Lecture 39

Question 1

macronutrients vs micronutrients

Answer 1

• macronutrients: consumed in large quantities, major source of energy
• micronutrients: consumed in small quantities, usually not a source of energy, essential for life (can not be synthesized endogenously)

pg 1026

Question 2

metabolism of vitamin A

Answer 2

• β-carotene and retinol can enter the intestinal cell -> become retinyl esters -> sent to chylomicrons
• chylomicrons go to lymph and blood and eventually the chylomicron remnants go to the liver
• all-trans retinol in liver released as retinol or stored as retinyl pamitate (vitamin A intermediates stored in stellate cells)
• retinol stored as retinyl esters in liver and adipose tissue

pg 1029

Question 3

role of vitamin A in retina

Answer 3

• retinol bound to RBP (retinol binding protein), which is bound to TTR (transthyretin) for transport to the retina (as retinol is hydrophobic)
• once in retina, all-trans retinol is eventually converted to 11-cis retinal which is a component of the visual pigment rhodopsin (11-cis retinal + opsin)
• vitamin A deficiency causes night blindness

pg 1030

Question 4

vitamin A role in other cells

Answer 4

• some transport system as to the retina
• in target tissues: retinol is oxidixed to retinoic acid, which binds to nuclear receptors; retinoic acid-receptor complex activates responsive genes

pg 1031

Question 5

functions of vitamin A

Answer 5

• acts as therapeutic agents: all-trans retinoic acid (treitinoin) for treatment of mild acne and skin aging, 13-cis retinoic acid (isotretinoin) for treatment of severe acne
• maintenance of reproduction, vision, promotion of growth, differentiation/maintenance of epithelial tissue, gene expression
• vision, normal differentiation of epithelial cells, reproduction

pg 1032-1033

Question 6

vitamin A deficiency

Answer 6

• night blindness
• severe: xerophthalmia (pathologic dryness of the conjunctiva and cornea) caused by increased keratin synthesis which may result in blindness

pg 1033

Question 7

vitamin A hypervitaminosis and toxicity

Answer 7

• dry, puritic skin
• cirrhotic liver
• fragile bones
• CNS - raise in intracranial pressure
• teratogen

pg 1033

Question 8

vitamin D synthesis

Answer 8

• skin cells produce vitamin D from cholesterol (cholecalciferol)
• storage form in plasma: 25-OH-D3 (calcidiol)
• vitamin D from diet: cholecalciferol (D3) from animals, ergocalciferol (D2) from plants -> chylomicron to lymph to blood to liver

pg 1034-1035

Question 9

active form of vitamin D

Answer 9

• storage form (calcidiol) goes to the kidney from the bloodstream
• kidney uses 1-hydroxylase to form 1,25-diOH-D3 (calcitriol)
• calcitriol is the active form of vitamin D

pg 1036

Question 10

active form of vitamin D pt 2

Answer 10

• active form goes to intestinal cells where it leads to increased absorption of calcium via calbindin (a Ca2+ binding protein)

pg 1037

Question 11

function of vitamin D

Answer 11

maintain adequate plasma levels of calcium

pg 1038

Question 12

vitamin D deficiency, hypervitaminosis and toxicity

Answer 12

• deficiency: demineralization of bone resulting in rickets and osteomalacia; renal osteodystrophy
• hypervitaminosis and toxicity: can be stored and is slowly metabolized; hypercalcemia -> leads to deposition of calcium in many organs, particularly the arteries and kidneys

pg 1038

Question 13

minerals (micronutrients)

Answer 13

• macrominerals: Ca, Cl, Mg, P, K, Na
• trace microminerals: Cr, Cu, F-, Fe, Mn, Zn
• ultratrace microminerals: I, Mo, Se

pg 1039

Question 14

chloride transporter CFTR

Answer 14

cystic fibrosis transmembrane conductance regulator (CFTR)

• ion channel transporter reponsible for luminal secretion of chloride -> PKA-mediated regulation
• also expressed in the epithelia of the lung and sweat glands
• loss-of-function mutations lead to cystic fibrosis

pg 1040

Question 15

nutrient malabsorption in cystic fibrosis

Answer 15

Pancreas

• pancreatic insuffiency (clogged duct)
• nutrient and fat malabsorption
• vitamin deficiency
• acute/chronic pancreatitis
• CF-related diabetes mellitus

GI Tract

• nutrient malabsorption
• GERD
• distal intestinal obstructive syndrome
• biliary duct obstruction
• focal biliary cirrhosis
• chronic constipation

pg 1041

Question 16

anemia and classification of anemias

Answer 16

• the term anemia refers to a reduction of hemoglobin or RBC concentration in the blood
• morphological anemia: based on a correlation between RBC size and Hb concentration (MCV, MCH, and MCHC) -> microcytic/hypochromic, normocytic/normochromic, macrocytic
• etiological anemia: based on the underlying cause for anemia (nutritional deficiency, ineffective RBC formation, etc)

pg 1043

Question 17

microcytic anemia

Answer 17

• deficiency in iron
• functional deficit: impaired hemoglobin synthesis
• other possible causes: mutation leading to thalassemia, lead poisoning

pg 1044

Question 18

dietary iron

Answer 18

• ~10% of dietary iron is actually absorbed
• red meat has heme (type of iron readily absorbed), plants have another form of iron that is not readily absorbed
• iron used by intestinal epithelial cells, liver, bone (erythropoiesis), RBCs (hemoglobin), RE cells, and other tissues (as cytochromes, iron-enzymes, myoglobin)
• iron loss: skin desquamation, sweat, urine, feces

pg 1045

Question 19

iron absorption by intestinal cells

Answer 19

• animal sources: heme -> straight to cells by HCP -> heme oxygenase converts to Fe²⁺ (ferrous/reduced iron)
• plant sources: Fe³⁺ (nonheme iron) -> vitamin C (aids in absorption) converts to Fe²⁺ -> enters the cell
• iron stored in cells as ferritin (Fe³⁺) or exported to blood stream via ferroportin as Fe²⁺ -> then oxidized to 3+ to bind to transferrin
• transferrin is transport protein to carry Fe³⁺ into circulation
• TfR on cells is regulated by mRNA stability

pg 1046

Question 20

hepcidin

Answer 20

protein produced in liver -> regulates iron absorption in gut (inhibits)

pg 1048

Question 21

iron overload

Answer 21

• diagnosis: increased serum iron & ferritin, iron saturation, decreased total iron-binding capacity; liver biopsy required
• treatment: repeated phlebotomy, liver transplant (in advanced cases)
• etiology: mutation in HFE gene leads to low hepcidin; abnormal iron sensing causes excess iron absorption; increased accumulation of iron (as ferritin and hemosiderin) generates hydroxyl free radicals that cause fibrosis of organ

pg 1049

Question 22

HFE protein

Answer 22

• HFE protein regulates iron levels in liver cells by preventing transferrin from binding to its receptor which results in low hepcidin
• loss-of-function mutations of HFE gene results in hereditary hemochromatosis (HH)

pg 1049

Question 23

hemochromatosis

Answer 23

autosomal recessive iron absorption disease

• clinical features: classic triad of liver disease, diabetes mellitus, bronze skin
• complications: cirrhosis & HCC, cardiomyopathy, arthritis, hypogonadism, hypothyroidism
• presents after 40

pg 1050

Question 24

copper metabolism

Answer 24

needed for a lot of enzymes to function; ex: lysyl oxidase which forms cross-links in collagen and elastin

pg 1052

Question 25

copper deficiency

Answer 25

• Menkes disease
• low copper concentration
• X-linked
• ATP7A affected

pg 1052

Question 26

copper overload

Answer 26

• Wilson disease
• high copper concentration
• autosomal recessive
• ATP7B affected

pg 1052

Question 27

Wilson Disease

Answer 27

• diagnosis: increased urine copper and LFTs, decreased ceruloplasmin and alkaline phosphatase; liver biopsy shows elevated Cu levels
• therapy: chelation (D-penicillamine or trientine to remove/detoxify excess Cu deposits) or oral zinc (prevents uptake of dietary Cu)
• etiology: autosomal recessive mutations in hepatocyte copper transporting ATPase (ATP7B gene); leads to decreased Cu excretion into bile
• clinical symptoms: Kayser-Flesicher rings (in eyes), liver disease (acute hepatitis, cirrhosis), renal involvement, neurological and psychological deficits (dystonia, tremor)

pg 1053-1054

Question 28

ATP7B transporter mutations

Answer 28

• decreased Cu export into the bile resulting in decreased seum ceruloplasmin
• Cu remains inside the liver and accumulates over time

pg 1053