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Amyloidosis

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GENERAL PRINCIPLES
Amyloidosis is the term for diseases caused by the extracellular deposition of insoluble polymeric protein fibrils
in tissues and organs. These diseases are a subset of a growing group of disorders attributed to misfolding of
proteins. Among these are Alzheimer's disease and other neurodegenerative diseases, transmissible prion
diseases, and genetic diseases caused by mutations that lead to misfolding, aggregation, and protein loss of
function, such as certain of the cystic fibrosis mutations. Amyloid fibrils share a common -pleated sheet
structural conformation that confers unique staining properties. The term amyloid was coined by the
pathologist Rudolf Virchow around 1854, who thought such deposits were cellulose-like under the microscope.
Amyloid diseases are defined by the biochemical nature of the protein in the fibril deposits and are classified
according to whether they are systemic or localized, acquired or inherited, and by their clinical patterns (Table
112-1). The accepted nomenclature is AX, where A indicates amyloidosis and X represents the protein in the
fibril. AL is amyloid composed of immunoglobulin light chains (LCs), and has been called primary systemic
amyloidosis; it arises from a clonal B cell disorder and may be associated with myeloma or lymphoma. AF
groups the familial amyloidoses, most commonly due to mutations in transthyretin, the transport protein for
thyroid hormone and retinol-binding protein. AA amyloid is composed of the acute-phase reactant serum
amyloid A protein and occurs in the setting of chronic inflammatory or infectious diseases and has been termed
secondary amyloidosis. A 2M is amyloid composed of 2-microglobulin and occurs in individuals with end-stage
renal disease (ESRD) of long duration. A is the most common form of localized amyloidosis. A is deposited in
the brain in Alzheimer's disease and is derived from abnormal proteolytic processing of the amyloid precursor
protein (APP).

Table 112-1 Amyloid Fibril Proteins and Their Clinical Syndromes

Term

Precursor

Clinical Syndrome

Clinical Involvement

Systemic Amyloidoses

AL

Immunoglobulin light chain

Primary or myeloma

Any

AH

Immunoglobulin heavy
chain

Primary or myeloma associated Any

(rare)

AA

Serum amyloid A protein

Secondary; reactiveb

Renal, any

Hemodialysis-associated

Synovial membrane, bone

Familial (mutant)

Cardiac, peripheral and

autonomic nerves

A 2M

-Microglobulin

ATTR

Transthyretin

associateda

Senile systemic (wild type)

AApoAI

Apolipoprotein AI

Familial

Hepatic, renal

AApoAII Apolipoprotein AII

Familial

Renal

AGel

Gelsolin

Familial

Corneas, cranial nerves, renal

AFib

Fibrinogen A

Familial

Renal

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ALys

Lysozyme

ALECT2 Leukocyte chemotactic

factor 2

Familial

Renal

Renal

Localized Amyloidoses

Amyloid

Alzheimers disease;

Down syndrome

ACys

Cystatin C

Cerebral amyloid angiopathy

CNS, vascular

APrP

Prion protein

Spongiform encephalopathies

CNS

AIAPP

Islet amyloid polypeptide

(amylin)

Diabetes-associated

Pancreas

ACal

Calcitonin

Medullary carcinoma of the

thyroid

Thyroid

AANF

Atrial natriuretic factor

Age-related

Cardiac atria

APro

Prolactin

Endocrinopathy

Pituitary

protein

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CNS

Localized deposits can occur in skin, conjunctiva, urinary bladder, and tracheobronchial tree.

bSecondary to chronic inflammation or infection, or to a hereditary periodic fever syndrome, e.g., familial

Mediterranean fever.
Diagnosis and treatment of the amyloidoses rest upon the pathologic diagnosis of amyloid deposits and

immunohistochemical or biochemical identification of amyloid type (Fig. 112-1). In the systemic amyloidoses,
the involved organs can be biopsied, but amyloid deposits may be found in any tissue of the body. Historically,
blood vessels of the gingiva or rectal mucosa were examined, but the most easily accessible tissue, positive in
more than 80% of patients with systemic amyloidosis, is fat. After local anesthesia, needle aspiration of fat
from the abdominal wall can be expelled onto a slide and stained, avoiding even a minor surgical procedure. If
this material is negative, biopsy of kidney, heart, liver, or gastrointestinal tract can be considered. The regular
-sheet structure of amyloid deposits exhibits a unique green birefringence by polarized light microscopy when
stained with Congo red dye; the 10-nm-diameter fibrils can be seen directly by electron microscopy of
paraformaldehyde-fixed tissue. Once amyloid is found, the protein type must be determined, usually by
immunohistochemistry, immunoelectron microscopy, or by extraction and biochemical analysis by mass
spectrometry or other technique. Careful evaluation of the patient's history, physical findings, and clinical
presentation, including age and ethnic origin, organ system involvement, underlying diseases, and family
history, can provide helpful clues to the type of amyloid.

Figure 112-1

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Algorithm for the diagnosis of amyloidosis and determination of type: Clinical suspicion: unexplained
nephropathy, cardiomyopathy, neuropathy, enteropathy, arthropathy, and macroglossia. ApoAI, apolipoprotein AI;
ApoAII, apolipoprotein AII; GI, gastrointestinal.

The mechanisms of fibril formation and tissue toxicity remain controversial. Factors that contribute to
fibrillogenesis include variant or unstable protein structure, extensive -sheet conformation of the precursor
protein, proteolytic processing of the precursor protein, association with components of the serum or
extracellular matrix (e.g., amyloid P-component, apolipoprotein E, or glycosaminoglycans), and local physical
properties, including pH of the tissue. Monomeric proteins appear to go through an oligomeric aggregation step
and then form higher order polymers. Once the polymers reach a critical size, they become insoluble and
deposit in extracellular tissue sites as fibrils. These large macromolecular deposits interfere with organ function

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and, due to cellular uptake of oligomeric amyloid precursors, may be toxic to target cells.
The clinical syndromes of the amyloidoses are associated with relatively nonspecific alterations in routine
laboratory tests. Blood counts are usually normal, although the erythrocyte sedimentation rate is frequently
elevated. Patients with renal involvement will usually have proteinuria, which can be as much as 30 g/d,
producing hypoalbuminemia that can be profound. Patients with cardiac involvement will often have elevation
of brain natriuretic peptide (BNP), pro-BNP, and troponin. These can be useful for monitoring disease activity
and have been proposed as prognostic factors; they can be falsely elevated in the presence of renal
insufficiency. Patients with liver involvement, even when it is advanced, usually develop cholestasis with an
elevated alkaline phosphatase but minimal elevation of the transaminases and preservation of synthetic
function. In AL amyloidosis, endocrinopathies can occur, with laboratory testing demonstrating
hypothyroidism, hypoadrenalism, or even hypopituitarism. None of these findings are specific for amyloidosis.
Thus, a diagnosis of amyloidosis rests upon a tissue biopsy that, after Congo red staining, shows "apple -green"
birefringence on polarization microscopy.

AL AMYLOIDOSIS
Etiology and Incidence
AL amyloidosis is most frequently caused by a clonal expansion of plasma cells in the bone marrow that
secrete a monoclonal immunoglobulin LC that deposits as amyloid fibrils in tissues. It may be purely
serendipitous whether the clonal plasma cells produce a LC that misfolds and leads to AL amyloidosis, or folds
properly, allowing the cells to inexorably expand over time and develop into multiple myeloma (Chap. 111). It
is also possible that the two processes have diverse molecular etiologies. AL amyloidosis can occur with
multiple myeloma or other B lymphoproliferative diseases, including non-Hodgkin's lymphoma (Chap. 110) and
Waldenstrm's macroglobulinemia (Chap. 111). AL amyloidosis is the most common type of systemic
amyloidosis in North America. Its incidence has been estimated at 4.5 per 100,000; however, ascertainment
continues to be inadequate, and the true incidence may be much higher. AL amyloidosis, like other plasma cell
diseases, usually occurs after age 40 and is often rapidly progressive and fatal if untreated.

Pathology and Clinical Features of AL Amyloidosis

Amyloid deposits are usually widespread in AL amyloidosis and can be present in the interstitium of any organ
outside of the central nervous system. The amyloid fibril deposits are composed of intact 23-kDa monoclonal
Ig LCs or smaller fragments, 1118 kDa in size, representing the variable (V) region alone, or the V region and
a portion of the constant (C) region. Although all kappa and lambda LC subtypes have been identified in AL
amyloid fibrils, lambda subtypes predominate. The lambda 6 subtype appears to have unique structural
properties that predispose it to fibril formation, often in the kidney.
AL amyloidosis is usually a rapidly progressive disease that presents with a pleiotropic set of clinical
syndromes, recognition of which is key to initiating appropriate workup. Nonspecific symptoms of fatigue and
weight loss are common; however, the diagnosis is rarely considered until symptoms referable to a specific
organ develop. The kidneys are the most frequently affected organ, in 7070% of patients. Renal amyloidosis
is usually manifested as proteinuria, often in the nephrotic range and associated with significant
hypoalbuminemia, secondary hypercholesterolemia, and edema or anasarca. In some patients, tubular rather
than glomerular deposition of amyloid can produce azotemia without significant proteinuria. The heart is the
second most commonly affected organ, in 5050% of patients, and the leading cause of mortality. Early on,
the electrocardiogram may show low voltage in the limb leads, with a pseudo-infarct pattern. Eventually, the
echocardiogram will display concentrically thickened ventricles and diastolic dysfunction, leading to a restrictive
cardiomyopathy; systolic function is preserved until late in the disease. A "sparkly" appearance is usually not
seen using modern high-resolution echocardiography equipment. Cardiac MRI can show an increased wall
thickness and also a characteristic subendocardial enhancement with gadolinium. Nervous system symptoms
include a peripheral sensory neuropathy and/or autonomic dysfunction with gastrointestinal motility

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disturbances (early satiety, diarrhea, constipation) and orthostatic hypotension. Macroglossia, with an
enlarged, indented, or immobile tongue, is pathognomonic of AL amyloidosis but is seen only in ~10% of
patients. Liver involvement causes cholestasis and hepatomegaly. The spleen is frequently involved, and there
may be functional hyposplenism in the absence of significant splenomegaly. Many patients have "easy
bruising" due to amyloid deposits in capillaries or to deficiency of clotting factor X, which can bind to amyloid
fibrils; cutaneous ecchymoses appear, particularly around the eyes, giving the "raccoon-eye" sign. Other
findings include nail dystrophy, alopecia, and amyloid arthropathy with thickening of synovial membranes in
wrists and shoulders (Fig. 112-2). The presence of a multisystem illness or general fatigue along with any of
these clinical syndromes should prompt a workup for amyloidosis.

Figure 112-2

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Clinical signs of AL amyloidosis.A. Macroglossia. B. Periorbital ecchymoses. C. Fingernail dystrophy.

Diagnosis
Identification of the underlying B lymphoproliferative process and clonal LC is key to the diagnosis of AL
amyloidosis. The serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) are NOT useful
screening tests if AL amyloidosis is suspected because the clonal LC or whole immunoglobulin, unlike in
multiple myeloma, is often not present in sufficient quantity in the serum to produce a monoclonal "M -spike" or
in the urine to cause LC (Bence Jones) proteinuria. However, more than 90% of patients have a serum or urine
monoclonal LC or whole immunoglobulin that can be detected by immunofixation electrophoresis of serum
(SIFE) or urine (UIFE) (Fig. 112-3A). Assaying for free immunoglobulin LCs circulating in the serum unbound
to heavy chains using commercially available nephelometric (FreeLite) assay demonstrates an elevation and

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abnormal free kappa:lambda ratio in more than 75% of patients. Examining the ratio as well as the absolute
amount is essential, because in renal insufficiency LC clearance is reduced, and both types of LCs will be
elevated. In addition, an increased percentage of plasma cells in the bone marrow, typically 55% of nucleated
cells, is noted in about 90% of patients. Kappa or lambda clonality can be demonstrated by flow cytometry,
immunohistochemical staining, or by in situ hybridization for LC mRNA (Fig. 112-3B).

Figure 112-3

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Laboratory features of AL amyloidosis. A. Serum immunofixation electrophoresis reveals an IgG monoclonal

protein in this example; the serum protein electrophoresis is often normal. B. Bone marrow biopsy sections from
another patient, stained with antibody to CD138 (syndecan, highly expressed on plasma cells) by
immunohistochemistry (left panel). The middle and right panels are stained using in situ hybridization with fluoresceintagged probes (Ventana Medical Systems) binding to and mRNA respectively in plasma cells. (Photomicrograph
courtesy of C. O'Hara; with permission.)

A monoclonal serum protein by itself is not diagnostic of amyloidosis, since monoclonal gammopathy of
uncertain significance (MGUS) is common in older patients (Chap. 111). However, when MGUS is present in
patients with biopsy-proven amyloidosis, the AL type should be strongly suspected. Similarly, patients thought
to have "smoldering myeloma" because of modest elevation of bone marrow plasma cells should be screened
for AL amyloidosis if they have evidence of organ dysfunction. Accurate typing is essential for appropriate
treatment. Immunohistochemical staining of the amyloid deposits is useful if they bind one light chain antibody
in preference to the other; some AL deposits bind many antisera nonspecifically. Immunoelectron microscopy
is more reliable and mass-spectrometry-based microsequencing of small amounts of protein extracted from
fibril deposits can also be done. In ambiguous cases, other forms of amyloidosis should be thoroughly excluded
with appropriate genetic and other testing.

Treatment: AL Amyloidosis
Extensive multisystem involvement typifies AL amyloidosis, and median survival with no treatment is usually
only about 12 years from the time of diagnosis. Current therapies target the clonal bone marrow plasma cells
using approaches employed for multiple myeloma. Treatment with cyclic oral melphalan and prednisone can
decrease the plasma cell burden but produces complete hematologicremission in only a few percent of patients
and minimal organ responses and improvement in survival (median 2 years), and it is no longer widely used.
The substitution of dexamethasone for prednisone produces a higher response rate and more durable

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remissions, although dexamethasone is not always well tolerated by patients with significant edema or cardiac
disease. High-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT)
produces complete hematologic responses in about 40% of treated patients, as measured by complete loss
(CR) of clonal plasma cells in the bone marrow and disappearance of the monoclonal LC by IFE and assay for
free LCs. Hematologic responses can be followed in the subsequent 612 months by improvement in organ
function and quality of life. The CRs after HDM/SCT appear to be more durable than those seen in multiple
myeloma, with remissions continuing in some patients beyond 15 years without additional treatment.
Unfortunately, only about half of AL amyloidosis patients are eligible for such aggressive treatment, and even
at specialized treatment centers, peritransplant mortality is higher than for other hematologic diseases
because of impaired organ function. Amyloid cardiomyopathy, poor nutritional status, impaired performance
status, and multiple-organ disease contribute to excess morbidity and mortality. The bleeding diathesis due to
adsorption of clotting factor X to amyloid fibrils also confers high mortality during myelosuppressive therapy;
however, this syndrome occurs in only a few percent of patients. The single randomized multicenter trial
comparing oral melphalan and dexamethasone to HDM/SCT to date failed to show a benefit to dose-intensive
treatment, although the transplant-related mortality in this study was very high.
For patients with impaired cardiac function or arrhythmias due to amyloid involvement of the myocardium,
median survival is only about 6 months without treatment, and stem cell mobilization and high-dose
chemotherapy are dangerous. In these patients, cardiac transplantation can be performed, followed by
treatment with HDM/SCT to prevent amyloid deposition in the transplanted heart or other organs.
Recently, novel agents have been investigated for treatment of plasma cell diseases. The immunomodulators
thalidomide and lenalidomide have activity; lenalidomide is well tolerated in doses lower than those used for
myeloma and, in combination with dexamethasone, produces complete hematologic remissions and
improvement in organ function. The proteasome inhibitorbortezomib has also been found to be effective in
single- and multicenter trials. Combination therapy trials are now under development, and studies are
examining the as yet unproven role of induction and maintenance treatment. Clinical trials are essential for
improving therapy for this rare disease.
Supportive care is important for patients with any type of amyloidosis. For nephrotic syndrome, diuretics and
supportive stockings can ameliorate edema; angiotensin-converting enzyme inhibitors should be used with
caution and have not been shown to slow renal disease progression. Congestive heart failure due to amyloid
cardiomyopathy is also best treated with diuretics; it is important to note that digitalis, calcium channel
blockers, and beta blockers are relatively contraindicated as they can interact with amyloid fibrils and produce
heart block and worsening heart failure. Amiodarone has been used for atrial and ventricular arrhythmias.
Automatic implantable defibrillators have reduced effectiveness due to the thickened myocardium, but they can
benefit some patients. Atrial ablation is an effective approach for atrial fibrillation. For conduction
abnormalities, ventricular pacing may be indicated. Atrial contractile dysfunction is common in amyloid
cardiomyopathy and is an indication for anticoagulation even in the absence of atrial fibrillation. Autonomic
neuropathy can be treated with agonists such as midodrine to support the blood pressure; gastrointestinal
dysfunction may respond to motility or bulk agents. Nutritional supplementation, either orally or parenterally,
is also important.
In localized AL, amyloid deposits can be produced by clonal plasma cells infiltrating local sites in the airways,
bladder, skin, or lymph nodes (Table 112-1). Deposits may respond to surgical intervention or radiation
therapy; systemic treatment is generally not appropriate. Patients should be referred to a center familiar with
management of these rare manifestations of amyloidosis.

AA AMYLOIDOSIS
Etiology and Incidence
AA amyloidosis can occur in association with almost any chronic inflammatory state [e.g., rheumatoid arthritis,
inflammatory bowel disease, familial Mediterranean fever (Chap. 330) or other periodic fever syndromes] or

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chronic infections such as tuberculosis or subacute bacterial endocarditis. In the United States and Europe, AA
amyloidosis has become less common, occurring in <2% of patients with these diseases, presumably because
of advances in anti-inflammatory and antimicrobial therapies. It has also been described in association with
Castleman's disease, and patients with AA amyloidosis should have CT scanning to look for such tumors, as
well as serologic and microbiologic studies. AA amyloidosis can also be seen without any identifiable underlying
disease. AA is the only type of systemic amyloidosis that occurs in children.

Pathology and Clinical Features

Deposits are more limited in AA amyloidosis than in AL amyloidosis; they usually begin in the kidneys.
Hepatomegaly, splenomegaly, and autonomic neuropathy can also occur as the disease progresses;
cardiomyopathy occurs albeit rarely. However, the symptoms and signs cannot be reliably distinguished from
those of AL amyloidosis. AA amyloid fibrils are usually composed of an 8-kDa, 76-amino-acid N-terminal
portion of a 12-kDa precursor protein, serum amyloid A (SAA). SAA is an acute-phase apoprotein synthesized
in the liver and transported by high-density lipoprotein, HDL3, in the plasma. Several years of an underlying
inflammatory disease causing chronic elevation of SAA usually precedes fibril formation, although infections
can lead to AA deposition more rapidly.

Treatment: AA Amyloidosis
The primary therapy in AA amyloidosis is treatment of the underlying inflammatory or infectious disease.
Treatment that suppresses or eliminates the inflammation or infection also decreases the SAA protein
concentration. For familial Mediterranean fever, colchicine in a dose of 1.21.8 mg/d is the appropriate
treatment. Colchicine has not been helpful for AA amyloidosis of other causes or for other amyloidoses. TNF
and IL-1 antagonists can also be effective in syndromes related to cytokine elevation. For this disease, there is
also a fibril-specific agent. Eprodisate was designed to interfere with the interaction of AA amyloid protein with
glycosaminoglycans in tissues and prevent or disrupt fibril formation. This drug is well tolerated and delays
progression of AA renal disease, regardless of the underlying inflammatory process. Eprodisate is awaiting FDA
approval.

AF AMYLOIDOSIS
The familial amyloidoses are autosomal dominant diseases in which a variant plasma protein forms amyloid
deposits, beginning in midlife. These diseases are rare, with an estimated incidence of <1 per 100,000 in the
United States, although there are isolated areas of Portugal, Sweden, and Japan where founder effects have
led to a much higher incidence of the disease. The most common form of AF is caused by mutation of the
abundant plasma protein transthyretin (TTR, also known as prealbumin). More than 100 TTR mutations are
known, and most are associated with ATTR amyloidosis. One variant, V122I, has a carrier frequency that may
be as high as 4% in the African-American population and is associated with late-onset cardiac amyloidosis. The
actual incidence and penetrance of disease in the African-American population is the subject of ongoing
research, but it would be wise to consider this in the differential diagnosis of African-American patients who
present with concentric cardiac hypertrophy and evidence of diastolic dysfunction, particularly in the absence
of a history of hypertension. Even wild-type TTR can form fibrils, leading to so-called senile systemic
amyloidosis (SSA) in older patients. It can be found in up to 25% of autopsies in patients older than age 80
years, and it can produce a clinical syndrome of amyloid cardiomyopathy that is similar to that occurring in
younger patients carrying a mutant TTR. Other familial amyloidoses, caused by variant apolipoproteins AI or
AII, gelsolin, fibrinogen A , or lysozyme, are reported in only a few families worldwide. New amyloidogenic
serum proteins continue to be identified periodically, including recently the leukocyte chemotactic factor
LECT2.
In ATTR and in other forms of familial amyloidosis, the variant structure of the precursor protein is the key
factor in fibril formation. The role of aging is intriguing, since patients born with the variant proteins do not
have clinically apparent disease until middle age, despite the lifelong presence of the abnormal protein. Further
evidence of an age-related "trigger" is the occurrence of SSA in the elderly, caused by the deposition of fibrils

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derived from normal TTR.

Clinical Features and Diagnosis

AF amyloidosis has a variable presentation but is usually consistent within affected kindreds with the same
mutant protein. A family history makes AF more likely, but many patients present sporadically with new
mutations. ATTR usually presents as a syndrome of familial amyloidotic polyneuropathy or familial amyloidotic
cardiomyopathy. Peripheral neuropathy usually begins as a lower-extremity sensory and motor neuropathy
and progresses to the upper extremities. Autonomic neuropathy is manifest by gastrointestinal symptoms of
diarrhea with weight loss and orthostatic hypotension. Patients with TTR V30M, the most common mutation,
have normal echocardiograms but may have conduction defects and require a pacemaker. Patients with TTR
T60A and several other mutations have myocardial thickening similar to that caused by AL amyloidosis,
although heart failure is less common and the prognosis is better. Vitreous opacities caused by amyloid
deposits are pathognomonic of ATTR amyloidosis.
Typical syndromes associated with other forms of AF included renal amyloidosis with mutant fibrinogen,
lysozyme, or apolipoproteins, or hepatic amyloidosis with apolipoprotein AI, and amyloidosis of cranial nerves
and cornea with gelsolin.
Patients with AF amyloidosis can present with clinical syndromes that mimic those of patients with AL, and AF
carriers can develop AL, or conversely, AF patients can develop a MGUS. Thus, it is important to screen for
both plasma cell disorders and for mutations in some patients with amyloidosis. Variant TTR proteins can
usually be detected by isoelectric focusing, but DNA sequencing is now standard for diagnosis of ATTR and the
other AF mutations.

Treatment: ATTR Amyloidosis

Without intervention, survival after ATTR disease onset is 515 years. Orthotopic liver transplantation removes
the major source of variant TTR production and replaces it with a source of normal TTR; it also arrests disease
progression and leads to improvement in autonomic and peripheral neuropathy in some patients.
Cardiomyopathy often does not improve, and in some patients it can worsen after liver transplantation,
perhaps due to deposition of wild-type TTR as seen in SSA. Compounds have been identified that stabilize TTR
in a nonpathogenic tetrameric conformation in vitro and are undergoing clinical testing in multicenter trials.

A 2M AMYLOIDOSIS
A 2M amyloidosis is composed of 2-microglobulin, the invariant chain of class I human leukocyte antigens,
and produces rheumatologic manifestations in patients on long-term hemodialysis. 2-Microglobulin is excreted
by the kidney, and levels become elevated in ESRD. The molecular mass of

2M is 11.8 kDa, above the cutoff

of some dialysis membranes. The incidence of this disease appears to be declining with newer high-flow
dialysis techniques.
A 2M amyloidosis usually presents with carpal tunnel syndrome, persistent joint effusions,
spondyloarthropathy, or cystic bone lesions. Carpal tunnel syndrome is often the first symptom of disease. In
the past, persistent joint effusions accompanied by mild discomfort were seen in up to 50% of patients on
dialysis for more than 12 years. Involvement is bilateral, and large joints (shoulders, knees, wrists, and hips)
are more frequently affected. The synovial fluid is noninflammatory, and
sediment is stained with Congo red. Although less common, visceral

M amyloid can be found if the

2M amyloid deposits do occasionally

occur in the gastrointestinal tract, heart, tendons, and subcutaneous tissues of the buttocks. There is no
specific therapy for A 2M amyloidosis, but cessation of dialysis after renal allografting may lead to
symptomatic improvement.

SUMMARY

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A diagnosis of amyloidosis should be considered in patients with unexplained nephropathy, cardiomyopathy

(particularly with diastolic dysfunction), neuropathy (either peripheral or autonomic), enteropathy, or the
pathognomonic soft tissue findings of macroglossia or periorbital ecchymoses. Pathologic identification of
amyloid fibrils can be made using Congo red staining of aspirated abdominal fat or of an involved organ biopsy
specimen. Accurate typing using a combination of immunologic, biochemical, and genetic testing is essential to
choosing the appropriate therapy (see algorithm for workup, Fig. 112-1). Tertiary referral centers can provide
specialized diagnostic techniques and access to clinical trials for patients with these rare diseases.

FURTHER READINGS
Benson MD et al: Leukocyte chemotactic factor 2: A novel renal amyloid protein. Kidney Int 74:218, 2008
[PMID: 18449172]
Connors L et al: Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of
transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J 158:607, 2009
Dember L et al: Eprodisate for the treatment of renal disease in AA amyloidosis. N Engl J Med 356:2349, 2007
Dey BR et al: Cardiac transplantation followed by dose-intensive melphalan and autologous stem-cell
transplantation for light chain amyloidosis and heart failure. Transplantation 90:905, 2010[PMID: 20733534]
Merlini G, Bellotti V: Molecular mechanisms of amyloidosis. N Engl J Med 349:583, 2003
Sanchorawala V et al: Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan
and stem-cell transplantation. Blood 110:3561, 2007
Skinner M et al: High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis:
An 8-year study. Ann Intern Med 140:85, 2004[PMID: 14734330]

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