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Chase Findley, MSIV

Vitamins, Fat Soluble, 94

Vitamins A, D, E, K
Absorption dependent on ileum and

pancreas
Accumulate in body fat, more potential for
toxicity
Fat malabsorption conditions may cause
deficiency
Cystic fibrosis, celiac sprue, mineral oil intake

Vitamins, Fat Soluble, 94

Vitamin A (Retinol)
Found: liver, leafy vegetables
Functions: antioxidant, constituent of retinal

visual pigment
Deficiency: night blindness, dry skin
Excess: head ache, arthralgias, fatigue, skin
changes, sore throat, alopecia
Teratogenic: cleft palate, cardiac problems
Remember bear hunter who eats liver!

Vitamins, Fat Soluble, 97

Vitamin D
Found: Fortified milk
Function: Increases intestinal absorption of

calcium and phosphate, bone resorption


Deficiency: Rickets (children), osteomalacia
(adults), hypocalcemic tetany
Excess: Hypercalcemia, hypercalciuria, loss
of appetite, stupor. (Seen in sarcoidosis)

Vitamins, Fat Soluble, 97

Vitamin D, continued
D2
Found in plants, pharmacological form
D3
Found in milk, formed in sun exposed skin
25-OH D3
Storage form

1,25-(OH)2D3 (Calcitriol)
Active form

Vitamins, Fat Soluble, 97

Vitamin E
Found: Vegetable oils, nuts, leafy

vegetables
Function: Antioxidant, protects RBCs and
membranes from free radical damage
Deficiency: Increased fragility of RBCs,
muscle weakness, neurodysfunction

Vitamins, Fat Soluble, 98

Vitamin K
Found: Leafy vegetables, some fruits
Function: Necessary for synthesis of

clotting factors II, VII, IX, X, protein C and S,


catalyzes -carboxylation of glutamic acid
residues
Deficiency: Hemorrhage with increased PT,
PTT, normal bleeding time.
Neonatal hemorrhage, give Vitamin K at birth
Warfarin antagonizes Vitamin K

Vitamins, Water Soluble, 94


Vitamins B1 (thiamine), B2 (riboflavin), B3
(niacin), B5 (pantothenic acid), B6
pyridoxine, B12 (cobalamin), C (ascorbic
acid, biotin, folate
All except B12 and folate wash out from
body, low risk of toxicity

Vitamins, Water Soluble, 94

Vitamin B1 (thiamine)
Function: Component of thiamine

pyrophosphate, cofactor in:


Pyruvate dehydrogenase (glycolysis)

-ketoglutarate dehydrogenase (TCA cycle)


Transketolase (HMP shunt)
Branched chain amino acid dehydrogenase

Vitamins, Water Soluble, 95

Vitamin B1 (thiamine), continued


Deficiency:
Wernike-Korsakoff syndrome
Seen in malnutrition, alcoholism
Confusion, ophthalmoplegia, confabulation

Beriberi (dry)
Polyneuritis, symmetrical muscle wasting
Beriberi (wet)
High-output cardiac failure (dilated cardiomyopathy)
edema

Vitamins, Water Soluble, 95

Vitamin B2 (riboflavin)
Function: Cofactor in oxidation and

reduction (FAD, FMN) B2=2 ATP


Deficiency: Cheilosis, corneal
vascularization

Vitamins, Water Soluble, 95

Vitamin B3 (niacin)
Function: Constituent of NAD, NADP, used in

redox reactions, B3=3 ATP


Derived from tryptophan, requires B6 for
synthesis
Deficiency: Pellagra (diarrhea, dermatitis,
dementia), glossitis
Hartnup disease (decreased tryptophan

absorption)
Malignant carcinoid syndrome (increased
tryptophan metabolism
INH (anti-TB) (decreased B6)

Vitamins, Water Soluble, 95

Vitamin B3 (niacin), continued


Clinical use: Treatment of hyperlipidemia

(decrease LDL, increase HDL)


Excess: Facial flushing, treat with aspirin

Vitamins, Water Soluble, 95

Vitamin B5 (pantothenate)
Function: Component of CoA (cofactor in

acyl transfers) and fatty acid synthase


Deficiency: Dermatitis, enteritis, alopecia,
adrenal insufficiency

Vitamins, Water Soluble, 95

Vitamin B6 (pyridoxine)
Function: Converted to pyridoxal,

phosphate, cofactor in transamination


(ALT/AST), decarboxylation reactions,
glycogen phosphorylase, heme synthesis
Required for synthesis of B3 (niacin)
Deficiency: Convulsions, hyperirritability,
peripheral neuropathy
May be induced by INH, OCPs

Vitamins, Water Soluble, 96

Vitamin B12 (cobalamin)


Found: Only in animal products, synthesized

by microorganisms (large reserves in liver)


Function: Cofactor for homocysteine
methyltransferase (transfers CH3 groups)
and methylmalonyl-CoA mutase

Vitamins, Water Soluble, 96

Vitamin B12 (cobalamin)


Deficiency:
Macrocytic-megaloblastic anemia
Neurological symptoms
Irreversible if prolonged
Paresthesias
Sub acute combined degeneration

- Posterior and lateral spinal columns

Vitamins, Water Soluble, 96

Vitamin B12 (cobalamin)


Causes of deficiency
Intestinal malabsorption
Sprue, enteritis, fish tapeworm

Lack of intrinsic factor


Pernicious anemia
Absence of terminal ileum
Crohns disease, surgical
Schilling test to detect etiology of deficiency

Vitamins, Water Soluble, 96

Folic Acid
Function: Converted to tetrahydrofolate

(THF), coenzyme used in 1-carbon


transfer/methylation reaction. Used in
synthesis of nitrogenous bases in DNA/RNA
Deficiency:
Macrocytic-megaloblastic anemia
Without neurological symptoms
Neural tube defects
Prevent with prenatal supplements

Vitamins, Water Soluble, 96

Folic acid, continued


Deficiency
Much smaller liver stores than B12
Most common US vitamin deficiency
Especially in pregnancy, alcoholism

Can be caused by phenytoin, sulfonamides,

methotrexate

Vitamins, Water Soluble, 97

Biotin
Function: Cofactor for carboxylation

enzymes, pyruvate carboxylase, acetyl-CoA


carboxylase, propionyl-CoA carboxylase
Avidin (raw egg whites) binds biotin and
prevents absorption
Deficiency: Dermatitis, alopecia, enteritis.
Antibiotic use or excessive raw eggs

Vitamins, Water Soluble, 97

Vitamin C (ascorbic acid)


Found: Fruits, vegetables
Function: Antioxidant, also:
Facilitates iron absorption by keeping Fe in
more absorbable Fe2+
Necessary for hydroxylation of proline and
lysine in collagen synthesis
Necessary for dopamine -hydroxylase
(converts dopamine to norepinephrine)

Vitamins, Water Soluble, 97

Vitamin C (ascorbic acid)


Deficiency: Scurvy
Swollen gums, bruising, anemia, poor wound
healing

Minerals, 98

Zinc
Function: Involved in activity of 100+

enzymes. Important in zinc finger


(transcription factor motif)
Deficiency: Delayed wound healing,
hypogonadism, decreased adult hair,
predisposes to alcoholic cirrhosis

Malnutrition, 98

Kwashiorkor
Protein deficiency
Skin lesions, liver malfunction (fatty change),

edema, anemia

Malnutrition, 98

Marasmus
Total calorie deficiency
Tissue and muscle wasting, loss of

subcutaneous fat, edema

Ethanol Metabolism, 98

Alcohol dehydrogenase operates via zero-order


kinetics
NAD+ is limiting reagent
Fomepizole inhibits alcohol dehydrogenase
Disulfiram inhibits acetaldehyde dehydrogenase

Universal Electron Acceptors,


101

NAD+, NADP+
Require Vitamin B3 (niacin) for production
NAD+
Catabolic processes, carry reducing equivalents
as NADH
NADP+
Anabolic processes, supply reducing equivalents
as NADPH
NADPH also used in respiratory burst, P-450

FAD+
Requires Vitamin B2 (riboflavin) for production

Metabolism, 101

ATP Production (Glycolysis)


Hydrolysis drives energetically unfavorable

reactions
Aerobic metabolism
Produces 32 (heart/liver) 30 (muscle) ATP per

glucose
Anaerobic metabolism
Produces 2 ATP per glucose

Hexokinase Vs. Glucokinase,


101
First step of glycolysis is glucose to G6P
Reaction catalyzed by hexokinase or
glucokinase, 1st regulation point
Hexokinase

Ubiquitous, high affinity (low Km), low capacity

(low Vmax), feedback inhibited by product

Glucokinase
Liver and pancreas -cells, low affinity (high Km)

and high capacity (high Vmax) induced by


insulin, sequesters excess glucose in liver.

Hexokinase Vs. Glucokinase,


101

Glycolytic Enzyme Deficiency,


103
Deficiency of pyruvate kinase or
phosphoglucose isomerase
Inability to maintain Na+-K+ ATPase
RBC swelling, lysis
Hemolytic anemia

RBCs depend solely on glycolysis of

glucose for metabolism

Pyruvate dehydrogenase
Deficiency, 103
Back up of substrate (pyruvate, alanine),
leads to lactic acidosis
Congenital and acquired (B1 deficiency)
forms
Neurologic deficits
Treat by increasing intake of ketogenic
nutrients (high fat, lysine, leucine)

Pyruvate Metabolism, 103


Alanine carries AA to
liver from muscle
Oxaloacetate used to
in TCA cycle or gluconeogenesis
Transition from glycolysis to TCA cycle
End of anaerobic
glycolysis

Cori Cycle, 103


Muscle and RBCs generate lactate via
anaerobic glycolysis
Lactate sent to liver to be used in
gluconeogenesis
Glucose can then be sent back and used
by muscle and RBCs
Loss of 4 ATP/Cycle

HMP Shunt, 105


Produces NADPH for fatty acid and steroid synthesis, and
glutathione reduction in RBCs
Oxidative (irreversible)
and non-oxidative
(reversible) phases
Occurs in lactating
mammary glands, liver,
adrenal cortex, RBCs

Respiratory Burst, 105

Produces reactive oxygen (HOCl) species for


immune response
Occurs in neutrophils, macrophages
Involves membrane-bound NADPH oxidase
(deficient in chronic
granulomatous disease)

Glucose-6-Phosphate
Dehydrogenase Deficiency, 106
G6PD produces NADPH, necessary to
keep glutathione reduced, which detoxifies
free radicals/peroxides
Decreased NADPH leads to hemolytic
anemia due to damage from oxidizing
agents
X-linked recessive,
most common
enzyme deficiency

Glucose-6-Phosphate
Dehydrogenase Deficiency, 106
Oxidizing agents include fava beans,
sulfanamides, primaquine, anti-TB drugs
Affected individuals have malarial
resistance
Heinz bodies

Altered precipitated hemoglobin in RBCs

Bite Cells
From phagocytic removal of Heinz bodies by

spleen

Glucose-6-Phoshate
Dehydrogenase Deficiency, 106

Heinz bodies, bite cells

Disorders of Fructose
Metabolism, 106

Fructose intolerance
Hereditary deficiency of aldolase B
Autosomal recessive
Fructose-1-phosphate accumulates, leading to

decrease in available phosphate, inhibits


glycogenolysis and gluconeogenesis
Hypoglycemia, jaundice, cirrhosis,
vomiting
Decrease intake of fructose and
sucrose

Disorders of Fructose
Metabolism, 106

Essential fructosuria
Defect in fructokinase
Autosomal recessive
Benign, asymptomatic

Fructose in blood and urine

Disorders of Galactose
Metabolism, 107

Classic galactosemia
Absence of galactose-1-phosphate

uridyltransferase.
Autosomal recessive
Toxic damage from galactitol
Failure to

thrive, jaundice,

hepatomegaly, infantile
cataracts, mental retardation
Exclude galactose and lactose
from diet

Disorders of Galactose
Metabolism, 107

Galactokinase deficiency
Autosomal recessive
Galactitol accumulates if galactose is present in

diet
Galactose appears in blood
and urine, infantile cataracts,
failure to track objects, lack of
social smile

Lactase Deficiency, 107


Age dependent or hereditary lactose
intolerance due to loss of brush-border
enzyme
Bloating, cramps, osmotic diarrhea
Avoid dairy products, lactase
supplements

Transport of alanine and


glutamine, 108

Glucose in muscle is oxidized to pyruvate,


producing energy
Pyruvate is transaminated to alanine, travels to
liver, providing nitrogen for urea cycle, and carbon
for gluconeogenesis

Hyperammonemia, 108
Acquired (liver disease) or hereditary
(urea enzyme deficiencies)
Results in excess NH4+, depletes ketoglutarate, inhibits TCA cycle
Tremor, slurring speech, somnolence,
vomiting, cerebral edema, blurred vision
Treat with benzoate, phenylbutyrate

Ornithine Transcarbamoylase
Defiency, 108
Most common urea cycle disorder
X-linked recessive
Interferes with elimination of ammonia
May present in first days of life
Excess carbamoyl phosphate converted
to orotic acid
Orotic acid in blood and urine,
decreased BUN, hyperammonemia

Phenylketonuria, 109
Decreased phenylalanine hydroxylase
or tetrahydrobiopterin cofactor.
Tyrosine can not be synthesized,
becomes essential
Autosomal recessive
Increased phenylalanine
leads to excess
phenylketones in urine.

Phenylketonuria, 109
Mental retardation, growth retardation,
seizures, fair skin, eczema, musty body
odor
Treat by increased tyrosine and
decreased phenylalanine in diet
Maternal PKU, (deficiency in pregnancy)
causes mental retardation, growth
retardation, microcephaly, heart defects

Alkaptonuria, 109
Congenital deficiency of homogentisic acid
oxidase in degradative pathway of tyrosine
Autosomal recessive
Dark connective tissue, pigmented sclera,
urine turns black on standing, arthralgias

Albinism, 109

Congenital defect in either:


Tyrosinase
Inability to synthesize melanin from tyrosine
Autosomal recessive
Tyrosine transporters
Variable inheritance,
locus heterogenity
Decreased availability of
tyrosine for melanin
synthesis

Albinism, 109
Can result from lack of migration of
neural crest cells.
Increased risk of skin cancer

Homocystinuria, 100

Autosomal recessive
3 forms, all result in excess homocysteine
1. Cystathionine synthase deficiency
2. Decreased affinity of
cystathionine synthase for
pyridoxal phosphate (treat
with increased B6 in diet)
3. Homocysteine
methyltransferase deficiency

Homocystinuria, 110
Cystine becomes essential
Increased homocysteine in urine, mental
retardation, osteoporosis, tall stature,
kyphosis, lens subluxation,
atherosclerosis (MI and stroke)

Cystinuria, 110
Hereditary defect of renal tubular amino
acid transporter for cysteine, ornithine,
lysine, arginine in proximal convoluted
tubule.
Excess cystine in precipitates, forms
cystine kidney stones.
Autosomal recessive
Treat with acetazolamide to
alkalinize urine.

Maple Syrup Disease, 110


Blocked degradation of branched amino
acids (Ile, Leu, Val), due to decreased ketoacid dehydrogenase.
Results in accumulation of -ketoacids
in blood
Severe CNS defects, mental retardation,
death.
Urine smells like maple syrup

Adenosine Deaminase
Deficiency, 111
Excess ATP and dATP imbalances
nucleotide pool (feedback inhibition of
ribonucleotide reductase)
Prevents DNA synthesis
Decreased lymphocyte count
Major cause of severe combined
immunodeficiency disorder

Lesch-Nyhan Syndrome,
111
Absence of HGPRT leads to defective
purine salvage pathway
Excess uric acid production
X-linked recessive

Mental retardation, self-mutilation,


aggression, hyperuricemia, gout,
choreoathetosis

Orotic aciduria, 111

Inability to convert orotic acid UMP in de


novo pyrimidine synthesis pathway
Defect in orotic acid

phosphoribosetransferase or orotidine 5phosphate decarboxylase

Autosomal recessive
Increased orotic acid in urine,
megaloblastic anemia, failure to thrive
Treat with oral uridine

Insulin, 112
Synthesized in pancreas cells
Released in response to ATP from
glucose metabolism (depolarizing K+
channels)
Anabolic effects:

Increases glucose transport, glycogen

synthesis and storage, triglyceride synthesis


and storage, protein synthesis
Increased Na+ retention, cellular K+ uptake

Insulin, 112
Inhibits glucagon release by pancreas
cells
Insulin dephosphorylates
Serum C-peptide only present with
endogenous protein

Lack of C-peptide indicated exogenous

insulin use

Insulin, 112
Insulin moves glucose into cells
Some cells do not need insulin, use a
glucose transporter

GLUT1: RBCs, brain

GLUT2: islet cells, liver, kidney


GLUT4: (insulin sensitive) adipose tissue,

skeletal muscle

Glycogen, 112
Branches: (1,6) bonds
Linkages: (1,4) bonds
Glycogen phosphorylates
Skeletal muscle

Glycogen undergoes glycogenolysis to form

glucose, which is metabolized during exercise

Hepatocytes
Glycogen is stored and undergoes

glycogenolysis to maintain blood glucose levels

Glycogen Storage Disease, 113


All cause abnormal glycogen metabolism and accumulation
within cells
Disease

Findings

Deficient enzyme

Von Gierkes (I)

Severe fasting
hypoglycemia,
increased glycogen in
liver, increased blood
lactate, hepatomegaly

Glucose-6-phosphate

Pompes (II)

Cardiomegaly

Lysosomal -1,4
glucosidase (acid
maltase)

Coris (III)

Milder type I, normal


blood lactate levels

Debranching enzyme

McArdles (V)

Increased glycogen in Skeletal muscle


muscle, muscle
glycogen
cramps, myoglobinuria phosphorylase

Ketone Bodies, 115


In liver, fatty acids and amino acids are
metobolized to acetoacetate and hydroxybutyrate for use in muscle and
brain
Produced in response to starvation,
alcoholism
Breath smells like acetone

Metabolic Fuel Use, 116

Exercise
1st (seconds) Stored ATP, creatine

phosphate, anaerobic glycolysis


2nd (minutes) +Oxidative phosphorylation
3rd (hours) Glycogen and FFA oxidation,
glucose conserved

Metabolic Fuel Use, 116

Fasting and starvation


Preserve glucose for brain and RBCs
Days 1-3
Hepatic glycogenolysis and glucose release
Adipose release of free fatty acids, used by
muscle and liver (in place of glucose)
Hepatic gluconeogenesis from peripheral
lactate and alanine, adipose tissue

Metabolic Fuel Use, 116

Fasting and starvation


After 3 days
Muscle protein used for hepatic formation of
ketone bodies for brain and heart
Several days
Ketone bodies become main energy source
for brain
Survival time determined by fat stores

Lipid Transport Enzymes,


117

Pancreatic lipase
Degradation of dietary lipase in small

intestine

Lipoprotein lipase
Degradation of TG in chylomicrons and

VLDL

Hepatic TG lipase
Degradation of TG in IDL

Hormone sensitive lipase


Degradation of TG in adipocytes

Cholesterol Synthesis, 116

Rate limiting step catalyzed by HMG-CoA


reductase
Enzyme inhibited by statins

2/3 plasma cholesterol is esterified by lecithincholesterol


acyltransferase (LCAT)
Cholesterol ester transport
protein (CETP) mediates
transfer of cholesterol esters to
lipoprotein particles

Essential Fatty Acids, 116


Can not be synthesized, must be in diet
Linoleic and linolenic acids
Arachidonic acid, if linoleic acid is
absent
Necessary for synthesis of eicosandoids

Lipoprotein Functions, 118


Lipoproteins are composed of varying
proportions of cholesterol, triglycerides,
phospholipids
LDL transports cholesterol from liver to
tissues
HDL transports cholesterol from tissues
to liver

Lipoprotein Functions, 118

Chylomicron
Delivers dietary TGs to tissue
Delivers cholesterol to liver as chylomicron

remnants (depleted of triacylglycerols)


Secreted by intestinal epithelial cells
B-48, A-IV, C-II, E
Familial dyslipidemia I
Increased chylomicrons
Elevated TG, cholesterol
Lipoprotein lipase deficiency or altered
apolipoprotein C-II

Lipoprotein, 118

VLDL
Delivers hepatic TGs to tissue
Secreted by liver
B-100, C-II, E
Hypertriglyceridemia
Increased VLDL
Elevated TG
Hepatic overproduction of VLDL

IDL
Formed by degradation of VLDL
Delivers TGs and cholesterol to liver, degraded to LDLs
B-100, E

Lipoprotein Functions, 118

LDL
Delivers hepatic cholesterol to tissues
Formed by lipoprotein lipase modification of

VLDL in tissue
Taken up by target cells via receptor-mediated
endocytosis
B-100
Familial dyslipidemia IIa
Increased LDL
Elevated cholesterol
Autosomal dominant, absent/decreased LDL
receptor

Lipoprotein Functions, 118

HDL
Mediates reverse cholesterol transport from

tissues to liver.
Repository of apoC and apoE
Secreted from liver and intestine

Abetalipoproteinemia, 118
Hereditary inability to synthesize
lipoproteins, because of deficiency in
apoB-100 and apoB-48
Autosomal recessive, appears early in life
Failure to thrive,
steatorrhea,
acanthocytosis, ataxia,
night blindness