Page 630 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 39 Megaloblastic Anemias 539

In contrast to musculoskeletal symptoms (arthralgia or frank lateral surface or gingival hyperplasia (antiepileptics). The neck may
arthritis) of autoimmune diseases, nocturnal cramps or pain in upper reveal thyromegaly (diffuse or with nodules) if there is associated
and lower extremities may indicate spinothalamic tract involvement. disease. Increased jugular venous distention should alert the examiner
Hypoparathyroidism or systemic lupus erythematosus, alone or to cardiovascular failure, with its attendant gallop, cardiomegaly (with
associated with pernicious anemia, leads to significant overlap of or without pericardial effusions), pulmonary basal crepitations,
cerebral, musculoskeletal, and neurologic presentations. pleural effusion, tender hepatomegaly, and pedal edema. Nontender
Review of skin symptoms may elicit a history of increased diffuse hepatomegaly, but more often mild splenomegaly, may rarely be
or blotchy generalized brownish skin pigmentation, especially of nail caused by extramedullary hematopoiesis in severe anemia, but a
beds and skin creases. This is common in cobalamin and folate midepigastrium mass raises the ominous possibility of gastric carci-
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deficiency; associated vitiligo suggests autoimmune disease. noma, which is up to seven times more likely in patients with
Although symptoms related to neurologic dysfunction may be pernicious anemia.
volunteered, a complete detailed questionnaire should be formulated An inverse correlation has been identified between the extent of
during the interview. Questions should be directed to perversions in anemia and neurologic dysfunction. Patients with normal complete
taste or smell, decreased visual acuity, changes in color vision, and blood count values often have neurologic signs and symptoms. In
eye pain (neuritis), tinnitus, or headache. Dizziness with orthostatic prolonged cobalamin deficiency, the neurologic examination reveals
hypotension and “blacking out” may be related to severe anemia or clear-cut evidence of involvement of posterior and pyramidal, spino-
cobalamin-deficient autonomic dysfunction, which can also be cerebellar, and spinothalamic tracts. Among the earliest signs of
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associated with night sweats. Vertigo or difficulty in walking in the posterior column dysfunction are loss of position sense in the index
dark (loss of proprioception and position sense), difficulty in ambula- toes (before great toe involvement), which is elicited by passive move-
tion (which may feel like “walking on cotton wool”), stiffness of ment, and loss of the ability to discern vibration of a high-pitched
extremities (corticospinal tracts), or ataxia (spinocerebellar tracts) (256 cycles/s) tuning fork. This is a very early elicitable, objective
may be indicative of a serious cobalamin myelopathy. Early symptoms sign, which invariably precedes by many months the loss of ability
are symmetrical tingling (“pins and needles”), extending from the tips to sense the vibration of a lower-pitched (128 cycles/s) tuning fork.
of the toes, to a glove and stocking distribution in later stages. Usually the patient loses vibration sense to 256 cycles/s from toe to
“Burning feet” syndrome, or more commonly, complaints of difficulty hip before loss of 128 cycles/s vibration sense even begins. Because
in performing simple tasks such as buttoning clothes, may also be a of the slow coalescence of contiguous spinal cord lesions, a constel-
presenting symptom. When loss of bladder and bowel control brings lation of elicitable signs may be obtained. Upper motor neuron
the patient to the physician, advanced neurologic dysfunction is disease is indicated by weakness and progressive spasticity with
invariably present. increased muscle tone, exaggerated deep tendon reflexes with clonus,
Genitourinary symptoms such as impotence or recurrent cystitis extensor plantar response, and incoordinate or scissor gait, which may
from bladder dysfunction can suggest cobalamin neuropathy. Mul- progress to spastic paraplegia. The involvement of peripheral nerves
tiple pregnancies with short intervals between delivery and concep- may markedly modify these signs to include flaccidity and the absence
tion predispose to a high risk for overt folate deficiency and contribute of deep tendon reflexes. A positive Romberg sign is not uncommon,
to fetal growth restriction in babies (cobalamin deficiency is more and a positive Lhermitte sign may be elicited. Loss of sphincter and
often associated with infertility). bowel control, altered cranial nerve dysfunction with altered taste,
smell, and visual acuity or color perception, and optic neuritis
(unexplained predominance in males) may be other physical signs
The Physical Examination indicating cobalamin deficiency. Inability to carry out serial subtrac-
tion of 7 from 100 is a valuable test to document reduced cerebral
Physical examination may reveal different features in well-nourished function (the electroencephalogram often reveals slow wave frequency)
patients (cobalamin-deficient vegetarians or pernicious anemia) and in pernicious anemia, which can progress over time to presentation
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poorly nourished (folate-deficient) individuals. The latter show evi- with catatonia or delirium. 260
dence of significant weight loss or other stigmata of multiple deficien-
cies because of either poor diet (malnutrition) or “broad-spectrum”
malabsorption. Associated deficiency of vitamins A, D, and K and Diagnostic Issues: Information from the Peripheral
protein-calorie malnutrition may give rise to angular cheilosis, bleed- Smear and Bone Marrow Aspirate
ing mucous membranes, dermatitis, osteomalacia, and chronic
infections. Various degrees of pallor with lemon-tint icterus (i.e., a Although not specific for megaloblastic anemia, macro-ovalocytes are
combination of pallor and icterus best observed in fair-skinned the hallmark of megaloblastosis (see Fig. 39.7). However, only one-
individuals) are common features of megaloblastosis. half with MCV values greater than 105 fL may have vitamin defi-
When anemia is severe, the patient may have a low-grade fever. ciency. In almost one-half of all cases, macrocytosis per se is not
The skin may reveal a diffuse, brownish pigmentation or abnormal associated with megaloblastosis, and additional tests are necessary for
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blotchy tanning. A macular hyperpigmentation with follicular complete diagnosis.
accentuation may be observed in the axilla and groin; hyperpigmenta- The frequency of hypersegmented PMNs (5% with five lobes or
tion can also involve the dorsal acral distal interphalangeal joints and 1% with six-lobed PMNs) in patients with megaloblastic hematopoi-
a reticular pigmentation in the mid–upper back can develop slowly esis is 98%. The sensitivity decreases to 78% in alcoholics, although
over a year (but resolves within 2 months of cobalamin replace- the specificity of this finding is approximately 95%. With a combina-
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ment). Special emphasis should be given to pigmentation of skin tion of hypersegmented PMNs and macro-ovalocytosis, the specificity
creases and nail beds and both palmar and dorsal aspects of hands is 96% to 98%, and the positive predictive value of folate or cobala-
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and feet. (Mucous membrane pigmentation is usually not observed, min deficiency is about 94%. Hypersegmentation of PMNs is
in contrast to Addison disease.) Premature graying, observed in light- insufficiently sensitive, when compared with metabolite levels, to be
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and dark-haired individuals, is reversible within 6 months of cobala- used as a clinical tool in the diagnosis of mild cobalamin deficiency
min therapy. (see box on Diagnostic Bone Marrow Aspiration).
A blunted masklike facies is extremely common in folate defi-
ciency. Alternatively, there may be evidence of classic hyperthyroid
or hypothyroid facies (associated with pernicious anemia). Special Masked Megaloblastosis
attention should be given to the eyes and eyebrows for the well-
known signs of thyroid dysfunction. The term masked megaloblastosis is reserved for conditions in which
Examination of the mouth may reveal glossitis with a smooth true cobalamin or folate deficiency with anemia is not accompanied
(depapillated), beefy red tongue with occasional ulceration of the by classic findings of megaloblastosis in the peripheral blood and