Anemia is defined as a reduction in Red
Blood Cell (RBC) mass, and is measured by estimating
hemoglobin (Hb) and hematocrit (Hct). Anemia in the elderly as
a laboratory finding incidentally detected in asymptomatic
persons was not aggressively investigated and treated in the
past. But the abnormality is increasingly being recognized as
a risk factor for a number of adverse outcomes in older
adults, including hospitalization, morbidity and mortality.
Elderly persons are defined as those older than age 65 years
for purposes of studies on anemia. Recent advances in
hematology have shown that the etiology of anemia in the
elderly differs significantly from the etiology in younger
adults. Today anemia in elderly persons is considered as a
distinct entity.
Definition (WHO)
Anemia was defined as hemoglobin less than 14g/dl in men and
12.3g/dl in women. However, this definition is being
challenged as the studies on which this definition is formed
did not include individuals above 65 years of age. It is also
difficult to determine the degree of anemia and the validity
of these numbers in populations with high incidence of chronic
disease or congenital hemoglobinopathies.
Newer studies to look at the prevalence of anemia in the
elderly have proposed definitions incorporating the above
issues. It is now accepted that elderly should not be
presumed to have lower "normal" range of hemoglobin so that
underlying treatable disorders are not overlooked. More
studies in the geriatric population have shown that lower
levels of hemoglobin can cause decrease in performance status
and increase in morbidity and mortality. These finding are
more relevant in populations with increasing proportion of
elderly people.
Prevalence and Clinical Importance
There is high variability of prevalence of anemia in the
elderly due to absence of a uniform definition. High
prevalence in hospitalized elderly patients is now widely
reported. The prevalence increases with advancing age with 26%
in men above 85 and 20% in women above 85 in published series.
Assessment of severity
Although this may vary from studies to studies anemia is
considered mild if the hemoglobin is more than 10g/dl,
moderate when it is 7-10g/dl and severe for less than 7g/dl.
Problems in interpretation
The causality of anemia was not addressed in many studies.
Making it difficult to ascertain if the morbidity and/or
mortality among the patients were due to underlying disease or
anemia per say. At present there is suggestive evidence of
increased cardiac output and local hypoxia aggravating the
functional decline in anemic elderly patients.
Effects on Physical functions
The Women's Health and Aging Study II [1] provided preliminary
evidence in support of the hypothesis that mild anemia might
be an independent risk factor for executive functional
impairments in community dwelling older adults. Whether such
an association is causal or non-causal remains to be
determined.
Effect on Mental Functions
Impaired cognitive performance among elderly patients even
with mild degrees of anemia are reported although the role of
underlying disease was not explored in the studies. Depressive
symptoms and reduced Quality of Life are also detected among
elderly patients with anemia.
Anemia and Mortality
Published Dutch study mortality risk among elderly anemic
patients without a clinical disease was twice that of
non-anemic patients. Among the 755 patients above 85 years old
with anemia the mortality among men was 1.6 times and among
women were 2.3 times compared to the controlled group.
A study to look into whether hemoglobin concentration defined
as anemia by WHO was associated with increased mortality in
older persons [2] concluded that an increase mortality risk in
persons aged 85 years and older validating WHO criteria for
Anemia in the elderly and suggesting a low hemoglobin
concentration at old age signifies disease.
Etiology of anemia in the elderly
National health and nutrition examination survey (NHANES)
reveal the following findings:
- One third of the causes was due to nutritional
deficiencies, Iron, folate or B12.
- One third due to chronic kidney disease or other chronic
diseases.
- One third unexplained among which 17% met criteria for
myelodysplastic syndrome
5q- Syndrome
Chromosome 5q deletion syndrome is an acquired hematological
disorder associated with myelodysplastic syndrome. Most
affected people have a stable clinical course but are often
transfusion dependent. Treatment with lenalidomide has
improved the prognosis of this patients by reducing
transfusion dependency.
Special issues in the elderly
Assessment of nutritional status in often over looked. Role of
alcohol in causing bone marrow dysplasia needs to be ruled
out. Absorptions of cobalamins can be at fault from concurrent
atrophic gastritis, H pyloric infection and drugs suppressing
gastric action production like proton pump inhibitors.
Assessment of the rate of fall in hemoglobin, absolute
reticulocyte count and other abnormalities in peripheral blood
smear are important in the diagnosis of anemia in the elderly.
Presences of monoclonal protein in serum or urine should alert
the possibility of plasma cell dyscrasias. It is important to
underscore the point that Iron deficiency anemia is very
common in anemia due to occult GI bleeding.
Serum ferritin being an acute phase reactant can be spuriously
elevated in patients with Iron deficiency and concurrent acute
inflammatory process. The gold standard to rule out Iron
deficiency is still staining of born marrow Iron although
rarely required in the workup of iron deficiency anemia.
Clinical Trial of response to Oral Iron Therapy
Sometimes a definite source of blood loss may not be detected
and the patient may have features of iron deficiency anemia
which may be treated with oral iron therapy to confirm iron
deficiency status. Such procedures though discouraged may be
necessary in facilities with limited resources. These clinical
trials should be time limited and carefully monitored. It
would help to distinguish from Anemia of chronic disease.
Renal disease/ hypoxia sensing abnormalities
The main limitation of measurement of serum EPO is the overlap
of the hormone levels with and without chronic disease. EPO
does not rise until anemia is severe.
Myelodysplastic syndrome
Increasing number of cases of MDS is being reported among the
elderly patients. The diagnostic clue may be unexplained
Macrocytosis in patients with deficiencies of B12, Folate,
liver disease, alcohol and thyroid disease ruled out. In a
British study 124 patients over the age of 75 assessed for the
cause of Macrocytosis (MCV > 95fl) 66% of the patients were
identified as having MDS [3].
Unexplained Anemia (Idiopathic anemia of aging)
At present this is a diagnosis of exclusion. Its incidence is
up to 30% among elderly in may societies and up to 50% among
those in nursing homes. Among the underlying suspected causes
hypogonadism among men was reported in small series of
patients. Age related decline in renal function and EPO is
also incriminated. Many experts believe that a substantial
number of this patients may have undiagnosed myelodysplastic
syndrome which will be unveiled by modern molecular markers.
Anemia in the elderly and inflammation
A pro inflammatory state is recognized in many elderly
patients with high levels of IL6 and C reactive protein among
many persons with advancing age. The inhibition of
erythropoiesis due to these molecules and the role of hepcidin
which is abnormally high in inflammation causing Iron trapping
are areas of ongoing research in the treatment of Anemia.
Management of Anemia in the elderly
The treatment should aim at detecting and correcting any
identifiable etiology like iron deficiency, Vitamin B 12
deficiency or folate deficiency. Some inflammatory processes
and malignances causing anemia of chronic disease can be
corrected when the underlying process in under control.
Myelodysplastic syndrome can be studies in detail
with molecular markers and clinical criteria to assess the
prognostic index. Though not curable at present the prognosis
of MDS is getting better with newer treatment. Anemia from
Renal disease usually resolves if the renal dysfunction is
reversible. Use of EPO in management of anemia of CKD is now
well established. Alcohol in addition to causing anemia from
folate deficiency and liver disease, is also a bone marrow
toxin damaging normoblastic erythropoiesis. Anemia from
hypothyroidism promptly reverses when thyroid function is
restored.
Symptomatic Anemia
Treatment decision depends on symptoms, functional status,
comorbidities and patient's wishes. No single threshold of
hemoglobin is accepted for initiation of therapies. Majority
of patients may not require treatment of their anemia. Those
with underlying cardiovascular or renal disease may benefit
with a hemoglobin more than 10g. Current therapeutic
interventions are limited to transfusions with packed Red
blood cells or use of EPO.
Red Cell Transfusion Challenges
Elderly patients with small stature, low body weight or poor
cardiac function are susceptible to Transfusion Associated
Circulatory Overload (TACO). Besides the benefit are transient
and the risks include Iron over load.
Erythropoietin and Darbepoetin (ESA)
Both molecules are recombinant human erythropoietin binding to
the erythropoietin receptor. Their efficacy in the treatment
of anemia is proven in anemia of renal disease, certain forms
of MDS and chemotherapy induced anemia. They may be relevant
in treating unexplained anemia in elderly due to decline in
renal function with advancing age. The risk benefit ratio had
to be determined.
Harmful effects of recombinant Erythropoietin
Mostly occur when anemia is aggressively corrected. FDA
recommends maintaining hemoglobin levels between 10 and 12
among patients with CKD and anemia of cancer based on serum
EPO levels. Value of EPO in chronic unexplained anemia in the
elderly is unclear at present.
Intravenous Iron in patients with unexplained anemia
A prospective randomized control trial of Intravenous iron
sucrose in older adults with unexplained anemia and serum
ferritin 20-200ng/ml was published from Standford [4]. This
study precluded making any conclusive recommendations as the
trial involved only 19 patients. It is assumed that a sub
group of patients may benefit.
Use of Testosterone in the treatment of anemia in elderly
men
The association of mild anemia in men with hypogonadism was
long recognized. Randomized control trials in such patients
above 65 years with low testosterones who received
testosterone replacement showed a rise in hemoglobin of at
least 1g/dl and resolution of anemia in 12 months. This
increase in hemoglobin correlated with statistically
significant improvement in 6 min walking distance.
However, benefits of testosterone therapy for anemia may be
compounded by possible risk and side effects. Therefore,
further studies are required in the treatment of unexplained
anemia with low testosterone.
Prevalence of Anemia in Kerala State, Southern India - A
systematic review [5]
The prevalence of anemia in Kerala is currently unknown thou
there are many studies and reports on this condition in
published literature. Those studies could not be combined in
the systematic review due to non-uniform hemoglobin estimation
methods. Standardized prospective study of general population
and elderly population is required.
The Nobel prize in physiology 2019 and the topic of
anemia
The Nobel prize in medicine 2019 was awarded jointly to
William G Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L
Semenza "for their discoveries of how cells sense and adapt to
oxygen availability".
Their work provides the potential for treating anemia of CKD
with the possibility of gaining the benefits of reversing
anemia while avoiding toxicity associated with current
treatments with high dose Iron and EPO. More over the hypoxia
inducing factor (HIF) inhibits hepcidin known to trap iron.
Thus, it has the potential to increase access to existing Iron
stores and to avoid the need to administer intravenous Iron.
At present Daprodustat, Molidustat, Roxadustat, Vadadustat and
Desidustat are molecules undergoing clinical trials based on
this breakthrough discovery.
References
1. Chaves PH, Carlson MC, Ferrucci L, Guralnik JM, Semba
R, Fried LP. Association between mild anemia and executive
function impairment in community-dwelling older women: The
Women's Health and Aging Study II. J Am Geriatr Soc. 2006
Sep;54(9):1429-35.
2. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia
in older persons. JAMA. 1999 May 12;281(18):1714-7.
3. Mahmoud MY, Lugon M, Anderson CC. Unexplained macrocytosis
in elderly patients. Age Ageing. 1996 Jul;25(4):310-2. doi:
10.1093/ageing/25.4.310. PMID: 8831877.
4. Price E, Artz AS, Barnhart H, Sapp S, Chelune G, Ershler
WB, Walston JD, Gordeuk VR, Berger NA, Reuben D, Prchal J, Rao
SV, Roy CN, Supiano MA, Schrier SL, Cohen HJ. A prospective
randomized wait list control trial of intravenous iron sucrose
in older adults with unexplained anemia and serum ferritin
20-200 ng/mL. Blood Cells Mol Dis. 2014 Dec;53(4):221-30.
5. Rakesh PS. Prevalence of Anaemia in Kerala State, Southern
India - A Systematic Review. J Clin Diagn Res. 2017
May;11(5):LE01-LE04.