AMYLOIDOSIS

By

DR. I. O. MBAH (FWACP)

Snr Lecturer & Chief Consultant Physician/ Nephrologist, CM&HS, BHUTH, JOS

INTRODUCTION

• Refers to a group of conditions in which a small subunit of a plasma protein undergoes polymerization and is deposited in the tissues as fibrils
• Usually with a beta-pleated sheet configuration
• Immunoglobulin light chains are culprits like in plasma cell dyscrasias or chronic infections

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• The word amylon was first used in 1834 by the German Botanist Mathias Schleiden¹ to describe the waxy starch in plants and Rudolph Virchow coined the word "amyloid in 1854 ¹.
• Congo red stain was introduced in 1920

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• Amyloid formation
• Amyloid fibrils cause functional and structural organ damage ^1,2.
• The unifying feature of these proteins is their tendency to form β pleated sheets.
• This then form rigid, non branching fibrils that resist proteolysis and cause mechanical distruption and local oxidative stress.
• heart, liver, kidney and gastrointestinal tract² .

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• Types of amyloidosis?
• 1. Primary amyloidosis- Affects the heart, lungs, skin, tongue, nerves and intestine as in the case to be presented⁴.
• 2. Secondary- amyloidosis- Associated with chronic diseases such as: tuberculosis, rheumatoid arthritis or chronic osteomyelitis.
• 3. Hereditary amyloidosis- This type often affects the nervous and digestive system

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Introduction�

• Amyloidosis is a rare clinical condition that affects several organs of the body.
• There is paucity of data, on the occurrence of this clinical condition
• This case illustrate the challenges of diagnosis, and management in this environment

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CASE PRESENTATION:�

• B. J 52 year old woman, that presented with a week history of generalized weakness, loss of appetite, and five days history of left leg pain.
• Examination findings- Middle aged woman, conscious and alert. Chronically ill looking.
• MSS- Left gluteal pain, no differential warmness
• Connective tissue disease R/O Polymyositis
• She was rehydrated and given analgesics.

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Results of investigations

• The urinalysis - turbid in appearance, glucose- negative, protein - 2+, blood 2+, and ketone +.
• Microscopy- pus cells - 0-2 /hpf.
• Culture yielded no growth
• FBC- WCC- 6.68 X 10^9, PCV- 32%, Platelet count- 257 x 10³
• Neutrophils 32.4%, lymphocytes- 60%.
• ESR- 30mm/hr. Blood sugar 100mg/dl

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E/U & Cr

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• Represented with exacerbation of initial symptoms
• General examination- a middle aged woman, lethargic, not pale, no pedal edema.
• Cardiovascular examination – pulse rate -68bpm, regular, normal volume
• Blood pressure- 100/60mmHg ( supine)
• sitting – 80/50mmHg
• Heart sound- I and II.

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• Assessment - ? Adrenal insufficiency
• She was admitted and commenced on:
• Normal saline and hydrocortisone in the initial 48hrs
• Tab prednisolone 10mg twice daily
• Tab fludrocortisone 0.1mg daily,
• Tab Rosuvastatin 10mg nocte

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Results of Investigation

• Random blood sugar- 158mg/dl,
• Cortisol: 187.36 (240-618),
• ACTH: 2.5pg/l (10.6-13.9pg/l)
• E/U & Cr
• Na-137mmol/L Hco3-24mmol/L
• K – 5.8mmol/L Urea- 45mg/dl
• Cl- 109mmol/L Cr- 1.5mg/dl

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• Presented at Lagos University Teaching hospitals with bilateral leg pain, recurrent vomiting, leg swelling and hypotension.
• An assessment of –Adrenal Insufficiency ? Cause
• Resuscitation- albumin infusion(40-50g daily for five days).
• Chest x ray- Bilateral pleural effusion
• Results of investigation: HB: 8.7g/dl, PCV: 23.9%,
• WBC: 5.5 X10^3, Neutrophils: 88.2% and lymphocyte -10.4% .

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INVESTIGATIONS

• total protein- 3.2mg/dl, albumin- 1.6mg/dl
• She then travelled to UK where various tests were done among which were:
• Renal biopsy - Congo red positive amorphous substance typical of amyloid.
• Capillary walls are unremarkable.
• Tubules and Interstitium - abundant protein re-absorption droplets in proximal tubular epithelium.

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• No evidence of acute tubular injury.
• Vessels: foci of amyloid deposits in hilar arterioles.
• Cytometry summary - 2% plasma cells. No evidence of atypical lymphoid population.
• Renal Amyloid, non AA type (most likely AL- type) .
• Transferred to Amyloid Centre.

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Echocardiography

• Two dimensional echocardiogram revealed marked thickening and speckle appearance of interventricular septum.
• Bi-atrial enlargement.
• The ejection fraction was preserved.
• Left systolic dysfunction.
• Restrictive diastolic dysfunction, pericardial effusion but no tamponade.
• Assessment of Amyloid heart disease.

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ECG

• ECG: Low voltage complexes in limb leads and augmented leads.
• Left ventricular hypertrophy and prolonged QT interval

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• Patient deteriorate progressively
• Patient condition continued to deteriorate subsequently died on 26/1/19 after 31 days from the first admission.

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• This patient had primary AL amyloidosis .
• Incidence of amyloidosis-
• Africans- low incidence of amyloidosis
• Close to 90% of patients, will have fatigue, weight loss and oedema⁴.
• Amyloid related adrenal dysfunction is an insidious process which may remain subclinical for a long time⁶

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What is it?

• A mass of abnormally folded proteins

Systemic Amyloidosis

• Amyloidosis is the term for diseases caused by the extracellular deposition of insoluble polymeric protein fibrils in tissues & organs
• These diseases are a group of disorders attributed to misfolding of proteins
• These Amyloid fibrils share a common ᵝ-pleated sheet structural conformation that confirms a unique staining properties
• Rudolf Virchow 1854, coined the term Amyloid (deposits were cullulose like)

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CLASSIFICATION

• Defined by the biochemical nature of the protein in the fibril deposits
• Classified according to whether they are
• Systemic or localized
• Acquired or Inherited
• By clinical patterns

NOMENCLATURE

• Accepted nomenclature is AX;
• A = Amyloidosis, X = the protein in the fibril
• Eg – AL is Amyloid composed of Immunoglobulin Light Chains & is called Pry Systemic Amyloidosis; which arises from a clonal B-cell disorder associated with Myeloma or Lymphoma
• AF- Familial Amyloidosis due to mutations transthyretin (transport prot for thyroid hormone & retinol-binding prot); ATTR
• AA- Secondary Amyloidosis (Chr inflammatory /Infectious dses

• Aᴃ₂M- Amyloid composed of ᴃ₂ microglobulin seen in ESRD of long duration
• AApoA1- Apolipoprotein A1 (Familial- Renal)
• AApoA11 (Familial– Renal)
• AFib– Fibrinogen Aἀ (Familial– Renal)

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• All these are systemic Amyloidoses

LOCALIZED AMYLOIDOSES

• A1APP– (Islet Amyloid polypeptide Amylin) affects the pancrease– DM
• AANF– (Atrial Naturetic Factor); Age related affects Cardiac atria etc

Which Organs are Affected?

• The kidneys can be affected by deposition of amyloid proteins into blood vessel walls and glomerular membrane disrupting filtration barrier
• Proteinuria is usually noticed which could occur in Nephrotic range
• It can also affect autonomic nerve fibres in systemic arteriolar walls →postural ↓BP →
• ↓RBF

AFFECTED KIDNEYS

AKI

CKD

The Heart & The Liver too etc

• When the liver is infiltrated it leads to unexplained HEPATOMEGALY
• The heart has both electrical and mechanical activity
• Infiltration affects both conduction and contractility
• The tongue could be infiltrated → Macroglossia

CARDIOMEGALY (DCM)

LIVER INFILTRATES

NORMAL LIVER

DISEASED LIVER

CLINICAL PRESENTATION

• Initial easy fatigability (unexplained)
• Easily missed, but suspected when there is organ involvement
• If renal, oedema (facial, LLs, Full blown Nephr syndr)
• Azotemia if tubular involvement (Uremic syndr)

If CNS?

• CNS – Peripheral N, Autonomic N
• Postural hypotension
• Reduced renal perfusion
• Loss of Valsalva maneuver

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And Cardiac?

• Cardiac– CCF or Arrhythmias (palpitations)
• Ventricular ectopics?
• Atrial Fib?

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PERICARDITIS

What of the Joints?

• All forms of arthritis
• Rheumatoid
• Osteo
• Any joint can be infiltrated

INVESTIGATION

• Urinalysis
• PCR (not polymerase Chain Rxn) but what?...
• 24 hr urinary protein
• Serum proteins (Alb & Diff)
• SEUCr
• ECG (Low voltages)
• Fat aspiration biopsy for staining with Congo Red ( if negative bx involved organ renal, heart GIT, Liver

Investigation continued

• Tissue Biopsy
• Serum protein electrophoresis
• Serum protein Immuno electrophoresis
• Bone marrow Biopsy / aspirate

• When the tissues are so stained it gives a unique green birefringence by polarised light microscopy
• Then you xterize the Amyloid type by immunohistochemistry/ electron microscopy/ mass spectrometry

Polarized light

Congo red stain

Algorithm for the Diagnosis & determination of type

• Clinical suspicion (Unexplained Nephropathy, Cardiomyopathy, Neuropathy, Enteropathy, Arthropathy, Macroglossia, Periorbital echymosis)
• Urinalysis (Qualitative & Quantitative)
• FBC + ↑ESR
• Serum Prot
• BNP/Troponin
• LFT ↑ALP, Transaminases minimal
• TFT (Hypothyroidism)
• SEUC
• ECG

• Serum prot electrophoresis (SPEP)
• Urine prot electrphoresis (UPEP)
• Finger nail dystrophy

TREATMENT

• AL– Poor prognosis if left untreated
• Median survival 1-2yrs
• Cyclical Melphalan + Prednisolone to reduce the plasma cell burden
• In cardiac involvement with arrhythmias, survival 6months
• If in CCF, Diuretics
• In Nephr Syndr , Diuretics, Supportive stockings, ACEIs

Management

• Suppress production of new light chain

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• Melphalan + prednisolone
• Intravenous Bortezomib 2mg on day: 1, 4, 8, 11, methylprednisolone 500mg in 500mls of 0.9% saline.
• Tab thalidomide 100mg daily,
• Tab ranitidine 150mg twice daily
• Tab allopurinol 100mgdaily.

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Conclusions

• Systemic amyloidosis is rare and the presentation is protean there is the need for high index of suspicion.
• Staining facility, cytochemistry and electron microscopy should be readily available.

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REFERENCE:�

• 1. Sipe J.D, Benson M.D, et al. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature Committee of the International Society of Amyloidosis. Amyloid 2010. Sep 17 (3-4): 101-4 (PubMed)
• 2. Merlini G, Balloti V. Molecular mechanism of amyloidosis. N Eng. J Med 2003. Aug 7; 349 (6): 583- 96 ( PubMed)
• 3. Kyle R.A. Amyloidosis: a convoluted story. Br. J Heamatol. 2001, Sep; 114 (3): 529- 38 ( PubMed)

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• 4. Dubrey S.W, Cha K, Andersen J et al. The Clinical features of Immunoglobulin light chain (AL), amyloidosis with heart Involvement. Q J M. 1998; Feb 91 (2): 141 - 57 ( PubMed).
• 5. Maclver A.G, Thomas S.M. J. Trop Med. Hyg. 1982; 85 (5): 209-12
• 6. Heller E.L, Camarata S.J. Addison's disease from amyloidosis of adrenal glands. Arch Pathol 1950; 49: 601-604.
• 7. Brandt K, Cathcart E.S, Cohen A.S. A Clinical analysis of the course and prognosis of forty two patients

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