Familial amyloidosis

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

Familial amyloidosis also known as hereditary amyloidosis, is a type of systemic 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. Genetic mutations in different genes may lead to misfolding protein product. Genes involved in the pathogenesis of familial amyloidosis include transthyretin, apolipoprotein AI, apolipoprotein AII, Lysozyme, gelsolin, fibrinogen Aa-chain, and cystatin C. Amyloid is an abnormal insoluble extracellular protein which may cause organ dysfunction and a wide variety of clinical syndromes. Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure. Familiar amyloidosis may be classified according to the type of mutant protein into 7 subtypes: Transthyretin amyloidosis (TTR), apolipoprotein AI, cystatin C, lysozyme, fibrinogen A alpha-chain, gelsolin, and apolipoprotein AII. The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. In familial amyloidosis, the mean age of presentation for TTR amyloidosis is after 50 years old and for other types is mostly third to forth decade of life. Men are more commonly affected by amyloidosis than women. The symptoms of familial amyloidosis usually develop after 50 years of age in TTR amyloidosis and late adulthood for other subtypes. Common symptoms of familial amyloidosis include parasthesia, muscle weakness, abdominal pain, edema,enlarged tongue, fatigue, skin and nail changes. Less common symptoms of familial amyloidosis include gastrointestinal bleeding, gross hematuria, and hoarseness. Physical examination of patients with familial amyloidosis is usually remarkable for hypertension, tachycardia, waxy thickening, easy bruising, purpura, macroglossia, parotid gland and submandibular gland enlargement, edema, numbness, hepatomegaly and paresthesia. In patients with familial amyloidosis, the most frequent complications include heart failure, nephrotic syndrome, hepatomegaly, and peripheral neuropathy. Prognosis is generally poor. The prognosis varies based on the type of organ involvement with amyloid heart disease have the worst prognosis. TTR amyloidosis patients have 60 months survival from presentation with heart failure symptoms. 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. Laboratory findings in amyloidosis include elevated erythrocyte sedimentation rate, increased BUN level, serum creatinine, protein, casts, or fat cast in urine. Serum troponin, B-type natriuretic peptide, and beta-2-microglobulin are prognostic markers for heart failure. We may also have elevated level of AST, ALT, bilirubin, ALP, and TSH. CT scan may be helpful in the diagnosis of familial amyloidosis. 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. MRI is moew specific in the diagnosis of familial amyloidosis. The optimal therapy for familial amyloidosis is preventing further organ damage and correcting the effects of organ failure. The mainstay of treatment for TTR amyloidosis is liver transplant. We may also use tafamidis, patisiran, Inoteresen, diflunisal, and epigallocathechin-3-gallate. 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. Familial 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.

Familiar amyloidosis may be classified according to the type of mutant protein into 7 subtypes: Transthyretin amyloidosis (TTR), apolipoprotein AI, cystatin C, lysozyme, fibrinogen A alpha-chain, gelsolin, and apolipoprotein AII.

It is understood that amyloidosis is the result of deposition of Amyloid. Amyloid is an abnormal insoluble extracellular protein which may cause organ dysfunction and a wide variety of clinical syndromes. Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure. Genetic mutations in different genes may lead to misfolding protein product. Genes involved in the pathogenesis of familial amyloidosis include transthyretin, apolipoprotein AI, apolipoprotein AII, Lysozyme, gelsolin, fibrinogen Aa-chain, and cystatin C.

Hereditary amyloidosis can be caused by genetic mutations in different genes.

Familial 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 incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. In familial amyloidosis, the mean age of presentation for TTR amyloidosis is after 50 years old and for other types is mostly third to forth decade of life. Men are more commonly affected by amyloidosis than women.

Common risk factors in the development of familial amyloidosis include older age, male gender, african american race, and positive family history.

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

The symptoms of familial amyloidosis usually develop after 50 years of age in TTR amyloidosis and late adulthood for other subtypes. In patients with familial amyloidosis, the most frequent complications include heart failure, nephrotic syndrome, hepatomegaly, and peripheral neuropathy. Prognosis is generally poor. The prognosis varies based on the type of organ involvement with amyloid heart disease have the worst prognosis. TTR amyloidosis patients have 60 months survival from presentation with heart failure symptoms.

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.

Common symptoms of familial amyloidosis include parasthesia, muscle weakness, abdominal pain, edema,enlarged tongue, fatigue, skin and nail changes. Less common symptoms of familial amyloidosis include gastrointestinal bleeding, gross hematuria, and hoarseness.

Physical examination of patients with familial amyloidosis is usually remarkable for hypertension, tachycardia, waxy thickening, easy bruising, purpura, macroglossia, parotid gland and submandibular gland enlargement, edema, numbness, hepatomegaly and paresthesia.

Laboratory findings in amyloidosis include elevated erythrocyte sedimentation rate, increased BUN level, serum creatinine, protein, casts, or fat cast in urine. Serum troponin, B-type natriuretic peptide, and beta-2-microglobulin are prognostic markers for heart failure. We may also have elevated level of AST, ALT, bilirubin, ALP, and TSH.  

Findings on an ECG suggestive of familial amyloidosis include low voltage in the limb leads, AV block, atrial fibrillation and heart block.

There are no characteristic x-ray findings associated with familial amyloidosis.

Echocardiography may be helpful in the diagnosis of familial amyloidosis. Findings on an echocardiography suggestive of familial amyloidosis include sparkling or speckled appearance of the left ventricular thickening, hypertrophied right ventricle, diastolic dysfunction with restrictive filling pattern (in the advanced stages), severe atrial dilatation, thickening of the interatrial septum, pericardial effusion, and prominent valves.

CT scan may be helpful in the diagnosis of familial amyloidosis. 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. Findings on liver CT scan suggestive of familial amyloidosis include liver enlargement with heterogeneous decreased attenuation, asymmetric and triangular hepatomegaly with the apex at the falciform ligament, and parenchymal calcification. Findings on renal CT scan suggestive of familial amyloidosis include kidney enlargement with heterogeneous decreased attenuation, and parenchymal calcification. Findings on cardiac CT scan suggestive of familial amyloidosis include heart enlargement with heterogeneous decreased attenuation, cardiac calcification, and pericardial effusion.

MRI may be helpful in the diagnosis of familial amyloidosis. Findings on liver MRI suggestive of familial amyloidosis include liver enlargement with heterogeneous decreased attenuation, asymmetric and triangular hepatomegaly with the apex at the falciform ligament, and parenchymal calcification. Findings on renal MRI suggestive of familial amyloidosis include hypodense lesions on T2, kidney enlargement with heterogeneous decreased attenuation, and parenchymal calcification. Findings on cardiac MRI suggestive of familial amyloidosis include thickening of ventricular and atrial walls and valvular leaflets due to deposition of amyloid fibrils, enlarged atria caused by diastolic dysfunction and/or valvular dysfunction due to amyloid deposition, heart enlargement with heterogeneous decreased attenuation, cardiac calcification, and pericardial effusion.

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 semi-quantitatively.

There are no other diagnostic studies associated with familial amyloidosis.

The optimal therapy for familial amyloidosis is preventing further organ damage and correcting the effects of organ failure. The mainstay of treatment for TTR amyloidosis is liver transplant. We may also use tafamidis, patisiran, Inoteresen, diflunisal, and epigallocathechin-3-gallate.

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 familial amyloidosis.

There is no role for secondary prevention in familial 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: Fahimeh Shojaei, M.D.

Familiar amyloidosis may be classified according to the type of mutant protein into 7 subtypes: Transthyretin (TTR), apolipoprotein AI, cystatin C, lysozyme, fibrinogen A alpha-chain, gelsolin, and apolipoprotein AII.

Familial amyloidosis may be classified according to the type of mutant protein into 7 subtypes:^[1][2][3]

• Transthyretin (TTR)
• Apolipoprotein AI
• Apolipoprotein AII
• Fibrinogen Aa
• Lysozyme
• Gelsolin
• Cystatin C

Genes involved in familial amyloidosis

Transthyretin (TTR)

Apolipoprotein AI

Gelsolin

Lysozyme

Cystatin C

Fibrinogen Aa-chain

Apolipoprotein AII

Mutations: • Asp18Glu • Leu55Gln • Asp18Gly • His56Arg • Asp18Asn • Leu58His • Val20Ile • Leu58Arg • Ser23Asn • Thr59Lys • Pro24Ser • Thr60Ala • Ala25Ser • Glu61Lys • Ala25Thr

Mutations: • Gly26Arg • Leu60Arg • Trp50Arg • del60-71 • del70-72 • Leu75Pro • Leu90Pro • Arg173Pro • Leu174Ser • Leu178His

Mutations: •Asp187Asn •Asp187Tyr

Mutations: • Ile56Thr • Asp67His • Trp64Arg • Phe57Ile

Mutation: • Leu68Gln

Mutations: • Arg554Leu • Glu526Val • 4904delG • 4897delT

Mutations: • stop78Gly • stop78Ser • stop78Arg

• Cys10Arg • Leu55Pro • Leu12Pro • Leu55Arg • Phe64Leu • Val28Met • Phe64Ser • Val30Met • Ile68Leu • Val30Ala • Tyr69His • Val30Leu • Tyr69Ile • Val30Gly • Lys70Asn • Phe33Ile • Val71Ala • Phe33Leu • Ile73Val • Phe33Val • Ser77Tyr • Phe33Cys • Ser77Phe • Arg34Thr • Tyr78Phe • Lys35Asn • Ala81Thr • Ala36Pro • Ile84Ser

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

It is understood that amyloidosis is the result of deposition of amyloid. Amyloid is an abnormal insoluble extracellular protein which may cause organ dysfunction and a wide variety of clinical syndromes. Amyloid deposition can disrupt the tissue structure of an involved organ and consequently leads to organ failure. Genetic mutations in different genes may lead to misfolded protein product. Genes involved in the pathogenesis of familial amyloidosis encode the culprit proteins, such as transthyretin, apolipoprotein AI, apolipoprotein AII, lysozyme, gelsolin, fibrinogen Aa-chain, and cystatin C.

• It is understood that amyloidosis is the result of deposition of amyloid.^[1]
• Amyloid is an abnormal insoluble extracellular protein which may cause organ dysfunction and a wide variety of clinical syndromes.
• These abnormal amyloids are derived from misfolding and aggregation of normally soluble proteins.
• Amyloid depositions also have glycosaminoglycans and serum amyloid P component (SAP) which alter the propensity for amyloid formation.^[2][3][4]
• Amyloid deposition can disrupt tissue structure of involved organ and consequently leads to organ failure.^[5]
• Genetic mutations in different genes may lead to misfolded protein product.

• Genes involved in the pathogenesis of familial amyloidosis encode the culprit proteins, such as:^[6][7][8]
  • Transthyretin (ATTR)^[9][10][11]
    • The most common type of familial amyloidosis.
    • Familial ATTR amyloidosis is transmitted in autosomal dominant pattern but it can have a heterogeneous nature of presentation.^[12][13][14]
    • Single nucleotide substitution on transthyretin gene on chromosome 18 leads to nonfunctional transthyretin protein.
    • Transthyretin protein is responsible for thyroid hormone and vitamin A transport and is produced by liver.
    • We can find normal transthyretin protein deposition in aged individuals.
    • Mutant transthyretin protein accelerates the process of deposition and leads to early onset disease.
  • Apolipoprotein AI amyloidosis (A ApoAI)^[15]
    • Single nucleotide substitutions in apolipoprotein AI gene.
    • The underlying pathogenesis is incomplete degradation of this protein in body.
    • The mode of inheritance is autosomal dominant with different penetrance.
  • Gelsolin amyloidosis (A Gel)^[16][17]
    • Gelsolin protein is produced in skeletal muscle and macrophages.
    • 2 different mutations in gelsolin gene on chromosome 9 including Asp187Asn and Asp187Tyr leads to amyloid deposition and Gelsolin amyloidosis.
  • Lysozyme amyloidosis (A Lys)^[18]
    • 4 different mutations in lysozyme gene including Ile56Thr, Asp67His, Trp64Arg, and Phe57Ile have been found to be associated with amyloidosis.
  • Cystatin C amyloidosis (A Cys)^[19][20]
    • Cystatin C is a serine protease inhibitor.
    • Leu68Gln mutation in its gene leads to cystatin C amyloidosis.
  • Fibrinogen Aa-chain amyloidosis (A Fib)^[21]
    • 4 different mutations including Arg554Leu, Glu526Val, 4904delG, and 4897delT have been found to be associated with amyloidosis.
  • Apolipoprotein AII amyloidosis (A ApoAII)^[22]
    • It was discovered recently.
    • 3 different mutations in the stop codon for the ApoAII gene, including stop78Gly, stop78Ser, and stop78Arg, have been found to be associated with amyloidosis.
    • These mutations lead to an extra 21-amino acid at the carboxyl terminal end of the protein.

Genes involved in familial amyloidosis

Transthyretin (TTR)

Apolipoprotein AI

Gelsolin

Lysozyme

Cystatin C

Fibrinogen Aa-chain

Apolipoprotein AII

Mutations: • Asp18Glu • Leu55Gln • Asp18Gly • His56Arg • Asp18Asn • Leu58His • Val20Ile • Leu58Arg • Ser23Asn • Thr59Lys • Pro24Ser • Thr60Ala • Ala25Ser • Glu61Lys • Ala25Thr

Mutations: • Gly26Arg • Leu60Arg • Trp50Arg • del60-71 • del70-72 • Leu75Pro • Leu90Pro • Arg173Pro • Leu174Ser • Leu178His

Mutations: • Asp187Asn • Asp187Tyr

Mutations: • Ile56Thr • Asp67His • Trp64Arg • Phe57Ile

Mutation: • Leu68Gln

Mutations: • Arg554Leu • Glu526Val • 4904delG • 4897delT

Mutations: • stop78Gly • stop78Ser • stop78Arg

• Cys10Arg • Leu55Pro • Leu12Pro • Leu55Arg • Phe64Leu • Val28Met • Phe64Ser • Val30Met • Ile68Leu • Val30Ala • Tyr69His • Val30Leu • Tyr69Ile • Val30Gly • Lys70Asn • Phe33Ile • Val71Ala • Phe33Leu • Ile73Val • Phe33Val • Ser77Tyr • Phe33Cys • Ser77Phe • Arg34Thr • Tyr78Phe • Lys35Asn • Ala81Thr • Ala36Pro • Ile84Ser

Conditions associated with amyloidosis include:^[23]

• 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:^[14][27]

• 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

Template:WH Template:WS

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

Hereditary amyloidosis can be caused by genetic mutations in genes encoding transthyretin, apolipoprotein AI, apolipoprotein AII, Lysozyme, gelsolin, fibrinogen Aa-chain, and cystatin C.

Common causes of familial amyloidosis may include genetic mutations in:^[1][2][3][4]

• Transthyretin (TTR)
• Apolipoprotein AI
• Apolipoprotein AII
• Fibrinogen Aa
• Lysozyme
• Gelsolin
• Cystatin C

Template:WH Template:WS

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

Familial 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.

Familial 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.

Organ System Involvement	Differential Diagnosis	Causes	Clinical Features	Laboratory Findings	Gold Standard Test	Therapy
Nephrotic Syndrome and Real Failure	Familial Amyloidosis	Genetic mutation	Parasthesia Muscle weakness Sexual problems Constipation/ diarrhea Urination problems Weakness Fatigue Edema Palpitation Dizziness	ncreased:I Troponin I or TroponinT BNP and NT-proBNP AST ALT Total bilirubin Alkaline phosphatase Serum creatinine Urinary protein	Biopsy: Apple green birefringence of the tissue sample under polarized light with Congo red stain.	Liver transplant for TTR amyloidosis Organ specific transplant Tafamidis Patisiran and Inoteresen Diflunisal Epigallocathechin-3-gallate
	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

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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] Fahimeh Shojaei, M.D.

The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. 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 mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries.^[2]

• In familial amyloidosis, the mean age of presentation can vary based on the type of protein involved:^{[3][4][5][6][7][8][9][10]}
  • Transthyretin (TTR): After 50 years of age
    • The age of onset in TTR Val30Met variant of the disease in northern Portugal is in the early 30s
  • Apolipoprotein AI: Third decade and older
  • Apolipoprotein AII: Early adulthood
  • Fibrinogen Aa: Fourth to fifth decade
  • Lysozyme: Third to fourth decade
  • Gelsolin: Late adulthood
  • Cystatin C: Third to fourth decade

• Hereditary amyloidosis subtypes include a substitution of an amino acid that is detected in approximately 4% of the African American population.^[11]

• Men are more commonly affected by amyloidosis than women.^[12]

• 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.^{[13][14][15][16][17][18][19][20][21][22][23]}
• 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 majority of gelsolin related amyloidosis cases are reported in the United States, Japan, Portugal, England, Germany, Spain, France, Brazil, Sewden, Denmark, the Czech Republic, and Iran.

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

Common risk factors in the development of familial amyloidosis include older age, male gender, African American race, and positive family history.

• Common risk factors in the development of familial amyloidosis include:^[1][2][3]
  • Older age
  • Male gender
  • African American race
  • Positive family history

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

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: Fahimeh Shojaei, M.D.

The symptoms of familial amyloidosis usually develop after 50 years of age in TTR amyloidosis and late adulthood for other subtypes. In patients with familial amyloidosis, the most frequent complications include heart failure, nephrotic syndrome, hepatomegaly, and peripheral neuropathy. Prognosis is generally poor. The prognosis varies based on the type of organ involvement with amyloid heart disease having the worst prognosis. TTR amyloidosis patients have 60 months survival from presentation with heart failure symptoms.

• The time at which symptoms of familial amyloidosis usually develop depends on the type of protein involved:^{[1][2][3][4][5][6][7]}
  • Transthyretin (TTR): After 50 years of age
  • Apolipoprotein AI: Third decade and older
  • Apolipoprotein AII: Early adulthood
  • Fibrinogen Aa: Fourth to fifth decade
  • Lysozyme: Third to fourth decade
  • Gelsolin: Late adulthood
  • Cystatin C: Third to fourth decade
• In amyloidosis, insoluble fibrils of amyloid are deposited in the organs, causing organ dysfunction and eventually death.^[8]

• In patients with familial amyloidosis, the most frequent complications include:^[9]
  • Heart failure
  • Nephrotic syndrome
  • Hepatomegaly
  • Peripheral neuropathy

• Prognosis is generally poor.^[10]
• The prognosis varies based on the type of organ involvement with amyloid heart disease having the worst prognosis.
• TTR amyloidosis patients have 60 months survival from presentation with heart failure symptoms.

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