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Education And Debate

Grand Rounds - Hammersmith Hospital: Cardiac transplantation for AL amyloidosis

BMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6962.1135 (Published 29 October 1994) Cite this as: BMJ 1994;309:1135
  1. R Hall,
  2. P N Hawkins
  1. University of Wales, emeritus professor of medicine. senior lecturer in medicine.

    Case presented by: R Hall, P N Hawkins

    Chairman: J Scott, professor of medicine

    Discussion group: M B Pepys, professor of immunological medicine; Julia M Polak, professor of endocrine pathology; K A Davies, senior lecturer in rheumatology.

    Systemic AL amyloidosis has a poor prognosis which corresponds closely with the severity of cardiac disease.1,2 Some patients benefit from chemotherapy directed at the underlying monoclonal gammopathy,3 but the median period of treatment required for a clinical response is one year, and patients with severe cardiac amyloid do not usually survive for more than six months.1 Cardiac transplantation has rarely been done, presumably because of concerns about the systemic nature of the disease. A personal account is given here by a professor of medicine who presented at the age of 53 with extensive AL amyloidosis and received a cardiac transplant in 1984.

    Case history

    I was born on 1 October 1931 and was healthy until 1978, when I noted muscle fatigue on climbing hills. Over the next five years a series of apparently unrelated symptoms developed including pruritus, hoarseness, snoring. In 1981 I developed paroxysmal atrial fibrillation, usually precipitated by effort. In 1982 I was investigated for atypical chest pain on exertion at the London Chest Hospital, when electrocardiography and coronary artery and left ventricular angiography gave normal results. By 1984 I had developed ankle oedema and right hypochondrial pain on exertion and right heart failure due to presumed cardiomyopathy was diagnosed. Later that year AL amyloidosis was diagnosed after a left ventricular biopsy. By this time electrocardiographic and echo findings were consistent with this condition. A normal bone marrow result excluded myeloma, although free lambda light chains were detected in my urine.

    I was referred to Harefield Hospital, and on 17 November 1984 I had an orthotopic cardiac transplantation with a heart from a 25 year old donor. Three early rejection episodes were treated with pulsed high dose corticosteroids and antilymphocyte globulins. The transplanted organ has functioned well since, and the only complications have followed routine investigations or have been associated with drug treatment. After a right heart biopsy I developed a left coronary artery/right ventricular fistula, which caused angina; this reflected underlying coronary artery disease as these fistulas are usually asymptomatic. After left heart catheterisation I developed rigors due to a reaction to the contrast medium. This led to acute adrenal failure, which responded rapidly to steroids. Another side effect is a reversed circadian rhythm of water excretion. This effect is seen in at least one third of patients. The large amounts of urine that are passed at night interfere with sleep, but I soon adapted to this. My main problems after transplantation can be divided into five categories: drug side effects; infections; trauma; coronary artery disease; and those relating directly to the amyloid itself.

    Drug side effects

    After transplantation I received the standard immunosuppressive regimen of cyclosporin A and azathioprine. The cyclosporin produced multiple adverse effects including drowsiness, anorexia, nausea, hirsutes, gingival hypertrophy, renal impairment, and anaemia. At one stage I required four units of blood every six weeks and had 32 units in all. The cyclosporin A was then stopped and replaced by prednisolone (eventual maintenance dose 8 mg daily), after which I required no further transfusions and my renal function improved.

    Other side effects included nausea due to azathioprine and many problems associated with antihypertensive drugs, notably oedema with (alpha) blockers and bowel stasis with angiotensin converting enzyme inhibitors. I have been stabilised on lisinoprilone taken twice daily for smoother control. Another curious symptom was aching in the hips on exertion, associated with a plasma sodium concentration of 126 mmol/l. I assumed that amyloid infiltration of the adrenals had led to mineralocorticoid deficiency, which was masked by prednisolone. I had no further investigations of mineralocorticoid function but the symptoms were relieved by 0.05 mg daily of fludrocortisone. Hypoadrenalism masked by concomitant steroid therapy has recently been described.

    Infections

    I am particularly vulnerable to respiratory infections, which spread from the upper respiratory tract to cause bronchitis within 24 hours and need early treatment with co-amoxiclav or other antibiotics. Recurrent conjunctivitis responds rapidly to chloramphenicol eye drops. After a visit to France I developed a fever that was eventually found to be due to toxoplasmosis, which responded to a three week course of doxycycline. I also get recurrent candidiasis, which usually presents as oral ulceration but once as endophthalmitis. I require a 10 day course of fluconazole every few weeks. Herpes zoster affecting the second division of the left fifth cranial nerve responded to systemic acyclovir and the subsequent neuralgia was helped by transcutaneous nerve stimulation.

    Trauma

    Spontaneous rib fractures due to steroid induced osteoporosis have been diminished by intranasal calcitonin. Vertebral crush fractures are not a problem, but I have to avoid lifting heavy loads and strenuous exercise. I had a fractured sacrum after a fall but it healed well. Magnetic resonance imagine showed that pain in my right hip was due to avascular necrosis, after plain radiography and computed tomography had given normal results. I treated it like a fracture, using a stick to reduce the load, and the pain resolved after nine months. I firmly resisted hip replacement because of my osteoporosis and propensity to infection. Minor skin lacerations and secondary infections are a constant problem; leaving the lesion uncovered and a spray of antibiotic power seem to promote the most rapid healing.

    Coronary artery disease

    Like most patients following transplantation my coronary arteries have narrowed, causing angina on exertion. I started a strict low fat diet plus simvastin (20 mg daily), and my cholesterol concentration has been <5 mmol/l and high density lipoprotein cholesterol count about 1.5 mmol/I for the past three years. My angina is now rarely a problem, my exercise electrocardiogram is acceptable at 8 minutes, and my last coronary artery angiogram showed no progression of the disease. Although coronary endarteritis may be inevitable, I can at least be positive about treatment for atheroma.

    Amyloid

    At the time of surgery there was evidence of amyloid deposition in my heart (cardiomyopathy), my tongue (limited movement), my kidneys (2 g/24 h proteinuria), my skin (panda sign and ecchymoses, confirmed on biopsy), and the bowel (stasis). In March 1987 I was the second patient to have scintigraphy with radiolabelled serum amyloid P component. This confirmed extensive generalised amyloidosis. Right ventricular biopsy specimens also became positive for amyloid, and echocardiography showed mild impairment of diastolic function (table). I had a course of chemotherapy from April 1987 to June 1988 to suppress the underlying monoclonal gammopathy. This followed a modified Medical Research Council myeloma protocol and comprised eight cycles of epidoxorubicin, carmustine, and cyclophosphamide.

    Results of evaluation of amyloid deposits, function of affected organs, and the underlying monoclonal gammopathy

    View this table:

    At clinical review in September 1993 I was generally well, although I had retired from the chair of medicine in Cardiff in October 1989 because of lack of stamina. I had no cardiac dysfunction, and the only abnormalities were lack of tear secretion and enlargement of the submandibular glands.

    Investigations showed normal full blood count and normal results in tests of renal and liver function, clotting studies, and serum electrophoresis. There was no significant proteinuria. Plasma immunoglobulin concentrations were normal, and there were no free (lambda) light chains in my urine. The bone marrow was hypocellular but otherwise normal. Follow up serum amyloid P component scintigraphy gave normal results, indicating that the systemic amyloid deposits had regressed. Cardiac scintigraphy showed a limited area of apical ischaemia. The most recent endomyocardial biopsy (November 1991) showed only a few scattered foci of amyloid compared with generalised deposition four years previously.

    My heart transplant 9/1/2 years ago was undoubtedly successful. My quality of life is good, though limited by lack of stamina, osteoporosis, a fragile skin, and repeated infections. The reasons for my survival are many. The amyloid responded to the course of chemotherapy. My medical colleagues in Cardiff and at Harefield have kept a close eye on me. My knowledge of infections and drug side effects and the immediate availability of a general physician, my wife, has meant that they have been recognised early and dealt with effectively.

    I think the message of my case is that cardiac transplantation can be a life saving intervention which buys time for chemotherapy in systemic amyloidosis. It certainly should raise the hope of others who suffer from this disease.

    Comment

    The diagnosis and management of AL amyloidosis are challenging. Clinical features are non-specific and the pattern and extent of organ disease as well as the type of underlying B cell dyscrasia are remarkably heterogeneous.4 Most patients die within two years of diagnosis, and many of the important factors that determine the prognosis, including the distribution and amount of amyloid and its rate of progression, have not been systematically evaluated. Quantitative scintigraphy with radiolabelled serum amyloid P component,5,6 a normal plasma protein that has a specific binding affinity for amyloid fibrils, has lately shown major regression of amyloid deposits in several conditions in which the supply of amyloid fibril precursor protein can be substantially reduced.*RF 7-9* Examples included AA amyloid complicating juvenile chronic arthritis and rheumatoid arthritis treated with aggressive anti-inflammatory drugs, familial amyloid polyneuropathy after liver transplantation, and several patients with AL amyloidosis treated with alkylating chemotherapy. Regression of amyloid was accompanied by clinical benefit in all patients, suggesting that the improvements reported in other patients treated with cytotoxic regimens are also likely to have resulted from amyloid regression.3,10 The main therapeutic challenges in AL amyloid are the slow and often limited response of benign plasma cell clones to cytotoxic drugs, and the narrow window of opportunity between diagnosis and death. This is especially true in patients with cardiac disease. Cytotoxic therapy after cardiac transplantation in AL amyloidosis has not been reported before, and our successful experience in this case suggests that the approach may have a more widespread application in this disease.

    Discussion

    MBP: Our favourable experience with Professor Hall has altered our approach to the management of systemic AL amyloidosis. When he presented in 1984, we thought that treatment was likely to benefit very few patients with this disease. Cardiac transplantation, in particular, seemed inadvisable because of amyloid deposits in other organs and the likelihood of deposition in the graft. Since then it has become clear that the medium term prognosis of cardiac replacement in patients with AL amyloidosis is no worse than for transplant patients in general11 and that alkylating chemotherapy can effectively retard and sometimes reverse the clinical progression of his disorder if the patient lives long enough for a response to occur. Professor Hall received these two approaches combined together for the first time and they have been remarkably successful, resulting in appreciable regression of the systemic amyloid deposits. Observation of the regression of amyloid directly with serum amyloid P component scintigraphy has encouraged us to take a more radical approach to the treatment of amyloidosis generally.

    JS: The development of angina after cardiac transplantation is rather unusual isn't it?

    RH: My chest pain is undoubtedly that of angina pectoris; it has been reproduced both by exercise testing and rapid atrial pacing and is associated with typical electrocardiographic changes. I believe that symptomatic angina occurs in about one quarter of heart transplant patients. Presumably the basis is reinnervation.

    JMP: We performed a study in 28 cardiac transplant patients having a second operation up to five years after transplantation, and we could not find any anatomical evidence of re-innervation.

    PNH: Perhaps there was some re-innervation in the present case which took longer than five years, although an alternative mechanism for pain might be ischaemia of the residual native atrial tissue left in situ.

    RH: My right atrium is certainly sensitive to manipulation at catheterisation, and about one in four of my 28 ventricular biopsies have been painful.

    KAD: Does the type of plasma concentration of paraprotein or the findings on serum amyloid P component scientigraphy have any prognostic value in systemic AL amyloidosis?

    PNH: A serum paraprotein is often completely absent in AL amyloidosis, and even free monoclonal immunoglobulin light chains cannot be found in the urine of 15% of patients. The biophysical properties of the monoclonal protein, which are unique in each case, presumably do have an influence on the disease. We have noted that long term survival is associated with, among other things, a small whole body load of amyloid, as shown by serum amyloid P component scanning. The factors that ultimately affect survival include not only the anatomical distribution and extent of the amyloid but also the effect it has on organ function, which varies remarkably from case to case and possibly at different times in the same patient.

    Footnotes

    • Footnotes Series edited by Dr. Moira Whyte

      Professor Hall has since died.

    References

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