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A Man with Dyspnea and Macroglossia

A Man with Dyspnea and Macroglossia. Elizabeth Soda KCMC Moshi , Tanzania. Clinical History. 51yrs M who presents to KCMC with a 4 month history of easy fatigability, palpitation, dyspnea, and enlarging tongue. Also with complaints of numbness, paresthesia, and painful extremities

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A Man with Dyspnea and Macroglossia

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  1. A Man with Dyspnea and Macroglossia Elizabeth Soda KCMC Moshi, Tanzania

  2. Clinical History • 51yrs M who presents to KCMC with a 4 month history of easy fatigability, palpitation, dyspnea, and enlarging tongue. • Also with complaints of numbness, paresthesia, and painful extremities • No significant past medical history or previous hospitalizations, life long nonsmoker and drinker

  3. Physical Exam • Vital signs: • BP: 100/60 • HR:110/m, RR: 24/m, TO:370C • Gen: sick appearing, older then stated age • HEENT: grossly enlarged tongue • CVS: No JVD, no m/r/g • Pulm: bilateral basal dullness and ↓ air entry • Abd: hepatosplenomegally • Skin: scaly rashes over extremities • CNS: ↓ ankle and knee reflexes

  4. Laboratory Data • Cr: 50 umol/L (0.5 mg/dl) • Hgb: 11.1 mg/dl • Serum Calcium: 7.7 mg/dl • Total Serum Protein: 9.6 g/dl • Urine protein: +1 • Liver enzymes: wnl • HIV negative • SED: not elevated

  5. Imaging • CXR: moderate cardiomegaly, right sided pleural effusion • Echo • 19mm pericardial effusion, right sided pleural effusion • U/S : Echodense kidneys, hepatomegaly • Skull and vertebral X-ray: normal in appearance

  6. Clinical Outcome • Patient ultimately dies soon after admission for unclear reasons-likely cardiac arrest • Postmortem Autopsy Ordered

  7. -Stiff rubbery heart -Pericardial Effusion -Enlarged Liver Autopsy Photo

  8. Heart Tissue Stained with Congo Red and evidence of amyloid deposition Histopathology

  9. Firm and Stiff Spleen Autopsy Photo

  10. Enlarged, stiff kidneys Autopsy Photo

  11. Congo Red Stain of the Kidneys showing amyloid deposition Histopathology

  12. Autopsy Findings • Amyloid deposition seen: • tongue • pleura • heart • liver, spleen • stomach • kidneys • skin • peripheral nerves No immunohistochemistry available so unclear of what form-no signs of active infection, inflammation, no plasma cells noted

  13. Amyloid • Fundamentally is the result of extracellular protein misfolding: • Occurs with or as an alternative to normal physiologic folding • Results in toxic, insoluble deposition of protein aggregates in the tissues • 25 different types of protein precursors are known • Amyloid fibrils share a common B-pleated sheet structural conformation that confers unique staining properties • apple-green birefringence under a polarized light microscope with congo red stain • rigid, nonbranching fibrils 7.5 to 10 nm in diameter on electron microscopy

  14. Pathogenesis • Process likely similar to normal folding • Except the polypeptide finds a relatively stable misfolded state • This allows for increased propensity to aggregate • May occur more frequently under certain conditions like increased temps or low pH • Likely Occurs in Multiple Ways: • Intrinsic Propensity with increase age (senile) or concentration (HD patients) of native protein to misfold • Replacement of single amino acids (hereditary amyloidosis) • Proteolytic remodeling of the protein precursor (AD)

  15. Classification • Classified according to whether it is • systemic or localized, • acquired or inherited, and • by clinical patterns • The accepted nomenclature is AX, where • A indicates amyloidosis and • X represents the protein in the fibril

  16. Types of Amyloidosis

  17. Types of Amyloidosis • AL • The deposition of immunoglobulin light chains • Can occur alone or in association with MM or Waldenstrom's macroglobulinemia • Most common in the developed world • AA • Associated with chronic inflammation states or infections • Most common in the developing world

  18. Type of Amyloidosis • Dialysis Related: • Deposition of beta-2-microglobulin commonly in the shoulder and wrist • Heritable Amyloidoses: • Ex: cardiomyopathicamyloidosis due to deposition of fibrils derived from transthyretin (also referred to as prealbumin) • Senile Systemic: • Deposition of transthyretin primarily in the myocardium in elderly men • Organ Specific: • Amyloid deposition can be isolated to a single organ, such as the skin, eye, heart, pancreas, or genitourinary tract, resulting in specific syndromes

  19. Major Clinical Manifestations • Renal: usually asymptomatic proteinuria but can be frank nephrotic syndrome. Rare progression to renal failure. • Cardiac: systolic or diastolic dysfunction, angina, syncope • GI: hepatomegaly is most common • Neuro: mixed sensory and motor peripheral neuropathy, sporadic or familial Alzheimer disease, cerebral amyloid angiopathy

  20. Major Clinical Manifestations • Pulm: tracheobronchial infiltration, persistent pleural effusions, parenchymal nodules (amyloidomas), and pulmonary hypertension. • Persistent pleural effusions occur in 1-2% of patients, poorer prognosis • Skin: waxy thickening, easy bruising (ecchymoses), and subcutaneous nodules or plaques. • MSK: macroglossia is characteristic of AL, arthropathy, bone disease, carpal tunnel • Heme: most prone to bleeding

  21. Treatment • Three general approaches: • Interfere with precursor protein production • Stabilize the native structure of the precursor protein to prevent its transition into the misfolded protein • Attempt to destabilize the amyloid fibrils themselves

  22. Interfere with the Source

  23. Stabilize the Native Protein • Prevent the precursor protein from transitioning into the misfolded protein • Clinical trials investigating diflunisal in pts with familial transthyretinamyloidosis • Binds the transthyretin protein and stabilizes it preventing the tendency to move to the beta-pleated form

  24. Destabilize the amyloid fibril • This approach targets the amyloid fibril itself not just the source • Attempt to reverse organ damage in a more timely manner • Target components common to all amyloid fibrils • Serum Amyloid P Component • Glycosaminoglycan Backbone

  25. Glycosaminoglycans • Thought to play an integral role in binding amyloid to the tissues • 2007 NEJM DB, placebo controlled study of the possible role of eprodisate in pts with AA Amyloidosis • Binds the glycosaminoglycan binding sites on the amyloid fibril

  26. Eprodisate • Rate of decline in creatinine clearance was lower in pt on drug vs placebo • No effect on progression to ESRD or death • No effect on proteinuria • Unclear role currently, possible adjuvant therapy?

  27. Prognosis • Overall median survival after diagnosis is <2years in most series. • Cardiac involvement is major determinant of prognosis and most common cause of death

  28. References • Dember et al.Eprodisate for the Treatment of Renal Disease in AA Amyloidosis. NEJM 2007;356: 2349-2360 • Rajkumar, S. Advances in the Treatment of Amyloidosis. NEJM 2007; 356: 2413-2415 • Merlini G, Molecular Mechanisms of Amyloidosis. NEJM 2003;349:583-96. • www.uptodate.com: An overview of amyloidosis

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