Wild-type (senile) amyloidosis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]
Overview
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. There is no established system for the classification of wild-type (senile) amyloidosis. Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organ dysfunction and a wide variety of clinical syndromes. Wild-type (senile) amyloidosis is a type of systemic amyloidosis as transthyretin (TTR) deposits can be found throughout the body. TTR results in pathologies due to misfolding, breaking apart, and deposition of the amyloid fibrils in healthy tissue. The condition mainly affects the heart. However, other organ systems, such as the nervous and musculoskeletal systems, can also be involved. There are no genes implicated in the causality of wild-type (senile) amyloidosis. Aging is very strongly associated with wild-type (senile) amyloidosis. Wild-type (senile) amyloidosis is caused by the folding and/breaking apart of a normal occurring protein, transthyretin (TTR). Wild-type (senile) amyloidosis can be differentiated from other conditions that present with heart failure, polyneuropathy, and organomegaly. The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. The actual incidence of wild-type (senile) amyloidosis in particular is unknown. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Patients with wild-type (senile) amyloidosis are almost always elderly (65 years of age or older). There is no racial predilection to wild-type (senile) amyloidosis. Men are traditionally more commonly affected by wild-type (senile) amyloidosis than women. Aging has been implicated to be a risk factor for the development of wild-type (senile) amyloidosis. There is insufficient evidence to recommend routine screening for wild-type (senile) amyloidosis. Wild-type (senile) amyloidosis, as the name suggests, is a disease of the elderly. The clinical picture of the disease corresponds to the type of organ or organ system involved. It most commonly affects the heart and hence, clinical features pertaining to cardiac pathologies, dominate the clinical course of the disease. If left untreated, wild-type (senile) amyloidosis can lead to heart failure with reduced ejection fraction (HFrEF) and eventually death. Wild-type (senile) amyloidosis is most commonly complicated by heart failure with reduced ejection fraction (HFrEF). The median duration of survival after diagnosis is 75 months. 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. The clinical features of wild-type (senile) amyloidosis depend on the type of organ or organ system involved. Cardiac and peripheral nerves involvement can result in clinically evident pathology. The most commonly involved organ is the heart and majority of the patients present with signs and symptoms of heart failure. Less common symptoms correspond to the involvement of organs or organ systems other than the heart. Physical examination of patients with wild-type (senile) amyloidosis can be significant for the condition in question and can also translate the variety of pathologies as a part of aging and age-related comorbidities. Wild-type (senile) amyloidosis is a diagnosis of exclusion. Laboratory tests are conducted to evaluate for the presence or absence AL amyloid protein deposition. The absence of AL amyloid provides a strong clue towards the provisional diagnosis of wild-type (senile) amyloidosis. Cardiac biomarkers are the most important predictors of outcome in amyloidosis. EKG findings encountered during the evaluation of a patient with wild-type (senile) amyloidosis include pseudoinfarct pattern, poor R wave progression, atrial fibrillation, first degree AV block, and nonspecific ST-T wave abnormalities. Voltage-to-mass ratio, calculated by the sum of S wave in lead V1 plus R wave in lead V5 or V6 (SV1 + RV5 or V6) divided by the echocardiographic muscle cross-sectional area, has been implicated to have high sensitivity and specificity for wild-type (senile) amyloidosis. There are no x-ray findings associated with wild-type (senile) amyloidosis. The most commonly encountered pathology on 2D echocardiography is increased left ventricular thickness (secondary to amyloid fibrils deposition in the extracellular matrix). Advanced echocardiographic techniques (strain and strain rate imaging) can differentiate cardiomyopathy secondary to amyloidosis from other causes of left ventricular hypertrophy. In regards to the evaluation of cardiac amyloidosis, EFSR has approximately 90% and 92% sensitivity and specificity, respectively. There are no CT scan findings associated with wild-type (senile) amyloidosis. T1 sequence of CMR with the use of gadolinium can differentiate extracellular tissue thickening due to myocardial hypertrophy vs. extracellular deposition. Using pre- and post-contrast T1 mapping, extracellular volume (ECV) can be calculated, which is a direct measurement of the cardiac interstitium. ECV expansion is a quantitative marker of the amyloid burden and can detect amyloid fibrils infiltration earlier than conventional testing. One of the benefits of T1 mapping is the fact that it does not require contrast, which is favorable in the setting of kidney disease. Bone-avid tracers, such as 99mTc-DPD (technetium-3,3-diphosphono-1,2-propanodicar-boxylic acid), 99mTc-PYP (technetium-pyrophosphate), and 99mTc-HMDP [technetium-hydroxymethylene diphosphonate (Tc-HMDP)] have been implicated to have high sensitivity and specificity for diagnosing cardiac amyloidosis and differentiating it from other cardiomyopathies with HFpEF. Combination of grade 2 or 3 cardiac uptake on a bone-avid tracer scan in the setting of absent monoclonal protein by serum immunofixation electrophoresis (IFE), urine IFE, and serum free light chain assay is diagnostic of wild-type (senile) cardiac amyloidosis. Other diagnostic studies that help in diagnosing wild-type (senile) amyloidosis include histopathological analysis and genetic testing. There is no treatment for wild-type (senile) amyloidosis; the mainstay of therapy is supportive treatment aimed at symptoms of the disease. Supportive treatment is with diuretics, antiarrhythmics or pacemaker implantation, anticoagulation where supraventricular arrhythmias are present, and an avoidance of digoxin and calcium channel blockers. Antihypertensives are usually poorly tolerated as these patients can be profoundly hypotensive. Pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated. Surgery is not the mainstay of therapy for wild-type (senile) amyloidosis. Left ventricular assist devices (LVAD) implantation can be considered but a review of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database is necessary to better evaluate the outcomes of LVAD implantation in these patients. Despite the the deteriorating cardiac function of such patients, they are rarely considered for heart transplantation due to their advanced disease presentation, age, and associated comorbidities. There are no established measures for the primary prevention of wild-type (senile) amyloidosis. There are no established measures for the secondary prevention of wild-type (senile) amyloidosis.
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.
Classification
There is no established system for the classification of wild-type (senile) amyloidosis.
Pathophysiology
Amyloid is an abnormal insoluble extracellular protein that deposits in the different tissues and causes organ dysfunction and a wide variety of clinical syndromes. Wild-type (senile) amyloidosis is a type of systemic amyloidosis as transthyretin (TTR) deposits can be found throughout the body. TTR results in pathologies due to misfolding, breaking apart, and deposition of the amyloid fibrils in healthy tissue. The condition mainly affects the heart. However, other organ systems, such as the nervous and musculoskeletal systems, can also be involved. There are no genes implicated in the causality of wild-type (senile) amyloidosis. Aging is very strongly associated with wild-type (senile) amyloidosis.
Causes
Wild-type (senile) amyloidosis is caused by the folding and/breaking apart of a normal occurring protein, transthyretin (TTR).
Differentiating Wild-type (senile) amyloidosis from Other Diseases
Wild-type (senile) amyloidosis can be differentiated from other conditions that present with heart failure, polyneuropathy, and organomegaly.
Epidemiology and Demographics
The incidence of amyloidosis is approximately 1.2 per 100,000 individuals per year worldwide. The actual incidence of wild-type (senile) amyloidosis in particular is unknown. The mortality rate of systemic amyloidosis is approximately 100 per 100,000 deaths in developed countries. Patients with wild-type (senile) amyloidosis are almost always elderly (65 years of age or older). There is no racial predilection to wild-type (senile) amyloidosis. Men are traditionally more commonly affected by wild-type (senile) amyloidosis than women.
Risk Factors
Aging has been implicated to be a risk factor for the development of wild-type (senile) amyloidosis.
Screening
There is insufficient evidence to recommend routine screening for wild-type (senile) amyloidosis.
Natural History, Complications, and Prognosis
Wild-type (senile) amyloidosis, as the name suggests, is a disease of the elderly. The clinical picture of the disease corresponds to the type of organ or organ system involved. It most commonly affects the heart and hence, clinical features pertaining to cardiac pathologies, dominate the clinical course of the disease. If left untreated, wild-type (senile) amyloidosis can lead to heart failure with reduced ejection fraction (HFrEF) and eventually death. Wild-type (senile) amyloidosis is most commonly complicated by heart failure with reduced ejection fraction (HFrEF). The median duration of survival after diagnosis is 75 months.
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, 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
The clinical features of wild-type (senile) amyloidosis depend on the type of organ or organ system involved. Cardiac and peripheral nerves involvement can result in clinically evident pathology. The most commonly involved organ is the heart and majority of the patients present with signs and symptoms of heart failure. Less common symptoms correspond to the involvement of organs or organ systems other than the heart.
Physical Examination
Physical examination of patients with wild-type (senile) amyloidosis can be significant for the condition in question and can also translate the variety of pathologies as a part of aging and age-related comorbidities.
Laboratory Findings
Wild-type (senile) amyloidosis is a diagnosis of exclusion. Laboratory tests are conducted to evaluate for the presence or absence AL amyloid protein deposition. The absence of AL amyloid provides a strong clue towards the provisional diagnosis of wild-type (senile) amyloidosis. Cardiac biomarkers are the most important predictors of outcome in amyloidosis.
Electrocardiogram
EKG findings encountered during the evaluation of a patient with wild-type (senile) amyloidosis include pseudoinfarct pattern, poor R wave progression, atrial fibrillation, first degree AV block, and nonspecific ST-T wave abnormalities. Voltage-to-mass ratio, calculated by the sum of S wave in lead V1 plus R wave in lead V5 or V6 (SV1 + RV5 or V6) divided by the echocardiographic muscle cross-sectional area, has been implicated to have high sensitivity and specificity for wild-type (senile) amyloidosis.
X-ray
There are no x-ray findings associated with wild-type (senile) amyloidosis.
Echocardiography and Ultrasound
The most commonly encountered pathology on 2D echocardiography is increased left ventricular thickness (secondary to amyloid fibrils deposition in the extracellular matrix). Advanced echocardiographic techniques (strain and strain rate imaging) can differentiate cardiomyopathy secondary to amyloidosis from other causes of left ventricular hypertrophy. In regards to the evaluation of cardiac amyloidosis, EFSR has approximately 90% and 92% sensitivity and specificity, respectively.
CT scan
There are no CT scan findings associated with wild-type (senile) amyloidosis.
MRI
T1 sequence of CMR with the use of gadolinium can differentiate extracellular tissue thickening due to myocardial hypertrophy vs. extracellular deposition. Using pre- and post-contrast T1 mapping, extracellular volume (ECV) can be calculated, which is a direct measurement of the cardiac interstitium. ECV expansion is a quantitative marker of the amyloid burden and can detect amyloid fibrils infiltration earlier than conventional testing. One of the benefits of T1 mapping is the fact that it does not require contrast, which is favorable in the setting of kidney disease.
Other Imaging Findings
Bone-avid tracers, such as 99mTc-DPD (technetium-3,3-diphosphono-1,2-propanodicar-boxylic acid), 99mTc-PYP (technetium-pyrophosphate), and 99mTc-HMDP [technetium-hydroxymethylene diphosphonate (Tc-HMDP)] have been implicated to have high sensitivity and specificity for diagnosing cardiac amyloidosis and differentiating it from other cardiomyopathies with HFpEF. Combination of grade 2 or 3 cardiac uptake on a bone-avid tracer scan in the setting of absent monoclonal protein by serum immunofixation electrophoresis (IFE), urine IFE, and serum free light chain assay is diagnostic of wild-type (senile) cardiac amyloidosis.
Other Diagnostic Studies
Other diagnostic studies that help in diagnosing wild-type (senile) amyloidosis include histopathological analysis and genetic testing.
Treatment
Medical Therapy
There is no treatment for wild-type (senile) amyloidosis; the mainstay of therapy is supportive treatment aimed at symptoms of the disease. Supportive treatment is with diuretics, antiarrhythmics or pacemaker implantation, anticoagulation where supraventricular arrhythmias are present, and an avoidance of digoxin and calcium channel blockers. Antihypertensives are usually poorly tolerated as these patients can be profoundly hypotensive. Pharmacologic therapies aimed at stabilizing the transthyretin molecule and thus preventing amyloid formation are being actively investigated.
Surgery
Surgery is not the mainstay of therapy for wild-type (senile) amyloidosis. Left ventricular assist devices (LVAD) implantation can be considered but a review of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database is necessary to better evaluate the outcomes of LVAD implantation in these patients. Despite the the deteriorating cardiac function of such patients, they are rarely considered for heart transplantation due to their advanced disease presentation, age, and associated comorbidities.
Primary Prevention
There are no established measures for the primary prevention of wild-type (senile) amyloidosis.
Secondary Prevention
There are no established measures for the secondary prevention of wild-type (senile) amyloidosis.