A GP guide to amyloidosis

Need to know:

• Amyloidosis may account for myriad clinical presentations and is worth keeping in mind once common causes have been excluded.
• Consider this diagnosis in cases of unexplained heart failure, fatigue, near-syncope, dyspnoea, weight loss, oedema, proteinuria, nephropathy, hepatomegaly or neuropathy (motor, sensory or autonomic).
• Clinical features that are more specific to amyloidosis are macroglossia, periorbital ecchymoses (leading to ‘raccoon eye’ appearance), bilateral carpel tunnel syndrome, unexpected hypotension with ACEIs, medication intolerance, autonomic neuropathy, spinal stenosis, gastrointestinal bleeding with normal endo/colonoscopy, strange skin lesions and hepatomegaly.
• In AL amyloidosis, a timely diagnosis can give the patient 10 or more good years. In contrast, a patient with advanced heart failure at diagnosis is unlikely to survive one year.
• If amyloidosis is suspected, early referral to an amyloidosis centre of excellence is vital.

Amyloidosis describes the group of diseases that result when amyloid fibrils accumulate in organs and result in organ dysfunction.

There are about 20,000 proteins that have structural and metabolic roles in humans.

As mRNA in cellular ribosomes makes a protein, the linear chain of amino acids folds into a complex three-dimensional structure that enables the protein to function.

Misfolding of the protein can result in production of amyloid fibrils. These fibrils may then deposit in the tissues, self-aggregate and accumulate to interfere with organ function.

The clinical manifestations that result can vary widely, depending on the type, location and amount of fibrils produced.

Amyloidosis is a rare disease. These are defined as conditions that occur in less than one in 2000 people. There are about 10,000 such rare diseases, of which about 80% are genetically determined and currently mostly untreatable.

That said, as a group, rare diseases can account for up 10% of a GP’s workload, so overall these constitute an important consideration in day-to-day practice.¹

As a result, a GP may come across amyloidosis perhaps once in a working lifetime. Although rare, it can be associated with significant end-organ effects, morbidity and mortality.

The diagnosis is often made late. But with awareness of its many presentations, earlier diagnosis has the potential to save many lives.

This article will outline the features and management approach to aid diagnosis to improve patient outcomes.

Classification

Over 40 proteins that can misfold to lead to amyloidosis have been identified. Each protein produces a specific amyloid that has its own pattern of organ involvement. The type of amyloidosis is classified based on amyloid protein type, named with a capital A followed by letters that specify the misfolding protein (see bolded letters in following descriptors). The commonest forms of amyloidosis are as follows:

AL amyloidosis 

This is the most common form, and results from misfolding of immunoglobulin free Light chains (FLCs). Plasma cells in the bone marrow make immunoglobulins that are, in turn, made of a pair of heavy chain proteins (immunoglobulin G [IgG], IgA, IgM, IgD, IgE) and a pair of light chain proteins (kappa or lambda). A clone of malfunctioning plasma cells can result in production of an excess of only one type of light chain that does not combine with a heavy chain. In AL, these FLCs misfold to form amyloid fibrils which can be nephrotoxic and cardiotoxic. 

Diagnosis of AL is often late, and most patients have a worse prognosis at diagnosis than that associated with many cancers. Heart failure is the most common cause of death.

ATTR amyloidosis

This form occurs due to the misfolding of transthyretin, the protein that Transports Thyroid hormone and Retinol to the liver. This may be the result of misfolded normal or ‘wild-type’ transthyretin (ATTRwt) or a misfolded variant protein due to an inherited mutation in the TTR gene (ATTRv).

ATTRwt amyloidosis causes cardiomyopathy with restrictive heart failure, especially in older men. ATTRv amyloidosis, a rarer form, causes restrictive cardiomyopathy and peripheral and autonomic neuropathy.

AA amyloidosis

Amyloidosis from serum amyloid A occurs in chronic inflammatory conditions such as rheumatoid disease, bronchiectasis and inflammatory bowel disease.

Others

There are a number of other rarer forms. These include AFib amyloidosis from misfolding Fibrinogen, Aβ2M amyloidosis from beta 2 microglobulin seen in chronic renal failure and long-term dialysis and AApoAI and AApoAIV that involve various apolipoproteins and are rare but significant causes of cardiac and vascular amyloidosis.

Alzheimer’s disease is a separate category of amyloidosis, caused by accumulation of beta-amyloid and neurofibrillary tangles of tau protein which destroy cerebral tissue.

Epidemiology

AL amyloidosis incidence is between one and two in 100,000 with about 450 new cases diagnosed per year in Australia. Prevalence is about five in 100,000 and is increasing with better diagnosis and improved survival.²

ATTR amyloidosis was previously believed to be a rarer manifestation but it is now recognised that up to 18% of cases of heart failure with preserved ejection fraction are secondary to ATTR.³

Clinical presentation

Amyloid fibrils can deposit in any part of the body which means amyloidosis can present in myriad ways. The most commonly affected organs are the heart and kidneys. That said, no organ is exempt from potential involvement.

Figure 1 demonstrates the effects that can occur with the most common form of the condition, AL amyloidosis.

Absence of an apparent cause for patients with dysphonia, vitreous opacities, gastroparesis, persistent diarrhoea or altered bowel habits, elevation of cholestatic enzymes, neurogenic bladder or biceps tendon rupture are just some of the potential clinical clues.

Additionally, it is important keep amyloidosis in mind in cases of poor or unusual responses to treatment.

The diagnosis of amyloidosis warrants consideration in the setting of any of the following features, particularly when otherwise unexplained, or when the clinical scenario is puzzling.

Proteinuria

When it comes to identifying amyloidosis, there is much to be said for the traditional practice of routinely testing every patient’s urine. Frothy urine suggests proteinuria; this is nephropathy until proven otherwise.

Even though amyloidosis is a far less common cause of proteinuria than diabetes and autoimmune glomerular diseases, it can cause rapid decline in renal function. A monoclonal gammopathy screen is indicated, including assessment for serum and urine protein electrophoresis and serum and urine FLCs.

Heart failure

Patients with amyloidosis who present with features of heart failure (dyspnoea, orthopnoea, cardiomegaly, pitting oedema, syncope or near-syncope) commonly have reduced ejection fraction on echocardiography. Preserved ejection fraction signifies restrictive heart failure. There can also be persistent low-grade elevation of troponin, right-sided heart failure, unexplained arrhythmias, and intolerance to ACEIs and beta blockers.⁴

Carpal tunnel syndrome

This is especially likely to be bilateral. In an older male with heart failure, this manifestation makes the diagnosis of ATTR amyloidosis more likely. Idiopathic peripheral and autonomic neuropathies may also be seen in amyloidosis.⁵

Spinal stenosis

This may be seen in ATTRwt, due to amyloid thickening of the ligamentum flavum and other structures that narrow the spinal canal. If operatively managed, tissue removed by the neurosurgeon can be tested for amyloid to confirm the diagnosis.⁶

Tissue or organ enlargement

Enlargement of the liver, tongue, salivary glands, or skeletal muscle (pseudohypertrophy) may occur due to amyloid infiltration.

Myeloma and monoclonal gammopathy of unknown significance

Myeloma accounts for 1.6% of all cancers and the lifetime risk of myeloma in the Australian population is 0.9%.⁷ The risk of monoclonal gammopathy of unknown significance (MGUS) increases with age, from 3% from age 50 to 5% from age 70.

Patients with both myeloma and MGUS are at greater risk of AL amyloidosis because monoclonal FLCs, aka Bence Jones proteins, are produced. AL amyloidosis is suspected when there is an abnormal lambda FLC to kappa FLC ratio.

Vague pervasive symptoms

These may include unintentional weight loss, fatigue, presyncope, postural hypotension, gastrointestinal disturbance, peripheral neuropathy including autonomic nervous dysfunction, erectile dysfunction and limb oedema.

Investigation

A few simple tests may confirm suspicions of amyloidosis. That said, the diagnosis is complex and diagnostic confirmation requires involvement of a specialised service. If amyloidosis is suspected, prompt referral is warranted.

Box 1 outlines clinical scenarios that warrant further investigation and immediate specialist referral on suspicion of amyloidosis. This may be to a haematologist, nephrologist, cardiologist, neurologist, gastroenterologist or dermatologist, depending on presenting organ involvement.

Definitive diagnosis may be complex. Biopsy samples, stained with Congo red for amyloid (staining apple-green birefringence under polarised light) may aid identification of the condition. However, biopsy of potentially affected organs, including liver, kidney and heart, carry significant rates of complications.

Additionally, even when amyloid is identified histologically, this does not determine whether the finding is localised (often not serious) or systemic (can range from incidental to rapidly fatal). Specialised amyloidosis centres of excellence can confirm the type of amyloidosis with immunohistochemistry, immunofluorescence or proteomics. The Australian Amyloidosis Network outlines where to locate these centres of excellence nationally (see resources).

Treatment

The treatment of amyloidosis is highly specialised and can be very effective when the condition is diagnosed early. Treatment varies widely based on the type of amyloidosis, and whether there is a disease process that may be directly targeted, to reduce amyloid deposits. For example, in AL amyloidosis, this involves measures to suppress the underlying plasma cell dyscrasia, and in AA amyloidosis, treatment of the underlying infectious or inflammatory disorder, where applicable.

A number of novel disease-modifying agents targeted at amyloidosis have been developed in recent years, which has resulted in significant improvements in disease survival and quality of life for these subtypes of amyloidosis.

These agents include daratumumab (an anti-CD38 monoclonal antibody) in combination with bortezomib (a proteasome inhibitor). This combination was PBS-listed in January 2023 for the initial treatment of AL amyloidosis.

Tafamidis, a selective stabiliser of TTR was PBS-listed in 2024 for the treatment of ATTR amyloidosis cardiomyopathy. This agent may delay disease progression. Similarly, patisiran, a double-stranded small interfering RNA that blocks TTR mRNA, was PBS-listed in 2024 for treatment of ATTRv with neuropathy.

There are ongoing trials of multiple promising new therapies both in Australia and internationally.

Conclusion

Amyloidosis is a rare condition which can present with myriad manifestations. Early identification and specialised targeted treatment is critical for improving morbidity and mortality outcomes for patients with this condition.

GPs have an important role to play in suspecting amyloidosis, particularly in those with suggestive presentations, when more typical diagnoses have been excluded.

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Dr Kun Gay Yap is a GP in Sydney, NSW and a member of the Australian Amyloidosis Network.

Associate Professor Peter Mollee is a consultant haematologist and head of the myeloma service at Princess Alexandra Hospital, Brisbane, and Associate Professor, University of Queensland Medical School, Brisbane. He is chair of the Australian Amyloidosis Network and director of the Queensland Amyloidosis Centre.

References on request from Dr Kate Kelso.