Biochemistry

Question 1

Carbon monoxide poisoning

Answer 1

CO is generated as a byproduct of incomplete hydrocarbon combustion (eg, emission from automobiles in poorly ventilated spaces or a faulty home heater). CO has 220 times more affinity for Hgb than oxygen. Inhaled CO rapidly diffuses across alveolar membrane and binds tightly with heme-bound iron in Hgb, forming carboxyhemoglobin. Decreases oxygen content of blood by occupying oxygen binding sites. CO also inhibits release of oxygen from Hgb in tissues by altering conformation of Hgb to relaxed form with high affinity for oxygen. RESULT: leftward shift of oxygen dissociation curve and tissue hypoxia 2/2 deficient oxygen unloading. Tx is with 100% or hyperbaric oxygen.

Question 2

Methemoglobinemia

Answer 2

Oxidation of ferrous iron (Fe++) to ferric iron (Fe+++) leading to formation of methemoglobin, which is unable to bind oxygen.

Question 3

Maturity-onset diabetes of the young (MODY)

Answer 3

Mild, nonprogressive hyperglycemia that often worsens with pregnancy-induced insulin resistance 2/2 heterozygous mutation of glucokinase causing less beta cell release of insulin.

Question 4

Glucokinase

Answer 4

1. Glucokinase functions as glucose sensor in pancreatic beta cells (and hepatocytes) by controlling rate of glucose entry into glycolytic pathway.
2. Has a lower glucose affinity (increased Km) than hexokinase, but increased efficacy (higher Vmax).
3. GK varies the rate of glucose entry into the glycolytic pathway based on blood glucose levels. Induced by insulin.
4. Heterozygous mutations of the glucokinase gene cause a decrease in beta cell metabolism of glucose, less ATP formation, and decreased insulin secretion, producing MODY.
5. Homozygous mutations lead to fetal growth retardation and severe hyperglycemia at birth.
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Question 5

Pyruvate carboxylase deficiency

Answer 5

Catalyzes conversion of pyruvate to oxaloacetate for gluconeogenesis, requires biotin (B7) as a cofactor. Takes place in the mitochondria. Deficiency causes lactic acidosis (build up of pyruvate shunted to lactate) and fasting hypoglycemia (no oxaloacetate to use as substrate for gluconeogenesis).

Question 6

Glucose-induced insulin release

Answer 6

1. Glucose enters beta cell through GLUT-2
2. Glucose is metabolized by glucokinase to glucose-6-phosphate.
3. G-6-P is further metabolized by glycolysis and TCA to produce ATP.
4. High ATP to ADP ratio within beta cell results in closure of ATP-sensitive potassium (Katp) channels.
5. Depolarization of beta cells results in opening of v-gated calcium channels.
6. High intracellular calcium causes insulin release.

Side note: GLP-1 receptor increases insulin exocytosis from beta cell by increasing intracellular cAMP.

Question 7

Lactate dehydrogenase deficiency

Answer 7

LDH catalyzes conversion of pyruvate to lactate during anaerobic glycolysis. Deficiency causes decreased exercise tolerance and muscle stiffness.

Question 8

G-protein coupled receptor pathway

Answer 8

1. G protein is a heterotrimer consisting of α, β, and γ subunits associated with intracellular domain of transmembrane receptor. α-subunit is bound to GDP.
2. Hormone binds and activates receptor causing α-subunit to undergo conformational change, releasing GDP and binding GTP.
3. GTP binding allows α-subunit to dissociate and act on other enzymes.
4. Gs α-subunit activates adenylate cyclase (AC), enzyme which converts ATP to cAMP.
5. cAMP activates protein kinase A, which is responsible for intracellular effects of G protein-mediated adenylate cyclase second messenger system.
6. PKA phosphorylates specific serine/threonine residues in various enzymes, leading to their activation or deactivation.
7. PKA also phosphorylates proteins that bind to regulatory regions of genes on DNA.
8. cAMP action is regulated by cAMP phosphodiesterase, which cleaves cAMP to its inactive form, 5’-AMP.
9. Drugs that inhibit cAMP phosphodiesterase lead to prolongation of actions of cAMP. eg, theophylline in bronchial asthma.
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Question 9

Hormone receptors that use Gs alpha-mediated cAMP second messenger system to mediate effects?

Answer 9

1. FLAT ChAMP + cGg
2. FSH
3. LH
4. ACTH
5. TSH
6. CRH
7. hCG
8. ADH (V2-receptor)
9. MSH
10. PTH
11. calcitonin
12. GHRH = growth hormone releasing hormone
13. glucagon
14. Also: β1, β2, β3 (adrenergic Rs), D1 (dopamine R), H2 (histamine R), V2 (vasopressin/ADH R)
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Question 10

Hormone receptors that use cGMP second messenger system to mediate effects?

Answer 10

1. BAD GraMP (vasodilators)
2. BNP = b-type natriuretic peptide
3. ANP = atrial natriuretic peptide
4. EDRF (NO) = endothelium-derived relaxing factor aka NO
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Question 11

Janus tyrosine kinase (JAK)

Answer 11

JAK is a cytoplasmic protein activated by ligand binding to transmembrane receptors that lack intrinsic tyrosine kinase activity. JAKs phosphorylate receptor and activate cytoplasmic transcription factors called STATs (signal transducers and activators of transcription), which enter nucleus to promote gene transcription.

Question 12

Hormone receptors that use JAK-STAT pathway (aka nonreceptor tyrosine kinase) to mediate effects?

Answer 12

1. PIGG(L)ET (think acidophils and cytokines)
2. Prolactin
3. Immunomodulators (aka cytokines IL-2, IL-6, IFN)
4. GH = growth hormone
5. G-CSF = granulocyte-colony stimulating factor
6. Erythropoietin (EPO)
7. Thrombopoietin (TPO)
8. When hormone binds, transmembrane receptors recruit Janus kinase from the cytoplasm, a tyrosine kinase that causes phosphorylation and activation of STAT nuclear transcription factors.
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Question 13

Receptor tyrosine kinase

Answer 13

1. Receptor with intrinsic kinase domain.
2. Receptor undergoes auto-phosphorylation when ligand binds.
3. SH2 (SHC?) adapter protein binds to phosphorylated tyrosine kinase, which then activates RAS.
4. RAS uses GTP to activate RAF, which then activates the MAP kinase pathway (MEK, MAPK), leading to amplification of signal and DNA transcription.
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Question 14

Hormone receptors that use receptor tyrosine kinases to mediate effects?

Answer 14

1. Insulin
2. IGF-1 = insulin-like growth factor 1
3. FGF = fibroblast growth factor
4. PDGF = platelet-derived growth factor
5. EGF = epidermal growth factor
6. MAP kinase pathway
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Question 15

Hormone receptors that use IP3 second messenger system to mediate effects?

Answer 15

1. GOAT HAG
2. GnRH
3. Oxytocin
4. ADH (V1-receptor)
5. TRH
6. Histamine (H1-receptor)
7. Angiotensin II
8. Gastrin
9. Also: HAVe 1 M and M.
10. H1
11. α1 adrenergic receptor
12. V1
13. M1 muscarinic receptor
14. M3 muscarinic receptor
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Question 16

Intracellular hormone receptors?

Answer 16

1. Progesterone
2. Estrogen
3. Testosterone
4. Cortisol
5. Aldosterone
6. T3
7. T4
8. Vitamin D
9. Think PET CAT on TV
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Question 17

Signaling pathway of steroid hormones

Answer 17

1. Steroid hormones are lipophilic and must circulate bound to specific binding globulins, which increase their solubility.
2. In men, increased sex hormone-binding globulin (SHBG) lower free testosterone leading to gynecomastia.
3. In women, decreased SHBG raises free testosterone leading to hirsutism.
4. OCPs and pregnancy cause increased SHBG, and thus OCPs can treat hirsutism and acne caused by androgens in PCOS.
5. Once hormones enter the cell, they can bind to the intracellular hormone receptor located in the nucleus or cytoplasm.
6. Binding of the hormone causes transformation of the receptor to expose DNA-binding domain and translocation to the nucleus, where it binds to enhancer elements in DNA.
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Question 18

Cyclic GMP signaling pathway (eg, in the corpus cavernosum)

Answer 18

1. Nitric oxide (NO) aka EDRF in corpus cavernosum binds to guanylate cyclase receptors.
2. Activated guanylate cyclase creates increased levels of cGMP.
3. cGMP activates protein kinase G, which mediates smooth muscle relaxation in blood vessels.
4. Smooth muscle relaxation (vasodilation) of the intimal cushions of helicon arteries leads to vasodilation and increased inflow of blood into the spongy tissue of the penis, causing an erection.
5. Sildenafil protects cGMP from degradation by cGMP-specific phosphodiesterase type 5 (PDE5) in the corpus cavernosum of the penis, leading to longer erections.
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Question 19

Pigment stones

Answer 19

Most common in rural Asian populations, with increased incidence in women and elderly. Pigment stones account for only 10-25% of gallstones in US. Brown pigment stones typically arise 2/2 infection of biliary tract by E coli, Ascaris lumbricoides, or liver fluke Opisthorchis sinensis, which results in release of beta-glucuronidase by injured hepatocytes and bacteria. Beta-glucuronidase hydrolyzes conjugated bilirubin into unconjugated bilirubin in bile. Increased amount of unconjugated bilirubin in bile makes pigment gallstones more likely to precipitate out.

Question 20

7-alpha-hydroxylase

Answer 20

Converts cholesterol to bile acids. Sufficient activity of 7-alpha-hydroxylase reduces likelihood of cholesterol gallstone formation.

Question 21

Heterozygous familial hypercholesterolemia

Answer 21

An AD LDL receptor defect that causes high LDL levels and increases risk of premature atherosclerosis. Homozygous familial hypercholesterolemia (rarer and more severe form) often presents with coronary heart disease/MI in childhood/adolescence.

Question 22

Scurvy

Answer 22

1. Vitamin C deficiency impairs hydroxylation of proline/lysine residues on pro-alpha-collagen in the rough endoplasmic reticulum.
2. Defective hydroxylation of these residues severely diminishes the amount of collagen secreted by fibroblasts and impairs triple helix stability and covalent crosslink formation that helps collagen attain maximum tensile strength.
3. Scurvy occurs primarily among malnourished populations in the US, such as alcoholics, poor, elderly (tea and toast diet).
4. Sx of scurvy reflect impaired collagen formation: gingival swelling/bleeding, petechiae, ecchymoses, poor wound healing, perifollicular hemorrhages, coiled corckscrew hair.
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Question 23

Collagen synthesis

Answer 23

1. Collagen genes transcribed in the nucleus and translated by RER-bound ribosomes. Signal sequence directs growing polypeptide chain into RER.
2. Pre-pro-alpha-chains become pro-alpha-chains once the signal sequence is cleaved.
3. Hydroxylation (post-translational modification) of selected proline and lysine residues (vitamin C dependent) by prolyl hydroxylase and lysyl hydroxylase, respectively.
4. Glycosylation of selected hydroxylysine residues with galactose and glucose.
5. Assembly of pro-alpha-chains into procollagen triple helix.
6. Procollagen transferred from RER to Golgi apparatus and secreted into extracellular matrix.
7. Terminal propeptides cleaved by N- and C- procollagen peptidases to form insoluble tropocollagen.
8. Tropocollagen molecules spontaneously self-assemble into collagen fibrils.
9. Covalent cross links are formed by lysyl oxidase.
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Question 24

What causes bruises to look green several days after an injury?

Answer 24

Heme oxygenase converts heme from broken down RBCs into biliverdin, a green pigment.

Question 25

How is heme metabolized?

Answer 25

1. Heme degraded to biliverdin (and CO and ferric iron) by Heme Oxygenase (contained in macrophages). Oxygen and electrons are provided by NADH and NADPH-cytochrome P450 reductase.
2. Biliverdin (green) is further converted to unconjugated bilirubin (yellow pigment) by Biliverdin reductase.
3. Unconjugated bilirubin is bound to albumin and transported to the liver.
4. In the liver, bilirubin is conjugated with glucuronic acid by bilirubin glucuronyl transferase (UGT) to form conjugated bilirubin, which is excreted by the liver as bile.
5. Conj. bilirubin is broken down in the colon by bacterial dehydrogenase to urobilinogen, which is then broken down to stercobilin, which gives stool its brown color.
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Question 26

Hemoglobin vs. myoglobin

Answer 26

Individual subunits of hemoglobin molecule are structurally analogous to myoglobin. If separated, monomeric subunits will demonstrate hyperbolic oxygen-dissociated curve similar to myoglobin, as myoglobin only has a single heme group and therefore does not experience heme-heme interactions. Myoglobin is a monomeric protein, the primary oxygen-storing protein in skeletal and cardiac muscle tissue, found only in the bloodstream after muscle injury.

Question 27

Peptide bond formation

Answer 27

Catalyzed by peptidyl transferase on eukaryotic ribosomes

Question 28

Lactic acidosis

Answer 28

An anion-gap metabolic acidosis that results from overproduction and/or impaired clearance of lactic acid. Ex. In septic shock, impaired tissue oxygenation decreases oxidative phosphorylation, leading to shunting of pyruvate to lactate after glycolysis, causing an increase in lactic acid formation. Hepatic hypoperfusion also contributes to the buildup of lactic acid, as the liver is the primary site of lactate clearance.

Question 29

Causes of lactic acidosis

Answer 29

1. Enhanced metabolic rate (eg, seizures, exercise)
2. Reduced oxygen delivery (eg, cardiac or pulmonary failure, shock, and tissue infarction)
3. Diminished lactate catabolism due to hepatic failure or hypoperfusion
4. Decreased oxygen utilization (eg, cyanide poisoning)
5. Enzymatic defects in glycogenolysis or gluconeogenesis
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Question 30

Chronic myelogenous leukemia (CML)

Answer 30

1. Philadelphia chromosome mutation
2. t(9:22) BCR-ABL fusion protein
3. Sx. constitutional symptoms (eg, fatigue, weight loss, excessive sweating), splenomegaly, leukocytosis with marked left shift (eg, myelocytes, metamyelocytes, band forms)
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Question 31

Essential thrombocytosis

Answer 31

1. JAK2 mutation (constitutive tyrosine phosphorylation activity leading to persistent activation of STAT).
2. Sx. Hemorrhagic and thrombotic symptoms (eg, easy bruising, microangiopathic occlusion), thrombocytosis, megakaryocytic hyperplasia.
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Question 32

Polycythemia vera

Answer 32

1. JAK2 mutation (constitutive tyrosine phosphorylation activity leading to persistent activation of STAT).
2. Sx. Pruritis, erythromelalgia, splenomegaly, thrombotic complications, erythrocytosis and thrombocytosis
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Question 33

Primary myelofibrosis

Answer 33

1. JAK2 mutation (constitutive tyrosine phosphorylation activity leading to persistent activation of STAT).
2. Myelofibrosis is caused by atypical megakaryocytic hyperplasia. Clonally expanded megakaryocytes activate fibroblast proliferation, resulting in progressive replacement of marrow space by extensive collagen deposition.
3. As disease progresses pancytopenia can result.
4. Hepatomegaly and massive splenomegaly occur in myelofibrosis b/c of loss of bone marrow hematopoiesis is compensated for by extramedullary hematopoiesis.
5. Sx. severe fatigue, massive splenomegaly (often causing early satiety/abdominal discomfort), hepatomegaly, anemia and bone marrow fibrosis.
6. Peripheral smear characteristically shows teardrop-shaped RBCs (dacrocytes) and nucleated RBCs.
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Question 34

Tx for primary myelofibrosis

Answer 34

JAK2 inhibitor (ruxolitinib)

Question 35

What is the classic mutation of chronic myeloproliferative disorders (except CML)?

Answer 35

V617F mutation in cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2), substituting bulky phenylalanine for conserved valine at position 617 resulting in constitutive tyrosine phosphorylation activity and consequently cytokine-independent activation of JAK-STAT pathway.

Question 36

Left shift on the oxygen-hemoglobin dissociation curve is caused by?

Answer 36

1. Decreased H+ (increased pH)
2. Decreased 2,3 BPG
3. Decreased temperature (think LUNGS = Left shift)
4. High oxygen affinity hemoglobin (eg, fetal hemoglobin or Hgb A under conditions of increased pH, decreased temperature, or decreased 2,3-BPG.)
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Question 37

Right shift on the oxygen-hemoglobin dissociation curve is caused by?

Answer 37

1. Increased H+ (decreased pH)
2. Increased 2,3 BPG
3. Increased temperature
4. Low oxygen affinity hemoglobin (eg, Hgb A has low affinity for oxygen under conditions such as decreased pH, increased temperature, and increased 2,3-BPG)
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Question 38

Glycolysis steps

Answer 38

1. Glucose —> G6P (glucokinase/hexokinase)
2. G6P >—> F6P (G6P isomerase)
3. F6P —> 2,6 FBP (phosphofructokinase 2)
4. 2,6 FBP —> F6P (FBPase-2)
5. F6P —> 1,6 FBP (phosphofructokinase 1)
6. 1,6 FBP >—> G3P and DHAP
7. G3P >—> 1,3 BPG (NAD+ to NADH)
8. 1,3 BPG >—> 3PG (phosphoglycerate kinase, +ATP)
9. 3PG >—> 2PG
10. 2PG >—> PEP
11. PEP —> pyruvate (pyruvate kinase +ATP)
12. Glycolysis takes place in CYTOPLASM
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Question 39

What are the regulators of phosphofructokinase-1?

Answer 39

1. • feedback: ATP, citrate
2. • feedback: AMP, 2,6 FBP
3. PFK-1 uses 1 ATP to turn F6P into 1, 6 FBP
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Question 40

What are the regulators of glucokinase and hexokinase?

Answer 40

1. F6P negatively inhibits glucokinase (in hepatocytes and pancreatic beta cells).
2. G6P negatively inhibits hexokinase.
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Question 41

What step in glycolysis do RBCs bypass and why?

Answer 41

1. Bypass ATP-producing step of 1,3 BPG —> 3PG by phosphoglycerate kinase.
2. Instead 1,3 BPG —> 2,3 BPG by bisphosphoglycerate mutase (BPGM).
3. 2,3-BPG binds with high affinity to Hgb (forming ionic bonds with the β subunits of deoxygenated Hb A), causing conformational change that results in release of oxygen, allowing local tissues to pick up free oxygen.
4. Also important in placental cells, where fetal and maternal blood come within close proximity. Placenta produces 2,3-BPG so that oxygen is released from nearby maternal hemoglobin A and can bind fetal hemoglobin F, which has a much lower affinity for 2,3-BPG.
5. 2,3-BPG can then be converted into 3PG by BPG phosphatase, and return to glycolysis.
6. No other cells except RBCs and placental cells contain these two enzymes as it is an energetically wasteful step.
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Question 42

What are the regulators of pyruvate kinase?

Answer 42

1. • feedback: ATP, alanine

2. + feedback: 1,6 FBP

Question 43

Kwashiorkor

Answer 43

1. Results from protein-deficient MEALS
2. Malnutrition
3. Edema
4. Anemia
5. Liver (fatty)
6. Skin lesions- dark, flaky
7. Caused by inadequate intake of protein in setting of adequate calorie intake. Typically seen in underdeveloped countries in children about 1 year of age, when weaning begins.
8. Results in skin lesions (dark, flaky patches), diarrhea, stunted growth, increased susceptibility to infections, pitting edema 2/2 decreased plasma oncotic pressure, and hepatomegaly/fatty liver changes 2/2 decreased apolipoprotein synthesis.
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Question 44

Marasmus

Answer 44

1. Total calorie malnutrition, caused by inadequate intake of calories, typically seen in underdeveloped countries in children younger than 1 year, when breast milk is supplemented with calorie-deficient cereals.
2. Emaciation (tissue and muscle wasting, loss of subcutaneous fat) +/- edema
3. Marasmus results in Muscle wasting. Increased susceptibility to infections, stunted growth, weakness, anemia.
4. Malnutrition affects every organ system in the human body. Initial effects include loss of body weight, fat stores, and muscle mass.
5. Protein mass lost from several organs, including heart, liver, and kidneys. Respiratory function is depressed as respiratory muscles atrophy, leading to decreased tidal volume. Cardiac output decreased.
6. Hepatic function suffers, leading to decreased albumin production (especially marked in kwashiorkor, causing characteristic edema).
7. Immune system depressed with decreased T lymphocytes and impaired complement and granulocytic activity.
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Question 45

Zinc deficiency

Answer 45

1. Mineral essential as a cofactor for the activity of 100+ metalloenzymes.
2. Important in formation of zinc fingers (transcription factor motifs).
3. Zinc deficiency results in dermatitis, increased susceptibility to infection, stunted growth, altered mental status, delayed wound healing, hypogonadism, decreased post-pubertal hair (axillary, facial, pubic), dysgeusia (altered sense of taste), anosmia, acrodermatitis enteropathica.
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Question 46

Phytomenadione deficiency

Answer 46

1. Vitamin K = phytomenadione, phylloquinone, phytonadione
2. Cofactor for glutamate carboxylase, an enzyme involved in post-translational γ-carboxylation of glutamic acid residues on clotting factors 2, 7, 9, 10.
3. Synthesized by intestinal flora.
4. Necessary for synthesis of clotting factors: II, VII, IX, X and proteins C and S.
5. Vitamin K not present in breast milk and poor diffusion of Vitamin K across placenta; neonates given Vitamin K injection at birth to avoid neonatal hemorrhage (aka hemorrhagic disease of newborns).
6. Neonates have sterile intestines and are unable to synthesize vitamin K.
7. Vitamin K deficiency occurs after prolonged use of broad spectrum antibiotics (suppress bowel flora) or with fat malabsorption syndromes.
8. May present with bleeding from mucus membranes, impaired blood clotting, or increased bruising. Labs reveal increased PT and aPTT but normal bleeding time and thrombin time.
9. Tx with Vitamin K supplementation.
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Question 47

Tocopherol deficiency

Answer 47

1. Vitamin E = tocopherol, tocotrienol
2. Believed to act as an antioxidant, reacting with free radicals and thereby protecting cellular membranes from damage (esp RBCs).
3. Vit E deficiency occurs in fat malabsorption syndromes and abetalipoproteinemia.
4. Manifests as vision disturbances, acanthocytosis (spur cells), hemolytic anemia (due to increased RBC membrane fragility), neurologic dysfunction (ataxic gait, areflexia, decreased proprioception due to posterior column and spinocerebellar tract demyelination) and myopathies.
5. Can enhance anticoagulant effects of warfarin (in excess)
6. Neurological presentation is similar to vitamin B12 deficiency but without megaloblastic anemia, hypersegmented PMNs or increased MMA.
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Question 48

Vitamin D

Answer 48

1. D2 = ergocalciferol (ingested from plants)
2. D3 = cholecalciferol (consumed in milk, formed in the stratum basal of sun-exposed skin)
3. 25-OH-cholecalciferol = storage form
4. 1, 25-(OH)2-cholecalciferol = calcitriol (active form, hydroxylated by liver/kidney)
5. Active vitamin D increases intestinal absorption of calcium (by stimulating synthesis of calcium-binding protein found in intestine) and phosphate, increases bone mineralization at low levels, and increases bone resorption at high levels (releasing calcium into blood). Also increases calcium reabsorption by the distal tubules of the kidneys.
6. Breast fed infants require oral vitamin D supplementation.
7. Causes of vitamin D deficiency include malnutrition, fat malabsorption syndromes, decreased exposure to sun, liver disease, and chronic renal failure.
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Question 49

Rickets

Answer 49

1. Vitamin D deficiency in young children
2. Sx. skeletal deformities (bow-legged, resulting from disruption of mineralization at epiphyseal plates), bone pain, shortened stature, pigeon breast (resulting from sternum protrusion), rachitic rosary (costochondral junction thickening), late closing of fontanelles, craniotabes (thinning of occipital and parietal bones), and hypocalcemic tetany.
3. Exacerbated by low sun exposure, pigmented skin, prematurity.
4. Vitamin D supplementation, adequate sunlight exposure.
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Question 50

Osteomalacia

Answer 50

1. Vitamin D deficiency in adults
2. Diffuse bone pain, muscle weakness, pathologic fractures, hypocalcemia, hypocalcemic tetany.
3. Causes of vitamin D deficiency include malnutrition (decreased milk consumption), fat malabsorption syndromes, pigmented skin, decreased exposure to sun, liver disease, and chronic renal failure.
4. Radiographs demonstrate diffuse radiolucency with thinning of cortical bone.
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Question 51

Vitamin D toxicity

Answer 51

1. Hypercalcemia, hypercalciuria, loss of appetite, stupor, calcification of soft tissues, nephrolithiasis, bone demineralization.
2. Seen in granulomatous disease (eg, sarcoidosis) secondary to increased activation of Vitamin D by epitheloid macrophages.
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Question 52

Ascorbic acid

Answer 52

1. Vitamin C = ascorbic acid
2. Antioxidant, facilitates iron absorption (“absorbic” acid) by reducing it to Fe2+ state, which is easier to absorb.
3. Vitamin C required as a cofactor for hydroxylation of proline and lysine in collagen synthesis.
4. Necessary for metabolism of tyrosine, conversion of dopamine to norepinephrine by dopamine beta-hydroxylase, and synthesis of carnitine.
5. Ancillary treatment for methemoglobinemia (reduces Fe3+ to Fe2+).
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Question 53

Vitamin C deficiency

Answer 53

1. Usually caused by dietary inadequacy. More often seen in elderly, alcoholics, homeless, or patients with chronic illnesses such as cancer or chronic renal failure.
2. Scurvy = “Vitamin C deficiency causes sCurvy due to a Collagen synthesis deficiency.”
3. Sx of scurvy: gingival swelling, bleeding gums, bruising, petechiae/purpura, hemarthrosis, anemia (iron deficiency due to decreased absorption), fatigue, weakness, poor wound healing, perifollicular hemorrhages, subperiosteal hemorrhages, “corkscrew” hair, weakened immune response, osteoporosis.
4. Tx Vitamin C supplementation.
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Question 54

Ascorbic acid toxicity

Answer 54

Vitamin C deficiency is characterized by nausea, vomiting, diarrhea, fatigue, calcium oxalate nephrolithiasis, and an increased risk of iron toxicity in predisposed individuals (eg, chronic transfusions, hemochromatosis).

Question 55

Retinol

Answer 55

1. Vitamin A (retinol) derivatives: 11-cis-retinol involved in synthesis of rhodopsin (visual pigment in retinal cells).
2. Retinoic acid regulates cell growth and differentiation and is essential for normal differentiation of epithelial cells into specialized tissue (eg, pancreas cells), prevents squamous metaplasia.
3. β-carotene (precursor for vitamin A) is an antioxidant.
4. Deficiency occurs due to fat malabsorption syndromes (pancreatic insufficiency, cystic fibrosis, cholestatic liver disease, celiac sprue, inflammatory bowel disease, gastrectomy), mineral oil laxative abuse, and malnutrition. Occurs most commonly in elderly and urban poor in the US.
5. Early sx. night blindness (nyctalopia), poor wound healing, increased susceptibility to infection, Bitot spots (white patches on conjunctiva).
6. Late sx. keratomalacia (corneal degeneration 2/2 ulceration and keratinization of cornea), xerosis cutis (dry, scaly skin due to hyperkeratinization), and eventually complete blindness.
7. Tx with vitamin A supplementation (30,000 IU daily for 1 week for early deficiency; 20,000 IU/kg for 5 days for late deficiency. Early signs of deficiency can often be reversed with supplementation.
8. Treats measles and AML type M3 (all-trans retinoid acid aka ATRA). Oral isotretinoin tx cystic acne.
9. Found in liver and leafy vegetables.
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Question 56

Vitamin A toxicity

Answer 56

Vitamin A toxicity occurs with ingestion of more than 50,000 IU per day of vitamin A for longer than 3 months. Sx of acute toxicity include nausea, vomiting, diarrhea, vertigo, blurred vision. Sx of chronic toxicity include alopecia, dry scaly skin, hepatomegaly and toxicity, arthralgia, pseudo tumor cerebra (headaches, papilledema). Vitamin A is teratogenic, do not supplement during pregnancy.

Question 57

Thiamine

Answer 57

1. Vitamin B1 = Thiamine
2. Precursor for thiamine pyrophosphate (TPP), a cofactor for several dehydrogenase enzymes involved in carbohydrate and AA metabolism: pyruvate dehydrogenase (pyruvate–> acetyl coA), α-ketoglutarate dehydrogenase (α-ketoglutarate–>succinyl coA), transketolase (HMP shunt)–> branched-chain ketoacid dehydrogenase (valine, isoleucine, leucine degradation).
3. TPP also implicated in nerve conduction.
4. B1 needed for ATP: Alpha-ketoglutarate, Transketolase, Pyruvate dehydrogenase.
5. Deficiency of B1 causes Ber1 Ber1.
6. Administration of IV glucose to malnourished patients can exhaust supply of thiamine and precipitate Wernicke-Korsakoff syndrome–> give thiamine prior to or simultaneously with glucose for patients at high risk for Wernicke encephalopathy.
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Question 58

Thiamine deficiency

Answer 58

1. Dx of B1 deficiency: increased RBC transketolase activity after giving vitamin B1.
2. Deficiency causes impaired glucose breakdown, leading to ATP depletion, which is worsened by glucose infusion. Highly aerobic tissues are affected first (brain and heart).
3. Most commonly associated with alcoholism. Leads to deficiency through poor dietary nutrition and impaired absorption of thiamine. Also associated with malnutrition (tea and toast diet), malabsorption syndromes, and dialysis treatment.
4. Wernicke-Korsakoff syndrome: a combination of Wernicke encephalopathy (characterized by triad of confusion, ataxia, ophthalmoplegia) and Korsakoff syndrome (amnesia, confabulation, personality changes 2/2 damage to the medial dorsal nucleus of the thalamus and mammillary bodies).
5. Dry beri beri: polyneuritis, symmetrical muscle wasting, muscle cramps, poor appetite, peripheral motor and sensory neuropathy.
6. Wet beri beri: dilated cardiomyopathy leading to high output heart failure and pulmonary edema.
7. Tx high-dose parenteral thiamine. Abt 50% of patients with have partial to no resolution of their sx.
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Question 59

Riboflavin

Answer 59

1. Riboflavin = vitamin B2
2. Coenzymes FAD and FMN are derived from riboFlavin.
3. FAD and FMN act as electron acceptors in many redox reactions (eg, succinate dehydrogenase in TCA, electron transport chain).
4. 2 C’s of B2 deficiency: Cheilosis (angular cheilitis, cracking/fissures at corners of lips) and Corneal neovascularization.
5. Other Sx. angular stomatitis, glossitis, keratitis, conjunctivitis, photophobia, lacrimation, seborrheic dermatitis.
6. Rare but can be seen in chronic alcoholics and severely malnourished (elderly living alone, tea and toast diet). Usually occurs in conjunction with other B vitamin deficiencies.
7. Dx with erythrocyte glutathione reductase assay or evaluation of urinary riboflavin excretion (expect to be very low).
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Question 60

Niacin

Answer 60

1. Niacin = Vitamin B3
2. Niacin is a constituent of NAD+ and NADP+, which are used in redox reactions. (B3 = 3 ATP = NAD makes approx 3 ATP in oxidative phosphorylation)
3. Niacin is supplied through dietary ingestion or derived by endogenous synthesis from tryptophan, which requires vitamin B2 and B6.
4. High doses of niacin lower levels of VLDL/LDL and raise HDL levels, and can be used to tx hypercholesterolemia and hypertriglyceridemia.
5. GI upset and facial flushing can occur with regular high-dose niacin supplementation due to increased prostaglandins causing vasodilation, which can be avoided by taking aspirin with niacin.
6. Vitamin B3 toxicity: hyperglycemia, hyperuricemia
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Question 61

Pellagra

Answer 61

1. Vitamin B3 (niacin) deficiency
2. Causes of pellagra include dietary inadequacy, alcoholism, Hartnup disease (deficiency of tryptophan), malignant carcinoid syndrome (2/2 increased tryptophan metabolism), and isoniazid treatment (2/2 decreased levels of vitamin B6 necessary to synthesize B3).
3. Sx of mild B3 deficiency include poor appetite with weight loss, weakness, and glossitis.
4. Sx of pellagra = 3 Ds of vitamin B3 deficiency: Diarrhea, Dementia (hallucinations, amnesia), Dermatitis (C3/C4 dermatome “broad collar” rash [Casal necklace], hyperpigmentation of sun-exposed areas).
   * ***********

Question 62

Hartnup disease

Answer 62

1. AR disorder caused by a deficiency of neutral amino acid (eg, tryptophan) transporters in the proximal renal tubular cells and on enterocytes.
2. This deficiency leads to defective intestinal absorption of tryptophan and neutral aminoaciduria.
3. Tryptophan = essential AA and precursor for nicotinic acid (niacin), serotonin, and melatonin. Decreased tryptophan leads to decreased conversion to niacin.
4. Hartnup disease causes pellagra = 3 Ds of B3 deficiency= Dementia, Dermatitis, Diarrhea.
5. Most children with Hartnup disease are asx but some experience waxing and waning photosensitivity and pellagra-like skin rashes as well as neurologic involvement most often leading to ataxia.
6. Labs reveal aminoaciduria with loss of neutral AAs in urine.
7. Tx with niacin supplementation and high-protein diet.
   * ***********

Question 63

Pantothenic acid

Answer 63

1. Vitamin B5 = “pento”thenic acid
2. Essential component of coenzyme A and fatty acid synthase
3. Deficiency is often seen with other B vitamin deficiencies.
4. Sx. Dermatitis, enteritis, alopecia, adrenal insufficiency.
   * ***********

Question 64

Pyridoxine

Answer 64

1. Vitamin B6 = pyridoxine
2. Pyridoxine is a precursor for pyridoxal phosphate (PLP).
3. PLP is a cofactor that acts as a carrier of amine groups during transamination reactions in amino acid breakdown (eg, ALT, AST), decarboxylation, and glycogen phosphorylase, and heme synthesis (rate-limiting step).
4. PLP also required for synthesis of cystathionine (cofactor for cystathionine synthase during methionine metabolism), heme, niacin, histamine, and some NTs (5-HT, epinephrine, NE, DA, GABA).
5. Vitamin B6 deficiency occurs most commonly as a side effect of isoniazid tx for TB. Also caused by dietary malnutrition, alcoholism, pregnancy, homocystinuria, or pharmacologic agents (eg, isoniazid, penicillamine, oral contraceptives) that interfere with pyridoxine metabolism or act as competitive inhibitors at pyridoxine-binding sites.
6. Mild deficiency results in personality disturbances (irritability depression), dermatitis, and glossitis.
7. Severe deficiency presents as convulsions (seizures), hyperirritability, peripheral neuropathy, and sideroblastic anemia.
8. Sideroblastic anemia due to impaired Hgb synthesis and iron excess. In protoporphyrin production, the rate limiting step (succinyl coA –> ALA by ALAS) requires B6 as a cofactor.
9. Pyridoxine (B6) toxicity can occur in patients receiving large doses of vitamin B6 over a long period of time. Will manifest as a sensory neuropathy that may be irreversible.
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Question 65

Biotin

Answer 65

1. Vitamin B7 = Biotin
2. Biotin deficiency is very rare. May be caused by long-term antibiotic use, long-term parenteral nutrition (TPN), or excessive ingestion of raw egg whites, which contain avidin (a protein that binds biotin and interferes with biotin digestion).
3. Biotin can be ingested in diet and is also synthesized in the bowel by intestinal flora.
4. Acts as a cofactor for 3 carboxylation enzymes (eg, pyruvate carboxylase (pyruvate–> oxaloacetate for gluconeogenesis), acetyl-coA carboxylase (acetyl coA–> malonyl-coA in fatty acid synthesis), propionyl-coA carboxylase (propionyl-coA–> methyl malonyl-coA, propionyl-coA is a product of beta-oxidation).
5. Sx. Dermatitis, alopecia, enteritis (GI upset, chronic diarrhea), generalized muscle pain with paresthesias, elevated cholesterol levels.
6. Avidin in egg whites AVIDly binds biotin.
7. Biotin supplementation for patients requiring TPN or long-term antibiotic use.
   * ***********

Question 66

Folate

Answer 66

1. Vitamin B9 = Folate = Folic acid = tetrahydrofolate (THF)
2. THF (reduced form of folic acid) is a cofactor for many one-carbon transfer reactions in nucleotide synthesis (dUMP –> dTMP), in methionine synthesis (homocysteine + THF-CH3 –> methionine + THF), and conversion of serine to glycine.
3. Found in leafy green veggies. FOLate is from FOLiage.
4. 3-4 month reserve pool in liver.
5. Absorbed in the JEJUNUM.
6. Most common vitamin deficiency in the US. Caused by poor diet (alcoholism, elderly), medications that decrease folate absorption in the jejunum (eg, phenytoin, sulfonamides such as sulfasalazine or TMP-SMX), celiac sprue, MTX use (inhibits conversion of folate to THF), or conditions in which folic acid requirements increase (eg, pregnancy, chronic hemolytic anemia).
7. Sx. macrocytic megaloblastic anemia, hypersegmented PMNs, glossitis, diarrhea, but NO neurologic sx (as in B12 deficiency) and normal MMA levels (unlike in B12 deficiency).
8. Increased homocysteine levels–> causing a hypercoagulable state and increasing risk for thrombosis.
9. Supplemental folic acid should be given early in pregnancy or to any women trying to conceive to reduce the risk of neural tube defects from maternal folate deficiency. Increased demand of synthesis during pregnancy .
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Question 67

Cobalamin

Answer 67

1. Vitamin B12 = Cobalamin
2. Cofactor for enzyme methionine synthase in methionine synthesis (transfers CH3 group from THF-CH3 as methyl cobalamin to homocysteine, creating methionine and THF).
3. Cofactor for enzyme methylmalonyl-coA mutase in the breakdown of fatty acids and branched chain amino acids (Isoleucine, Leucine, Valine). Methylmalonyl-coA mutase converts methylmalonyl-coA –> Succinyl-coA (for TCA or heme synthesis).
4. Found in animal products, synthesized only by microorganisms.
5. Absorbed in the terminal ILEUM as a B12-IF complex and stored in the liver. Intrinsic factor is produced by the parietal cells of the gastric mucosa in the body of the stomach. B12 is bound to IF in the stomach when ingested.
6. 3-4 year B12 reserve pool in the liver.
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Question 68

Vitamin B12 deficiency

Answer 68

1. Insufficient dietary intake (vegan for many years).
2. Malabsorption or decreased ileal absorption: eg, pancreatic insufficiency, celiac sprue, enteritis, Diphyllobothrium latum (fish tapeworm)infection, Crohn disease
3. Decreased production of intrinsic factor: eg, pernicious anemia (anti-IF antibodies), gastrectomy (removal of IF-producing parietal cells
4. Absence of terminal ileum due to surgical resection for Crohn’s disease
5. Blind loop syndrome leading to bacterial overgrowth and resulting competition for vitamin B12.
6. Sx. fatigue, glossitis, diarrhea, sensory ataxia, impaired proprioception, paresthesias and subacute combined degeneration of spinal cord (dorsal columns + lateral corticospinal + spinocerebellar tracts) 2/2 increased serum MMA damaging myelin in periphery and CNS. + Sx of autoimmune chronic gastritis if B12 deficiency caused by pernicious anemia.
7. Labs reveal macrocytic megaloblastic anemia, hypersegmented PMNs on blood smear, decreased serum vitamin B12, increased levels of homocysteine (hypercoagulability), increased MMA levels. Prolonged B12 deficiency leads to irreversible nerve damage.
8. If caused by pernicious anemia will detect anti-intrinsic factor antibodies and an abnormal Schilling test (tests for decreased absorption of vitamin B12).
9. Vitamin B12 and folate supplementation.
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Question 69

Iron deficiency

Answer 69

1. Iron (Fe) is a key component of heme molecules (hemoglobin and myoglobin), playing a role in oxygen transportation in blood.
2. Iron also a constituent of cytochrome molecules (complexes III, IV, and cytochrome c) of the electron transport chain in mitochondria.
3. Deficiency caused by dietary inadequacy, decreased absorption from GI tract (eg, vitamin C deficiency, or overuse of antacids can interfere with Fe absorption), blood loss (eg, menstrual or GI bleeding), increased need for iron (pregnancy or breastfeeding), or hemoglobinuria (usually associated with hemolysis).
4. Iron is primarily absorbed in the DUODENUM, after which it is transported into blood by transferrin.
5. Sx. fatigue, pallor, tachycardia and dyspnea during exercise, smooth tongue, brittle nails, development of pica (craving for odd foods such as ice or dirt).
6. Labs reveal microcytic, hypochromic anemia, decreased serum Fe, decreased serum ferritin (storage form of iron), increased TIBC, increased transferrin.
7. Iron toxicity can occur in people taking excessive amounts of iron. Excess iron promotes formation of free radicals, leading to oxidation of LDL and promoting development of CV disease.
   * ***********

Question 70

Calcium deficiency

Answer 70

1. Calcium circulates in body as free ionized form or bound to albumin. Ionized calcium required for normal muscle contraction and nerve function.
2. Calcium also a major component of skeletal system and teeth, and involved in facilitating coagulation cascade (activation of several clotting factors is calcium dependent.
3. Calcium deficiency caused by malnutrition, alcoholism, vitamin D deficiency, increased loss of calcium (renal failure, loop diuretic use), and endocrinologic disease (hypoparathyroidism, pseudohypoparathyroidism, MTC with calcitonin release).
4. Sx. muscular cramps, tetany, paresthesias, neuromuscular irritability, prolonged QT interval (ventricular arrhythmias), Trousseau sign (carpal spasm 2 mins after inflation of BP cuff above systolic BP), Chvostek sign (twitching of facial muscles on superficial tapping of facial nerve), bone pain with pathologic fractures.
5. Tx calcium and vitamin D supplementation.
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Question 71

Hypercalcemia

Answer 71

1. Most commonly caused by hyperparathyroidism or malignancy (multiple myeloma, lung, ovary, or kidney neoplasm).
2. Other causes: sarcoidosis, milk-alkali syndrome (increased calcium ingestion), vitamin D toxicity, Paget disease of bone.
3. Sx. constipation, polyuria, ventricular arrhythmias, coma.
4. Tx with IV saline and furosemide to enhance renal calcium excretion.
   * ***********

Question 72

Iodine deficiency

Answer 72

1. Necessary for thyroid hormone synthesis.
2. Hypothyroidism manifesting as cretinism (mental retardation, stunted growth) in children and myxedema (periorbital edema, thick facial features) in adults.
   * ***********

Question 73

Magnesium deficiency

Answer 73

1. Mg++ binds to ATP to facilitate ATP-dependent reactions
2. Deficiency manifests as increased excitability at NMJ leading to muscular spasms and tetany, seizures, confusion, ventricular arrhythmias, decreased PTH release resulting in hypocalcemia, hypokalemia.
3. Hypomagnesemia –> hypocalcemia and hypokalemia
   * ***********

Question 74

Phosphorus deficiency

Answer 74

1. Phosphorus is a constituent of nucleic acids, cell membranes, bone matrix.
2. Deficiency is RARE but may include bone pain with skeletal malformations or fractures, hemolytic anemia, platelet dysfunction, and encephalopathy.
   * ***********

Question 75

Ethanol metabolism

Answer 75

1. Metabolism occurs in hepatocytes and renal parenchymal cells.
2. Ethanol oxidized to acetaldehyde by alcohol dehydrogenase (requires NAD+ –> NADH, and zinc) in the cytoplasm. NAD+ is the limiting reagent to EtOH metabolism.
3. Alcohol dehydrogenase operates via zero-order kinetics, so lots of EtOH takes a while to metabolize due to fixed rate of oxidation.
4. Microsomes can also metabolize EtOH to acetaldehyde by using CYP2E1 and NADPH. Peroxisomes can metabolize EtOH by using catalase to reduce H2O2 to water.
5. Acetaldehyde oxidized to acetate by acetaldehyde dehydrogenase (NAD+ –> NADH) in the mitochondria. Acetate mostly excreted in urine. Some converted to acetyl coA by acetyl-coA synthase, which uses ATP.
6. Acetaldehyde is an unstable molecule, prone to forming free radicals, which are toxic to the liver and lead to eventual cirrhosis.
7. Acetaldehyde is also damaging to embryologic neural crest tissue and involved in the neurologic manifestations of fetal alcohol syndrome (IUGR, smooth philtrum, developmental delay, neurologic impairments).
8. Acetaldehyde dehydrogenase inhibited by disulfiram, drug marketed to tx alcoholism.
   * ***********

Question 76

Ethanol intoxication

Answer 76

1. Labs during alcohol intoxication reveal hypoglycemia and elevated serum ethanol levels.
2. Mild intoxication = AMS, euphoria, ataxia, slurred speech.
3. Severe intoxication = respiratory depression, bradycardia, hypotension, coma.
4. Alcoholics are at risk for hypoglycemia when ingesting ethanol due to gluconeogenesis inhibition.
5. EtOH metabolism increases NADH/NAD+ ratio in the liver by causing pyruvate reduction to lactate (lactic acidosis) and oxaloacetate reduction to malate in order to create more NAD+ for EtOH metabolism.
6. Gluconeogenesis is impaired (since pyruvate and oxaloacetate are necessary substrates) and fasting hypoglycemia can result in people with poor glycogen stores, such as alcoholics who are malnourished.
7. Increased NADH/NAD+ ratio also drives DHAP –> glycerol-3-phosphate, which combines with fatty acids to make triglycerides.
8. Increased utilization of acetyl-coA for ketogenesis and lipogenesis leads to hepatosteatosis over time.
   * ***********

Question 77

Macronutrients

Answer 77

1. Carbohydrates: 4 kcal/g, metabolized to glucose for fuel, fibers assist in bowel elimination.
2. Fats: 9 kcal/g, precursors for prostaglandin and leukotriene synthesis, carrier molecules for fat-soluble vitamins.
3. Proteins 4 kcal/g: source of 9 essential amino acids for synthesizing proteins and other nitrogen-containing substances.
   * ***********

Question 78

9 essential amino acids

Answer 78

1. Methionine (Met) - glucogenic
2. Valine (Val) - glucogenic
3. Histidine (His) - glucogenic (required during periods of growth)
4. Isoleucine (Ile) - glucogenic and ketogenic
5. Phenylalanine (Phe) - glucogenic and ketogenic
6. Threonine (Thr) - glucogenic and ketogenic
7. Tryptophan (Trp) - glucogenic and ketogenic
8. Leucine (Leu) - ketogenic
9. Lysine (Lys) - ketogenic
10. Essential AAs cannot be made by the body and therefore must come from diet.
    * ***********

Question 79

Nonessential amino acids

Answer 79

1. Alanine (Ala) - from pyruvate
2. Aspartic acid (Asp) - from TCA intermediates
3. Asparagine (Asn) - from TCA intermediates
4. Arginine (Arg) - from TCA intermediates (semi-essential)
5. Glutamic acid (Glu) - from TCA intermediates
6. Glutamine (Gln) - from TCA intermediates
7. Proline (Pro) - from TCA intermediates
8. Serine (Ser) - from 3-phosphoglycerate
9. Glycine (Gly) - from serine
10. Cysteine (Cys) - from serine
11. Tyrosine (Tyr) - from phenylalanine
12. ALL glucogenic, except tyrosine is also ketogenic.
    * ***********

Question 80

Break down products of glucogenic and ketogenic AAs

Answer 80

1. Isoleucine: acetyl coA and succinyl coA
2. Threonine: acetyl coA and succinyl coA
3. Tryptophan: acetoacetyl coA/acetyl coA and pyruvate
4. Phenylalanine: acetoacetyl coA and fumarate
5. Tyrosine: acetoacetyl coA and fumarate
   * ***********

Question 81

Break down products of strictly glucogenic AAs

Answer 81

1. Methionine (Met): succinyl coA
2. Valine (Val): succinyl coA
3. Histidine (His): α-ketoglutarate
4. Arginine (Arg): α-ketoglutarate
5. Glutamic acid/Glutamate (Glu): α-ketoglutarate
6. Glutamine: α-ketoglutarate
7. Proline: α-ketoglutarate
8. Alanine (Ala): pyruvate
9. Serine: pyruvate
10. Glycine: pyruvate
11. Cysteine: pyruvate
12. Aspartic acid/Aspartate (Asp): oxaloacetate
13. Asparagine: oxaloacetate
    * ***********

Question 82

Break down products of strictly ketogenic AAs

Answer 82

1. Leucine: acetoacetyl coA/acetyl coA
2. Lysine: acetoacetyl coA
3. Carbon skeleton used for ketogenesis
   * ***********

Question 83

Basic AAs (positively charged)

Answer 83

1. Arginine (Arg): semi-essential, required during periods of growth, Arg and Lys are increased in histones to bind negatively charged DNA.
2. Lysine (Lys)
3. Histidine (His): required during periods of growth, not charged at body pH.
   * ***********

Question 84

Acidic AAs (negatively charged)

Answer 84

1. Negatively charged at body pH
2. Aspartic acid (aspartate)
3. Glutamic acid (glutamate)
   * ***********

Question 85

Hyperammonemia

Answer 85

1. Can be acquired (due to liver disease) or hereditary (due to urea cycle enzyme deficiencies)
2. Results in excess NH3, which depletes α-ketoglutarate, leading to TCA inhibition.
3. Tx. limit protein in diet
4. Tx. Lactulose acidifies GI tract and traps ammonia as NH4+ for excretion.
5. Tx. Rifaximin: decreased colonic ammoniagenic bacteria.
6. Tx. Benzoate, phenylacetate, phenylbutyrate to bind NH4+ for excretion.
   * ***********

Question 86

Irreversible (unidirectional) enzymes of gluconeogenesis

Answer 86

1. Pyruvate carboxylase: requires B7, ATP (pyruvate –> oxaloacetate), mitochondria
2. PEP carboxykinase: requires GTP (oxaloacetate –> PEP), cytoplasm
3. Fructose-1,6-bisphosphatase: stimulated by citrate, inhibited by 2,6-FBP, insulin, and AMP, (1,6-FBP –> F6P), cytoplasm. Phosphatases remove a phosphate group.
4. Glucose-6-Phosphatase: muscle lacks G6Pase, occurs in endoplasmic reticulum.
5. Pathway Produces Fresh Glucose (gluconeogenesis)
   * ***********

Question 87

Why are 2,3-BPG levels increased in patients with DM?

Answer 87

1. HbA1c is formed by non enzymatic glycosylation of Hb A.
2. Glycosylation interferes with the 2,3-BPG binding pocket on the β-chains of HbA, making it more difficult for 2,3-BPG to bind.
3. Body compensates by producing increased levels of RBC 2,3-BPG in patients with DM.
   * ***********

Question 88

Pyruvate dehydrogenase complex

Answer 88

1. Mitochondrial enzyme complex linking glycolysis and TCA cycle by converting pyruvate to acetyl coA.
2. Active in the fed state.
3. Similar to α-ketoglutarate dehydrogenase complex (same cofactors and action).
4. Activated by exercise, due to increased NAD+/NADH ratio, ADP, and calcium. Inhibited by increased ATP, acetyl coA, and NADH.
5. 5 Cofactors required:
6. Vitamin B1 = thiamine pyrophosphate (TPP)
7. Vitamin B2 (riboflavin) = FAD
8. Vitamin B3 (niacin) = NAD+
9. Vitamin B5 (pantothenic acid) = co A
10. Lipoid acid
    * ***********

Question 89

Pyruvate dehydrogenase deficiency

Answer 89

1. X-linked recessive disorder
2. Deficiency of pyruvate dehydrogenase causes a build up of pyruvate that gets shunted to lactate (via LDH) and alanine (via ALT).
3. Sx. neurologic defects, lactic acidosis, increased serum alanine in infancy.
4. Tx. increase intake of ketogenic nutrients (eg, high fat content or increased lysine and leucine.)
5. Lysine and Leucine are the onLy pureLy ketogenic AAs.
   * ***********

Question 90

Rate limiting step of glycolysis and its regulators?

Answer 90

1. Phosphofructokinase 1 (PFK-1), a kinase phosphorylates by transferring a phosphate group from a high energy substrate.
2. F6P –> 1,6 FBP (uses ATP)
3. Activated by AMP and 2,6-FBP
4. Inhibited by ATP and citrate
   * ***********

Question 91

Rate limiting step of the TCA cycle and its regulators?

Answer 91

1. Isocitrate dehydrogenase (IDH)
2. Isocitrate –> α-ketoglutarate
3. Activated by ADP
4. Inhibited by ATP and NADH
   * ***********

Question 92

Ketogenesis

Answer 92

1. Fatty acid degradation results in a fatty-acyl coA being broken down by β-oxidation into acetyl-coA. Acetyl-co A can either be used in the TCA cycle or be broken down into ketone bodies through ketogenesis. HMG-coA synthase is the rate limiting step of ketogenesis.
2. acetyl coA + acetyl coA –> acetoacetyl coA (Thiolase)
3. acetoacetyl coA + acetyl coA –> HMG coA (HMG-coA synthase, rate limiting step)
4. HMG coA –> acetoacetate + acetyl coA
5. acetoacetate –> acetone (decarboxylation)
6. acetoacetate –> β-hydroxybutyrate (β-hydroxybutyrate dehydrogenase)
7. Alternatively HMG coA can be used in cholesterol synthesis instead of broken down into acetoacetate ad acetyl coA.
   * ***********

Question 93

Rate limiting step of fatty acid β-oxidation and its regulators?

Answer 93

1. Carnitine acyltransferase I (CAT I)
2. Inhibited by malonyl coA (substrate for fatty acid synthesis)
   * ***********

Question 94

Rate limiting step of Fatty Acid Synthesis and its regulators?

Answer 94

1. Acetyl-coA carboxylase (ACC)
2. Acetyl coA —> malonyl coA (ACC, requires biotin as cofactor)
3. Activated by insulin and citrate
4. Inhibited by glucagon and palmitoyl coA
   * ***********

Question 95

Rate limiting step of the urea cycle and its regulators?

Answer 95

1. Carbamoyl phosphate synthetase I (CAP synthetase)
2. CO2 + NH3 + N-acetylglutamate –> carbamoyl phosphate
3. CAP synthetase activated by N-acetylglutamate.
   * ***********

Question 96

Rate limiting step of de novo purine synthesis and its regulators?

Answer 96

1. PRPP synthetase and Glutamine-PRPP amidotransferase
2. Ribose-5-P + ATP –> PRPP (PRPP synthetase)
3. PRPP + glutamine –> glutamate + 5-phosphoribosyl amine (PRPP amidotransferase)
4. Both enzymes inhibited by AMP, IMP, GMP.
5. PRPP amidotransferase activated by PRPP.
6. PRPP= phosphoribosyl pyrophosphate
   * ***********

Question 97

Rate limiting step of de novo pyrimidine synthesis and its regulators?

Answer 97

1. Carbamoyl phosphate synthetase II
2. Glutamine + CO2 + 2 ATP–> carbamoyl phosphate
3. Activated by ATP and PRPP
4. Inhibited by UTP
   * ***********

Question 98

Rate limiting step of HMP shunt and its regulators?

Answer 98

1. HMP = hexose monophosphate shunt (aka pentose phosphate pathway)
2. Glucose-6-phosphate dehydrogenase (G6PD)
3. G6P —> Ribulose5-P
4. Activated by NADP+
5. Inhibited by NADPH
   * ***********

Question 99

Rate limiting step of glycogenolysis and its regulators?

Answer 99

1. Glycogen phosphorylase
2. Glycogen (branched) –> glycogen w/ 4 glucose branch
3. Activated by glucagon, epinephrine, AMP, calcium.
4. Inhibited by insulin, ATP, G6P.
   * ***********

Question 100

Rate limiting step of glycogenesis and its regulators?

Answer 100

1. Glycogen synthase
2. UDP glucose –> glycogen
3. Activated by G6P, insulin, cortisol
4. Inhibited by glucagon, epinephrine
   * ***********

Question 101

Rate limiting step of cholesterol synthesis and its regulators?

Answer 101

1. HMG-coA reductase
2. HMG coA –> mevalonate
3. Activated by insulin, thyroxine
4. Inhibited by glucagon, cholesterol
   * ***********

Question 102

Irreversible enzymes of TCA cycle and their regulators?

Answer 102

1. Citrate synthase: inhibited by ATP, NADH, succinyl coA
2. Isocitrate dehydrogenase (rate limiting step): inhibited by ATP, NADH, activated by ADP.
3. α-ketoglutarate dehydrogenase: inhibited by ATP/GTP, NADH, succinyl coA.
   * ***********

Question 103

Each molecule of acetyl coA entering the TCA cycle yields?

Answer 103

1. 2 CO2
2. 3 NADH
3. 1 FADH2
4. 1 GTP
5. = approximately 10 ATP molecules
   * ***********

Question 104

Cori cycle

Answer 104

1. Lactate created by active muscle is taken up by the liver and converted to glucose through gluconeogenesis. Glucose is then released back to the blood for muscle to use.
2. Allows muscle to function anaerobically for net 2 ATP molecules per glycolytic cycle.
   * ***********

Question 105

Metabolic processes that occur exclusively in mitochondria

Answer 105

1. TCA cycle
2. Oxidative phosphorylation
3. Ketogenesis
4. Acetyl coA production
5. β-oxidation of fatty acid degradation
   * ***********

Question 106

Metabolic processes that occur in the cell cytoplasm

Answer 106

1. Glycolysis
2. HMP shunt
3. Steroid synthesis (SER)
4. Protein synthesis (RER)
5. Fatty acid synthesis
6. Cholesterol synthesis
7. Nucleotide synthesis
   * ***********

Question 107

Metabolic processes that occur in mitochondria and cytoplasm

Answer 107

1. HUGs take two.
2. Heme synthesis
3. Urea cycle
4. Gluconeogenesis
   * ***********

Question 108

Complex I

Answer 108

1. Complex I = NADH dehydrogenase
2. Contains Fe atoms.
3. Oxidizes NADH –> NAD+ by reducing FMN –> FMNH2.
4. Generates H+ to create proton gradient.
5. Complex I inhibitors: Amobarbital and Rotenone
6. RotenONE is a complex ONE inhibitor (insecticide/pesticide).
   * ***********

Question 109

Complex II

Answer 109

Complex II (succinate dehydrogenase) creates FADH2 from succinate–>fumarate, and then oxidizes FADH2 –> FAD and transfers e- to coQ.

Question 110

Coenzyme Q

Answer 110

CoQ accepts e- from FMNH2 (complex I) and FADH2 (complex II) and transfers these electrons to cytochrome b in the electron transport chain.

Question 111

Complex III

Answer 111

1. Complex III = cytochrome b
2. Contains heme group with Fe3+ to accept e- from coQ and transfer e- to cytochrome c.
3. Generates H+ to create proton gradient.
4. Inhibited by Antimycin A.
5. “An-3-mycin A inhibits complex 3.”
   * ***********

Question 112

Cytochrome c

Answer 112

Contains heme group with Fe3+ accepting e- from complex III reducing Fe3+ to Fe2+. Transfers e- to cytochrome a.

Question 113

Complex IV

Answer 113

1. Complex IV = cytochrome a = cytochrome c oxidase
2. Contains cytochrome a with Fe3+ to accept e- from cytochrome c and reduce Fe3+ to Fe2+.
3. Fe2+ transfers e- to O2, which combines with H+ to make H2O.
4. Generates H+ to create proton gradient.
5. Complex IV is inhibited by cyanide, carbon monoxide, and sodium azide.
   * ***********

Question 114

ATP synthase

Answer 114

1. Complex V = ATP synthase
2. Proton channel allows for H+ to cross into matrix using H+ gradient to form ATP.
3. Oligomycin is a direct inhibitor of ATP synthase.
4. Antibiotic.
   * ***********

Question 115

Uncoupling agents of the ETC and oxidative phosphorylation

Answer 115

1. 2,4-dinitrophenol - used for illicit weight loss
2. Aspirin overdose - fevers often occur
3. Thermogenic in brown fat
4. Act to uncouple ATP formation by ATP synthase from electron transport chain by increasing membrane permeability and dissipating the proton gradient.
5. Oxygen consumption increases but ATP synthase stops functioning.
6. Electron transport continues, producing heat (fever).
   * ***********

Question 116

Malate shuttle

Answer 116

1. Used to shuttle oxaloacetate across the mitochondrial membrane.
2. Aspartate—-> oxaloacetate —> malate (NADH –> NAD+)
3. Malate and aspartate can travel across membrane.
4. Malate –> oxaloacetate (NAD+ –> NADH) once inside mitochondria.
5. Oxaloacetate inside mitochondria can —-> aspartate and then traverse the mitochondrial membrane into the cytosol.
   * ***********

Question 117

Lead poisoning

Answer 117

1. Increased blood lead level (BLL > 10 µg/dL) leads to the inhibition of sulfhydryl-dependent enzymes such as γ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase, both enzymes involved in heme synthesis.
2. Inorganic lead is absorbed via lungs and GI tract.
3. Lead disrupts heme synthesis by inhibiting ALAD and ferrochelatase, leading to an increase in free erythrocyte porphyrin (FEP) levels (eg, ALA), which contribute to oxidative damage to several organ systems, including demyelination and axonal degeneration, decreased RBC survival time, increased hemolysis, renal toxicity, and hypertension.
4. Sx. abdominal pain (lead colic), constipation, irritability, difficulty concentrating, arthralgia, myalgia, encephalopathy, anorexia, decreased libido, “lead line” (bluish pigmentation seen at gum-tooth line), peripheral neuropathy (extensor weakness or wrist/ankle drop).
5. Labs reveal elevated BLL, elevated FEP, microcytic hypochromic anemia, basophilic stippling on peripheral blood smear. Lead lines on x-ray film of long bone epiphyses.
6. Tx. reduce lead exposure. Chelation with succimer (2,3-dimercaptosuccinic acid = DMSA) if BLL higher than 45 µg/dL and less than 80 µg/dL. Can also use penicillamine for BLL 20-40 µg/dL.
7. IV therapy with combination of dimercaprol and CaNa2 EDTA (edetic acid) preferable for persons with BLLs > 70 µg/dL and in the presence of lead encephalopathy.
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Question 118

Heme synthesis

Answer 118

1. Succinyl CoA + Glycine —> D-aminolevulinic acid (ALA synthase i.e., ALAS)
2. ALA —> porphobilinogen (ALA dehydrogenase i.e., ALAD)
3. PBG —> hydroxymethylbilane (PBG deaminase)
4. HMB —> uroporphyrinogen III (UP III synthase, ring closure, aka UP III cosynthase)
5. UP III —> coproporhyrinogen III (uroporphyrinogen decarboxylase i.e., UROD)
6. CP III —> protoporphyrinogen IX (coproporphyrinogen oxidase i.e., CPOX)
7. Protoporphyrinogen IX –> protoporphyrin IX (protoporphyrinogen oxidase)
8. Protoporphyrin IX + Fe++ —>Heme (Ferrochelatase)
9. Glucose and Heme inhibit ALAS.
10. CYP450 inducers (barbiturates, antiepileptics, EtOH, smoking) activate ALAS.
11. Lead poisoning inhibits ALAD and Ferrochelatase.
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Question 119

Ferrochelatase

Answer 119

Final enzyme in heme synthetic pathway (turns Fe++ and protoporphyrin IX into heme). Inhibited by lead in lead poisoning, leading to sideroblastic anemia. Lead also inhibits ALAD in heme synthetic pathway.

Question 120

Acute intermittent porphyria (AIP)

Answer 120

1. Rare AD metabolic disorder caused by a deficiency of porphobilinogen (PBG) deaminase due to a mutation in the HMBS gene. (PBG deaminase also known as uroporphyrinogen I synthetase). Second most common form of porphyria.
2. PBG deaminase catalyzes the conversion of porphobilinogen to hydroxymethylbilane (HMB). Lack of enzyme causes ALA and PBG to accumulate, resulting in neurologic damage.
3. PBG thought to be neurotoxic and ALA promotes oxidative damage to CNS.
4. Sx. intermittent, recurrent, severe and poorly localized abdominal pain (resulting from autonomic dysregulation), neuropsychiatric signs and sx (blurred vision, hallucinations, hyporeflexia, peripheral neuropathy) and urine that darkens on exposure to air (port-wine colored urine). Patients are NOT photosensitive and have no rash.
5. Labs reveal elevated urine and plasma PBG and ALA as well as hyponatremia (2/2 SIADH, may cause seizures but many seizure meds precipitate AIP attacks).
6. Tx. Hemin decreases synthesis of ALA synthase and thus decreases PBG and ALA accumulation; must be given early in an attack.
7. Discontinuation of precipitating factors (eg, exogenous/endogenous gonadal steroids, alcohol, barbiturates, valproate, low-calorie diets).
8. Symptomatic AIP occurs in patients with the defective enzyme as well as exposure to drugs or environmental situations (such as fasting) that stimulate heme synthesis.
9. Precipitated by one of the “four Ms”: medication, menstruation (loss of blood), malnutrition, maladies (infection).
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Question 121

Hereditary coproporphyria (HCP)

Answer 121

1. AD porphyria disorder caused by deficiency in coproporphyrinogen oxidase due to mutations in CPOX gene.
2. Coproporphyrinogen oxidase (CPOX) catalyzes conversion of coproporphyrinogen III to protoporphyrinogen IX.
3. Deficiency of enzyme leads to build up of PBG and ALA, resulting in central and peripheral neurologic damage as well as skin damage due to deposition of porphyrin precursors in skin.
4. Sx. Intermittent, recurrent colicky abdominal pain (resulting from autonomic dysregulation), psychiatric sx, autonomic neuropathies that can manifest as seizures, constipation, hypertension, or peripheral neuropathy.
5. Patients are photosensitive and can develop blisters with long-term sun exposure.
6. Labs reveal elevated stool and urinary coproporphyrins as well as hyponatremia.
7. Tx. hemin (decrease ALAS synthesis) and discontinue precipitating factors (gonadal steroids, alcohol, barbiturates, valproate, low-calorie diets). Seizure control as needed.
8. Symptomatic HCP occurs in patients with the defective enzyme as well as exposure to drugs or environmental situations (such as fasting) that stimulate heme synthesis.
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Question 122

Congenital erythropoietic porphyria

Answer 122

1. AR heme synthesis disorder characterized by markedly deficient activity of uroporphyrinogen III synthase.
2. UP III synthase catalyzes the conversion of hydroxymethylbilane (HMB) into uroporphyrinogen III during heme synthesis.
3. Deficiency of UP III synthase leads to accumulation of uroporphyrinogen I and coproporphyrinogen I (derivatives/isomers of HMB) in bone marrow, erythrocytes, teeth, plasma, and urine.
4. Porphyrin deposition in teeth leads to discoloration.
5. Increased porphyrins in RBCs leads to hemolysis and splenomegaly.
6. Porphyrin damage to BM leads to increased susceptibility to infections.
7. Porphyrin deposition in the skin results in formation of free radicals, damaging cells and leading to photosensitivity.
8. Manifests as severe cutaneous photosensitivity in early infancy with appearance of friable bullae and vesicles.
9. Other skin sx include skin thickening, focal pigmentation, facial and extremity hypertrichosis. Disfigurement of face and hands, reddish-brown teeth, and splenomegaly.
10. Labs reveal elevated levels of uroporphyrinogen I and coproporphyrinogen I in the urine.
11. Tx. Blood transfusions to suppress erythropoiesis, splenectomy to reduce hemolysis, β-carotene supplementation (free radical scavenger), and possible BM transplantation in severe cases.
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Question 123

Porphyria cutanea tarda

Answer 123

1. AD disorder caused by hepatic uroporphyrinogen decarboxylase (UROD) deficiency. Sporadic cases may occur.
2. Most common porphyria.
3. UROD catalyzes conversion of uroporphyrinogen III to coproporhyrinogen III.
4. When UROD defective, uroporphyrinogen III accumulates, resulting in deposition of excess porphyrins in the skin, which cause free radicals that damage skin cells and lead to photosensitivity.
5. Sx. cutaneous photosensitivity presents as fluid-filled vesicles and bullae over sun-exposed areas of face, dorsum of hands and feet, forearms, and legs. Often, small white milia precede vesicle formation.
6. Sx. Hypertrichosis (excess hair), hyperpigmentation, skin thickening. No neurologic manifestations.
7. Labs reveal elevated porphyrins in plasma and urine. Urinary ALA slightly increased. Urinary PBG normal.
8. Tx. repeated phlebotomy to reduce hepatic iron. Low dose chloroquine. Stop use of alcohol, iron supplements, and estrogen, which can all exacerbate symptoms.
9. HIV and hepatitis can precipitate symptom onset.
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Question 124

Healthy 2 year old with clouding of eye lenses consistent with cataracts. Normal height weight and developmental milestones.

Answer 124

1. Galactokinase deficiency
2. Benign AR d/o caused by deficiency of galactokinase in liver cells.
3. Galactokinase phosphorylates galactose into galactose-1-phosphate in galactose metabolism.
4. If galactokinase deficiency, galactose and galactitol accumulate in serum and other tissues.
5. In lens of eye, galactose reductase and aldose reductase convert excess galactose into galacitol which causes entry of water into lens leading to development of cataracts.
6. Infant cataracts are the sole manifestation of galactokinase deficiency. No hepatic symptoms. Infantile cataracts may manifest as failure to track objects or develop a social smile.
7. Serum galactose and urine galactose will be elevated.
8. Tx is dietary restriction of galactose.
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Question 125

14 year old boy presents for physical exam with nothing remarkable other than lab studies showing positive reducing sugar in serum and urine. Blood glucose level normal at 85.

Answer 125

1. Essential fructosuria (fructokinase deficiency)
2. AR disorder caused by deficiency of fructokinase, enzyme that normally converts fructose to fructose-1-phosphate.
3. Deficiency of fructokinase activity in liver and intestine significantly reduces capacity to assimilate fructose into cells.
4. Patients usually asymptomatic and d/z comes to light incidentally. Fructose not trapped in cells as can be converted by hexokinase to F6P and be used in glycolysis (not normally a major pathway).
5. Labs reveal positive reducing sugar in the blood and urine after meals rich in fructose.
6. No tx required.
7. Essential fructosuria may be confused with DM if nature of reducing sugar in urine not defined.
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Question 126

6 month old girl brought in because baby lethargic and irritable for last several weeks. Mother just began feeding baby fruit juices several weeks ago. Child is slow in her movements, mildly jaundiced and small for her age. Has mild hepatomegaly.

Answer 126

1. Fructose intolerance
2. AR disorder caused by deficiency of fructose-1,6-bisphosphate aldolase B in the liver, kidney and intestine.
3. Aldolase B catalyzes hydrolysis of fructose-1-phosphate and 1,6-FBP into 3C sugars (DHAP, G3P, glyceraldehyde) in fructose metabolism pathway.
4. Deficiency of 1,6-FBP aldolase B causes rapid accumulation of serum fructose-1-phosphate, which has a toxic effect on the liver, impeding glycolysis, glycogenolysis, and gluconeogenesis. Increased F1P decreases free phosphate, leading to phosphate depletion.
5. Infants are asymptomatic until fructose or sucrose is first ingested (fruit, juice, sugar, sweetened cereal).
6. Clinical manifestations include lethargy, irritability, jaundice, hepatomegaly, vomiting, convulsions. Cirrhosis and kidney failure possible.
7. Labs reveal hypoglycemia yet urine dipstick negative (tests only for glucose), fructosemia, prolonged clotting time (impaired liver function), hypoalbuminemia, elevated bilirubin, transaminases.
8. Tx. Dietary elimination of sucrose, fructose, sorbitol.
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Question 127

1 month old foreign-born boy with vomiting after feedings and has been gaining weight poorly. Child did not have screening tests before or after delivery. Infant small for his age, appears jaundiced with mild heaptomegaly. Notice on PE that child’s lenses are clouded as though developing cataracts.

Answer 127

1. Classic galactosemia
2. AR disorder caused by galactose-1-phosphate uridyl transferase deficiency.
3. G1PUT usually converts galactose-1-p into glucose-1-p.
4. Deficiency results in buildup of galactose-1-phosphate, galactose, and galactitol, which are toxic to parenchymal cells of kidney, liver, lens, spleen, and brain. Increased galactose-1-phosphate decreases free phosphate, causing phosphate depletion.
5. Infants present with lethargy, irritability, feeding difficulties, poor weight gain, failure to thrive, jaundice, hepatomegaly, ascites, splenomegaly, convulsions, cataracts, and intellectual disability.
6. Labs notable for hypoglycemia, galactosuria, aminoaciduria. Hyperchloremic metabolic acidosis. Markedly reduced galactose-1-phosphate uridyl transferase activity. E. coli sepsis in neonates.
7. Tx. Exclude intake of milk and other foods rich in lactose or galactose.
8. Note: Neonates are routinely screened for galactosemia, which consists of demonstration of a reducing substance in urine specimens collected while patient is receiving milk or formula containing lactose.
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Question 128

3-year-old presents with restlessness and fatigue. Becomes fidgety between meals. Child has very fat cheeks with a “doll-like” face and protuberant abdomen. Child is short for age and arms and legs are thin compared to trunk. Expect to find marked hypoglycemia, elevated serum uric acid, and elevated serum lipids on labs.

Answer 128

1. Von Gierke Disease (Type I GSD)
2. AR disorder caused by defective glucose-6-phosphatase (G6Pase) enzyme in liver.
3. G6Pase required for conversion of G6P into glucose during gluconeogenesis and glycogenolysis. Patients unable to produce glucose from gluconeogenesis/glycogenolysis and become susceptible to fasting hypoglycemia.
4. G6P accumulates as structurally normal glycogen in the liver causing hepatomegaly.
5. Pts present at age 3-4 months with hepatomegaly or severe fasting hypoglycemia. Often have “doll-like facies” (fat cheeks), thin extremities, short stature, and protuberant abdomen (hepatomegaly).
6. Labs reveal hypoglycemia, lactic acidosis, hyperuricemia (gout), hyperlipidemia. Bxp reveals increased glycogen in liver and hepatic steatosis (due to increased TGs).
7. Tx. involves continuous NG infusion of glucose or frequent oral meals of cornstarch. Restriction of fructose and galactose from diet b/c these molecules cannot be converted to glucose. Dietary supplements of multivitamins and calcium. Allopurinol to lower levels of uric acid.
8. Other hepatic GSDs characterized by hepatomegaly and hypoglycemia: Hers’ disease (Type VI, liver glycogen phosphorylase deficiency) and phosphorylase kinase deficiency (type IX).
   * ***********

Question 129

Glycogen storage diseases (GSDs)

Answer 129

1. Very Poor Carbohydrate Metabolism Happens
2. Von Gierke disease (GSD type I) - glucose-6-phosphatase (liver only)
3. Pompe disease (GSD type II) - α-1,4-glucosidase (lysosomal acid maltase), all lysosomes
4. Cori disease (GSD type III) - α-1,6-glucosidase, debranching enzyme, all organs
5. McArdle disease (GSD type V) - glycogen phosphorylase in muscle
6. Hers disease (GSD VI) - glycogen phosphorylase in liver
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Question 130

Glycogenesis

Answer 130

1. G6P —> G1P (phosphoglucomutase)
2. G1P + UTP —> UDP-glucose (UDP-glucose pyrophosphorylase)
3. UDP-glucose (uridine diphosphoglucose) —> glycogen (glycogen synthase, stimulated by insulin, inhibited by glucagon and epinephrine)
4. less branched glycogen —> branched glycogen (branching enzyme).
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Question 131

Glycogenolysis

Answer 131

1. Glycogen –> glycogen w/ limit dextrin (4 glucose branch) (glycogen phosphorylase, stimulated by glucagon, epinephrine, calcium, inhibited by insulin)
2. Glycogen with limit dextrin —> glycogen with 1 glucose (debranching enzyme, 4-α-glucanotransferase)
3. Glycogen with 1 glucose branch–> glycogen + G1P (α-1,6-glucosidase)
4. G1P —> G6P (phosphoglucomutase)
5. G6P —> glucose (G6Pase, liver only)
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Question 132

3-month-old girl not feeding well and has poor weight gain. On exam has a large tongue, mild hepatomegaly, and is flaccid and hypotonic. EKG shows short PR interval and wide QRS. Serum studies show elevated creatine kinase, aspartate transaminase, and lactate dehydrogenase.

Answer 132

1. Pompe disease (Type II GSD)
2. AR disorder caused by deficiency of lysosomal acid α-1,4-glucosidase.
3. Lysosomal α-1,4-glucosidase (lysosomal acid maltase) breaks down glycogen in lysosomal vacuoles. If defective, lysosomal glycogen accumulates in skeletal muscle, cardiac muscle, liver, and kidneys, leading to myopathy, cardiomyopathy, and hepatic dysfunction.
4. Infantile-onset: patients present by 4-8 months with hypertrophic cardiomyopathy, cardiomegaly, hypotonia, failure to thrive, macroglossia, and hepatomegaly. Death occurs by age 1 due to respiratory weakness and heart failure. “Pompe trashes the pump (heart).”
5. Juvenile-onset: presents as delayed motor milestones, difficulty walking, swallowing difficulties, and respiratory muscle weakness with death 2/2 respiratory failure in 30s.
6. Adult-onset: presents as slowly progressive proximal muscle weakness with truncal involvement. No significant cardiac involvement in juvenile or adult forms.
7. Labs reveal elevated serum CK, AST, LDH.
8. Muscle biopsy shows vacuoles staining positively for glycogen (PAS+).
9. No effective treatment for infantile form. High protein diet for juvenile and adult forms, ventilatory support as needed.
10. Pompe disease is the only GSD characterized by lysosomal accumulation of glycogen instead of cytoplasmic.
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Question 133

7-year-old complaining of muscle weakness for a year. Gets tired very quickly when playing. Moderate hepatosplenomegaly, short stature, marked muscle wasting. Serum studies reveal hypoglycemia, hyperlipidemia, fasting ketosis, and elevated liver transaminases.

Answer 133

1. Cori disease (Type III GSD)
2. AR disorder caused by deficiency of glycogen debranching enzyme (α-1,6-glucosidase), which aids in glycogen degradation by breaking α-1,6 bonds between glucose residues.
3. When debranching enzyme defective/deficient, glycogen breakdown incomplete and abnormal glycogen with short outer chains (limit dextrin) accumulates in cytosol of liver and muscle, leading to hepatomegaly.
4. Hypoglycemia results from ineffective glycogen breakdown.
5. Patients present with hepatosplenomegaly, hypoglycemia, hyperlipidemia (increased TGs), ketoacidosis, slowed growth, short stature, skeletal myopathy (progressive muscle wasting), and cardiomyopathy. Hepatomegaly improves with age and disappears after puberty.
6. Milder than von Gierke disease as have normal blood lactate levels, gluconeogenesis remains intact, no hepatic steatosis.
7. Labs reveal hypoglycemia, hyperlipidemia, elevated liver enzymes in childhood, and fasting ketosis.
8. Tx with high-carbohydrate meals with cornstarch or nocturnal gastric drip feedings for hypoglycemia. High-protein diet during the day plus overnight protein infusion for myopathy.
9. Cori disease is of high prevalence in non-Ashkenazi Jews of North African descent.
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Question 134

22-year-old presents with painful muscle cramps when walking eight flights of stairs to new apartment. Also experiences severe muscle cramps after lifting weights at the gym. Occasionally has reddish-purple urine after exercising.

Answer 134

1. McArdle Disease (Type V GSD)
2. AR disorder caused by deficiency of muscle glycogen phosphorylase (aka myophosphorylase).
3. Muscle glycogen phosphorylase breaks down α-1,4 linkages of glycogen in muscle.
4. Deficiency results in deficient glycogen breakdown, leading to glycogen accumulation in muscle and painful muscle cramps.
5. Without effective glycogen breakdown, body must use other means to generate ATP (often through breakdown of muscle fibers), leading in eventual muscle degradation.
6. Present in adulthood with exercise intolerance and muscle cramps. Sx triggered by brief exercise of great intensity (eg, sprinting, weight lifting) or less intense but sustained activity (eg, climbing stairs). May have arrhythmias 2/2 electrolyte abnormalities.
7. 50% of patients report burgundy-colored urine after exercise (myoglobinuria due to muscle breakdown).
8. Labs reveal elevated serum creatine kinase even at rest. Decreased blood lactate after exercise. Blood glucose levels normal. May have second wind during exercise due to increased muscular blood flow.
9. Tx. avoid strenuous exercise. Augment exercise tolerance by aerobic training or by prior ingestion of glucose/sucrose. High-protein diet may increase exercise tolerance. Vitamin B6 supplementation may improve fatigue.
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Question 135

5-year-old has not met expected growth milestones. Evidence of hepatomegaly. Labs reveal mild hypoglycemia, mildly elevated liver enzymes, mild hyperlipidemia.

Answer 135

1. Hers disease (Type VI GSD)
2. AR disorder caused by defective liver glycogen phosphorylase.
3. Glycogen phosphorylase breaks down α-1,4 glycosidic linkages within glycogen in the liver.
4. Defective glycogen phosphorylase results in failure to efficiently break down glycogen, resulting in accumulation of glycogen in liver, leading to hepatomegaly and hypoglycemia.
5. Patients present early in childhood with hepatomegaly, mild hypoglycemia, and slowed growth. Often also have muscle weakness.
6. Labs reveal mild hypoglycemia, mildly elevated liver enzymes, mild hyperlipidemia.
7. Tx. High carbohydrate diet and frequent meals to avoid hypoglycemia. Disease usually mild with most abnormalities resolving by adolescence.
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Question 136

6-year-old complains of severe muscle cramps in both legs and nausea after soccer over the past year. Urine red occasionally. Labs reveal hyperuricemia, hemolytic anemia, and elevated CK levels.

Answer 136

1. Tarui Disease (Type VII GSD)
2. AR disorder caused by deficiency of muscle phosphofructokinase.
3. PFK catalyzes conversion of fructose-6-phosphate to fructose-1,6-bisphosphate during glycolysis. Absent PFK significantly impairs glycolysis.
4. Patients present in childhood with exercise intolerance, muscle cramps, and weakness after exercise. Many patients report burgundy-colored urine after exercise (myoglobinuria caused by muscle breakdown) as well as nausea and vomiting.
5. Labs reveal hyperuricemia worsened by exercise, hemolytic anemia, elevated creatine kinase levels.
6. Tx. avoid strenuous exercise. High protein diet. Usually does not progress to severe disability.
7. More prevalent among people of Ashkenazi Jewish descent.
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Question 137

4-year-old with developmental delay, marked hypotonia, ataxic gait, choreoathetosis. Ophthalmologic exam reveals poor visual tracking, grossly disconjugate eye movements, and poor pupillary response bilaterally. Labs reveal lactic acidosis and elevated pyruvate levels.

Answer 137

1. Pyruvate dehydrogenase complex deficiency (PDCD)
2. X-linked dominant disorder caused by deficiency in pyruvate dehydrogenase complex (PDC). Typically more symptomatic in males than in females.
3. PDC converts pyruvate to acetyl coA for citrate production and use in the TCA cycle.
4. Deficiency of PDC limits citrate production, and causes an energy deficit in the CNS leading to neurologic dysfunction.
5. Backup of substrates develops leading to high levels of lactate and pyruvate, resulting in lactic acidosis.
6. Sx. progressive neurologic symptoms that start in infancy or childhood including developmental delay, intermittent ataxia, poor muscle tone, abnormal eye movements, seizures. Exacerbated by thiamine deficiency.
7. Labs reveal lactic acidosis and elevated lactate and pyruvate levels.
8. Increase intake of high-fat foods with ketogenic nutrients. Lysine and leucine are the two purely ketogenic AAs. Catabolism of these two AAs leads to products that can be used in the TCA cycle without having to route through the pyruvate dehydrogenase complex first.
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Question 138

Galactose metabolism

Answer 138

1. Cytoplasm of hepatocytes
2. Galactose —> Galactose-1-P (galactokinase, uses ATP)
3. or Galactose —> Galactitol (aldose reductase)
4. Galactose-1-P —> Glucose-1-P (Galactose-1-P uridyltransferase, and 4-epimerase)
5. Glucose-1-P —> Glucose-6-P (phosphoglucomutase)
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Question 139

Fructose metabolism

Answer 139

1. Cytoplasm of hepatocytes
2. Fructose —> Fructose-1-P (fructokinase, uses ATP)
3. Fructose-1-P —> dihydroxyacetone-P (DHAP) + glyceraldehyde (aldolase B)
4. DHAP —> glyceraldehyde-3-P (triose phosphate isomerase) —> glycolysis
5. Glyceraldehyde —> glyceraldehyde-3-P (triose kinase, uses ATP) —> glycolysis
6. or Glyceraldehyde —> glycerol (glycerol dehydrogenase, uses NADH) —> TG synthesis
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Question 140

Familial chylomicronemia (Type I)

Answer 140

• Lipoprotein affected: chylomicron
• Etiology: AR d/o caused by deficiency of LPL or ApoC-II
• Pathophysiology: ApoC-II activates LPL, which hydrolyzes CMs. Deficiency of either renders body unable to break down CMs, which accumulate in plasma.
• Triglycerides: extremely elevated
• Xanthomas: eruptive xanthomas (small non-painful orange-red papules)
• Clinical consequences: pancreatitis (usually initial presentation), lipemia retinalis
• Lab findings: elevated fasting plasma TGs (>750)
• Ex: 45 year old male with obesity and DM presents with painless non-pruritic rash on body. Small orange-red papules on scalp, elbows, and knees that are not painful to touch. Labs reveal elevated TG levels and chylomicrons.
• Tx. Lifelong fat-free diet, niacin, gemfibrozil, fish oil supplements.
• Obesity, inactivity, alcohol use, and insulin resistance associated with hypertriglyceridemia.
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Question 141

Familial hypercholesterolemia (Type IIa)

Answer 141

• Lipoprotein affected: primarily LDL
• Etiology: mutations in LDL-R gene (codominant) or AD mutation in ApoB-100
• Pathophysiology: ApoB-100 facilitates binding of LDL to LDL-R. Deficiency of LDL-R or ApoB-100 renders liver unable to take up LDL, increasing LDL levels and leading to intracellular and extracellular deposition of cholesterol. Liver senses decreased LDL levels and responds by secreting for IDL and VLDL (LDL precursors).
• Triglycerides: normal
• Xanthomas: tendon xanthomas (Achilles and MCP extensor tendons), cutaneous xanthomas, corneal arcus (white band around cornea), xanthelasmas (deposits of cholesterol on eyelids).
• Clinical consequences: premature atherosclerotic disease, homozygotes develop severe atherosclerosis with early onset heart disease (MI in childhood) - few live greater than 30 yo.
• Lab findings: elevated serum cholesterol (275-500), elevated LDL, normal plasma TGs, HDL, VLDL levels
• Ex. 31 yo male presents with sharp retrosternal chest pain that lasts for 2 mins and radiates to his left jaw when walking up flights of stairs. Pain is relieved by rest. Patient’s father and two paternal uncles had heart attacks in their 30s.
• Tx. Low fat, low cholesterol diet, exercise, HMG-CoA reductase inhibitor (statin) in combination with cholestyramine (bile sequestrant). Niacin can be added as 3rd agent.
• HMG-CoA reductase inhibitors ineffective at tx-ing homozygous LDL-R mutation.
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Question 142

Familial combined hyperlipidemia (Type IIb)

Answer 142

• Lipoprotein affected: LDL and VLDL
• Etiology: AD disorder, unknown mutation
• Pathophysiology: overproduction of apo B-100, resulting in increased circulation of VLDL particles
• Triglycerides: elevated
• Xanthomas: none
• Clinical consequences: premature vascular disease in 5th decade, insulin resistance.
• Lab findings: moderately elevated TGs and total cholesterol levels
• Ex. 52 yo male with PMHx of PAD, DM, high cholesterol. Family hx significant for early-onset CAD and hyperlipidemia. Labs reveal moderately elevated total cholesterol and TGs.
• Tx. HMG-CoA reductase inhibitors (statin), cholestyramine (bile sequestrant), and/or niacin.
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Question 143

Familial dysbetalipoproteinemia (Type III)

Answer 143

• Lipoprotein affected: chylomicron remnants
• Etiology: AR homozygous mutation in ApoE. Humans have 3 ApoE genetic isoforms (ApoE-3 is wild type, ApoE-2 is defective in mediating uptake by LDL-R, homozygous ApoE-4 confers high risk for Alzheimer dz).
• Pathophysiology: CM remnants, VLDL, and IDL cannot bind to LDL-R to be taken up by liver. Defective ApoE results in elevations of VLDL TGs and VLDL cholesterol levels.
• Triglycerides: elevated
• Xanthomas: tuberous xanthomas (elbow/knee), striae palmaris (deposits of cholesterol in palmar creases making creases appear orange)- pathognomonic
• Clinical consequences: peripheral vascular disease or CAD present by 5th decade.
• Lab findings: normal LDL and HDL, elevated VLDL and IDL, CM remnants in plasma
• Ex. 38 yo woman presents after being admitted to hospital for MI. Eats regular diet and exercises 2x a week. Cholesterol deposits in palmar creases of both hands, and 2 small tuberous xanthomas near buttocks. Lipid panel reveals elevated VLDL and IDL with normal LDL and HDL levels.
• Tx. Niacin, fibrates (eg, gemfibrozil, clofibrate)
******

Question 144

Familial hypertriglyceridemia (Type IV)

Answer 144

• Lipoprotein affected: VLDL
• Etiology: AD disorder, unknown underlying mutation
• Pathophysiology: thought to be due to overproduction of VLDL in the liver and reduced catabolism of TG-rich lipoproteins
• Triglycerides: elevated
• Xanthomas: none
• Clinical consequences: usually asymptomatic, increased risk of coronary vascular disease, risk of pancreatitis if TG >1000, lipemia retinalis.
• Lab findings: elevated fasting TGs (200-750), elevated VLDL, elevated total cholesterol.
• Ex. 34 year old man c/o chronic, recurrent abdominal pain. Hx of pancreatitis. Several family members including mother and 2 sisters suffer from inherited metabolic disease. On fundoscopic exam, discover lipemia retinalis. Moderate hepatosplenomegaly present. Elevated fasting plasma TGs.
• Tx. fat-free diet, niacin/nicotinic acid, gemfibrozil, fenofibrate, fish oil supplements.
• Obesity, inactivity, alcohol, and insulin resistance associated with hypertriglyceridemia.
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Question 145

Gemfibrozil

Answer 145

• Fibrate
• Activates peroxisome proliferator-activated receptor-alpha (PPARα), a nuclear receptor that increases synthesis of lipoprotein lipase (LPL) thereby increasing clearance of triglycerides.
• Reduces TG levels and VLDL levels, modest reduction in LDL and increase in HDL levels
• Adverse effects: myalgias, GI upset, gallstones
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Question 146

Lipoprotein structure

Answer 146

• Hydrophobic/non-polar core = cholesterol esters, TGs
• Hydrophilic/polar surface = phospholipids, free cholesterol, apolipoproteins
• Apolipoproteins provide particle structure and direct processing of particle
• Chylomicrons = ApoB-48, ApoC-2
• VLDL = ApoB-100, ApoC-2
• IDL = ApoB-100, ApoE
• LDL = ApoB-100
• HDL = ApoA-1, ApoA-2, ApoE
• ApoB-containing lipoproteins are atherogenic (B is for BAD) and deposit in artery walls.
• ApoB-48 and B-100 are from the same gene, but one base is made into a stop codon creating a truncated 48% protein. Intestine only makes apoB-48.
• ApoC-2 is a cofactor for LPL, which hydrolyzes TGs into free fatty acids.
• Chylomicrons undergo remodeling by LPL and gain ApoE, which mediates uptake by the liver.
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Question 147

Endogenous pathway of lipoprotein metabolism

Answer 147

• During fasting, adipose tissue stimulated to release FFAs, which travel to liver.
• Liver creates VLDL particles with ApoB-100 and ApoC-2
• LPL (with cofactor ApoC-2) releases FFAs from VLDLs to provide heart and skeletal muscle with FFAs for energy.
• IDLs can go back to the liver for breakdown or be remodeled by hepatic lipase into LDL particles, which causes loss of ApoE
• LDLs are less likely to interact with LDL-R in the liver and more likely to continue circulating.
• Insulin resistance causes increased circulating insulin, which increases FFAs released from adipose, VLDLs overproduced by liver and VLDLs become LDL.
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Question 148

Lipoprotein (a)

Answer 148

• Does not follow traditional relationship of density and size
• LDL-like particle with apolipoprotein(a) covalently bound at a specific disulfide bond to apoB-100.
• Lp(a) concentrations are highly heritable and controlled by Lp(a) gene
• Fxn unknown, yet Lp(a) is highly homologous in structure to plasminogen and may compete with it for binding site, leading to less fibrinolysis.
• Independent risk factor for atherosclerotic disease.
• Statins do not decrease levels, niacin and aspirin do.
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Question 149

HDL and reverse cholesterol transport

Answer 149

• Lipoprotein with mostly cholesterol esters in the center, highest ratio of proteins to cholesterol = high density
• Nascent HDLs produced by liver (ApoA-1, ApoA-2) and intestine (ApoA-1)
• HDL promotes free cholesterol efflux from cells via ABCA1 transporter
• LCAT on HDL adds a FFA to each FC, esterifying free cholesterol into cholesterol ester and sending it to core, creating a mature HDL particle
• Mature HDL is taken up by SR-B1 receptor in liver
• Cholesterol esters are then broken down into free cholesterol and excreted in bile.
• ApoA-1 is catabolized by kidneys
• CETP (cholesteryl ester transfer protein) = plasma protein that facilitates transport of cholesterol esters and TGs between VLDL/LDL (TGs) and HDL (CEs)
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Question 150

ApoA-1 mutation

Answer 150

• Genetic mutation in ApoA-1 gene causes nascent HDL to be non-functional and catabolized rapidly by kidneys.
• Patients have very low HDL but do not seem to have a higher risk for CVD.
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Question 151

Tangier disease

Answer 151

• ABCA1 mutation leads to faulty transport of FC out of cells and into nascent HDL. Nascent HDLs are catabolized by the kidneys.
• Build up of cholesterol-laden Møs
• Patients may have enlarged fatty tonsils
• In absence of ABCA1, ApoA-1 cannot be lipidated and mature HDL cannot be formed.
• Not associated with higher risk of CVD despite data showing low HDL is associated with increased CVD risk.
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Question 152

LCAT deficiency

Answer 152

• Unesterified cholesterol builds up as free cholesterol
• Rapid catabolism of nascent HDL
• Not associated with higher risk of CVD despite data showing low HDL is associated with increased CVD risk.
• Free cholesterol build up evident in cornea
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Question 153

Fatty acid synthesis

Answer 153

• Oxaloacetate from mitochondria leaves to cytosol through the citrate-oxaloacetate-malate shuttle.
• Pyruvate —> Oxaloacetate (pyruvate carboxylase + B7)
• Oxaloacetate + acetyl CoA —> citrate
• Citrate —> acetyl coA (ATP citrate lyase, uses ATP, occurs in cytosol)
• Acetyl coA —> malonyl coA (Acetyl coA carboxylase, uses CO2 + biotin)
• Malonyl coA is starting substrate for fatty acid synthesis, which creates palmitate (16 carbon fatty acid)
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Question 154

Long-chain fatty acid (LCFA) degradation

Answer 154

• LCFA degradation requires carnitine dependent transport into the mitochondria
• Inherited defects in the carnitine shuttle present with “hypoketotic” hypoglycemia (cannot make ketone bodies), muscle pain, muscle atrophy, weakness, and hypotonia due to toxic accumulation of fat in muscle.
• Affected infants benefit from food with medium-chain triacylglycerols (in butter fat) b/c medium-chain fatty acids can bypass the carnitine shuttle.
• LCFA and coA are combined in the cytosol by fatty acid coA synthase to make Fatty Acyl-CoA
• CAT I uses carnitine shuttle to make fatty-acyl carnitine, which is able to traverse the mitochondrial membrane into the mitochondria where β-oxidation occurs.
• Fatty acyl-CoA + carnitine —> fatty-acyl carnitine + coA (CAT I)
• Once inside the mitochondrion, CAT II uses coA to turn fatty acyl carnitine into carnitine (which diffuses back into the cytosol to be reused) and fatty-acyl coA, which can be transformed via β-oxidation into acetyl coA
• Acetyl coA can then be used in the TCA cycle or transformed into ketone bodies for excretion
• Acyl CoA dehydrogenase is a major enzyme in β-oxidation.
• CAT = carnitine acyl transferase
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Question 155

Medium-chain acyl-coA dehydrogenase deficiency

Answer 155

• AR defect in medium-chain acyl-coA dehydrogenase
• Decreased ability to break down fatty acids into acetyl-coA
• Accumulation of 8-10 carbon fatty acyl carnitines in blood
• Hypoketotic hypoglycemia
• Tx. avoid fasting, minor illness can lead to sudden death
• May present in infancy/early childhood with vomiting, lethargy, seizures, coma, and/or liver dysfunction.
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Question 156

What is sphingomyelin? Gangliosides? Cerebrosides?

Answer 156

• Sphingomyelin = principal lipid of nervous tissue membranes
• Gangliosides = acidic glycosphingolipids that contain neuraminic acid and are found in high concentrations in ganglion cells of CNS
• Cerebrosides = galactocerebroside, glucocerebroside = neutral glycosphingolipids found primarily in CNS myelin
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Question 157

Hurler disease

Answer 157

• AR disorder caused by deficiency of α-L-iduronidase, a lysosomal enzyme necessary for the breakdown of glycosaminoglycans (GAGs)
• Deficiency of α-L-iduronidase leads to buildup of dermatan (chondroitin) sulfate and heparan sulfate (GAGs linked to proteins in connective tissue).
• These GAGs tend to accumulate in skin and bones (leading to physical deformities) and in the heart, liver, brain.
• Affected infants normal at birth but exhibit mild coarsening of facial features (gargoylism) and growth retardation in first year.
• Sx. CORNEAL CLOUDING, coarse facies (gargoylism), joint stiffness, short stature, valvular heart disease, hepatosplenomegaly, developmental delay, airway obstruction due to large tongue, dwarfism, hearing loss, intellectual disability.
• Labs reveal dermatan sulfate and heparan sulfate in urine.
• Tx. symptomatic therapies include corneal transplantation, heart valve replacement, PT for joint contractures. BM transplantation and enzyme replacement experimental.
• Death usually before age 10.
• Scheie syndrome = adult variant of Hurler disease also caused by deficiency of α-L-iduronidase.
• Ex. 1 year old with corneal clouding on routine exam. Small for age, macroglossia, mild coarsening of facial features. Ophthalmologic exam reveals bilateral corneal opacities and papilledema.
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Question 158

Mucopolysaccharidoses

Answer 158

• Mucopolysaccharidoses = group of lysosomal storage diseases in which abnormal accumulations of glycosaminoglycans occur because of enzyme deficiencies
• Hurler syndrome (AR) - α-L-iduronidase - corneal clouding, HSM, macroglossia, ID, joint stiffness, coarse facial features
• Hunter syndrome (XLR) - iduronate sulfates - similar to Hurler syndrome but no corneal clouding, pebbly skin lesion on back
• Scheie syndrome (AR) - adult onset, α-L-iduronidase
• Sanfilippo disease (AR) - heparan N-sulfatase - heparan sulfate buildup, severe ID, progressive behavioral problems, seizures
• Sly syndrome (AR) - β-glucuronidase - short stature, coarse facies, kyphosis/scoliosis, ID, BM dysfunction leading to recurrent infections, HSM.
• Glycosaminoglycans (GAGs) aka mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit.
• GAGs are highly polar and attract water, acting as a lubricant or shock absorber in the body.
• Heparan sulfate, chondroitin sulfate, keratan sulfate, hyaluronic acid
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Question 159

Hunter disease

Answer 159

• X-linked recessive disorder caused by deficiency of iduronate sulfatase, a lysosomal enzyme involved in breakdown of glycosaminoglycans (GAGs).
• Deficiency of iduronate sulfatase leads to buildup of dermatan sulfate and heparan sulfate as in Hurler’s disease.
• Dermatan/heparan sulfate accumulate in skin, bones, heart, liver, and brain.
• Sx. Affected infants normal at birth but develop coarse facies, growth retardation, joint stiffness, HSM, macroglossia, small jaw, intellectual disability, and valvular heart disease as they age.
• Unlike Hurler disease, patients with Hunter have retinal degeneration but NO corneal clouding, and milder sx.
• Patients with Hurler have distinctive pebbly skin lesions and tend to exhibit aggressive behavior.
• Labs reveal dermatan sulfate and heparan sulfate in urine.
• Tx. symptomatic therapies include heart valve replacement and PT for joint contractures. BM transplantation unsuccessful and enzyme replacement therapy experimental.
• Ex. 8-year-old boy presents with prominent joint stiffness. Has coarse facial features, large tongue, small jaw, and marked HSM. Has distinctive non painful, pebbly skin lesion on upper back. Exhibits remarkable joint stiffness with movement and unable to touch toes.
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Question 160

Tay-Sachs Disease

Answer 160

• AR disorder caused by deficiency in hexosaminidase A, leading to an accumulation of GM2 gangliosides.
•[Hexosaminidase A]= lysosomal enzyme involved in the breakdown gangliosides.
• [GM2 gangliosides] are toxic to neurons and lead to progressive neurologic damage.
• Infantile-onset form: progressive neurodegenerative disease characterized by developmental delay, macrocephaly, loss of motor skills, increased startle reaction to noise (hyperacusis), and macular pallor with “cherry-red spot” on retinal examination. Usually fatal by age 3.
• Juvenile-onset form: presents with dementia and ataxia. Usually fatal by age 15.
• Adult-onset form: childhood clumsiness, progressive motor weakness in adolescence, spinocerebellar or lower motor neuron sx in adulthood, and eventual development of psychosis.
• Screening for Tay-Sachs disease carriers recommended among Ashkenazi Jews because 1 in 30 people of this descent carries the allele for this disease.
• Ex. 7 month old boy of Ashkenazi Jewish descent with lethargy. Child has exaggerated startle reaction to noise but otherwise limp and sleepy. Fixed gaze and larger than normal head size. On fundoscopic exam, macular pallor and distinctive cherry-red spot.
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Question 161

Pathologic findings for lysosomal storage diseases

Answer 161

• Fabry disease (XLR) - ø α-galactosidase A –> ceramide trihexose –>
• Gaucher disease (AR) - ø Glucocerebrosidase –> glucocerebroside
• Niemann-Pick disease (AR) - ø Sphingomyelinase –> sphingomyelin –> foam cells = lipid-laden macrophages
• Tay-Sachs disease (AR) - ø Hexosaminidase A –> GM2 ganglioside –> lysosomes with onion skin
• Krabbe disease (AR) - ø Galactocerebrosidase –> galactocerebroside, psychosine
• Metachromatic leukodystrophy (AR) - ø Arylsulfatase A –> cerebroside sulfate
• Hurler syndrome (AR) - ø α-L-iduronidase –> heparan/dermatan sulfate –>
• Hunter syndrome (XLR) - ø iduronate sulfatase –> heparan/dermatan sulfate –>
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