Download PDF

Case Studies
Resolving the Baneful and Banal: Bisalbuminemia
in an Adult With Waldenström Macroglobulinemia
Mark A. Valasek,1 Richard T. Hopley, MD,2 Frank H. Wians Jr., PhD, MT(ASCP), DABCC, FACB2
(1Medical Scientist Training Program and 2Department of Pathology, University of Texas Southwestern Medical Center, Dallas,TX)
DOI: 10.1309/LMD51RR5FXHKDHRX
Abstract
Case reports of bisalbuminemia (patient serum
containing albumin A and an albumin variant
differing by single amino-acid substitutions)
have included different races or ethnic groups
and are often reported in association with
various pathologic states. Here, we describe
a 70-year-old woman with vague symptoms,
the most concerning of which was worsening
vision with retinal hemorrhages found on
exam. During the workup, serum protein
electrophoresis was performed demonstrating a
prominent monoclonal component (IgM kappa)
and bisalbuminemia as an incidental finding.
This represents the first reported case in the
literature of the coexistence of bisalbuminemia
and Waldenström macroglobulinemia. The
possibility exists that some endogenous or
pharmacologic substances may interact
differently with albumin variants as compared
with normal albumin; however, the finding of
bisalbuminemia did not influence the diagnosis,
management, course, or prognosis of this
patient’s lymphoma.
Clinical History
Patient
70-year-old Hispanic female.
Chief Complaint
The patient was admitted for increased fatigue,
chest discomfort, and myalgia.
History of Present Illness
The patient reported that her fatigue and chest
discomfort have been present for 2 years but
have become worse over the last 2 months.
She also complained of left shoulder pain
(occasionally radiating to the left jaw) and
generalized myalgia. Review of systems was
also positive for weight loss of 14 pounds
over the previous year, blurry vision for 4
months, nosebleeds, chest pain with exertion,
weakness, and depression.
labmedicine.com
Past Medical History
The patient has a past medical history
significant for hypertension. She has had no
surgeries.
Current Medications
Her only medication was ibuprofen at 600 mg
PO (3 times daily) for myalgia. She was not
taking any medications for her hypertension.
Family History
Her mother had diabetes and died at 60 years
of age. Her father died of unknown causes. Her
sister was diagnosed with renal cancer. Her
daughter has “liver and uterine cysts.”
Social History
The patient denied alcohol, tobacco, and illicit/
intravenous drug abuse. She currently lives at
home with her son.
Physical Examination Findings
Exam was significant for mild systolic
hypertension, obesity (body mass index of
38.5), and bilateral ankle-level pitting edema.
Fundoscopic examination showed retinal
exudates and hemorrhages.
Principal Laboratory Findings
Initial laboratory studies showed pancytopenia
with elevated serum total protein and viscosity
(Table 1).
Results of Additional Diagnostic Procedures
Computed tomography (CT) imaging of
the abdomen and pelvis showed moderate
splenomegaly without lymphadenopathy.
Magnetic resonance imaging (MRI) of the
spine showed patchy abnormal bone marrow
signaling, most prominently involving the
T12 vertebra consistent with metastases
or myeloma. In addition, ophthalmologic
evaluation revealed bilateral retinal
hemorrhages.
aspirate smear prepared with Wright-Giemsa
stain revealed a hypercellular sample
(greater than 95% cellularity) with markedly
decreased numbers of megakaryocytes,
granulocytes, and erythroid precursors, all
exhibiting unremarkable morphology. A manual
differential showed relative suppression
of the myeloid and erythroid lines with a
predominance of lymphocytes/plasmacytoid
lymphocytes, and plasma cells (57% and
37%, respectively.) Many of the plasma cells
showed cytoplasmic accumulation of abundant
eosinophilic material, likely representing
immunoglobulin. A periodic acid-Schiff (PAS)
staining within plasma cells further supported
the presence of cytoplasmic immunoglobulin
within numerous enlarged plasma cells.
By immunohistochemistry, the neoplastic
plasma cells were IgM/kappa-restricted
(lambda negative), CD79a positive, and
CD20 negative, consistent with a monoclonal
proliferation of plasma cells. The neoplastic
small lymphocytes were CD79a and CD20
positive. Flow cytometric analysis revealed
a CD5 (predominantly negative)/CD10
(negative) B-cell lymphoproliferative disorder
of predominantly small cells, consistent with
lymphoplasmacytic lymphoma. A peripheral
blood smear showed a markedly decreased
number of erythrocytes with a normocytic and
hypochromic anemia. Mild anisopoikilocytosis
and mild rouleaux formation were present.
Also consistent with the findings within the
marrow cavity, platelets and white blood cells
were also decreased in number with otherwise
unremarkable morphology. No plasma cells
or plasmacytoid lymphocytes were identified
in the peripheral blood. Protein analysis of
serum and urine included serum and urine
protein electrophoresis (SPEP/UPEP) and
immunofixation electrophoresis (IFE) of serum
(Figure 1).
A bone marrow biopsy was also performed
(Image 1). Both the core biopsy and an
December 2008 j Volume 39 Number 12 j LABMEDICINE
723
Case Studies
Questions
Table 1_Principal Laboratory Findings
Test
Patient’s Result Ref Range
Chemistry
Sodium
Potassium
Chloride
Bicarbonate
Anion Gap
Creatinine
BUN
Glucose
Calcium
Phosphorus
Magnesium
134 mmol/L
4 mmol/L
103 mmol/L
20 mmol/L
11 mmol/L
0.59 mg/dL
10 mg/dL
120 mg/dL
8.2 mg/dL
3.7 mg/dL
1.6 mEq/L
Direct bilirubin <0.1 mg/dL
Total bilirubin 0.7 mg/dL
ALT 9 Units/L
Alk Phos 42 Units/L
AST 19 Units/L
LD 136 Units/L
GGT 11 Units/L
CK 41 Units/L
CK-MB <1 ng/mL
Troponin I <0.1 ng/mL
Coagulation
PT 12.7 sec
INR 1.3
PTT 33.2 sec
D-dimer 2.1 mg/L FEU
Fibrinogen 267 mg/dL
Hematology
WBC 1.7 x109/L
RBC 2.14 x1012/L
Hemoglobin 6.5 g/dL
HCT 21.4%
MCV 100 femtoliter
MCH 30.4 pg
MCHC 30.4 g/dL
RDW-CV 19.5%
Platelet 68 x 109/L
MPV 9.9 femtoliter
Differential
Neutrophils 25%
Lymphs 60%
Monocytes 14%
Myelocytes 1%
135–145
3.6–5.0
98–109
22–31
6.0–16.0
0.60–1.20
7.0–21
65–200
8.4–10.2
2.4–4.5
1.4–1.8
0.0–0.3
0.2–1.3
10.0–40
38–126
13–40
140–271
8.0–78
30–135
0–3
N/A
9.2–12.8
0.9–1.3
23.5–33.5
0.0–3.0
190–400
3.90–10.70
4.01–5.31
12.1–16.1
36.8–48.7
76.2–98.6
24.6–33.4
31.6–35.4
11.5–15.0
174–404
9.4–12.9
36–72
20–51
4.0–11.0
N/A
Total protein 11.4 g/dL 6.3–8.2
Albumin 3.71 g/dL 3.90–5.10
Viscosity
4.1 centipoise
≤1.5
1.
2.
3.
4.
5.
6.
7.
8.
What is bisalbuminemia?
Are there albumin variants that cause disease?
What is Waldenström macroglobulinemia?
When does hyperviscosity syndrome occur?
How is Waldenström macroglobulinemia treated?
Is there any known association between these 2 entities?
What types of bisalbuminemia are there?
Do albumin variants cause significant differential binding
of compounds?
9. What other diagnoses should be considered in this case?
Possible Answers
1. Bisalbuminemia (also called alloalbuminemia) is a clinically benign condition defined by the presence of differentially
migrating albumin variants on agarose gel electrophoresis (AGE).
Usually, this is seen as 2 distinct bands on AGE but can sometimes
appear as a single widened band. Hereditary forms of bisalbuminemia account for approximately 39% of the sequence polymorphisms known to exist in the albumin gene, and they are generally
caused by single point mutations.1 However, because albumin
variants are rare, the overall prevalence of bisalbuminemia is low,
generally ranging from 1:10,000 to 1:1,000.
2. Are there albumin variants that cause disease? Yes. Twelve
mutations have been identified that lead to a rare condition called
analbuminemia in which patients have serum albumin concentrations less than 0.1 g/dL. Given the fundamental roles of albumin
in maintaining oncotic pressure and transporting lipophilic
compounds, it is surprising that this disease results only in mild
edema, mild fatigability, and hyperlipidemia. (In many cases the
disease is entirely asymptomatic.) It should be noted that albumin
mutations can display biochemical evidence of differential binding
to lipophilic hormones, ions, or drugs, but it is unclear at present
whether or not these represent disease states. It has been discovered that 3 mutations in albumin can cause enhanced binding
of thyroid hormones, thereby causing familial dysalbuminemic
hyperthyroxinemia and familial dysalbuminemic hypertriiodothyroninemia.2-4 These individuals can have elevated free and total
thyroid hormone, but are clinically in a euthyroid state. The only
potential clinical concern is confusion with hyperthyroidism or
thyroid hormone resistance syndromes, which might lead to unnecessary treatment.5 These particular mutations do not cause
bisalbuminemia.1
A B C
Image 1_Hypercellular bone marrow consisting of lymphoplasmacytic infiltrate. (A) Bone marrow core biopsy showing predominantly lymphplasmacytoid cells. (B) Clot section showing lymphoplasmacytoid cells with abundant eosinophilic material. (C) Immunohistochemistry of clot
section using CD79a, a B-cell/plasma cell marker, showed almost universal staining of cells.
724
LABMEDICINE j Volume 39 Number 12 j December 2008
labmedicine.com
Case Studies
A B
C D
Figure 1_Serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). (A) A quality control sample serum along with sera
from 4 patients. Arrows indicate albumin bands and asterisks indicate M-components. Note 2-band albumin pattern for patient 1. (B, C)
Quantification of bands for patient 1. (D) Immunofixation showing M-component consists of IgM kappa. Arrow indicates M-component in total
protein (Tot) lane and asterisks indicate positive bands for IgM (lane M) and kappa light chain (lane K).
3. Waldenström macroglobulinemia, along with multiple
myeloma (MM) and monoclonal gammopathy of uncertain
significance (MGUS), is classified as a plasma cell dyscrasia. It is
considered a low-grade non-Hodgkin’s lymphoma (specifically,
lymphoplasmacytic lymphoma) that leads to secretion of IgM into
the blood. In approximately 15% of cases, the elevated levels of
circulating IgM can cause hyperviscosity syndrome characterized by
neurologic deficits such as blurred vision, headache, dizziness, and
altered mental status. On fundoscopic examination, abnormal “sausage” retinal veins or hemorrhages may be seen. Congestive heart
failure and/or pulmonary infiltrates are also presentations of a hyperviscous state. IgM can also cause damage by deposition in tissues
causing amyloidosis, glomerulopathy, and peripheral neuropathy.
In addition, patients can have cytopenias with corresponding symptoms, hepatomegaly, splenomegaly, and lymphadenopathy.
4. Serum is normally approximately 1.8 times more viscous
than water; however, hyperviscosity syndrome generally occurs
when the plasma viscosity becomes elevated to 5 times that of
water. This is reflected in the absolute measurement of viscosity by
units of poise (P) at a given temperature. One poise is equal to 1g/
(cm • s), and this patient’s value was given as 4.1 centipoise (cP).
Water has a viscosity of 0.89 cP at room temperature and therelabmedicine.com
fore the patient’s serum was approximately 4.6 times as viscous as
water at room temperature. For comparison, olive oil has a viscosity of 81 cP at room temperature. In this patient, the elevated viscosity was primarily due to increased IgM kappa (Figure 1).
5. Waldenström macroglobulinemia is treated by removing the excess IgM protein (by plasmapheresis) and by inhibiting
production of the excess immunoglobulin via chemotherapeutic
regimens to target the lymphoplasmacytic cells. Chemotherapies
can include either monotherapy with chlorambucil, fludarabine,
cladribine, or rituximab, or a combination of agents. Thalidomide
and hematopoietic stem cell transplantation (HSCT), as well as
additional molecular targets, are currently being investigated.6-9
6. There is no known association between these 2 entities. To
the best of our knowledge, this is the first report in the literature
of the coexistence of bisalbuminemia and Waldenström macroglobulinemia and there is currently no known pathophysiological
relationship between the 2 conditions. The recognition of bisalbuminemia here is likely simply due to the fact that SPEP/UPEP
studies are commonly performed on this patient population. The
incidence in these patients is expected be similar to that of the
general population.
December 2008 j Volume 39 Number 12 j LABMEDICINE
725
Case Studies
7. Bisalbuminemia can be either hereditary or acquired. As
discussed above, hereditary bisalbuminemia is generally caused by
a single point mutation in the albumin gene. Although there is no
known causal connection between hereditary bisalbuminemia and
disease, bisalbuminemia has been identified in individual patients
with diabetes, Alzheimer’s disease, chronic kidney disease, nephrotic syndrome, multiple myeloma, and other diseases. In contrast,
acquired transient bisalbuminemia can result from pancreatitis
and beta-lactam ingestion.10
8. Do albumin variants cause significant differential binding
of lipophilic compounds? Yes. Several albumin variants have been
shown to have decreased binding to warfarin, bilirubin, Ni2+, or
Cu2+, or increased binding to prostaglandins, thyroid hormones,
or fatty acids; however, these have not been implicated in causing
disease states.
9. The differential diagnosis of an additional band in the
same region as albumin includes the following: the band may represent an artifact of electrophoresis, although bands of this type are
usually easily recognized as such (eg, air bubbles, distortions of the
gel, overloading, etc). In addition, proteins that normally migrate
in the same region of albumin may be elevated and mimic the appearance of bisalbuminemia. These include prealbumin (increased
after recent food ingestion), alpha 1 acid glycoprotein (an acute
phase reactant), and alpha lipoproteins. However, any unusual
band in a serum protein electrophoresis may indeed be a true
paraprotein, and a monoclonal gammopathy must be considered,
especially since light chains can migrate to abnormal locations.
In addition to bisalbuminemia, our patient was also found
to have a monoclonal protein (M protein) in the gamma region.
Monoclonal gammopathies occur in multiple myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia. If a
monoclonal gammopathy is discovered in a patient with no clinical disease, then it is termed monoclonal gammopathy of undetermined significance (MGUS). In our patient, the M protein was
determined to be of IgM kappa type consistent with Waldenström
macroglobulinemia (Figure 1D).
As our patient presented with retinal hemorrhages in the
clinical context of a monoclonal gammopathy, the diagnosis of
acquired von Willebrand syndrome (AVWS) may also be considered. Acquired von Willebrand syndrome is a rare entity, with
approximately 300 cases reported in the literature.11 The presence
of an inhibitor to von Willebrand factor (vWF) or the factor
VIII/vWF complex has been demonstrated in 15% of reported
726
LABMEDICINE j Volume 39 Number 12 j December 2008
cases, the majority of which were associated with a monoclonal
protein which may or may not have specificity for the factor or the
complex. It can also exist in the presence of a normal coagulation
profile, as in our patient.
Patient’s Treatment and Course
Due to the concern for the patient’s vision, she was initially
treated with plasmapheresis and her serum viscosity decreased
from 4.1 to 1.6 cP. She did experience improvement in vision,
albeit minimal, possibly due to the chronicity of her ocular symptoms. She was started on a chemotherapeutic regimen (chlorambucil at 0.2mg/kg for 5 days, every 4 weeks). Her monoclonal
component subsequently decreased, and her cytopenia improved
significantly. She continues to follow up with Hematology/
Oncology on an outpatient basis. LM
1. Minchiotti L, Galliano M, Kragh-Hansen U, et al. Mutations and
polymorphisms of the gene of the major human blood protein, serum
albumin. Hum Mutat. 2008;29:1007–1016
2. Ruiz M, Rajatanavin R, Young RA, et al. Familial dysalbuminemic
hyperthyroxinemia: A syndrome that can be confused with thyrotoxicosis.
N Engl J Med. 1982;306:635–639.
3. Petersen CE, Scottolini AG, Cody LR, et al. A point mutation in the human
serum albumin gene results in familial dysalbuminaemic hyperthyroxinaemia.
J Med Genet. 1994;31:355–359.
4. Sunthornthepvarakul T, Likitmaskul S, Ngowngarmratana S, et al. Familial
dysalbuminemic hypertriiodothyroninemia: A new, dominantly inherited
albumin defect. J Clin Endocrinol Metab. 1998;83:1448–1454.
5. Heufelder AE, Klee GG, Wynne AG, et al. Familial dysalbuminemic
hyperthyroxinemia: Cumulative experience in 29 consecutive patients. Endocr
Pract. 1995;1:4–8.
6. Leleu X, Roccaro AM, Moreau AS, et al. Waldenström macroglobulinemia.
Cancer Lett. 2008;270:95–107.
7. Treon SP, Hatjiharissi E, Leleu X, et al. Novel agents in the treatment of
Waldenström’s macroglobulinemia. Clin Lymphoma Myeloma. 2007;7:S199–
S206.
8. Dimopoulos MA, Anagnostopoulos A. Treatment of Waldenström’s
macroglobulinemia. Curr Treat Options Oncol. 2007;8:144–153.
9. Burwick N, Roccaro AM, Leleu X, et al. Targeted therapies in Waldenström
macroglobulinemia. Curr Opin Investig Drugs. 2008;9:631–637.
10.Faviou E, Nounopoulos C, Dionyssiou-Asteriou A. Bisalbuminemia from a
clinical chemist’s viewpoint: A case report and review of the recent literature.
Minerva Med. 2006;97:287–293.
11.Kumar S, Pruthi RK, Nichols WL. Acquired von Willebrand’s syndrome:
A single institution experience. Am J Hematol. 2003;72:243–247.
labmedicine.com