Secondary amyloidosis

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

Secondary amyloidosis, also known as reactive amyloidosis is the condition of amyloid deposition particularly in the kidneys secondary to an underlying disorder, most commonly a chronic inflammatory disorder. 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. AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors. In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis). Causes of secondary amyloidosis can include any persistent inflammatory process such as rheumatologic, autoinflammatory, chronic infectious, and other disorders. Echocardiography is critical in the diagnosis of cardiac amyloidosis. Secondary amyloidosis needs to be differentiated from other conditions causing nephrotic syndrome, hepatosplenomegaly, and peripheral neuropathy. The incidence of AA amyloidosis is approximately 0.16 per 100,000 individuals in 2008 in the united kingdom. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Secondary amyloidosis more commonly affects children. Men are more commonly affected by amyloidosis than women. 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. Prognosis is poor and 5-years survival rate is 51.3%.Infection and renal failure are the most common cause of death. The diagnostic study of choice in amyloidosis is tissue biopsy of the affected organ. Urinary protein measurement followed by renal biopsy is the gold standard of the diagnosis. Common physical examination findings of secondary amyloidosis include periorbital edema, pitting edema of the lower extremity, and signs of the underlying inflammatory disorder. An elevated urinary protein is suggestive of secondary amyloidosis. Elevated level of acute phase reactant, abnormal liver function test, and other findings may also be observed. An ECG may be helpful in the diagnosis of secondary amyloidosis. Possible ECG findings associated with the diagnosis of cardiac involvement include low voltage QRS complexes, Left ventricular hypertrophy, Right ventricular hypertrophy, and atrioventricular block. An x-ray may be helpful in the diagnosis of secondary amyloidosis. Findings suggestive of amyloid deposition may include nodular densities. 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. Echocardiogram should be done at diagnosis and routinely thereafter to monitor response to therapy. Total body SAP component scintigraphy may be used in the workup and follow-up of patients with amyloid deposition. This method has been observed to have high sensitivity (90%) and requires a low radioactive dose which makes it a safe and effective method. The radiolabeled SAP binds to aa amyloid and localizes its deposition semiquantitatively. Medical or surgical treatment of the underlying chronic infection or inflammatory disease is recommended among all patients who develop AA amyloidosis.

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 can also be classified based on the extent of organ system involvement

AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors. In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).

Causes of secondary amyloidosis can include any persistent inflammatory process such as rheumatologic, autoinflammatory, chronic infectious, and other disorders.

Secondary amyloidosis needs to be differentiated from other conditions causing nephrotic syndrome, hepatosplenomegaly, and peripheral neuropathy.

The incidence of AA amyloidosis is approximately 0.16 per 100,000 individuals in 2008 in the united kingdom. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Secondary amyloidosis more commonly affects children. Men are more commonly affected by amyloidosis than women.

The most potent risk factor in the development of secondary amyloidosis is a persistent inflammatory disorders. Chronic infections and inflammatory arthritis are among the most common risk factors.

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. Prognosis is poor and 5-years survival rate is 51.3%.Infection and renal failure are the most common cause of death.

The diagnostic study of choice in amyloidosis is tissue biopsy of the affected organ. Urinary protein measurement followed by renal biopsy is the gold standard of the diagnosis.

Symptoms of secondary amyloidosis may vary depending on the primary disorder and the affected organs. Secondary amyloidosis most commonly presents with kidney involvement and patients usually have a positive history of periorbital edema and frothy urine.

Common physical examination findings of secondary amyloidosis include periorbital edema, pitting edema of the lower extremity, and signs of the underlying inflammatory disorder.

An elevated urinary protein is suggestive of secondary amyloidosis. Elevated level of acute phase reactant, abnormal liver function test, and other findings may also be observed.

An ECG may be helpful in the diagnosis of secondary amyloidosis. Possible ECG findings associated with the diagnosis of cardiac involvement include low voltage QRS complexes, Left ventricular hypertrophy, Right ventricular hypertrophy, and atrioventricular block.

An x-ray may be helpful in the diagnosis of secondary amyloidosis. Findings suggestive of amyloid deposition may include nodular densities.

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.

Total body SAP component scintigraphy may be used in the workup and follow-up of patients with amyloid deposition. This method has been observed to have high sensitivity (90%) and requires a low radioactive dose which makes it a safe and effective method. The radiolabeled SAP binds to aa amyloid and localizes its deposition semiquantitatively.

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.

Medical or surgical treatment of the underlying chronic infection or inflammatory disease is recommended among all patients who develop AA amyloidosis.

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.

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]

There is no established system for the classification of secondary amyloidosis.

There is no established system for the classification of secondary amyloidosis.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[2] Shaghayegh Habibi, M.D.[3] Sabawoon Mirwais, M.B.B.S, M.D.[4]

AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors. In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes. In secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments that accumulate within extracellular space and form the insoluble amyloid deposits. Secondary amyloidosis is associated with chronic inflammation (such as tuberculosis or rheumatoid arthritis).

• AA amyloid is an abnormal insoluble extracellular protein derived from the spontaneous aggregation of fibrils composed of misfolded proteins, called amyloid precursors.^[1][2]
• In secondary amyloidosis, the amyloid precursor is SAA, an acute phase reactant, encoded by SAA 1&2 genes.
• Normally, SAA increased during the inflammatory process and then taken up by macrophages and degraded within lysosomal compartments.
• In patients with secondary amyloidosis, intermediate products of SAA metabolism tend to aggregate and form protofilaments.
• These protofilaments with other protein materials accumulate within extracellular space and form the insoluble amyloid deposits.
• Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.^[3]
• This algorithm explains the simplified pathogenesis of secondary amyloidosis.

Infection/Inflammation

Increased production of IL-1/IL-6/TNF-α

Upregulation of hepatic serum amyloid A production

SAA production uptake by macrophages

C-terminal cleavage of SAA

β-sheet configuration of SAA

Fibril deposition in extracellular space

Binding of glycosaminoglycan, serum amyloid P, and lipid components

Resistant to proteolysis

The above algorithm is adopted from International Journal of Nephrology and Renovascular Disease[4]

• Conditions associated with AA amyloidosis include:^[5][6][7]

Associated Conditions
Conditions	Examples
Chronic infections	Tuberculosis Leprosy Whipple Disease Osteomyelitis Chronic pyelonephritis Subacute bacterial endocarditis Chronic cutaneous ulcers
Monogenic periodic fever syndromes	TNF Receptor associated periodic syndrome (TRAPS) Cryopyrin-associated periodic fever syndrome Mevalonate kinase deficiency Familial mediterranean fever
Conditions predisposing to recurrent infections	Cystic fibrosis Bronchiectasis Kartagener syndrome Epidermolysis bullosa Injected drug abuse Jejuno-ileal bypass Paraplegia Sickle cell anemia Immunodeficiency Common variable immunodeficiency Cyclic neutropenia Hyperimmunoglobulin M syndrome Hypogammaglobulinemia Sex-linked agammaglobulinemia Human immunodeficiency virus/AIDS
Neoplasia	Adenocarcinoma Basal cell carcinoma Carcinoid tumor Castleman disease Gastrointestinal stromal tumor Hairy cell leukemia Hepatic adenoma Hodgkin disease Mesothelioma Renal cell carcinoma Sarcoma
Inflammatory Arthritis	Adult-onset Still disease Ankylosing spondylitis Juvenile idiopathic arthritis Psoriatic arthropathy Reiter syndrome Rheumatoid arthritis Gout
Systemic Vasculitis	Antineutrophil cytoplasmic antibody-associated vasculitis Behcet disease Giant cell arteritis Polyarteritis nodosa Polymyalgia rheumatica Systemic lupus erythematosus Takayasu arteritis Inflammatory Bowel Disease Ulcerative colitis Crohn disease
Others	Atrial myxoma Inflammatory abdominal aortic aneurism Retroperitoneal fibrosis SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome Sarcoidosis Sinus histiocytosis with massive lymphadenopathy

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, aa amyloidosis is characterized by:^[11][12]

• 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

On electron microscopy, amyloid fibrils have the following characteristics:^[13]

• 10 to 15 nm diameter
• Straight, rigid, and nonbranching
• Composed of twisted protofilaments

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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]

Causes of secondary amyloidosis can include any persistent inflammatory process such as rheumatologic, autoinflammatory, chronic infectious, and other disorders.

• Most common causes of secondary amyloidosis include:^[1]

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

• Less common causes of acquired amyloidosis include:^[2][3][4]

• • Ankylosing spondylitis
  • Psoriatic arthritis
  • Crohn’s disease
  • Osteomyelitis
  • Common variable immunodeficiency
• For more information on possible causes, click here.

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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] Sahar Memar Montazerin, M.D.[3]

Secondary amyloidosis needs to be differentiated from other conditions causing nephrotic syndrome, hepatosplenomegaly, and peripheral neuropathy.

• Secondary amyloidosis needs to be differentiated from other conditions causing nephrotic syndrome, hepatosplenomegaly, and peripheral neuropathy.
• Also, secondary amyloidosis should be differentiated from other types of amyloidosis, including:^[1][2]
  • Immunoglobulin light chain amyloidosis
  • Hereditary amyloidosis
  • Dialysis-related amyloidosis
  • Age-related (senile) systemic amyloidosis

Amyloisosis subtype	Protein	Organ involvement (%)
		Kidney	Liver	Heart
Primary	Monoclonal immunoglobulin light chains	50-100	10-25	50-100
Secondary	Serum amyloid A	50-100	<10	_
Hereditary	Transthyretin (mutated)	<10	_	25-50
DRA (dialysis related amyloidosis)	Beta‐2 microglobulin	_	_	_
Senile systemic (cardiac) amyloidosis	Transthyretin (wild type)	_	_	50-100
Meretoja syndrome	Gelsolin	_	_	_

• Tables below provide information on the differential diagnosis of secondary amyloidosis.

Differential diagnosis of secondary amyloidosis
Nephrotic syndrome causes[3][4][5][6][7][8][9]	Minimal change disease
	Membranous nephropathy
	Focal segmental glomerulosclerosis
	Diabetic nephropathy
	Lupus nephritis
	IgA nephropathy
Hepatosplenomegaly causes[10][11]	Metabolic disorders	Niemann-Pick disease Galactosemia Gaucher disease Glucose-6 phosphate deficiency
	Chronic liver disease and portal hypertension	Budd-Chiari Syndrome Cirrhosis Congested liver
	Infectoins	Acute viral hepatitis Infectious mononucleosis Cytomegalovirus Brucellosis
	Hematologic disorders	Chronic myelogenous leukemia Thalassemia Myeloproliferative disorders
	Rare disorders	Bang’s Disease Banti’s Disease Bilharziosis
Peripheral neuropathy causes[12][13][14][15][16][17][18][19][20][21][22]	Neurologic disorders	Guillain-Barré syndrome
	Inflammatory disorders	Systemic lupus erythematosus Leprosy Sjögren’s syndrome
	Toxins	Alcoholism Drugs
	Vitamin deficiencies	vitamin B12 Vitamin A Vitamin E Vitamin B1
	Metabolic disorders	Chronic renal failure Porphyria Liver failure Hypothyroidism
	Genetic disorders	Friedreich’s ataxia Charcot-Marie-Tooth syndrome

Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Nephrotic Syndrome and Renal Failure[3][4][5][6][7][8][9]	Secondary (AA) Amyloidosis	Chronic inflammatory disorders Chronic infections	Periorbital edema Lower extremity edema Signs/symptoms of underlying inflammatory disorder	Proteinuria Elevated level of acute phase reactant due to underlying inflammatory condition	Biopsy and congo-red staining of the sample	Treatment of the undelying inflammatory disorder
	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[12][13][14][15][16][17][18][19][20][21][22]	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)[23][24]	Malaria[25]	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[26]	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)[27][28]	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

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

The incidence of AA amyloidosis is approximately 0.16 per 100,000 individuals in 2008 in the United kingdom. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Secondary amyloidosis more commonly affects children. Men are more commonly affected by amyloidosis than women.

• The incidence of AA amyloidosis is approximately 0.16 per 100,000 individuals in 2008 in the United kingdom.^[1]

• The prevalence of AA amyloidosis is 5,000 to 10,000 per 100,000 individuals with chronic inflammatory process per year worldwide.^[2]

• The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.^[3]

• Secondary amyloidosis more commonly affects children.^[4]

• There is no racial predilection to secondary amyloidosis.

• Men are more commonly affected by amyloidosis than women.^[5]

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

The most potent risk factor in the development of secondary amyloidosis is a persistent inflammatory disorders. Chronic infections and inflammatory arthritis are among the most common risk factors.

• The most potent risk factor in the development of secondary amyloidosis is a persistent inflammatory disorders.^[1]
• Chronic infections and inflammatory arthritis are among the most common risk factors.^[2][3][4]
• Other possible risk factors include:
  • Obesity
  • Aging
  • SAA1 gene alleles
  • Monogenic periodic fever syndromes, such as:
    • FMF
    • TNF Receptor associated periodic syndrome (TRAPS)
    • Cryopyrin-associated periodic fever syndrome
    • Mevalonate kinase deficiency
  • Tuberculosis
  • Leprosy
  • Whipple Disease
  • Osteomyelitis
  • Chronic pyelonephritis
  • Subacute bacterial endocarditis
  • Chronic cutaneous ulcers
• Conditions Predisposing to chronic infections include:
  • Cystic fibrosis
  • Bronchiectasis
  • Kartagener syndrome
  • Epidermolysis bullosa
  • Injected drug abuse
  • Jejuno-ileal bypass
  • Paraplegia
  • Sickle cell anemia
  • Immunodeficiency
  • Common variable immunodeficiency
  • Cyclic neutropenia
  • Hyperimmunoglobulin M syndrome
  • Hypogammaglobulinemia
  • Sex-linked agammaglobulinemia
  • Human immunodeficiency virus/AIDS
  • Neoplasia
  • Adenocarcinoma
  • Basal cell carcinoma
  • Carcinoid tumor
  • Castleman disease
  • Gastrointestinal stromal tumor
  • Hairy cell leukemia
  • Hepatic adenoma
  • Hodgkin disease
  • Mesothelioma
  • Renal cell carcinoma
  • Sarcoma
  • Inflammatory Arthritis
  • Adult-onset Still disease
  • Ankylosing spondylitis
  • Juvenile idiopathic arthritis
  • Psoriatic arthropathy
  • Reiter syndrome
  • Rheumatoid arthritis
  • Gout
  • Systemic Vasculitis
  • Antineutrophil cytoplasmic antibody-associated vasculitis
  • Behcet disease
  • Giant cell arteritis
  • Polyarteritis nodosa
  • Polymyalgia rheumatica
  • Systemic lupus erythematosus
  • Takayasu arteritis
  • Inflammatory Bowel Disease
  • Ulcerative colitis
  • Crohn disease
• Others include:
  • Atrial myxoma
  • Inflammatory abdominal aortic aneurism
  • Retroperitoneal fibrosis
  • SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome
  • Sarcoidosis
  • Sinus histiocytosis with massive lymphadenopathy

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] Sahar Memar Montazerin, M.D.[3]

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. Prognosis is poor and 5-years survival rate is 51.3%.Infection and renal failure are the most common cause of death.

• In amyloidosis, insoluble fibrils of amyloid are deposited in the organs, causing organ dysfunction.^[1]
• Patients with amyloidosis may eventually suffer from nephrotic syndrome, renal failure, and death.

• In patients with amyloidosis, the most frequent complications include:^[2]
  • Nephrotic syndrome, the most common
  • Hepatomegaly
  • Peripheral neuropathy 
  • Heart failure

• Prognosis is poor and 5-years survival rate is 51.3%.^[3]
• Following factors are associated with higher rates of mortality:
  • Older age
  • Male gender
  • lower BMI
  • Lower GFR
  • Lower serum albumin and calcium
  • Higher levels of phosphor with intact parathyroid hormone
• It has been reported that, survival rate is not affected by the underlying etiology.^[4]
• Infection and renal failure are the most common cause of death.
• Median survival has been reported between 6 to 9 years.^[1]
• The most important predictable factor for development of renal failure and death is higher production of SAA.

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