Amyloidosis


Article Author:
Jean Bustamante


Article Editor:
William Gossman


Editors In Chief:
Rodrigo Kuljis
Oleg Chernyshev
Aninda Acharya


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
5/15/2019 11:34:58 PM

Introduction

Amyloidosis is a heterogeneous disease that results from the deposition of toxic insoluble beta-sheet fibrillar protein aggregates in different tissues. Amyloidosis can be acquired or hereditary. The disease can be localized or systemic. Amyloid can accumulate in liver, spleen, kidney, heart, nerves, and blood vessels causing different clinical syndromes including cardiomyopathy, hepatomegaly, proteinuria, macroglossia, autonomic dysfunction, ecchymoses, neuropathy, renal failure, hypertension, and corneal and vitreous abnormalities.[1][2][3]

Etiology

The most common causes of amyloidosis are the immunoglobulin-light-chain relate amyloidosis (AL), ATTR amyloidosis, and reactive amyloidosis (AA) due to chronic inflammatory diseases like chronic infections and rheumatoid arthritis. AL amyloidosis is acquired and is caused by a small plasma cell clone that produces misfolded amyloidogenic light chains that deposit in different organs and tissues.[4][5]

Epidemiology

AL amyloidosis has an incidence of 1 case per 100,000 person-years in Western countries. In the United States, there are approximately 1275 to 3200 new cases per year. The annual proportion of new cases with AL is 78%. Familial transthyretin-associated amyloidosis (ATTR) is a less common systemic type of amyloidosis with unknown incidence, but approximately 10% to 20% of diagnosed cases in tertiary centers are secondary to ATTR amyloidosis. Of these cases, seven percent are hereditary and result from mutated transthyretin (ATTRm) and approximately six percent represent the acquired age-related, wild-type ATTRwt amyloidosis. ATTRwt is seen more commonly in males and was formerly known as senile systemic amyloidosis. Secondary or AA amyloidosis represents 6% of all the amyloidosis cases diagnosed each year. AA amyloidosis is an acquired process and reactive due to chronic inflammation.[6][7]

Pathophysiology

Twenty-one different proteins have been identified as amyloidogenic agents. Polypeptides can adopt alternative misfolded states making them prone to aggregate. There are multiple processes by which misfolding of protein precursors occur. The protein may be intrinsically likely to acquire a pathologic conformation with aging as seen in patients with wild-type transthyretin senile systemic amyloidosis. This can also happen when there is high serum concentration of protein precursors as seen in long-term hemodialysis patients with increased levels of beta-2-microglobulin. In hereditary amyloidosis, replacement of single amino acids can lead to amyloidogenic misfolded proteins losing the biologic function of the native proteins and aggregate. Proteolytic remodeling of beta-amyloid precursor proteins has been identified in Alzheimer disease. In patients with AA amyloidosis, serum amyloid A, an acute phase protein deposits in different tissues. The amyloidogenic variants of the various precursor proteins are thermodynamically less stable, resulting in tetramers dissociation into monomers in the case of transthyretin and destabilization of the tertiary structure leading to partially folded conformers in the case of lysozyme. Transthyretin monomers and lysozyme partially folded conformers have the propensity to aggregate and assemble into fibrils. Charged residues also play a role in modulating the aggregation using repulsive forces resulting in partial unfolding, rendering the protein susceptible to proteases attacks and release of amyloidogenic polypeptides. This is the case of gelsolin, an amyloidogenic protein which causes systemic amyloidosis. Low pH, increased temperatures, limited proteolysis, osmolytes, and metal ions can alter the tridimensional structure of proteins shifting the equilibrium towards the amyloidogenic state. The mechanism of tissue damage in amyloidosis involves alteration of tissue architecture, interaction with cell surface receptors, inflammation elicited by the amyloid protein deposition, oxidative stress, and apoptosis activation.

History and Physical

The clinical features of amyloidosis vary depending on which type of amyloid fibrils are responsible. Systemic amyloidosis can lead to heart failure with left ventricular hypertrophy on echocardiogram with standard or low voltage electrocardiogram. Hepatomegaly, nephrotic syndrome, macroglossia, orthostatic hypotension, ecchymosis and autonomic and peripheral neuropathy can be present. Carpal tunnel syndrome, jaw claudication, and articular deposits of amyloid can also be a manifestation of systemic amyloidosis. In secondary amyloidosis (AA), hepatosplenomegaly, proteinuria, renal failure, and orthostasis can be seen. ATTR amyloidosis onset is during midlife and presents with peripheral and autonomic neuropathy, cardiomyopathy, and vitreous opacities. Amyloid beta-amyloidosis is localized to the central nervous system and presents as sporadic Alzheimer disease and aging.

Other physical exam findings can lead to suspicion of amyloidosis diagnoses like shoulder pads from amyloid deposition, amyloid purpura, and raccoon eyes secondary to factor-X deficiency in the case of AL amyloidosis and prolonged PT, PTT, that correct with mixing studies pointing towards the involvement of factor deficiencies in the common pathway of coagulation.

Evaluation

Clinical suspicion, family history, and tissue biopsy establish the diagnosis.[8][9]

Tissue biopsy

  • The subcutaneous abdominal fat aspirate is an easy and innocuous procedure that will stain Congo red positive with apple green birefringence and has an 81% diagnostic sensitivity in AL amyloidosis.
  • Biopsy of minor salivary glands can establish systemic amyloidosis diagnosis 60% of the times when fat aspirates are negative.
  • Biopsy of the liver should be done by the transjugular route, since an amyloid-loaded liver may result in fatal bleeding.

Plasma cell clone identification

Serum and urine electrophoresis with immunofixation and free light chains (FLC) should be requested to rule out plasma cell dyscrasia. When monoclonal light chains are not present, bone marrow biopsy can help establish the diagnosis by immunohistochemical staining. Immunofluorescence in situ hybridization should be ordered as well and skeletal survey.

When plasma cell dyscrasia is ruled out, other types of amyloidosis should be considered. Tissue typing can be done by mass spectrometry, immune electron microscopy or immunohistochemistry. Transthyretin can be detected by isoelectric focusing on the serum which separates wild-type (or formerly known senile cardiac amyloidosis) and variant transthyretin.

Gene sequencing

Should be done when hereditary amyloidosis has to be ruled out based on clinical grounds.

When transthyretin has not been identified, and patients have macroglossia and other typical organ involvement, AL should still be suspected despite plasma cell dyscrasia absence. ATTRwt is diagnosed by cardiac biopsy showing positivity to antibodies against normal transthyretin. Cardiac Scintigraphy with bone tracers can help differentiate AL amyloidosis which shows mild or no uptake from transthyretin amyloidosis which has strong uptake. This could potentially spare cardiac biopsy.

AA amyloidosis is considered when transthyretin and AL have been ruled out, and there are kidney involvement and neuropathy. Immunohistochemistry aids in the diagnosis of AA.

Organ involvement and staging of the disease should be established to design the treatment plan. For cardiac function, evaluation should include an echocardiogram with an assessment of strain, NT-proBNP, troponins, ECG, Holter ECG, and cardiac MRI should be solicited. For kidney function, evaluation 24-hour urinary protein and eGFR are needed. Liver function test and imaging (ultrasound (US), MRI, or CT scan) can help with hepatic function assessment.

Treatment / Management

AL amyloidosis: This disease is treated most likely in the framework of clinical trials and depending on the risk stratification according to the Standard Mayo Clinic staging system.[10][11][12]

  • Low risk patients (NT-proBNP less than 5000 ng/L, troponins of less than 0.06 ng/ml, eGFR more than 50 ml/min per 1.73m, age less than 65 years, performance status of 0-2, NYHA class less than III, ejection fraction above 45%, systolic blood pressure above 90 mmHg standing and DLCO above 90%). Low-risk patients receive autologous stem cell transplant (ASCT) with Melphalan 200mg/m2. Induction with cyclophosphamide, bortezomib, and dexamethasone should be considered if the bone marrow, plasma cell infiltration is more than 10% or if a patient refuses transplant. Post-transplant treatment with bortezomib increases the complete response (CR) rates, and if CR is not achieved, bortezomib and dexamethasone combination should be given.
  • Intermediate risk patients (ineligible for ASCT and stage I-IIIa): Melphalan and Dexamethasone are the preferred regimens especially in the case of neuropathy or t(11;14) translocation. Cyclophosphamide with Bortezomib and dexamethasone combination is a stem cell sparing regimen preferred in patients with renal failure and with 1q21 gain. If noninvolved Free Light Chains (dFLC) is above 180 mg/l, the preferred regimen is bortezomib, melphalan, and dexamethasone combination.
  • High-risk patients (stage IIIb, NYHA class III or above): bortezomib can be preferred due to a rapid onset of action or low-dose combination regimens are preferred as well.

ATTR amyloidosis: Transthyretin is a protein predominantly synthesized in the liver. Upon liver transplant, mutant transthyretin disappeared from blood and neuropathy improvement was observed.

Supportive therapy: The treatment of systemic amyloidosis involves supportive therapy aiming to maintain the quality of life and prevent organ dysfunction. If patients are on a heart transplant waiting list, they should receive low-dose chemotherapy due to increased survival. 

Splenectomy: An option with proper prior vaccination when there is severe factor-X deficiency leading to bleeding diathesis. Factor X deficiency is seen in 2.5% of patients with AL amyloidosis. Splenectomy is effective in patients who have splenomegaly, but not usually in patients with a normal size spleen.

Enhancing Healthcare Team Outcomes

Amyloidosis is a heterogeneous disease that results from the deposition of toxic insoluble beta-sheet fibrillar protein aggregates in different tissues. Amyloidosis can be acquired or hereditary. The disease can be localized or systemic. Thus, it is best managed by a multidisciplinary team that includes an oncologist, hematologist, internist, nephrologist, and a neurologist. Amyloid can accumulate in liver, spleen, kidney, heart, nerves, and blood vessels causing different clinical syndromes including cardiomyopathy, hepatomegaly, proteinuria, macroglossia, autonomic dysfunction, ecchymoses, neuropathy, renal failure, hypertension, and corneal and vitreous abnormalities. This disease is treated most likely in the framework of clinical trials and depending on the risk stratification according to the Standard Mayo Clinic staging system.


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Amyloidosis - Questions

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Which of the following is most likely involved in primary systemic amyloidosis?



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Which medication does not play a role in the treatment of amyloidosis?



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What is the most common cause of amyloidosis in North America?



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A 64-year-old with lupus develops nephrotic syndrome. A biopsy is performed, and the specimen is evaluated under a microscope. The mesangial nodules are stained with Congo red and appear green-red under polarized light. The patient has developed which of the following?



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A 65-year-old male presents with a 4-month history of general malaise and bone pain. X-rays show lytic lesions. Biopsy of a lesion in his spleen stains positive with Congo red. What is the most likely composition of the stained lesion?



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What causes dialysis-related amyloidosis?



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In a patient with restrictive cardiomyopathy secondary to amyloidosis, which treatment is NOT recommended?



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Which of the following stains would give a definitive diagnosis of amyloidosis from biopsied tissue?



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A 62-year-old female is hospitalized for congestive heart failure and renal failure. An initial exam is remarkable for jugular venous distention; heart sounds show S1S 2 regular with an S3 no murmurs. Lungs have rales ½ way up bilaterally. There is 2+/4 pitting pedal edema. There are waxy papules in the axilla and inguinal region. Admission labs show electrolytes to be normal, but BUN is 85 mg/dL and a creatinine of 6.1 mg/dL. Total protein was 9.2 g/dL, with an albumin of 3.0 g/dL. Hematocrit was 24 percent, and white blood cell and platelet counts were normal. Urinalysis shows 3+ protein but no cells or cellular casts. Echocardiogram shows a thickened left ventricle with preserved systolic function. Select the appropriate diagnostic test.



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What condition is most likely to cause secondary amyloidosis?



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A 62-year-old female has had worsening congestive heart failure for 3 years. Echocardiogram shows a restrictive cardiomyopathy. Cardiac catheterization shows no coronary artery disease, but right endomyocardial biopsy shows myocardial replacement with acellular eosinophilic material. Congo red stains it apple green. What is this material?



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Which of the following is LEAST likely to be associated with the secondary form of amyloidosis?



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A 76-year-old woman notes flesh-colored papules on the trunk and eyelids. Intracutaneous bleeding develops in these lesions, both spontaneously and after minimal trauma, such as rubbing the eyelid. What is the most likely diagnosis?



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Which of the following is the most common and, potentially, most serious form of organ involvement in amyloidosis?



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Senile systemic amyloidosis is most often clinically significant when it affects which organ?



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Uremia is not associated with hypertension in which of the following situations?



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A 47-year-old female presents with anasarca. She was found to have nephrotic range proteinuria. Her EKG showed low voltage and echocardiogram left ventricle hypertrophy (LVH). Her creatinine was 1.7 mg/dL and a renal biopsy was decided. After the procedure, severe bleeding at the biopsy site developed only controlled with prothrombin complex concentrate (PCC), embolization and required multiple transfusions. Which is the most likely etiology of this profuse bleeding?



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A 47-year-old patient with a past medical history of myeloma presented with long-lasting respiratory symptoms. Chest x-ray showed an enlargement of the mediastinum. CT-scan showed multiple mediastinal lymph nodes. Mediastinoscopy was performed, and the microscopic exam showed a lymph node parenchyma characterized by the presence of an abundant eosinophilic and acellular material. A congo red stain was positive, and the immunohistochemical study revealed positivity of the material using kappa chain antibody. What is the diagnosis?



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Amyloidosis - References

References

Tini G,Vianello PF,Gemelli C,Grandis M,Canepa M, Amyloid Cardiomyopathy in the Rare Transthyretin Tyr78Phe Mutation. Journal of cardiovascular translational research. 2019 Jan 2;     [PubMed]
Baiardi S,Rossi M,Capellari S,Parchi P, Recent advances in the histo-molecular pathology of human prion disease. Brain pathology (Zurich, Switzerland). 2018 Dec 26;     [PubMed]
Gavriatopoulou M,Fotiou D,Ntanasis-Stathopoulos I,Kastritis E,Terpos E,Dimopoulos MA, How I treat elderly patients with plasma cell dyscrasias. Aging. 2018 Dec 18;     [PubMed]
Yakupova EI,Bobyleva LG,Vikhlyantsev IM,Bobylev AG, Congo red and amyloids: History and relationship. Bioscience reports. 2018 Dec 19;     [PubMed]
Sekijima Y, Hereditary Transthyretin Amyloidosis 1993;     [PubMed]
Alwahaibi NY,Al Issaei HK,Al Dhahli BS, Spectrum of glomerular diseases in Arab countries: A systematic review. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. 2018 Nov-Dec;     [PubMed]
Andreou S,Panayiotou E,Michailidou K,Pirpa P,Hadjisavvas A,El Salloukh A,Barnes D,Antoniou A,Agathangelou P,Papastavrou K,Christodoulou K,Tanteles GA,Kyriakides T, Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset. Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. 2018 Dec 20;     [PubMed]
Kapoor M,Rossor AM,Jaunmuktane Z,Lunn MPT,Reilly MM, Diagnosis of amyloid neuropathy. Practical neurology. 2018 Dec 30;     [PubMed]
Koop AH,Mousa OY,Wang MH, Clinical and endoscopic manifestations of gastrointestinal amyloidosis: a case series. Clujul medical (1957). 2018 Oct;     [PubMed]
Westerland OA,Pratt G,Kazmi M,El-Najjar I,Streetly M,Yong K,Morris M,Mehan R,Sambrook M,Hall-Craggs M,Silver D,Goh V, National survey of imaging practice for suspected or confirmed plasma cell malignancies. The British journal of radiology. 2018 Dec;     [PubMed]
Kalle A,Gudipati A,Raju SB,Kalidindi K,Guditi S,Taduri G,Uppin MS, Revisiting renal amyloidosis with clinicopathological characteristics, grading, and scoring: A single-institutional experience. Journal of laboratory physicians. 2018 Apr-Jun;     [PubMed]
Eddou H,Zinebi A,Maaroufi HE,Moudden MK,Doghmi K,Mikdame M,Baaj ME, [Treatment of systemic AL amyloidosis: about 25 cases]. The Pan African medical journal. 2017;     [PubMed]

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