Download 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
 No significant past medical history or previous
hospitalizations, life long nonsmoker and drinker
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
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
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
Clinical Outcome
 Patient ultimately dies soon after admission for
unclear reasons-likely cardiac arrest
 Postmortem Autopsy Ordered
-Stiff rubbery
heart
-Pericardial
Effusion
-Enlarged
Liver
Autopsy Photo
Heart Tissue
Stained with
Congo Red
and evidence
of amyloid
deposition
Histopathology
Firm and Stiff
Spleen
Autopsy Photo
Enlarged, stiff
kidneys
Autopsy Photo
Congo Red
Stain of the
Kidneys
showing
amyloid
deposition
Histopathology
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
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
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)
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
Types of Amyloidosis
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
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
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
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
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
Interfere with the Source
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
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
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
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?
Prognosis
 Overall median survival after diagnosis is
<2years in most series.
 Cardiac involvement is major determinant of
prognosis and most common cause of death
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