Iron and anemia in CCM

IRON AND ANEMIA
IN
CRITICAL CARE
PHYSIOLOGY
Reza Nejat, M.D.,
Anesthesiologist, FCCM,
Former Assistant Professor, SBMU

IRON and ANEMIA(CCP)
Part 1
IRON and Evolution

Living objects are complex systems:
have distinct components with distinct
properties but related to each other and as a
whole have nonlinearity, ability to emerge,
have spontaneous order, adaptation, and
feedback loops, ….
Living objects increase their enthalpy and
decrease entropy:
𝑯 = 𝑼 + 𝒑𝑽

 Primitive living objects were
acellular organisms (complex
systems) :
 drastically different from anything we
know.
 lacking of a mechanism for division, yet
were able to grow.
 lacking of enzymes or a mechanism for
translation, but with an autocatalytic
metabolism.
 lacking of nucleic acids or any other
template, yet with inheritance and
selection.
 with capacity for evolution.

Three hypothesis to explain the origin of
prebiotic molecules:
 synthesis in a reducing atmosphere,
 input in meteorites and
 synthesis on metal sulfides in deep-
sea vents
It is unclear whether the RNA world was
the first biological world or whether
some simpler world preceded it.

RNA world hypothesis
 Self-replicating RNA molecules
proliferated before the evolution of
DNA and Proteins
Iron-Sulfur world (Wächtershäuser
proposed) hypothesis
 early life may have formed on the
surface of pyrite (𝑭𝒆𝑺 𝟐)

 Central to the proposed
theory is the idea that life at
its early stage was:
 autotrophic
 consisted of an autocatalytic
metabolism
 confined to an essentially two
dimensional monomolecular
organic layer.
 surface organisms or metabolists

Autotroph:
 an organism that is able to form
nutritional organic substances from
simple inorganic substances such as
carbon dioxide
 The energy for carbon fixation on these
surface metbolists is provided by:
the redox process of converting
ferrous ions and hydrogen sulfide
into
pyrite (𝑭𝒆𝑺 𝟐)

 Iron is required by most organisms to
serve as a prosthetic group for
metalloproteins involved in central
cellular processes:
 Respiration (electron transfer),
 DNA synthesis and repairment,
 Oxygen sensing and transport.

 Iron is the catalytic element that allowed
the formation of macromolecules from
CO2 and H2
 Wächtershäuser proposed:
 an early form of metabolism predated genetics
 Metabolism?

Increasing ambient OXYGEN
concentration after photosynthesis
started and declined 𝑭𝒆+𝟐
concentration by reducing it to its
insoluble oxidized form 𝑭𝒆+𝟑

Fenton’s Reaction
H.J.H Fenton discovered in 1894 that
several metals have a special oxygen
transfer properties which improve the
use of 𝑯 𝟐 𝑶 𝟐. Actually, some metals have
a strong catalytic power to generate
highly reactive 𝑶𝑯−•.
𝑭𝒆 𝟐+
+ 𝑯 𝟐 𝑶 𝟐 → 𝑭𝒆 𝟑+
+ 𝑶𝑯 + 𝑶𝑯−•
𝑭𝒆 𝟑+
+ 𝑯 𝟐 𝑶 𝟐 → 𝑭𝒆 𝟐+
+ 𝑶𝑶𝑯−•
+ 𝑯+

 Excess of iron in cells:
 Generation of Free Radicals
 Damage proteins, DNA, Lipids
 Cirrhosis,Cardiomyopathy, DM,
 NBIA (neurodegeneration with brain iron
accumulation)
 FA (Friedreich's ataxia)
 Parkinson’s and Alzheimer's diseases
 Deficiency of iron in cells:
 Impaires cellular proliferation
 Cognitive Disorders
 Anemia

Body Content of IRON:
 3-4 g
 2.0-2.5 g (within hemoglobin of erythrocytes)
 Average 2.3 g in males
 Average 2.1 g in females
 0.5-1.0 g (deposited in ferritin within hepatocytes
and macrophages)
 0.5 g (myoglobin, ferritin and iron-containing
enzymes)
 3 mg (in serum as transferrin-bound)

 Iron is biologically functional due to
its chemical properties:
 its capacity to form a variety of
coordination complexes with organic
ligands in a dynamic and flexible mode,
 favorable redox potential to switch
between the ferrous, Fe(II), and ferric,
Fe(III)

Iron Absorption:
 1-3 mg/day
 (through the gut)
Iron Loss:
 1-3 mg/day
 through urine, sweating,
desquamated enterocytes,
menstruation)
 23 mg/day
 recycled (dying RBC to M𝛗 to BM)

Iron Absorption:
 1-3 mg/day
 (through gut)
Iron Loss:
 1-3 mg/day
 through urine, sweating,
desquamated enterocytes,
menstruation)
 mammals lack a regulated physiological
mechanism for iron excretion,
 intestinal iron absorption is a tightly
regulated process

Iron Absorption by enterocytes:
 Dietary non-heme 𝑭𝒆 𝟑+:
 After being reduced to 𝑭𝒆 𝟐+:
 by membrane bound ferrireductases
 Duodenal cytochrome B
 DMT 1 (divalent metal transporter 1)
 Dietary heme Iron:
 by enterocytes by an undefined
mechanism?

Body Iron:
 Most of it is found within
hemoglobin in red cells (the
erythron),
 A smaller amount being
distributed in other tissues such as
muscles and in deposits.

Hepcidin (Liver-derived)
Decreases Iron Availability:
 blocks iron absorption
 directs iron towards deposits
Erythroferrone (erythroblast-derived)
Increases Iron Availability
 inhibits hepcidin synthesis

Hepcidin
 a peptide hormone made in the liver
 the principal regulator of systemic
iron homeostasis which controls:
 plasma iron concentration
 tissue distribution of iron by
inhibiting:
intestinal iron absorption,
iron recycling by macrophages,
iron mobilization from hepatic stores

Hepcidin synthesis:
 increased by iron loading,
 decreased by anemia and hypoxia.
 elevated during infections and
inflammation (Inflammatory cytokines
like IL-1, IL-6, IL-22, Oncostatin M):
 causing a decrease in serum iron levels
 the development of anemia of inflammation,
 probably a host defense mechanism to limit the
availability of iron to invading microorganisms

Hepcidin acts by:
 inhibiting cellular iron efflux through
binding to and inducing the
degradation of ferroportin.
 Ferroportin:
the sole known cellular iron exporter

molecules involved in Iron metabolism:
TfR1 &TfR2
IRE
IRP1 & IRP2
divalent metal transporter-1
Dcytb
heme carrier protein-1
ferroportin-1, FPN1
Hepcidin
EPO & erythroferron
hemojuvelin, HJV
hemochromatosis gene product, HFE
lactoferrin, Lf
melanotransferrin, MTf

Hepcidin deficiency:
 the ultimate cause of most forms of
hemochromatosis, either due to
mutations in the genes encoding:
 hepcidin
 regulators of hepcidin synthesis.

Part 2
ANEMIA

WHO
anemia afflicts 1.6 billion people
worldwide
about one-fourth
of
the world’s population

Definition of Anemia:
 Hb level
 less than 13 g/dL for adult males
range from 13 to 14.2 g/dL
 less than 12 g/dL for adult
nonpregnant females
11.6 to 12.3 g/dL in women
 the exact cutoff to establish a
diagnosis can be elusive

 RBC formation:
 under steady-state conditions
 Basal rate of 15–20 ml/day
 After hemolysis or heavy blood
loss
 Rises to 200 ml/day (in iron-replete
healthy persons)

Blood. 2006; 107(5): 1747-1750

 RBC rheology:
 contributes to vasoregulation,
particularly at the microvascular
level
 has an influence on vascular
tone by:
 Altering wall shear stress
 Modifying nitric oxide generation,
 homogenizing flow distribution at
capillary branch points

RBCs and hemoglobin through three mechanisms match
local flow and metabolic demand:
1. bioactive NO production is proportionated with
deoxyhemoglobin acting as a nitrite reductase
2. NO is bound by oxyhemoglobin in the lungs and
released by deoxyhemoglobin in the tissues,
3. Mechanical deformation of RBCs and
desaturation of hemoglobin initiates
vasodilation by release of ATP that binds to
endothelial cell purinergic receptors and
stimulates NO synthesis
⌂critical contribution of healthy RBCs to
active vasoregulation.

Deleterious effects of ANEMIA:
 Cardiac Related:
 Morbidity
 Mortality
 Generalized low 𝑶 𝟐 transport
𝑫𝑶 𝟐 = 𝑪𝑶 × 𝑪 𝒂 𝑶 𝟐
𝑫𝑶 𝟐 = 𝑪𝑶 × (𝟏. 𝟑𝟒 × 𝑯𝒈𝒃 × 𝑺 𝒂 𝑶 𝟐)

anemia and adverse outcomes in
 congestive heart failure
 acute myocardial infarction
 type 2 myocardial infarction
 chronic kidney disease
 mechanical ventilation weaning off
 increased risk of death

 Acute isovolemic
 ↓ [Hb] →5 g/dl in resting healthy
humans with no evidence of tissue
hypoxia →progressive increases in:
 heart rate,
 stroke volume,
 oxygen extraction, and
 cardiac index
 Chronic drop in Hb is more tolerable:
 HIF

 patients with acute respiratory
failure with Hb<10 g/dL have
more than five times risk to
require reintubation after an
initial successful spontaneous
breathing trial and extubation

 Anemia may overestimate serum
glucose by point-of-care
glucometers,
 creating a risk of hypoglycemia if
these values are used to calculate
insulin needed.

 A large proportion of critically ill
patients are anemic on admission,
 the majority of non-anemic patients
becomes anemic during their ICU stay
 The incidence of anemia at ICU is
proportionally related to the duration
of ICU stay

in critically ill patients:
ABC study
Common occurrence of anemia
Large use of BT
ABC study
revealed association between:
BT and diminished organ function
BT and Mortality
JAMA. 2002; 288: 1499-1507

 Anemia:
 common in the critically ill and
 results in a large number of RBC transfusions.
 The number of transfused RBC units:
 independent predictor of worse clinical
outcome.
 Crit Study;
 Critical Care Medicine. 32(1):39-52, JAN 2004

Etiology:
Three pathophysiological pathways
end up with ANEMIA:
 Low production
 Low EPO, ACD (IL1, IL6,TNFα), relative
Iron Def.,
 Destruction before maturation
 Ineffective erythropoiesis
 Destruction after maturation
 Hemolysis, bleeding (GI), phlebotomy,…

Classification of anemia
cause
Blood Loss
Inadequate
production
Excessive
destruction
morphology
Normocytic microcytic macrocytic

Anemia in critical illness and injury results from:
 a shortened RBC circulatory life span
 hemolysis,
 phlebotomy losses (“anemia of chronic
investigation”)
 oozing at injury sites,
 invasive procedures,
 GI bleeding
 diminished RBC production
 nutritional deficiencies
 and the “anemia of inflammation.”

Eryptosis and Neocytolysis

 Eryptosis:
 the premature death of mature RBCs,
 triggered by excessive oxidant RBC
injury, and other stressors
 Is inhibited by EPO
 excessive eryptosis may lead to the
development of anemia
 Neocytolysis:
 removal of RBCs just released from the
marrow

 Eryptosis is characterized by:
 a cascade of biochemical and
biomechanical changes, leading to:
 cell shrinkage,
 dysregulation of normal membrane
asymmetry
 exposure of normally sequestered
phosphatidylserine on the outer
membrane leaflet,
 the formation of membrane blebs and
microparticles.

 Neocytolysis:
 the process of selectively removing
young circulating RBCs,
 initiates by a sudden fall in EPO
levels
 was first noted in the study of RBC
mass reduction that occurs during
spaceflight (microgravity) and after
descent from high altitude;

 Eryptosis and Neocytolysis:
 are negatively regulated by EPO
 acting at different points in the life
span of the RBC,
 provide flexibility and fine control in
regulation of total RBC mass

“Anemia of Inflammation”
 Inflammatory processes leading to
impaired:
 RBC proliferation,
 iron metabolism,
 EPO production and signaling
 evolutionary response to sequester
and harness iron trafficking
 invading micro-organisms cannot
reach iron.

proinflammatory cytokines
 impair iron homeostasis and normal RES
functioning:
 IL-1,
 IL-6,
 tumor necrosis factor (TNF)-α,
 Decrease regulatory feedback between
body iron needs and intestinal iron
absorption

 Inflammation results in minimal
response by the bone marrow due to:
 reduced transcription of the EPO gene
 IL-1,TNF-a,TGF-β
 Inhibition of RBC production through
direct interaction of mediators with
erythroid progenitor cells

 in the setting of shock, vasopressor
at high concentrations directly
inhibit hematopoietic precursor
maturation
 norepinephrine
 phenylephrine

 Key tests for a complete diagnosis of
anemia of critical illness:
1. serum iron concentration,
2. serum transferrin concentration,
3. transferrin receptor protein concentration,
4. total iron binding capacity,
5. serum ferritin concentration,

Serum iron levels:
 the amount of circulating iron bound
to transferrin.
The total iron-binding capacity:
 an indirect measure of the circulating
transferrin concentration.

 Serum ferritin level correlates
with total body iron stores:
 suitable laboratory estimate of iron
store
 Levels of transferrin receptor
protein in circulation:
 a quantitative measure of total
erythropoiesis
 can be used to measure the expansion
of the erythroid marrow in response to
rEPO therapy.

EPO
 tightly regulates erythropoiesis
 normally increases with anemia,
 circulating EPO concentrations fall quickly and
remain low in critical illnesses:
 decreased renal function
 proinflammatory cytokine
 a sudden and continued drop in EPO production
promotes neocytolysis and eryptosis

EPO
 In critical illnesses EPO receptor downregulation:
 limits the availability of iron for cell proliferation and
hemoglobin synthesis
 Its release by the kidneys in response to
hypoxemia and anemia is suppressed by:
 angiotensin-converting enzyme inhibitors,
 angiotensin receptor blockers,
 calcium channel blockers,
 theophylline,
 b-adrenergic blockers,

 Hepcidin, an iron regulatory
protein:
 is up-regulated in inflammatory
conditions and
 Is suppressed by EPO,
 decreases duodenal iron
absorption
 blocks iron release from
macrophages.

 Hepcidin, an iron regulatory
protein:
 limits iron availability
 leading to iron restricted
erythropoiesis
 impairs heme biosynthesis
 during systemic infection there is
 up-regulation of the IL-6–hepcidin
axis,
 responsible for low serum iron levels
observed in inflammation

Erythroferrone, ERFE
 A new hormone identified,
 Mediates hepcidin suppression
 Allows increased iron absorption
and mobilization from iron stores.
 Is produced by erythroblasts in
response to erythropoiesis-
stimulating agent (ESA) treatment

ACritD Iron Def
↓ 𝐹𝑒 ↓ 𝐹𝑒
↓ 𝑇𝐼𝐵𝐶 ↑ 𝑇𝐼𝐵𝐶
↓ 𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑟𝑖𝑛 𝑠𝑎𝑡𝑢𝑟𝑎𝑡𝑖𝑜𝑛
=
(𝑠𝑒𝑟𝑢𝑚 𝐹𝑒)
𝑇𝐼𝐵𝐶
↓↓↓ 𝑡𝑟𝑎𝑛𝑠𝑓𝑒𝑟𝑟𝑖𝑛 𝑠𝑎𝑡𝑢𝑟𝑎𝑡𝑖𝑜𝑛
=
(𝑠𝑒𝑟𝑢𝑚 𝐹𝑒)
𝑇𝐼𝐵𝐶
< 18%
𝑁𝑙 𝑠𝑇𝑓𝑅𝑃 ↑ 𝑠𝑇𝑓𝑅𝑃
𝑁𝑙 −↑ 𝐹𝑒𝑟𝑟𝑖𝑡𝑖𝑛 ↓ 𝐹𝑒𝑟𝑟𝑖𝑡𝑖𝑛
TfR-F<1 TfR-F>2
𝒃𝒐𝒅𝒚 𝑰𝒓𝒐𝒏
𝒎𝒈
𝒌𝒈
= −[𝐥𝐨𝐠
𝑻𝒇𝑹
𝒇𝒆𝒓𝒓𝒊𝒕𝒊𝒏
− 𝟐. 𝟖𝟐𝟐𝟗]/𝟎. 𝟏𝟐𝟎𝟕
TfR-F=(𝑻𝒇𝑹/ 𝐥𝐨𝐠 𝑭𝒆𝒓𝒓𝒊𝒕𝒊𝒏)

In a teaching general hospital:
 Of 520 BT episodes with 1218 units of
packed red blood cells 88% were
appropriate;
 Of 106 episodes with 405 units of FFP
90% were deemed appropriate;
 Of 187 episodes with 320 units of
albumin given 64% were considered
appropriate.
CMAJ. 1989; 140: 812-815

 The long-term ICU population
receive a large number of BT.
 No clear indication for a large
number of the BT given.
 Many BTs are administered due to:
 an arbitrary "transfusion trigger"
 not a physiologic need for blood.
CHEST 1995; 108:767-71

 Blood Transfusion:
 A physiologic need? Or
 A response to transfusion trigger
 Trials:
 ABC
 Crit
 Walsh and colleagues
 the American Burn Association
 North Thames Blood Interest Group
 ↑ ICU stay and mortality??!!!

 Blood transfusion is associated with
an increased risk of:
 death,
 infectious complications,
 acute respiratory distress syndrome
(ARDS)
 The only absolute indication for PRBC
transfusion is in the therapy of
hemorrhagic shock
 Take care of ACS and MI

Serious risks of BT:
 Transmission of infectious diseases,
 immune-mediated reactions:
 acute or delayed hemolytic reactions,
 febrile allergic reactions,
 anaphylaxis,
 graft-versus-host disease,
 non–immune-related complications:
 fluid overload,
 electrolyte toxicity,
 iron overload

 The decision to transfuse blood must be
based rather on the patient’s
 intravascular volume status,
 evidence of shock,
 duration and extent of anemia,
 cardiopulmonary physiologic parameters.
 The only absolute indication for PRBC
transfusion is in the therapy of
hemorrhagic shock
 Take care of ACS and MI

Normal RBC aging leads to:
 changes in membrane characteristics:
 reduced fluidity and deformability,
 loss of volume and surface area,
 increased cell density and viscosity,
 deleterious alterations in the
intracellular milieu
 decreased ATP and 2,3-DPG,
 Lowered hexokinase
 Low G6PD activity

 Phosphatidylserine↑:
 marks cells for engulfment by
macrophages,
 may carry important downstream
effects related to:
 inflammation,
 coagulation,
 cell signaling,
 immune modulation

Normal RBC aging leads to:
 a fall in cellular energy level,
 increased Hb–oxygen affinity,
 reduced repair of oxidant injury,
 diminished ability of cells to deform
normally during microvascular transit
 mark RBCs for removal by the spleen and
RES
 Alterations in rheology with normal
aging in critically ill patients:
 may occur sooner
 may be associated with poor outcomes

Potentially deleterious changes during
preservation and storage of blood:
 Decreased concentrations of ATP, 2,3-DPG, and
S-nitrosylhemoglobin;
 Accumulation of proinflammatory cytokines;
 Release of hemoglobin and red cell arginase;
 Accumulation of RBC membrane microparticles
 Decreased RBC membrane inactivation of
cytokines by Duffy antigen
These changes may result in:
 potent NO scavenging and vasoconstriction,
 loss of normal RBC-mediated vasoregulation,
 immunosuppression.

Preventive measures
 Reduction in phlebotomy
 Use of pediatric or low-volume
adult blood sampling tubes
 Use of in-line closed blood
conservation devices on arterial and
central lines
 Cell salvage during surgical
procedures,

Erythropoiesis-stimulating agents
 indicated for treatment of critically ill
patients with chronic kidney disease
 ESAs are not currently recommended for
treatment of anemia in critically ill patients
 ESA use in trauma critically ill patients
was associated with significantly increased
survival in 2 large RCTs

Iron Supplementation
 A recent meta-analysis of 5 RCTs of iron
supplementation:
 no difference in RBC transfusion rates or Hb
 no difference in secondary outcomes of mortality, in
hospital infection, or length of stay.
 IRONMAN
 compared IV iron (500 mg ferric carboxymaltose,FCM) to
placebo in 140 critically ill patients
 no significant difference between the groups in any
safety outcome.

 www.rezanejat.com

Iron and anemia in CCM

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