INTRODUCTION That nutrition and health are intimately linked has been known since ancient times. It is now essential to realize the vital importance of micronutrients to health and that several micronutrients have antioxidant roles[1].

1

• ??? ???? ?????? ??????

2
Microneutrients

• By
• Dr Noha M. Elsharnouby
• Lecturer
• of Anesthesia and intensive care and
  pain management
• Ain Shams university

3

• That nutrition and health are intimately linked
  has been known since ancient times. It is now
  essential to realize the vital importance of
  micronutrients to health and that several
  micronutrients have antioxidant roles.

4
What is the evidence in ICU?

• Early enteral feeding is best
• Hyperglycaemia/overfeeding are bad
• Nutritional deficit causes worse outcome
• EN causes aspiration and VAP, while PN cause
  infection
• EN and PN can be used to achieve goals
• Protocols improve delivery of feeding
• Some nutrients show promising results

5
Anti-oxidants

• Normal state reduction gt oxidation
• Acute stress injury/sepsis causes acute
  dysregulation ROS/RNOS formed
• Mitochondria are both sources and targets
• Observational studies anti-oxidant capacity
  inversely correlated with disease severity due to
  depletion during oxidative stress

6
Reactive Oxygen Species O-, NO-

• Positive actions
• Bactericidal
• Regulation of vascular tone
• Cell signalling

• But mostly detrimental
• Cell injury (ischaemia /reperfusion)
• DNA, Lipids, Proteins
• Organ dysfunction
• Lungs, Heart, Kidney
• Liver, Blood, Brain

7
ACUTE INSULT
Inflammatory mediators
ROS/RNOS

• Exacerbation of cell and tissue injury

Healing/repair/defence
8
Microneutrient

• Present in the body in amounts less than 50 ug
  per gram of body tissues.
• Essential nutrients for an optimal functioning of
  organs and tissues, including the immune system
  and the heart.
• In hypermetabolic patients in the ICU the trace
  element requirements may be far greater.

9

• Nine trace elements are required by humans in
  small amounts iron, iodine, fluorine, zinc,
  chromium, selenium, manganese, molybdenum, and
  copper.
• All trace minerals are toxic at high levels, and
  some (arsenic, nickel, and chromium) have been
  implicated in carcinogenesis.
• Except for deficiencies of iron, zinc, and
  iodine, mineral deficiencies do not often develop
  spontaneously in adults on ordinary diets
  however, infants are more vulnerable because of
  their rapid growth and variation in intake.

10
Selenium

• Humans and animals require selenium for the
  function of a number of selenium-dependent
  enzymes, also known as selenoproteins.
• Seleinum function involves selenoproteins,
  glutathione peroxidases, thioredoxin, and
  iodothyronine deiodinases (thyroid hormone
  deiodinases).

11
Nutrient interactions

• Selenium appears to support the activity of
  vitamin E (a-tocopherol) in limiting the
  oxidation of lipids.
• Thioredoxin reductase also maintains the
  antioxidant function of vitamin C by catalyzing
  its regeneration.
• Selenium deficiency may exacerbate the effects of
  iodine deficiency.
• Deficiency
• Muscular weakness, muscle wasting, and
  cardiomyopathy
• down-regulation of the nuclear transcription
  factor kB,

12
Disease Prevention

• Immune function stimulation expression of cell
  signaling molecules called cytokines, which
  orchestrate the immune response, selenium
  deficiency is associated with impairment of both
  cell-mediated immunity and B-cell function.
• Viral infection prevention

13
Disease Prevention

• Cancer increasing the levels of selenium
  metabolites that inhibit tumor cell growth.
• Cardiovascular diseases decrease the risk of
  cardiovascular diseases by decreasing lipid
  peroxidation and influencing the metabolism of
  prostaglandins.

14
Toxicity

• high doses can be toxic.
• Acute and fatal toxicities have occurred with
  accidental or suicidal ingestion of gram
  quantities of selenium.
• Chronic selenium toxicity (selenosis) may occur
  with smaller doses of selenium over long periods
  of time.
• symptoms of selenosis are hair and nail
  brittleness and loss, gastrointestinal
  disturbances, skin rashes, a garlic breath odor,
  fatigue, irritability, and nervous system
  abnormalities.
• The Food and Nutrition Board (FNB) recently set
  the tolerable upper level (UL) for selenium at
  400 mcg/day in adults based on the prevention
  chronic selenium toxicity.

15
Drug Interactions

• At present the anticonvulsant medication,
  valproic acid, has been found to decrease plasma
  selenium levels.
• The Recommended Dietary Allowance (RDA) (55
  mcg/day)

16
MOLYBDENUM

• function as a cofactor for three enzymes.
• Sulfite oxidase catalyzes the transformation of
  sulfite to sulfate, a reaction that is necessary
  for the metabolism of sulfur-containing amino
  acids, such as cysteine. crucial for human
  health.
• Xanthine oxidase catalyzes the breakdown of
  nucleotides (precursors to DNA and RNA) to form
  uric acid, which contributes to the antioxidant
  capacity of the blood.
• Xanthine oxidase and aldehyde oxidase also play
  a role in the metabolism of drugs and toxins.

17
Deficiency

• has never been observed in healthy people.
• The only documented case of acquired molybdenum
  deficiency occurred in a patient with Crohn's
  disease on long-term TPN without molybdenum
  added.
• The patient developed rapid heart and respiratory
  rates, headache, night blindness, and ultimately
  became comatose.
• The symptoms disappeared when the administration
  of amino acid solutions was discontinued.
• Molybdenum supplementation (160 mcg/day) reversed
  the amino acid intolerance and improved his
  clinical condition.

18
The Recommended Dietary Allowance (RDA)

• (45 mcg/day for adults) is sufficient to prevent
  deficiency. And the tolerable upper intake level
  (UL) of 2,000 mcg/day which should be safe for
  adults.

19
ZINC

• Zinc plays important roles in growth and
  development, the immune response, neurological
  function, and reproduction.
• On the cellular level, the function of zinc can
  be divided into three categories 1) catalytic,
  2) structural, and 3) regulatory.

20

• Catalytic role
• Nearly 100 different enzymes depend on zinc
  for their ability to catalyze vital chemical
  reactions.
• Structural role
• Zinc plays an important role in the structure
  of proteins and cell membranes. A finger-like
  structure, known as a zinc finger motif,
  stabilizes the structure of a number of proteins.
• Loss of zinc from biological membranes
  increases their susceptibility to oxidative
  damage and impairs their function.

21

• Regulatory role
• Regulate gene expression by acting as
  transcription factors (binding to DNA and
  influencing the transcription of specific genes).
  
• A role in cell signaling and has been found to
  influence hormone release and nerve impulse
  transmission.
• A role in apoptosis , a critical cellular
  regulatory process with implications for growth
  and development, as well as a number of chronic
  diseases.

22
Nutrient Interactions

• Copper interfere with copper bioavailability
• Iron Supplemental but not dietary levels of iron
  may decrease zinc absorption.
• Calcium Calcium in combination with phytic acid
  reduces zinc absorption, and folic acid
• Folate the bioavailability of dietary folate
  is increased by the action of a zinc-dependent
  enzyme.

23
Prevention of Diseases

• Impaired growth and development
• zinc availability affects cell signaling
  systems that coordinate the response to the
  growth-regulating hormone, insulin-like growth
  factor-1 (IGF-1)
• Impaired immune system function
• Increased susceptibility to infectious
  disease in children
• and elderly ( vulnerable to mild zinc
  deficiency)

24
Drug Interactions

• Certain antibiotics as tetracyclines and
  quinolones, may decrease absorption of the
  antibiotic
• The therapeutic use of metal chelating (binding)
  agents like penicillamine (as in Wilson's
  disease) has resulted in severe zinc deficiency.
• Anticonvulsant drugs, especially sodium
  valproate, may also precipitate zinc deficiency.
• Prolonged use of diuretics may increase urinary
  zinc excretion

25
The Recommended Dietary Allowance (RDA)

• The RDA for zinc (8 mg/day for adult women and 11
  mg/day for adult men)

26
FLOURIDE (FLOURINE)

• occurs naturally in the Earth's crust, water, and
  food as the negatively charged ion, fluoride
  (F-).
• About 95 of the total body fluoride is found in
  bones and teeth.
• fluoride is not generally considered an essential
  mineral element because humans do not require it
  for growth or to sustain life.

27
Nutrient Interactions

• Calcium and magnesium form insoluble complexes
  with fluoride and significantly decreasing
  fluoride absorption
• DeficiencyAn increased risk of dental caries for
  individuals of all ages.
• The Adequate Intake (AI)
• 0.05 mg/kg of body weight most effectively
  without causing the unwanted side effect of tooth
  enamel mottling known as dental fluorosis.
• Disease PreventionPrevention of Dental caries ,
  and osteoporosis.

28
Drug Interactions

• Calcium supplements, as well as calcium and
  aluminum containing antacids, can decrease the
  absorption of fluoride.
• It is best to take these products 2 hours before
  or after fluoride supplements

29
CHROMIUM

• The two most common forms of chromium are
  trivalent chromium (III) and hexavalent chromium
  (VI)
• Recent research suggests that a
  low-molecular-weight chromium-binding substance
  (LMWCr) may enhance the response of the insulin
  receptor to insulin. The ability of the LMWCr to
  activate the insulin receptor is dependent on its
  chromium content.
• Nutrient InteractionsIron, Vitamin C, and
  Carbohydrates

30

• Deficiency
• Chromium deficiency was reported in patients on
  long-term intravenous feeding who did not receive
  supplemental chromium in their intravenous
  solutions.
• These patients developed evidence of abnormal
  glucose utilization and increased insulin
  requirements that responded to chromium
  supplementation.
• chromium insufficiency has been hypothesized to
  be a contributing factor to the development of
  Type 2 diabetes.
• The Adequate Intake (AI)
• from 20 -30 mcg\day.

31
Disease Prevention

• Impaired glucose tolerance and type 2
  (non-insulin dependent) diabetes.
• Cardiovascular diseases
• Impaired glucose tolerance and type 2
  diabetes are associated with adverse changes in
  lipid profiles and increased risk of
  cardiovascular diseases.
• Increases muscle mass
• Claims that chromium supplementation increases
  lean body mass and decreases body fat are based
  on the relationship between chromium and insulin
  action.

32
MANGANESE

• The derivation of its name from the Greek word
  for magic
• Manganese (Mn) plays an important role in a
  number of physiologic processes as a constituent
  of some enzymes and as an activator of other
  enzymes
• Antioxidant function
• Manganese superoxide dismutase (MnSOD) is the
  principal antioxidant enzyme of mitochondria.
• MnSOD catalyzes the conversion of superoxide
  radicals to hydrogen peroxide, which can be
  reduced to water by other antioxidant enzymes.

33

• Metabolism
• A number of manganese-activated enzymes play
  important roles in the metabolism of
  carbohydrates, amino acids, and cholesterol.
• Pyruvate carboxylase, and phosphoenolpyruvate
  carboxykinase (PEPCK), manganese-activated
  enzymes, play critical roles in gluconeogenesis.
• Arginase, other manganese-containing enzyme, is
  required by the liver for the urea cycle

34

• Bone development
• Manganese is the preferred cofactor of enzymes
  called glycosyltransferases, which are required
  for the synthesis of proteoglycans that are
  needed for the formation of healthy cartilage and
  bone.
• Wound healing
• manganese is required for the activation of
  prolidase, an enzyme that functions to provide
  the amino acid, proline, for collagen formation
  in human skin cells.

35

• Nutrient Interactions iron, magnesium and
  calcium.
• Drug InteractionsMagnesium-containing antacids
  and laxatives and the antibiotic medication,
  tetracycline, may decrease the absorption of
  manganese .
• The adequate intake (AI)
• 2.3 mg/day for adult men and 1.8 mg/day for
  adult women.

36
IRON

• In humans, iron is an essential component of
  hundreds of proteins and enzymes.
• Oxygen transport and storage Hemoglobin and
  myoglobin
• Electron transport and energy metabolism
  Cytochromes are heme-containing compounds that
  are critical to cellular energy production and
  therefore life, through their roles in
  mitochondrial electron transport.
• Nonheme iron-containing enzymes, such as NADH
  dehydrogenase and succinate dehydrogenase, are
  also critical to energy metabolism.

37

• Antioxidant and beneficial pro-oxidant functions
  Catalase and peroxidases are heme-containing
  enzymes that protect cells against the
  accumulation of hydrogen peroxide, a potentially
  damaging reactive oxygen species.
• DNA synthesis
• Ribonucleotide reductase is an iron-dependent
  enzyme that is required for DNA synthesis.
• Regulation of intracellular iron
• Iron response elements are short sequences of
  nucleotides found in the messenger RNA (mRNA)
  that codes for key proteins in the regulation of
  iron storage and metabolism.

38

• Oxygen sensing
• Under hypoxic conditions transcription factors,
  known as hypoxia inducible factors (HIF), bind to
  response elements in genes that encode various
  proteins involved in compensatory responses to
  hypoxia and increase their synthesis.
• Recent research indicates that an iron-dependent
  prolyl hydroxylase enzyme plays a critical role
  in regulating HIF and consequently, physiologic
  responses to hypoxia.

39
Nutrient Interactions

• Vitamin A deficiency may exacerbate iron
  deficiency anemia.
• Copper Adequate copper nutritional status
  appears to be necessary for normal iron
  metabolism and red blood cell formation.
• Zinc iron supplements can inhibit the absorption
  of zinc.
• calcium decrease the absorption of iron.

40
Disease Prevention

• Impaired intellectual development in children
• Lead toxicity
• Iron deficiency may increase the risk of lead
  poisoning in children.
• Pregnancy complications
• severe anemia in pregnant women are
  associated with adverse pregnancy outcomes.
• Impaired immune function
• Iron is required by most infectious agents,
  as well as by the infected host in order to mount
  an effective immune response, including the
  differentiation and proliferation of T
  lymphocytes and the generation of reactive oxygen
  species (ROS), which are used for killing
  pathogens.

41
Adverse Effects

• At therapeutic levels for iron deficiency, iron
  supplements may cause
• gastrointestinal irritation
• nausea, and vomiting
• diarrhea, or constipation.
• Stools will often appear darker in color

42
Drug Interactions

• Medications that decrease stomach acidity, such
  as antacids, histamine (H2) receptor antagonists,
  and proton pump inhibitors may impair iron
  absorption.
• Decreased absorption and efficacy of the
  medication levodopa, levothyroxine, methyldopa,
  penicillamine, quinolones, tetracyclines, and
  bisphosphonates.
• Cholestyramine resin interferes with iron
  absorption.

43
The Linus Pauling Institute Recommendation

• A multivitamin/multimineral supplement containing
  100 of the daily value (DV) for iron provides 18
  mg of elemental iron.

44
COPPER

• An essential trace element.
• The ability of copper to easily accept and donate
  electrons explains its important role in
  oxidation-reduction (redox) reactions and the
  scavenging of free radicals.
• Copper is a critical functional component of a
  number of essential enzymes, known as
  cuproenzymes.

45

• Energy production
• The copper-dependent enzyme, cytochrome c
  oxidase, plays a critical role in cellular energy
  production. By catalyzing the reduction of
  molecular oxygen (O2) to water (H2O).
• Connective tissue formation
• Another cuproenzyme, lysyl oxidase, is
  required for the cross-linking of collagen and
  elastin, which are essential for the formation of
  strong and flexible connective tissue.

46

• Iron metabolism
• Two copper-containing enzymes, ceruloplasmin
  (ferroxidase I) and ferroxidase II have the
  capacity to oxidize ferrous iron (Fe2) to ferric
  iron (Fe3).
• Central nervous system
• A number of reactions essential to normal
  function of the brain and nervous system are
  catalyzed by cuproenzymes
• Neurotransmitter synthesis, metabolism and the
  formation and maintenance of myelin
• The myelin sheath is made of phospholipids
  whose synthesis depends on cytochrome c oxidase
  activity.
• Melanin formation
• The cuproenzyme, tyrosinase, is required for
  the formation of the pigment melanin.

47

• Antioxidant Functions
• Superoxide dismutase
• functions as an antioxidant by catalyzing the
  conversion of superoxide radicals to hydrogen
  peroxide, which can subsequently be reduced to
  water by other antioxidant enzymes.
• Ceruloplasmin Free copper and iron ions are
  powerful catalysts of free radical damage.
• By binding copper, ceruloplasmin prevents free
  copper ions from catalyzing oxidative damage.
• The ferroxidase activity of ceruloplasmin
  (oxidation of ferrous iron) facilitates iron
  loading onto its transport protein, transferrin,
  and may prevent free ferrous ions (Fe2) from
  participating in harmful free radical generating
  reactions.

48

• Regulation of gene expression
• Copper-dependent transcription factors regulate
  transcription of specific genes.

49
Deficiency

• Clinically evident or frank copper deficiency is
  relatively uncommon.
• Anemia that is unresponsive to iron therapy but
  corrected by copper supplementation.
• Abnormal neutropenia and increased susceptibility
  to infection.
• Less common features of copper deficiency may
  include loss of pigmentation, neurological
  symptoms, and impaired growth

50
Disease Prevention

• Cardiovascular diseases
• Increased serum copper levels have been
  associated with increased cardiovascular disease
  risk .
• Immune system function
• Development and maintenance of immune system
  function, but the exact mechanism of its action
  is not yet known.
• Osteoporosis lysyl oxidase, is required for
  cross-linking of collagen, a key element in the
  organic matrix of bone.
• The Adequate Intake (AI)
• The RDA for copper 900 mcg/day for adults

51
IODINE

• Iodine, a non-metallic trace element. 
• Iodine is an essential component of the thyroid
  hormones, T3 and T4 and is therefore, essential
  for normal thyroid function
• Deficiency Thyroid enlargement (goiter)
• Disease Prevention Radiation-induced thyroid
  cancer.
• Disease Treatment Fibrocystic breast condition.

52

• Nutrient Interactions
• Selenium deficiency can exacerbate the effects of
  iodine deficiency.
• Acute ToxicityIs rare and usually occurs only
  with doses of many grams.
• Symptoms of acute iodine poisoning include
  burning of the mouth, throat, and stomach, fever,
  nausea, vomiting, diarrhea, a weak pulse, and
  coma.

53

• Drug Interactions
• Amiodarone contains high levels of iodine and may
  affect thyroid function.
• Medications used to treat hyperthyroidism, such
  as propylthiuracil (PTU) and methimazole may
  increase the risk of hypothyroidism.
• Lithium in combination with pharmacologic doses
  of potassium iodide may result in hypothyroidism.
• Pharmacologic doses of potassium iodide may
  decrease the anticoagulant effect of warfarin .
• The Adequate Intake (AI)
• Given the importance of sufficient iodine
  during prenatal development and infancy, pregnant
  and breastfeeding women should consider taking a
  supplement providing 150 mcg of iodine/day.

54

• OPTIMIZATION OF INTAKE OF TRACE ELEMENTS
• Prevention of deficiency states cannot be
  regarded as the only end point in terms of
  provision of micronutrients. Some measure of
  functional benefit would appear to be most
  valuable, as improved immune function and
  improved antioxidant .
• Laboratory tests are of relatively little value
  with regards to assigning optimal levels of
  intake.
• Most of the laboratory tests are affected by
  illness, either by the acute-phase reaction with
  changes in carrier proteins, or by altering the
  distribution of the trace elements themselves.

55
SUGGESTED PROVISION OF MICRONUTRIENTS IN
CRITICALLY-ILL PATIENTS

• Ideally, most critically-ill patients will meet
  their micronutrient requirements by the enteral
  route.
• In practice, intake of nutrients by the enteral
  route will be limited and hence intravenous
  supply should be considered.
• Berger Shenkin have suggested provision of
  approximately 10 mg Zn, 13 mg Cu, chromium 20-35
  mcg and 100 mg Se in the intensive care patient.
• This level of provision rising to 40 mg Zn, 375
  mg Cu and 375 mg Se in burn patients.

56
FACTORS AFFECTING THE MICRONUTRIENT STATUS OF A
SEVERLY-INJURED PATIENT

• 1) The status on admission as those consuming
  excess alcohol, or the elderly.
• 2) Increased requirements to meet metabolic
  demandsdue to hypercatabolism which is
  associated with severe illness

57

• 3) Increased losses
• Severely-ill patients , blood loss, those who
  require haemodialysis or peritoneal dialysis, or
  who develop complications of surgery leading to
  gastric aspirate or intestinal fistula losses,
  will all lose trace elements.
• 4) Reduced provisionDue to the delay in the full
  nutrition regimen whilst stabilization the
  patient condition, so that the prescribed amounts
  are not provided in each 24 h period.

58
CONSEQUENCES OF IMPAIRED MICRONUTRIENT STATUS

• Subclinical Deficiency
• Initially there is depletion of stores and of
  tissue content, with attempts to compensate
  either by increased absorption from the gut or by
  reduced excretion.
• This stage is followed by a period of reduced
  intracellular concentration, leading to some
  impairment of biochemical functions. This stage
  in turn may lead on to a period of non-specific
  functional defects where there may be
  identifiable problems in metabolism, immune
  function, certain types of cognitive function, or
  in fatigue and work capacity.
• Clinical Deficiency StatesSevere micronutrient
  deficiency leads to deficiency states, with
  specific structural or functional changes which
  are reversible on provision of the individual
  micronutrient.

59
The main effects of subclinical deficiency are

• (a) an altered balance of reactive oxygen species
  and antioxidants
• leading to oxidative damage of polyunsaturated
  fatty acids and nucleic acids, with increased
  production of pro-inflammatory cytokines
• (b) impaired immune function with increased
  likelihood of infectious complications.

60
CONCLUSION

• It is often very difficult to correlate the
  biochemistry of a dietary deficiency with
  clinical symptoms because trace elements have
  multiple roles in metabolism.
• The development of biomarkers to measure
  oxidative stress means that more reliable and
  precise estimates of oxidative stress may be
  made.

61

• Any Questions ?

62

• Thank you