Elizabeth Soda

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
• HR110/m, RR 24/m, TO370C
• 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
Autopsy Photo

• -Stiff rubbery heart
• -Pericardial Effusion
• -Enlarged Liver

8
Histopathology

• Heart Tissue Stained with Congo Red and evidence
  of amyloid deposition

9
Autopsy Photo

• Firm and Stiff Spleen

10
Autopsy Photo

• Enlarged, stiff kidneys

11
Histopathology

• Congo Red Stain of the Kidneys showing amyloid
  deposition

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 cardiomyopathic amyloidosis 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 transthyretin amyloidosis
• 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
  lt2years 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 2007356
  2349-2360
• Rajkumar, S. Advances in the Treatment of
  Amyloidosis. NEJM 2007 356 2413-2415
• Merlini G, Molecular Mechanisms of Amyloidosis.
  NEJM 2003349583-96.
• www.uptodate.com An overview of amyloidosis