RESIDENTS’ CLINIC

79-Year-Old Woman With Jaundice and

Anemia
Mazie Tsang, MD; Jayme L. Dahlin, MD, PhD; and Karna K. Sundsted, MD

A
79-year-old woman was referred by Physical examination was notable for scleral See end of article
her primary care physician to the icterus, jaundiced skin, and edema to the for correct answers
emergency department for evaluation mid-tibial region bilaterally. No lymphadenop- to questions.
and management of a 2-week history of jaun- athy was found. Her abdomen was soft, mini-
Resident in Internal Medicine,
dice, bilateral leg edema, and increased dys- mally distended, and had no tenderness. Her Mayo Clinic School of Grad-
pnea. A complete blood count (CBC) liver was palpated 4 cm below the costal uate Medical Education,
obtained by her primary care physician was margin, but no splenomegaly was present. Rochester, MN (M.T.); Resi-
dent in Clinical Pathology,
remarkable (reference ranges provided paren- Hemoccult stool test results were negative. Brigham and Women’s Hos-
thetically) for a hemoglobin level of 5.8 g/dL Additional laboratory studies revealed the pital, Boston, MA (J.L.D.);
(12.0-15.5 g/dL), which had decreased from following: mean corpuscular volume 122.2 Advisor to residents and
Consultant in General Internal
11.0 g/dL 4 months before presentation. She fL (81.6-98.3 fL); red blood cell (RBC) distri- Medicine, Mayo Clinic,
reported a 2-month history of intermittent bution width, 22.7% (11.9%-15.5%); platelet Rochester, MN (K.K.S.).
right upper-quadrant pain, generalized weak- count, 487  109/L (150-450  109/L); and
ness, fatigue, increased urinary frequency, leukocytes 13.4  109/L (3.5-10.5  109/L).
decreased appetite, and subjective fevers and Initial chemistry study results were notable
chills. She described dark-colored urine that for the following: international normalized ra-
began 2 days before her admission and tio, 1.2 (0.9-1.1); prothrombin time, 13.6 sec
progressive back and hip pain during the pre- (9.4-12.5 sec); creatinine, 0.8 U/L (38-176
ceding year. U/L); NT-pro-B typenatriuretic peptide, 1793
Review of systems was negative for pg/mL (10-244 pg/mL for females 79 years
hemoptysis, melena, and hematochezia. She of age; 1800 pg/mL suggested diagnostic cut-
reported that she had had no sick contacts, off for acute congestive heart failure in adults
recent travel, or recent illnesses. She had no >75 years of age without renal failure). Elec-
history of venous thromboembolism, personal trolytes were within reference ranges. An
or family history of hematologic or autoim- initial chest radiograph revealed cardiac
mune diseases, Raynaud’s phenomenon, or enlargement with pulmonary venous hyper-
association of her symptoms with cold- tension and mild interstitial edema.
temperature exposure.
Her medical history was notable for severe 1. Which one of the following is the most
chronic obstructive pulmonary disease, appropriate next step in the management
chronic hypoxia on home oxygen, history of of this patient?
transient ischemic attack, coronary artery dis- a. RBC transfusion
ease, myocardial infarction with coronary stent b. Serum protein electrophoresis
placed 15 years earlier, hypertension, and c. Echocardiogram
hypothyroidism. Medications at the time of d. Administration of intravenous immune
presentation included albuterol, apixaban, lev- globulin (IVIG)
othyroxine, lisinopril, furosemide, metoprolol, e. Administration of intravenous
and simvastatin. She was not on any known glucocorticoids
nonprescription medications or supplements.
On admission, her blood pressure was 143/ Stabilizing the patient takes immediate
48 mm Hg; heart rate, 78 beats per min; tem- precedence, including correcting symptomatic
perature, 36.8 C (oral); and respiratory rate, anemia with RBC transfusions to provide
21 breaths/min. Her SpO2 fluctuated between adequate tissue oxygenation.1 Our patient
85% and 95% on 3 L/min via nasal cannula. exhibited symptomatic anemia, as manifested

Mayo Clin Proc. n March 2018;93(3):381-385 n http://dx.doi.org/10.1016/j.mayocp.2017.03.025 381

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 MAYO CLINIC PROCEEDINGS

by weakness, dyspnea, fatigue, and a hemoglo- polychromatic cells, whereas the white blood
bin level of 5.8 g/dL (12.0-15.5 g/dL). Given cells and platelets were morphologically
her history of coronary artery disease, she unremarkable.
was transfused with 2 units of packed RBCs Additional laboratory workup was notable
while medical workup proceeded. for positive direct antiglobulin test (DAT) re-
Further diagnostic studies, such as plasma sults. In this test, patient RBCs are washed to
electrophoresis and an echocardiogram, are eliminate weakly binding proteins and then
reasonable elements of the workup, but they are reacted with titers of antiserum or mono-
should be performed after patient stabilization. clonal antibodies to various immunoglobulins
The use of IVIG or glucocorticoids would be (the most common targets being IgG and
premature until a working diagnosis is estab- C3d). RBCs with autoantibodies will bind
lished, because these particular interventions the anti-immunoglobulin reagents and aggluti-
are associated with several adverse effects, nate to yield a positive test result.2 In our pa-
such as hemolysis and thromboembolic events tient, the monospecific DATs were weakly
in the case of IVIG, and hyperglycemia and positive for anticomplement and strongly pos-
increased susceptibility to infection with itive for anti-IgG. She had positive cold agglu-
glucocorticoids. tinin screen results with positive titers at 1:64.
Additional laboratory studies were ordered
to investigate her profound anemia. 3. Based on the available data, which one of
the following is the most likely diagnosis
2. Which one of the following laboratory for this patient?
findings would be most consistent with a. Cold agglutinin disease
an underlying hemolysis in this patient? b. Cryoglobulinemia
a. Myoglobinuria c. Idiopathic autoimmune hemolytic anemia
b. Decreased absolute reticulocyte count (AIHA)
c. Elevated serum lactate dehydrogenase d. Severe aortic stenosis
(LDH) e. Drug-related AIHA
d. Elevated direct bilirubin
e. Elevated serum haptoglobin A positive DAT can be observed in cold
agglutinin disease, paroxysmal cold hemoglo-
Hemoglobinuria and hemosiderinuria can binuria, idiopathic AIHA, and drug-related
accompany hemolysis, whereas myoglobinuria AIHA (with drug-related AIHA being less
is more associated with rhabdomyolysis. Labo- common than idiopathic AIHA). Cold agglu-
ratory findings that are associated with hemoly- tinin disease is associated with acrocyanosis
sis include anemia, an increase in the absolute or Raynaud’s phenomena with cold exposure,
reticulocyte count, the presence of microspher- as well as IgM autoantibodies that bind RBCs
ocytes or schistocytes on peripheral blood at temperatures below 37 C. In cold agglu-
smears, and elevated serum LDH levels. Serum tinin disease, the DAT is typically C3-positive
indirect bilirubin is usually elevated, and the and IgG-negative, and cold agglutinin titers
concentration of serum haptoglobin, which are often greater than 1:1000.3 Our patient,
binds free hemoglobin in blood plasma, is however, had strongly positive anti-IgG titers,
usually substantially reduced in hemolysis. and only weakly positive cold agglutinin titers
Consistent with the preceding description, (<1:64). In general, a subset of patients
our patient had the following additional labora- (approximately 5%-10%) who have AIHA pre-
tory test results: serum haptoglobin <14 mg/ sent with clinical and laboratory findings that
dL (30-200 mg/dL); total serum bilirubin 4.9 are suggestive of warm AIHA but also positive
mg/dL (0.1-1.2 mg/dL); indirect serum bili- cold agglutinin titers. In many of these
rubin, 4.4 mg/dL (0.0-1.2 mg/dL); serum “mixed” cases, the magnitude of cold agglu-
LDH, 1266 U/L (122-222 U/L); and absolute tinin titers are generally low, as was the case
reticulocyte count, 369.7  109/L (38.1- with our patient. The DAT result is often nega-
112.6  109/L). A peripheral blood smear tive in cases of cryoglobulinemia.
was notable for marked anisopoikilocytosis Hemolytic anemia can also be drug
with markedly increased spherocytes and induced, and the list of offending agents is

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RESIDENTS’ CLINIC

extensive.4 However, the patient was not tak- be associated with certain types of lymphopro-
ing any of the most commonly associated liferative disorders (LPDs). In one study, 18%
medications, such as cephalosporins and peni- of patients with idiopathic AIHA went on to
cillin derivatives. Therefore, her presentation develop an LPD, with a median presentation
(ie, positive DAT results and strongly positive time of 24 months.6 Some reported risk fac-
anti-IgG test results) is most closely associated tors for a malignant LPD include advanced
with idiopathic AIHA. Although malfunction- age, underlying autoimmune disease, and the
ing heart valves can cause hemolysis, her presence of an underlying IgM monoclonal
aforementioned echocardiogram did not reveal gammopathy.
evidence of abnormal heart valves or cardiac Additional evaluation was unrevealing.
blood flow. Her total serum protein level was 6.5 g/dL
After primary stabilization of the patient (6.3-7.9 g/dL). Serum electrophoresis results
and diagnosis, several treatment strategies are revealed only a mild polyclonal hypergamma-
available for idiopathic AIHA.5 globulinemia. Serum immunofixation test
results were negative for the presence of
4. Which one of the following is most appro- monoclonal protein, and a urine electropho-
priate to use as a first-line agent for resis test revealed only a small abnormality
treatment of AIHA? in the gamma globulin fraction. Test results
a. Glucocorticoids for serum antinuclear, double-stranded deoxy-
b. Rituximab ribonucleic acid, and Mycoplasma pneumoniae
c. Glucocorticoids plus rituximab antibodies were all negative. A computed to-
d. Azathioprine mography (CT) scan of the abdomen and
e. Splenectomy pelvis revealed lytic bone lesions with a radio-
graphic differential of multiple myeloma
Historically, single-agent glucocorticoids versus aggressive osteoporosis; otherwise, no
are a reasonable first-line option because acute processes were found within the
most AIHA patients treated with steroids abdomen or pelvis.
exhibit clinical response in the form of rising
hemoglobin levels within the first few weeks 5. Given the patient’s history and findings on
of treatment. Once the hemoglobin concentra- evaluation, which one of the following
tion is above a certain threshold (eg, 10 g/dL), additional tests is the most appropriate?
the dose is usually tapered to attain the lowest a. Magnetic resonance imaging of the spine
dose capable of maintaining disease remission. b. Cerebrospinal fluid oligoclonal bands
Second-line agents can be used for AIHA that c. Serum anti-Xa levels
is refractory to glucocorticoids, as well as for d. Kidney biopsy
relapsing cases. These options include rituxi- e. Bone marrow biopsy
mab, glucocorticoids plus rituximab, azathio-
prine, and splenectomy. Third-line treatment In our patient, we considered an accompa-
options include various cytotoxic agents and nying LPD, including multiple myeloma, given
immunosuppressive agents.5 her advanced age, the CT findings of bone le-
Our patient began taking daily oral predni- sions, and her increased back pain. Although
sone (60 mg, or 1 mg/kg), iron, and folic acid our patient had lytic bones lesions on CT,
because folate and iron deficiency can accom- magnetic resonance imaging would be un-
pany chronic hemolysis. She was given likely to yield additional diagnostic informa-
sulfamethoxazole-trimethoprim and omepra- tion with respect to a potential malignancy
zole for Pneumocystis jirovecii and gastrointes- or LPD. Although cerebrospinal fluid oligoclo-
tinal ulcer prophylaxis while on prednisone, nal bands are immunoglobulins, they are asso-
respectively. ciated with multiple sclerosis, and she did not
After initiating therapy for AIHA, we inves- have any remarkable neurologic findings on
tigated an underlying etiology, including a history or examination. Anti-Xa levels, which
possible malignancy, because the patient also detect presence of circulating heparins and
reported constitutional symptoms, including Xa inhibitors such as apixiban, would not
fevers, night sweats, and anorexia. AIHA can rule out a potential LPD or yield additional

Mayo Clin Proc. n March 2018;93(3):381-385 n http://dx.doi.org/10.1016/j.mayocp.2017.03.025 383

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 MAYO CLINIC PROCEEDINGS

diagnostic clues. Multiple myeloma can autoimmune diseases, drugs, or infection.

involve the kidneys, but this patient had Once AIHA is suspected clinically, the
normal creatinine values. A bone marrow bi- highest-yielding assay is generally considered
opsy would therefore be the most useful test to be the DAT, which detects the presence of
in diagnosing a potential LPD. Her bone RBC-binding autoantibodies.2
marrow biopsy results revealed hypercellular Given the seminal importance of the DAT
bone marrow with moderate panhyperplasia in diagnosing AIHA, the possibility of DAT-
but no definitive morphologic or immunophe- negative AIHA is important to note. Such
notypic features of an LPD, plasma cell disor- false-negative readings can result from the
der, or other malignancy. following: (1) IgG sensitization below the
The patient was discharged on hospital threshold of detection; (2) low-affinity IgG
day 7 and had subsequent outpatient follow- removed by preparatory washes that are not
up for her presumed idiopathic AIHA. She conducted at 4 C or are at low ionic strength;
eventually completed 4 weekly infusions of and (3) by red-cell sensitization by IgA or IgM
rituximab (an anti-CD20 monoclonal anti- alone, but without complement fixation.9 If a
body), based on evidence, from a single-arm DAT result is negative, yet clinical suspicion
prospective trial, that low doses can induce for AIHA is still high, reasonable next steps
sustained responses in patients who have include ruling out plausible alternative diagno-
AIHA.7,8 Her response was monitored with ses and conducting secondary tests for hemo-
weekly CBCs. At 12 weeks postdischarge, rele- lysis (eg, augmented sensitivity tests, DATs
vant laboratory findings were as follows: with alternative washing steps, DATs with
hemoglobin, 11.2 g/dL; absolute reticulocyte anti-IgA sera), which often need to be sent
count, 121.1  109/L; indirect serum bili- out to reference laboratories.9
rubin, 0.0 mg/dL; and serum LDH, 604 U/L. Empiric treatment of suspected DAT-
Once her hemoglobin level reached 10 g/dL, negative AIHA may be warranted, with
her daily prednisone dose was tapered by 10 treatment being the same as that for
mg each week until the dose was 20 mg per DAT-positive AIHA.9 Patients who were
day, after which her taper was adjusted to 5 treated for DAT-negative AIHA had outcomes
mg each week. similar to those of patients who had DAT-
positive AIHA; in addition, they required a
DISCUSSION lower dose of steroid maintenance therapy
Hemolysis can be broadly organized into intra- and typically had a milder anemia and hemo-
and extra-corpuscular etiologies. The former lysis compared with patients with DAT-
are usually hereditary, not acquired, and positive AIHA.10
include defects in hemoglobin, membrane Polyspecific DAT reagents, which include
components (eg, congenital spherocytosis), antisera to both human IgG and C3d, are often
and metabolism (eg, pyruvate kinase, used for screening purposes in transfusion
glucose-6-phosphate dehydrogenase defi- medicine. Monospecific DATs, which contain
ciencies), all of which can make the red cells antisera to either IgG or C3d (plus IgM and/
susceptible to oxidant-mediated damage/ or IgA in more specific cases), can be useful
hemolysis. The latter are usually an acquired for narrowing the differential diagnosis in
process that destroys otherwise normal RBCs. DAT-positive hemolytic anemias. Specifically,
Etiologies include antibodies directed against complement-positive DATs are more highly
RBC components, splenic destruction, me- suggestive of paroxysmal cold hemoglobinuria
chanical trauma, excessive oxidant exposure, or cold agglutinin disease, whereas IgG-
and certain pathogens. positive DATs are more suggestive of warm
Autoimmune hemolytic anemia is an un- antibody or drug-related hemolytic anemias.
common yet potentially fatal autoimmune Clinicians should search for an underlying
phenomenon caused by autoantibodies that cause in cases of idiopathic AIHA. A reason-
bind to the surface of RBCs, targeting them able workup includes a detailed history for
for destruction by the immune system. Many drug-induced AIHA, infection, autoimmune
cases are idiopathic (approximately 50%), disease, and malignancy, as well as supportive
although some are linked to LPD, laboratory diagnostics, such as autoimmune
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RESIDENTS’ CLINIC

and infectious serology testing. A search for an and clinical immunology (immunoglobulin
underlying LPD or other malignancy by phys- electrophoresis). Lastly, this case emphasizes
ical examination (eg, lymphadenopathy, that a complete workup should evaluate for
splenomegaly), abdominal imaging, immuno- causes of AIHA, such as LPDs.
globulin testing (eg, serum protein electropho-
Potential Competing Interests: The authors report no
resis, IFE), and a bone marrow biopsy, along competing interests.
with its ancillary studies, may be warranted.
The first-line treatment of warm AIHA is to Correspondence: Address to Karna K. Sundsted, MD, Divi-
sion of General Internal Medicine, Mayo Clinic, 200 First St
administer glucocorticoids, which generate
SW, Rochester, MN 55905 (sundsted.karna@mayo.edu).
initial responses in most patients. In refractory
cases, clinicians typically employ splenectomy
or rituximab with or without glucocorticoids REFERENCES
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serum studies (bilirubin, LDH, haptoglobin);
autoantibodies (DAT); bone marrow biopsy; CORRECT ANSWERS: 1. a. 2. c. 3. c. 4. a. 5. e.

Mayo Clin Proc. n March 2018;93(3):381-385 n http://dx.doi.org/10.1016/j.mayocp.2017.03.025 385

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