Amyloidosis 66.
e3
BASIC INFORMATION
DEFINITION
The term amyloidosis refers to a heterogeneous
group of disorders that are all characterized by
the deposition of an amorphous, extracellular
fibrillar protein in various organs and tissues of
the body. It has the following subtypes:
Primary amyloidosis (AL)
Secondary amyloidosis (AA)
Hereditary amyloidosis
Localized amyloidosis
ICD-10CM CODES
E85.9Amyloidosis, unspecified
E85.0Non-neuropathic heredofamilial
amyloidosis
E85.1Neuropathic heredofamilial amyloidosis
E85.2Heredofamilial amyloidosis, unspecified
E85.3Secondary systemic amyloidosis
E85.4Organ-limited amyloidosis
E85.8Other amyloidosis
EPIDEMIOLOGY &
DEMOGRAPHICS
INCIDENCE (IN U.S.): Between 1500 and 3500
new cases are diagnosed annually. The most
common type is AL.
PREVALENCE: Amyloidosis primarily affects
men between the ages of 60 and 70 yr.
PHYSICAL FINDINGS & CLINICAL
PRESENTATION
The most common presenting symptoms of
amyloidosis are fatigue, dyspnea, edema,
paresthesias, and weight loss. Other findings
depend on organ system involvement.
Signs and symptoms of nephrotic syndrome
may be present with renal involvement.
Fatigue and dyspnea may occur with pulmo-
nary involvement.
GI involvement is uncommon but presents
with diarrhea, nausea, abdominal pain, and
macroglossia (Fig. E1A-55).
Patients with cardiac involvement have an
infiltrative cardiomyopathy and present with
FIGURE E1A-55 Macroglossia in a patient with primary amy-
loidosis, demonstrating peripheral ridging caused by teeth
indentation. (From Hochberg MC et al: Rheumatology, ed 5, St Louis,
2011, Mosby.)
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a preserved ejection fraction (EF) and dia-
stolic dysfunction.
Patients may present with bleeding problems
caused by either factor X deficiency or fragile
blood vessels caused by infiltration by amy-
loid. Bleeding around the eyes (raccoon eyes)
is a characteristic finding.
Involvement of the nervous system presents
with peripheral neuropathy, tendinopathy (Fig.
E1A-56), muscle weakness, numbness, synco-
pe, or dizziness. Associated autonomic neuropa-
thy can also cause severe disabling symptoms.
ETIOLOGY
The deposition of an amorphous, extracellular
fibrillar protein in various tissues that stains
with Congo red is the common underlying
mechanism, but there are important differences
among various subtypes:
AL is associated with an underlying clonal
plasma cell disorder making an abnormal
light chain protein with possible deposition in
multiple organ systems.
AA has no underlying plasma cell disor-
der and is a consequence of longstanding
systemic inflammation (e.g., tuberculosis,
leprosy, malaria, untreated syphilis).
Localized amyloidosis results from localized
synthesis of fibrillar material with no underly-
ing plasma cell disorder.
Familial amyloidosis is another subtype, with
the most common form resulting from muta-
tion of transthyretin gene (TTR). Transthyretin
amyloidosis is caused by the deposition of
hepatocyte-derived transthyretin amyloid in
peripheral nerves and the heart.
A classification of amyloidosis is described in
Table E1A-27.
DIAGNOSIS
DIFFERENTIAL DIAGNOSIS
Differential diagnosis varies depending on the
organ involvement:
Renal involvement (toxin- or drug-induced
necrosis, glomerulonephritis, renal vein
thrombosis)
FIGURE E1A-56 Hand involvement in A2M amyloidosis. Hand of a long-
term hemodialysis patient showing maximal extension. Note the prominence of
shrunken flexor tendons (arrows). This is also known as the guitar string sign.
(From Floege J etal: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010,
Saunders.)
Interstitial lung disease (sarcoidosis, con-
nective tissue disease, infectious causative
factors)
Restrictive cardiomyopathy (endomyocardial
fibrosis, viral myocarditis)
Carpal tunnel (rheumatoid arthritis, hypothy-
roidism, overuse)
Peripheral neuropathy (alcohol abuse, vita-
min deficiencies, diabetes mellitus)
WORKUP
Workup consists of performing blood and urine
tests to look for abnormal light chain in urine or
blood, performing various tests to look for tar-
get organ damage, and getting histologic con-
firmation by doing a fat pad and bone marrow
biopsy and then performing Congo red staining
on that. Fig. E1A-57 describes an algorithm for
diagnosis of amyloidosis and determination of
type.
LABORATORY TESTS
Immunofixation of serum and urine (SPEP,
UPEP) to look for immunoglobulin light chain
is a sensitive screening test.
CBC, blood urea nitrogen (BUN)/creatinine,
liver function tests, thyroid functions, and
urine for albumin.
Histologic confirmation is necessary with a
fat pad and bone marrow biopsy with Congo
red staining to establish a diagnosis.
If a noninvasive fat pad biopsy does not
establish a diagnosis, then a biopsy of the
affected organ may be needed.
IMAGING STUDIES
Two-dimensional Doppler echocardiography
to study diagnostic filling is useful to evaluate
for cardiac involvement.
Nuclear imaging with technetium-labeled
aprotinin may detect cardiac amyloidosis.
Labeled diphosphonates play an important
role in the typing of amyloidosis and in diag-
nosing heart involvement in patients with
transthyretin cardiac amyloidosis. Cardiac
involvement in transthyretin patients may be
diagnosed earlier with bone scintigraphy in
Amyloidosis 66.e4

transthyretin patients compared with echo-
cardiography. Serum amyloid P component
(SAP) scintigraphy has high sensitivity for the
detection of amyloid deposits in liver, spleen,
kidneys, adrenal glands, and bones.
TREATMENT
ACUTE GENERAL Rx
The goal of therapy is to decrease the pro-
duction of the amyloidogenic light chain with
therapy directed at the clonal plasma cells.
All agents used to treat multiple myeloma
are effective against AL, including melphalan,
prednisone, oral dexamethasone, systemic
chemotherapy such as cyclophosphamide,
doxorubicin (Adriamycin), and more recently
immunomodulatory compounds (IMiDs) such
as thalidomide or lenalidomide, or proteo-
some inhibitors, but none has shown to be
superior to melphalan and prednisone, which
remain the treatment of choice. Table E1A-
28 summarizes major treatment options for
amyloidosis.
Antitumor necrosis factor drugs may be
useful to treat kidney amyloid A amyloidosis
but may increase the risk and severity of
infection.
Diflusinal, an NSAID, stabilizes transthyre-
tin tetramers and prevents amyloid forma-
tion in vitro. Recent trials have shown that
diflusinal reduces the rate of progression of
neurologic impairment and preserves quality
of life.1
Recent phase 1 trials have shown that treat-
ment with CPHPC followed by anti-SAP anti-
body safely triggered clearance of amyloid
deposits from the liver and some other
tissues.2
The use of high-dose chemotherapy and
stem cell transplantation (SCT) for patients
with amyloidosis remains controversial
because of high treatment-related mortality.
In highly selected patients with preserved
organ function, autologous bone marrow
transplant can have good results.
Patients who develop renal failure can be
supported with hemodialysis or renal trans-
plant.
Liver transplantation has been used success-
fully in patients with familial amyloidosis.
Recognition and treatment of the underlying
disorder is needed for secondary amyloidosis.
Table E1A-29 summarizes supportive treat-
ment options for all types of amyloidosis.
1Berk JL etal: Repurposing diflusinal for familial amy-
loid polyneuropathy. A randomized clinical trial, JAMA
310(24): 262-267, 2013.
2Richards BD etal: Therapeutic clearance of amyloid
by antibodies to serum amyloid P component. N Engl
J Med 373:1106-1114, 2015
DISPOSITION
Prognosis is determined primarily by the pres-
ence or absence of cardiac involvement and the
form of amyloidosis:
In patients with endomyocardial biopsydoc-
umented cardiac amyloidosis, longer-term
survival is more strongly associated with
New York Heart Association functional class
compared with ECG or echocardiography
variables.
In AA, eradication of the predisposing disease
slows and can occasionally reverse the pro-
gression of amyloid disease. Median survival
after diagnosis is 133 mo.
Patients with familial amyloidotic polyneu-
ropathy generally have a prolonged course
lasting 10-15 yr.
The progression of amyloidosis associated
with renal hemodialysis can be improved
with newer dialysis membranes that can
pass beta-2-microglobulin.
Median survival in patients with overt CHF is
6 mo; it is 30 mo without CHF.
SUGGESTED READINGS
Available at www.expertconsult.com
AUTHORS: BILAL H. NAQVI, M.D., and
FRED F. FERRI, M.D.

TABLE E1A-27 Classification of Amyloidosis*

Type Fibril Precursor Protein Clinical Syndrome
Primary Serum amyloid A protein Systemic amyloidosis usually with predominant renal involvement associated with acquired or heredi-
amyloidosis (AA) tary chronic inflammatory diseases. Formerly known as secondary or reactive amyloidosis.
Secondary Monoclonal immunoglobulin light Systemic amyloidosis potentially involving many organ systems associated with myeloma, monoclonal
amyloidosis (AL) chains gammopathy, and occult B-cell dyscrasias. Formerly known as primary amyloidosis.
ATTR Normal plasma transthyretin Senile systemic amyloidosis with predominant cardiac involvement (senile cardiac amyloidosis).
ATTR Genetic variants of transthyretin Familial amyloid polyneuropathy (FAP), often with prominent amyloid cardiomyopathy. Predominant car-
(e.g., ATTR Met30, Ala60, Ile122) diac involvement without neuropathy with certain mutations (e.g., TTR Ile122).
Ab2M 2-Microglobulin Dialysis-related amyloidosis (DRA) associated with renal failure and long-term dialysis. Predominant
articular and periarticular involvement.
Ab -Protein precursor (and rare Cerebrovascular and intracerebral plaque amyloid in Alzheimers disease. Occasionally familial.
genetic variants)
AApoAI Genetic variants of apolipoprotein Autosomal-dominant systemic amyloidosis. Predominantly non-neuropathic with prominent visceral
AApoAII AI (e.g., AApoAI Arg26, Arg60) involvement, especially nephropathy. Minor wild-type ApoAI amyloid deposits may occur in the aorta
Genetic variants of apolipopro- in aging individuals.
tein AII Autosomal-dominant systemic amyloidosis with predominant renal involvement.
AFib Genetic variants of fibrinogen A Autosomal-dominant systemic amyloidosis. Non-neuropathic with predominant nephropathy.
-chain (e.g., AFib Val526)
ALys Genetic variants of lysozyme Autosomal-dominant systemic amyloidosis. Non-neuropathic with predominant renal and gastrointesti-
(e.g., ALys His67) nal involvement. Rarely presents with hepatic rupture.
ACys Genetic variant of cystatin C Hereditary cerebral hemorrhage with cerebral and systemic amyloidosis in Icelandic subjects.
(ACys Gln68)
AGel Genetic variants of gelsolin Autosomal-dominant systemic amyloidosis. Predominant cranial nerve involvement plus lattice corneal
(e.g., AGel Asn187) dystrophy. Described and most common in Finland.

ATTR, Transthyretin.
*Not exhaustive, and amyloid composed of peptide hormones, prion protein, and unknown proteins not included.
Modified from Hochberg MC etal: Rheumatology, ed 5, St Louis, 2011, Mosby.

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Amyloidosis 66.e5

Tissue biopsy TABLE E1A-28 Major Treatment Options for

(e.g., abdominal fat aspirate) Amyloidosis

AL Amyloidosis
Intravenous melphalan with autologous stem cell rescue
Granulocyte colony-stimulating factormobilized peripheral
Positive Negative blood stem cell collection
Intravenous melphalan 140-200 mg/m2
Autologous stem cell reinfusion
Cyclic oral melphalan and dexamethasone
More invasive biopsy of Melphalan 0.22 mg/kg/day 4 days
heart, kidney, liver, etc. Dexamethasone 20-40 mg/day 4 days, or weekly
Repeat administration every 4 weeks
Immunomodulators
Lenalidomide 5-15 mg/day 21 days
Positive Negative
Dexamethasone 20-40 mg/day weekly
Repeat administration every 4 weeks
Determine
type Proteasome inhibitors
No further Intravenous bortezomib, 0.7-1.6 mg/m2 1-2 times per week
workup Repeat every 3-5 weeks
Look for: AA Amyloidosis
AL (primary) Aggressive treatment of underlying inflammatory disease
Monoclonal protein in serum or urine Medical or surgical treatment of underlying infection
Multisystem involvement Colchicine 1.2-1.8 mg/day for AA amyloidosis secondary to fa-
Macroglossia milial Mediterranean fever
AA (secondary) Antifibril drug, eprosidate (investigational)
Underlying chronic inflammation
Renal involvement ATTR Amyloidosis
Familial Orthotopic liver transplantation
ATTR Mutant transthyretin protein Transthyretin stabilizers: tafamadis, diflunisal (investigational)
Family history
Polyneuropathy, cardiomyopathy From Firestein GS, Budd RC, Gabriel SE, etal: Kellys textbook of rheumatology, ed
Vitreous opacities 9, Philadelphia, 2013, Saunders.

AApoA-I Mutant apolipoprotein A-I

Renal disease
Mutant fibrinogen
AFib
Renal disease
Mutant gelsolin
AGel
Cranial neuropathy
Mutant lysozome, renal,
ALys
gastrointestinal disease

FIGURE E1A-57 Algorithm for the diagnosis of amyloidosis and determi-

nation of type. (From Firestein GS, Budd RC, Gabriel SE, et al: Kellys textbook of
rheumatology, ed 9, Philadelphia, 2013, Saunders.)

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Amyloidosis 66.e6

TABLE E1A-29 Supportive Treatment for All Types of Amyloidosis

Organ System Symptom Treatment Options
Cardiac Congestive failure Salt restriction of 1-2 g/day
Diuretics: furosemide, spironolactone, metolazone
Arrhythmia Pacemaker
Automatic implantable cardiac defibrillator
Antiarrhythmics
Renal Nephrotic syndrome Salt restriction of 1-2 g/day
Elastic stockings, leg elevation
Maintaining dietary protein
Angiotensin-converting enzyme inhibitor, if blood pressure tolerates
Renal failure Dialysis (long-term ambulatory peritoneal dialysis or hemodialysis)
Autonomic nervous Orthostatic hypotension Midodrine
Increased dietary salt or added fludrocortisone, depending on edema
Elastic stockings
Gastric atony or ileus Small frequent feedings (6/day) low in fat
Oral nutritional supplements
Jejunostomy tube feeding
Parenteral nutrition
Gastrointestinal Diarrhea Low-fat diet (40 g)
Psyllium hydrophilic mucilloid (Metamucil)
Loperamide hydrochloride (Imodium)
Tincture of opium
Parenteral nutrition
Macroglossia Soft solid diet
Partial glossectomy (rarely effective)
Peripheral nervous Sensory neuropathy Avoiding trauma
Gabapentin (Neurontin) 100-300 mg 3 times daily
Amitriptyline 25-50 mg at bedtime
Pregabalin (Lyrica) 50-100 mg 3 times daily
Motor neuropathy Ankle-foot orthotics for footdrop
Physical therapy
Hematologic Intracutaneous bleeding Avoiding trauma, antiplatelet agents
Factor X deficiency Factor replacement (recombinant factor VIIa, prothrombin complex
concentrates)
Splenectomy for splenomegaly

SUGGESTED READINGS
Austin BA, et al.: Comparison of functional status, ECG and echocardiography
parameters to mortality in endomyocardial-biopsy proven cardiac amyloidosis,
Am J Cardiol 103:14291433, 2009.
Coelho T, etal.: Safety and efficacy of RNA: therapy for transthyretin amyloidosis,
N Engl J Med 369:819829, 2013.
Fernandes-Nebro A, etal.: Long-term TNF-alpha blockade in patients with amy-
loid A amyloidosis complicating rheumatic diseases, Am J Med 123:454461,
2010.
Kumar SK, et al.: Recent improvements in survival in primary systemic amy-
loidosis and the importance of an early mortality risk score, Mayo Clin Proc
86(1):1218, 2011.
Kyle RA, etal.: A trial of three regimens for primary amyloidosis: colchicine alone,
melphalan and prednisone, and melphalan, prednisone, and colchicine, N Engl
J Med 336(17):12021207, 1997.
Maurer MS: Non-invasive identification of ATTRwt cardiac amyloid: the re-emer-
gence of nuclear cardiology. Am J Med 128:12751280, 2015.
Sideras K, etal.: Amyloidosis, Adv Clin Chem 47:144, 2009.
Wang AK, et al.: Patterns of neuropathy and autonomic failure in patients with
amyloidosis, Mayo Clin Proc 83(11):12261230, 2008.

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