Amyloidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess, and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo Red staining of amyloid that remains the gold standard for diagnosis.

Amyloidosis may be classified on the basis of type of amyloidogenic protein and associated clinical syndromes into primary (AL) amyloidosis, secondary (AA) amyloidosis, familial (AF) amyloidosis, transthyretin (ATTRwt) amyloidosis and dialysis-associated (AH) amyloidosis. It can also be classified based on extent of organ system involvement

Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues. Primary (AL) amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis). Hereditary (or familial) amyloidosis are autosomal dominant diseases that inherited variant proteins cause the production and deposition of amyloid fibrils. Some neurodegenerative disorderssuch as Parkinson’s disease, Alzheimer, and Huntington’s disease may occur in localised amyloidosis. On microscopic pathology, typical green birefringence under polarized light after Congo red staining (appears in red under normal light)

Hereditary amyloidosis can be caused by genetic mutations in different genes. Causes of acquired amyloidosis can include tuberculosis, familial Mediterranean fever, rheumatoid arthritis, multiple myeloma, ankylosing spondylitis, and psoriatic arthritis.

Amyloidosis needs to be differentiated from acute myocarditis, bronchiectasis, multiple myeloma and other systemic diseases .

The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. The prevalence of AL amyloidosis increased significantly between 2007 and 2015, from 1.6 per 100,000 in 2007 to 4.0 per 100,000 in 2015. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. In amyloidosis, the mean age of presentation is 55 – 60 years. Men are more commonly affected by amyloidosis than women.

There are no established risk factors for amyloidosis. Some inflammatory conditions might increase the likelihood of amyloid deposition in the body.

There is insufficient evidence to recommend routine screening for amyloidosis.

In amyloidosis, insoluble fibrils of amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis, the survival rate depends upon the type of organ involvement and the hematological response to treatment. In AL amyloidosis, untreated individuals have the worst prognosis. In this group of patients, the median survival is one to two years.

The diagnostic study of choice in amyloidosis is tissue biopsy of the affected organ. Congo Red staining will show apple green birefringence of the tissue sample under polarized light, and subtyping of light chains(for light chain amyloidosis) can be done via mass spectrometry. Bone marrow biopsy and organ-specific laboratory measurements are also important ancillary tests.

In amyloidosis, the range of symptoms depends on specific tissues and organs involved. Symptoms can be quite diverse.

Common findings in amyloidosis include petechiae, ecchymosis, parotid gland enlargement, increased intraocular pressure, enlarged tongue, hepatomegaly, carpal tunnel syndrome, and Raynaud’s phenomenon.

Laboratory findings in amyloidosis include elevated erythrocyte sedimentation rate, increased BUN level, serum creatinine, protein, casts, or fat bodies in urine. Serum troponin, B-type natriuretic peptide, and beta-2-microglobulin are prognostic markers for heart failure. Amyloid deposits can be identified histologically by Congo red staining and viewing under polarized light where amyloid deposits produce a distinctive ‘apple green birefringence’. Alternatively, thioflavin T stain may be used. An abdominal fat pad aspiration, rectal mucosa biopsy, or bone marrow biopsy can help confirm the diagnosis. They reveal positive findings in 80% patients.

Electrocardiogram is particularly useful for cardiac amyloidosis. Findings on electrocardiogram include low voltage QRS complexes, left and right ventricular hypertrophy, left atrial abnormalities, pathological Q waves, and AV block.

Chest x-ray findings in a case of amyloidosis include a coin lesion.

CT scan can be done to assess for amyloid deposition in particular organs. It can also be done to rule out other causes of organ dysfunction. However, MRI is more sensitive than CT in the diagnosis of amyloidosis.

MRI is commonly done to assess for amyloid deposition in particular organs. It can also be done to rule out other causes of organ dysfunction. A cardiac MRI is used when an echocardiogram fails to differentiate amyloidosis from hypertrophic cardiomyopathy.

Echocardiography is critical in the diagnosis of cardiac amyloidosis. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy.

Tissue doppler echocardiography and myocardial strain rate imaging has been shown to be very sensitive for the assessment of myocardial dysfunction in restrictive cardiomyopathy. The developmend of serum amyloid P component (SAP) scans has given physicians the ability to specifically locate amyloid deposits.

A tissue biopsy or fat aspirate should be done to confirm the presence or type of amyloid protein which is involved in the pathogenesis of the disease.

There is no treatment for primary amyloidosis. The initial target in the treatment of this disorder is to correct the organ failure, as the disease is discovered at an advanced stage.

There are few available treatments for primary amyloidosis. Since the disease is typically discovered at an advanced stage, the initial treatment is aimed at preventing further organ damage and correcting the effects of organ failure. The most commonly used regimen for AL amyloidosis is CyBorD, which consists of cyclophosphamide, bortezomib, and dexamethasone.

Organ-specific transplant may need to be done, depending on the organ involved. However, surgery is not commonly done in patients with amyloidosis, since it is usually a systemic disease that requires treatment of the underlying cause.

There is no role for primary prevention in amyloidosis.

There is no role for secondary prevention in amyloidosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess and splenomegaly and his report has been the first description of amyloidosis. There is no significant data regarding the historical perspective of amyloidosis throughout the 18th century. Rudolph Virchow and Weber are the prominent figures with substantial work on amyloidosis during the 19th century. In 1922, Bennhold introduced Congo red staining of amyloid that remains the gold standard for diagnosis.

• In 1639, Nicolaus Fontanus autopsied a young man who had ascites, jaundice, liver abscess and splenomegaly and his report has been the first description of amyloidosis.^[1]
• In 1854, Rudolph Virchow introduced the term of amyloid as an macroscopic abnormality in some tissues.^[2]
• In 1867, Weber reported the first case of amyloidosis associated with multiple myeloma.^[1]
• In 1922, Bennhold introduced Congo red staining of amyloid that remains the gold standard for diagnosis.^[3]
• In 1959, Cohen and Calkins used ultrathin sections of amyloidotic tissues and assessed by electron microscopic examination, explained the presence of nonbranching fibrils with indeterminate length and variable width.^[2][1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]Shaghayegh Habibi, M.D.[3]

Amyloidosis may be classified on the basis of type of amyloidogenic protein and associated clinical syndromes into primary (AL) amyloidosis, secondary (AA) amyloidosis, familial (AF) amyloidosis, transthyretin (ATTRwt) amyloidosis and dialysis-associated (AH) amyloidosis. It can also be classified based on extent of organ system involvement.

Type	Abbreviation	Amyloidogenic Protein/Fibril	Acquired/Inherited	Most Common Organ Involvement	Associated Conditions
Primary amyloidosis	AL	Light chains of immunoglobulines (most common type)	Acquired	Heart and kidneys	Monoclonal gammopathy
Secondary amyloidosis	AA	Serum amyloid A protein	Acquired	Kidneys (early), heart and liver (late)	Chronic inflammatory diseases: Rheumatoid arthritis Juvenile inflammatory arthritis Intravenous drug use Familial periodic fever syndromes
Senile systemic or wild-type amyloidosis	ATTRwt/ATTRvar	Wild-type transthyretin (TTRwt) Abnormal TTR gene (TTRvar)	Acquired (ATTRwt) or Hereditary (ATTRvar)	Heart and nerves (more common in hereditary type)	Senile restrictive cardiomyopathy/Transthyretin-related amyloidosis wild-type ATTRwt common in males and exhibits involvement of ligaments and tenosynovium ATTRvar may involve eyes and leptomeninges
β2-microglobulin related amyloidosis	AH	ß2-microglobulin	Acquired or Hereditary	Nerves (peripheral and autonomic)	Long-term hemodialysis
Leucocyte cell–derived chemotaxin 2 related amyloidosis	ALect2	Leucocyte cell–derived chemotaxin 2	Acquired	Kidneys and liver	Nephrotic syndrome Proteinuria
Fibrinogen A alpha-chain associated amyloidosis	AF	Fibrinogen	Hereditary	Kidneys and liver	Familial polyneuropathy/cardiomyopathy/nephropathy
Abnormal Apolipoprotein A-I, AII, and AIV related amyloidosis	AApoA-I	Aberrant apolipoprotein A-I, A-II and A-IV proteins	Hereditary	Kidneys, liver and nerves (peripheral)	Testicular involvement (possible relation to steroidogenic tissues)
Lysozyme amyloid related amyloidosis	ALys	Aberrant lysozyme	Hereditary	Liver and kidneys	Gastrointestinal involvement
Gelsolin related amyloidosis	AGel	Abnormal gelsolin	Hereditary	Kidneys and nerves (peripheral and cranial)	Cranial neuropathy

Classification	Subtypes	Causes	Clinical Features
Systemic amyloidosis	Primary amyloidosis (AL)	Aggregation and deposition of immunoglobulin light chains that usually produced by plasma cell clones	Nephrotic syndrome Restrictive cardiomyopathy Peripheral neuropathy Hepatomegaly with elevated liver enzymes Macroglossia Purpura and an unexplained bleeding diathesis
	Secondary amyloidosis (AA)	Chronic inflammation (TB, familial mediterranean fever, rheumatoid arthritis and multiple myeloma)	Nephrotic syndrome Heart failure
	Hereditary amyloidosis	Amyloidogenic mutations and subsequently deposition of amyloids	Heart failure Arrhythmia
Organ-specific amyloidosis	Renal amyloidosis	Immunoglobulin light-chain amyloidosis (AL amyloidosis) Transthyretin-related amyloidosis (associated with familial/mutant or senile/wild-type TTR)	Proteinuria Nephrotic syndrome Chronic renal failure
	Cardiac amyloidosis		Systolic dysfunction Diastolic dysfunction Arrhythmia
	Hepatic amyloidosis		Hepatomegaly Elevated liver enzymes
	Amyloid neuropathy		Peripheral neuropathy and autonomic neuropathy Neurodegenerative disorders: Parkinson, Alzheimer, and Huntington’s disease
	Gastrointestinal amyloidosis		Nonspecific findings: Dyspepsia, abdominal pain, diarrhea, malabsorption

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]Sabawoon Mirwais, M.B.B.S, M.D.[3]

Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes. In systemic amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera, blood vessel walls, and in the different connective tissues. Primary (AL) amyloidosis) is the most common type of amyloidosis. It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that usually produced by plasma cell clones. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis). Hereditary (or familial) amyloidosis are autosomal dominant diseases that inherited variant proteins cause the production and deposition of amyloid fibrils. Some neurodegenerative disorders such as Parkinson’s disease, Alzheimer, and Huntington’s disease may occur in localised amyloidosis. On microscopic pathology, typical green birefringence under polarized light after Congo red staining (appears in red under normal light).

• Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organic dysfunction and a wide variety of clinical syndromes.^[1]
• These abnormal amyloids are derived from misfolding and aggregation of normally soluble proteins.
• Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.^[2]

• In systemic amyloidosis, amyloid gradually accumulates and amyloid deposition is widespread in the viscera, blood vessel walls, and different connective tissues.^[3][4]

• Primary (AL) amyloidosis) is the most common type of amyloidosis.^[5]
• It results from aggregation and deposition of monoclonal immunoglobulin (Ig) light chains that are usually produced by plasma cell clones.
• Change in the secondary structure or tertiary structure of a monoclonal light chain results in abnormal folding of the light chain that abnormally form amyloid fibrils.
• This type of amyloidosis most frequently involve the kidney (nephrotic syndrome) and the heart.
• In primary (AL) amyloidosis survival rate depends on:
  • Type of organ involvement (amyloid heart disease is the main prognostic factor)
  • The severity of different organ involvement
  • Hematological response to treatment
• The median survival of patients with AL amyloidosis is approximately 3.8 years.

• Secondary amyloidosis occurs as a reaction to an existing illness.
• Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).^[6]
• Secondary or reactive amyloidosis (AA) comprises approximately 45% of the systemic amyloidoses.
• Pathogenesis of secondary amyloidosis is multifactorial, including:
  • Primary structure of the precursor protein
  • Acute phase response
  • Nonfibril proteins (amyloid P component, apo E, GAGs, proteoglycans and basement membrane proteins)
  • Receptors
  • Lipid metabolism
  • Proteases

• Hereditary amyloidosis is an autosomal dominant disorder.^[7]
• It can have a heterogeneous nature of presentation and can be complicated by significant disability and mortality.^[8]
• Inherited variant proteins cause the production and deposition of amyloid fibrils.^[6]
• Hereditary amyloidosis is due to amyloidogenic mutations and the subsequent deposition of amyloids which include:
  • Transthyretin (TTR) (most common inherited mutation)
  • Fibrinogen
  • Apolipoprotein A1
  • Apolipoprotein A2
  • Lysozyme
  • Gelsolin genes

• In this type of amyloidosis, amyloid deposition occurs only in the organ of origin or tissue of precursor protein.
• Neurodegenerative disorders, such as Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease, may occur in localized amyloidosis.

• Localized amyloidoses can develop due to the deposition of intracellular and/or extracellular amyloid.
  • Huntington’s disease: intracellular protein deposition
  • Parkinson’s disease: intracellular protein deposition
  • Alzheimer’s disease: intracellular (Tau protein fibrils) and extracellular (amyloid β fibrils) deposition

• Hereditary amyloidosis involves mutations in the following genes:^[9]
  • LYZ gene
  • Fibrinogen A alpha polypeptide gene
  • FGA gene
  • APOA1 gene
  • Lysozyme gene
  • B2M gene

• Primary localized cutaneous amyloidosis is inherited in autosomal dominant manner.^[10]

• Primary localized cutaneous amyloidosis involves mutations in the following genes:^[11]
  • OSMR gene

Conditions associated with amyloidosis include:^[12]

• MEN2A

On gross pathology, the organs affected by amyloidosis can be characterized by the following features:

• Porcelain like or waxy appearance
• Enlargement

On microscopic histopathological analysis, amyloidosis is characterized by:^[6][16]

• Green birefringence under polarized light after Congo red staining (appears red under normal light)
• Linear non-branching fibrils (indefinite length with an approximately same diameter)
• Distinct X-ray diffraction pattern consistent with Pauling’s model of a cross-beta fibril

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

Hereditary amyloidosis can be caused by genetic mutations in different genes. Causes of acquired amyloidosis can include tuberculosis, familial Mediterranean fever, rheumatoid arthritis, multiple myeloma, ankylosing spondylitis, and psoriatic arthritis.

Genetic mutations responsible for the development of amyloidosis can involve the following genes:^[1]

• LYZ gene
• Fibrinogen A alpha polypeptide gene
• FGA gene
• APOA1 gene
• Lysozyme gene
• B2M gene

• Most common causes of acquired amyloidosis include:^[2]

• • Tuberculosis (50%)
  • Familial Mediterranean fever (26 – 40%)
  • Rheumatoid arthritis (20 – 25%)
  • Multiple myeloma (10 – 15%)

• Less common causes of acquired amyloidosis include:^[3][4][5]

• • Ankylosing spondylitis
  • Psoriatic arthritis
  • Crohn’s disease
  • Osteomyelitis
  • Common variable immunodeficiency

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Amyloidosis needs to be differentiated from systemic diseases including acute myocarditis, bronchiectasis, and multiple myeloma.

Amyloidosis should be differentiated from the following systemic diseases:

• Acute myocarditis
• Bechterew’s Disease
• Bronchiectasis
• Carpal Tunnel Syndrome
• Collagen Vascular Disease
• Drug/toxic nephropathy
• Familial Mediterranean Fever
• Glomerulonephritis
• Hemodialysis Amyloidosis
• Interstitial lung diseases
• Leprosy
• Monoclonal gammopathies
• Multiple Myeloma
• Myocardial fibrosis
• Nephrotic Syndrome
• Osteomyelitis
• Peripheral neuropathy
• Restrictive cardiomyopathy
• Rheumatoid Arthritis
• Rheumatoid Polyarteritis
• Syphilis
• Systemic Lupus Erythematosus
• Tuberculosis
• Ulcerative colitis
• Vitamin deficiencies

Cardiac amyloidosis (AL and TTRwt) should be differentiated from other causes of heart failure:

Differential Diagnosis	History and Symptoms	Physical Examination	Laboratory Findings	Imaging Findings
Cardiac amyloidosis	Fatigue Dyspnea Dizziness Orthopnea Peripheral edema Weight loss due to cardiac cachexia Ascites Syncope on exertion Transthyretin (TTR) associated more common in African-Americans during sixth to seventh decade of life	Elevated jugular pressure Periorbital purpura: Often occurs with sneezing, coughing or with minor trauma. Indicates capillary involvement of AL type amyloidosis. Macroglossia Abnormal phonation Hepatomegaly Ascites may be present in the setting of heart failure Valvular involvement murmurs of mitral and tricuspid regurgitation (systolic).	Normocytic mormochromic anemia Serum free-light-chain assay positive Increased BNP, ANP and β2 microglobulin Voltage-to-mass ratio is more sensitive than EKG, 2D Echo and nuclear scanning alone	Granular or sparkling appearance of the left ventricular (LV) myocardium Increased left and right atrial volumes and reduced atrial function on cardiac MRI Atrial septal thickening Dynamic LV flow Mildly or moderately increased wall thickness in the early asymptomatic phase and severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum
ST Segment Elevation Myocardial Infarction	Chest pain with possible radiation to left arm and lower jaw Squeezing, crushing chest pain Sweating Nausea and vomiting	Anxious patient in pain with diaphoresis Signs of heart failure may be present Arrhythmia	ST elevation, new left bundle branch block, and Q wave on EKG Elevated cardiac biomarkers	Either complete or subtotal occlusion of an epicardial coronary artery on coronary angiography Confluent hyperenhancement extending from the endocardium
Non ST Elevation Myocardial Infarction	Crushing, left-sided substernal chest pain or pressure that radiates to the neck or left arm	Same as ST-elevation MI	ST-segment depression or T-wave inversion on EKG Elevated cardiac biomarkers
Pericarditis	Chest pain relieved by sitting up and leaning forward and worsened by lying down Fever, anxiety, difficulty breathing	Pericardial friction rub Signs of cardiac tamponade may be present	PR segment depression and electrical alternans on EKG	A flask-shaped, enlarged cardiac silhouette on CXR Pericardial thickness of more than 4 mm on MRI Pericardial effusion and cardiac chamber indentation or collapse on echo when cardiac tamponade is present
Alcoholic Cardiomyopathy	History of alcohol abuse Fatigue, weakness, anorexia, palpitations, and shortness of breath on activity Leg swelling and pedal edema	Signs of heart failure such as presence of S3 and S4 heart sounds, pedal edema, and jugular venous distension Signs of alcoholic liver disease may be present	Elevated MCV and MCHC on CBC Elevated LDH, AST, ALT, creatine kinase, gammaglutamyl transpeptidase, malic dehydrogenase, and alpha-hydroxybutyric dehydrogenase Q waves and non specific ST and T wave changes on EKG	Cardiomegaly, pulmonary congestion, and pleural effusions on CXR Left ventricular dilatation on echo

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. The prevalence of AL amyloidosis increased significantly between 2007 and 2015, from 1.6 per 100,000 in 2007 to 4.0 per 100,000 in 2015. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. In amyloidosis, the mean age of presentation is 55 – 60 years. Men are more commonly affected by amyloidosis than women.

• The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide.^[1]
• The incidence of AL amyloidosis in USA ranged from 1 per 100,000 to 1.4 per 100,000 from 2007 to 2015.^[2]
• Transthyretin-related hereditary amyloidosis is endemic in Portuguese locations Póvoa de Varzim and Vila do Conde (Caxinas), with more than 1000 affected people, coming from about 500 families, where 70% of the people develop the illness. In northern Sweden, more specifically Piteå, Skellefteå and Umeå, 1.5% of the population has the mutated gene. There are many other populations in the world who exhibit the illness after having developed it independently.

• The prevalence of AL in USA amyloidosis increased significantly between 2007 and 2015, from 1.6 per 100,000 in 2007 to 4.0 per 100,000 in 2015.^[3]

• The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.^[4]

• In amyloidosis, the mean age of presentation is 55-60 years.^[5]

• Hereditary amyloidosis subtypes include a substitution of an amino acid that is detected in approximately 4% of the black population.^[6]

• Men are more commonly affected by amyloidosis than women.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

There are no established risk factors for amyloidosis. Some inflammatory conditions and chronic infections may increase the likelihood of amyloid deposition in the body.

There are no established risk factors for amyloidosis. Some inflammatory conditions and chronic infections may increase the likelihood of amyloid deposition in the body.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

There is insufficient evidence to recommend routine screening for amyloidosis.

There is insufficient evidence to recommend routine screening for amyloidosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shaghayegh Habibi, M.D.[2]

In amyloidosis, insoluble fibrils of amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis, the survival rate depends upon the type of organ involvement and the hematological response to treatment. In AL amyloidosis, untreated individuals have the worst prognosis. In this group of patients, the median survival is one to two years.

• In amyloidosis, insoluble fibrils of amyloid are deposited in the organs, causing organ dysfunction and eventually death.^[1]
• In AL amyloidosis, untreated individuals have the worst prognosis. In this group of patients, median survival is one to two years.^[2]
• Patients with amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy.

In patients with amyloidosis, the most frequent complications include:^[3]

• Heart failure
• Nephrotic syndrome
• Hepatomegaly
• Peripheral neuropathy 

• In primary (AL) amyloidosis, survival rate depends on:^[4]
  • Type of organ involvement (amyloid heart disease is the main prognostic factor)
  • The severity of various organ involvement
  • Hematological response to treatment
• The median survival of patients with AL amyloidosis is aproximately 3.8 years.^[5]
• In primary (AL) amyloidosis 27% of the patients die within 1 year of diagnosis.
• The major determinant of outcome in amyloidosis is the extent of cardiac involvement.
  • Cardiac amyloidosis is the cause of death in 75% of the patients who died, including sudden death in 25%.

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