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.

Consultation and physical examination

In addition to the usual questions, the patient consultation must be focused on symptoms that can occur with amyloidosis. The importance of family history is often seriously 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, symptoms of (right-sided) heart failure, tendency to dizziness and fainting upon standing, 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).
During physical examination the treating physician should look out for jaundice, pale waxy skin, skin fragility with subcutaneous ecchymoses, hypertension or (orthostatic) hypotension, arrhythmias, enlargement of the tongue with indentations of the teeth, enlargement of internal organs such as thyroid, liver or spleen, the presence of edema, ascites and pleural fluid, muscle tissue pseudo hypertrophy, swollen shoulders (“shoulder pads”) and signs of arthropathy of the shoulders or hands, and evidence of peripheral neuropathy (altered or reduced feeling, changes in hair pattern, trophic disorders, diminished reflexes, difficulty walking on heels and toes, muscle atrophy) and 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 indicate whether amyloid has deposited in the liver. The albumin, creatinine and amount of protein in the urine indicate whether the kidneys are affected. By measuring serum Neurofilament light (sNfL), one can get an impression of whether neuropathy is present. A technique known as the “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 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 we are able to perform an SAP scan, which can assess the extent and severity of amyloid deposition in different organs. However, the technique is unreliable for 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 are some examples of SAP scans in patients with AL amyloidosis. This technique 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 coupled to a small amount of radioactive iodine (¹²³-I). This SAP 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 know first 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 spreads throughout all the 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) is visible. Because these are precisely the organs in which we are interested, this 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. If the “blood pool” uptake in the heart and blood vessels is lower than expected, this contrast becomes especially visible. Rapid disappearance of activity from the blood to the part of the body outside of the blood vessels is characteristic of extensive amyloidosis.

After 6 hours, an unhelpful 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 can the salivary glands, oral cavity, nose, stomach, (kidneys, slightly) and bladder, before the radioactivity disappears via urination. 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 characteristic of extensive amyloidosis or very poor renal function. Secretion of radioactivity into the stomach can make it difficult to assess activity in the spleen, especially with a large stomach and due to, for example, reduced manoeuvrability of the stomach.

Bone scan
A bone scan, also known as skeletal scintigraphy, is a procedure in which an image is made of the skeleton using a radioactive substance, known as a 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 of ATTR amyloid deposition in the heart. But also in cases with AL or Apolipoprotein AI amyloid in the wall of the heart, staining 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 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 control 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 control the heart.

Further supporting 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 procedure called a Sudoscan, the sensory nerves of the hands and feet can be looked at 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 Fibroscan 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 important is the involvement of vital organs such as the 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 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.

Investigations to map organ involvement: