Amyloidosis Definition : In medicine, amyloidosis refers to a variety of conditions in which amyloid proteins are abnormally deposited in organs causing disease. A protein is amyloid if, due to an alteration in its secondary structure, it takes on a particular insoluble form, called the beta-pleated sheet.medicineamyloidproteinsorganssecondary structureinsolublebeta-pleated sheet

AMYLOIDOSIS Disease characterized by extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues. Term amyloid first coined by Virchow in mid 19 th century (meaning starch or cellulose). Amyloid found to stain with congo red, appearing red microscopically in normal light but apple green when viewed in polarized light. Fibrillar nature and beta pleated sheet configuration described by electron microscopy in 1959.

Misfolded proteins are normally detected and cleared from cell (or stored in aggresomes)

General mechanism of aggregation to form amyloid fibrils

Pathogenesis of the major forms of amyloid fibrils

Systemic amyloidoses are those which affect more than one body organ or system. Localised amyloidoses affect only one body organ or tissue type. Primary amyloidoses arise from a disease with disordered immune cell function such as multiple myeloma and other immunocyte dyscrasias.multiple myeloma Secondary (reactive) amyloidoses are those occurring as a complication of some other chronic inflammatory or tissue destructive disease.

Imaging techniques – Technetium Tc 99m pyrophosphate binds avidly to many types of amyloid. Quantitative assessment not possible and strongly positive results usually only occur in pt’s with severe disease. Technetium labeled aprotinin may be more sensitive. Quantitative scintigraphy can be done with iodine-123- labeled serum amyloid P component (sensitive for AL, ATTR and AA amyloid).

IgH chain translocations are also found in AL especially t(11;14). Monosomy 18 is also frequently found as well as deletions of chromosome 13. κ to λ ratio is approx 1:3 LCD – Non amyloid Ig deposition predominantly of κ and usually the constant region. Forms granular rather than fibrillar deposits and mainly affects the kidneys.

CategoryAmyloid typePrecursor proteinAmyloidosis Systemic acquiredAL Immunoglobin light chainsImmunoglobin light chains (Bence Jones protein)Bence Jones protein AL amyloidosis AL amyloidosis (primary amyloidosis) Systemic acquiredAASAA AA amyloidosis AA amyloidosis (secondary amyloidosis) Systemic acquired Aβ2 mAβ2 m β 2 microglobulin Haemodialysis associated Systemic hereditaryAASAA Familial mediterranean fever Systemic hereditaryATTRtransthyretin Familial amyloidotic polyneuropathies Systemic hereditaryATTRtransthyretin Systemic senile amyloidosis

Primary Amyloidosis: Histopathology

Primary Amyloidosis: Conventional Therapy General measures ◦ Delay target organ failure ◦ Improve quality of life Specific interventions ◦ Melphalan and Prednisone

Experimental approaches for the treatment of Multiple Myeloma Allogeneic transplantation (8 studies) ◦ Complete response rate26-51% ◦ Median event free survival12-36 months Revimid (CC-5013) Thalidomide derivative ◦ Phase II study PS-341 Proteosome inhibitor - Cytotoxic to plasma cells ◦ Phase II study

AA Amyloidogenesis IL-1, IL-6, TNF-  SAA1 (>70%) and SAA2 HDL-SAA Specific receptors on macrophages (spleen, liver, kidney ) Plasma concentration changes from 3–10 mg/L  100–1000 mg/L Tissue injury, infections

Chronic Inflammatory DiseasesChronic InfectionsNeoplasia Rheumatoid arthritis Psoriatic arthritis Chronic juvenile arthritis Ankylosing spondylitis Behcet’s syndrome Reiter’s syndrome Adult Still's disease Inflammatory bowel disease Hereditary periodic fevers Tuberculosis Osteomyelitis Bronchiectasis Leprosy Pyelonephritis Decubitus ulcers Whipple’s disease Acne conglobata Common variable immunodeficiency Hypo/agammaglobulinemia Cystic fibrosis Hepatoma Renal carcinoma Castleman's disease Hodgkin's disease Adult hairy cell leukemia Waldenström's disease Conditions Associated With AA Amyloidosis

Presenting Clinical Features in AA Amyloidosis Feature% Proteinuria/renal insufficiency Diarrhea/malabsorption Goiter Neuropathy/carpal tunnel syndrome Hepatomegaly Lymphadenopathy Cardiac

Macroglossia – occurs in % Amyloid can be found within any part of the GI tact and may infiltrate parenchyma, organs and nerves. Peripheral neuropathy may be presenting manifestation or develop subsequently during the course of the illness (history of carpal tunnel frequently elicited). Neuropathy usually distal, symmetric and progressive. Cranial nerve and autonomic nerve involvement also well described. Motor neuropathy rare.

Macroglossia

Purpura

HEPATIC/SPLENIC Involvement of liver common. Hepatomegaly may be striking at presentation and usually disproportionate to extent of liver enzyme abnormalities (except alkaline phosphatase which is frequently elevated). Presence of jaundice is an adverse prognostic factor and MST from onset of jaundice is only 3 months. Patients may present with severe intrahepatic cholestasis. Massive splenic deposition may result in functional hyposplenism.

Plasma-cell-type Castleman’s disease (H & E) Amyloid in the lymph node, green birefringence in polarized light Plasma-cell-Type Castleman’s disease with IL-6 release and increased SAA synthesis

Extensive hypertrophy with yellow amyloid deposits

CARDIAC May present with rapid and progressive onset of CHF. Characteristically, features are predominantly of right sided CHF. ECG – low voltage and may have a pattern of MI in absence of CAD. ECHO – concentrically thickened ventricles with normal-small cavity and diastolic dysfunction on doppler. Clinical clue is marked worsening of failure when CCB used.

Echocardiogram revealing thickened walls with small chambers

RENAL Nephrotic syndrome present in 30-50% at diagnosis. Nephrotic syndrome and renal failure develop only rarely during course of the illness if not present at time of diagnosis. λ BJP have been associated with inferior survival as compared with κ BJP or no monoclonal protein, irrespective of serum creatinine.

LambdaKappa

PATHOLOGIC CALCIFICATION

Objectives Define calcification Types of calcification Causes, feature and effect of dystrophic calcification Causes, feature and effect of metastatic calcification

Pathologic calcification is a common process in a wide variety of disease states it implies the abnormal deposition of calcium salts with smaller amounts of iron, magnesium, and other minerals.

Types of Pathologic calcification Dystrophic calcification: ◦ When the deposition occurs in dead or dying tissues ◦ it occurs with normal serum levels of calcium Metastatic calcification: ◦ The deposition of calcium salts in normal tissues ◦ It almost always reflects some derangement in calcium metabolism (hypercalcemia)

INTRACELLULAR ACCUMULATIONS

Objectives To study: Overview of intracellular accumulations Accumulation of Lipids Accumulation of Cholesterol Accumulation of Proteins Accumulation of Glycogen Accumulation of Pigments Pathologic Calcification

Lecture will include  Overview of intracellular accumulations  Accumulation of Lipids  Accumulation of Cholesterol  Accumulation of Proteins  Accumulation of Glycogen  Accumulation of Pigments  Pathologic Calcification

Fatty Change (Steatosis)

Fatty Change Fatty change refers to any abnormal accumulation of triglycerides within parenchymal cells. Site: liver, most common site ◦ it may also occur in heart, skeletal muscle, kidney, and other organs.

Causes of Fatty Change Toxins (most importantly: Alcohol abuse) diabetes mellitus Protein malnutrition (starvation) Obesity Anoxia

Lecture will include  Overview of intracellular accumulations  Accumulation of Lipids  Accumulation of Cholesterol  Accumulation of Proteins  Accumulation of Glycogen  Accumulation of Pigments  Pathologic Calcification

Cholesterol and Cholesteryl Esters

Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation

Proteins

Morphologically visible protein accumulations are much less common than lipid accumulations They may occur because excesses are presented to the cells or because the cells synthesize excessive amounts

Protein accumulations Example: 1. Nephrotic syndrome:  In the kidney trace amounts of albumin filtered through the glomerulus are normally reabsorbed by pinocytosis in the proximal convoluted tubules  After heavy protein leakage, pinocytic vesicles containing this protein fuse with lysosomes, resulting in the histologic appearance of pink, hyaline cytoplasmic droplets

The process is reversible; if the proteinuria abates, the protein droplets are metabolized and disappear.

Protein accumulations Example: 2. marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies.

Protein accumulations Example: 3. Mallory body, or "alcoholic hyalin," is an eosinophilic cytoplasmic inclusion in liver cells that is highly characteristic of alcoholic liver disease  These inclusions are composed predominantly of aggregated intermediate filaments

Protein accumulations Example: 4. The neurofibrillary tangle found in the brain in Alzheimer disease is an aggregated protein inclusion that contains microtubule-associated proteins

Lecture will include  Overview of intracellular accumulations  Accumulation of Lipids  Accumulation of Cholesterol  Accumulation of Proteins  Accumulation of Glycogen  Accumulation of Pigments  Pathologic Calcification

Pigments

 Pigments are colored substances that are either:  exogenous, coming from outside the body, or  endogenous, synthesized within the body itself.

Exogenous pigment The most common is carbon When inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes.

Exogenous pigment Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).

Hemosiderosis is systemic overload of iron, hemosiderin is deposited in many organs and tissues It is found at first in the mononuclear phagocytes of the liver, bone marrow, spleen, and lymph nodes and in scattered macrophages throughout other organs. With progressive accumulation, parenchymal cells throughout the body (principally the liver, pancreas, heart, and endocrine organs) will be affected

Hemosiderosis Hemosiderosis occurs in the setting of: 1.increased absorption of dietary iron 2.impaired utilization of iron 3.hemolytic anemias 4.transfusions (the transfused red cells constitute an exogenous load of iron)..