CLINICAL MANIFESTATIONS OF AMYLOIDOSIS

 

 - Fatigue, weight loss
 - Macroglossia
 - CHF, restrictive cardiomyopathy
 - Hepatomegaly, splenomegaly
 - Renal insufficiency, nephrotic syndrome
 - Arthropathy
 - Neuropathy
   Peripheral neuropathy:
      symmetric sensory neuropathy
      carpal tunnel syndrome
   Autonomic neuropathy:
      orthostatic hypotension, syncope
      altered gastrointestinal motility (diarrhea, constipation, pseudo-obstruction)
      impotence
 - Skin involvement: spontaneous purpura, ecchymoses

Primary amyloidosis
   Kidneys and the heart are the organs most commonly involved.
Secondary amyloidosis
   Patients typically present with renal dysfunction and hepatosplenomegaly.
   Cardiac involvement is rare.
Familial amyloidosis
   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 myeloma.
J Clin Oncol. 2008 Jan 20;26(3):504-6.
Chim CS, Wong M, Fan Y.

 

 


LABORATORY FINDINGS OF AMYLOIDOSIS

 

 - Anemia
 - 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.
Biopsy
 - abdominal fat-pad biopsy
 - rectal biopsy
 - renal biopsy
 - BM biopsy
 - right ventricular endomyocardial biopsy
Echocardiography
 - restrictive cardiomyopathy
 - increased IVS
 - areas of increased reflectivity or stippling of the myocardium
Cardiac MRI
 - Late gadolinium enhancement
EKG
 - low voltages
 - arrhythmias

A basic assessment of organ involvement should include:
  - History
  - 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):

 

 

Fine-needle 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, SAP imaging (with labeled serum amyloid P component), and DNA analysis.
The mutant protein should be confirmed by mass spectrometry.
Laboratory findings for primary amyloidosis:
  - Serum and urinary protein immunofixation electrophoresis
  - SPEP
  - Serum free light chains

 


RESPONSE CRITERIA

 

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 paraprotein (VGPR).
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 2004.
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

Hematologic response
  - PR      = dFLC (difference between involved and uninvolved FLC) decrease >50%
  - VGPR    = dFLC <4 mg/dL
  - CR      = Negative IFE and uIFE, and normal FLC ratio

Organ response
  - 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.

Treatment of 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.

 

Clinical 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.