Page 161 - Williams Hematology ( PDFDrive )

136 Part III: Epochal Hematology Chapter 9: Hematology in Older Persons 137

CLINICAL CONSEQUENCES
? Replicative
senescence Environmental Marrow Aging
Genetic factors factors, ROS Genetic factors Although a number of measureable changes occur in the marrow, not
the least of which is a reduction in cellularity, apparent compensatory
Chronic Ag Endocrine
exposure senescence stem cell changes allow the sustenance of normal or near-normal blood
counts throughout the life span. It is notable from transplant experi-
Thymic involution ence that even when marrow is donated from a 65-year-old person to an
human leukocyte antigen (HLA)-matched younger recipient, the donor
Immune or inflammatory marrow supports hematopoiesis for the life of the recipient, although
Qualitative dysregulation allogeneic marrow from older donors has a greater chance of being
T-cell defects associated with graft-versus-host disease. 276
Accumulation of memory Cytokine Autoantibody
cells, fewer naïve cells imbalance Unexplained Anemia
Paraproteinemia To the extent that marrow contains continuously repopulating cell lines,
it is quite remarkable that changes attributable to aging alone (i.e., in the
Mild to moderate Chronic low-level absence of disease) are quite subtle. Nonetheless “unexplained anemia”
immune deficiency inflammation (UA) accounts for up to one-third of cases of anemia in older patients
and its frequency increases with advancing age. 20
Figure 9–2. Immunity and aging. A variety of factors have been asso- UA is usually mild, with hemoglobin levels approximately 1 g/dL
ciated with thymic involution, the consequence of which is a mild to lower than the WHO standard. The red cells are typically of normal size
moderate immune deficiency. Dysregulated inflammatory pathways and examination of the blood film reveals no evidence for intravascu-
are also observed with advancing age and these may be of greater clin- lar destruction or morphologic features suggestive of myelodysplasia.
ical importance. Ag, antigen; ROS, reactive oxygen species. Although inflammatory cytokine levels may be elevated, the intensity
of inflammation is insufficient to produce increased levels of hepcidin;
thus, UA has a distinct pathogenesis from the anemia of chronic disease
may also be a result of alterations in antigen presentation with age. (Chap. 37). Because UA is typically mild, it is likely to be overlooked. In
Within the T-helper cell fraction there is a shift to the T-helper (Th) type fact, in one population-based cohort that included elderly patients with
2 subset and away from Th1, thereby influencing cytokine production even more significant anemia, the medical records of affected individ-
258
and overall immune response. uals did not mention anemia as a problem in 75 percent of the cases.
171
In addition to the anatomic changes within marrow and thymus However, there is now evidence that this casual acceptance of lower
(see Figs. 9–1 and 9–2), similar age-associated morphologic changes hemoglobin levels in older populations may not be advisable. Not
168
within the paracortical and medullary zones of secondary lymphoid only can a decline in important functional measures be related to mild
tissues (spleen, and lymph nodes) occur, including a decline in the par- anemia, 172,277–280 but longitudinal studies demonstrate increased mortal-
acortical and medullary zones and increased deposition of fat within the ity among individuals with even mild anemia. 174,179,281 Furthermore, a
germinal centers. 259,260 It remains unclear to what extent these changes retrospective cohort study of the U.S. Veterans Administration National
contribute to the overall change in immune function with age. Surgical Quality Improvement database, indicated that of 310,311 sub-
A wide range of lymphocyte functional changes have been jects age 65 years and older who underwent noncardiac surgery, the
described in the context of aging; however, cataloguing these would be 30-day mortality and cardiac event rates increased by 1.6 percent for
beyond the scope of this chapter. Such changes are detailed in several each 1 percent decrease in hematocrit below the level of 39 percent.
275
excellent reviews. 24,261–264 Briefly stated, there is a shift in the T-cell pop- Thus, although in younger individuals mild anemia may be well toler-
ulation toward memory T cells, which attain replicative senescence in ated, in many older individuals it is associated with important negative
256
response to repeated antigen exposures. With the relative and abso- consequences. That stated, it remains to be established whether the cor-
257
lute decrease in numbers of naïve T cells in the peripheral lymphatic rection of anemia for those with UA will result in improved quality of
tissue and the accumulation of functionally diminished memory senes- life, physical function, or survival.
cent T cells, primary and secondary immune responses are reduced in For elderly patients with UA, the presence of macrocytosis; throm-
elderly persons. bocytopenia; neutropenia; splenomegaly; or unexplained constitutional
Coincident with the age-related changes in lymphocyte function findings of fever, chills, or weight loss; or symptoms of early satiety; or
is the increase in levels of circulating proinflammatory cytokines, mea- bone pain should prompt consideration of a marrow examination to
sureable in some, even in the absence of definable inflammatory dis- rule out myelodysplasia or other diseases affecting marrow function,
ease. IL-6 is the prototype in this regard. In young adults, expression most of which occur with increasing frequency with advancing age.
of IL-6 is tightly regulated and serum levels are usually unmeasurable
or very low in the absence of inflammatory conditions. Animal stud- Immune Senescence
ies reveal an increased production of IL-6 265,266 from mononuclear cells The complex alterations in immune function with age have been
and lymphoid cells after stimulation with lipopolysaccharide or other described comprehensively in several reviews. 261–264 The changes may
mitogens. Similarly, in humans serum IL-6 levels increase significantly explain an age-associated predisposition to certain infections (herpes
with age. 267–271 Other inflammatory proteins, including tumor necrosis zoster, tuberculosis reactivation) and perhaps a failure to mount a suf-
factor-α (TNF-α) and C-reactive protein are also seen at higher levels in ficient vaccine response (e.g., influenza hemagglutinin 282–286 ). The more
the elderly. 272–274 Visceral adipose tissue from older mice express greater profound immune deficiency commonly observed in older people most
levels of both IL-6 and TNF-α mRNA than tissue from younger mice, often reflects the debilitating effects of concurrent diseases, most of
275
and thus, some of the age-associated rise in IL-6 may be the conse- which occur more commonly with age, and side effects of the medicines
quence of those metabolic shifts mentioned above. used to manage those diseases.

Kaushansky_chapter 09_p0129-0142.indd 136 17/09/15 6:16 pm