Ferri – Amyloidosis

Mar 13, 2020 admin CƠ XƯƠNG KHỚP 0

Amyloidosis

  • Bilal H. Naqvi, M.D.
  • Fred F. Ferri, M.D.

 Basic Information

Definition

The term amyloidosis refers to a heterogeneous group of disorders that are all characterized by the deposition of an amorphous, extracellular fibrillar protein in various organs and tissues of the body. It has the following subtypes:

  1. •

    Primary amyloidosis (AL)

  2. •

    Secondary amyloidosis (AA)

  3. •

    Hereditary amyloidosis

  4. •

    Localized amyloidosis

ICD-10CM CODES
E85.9 Amyloidosis, unspecified
E85.0 Non-neuropathic heredofamilial amyloidosis
E85.1 Neuropathic heredofamilial amyloidosis
E85.2 Heredofamilial amyloidosis, unspecified
E85.3 Secondary systemic amyloidosis
E85.4 Organ-limited amyloidosis
E85.8 Other amyloidosis

Epidemiology & Demographics

Incidence (In U.S.)

Between 1500 and 3500 new cases are diagnosed annually. The most common type is AL.

Prevalence

Amyloidosis primarily affects men between the ages of 60 and 70 yr.

Physical Findings & Clinical Presentation

  1. •

    The most common presenting symptoms of amyloidosis are fatigue, dyspnea, edema, paresthesias, and weight loss. Other findings depend on organ system involvement.

  2. •

    Signs and symptoms of nephrotic syndrome may be present with renal involvement.

  3. •

    Fatigue and dyspnea may occur with pulmonary involvement.

  4. •

    GI involvement is uncommon but presents with diarrhea, nausea, abdominal pain, and macroglossia (Fig. E1).

    FIG.E1 

    Macroglossia in a patient with primary amyloidosis, demonstrating peripheral ridging caused by teeth indentation.
    From Hochberg MC et al.: Rheumatology, ed 5, St Louis, 2011, Mosby.
  5. •

    Patients with cardiac involvement have an infiltrative cardiomyopathy and present with a preserved ejection fraction (EF) and diastolic dysfunction.

  6. •

    Patients may present with bleeding problems caused by either factor X deficiency or fragile blood vessels caused by infiltration by amyloid. Bleeding around the eyes (raccoon eyes) is a characteristic finding.

  7. •

    Involvement of the nervous system presents with peripheral neuropathy, tendinopathy (Fig. E2), muscle weakness, numbness, syncope, or dizziness. Associated autonomic neuropathy can also cause severe disabling symptoms.

FIG.E2 

Hand involvement in Aβ2M amyloidosis.
Hand of a long-term hemodialysis patient showing maximal extension. Note the prominence of shrunken flexor tendons (arrows). This is also known as the “guitar string” sign.
From Floege J et al.: Comprehensive clinical nephrology, ed 4, Philadelphia, 2010, Saunders.

Etiology

The deposition of an amorphous, extracellular fibrillar protein in various tissues that stains with Congo red is the common underlying mechanism, but there are important differences among various subtypes:

  1. •

    AL is associated with an underlying clonal plasma cell disorder making an abnormal light chain protein with possible deposition in multiple organ systems.

  2. •

    AA has no underlying plasma cell disorder and is a consequence of longstanding systemic inflammation (e.g., tuberculosis, leprosy, malaria, untreated syphilis).

  3. •

    Localized amyloidosis results from localized synthesis of fibrillar material with no underlying plasma cell disorder.

  4. •

    Familial amyloidosis is another subtype, with the most common form resulting from mutation of transthyretin gene (TTR). Transthyretin amyloidosis is caused by the deposition of hepatocyte-derived transthyretin amyloid in peripheral nerves and the heart.

  5. •

    A classification of amyloidosis is described in Table E1.

TABLEE1 Classification of Amyloidosis∗Modified from Hochberg MC et al.: Rheumatology, ed 5, St Louis, 2011, Mosby.
Type Fibril Precursor Protein Clinical Syndrome
Primary amyloidosis (AA) Serum amyloid A protein Systemic amyloidosis, usually with predominant renal involvement associated with acquired or hereditary chronic inflammatory diseases. Formerly known as secondary or reactive amyloidosis.
Secondary amyloidosis (AL) Monoclonal immunoglobulin light chains Systemic amyloidosis potentially involving many organ systems associated with myeloma, monoclonal gammopathy, and occult B-cell dyscrasias. Formerly known as primary amyloidosis.
ATTR Normal plasma transthyretin Senile systemic amyloidosis with predominant cardiac involvement (senile cardiac amyloidosis).
ATTR Genetic variants of transthyretin (e.g., ATTR Met30, Ala60, Ile122) Familial amyloid polyneuropathy (FAP), often with prominent amyloid cardiomyopathy. Predominant cardiac involvement without neuropathy with certain mutations (e.g., TTR Ile122).
Ab2M β2-Microglobulin Dialysis-related amyloidosis (DRA) associated with renal failure and long-term dialysis. Predominant articular and periarticular involvement.
Ab β-Protein precursor (and rare genetic variants) Cerebrovascular and intracerebral plaque amyloid in Alzheimer’s disease. Occasionally familial.
AApoAI
AApoAII		 Genetic variants of apolipoprotein AI (e.g., AApoAI Arg26, Arg60)
Genetic variants of apolipoprotein AII		 Autosomal-dominant systemic amyloidosis. Predominantly non-neuropathic with prominent visceral involvement, especially nephropathy. Minor wild-type ApoAI amyloid deposits may occur in the aorta in aging individuals.
Autosomal-dominant systemic amyloidosis with predominant renal involvement.
AFib Genetic variants of fibrinogen A α-chain (e.g., AFib Val526) Autosomal-dominant systemic amyloidosis. Non-neuropathic with predominant nephropathy.
ALys Genetic variants of lysozyme (e.g., ALys His67) Autosomal-dominant systemic amyloidosis. Non-neuropathic with predominant renal and gastrointestinal involvement. Rarely presents with hepatic rupture.
ACys Genetic variant of cystatin C (ACys Gln68) Hereditary cerebral hemorrhage with cerebral and systemic amyloidosis in Icelandic subjects.
AGel Genetic variants of gelsolin (e.g., AGel Asn187) Autosomal-dominant systemic amyloidosis. Predominant cranial nerve involvement plus lattice corneal dystrophy. Described and most common in Finland.

ATTR, Transthyretin.

Diagnosis

Differential Diagnosis

Differential diagnosis varies depending on the organ involvement:

  1. •

    Renal involvement (toxin- or drug-induced necrosis, glomerulonephritis, renal vein thrombosis)

  2. •

    Interstitial lung disease (sarcoidosis, connective tissue disease, infectious causative factors)

  3. •

    Restrictive cardiomyopathy (endomyocardial fibrosis, viral myocarditis)

  4. •

    Carpal tunnel (rheumatoid arthritis, hypothyroidism, overuse)

  5. •

    Peripheral neuropathy (alcohol abuse, vitamin deficiencies, diabetes mellitus)

Workup

Workup consists of performing blood and urine tests to look for abnormal light chain in urine or blood, performing various tests to look for target organ damage, and getting histologic confirmation by doing a fat pad and bone marrow biopsy and then performing Congo red staining on that. Fig. E3 describes an algorithm for diagnosis of amyloidosis and determination of type.

FIG.E3 

Algorithm for the diagnosis of amyloidosis and determination of type.
From Firestein GS et al.: Kelly’s textbook of rheumatology, Philadelphia, 2013, Saunders.

Laboratory Tests

  1. •

    Immunofixation of serum and urine (SPEP, UPEP) to look for immunoglobulin light chain is a sensitive screening test.

  2. •

    CBC, blood urea nitrogen (BUN)/creatinine, liver function tests, thyroid functions, and urine for albumin.

  3. •

    Histologic confirmation is necessary with a fat pad and bone marrow biopsy with Congo red staining to establish a diagnosis.

  4. •

    If a noninvasive fat pad biopsy does not establish a diagnosis, then a biopsy of the affected organ may be needed.

Imaging Studies

  1. •

    Two-dimensional Doppler echocardiography to study diagnostic filling is useful to evaluate for cardiac involvement.

  2. •

    Nuclear imaging with technetium-labeled aprotinin may detect cardiac amyloidosis. Labeled diphosphonates play an important role in the typing of amyloidosis and in diagnosing heart involvement in patients with transthyretin cardiac amyloidosis. Cardiac involvement in transthyretin patients may be diagnosed earlier with bone scintigraphy in transthyretin patients compared with echocardiography. Serum amyloid P component (SAP) scintigraphy has high sensitivity for the detection of amyloid deposits in liver, spleen, kidneys, adrenal glands, and bones.

Treatment

Acute General Rx

  1. •

    The goal of therapy is to decrease the production of the amyloidogenic light chain with therapy directed at the clonal plasma cells.

  2. •

    All agents used to treat multiple myeloma are effective against AL, including melphalan, prednisone, oral dexamethasone, systemic chemotherapy such as cyclophosphamide, doxorubicin (Adriamycin), and more recently immunomodulatory compounds (IMiDs) such as thalidomide or lenalidomide, or proteasome inhibitors, but none has shown to be superior to melphalan and prednisone, which remain the treatment of choice. Table E2 summarizes major treatment options for amyloidosis.

TABLEE2 Major Treatment Options for AmyloidosisFrom Firestein GS et al.: Kelly’s textbook of rheumatology, ed 9, Philadelphia, 2013, Saunders.
AL Amyloidosis
Intravenous melphalan with autologous stem cell rescue
  1. •

    Granulocyte colony-stimulating factor–mobilized peripheral blood stem cell collection
  1. •

    Intravenous melphalan 140-200 mg/m2
  1. •

    Autologous stem cell reinfusion
Cyclic oral melphalan and dexamethasone
  1. •

    Melphalan 0.22 mg/kg/day × 4 days
  1. •

    Dexamethasone 20-40 mg/day × 4 days, or weekly
  1. •

    Repeat administration every 4 weeks
Immunomodulators
  1. •

    Lenalidomide 5-15 mg/day × 21 days
  1. •

    Dexamethasone 20-40 mg/day weekly
  1. •

    Repeat administration every 4 weeks
Proteasome inhibitors
  1. •

    Intravenous bortezomib, 0.7-1.6 mg/m2 1-2 times per week
  1. •

    Repeat every 3-5 weeks
AA Amyloidosis
  1. •

    Aggressive treatment of underlying inflammatory disease
  1. •

    Medical or surgical treatment of underlying infection
  1. •

    Colchicine 1.2-1.8 mg/day for AA amyloidosis secondary to familial Mediterranean fever
  1. •

    Antifibril drug, eprosidate (investigational)
ATTR Amyloidosis
  1. •

    Orthotopic liver transplantation
  1. •

    Transthyretin stabilizers: tafamadis, diflunisal (investigational)
  1. •

    Anti–tumor necrosis factor drugs may be useful to treat kidney amyloid A amyloidosis but may increase the risk and severity of infection.

  2. •

    Diflunisal, an NSAID, stabilizes transthyretin tetramers and prevents amyloid formation in vitro. Trials have shown that diflunisal reduces the rate of progression of neurologic impairment and preserves quality of life.1

  3. •

    Recent phase 1 trials have shown that treatment with CPHPC followed by anti-SAP antibody safely triggered clearance of amyloid deposits from the liver and some other tissues.2

  4. •

    The use of high-dose chemotherapy and stem cell transplantation (SCT) for patients with amyloidosis remains controversial because of high treatment-related mortality. In highly selected patients with preserved organ function, autologous bone marrow transplant can have good results.

  5. •

    Patients who develop renal failure can be supported with hemodialysis or renal transplant.

  6. •

    Liver transplantation has been used successfully in patients with familial amyloidosis.

  7. •

    Recognition and treatment of the underlying disorder is needed for secondary amyloidosis.

  8. •

    Table E3 summarizes supportive treatment options for all types of amyloidosis.

TABLEE3 Supportive Treatment for All Types of Amyloidosis
Organ System Symptom Treatment Options
Cardiac Congestive failure Salt restriction of 1-2 g/day
Diuretics: furosemide, spironolactone, metolazone
Arrhythmia Pacemaker
Automatic implantable cardiac defibrillator
Antiarrhythmics
Renal Nephrotic syndrome Salt restriction of 1-2 g/day
Elastic stockings, leg elevation
Maintaining dietary protein
Angiotensin-converting enzyme inhibitor, if blood pressure tolerates
Renal failure Dialysis (long-term ambulatory peritoneal dialysis or hemodialysis)
Autonomic nervous Orthostatic hypotension Midodrine
Increased dietary salt or added fludrocortisone, depending on edema
Elastic stockings
Gastric atony or ileus Small frequent feedings (6/day) low in fat
Oral nutritional supplements
Jejunostomy tube feeding
Parenteral nutrition
Gastrointestinal Diarrhea Low-fat diet (≤40 g)
Psyllium hydrophilic mucilloid (Metamucil)
Loperamide hydrochloride (Imodium)
Tincture of opium
Parenteral nutrition
Macroglossia Soft solid diet
Partial glossectomy (rarely effective)
Peripheral nervous Sensory neuropathy Avoiding trauma
Gabapentin (Neurontin) 100-300 mg 3 times daily
Amitriptyline 25-50 mg at bedtime
Pregabalin (Lyrica) 50-100 mg 3 times daily
Motor neuropathy Ankle-foot orthotics for footdrop
Physical therapy
Hematologic Intracutaneous bleeding Avoiding trauma, antiplatelet agents
Factor X deficiency Factor replacement (recombinant factor VIIa, prothrombin complex concentrates)
Splenectomy for splenomegaly

Disposition

Prognosis is determined primarily by the presence or absence of cardiac involvement and the form of amyloidosis:

  1. •

    In patients with endomyocardial biopsy–documented cardiac amyloidosis, longer-term survival is more strongly associated with New York Heart Association functional class compared with ECG or echocardiography variables.

  2. •

    In AA, eradication of the predisposing disease slows and can occasionally reverse the progression of amyloid disease. Median survival after diagnosis is 133 mo.

  3. •

    Patients with familial amyloidotic polyneuropathy generally have a prolonged course lasting 10-15 yr.

  4. •

    The progression of amyloidosis associated with renal hemodialysis can be improved with newer dialysis membranes that can pass beta-2-microglobulin.

  5. •

    Median survival in patients with overt CHF is ∼6 mo; it is 30 mo without CHF.

Suggested Readings

  • T. Coelho, et al.: Safety and efficacy of RNA: therapy for transthyretin amyloidosis. N Engl J Med. 369:819–829 2013 23984729

  • A. Fernandes-Nebro, et al.: Long-term TNF-alpha blockade in patients with amyloid A amyloidosis complicating rheumatic diseases. Am J Med. 123:454–461 2010 20399323

  • S.K. Kumar, et al.: Recent improvements in survival in primary systemic amyloidosis and the importance of an early mortality risk score. Mayo Clin Proc. 86 (1):12–18 2011 21193650

  • M.S. Maurer, et al.: Non-invasive identification of ATTRwt cardiac amyloid: the re-emergence of nuclear cardiology. Am J Med. 128:1275–1280 2015 26091765

 

 

 

BÀI LIÊN QUAN