Severity and extent

Once the amyloid has been detected and typed, it is important for the prognosis and treatment to gain insight into the severity of the amyloid deposition in the organs (such as heart, liver and kidneys) and tissues (such as bone marrow, joints, peripheral and autonomic nerves) . By looking specifically at the functioning and size of vital organs and tissues, the treating physician can get a good impression of the severity and extent of the amyloidosis.

Case history and physical examination

In addition to the usual questions, the history must be focused on symptoms that can occur with amyloidosis. The importance of family history is often underestimated. In addition, questions should be asked about the presence of neuropathic complaints (tingling, numbness, shooting pains, loss of strength, perspiration, impotence, orthostasis, micturition disorders, nausea, vomiting, diarrhea and constipation), swelling of the face or ankles, atypical anginal complaints, complaints of (right-sided) heart failure, collapse tendency, arrhythmias, hoarseness, fatigue, weight loss, enlarged tongue with swallowing or speaking problems, and joint complaints of shoulders and hands in particular. The severity of shortness of breath should be graded on the NYHA scale (from 1 to 4). The performance score is graded according to the WHO scale (from 0 to 4).
Physical examination should include jaundice, pale waxy skin, skin fragility with subcutaneous ecchymoses, hypertension or (orthostatic) hypotension, arrhythmias, enlargement of the tongue with indentations, enlargement of internal organs such as thyroid, liver or spleen, the presence of edema, ascites and pleural fluid, muscle tissue pseudo hypertrophy, shoulder pads and signs of arthropathy of the shoulders or hands, and evidence of peripheral neuropathy (altered or diminished feeling, hair pattern, trophic disorders, reflexes, walking on heels and toes, muscle atrophy) or carpal tunnel syndrome (sign of Tinel and Phalen, thenar muscle atrophy).


Blood and urine

Blood and urine tests can provide a good first impression of which organs are involved. In blood tests the substances NT-proBNP and Troponin T can give an impression of whether amyloid is deposited in the wall of the heart. AF, GGT and bilirubin give a suggestion of whether amyloid has deposited in the liver. The albumin, creatinine and amount of protein in the urine indicate whether the kidneys are affected. With a so-called “hand differentiation” of white blood cells, it is possible to look for Howell Jolly bodies and target cells as evidence of reduced spleen function. TSH and a morning cortisol are determined to gain an impression of thyroid and adrenal function, respectively.


Imaging

Conventional imaging techniques, such as a chest radiograph, an ultrasound scan of the abdomen, an MRI scan of the heart or a CT scan of the lungs, are regularly used to map organ involvement. There are also more specific techniques for detecting organ involvement in the context of amyloidosis.

In Groningen there is the possibility to perform a so-called SAP scan. With this scan an impression can be gained of the extent and severity of amyloid deposition in different organs, however, the technique is insufficient in some organs such as the heart. For an individual patient, this technique can be helpful to map the severity of the amyloidosis and to monitor the effect of the treatment.

SAP scan

SAP scan examples of four patients with different organ involvement. You see uptake in the spleen in A, the liver and spleen in B, the spleen and kidneys in C and the liver, spleen and kidneys in D.

 
Above some examples of a so-called SAP scan in patients with AL amyloidosis. This technique was developed in London by Prof. dr. P.N. Hawkins and Prof. dr. M.B. Pepys and is also used in Groningen (Nuclear Medicine department). In this study, the SAP protein (SAP stands for serum amyloid P component) is coupled to a small amount of radioactive iodine (123-I). This substance is isolated and purified from the blood of blood donors. The SAP behaves as a sort of tracker after injection into the bloodstream and binds to (easily accessible) amounts of amyloid in vital organs (such as liver, kidneys, spleen, adrenal glands, joints and bone marrow, but not in the heart).

For example, in the second patient (B), clear uptake in liver and spleen is visible 20 hours after administration. When a treatment is started, it is possible to see whether the scan changes (improvement, stabilization or deterioration) so that the effect of the treatment can be better assessed.

To assess the SAP scan, it is good to first know how the body deals with both SAP and the iodine with which the SAP is labeled. After administration into the bloodstream, the SAP (which consists of large molecules) first distributes itself to the total amount of blood in the body (the “blood pool”). As a result, on the first day of the scanning procedure, the blood in the heart, the large blood vessels and the organs with strong blood circulation (such as the liver, spleen and kidneys) are visible. Because these are precisely the organs in which we are interested, this seems difficult for the interpretation. Yet a deviating pattern (for example, greatly increased uptake in the liver) is visible immediately after administration because relatively much more radioactivity goes to the liver than expected and lingers there. Certainly if the “bloodpool” uptake in the heart and blood vessels is lower than expected, this contrast becomes more visible. Rapid disappearance of activity from the blood to the part of the body outside of the blood vessels is a characteristic of extensive amyloidosis.

After 6 hours, another disturbing phenomenon will occur, namely the normal excretion of (radioactive) iodine. Despite blockage of iodine uptake by the thyroid gland, it can still absorb some activity, as well as the salivary glands, oral cavity, nose, stomach, (vague kidneys) and bladder before the radioactivity disappears through the urine. The slow appearance in the urine of only a small percentage of the administered radioactivity indicates a strong binding in the part of the body outside the blood vessels, and is also a characteristic of extensive amyloidosis or very poor renal function. Excretion of radioactivity in the stomach can make it difficult to assess activity in the spleen, especially with a large stomach and due to, for example, reduced mobility of the stomach.

Bone scan
A bone scan, also known as skeletal scintigraphy, is a study in which a picture is made of the skeleton using a radioactive substance, a so-called tracer. The tracer used for the bone scan binds not only to the bones but also to certain types of amyloid in the wall of the heart. If the heart shows strong tracer uptake on the bone scan, this is very suggestive for ATTR amyloid deposition in the heart. But also with AL or Apolipoprotein AI amyloid in the wall of the heart can sometimes be seen on the bone scan staining of the heart.

Bone scan (Technetium-99m-HDP)

 
Above an example of a patient with ATTR amyloidosis. In this study the substance oxidronate (HDP), deoxypyridinolin (DPD) or pyridinoline (PYP) is coupled to a small amount of radioactive Technetium. The HDP, DPD, or PYP behaves as a sort of tracker after administration into the bloodstream and binds to ATTR amyloid (but sometimes also to Apolipoprotein AI and AL amyloid) in the wall of the heart.
MIBG scan of the heart.

MIBG scan of the heart
With certain types of amyloidosis, the autonomic nervous system may be affected. The nerves that drive the heart are part of the autonomic nervous system. An iodine 123-meta-iodine-benzylguanidine (123-MIBG) scan can be used to examine the nerve pathways that drive the heart.


Other supportive tests

The patient’s complaints and physical examination remain the basis of the assessment of nerve involvement. An electromyographic (EMG) examination helps to determine the presence and severity of nerve damage. The function of the sensory nerves can also be mapped by means of Quantitative Sensory Testing (QST). With a so-called Sudo scan you look at the nerves of the hands and feet in a different way. Vascular testing (the so-called Ewing battery) and measuring the variation in heart rhythm can be used to map the functioning of the involuntary (autonomic) nervous system.
Measuring liver stiffness with a Fibro scan is a simple method to get an impression of whether there is amyloid deposition in the liver and is very helpful in evaluating the effect of treatment in patients with AL amyloidosis.


Organ involvement

After extensive evaluation, a list should be made of which organs are clinically involved. Especially involvement of vital organs such as heart, kidneys, liver and peripheral nerves is important. International criteria for organ involvement have been established in collaboration with other amyloidosis experts. Agreements have also been made about criteria that are used to determine improvement or deterioration of the organs and to get an impression of the potential effectiveness of an established treatment and the course of the disease (1,2).

  1. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, Sanchorawala V, Sezer O, Solomon O, Grateau G. Definition of Organ involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): a consensus opinion from the 10th international symposium on amyloid and amyloidosis. American Journal of Hematology 2005; 79:319–328.
  2. Adams D, Suhr OB, Hund E, Obici L, Tournev I, Campistol JM, Slama MS, Hazenberg BP, Coelho T; European Network for TTR-FAP (ATTReuNET). First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. 2016 Feb;29 Suppl 1: S14-26.

Investigations to map organ involvement:

Blood and urine tests Functieonderzoek Beeldvormend onderzoek
Heart NT-proBNP, troponin T ECG Echo, MRI, bone scan, MIBG
Kidneys Creatinine, albumin, proteinuria Endogenous creatinine clearance, GFR, ERPF ultrasound, SAP scan
Liver AF, GGT, total bilirubin Fibro scan, ultrasound, SAP scan
Spleen Diff: Howell Jolly bodies, target cells ultrasound, SAP scan
Peripheral nervous system EMG, QST, Sudo scan MRI (MRN)
Autonomic nervous system Autonomefunctie-onderzoek MIBG
Lung Volumetry, CO diffusion HRCT scan, PET scan
Adrenal / thyroid gland TSH, Cortisol Synacthen test
Gastrointestinal system Resorption testing Gastro- and colonoscopy
joints MRI scan
Soft tissue MRI scan
Eyes Ophthalmoscopy / fundoscopy
Brains MRI-scan, 11C-PIB-PET scan

In het kort

Voor de behandeling en het inschatten van de prognose van het type amyloïdose is het van belang de ernst en uitgebreidheid van orgaanbetrokkenheid van de amyloïdose in kaart te brengen.

  • Anamnese, lichamelijk onderzoek en bloedonderzoek geven een eerste indruk welke organen en weefsels zijn aangetast.
  • In sommige gevallen kan de SAP-scan worden gebruik om de ernst van de amyloïdose in kaart te brengen en het effect van de behandeling te vervolgen.
  • In sommige gevallen helpt de botscan bij het opsporen van amyloïd in de wand van het hart.
  • Er zijn internationale criteria voor orgaanbetrokkenheid opgesteld. Ook zijn er afspraken gemaakt over criteria die gebruikt worden om verbetering of verslechtering van de organen vast te stellen en een indruk te krijgen van eventuele effectiviteit van een ingestelde behandeling en het beloop van de ziekte.