249
Case report
Bilateral periorbital ecchymoses
An often missed sign of amyloid purpura
G. Colucci1; L. Alberio1, 2; F. Demarmels Biasiutti1; B. Lämmle1, 3
1Department
of Haematology and Central Haematology Laboratory, Inselspital, University Hospital and University of
Bern, Switzerland; 2Service of Haematology and Central Haematology Laboratory, CHUV, University Hospital of
Lausanne, Switzerland; 3Center for Thrombosis and Haemostasis, University Medical Center, Mainz, Germany
Keywords
Immunoglobulin light chain amyloidosis,
multiple myeloma, amyloid purpura, raccoon
eyes
Summary
Immunoglobulin light chain (AL) amyloidosis
is a systemic disease caused by a plasma cell
clone synthesizing an unstable light chain,
which forms amyloid fibrils. Deposition of
amyloid fibrils affects primarily kidney, heart,
nervous system, spleen, liver, gastrointestinal
tract and the skin. Skin bleeding in these patients is called amyloid purpura. Classically, it
occurs spontaneously and bilaterally in the
periorbital region. Vessel wall fragility and
damage by amyloid are the principal causes
of periorbital and gastrointestinal bleeding.
Additionally, coagulation factor inhibitory
circulating paraprotein, hyperfibrinolysis,
platelet dysfunction or isolated acquired factor X deficiency may contribute to even more
severe, diffuse bleedings.
Early diagnosis remains essential for improving prognosis of patients with AL amyloidoCorrespondence to:
Giuseppe Colucci, MD
Department of Haematology and Central Haematology
Laboratory, University Hospital Inselspital
Freiburgstr. 10, 3010 Bern, Switzerland
Tel. +41/31/632 02 64, Fax +41/31/632 34 06
E-mail: [email protected]
Extracellular tissue deposition of amyloid fibrils causing amyloidosis leads to progressive organ dysfunction and clinical symptoms. The clinical features are dependent on
the organs involved and often may reflect
advanced organ damage (1). Immunoglobulin light chain (AL) amyloidosis is the
most common type of amyloidosis and may
sis. Although pictures of amyloid purpura have
been often reported in the literature, the
clinical diagnosis may be delayed. We report a
case of cutaneous manifestation of AL amyloidosis diagnosed not until one year after the
appearance of the first symptoms. Diagnostic
work-up revealed that the patient suffered
from multiple myeloma with secondary AL
amyloidosis. Atraumatic ecchymoses at the
face, particularly the eyelids as well as in the
neck should raise the suspicion of AL amyloidosis.
Schlüsselwörter
Immunglobulin-Leichtketten-Amyloidose,
Multiples Myelom, Amyloidpurpura, Raccoon-Augen
Zusammenfassung
Die Immunglobulin-Leichtketten- (AL-)Amyloidose ist eine systemische Krankheit infolge
Ablagerung pathologischer Amyloidfibrillen.
Ein Plasmazell-Klon produziert und sezerniert
Bilaterale periorbitale Ekchymosen
Ein häufig verpasstes Zeichen der Amyloidpurpura
Hämostaseologie 2014;34: 249–252
http://dx.doi.org/10.5482/HAMO-14-03-0018
received: March 9, 2014
accepted in revised form: June 18, 2014
epub ahead of print: June 30, 2014
involve any organ (2). Clinical manifestations of AL amyloidosis are variable but
typically include bleeding tendency (3).
Skin bleeding in these patients is called
amyloid purpura and classically occurs
spontaneously and bilaterally in the periorbital region (4).
monoklonale, instabile Leichtketten, die als
Fibrillen in diversen Organen abgelagert
werden. Vorzugsweise sind Nieren, Herz, Nervensystem, Milz, Leber, Gastrointestinaltrakt
und Haut betroffen. Ein Hautbefall äußert
sich in Form spontan auftretender, typischerweise beidseits periorbital lokalisierter, subkutaner Blutungen. Diese Amyloidpurpura
sowie gastrointestinale Blutungen sind bedingt durch die Fragilität der Gefäße infolge
der
Amyloidablagerung.
Gerinnungsfaktoren-inhibierendes Paraprotein, Hyperfibrinolyse, Thrombozytendysfunktion oder
akquirierter isolierter Faktor-X-Mangel können zu einer schweren, diffusen Blutungsneigung beitragen.
Frühdiagnose und -therapie sind für die Prognose der AL-Amyloidose essenziell. Wir
berichten über einen Patienten mit kutaner
Manifestation einer AL-Amyloidose, bei dem
die klinische Diagnose erst ein Jahr nach Auftreten erster Symptome und Konsultation
mehrerer Spezialisten gestellt wurde. Die
weitere Abklärung ergab ein multiples
Myelom mit sekundärer AL-Amyloidose.
Atraumatische Ekchymosen im Gesicht, v. a.
im Bereich der Lider, periorbital und im
Nacken, sollten den dringenden Verdacht auf
AL-Amyloidose wecken und unverzüglich zur
Abklärung führen.
Early diagnosis before development of
organ failure is absolutely essential for improving the prognosis (5). However, the
diagnosis is often delayed in clinical practice. We present a patient with cutaneous
manifestation of AL amyloidosis. The diagnosis was delayed and only made one year
after the appearance of the first symptoms
© Schattauer 2014
Hämostaseologie 3/2014
Downloaded from www.haemostaseologie-online.com on 2017-06-17 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.
250
G. Colucci et al.: Amyloid purpura
Fig. 1
Periorbital region of
our patient showing
bilateral ecchymoses
and after consultations with several medical specialists.
Case
A man (age: 58 years) had been well until
one year before consultation at our haematologic outpatient ward, when recurrent bilateral periorbital, atraumatic ecchymoses
developed (▶ Fig. 1). These had occurred
on both sides simultaneously, persisted,
were painless and occasionally were less accentuated but never disappeared completely. Moreover, the patient suffered from
arterial hypertension and diverticulosis.
His only medication was a diuretic (torasemide).
The patient initially consulted his family
physician who referred him to an otorhinolaryngologist, to a radiologist and to an angiologist. Multiple clinical and diagnostic
investigations (i. e. computerized tomography and MRI of the head, arterial/
venous Doppler ultrasound and angiography) were performed in order to exclude a local tumour, a venous thrombosis,
a vascular malformation as well as a skull
fracture. However, no pathologic results
were found and the diagnosis remained
unclear.
Subsequently, the patient was referred to
the Department of Ear Nose Throat Head
and Neck Surgery at our University Hospital. Again, diagnostic procedures were inconclusive and finally, one year after appearance of the first skin bleeding signs, he
was addressed to our outpatient ward for
investigation of a haemostatic disorder.
The personal bleeding history was otherwise negative and no haemorrhagic diathesis was known in his family. He did neither
take aspirin nor anticoagulants. No further
skin or mucosal bruises were found and the
clinical examination was normal.
The typical clinical finding immediately
suggested the diagnosis of AL amyloidosis
(6–13). Spontaneous bilateral periorbital
Fig. 2
Serum protein electrophoresis showing in
the gamma region a
paraprotein of 11.8 g/l
(↓). The immunofixation demonstrated
the paraprotein to be
IgG lambda.
ecchymoses, although apparent in a minority of patients with AL amyloidosis, are almost pathognomonic for this diagnosis.
Raccoon eyes may be a sign of advanced
amyloid deposition. Therefore, we performed a complete staging.
Serum electrophoresis (▶ Fig. 2) and
immunofixation demonstrated an IgG
lambda paraprotein at a concentration of
11.8 g/l. Serum free light chains type lambda were elevated (217.1 mg/l, normal
5.7–26.3 mg/l) whilst the free light chains
type kappa were within the reference range
(7.5 mg/l, normal 3.3–19.4 mg/l) and the
ratio free kappa/lambda light chains was
abnormal (0.03, normal 0.26–1.65).
The patient presented with a proteinuria
of 0.61 g/l with monoclonal lambda light
chains detected by immunofixation. The
NT-proB natriuretic peptide was elevated
(352 pg/ml, normal < 160 pg/ml), the
troponin T was not elevated (<0.003 µg/l,
normal <0.014 µg/l).
The electrocardiogram was normal
without low voltage signs. The echocardiogram showed a left ventricular hypertrophy
with diastolic dysfunction, compatible with
but not specific for amyloidosis (14). A
heart biopsy was not performed. Bone
marrow aspirate and biopsy revealed a
plasma cell infiltration of 15–20% plasma
cells with lambda light chain restriction.
Conventional karyotyping detected hyperdiploidy (+3, +6, +9) and fluorescent in situ
hybridization (FISH) detected t(6;14).
No amyloid deposits were present in the
bone marrow biopsy. A rectal biopsy
showed amorphous Congo red-positive deposits in vessel walls and interstitium
showing apple-green birefringence under
polarized light. Lambda immunostaining
results were positive. Serum creatinine,
urea nitrogen and serum calcium were normal. No osteolytic bone lesions were found
by whole body X-ray studies. All haemostatic tests (▶ Tab. 1) as well as the platelet
count (210 G/l, reference range: 140–380
G/l) and platelet aggregation in platelet
rich plasma were within normal limits demonstrating that in our patient vascular
fragility secondary to amyloid deposition
was the only abnormality underlying the
bleeding tendency.
Hämostaseologie 3/2014
© Schattauer 2014
Downloaded from www.haemostaseologie-online.com on 2017-06-17 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.
G. Colucci et al.: Amyloid purpura
A diagnosis of multiple myeloma IgG
lambda, Durie-Salmon stage I, International Staging System Score II with
secondary lambda light chain amyloidosis
was made.
As troponin T was negative, an antineoplastic therapy with three cycles dexamethasone and bortezomib was started
(15–17). This initial therapy was followed
by high-dose melphalan and autologous
peripheral blood stem cell transplantation
achieving a complete remission and by
maintenance therapy with lenalidomide
during one year. Serum free light chains
normalized. At last clinical control, four
months after discontinuation of lenalidomide and two and a half years after diagnosis, a complete remission was demonstrated.
Discussion
Periorbital ecchymoses or the so-called
raccoon eyes are a sign of bleeding into the
soft tissues around the eyes [18]. Raccoon
eyes may be accompanied by Battle’s sign,
an ecchymosis behind the ear along the
posterior auricular artery [19]. These
symptoms may be the only sign of a basal
skull fracture, most often involving the anterior cranial fossa, that ruptured the meninges. Raccoon eyes may be bilateral or
unilateral. If bilateral, they are highly suggestive of basal skull fracture, amyloidosis
or neuroblastoma, the latter classically occurring in children.
Amyloidosis indicates a group of diseases characterized by extracellular tissue
deposition of insoluble, rigid and toxic fibrils. To date, thirty heterogeneous human
protein precursors are known to form morphologically indistinguishable amyloid fibrils causing localized or systemic amyloidosis (20). Conversion of soluble precursors to fibrils, so-called fibrillogenesis,
starts with folding and conformational
changes of soluble precursors which assume an antiparallel beta-sheet configuration (21). These fibrils, which have a diameter of 7.5 to 10 nm, form extracellular
deposits in the interstitium of organs and
/or tissues and cause systemic amyloidosis.
Distribution of amyloid deposits in the or-
Tab. 1
Results of haemostatic
tests
assay
patient
reference range
prothrombin time (s)
10.2
8.5–11.5
activated partial thromboplastin time
(s)
31.3
25.0–36.0
thrombin time (s)
12.1
11.5–15.0
90
68–140
116
78–153
VII
116
70–139
X
82
78–144
VIII
138
55–164
IX
114
79–138
clotting activity II
(%) of factor
V
XI
97
70–139
5.41*
1.75–3.75
100
70–139
von Willebrand antigen (%)
factor
ristocetin cofactor
activity (%)
191*
42–168
202*
42–136
VWF activity / antigen ratio
1.06
≥ 0.7
alpha 2 antiplasmin (%)
102
73–126
fibrinogen (g/l)
factor XIII activity (%)
* above the reference range
gans is varying because proteins have a different tropism and aggregate predominantly in defined target organs. In light
chain amyloidosis the deposits can involve
theoretically any organ (21).
Immunoglobulin light chain (AL) amyloidosis is a systemic disease caused by
either a small plasma cell clone or, as in the
case presented here, by plasma cell myeloma synthesizing an unstable light chain.
These monoclonal light chains undergo
conformational changes, aggregate and
form amyloid fibrils. Deposition of amyloid fibrils leads to progressive organ dysfunction and affects primarily the kidney,
heart, autonomic and peripheral nervous
system, spleen, liver, gastrointestinal tract
and the skin (4). Clinical manifestations of
AL amyloidosis reflect advanced organ
damage. Typical isolated or combined
symptoms and signs include fatigue, renal/
heart failure, oedema, organomegaly, peripheral and autonomic neuropathy, postural hypotension, carpal tunnel syndrome,
weight loss, diarrhea, constipation, dyspnea, macroglossia and bleeding tendency
(22–24). Skin bleeding in these patients is
called amyloid purpura and classically occurs bilaterally in the periorbital region.
Bleeding diathesis is mainly due to vessel
wall damage by amyloid deposition leading
to vascular fragility. The same underlying
pathological mechanism predisposes to
gastrointestinal bleeding. Moreover, coagulation factor inhibitory circulating paraprotein (25), hyperfibrinolysis (26, 27), platelet dysfunction or isolated acquired factor
X deficiency (28–30) may contribute to
severe bleeding tendency also in other localizations.
The diagnosis of amyloidosis is based
on histological demonstration of positive
staining with Congo-red and applegreen
birefringence in polarized light. Periumbilical fat, rectum or labial salivary glands
are the most accessible sites for biopsy
searching amyloid deposits.
Bone marrow aspirate/biopsy to detect an
underlying plasma cell clone including
FISH is mandatory.
Often patients with AL amyloidosis have a
small clonal burden, only 12 to 15 percent
of patients with myeloma have symptomatic AL amyloidosis (21). The morbidity
and mortality from primary or secondary
AL amyloidosis are high and early diag-
© Schattauer 2014
Hämostaseologie 3/2014
Downloaded from www.haemostaseologie-online.com on 2017-06-17 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.
251
252
G. Colucci et al.: Amyloid purpura
nosis remains the principal factor for improving the prognosis of patients with AL
amyloidosis (4). The diagnosis may be delayed in the case of unspecific features.
Treatment modalities of light chain amyloidosis have recently been updated by Leung
et al. (31) and by Mahmood et al. (32).
Conclusion
Amyloid purpura is a cutaneous manifestation of AL amyloidosis typically apparent
in the periorbital region. Deposition of immunoglobulin light chains in the vascular
wall is considered the principal mechanism
leading to vascular fragility and bleeding.
In order to avoid unnecessary examinations, the clinician should be alert and suspect this disease in case of spontaneous
bilateral periorbital ecchymoses. Besides a
systematic analysis of coagulation and
fibrinolytic systems, von Willebrand factor
and platelet function, the clinical examination and consideration of hereditary or
acquired vascular defects are important in
patients with abnormal bleeding such as
the one presented here.
Conflict of interest
The authors declare no conflict of interest.
References
1. Palladini G, Merlini G. Systemic amyloidoses:
what an internist should know. Eur J Intern Med
2013; 24: 729–739.
2. Merlini G et al. Immunoglobulin light chain amyloidosis. Exp Rev Hematol 2014; 7: 143–156.
3. Matsuda M, Katoh N, Ikeda S. Clinical manifestations at diagnosis in Japanese patients with systemic AL amyloidosis: a retrospective study of 202
cases with a special attention to uncommon symptoms. Intern Med 2014; 53: 403–412.
4. Merlini G, Wechalekar AD, Palladini G. Systemic
light chain amyloidosis: an update for treating
physicians. Blood 2013; 121: 5124–5130.
5. Gillmore JD, Hawkins PN. Pathophysiology and
treatment of systemic amyloidosis. Nat Rev Nephrol 2013; 9: 574–586.
6. Passos Rda H et al. Clinical image: bilateral black
eyes (raccoon’s eyes) in AL amyloidosis. Arthritis
Rheum 2006; 54: 3724.
7. Eder L, Bitterman H. Image in clinical medicine.
Amyloid purpura. N Engl J Med 2007; 356: 2406.
8. Weingarten TN et al. Periorbital ecchymoses during general anesthesia in a patient with primary
amyloidosis: a harbinger for bleeding? Anesth
Analg 2007; 105: 1561–1563.
9. Aissi K et al. Facial signs leading to the diagnosis of
cardiac amyloidosis. Am J Med 2009; 122: e1–e2.
10. Green WH, Schosser RH. Images in clinical medicine. Dermatologic signs of multiple myeloma. N
Engl J Med 2011; 365: 71.
11. Nicholson JA, Tappin J. Raccoon eyes in systemic
AL amyloidosis. Br J Haematol 2011; 153: 543.
12. De Moura CG, Cruz CM, de Souza SP. Raccoon
sign. Arthritis Rheum 2013; 65: 692.
13. Prystajecky M, Rehman HU. Medical image. Raccoon eyes in amyloidosis. N Z Med J 2013; 126:
102–103.
14. Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation 2005; 112:
2047–2060.
15. Kastritis E et al. Treatment of light chain (AL)
amyloidosis with the combination of bortezomib
and dexamethasone. Haematologica 2007, 92:
1351–!358.
16. Jagannath S et al. Bortezomib therapy alone and in
combination with dexamethasone for previously
untreated symptomatic multiple myeloma. Br J
Haematol 2005; 129: 776–783.
17. Stewart AK, Richardson PG, San-Miguel JF. How I
treat multiple myeloma in younger patients.
Blood, 2009: 114: 5436–5443.
18. Somasundaram A, Laxton AW, Perrin RG. The
clinical features of periorbital ecchymosis in a
series of trauma patients. Injury 2014; 45:
203–205.
19. Watanabe K, Kida W. Images in clinical medicine.
Battle’s sign. N Engl J Med 2012; 367: 1135.
20. Sipe JD et al. Amyloid fibril protein nomenclature:
2012 recommendations from the Nomenclature
Committee of the International Society of Amyloidosis. Amyloid 2012; 19: 167–170.
21. Merlini G, Bellotti V. Molecular mechanisms of
amyloidosis. N Engl J Med 2003; 349: 583–596.
22. Yood RA et al. Bleeding manifestations in 100 patients with amyloidosis. JAMA 1983; 249:
1322–1324.
23. Mumford AD et al. Bleeding symptoms and coagulation abnormalities in 337 patients with ALamyloidosis. Br J Haematol 2000; 110: 454–460.
24. Eby C. Pathogenesis and management of bleeding
and thrombosis in plasma cell dyscrasias. Br J Haematol 2009; 145: 151–163.
25. Gamba G et al. Clotting alterations in primary systemic amyloidosis. Haematologica 2000; 85:
289–292.
26. Meyer K, Williams EC. Fibrinolysis and acquired
alpha-2 plasmin inhibitor deficiency in amyloidosis. Am J Med 1985; 79: 394–396.
27. Colucci G et al. Effective therapy with tranexamic
acid in a case of chronic disseminated intravascular coagulation with acquired alpha2-antiplasmin
deficiency associated with AL amyloidosis.
Thromb Haemost 2009; 102: 1285–1287.
28. Lucas FV et al. Acquired factor X deficiency in systemic amyloidosis. Cleve Clin J Med 1987; 54:
399–406.
29. Bohler A, Lämmle B. Decreased Quick percentage,
acquired factor X deficiency, hemarthrosis and ecchymosis: amyloidosis. Ther Umsch 1999; 56:
523–525.
30. Thompson CA et al. Systemic AL amyloidosis with
acquired factor X deficiency: A study of perioperative bleeding risk and treatment outcomes in 60
patients. Am J Hematol 2010; 85: 171–173.
31. Leung N, Nasr SH, Sethi S. How I treat amyloidosis: the importance of accurate diagnosis and amyloid typing. Blood 2012; 120: 3206–3213.
32. Mahmood S et al. Update on treatment of light
chain amyloidosis. Haematologica 2014; 99:
209–221.
Hämostaseologie 3/2014
© Schattauer 2014
Downloaded from www.haemostaseologie-online.com on 2017-06-17 | IP: 88.99.165.207
For personal or educational use only. No other uses without permission. All rights reserved.