(Amyloidosis Support Group, October 2019, Conference Notes)
Amyloidosis = Protein folding disorder
TTR = transthyretin: Transports thyroxine (a thyroid hormone) and retinol (vitamin A). Also known as Prealbumin
Over 95% of TTR is produced in the liver. But some is produced by the eye and brain (choroid plexus).
ATTR = amyloid TTR (abnormal TTR, misTTR, the TTR than misfolds)
ATTR production can be caused by one of over 100 genetic mutations (hereditary ATTR (hATTR, ATTRh, ATTRm (m=mutant))), or by age (wild type ATTR, (ATTRwt, wtATTR)).
About 4% of African Americans have hATTR, with the mutation TTR V122I)
Other (non-ATTR) hereditary amyloidosis
See Hereditary systemic amyloidosis in “Organ Transplant as therapy” section below.
Amyloid deposits look white, so they look like starch, which is why it got the name Amyloid.
When the protein is mis-folded, it is sticky – it sticks together, creating insoluble fibrils that resist degradation – but the mis-folded TTR has binding sites for Congo red stain, so we can use Congo red stain to detect it.
The body’s protein quality control systems break down proteins. With age, our quality controls become less effective, so older people can get “wild type” amyloidosis, with mis-folded proteins not getting cleared out, and building up, to create problems.
How amyloidosis is usually diagnosed:
First, Congo red stain helps detect it
Secord, laboratory tests determine the type of amyloidosis
Additional tests may support the diagnosis
Differential diagnosis (other diseases that look like Amyloidosis)
Proteinuria/nephritic syndrome in adults may be caused by:
Focal and Segmental Glomerular Sclerosis/Minimal change disease
Earlier on, amyloidosis was not easily detected with Congo red seeing as there were not as much misfolded protein to detect.
Where do we investigate with Congo red? Could do the effected organ, but testing in body fat can be better. Early diagnosis can result in much better outcomes, but is difficult to achieve.
ATTR detection in fat:
Sensitivity is 54-93% = chance of detecting it, if it is there
Specificity is 93-100% = chance of having a negative test, if you do not have ATTR
Testing in fat is easy, but a biopsy of heart muscle will be more sensitive (more likely to detect disease, if it is present)
TTR protein becomes unstable with age, and gets stuck in various places in your body, causing problems.
Alternate names for wild type amyloidosis
Senile Cardiac Amyloidosis (SCA)
Senile Systemic Amyloidosis (SSA)
Age-related Cardiac Amyloidosis
Wild type generally hits around age 70, but can hit in the 40s or 50s
How proteins are made
RNA in your body’s cells help Amino acids join together to form proteins. The folding creates the “secondary structure”, and then folds further to create the “tertiary structure”. TTR has 4 proteins, so they fold ever more, forming a “quadrinary structure”. The mid-folded TTR protein happens to be folded such that it sticks to other TTR proteins. We don’t know yet why it tends to accumulate in certain places, like the heart.
The heart wall gets infiltrated with the mis-folded amyloid, getting thick and stiff, so the heart can’t beat as well.
Wild type vs. hereditary ATTR – who gets which?
Age (Years) ; ATTRm (Variable) (depends on mutation) | ATTRwt >65 y.o
Gender (% M| % F); ATTRm 50% | 50% | ATTRwt 95%| 5%
Race (To date); Depend of mutation | Predominantly Caucasian
Affected Organs; Nerves, Heart, Eyes | Heart
Ejection Fraction in Cardiac Amyloidosis
Ratio of blood out vs. total blood held in heart – in amyloidosis patients, outwardly it looks fine (Because the heart holds less blood to start – the denominator is small), even though the blood volume ejected is small.
PYP scans can detect amyloid in the heart
Restrict Salt! – the mainstay, along with diuretics
Atrial Fib – use a blood thinner, maybe for life
Calcium channel blockers – maybe. For some patients, these can cause more harm than good.
Hypertension – compression stockings and midodrine
AICD / pacer (use of a pacemaker) – More of a role for pacing
Tafamidis – FDA approved for Amyloidosis treatment. Expensive.
Diflunisal – Not FDA approved for Amyloidosis treatment. Cheap. Not good for patients with certain conditions:
no recent decompensation
Good renal function
Daily diuretic dose < 80 mg Lasix, no metolazone
Use with anticoagulation
*Several other medications are approaching approval
hATTR – hereditary amyloidosis
Alternate names of hATTR
Also called “Variant TTR” or “mutated TTR”, familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC) (see later slides)
How the body makes proteins
DNA, made of nucleotides, guides the formation of RNA, which guides the formation of proteins
A series of 3 nucleotides form one of twenty amino acids, which are strung together into proteins.
Polymorphism – the differences between people
In DNA, polymorphisms can be a change in nucleotides. Sometimes this doesn’t matter, but sometimes it changes how the protein that in produced.
TTR is on chromosome 18 (chromosome – a bunch of DNA). If the wrong nucleotide is in a certain place on this, you can have hereditary ATTR (amyloid TTR)
Effects of different types
ATTR affects heart and nervous system, in general. But there is a lot of variability. Different mutations have different sets of symptoms. For instance:
How common is ATTR
50,000 worldwide with manifest disease.
V122i occurs in about 3.5% of African Americans, 150,000 over age 65 at highest risk for hATTR.
Even at Boston, a top center for ATTR, it goes undetected. We need to keep increasing doctors’ awareness.
Distribution of different types of ATTR varies by country.
Type affects treatment
Different types need different treatments.
Knowing your type
“23&me” genetic testing looks for a few TTR mutations
What do we tell children of those diagnosed with hATTR symptoms? Doctors are still unsure of when to start therapy/ therapy for those with the genetic mutation, but still without symptoms.
Disease progression and tests
- See Dr. Maurer et al. paper about progressive testing and treatment: “Expert Consensus Recommendations for The Suspicion And Diagnosis Of Transthyretin Cardiac Amyloidosis” Maurer, Circulation: Heart Failure 2019.
- 1st guidelines for Amyloidosis! From ASNC: how to use imaging testing to detect ATTR
Orthopedic manifestations – early sign of ATTR? Tests of tissue removed during carpel tunnel showed about 10% with ATTR, 2 which were hATTR (Sperry, Hanna JACC 2018)
Bilateral carpal tunnel
Spontaneous biceps tendon rupture
hATTR results from a single base pair change in the TTR gene, that causes a change in the TTR protein resulting in misfolding and amyloid fibril formation
hATTR is passed down to children in an autosomal dominant manner (50% chance of passage)
The type of mutation determines the predicted symptoms and organ systems that are affected
Determination of genotype is critical to selecting treatment
We must move toward early identification to give treatments the best chance to work
Organ Transplant Therapy ; Angela Dispenzieri, M.D., Professor of Medicine & of Lab. Medicine, Mayo Clinic.
Used in some ATTR, and other amyloidosis types (AFib, …)
The liver produces TTR, but is generally not affected by the ATTR.
Hereditary Systemic Amyloidosis
FIBRIL NAME | MUTATED PRECURSOR PROTEIN | TARGET TISSUE
ATTR | Transthyretin | PNS, ANS, heart, eye, leptomeninges, tenosynovium
AFib | Fibrinogen a-chain | Kidney
ALys | Lysozyme | Kidney (primarily)
AApoAI | Apolipoprotein A-I | Heart, liver, kidney, PNS, testis, larynx, skin
AApoAII | Apolipoprotein A-II | Kidney
AGel | Gelsolin | PNS, cornea
ACys | Cystatin C | PNS, skin
ABri | Abri-PP | CNS
Ab2M | b2-microglobulin | Musculoskeletal system
What to do with involved organs
Replace the liver – the main source of most of these proteins
Replace the affected organs (heart, kidney, … – but we can’t replace nerves or skin)
Liver ATTR transplants:
1st liver transplant for ATTR done in 1990
1st domino transplant for ATTR in 1995
1st partial liver transplant for ATTR in 1995
ATTR pt gets new liver, ATTR pt’s liver goes to someone else who would not get one otherwise (but it may produce hATTR in the recipient, even within 10 years, so that needs to be considered).
Partial liver transplants
family member gives part of their liver to the person with ATTR.
Does liver transplant cure the disease? Not always
Symptoms may continue to get worse, even after transplant. Why? It seems like normal TTR may stick to ATTR, if ATTR has already accumulated.
ValMet30 pts usually DO get better after transplant
Other types have smaller portion of pts getting better after transplant:
ATTR wild-type: replacing the liver does not affect things – the problem is in cleaning up TTR is the body, not in what is produced.
10 year survival rate varies by type of ATTR:
Val30Met early onset (85%)
Val30Met late onset (45%)
Val71Ala (N) (85%)
Leu111Met (H) (83%)
Leu58His (H/N) (76%)
Thr60Ala (H/N) heart & liver (58%)
Thr60Ala (H/N) liver Tx only (36%)
Ser50Arg <50% (less than 50%)
Note: Quality of life may be poor after a transplant.
Will organ transplant make a difference?
We don’t know for sure. The ATTR type gives us some clue, but there are still uncertainties. Some of the new drugs may help, with or without a liver transplant.
What we know:
Survival improved with liver transplant in V30M. But would the new drugs help even more?
Most effective if early. But how early?
Major benefit in nutrition
Combined “liver + heart” or “liver + kidney” feasible
What we don’t know: