Amyloidosis

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.

Or tissues1AMYLOIDOSISDisease characterized by extracellular deposition of pathologic insoluble fibrillar proteins in organs and tissues.Term amyloid first coined by Virchow in mid 19th 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)3Regulation of protein folding in the ER. Many newly synthesized proteins are translocated into the ER, where they fold into their three-dimensional structures with the help of a series of molecular chaperones and folding catalysts (not shown). Correctly folded proteins are then transported to the Golgi complex and then delivered to the extracellular environment. However, incorrectly folded proteins are detected by a quality-control mechanism and sent along another pathway (the unfolded protein response) in which they are ubiquitinated and then degraded in the cytoplasm by proteasomes

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General mechanism of aggregation to form amyloid fibrils5Unfolded or partially unfolded proteins associate with each other to form small, soluble aggregates that undergo further assembly into protofibrils or protofilaments (a) and then mature fibrils (b). The fibrils often accumulate in plaques or other structures such as the Lewy bodies associated with Parkinsons disease (c). Some of the early aggregates seem to be amorphous or micellar in nature, although others form ring-shaped species with diameters of approximately 10 nm (d).

Pathogenesis of the major forms of amyloid fibrils

6Figure 6-54 Proposed schema of the pathogenesis of the major forms of amyloid fibrils.Robbins-CotranSystemic 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.

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 pts 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. to ratio is approx 1:3LCD Non amyloid Ig deposition predominantly of and usually the constant region. Forms granular rather than fibrillar deposits and mainly affects the kidneys. CategoryAmyloid typePrecursor proteinAmyloidosisSystemic acquiredALImmunoglobin light chains (Bence Jones protein)AL amyloidosis (primary amyloidosis)Systemic acquiredAASAAAA amyloidosis (secondary amyloidosis)Systemic acquiredA2 m2 microglobulinHaemodialysis associatedSystemic hereditaryAASAAFamilial mediterranean feverSystemic hereditaryATTRtransthyretinFamilial amyloidotic polyneuropathiesSystemic hereditaryATTRtransthyretinSystemic senile amyloidosis

Primary Amyloidosis: Histopathology

Tongue(Macroglossia)Tongue(Macroglossia)

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Primary Amyloidosis: Conventional TherapyGeneral measuresDelay target organ failureImprove quality of life

Specific interventionsMelphalan and Prednisone

Experimental approaches for the treatment of Multiple MyelomaAllogeneic transplantation (8 studies)Complete response rate26-51%Median event free survival12-36 monthsRevimid (CC-5013) Thalidomide derivativePhase II studyPS-341 Proteosome inhibitor - Cytotoxic to plasma cellsPhase II studyAA AmyloidogenesisIL-1, IL-6, TNF- SAA1 (>70%) and SAA2 HDL-SAA Specific receptors on macrophages (spleen, liver, kidney) Plasma concentration changes from310 mg/L 1001000 mg/LTissue injury, infections 21Chronic Inflammatory DiseasesChronic InfectionsNeoplasiaRheumatoid arthritis Psoriatic arthritisChronic juvenile arthritisAnkylosing spondylitisBehcets syndrome Reiters syndromeAdult Still's disease

Inflammatory bowel disease

Hereditary periodic feversTuberculosisOsteomyelitis Bronchiectasis Leprosy Pyelonephritis Decubitus ulcers Whipples diseaseAcne conglobata

Common variable immunodeficiencyHypo/agammaglobulinemia

Cystic fibrosis HepatomaRenal carcinomaCastleman's diseaseHodgkin's diseaseAdult hairy cell leukemiaWaldenstrm's disease

Conditions Associated With AA Amyloidosis22 Presenting Clinical Features in AA AmyloidosisFeature%Proteinuria/renal insufficiency Diarrhea/malabsorption Goiter Neuropathy/carpal tunnel syndrome Hepatomegaly Lymphadenopathy Cardiac 912293521-2Macroglossia occurs in 10-20 %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/SPLENICInvolvement 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.

Amyloidosisof the liver

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Red Arrow atropic hepatocytesBlack Arrow amyloid deposition 31

Liver biopsy. Hyaline material within the sinusoids is compressing the hepatocytes (hematoxylin and eosin).

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Liver biopsy. Immunohistochemical stain for amyloid P component shows a brown label in the same sinusoidal location as the hyaline matrix material. Amyloid P component is present in all form of amyloid.

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Plasma-cell-type Castlemansdisease (H & E)Amyloid in the lymph node, green birefringence in polarized light

Plasma-cell-Type Castlemansdisease with IL-6 release and increased SAA synthesis34

Extensive hypertrophy with yellow amyloid deposits

Amyloidosis is a collection of disease entities that produce considerable morbidity and mortality and are increasing in prevalence. The imaging findings are problematically nonspecific and diverse. This lack of specificity is compounded by the fact that amyloidosis is strongly associated with and frequently coexists with many other chronic disease states that have their own imaging findings. Amyloidosis can involve any organ singly or in conjunction with other organs and can do so in the form of a focal, tumorlike lesion or an infiltrative process. In the proper clinical setting, that is, in a patient with chronic inflammatory disease and especially in a patient with multiple myeloma, amyloidosis should be considered as a possible cause of worsening or new symptoms or imaging findings. Occasionally, the radiologic findings may precede the clinical findings, thus providing the radiologist with the opportunity to contribute to the patients care. However, to make a difference in patient care, the radiologist must be familiar with the diverse imaging findings of amyloidosis as well as the patients clinical history, which could raise the suspicion of amyloidosis. 36CARDIACMay 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

This heart from a patient with primary amyloidosis is enlarged to more than five times the size of the normal organ as a result of extensive amyloid deposition39

Amyloidosis is characterized by slow deposition over years of increasing amounts of an amorphous proteinaceous material in one or more tissues. Seen here in the heart between the darker red myofibers are pale pink amyloid deposits.

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When stained with Congo red and observed under polarized light, the amyloid has a characteristic "apple green" birefringence as seen here in a deposit around an artery in the heart.

41RENALNephrotic 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. BJP have been associated with inferior survival as compared with BJP or no monoclonal protein, irrespective of serum creatinine.

Amyloidosis, a chronic renal disease that may actually increase the size of the kidney. Pale deposits of amyloid are present in the cortex, most prominently at the upper center.

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Renal amyloidosis. Notice expansion of the mesangium by amorphous, acellular material. Several capillaries have been occluded by the infiltrating material PAS. Amyloid is not a unique protein, immunohistochemical stains are essential to elucidate the nature and composition of the amyloid deposits.

Renal amyloidosis. The material is Congo Red positive, as illustrated on this slide (Congo Red stain). Examination of this and the control slide under polarized light is essential (see next image)

Renal amyloidosis. Characteristic green dicroism (birefringence) of the amyloid stained with Congo red and viewed under polarized light (right panel) and conventional light microscopy on the left. (Congo red stain, polarized light on the right panel). Examination of the Con red-stained slides is absolutely essential in the evaluation of the biopsy for amyloidosis.

Renal amyloidosis. Predominantly interstitial amyloid deposits. Some patients with amyloidosis can have symptoms attributable to tubulo-interstitial involvement. Notice amyloid deposits between the tubular basement membranes and the epithelium (arrows). (PAS)

Renal amyloidosis. Predominantly vascular involvement. These patients tend to present with mild proteinuria only, however, renal failure and other organ involvement (heart disease) is often the main clinical feature. (PAS)

LambdaKappaRenal amyloidosis. The immunofluorescence microscopy in patients with AL amyloid (light chain-derived amyloid) shows a positive reactivity for only one of the light chains. About 85% of AL amyloidosis is lambda light chain-reactive, 15% are composed of kappa light chains.

Renal amyloidosis. Characteristic infiltration of the capillary wall (subendothelial and subepithelial spaces) and of the mesangium by amorphous material. Notice the extensive degenerative changes and effacement of foot processes. On higher magnification this material is fibrillary in nature.

Renal amyloidosis. Characteristic amyloid fibrils (10-12 nanometer in diameter) are seen on this EM. The material is located in the mesangium.

Extracellular amorphous eosinophilic masses in the papillary dermis and thinning and obliteration of the rete ridges. There are diffuse deposits in the reticular dermis and subcutis with infiltration into blood vessel walls and pilosebaceous units. There is a marked infiltration of plasma cells.

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By electron microscopy, amyloid is composed of fibrils, seen here as irregular grey material.

53PATHOLOGIC CALCIFICATION 54ObjectivesDefine calcificationTypes of calcificationCauses, feature and effect of dystrophic calcificationCauses, feature and effect of metastatic calcificationPathologic calcificationis 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. 56Types of Pathologic calcificationDystrophic 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 58ObjectivesTo study:Overview of intracellular accumulationsAccumulation of LipidsAccumulation of CholesterolAccumulation of ProteinsAccumulation of GlycogenAccumulation of PigmentsPathologic Calcification59Lecture will includeOverview of intracellular accumulationsAccumulation of LipidsAccumulation of CholesterolAccumulation of ProteinsAccumulation of GlycogenAccumulation of PigmentsPathologic Calcification60

Fatty Change(Steatosis)61Fatty ChangeFatty change refers to any abnormal accumulation of triglycerides within parenchymal cells. Site: liver, most common siteit may also occur in heart, skeletal muscle, kidney, and other organs. 62Causes of Fatty ChangeToxins (most importantly: Alcohol abuse)diabetes mellitus Protein malnutrition (starvation)ObesityAnoxia 63Lecture will includeOverview of intracellular accumulationsAccumulation of LipidsAccumulation of CholesterolAccumulation of ProteinsAccumulation of GlycogenAccumulation of PigmentsPathologic Calcification64Cholesterol and Cholesteryl Esters 65Cellular cholesterol metabolism is tightly regulated to ensure normal cell membrane synthesis without significant intracellular accumulation 66Proteins 67Morphologically visible protein accumulations are much less common than lipid accumulationsThey may occur because excesses are presented to the cells or because the cells synthesize excessive amounts 68Protein accumulations Example: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

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

70Protein accumulations Example:2. marked accumulation of newly synthesized immunoglobulins that may occur in the RER of some plasma cells, forming rounded, eosinophilic Russell bodies. 71Protein 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 filaments72Protein accumulations Example:4. The neurofibrillary tangle found in the brain in Alzheimer disease is an aggregated protein inclusion that contains microtubule-associated proteins

73Lecture will includeOverview of intracellular accumulationsAccumulation of LipidsAccumulation of CholesterolAccumulation of ProteinsAccumulation of GlycogenAccumulation of PigmentsPathologic Calcification74Pigments 75Pigments are colored substances that are either: exogenous, coming from outside the body, or endogenous, synthesized within the body itself. 76Exogenous pigmentThe most common is carbonWhen inhaled, it is phagocytosed by alveolar macrophages and transported through lymphatic channels to the regional tracheobronchial lymph nodes. 77Exogenous pigmentAggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (anthracosis).

78Hemosiderosis

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 affected79HemosiderosisHemosiderosis occurs in the setting of: increased absorption of dietary iron impaired utilization of ironhemolytic anemiastransfusions (the transfused red cells constitute an exogenous load of iron). . 80