A Man with Dyspnea and Macroglossia
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Transcript 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