Amyloidosis is a group of diseases caused by the abnormal accumulation of misfolded proteins, called amyloid fibrils, in tissues and organs. These deposits can interfere with normal organ structure and function and may affect the heart, kidneys, nervous system, gastrointestinal tract, liver and other tissues (1).

Amyloidosis is not a single disease. Different precursor proteins can form amyloid, and the protein responsible determines the type of amyloidosis. Correctly identifying the amyloid type is essential because the diagnostic pathway, treatment and prognosis can differ substantially between types (1).

Proteins normally fold into specific three-dimensional structures that allow them to perform their biological functions. In amyloidosis, particular proteins or protein fragments misfold and aggregate into insoluble amyloid fibrils. These fibrils accumulate extracellularly within tissues. Over time, amyloid deposition and, in some forms, direct toxicity from circulating precursor proteins can impair organ function (1, 2).

More than 40 human proteins have been identified as capable of forming amyloid fibrils in vivo (1).

There are many types of amyloidosis. Among the most clinically important systemic forms are:

• AL amyloidosis – caused by immunoglobulin light chains
• ATTR amyloidosis – caused by transthyretin
• AA amyloidosis – caused by serum amyloid A protein

These conditions have different underlying mechanisms and require different treatments (1, 2, 3).

Immunoglobulin light-chain (AL) amyloidosis is a clonal plasma-cell or, less commonly, other B-cell disorder in which an abnormal immunoglobulin light chain or light-chain fragment misfolds and forms amyloid deposits (2).

AL amyloidosis can affect multiple organs, including the:

• Heart
• Kidneys
• Peripheral nerves
• Autonomic nervous system
• Liver
• Gastrointestinal tract
• Soft tissues

Common clinical presentations include heart failure, nephrotic-range proteinuria or nephrotic syndrome, peripheral or autonomic neuropathy and other manifestations determined by the organs involved (2).

Cardiac involvement is particularly important because it strongly influences prognosis (2).

Transthyretin amyloidosis (ATTR) results from the misfolding and aggregation of transthyretin (TTR), a protein produced predominantly by the liver. ATTR amyloidosis occurs in two major forms: variant/hereditary ATTR (ATTRv) and wild-type ATTR (ATTRwt) (3, 4).

ATTRv is caused by a pathogenic variant in the TTR gene and follows an autosomal dominant inheritance pattern. However, penetrance, age at onset, and clinical phenotype vary according to the specific variant and other genetic, geographic and environmental factors (4).

ATTRv can involve the:

• Heart
• Peripheral nerves
• Autonomic nervous system
• Gastrointestinal system
• Eyes
• Other tissues

Patients may therefore present predominantly with cardiomyopathy, polyneuropathy or a mixed phenotype (4).

Because ATTRv is hereditary, identifying a pathogenic TTR variant has implications not only for the patient but potentially for biological relatives. Genetic counselling is therefore an important component of care.

ATTRwt occurs without a pathogenic TTR variant and is predominantly diagnosed in older adults, particularly men. Cardiac involvement is the dominant clinical manifestation (3).

Several musculoskeletal conditions may precede recognition of ATTR cardiomyopathy by years, including:

• Bilateral carpal tunnel syndrome
• Lumbar spinal stenosis
• Spontaneous distal biceps tendon rupture

These conditions are common in the general population and do not by themselves diagnose ATTR amyloidosis. However, their presence alongside compatible cardiac findings can increase clinical suspicion (3, 5).

AA amyloidosis is a systemic form of amyloidosis in which the deposited fibrils are derived from serum amyloid A (SAA), an acute-phase protein. It is associated with sustained inflammatory activity caused by conditions such as chronic inflammatory diseases, autoinflammatory disorders and some chronic infections (6).

The kidneys are frequently affected, and patients may develop proteinuria, nephrotic syndrome and progressive kidney dysfunction (6).

Treatment is directed primarily at controlling the underlying inflammatory disease and suppressing persistent SAA production (6).

The organs involved depend strongly on the type of amyloidosis.

Amyloid deposition in the myocardium can produce cardiac amyloidosis, an infiltrative cardiomyopathy characterized by progressive myocardial dysfunction. ATTR and AL are the principal causes of cardiac amyloidosis encountered in clinical practice (3, 7, 8).

• Shortness of breath
• Exercise intolerance
• Fatigue
• Peripheral oedema
• Atrial fibrillation
• Conduction abnormalities
• Syncope or presyncope

Renal involvement is particularly important in AL and AA amyloidosis. Manifestations can include proteinuria, nephrotic syndrome, peripheral oedema and progressive kidney dysfunction (2, 6).

Neuropathy is particularly associated with ATTRv and AL amyloidosis (2, 4).

• Numbness or tingling
• Neuropathic pain
• Muscle weakness
• Orthostatic hypotension
• Altered gastrointestinal motility
• Bladder dysfunction
• Sexual dysfunction

Gastrointestinal involvement or autonomic dysfunction may produce diarrhoea, constipation, nausea, early satiety and unintentional weight loss (2, 4).

Certain extracardiac manifestations can provide useful diagnostic clues, including:

• Bilateral carpal tunnel syndrome
• Lumbar spinal stenosis
• Spontaneous distal biceps tendon rupture
• Macroglossia in some patients with AL amyloidosis
• Periorbital purpura in some patients with AL amyloidosis

None of these findings alone establishes amyloidosis (2, 3, 5).

There is no single symptom that identifies amyloidosis. Symptoms vary according to the amyloid type, organs affected and severity of disease. Early manifestations can also resemble much more common conditions.

• Fatigue
• Shortness of breath
• Reduced exercise tolerance
• Swelling of the legs or ankles
• Unexplained weight loss
• Numbness or tingling in the hands or feet
• Dizziness when standing
• Carpal tunnel syndrome
• Diarrhoea or constipation
• Proteinuria
• Easy bruising

The multisystem and often nonspecific presentation of amyloidosis contributes to diagnostic difficulty (2, 3, 4, 7).

Cardiac amyloidosis should be considered when compatible cardiac abnormalities occur alongside characteristic cardiac or extracardiac red flags (7, 8).

• Unexplained increased left ventricular wall thickness
• Heart failure with preserved or mildly reduced ejection fraction in an appropriate clinical context
• A discrepancy between increased ventricular wall thickness and relatively low ECG voltage
• Atrial arrhythmias
• Conduction disease
• Bilateral carpal tunnel syndrome
• Lumbar spinal stenosis
• Peripheral or autonomic neuropathy
• Unexplained proteinuria
• Characteristic cardiac magnetic resonance findings
• Family history suggestive of hereditary ATTR amyloidosis

There is no single diagnostic pathway appropriate for every form of amyloidosis. Evaluation is guided by the suspected amyloid type and organ involvement and may include clinical assessment, blood and urine testing, cardiac imaging, nuclear scintigraphy, tissue biopsy and genetic testing (2, 7, 8).

When cardiac amyloidosis is suspected, one of the first critical questions is whether there is evidence of a monoclonal protein that could indicate AL amyloidosis.

• Serum free light-chain assay
• Serum immunofixation electrophoresis
• Urine immunofixation electrophoresis

These tests are particularly important before interpreting bone-avid tracer scintigraphy as diagnostic of ATTR-CM (7, 8, 9).

Echocardiography can identify structural and functional abnormalities that raise suspicion for cardiac amyloidosis.

• Increased ventricular wall thickness
• Diastolic dysfunction
• Biatrial enlargement
• Reduced longitudinal myocardial deformation
• Other features compatible with an infiltrative cardiomyopathy

A pattern of relative preservation of apical longitudinal strain compared with basal and mid-ventricular segments, often termed relative apical sparing, can support suspicion for cardiac amyloidosis. However, apical sparing is not diagnostic by itself and should be interpreted within the broader clinical and imaging context (7, 8).

Cardiac magnetic resonance (CMR) provides detailed myocardial tissue characterization.

• Characteristic late gadolinium enhancement patterns
• Abnormal gadolinium kinetics
• Increased native T1
• Increased extracellular volume

CMR can provide strong evidence of an infiltrative cardiomyopathy, but it generally cannot reliably determine whether the underlying amyloid is AL or ATTR without additional testing (7, 8).

Bone-avid tracer scintigraphy has transformed the diagnostic approach to ATTR cardiac amyloidosis. Validated tracers include:

• ^99mTc-PYP
• ^99mTc-DPD
• ^99mTc-HMDP

In the appropriate clinical context, grade 2 or 3 myocardial uptake on validated bone scintigraphy can establish a non-biopsy diagnosis of ATTR cardiac amyloidosis when AL amyloidosis has been appropriately excluded through monoclonal protein testing (7, 8, 9).

The complete diagnostic pathway depends on clinical context. The presence of a monoclonal gammopathy may require tissue confirmation and amyloid typing.

Amyloid deposits can be demonstrated histologically using Congo red staining, with characteristic birefringence under polarized light (1, 2).

Depending on the clinical situation, tissue may be obtained from:

• Abdominal fat
• Bone marrow
• An affected extracardiac organ
• The myocardium

Finding amyloid is only part of the diagnosis. The amyloid protein must also be correctly typed, because treatment differs fundamentally between AL, ATTR and other forms of amyloidosis. Mass spectrometry-based proteomic analysis is an important method for amyloid typing where available (1, 2).

Once ATTR amyloidosis is diagnosed, TTR genetic testing is recommended to distinguish ATTRv from ATTRwt (7, 8).

This distinction is important because a pathogenic TTR variant has implications for genetic counselling and potentially for biological relatives.

Treatment depends on the amyloid precursor protein and the organs involved. There is no single treatment for all forms of amyloidosis.

Treatment of systemic AL amyloidosis aims to rapidly suppress production of the amyloid-forming immunoglobulin light chain by targeting the underlying plasma-cell or B-cell clone (2).

Modern first-line therapy commonly includes a daratumumab-based regimen combined with bortezomib, cyclophosphamide and dexamethasone in appropriate patients. Autologous stem-cell transplantation remains an option for carefully selected patients (2).

Treatment should be individualized and managed by clinicians experienced in AL amyloidosis because organ involvement, particularly advanced cardiac disease, substantially affects therapeutic decisions and treatment tolerance.

Disease-modifying treatment for ATTR amyloidosis targets different stages of TTR biology.

• TTR stabilization
• Reduction of hepatic TTR production
• Supportive treatment of cardiac and neurological manifestations

The appropriate treatment depends on whether the patient has ATTR cardiomyopathy, ATTR polyneuropathy or a mixed phenotype, as well as disease severity, regulatory approval, contraindications and local availability (3, 7).

The principal objective in AA amyloidosis is to control the underlying inflammatory or infectious condition and thereby suppress sustained serum amyloid A production. Effective control of inflammation can reduce ongoing amyloid formation and improve outcomes (6).

Amyloidosis can cause progressive organ damage. This is particularly important because effective disease-modifying therapies now exist for major forms of systemic amyloidosis, while advanced cardiac, renal or neurological injury may be difficult to reverse completely (2, 3, 7).

Earlier recognition therefore creates an opportunity to:

• Establish the correct amyloid type
• Begin appropriate disease-specific treatment
• Manage organ complications
• Identify hereditary disease where relevant
• Consider genetic counselling for affected families
• Reduce further organ damage

The epidemiology and clinical burden of amyloidosis in African populations remain incompletely characterized. Published literature has highlighted important gaps in disease recognition, diagnostic infrastructure, access to specialized testing and locally generated epidemiological data (10).

This is particularly relevant to ATTR amyloidosis. The TTR p.Val142Ile variant, historically called V122I, is strongly associated with West African ancestry. A genetic study involving samples from several African populations found comparatively high allele frequencies in parts of West Africa (11).

Importantly, the presence of a pathogenic variant does not mean that every carrier will develop clinically apparent amyloidosis. Penetrance and clinical expression vary. At the same time, much of the clinical evidence informing contemporary ATTR-CM diagnosis and treatment has historically been generated outside Africa (10).

This creates several priorities for the continent:

• Increasing awareness among healthcare professionals
• Strengthening pathways for early diagnosis
• Expanding access to appropriate diagnostic testing
• Improving access to disease-modifying treatment
• Characterizing TTR variants and phenotypes in African populations
• Developing African registries and prospective research networks
• Generating high-quality epidemiological and clinical data from African patients

Building this evidence base is essential to understand the true burden and clinical spectrum of amyloidosis across Africa rather than simply extrapolating findings from populations studied elsewhere.

• Amyloidosis is a group of diseases, not a single condition.
• It results from the deposition of misfolded proteins as amyloid fibrils within tissues.
• AL, ATTR and AA amyloidosis are among the major systemic forms.
• ATTR amyloidosis can be hereditary/variant (ATTRv) or wild-type (ATTRwt).
• The heart, kidneys and nervous system are among the organs commonly affected, depending on amyloid type.
• ATTR and AL are the principal causes of cardiac amyloidosis in clinical practice.
• Correct amyloid typing is essential because treatment differs substantially between amyloid types.
• Appropriate monoclonal protein testing is a critical part of the diagnostic pathway for suspected cardiac amyloidosis.
• A positive bone scintigraphy scan alone is not sufficient to diagnose ATTR-CM without appropriate exclusion of AL amyloidosis.
• Genetic testing distinguishes hereditary ATTR from wild-type ATTR after ATTR amyloidosis is established.
• The burden of amyloidosis in Africa remains insufficiently characterized, strengthening the need for African-led research, registries, education and improved diagnostic access.

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9. Gillmore JD, Maurer MS, Falk RH, Merlini G, Damy T, Dispenzieri A, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation. 2016;133(24):2404-2412. doi:10.1161/CIRCULATIONAHA.116.021612.
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