Primary amyloidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Syed Hassan A. Kazmi BSc, MD [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. 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 primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), 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. The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (a component of an antibody). There are approximately 4000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65. The most common risk factor for the development of primary amyloidosis is the presence of an underlying plasma cell dyscrasia. In primary amyloidosis, insoluble fibrils of AL amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with primary amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis or AL 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 primary 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. Symptoms can be quite diverse and range from dyspnea, lethargy, weight loss, fevers/chills to anasarca, bleeding tendency, frothy urine, numbness/tingling and diarrhea/constipation. Common findings in primary 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. Findings on electrocardiogram include low voltage QRS complexes, left and right ventricular hypertrophy, left atrial abnormalities, pathological Q waves, and AV block. Echocardiography is critical in the diagnosis of cardiac involvement in primary amyloidosis. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy. 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. 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 development of serum amyloid P component (SAP) scans has given physicians the ability to specifically locate amyloid deposits. Patients with systemic AL amyloidosis are not cured with conventional immunosuppressant treatment. However, early mortality rates have decreased and survival has improved as there has been a shift toward earlier diagnosis and therapy aimed at achieving remissions. 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.

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 primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), 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.

The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (a component of an antibody).

Primary amyloidosis may affect any organ in the body but the most commonly affected organs are the heart, kidneys and nerves. Involvement of these organ systems may give rise to organ failure, therefore early diagnosis is imperative for optimal treatment. Organ specific amyloidosis should be differentiated from other diseases that mimic amyloidosis and may present as organ dysfunction, specifically, nephrotic syndrome leading to renal failure, cardiac failure and polyneuropathy.

There are approximately 4000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.

The most common risk factor for the development of primary amyloidosis is the presence of an underlying plasma cell dyscrasia.

There is insufficient evidence to recommend routine screening for primary amyloidosis.

In primary amyloidosis, insoluble fibrils of AL amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with primary amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis or AL 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 primary 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 primary amyloidosis, the range of symptoms depends on specific tissues and organs involved. Symptoms can be quite diverse and range from dyspnea, lethargy, weight loss, fevers/chills to anasarca, bleeding tendency, frothy urine, numbness/tingling and diarrhea/constipation.

Common findings in primary 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 involvement in primary 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.

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

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. However, MRI is more sensitive than CT in the diagnosis of amyloidosis. A cardiac MRI is used when an echocardiogram fails to differentiate amyloidosis from hypertrophic cardiomyopathy.

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 development 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.

Patients with systemic AL amyloidosis are not cured with conventional immunosuppressant treatment. However, early mortality rates have decreased and survival has improved as there has been a shift toward earlier diagnosis and therapy aimed at achieving remissions. 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 “amyloid” as a 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 microscopy, explained the presence of non-branching 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 amyloid 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: Syed Hassan A. Kazmi BSc, MD [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 primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, nerves and in 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.

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 primary amyloidosis, amyloid gradually accumulate and amyloid deposition is widespread in the viscera (mainly kidneys, heart and liver), blood vessel walls, and in different connective tissues.

Amyloids

• Amyloids consist of aggregated proteins that accumulate extracellularly as insoluble fibrils of misfolded proteins. Pathogenic amyloids are the consequence of previously normal proteins that lose their physiological properties and assume a beta-pleated quaternary configuration with a characteristic appearance on electron microscopy. The axis of the fiber (5-15nm in width) in these deposits is perpendicular to antiparallel chains of beta peptides.

• These misfolded proteins are seen in various diseases such as Alzheimer’s disease (beta-amyloid), diabetes mellitus type 2 (amylin), Parkinson’s disease (alpha-synuclein), fatal familial insomnia (PrPsc), Huntington’s disease (Huntingtin), medullary carcinoma of the thyroid (calcitonin), atherosclerosis (apolipiprotein A-I), rheumatoid arthritis (serm amyloid A), Lattice corneal dystrophy (keratoepithelin) and trasnmissible spongiform encephalopathy (PrP).
• Amyloid fibrils are composed of smaller amyloid oligomers, which are toxic. Amyloid fibrils, once formed, catalyze the formation of these toxic oligomers.

Light chain amyloid or AL amyloid

• Primary amyloidosis is characterized by multi-organ deposition of immunoglobulin light chains of lambda variety. These light chains are normal components of antibodies produced by plasma cells (fully differentiated B cells). The plasma cells are involved in antibody production under physiological conditions via reorganization of immunoglobulin heavy and light chains.
• Since primary amyloidosis occurs in patients suffering from plasma cell dyscrasias, the inciting event for primary or AL amyloidosis is formation of an unstable misfolded secondary or tertiary structure of a monoclonal plasma cell-derived immunoglobulin light chain.

Role of plasma cells in primary (AL) amyloidosis

• In primary amyloidosis, the marrow plasma cell burden is < 10% therefore, primary amyloidosis is not considered a neoplasm. Due to monoclonal proliferation of these mature B cells, only one type of a unique protein sequence is synthesized.
• The mutational pattern of primary amyloidosis is intermediate between those of monoclonal gammopathy of undetermined significance and multiple myeloma.
• Studies have shown that in immunoglobulins produced by monoclonal plasma cell proliferation, there is alteration in the dimer interface formed between the variable domain of the light chains and the variable domain of the heavy chains. Mutations that disrupt immunoglobulin folds (structural domain) of beta strands lead to abnormal folding (N– and C-terminals oriented in opposite directions) and decreased thermodynamic stability.
• Therefore, destabilizing somatic mutations are present in both the complementarity-determining regions and structural regions of light chains and are thought to increase the propensity to develop insoluble aggregates.
• Because of somatic hypermutations, the amino acid sequence of the pathogenic AL protein differs in each patient.

Interaction of amyloid fibrils with microenvironment

• Accumulation of insoluble amyloid fibrils in tissues leads to activation proteosomes that lead to their endoproteolysis and release of amyloidogenic light chain fragments.
• Interaction of these deposits with extracellular chaperones, matrix components including glycosaminoglycans (GAGs) and collagen, shear forces, endoproteases, and metals modulate aggregation and oligomer formation.

Tissue damage

• The deposition of amyloid aggregates leads to architectural disruptions in tissues.
• Amyloid fibrils may also produce organ dysfunction via interaction with ligands and disruption of cell membranes.
• Both cytotoxicity and apoptosis have been implicated as mechanisms leading to tissue injury in primary amyloidosis.^[1]
• Specificity for a particular organ in primary amyloidosis depends upon the light chain variable region gene and gene family of the clone. Germ line gene LV6-57 is more common in AL systemic amyloidosis and is associated with renal involvement, while LV1-44 preferentially leads to fibril deposition in the heart and KV1-33 is associated with hepatic involvement.^[2]
• It has also been shown that cardiac fibroblasts internalize amyloid deposits which then migrate to mitochondrial optic atrophy 1-like protein and peroxisomal acyl-coenzyme A oxidase 1 leading to toxicity.^[3]

Primary amyloidosis has been associated with the following conditions:

• Plasma cell dyscrasia
• Monoclonal gammopathy of undetermined significance
• Multiple myeloma

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

The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (a component of an antibody).

• The cause of AL amyloidosis is usually a plasma cell dyscrasia, an acquired abnormality of the plasma cell in the bone marrow with production of an abnormal light chain protein (a component of an antibody).
• The increased production of plasma cell clone leads to extra-cellular deposition of fibril-forming monoclonal immunoglobulin (Ig) light chains (LC) (most commonly of lambda isotype)
• Typically, an excess amount of antibody protein is produced and the abnormal light chain portion or the whole antibody molecule accumulates in the organs in the form of amyloid deposits.

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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]

Primary amyloidosis may affect any organ in the body but the most commonly affected organs are the heart, kidneys and nerves. Involvement of these organ systems may give rise to organ failure, therefore early diagnosis is imperative for optimal treatment. Organ specific amyloidosis should be differentiated from other diseases that mimic amyloidosis and may present as organ dysfunction, specifically, nephrotic syndrome leading to renal failure, cardiac failure and polyneuropathy.

Primary amyloidosis may affect any organ in the body but the most commonly affected organs are the heart, kidneys and nerves. Involvement of these organ systems may give rise to organ failure, therefore early diagnosis is imperative for optimal treatment. Organ specific amyloidosis should be differentiated from other diseases that mimic amyloidosis and may present as organ dysfunction, specifically, nephrotic syndrome leading to renal failure, cardiac failure and polyneuropathy. The differentials include the following:

Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Nephrotic Syndrome and Real Failure	Primary (AL) Amyloidosis	Monoclonal plasma cell proliferation Extracellular amyloid fibril deposition	Anasarca Bleeding tendency Swelling of lower limbs Frothy urine Chest pain Numbness or tingling Early satiety Joint pains Enlarged tongue Taste loss Hoarseness of voice Hair loss	Increased erythrocyte sedimentation rate (ESR) Increased alanine aminotrasnferase (ALT) and aspartate aminotrasnferase (AST) Increased cardiac troponins Increased brain natriuretic peptide (BNP) Increased blood urea nitrogen (BUN) and creatinine Proteinuria Urinary hyaline and fatty casts Hypercholesterolemia	Biopsy: Diffuse glomerular deposition of amorphous hyaline material (nodular pattern – 8 to15 nm in diameter), in mesangium (weakly staining with periodic acid-Schiff (PAS)	Melphalan–prednisone/dexamethasone Dexamethasone plus Cyclophosphamide–thalidomide Stem cell transplantation Kidney transplantation
	Diabetic Nephropathy	Hyperfiltration Constriction of efferent arteriole Microalbuminuria Mesangial proliferation	Nocturia Fatigue Pruritis Peripheral edema	Hyperglycemia (random plasma glucose ≥200 mg/dL) Proteinuria Glucosuria HbA1C ≥6.5% (48 mmol/mol).	Biopsy: PAS positive Kimmelstiel-Wilson nodules Glomerulosclerosis	ACE inhibitors Angiotensin receptor blockers Glycemic control
	Minimal Change Disease	Upper respiratory tract infection Allergy to bee sting NSAID Gold Penicillamine Ampicillin Mercury Hodgkin’s and non-Hodgkin’s lymphoma	Peripheral edema Hypertension Peripheral edema	Proteinuria Hypertension Hyperlipidemia Hypoalbuminemia Microscopic hematuria	Biopsy: Fused podocytes/effacement	Prednisone with taper ACE inhibitors Angiotensin receptor blockers Salt restriction
	Focal Segmental Glomerulosclerosis	HIV Parvovirus B19 Cytomegalovirus Heroin Interferon alpha Lithium Pamidronate/aledronate Anabolic steroids Diabetes mellitus Hypertension Obesity Cyanotic congenital heart disease Sickle cell anemia	Peripheral edema Hypertension Peripheral edema	Proteinuria Hypertension Hyperlipidemia Hypoalbuminemia Microscopic hematuria	Biopsy: Podocyte foot process effacement Capillary lumen abolished by the segmental increase in matrix	Prednisone Calcineurin inhibitors (Cyclosporin, tacrolimus) Rituximab Cyclophosphamide/chlorambucil Mycophenolate motefil
	Fabry’s Disease	Deficient alpha galactosidase A	Abdominal pain Arthralgia Febrile episodes Angiokeratomas Burning pain and tingling (peripheral neuropathy) Hypohidrosis X-linked recessive inheritance	Deficient alpha galactosidase A Increased ceramide trihexoside (globotriaosylceramide)	Alpha-galactosidase A activity GLA gene analysis for heterozygotes	Enzyme replacement therapy ACE inhibitors Gabapentin, carbamazepine Migalastat
	Light Chain Deposition Disease	Multiple myeloma Waldenström’s macroglobulinemia Monoclonal gammopathy of undetermined significance	Asymptomatic Fatigue Weight loss Dyspnea Peripheral edema	Proteinuria Portal hypertension Increased ALT, AST	Biopsy: Non-amyloid granules	Bortezomib Autologous stem cell transplantation Immunomodulatory drugs Kidney transplant
	Membranous Glomerulonephritis	Hepatitis B and C HIV Non-Hodgkin`s lymphoma Chronic lymphocytic leukemia Hodgkin`s lymphoma Solid tissue tumors Schistosomiasis Leprosy Hydatid disease Loaiasis (filaria) Quartan malaria Systemic lupus erythematosis (SLE)	Headache Edema affecting any area of the body Foamy appearance of urine Weight gain Poor appetite Nocturia Fatigue Hematuria	Proteinuria Hypertension Hyperlipidemia Hypoalbuminemia Microscopic or gross hematuria Hypoalbuminemia ANA and anti-dsDNA positivity	Biopsy: IgG and C3 deposits with thickened basement membrane with spikes and vacuolization Glomerulosclerosis	Prednisone Methylprednisolone with cyclophosphamide Tacrolimus with a six-month taper Rituximab
	Fibrillary-Immunotactoid Glomerulopathy	Idiopathic Hepatitis C	Microscopic or gross hematuria	Proteinuria Hypertension Increased blood urea nitrogen (BUN) and creatinine	Biopsy: Polycloncal IgG deposits Infiltration of glomerular structures by amorphous acellular material (nonbranching fibrils 12-24nm in diameter) Ig heavy-chain and one light-chain subclass
Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Polyneuropathy	POEMS syndrome (Demyelinating)	Monoclonal plasma cell proliferation Cytokine storm (IL-1, IL-6, IL-12, TNF alpha, VEGF)	Symmetrical, ascending chronic progressive polyneuropathy with both sensory (pin-prick and vibration) and motor disability (motor > sensory) Generalized/extermity pain Areflexia	Increased number of thrombocytes Increased number of erythrocytes Elevated cerebrospinal fluid (CSF) protein content Increased number of leukocytes High levels of IgG lambda or IgA lambda M-protein in the serum Increased number of plasma cells in the bone marrow Increased serum VEGF level Elevated levels of antitiroglobulin antibody and antithyroid peroxydase antibody	International Myeloma Working Group (IMWG) clinical and laboratory diagnostic criteria
	Metabolic Syndrome (Axonal pathology)	Diabetes mellitus	Symmetric sensorimotor distal polyneuropathy Asymmetric proximal neuropathy 3rd nerve palsy Carpel tunnel syndrome Autonomic neuropathy “Glove and stocking” type pain Muscle wasting Hammer toes Polyuria Polydipsia	Uncontrolled hyperglycemia Slowed nerve conduction Small fiber dysfunction Monofilament testing	Fasting blood sugar level greater than equal to 126 mg/dl on 2 separate occasions	Anti-diabetic therapy Gabapentin Carbamazepine Foot care
	Vitamin Deficiencies (Axonal Pathology)	Vitamin B12 deficiency (Decreased S-adenosyl methionine) Vitamin B1 deficiency	Primarily sensory deficits Vibration and proprioception affected Gait abnormalities Cognitive impairment Irritability Glossitis	Anemia (megaloblastic in case of B12 deficiency) Decreased serum Vitamin B12 levels (< 200 pg/ml) Elevated methylmalonic acid	Serum Vitamin B12 levels Methylmalonic acid levels Intrinsic factor antibodies	Vitamin B12 supplement (parenteral)
	Guillain-Barre Syndrome (Demyelinating)	Anti-ganglioside and anti-myelin antibodies Viral infections: Epstein Barr virus HIV Cytomegalovirus Varicella Zoster virus Bacterial infections: Campylobacter infection Mycoplasma pneumoniae	Rapid onset and quick progression Progression stops after 2-3 weeks Bilateral ascending paraesthesias and paralysis (generalized) Weakness Ataxia Areflexia No fever 4 sub-types: Acute inflammatory demyelinating polyneuropathy Acute motor axonal neuropathy Acute motor and sensory axonal neuropathy Miller Fisher syndrome	Delayed F waves	Clinical diagnostic criteria (progressive weakness of more than two limbs, areflexia, and progression for no more than four weeks)	Intravenous immunoglobulins Plasma exchange Respiratory support DVT/PE prevention
	Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (Mixed axonal and demyelinatiing)	Abnormal immune response (both IgG based humoral and T-Cell mediated) response to unknown antigen (possible culprits include myelin proteins P0, P2 and PMP22)	Slow onset and gradual progression Relapsing and remitting course Symmetrical proximal and distal motor and sensory weakness (legs>arms) Foot drop Numbness, tingling and pain Areflexia	Elevated CSF protein (oligoclonal bands with normal WBCs) Slowed motor nerve conduction velocities Prolonged distal motor latencies (period between F wave and initial stimulation) Delayed F wave latencies (recorded from the feet, hence called “F” waves) MRI contrast enhancement and enlargement of T2 spinal segments	EFNS/PNS criteria Koski criteria	Corticosteroids Intravenous immunoglobulin (IVIG) Immunosupressants (Alemtuzemab Azathioprine Cyclophosphamide Cyclosporin Etanercept Interferon-alpha)
	Multifocal Motor Neuropathy	Abnormal immune response (Anti ganglioside GM-1 IgM antibodies)	Progressive, asymmetric, distal and upper limb predominant weakness No significant sensory abnormalities Areflexia	Elevated CSF protein	Clinical criteria (EFNS/PNS): Slowly progressive or step-wise progressive, focal, asymmetric limb weakness; i.e., motor involvement in the motor nerve distribution of at least two nerves for > 1 month. No objective sensory abnormalities except for minor vibration sense abnormalities in the lower limbs	Intravenous immunoglobulins Cyclophosphamide Rituximab
Organ System Involvement	Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
Organomegaly (Hepatosplenomegaly and Lymphadenopathy)	Malaria	Plasmodium falciparum P. ovale P. malariae P. knowlesi	Tertian (vivax, ovale, falciparum), quartan (malariae), quotidian fever (knowlesi) Vector is female Anopheles mosquito Hepatosplenomegaly Lymphadenopathy Jaundice Icterus Tachycardia Tachypnea Productive cough Hematuria Altered mental status	Microcytic anemia Thick and thin blood films (Giemsa staining) Rapid diagnostic test (antigen detection Polymerase chain reaction (PCR) Enzyme linked immunosorbent assay (ELISA)	Thick and thin films	Non-falciparum species: Chloroquine (in susceptible) Artemisinin plus mefloquin or lumefantrine (in chloroquine resistant) Falciparum species: Chloroquine (in susceptible) Artemether plus lumefantrine (in chloroquin resistant) OR Artesunate plus mefloquin OR Artesunate plus sulfadoxine-pyrimethamine Atovaquone plus proguanil
	Kala-azar	Leshmania donovani L. infantum L. chagasi	Fever Vector is sandfly Hepatosplenomegaly Lymphadenopathy Hyperpigmentation	Anemia Direct agglutination test (DAT) rk39 dipstick ELISA	Splenic aspiration	Liposomal amphotericin B Sodium stibogluconate Pentamidine
	Infective Hepatitis	Hepatitis A virus (HAV) HBV HCV HDV (co-infection with HBV) HEV	Fever Transmitted via fecal-oral route (HAV, HBV, HDV, HEV), infected sera (HCV), sexual contact with infected individuals Hepatosplenomegaly (may become shrunken in cases of cirrhosis due to chronic infection) Lymphadenopathy Jaundice Palmar erythema Spider angiomata Gynecomastia Arthritis-dermatitis syndrome	Antigen and antibody detection Total and direct bilirubin (increased) Severe disease is often associated with persistent bilirubin levels >340 mmol/L ALT and AST (increased) Alkaline phosphatase (normal or mildly elevated) Prothrombin time (prolonged from synthetic defect, caused by hepatocellular necrosis) Total protein (decreased) Globulin (mildly elevated) Initial lymphopenia and neutropenia, followed by relative lymphocytosis Low hemoglobin	Antigen and antibody detection	Interferon (IFN) Nucleoside analogs Nucleotide analogs
	Chronic Myelogenous Leukemia (CML)	BCR/ABL gene fusion product due to translocation mutation t(9;22)(q34;q11)	Fever Weight loss Hepatosplenomegaly Lymphadenopathy Bruises Petechiae Ulcers Vesicles Malaise Early satiety	Anemia Leukocytosis (median of 100,000/µL) with a left shift Thrombocytosis Blasts usually <2% Absolute basophilia Absolute eosinophilia Monocytosis Thrombocytosis Thrombocytopenia suggests an alternative diagnosis or the presence of advanced stage Elevated uric acid Elevated histamine levels	Fluoroscent insitu hybridization (FISH)	Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Cytarabine HDAC (high-dose cytarabine) Hydroxyurea Busulfan Busulfex Stem cell transplantation
	Lymphoma	Various causes based on type: Hodgkin’s Non-Hodgkin’s	Fever Weight loss Lymphadenopathy Hepatosplenomegaly Night sweats, constant fatigue Purplish scaly rash in cases of cutaneous lymphoma	Elevated ESR Increased CRP Increased LDH Anemia of chronic disease	Lymph node biopsy
	Primary (AL) Amyloidosis	Aggregation and deposition of immunoglobulin light chains that are usually produced by plasma cell clones	Nephrotic syndrome (peripheral edema) Restrictive cardiomyopathy (fatigue, dyspnea, syncope) Peripheral neuropathy (numbness, tingling) Hepatomegaly with elevated liver enzymes Macroglossia Purpura Bleeding diathesis	Typical green birefringence under polarized light after Congo red staining (appears in red under normal light)	Congo red staining	Melphalan-prednisone/dexamethasone Dexamethasone plus Cyclophosphamide-thalidomide Stem cell transplantation
	Gaucher’s Disease	GBA gene mutation Aberrant metabolism of glucocerebroside (lipid)	Hydrops fetalis Dry, scaly skin (ichthyosis) or other skin abnormalities Hepatosplenomegaly Distinctive facial features Neurological problems Gall stones Growth retardation	Hypocholesterolemia Splenic nodules Cytopenias (especially thrombocytopenia) Increased ferritin levels Increased tartarate resistant acid phosphatase (TRAP) levels	Enzyme assay for glucocerebrosidase DNA analysis for GBA mutation	Enzyme replacement Splenectomy Blood transfusion
Organ System Involvement	Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
Cardiac Failure	Cardiac amyloidosis (AL and ATTRwt)	Monoclonal plasma cell proliferation Extracellular amyloid fibril deposition	Fatigue Dyspnea Dizziness Orthopnea Peripheral edema Weight loss due to cardiac cachexia Ascites Syncope on exertion Transthyretin (ATTRwt) associated more common in African-Americans during sixth to seventh decade of life	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	Biopsy: Diffuse deposition of amorphous hyaline material (nodular pattern – 8 to15 nm in diameter), in mesangium (weakly staining with periodic acid-Schiff (PAS)	Supportive care Tafamidis Melphalan-prednisone/dexamethasone Dexamethasone plus Cyclophosphamide-thalidomide
	Hypertrophic obstructive cardiomyopathy	Mutation in sarcomeric protein (beta myosin heavy chain and myosin binding protein C) Autosomal dominant inheritance	Chest pain (also known as angina) Dizziness Dyspnea (shortness of breath) which is due to increased stiffness of the hypertrophied left ventricle Exercise intolerance Fainting, presyncope or frank syncope, especially during exercise Fatigue) Light-headedness Shortness of breath Reduced activity tolerance Shortness of breath Sudden cardiac death	Increased BNP Increased creatine kinase	Echocardiography: Left ventricular asymmetric hypertrophy Parasternal long axis shows relationship of the septal hypertrophy and the outflow tract Left ventricular diastolic dysfunction SAM (systolic anterior motion) of the mitral leaflet Mid-systolic closure of the aortic valve Late peaking, high velocity flow in the outflow tract Variability of obstruction with maneuvers (exercise, amyl nitrate inhalation, and post-PVC beats)	Beta blockers Calcium channel blockers Septal myectomy
	Alcoholic cardiomyopathy	Alcohol consumption	Exercise intolerance Fainting, presyncope or frank syncope, especially during exercise Fatigue) Light-headedness Shortness of breath Reduced activity tolerance Shortness of breath	Elevated mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCHC) Mild thrombocytopenia Elevated LDH, AST, ALT, creatine kinase, malic dehydrogenase and alpha-hydroxybutyric dehydrogenase Elevated gammaglutamyl transpeptidase Serum concentrations of magnesium and zinc may be reduced	Endomyocardial biopsy	Restriction of dietary salt ACE inhibitors or angiotensin II receptor blockers Beta blockers Diuretics Digoxin
	ST-elevation myocardial infarction	Myocardial ischemia Atherosclerosis	Exercise intolerance Fainting, presyncope or frank syncope, especially during exercise Fatigue) Light-headedness Shortness of breath Reduced activity tolerance Shortness of breath	Increased cardiac troponins Increased LDH Leukocytosis ST segment elevation on EKG	Elevation of cardiac troponins	Percutaneous coronary intervention or coronary artery bypass graft Aspirin Clopidogrel Beta blockers Diuretics
	Pericarditis	HIV Dressler’s syndrome Tuberculosis Uremia Radiation Malignancy	Chest pain (relieved by sitting up and leaning forward and is worsened by lying down) Cough (either dry or productive) Fever Fatigue Anxiety Breathlessness	Creatine kinase: Acute pericarditis may be associated with a modest increase in serum creatine kinase-MB (CK-MB) depending upon the extent of involvement of the underlying myocardium. Increased cardiac troponin-I (cTnI) Increased LDH Increased serum myoglobin Increased SGOT (AST)	Two of the following four criteria: Pericarditic chest pain Pericardial rub New widespread ST-segment elevation or PR depression New or worsening pericardial effusion. Supporting findings can include elevation of inflammatory markers (C-reactive protein, ESR, white blood cell count), and evidence of pericardial inflammation on imaging(CT scan and cardiac MRI).
Organ System Involvement	Differential Diagnosis	Causes	Features	Laboratory Findings	Gold Standard Test	Therapy
Plasma Cell Dyscrasias	Multiple myeloma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Diffuse bone pain and tenderness with osteolytic lesions Renal failure Hypercalcemia Anemia	Anemia Thrombocytopenia Leukopenia Decreased albumin (reversed albumin:globulin ratio) Increased serum creatinine, urea Hypercalcemia Elevated ESR Normal-low alkaline phosphatase RBC rouleaux formation Bence-Jones proteins in urine	Clonal plasma cells on bone marrow exam greater than equal to 10% AND Any one of the following: Evidence of end-organ damage Hypercalcemia (>11 mg/dl) Renal insufficiency Anemia (Hb < 10 mg/dl) Bone lesions Greater than 1 lesions on MRI	Induction chemotherapy with bortezomib, lenalidomide, and dexamethasone Bisphosphonates RANK ligand inhibitors (denosumab) Autologous stem cell transplantation
	Monoclonal gammopathy of undetermined significance (MGUS)	Chromosomal aberrations or other genetic insults Clonal plasma cell proliferation	Asymptomatic	Serum M protein of <3 g/L Fewer than 10% plasma cells in the bone marrow No evidence of bone or organ damage	Serum M protein (IgG or IgA) <3g/dl AND Clonal bone marrow plasma cells < 10% AND No end-organ damage	Observation
	Asymptomatic Plasma Cell Myeloma (Smoldering and Indolent plasma cell myeloma)	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells Clonal plasma cell proliferation	Asymptomatic	Serum M protein of greater than equal to 3 g/L Greater than 10% plasma cells in the bone marrow No evidence of bone or organ damage	Serum M protein (IgG or IgA greater than equal to 3 g/dl OR Urinary M protein greater than equal to 500 mg/24 h AND/OR Clonal bone marrow plasma cells 10-60% AND No end-organ damage	Observation
	Plasmacytoma	Chromosomal aberrations or other genetic insults Malignant transformation of plasma cells	Solitary bone plasmacytoma (bone) Extramedullary plasmacytoma (soft tissues) Clinical manifestations related to tumor mass and compression symptoms	On biopsy: Solitary infiltrate of clonal plasma cells in bone (SBP) or soft tissue (EMP). No evidence of infiltration by clonal plasma cells. Negative skeletal survey plus MRI/CT spine and pelvis except for the solitary lesion. Lack of hypercalcemia, renal insuffieciency, anemia, multiple bone lesions which would suggest MM	Diagnosis of exclusion	Radiotherapy
Skin Changes	Scurvy	Vitamin C deficiency Malabsorption Hemodialysis	Gum disease such as gum bleeding Loose teeth Easy bruising Impaired immune response Impaired wound healing			Vitamin C supplementation Citrus fruits

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

There are approximately 4000 new cases of AL amyloidosis annually in the United States, though actual incidence may be somewhat higher as a result of under-diagnosis. While the incidence is thought to be equal in males and females, about 60% of patients referred to amyloid centers are male. AL amyloidosis has been reported in individuals as young as 20 years of age but is typically diagnosed at about age 50-65.

• 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]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The most common risk factor for the development of primary amyloidosis is the presence of an underlying plasma cell dyscrasia.

The most common risk factor for the development of primary amyloidosis is the presence of an underlying plasma cell dyscrasia.^[1][2]

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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]

There is insufficient evidence to recommend routine screening for primary amyloidosis.

There is insufficient evidence to recommend routine screening for primary 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] Syed Hassan A. Kazmi BSc, MD [3]

In primary amyloidosis, insoluble fibrils of AL amyloid are deposited in organs, causing organ dysfunction and eventually death. Patients with primary amyloidosis may eventually suffer from heart failure, nephrotic syndrome, hepatomegaly and peripheral neuropathy. In primary amyloidosis or AL 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 primary amyloidosis, insoluble fibrils of AL 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 primary amyloidosis, the most frequent complications include:^[3]

• Heart failure
• Nephrotic syndrome
• Hepatomegaly
• Peripheral neuropathy
• Autonomic 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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