It is essential for assessment of prognosis and treatment to be informed about the severity of amyloid deposition in vital organs (such as heart, liver, and kidneys) and other tissues (such as bone marrow, joints, peripheral and autonomic nervous system).
In taking history of the patient, apart from the usual questions, emphasis should be laid on symptoms specifically related to amyloidosis. Very important in this respect is the family history. Questions should be directed to the presence of neuropathy (tingling or numbness sensations, loss of muscle strength, impotence, orthostatic dizziness, urine bladder voiding problems, nausea, emesis, diarrhoea, and constipation), oedematous swelling around the eyes or around the ankles, atypical angina pectoris, right sided heart failure, collapse, arrhythmia, hoarseness, fatigue, weight loss, enlarged tongue with problems of swallowing or talking, and joint complaints of especially shoulders and hands. Severity of the dyspnoea should be graded according to the NYHA scale (from 1 to 4). Performance score should be graded according to the WHO scale (0-4).
Physical examination should be focussed on jaundice, waxy skin, fragility of the skin with subcutaneous bruising, hypertension or (orthostatic) hypotension, arrhythmia, enlargement of the tongue with indentations, enlargement of organs such as thyroid, liver, or spleen, the presence of oedema, abdominal dropsy, pleural fluid, pseudo-hypertrophy of muscles, shoulder pads, arthropathy of especially shoulders and hands, signs of peripheral neuropathy (sensibility, reflexes, ability to walk on toes and heels) or carpal tunnel syndrome (signs of Tinel and Phalen).
Beside results of history and physical examination pointing into the direction of cardiac involvement the first additional examinations are ECG (electrocardiogram) and chest X-ray. The ECG may show a low-voltage pattern, a pseudo-anteroseptal infarct, or some kind of block or arrhythmia. The chest X-ray often shows a normal sized heart despite a clinical picture of heart failure. It is important to look for pleural fluid and increased interstitial density of the lungs. Echocardiography is mandatory. It is important to look at the thickness of the intraventricular septum, the left ventricular posterior wall and the right ventricular wall, a sparkling pattern, the inflow (E/A ratio), and the heart valves. A 24-hour Holter ECG registration provides insight in conduction blocks and the presence of ventricular or supraventricular arrhythmias. The 24-hour Holter registration can also be used to calculate the HRV (heart rate variability), an indicator of the effect of the autonomic nervous system on the (normal or affected) heart. A so-called MUGA scan can provide a reliable measurement of the ejection fraction of the heart. If - in case of ATTR amyloidosis - liver transplantation is considered to be a therapeutic modality, cardiac catheterisation (and if indicated also coronary angiography) may be needed to get a reliable estimate of the cardiac risk of this type of major surgery.
Beside results of physical examination such as blood pressure and oedema it is necessary to look at serum albumin, urine sediment, creatinine clearance (ml/min), and proteinuria (grams/24 h). Neuropathy of the bladder can lead to a clinical picture of post-renal obstruction. If indicated echography is useful to assess size end echogenicity of the kidneys, as well as a defective emptying of the urine bladder. More precise renal function tests such as GFR (glomerular filtration rate), ERPF and FF can be tested if necessary.
Beside the results of physical examination such as jaundice, ascites, liver enlargement, and spleen enlargement it is important to do some blood tests: liver function tests (alkaline phosphatase, total bilirubin, and gamma GT), albumin, coagulation tests (fibrinogen, PT, APTT, AT-III), and cholinesterase. But also a differential count ("by hand") of the leukocytes in order to look for Howell Jolly bodies and target cells as signs of a diminished function of the spleen. If indicated echography is the method of choice to assess size and echogenicity of liver and spleen.
Problems with swallowing, food passage problems ("quickly saturated"), loss of weight, diarrhoea, and constipation all may indicate involvement of the gastrointestinal tract. Often this is caused by a defective control of the bowel movement and timing of the function of the glands by the autonomic nervous system. This may be caused by direct damage to autonomic nerves, but also by infiltration of and damage of the plexus myentericus. In severe cases this can lead to the clinical picture of the so-called intestinal pseudo-obstruction. Also defective absorption, polyps, pseudo-polyps, ulcers, bleeding, and bowel wall perforation can occur. In these situations absorption tests (such as fat absorption, vitamine A curve, Schilling test, double-sugar test) and direct inspection by endoscopy are useful to evaluate the situation. Beside it the clinician should look for treatable other conditions such as bacterial overgrowth and bile acid malabsorption.
Physical examination is used to assess the size of the thyroid gland. The TSH (thyroid stimulating hormone) level in blood helps to assess the function of the thyroid gland. Fasting cortisol may be useful to assess the function of the adrenal gland. If indicated an ACTH stimulation test may be necessary for this evaluation.
Essential for assessing involvement of nerves is the history and physical examination of the patient, if indicated performed by the neurologist. An EMG (electromyogram) may be very helpful to establish the presence and severity of polyneuropathy. Orthostatic hypotension indicates the presence of autonomic neuropathy or cardiomyopathy. Autonomic nerve testing (by the so-called Ewing battery) and measurement of the HRV (heart rate variability) is useful for the clinician to detect involvement of the autonomic nervous system. Scintigraphy of oesophagus and stomach may be helpful to detect disturbed motility of the upper part of the gastrointestinal tract caused by autonomic dysfunction. Sophisticated investigations often show changes in smell and taste. Dryness of mouth and eyes (sicca complaints) can sometimes occur.
A bone marrow biopsy can help in AL amyloidosis to get an impression of severity of amyloid deposition in bone marrow. Skeletal X-ray is necessary to search for signs of multiple myeloma and apart from the presence of lytical lesions it is also useful to look at the bone mineral density, especially in the vertebral column. If deemed necessary a bone densitometry may be useful.
In case of suspicion of interstitial pulmonary involvement extensive lung function measurement can be useful, but a lung biopsy is often needed to establish serious pulmonary involvement. If pleural fluid is persistent without signs of cardiac failure, a pleural biopsy may be indicated. The skin as well as the nails must be inspected carefully. Sometimes the clinical picture resembles that of temporal arteritis. Bleeding as well as thrombosis may be observed frequently. Therefore it is good to know the bleeding time and coagulation (with factor analysis if deemed necessary).
After this extensive investigation it is important to summarise which organs are clinically affected by the disease. This is especially important for vital organs such as heart, kidneys, liver and peripheral nerves. Most clinical research groups in the world do not use identical criteria for organ involvement. However, at the Xth international Symposium on Amyloid and Amyloidosis in Tours some progress has been made in this field and a set of generally accepted criteria for organ involvement in AL amyloidosis has been proposed by Morie Gertz from the Mayo Clinics in Rochester. Also criteria have been proposed for improvement, stabilisation, and worsening of the affected organs and the underlying clonal plasma cell dyscrasia in order to use world wide the same set of criteria for assessment of the effect of therapy during the course of the disease.
Until the new criteria have been published we will continue to use in our hospital our current criteria for organ involvement:
| Kidney: Proteinuria (albumin) > 0.5 g/day or clearance < 90 ml/min |
| Heart: Mean left ventricular wall thickness > 11 mm or low voltage ECG |
| Liver: Liver span > 15 cm without clinical heart failure (more than 5 cm below costal margin) or alkaline phosphatase > 180 kU/l |
| Spleen: Spleen span > 13 cm or Howell Joly bodies or target cells |
| Nervous system, peripheral: Clinical picture (if possible confirmed by EMG) |
| Nervous system, autonomic: Ewing score > 5, orthostatic hypotension, disturbed gastric emptying, pseudo-obstruction or urine bladder voiding problems |
| Stomach and bowel: severe diarrhoea, weight loss > 10% of the body weight, positive biopsy |
| Lung: Interstitial picture, biopsy confirmation |
| Joints: Shoulder pads or pseudo-RA of the hands |
| CTS: Clinical picture (if possible confirmed by EMG) |
| Soft tissues: Tongue enlargement, claudicatio of calves or jaw (blood vessels), pseudo-hypertrophy or atrophy of muscles (or in muscle biopsy), lymph node (in biopsy). |
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