Amyloidosis

Marwa Bawab ± Sp 10

Amyloidosis

Amyloidosis is not a single disease but a heterogeneous group of diseases that have in common the extracellular deposition of insoluble fibrillar proteins (Amyloid) in tissues and organs.

Amyloid
Amyloid (meaning starch-like) is the name of a group of proteins or glycoproteins which, when deposited in tissues, share the following properties: 
Extracellular ß-pleated sheet material with affinity for Congo red or Sirius red dyes (Fig.01) (Fig.02)  Composed of immunoglobulin light chains, serum amyloid protein A, peptide hormones, prealbumin, etc.  Fibrillar ultrastructure (Fig.03)  Extracellular location, often on basement membranes  Resistance to removal by natural processes  Affected tissue becomes hardened and waxy  Impairs the function of the organ in which it is deposited....death  Heart failure and nephrotic syndrome

Fig.01 Beta-Sheet Structure

Fig.02

Congo red staining of a cardiac biopsy containing amyloid, viewed under polarized light

Amyloid substances are characterised by a fibrillar appearance on electron microscopy. .03 Amyloid Structure.Fig.

Classification Amyloid can be classified according to: ‡ Chemical composition ‡ Tissue distribution ‡ Etiology .

3. ‡ Localized . 2. Secondary Amyloidosis Associated with Chronic Inflammatory Disease (AA) . 4. Dialysis-Associated ß2-m Amyloidosis. Primary or Ig Light-Chain Protein-Related Amyloidosis (AL).Classification ‡ Systemic 1. Hereditary Amyloidosis.

g.04) ‡ Localised amyloid deposits occur in some peptide hormone-producing tumors . myeloma) or to a chronic inflammatory disorder (Fig.‡ Systemic amyloidosis may be due to a plasma cell neoplasm (e.

. In AA amyloidosis the production of AA amyloid by the liver is stimulated by cytokines secreted by chronic inflammatory cells.Fig. In AL amyloidosis light chains are secreted by neoplastic plasma cells.04 Common Causes & Consequences of Systemic Amyloidosis.

Fig.05 Organ Systems Commonly Involved in Amyloidosis .

‡ Bone marrow examination usually shows a monoclonal population of plasma cells . ‡ 90% have detectable serum or urine monoclonal Ig light.chain protein. nephrotic syndrome.AL AMYLOIDOSIS ESSENTIALS OF DIAGNOSIS ‡ Suspected in all patients with unexplained heart failure. ‡ Displays apple-green appearance when viewed under polarized light after staining with Congo red. neuropathy. and hepatomegaly.

Rare disease / 8 cases per 1 million persons per year >40 years of age Men (65%) more than women 10-15% of patients with multiple myeloma. . short survival. have AL amyloidosis ‡ AL amyloidosis affects most organs and the vascular system.General Considerations ‡ ‡ ‡ ‡ ‡ Rapid progression.

g. weakness. joint tenderness on palpation.Clinical Manifestations ‡ The symptoms and signs are nonspecific. ‡ Rheumatic manifestations:  25% of patients have CTS. stiffness. swelling  palpable nodules  Unlike patients with RA. But temporal artery biopsy indicates amyloid involvement of the temporal artery. jaw claudication).  Patients with muscle involvement present with stiffness. no fevers. and enlargement of muscles.  Giant cell arthritis .symptoms suggestive of giant cell arthritis (e.  Joint disease resembling RA:  bilateral symmetric arthritis of the large and small joints  pain.  Sensory abnormalities neuropathic joint destruction (Charcot joint). ‡ Common symptoms are fatigue and involuntary weight loss. or inflammation on synovial fluid analysis. .

.  Motor neuropathy is rare.Clinical Manifestations (Cont¶d)  Nephrotic syndrome  Urinary excretion of more than 3g of protein in 24 hours  Hypoalbuminemia & edema (initial manifestation of kidney involvement)  Cardiac involvement (40%)  Angina & myocardial infarction  Rhythm disturbances  Neuropathy (20%)  Lower extremity paresthesias  Pain and temperature senses are lost before light touch and vibratory senses.

Clinical Manifestations (Cont¶d)  Diarrhea.08)  Bruised appearance to the skin. and orthostatic hypotension. bladder control problems.06)  < 20% have pathologic enlargement of the tongue / Macroglossia.(Fig.  Hepatomegaly (25%)  Swelling of the shoulder joints (Fig. (Fig. (Fig.09 . impotence.07)  Nodular deposits on the fingers. Bruises of the skin around the eyes are referred to as the characteristic "pinched purpura".10) .

06 Swelling of the Shoulder Joint Fig. Enlargement of the tongue due to increased amount of tissue and not because of a tumor .Fig.07 Macroglossia.

Fig. . Fig. Fig.08 Amyloid Nodules on the Fingers.09 Bruised Appearance of the Skin.10 Pinched Purpura.

11) ‡ Increased plasma cells in the bone marrow. (Fig. ‡ Bone marrow examination usually indicates a monoclonal population of plasma cells. .Laboratory Findings ‡ Immunoelectrophoresis of the serum or urine detects a monoclonal Ig light-chain protein in 90% of patients with AL amyloidosis.

which indicates amyloid in 70²80% of patients with AL amyloidosis. ‡ Bone marrow biopsy (usually performed to evaluate a monoclonal protein) shows amyloid in 50% of patients. . (Fig.12) ‡ Aspiration of subcutaneous abdominal fat.Tissue Biopsy ‡ Tissue biopsy is necessary to establish the diagnosis of amyloidosis. ‡ Apple-green when viewed under polarized light after staining with Congo red.

Fig. Evidence for a monoclonal plasma cell disease provided by intense staining for lambda chains.11 Monoclonal Plasma Cells in AL. Staining of a BM biopsy from a patient with AL. .

12 Congo Red Stain in Amyloidosis.Fig. Apple green (white arrows) of interstitial amyloid deposits can be seen . Congo red stain viewed under polarized light of renal biopsy.

‡ The aims of supportive treatment are to relieve symptoms and to prolong survival. ‡ Combination of melphalan and prednisone (ineffective if the disease involves the heart or kidneys) ‡ If cardiomyopathy or involvement of two or more other major organs: High-dose dexamethasone ‡ Organ transplantation to treat organ failure ‡ Supportive treatment (Fig. .13).Treatment ‡ Goal: Elimination or decrease the number of monoclonal plasma cells.

.Fig.13 Supportive Measures for All Forms of Amyloidosis.

. ‡ Most deaths are attributable to cardiac involvement (congestive heart failure and sudden death). ‡ The median survival is 1²2 years.Prognosis ‡ The prognosis of AL amyloidosis is poor.

nephrotic syndrome. or other symptoms and signs of AA amyloidosis. .AA AMYLOIDOSIS ESSENTIALS OF DIAGNOSIS ‡ Suspected in all patients with chronic inflammatory conditions with renal insufficiency. gastrointestinal tract symptoms. ‡ Tissue immunohistochemical analysis identifies the serum Amyloid A (AA) precursor protein from which AA amyloid fibrils derive.

and prevents the development of AA amyloidosis ‡ Incidence of AA amyloidosis has decreased 2/3 are caused by chronic rheumatic diseases ‡ AA amyloidosis may occur at any age ‡ RA is the most common rheumatic cause of AA amyloidosis (75% of cases). including rheumatic conditions. serum AA protein levels. infectious diseases. malignancies ‡ The liver produces serum AA protein in response to inflammation ‡ Treating the underlying inflammatory disease suppresses the acute-phase response.General Considerations ‡ Amyloidosis is an uncommon complication of Chronic inflammatory diseases. .

and poor energy intake. ‡ Rarely have cardiac or peripheral nerve involvement. in RA ‡ Gastrointestinal tract manifestations (20%) include nausea. ‡ > 90% present with renal insufficiency.Clinical Manifestations ‡ Renal and gastrointestinal tract manifestations are common. proteinuria ‡ Most common cause of nephrotic synd. diarrhea. ‡ Macroglossia is not a feature of AA amyloidosis .

RA). imaging findings usually are associated with the underlying inflammatory condition (eg. Abnormalities reflect amyloid involvement of organs and tissues. Imaging Studies Imaging studies usually do not indicate findings specific for AA amyloidosis.Laboratory Findings No laboratory findings specific of AA amyloidosis. Tissue biopsy As before (Fig. Instead.14) .

Fig.14 Renal Biopsy in AA .

decrease levels of serum AA protein prevent AA amyloid fibril formation and deposition reverse organ dysfunction improve survival ‡ ‡ ‡ ‡ Methotrexate and Prednisolone and Colchicine prevent inflammatory attacks Tumor necrosis factor-a (TNF-a) antagonists (eg. 3. 4. 2. infliximab) Dialysis or kidney transplantation Supportive treatment .Treatment ‡ ‡ Treating the underlying inflammatory disease Goal 1.

Prognosis ‡ Having AA amyloidosis decreases survival. RA patients without AA amyloidosis live nearly 8 years longer than RA patients with AA amyloidosis. . ‡ Progresses slowly. For example. and survival is often longer than 10 years.

develop ‡ Apple-green when viewed under polarized light after staining with Congo red ‡ Aspiration of subcutaneous abdominal fat is of little value ‡ Tissue immunohistochemical analysis identifies ß2-m precursor protein from which ß2-m amyloid fibrils derive. .DIALYSIS-ASSOCIATED ß2-m AMYLOIDOSIS ESSENTIALS OF DIAGNOSIS ‡ Suspected in all patients treated with long-term dialysis in whom rheumatic symptoms and signs. especially CTS.

General Considerations ‡ ß2-m Amyloidosis is a frequent complication of long.term dialysis ‡ Major cause of skeletal morbidity in dialysisdependent patients. . ‡ Patients with renal failure have chronically elevated serum levels because 95% of this protein is eliminated by glomerular filtration. ‡ ß2-m is only partially cleared during dialysis.

arthritis. tendon rupture. spondyloarthropathy) ‡ CTS is the most common (and usually the first) manifestation. develops after only 5 years of dialysis ‡ 50% joint pain & mild discomfort ‡ Joint involvement is bilateral and includes large joints ‡ Spondyloarthropathy is caused by destruction of the IVDs ‡ Pathologic fractures . especially synovial membranes ‡ Rheumatic manifestations (CTS.Clinical Manifestations ‡ Affects the joints. trigger finger.

Tissue Biopsy ‡ Aspiration of subcutaneous abdominal fat is of little value ‡ Other tissue must be obtained to establish the diagnosis (usually from joints and synovial membranes). ‡ Tissue immunohistochemical analysis identifies the ß2-m precursor protein. .

Treatment ‡ Largely symptomatic ‡ Rheumatic manifestations are treated with NSAIDs and local glucocorticoids ‡ Surgery (eg. carpal tunnel release and stabilization of areas of bone destruction) ‡ Kidney transplantation .

especially if there is a family history of these problems. or renal insufficiency. ‡ Displays apple-green when viewed under polarized light after staining with Congo red. cardiomyopathy. ‡ DNA analysis of blood and tissue immunohistochemical analysis can be used to identify the mutant precursor protein. .HEREDITARY AMYLOIDOSIS ESSENTIALS OF DIAGNOSIS ‡ Suspected in all patients with unexplained neuropathy.

General Considerations ‡ Autosomal dominant diseases in which amyloid fibrils derive from mutant serum proteins. ‡ Detailed family history. ‡ Mistakenly assumed AL amyloidosis (presence of monoclonal cells). ‡ Amino acid substitution of these proteins via gene mutations amyloidogenic. ‡ Amyloid fibrils form in midlife. .

Clinical Manifestations ‡ Peripheral neuropathy is the most common. . ‡ Cardiac involvement is also common. ‡ Macroglossia does not occur. whereas kidney involvement is less common. ‡ Patients with hereditary amyloidosis caused by fibrinogen A chain mutations usually have kidney disease but not neuropathy.

Tissue Biopsy ‡ Apple-green when viewed under polarized light after staining with Congo red. . ‡ DNA analysis of blood and tissue immunohistochemical analysis identify the mutant precursor protein.

‡ Supportive measures .Treatment ‡ Liver transplantation result in disappearance of the mutant protein from the blood and improvement of neuropathy.

and fibrinogen A a-chain mutations is usually slow. lysozyme.Prognosis ‡ Patients with hereditary amyloidosis caused by mutant proteins synthesized by the liver and who undergo liver transplantation have improved symptoms and prolonged survival ‡ The rate of progression of hereditary amyloidosis caused by apolipoprotein Al. ‡ Usually responds well to supportive measures. .

lungs and urinary tract seem to be the most frequent sites.Localized amyloidosis ‡ Amyloid material is often found in the stroma of tumors producing peptide hormones. ‡ The skin. ‡ Cerebral amyloid is found in Alzheimer¶s disease . (a tumor of the calcitonin-producing interfollicular Ccells). the amyloid contains calcitonin-precursor molecules arranged in a ß-pleated sheet configuration. ‡ Localised deposits of amyloid may be found in any organ. ‡ It is particularly characteristic of medullary carcinoma of the thyroid. ‡ Rare occurrence. ‡ In this instance.

Case Presentation .

.Case Presentation ‡ 53 yr old white female with past medical Hx of HTN. ‡ Found to have elevated alkaline phosphatase and was referred for further evaluation. GERD and depression presented with a 6 week history of fatigue and progressive weight loss (210-176) over 4 months.

and pain.Case Presentation ‡ No further significant past medical or surgical history ‡ No significant family history ‡ Non smoker and non drinker ‡ Only relevant history was intermittent tingling in fingertips for many months. occasional nausea. .

‡ 10cm liver edge felt below RCM .Case Presentation ‡ Relevant physical findings ± Normal vitals except tachycardia at 100 BPM.

Case Presentation ‡ ‡ ‡ ‡ ‡ UA: prot >300mg/dl 24 hour urine protein: 4485 mg/24hr SPEP ± No monoclonal protein IF serum ± negative IF urine ± light chain .

Case Presentation ‡ BM biopsy ± 5% plasma cells. Areas of marrow replaced by eosinophilic dense material stained by congo red. ‡ Liver biopsy ± extensive eosinophilic dense material throughout portal tracts. .

Case Presentation Diagnosis was made to be AL Amyloidosis .

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