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)
  • Localized amyloidosis (aging, diabetes)
  • 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 by plasma 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 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). Overview and Types of Dialysis 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:
  • Calcitonin amyloid (ACal) is associated with medullary carcinoma of the thyroid.
  • Prolactin amyloid (APro) is associated with the aging pituitary.
• 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.
• Prion protein-associated amyloid (APrP) disease is caused by infectious proteins 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, Creutzfeldt-Jakob disease, 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.)

Epidemiology

• Most common systemic cause in clinical practice is AL:
  • > 80% are idiopathic.
  • < 20% are due to multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma.
    • Multiple myeloma is the most common identifiable cause in clinical practice.
• Most common inflammatory cause in clinical practice is rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis:
  • 6% of amyloidotic cases are associated with an inflammatory condition.
  • 3% of rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis patients have an amyloid deposition.
• Most common hereditary cause in clinical practice is ATTR.
• Most common causes of death are heart disease and renal failure.
• AL survival is approximately 12 months after diagnosis.
• Familial amyloidosis survival is approximately 7–15 years after diagnosis.

Pathophysiology

• Misfolded proteins (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 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.
  • Extracellular matrix 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 constituents

Clinical Presentation

Clinical presentation depends on the organ/organs involved.

• Heart:
  • Myocardial deposition causes restrictive 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). Overview of Cardiomyopathies:
    • 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 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, and fatigue.
  • Conduction system involvement causes arrhythmia:
    • Symptoms include palpitations, fatigue, 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.
• 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. Structure and Function of the Skin:
  • 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:
  • Ranges from mild proteinuria to frank nephrosis
  • Possible progression to azotemia and death
  • Dialysis or transplant improves prognosis.
• Liver:
  • Hepatomegaly is common in most forms of amyloid (except in ATTR).
  • Liver 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 involvement:
    • Symptoms (GI tract):
      • Obstruction, ulceration, malabsorption Malabsorption Malabsorption involves many disorders in which there is an inability of the gut to absorb nutrients from dietary intake, potentially including water and/or electrolytes. A closely related term, maldigestion is the inability to break down large molecules of food into their smaller constituents. Malabsorption and maldigestion can affect macronutrients (fats, proteins, and carbohydrates), micronutrients (vitamins and minerals), or both. Malabsorption and Maldigestion, and/or hemorrhage
    • Symptoms (GI autonomics):
      • Dysmotility, nausea, vomiting, 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. Oral Cavity: Lips and Tongue:
  • 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. Oral Cavity: Lips and Tongue involvement is a common manifestation of AL.
    • Symptoms: stiffened musculature → dysarthria, firmness to palpation → occasional macroglossia → risk for obstructive sleep apnea Obstructive sleep apnea Obstructive sleep apnea (OSA) is a disorder characterized by recurrent obstruction of the upper airway during sleep, causing hypoxia and fragmented sleep. Obstructive sleep apnea is due to a partial or complete collapse of the upper airway and is associated with snoring, restlessness, sleep interruption, and daytime somnolence. Obstructive Sleep Apnea
• Brain:
  • 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 development in Aβ → neurodegenerative changes typical of Alzheimer’s disease
• Peripheral nerves:
  • 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. Overview of the Cranial Nerves usually spared:
    • Symptoms (sensory):
      • Numbness, neuropathic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, paresthesia, dysesthesia, and/or allodynia
    • Symptoms (motor):
      • Weakness, cramping, and/or discoordination
    • Carpal tunnel 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. Overview of the Cranial Nerves 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. Physiology and Abnormalities of the Pupil 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. Physiology and Abnormalities of the Pupil:
        • 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, sphincter failure, GI dysmotility, and/or loss of sweat reflex
• Musculoskeletal: 
  • Articular involvement is rare, almost exclusively in AL due to multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma, presents like rheumatic disease with symmetrical small joint involvement.
  • Muscle infiltration → pseudomyopathy, pseudohypertrophy (shoulder involvement → “shoulder pad” sign)
• Hematologic:
  • Factor X binding to amyloid fibrils → splenic sequestration → increased bleeding risk
  • Fibrinogen deficiency, increased fibrinolysis, and an increase in endothelial damage compound bleeding risk.
• Pulmonary:
  • Tracheobronchial infiltration → hoarseness, stridor, and/or airway obstruction Airway obstruction Airway obstruction is a partial or complete blockage of the airways that impedes airflow. An airway obstruction can be classified as upper, central, or lower depending on location. Lower airway obstruction (LAO) is usually a manifestation of chronic disease, such as asthma or chronic obstructive pulmonary disease (COPD). Airway 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
• History of hematologic disorders/plasma cell dyscrasias
• Autoimmune conditions ( rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis, 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:

• 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, 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 of the specific organ for localized involvement:
  • Muscle, peripheral nerves, and/or skin

Tests specific to the underlying disease: 

• Hereditary amyloidosis:
  • Gene sequencing
• Suspected AL:
  • IgM–associated disorders:
    • Multiple myeloma
    • Waldenstrom’s macroglobulinemia
  • Workup includes:
    • Serum and/or urine electrophoresis
    • Bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow biopsy
• Suspected AA:
  • Chronic inflammatory conditions and systemic conditions
  • Workup may include:
    • Rheumatoid arthritis:
      • Rheumatoid factor assay
    • Sjogren’s syndrome:
      • Antibodies 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). Overview of Cardiomyopathies)
    • 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 for AL amyloidosis
  • Promote proteolysis or mobilization of existing deposits:
    • Gantenerumab:
      • An antibody that binds to aggregated Aβ
    • Tocilizumab:
      • Used for arthritis
• Supportive treatment (e.g., symptomatic management of organ decompensation)
• Hemodialysis for renal involvement
• Colchicine for familial Mediterranean fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever (AA)
• Melphalan, iododoxorubicin, and alkylating agents for plasma cell dyscrasias (AL)
• Stem cell transplantation for AL due to multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
• Splenectomy for Factor X 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 associated with glomerular basement membrane thickening. This condition presents with proteinuria, 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 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, 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 accumulation in 1 or multiple organs. This condition can involve skin (primarily) or multiple organs. Symptoms depend on the organs involved and can include maculopapular rash, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, vomiting, 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. Diagnosis is established with skin and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones marrow biopsy. Treatment is mostly with medications.
• Pseudoxanthoma elasticum: the ectopic mineralization and fragmentation of elastic fibers in the skin, eyes, vascular system, and/or GI system. This condition presents with characteristic skin changes and eye/cardiovascular manifestations. Diagnosis is established from a combination of clinical findings, skin biopsy, and genetic testing. Management is mostly supportive.