Familial amyloidosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.
Overview
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.
Historical Perspective
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.
Classification
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.
Pathophysiology
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.
Causes
Hereditary amyloidosis can be caused by genetic mutations in different genes.
Differentiating Familial amyloidosis from Other Diseases
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.
Epidemiology and Demographics
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.
Risk Factors
Common risk factors in the development of familial amyloidosis include older age, male gender, african american race, and positive family history.
Screening
There is insufficient evidence to recommend routine screening for familial amyloidosis.
Natural History, Complications, and Prognosis
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.
Diagnosis
Diagnostic Study of Choice
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.
History and Symptoms
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
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
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.
Electrocardiogram
Findings on an ECG suggestive of familial amyloidosis include low voltage in the limb leads, AV block, atrial fibrillation and heart block.
X-ray
There are no characteristic x-ray findings associated with familial amyloidosis.
Echocardiography and Ultrasound
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
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
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.
Other Imaging Findings
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.
Other Diagnostic Studies
There are no other diagnostic studies associated with familial amyloidosis.
Treatment
Medical Therapy
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.
Surgery
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.
Primary Prevention
There is no role for primary prevention in familial amyloidosis.
Secondary Prevention
There is no role for secondary prevention in familial amyloidosis.