Transcript MicronutrientDeficiencies.ppt

Micronutrient Deficiencies
PRANITHI HONGSPRABHAS MD
DIVISION OF CLINICAL NUTRITION
D E P A R T M E N T O F M E D I C I N E , F A C U L AT Y O F M E D I C I N E , K K U
The Known 51 Essential Nutrients for Sustaining Human
Life*
Air, Water &
Energy
(3)
Oxygen
Water
Carbohydrates
Protein
(amino acids)
(9)
Histidine
Isoleucine
Leucine
Lysine
Methionine
Phenylalanine
Threonine
Tryptophan
Valine
Lipids-Fat
(fatty acids)
(2)
Linoleic acid
Linolenic acid
MacroMinerals
(7)
Na
K
Ca
Mg
S
P
Cl
Trace
Elements
(17)
Fe
Zn
Cu
Mn
I
F
Se
Mo
Co (in B12)
B
Ni
Cr
V
Si
As
Li
Sn
Vitamins
(13)
A
D
E
K
C (Ascorbic acid)
B1 (Thiamin)
B2 (Riboflavin)
B3 (Niacin)
B5 (Pantothenic acid)
B6 (Pyroxidine)
B7/H (Biotin)
B9 (Folic acid, folacin)
B12 (Cobalamin)
*Numerous other beneficial substances in foods are also known to contribute to good health.
Development of Deficiency
Water Soluble Vitamin
Case 1
 16 yr old male presented with progressive DOE, orthopnea and
edema for 2 days
6 d PTA, he got bilateral calf pain and cannot play football as before due to
calf pain and fatigue, afebrile
 2 d of progressive DOE, orthopnea
 Absent alcohol intake, numbness
PE: PR 130/min with AF, BP150/50 mmHg, icteric, BMI ~29 kg/m2
Puffy face, engorge neck vein, bilateral basal crepitation
Hepatomegaly, calf tenderness and leg edema
Lab: mild hyponatremia, wild gap metabolicacidosis (HCO3 8)
Cr 2.2, BUN 28, elevated CK
CBC: leukocytosis, mild thrombocytopenia
LFT: DB 4, mild transaminitis
Lactate: high

 After 12 hr of CHF treatment (diuretic, vasodilator, inotropic)
and antibiotic (?) fail to improve, but further progressive
acidosis and oliguria
Diagnosis
 Diagnosis
 Investigation
 Treatment
Thiamin(e)
VITAMIN B1
ANEURINE
Thiamin
 Absorption (rate limiting step)

Active thiamin transport in jejunum and ileum inhibited by alc
 Form in body



Free thiamin
Phosphorylated form: TMP, TTP, TPP (TDP)
Stored (small amount) in heart, brain, liver, and kidney
 TPP: coenzyme



CHO metabolism: pyruvate dehydrogenase, α-ketoglutarate
dehydrogenase
BCAA BCKA:branched-chain α-keto acid dehydrogenase
Pentose phosphate pathway (PPP): trans-ketolase
Reducing substance NADPH
 Ribose-5-phosphat[R5P]: neucleic synthesis
 Erythrose-4-phosphate[E4P]aromatic aa.

 RDA



Men - 1.5 Women - 1.1 mg
Pregnant/lactation- 1.5 mg
Children - 1.1 mg
Determination of Thiamin Status: 3 Methods
 Erythrocyte Transketolase Activity (ETKA) and TPP effect
 TPP effect 0-15%
= normal
15-25% = marginal thiamin deficiency
>25%
= thiamin deficiency
(non-specificity, poor sensitivity, poor precision, and lack of specimen
stability)
 Urinary excretion of thiamin before and after thiamin
administration
(inconvenience of sample collection, interfered by intake, others)
 Serum thiamin: poor sensitivity and specificity, represent
recent intake
 Erythrocyte, or whole blood thiamine levels (HPLC)
[most appropriate measurement to assess thiamine status, sensitive
and specific]
Normal :90 to 160 μg sedoheptulose formed/mL/hour
Thiamine Deficiency: Mild Deficiency
Anorexia, irritability, fatigue, aching
Burning sensation in the hands and feet
Indigestion
Sleep disturbances, and depression
6-8
wk
Slight fall in blood pressure and
moderate weight loss
2-3
mo
Apathy
Weakness become extreme,
Calf muscle tenderness
Loss of recent memory, confusion, ataxia
and sometimes persistent vomiting
Deficiency:
Beriberi = I Can Not
 Dry (paralytic or nervous) beriberi: peripheral
neuropathy (sensori-motor axonopathy)
 Wet beriberi: tachycardia, cardiomegaly, severe
edema, CHF
 Cerebral beriberi: Wernicke's encephalopathy



opthalmoplegia, nystagmus
ataxia
abnormalities in mental function [confused apathetic state 
 profound memory disorder; Korsakoff's amnesia or
Korsakoff's psychosis) (WKS)
 Musculoskeletal system
 Myopathy: myalgia and tenderness, cramp
Risk Of Thiamin Deficiency
 Inadequate intake


Alcohol
diets high in CHO and low thiamin (e.g., milled or polished
rice)
 Increased requirement

strenuous physical exertion, pregnancy, breast-feeding, and
adolescent growth, infection (malaria, HIV), hyperthyroidism
 Excessive loss

Alcohol, CKD on HD, diuretic?
 Anti-thiamin factors (ATF)


Antithiamin compounds:Tea leafs, betel nut
Thiaminase (heat labile): raw freshwater fish, shellfish,
silkworm
Genetic Diseases Of Thiamine Transport
 Rare but serious
 Thiamine responsive megaloblastic
anemia (TRMA)



DM and sensorineural deafness
Autosomal recessive disorder caused by gene mutation
High affinity thiamine transporter
Treatment of Thiamin Deficiency
 Thiamine 100 mg/d given parenterally for 7 days
 Followed by 10 mg/d orally until there is complete
recovery
 Clinical response




Cardiovascular improvement occurs within 24 h,
Ophthalmoplegic improvement occurs within 24 h
Recovery of neuropathy may take several wks or mo
Psychosis in Wernicke-Korsakoff syndrome may be permanent
or persist for several months
Drug Interactions
 Anticonvulsants: long term phenytoin  vitamin
level
 5-FU inhibits the phosphorylation of thiamin to TPP
 Diuretics, especially furosemide  urinary
excretion
 Chronic alcohol abuse: thiamin def



Low dietary intake
Impaired active absorption and cellular utilization
 Urinary excretion of thiamin
Toxicity
 No well-established toxic effects from the
consumption of excess thiamin in food or long-term
supplementation
 Report of life threatening anaphylactic reactions in
large IV dose
Riboflavin
Function: Flavoenzymes
Enzymes contain flavin adenine dinucleotide (FAD) or flavinmononucleotide (FMN) e.g., succinic acid dehydrogenase,
monoamine oxidase, glutathione reductase
 Oxidation-reduction (redox) reactions
 Metabolism of fat, CHO, and protein: electron donor
 Metabolism of drugs and toxins (CYP450)
 Antioxidant functions
Glutathione reductase: FAD dependent enz
 Glutathione peroxidase
 Xanthine oxidase: FAD-dependent enzyme

Nutrient Interactions
 Flavoproteins are involved in the metabolism of several
other vitamins (B6, niacin, folic acid)
 Vitamin B6:

B6 pyridoxal 5 phosphate (PLP) require FMN dependent enz
 Niacine

Niacine containing enz(NAD, NADP) from Tryp require FAD
dependent enz
 Folic

Methylene tetrahydrofolate reductase (MTHFR) require FAD
dependent enz to convert Hcy to methionine
 Fe:

Riboflavin deficiency impaired Fe absorption,  intestinal Fe loss,
and/or impair iron utilization for the synthesis of Hb
Riboflavin Rich Food
Recommended Dietary Allowance (RDA) for
Riboflavin
Males
(mg/day)
Females
(mg/day)
14-18 years
1.3
1.0
Adults
19 years
and older
1.3
1.1
Pregnancy
all ages
-
1.4
Breastfeeding
all ages
-
1.6
Life Stage
Adolescents
Cereal, nut, milk, egg, lean
meat, Green leafy vegetable
Age
Riboflavin Deficiency
 Rarely found in isolation
 Mouth: angular stomatitis, cheilitis
 -moist, erosion, white, and ultimately
cracks, showed bright red color of the upper
and lower lip mucosa, lips longitudinal
cracks increased and bleeding;
 Tongue: atrophic glossitis
 bright red, tongue cracks, pain and sense
of taste
 Eye: conjuntivitis, blephalitis
 inflammation of the conjunctiva by the
proliferation of capillaries invade the
cornea, light sensitive, tearing, itching and
burning, and even can lead to corneal ulcers
 Skin: seborrheic dermatitis
 Blood: anemia
Risk Factors For Riboflavin Deficiency
 Alcoholics
 decreased intake/decreased absorption/impaired utilization
 Anorexic individuals
 Impaired conversion of riboflavin  FAD and FMN:
in hypothyroidism and adrenal insufficiency
 Very active physically (athletes, laborers) may have
a slightly increased riboflavin requirement
Determination Status of Riboflavin
 Measurement of
 urinary riboflavin (<80 mcg per g Cr)
 red blood cell riboflavin concentrations (<10 μg)/dL
 Measurement of erythrocyte glutathione reductase
activity, with and without added FAD

Coefficient:
<1.2
1.2 to 1.4c
>1.4
= acceptable
= low
= deficient
Riboflavin Supplement
 RDAs are 1.2-1.6 mg.
 Therapeutic daily dosages: varies
 Therapeutic dosages of 30-50 mg/d:
 Deficiency states associated with angular stomatitis,
seborrheic dermatitis, and neuropathy.
Typical B-vitamin complexes contain Vit B1 5 mg, vit B2 2 mg, vit
B6 2 mg, nicotinamide 20 mg
 Riboflavin tablet: 10mg

 400 mg riboflavin daily can be used for migraine
prophylaxis
Drug Interactions
 Inhibit the incorporation of riboflavin into FAD and
FMN



Phenothiazine derivatives and tricyclic antidepressant
Anti-malarial: quinacrine
Adriamycin
 Long-term use of phenobarbitol may  destruction
of riboflavin risk of deficiency
Toxicity
 No toxic or adverse effects of high riboflavin intake
in humans are known
 High-dose riboflavin Rxintensify urine color to a
bright yellow (flavinuria), harmless side effect
Case 2
 A 45 yo alcoholic man admitted to psy ward with
confusion and skin lesion
Niacin Deficiency
Casal's necklace
Niacin
 Nicotinic acid and Nicotinamide
 Absorption: passive absorption
 Precursors of 2 coenzs, nicotinamide adenine
dinucleotide (NAD) and NAD phosphate (NADP)
 Oxidation-reduction (redox) reactions: accept or
donate electrons for redox reactions


Catabolic: CHO, Fat , Protein catabolism (NAD)
Anabolic: synthesis FA, chl (NADP)
 Non-redox reactions
 cell signaling, transcription, regulation or apoptosis,
chromatin structure, and cell differentiation
 Can be synthesized from Trp
B2,B6
Fe++
Niacin Requirement
Recommended Dietary Allowance
(RDA) for Niacin
Life Stage
Adolescents
Adults
Pregnancy
Breastfeeding
Meat,paultry, fish,
mushroom, nut, cereal
Males (mg
NE*/day)
Females
(mg
NE/day)
16
14
16
14
all ages
-
18
all ages
-
17
Age
14-18
years
19 years
and
older
*NE, niacin equivalent: 1 mg NE = 60 mg of tryptophan =
1 mg niacin
Risk of Niacin Deficiency
 Inadequate intake of niacin and/or tryptophan (Trp)
 Carcinod syndrome:, increased utilization of Trp
for 5-HT >>niacin synthesis
 Hartnup’s disease a hereditary disorder resulting in
defective Trp absorption (GI, kidney)
 Prolonged Isoniazid has resulted in niacin deficiency
Niacin (Vitamin B3) Deficiency
Symptoms of deficiency: non-specific, often found in
combination with other vitamin deficiencies
 Mild deficiency




Poor appetite, weakness, loss of energy, dizziness
Burning or numbness of the skin
Cracking of the of the skin/lips at the corners of the mouth
Red, sore tongue
 Severe deficiency



Skin: a thick, scaly, darkly pigmented rash develops symmetrically
in areas exposed to sunlight
GI: bright red tongue, vomiting, and diarrhea.
Nervous system: headache, apathy, fatigue, depression,
disorientation, and memory loss
Pellagra (= rough or raw skin) 4 D: Dermatitis, Diarrhea,
Dementia Death
Determination of Niacin Status
 Urinary niacin metabolite N1-methylnicotinamide
and of its 2-pyridone derivatives
 Excretion
N1-methylnicotinamide
< 0.8 mg/d =deficiency
 N+-methyl-5-carboxamide-2-pyridone: N1methylnicotinamide
1.3 to 2.0 = normal
<1.0
= Deficiency
Therapeutic Use
 Pellagra treatment
 Oral supplementation of 100–200 mg of nicotinamide or
nicotinic acid three times daily for 5 days (2x3 of 50mg)
 Hypertriglyceridemia/hypercholesterolemia Rx
 nicotinic acid (2 g/d in a time-release form
Drug Interaction
 Combination with lovastatin: report of
rhabdomyolysis
 Inhibit uricosuric effect of Sulfinpyrazone
 INH; niacin antagonist
Toxicity
 Niacin from foods is not known to cause adverse effects
 Nicotinic acid:
 Common : Prostaglandin-mediated flushing, itching, and N&V
 Hepatotoxicity (liver cell damage)
 Skin rashes and dry skin
 Transient episodes of low blood pressure (hypotension) and headache
 IGTT, hyperglycemia
 Hyperuricemia, occasionally gout attack
People with liver disease of abn LFT, DM, active PU,gout,
arrhythmias, inflammatory bowel disease, migraine
headaches,and alcoholism more susceptible ADR
 Nicotinamide:


nausea, vomiting, and signs of liver toxicity (elevated liver enzymes,
jaundice) have been observed at doses of 3 g/d, less flushing
hyperglycemia
Tolerable Upper Intake Level (UL) for Niacin
Age Group
UL (mg/day)
Not possible to
Infants 0-12 months
establish*
10
Children 1-3 years
15
Children 4-8 years
20
Children 9-13 years
30
Adolescents 14-18 years
Adults 19 years and
35
older
Vitamin B6
Vitamin B6
 3 Forms of vitamin B6: Pyridoxal (PL), Pyridoxine
(PN), Pyridoxamine (PM)
 Pyridoxol 5'-phosphate (PLP):Principal coenzyme





Metabolism: glycogenolysis, gluconeogenesis, crucial to
protein metabolism
Nervous system function: using PLP to synthesis 5-HT, DA,
NE, GABA
Red blood cell formation and function: PLP coenzyme in the
synthesis of heme
Niacin formation
Hormone function: Steroid hormones


PLP bind to steroid receptors   effect
Nucleic acid synthesis: PLP coenzyme for a key enzyme
involved in synthesis of nucleic acids
Pyridoxine Rich food
Recommended Dietary Allowance (RDA) for
Vitamin B6
Males
Females
Life Stage Age
(mg/day) (mg/day)
B6
Potato
Banana
Garbanzo beans
Meat, poultry, fish
Adolescents 14-18 years
1.3
1.2
Adults
19-50 years
1.3
1.3
Adults
51 years and
older
1.7
1.5
Pregnancy
all ages
-
1.9
Breastfeeding
all ages
-
2.0
Deficiency
Risk of deficiency
Deficiency
 Severe deficiency:
 Neuro:
uncommon
 Alcoholics: most at risk
of vitamin
B6 deficiency due to


low dietary intakes
impaired metabolism of
the vitamin



irritability, depression, and
confusion
Peripheral neuropathy
seizure
 Epithelial changes

Glossitis, oral ulcer
 Anemia: microcytic
 Hyperhomocysteinemia
Determination Of B6 Status
 Diagnosis of vitamin B6 deficiency is generally made
on the basis of low plasma PLP values (<20 nmol/L)
Treatment of Deficiency
 50 mg/d for Rx of deficiency
 100–200 mg/d are given if vitamin B6 deficiency
related to medication use
Other Therapeutic Use
 Vitamin B6 dependency syndromes
 Homocystinuria: cystathionase deficiency
 pyridoxine-responsive (primarily sideroblastic) anemias
 Gyrate atrophy with chorioretinal degeneration
 Need 100 -200mg/d
Drug Interaction
Medication Interfere With B6
B6 Interferes With Medication
 Form complex with
 High dose
PLP
Anti-TB: INH, cycloserine
 D-penicillamine
 L-dopa
 functional deficiency

B6decrease the
efficacy:


phenobarbital and
phenytoin,
L-dopa
Toxicity
 No adverse effects have been associated with high
intakes of vitamin B6 from food sources
 Safe upper limit for vitamin B6 has been set at 100
mg/d, although
 Toxicity


Severe sensory neuropathy, leaving patients unable to walk.
Photosensitivity and dermatitis
Vitamin B7 (Vitamin H, Biotin)
 1o function: coenzyme in
CHO, aa., and lipid
metabolism.
 Essential for cell growth
and replication (DNA and
RNA)
 Origin/Sources: cheese,
kidney, liver, cauliflower,
eggs, mushrooms, nuts,
sardines and salmon.
 Also synthesised by
microorganisms in the GI
tract
Deficiency
• Hair loss, A scaly red rash in
the face around the mouth,
nose, eyes, and genitals
• Depression, lethargy,
hallucination, and peripheral
neuropathy
Biotin: The Forgotten Vitamin (B7)
 Member of the B complex group of vitamins
 Binding with ‘AVIDIN’; resist to pancreatic protease
enzyme 
 Situation of biotin def\


prolonged consumption of raw egg whites
PN nutrition without biotin supplementation in patients with
SBS
Thiamine, Riboflavin, Niacin, Pyridoxine: Cofactors to enzymes in
energy metabolism Deficiencies show up in quickly growing tissues;
Epithelium
Typical symptoms for the
group include:
 √Dermatitis
 √ Glossitis
 √ Cheilitis
 √ Diarrhea
Nerve cells use lots of
energy, so symptoms also
show up in the nervous
tissue:
 √ Peripheral neuropathy
 √ Depression
 √ Mental confusion
 √ Lack of motor
coordination
 √ Malaise
The Hematopoietic
Vitamins
Folate
Structure Of Folic Acid
 Folic acid = pteridine base attached to p-aminobenzoic
acid and glutamic acid -and single carbon substitution
group: formyl, methyl, and methylene -pteroylglutamic
acid –parent
Folic acid carrying polyglutamic acid cannot be transported back out of the cell
Activation Of Folic Acid
 Folic acid is not the active form of the vitamin & needs to
be reduced to tetrahydrofolate (THF)
•Single carbon substitution gr: formyl-,methyl-, and methylene-
 Food Folate: Major forms of dietary folate are methyl-THF
and formyl-THF and polyglutamate >monoglutamate
 Degraded by prolonged boiling
 Absorption: monoglutamate>> polyglutamate


Specific absorption ‘carrier”: jejunum-reduced folate
Non specific absorption: ileum-unreduced folic acid
 Enter various compartments for metabolism, storage, or




enterohepatic recirculation
Circulating and transport form: monoglutamate
Storage: most stored in polyglutamate form
Excretion: urine and bile
Folate free diet causes deficiency in few wks
Folate Rich Food
Recommended Dietary Allowance for Folate
in Dietary Folate Equivalents (DFE)
Males
Females
Life Stage Age
(mcg/day) (mcg/day)
Adolescents 14-18 years
Folate
Lentils
legumes
Asparagus
Dark green leafy
vegetable
Orange juice
Paultry, pork, liver,
shellfish
400
400
400
400
Adults
19 years
and older
Pregnancy
all ages
-
600
Breastfeeding
all ages
-
500
Function: Folate Coenzyme
 One-carbon metabolism: Folate coenzymes act as
acceptors /donors of one-carbon units critical to nucleic
and amino acids metabolism
 Nucleic acid metabolism


Synthesis of DNA: depend on folate coenzymes
Folate coenzyme required for the synthesis of Met, and Sadenosylmethionine (SAM); methyl group (one-carbon unit) donor for
methylation reactions
 Amino acid metabolism
 -Red blood cell synthesis
 -Critical for cell division in embryos
 - GI tract mucosa
Nutrient Interactions
 B6, B12, Folate,
B2, Niacin
Folate Deficiency
 Dietary insufficiency

Elderly, infancy, alcoholism,
psychiatrically disturbed
 Malabsorption

SB disease: sprue, CD, lymphoma

Motility disorder:DAN, scleroderma

Gastric bypass surgery

Salazopyrine
 Altered utilization

Pregnancy and lactation

Hematologic diseases: chronic
hemolytic anemias,
myelofibrosis

Malignant diseases: carcinoma,
lymphoma, leukemia, myeloma

Inflammatory diseases:
tuberculosis, Crohn's disease,
psoriasis, exfoliative dermatitis,
malaria

Metabolic disease:
homocystinuria
 Anti-folate drug and toxin

Alcohol

Anticonvulsant drugs (phenytoin,
primidone, barbiturates, valproate)

Dihydrofolate reductase inhibitors:
MTX, bactrim, pyrimethamine,
triamterene

Sulfasalazine
 Excess urinary loss:

Congestive heart failure

Hemodialysis, PD, Cancer
Folate Deficiency
 Hematologic

Megaloblastic anemia
 GI: diarrhea (intestinal megaloblastosis from severe B12 or folate
deficiency)
 Neuro: mental confusion, and depression, mild
neuropathy
 Neural tube defect
 Subclinical features: hyperhomocysteinemia
Treatment
 Oral folic acid 5–15 mg/d, as sufficient folate even




in severe malabsorption
Duration depends on the underlying disease
Customary to continue Rx for ~ 4 mo
Before large doses of folic acid given, cobalamin
deficiency must be excluded/corrected otherwise
cobalamin neuropathy may develop
Folinic Acid: orally or parenterally to overcome the
toxic effects of MTX or other DHF reductase
inhibitors
Case 3
 42yo female presented
with numbness of legs
and difficult walking
 PH: Dx of Grave’s
disease 3 years ago
 FH: hyperthyroid
Vitamin B12: Cobalamin
Replace R with
 Deoxyadenosine 
deoxyadenosyl-cobalamin
 CH3  methylcobalamin
 CN  cyanocobalamin
Corin nucleus and
nucleotides
 Cofactor for methionine synthase
 Cofactor for L-methylmalonyl-CoA mutase: production
of energy from fats and proteins
Cobalamin Rich Food
Recommended Dietary Allowance (RDA) for Vitamin B12
B12
Clams
Rainbow trout
Sockeye salmon
Beef
Males
(mcg/day)
Females
(mcg/day)
14-18 years
2.4
2.4
Adults
19-50 years
2.4
2.4
Adults
51 years and
older
2.4*
2.4*
Pregnancy
all ages
-
2.6
Breast-feeding all ages
-
2.8
Life Stage
Age
Adolescents
Cobalamin Deficiency
 Hematological: megaloblastic anemia
 Neurological:
 Bilateral peripheral neuropathy (leg> arm)

vibration and JPS in toe ascending to legs and armsataxia,
spasticity
Degeneration (demyelination) of the posterior and pyramidal
tracts of the spinal cord
 Memory loss, disorientation, and dementia
Neurologic complications (25% of B12Def): not always
associated with megaloblastic anemia

 GI:
 Glossitis, appetite loss, and constipation
Cobalamin Deficiency
Nutritional
Malabsorption
Gastric causes
Vegans
Pernicious anemia
Congenital absence of intrinsic factor or functional abnormality
Total or partial gastrectomy
Intestinal causes
Intestinal stagnant loop syndrome: jejunal diverticulosis, ileocolic
fistula, anatomic blind loop, intestinal stricture
Ileal resection and Crohn's disease
Selective malabsorption with proteinuria
Tropical sprue
Transcobalamin II deficiency
Fish tapeworm
Malabsorption of Cobalamin May Occur, But Is Not Usually Sufficiently Severe and Prolonged
to Cause Megaloblastic Anemia
Gastric causes
Simple atrophic gastritis (food cobalamin malabsorption)
Zollinger–Ellison syndrome
Gastric bypass surgery
Use of proton pump inhibitors
Intestinal causes
Gluten-induced enteropathy
Severe pancreatitis
HIV infection
Radiotherapy
Graft-versus-host disease
Deficiencies of cobalamin, folate, protein, ?riboflavin, ?nicotinic acid
Rx with colchicine, para-aminosalicylate, neomycin, slow-release potassium chloride,
anticonvulsant drugs, metformin, phenformin, cytotoxic drugs
Alcohol
Determination of Status
 Serum cobalamin
 Normal:

borderline
deficiency
160–200 to 1000 ng/L
100 and 200 ng/L
<100 ng/L
 Schilling test relies on 24-hour Urinary excretion to
measure the absorption of oral, radioisotopically
labeled cobalamin
 Ab to IF
Treatment of Deficiency
 Six 1000 g IM injections of hydroxocobalamin given
at 3- to 7-day intervals (more frequent doses
cobalamin neuropathy)
 Maintenance Rx 1000 g hydroxocobalamin IM once
every 3 months is satisfactory

protocols generally use higher and more frequent doses, e.g.,
1000 g IM monthly for maintenance treatment
Drug Interactions
 Large doses of folic acid given to undiagnosed
vitamin B12 deficiency could correct megaloblastic
anemia without at risk of developing irreversible
neurologic damage
 PPI, H2 Blocker:  absorption of cobalamin
 Cholestyramin: absorption of cobalamin
Vitamin C
Ascorbic Acid
 Synthesis of collagen
 Synthesis of the neurotransmitter,
 DA NE
 Synthesis of carnitine
 Promotion of nonheme iron absorption
 Involved in the metabolism of cholesterol to bile
acids
 Component of metabolizing enzyme systems,
particularly the mixed-function oxidase systems
 Antioxidants
Vitamin C rich Foods
Recommended Dietary Allowance (RDA) for Vitamin C
Vitamin C
Broccoli
Red bell pepper
Brussels sprouts
Papaya
Males
(mg/day)
Females
(mg/day)
14-18 years
75
65
Adults
19 years and
older
90
75
Smokers
19 years and
older
125
110
Pregnancy
18 years and
younger
-
80
Pregnancy
19 years and
older
-
85
Breastfeeding
18 years and
younger
-
115
Breast-feeding
19 years and
older
-
120
Life Stage
Age
Adolescents
Scurvy and Treament
Vitamin C 200 mg/d
Case 4
 68 yo man presented with aspiration pnuemonia. He got
hypoxic encephalopathy for 5 yr and became bedridden
thereafter. Skin rash was noted on his legs
Toxicity
 Taking >2 g of vitamin C in a single dose
 abdominal pain, diarrhea, and nausea.
 Since vitamin C may be metabolized to oxalate
 chronic, high-dose vitamin C supplementation could result in an 
kidney stones
 High doses of vitamin C can induce hemolysis in G6PD
deficiency patients
 Doses >1 g/d can cause false-negative guaiac reactions
Tolerable Upper Intake Level (UL) for Vitamin C
Age Group
UL (mg/day)
Infants 0-12 months
Not possible to establish*
Children 1-3 years
400
Children 4-8 years
Children 9-13 years
Adolescents 14-18 years
Adults 19 years and older
650
1,200
1,800
2,000
Fat Soluble Vitamins
Fat Soluble Vitamins
 Found in foods containing fats and/stored either in liver
andor adipose tissue until needed
 Excessive intake of A or D causes them to be stored and
can be undesirable
 Fat-soluble vitamins are absorbed and transported around
the body like other fats.
 Interfering with fat maldigestion or malabsorption fat
soluble vitamin deficiencies
Vitamin E
Tocopherol
•Describe a 8 antioxidants
•4 tocopherols (,,, and-)
•4 tocotrienols (,,, and-)
•-Tocopherol Is The Active Form Of
Vitamin E In Human Body
Vitamin E Function
 Main function: antioxidant
 Protect lipid peroxidation; LDL
 Inhibit platelet aggregation
 Inhibit protein kinase C
 Enhance vasodilatation
Vitamin E Rich Foods
Vitamin E
Corn
Nuts: Almonds, hazelnuts
Sunflower seeds and oils
Green leafy vegetables
Wheat germs
The Recommended Dietary Allowance (RDA) for Alpha-Tocopherol
Males; mg/day
(IU/day)
Females; mg/day
(IU/day)
0-6 months
4 mg (6 IU)
4 mg (6 IU)
Infants (AI)
7-12 months
5 mg (7.5 IU)
5 mg (7.5 IU)
Children
1-3 years
6 mg (9 IU)
6 mg (9 IU)
Children
4-8 years
7 mg (10.5 IU)
7 mg (10.5 IU)
Children
9-13 years
11 mg (16.5 IU)
11 mg (16.5 IU)
Adolescents
14-18 years
15 mg (22.5 IU)
15 mg (22.5 IU)
Adults
19 years and older
15 mg (22.5 IU)
15 mg (22.5 IU)
Pregnancy
all ages
-
15 mg (22.5 IU)
Breast-feeding
all ages
-
19 mg (28.5 IU)
Life Stage
Age
Infants (AI)
Vitamin E Deficiency
Risk of deficiency
 Severe malnutrition
 Genetic defects
affecting the tocopherol transfer
protein
 Fat malabsorption
syndrome
 True vitamin E
deficiency is rare
 Neurological: impaired
coordination and
weakness



Ataxia
Peripheral neuropathy
Myopathy
 Retinopathy
 Risk of cardiovascular
disease
 Hemolytic anemia in
children
Toxicity
 Risk of bleeding
 Recommend to stop 1 month before elective
surgery
Tolerable Upper Intake Level (UL) for Alpha-Tocopherol
Age Group
mg/day (IU/day d-alphatocopherol)
Infants 0-12 months
Not Possible to Establish*
Children 1-3 years
200 mg (300 IU)
Children 4-8 years
300 mg (450 IU)
Children 9-13 years
600 mg (900 IU)
Adolescents 14-18 years
800 mg (1,200 IU)
Adults 19 and older
1,000 mg (1,500 IU)
*Source of intake should be from foods or formula only.
Drug Interactions
 Vitamin E supplements
increase the risk of
bleeding in individuals taking




Anticoagulant : warfarin
Antiplatelet
NSAIDs
Vitamin K deficient
 Medication decrease vitamin E absorption
 Cholestyramine, isoniazid, mineral oil, orlistat, sucralfate,
and the fat substitute, olestra.
 Medication decrease vitamin E level
 Anticonvulsant: phenobarbital, phenytoin, or carbamazepine,
Metaanalysis Of Vitamin E On CVD
CVD
Alldeath
cause
Stroke
All
cause
mortality
Lancet 2003; 361: 2017–23
Supplementation: All Cause Mortality
Ann Intern Med. 2005;142:37-46
Vitamin A
Structure of Vitamin A and Related Compounds
Vitamin A: First Vitamin Discovered (1913)
Functions
 Maintenance of Normal




Vision
Growth, Repair and Cell
Differentiation
Health of Epithelial Cells
Pregnancy and Fetal
Development
Protection Against
Infection
Summmary Of Functions Of Vitamin A
Compounds
Beta carotene
(Antioxidants)
Retinol
(Steroid hormones-Growth and differentiation)
Retinal
(Visual Cycle)
Retinyl Phosphate
(Glycoprotein synthesis)
Retinoic acid
(Steroid hormone-Growth and differentiation)
Vitamin A Deficiency
Effect on eyes and vision:
Night blindness (nyctalopia)
Dark adaptation time
 Severe deficiency xeropthalmia (dryness in conjuctiva and
cornea, keratinization of epithelial cells),  keratomalacia (corneal
ulceration/degeneration and destruction) blind

Effect on Growth: growth retardation due to impairment
in skeletal formation
Effect on Reproduction : Degeneration of germinal
epithelium sterility in males
Effect on Skin and epithelial cells:
Skins becomes rough and dry
 Keratinization of GI, GU and respiratory epithelial cells  infection

Vitamin A Deficiency:
Eye failsNight
to Blindness
Night Blindness
adapt quickly to
decreased light.
Car passes. Notice distance down the road, signs.
Vitamin A Deficiency
•Night blindness
•Xerophtalmia
•Increased susceptability to infections
•Growth failure
•Follicular hyperkeratosis
Risk of Vitamin A Deficiency
 Malabsorption of vitamin A



Intestinal disease
Chronic pancreatitis
Obstructive
jaundice/cholestasis
 Decreased storage

Cirrhosis
 Over excretion (RARE!)

TB, UTI, nephritis, cancer,
pneumonia
 Increased needs



New born ŝ breast feeding
Pregnancy
Lactation
Investigation
 Dark adaptation
 Vitamin A level <0.7 mg/L
 Low serum RBP
 Zinc level
Treatment of Vitamin A Deficiency (VAD)
 Beta-carotene
Carrots/juice
pumpkin
spinach
Sweet potato
Age
Vitamin A supplementation /day
≤3 y
600 μg
2000 IU
4-8 y
900 μg
3000 IU
9-13 y
1700 μg
5665 IU
14-18 years
2800 μg
9335 IU
All adults
3000 μg
10,000 IU
Vitamin A Toxicity: high doses (~ 10 x RDA)
 Symptoms:
 Nausea/loss of appetite
 Dermatitis (dry itchy redness of skin)
 Headache/ pseudotumor cerebri
 Bone decalcification
 Bone and joint pain
 Liver toxicity: congestion, fat deposition, fibrosis
 Elderly people and people who drink alcohol heavily
are more susceptible to vitamin A toxicity
Vitamin D

Vitamin D2 (ergocalciferol) present in plants

-Vitamin D3 (cholecalciferol) present in skin of
animals

-Vitamin D3 25(OH)D (calcidiol) in liver
1,25(OH)D (calcitriol) in kidney
Vitamin D2 (ergocalciferol) present in
plants
-Vitamin D3 (cholecalciferol) present in
skin of animals
-Vitamin D3 25(OH)D (calcidiol) in liver
1,25(OH)D (calcitriol) in kidney
Holick MF N Engl J Med 2007; 357:266-281
Non Skeletal Action of Vitamin D
 Cell Differentiation
 inhibits proliferation and
stimulates differentiation of
cells
 Immunity
 potent immune system
modulator
 enhance innate immunity and
inhibit development
of autoimmunity
 Insulin Secretion
 Blood Pressure Regulation
 Inhibit renin
Holick MF N Engl J Med 2007; 357:266-281
Vitamin D Requirement
Recommended Dietary Allowance (RDA) for Vitamin D (Set by the Institute of Medicine)
Life Stage
Age
Infants
0-6 months
Males
mcg/day (IU/day)
Females
mcg/day (IU/day)
10 mcg (400 IU) (AI)
10 mcg (400 IU) (AI)
However,
Infants
most experts
6-12 monthsagree that
10 without
mcg (400 IU)adequate
(AI)
10 mcgsun
(400 IU) (AI)
exposure, children and adult require 800-1000 IU/d
Children
1-3 years
15 mcg (600 IU)
15 mcg (600 IU)
Children
4-8 years
15 mcg (600 IU)
15 mcg (600 IU)
Children
9-13 years
15 mcg (600 IU)
15 mcg (600 IU)
Adolescents
14-18 years
15 mcg (600 IU)
15 mcg (600 IU)
Adults
19-50 years
15 mcg (600 IU)
15 mcg (600 IU)
Adults
51-70 years
15 mcg (600 IU)
15 mcg (600 IU)
Adults
71 years and older
20 mcg (800 IU)
20 mcg (800 IU)
Pregnancy
all ages
-
15 mcg (600 IU)
Breast-feeding
all ages
-
15 mcg (600 IU)
Vitamin D Rich Food
Holick MF N Engl J Med 2007; 357:266-281
Assessing Vitamin D Nutritional Status
 25-hydroxyvitamin D level is the best indicator of
vitamin D deficiency and sufficiency
 Vitamin D deficiency Ca absorption not be
increased enough to satisfy needs  PTH
production


 mobilize Ca from the skeleton to maintain normal Ca
levels (2ohyperparathyroidism)
Stimulate 25(OH)D  1,25(OH)2D
Definithion Of Vitamin D Status
No consensus on optimal levels of 25-(OH)D as measured in serum
Status
ng/dL
nmol /L
Severe deficiency
8-10
20-25
Vitamin D deficiency
<20
<50
Relative vitamin D insufficiency
21-29
52-72
Sufficiency of vitamin D (preference
range)
30-60
75-125
Vitamin D intoxication
>150
>374
Vitamin D Requirement
Recommended Dietary Allowance (RDA) for Vitamin D (Set by the Institute of Medicine)
Life Stage
Age
Infants
0-6 months
Males
mcg/day (IU/day)
Females
mcg/day (IU/day)
10 mcg (400 IU) (AI)
10 mcg (400 IU) (AI)
However,
Infants
most experts
6-12 monthsagree that
10 without
mcg (400 IU)adequate
(AI)
10 mcgsun
(400 IU) (AI)
exposure, children and adult require 800-1000 IU/d
Children
1-3 years
15 mcg (600 IU)
15 mcg (600 IU)
Children
4-8 years
15 mcg (600 IU)
15 mcg (600 IU)
Children
9-13 years
15 mcg (600 IU)
15 mcg (600 IU)
Adolescents
14-18 years
15 mcg (600 IU)
15 mcg (600 IU)
Adults
19-50 years
15 mcg (600 IU)
15 mcg (600 IU)
Adults
51-70 years
15 mcg (600 IU)
15 mcg (600 IU)
Adults
71 years and older
20 mcg (800 IU)
20 mcg (800 IU)
Pregnancy
all ages
-
15 mcg (600 IU)
Breast-feeding
all ages
-
15 mcg (600 IU)
Risk of Vitamin D Deficiency
 Reduced skin synthesis
 Sun screen/dark skin
 Elderly
 Skin graft for burn
 Latitude/season
 Decreased bioavailability
 Fat malabsorption
 SB disease
 Pancreatic failure
 Cholestasis
 Obesity
 Decreased intake
 Exclusive breast feeding
 Increased catabolism
 Anticonvulsants,
glucocorticoids, HAART and
antirejection med — binding
to the steroid and
xenobiotic ® or pregnane X
®
 Decreased synthesis
 25(OH)D: liver failure
 Mild-mod dysfunction: vit
D absorption
 Severe dysfunction (90%):
synthesis
 1,25 (OH)2D: CKD (begin
with stage 2-3)
Holick MF N Engl J Med 2007; 357:266-281
Risk of Vitamin D Deficiency
Heritable Disorders: Rickets
Acquired Disorder
 Tumor-induced osteomalacia
 renal 25(oh)D-1α-hydroxylase
activity, low-normal or low 1,25
(OH)2D
 Primary hyperparathyroidism
  metabolism of 25(OH)D to 1,25
(OH)2D
  levels of 25(OH)D,  1,25 (OH)2D
 Granulomatous disorders
 Conversion 25(OH)D  1,25 (OH)2D
by macrophages
  levels of 25(OH)D,  1,25 (OH)2D
 Hyperthyroidism
  25-(OH)D metabolism  levels of
25-(OH)D
 Pseudovitamin D deficiency rickets




(vitamin D–dependent rickets type
1)
Vitamin D–resistant rickets (vitamin
D–dependent rickets type 2)
Vitamin D–dependent rickets type 3
Autosomal dominant
hypophosphatemic rickets
X-linked hypophosphatemic rickets
Holick MF N Engl J Med 2007; 357:266-281
Vitamin D Deficiency
 Rickets
 Osteomalacia
 Effect on osteoporotic Fx
 Muscle weakness and pain
 Effect on performance
 Effect on fall
Cause of Deficiency
Preventive and
Maintenance Measures
to Avoid Deficiency
Treatment of Deficiency
Inadequate sun exposure
or intake, or aging
•800–1000 IU vitD3/d
•50,000 IU vitD2 q wk for 8
wk, repeat for another 8
wk if 25(OH)D <30 ng/ml
•50,000 IU vitD2 q 2 wk or q
mo
•sensible sun
•maintenance dose is 50,000
IU VitD2 q 2 wk or q mo
Pregnant or lactating
•1000–2000 IU vitD3/d
inadequate sun exposure
or supplementation
•50,000 IU vitD2 q 2 wk,
Obesity
•1000–2000 IU vitD3/d
•50,000 IU vitD2 q wk for
•50,000 IU vitD2 q1 or 2 wk
•8-12 weeks, repeat for
another 8-12 wk if
•25(OH)D <30 ng/ml
•maintenance dose is 50,000
IU vitD2 q 2 or 4wk
•Maintenance dose is 50,000
IU vit D2 q 1, 2, or 4 wk
•50,000 IU vitD2 q wk for 8
wk, repeat for another 8
wk if 25(OH)D <30 ng/ml
Cause of Deficiency
Preventive and
Maintenance Measures
to Avoid Deficiency
Treatment of Deficiency
Malabsorption syndromes
(malabsorp-tion of
vitamin D,2,3,86,87
inadequate sun exposure
or sup-plementation)
•50,000 IU vitD2 OD, EOD or
weekly
•UVB irradiation
•up to 10,000 IU vit D3/d
safe for 5 mo
•50,000 IU of vitamin D2
OD or EOD
•Adequate exposure to sun
or UV radiation
•Maintenance dose is 50,000
IU VitD2 q 1 wk
Drugs that activate
steroid and xenobiotic ®,
drugs used in
transplantation
•50,000 IU vitD2 1-2/wk
•50,000 IU vitD2 q2 wk for
•Maintenance dose is 50,000 8-10 wk, or q wk if
IU vitD2 q 2-4wk
•25(OH)D <30 ng/ml
Nephrotic syndrome
•1000–2000 IU vitD3/d
•50,000 IU vitD2 q1 or 2 wk
•50,000 IU vitD2 2/wk for
•8-12 weeks, repeat for
•Maintenance dose is 50,000 another 8-12 wk if
IU vit D2 q 1, 2, or 4 wk
•25(OH)D <30 ng/ml
Cause of Deficiency
Preventive and Maintenance
Measures
to Avoid Deficiency
Treatment of Deficiency
CKD
Stages 2 and 3
•50,000 IU vitD2 OD, EOD or
weekly
•50,000 IU vitD2 q 1 wk for
8 wk, repeat for another 8
wk if 25(OH)D <30 ng/ml
•up to 10,000 IU vit D3/d safe
for 5 mo
•Adequate exposure to sun or
UV radiation
•Maintenance dose is 50,000 IU
VitD2 q 1 wk
CKD
Stages 4 and 5
•Control serum phosphate
•1000 IU vitD3/d
•50,000 IU vitD2 q2wk
•Maintenance dose is 50,000 IU
vitD2 q 2-4wk
•May also need to treat with an
active vitamin D analog
Holick MF N Engl J Med 2007; 357:266-281
Trace Elements
Trace Elements
 Naturally occurring, homogeneous, inorganic
substance required in humans in amounts <100
mg/day
 Essential nutrients in trace amounts
Assesssment of Trace Element Status
 Difficult and require specialized analytical
instruments (atomic absorption spectrometry)
 Serum measurements are complicated by
associated disease states; affect levels of
circulating binding proteins (e.g., albumin)
 Diagnosis is dependent on:




high degree of suspicion
understanding of predisposing causes
careful inspection for signs and symptoms
Resolution of symptoms with therapeutic trial
Zinc
An Essential But Elusive Nutrient
ESSENTIAL FOR NORMAL
METABOLISM
Am J Clin Nutr 2011;94(suppl):679S–84S
21 year old male patient in the Iranian city of
Shiraz presented with dwarfism,
hypogonadism, hepatosplenomegaly, rough and
dry skin, mental lethargy, geophagia, and iron
deficiency anaemia. In the following three
months 10 more patients with a similar illness
were seen in the same hospital.
Prasad AS, Halsted JA, Nadimi M. Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and
geophagia. Am J Med 1961; 31: 532-546
Role of Zinc: 3 Basic Function
 Catalytic function: Catalyst >100 different enzymes
 Zinc Metalloenzymes
 Structural function : structure of proteins and cell
membranes: Zinc finger (finger like structure)


Cellular differentiation/proliferation, signal transduction, cellular
adhesion, or transcription
maintaining the structure of enzymes: CuZn superoxide dismutase
 Regulatory function: Gene expression
 Promoter of the regulated gene: metal-binding transcription factor
(MTF) and metal response element (MRE)
 adaptive changes in lipid peroxidation, apoptosis, immunity, and
neuronal function occur with zinc depletion
Zinc: Cofactor for Almost 200 Enzymes
 Wound healing
 Taste perception
 Immunity
 Vitamin A activity
 DNA synthesis: fetal
growth and development
 General tissue growth
and maintenance
 Development of sexual
organs
 Metabolism: Protein,
carbohydrate, and fat
 Bone formation
 Protection of cell
membranes from freeradical attacks
 Storage and release of
insulin
 Production of brain
neurotransmitters
Zinc: Unique Feature Of Type 2 Nutrients
Inadequate intake
Reduction of excretory losses to conserve zinc
Fecal
Urinary
Additional metabolic adjustments:
Mobilize zinc from a small vulnerable pool for zinc function
Small Vulneralble Zn Pools
 Cellular organelles; ‘Zinctosome’: Golgi,
endoplasmic reticulum:
 Cellular metallothionein: “Park” Zn temporarily for
future needs


Highest [metallothionein]: liver, kidney, intestine& pancreas
In inflammatory state: hepatic metallothionein  to 100x
within 2–4 h  hepatic
 Plasma Zn


Albumin bound(70%), 2-macroglobulin(18%), remainder
bound tightly to aa and proteins
Ref range 80-110 µg/dL (9.2-17 µmol/L)
Plasma Zn: Not Good Indicator Of Zn Status
Low plasma Zn level in
 Redistribution from pools to tissue: metallothionein





catabolic illness
smoking
alcoholism
chronic strenuous exercise
 Protein bound: hypoalbuminemia
 Volume expansion: overhydration, pregnancy
 Steroid use
 Contraceptive use
 Low Zn intake, Zn def
Requirement
Table 1: Recommended Dietary Allowances (RDAs) for Zinc [2]
Age
Male
Female
0–6 months
2 mg*
2 mg*
7–12 months
3 mg
3 mg
1–3 years
3 mg
3 mg
4–8 years
5 mg
5 mg
9–13 years
8 mg
8 mg
14–18 years
11 mg
19+ years
11 mg
* Adequate Intake (AI)
Pregnancy
Lactation
9 mg
12 mg
13 mg
8 mg
11 mg
12 mg
Zinc Rich Foods
 Protein foods: shellfish,




meat, poultry
Legumes
Dairy foods
Whole grains
Fortified cereals
 Absorbed better from
animal sources.
 Phytates decrease
absorption
Effects Of Illness On Distribution Of
Micronutrients In The Body
Fraser et al Clin Chem 1989;35:2243 –7
Deficiency
 Severe Deficiency
 Acrodermatitis enteropathica
 Syndrome of hypogonadism, stunting, anemia, anorexia and
hepatosplenomegaly
 Mild/Subclinical Deficiency

True estimate: currently not possible : Lack of valid
marker for nutriture

? common in children/women developing world
  susceptibility to infection/wound-healing time.
 ? Growth retardation/? Pregnancy related complications and
LBW
Symptoms of Zinc Deficiency
 Growth retardation
 Dwarfism/ Short stature
 Delayed puberty in







adolescents
Hypogonadism in males
Lack of sexual
development in females
Weight loss
Mental lethargy,
depression
Loss of appetite
Loss of taste (hypogeusia)
Diarrhea
 Reduction in collagen and









crosslink
Delayed wound healing
Defective connective
tissue
Rough skin
Skin rash
White spots on fingernails
Poor Immune system
Intercurrent infections
Atopic dermatitis
Macular degeneration
Deficiency Risk:
 GI disease
 Malabsoption syndrome
 Protein losing enteropathy, fistulae
 Cirrhosis
 Alcoholism
 Nephrotic syndrome
 Pregnancy and lactatingwomen
 Infant exclusively breastfed
 Elderly
 Vegetarians
Toxicity
 Acute toxicity: Nausea, vomiting, loss of appetite, diarrhea,
abdominal cramps, headache
 Chronic toxicity: long-term intake of Zn> upper limit Cu
deficiency,  immune function, and  HDL-C
Tolerable Upper Intake Levels (ULs) for Zinc
Age
Male
Female
Pregnant
Lactating
0–6 months
4 mg
4 mg
7–12 months
5 mg
5 mg
1–3 years
7 mg
7 mg
4–8 years
12 mg
12 mg
9–13 years
23 mg
23 mg
14–18 years
34 mg
34 mg
34 mg
34 mg
19+ years
40 mg
40 mg
40 mg
40 mg
Interaction with Medication
 Antibiotic: quinolones, tetracyclin
 Inhibit Zn absorption, Zn inhibit ATB absorption
 Give ATB at least 2 hr before or 4-5 hr after Zn supplement
 Depenicillamine
 Zn  depenicillamine absorption
 Take med at least 2 hr after Zn supplement
 Diuretic: thiazide
 Thiazide  urinary Zn loss 60%
Zinc Supplementation
 Zinc deficiency
 Acrodermatitis enteropathica (AE) 660 mg ZnSO4
 Wilson’s disease: 660 mg ZnSO4
 Treat acute childhood diarrhea(WHO: 20 mg of Zn/d
or 10 mg for infants < 6 m, for 10–14 days)
Copper
Copper Metabolism
 Intestinal absorption/membrane translocation
mediated by specific transporters
 Cu circulates bound to ceruloplasmin
 Relative tissue distribution: reflects levels of
cuproenzymes
 Excretion: occurs via transport of copper into bile
and elimination in feces
Copper Metabolism
Cu: Biochemical Function
Essential catalytic cofactor for many cuproenzymes
including:
 Cu, Zn-superoxide dismutase (antioxidant)
 Cytochrome C oxidase (ATP synthesis, neurologic
function)
 Lysyl oxidase (cross links and stabilizes connective
tissue proteins)
 Tyrosinase (melanin synthesis)
 Ceruloplasmin (6 atoms per molecule)

Functions to oxidize Fe+2 to Fe+3 for binding to transferrin.
Congenital absence of this protein leads to tissue iron
accumulation and iron overload syndrome (hemochromatosis)
Cu Physiology/Deficiency
Risk of Deficiency
Acquired deficiency is
rare
 Omission from TPN
 High intake of Zinc
 Renal dialysis patients
 Use of Cu chelating
agents (penicillamine)
Manifestations:
 Hypochromic microcytic anemia
 Neutropenia
 Hypopigmentation of hair and
skin
 Structural abnormalities in
connective tissue (hair, teeth,
bone demineralization, vascular
system with arterial aneurysms)
 Fetal and neonatal deprivation
neurologic dysfunction
 levels of Cu and ceruloplasmin
Food Sources
 organ meats, seafood, nuts, seeds, cereals, whole
grains, cocoa
Inborn Errors of Copper Metabolism: Wilson’s
Disease (Hepatolenticular Degeneration)
 AR defect in ATP7B  in copper storage disease (1o :liver,
CNS, eye cornea)
 Inability to transport copper out of liver


Toxicity: liver, CNS, cornea
deficiency in some organs (bones demineralization, anemia and low
ceruloplasmin level)
 Diagnosis based on:
 Low Ceruloplasmin levels
 Corneal copper deposition (Kayser-Fleisher Rings)
 High liver copper levels
Treatment:
 Zinc: inhibit GI Cu (re)absorption
 D-penicillamine (chelation increases urinary copper
excretion)
 Copper deficient diet of little value
KF Ring
Slit Lamp Analysis
Inborn Errors of Copper Metabolism: Menkes Kinky
Hair Syndrome
 X-linked neurodegenerative
disease
 associated with all symptoms of
Cu deficiency including:



Brittle, kinky hair characterized by pili
torti or cork screw hair (this feature is
unique to MKH syndrome and is not
seen in other copper deficiency
syndromes)
Death by year 3 of life is usual
Disease is due to mutation in ATP7A
transporter resulting in low serum
copper levels and accumulation in
intestinal cells.
Pili torti (Menkes
Disease)
Selenium
Selenium
 Acts with other
 Serves as a catalytic
antioxidants and free
radical scavengers
 Overlaps with vit E for
antioxidant effects
 Function with vit E to
protect cell and
organelle membranes
from oxidative damage
component in enzymes
and proteins
 Iodothyronine 5’deiodinase
 Thioredoxin reductase
 Glutathione peroxidase
(destroys hydrogen
peroxide)
Relationship of glutathione peroxidase,
selenium, and vitamin E
GSH peroxidase
contains selenocysteine
Absorption, Storage, and Excretion
 Absorption
 Upper small bowel
 absorption with deficiency
 Selenium is stored in the body as selenocysteine in
selenoproteins
 Assessment of Se status:


measuring Se or glutathione peroxidase in plasma, platelets,
and RBC’s or selenium levels in whole blood or urine
RBC selenium is an indicator of long-term status
 Excreted in urine and in breath as dimethyl
selenide with a garlic-like odor
Food Sources
 Food content tends to
follow Se content of soil –
richest food sources are
organ meats and sea foods,
followed by cereals and
grains, dairy products,
fruits and vegetables

Se content of grains can vary by
10,000 fold
Selenium Deficiency Diseases
 Human deficiency is rare except in areas with low
Se content in soil
Keshan disease occurs in Keshan China: endemic
cardiomyopathy and muscle weakness (due to oxidized
lipids)
 Aggressive supplementation has eliminated disease

 Iatrogenic deficiency
 TPN without supplemental Se
 Requirements determined based on serum
glutathione peroxidase activity
Selenium Toxicity
 Range of dietary Se intake without toxicity is
narrow
 Acute selenium poisoning can result in
cardiorespiratory collapse (gram amounts)
 Chronic toxicity (selenosis) changes in nail structure
and loss of hair (intakes ~6x UL)
 Hair and nail brittleness
Chromium
Chromium--Functions
 Required for normal lipid and CHO metabolism and
for the function of insulin
 ? supplementation raise HDL
Absorption and Excretion
 10-25% Cr absorption in trivalent form
 Amount absorbed remains constant at dietary
intakes >40 μg at which point excretion in urine is
proportional to intake
  Intake of simple sugar, strenuous exercise, or
physical trauma  urinary excretion
 Cr are carried by Transferrin, albumin
Food Sources
 cereals, meats, poultry, fish, beer
Deficiency
 Altered CHO metabolism, impaired glucose tolerance,
glycosuria, fasting hyperglycemia, increased insulin
levels and decreased insulin binding
 Hyperglycemia and wt loss reverse with IV
supplementation in TPN
 Impaired growth, peripheral neuropathy, negative
nitrogen balance
  chromium losses in stress
Toxicity
 Chronic renal failure
Cobalt
Cobalt
 Most stored with vitamin B12
 Component of B12—cobalamin
 Essential for maturation of RBC’s and normal
function of all cells
Absorption and Excretion
 Shared with Fe
 Absorption is increased in pts with deficient Fe
intake, portal cirrhosis with Fe overload, and
hemochromatosis
 Excretion is mainly thru the urine
 small amounts in feces, hair, sweat
Sources and Intakes
 Microorganisms are able to synthesize B12
 ***Humans must obtain B12 and cobalt from animal
foods such as organ and muscle meat
 ***Takes a long time to become deficient—happens
in vegetarians
Deficiency
 Related to vit B12 deficiency
 **macrocytic anemia
 Genetic defect: pernicious anemia
Toxicity
Massive supplementation
 Polycythemia
 Hyperplasia of BM
 Reticulocytosis
 Increased blood volume
Molybendum
Molybendum
 Relationship with Cu and sulfate
 Cofactor of many enzymes involved in catabolism of
sulfur AA, purines and pyridines
Deficiency
 Increased risk with co-existing copper deficiency, TPN
Toxicity
 Gout-like syndrome, reproductive SE’s