Autopsy findings, 65 y. old male with sistemic amyloidosis.

1. Š.Ž., muškarac, 1948.g.
Kl. dg:
Amyloidosis.
Cardiomyopathia secundaria.
Fibrilatio atriorum persistens.
Cor decompensatum.

2. Srce: 15x12x7 cm; 800 g. Izražena hipertrofija obje klijetke.

3. Koronarne arterije prohodne, mjestimice s manjim
plakovima.

4. Pluća: 600 i 700 g.
Obostrano 1000mL serozne tekućine u prsištu.
Edematozan parenhim, čvršći, svijetlo crveni, voštani izgled.

5. Jetra zastojna, slezena,
gušterača i jetra na prerezu
sjajni, “voštani” odsjaj.
Slezena-16x8x6 cm; 430g.
Jetra- 25x19x13 cm; 1650g.

7. Congo red.

13. Zelena birefringencija u polarizacijskom mikroskopu.

14. PHD:
Amyloidosis generalisata (GB).
Cardiomyopathia restrictiva (US).
• Na temelju dobivenih kliničkih podataka, obdukcijskog
nalaza, te patohistološke analize zaključuje se da je
pokojnik preminuo zbog srčane insuficijencije
(restriktivne kardiomiopatije), a kao posljedice
generalizirane amiloidoze. Obilno odlaganje amiloida
nalazi se u svim organima (štitnjača, srce, pluća, bubreg,
slezena, jetra, gušterača), a srce je izrazito veliko s
jakom hipertrofijom obje komore.

15. AMYLOIDOSIS
• A heterogeneous group of disorders in which a disorder
of protein structure results in the formation and
deposition of insoluble fibrillary proteins (amyloid) in
extracellular spaces of organs and tissues, causing
structural and functional organ damage.

16. AMYLOIDOSIS
• Although amyloid fibrils involve unique proteins, they share a common
secondary structure, a beta-pleated sheet conformation, and all amyloid
deposits contain pentraxin serum amyloid P (SAP) and glycosaminoglycans.
At least 24 such proteins have been recognized as causative of amyloidosis
• Can involve almost any organ, most importantly the kidneys, heart, and
peripheral nervous system
• Diagnosis is dependent on identification of amyloid deposits in biopsy or
autopsy tissue
• Overall incidence is about 0.5-1.3/100,000 annually, with the
distribution of types of amyloidosis as approximately 80%
representing AL, 5-10% representing all familial forms, AA
(secondary amyloidosis) comprising 2-3%, and senile cardiac
amyloidosis approximately 2%
• Localized amyloidosis comprises about 8% of cases overall

17. AMYLOIDOSIS
The various forms of amyloidoses are classified based on
the underlying protein type and pathological process
• AL amyloidosis (primary amyloidosis)
• AA amyloidosis (secondary amyloidosis)
• Familial amyloidosis
• Beta-2-microglobulin (dialysis-related)
amyloidosis
• AH: Ig heavy chain amyloidosis (primary)
• ATTR: transthyretin amyloidosis (familial or as in
senile cardiac amyloidosis)

18. AL amyloidosis
• AL: immunoglobulin (Ig) light chain amyloidosis (primary)
• 80% of cases
• Causative protein is immunoglobulin light chains
• Associated with an underlying plasma-cell dyscrasia
(multiple myeloma, clonal plasma cell dyscrasias that do
not fulfill the diagnostic criteria for myeloma,
Waldenstroms macroglobulinemia)

19. AA amyloidosis
• AA or SAA: (Apo) serum AA amyloidosis (secondary)
• 3% of cases
• Causative protein is serum amyloid A protein (SAA - an
acute phase protein)
• Associated with a chronic inflammatory state
(rheumatoid arthritis, inflammatory bowel disease,
familial Mediterranean fever, TB, bronchiectasis)

20. AA amyloidosis
• Usually presents with proteinuria; the severity of albuminuria
correlates with the patient's prognosis
• In contrast with AL amyloidosis, congestive heart failure, peripheral
neuropathy, and carpaltunnel syndrome occur occasionally but are
seldom presenting complaints
• Pathologically, amyloid deposits in the spleen precede liver and
kidney deposition of amyloid, then generalized vascular and
interstitial deposits
• Adrenocortical insufficiency can result from adrenal deposits
• Therapy involves treating the underlying inflammatory disease
• Supportive measures are taken to preserve organ function
• Renal transplantation is sometimes considered, particularly once the
underlying inflammatory disease is under control

21. Familial amyloidosis
• Hereditary amyloidoses are a heterogeneous group of autosomal-dominant
disorders, caused by mutations in genes coding for plasma proteins.
Hundreds of mutations have now been identified. Some of the proteins
include:
• Transthyretin (TTR amyloid)
• Apolipoprotein A-I (apoA-I amyloid)
• Apolipoprotein A-II (Apo A-II amyloid)
• Gelsolin (AGel amyloid)
• Lysozyme (Alys amyloid)
• Accounts for approx. 5% of cases
• Major presentation is cardiac, followed by peripheral neuropathy, including
carpal tunnel syndrome
• Cardiac and renal amyloidosis are common
• No specific pharmacotherapy exists
• Symptomatic therapy

22. Beta-2-microglobulin (dialysis-related)
amyloidosis
• Occurs in association with chronic hemodialysis, usually after 8-12 years of hemodialysis and
almost never before 5 years of treatment
• Amyloid protein is beta2M-globulin
• Visceral deposits are rare
• Osteoarticular deposits are common; presenting complaints include carpal
tunnel syndrome, flexor tenosynovitis, bone cysts, and pathologic fractures
• Systemic manifestations usually only occur after 15 years of hemodialysis,
and include cardiac, gastrointestinal, and renal involvement
• As well as supportive treatment, therapy may involve use of high-flux
biocompatible polyarylonitrile and polysulfone dialysis membranes, which
enhance removal of beta2M proteins
• Renal transplantation may be considered

23. Systemic amyloidosis:
• Multi-system organ involvement - the nature of which may be
dependant on the underlying amyloid form
• AL amyloidosis - typically affects the kidneys, heart, and peripheral
nervous system. AL amyloidosis has the widest spectrum of organ
involvement of all the amyloidoses
• AA amyloidosis - typically affects the kidneys and other viscera.
Cardiac involvement is uncommon (10% of cases)
• Beta2M-globulin amyloidosis - typically affects the peripheral
nervous system and muskuloskeletal system
• TTR amyloidosis - typically affects the peripheral nervous system.
Gastrointestinal upset is associated with autonomic NS dysfunction.
Renal disease is less common. Cardiac involvement is variable

24. Localized amyloidosis
• Organ/tissue restriction of amyloidosis, which occurs as a result of a
variety of mechanisms
• The majority of cases - where localized amyloidosis is found
distributed in, for example, the GI tract, respiratory tree, or urinary
tract - arise as a result of localized excess light chain deposition
• Localized deposition within the CNS is associated with a variety of
genetic mutations (e.g. certain familial dementias)
• Amyloid depsits occasionally arise as a result of the deposition of
hormone/pro-hormone proteins as amyloid proteins within a tissue.
This is found in association with a variety of diseases. Most
commonly it is found in relationship to tumors e.g. medullary thyroid
carcinoma, prolactinoma, or insulinoma

25. AMYLOIDOSIS
• 60% of AL amyloidosis patients are 50-70 years of age at diagnosis
• Only 10-20% of AL amyloidosis patients are diagnosed under age
50
• Pediatric patients are most likely to have familial periodic fevers or
inflammatory diseases such as juvenile rheumatoid arthritis or
Crohns disease
• In the US, AA is more common in females, probably because one
of the major predisposing diseases, rheumatoid arthritis, is more
common in women than men
• In familial Mediterranean fever, men are more commonly affected
than women (3:2)
• ATTR amyloidosis occurs equally among males and females

26. AMYLOIDOSIS
• Symptoms of amyloidosis are nonspecific, and diagnosis
requires a high index of suspicion
• Diagnosis is based on the finding of amyloid protein
deposition in tissue biopsy or autopsy specimens
• Amyloidosis must be considered in the differential
diagnosis of any patient presenting with nondiabetic
nephrotic syndrome, nonischemic restrictive
cardiomyopathy, hepatomegaly, or idiopathic peripheral
neuropathy
• Effective therapy is based on early diagnosis and correct
typing of amyloid protein

27. • Symptoms depend on the organs in which amyloid is concentrated,
but are generally nonspecific, e.g. fatigue, weight loss, and edema
• Nephrotic syndrome is one of the most common presenting
manifestations
• Cardiac involvement is common - the extent of which strongly
influences prognosis
• Peripheral neuropathy
• Treatment involves suppression of the underlying plasma cell
dyscrasia
• High-dose melphalan chemotherapy followed by peripheral stem
cell transplantation is the most effective therapy. However, the
majority of patients are not candidates due to poor prognostic
indicators
• Alternative treatments to suppress abnormal plasma clone/Ig
production are based upon strategies used in multiple myeloma
• Supportive measures are taken to preserve organ function

28. AMYLOIDOSIS
• Treatment is directed at reducing production and
extracellular deposition of amyloid fibrils and
promoting lysis and/or mobilization of existing
amyloid deposits - plus supportive treatment for
underlying organ dysfunction.
• Generalized amyloidosis is usually a progressive
disease, with survival in most series ranging
from 12 months to 15 years. Untreated, 80% of
patients will die within 2 years of diagnosis.

29. THE END!