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oimbra

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2014; 60(5):490-499

disorders that are the source of hemorrhagic manifesta-

tions.

Monoclonal IgM may exhibit “cold agglutinin” acti-

vity, binding to erythrocyte antigens at a temperature lo-

wer than physiological temperature, determining the de-

velopment of chronic cold antibody hemolytic anemia.

This monoclonal immunoglobulin is generally IgM Kap-

pa, which often interacts with I/i antigens on the surfa-

ce of erythrocytes.

23,24

Anemia manifests in less than 10%

of patients and is generally associated with “cold agglu-

tinins” levels above 1:1000.

The reduction in the tem-

perature of blood flowing through the peripheral blood

vessels favors the binding of IgM “cold agglutinins” to

the surface of erythrocytes.

This agglutination of eryth-

rocytes in peripheral blood vessels is responsible for

Raynaud’s phenomenon, acrocyanosis and

livedo reticula-

ris

, which is reversible when large blood circulation resu-

mes.

Type II cryoglobulinemia (mono and polyclonal) is

characterized by the deposition of monoclonal IgM-poly-

clonal IgG immunocomplexes at the level of blood ves-

sels, with consequent activation of the complement.

The

main clinical manifestations are vasculitis,

purpura

, arth-

ralgia, digital necrosis, Raynaud’s phenomenon, periphe-

ral neuropathy in lower limbs, renal impairment (

protei-

nuria

hematuria

, nephrotic syndrome), and liver

impairment (hepatomegaly, liver dysfunction).

Around 20% of patients may be experiencing neuro-

logical symptoms at the time of diagnosis. The most fre-

quent neurological disorder is a demyelinating distal sym-

metrical sensorimotor peripheral neuropathy, which

manifests itself slowly and progressively, causing pares-

thesia and asthenia. About 50% of these patients have

myelin-associated glycoprotein antibodies (MAG anti-an-

tibodies).

These are generally monoclonal IgM kappa

and are often involved in demyelinating neuropathies.

Monoclonal IgM can also connect nonspecifically to

multiple antigens of the peripheral nerves, triggering axo-

nal impairment.

20,28

The biological function of various tissues and/or or-

gans may be altered by the formation and deposition of

monoclonal IgM aggregates, however, the clinical mani-

festations related to their deposition are not frequent.

The deposition of monoclonal IgM in the basal mem-

brane of the epidermis is associated with bullous skin di-

sease.

If it occurs at the level of the dermis it contribu-

tes to the formation of papular-nodular lesions on the

surface (

Macroglobulinemia cutis

30,31

Some patients may

have chronic

urticarial erythema

, fever and arthralgia (Sch-

nitzler syndrome).

The deposition of monoclonal IgM in the

lamina pro-

pria

and/or submucosa of the intestine can be associated

with diarrhea, malabsorption and gastrointestinal blee-

ding.

Renal failure is not very common; however, mono-

clonal IgM may accumulate in the renal

glomeruli

, for-

ming subendothelial deposits that clog glomerular capil-

laries.

In this case, there may be moderate but reversible

proteinuria

, being the majority of patients asymptomatic.

In primary or light chain amyloidosis (AL amyloido-

sis), amyloid fibrils may be deposited in the heart, kid-

neys, liver, lungs and peripheral nerves.

Cardiac and pul-

monary involvement is more frequent in patients with

amyloidosis associated with monoclonal IgM.

35,36

AL amy-

loidosis may be related to the development of symmetri-

cal or asymmetrical sensory-motor polyneuropathy. Pa-

tients experience pain, the sensation of “electric shocks”

and thermal sensitivity in the lower limbs. AL amyloido-

sis may further affect the autonomic nervous system, cau-

sing diarrhea, hypotension, impotence and bladder dys-

function.

The deposition of amyloid A protein (AA amyloido-

sis) has been documented, although rare,

37,38

and may oc-

cur in the kidneys and intestines, causing nephrotic syn-

drome and intestinal malabsorption.

IgG and IgA hypogammaglobulinemia may occur si-

multaneously with monoclonal IgM hypergammaglobu-

linemia, which can contribute to recurrent respiratory tract

infections, but its cause is not well understood and could

be associated with alterations in the development of plas-

ma cells and/or the production of immunoglobulins.

LPL primarily involves the bone marrow, but the di-

sease can reach the lymph nodes, spleen and liver, among

other organs. Lymphoplasmocytoid/plasmacytic infiltra-

tion is responsible for asthenia, fatigue, recurrent fever,

night sweats, weight loss, cytopenia, lymphadenopathy

and organomegaly.

Fatigue is one of the most common symptoms and

is often associated with normocytic normochromic ane-

mia; around 80% of symptomatic patients have modera-

te to severe anemia.

Anemia is not only due to the chan-

ge in medullary erythropoiesis. Other factors may

contribute to its aggravation, such as gastrointestinal

bleeding, hyperhemolysis, and hyperviscosity itself, which

may cause a decrease in the erythropoietin synthesis.

should be noted that false anemia may be observed in

some patients caused by the high concentration of mo-

noclonal IgM, which contributes to the increase in plas-

ma volume and consequent hemodilution.