS OF ACTION ADVERSE EFFECTS/PROBLEMS
Inhibitors Inhibit conversion of 1--IMC I lepatotoxicity(t LFTs),
(eg, atorvastatin, CoA lo mevalonate, a myopathy (esp when
simvastatin) cholesterol precursor; used with fibrate or
t LDL rccyclmg; niacin)
l mortality in CAD
BIie acid resins u T s lig htlr T slightly patients
Cholestyramine, CI upset, l absorption of
colestipol, Prevent intcstmal other drugs and fat
colesevelam rcabsorphon of bile acids, soluble vita mins
liver must use cholesterol to
Ezetimibe u ti- 11-
male more
Rare t LFTs, diarrhea
Prevents eholeslcrol
absorption at \mall inlc\tinc
Fibrates
t lU bmsh border
Gemfibrozil, Myopathy (t risk with
bezafibrate, Upregulate LPL-+ t TC stalins), cholesterol
clearance gallstones (viJ
fenofibrate
Ach\alcs PP•\ R-u to induce inhibition of cholesterol
I IDL srnthes1s 7a-hydroxyla )
Niacin u ft ' Flushed face (l by 'ISAIDs
Inhibits lipol is (hormonc or long-term use)
scnsiti\e lipase) in adipose l lyperglycemia
tissue; reduces hepatic
u,
I lypemricemia
PCSK9 Inhibitors VI.DL synthesis
t-.Iyalgias, delirium,
Alirocumab, Inachvahon of 1.DL-receplor dementia, other
evolocumab degradation......t removal of nemocogniti\e effects.,,.-
LDL from bloochlrearn
Fish oil and marine t slightly t \lightly I at high Bclic\ed lo decrease Ff• \ \Jausea, fish-like taste
omega-3 fatty doses delivery lo liver and decreaM:
acids :ic-ti\ily of TC-synthesizing
enzymes

-
lipid-towering agents (continued)
--
Liver Blood Entffocyte Intestinal lumtn
Actryl<o,\

I.J1t¥ OfY

ro;;k 'e -=i

- ,
$ 0./

I Oicltslm,r

Su,t,m
l.o\,j<, lln
p,,..

-
s;n... Hill 1 ,t
A
Rloowr filwM .
v n
,_, ., Cttmt,,
OIJI
Bmlit,

rLfUilll)l(lf -L·
L

-+I Aot,OK L»OI.YSIS

PCSK9 0-
Nacln

PCSK9........,
Airocwnab
l.oloclnUII
II
 4
Lysosomal Storage Disorders
ALL disorders are AR-inheri tanc e, except for Fabry/Hunter
(XR)
Sphingolipidoses
Tach-Sachs Disease
Defective metabolism of sphingolipids
Niemann-Pick Disease
Fabry Disease (XR)
Gaucher Disease
Metachromatic Leukodystrophy
Krabbe Disease
M ucopolysaccha ridoses Hurler Syndrome
Defective metabolism of mucopolysaccharidoses Hunter Syndrome (XR) J

Tay-Sachs Disease
• AR frameshift mutation
t incidence of Tay-Sachs. '\iicmann-Pick, some
• Deficiency: Hexosaminidase A
forms of Gaucher disease 111 ,\shkenaz1 Je\\' :>.
• Accumulation: GM2 ganglioside
• Findings:
• Progressive neurodegeneration , developmental delay, hyperreflexia (1' startle resposne )
• Cherry-red spot on macula
• Lysosomes with onion skin

Niemann-Pick Disease
• Deficiency: Sphingomyelinase
• Accumulat ion : Sphingomyelin
• Findings:
•
Progressive neurodegeneration,hepatosplenomegaly
• Foam cells (lipid-laden macrophages) Fobry's Disease fABRY'C (S):
• Cherry-red spot on macula (similar to Tay-Sachs) • f,bul.,,,..,.i,..
• A neiolm.t omu/ Alplw c•l.ctoo,d...

Fabry Disease
A J,fic,,ncy
-i . 8 urn1nc p&ID (puipl11,r•I
• X-linked recessive; can live into 40s with this disease ./ nnarop.lliy ol h&ndJl«t)
• Ren&! (.,lure
• Deficiency: a-galactosidase A
·• Youlh Je&th
• Accumulation: Globotriaosylceramide (ceramide trihexoside) • C" • madr TnhuouJr (,\tcumul.t..d J.,1,.1,)
•
Fin dings· • ardiav.."ul..ar J:, Aff'
• C
L 1

• Early: Episodic peripheral neuropathy + angiokeratomas + hypohidrosis (lack of sweat)

■ Late: Progressive renal failure and cardiovascular disease (LV hypertrophy, stroke)

Gaucher Disease
• MC lysosomal storage disorder
• Deficiency: Glucocerebrosidase (B-glucosidase)
• Accumulation: Glucocerebroside
• Findings: Liver+ Spleen + Bones
■ Hepatosplenomegaly, pancytopenia, osteoporosis, avascular necrosis of femur, bone pain
• Gaucher cells (lipid-laden macrophages resembling crumpled tissue paper)
• Treatment: Recombinant glucocerebrosidase
 4

Metachrom,c Leukodystrophy
• Deficiency: Arylsulfatase A
• Accumulation : Cerebroside sulfate
• Sulfatide accumulation in lysosomes of oligodendrocytes Myelin cannot be
degraded
• Findings:
• Demyelination with gliossi, macrophages scattered throughout CNS white matter
• Ataxia and dementia
• Sulfatldes shifts color of toluldine blue Metachromas
• Metachromic reaction to sulfatides in urine

.
Krabbe Disease (Globoid Cell Leukodystrophy)
Deficiency: Galactocerebrosidase (galactosylceramidase)
• Enzyme is needed for catabollsm of galactocerebroside Ceramide +
galactose
• Accumulation: Galactosylsphingosine
• Globold cells (aggregation of galactocerebroslde-lflled macrophages in brain )
• loss of myelin in both CNS and PNS
• Neonatal onset; irr itability, developmental delay, micro cephaly
• Rapidly progressive motor symptoms with death by age 6mos

Hurler Syndrome
Deficiency'. a-t-lduronidase
• Accumulation ; Heparan sulfate, dermatan sulfate
• Findings:
• .J, lduronidase, mental retardation
• Gargoyllsm, airway obstruction, corneal clouding, hepatosplenomegaly

Hunter Syndrome I luntcr\ scc dcarh (no cornealclouding) and

• X-linked recessive a rc\ um for the :X (:X- link cd recessive)
• Deficiency: lduronate-2-Sulfatase m·cl,)
• Accumulation: Heparan sulfate, dermatan
sulfate
• Findings:
• .J, lduronate sulfatase
• Mil d Hurler symptoms, aggressive behavior, NO corneal clouding

I-cell disease (inclusion cell disease/mucolipidosis type 11)- inherited lysosomal storage disorder
(autosomal recessive); defect in N-acetylglucosaminyl-1-phosphotransfcrase - faiJure of the
Golgi to phosphorylate mannose residues (l mannosc-6-phosphatc) on glycoproteins - proteins
are secreted cxtrace1lularly rather than delivered to lysosomes. Results in coarse facial features,
gingi\'al hyperplasia, clouded corneas, restricted joint movements, claw hand deformities,
:kp, r hoscoliosis,and high plasma levels oflysosomal enzymes. Often fatal in childhood.
Inclusion Cell Disease
Subtype of mucolipidosis disorders
Combined features of sphingolipid and mucopolysaccharide

j,,oteins