Severity and extent

Once the amyloid has been detected and typed, it is important for prognosis and treatment to understand 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 closely 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.

Consultation and physical examination

In addition to the usual questions, the anamnesis should be focused on symptoms that can occur with amyloidosis. The importance of family history is seriously underestimated in this context. In addition, questions should be asked about the prevention of neuropathic complaints (tingling, numbness, shooting pains, loss of strength, perspiration, impotence, orthostatic dizziness, micturition disorders, nausea, vomiting, diarrhea and constipation), swelling of the face or ankles, atypical anginal complaints, complaints of (right-sided) congestive heart failure, tendency to collapse, arrhythmias, hoarseness, fatigue, weight loss, enlarged tongue with swallowing or speaking problems, and joint complaints especially of the shoulders and hands. 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 look for jaundice, pale-waxy skin, fragility of the skin 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, pseudohypertrophy of muscle tissue, “shoulder pads” and signs of arthropathy of the shoulders or hands, and indications of peripheral neuropathy (altered or decreased feeling, changes in hair pattern, trophic disorders, reflexes, walking on heels and toes, muscle atrophy) or carpal tunnel syndrome (sign of Tinel and van Phalen, thumb mouse 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 wether amyloid is deposited in the wall of the heart. AF, GGT and bilirubin indicate wetheramyloid has deposited in the liver. The albumin, creatinine and amount of protein in the urine indicate wether the kidneys are affected. By measuring serum Neurofilament light (sNfL), one can get an impression of whether neuropathy is present. A technique called “hand differentiation” of white blood cells enables the detection of Howell Jolly bodies and target cells as evidence of reduced spleen function. TSH and a morning cortisol are required to gain an impression of thyroid and adrenal function, respectively.

Imaging

Conventional imaging techniques, such as a chest X-ray, abdominal ultrasound, MRI scan of the heart or 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, we are able to perform an SAP scan in some people with extensive systemic amyloidosis. This can give an impression of the severity of accumulation in different organs, although the technique is inadequate in some organs such as the heart. For an individual patient, this technique can help to assess the severity of amyloidosis and monitor the effect of treatment.

SAP scan

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

 
Above are examples of the SAP scan in patients with AL amyloidosis. This research was developed in London by Prof. P.N. Hawkins and Prof. 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 linked to a small amount of radioactive iodine (¹²³-I). This SAPis isolated and purified from the blood of blood donors. The SAP behaves like a 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).

In the second patient (B), for example, uptake in the liver and spleen is clearly visible 20 hours after administration. When treatment is started, it is possible to see if 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 the normal metabolism of both SAP and the iodine with which the SAP is labelled. After administration into the bloodstream, the large-molecular SAP spreads throughout 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 strongly perfused organs (such as the liver, spleen and kidneys) are especially visible. Because these are the organs we are interested in, it makes interpretation difficult. However, a deviating pattern (for example greatly increased uptake in the liver) is visible immediately after administration because a relatively higher amount of radioactivity than expected travels to the liver and remains there. This contrast becomes more visible, especially if the blood pool absorption in the heart and blood vessels is lower than expected. Rapid disappearance of activity from the blood to the extravascular body compartment is a hallmark of extensive amyloidosis.
After 6 hours, an unhelpful phenomenon will occur, namely the normal excretion of (radioactive) iodine. Despite blockage, the thyroid gland can take up some activity, absorb the salivary glands as well as the oral cavity, nose, stomach, (fade the kidneys) and blow before the radioactivity disappears through the urine. The slow appearance in urine of only a small percentage of the administered radioactivity indicates strong binding in the extravascular body compartment, and is also a hallmark of extensive amyloidosis or very poor kidney function. Excretion of radioactivity in the stomach can make it difficult to assess activity in the spleen, especially on a large stomach due to gastroparesis or motility disorders, for example.

Bone scan
A bone scan, also known as skeletal scintigraphy, is an examination that shows an image of the tracer in the skeleton. 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 evidence of ATTR amyloid in the heart. But also in patients with AL or Apolipoprotein AI amyloid in the wall of the heart, discoloration of the heart can sometimes be seen on the bone scan.

Bone scan (Technetium-99m-HDP)

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

MIBG scan of the heart
The autonomic nervous system may be affected in certain types of amyloidosis. The nerve pathways that control the heart are part of the autonomic nervous system. An iodine¹²³-meta-iodine-benzylguanidine (¹²³I-MIBG) scan can be used to examine the nerve pathways that control the heart, sometimes helping to detect cardiac amyloid.

Further supporting tests

The anamnesis and physical examination remain the basis of the assessment of nerve involvement. An electromyographic (EMG) examination helps determine the presence and severity of polyneuropathy. The function of the sensory nerves can also be mapped by means of “Quantitative sensory testing” (QST). The functioning of the autonomic nervous system can be assessed by vascular tests (the Ewing battery) and measuring the heart rhythm variability. A Sudoscan can also be useful here.

Measuring liver stiffness using a Fibroscan is a simple method of gaining an impression of amyloid deposition in the liver and is very helpful in evaluating the effect of treatment in patients with AL amyloidosis.

Organ involvement

After extensive research, an assessment should be made of which organs show clinical involvement. It is especially important to determine the involvement of the vital organs such as the heart, kidneys, liver and peripheral nerves. International criteria for organ involvement have been drawn up for this. Agreements have also been made about the criteria used to determine improvement or deterioration of the organs and to get an impression of the possible effectiveness of 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 10^th 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.

Tests to map organ involvement: