Amyloidosis

AL is caused by overproduction of an amyloidogenic immunoglobulin light chain in patients with a monoclonal plasma cell or other B cell lymphoproliferative disorder. Light chains can also form nonfibrillar tissue deposits (ie, light chain deposition disease). Rarely, immunoglobulin heavy chains form amyloid fibrils (called AH amyloidosis).

Common sites for amyloid deposition include the skin, nerves, heart, gastrointestinal tract (including the tongue), kidneys, liver, spleen, and blood vessels. Usually, a low-grade plasmacytosis is present in the bone marrow, which is similar to that in multiple myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones that cause... read more , although most patients do not have true multiple myeloma (with lytic bone lesions, hypercalcemia, renal tubular casts, and anemia). However, about 10 to 20% of patients with multiple myeloma develop AL amyloidosis.

AF is caused by inheritance of a gene encoding a mutated aggregation-prone serum protein, usually a protein abundantly produced by the liver.

Serum proteins that can cause AF include transthyretin (TTR), apolipoprotein A-I, apolipoprotein A-II, lysozyme, fibrinogen, gelsolin, and cystatin C. A form that is speculated to be familial is caused by the serum protein leukocyte chemotactic factor 2 (LECT2); however, a specific inherited gene mutation for this latter type has not been clearly demonstrated.

Amyloidosis caused by TTR (ATTR) is the most common type of AF. More than 130 mutations of the TTR gene have been associated with amyloidosis. The most prevalent mutation, V30M, is common in Portugal, Sweden, Brazil, and Japan, and a V122I mutation is present in about 4% of American and Caribbean Black people. Disease penetrance and age of onset are highly variable but are consistent within families and ethnic groups (1 Etiology references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

ATTR causes peripheral sensorimotor neuropathy and autonomic neuropathy Autonomic Neuropathies Autonomic neuropathies are peripheral nerve disorders with disproportionate involvement of autonomic fibers. (See also Overview of the Autonomic Nervous System.) The best known autonomic neuropathies... read more , chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more , and cardiomyopathy Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more . Carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome is compression of the median nerve as it passes through the carpal tunnel in the wrist. Symptoms include pain and paresthesias in the median nerve distribution. Diagnosis... read more commonly precedes other neurologic disease manifestations. Vitreous deposits may develop due to production of mutant TTR by the retinal epithelium, or leptomeningeal deposits may develop as the choroid plexus produces mutant TTR. When cardiomyopathy is the predominant manifestation of TTR deposition in the heart, it is referred to as transthyretin amyloid cardiomyopathy (ATTR-CM).

ATTRwt is caused by aggregation and deposition of wild-type TTR, principally targeting the heart.

ATTRwt is increasingly recognized as a cause of infiltrative cardiomyopathy Restrictive Cardiomyopathy Restrictive cardiomyopathy is characterized by noncompliant ventricular walls that resist diastolic filling; one (most commonly the left) or both ventricles may be affected. Symptoms include... read more in older men. Approximately 16% of patients with aortic stenosis Aortic Stenosis Aortic stenosis (AS) is narrowing of the aortic valve, obstructing blood flow from the left ventricle to the ascending aorta during systole. Causes include a congenital bicuspid valve, idiopathic... read more undergoing transcatheter aortic valve replacement (2 Etiology references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ) and 13% of those hospitalized for heart failure with preserved ejection fraction (HFpEF) Heart failure with preserved ejection fraction (HFpEF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more also have transthyretin amyloid cardiomyopathy, in this case designated as wATTR-CM to denote deposition of wild-type TTR in the heart (3 Etiology references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ). Soft-tissue manifestations of ATTRwt amyloid, including carpal tunnel syndrome, bicipital tendon rupture, rotator cuff tears, and spinal stenosis, may precede clinical expression of infiltrative cardiomyopathy by years.

The genetic and epigenetic factors leading to ATTRwt are unknown. Because ATTRwt and AL amyloidosis both can cause cardiomyopathy, and because amyloidogenic monoclonal gammopathies may be present in patients in this age group, it is essential to accurately type the amyloid so that patients with ATTRwt are not inappropriately treated with chemotherapy (which is used for AL).

This form can occur secondary to several infectious, inflammatory, and malignant conditions and is caused by aggregation of isoforms of the acute-phase reactant serum amyloid A.

Common causative infections include

Predisposing inflammatory conditions include

Inflammatory cytokines (eg, interleukin [IL]-1, tumor necrosis factor [TNF], IL-6) that are produced in these disorders or ectopically by tumor cells cause increased hepatic synthesis of serum amyloid A (SAA).

AA amyloidosis shows a predilection for the kidneys, spleen, liver, adrenal glands, and lymph nodes. Involvement of the heart or peripheral and autonomic nerves occurs late in the disease course.

Localized amyloidosis outside the brain is most frequently caused by deposits of clonal immunoglobulin light chains; within the brain, amyloid beta protein predominates.

Localized amyloid deposits typically involve the airways and lung tissue, bladder and ureters, skin, breasts, and eyes. Rarely, other locally produced proteins cause amyloidosis, such as keratin isoforms that can form deposits locally in the skin. Clonal immunoglobulin light chains produced by mucosal-associated lymphoid tissue in the gastrointestinal tract, airways, and bladder can lead to localized AL in those organs.

Amyloid beta protein deposits in the brain contribute to Alzheimer disease Alzheimer Disease Alzheimer disease causes progressive cognitive deterioration and is characterized by beta-amyloid deposits and neurofibrillary tangles in the cerebral cortex and subcortical gray matter. Diagnosis... read more or cerebrovascular amyloid angiopathy. Other proteins produced in the central nervous system can misfold, aggregate, and damage neurons, leading to neurodegenerative diseases (eg, Parkinson disease Parkinson Disease Parkinson disease is a slowly progressive, degenerative disorder characterized by resting tremor, stiffness (rigidity), slow and decreased movement (bradykinesia), and eventually gait and/or... read more , Huntington disease Huntington Disease Huntington disease is an autosomal dominant disorder characterized by chorea, neuropsychiatric symptoms, and progressive cognitive deterioration, usually beginning during middle age. Diagnosis... read more ).

Diagnosis of amyloidosis is made by demonstration of fibrillar deposits in an involved organ. Aspiration of subcutaneous abdominal fat detects amyloid deposits in about 80% of patients with AL but less than 25% of patients with ATTRwt (1 Diagnosis references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ). If the fat biopsy result is negative, a clinically involved organ should be biopsied. The diagnostic sensitivity of kidney and heart biopsies is nearly 100% when these organs are clinically involved. Tissue sections are stained with Congo red dye and examined with a polarizing microscope for characteristic birefringence. Nonbranching 10-nm fibrils can also be recognized by electron microscopy on biopsy specimens from the heart or kidneys.

Nuclear scanning using bone-avid tracers can diagnose ATTR amyloid cardiomyopathy without heart biopsy, provided AL amyloidosis is ruled out.

After amyloidosis has been confirmed by biopsy, the type is determined using a variety of techniques. For some types of amyloidosis, immunohistochemistry or immunofluorescence may be diagnostic, but false-positive typing results occur. Other useful techniques include gene sequencing for AF and biochemical identification by mass spectrometry to accurately identify protein variants in amyloid deposits (the most sensitive and specific method).

If AL is suspected, patients should be evaluated for an underlying plasma cell disorder Overview of Plasma Cell Disorders Plasma cell disorders are a diverse group of disorders of unknown etiology characterized by Disproportionate proliferation of a single clone of B cells Presence of a structurally and electrophoretically... read more using quantitative measurement of serum free immunoglobulin light chains, qualitative detection of serum or urine monoclonal light chains using immunofixation electrophoresis (serum protein electrophoresis and urine protein electrophoresis are insensitive in patients with AL), and a bone marrow biopsy with flow cytometry or immunohistochemistry to establish plasma cell clonality.

Patients with > 10% clonal plasma cells should be tested to see if they meet criteria for multiple myeloma Diagnosis Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones that cause... read more , including screening for lytic bone lesions, anemia, renal insufficiency, and hypercalcemia.

Patients are screened for organ involvement beginning with noninvasive testing:

Cardiac involvement can be suggested by low voltage on ECG (caused by a thickened ventricle) and/or dysrhythmias. If cardiac involvement is suspected because of symptoms, in addition to ECG findings and cardiac biomarkers, echocardiography is done to measure diastolic relaxation and global longitudinal strain (a measure of left ventricular systolic function) and to screen for biventricular hypertrophy. In ambiguous cases, cardiac MRI can be done to detect persistent subendocardial gadolinium enhancement, a characteristic finding. Cardiac technetium pyrophosphate nuclear scans improve detection of ATTR amyloid heart disease and can avoid the need for heart biopsies provided blood tests rule out AL amyloidosis (2, 3 Diagnosis references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

Supportive care measures are directed at the affected organ system:

Orthostatic hypotension Orthostatic Hypotension Orthostatic (postural) hypotension is an excessive fall in blood pressure (BP) when an upright position is assumed. The consensus definition is a drop of > 20 mm Hg systolic, > 10 mm Hg... read more often improves with high doses of midodrine; this medication can cause urinary retention in older males, but the medication complication of supine hypertension is rarely a problem in this population. Support stockings can also help, and fludrocortisone can be used in patients without peripheral edema, anasarca, or heart failure. In patients with refractory orthostatic hypotension, midodrine, fludrocortisone, or droxidopa may be added.

For AL amyloidosis:

Most medications used for multiple myeloma Treatment Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones that cause... read more have been used in AL amyloidosis; choice of medication, dose, and schedule often must be modified when organ function is impaired.

Chemotherapy using an alkylating agent (eg, melphalan, cyclophosphamide) combined with corticosteroids was the first regimen to show any benefit. High-dose IV melphalan, combined with autologous stem cell transplantation Hematopoietic Stem Cell Transplantation Hematopoietic stem cell (HSC) transplantation is a rapidly evolving technique that offers a potential cure for hematologic cancers ( leukemias, lymphomas, myeloma) and other hematologic disorders... read more can be highly effective in selected patients (1 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

Proteasome inhibitors (eg, bortezomib) and immunomodulators (eg, lenalidomide) also can be effective. A trial of the monoclonal antibody daratumumab plus cyclophosphamide, bortezomib, and dexamethasone in patients with newly diagnosed AL amyloidosis (excluding those with NYHA class III and IV heart failure, N-terminal pro-B-type natriuretic protein [NTproBNP] > 8,500 pg/mL [> 1003 pmol/L], and eGFR < 20 mL/minute/m²) showed an unprecedented high rate of hematologic response (2 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ). Hematologic response is based on monoclonal protein in serum and urine levels determined by immunofixation electrophoresis and serum light chain levels with kappa/lambda ratios. However, long-term survival data are lacking.

All available treatments target clonal B-cells or plasma cells in AL amyloidosis. Studies of antifibril antibodies, such as birtamimab and CAEL-101, are in progress (3 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

Localized AL amyloidosis can be treated with low-dose external beam radiation therapy because plasma cells are highly radiosensitive.

For ATTR amyloidosis:

Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more —which replaces the primary site of synthesis of the mutant protein with a new organ producing normal TTR—can be effective in certain TTR mutations if done at disease onset (early neuropathy and no heart involvement). Transplantation later in the course of the disease often leads to progressive amyloid cardiomyopathy and neuropathy due to the misfolding and deposition of wild-type TTR protein onto pre-existing amyloid deposits.

Several medications have been shown to stabilize TTR tetramers circulating in the plasma, inhibiting TTR misfolding and fibril formation and effectively slowing neurologic disease progression while preserving quality of life. These TTR stabilizers include diflunisal, a widely available generic anti-inflammatory drug, and tafamidis (4, 5 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

TTR gene silencing using anti-sense RNA or RNA interference to block translation of TTR mRNA efficiently reduces serum levels of TTR, improves neurologic outcomes in about 50% of patients, and, in some patients, appears capable of repairing injured nerves (6, 7 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ). The gene silencing medications, patisiran, inotersen, and vutrisiran are available.

A trial of vutrisiran, a second-generation gene silencer,demonstrated improved functional outcomes in patients with familial amyloid polyneuropathy (8 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ). Preliminary data from another trial suggests that gene silencers may be effective in the treatment of cardiomyopathy in patients with ATTR amyloidosis (9 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

For ATTRwt amyloidosis:

TTR stabilization using tafamidis, in patients with ATTR or ATTRwt amyloid cardiomyopathy has been shown to decrease all-cause mortality and cardiovascular-related hospitalizations (5 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ). Clinical trials are underway examining the effect of TTR gene silencers on the cardiomyopathy that occurs in patients with ATTRwt amyloidosis as well as the cardiomyopathy that occurs in patients with ATTR amyloidosis characterized by the mutant protein (10 Treatment references Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more ).

Unlike hereditary ATTR amyloidosis, liver transplantation is not effective for patients with ATTRwt because the amyloidogenic protein is a structurally normal TTR.

For AA amyloidosis caused by familial Mediterranean fever, oral colchicine is effective.

For other AA types, treatment is directed at the underlying infection, inflammatory disease, or cancer.

Colchicine or anti-IL1, anti-IL6, or anti-TNF medications may be used to interrupt the cytokine signaling, diminishing the inflammatory process driving hepatic production of serum amyloid A (SAA).