References

The Basic Workup and Approach

General Overview

This part of the website discusses the basic workup and management approach of suspected systemic amyloidosis.

The presence of amyloid can now be identified using either;

  • Cardiac amyloid bone scintigraphy (for cardiac ATTR)
  • OR
  • Biopsy (for all other amyloidoses)

All cases still require;

  • Monoclonal gammopathy tests (to screen for AL)
  • AND
  • Organ staging

Some cases may require further amyloid typing testing with;

  • Mass spectrometry for protein typing
  • Genetic testing for amyloidogenic mutations

The typing of amyloidosis is a clinico-pathologic process requiring multiple correlates to accurately type the amyloidosis. There is no singular test that can definitively type the amyloid in isolation.

The most common and critical pitfalls to be aware of are that;

  • Immunohistochemical amyloid typing stains only have a positive predictive value of ≈ 60%
  • AND THAT
  • Cardiac amyloid bone scintigraphy has a high positive predictive rate for cardiac ATTR amyloidosis but can be positive in cardiac AL and does not exclude non-ATTR cardiac amyloidosis

One of the primary purposes of the State based AAN clinico-pathologic services is to assist with the typing of amyloidosis. Referrals for this purpose are welcomed and strongly encouraged. Performing the basic workup expedites the diagnostic process.

The Basic Workup and Approach: in detail

When to Suspect Amyloidosis

KEY POINT

The question “Could this be Amyloidosis” should be asked when there is;

  • Unexplained single organ or multi-organ failure with amyloid-like manifestations
  • Presentation with a classical clinical phenotype of one of the amyloidoses

In systemic amyloidosis the vital organs are affected in similar ways no matter the type of amyloidosis;

  • Heart: diastolic heart failure with preserved ejection fraction (HFpEF), atrial fibrillation and other dysrhythmias
  • Kidneys: proteinuria, nephrotic syndrome, renal failure
  • Nerves: length dependent peripheral sensory and motor neuropathy, autonomic neuropathy
  • Gastrointestinal tract (GIT): (upper GIT) weight loss, early satiety, peptic ulceration and (lower GIT) diarrhoea, alternating bowel habit, per rectal bleeding, colic
  • Liver: hepatomegaly, obstructive liver function test abnormalities
  • Spleen: hyposplenism, splenomegaly

The diagnosis of amyloidosis is usually delayed as these organ failure syndromes are commonly caused by other disorders. The key is to consider amyloidosis when there is unexplained;

  • Amyloid-like cardiac failure e.g. HFpEF without a history of hypertension (a common presentation of cardiac ATTRwt)
  • or
  • Multiple amyloid-like organ failure syndromes occurring concurrently e.g. HFpEF and proteinuria without obvious causes (a common presentation of AL)

There are classical “phenotypes” for the systemic amyloidoses that can aid in their identification. Phenotypic presentations for the most common types of amyloidosis are summarised in Table 1. As there is overlap between these phenotypes, they cannot be used to robustly type the amyloidosis.

Table 1: Classical Clinical Phenotypes for Amyloidosis Types or Groups1

AMYLOID TYPE/GROUP Fibril Protein % AAN referrals
 CLASSICAL CLINICAL PHENOTYPE

COMMON
Wild type transthyretin ATTRwt 45 Male of older age with slowly progressive cardiac infiltration/thickening on TTE presenting with diastolic heart failure (with preserved EF) and/or atrial fibrillation. Notably, ATTRwt does not deposit in the kidneys to cause proteinuria.

Background of (often bilateral) carpel tunnel syndrome.
Systemic light chain AL 30 Male or female with heart failure and/or nephrotic syndrome without a clear cause.

Commonly ≥ 2 vital organs are involved but single organ involvement is not uncommon.
Localised amyloid group AL

12

10

 Localised AL is most commonly identified within mucosal tissues and presents with site-specific symptoms e.g. intermittent haematuria (bladder), hoarse voice (larynx), rash (skin).
ASem1

1

 Semenogelin amyloid is produced in the seminal vesicles and most commonly presents with intermittent haematospermia but is also incidentally detected in prostate tissue.
AIns

1

 Amyloidoma at insulin injection sites from bovine or porcine derived insulin preparations.

UNCOMMON
Hereditary TTR ATTRv 5-7 Mixed heart and nerve disease with one organ predominating.

Nerve disease commonly involves peripheral sensory and motor nerves and autonomic nerves.

Endemic in the Portuguese, Swedish, Japanese and Irish but not infrequently occurs “sporadically” in other ethnic groups.
Serum Amyloid A AA 3 Nephrotic syndrome on a background of an active chronic auto-inflammatory disorder and/or infection.

RARE
Leucocyte Chemotactic Factor-2 ALECT2 ≈1 Typically presents with a slowly progressive subnephrotic proteinuria in non-Anglo-Saxon ethnic groups.
Hereditary non-TTR amyloidosis group AFib

ALys

AApoAII

AApoAI

AGel

 ≈1 The non ATTR hereditary amyloidoses are rare with differing organ tropism patterns depending on the genetic mutation involved.

The most common is AFib which targets the kidneys and presents with nephrotic syndrome and renal failure.
Immunoglobulin heavy chain AH <1 AH presents similarly to AL.
Aβ2M β2-Microglobulin wild type <1 Joint pain or arthropathy in a heamodialysis patient. This type does not involve the heart or kidneys.

Key: A=acquired, ANS= autonomic nervous system, CNS= central nervous system, H= hereditary, HT= hypertension, IHD= ischaemic heart disease, L= localised, PNS= peripheral nervous system, Rare = <1% AAN clinic referrals, S=systemic, TTE= transthoracic echocardiogram, Uncommon = <10% of AAN clinic referrals

Amyloid Identification

KEY POINT

  • Cardiac Amyloid Bone Scintigraphy can sensitively and specifically identify cardiac ATTR without the need for biopsy
  • A biopsy is required to identify all other types of systemic amyloidosis
  • A biopsy is also required for those with both positive uptake on cardiac amyloid scintigraphy and a monoclonal gammopathy

Cardiac Amyloid Bone Scintigraphy

Cardiac amyloid bone scintigraphy can sensitively and specifically detect cardiac amyloid of ATTR type without the need for biopsy2. Three specific Technetium labelled bone tracers; DPD, PYP and HMDP have been validated for this purpose but DPD and PYP are recommended as the validation cohort for HMDP was small.

Cardiac amyloid scintigraphy has the unique capacity to both identify and type cardiac ATTR however some cardiac AL can also show uptake (usually of lower intensity). Cardiac uptake greater than or equal to bone without any detectable monoclonal gammopathy is 100% specific, with 100% positive predictive value for cardiac ATTR. But in the presence of a monoclonal gammopathy the specificity of cardiac uptake decreases to 91% as some cardiac AL may also show uptake.

Hence, those with both a positive cardiac amyloid scintigraphy scan and a monoclonal gammopathy require a biopsy to differentiate between cardiac ATTR type vs cardiac AL.

A negative cardiac amyloid scintigraphy scan effectively excludes cardiac amyloid of ATTR type but does not exclude other types of cardiac amyloidoses.

Biopsy

KEY POINT

Amyloid is identified on biopsy by Congo Red staining followed by examination under polarised light

  • A biopsy is required to identify all non-cardiac ATTR amyloidoses
  • Targeted biopsies of an involved organ is superior to “off-target” biopsies
  • Baseline protein typing is performed by TTR, kappa, lambda and AA immunohistochemical staining
  • Immunohistochemical subtyping stains only have a positive predictive value of ≈ 60%
  • immunohistochemical typing stains cannot be interpreted in isolation and must always be correlated with organ staging, monoclonal gammopathy screening and other typing tests (such as cardiac amyloid scintigraphy)

General

Amyloid is identified on biopsy by salmon pink Congo Red staining exhibiting apple green birefringence and dichroism effects under polarised light.

Biopsy evidence of amyloid is required to identify all cases of non-cardiac ATTR amyloidosis. Tissue is also required to differentiate between cardiac ATTR and cardiac AL in cases with positive cardiac amyloid scintigraphy and a co-incident monoclonal gammopathy.

For diagnostic and typing purposes, it is recommended to perform targeted biopsies of involved organs rather than “off-target” biopsies of the abdominal fat pad, rectum and buccal mucosa. This is because targeted biopsies are more sensitive for amyloid detection and yield greater amounts of amyloid for subtyping purposes. The involved organs can be identified by using simple organ screening procedures.

Table 2: Fat Pad Biopsy Amyloid Detection Rate

AMYLOID TYPE Detection Rate of Amyloid (%)
ATTRwt 12-15
ATTRv 30-45
AL Burden of Amyloid (as determined by SAP scan) 64-78
Small
Moderate 84-97
Large 90-100

Fat pad biopsies are particularly insensitive in ATTR. 3,4,5. For AL, international reference centres have reported fat pad biopsy detection rates which are dependent on the burden of disease 4. However, in the general Australian setting, lower sensitivity rates are observed when using “off target” biopsies in AL.6

“Look back” or “add-on” Congo Red staining upon archived tissue samples can be a useful way to identify amyloid deposits.

  • This is most relevant for ATTRwt where vascular amyloid may be present in tissues (such as the prostate and colon) for years before the onset of cardiac ATTR.

Anatomical Pathology Basics

Amyloid is identified using Congo red staining followed by examination under polarised light. Congo Red stains amyloid deposits salmon pink which then exhibit apple green birefringence and dichroism effects under polarised light. The Congo Red staining technique can be falsely positive or falsely negative when performed in non-reference labs;

  • 9% of biopsies referred to an AAN reference lab were falsely negative in one study. Of the biopsies referred to the UK’s National Amyloidosis Centre’s reference lab in 2018, 24% were falsely positive and 12% falsely negative for the presence of amyloid 8
  • False positives can occur when the diagnosis is based solely on salmon pink staining of extracellular tissues (a not uncommon finding) without confirmation of apple green birefringence under polarised light. False negatives can occur when the Congo Red stain is not properly maintained

Once amyloid has been identified on a biopsy, it is recommended to perform amyloid typing by immunohistochemical staining for the most common amyloid forming proteins: TTR, kappa, lambda and AA. Although antisera to many other amyloid fibril proteins are commercially available these are not routinely required or easily accessible as;

  • Stains for the rare hereditary amyloidosis types have largely been supplanted by mass spectrometry analysis and/or genetic screening
  • LECT 2 stains are currently not available in Australia

Select Australian laboratories routinely perform the basic panel of amyloid stains and have acquired the expertise to interpret them.

It is critically important to be aware that immunohistochemical subtyping stains are inherently prone to false negative and false positive results. The positive predictive value of amyloid typing stains is ≈ 60% 9. Even the immunohistochemical stains at the UK National Amyloidosis Centre’s international reference lab only provide a definitive result in 76% of cases 10.

Immunohistochemical typing stains have a low positive predictive value as the anti-sera have been developed against physiologic proteins leading to;

  • False positive staining of non-amyloidogenic (or physiologic) proteins and increased background staining
  • False negative results as the stains are not specific for variant forms of amyloid proteins (e.g. not specific for misfolded light chain or variant hereditary TTR proteins)
    • Kappa and lambda light chain stains have a particularly high false negative rate in the order of 20-30% 11

The immunohistochemical typing result cannot be interpreted in isolation and must always be correlated with organ staging, monoclonal gammopathy screening and other typing tests (such as cardiac amyloid scintigraphy).

In addition, it is not always necessary to type the constituent amyloid protein for all amyloidosis cases e.g.

  • Localised mucosal amyloid deposits are almost always derived from light chain and hence a negative vital organ and monoclonal gammopathy screen are all that is required to type as localised AL
  • For systemic AL, specific combinations of organ staging, monoclonal gammopathy and cardiac scintigraphy findings can be sufficiently specific to type as systemic AL without the need to type the constituent amyloid protein

AL and Organ Screening

KEY POINT

  • For all amyloidosis cases it remains necessary to perform;
    • Monoclonal gammopathy testing to screen for AL
    • Organ staging
  • These screening procedures are also useful to perform in cases of suspected amyloidosis

AL Screening: Monoclonal Gammopathy Investigations

KEY POINT

  • Screening for the clone causing AL amyloidosis requires all three of the following tests:
    • Serum Free Light Chains (SFLC)
    • Serum Protein Electrophoresis + immunofixation (SPEP + IFE)
    • Urine Protein Electrophoresis + immunofixation (UPEP + IFE)
  • These tests will detect the AL producing clone in ≈ 99% of cases
  • A bone marrow biopsy is not required to screen for AL

A monoclonal gammopathy is present in ≈ 99% of systemic AL cases 12 and screening requires all three of the following tests:

  • Serum free light chain assay (SFLC)
  • Serum Protein Electrophoresis + immunofixation (SPEPG + IFE)
  • Urine Protein Electrophoresis + immunofixation (UPEPG + IFE)

The SFLC is the most sensitive test as it detects the amyloidogenic light chain in ≈ 98% of AL cases.

The presence of a monoclonal gammopathy is not specific for AL as it may be a benign finding not linked to any disorder. This benign situation is referred to as “monoclonal gammopathy of uncertain significance” (MGUS)

  • The prevalence of MGUS increases with age and is present in ≈ 3.8% of those over the 70 years and ≈ 5.8% over 80 years of age 13
  • MGUS can commonly confound the diagnostic process for the age related amyloidosis ATTRwt and is present in 25-30% of confirmed ATTRwt 14,15

Screening for AL is still required for those with a positive cardiac amyloid scan as ≈ 9% of cases with a co-incident monoclonal gammopathy will have cardiac AL. A biopsy is required in these cases to definitively type the amyloid using tissue based methods.

Organ staging

KEY POINT

  • Organ staging;
    • Identifies sites for diagnostic biopsy
    • Can assist in the typing of amyloidosis
  • Organ staging can differentiate between the two most common systemic amyloidoses;
    • There are pathognomonic manifestations for AL and ATTRwt
    • Renal amyloid occurs in AL but never in ATTRwt

Organ staging is an essential component of the basic workup for amyloidosis as this;

  • Identifies the most sensitive sites for diagnostic biopsy
  • Differentiates between localised and systemic amyloidosis
  • Organ tropism patterns can assist with typing

Basic organ screening can be performed using a combination of clinical assessment and simple blood and urine tests

  • Investigations such as cardiac magnetic resonance imaging and nerve conduction studies are not routinely required to screen for organ involvement
  • The Serum Amyloid P scan, which can determine the burden of amyloid in organs except for the heart and GIT, is not available in Australia.

Table 3: Basic Organ Screening for Amyloidosis

ORGAN
 ASSESSMENT MODALITY ASSESSING FOR
Heart Clinical Heart Failure

Arrhythmia
Blood test Elevated NT-ProBNP, troponin
+/- TTE

(in clinically suspected cardiac amyloidosis)

 Thickened intraventricular septum and left ventricular wall

Reduced global longitudinal strain with apical sparing

(“Cherry on top”/ Bullseye” pattern of GLS)
Kidney Urinalysis Proteinuria by:
Random urine protein creatinine and albumin creatinine ratio
or
24 hour urine protein
Blood test Creatinine, eGFR
Liver Clinical Hepatomegaly
Blood test Liver dysfunction (obstructive pattern)
Gastrointestinal tract (GIT) Clinical Upper and lower GIT symptoms:

Weight loss, early satiety, peptic ulceration, diarrhoea,

alternating bowel habit, per rectal bleeding, colic
Peripheral nervous system Clinical Sensory +/- motor peripheral neuropathy

Autonomic nerve dysfunction:

Gastric-emptying disorder, pseudo-obstruction, voiding dysfunction

abnormal sweating, postural hypotension, sexual dysfunction
Tenosynovium Clinical Carpel tunnel syndrome

Hand tendon contractures

Symptoms of spinal canal stenosis (due to ligamentum flavum deposition)

Biceps tendon rupture

Key: eGFR = estimated glomerular filtration rate, GIT = gastrointestinal tract, GLS = global longitudinal strain, NT-ProBNP= N-terminal pro brain natriuretic peptide, TTE = transthoracic echocardiogram

Organ tropism or the clinical phenotype and can assist in the typing of amyloidosis;

  • ATTRwt typically affects the tenosynovial tissues (often many years before affecting the heart)
  • AA amyloidosis almost always affects the kidneys (and rarely the heart)

However, generally, there is considerable overlap of these organ tropism patterns and hence these cannot be solely relied upon to type the amyloidosis.

There are organ tropism patterns that are strong negative predictors of amyloid types. The most useful being for:

  • ATTRwt: which does not deposit in the kidneys
    • Cardiac amyloid with unexplained proteinuria indicates another type of amyloidosis most typically AL amyloidosis

There are pathognomonic organ manifestations with strong positive predictive value for the two most common types of systemic amyloidosis (AL and ATTRWwt). Although these pathognomonic features can be very useful for typing their utility is limited due to their rarity:

  • AL
    • Periorbital bruising
    • Palmar blood blisters
    • Macroglossia
    • Coagulopathy from Factor X deficiency
  • ATTRwt
    • Spontaneous biceps tendon rupture

Second-Line Investigations

KEY POINT

  • Mass spectrometry analysis of the constituent amyloid protein is required when the type of amyloidosis remains uncertain after the basic work-up has been performed
  • Genetic screening is recommended when the constituent amyloid protein can be formed by a hereditary process
    • Genetic testing is commonly indicated in cardiac ATTR to differentiate between wild type and hereditary ATTR

Mass Spectrometry Analysis of the Amyloid Protein

In certain circumstances light dissection of the amyloid from the paraffin embedded tissue block followed by (trypsin digestion and) tandem mass spectrometry analysis of the constituent amyloid proteins is required to identify the precursor amyloid protein.16 This method has become an invaluable tool in identifying the amyloid precursor protein in difficult cases. Common situations where this technique is required are;

  • Isolated cardiac amyloidosis
    • Particularly in cases with a monoclonal gammopathy where the TTR, kappa, lambda stains are inconclusive. Mass spectrometry is then required to differentiate between;
      • cardiac ATTR with an unrelated monoclonal gammopathy vs cardiac AL
  • Isolated renal disease
    • Particularly in cases without a monoclonal gammopathy or chronic inflammatory disorder. Mass spectrometry is then required to diagnose;
      • ALect
      • Rare hereditary amyloidoses e.g. AFib, AApoA and C variants
      • Rare acquired amyloidoses e.g. Heavy Chain amyloidosis

Genetic testing

Genetic testing is indicated when the constituent amyloid protein or clinical syndrome may be caused by an inheritable gene mutation. Genetic testing is most commonly required in;

  • Confirmed ATTR to differentiate between ATTRwt and ATTRv
    • ATTR is the most common systemic amyloidosis type and one of the few that can be both wild type or hereditary in nature
  • Isolated renal amyloidoses of non-AL and non-AA type as hereditary amyloidoses (such as AFIb and AApo) are then possible

In select circumstances, genetic screening is utilised without confirmation of the presence of amyloid;

  • Screening for amyloidogenic TTR gene mutations is indicated in length dependent small and large fibre peripheral sensory neuropathy without diabetes, especially if there is autonomic neuropathy (with or without a family history of hereditary neuropathy).
  • Predictive testing for those with a family history of amyloidosis

There are over 100 gene mutations that can cause systemic amyloidosis but most affect just four proteins’ encoding regions. Screening for the known amyloidogenic genetic mutations is performed on a blood sample;

  • Genes are extracted from the nucleated white cells and polymerase chain reaction of the exons of the gene region(s) of interest is followed by bi-directional Sanger sequencing

Genetic screening is not required in AL amyloidosis

The Basic Management Approach

KEY POINT

  • Management of amyloidosis is divided into supportive care and disease modifying therapy
  • Disease modifying therapies can be subdivided into;
    • Reducers or suppressors of amyloid protein production
    • Targeted molecular therapies
    • Amyloid eliminators
  • Notably, de-novo or endogenous macrophage clearance of amyloid can also occur

Management of the amyloidoses is divided into disease modifying and supportive therapies. Supportive care is described within “The Organ” sections of this website. Disease modifying therapy can be subcategorised into the following approaches;

  1. Reducers or suppressors of amyloid precursor protein production. Examples of this approach are;
    • Silencing RNA therapy to decrease liver TTR production
    • Anti- plasma cell chemotherapy to decrease monoclonal amyloidogenic light chain production in AL
    • Disease modifying drugs for Rheumatoid Arthritis driven AA
    • Surgical resection of the cells producing localised AL in mucosal tissue
  2. Targeted molecular therapies directed against the kinetics of amyloid formation
    • The best examples of this approach are in ATTR therapy. TTR tetramer dissociation into amyloidogenic monomers is the first step in TTR amyloid fibril formation. Tafamidis and AG110 “stabilise” the TTR tetramer preventing dissociation into amyloidogenic TTR monomers (view the Management tab on this page).
  3. Amyloid eliminators
    • A limited number of therapies have been shown to eliminate amyloid with variable success in early phase research
    • “CPHPC” followed by anti-SAP monoclonal antibody holds the most promise as a pan-amyloid eliminator but progress has been stalled in early phase clinical trials.17 This therapy targets a ubiquitous constituent protein in all amyloid deposits (SAP) and triggers macrophage driven clearance.

Amyloid can also be cleared slowly by endogenous de-novo macrophage processes;

  • For organ recovery, the rate of production of amyloid needs to be less than the native macrophage clearance rate
  • The efficacy of macrophage mediated amyloid clearance varies between individuals
  • The likelihood of amyloid clearance also differs between organs
  • The macrophage clearance rate is slow and signs of organ recovery can take up to ≈ 18 months

Common Misconceptions

KEY POINT

  • Amyloidoses is commonly misdiagnosed
  • The most common erroneous assumptions are that;
    • Immunohistochemical typing stains have a high degree of accuracy
    • Cardiac amyloid bone scintigraphy uptake is confined to transthyretin type cardiac amyloidosis

Amyloidosis is commonly misdiagnosed and one study showed that the misdiagnosis rates for AL was 39%, ATTRwt 26% and ATTRv 29% 18. Common misconceptions regarding the workup of amyloidosis are addressed in this section.

Medical History

Misconception

“There is no family history and so my patient cannot have hereditary amyloidosis”

Explanation

Approximately 50% of proband cases of hereditary amyloidosis do not have a clear family history of inherited neuropathy, cardiac failure or sudden cardiac death. 19

Misconception

“There is no inflammatory disorder and so my patient does not have AA amyloidosis”

Explanation

Approximately 20-30% AA patients do not have an auto-inflammatory condition aor chronic infection. In most of these cases have obesity appears to be the inflammatory risk factor. 20

Misconception

“My patient with cardiac amyloidosis does not look too sick and has a good exercise tolerance ….so they cannot have cardiac AL.”

Explanation

Some cardiac AL patients may have a period of asymptomatic cardiac disease before the amyloid cardiac load becomes clinically significant. Symptom burden is not specific enough to differentiate between cardiac ATTR and cardiac AL.

Misconception

“My patient has had findings of cardiac amyloidosis for several years and so they cannot have AL amyloidosis and they must have cardiac ATTRwt”

Explanation

The median time to diagnosis from symptom onset of AL is two years. 21 The pace of disease is not specific enough to differentiate between the amyloidoses.

Anatomical Pathology Identification and Typing

Misconception

“Congo Red Staining was positive/negative report for amyloid on the biopsy and so it is or is/is not present in my patient.”

Explanation

There is a low false positive and false negative rate for diagnosis of amyloid by Congo red staining. False positives can occur when a diagnosis of amyloid is based solely on salmon pink staining of extracellular tissues (a not uncommon finding) without confirmation of apple green birefringence under polarised light. False negatives can occur when the Congo Red stain is not properly maintained.

Misconception

“The immunohistochemical stain of my patient’s heart biopsy is positive for AA and so my patient has cardiac AA.”

Explanation

Immunohistochemical typing stains only have ≈ 60% positive predictive value. A clearly positive typing result is where there is strong positivity for only one amyloid typing stain and where corollary findings (such as the clinical phenotype, monoclonal gammopathy results and cardiac scintigraphy) support the typing. No one test result can ever be used in isolation to type amyloidosis.

Misconception

“Every amyloid patient’s biopsy needs protein typing by light dissection and mass spectrometry analysis”.

Explanation

Mass spectrometry typing of amyloid deposits is indicated in unclear systemic cases where the immunohistochemical typing stains are non-contributory and/or do not match the other corollary findings. Mass spectrometry is usually not required in localised amyloid and in a significant proportion of cases of systemic AL.

Cardiac Amyloid Bone Scintigraphy

Misconception

“My patient has a positive cardiac amyloid bone scintigraphy scan and so they must have cardiac ATTR”.

Explanation

Some AL patients may also show uptake on cardiac amyloid scintigraphy. Every patient who has a positive cardiac amyloid scintigraphy scan must therefore undergo monoclonal gammopathy testing to screen for the presence of AL. If there is a monoclonal gammopathy then a biopsy is required to distinguish between 1. ATTR with an intercurrent uninvolved MGUS vs 2. Cardiac AL.

Organ staging

Misconception

“I need to biopsy every organ to confirm the presence of amyloid involvement.”

Explanation

Once amyloid is detected at one site, organ staging can be performed using non-invasive techniques.

Misconception

“Every patient with suspected cardiac amyloidosis needs a cardiac MRI”

Explanation

In most cases, sufficient features of cardiac amyloidosis can be identified by the combination of clinical assessment, cardiac biomarkers, ECG and TTE (with global longitudinal strain) to support proceeding to diagnostic tests. Cardiac MRI is a useful adjunct when other potential disorders such as hypertension and non-amyloid cardiomyopathies are being considered. Cardiac MRI cannot confirm the presence of cardiac amyloid nor type cardiac amyloid. For these purposes, cardiac amyloid bone scintigraphy (for cardiac ATTR) or biopsy (for all other types of cardiac amyloidosis) are required.

Monoclonal Gammopathy Tests

Misconception

“My cardiac amyloid patient has a monoclonal gammopathy and so they have cardiac AL”.

Explanation

Although a monoclonal gammopathy is present in 99% of those with AL the prevalence of MGUS increases as we age. As the prevalence of MGUS increases with age it often confounds the diagnostic process for the age related amyloidosis ATTRwt. 25-30% of ATTRwt have a co-incident MGUS.14, 15

Misconception

“My patient only has a mildly elevated (kappa or lambda) light chain and so they cannot have AL”.

Explanation

The degree of light chain elevation is lower in AL than in light chain multiple myeloma. The range of the monoclonal free light chain level at diagnosis for patients with systemic AL is between 30-500mg/L. 22 Approximately 13-19% of AL patients will have a low amyloidogenic free light chain level at presentation. (“Low level” is defined as a <50mg/L difference between the involved free light chain and uninvolved free light chain). 23

Misconception

“My patient has a slightly elevated kappa light chain and so they have AL amyloidosis”.

Explanation

SFLC results can be affected by both laboratory clinical issues. Clinically, kappa and lambda free light chains can be elevated by renal impairment and inflammation. Renal impairment leads to a disproportionately greater increase in physiologic kappa free light chain as monomeric kappa free lights are renally excreted quicker than dimeric lambda free light chains. In end-stage kidney disease, kappa: lambda FLC ratios of up to 3.1 have been reported. 24

Genetic screening

Misconception

“Every patient with amyloidosis needs genetic screening”.

Explanation

Many types of amyloidosis are not inherited. Systemic AL and AA are acquired amyloidoses where genetic testing is not required. There are now improved amyloid typing techniques along with better knowledge of which amyloidosis types may be hereditary to indicate when genetic testing is required.

Misconception

“ATTR patients do not require genetic screening as inherited ATTRv is rare and there is “nothing” we can do about it”.

Explanation

A significant minority of ATTR cases carry an amyloidogenic TTR gene mutation. In one AAN clinic, ≈10% of the ATTR cohort and ≈ 5% of the cardiac ATTR cohort carried a TTR gene mutation. 25 In the UK, 17% of screened ATTR cases had an inherited TTR mutation. 26 Disease modifying therapies are now becoming increasingly available for those with ATTR and their kindred.