CLINICAL MANIFESTATIONS OF AMYLOIDOSIS
- Fatigue, weight loss
- CHF, restrictive cardiomyopathy
- Hepatomegaly, splenomegaly
- Renal insufficiency, nephrotic syndrome
symmetric sensory neuropathy
carpal tunnel syndrome
orthostatic hypotension, syncope
altered gastrointestinal motility (diarrhea, constipation, pseudo-obstruction)
- Skin involvement: spontaneous purpura, ecchymoses
Kidneys and the heart are the organs most commonly involved.
Patients typically present with renal dysfunction and hepatosplenomegaly.
Cardiac involvement is rare.
Peripheral sensorymotor and autonomic neuropathies are the most prominent clinical manifestations.
Macroglossia is not a feature.
Amyloidosis involving the tongue (macroglossia) and skin (my personal archive):
Amyloid arthropathy in the
course of multiple myeloma.
J Rheumatol. 2002 Jul;29(7):1473-81.
Fautrel B, Fermand JP, Sibilia J, Nochy D, Rousselin B, Ravaud P.
Pulmonary interstitial amyloidosis complicating multiple
J Clin Oncol. 2008 Jan 20;26(3):504-6.
Chim CS, Wong M, Fan Y.
LABORATORY FINDINGS OF AMYLOIDOSIS
- Proteinuria (75%), renal insufficiency (50%)
- Elevated alkaline phosphatase
- Hypothyroidism (amyloidosis of the thyroid)
- Elevated monoclonal protein level in the serum or urine (primary amyloidosis)
- Abnormal transthyretin protein (familial amyloidosis)
Laboratory screening of AL amyloidosis is done with serum immunofixation, urine immunofixation, and serum free light chains. If all these 3 tests are negative, the presence of AL amyloidosis is unlikely.
DIAGNOSIS OF AMYLOIDOSIS
PRESENCE OF AMYLOID
The diagnosis of amyloidosis is confirmed by the presence of birefringence by
polarized microscopy of specimen stained with Congo red.
- abdominal fat-pad biopsy
- rectal biopsy
- renal biopsy
- BM biopsy
- right ventricular endomyocardial biopsy
- restrictive cardiomyopathy
- increased IVS
- areas of increased reflectivity or stippling of the myocardium
- Late gadolinium enhancement
- low voltages
A basic assessment of organ involvement should include:
- Physical examination, including measurement of orthostatic blood pressure
- Serum creatinine, 24-hour urine collection (renal involvement if urine proteins >500 mg/24 hours)
- Serum alkaline phosphatase (liver involvement)
- Troponins, pro-BNP (cardiac involvement)
Low voltages seen in the ECG of patient with cardiac amyloidosis (my personal archive):
aspiration of abdominal fat pad for amyloid detection: a clinically useful test?
Diagn Cytopathol. 2004 Mar;30(3):178-81.
Ansari-Lari MA, Ali SZ.
This study evaluated the use of fine-needle aspiration of abdominal fat pad in 91 consecutive patients, to rule out amyloidosis. The test was positive for amyloidosis in 22% of cases. Sensitivity was 75% and specificity 92%.
TYPING OF AMYLOID
Biopsy specimens can be examined by immunohistochemistry (IHC), SAP imaging (with
labeled serum amyloid P component), and DNA analysis.
The mutant protein should be confirmed by mass spectrometry, which is the gold standard method for amyloid typing. IHC may not be reliable, because of loss of light chain segments recognized by the antibody used in the assay, or due to the presence of normal light chains in the background. Moreover, MGUS can be a concomitant finding in a patient with non-AL amyloidosis.
Laboratory findings for primary amyloidosis:
- Serum and urinary protein immunofixation electrophoresis
- Serum free light chains
The presence of MGUS should not lead to the assumption that amyloid is of AL type, as MGUS can coexist in patients with non-AL amyloidosis.
Prevalence of Monoclonal Gammopathy in Wild-Type
Geller HI, Singh A, Mirto TM, Padera R, Mitchell R, Laubach JP, Falk RH.
Mayo Clin Proc. 2017 Dec;92(12):1800-1805.
In this retrospective analysis, 113 patients with wild-type TTR amyloidosis were screened for the presence of monoclonal proteins, by SPEP, IFE, and FLC. Monoclonal gammopathy was found in 23% of cases. This is an important finding, because it shows that MGUS can coexist in patients with non-AL amyloidosis. These results underscore the possibility of misclassification of the amyloid type by laboratory test screening, and indicates the need for a precise amyloid typing by either IHC or (preferably) tandem mass spectrometry.
It is difficult to evaluate organ responses in amyloidosis, because these are difficult to be quantified. Moreover, organ responses in amyloidosis are uncommon and often very slow (more than 1-2 years), even in those patients who achieve complete hematologic remission after chemotherapy. Serial measurements of the free light chain assay are useful, as well as BNP in those patients with cardiac involvement.
The goal of treatment is a deep response, defines as a >90% reduction of the
In patients with cardiac involvement, the goal of treatment should be a >30% reduction in the pro-BNP.
The first consensus on definition of response criteria in primary amyloidosis was published in 2005:
Definition of organ involvement and treatment response in
immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th
International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April
Am J Hematol. 2005 Aug;79(4):319-28.
Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, Sanchorawala V, Sezer O, Solomon A, Grateau G.
2012 RESPONSE CRITERIA
- PR = dFLC (difference between involved and uninvolved FLC) decrease >50%
- VGPR = dFLC <4 mg/dL
- CR = Negative IFE and uIFE, and normal FLC ratio
- Renal = urine proteins decreased by >30% or
urine proteins decreased to <500 mg/day
- Hepatic = Alkaline phosphatase decreased by >50 or
radiographic liver size decreased by >2 cm
- Cardiac = NT-proBNP decreased by >30% and 300 pg/dL or
NYHA class decreased (if III or IV at baseline)
New criteria for response
to treatment in immunoglobulin light chain amyloidosis based on free light chain
measurement and cardiac biomarkers: impact on survival outcomes.
J Clin Oncol. 2012 Dec 20;30(36):4541-9.
Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, Schönland S, Hegenbart U, Comenzo R, Kastritis E, Dimopoulos MA, Jaccard A, Klersy C, Merlini G.
Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and
Risk-Adapted Therapy (mSMART) Consensus Statement.
Mayo Clin Proc. 2015 Aug;90(8):1054-81.
Dispenzieri A, Buadi F, Kumar SK, Reeder CB, Sher T, Lacy MQ, Kyle RA, Mikhael JR, Roy V, Leung N, Grogan M, Kapoor P, Lust JA, Dingli D, Go RS, Hwa YL, Hayman SR, Fonseca R, Ailawadhi S, Bergsagel PL, Chanan-Khan A, Rajkumar SV, Russell SJ, Stewart K, Zeldenrust SR, Gertz MA.
LIGHT CHAIN DEPOSITION DISEASE
Light chain deposition disease (LCDD), or monoclonal immunoglobulin deposition disease (MIDD), have pathogenesis and clinical features similar to those of amyloidosis. However, the proteins deposited in the tissues are not birefringent when viewed under polarized light after staining with Congo red.
characteristics and prognostic factors in multiple myeloma patients with light
chain deposition disease.
Am J Hematol. 2017 Aug;92(8):739-745
Mohan M, Buros A, Mathur P, Gokden N, Singh M, Susanibar S, Jo Kamimoto J, Hoque S, Radhakrishnan M, Matin A, Davis C, Grazziutti M, Thanendrarajan S, van Rhee F, Zangari M, Davies F, Morgan G, Epstein J, Barlogie B, Schinke C.
This is a retrospective study of 69 patients with multiple myeloma and concomitant light chain deposition disease (LCDD). One-third of these patients had cardiac involvement and, as expected, had a worse survival.
Giampaolo Talamo, M.D.