Abstract
Anemia affects a significant number of the elderly population, representing a worldwide public health problem that is predicted to increase further in the coming years because of the demographic drive. Being typically mild, it is falsely perceived as a minor problem, particularly in the elderly with multimorbidity, so that it often remains unrecognized and untreated. Anemia in the elderly (ae) is independently associated with mortality and loss of physical function in older people and is generally multifactorial. Anemia of inflammation (ai), iron deficiency, cobalamin deficiency, and renal insufficiency are the most common causes of ae. The proportion of unexplained anemia is consistently declining due to recent advances highlighting the role of several conditions, including clonal hematopoiesis, “inflammaging,” treatable androgen deficiency in men, and under-recognized iron deficiency. We review ae’s main clinical and pathophysiological aspects, giving practical insights into managing the treatment of id, including oral iron and iv iron, the cause and severity of anemia, comorbidities, the time remaining until delivery, and the patient’s wishes are important factors that must be considered when deciding the therapeutic approach.
Keywords: anemia; iron deficiency; anemia of inflammation; older adult
1. Introduction and contextualization
Population aging has occurred rapidly in developed countries since the beginning of the 20th century. Since the 1960s in brazil, it has brought one of the biggest challenges to contemporary public health1-3. According to the world health organization (who), it is estimated that the number of people over 60 will increase from 900 million (12% of the population) in 2015 to 2 billion (22% of the population) in 2050 (http://www.who.int/mediacentre/ factsheets/fs404/en/).
Two epidemiological phenomena were decisive for this demographic transition: the reduction in mortality and the progressive decline in fertility in the second half of the last century. This rapid and progressive increase in the number of adults and older adults was responsible for the change in the profile of diseases in the world, or epidemiological transition, with chronic health conditions predominating4.
In general, the presence of at least one chronic condition occurs in more than 80% of older adults, and at least 40% of these individuals present, simultaneously, multiple diseases (multimorbidity). The most significant impact of chronic conditions on the health of older adults is the functional impairment in carrying out their daily activities. In this sense, health should no longer or cannot be measured by the presence or absence of diseases but rather by the degree of preservation of functional capacity, thus determining successful or unsuccessful aging1,2.
2. Anemia: definition
Anemia is the hematological alteration
most commonly found in medical practice. It is defined as a sign or
manifestation of an underlying disease, not a clinical entity. This means that
anemia does not represent a definitive diagnosis but rather a laboratory
finding that demands careful diagnostic investigation – a detailed clinical
history and physical examination, followed by appropriate laboratory tests.
This practice allows, in most cases, the correct diagnosis of the cause of
anemia, therefore enabling appropriate treatment5,6.
For more than two decades, several
clinical studies have drawn attention to the importance of anemia as an
independent factor in a worse prognosis for the patient as well as a worse
prognosis for the disease. That is, it is associated with higher rates of
morbidity and mortality, worse quality of life, and worse results about
clinical, surgical, chemotherapy, and radiotherapy treatment. Therefore, it is
an actual pathological condition, often treatable, and should not be seen
simply as an abnormal laboratory parameter5-7.
From a pathophysiological point of view,
the state of anemia is due to a reduction in the number of red blood cells or
the concentration of circulating hemoglobin (hb), which, regardless of its
cause, causes a decrease in tissue oxygenation resulting from a reduced oxygen
transport capacity to tissues. According to the criteria proposed by the who,
anemia is laboratory defined as hb less than 13 g/dl for men and 12 g/dl for
women8.
1.1
Anemia in the elderly (ae):
clinical implications and leading causes
Until recently, the decline in hb levels
was considered an inevitable consequence of aging. According to epidemiological
studies, anemia in the elderly is primarily mild (hb between 10 and 12 g/dl),
which often makes it not adequately valued or mistakenly perceived as a minor
problem, particularly in older adults with multimorbidity. In this sense,
anemia, even if mild, is clinically relevant in older people, reflecting some
degree of impairment or worsening of health and increased vulnerability to important
adverse outcomes, including mortality1,6,8.
According to the who, the prevalence of
ae is 23.9%, and this rate increases with age (it can reach 60% in people over
80 years old) and with the presence of comorbidities such as diabetes, heart
failure, cardiovascular disease, inflammatory and neoplastic diseases. In this
way, ae is considered a public health problem1,6,8.
The presence of anemia is an indicator
of a worse prognosis concerning the disease, whatever it may be, and brings the
following main complications for the patient:
• reduced
physical, mental, emotional health, and cognitive functions
• reduced
thermal regulation and immune function
• increased
morbidity and hospitalization
• increase in
mortality
2.2 main causes of anemia in the elderly
Ae generally has multiple underlying
causes and is often associated with more than one predisposing factor1,8,9. The
leading causes of ae are listed in (table
1).
Table 1. Leading
causes of anemia in the elderly
|
Parâmetro |
Prevalência |
|
Anemia of inflammation |
30-60% |
|
Iron deficiency |
15-30% |
|
Vitamina b12/folato
deficiency |
15-20% |
|
Renal insuficiency |
8-12% |
|
Unknown cause |
20-30% |
2.3 anemia of inflammation
Anemia of inflammation (ai) is a
clinical syndrome characterized by the development of anemia in patients with
infectious, inflammatory, or neoplastic disease. The peculiar aspect of this
syndrome is the presence of anemia associated with a decrease in serum iron
concentration and transferrin saturation index and, paradoxically, normal or
increased serum ferritin and medullary iron levels. It is the most common cause
of anemia in hospitalized patients, particularly when analyzing patients over
65. It is the second most common cause of anemia, after iron deficiency anemia
(ida). The main clinical entities associated with ainfla are rheumatoid
arthritis, crohn's disease, chronic kidney disease, heart failure, infection,
inflammation, cancer, trauma, and surgery1,6,8-10.
The three main mechanisms involved in
the etiopathogenesis of ai are:
• decreased red blood cell survival,
• inadequate erythropoietic response to
anemia associated with inappropriately low secretion of erythropoietin and
reduced iron supply to the bone marrow, resulting in the inability of the bone
marrow to increase its erythropoietic activity sufficiently to compensate for
the reduced survival of red blood cells,
• iron metabolism disorder is
undoubtedly the most important mechanism. The pro-inflammatory state or
"inflammatory aging" is characterized by increased synthesis of
pro-inflammatory cytokines (il-1, il-6, and of alpha tumor necrosis), increased
hepcidin synthesis, reduced autophagy secondary to increased nf-κb and
increased reactive oxygen species that can lead to increased inflammasome
response.
As a rule, ai is mild to moderate in
intensity (hb between 9 and 12 g/dl, rarely less than eight g/dl), with
normochromic and normocytic red blood cells. However, in 30% of cases, they are
hypochromic and microcytic. The reticulocyte count is normal or slightly
elevated, or rather, inadequately increased about the intensity of the anemia5,8,10-12.
Serum ferritin concentration is normal
or increased. However, as ai is considered an inflammatory state (acute or
chronic), ferritin, as an acute phase protein, can present normal or elevated
values, which do not truly express the amount of iron in the body. Therefore,
these patients may present id with normal or elevated ferritin values5,8,10-12.
It is important to remember that there
is no other cause of low ferritin (< 30 ng/ml) than iron deficiency;
however, the reverse is invalid. Ferritin values between 30 and 300 ng/ml
should be interpreted cautiously in an inflammatory, infectious, or neoplastic
state because they may hide the associated iron deficiency. A detailed clinical
history, physical examination, and crp measurement greatly help in these
clinical situations5,8,10-12.
2.4 iron deficiency anemia (ida)
The primary cause of iron deficiency is
the imbalance between the amount absorbed and consumption and losses, which
occur through several pathways, resulting in a reduction in total body iron,
with depletion of stores and some degree of tissue deficiency. Iron deficiency
generally results from a combination of two or more factors (table 2)1,5-9.
Androgen deficiency is a plausible
cofactor of unexplained ai, especially in older men.70 a recent randomized,
placebo-controlled study including older men with low testosterone levels
(<275ng/dl) and mild anemia (hb > 10g/dl) observed that administration of
testosterone gel (1%) for 12 months was more effective in correcting anemia
than placebo (in 58% versus 22% of cases, respectively; p=0.002). A possible
explanation for the increase in hb with the use of testosterone is that
testosterone has the ability to suppress the production of hepcidin and, thus,
subsequently, increase the absorption and mobilization of iron for
erythropoiesis13,14.
Vitamin d deficiency, often seen in the
elderly, increases the risk of anemia. Possible mechanisms proposed for this
association are modulation of pro-inflammatory cytokines, lower bone marrow
response to the action of erythropoietin, and modulation of hepcidin levels13,14.
Id in the elderly is often
multifactorial and overlooked. Serum ferritin is the most reliable marker of
id. Ferritin levels tend to increase in the elderly due to a pro-inflammatory
state associated with aging and comorbidities, predominantly renal and heart
failure(table 2)5,8,10-12.
Table 2. Main causes of iron deficiency1,5-9
|
Increased iron requeriment |
Excessive loss of iron (blood loss) |
|
·
Growth* ·
Menstruation** ·
Pregnancy*** ·
Lactation ·
Esa
therapy |
·
Gastrointestinal
bleeding •
Esophageal:
varicose veins, carcinoma, ulceration, reflux esophagitis •
Gastric:
polyp, cancer, ulcer, gastritis, angiodysplasia, telangiectasia, antral
gastric vascular ectasia, associated with the use of aspirin, non-steroidal
anti-inflammatory drugs, anticoagulants, antiplatelet agents •
Small
intestine: inflammatory bowel disease, duodenal ulcer, ancylostoma duodenale
and necator americanus infection, cancer, polyp, angiodysplasia,
telangiectasia, meckel's diverticulum, associated with intense exercise, milk
allergy •
Large
intestine: cancer, polyp, diverticular disease, angiodysplasia, inflammatory
bowel disease, heyde's syndrome# •
Anus:
hemorrhoid •
Entire
gastrointestinal tract: hereditary hemorrhagic telangiectasia ·
Gynecological
bleeding: abnormal uterine bleeding##; uterine cancer or other
cancers of the reproductive tract, intrauterine device ·
Urinary
bleeding: cancer: kidney, bladder, prostate ·
Intravascular
hemolysis: pnh, gait hemoglobinuria, thrombotic microangiopathy, gait
hemoglobinuria, malaria ·
Respiratory
bleeding: hemoptysis (cancer, infection) ·
Blood
donation ·
Exercise ·
Excessive iatrogenic blood loss### |
|
Inadequate dietary intake and/or
defective absorption of iron |
|
|
·
Low
bioavailability of fe diet@ ·
Vegetarian
or vegan practice ·
Inflammatory
bowel disease ·
Celiac
disease ·
Parasitosis ·
Obesity ·
Post-gastroplasty
(gastric bypass) ·
Post-gastrectomy ·
Atrophic
gastritis ·
Helicobacter
pylori infection ·
Medications:
antacids, proton pump inhibitors, calcium, tannin ·
Irida@@ |
Esa, erythropoiesis-stimulating agents; *during early
childhood and adolescence; ** physiological blood loss exceeding daily iron
intake; *** additional iron requirement for each pregnancy of approximately
1000 mg for expansion of maternal erythrocyte mass and placental and fetal
development; @resulting from poverty, especially in low-income countries, early
cessation of breastfeeding, inadequate transition diet;@@ irida,
iron-refractory iron deficiency anemia caused by mutations in the tmprss6 gene;
#heyde's syndrome (severe aortic stenosis, syndrome type 2 acquired von
willebrand disease, angiodysplasia and ecd); ##abnormal uterine bleeding
usually related to uterine fibroid, adenomyosis, endometrial hyperplasia or
dysfunctional uterine hemorrhage fibroid; exacerbated by bleeding disorders
(von willebrand disease, hemophilia a or b and platelet dysfunction); pnh,
paroxysmal nocturnal hemoglobinuria; ###excessive blood collection for
diagnostic tests and iron losses during hemodialysis.
The laboratory tests and their
respective results for the differential diagnosis between ai, iron deficiency
(id), and ida are presented in (table 3)1,5-12. The
reticulocyte hemoglobin (rethe) content indicates the amount of iron available
for incorporation into the young red blood cells in the bone marrow in
real-time. It has been used as an important biomarker in the differential
diagnosis between ai and iron ida5,8,10-12.
Table 3. Differential diagnosis of types of iron deficiency1-5,12
|
Parameter |
Id |
Ida |
Ai |
Ida +
ai |
|
Symptoms |
Asymptomatic
or mild symptoms Of
anemia |
Mild-severe
symptoms Of
anemia |
Symptoms
of the underlying disease, symptoms of anemia |
Symptoms
of the underlying disease, symptoms of anemia |
|
Hemoglobin |
Nl /↓ |
↓ |
↓ |
↓ |
|
Mcv |
Nl /↓ |
↓ |
Nl/↓ |
↓ |
|
Tsat |
20-45% |
<
20% |
<
20% |
<
20% |
|
Ferritin,
ng/ml |
<
30 |
<
30 |
Nl/ |
Nl/ |
|
Reticulated hemoglobin content |
↓ |
↓ |
↓ |
↓ |
|
Hepcidin |
Nl/↓ |
↓ |
|
Nl /↓ |
Id, iron deficiency; ida, iron
deficiency anemia; ai, anemia of inflammation
2.5 current recommendations regarding treatment
with oral iron
Iron is an essential element for the
proper functioning of most organs in the human body, playing a central role in
cellular energy metabolism. As a form of protection against excess iron, since
there is no physiological mechanism capable of increasing iron excretion, the
rate of iron absorption is low (3% to 30%) due to the action of hepcidin at the
level of duodenal enterocytes. Therefore, much of the supplemental iron
ingested is not absorbed and is responsible for the high rates of
gastrointestinal adverse events (aes) (nausea, vomiting, diarrhea,
constipation, metallic taste), especially with supplements with iron in the
ferrous form5,15-17.
It is estimated that a single dose of
100 mg to 200 mg increases serum hepcidin, which remains elevated for 24 hours,
returning to baseline within 48 hours. The higher the daily dose of iron, the
more significant the increase in serum hepcidin level and, consequently, the
lower the absorption rate the following day9,16,17.
In an attempt to overcome the inhibitory
action of hepcidin, reduce aes, and improve tolerance and adherence to oral
iron, the current recommendations for treating id with oral iron are presented
in (table 4)8-10,15-17.
Table 4. Current recommendation for the treatment of iron deficiency with oral iron8-10,15-17
|
Current
recommendation for the treatment of iron deficiency with oral iron |
|||||||||||||||||||||||||||||||||
|
A single daily dose of oral iron is preferable to
divided doses because divided doses twice or three times a day are
physiologically ineffective. ·
Ferrous
salts should be taken 1h before meals, between meals, or before bedtime (the
time of greatest gastric acid production) ·
Ferric
salts can be given during or after a meal. ·
The
major problem with oral iron supplements is that 20-56% of patients cannot
tolerate them because of gi aes, including abdominal distress, nausea,
vomiting, constipation, diarrhea, metallic taste, and dark stool; and the
discontinuation of treatment is up to 20%. ·
It
is important for prescribers to inform patients of these potential ads before
commencing oral iron therapy and to encourage an open dialogue so that should
negative effects occur, alternative therapies can be provided. ·
The
common practice of administering ferrous salts with food in an attempt to
alleviate gi aes can effectively decrease absorption by 40% to 66%. ·
Ae
rates related to oral iron are dose-dependent. It is important for the
physician to be aware of the amount of elemental iron present in different
medications, as this varies considerably according to the compound used or
available. · Doses
up to 100 mg of elemental iron should be prescribed once a day. Doses >
100 mg – 200 mg of elemental iron, should be prescribed on an alternate-day
regimen to optimize iron absorption, reduce the rate of gi aes, and improve
treatment tolerance. The rate of iron absorption is 40%-50% greater on
alternate days versus consecutive days for doses between >100 and 200 mg
of elemental iron. ·
Avoid
daily dose of elemental iron > 200 mg ·
With
consistent oral iron supplementation, reticulocytosis starts in 4 to 5 days,
and hb begins to improve by the second week. The main criteria for a good
response to treatment is an increase of at least 2 g/dl is expected after 3-4
weeks of treatment. ·
As
an overarching principle, with any ida patient, provide enough iron to not
only correct the hb deficit, but enough to provide measurable storage iron as
reflected by the sf. The sf can then be monitored for ongoing iron losses and
prevent id and ida with appropriate administration of supplemental iron. ·
Oral
iron therapy is often required for at least 3 to 6 months, depending on the
intensity of the id, continuity of blood loss, occurrence of aes and,
consequently, adherence to treatment. The goal of iron replacement is not
only to correct the hb deficit but to provide enough iron to replete iron
stores and normalize ferritin levels (serum ferritin > 30 ng/ml and tsat
> 20%). ·
Periodic
monitoring (sf and tsat) and retreatment prior to the recurrence of id are
recommended among high-risk populations: pregnant women (at the first
prenatal visit and in each trimester during pregnancy) and among specific
groups of nonpregnant women of childbearing age. ·
There
are no biochemical markers to predict the likelihood of response to oral
iron. In addition to the problem of aes, impaired iron absorption such as
inflammatory bowel disease and other malabsorption states, prior gastric
bypass surgery, and concomitant administration of drugs can inhibit iron
absorption can decrease responsiveness to oral iron. ·
Intake
of citrus fruits containing vitamin c (orange, lemon, acerola) before or
during a meal increases iron absorption. Multivitamins containing divalent
metals (zinc, copper, manganese) and various dietary components (phytates,
polyphenols, calcium and phosphates) reduce the absorption of ferrous salt.
Therefore, it is recommended that they be administered separately from other
vitamin supplements.
|
|||||||||||||||||||||||||||||||||
|
comparison between the four main iron
supplements marketed in brazil
|
|||||||||||||||||||||||||||||||||
|
Definition of treatment failure with oral iron: Hb ≤ 2 g/dl after 3 to 4 weeks of treatment with
100 to 200 mg of elemental iron/day. |
|||||||||||||||||||||||||||||||||
|
Most frequent causes of treatment failure with
oral iron: ·
Continuing
blood loss due to failure to identify bleeding and/or iron absorption
disorder. ·
Medication
inappropriately used - poor adherence to treatment due to gastrointestinal
aes and/or inadequate dose and/or insufficient duration. ·
Coexisting
disease interfering with the response (reducing iron absorption and/or
favoring bleeding) to oral iron treatment - chronic kidney disease associated
inflammatory or infectious disease. ·
Diseases
associated with iron absorption disorder - celiac disease, autoimmune
atrophic gastritis and helicobacter pylori infection; incorrect diagnosis. ·
Combined
nutritional deficiencies. |
|||||||||||||||||||||||||||||||||
2.6 current recommendations regarding
treatment with intravenous iron
The preferred route for treating id with
iron is ora due to its effectiveness and low cost. However, in situations of
intolerance to oral iron or failure of response (for example, continued blood
loss, post-gastroplasty, concomitant disease interfering with the response
(chronic kidney disease, associated inflammatory or infectious disease, celiac
disease, autoimmune atrophic gastritis, and helicobacter pylori infection),
treatment with intravenous iron should be considered18-26.
The objective of treatment is to correct anemia and normalize iron stores, that is, to achieve serum ferritin levels greater than 30 ng/ml. To this end, it is recommended that the response to treatment be assessed using blood counts, serum iron levels, total iron binding capacity, and ferritin after six weeks of administration of the total dose of iron calculated for the patient. Regardless of the product used, it is recommended that iv iron be applied in a hospital environment or, preferably, in clinics or infusion units by nursing professionals with experience in applying iv medications and with medical supervision. The current recommendations for treating iron deficiency with iv iron are available in (table 5)18-29.
Table 5. The current recommendation for the treatment of iron deficiency with iv iron18-29
|
Main
indications for iv iron treatment |
|||||||||||
|
·
Oral iron intolerance determined by the occurrence of aes. ·
Unsatisfactory response with oral iron due to intestinal absorption
disorder associated with conditions such as: gastric bypass, gastrectomy,
chronic gastrointestinal inflammatory disease (h. Pylori infection, celiac
disease, crohn's disease, ulcerative colitis and atrophic gastritis). ·
Recurrent bleeding (gastrointestinal, gynecological) in which the
amount of iron absorbed orally is not sufficient to meet the demand resulting
from excessive iron loss. ·
Rapid iron
replacement in order to reduce
transfusion requirement in patients with ida scheduled for medium to major
elective surgery, including childbirth and the puerperium. ·
Faster normalization of iron stores avoiding prolonged use of oral
therapy and its aes. ·
Patients with non-dialytic chronic kidney disease with serum ferritin
< 100 ng/ml or on hemodialysis with serum ferritin < 200 ng/ml in order
to ensure and optimize the response to erythropoietin administration. ·
Special situations such as: pre-deposit autotransfusion programs,
religious issues (jehovah's witness patients) |
|||||||||||
|
Goals of iv iron treatment |
|||||||||||
|
·
Faster
correction of anemia (an increase of 2 to 3 g/dl of hb after 4 weeks of
treatment) and iron stores ·
Reduce/eliminate
the need for blood transfusions ·
Optimize the
use of erythropoietin (cancer, chronic kidney disease) |
|||||||||||
|
Main practical guidelines for the use of iv
ferric saccharate |
|||||||||||
|
·
To calculate
the total dose in mg of iron to be replaced, the ganzoni formula can be used:
body weight (kg) x (target hb – current hb) x 2,4 + 500. ·
There is no
need to perform a test dose before application. ·
Dilute the
compound only in 0.9% saline solution (sf). Do not dilute in glucose
solution. ·
Dilute each
ampoule (5 ml, 100 mg) in at least 100 ml of saline solution. ·
For each
solution containing 100 mg of ferric saccharate, the infusion time should be
at least 15 minutes. Therefore, the infusion of the solution containing 200
ml (or more) of ss and 200 mg of ferric saccharate should be done within 30
to 60 minutes. ·
It is
important to respect the drug infusion time. ·
Respect the
interval between applications, which is at least 24 hours. ·
Respect the
maximum dose limit per application, which is 200 mg (2 ampoules) and the
maximum weekly dose, which is 600 mg. |
|||||||||||
|
Main practical guidelines for the use of iv
ferric carboxymaltose |
|||||||||||
|
Ferric carboxymaltose (fcm) has been available
for over a decade and is indicated for the treatment of ida in various
clinical situations. It is an innovative iron complex composed of a core of
ferric hydroxide surrounded by a layer of carbohydrate (maltose) that
combines the advantages of iron dextran (high stability) with the advantages
of ferric saccharate (low immunogenicity). After administration, fcm is
phagocytosed by macrophages, especially in the bone marrow, maltose is
degraded and iron molecules are released to form the intracellular pool of
iron in the form of ferritin or destined for erythropoiesis via plasma
transferrin. Another important advantage of this product is its convenient
dosage, that is, fcm can be administered in high doses (dose of up to 1000 mg
of iron or maximum dose of 15 mg/kg per application) iv in at least 15
minutes and without the need for a test dose.
·
There is no
need to perform a test dose before the first infusion. ·
Dilute the
compound only in 0.9% saline solution (sf), 50-100 ml and 200 ml for 500 mg
and 1000 mg of fcm, respectively. Do not dilute in glucose solution. ·
Dilute each
ampoule (10 ml, 500 mg) in at least 100 ml of saline solution. ·
The
recommended minimum infusion rate is 100 mg/min. Infusion time is, at least,
6 minutes for up to 500 mg and 15 minutes for doses between >500 mg and
1000 mg. ·
The maximum
dose per application should not exceed 1000 mg (>15 mg/kg body weight) of
iron per application. ·
Doses >
15 mg/kg should be divided into 2 infusions 7 days apart do not administer
more than 1000 mg of fcm per week. Therefore, the interval between 2 or 3
applications of 1000 mg is at least 7 days. ·
Fcm is for
iv use only and should not be administered subcutaneously or intramuscularly. ·
Ferinject®
100 mg/ml solution for infusion (5 ml or 10 ml vial) |
|||||||||||
|
Main practical guidelines for the use of iv
ferric derisomaltose |
|||||||||||
|
Ferric derisomaltose (fd) is available in europe
and has recently been licensed in the us, australia and brazil. Like fcm, it
is an innovative iron complex composed of a core of ferric hydroxide
surrounded by a layer of carbohydrate (maltose) that combines the advantages
of iron dextran (high stability) with the advantages of ferric saccharate
(low immunogenicity); it can be administered in high doses (maximum allowed
dose of 20 mg of iron/kg of body weight). If the total iron dose calculated
is > 20 mg/kg/weight, the supplementary dose should be performed after ≥ 7
days.
·
Whenever
possible, administer the total dose in the 1st infusion as long as it does
not exceed the maximum allowed dose (> 20 mg of iron/kg of body weight) ·
If total
dose > 20 mg/kg/weight: 2nd dose after ≥ 7 days. ·
Dilution ≥ 1
mg/ml for stability reasons. For a 500 mg dose, dilute 100 ml in saline
solution and infuse the solution in at least 15 minutes. For doses ≥1000 mg,
dilute 200 ml in saline solution and infuse the solution over at least 30
minutes. ·
Monofer®
solution for infusion of 100 mg/ml in packaging containing 1 vial of 5 ml or
10 ml. |
|||||||||||
|
Contraindications
to the use of iv iron |
|||||||||||
|
·
Any type of
anemia unrelated to iron deficiency. ·
Tsat >
45% ·
Serum
ferritin ≥ 500 ng/ml, regardless of tsat value. ·
Patients
with acute infection, especially in the presence of bacteremia/septicemia ·
Patients
with known hypersensitivity to iron or any component of its formulation |
|||||||||||
|
Warnings and
recommendations with iv iron |
|||||||||||
|
·
The use of
iv iron should be done with caution in patients with asthma, eczema or atopic
allergies, especially in those with a past history of moderate to severe
hypersensitivity reactions, including anaphylactic reactions. In these cases,
the use of antiallergic drugs (iv diphenhydramide) and/or corticosteroid
therapy (iv hydrocortisone) as premedication is recommended. ·
Due
precautions must be taken to avoid venous extravasation during drug
administration, which can cause local changes such as: pain, irritation and
browning of the skin. If this occurs, administration of the product must be
stopped immediately. ·
The use of
iv iron should be avoided in patients with severe hepatic impairment. ·
The use of
iv iron should be avoided in pregnant women ≤ 13 weeks of gestation ·
To date, fcm
and fd are not recommended in children or adolescents (< 18 years) ·
Iv oral
should not be administered concomitantly with oral iron ·
Regardless
of the product used, it is recommended that iv iron be applied in a hospital
environment or, preferably, in clinics or infusion units with experience in
iv drug administration, by duly trained nursing professionals with medical
supervision. ·
Observation
of the patient for at least 30 minutes after the end of iv iron infusion is
recommended. |
|||||||||||
|
When
and how to assess response to iv iron treatment |
|||||||||||
|
It is recommended to carry out complete blood
count, reticulocytes, serum iron, total binding capacity of iron and ferritin
after 4-6 weeks of administration of the total dose of iron calculated for
the patient. |
|||||||||||
|
Iv iron
safety profile |
|||||||||||
|
·
Minor
reactions (eg, headache, symptomatic hypotension, back pain, heartburn, chest
tightness, dyspnea, nausea, tachycardia, rash, and vomiting) are due to
labile free iron and consist of pressure in the chest or back or facial
flushing – symptoms not seen with severe hypersensitivity. Further,
premedication with antihistamines can cause somnolence, diaphoresis,
tachycardia, and hypotension which may be attributed to the intravenous iron.
Intervention with antihistamines or vasopressors can convert these minor
reactions, which usually resolve in minutes without therapy, into
hemodynamically significant aes, ostensibly due to the intravenous iron. ·
Fcm has a
lower risk of hypersensitivity, but a higher incidence of hypophosphatemia,
which in most cases is not severe, is temporary and asymptomatic. ·
Although
very rare, severe hypersensitivity reaction can occur with iv iron |
|||||||||||
2.7 megaloblastic anemia due to vitamin
b12 (cobalamin) deficiency
Megaloblastic anemia (ma) comprises a
group of diseases characterized by delayed maturation of the nucleus of
hematopoietic cells resulting from insufficient dna synthesis due to blockage
of the conversion of uridine monophosphate to thymidine monophosphate. Ma's
main aspect is ineffective erythropoiesis, the intramedullary destruction of
erythropoietic precursors. The same phenomenon also occurs in the granulocytic
and megakaryocytic series, which justifies, in addition to anemia, the presence
of leukopenia and thrombocytopenia30,31.
The prototype of ma is pernicious anemia
characterized by a deficiency of vitamin b12 (cobalamin) resulting from the
lack of intrinsic factor, necessary for its absorption, and common in elderly
people30,31.
The main causes of vitamin b12
deficiency are:
• gastric atrophy
• autoimmune diseases (vitiligo,
hashimoto's thyroiditis)
• h. Pylori infection
• gastroplasty, gastrectomy, intestinal
resection
• medications (long-term use of
antacids, proton pump inhibitors, biguanides [metformin])
• alcoholic beverage
Ma is characterized by anemia of
insidious onset, and, when it intensifies, symptoms such as weakness,
palpitation, dyspnea, and neurocognitive dysfunction are common. The skin takes
on a lemon-yellow hue due to the pallor associated with mild jaundice. Atrophy
of the lingual papillae may occur, with a smooth, red tongue30,31.
Vitamin b12 acts as a cofactor in the
synthesis of methionine and tetrahydrofolate. Methionine is metabolized into
5-adenosylmethionine, a substance necessary for the methylation of
phospholipids in the myelin sheath. The main neurological manifestations of
patients with ma are subacute combined degeneration of the spinal cord,
peripheral polyneuropathy, optic neuropathy, and neuropsychiatric changes30,31.
Cobalamin deficiency can cause
drowsiness, perversion of taste and smell, worsening of visual acuity; memory
loss, confusion, personality change, paresthesia, ataxia, dementia or
psychosis, impotence, urinary and fecal incontinence, convulsions, choreiform,
and athetoid movements. On physical examination, it is common to find
neurological changes such as romberg's sign, ataxic gait, abolition of
kinetic-postural sensitivity, abolition of vibratory sensitivity, paresthesia
sensation in the hands, and atrophy of the optic nerve30-32.
In most cases, the first suspicion of
the diagnosis of ma is usually the finding of increased mcv (> 100 fl,),
regardless of the presence or absence of anemia. There are other conditions
that cause macrocytosis in addition to ma, including myelodysplastic syndrome,
multiple myeloma, aplastic anemia, pregnancy, excessive alcohol use, liver
disease, hypothyroidism, and reticulocytosis secondary to hemolysis or
hemorrhage33-34.
The changes in peripheral blood and bone
marrow resulting from a lack of folic acid and vitamin b12 are
indistinguishable (megaloblastosis), but only vitamin b12 deficiency can cause
serious neurological changes, sometimes irreversible, even before the onset of
anemia33,34.
2.8 anemia of unknown cause
The main situations of anemia of unknown
cause or not properly studied are:
• unexplained anemia
• myelodysplastic syndrome
• idiopathic/clonal cytopenia of
undetermined significance
• clonal hematopoiesis of undetermined
potential (chip)
Myelodysplastic syndrome (mds) is
characterized by a group of clonal hematopoietic disorders that occur more
commonly in the elderly, with a median age at diagnosis in most series of ≥65
years. In fact, isolated anemia is often the first clinical manifestation of
low-risk mds, but many suspected cases are not properly studied with tests such
as boné marrow evaluation with biopsy, immunohistochemistry, myelogram,
immunophenotyping, karyotyping, flow cytometry, and if necessary, related
molecular studies20,22,35.
Up to 30% of anemias of unknown cause
are estimated to be related to low-risk mds. Remember that, in these cases,
anemia can be corrected with treatment with erythropoietin or with new agents
that inhibit the beta superfamily of erythropoiesis transforming growth factor
(luspatercept)35-41.
Emerging evidence indicates that changes
in the hematopoietic system with aging (decline in blood cell production,
changes in chemokine/cytokine production and in the bone marrow
microenvironment) are largely due to the selection of mutant hematopoietic stem
clones. Age-related clonal hematopoiesis can be detected by studies with
specific peripheral leukocyte tests (next generation sequence), showing the
presence of somatic mutations in certain key genes, such as dnmt3a, tet2,
asxl1, and others also involved in malignancies hematological. Such mutations
are present in almost 10% of otherwise healthy individuals over 70 years of age
(a condition called “clonal hematopoiesis of undetermined potential [chip]),”
and their prevalence tends to increase with aging. Molecular studies in elderly
people with unexplained cytopenias support the hypothesis of clonal
hematopoiesis as the underlying phenomenon in one of the elderly people with
anemia and a single clonal mutation (idiopathic/clonal cytopenia of undetermined
significance) who do not meet all the diagnostic criteria for mds20,22,35-41.
1.
Final
considerations
• anemia in the elderly is common,
requires extra attention, and should not be considered normal for their age;
that is, a “physiological” consequence of aging.
• anemia, even if mild, is clinically
relevant in elderly people, reflecting some degree of impairment or health
impairment and increased vulnerability to important adverse outcomes, including
mortality.
• iron deficiency is the most common
cause of anemia in the elderly, and its clinical and laboratory investigation
and, when necessary and possible, endoscopic investigation are of great value.
• adequate treatment of anemia in the
elderly improves quality of life and can reduce morbidity and mortality.
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