Amyloidosis

Overview

Definition

Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits.

Classification

• Based on the identity of the fibril-forming protein:
  • Systemic amyloidosis (neoplastic, inflammatory, genetic, iatrogenic Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome)
  • Localized amyloidosis (aging, diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus)
  • Hereditary amyloidosis
• Named with a capital letter A (for amyloid) followed by precursor protein designation (e.g., AL = amyloid light chain)

Etiology

Systemic amyloidosis:

• Light chain amyloid (AL) disease results from disproportionate production of immunoglobulin light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions by plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cells (lambda > kappa).
• Amyloid A amyloidosis (AA) disease manifests as a systemic complication of inflammatory disease.
• β₂-microglobulin amyloid (Aβ₂M) is observed in the setting of long-term hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome due to inadequate filtration by the dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis membrane.

Localized amyloidosis:

• Amyloid deposits form in the vicinity of tissues/organs/tumors that produce polypeptide hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types:
  • Calcitonin Calcitonin A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. Other Antiresorptive Drugs amyloid (ACal) is associated with medullary carcinoma of the thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy.
  • Prolactin Prolactin A lactogenic hormone secreted by the adenohypophysis. It is a polypeptide of approximately 23 kd. Besides its major action on lactation, in some species prolactin exerts effects on reproduction, maternal behavior, fat metabolism, immunomodulation and osmoregulation. Breasts: Anatomy amyloid (APro) is associated with the aging pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types.
• Alzheimer’s-associated amyloid (Aβ) disease manifests as deposits in cerebrovascular walls and neuritic plaques in Alzheimer’s disease and Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21).
• Prion protein-associated amyloid (APrP) disease is caused by infectious proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis associated with the transmissible spongiform encephalopathies Transmissible Spongiform Encephalopathies Transmissible spongiform encephalopathies (TSEs) are diseases caused by prions. Prions differ from viruses in that they are small, infectious pathogens that do not contain nucleic acid. Recognized TSEs include Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), Kuru, fatal familial insomnia (FFI), and Gerstmann-Straussler syndrome (GSS). Transmissible Spongiform Encephalopathies ( Kuru Kuru A prion disease found exclusively among the fore linguistic group natives of the highlands of new guinea. The illness is primarily restricted to adult females and children of both sexes. It is marked by the subacute onset of tremor and ataxia followed by motor weakness and incontinence. Death occurs within 3-6 months of disease onset. The condition is associated with ritual cannibalism, and has become rare since this practice has been discontinued. Pathologic features include a noninflammatory loss of neurons that is most prominent in the cerebellum, glial proliferation, and amyloid plaques. Transmissible Spongiform Encephalopathies, Creutzfeldt-Jakob disease Creutzfeldt-Jakob Disease A rare transmissible encephalopathy most prevalent between the ages of 50 and 70 years. Affected individuals may present with sleep disturbances, personality changes, ataxia; aphasia, visual loss, weakness, muscle atrophy, myoclonus, progressive dementia, and death within one year of disease onset. A familial form exhibiting autosomal dominant inheritance and a new variant cjd (potentially associated with bovine spongiform encephalopathy) have been described. Pathological features include prominent cerebellar and cerebral cortical spongiform degeneration and the presence of prions. Transmissible Spongiform Encephalopathies, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).).
• Systemic amyloidosis can be observed as localized deposits.

Hereditary amyloidosis:

• Associated with protein mutations
• Abnormal folding → fibril formation (transthyretin amyloid = ATTR, apolipoprotein I amyloid = AApoAI, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).)

Epidemiology

• Most common systemic cause in clinical practice is AL:
  • > 80% are idiopathic Idiopathic Dermatomyositis.
  • < 20% are due to multiple myeloma.
    • Multiple myeloma is the most common identifiable cause in clinical practice.
• Most common inflammatory cause in clinical practice is rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis:
  • 6% of amyloidotic cases are associated with an inflammatory condition.
  • 3% of rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have an amyloid deposition.
• Most common hereditary cause in clinical practice is ATTR.
• Most common causes of death are heart disease and renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome.
• Untreated AL amyloidosis has a median survival of 12 months, but with treatment, it now exceeds 3 years
• Familial amyloidosis survival is approximately 7–15 years after diagnosis.

Pathophysiology

• Misfolded proteins Misfolded Proteins Cell Injury and Death (almost always in β-pleated sheet configuration) aggregate into insoluble fibrils.
• Deposition and amyloid formation within the tissue interferes with tissue physiology.
• Cellular injury and apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage results.
• Under “normal” physiologic conditions:
  • Amyloidogenic precursors are not produced in excess.
  • No genetic predisposition for amyloid formation
  • Proteolytic mechanisms exist to degrade excess proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis.
  • Extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars constituents do not allow protein deposition.
• There are 4 pathophysiologic features common to all types of amyloid formation:
  • Amyloidogenic protein precursors present in excessive concentration
  • Genetic predisposition
  • Inadequate proteolytic mechanisms
  • Abnormalities in extracellular matrix Extracellular matrix A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. Hypertrophic and Keloid Scars constituents

Types of Amyloidosis

Systemic amyloidosis

• AL:
  • Precursor is immunoglobulin light chains Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions (lambda type).
  • Associated with plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell dyscrasias (e.g., multiple myeloma, Waldenstrom’s macroglobulinemia)
• AA:
  • Precursor protein is serum amyloid A protein.
  • Produced by the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy in response to cytokines Cytokines Non-antibody proteins secreted by inflammatory leukocytes and some non-leukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner. Adaptive Immune Response (e.g., IL-1)
  • Associated with chronic inflammatory conditions and infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (e.g., rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis)
• Aβ₂M:
  • β₂-microglobulin is the precursor protein.
  • Associated with chronic hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome
  • ↑ β₂-microglobulin concentration due to inefficient filtration through dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis membranes

Localized amyloidosis

• Aβ:
  • Precursor protein is a novel β protein.
  • Associated with Alzheimer’s disease and Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down syndrome (Trisomy 21)
  • Deposits mainly around cerebral blood vessels and neuritic plaques
• ACal:
  • Precursor protein is calcitonin Calcitonin A peptide hormone that lowers calcium concentration in the blood. In humans, it is released by thyroid cells and acts to decrease the formation and absorptive activity of osteoclasts. Its role in regulating plasma calcium is much greater in children and in certain diseases than in normal adults. Other Antiresorptive Drugs.
  • Associated with thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy medullary carcinoma
  • Deposits in the thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy gland
• AIAPP:
  • Precursor protein is islet amyloid polypeptide (IAPP) or amylin.
  • Associated with type 2 diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus
  • Deposits in the pancreas Pancreas The pancreas lies mostly posterior to the stomach and extends across the posterior abdominal wall from the duodenum on the right to the spleen on the left. This organ has both exocrine and endocrine tissue. Pancreas: Anatomy
• AANP:
  • Precursor protein is atrial natriuretic peptide Atrial natriuretic peptide A potent natriuretic and vasodilatory peptide or mixture of different-sized low molecular weight peptides derived from a common precursor and secreted mainly by the heart atrium. All these peptides share a sequence of about 20 amino acids. Renal Sodium and Water Regulation.
  • Causes isolated atrial amyloidosis
  • Deposits in the atria → affect electrical conduction → arrhythmia

Hereditary amyloidosis

• AA:
  • Associated with familial Mediterranean fever Mediterranean fever Brucellosis (also known as undulant fever, mediterranean fever, or malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Brucella/Brucellosis
• ATTR:
  • Precursor protein is mutated transthyretin.
  • Associated with familial amyloid neuropathy Neuropathy Leprosy and familial amyloid cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types
  • Deposits in peripheral nervous system Peripheral nervous system The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. Nervous System: Anatomy, Structure, and Classification, autonomic nervous system Autonomic nervous system The ANS is a component of the peripheral nervous system that uses both afferent (sensory) and efferent (effector) neurons, which control the functioning of the internal organs and involuntary processes via connections with the CNS. The ANS consists of the sympathetic and parasympathetic nervous systems. Autonomic Nervous System: Anatomy, and myocardium Myocardium The muscle tissue of the heart. It is composed of striated, involuntary muscle cells connected to form the contractile pump to generate blood flow. Heart: Anatomy

Clinical Presentation

Clinical presentation depends on the organ/organs involved.

• Heart:
  • Myocardial deposition causes restrictive cardiomyopathy Restrictive Cardiomyopathy Restrictive cardiomyopathy (RCM) is a fairly uncommon condition characterized by progressive stiffening of the cardiac muscle, which causes impaired relaxation and refilling of the heart during diastole, resulting in diastolic dysfunction and eventual heart failure. Restrictive Cardiomyopathy:
    • Symptoms include dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, peripheral edema Peripheral edema Peripheral edema is the swelling of the lower extremities, namely, legs, feet, and ankles. Edema, and fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia.
  • Conduction system involvement causes arrhythmia:
    • Symptoms include palpitations Palpitations Ebstein’s Anomaly, fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, and sudden cardiac death Sudden cardiac death Cardiac arrest is the sudden, complete cessation of cardiac output with hemodynamic collapse. Patients present as pulseless, unresponsive, and apneic. Rhythms associated with cardiac arrest are ventricular fibrillation/tachycardia, asystole, or pulseless electrical activity. Cardiac Arrest.
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions:
  • Raised waxy papules or plaques
  • Found in axillary, anal, and/or inguinal folds
  • Periorbital ecchymosis (also known as “black eyes” or “raccoon eyes”)
• Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy:
  • Ranges from mild proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children to frank nephrosis
  • Possible progression to azotemia Azotemia A biochemical abnormality referring to an elevation of blood urea nitrogen and creatinine. Azotemia can be produced by kidney diseases or other extrarenal disorders. When azotemia becomes associated with a constellation of clinical signs, it is termed uremia. Acute Kidney Injury and death
  • Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Peritoneal Dialysis and Hemodialysis or transplant improves prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas.
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy:
  • Hepatomegaly is common in most forms of amyloid (except in ATTR).
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy function abnormalities are minimal and occur late in the disease.
• Intestine:
  • GI involvement is common in all systemic amyloidosis. The symptoms could either be direct GI tract infiltration or autonomic nervous system Autonomic nervous system The ANS is a component of the peripheral nervous system that uses both afferent (sensory) and efferent (effector) neurons, which control the functioning of the internal organs and involuntary processes via connections with the CNS. The ANS consists of the sympathetic and parasympathetic nervous systems. Autonomic Nervous System: Anatomy involvement:
    • Symptoms (GI tract):
      • Obstruction, ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers, malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion, and/or hemorrhage
    • Symptoms (GI autonomics):
      • Dysmotility, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, and/or constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
• Tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy:
  • Tongue Tongue The tongue, on the other hand, is a complex muscular structure that permits tasting and facilitates the process of mastication and communication. The blood supply of the tongue originates from the external carotid artery, and the innervation is through cranial nerves. Lips and Tongue: Anatomy involvement is a common manifestation of AL.
    • Symptoms: stiffened musculature → dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease, firmness to palpation Palpation Application of fingers with light pressure to the surface of the body to determine consistency of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. Dermatologic Examination → occasional macroglossia Macroglossia The presence of an excessively large tongue, which may be congenital or may develop as a result of a tumor or edema due to obstruction of lymphatic vessels, or it may occur in association with hyperpituitarism or acromegaly. It also may be associated with malocclusion because of pressure of the tongue on the teeth. Wilms Tumor → risk for obstructive sleep apnea Sleep apnea Repeated cessation of breathing for > 10 seconds during sleep and results in sleep interruption, fatigue, and daytime sleepiness. Obstructive Sleep Apnea
• Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification:
  • Cerebrovascular endothelial amyloid deposition in Aβ → increased risk of cerebrovascular accident Cerebrovascular accident An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke
  • Neuritic plaque Plaque Primary Skin Lesions development in Aβ → neurodegenerative changes typical of Alzheimer’s disease
• Peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology:
  • Peripheral nerve damage (especially in hereditary amyloidosis) with the cranial nerves Cranial nerves There are 12 pairs of cranial nerves (CNs), which run from the brain to various parts of the head, neck, and trunk. The CNs can be sensory or motor or both. The CNs are named and numbered in Roman numerals according to their location, from the front to the back of the brain. The 12 Cranial Nerves: Overview and Functions usually spared:
    • Symptoms ( sensory Sensory Neurons which conduct nerve impulses to the central nervous system. Nervous System: Histology):
      • Numbness, neuropathic pain Neuropathic pain Caused by lesion or disease affecting the nervous system (PNS or CNS). Pain: Types and Pathways, paresthesia, dysesthesia Dysesthesia Complex Regional Pain Syndrome (CRPS), and/or allodynia Allodynia Pain due to a stimulus that does not typically provoke pain. Pain Management
    • Symptoms ( motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology):
      • Weakness, cramping, and/or discoordination
    • Carpal tunnel Carpal Tunnel The carpal tunnel is formed by the transverse carpal ligament (flexor retinaculum) superiorly and the carpal bones inferiorly. Carpal Tunnel Syndrome syndrome is common in AL, Aβ₂M, and ATTR.
  • Autonomic nerve damage (especially in hereditary amyloidosis) with the cranial nerves Cranial nerves There are 12 pairs of cranial nerves (CNs), which run from the brain to various parts of the head, neck, and trunk. The CNs can be sensory or motor or both. The CNs are named and numbered in Roman numerals according to their location, from the front to the back of the brain. The 12 Cranial Nerves: Overview and Functions not spared:
    • Symptoms (CN3):
      • Tonic pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities or Adie’s pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities:
        • CN3 parasympathetic dysfunction (does not dilate in the dark)
    • Symptoms (peripheral):
      • Postural hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, urinary retention Urinary retention Inability to empty the urinary bladder with voiding (urination). Delirium, sphincter failure, GI dysmotility, and/or loss of sweat reflex
• Musculoskeletal:
  • Articular involvement is rare, almost exclusively in AL due to multiple myeloma, presents like rheumatic disease with symmetrical Symmetrical Dermatologic Examination small joint involvement.
  • Muscle infiltration → pseudomyopathy, pseudohypertrophy (shoulder involvement → “shoulder pad” sign)
• Hematologic:
  • Factor X Factor X Storage-stable glycoprotein blood coagulation factor that can be activated to factor Xa by both the intrinsic and extrinsic pathways. A deficiency of factor X, sometimes called stuart-prower factor deficiency, may lead to a systemic coagulation disorder. Hemostasis binding to amyloid fibrils → splenic sequestration Splenic sequestration Severe Congenital Neutropenia → increased bleeding risk
  • Fibrinogen Fibrinogen Plasma glycoprotein clotted by thrombin, composed of a dimer of three non-identical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides a and b, the proteolytic action of other enzymes yields different fibrinogen degradation products. Hemostasis deficiency, increased fibrinolysis, and an increase in endothelial damage compound bleeding risk.
• Pulmonary:
  • Tracheobronchial infiltration → hoarseness Hoarseness An unnaturally deep or rough quality of voice. Parapharyngeal Abscess, stridor Stridor Laryngomalacia and Tracheomalacia, and/or airway Airway ABCDE Assessment obstruction
  • Pleural infiltration → pleural effusions
  • Parenchymal nodules
  • Pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension (rare)

Diagnosis and Management

Diagnosis

History and physical exam:

• Family history Family History Adult Health Maintenance
• History of hematologic disorders/ plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell dyscrasias
• Autoimmune conditions (rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, Sjogren’s syndrome)
• Nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome in association with another systemic disease
• Physical exam findings may or may not be significant depending on the organs involved.

Tissue biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:

• Definitive diagnosis
• Usually abdominal fat, renal, salivary glands Salivary glands The salivary glands are exocrine glands positioned in and around the oral cavity. These glands are responsible for secreting saliva into the mouth, which aids in digestion. There are 3 major paired salivary glands: the sublingual, submandibular, and parotid glands. Salivary Glands: Anatomy, or rectal
• Amorphous extracellular depositions stain red or pink with H&E stain.
• Apple green birefringence under a polarized microscope with Congo red stain
• Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma of the specific organ for localized involvement:
  • Muscle, peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology, and/or skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions

Tests specific to the underlying disease: 

• Hereditary amyloidosis:
  • Gene sequencing Gene sequencing Polymerase Chain Reaction (PCR)
• Suspected AL:
  • Plasma-cell and lymphoplasmacytic disorders:
    • Multiple myeloma
    • Waldenstrom’s macroglobulinemia
  • Workup includes:
    • Serum and/or urine electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques
    • Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma
• Suspected AA:
  • Chronic inflammatory conditions and systemic conditions
  • Workup may include:
    • Rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis:
      • Rheumatoid factor Rheumatoid factor Antibodies found in adult rheumatoid arthritis patients that are directed against gamma-chain immunoglobulins. Autoimmune Hepatitis assay
    • Sjogren’s syndrome:
      • Antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions SS-A and SS-B

Management

• Varies based on the fibril type and the organs involved.
• Treatment of the underlying cause:
  • Reduce precursor protein production:
    • Tafamidis:
      • Stabilizes native transthyretin (approved for cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Cardiomyopathy: Overview and Types)
    • Patisiran:
      • Inhibits mutant transthyretin production (for polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy)
  • Inhibit extracellular protein deposition:
    • Daratumumab/ hyaluronidase Hyaluronidase Bacteroides for AL amyloidosis
  • Promote proteolysis or mobilization of existing deposits:
    • Gantenerumab:
      • An antibody that binds to aggregated Aβ
    • Tocilizumab Tocilizumab Immunosuppressants:
      • Used for arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis
• Supportive treatment (e.g., symptomatic management of organ decompensation)
• Hemodialysis Hemodialysis Procedures which temporarily or permanently remedy insufficient cleansing of body fluids by the kidneys. Crush Syndrome for renal involvement
• Colchicine Colchicine A major alkaloid from colchicum autumnale l. And found also in other colchicum species. Its primary therapeutic use is in the treatment of gout. Gout Drugs for familial Mediterranean fever Mediterranean fever Brucellosis (also known as undulant fever, mediterranean fever, or malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Brucella/Brucellosis (AA)
• Melphalan Melphalan An alkylating nitrogen mustard that is used as an antineoplastic in the form of the levo isomer – melphalan, the racemic mixture – melphalan, and the dextro isomer – melphalan; toxic to bone marrow, but little vesicant action; potential carcinogen. Alkylating Agents and Platinum, iododoxorubicin, and alkylating agents for plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell dyscrasias (AL)
• Stem cell transplantation for AL due to multiple myeloma
• Splenectomy Splenectomy Surgical procedure involving either partial or entire removal of the spleen. Rupture of the Spleen for Factor X Factor X Storage-stable glycoprotein blood coagulation factor that can be activated to factor Xa by both the intrinsic and extrinsic pathways. A deficiency of factor X, sometimes called stuart-prower factor deficiency, may lead to a systemic coagulation disorder. Hemostasis deficiency
• Organ transplantation Organ Transplantation Transplantation is a procedure that involves the removal of an organ or living tissue and placing it into a different part of the body or into a different person. Organ transplantations have become the therapeutic option of choice for many individuals with end-stage organ failure. Organ Transplantation once tissue deposition has been confirmed

Differential Diagnosis

• Membranous nephropathy: a nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome associated with glomerular basement membrane Basement membrane A darkly stained mat-like extracellular matrix (ecm) that separates cell layers, such as epithelium from endothelium or a layer of connective tissue. The ecm layer that supports an overlying epithelium or endothelium is called basal lamina. Basement membrane (bm) can be formed by the fusion of either two adjacent basal laminae or a basal lamina with an adjacent reticular lamina of connective tissue. Bm, composed mainly of type IV collagen; glycoprotein laminin; and proteoglycan, provides barriers as well as channels between interacting cell layers. Thin Basement Membrane Nephropathy (TBMN) thickening. This condition presents with proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, weight gain, and/or lower extremity edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema. Diagnosis is established with renal biopsy Renal Biopsy Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis or serological studies. Treatment is mostly supportive but can include immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants in severe cases.
• Cutis verticis gyrata: the thickening and folding of the scalp skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, which may occur in association with amyloidosis or other diseases. However, cutis verticis gyrata can be a primary condition. Diagnosis is established clinically and a workup for associated conditions is usually performed. Treatment for a primary condition involves cosmetic surgical procedures.
• Mastocytosis: an excessive mast cell Mast cell Granulated cells that are found in almost all tissues, most abundantly in the skin and the gastrointestinal tract. Like the basophils, mast cells contain large amounts of histamine and heparin. Unlike basophils, mast cells normally remain in the tissues and do not circulate in the blood. Mast cells, derived from the bone marrow stem cells, are regulated by the stem cell factor. Angioedema accumulation in 1 or multiple organs. This condition can involve skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions (primarily) or multiple organs. Symptoms depend on the organs involved and can include maculopapular Maculopapular Dermatologic Examination rash Rash Rocky Mountain Spotted Fever, abdominal pain Abdominal Pain Acute Abdomen, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, neuropsychiatric manifestations, and/or myalgias Myalgias Painful sensation in the muscles. Tick-borne Encephalitis Virus. Diagnosis is established with skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions and bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Treatment is mostly with medications.
• Pseudoxanthoma elasticum: the ectopic mineralization and fragmentation Fragmentation Chronic Apophyseal Injury of elastic Elastic Connective Tissue: Histology fibers in the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, eyes, vascular system, and/or GI system. This condition presents with characteristic skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions changes and eye/cardiovascular manifestations. Diagnosis is established from a combination of clinical findings, skin biopsy Skin Biopsy Secondary Skin Lesions, and genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management is mostly supportive.