Amyloidosis overview

Amyloidosis Microchapters

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Overview

Historical Perspective

Classification

• Primary amyloidosis

• Secondary amyloidosis

• Familial amyloidosis

• Wild-type (senile) amyloidosis

• Cardiac amyloidosis

• Beta-2 microglobulin related amyloidosis

• Gelsolin related amyloidosis

• Lysozyme amyloid related amyloidosis

• Leucocyte cell-derived chemotaxin 2 related amyloidosis

• Fibrinogen A alpha-chain associated amyloidosis

Pathophysiology

Causes

Differentiating Amyloidosis from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

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

## Overview

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## Historical Perspective

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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.

## Classification

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

## Pathophysiology

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

## Causes

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

## Differentiating Amyloidosis from other Diseases

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

## Epidemiology and Demographics

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

## Risk Factors

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

## Screening

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There is insufficient evidence to recommend routine screening for amyloidosis.

## Natural History, Complications and Prognosis

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

## Diagnosis

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### Diagnostic Study of Choice

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

### History and Symptoms

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

### Physical Examination

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

### Laboratory Findings

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

### Electrocardiogram

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

### Chest X-Ray

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

### CT Scan

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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

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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

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

### Other Imaging Findings

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

### Other Diagnostic Studies

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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.

## Treatment

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

### Medical Therapy

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

### Surgery

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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.

## Prevention

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### Primary Prevention

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There is no role for primary prevention in amyloidosis.

### Secondary Prevention

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There is no role for secondary prevention in amyloidosis.

## References

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