Chapter 71: Amyloidosis

• Amyloidosis is a heterogeneous group of diseases characterized by tissue infiltration with misfolded protein precursors.

• The term amyloid is used to describe a substance with a homogeneous eosinophilic appearance by light microscopy, a green birefringence on polarizing light microscopy, and a characteristic β-pleated sheet appearance by x-ray diffraction.

• Terms such as primary, secondary, senile, dialysis-associated, and myeloma-associated have been abandoned in favor of the etiologically based, chemical terminology (Table 71–1) (eg, immunoglobulin light chain amyloidosis is termed AL amyloidosis).

• The incidence of AL amyloidosis is rare, with an incidence of 8 per million persons per year and a median age at diagnosis of 67 years.

• Amyloid A (AA) amyloidosis is increasingly rare, occurring in less than 1% of persons with chronic inflammatory diseases in the United States and Europe.

• AA amyloidosis is more common in Turkey and the Middle East, where it occurs in association with familial Mediterranean fever.

• AA is the only type of amyloidosis that occurs in children.

• Amyloid β₂-microglobulin (Aβ₂M) amyloidosis usually manifests as deposits in the joint synovial and occurs in patients on long-term dialysis. The incidence is declining with changes in dialysis techniques.

• The inherited amyloidoses are rare in the United States, with an estimated incidence of less than approximately 1 per 100,000 persons.

• Amyloidogenic transthyretin (ATTR) amyloidosis is the most common form of familial amyloidosis and is associated with mutations of the gene encoding transthyretin (TTR).

• The exact mechanism of fibril formation is unknown and may be different among the various types of amyloid.

• Amyloid precursor proteins typically consist of long fibrils composed of relatively small precursor proteins with molecular weights between 4000 and 25,000 daltons.

• Each amyloid fibril protein has a precursor molecule in the serum.

  — The secondary structures of many of the proteins have substantial β-pleated sheet structure. The known exceptions include serum amyloid A (SAA) and cellular prion protein (PrP^c), which contain little or no β folding in the precursor protein despite extensive β-sheet in the deposited fibrils.

• Amyloid formation involves:

  — Stimulus-generated change in the serum concentration or primary structure of amyloid precursor proteins.

  — Conversion of the precursor protein to amyloid fibrils.

• In some cases, the aberrant secondary structure seen in amyloid formation reflects a hereditary alteration in amino acid sequence that predisposes to fibril formation.

  — Examples include TTR, lysozyme, fibrinogen, cystatin c, gelsolin, amyloid-β protein precursor (AβPP), or apolipoprotein A-I (ApoA1).

• In other cases, wild-type molecules are the fibril precursor.

  — Examples include immunoglobulin light chain, β₂-microglobulin, ApoA1, and others.

• AL protein (immunoglobulin light chain):

  — AL amyloidosis is usually caused by a plasma cell neoplasm in the marrow and can occur in isolation or along with myeloma (see Chap. 68).

  — Marrow fibril deposits are composed of intact 23-kDa monoclonal immunoglobulin light chains.

  — Although both kappa (κ) and lambda (λ) light-chain subtypes have been identified in amyloid fibrils, λ subtypes predominate.

  — λ VI subtype appears to have unique structural properties that predispose it to fibril formation, often in the kidney.

• AL amyloidosis can be seen in other B lymphoproliferative disorders, including macroglobulinemia and other types of lymphoma.

• AL amyloidosis should be distinguished from nonamyloid monoclonal immunoglobulin deposition disease, in which the deposited immunoglobulin consists of both heavy and light chains, of which κ chains predominate.

• AA proteins (amyloid A proteins):

  — AA amyloidosis occurs in response to inflammation and as familial periodic and Mediterranean fever syndromes.

  — The AA amyloid fibrils are usually composed of an 8-kDa, 76-amino-acid amino-terminal portion of the 12-kDa precursor, SAA.

  — SAA is a polymorphic protein encoded by a family of active serum amyloid A (SAA) genes, which are acute phase apoproteins synthesized in the liver and transported by high-density lipoprotein (HDL3) in the plasma.

  — Years of an underlying inflammatory disease causing an elevated SAA usually precedes fibril formation.

• ATTR proteins (transthyretin):

  — These proteins occur in several familial syndromes and in senile amyloid.

  — ATTR amyloidosis also is known as familial amyloidotic polyneuropathy or cardiomyopathy.

  — Variant TTR molecules are prone to dissociation from stable tetramers and to unfolding, leading to misfolding, polymerization, and fibril formation.

  — Evidence of an age-related “trigger” is that senile cardiac amyloidosis, caused by the deposition of fibrils derived from normal wild-type TTR, is exclusively a disease of older people.

• Aβ₂M (β₂-microglobulin):

  — This occurs in chronic hemodialysis patients.

  — Carpal tunnel and joint synovial membrane involvement is common.

• AP protein (P component):

  — This is a minor protein component of amyloid deposits.

  — Intravenously injected purified P component preferentially binds to amyloid deposits.

  — This property has been exploited clinically, using radiolabeled P component, to localize and quantify the total body burden of amyloid in the so-called serum amyloid P (SAP) scan.

  — There is structural homology with C-reactive protein.

• Apo E allele (Apo E4):

  — This is strongly associated with Alzheimer disease.

• In some instances, the amyloid precursors undergo proteolysis, which may enhance the kinetics of folding into a prefibrillar structural intermediate.

• In some of the amyloidoses (eg, Aβ or AA), a normal proteolytic process may be disturbed, yielding a higher than normal concentration of a prefibrillar molecule.

• The clinical manifestations of amyloidosis vary widely and arise because of amyloid deposition and interference with normal organ function.

• Common presenting symptoms and signs are:

  — Weakness and weight loss

  — Purpura, particularly in loose facial tissue (Figure 71–1)

  — Symptoms and physical findings that reflect the extent of organ dysfunction because of amyloid involvement

AL Amyloidosis

• AL amyloidosis affects several organs.

• Kidney:

  — Nephrotic syndrome and renal insufficiency

  — In a small proportion of patients (~10%), amyloid deposition in the renal vasculature or tubulointerstitium. This causes renal dysfunction without significant proteinuria.

• Liver and spleen:

  — Organ enlargement, hepatic cholestasis, and rarely traumatic rupture of enlarged spleen.

  — Profound elevation of alkaline phosphatase with only mild elevation of transaminase. This is characteristic of hepatic amyloidosis.

• Gastrointestinal tract:

  — Macroglossia, obstruction, ulceration, hemorrhage, malabsorption, and/or diarrhea

• Heart:

  — Congestive heart failure, cardiomegaly, and/or arrhythmias

  — Low voltage R waves in the echocardiogram

  — Restrictive cardiomyopathy

• Skin:

  — Lesions ranging from papules to large nodules and purpura

• Nervous system:

  — Peripheral neuropathies, postural hypotension (autonomic neuropathy)

• Blood:

  — Characteristic coagulopathy because of depletion of factor X. Other factor deficiencies (eg, fibrinogen and factor IX) are related to liver disease.

• Soft tissues:

  — Macroglossia, carpal tunnel syndrome, skin nodules, arthropathy, alopecia, nail dystrophy, submandibular gland enlargement, periorbital purpura, and hoarseness of voice

AA Amyloidosis

• This type of amyloidosis can occur at any age.

• Primary clinical manifestation is proteinuria and/or renal insufficiency.

• Hepatosplenomegaly occurs in association with chronic inflammatory disorders.

• Cardiomyopathy rarely occurs.

• With chronic inflammatory diseases, amyloid progression is slow and survival is often more than 10 years, particularly with treatment for end-stage renal disease.

Aβ₂M Amyloidosis

• Several distinct rheumatologic conditions are observed in Aβ₂M amyloidosis, including carpal tunnel syndrome, persistent joint effusions, spondyloarthropathy, and cystic bone lesions.

• Carpal tunnel syndrome usually produces the first symptom of disease.

• Persistent joint effusions accompanied by mild discomfort occur in up to 50% of patients on dialysis for more than 12 years.

ATTR Familial Amyloidosis

• Some clinical features are similar to AL amyloidosis.

• The TTR variant, Val-122-IIe, is a common allele in the African American population and is associated with cardiomyopathy.

• A tissue biopsy demonstrating amyloid fibrils is necessary for the diagnosis of amyloidosis.

  — Amyloidosis is diagnosed by demonstration of Congo red–binding material with characteristic apple-green fluorescence under polarized light microscopy in a biopsy specimen.

  — Subcutaneous fat aspiration and marrow biopsy will identify 80% to 90% of patients later found to have amyloid elsewhere (Figure 71–2). Rectal biopsies are no longer favored.

  — Biopsy of an organ with impaired function is a high-yield procedure.

• Identification of a plasma cell neoplasm distinguishes AL amyloidosis from other types of amyloidosis, but these are a minority of cases.

  — There may be an increased percentage of plasma cells in the marrow.

  — Serum free light chain assay is the most frequent abnormality and is found in approximately 90% of patients.

  — A monoclonal serum protein by itself is not diagnostic of amyloidosis, because essential monoclonal gammopathy is common in older patients.

• Consider the diagnosis in patients with:

  — Unexplained kidney disease with nephrotic syndrome

  — Unexplained neuropathy, congestive heart failure, or malabsorption

• The cardinal finding in AL amyloidosis is a monoclonal immunoglobulin light chain.

• AA amyloidosis should be suspected in patients with renal amyloidosis and a chronic inflammatory condition or infection.

• The suggested laboratory and radiographic testing for a patient with amyloid is shown in Table 71–2.

• The hereditary renal amyloidoses (amyloidosis ApoA-I [AApoAI], ApoA-II [AApoAII], amyloidosis fibrinogen α-chain [AFib], and amyloidosis lysozyme [ALys]) can resemble AL amyloidosis with renal involvement.

• The clinical differentiation is suggested by the family history and immunohistologic staining of biopsy material with antibodies specific for candidate amyloid precursor proteins.

Amyloidoses Localized to the Central Nervous System

• AL amyloidosis deposits are rarely found in the central nervous system, although they may be found in the cerebral vessels.

• The primary central nervous system amyloidoses include amyloidosis cystatin C (ACys) and hereditary cerebral hemorrhage with amyloidosis-Icelandic type, in which the precursor is the protease inhibitor cystatin c.

Localized Light Chain Amyloidosis

• The tracheobronchial tree is the most common site of localized AL amyloidosis; it does not progress to systematic disease.

Other Localized Amyloidosis

• Atrial natriuretic factor amyloidosis (AANF) affects older persons, often with congestive heart failure.

• In calcitonin amyloid (ACal), the precursor protein is calcitonin.

• In pancreatic islet cell amyloid polypeptide amyloidosis (AIAPP), the precursor protein is a polypeptide (IAPP), also known as amylin.

• In prolactin amyloid (Apro), prolactin or its fragments are found in the pituitary amyloid.

• Three proteins (gelsolin, keratoepithelin, and lactoferrin) have been found in fibrils from patients with autosomal dominant corneal amyloidosis.

  — Medin, an integral fragment of lactadherin, which is produced in aortic smooth muscle cell, forms the amyloid seen in the aorta of all older humans.

  — Insulin has been found in fibrils at the site of insulin injection.

  — Cytokeratin has been found in amyloidosis localized to the skin.

• No specific treatment is available for amyloid disorders other than that caused by AL amyloidosis.

• Assessment of treatment response

  — Complete hematologic response is defined as absence of monoclonal protein in serum and urine by immunofixation electrophoresis, normal serum-free light-chain ratio and marrow biopsy with less than 5% plasma cells with no clonal predominance by immunohistochemistry.

• Prognosis (in AL amyloidosis)

  — Prognosis is determined by the extent of cardiac involvement using the degree of elevation of cardiac biomarkers (troponin T > 0.025 ng/mL; N-terminal pro-brain natriuretic peptide > 1800 pg/mL) and the plasma cell burden using the difference in serum free light chains (> 180 mg/L serum) as a quantitative reflection of plasma cell burden.

  — An elevation in each test is assigned 1 point. Four equal sized groups emerge: 0 points, 1 point, 2 points, and 3 points. The median survival for each group is 94, 40, 14, and 6 months, respectively.

AL Amyloidosis

• Melphalan and dexamethasone, which has supplanted melphalan and prednisone therapy, has a very low therapy-related mortality; 5-year actuarial survival may approach 50% but is highly dependent on the population treated.

  — Median responses as short as 11 to 18 months have been reported.

  — This therapy is considered the standard of care in patients who are not eligible for stem cell transplantation.

  — Clinically apparent cardiac involvement is an important adverse determinant of outcome.

• High-dose intravenous melphalan chemotherapy followed by autologous blood stem cell transplantation is presently considered the most effective treatment for patents with AL amyloidosis who do not have severe end-organ dysfunction (no more than 20% of patients will be eligible). The 10-year survival is approximately 40%.

• Melphalan, dexamethasone, and lenalidomide combination therapy has been reported for treatment of AL amyloidosis with overall response rates of about 60% and 2-year overall survival of 80%.

• Cyclophosphamide, thalidomide, and dexamethasone combination therapy has been reported to result in a 3-year estimated overall survival of about 80%.

• Bortezomib in combination with dexamethasone is effective, particularly in previously untreated patients; hematologic responses of 50% to 88% are seen.

  — This treatment has also been used as consolidation therapy following transplantation to deepen the response in patients who do not achieve a complete response.

• Supportive care to decrease symptoms and support organ function plays an important role in the management of this disease.