- Email: [email protected]
Long-term survival in systemic amyloid A amyloidosis complicating Crohn's disease
GASTROENTEROLOGY 1997;112:1362–1365
CASE REPORTS Long-term Survival in Systemic Amyloid A Amyloidosis Complicating Crohn’s Disease LAURENCE B. LOVAT, SHERIL MADHOO, MARK B. PEPYS, and PHILIP N. HAWKINS Immunological Medicine Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England
Systemic AA amyloidosis is a serious and potentially fatal complication of Crohn’s disease. Proteinuria is the most common presentation, but the diagnosis can only be confirmed by showing amyloid in the tissues and is often delayed. Recently, scintigraphy has been developed using 123I–serum amyloid P component (SAP) as a noninvasive and quantitative alternative to histology in which this nuclear medicine tracer specifically targets amyloid deposits in vivo. This study investigates 4 patients with Crohn’s disease who, despite having only low-grade clinical activity, developed progressive AA amyloidosis and renal failure. One patient died while receiving hemodialysis, but in the other 3 cases, renal transplantation and standard antirejection therapy were associated with remission of inflammatory activity. Serial SAP scintigraphy showed regression of amyloid in 2 of these patients and absence of progression in the other. These case studies show the dynamic but variable behavior of AA deposits in different patients and show the use of radiolabeled SAP for diagnosis and monitoring of amyloidosis in Crohn’s disease.
S
ystemic AA amyloidosis occurs in up to 6% of patients with chronic inflammatory disorders such as Crohn’s disease or any condition that is associated with a sustained acute-phase response.1 The diagnosis can only be confirmed by showing amyloid deposits in the tissues and frequently remains unrecognized until a late stage. The prognosis is poor, but treatment that suppresses the acute-phase response can lead to regression of amyloid, preservation or improvement of function of affected organs, and long-term survival.2,3 Radiolabeled serum amyloid P component (SAP) has been developed as a diagnostic tracer in amyloidosis,4 and we report its use in this study for the diagnosis and quantitative monitoring of AA amyloid deposits in 4 patients with Crohn’s disease.
bowel movements and onset of a large joint arthropathy, histological confirmation of Crohn’s disease was obtained at appendectomy. Postoperative barium enema showed severe rightsided colitis necessitating right hemicolectomy 3 weeks later. Clinically, the disease was controlled for more than 10 years on low-dose prednisolone, which was withdrawn eventually. He required a further laparotomy for division of adhesions in 1972, at which time the terminal ileum was thickened. In 1983, he became hypertensive and developed proteinuria (Table 1); although amyloid was suspected, rectal biopsy specimen was reported as normal. The proteinuria persisted and amyloid was confirmed by the renal biopsy specimen 18 months later. End-stage renal failure supervened, and in 1990, he received a renal transplant from a live related donor. Antirejection treatment has comprised prednisolone, cyclosporine, and azathioprine. 123I-SAP scintigraphy performed soon after transplantation showed extensive amyloid deposits in the spleen and adrenal glands, but as is frequently the case in end-stage renal failure, the patient’s own kidneys were not visible. Subsequently, the Crohn’s disease has been inactive clinically, and serial plasma levels of C reactive protein and serum amyloid A (SAA) protein have been completely normal. Follow-up 123ISAP scans have shown regression of amyloid and no deposition in the transplanted kidney (Figure 1).
Patient 2 A 16-year-old boy presented in 1983 with acute watery diarrhea, anorexia, weight loss, aphthous ulceration, symmetrical peripheral arthropathy, and erythema nodosum. Barium enema and the rectal biopsy specimen were normal, but barium follow-through suggested terminal ileitis and a clinical diagnosis of Crohn’s disease was made. The gastrointestinal symptoms responded well to oral prednisolone and sulfasalazine during the next 4 years, but the arthropathy persisted and sedimentation rate remained elevated at between 40 and 100 mm in the first hour. In March 1990, the patient developed acute renal failure and the renal biopsy specimen showed amyloid (Table 1). He underwent cadaveric renal transplantation within 6
Case Reports Patient 1 A 9-year-old boy presented in 1962 with diarrhea and erythema nodosum. Seven years later, after persistently loose
/ 5e1b$$0021
03-14-97 01:31:02
gasa
Abbreviations used in this paper: AA, amyloid A; SAA, serum amyloid A; SAP, serum amyloid P component. q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
WBS-Gastro
April 1997
AA AMYLOIDOSIS IN CROHN’S DISEASE 1363
Table 1. Features in 4 Patients With Crohn’s Disease Who Developed Systemic AA Amyloidosis and Renal Failure Patient 1
Patient 2
Patient 3
Patient 4
Sex Age at diagnosis of Crohn’s disease ( yr ) Duration of Crohn’s disease when amyloid diagnosed ( yr ) Clinical presentation of systemic amyloidosis Time between diagnosis of amyloidosis and end-stage renal failure ( yr ) Site of amyloid deposition at initial SAP scintigraphy Acute-phase response after initial scintigraphy Evolution of deposits at serial SAP scintigraphy
M 15
M 16
M 25
F 37
24
7
1.5
21
Proteinuria (2.3 g/day)
Acute renal failure
Proteinuria (40 g/day)
Proteinuria (2.3 g/day)
5
0
10
1.5
S / Aa
S / Lb
S / Aa
S/K
None
Variable
None
Large
Substantial regression at 4 years
Substantial regression at 4 years
Progression at 1 yr
Follow-up postrenal transplantation ( yr )
6 (Still alive)
Regression at 2 years, reaccumulation at 4 years 6 (Still alive)
11 (Still alive)
Died while receiving hemodialysis
A, adrenals; K, kidneys; L, liver; S, spleen. a Kidneys not visible because patient already had end-stage renal failure. b Kidneys not visible because patient already had end-stage renal failure. Adrenals were obscured by massive uptake of tracer to deposits in liver and spleen.
months and received prednisolone and cyclosporine as antirejection therapy. 123I-SAP scanning after transplantation showed extensive amyloid deposition in the spleen and liver, obscuring evaluation of the native kidneys (Figure 2A). Subsequently, the Crohn’s disease has remained in clinical remission but plasma levels of SAA have remained moderately and variably elevated. Follow-up SAP scans initially showed regression of amyloid, but subsequently there has been some reaccumulation (Figure 2B and C). Data from 2 additional patients are summarized in Table 1.
Figure 1. Case 1, renal transplant 1990. (A) Anterior (left) and (B ) posterior (right) whole-body scintigraphy 24 hours after IV injection of 123 I-labeled SAP in 1990. There is massive abnormal uptake of tracer in the spleen and in the adrenal glands, indicating advanced amyloidosis. There is very little blood-pool background signal. (B) Followup scans in 1994 show much less specific uptake of tracer into the amyloidotic organs and much more unbound tracer in the circulation, indicating substantial regression of amyloid. The intensity of uptake into the transplanted kidney (seen in the left, anterior image) is the same as the blood-pool background, excluding graft amyloidosis.
/ 5e1b$$0021
03-14-97 01:31:02
gasa
Discussion Systemic AA amyloidosis is caused by extracellular deposition of the N-terminal AA fragment of the circulating acute-phase plasma protein SAA in an abnormal fibrillar form. AA amyloidosis can complicate any
Figure 2. Case 2, renal transplant 1990. Serial anterior whole-body 123 I-SAP scans performed in (A) 1991, (B) 1992, and (C) 1994. The initial study shows massive amounts of amyloid in the liver and spleen, which had regressed substantially (particularly that in the liver) at follow-up. Subsequently, there has been reaccumulation of both hepatic and splenic amyloid but no involvement of the transplanted kidney. Concurrently, the relative intensity of the blood-pool background initially increased and then decreased. The findings in this patient highlight the dynamic nature of amyloid deposition and regression, which, furthermore, also varies in different anatomic sites.
WBS-Gastro
1364 LOVAT ET AL.
GASTROENTEROLOGY Vol. 112, No. 4
inflammatory or infective condition in which there is a sustained acute-phase response including Crohn’s disease, rheumatoid arthritis, and chronic sepsis.1 In contrast, in inflammatory disorders characterized by modest or absent acute-phase responses, such as ulcerative colitis or systemic lupus erythematosus, amyloidosis is very rare.5 – 8 There is wide geographical variation in the incidence of AA amyloid, occurring in 6% of patients with Crohn’s disease in northern Europe,9,10 2% in England,11 but only 0.5% in the United States.8 The frequency of AA amyloidosis complicating other inflammatory illnesses shows a similar geographical variation, but the underlying mechanisms are not clear. In addition, little is known about the factors that determine the anatomic distribution and clinical effects of the amyloid deposits and the highly variable latency between onset of inflammatory disease and development of AA amyloidosis. All our patients presented with proteinuria or renal failure as do 95% of patients with AA amyloidosis.12,13 Therefore, regular urinary dipstick testing for proteinuria is an important aid to early diagnosis. Confirmation of amyloid has hitherto required histological proof, but although renal biopsy specimens are almost always diagnostic, rectal biopsy specimens and other screening tests may be negative in 50% of cases in routine practice. Rectal biopsy diagnostic sensitivity can be increased by obtaining adequate submucosa in the biopsy specimen, but inexperience in histochemical processing and interpretation causes many false-negative results. Furthermore, biopsy specimens can never show the quantity or distribution of amyloid deposits in the body. In contrast, 123 I-SAP scintigraphy has a diagnostic yield for amyloid of almost 100% in AA amyloidosis,14 and because of the specific reversible nature of the interaction between SAP and amyloid fibrils, it can be used repeatedly to monitor serially the amyloid regardless of whether the deposits are accumulating, in steady state, or regressing.15 Although SAP scintigraphy is currently available at only a few centers, we have lately succeeded in radiolabeling SAP with 99mTc, which should improve availability of the technique in due course.16 It has long been known that active inflammatory disease causing persistently high serum levels of SAA is associated with progressive AA amyloidosis,17 and, conversely, occasional cases of clinical improvement suggesting amyloid regression have been reported in patients in whom the underlying disease has remitted.18 With the introduction of SAP scintigraphy, net accumulation of amyloid has been shown in most patients whose underlying inflammatory disorder remains active, and substantial and fairly rapid regression of amyloid has been shown in about one half of patients whose underlying acute/ 5e1b$$0021
03-14-97 01:31:02
gasa
phase response is controlled.19 AA amyloidosis is evidently a dynamic process, but the natural history of the underlying diseases that cause it favors accumulation of the deposits. Also, serial SAP scintigraphy has shown regression of amyloid in other forms of systemic amyloidosis after treatments that correct the underlying metabolic abnormalities. These include systemic AL amyloidosis after chemotherapy that reduces production of monoclonal immunoglobulin light chains,3,20 dialysisrelated amyloidosis after renal transplantation,21 and familial amyloid polyneuropathy after orthotopic liver transplantation.22,23 However, there is a poor and inconsistent correlation between the quantity of amyloid and the degree of resulting organ dysfunction, and the rate of amyloid regression is highly variable. In the absence of any direct therapy that promotes mobilization of amyloid, a vital objective in AA amyloidosis is to reduce the supply of the amyloid fibril precursor SAA; frequent estimation of the plasma SAA is therefore highly desirable.24 In Crohn’s disease, suppression of the acute-phase response may require aggressive anti-inflammatory therapy or surgery to remove segments of diseased bowel. However, conservative management is best because of increased bleeding and poor healing of amyloidotic tissue and because amyloidotic kidneys are exquisitely sensitive to episodes of reduced perfusion. It is now clear that aggressive anti-inflammatory therapy can improve survival and preserve organ function in AA amyloidosis associated with many conditions.2,12 The acute-phase response was abolished completely in two of our renal transplant patients treated with immunosuppressive therapy and was associated with impressive regression of amyloid. Late reaccumulation of amyloid in the third case highlights the need to monitor serum SAA levels indefinitely in patients with AA amyloidosis and consider increasing anti-inflammatory therapy even when there is no clinical evidence of disease activity. However, even in this case, there has been no evidence of amyloid deposition in the transplanted kidney. Renal transplantation may offer the best prospect for patients with Crohn’s disease who develop amyloidosis and end-stage renal failure.
References 1. Pepys MB. Amyloidosis. In: Frank MM, Austen KF, Claman HN, Unanue ER, eds. Samter’s immunologic diseases. 5th ed. Boston: Little, Brown, 1994:637–655. 2. David J, Vouyiouka O, Ansell BM, Hall A, Woo P. Amyloidosis in juvenile chronic arthritis: a morbidity and mortality study. Clin Exp Rheumatol 1993;11:85–90. 3. Hawkins PN, Richardson S, MacSweeney JE, King AD, Vigushin DM, Lavender JP, Pepys MB. Scintigraphic quantification and serial monitoring of human visceral amyloid deposits provide
WBS-Gastro
April 1997
4.
5.
6.
7.
8.
9.
10. 11. 12. 13.
14.
15. 16.
AA AMYLOIDOSIS IN CROHN’S DISEASE 1365
evidence for turnover and regression. Q J Med 1993;86:365– 374. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med 1990;323:508–513. Fagan EA, Dyck RF, Maton PN, Hodgson HJF, Chadwick VS, Pepys MB. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur J Clin Invest 1982;12:351–360. de Beer FC, Mallya RK, Fagan EA, Lanham JG, Hughes GRV, Pepys MB. Serum amyloid A protein (SAA) concentration in inflammatory diseases and its relationship to the incidence of reactive systemic amyloidosis. Lancet 1982;ii:231–234. Saverymuttu SH, Hodgson HJF, Chadwick VS, Pepys MB. Differing acute phase responses in Crohn’s disease and ulcerative colitis. Gut 1986;27:809–813. Greenstein AJ, Sachar DB, Panday AK, Dikman SH, Meyers S, Heimann T, Gumaste V, Werther JL, Janowitz HD. Amyloidosis and inflammatory bowel disease: a fifty year experience with 25 patients. Med Baltimore 1992;71:261–270. Weterman IT, Biemond I, Pena AS. Mortality and causes of death in Crohn’s disease. Review of 50 years’ experience in Leiden University Hospital. Gut 1990;31:1387–1390. Lind E, Fausa O, Elgjo K, Gjone E. Crohn’s disease. Clinical manifestations. Scand J Gastroenterol 1985;20:665–670. Cooke WT, Mallas E, Prior P. Crohn’s disease: course, treatment and long term prognosis. Q J Med 1980;49:363–384. Schnitzer TJ, Ansell BM. Amyloidosis in juvenile chronic polyarthritis. Arthritis Rheum 1977;20:245–252. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Med Baltimore 1991;70:246– 256. Hawkins PN, Richardson S, Vigushin DM, David J, Kelsey CR, Gray RES, Hall MA, Woo P, Lavender JP, Pepys MB. Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis. Arthritis Rheum 1993;36:842–851. Hawkins PN, Pepys MB. Imaging amyloidosis with radiolabelled SAP. Eur J Nucl Med 1995;22:595–599. Hutchinson WL, Mather SJ, Staltieri M, Noble GE, Vigushin DM, Tan SY, Seymour A, Pepys MB, Hawkins PN. Scintigraphic imaging of amyloid deposits with 99mTc-labelled serum amyloid P component. In: Kisilevsky R, Benson MD, Frangione B, Gauldie
/ 5e1b$$0021
03-14-97 01:31:02
gasa
17.
18.
19.
20.
21.
22.
23.
24.
J, Muckle TJ, Young ID, eds. Amyloid and amyloidosis 1993. Pearl River, NY: Parthenon, 1994:682–684. Maury CP, Wegelius O. Clinical value of serum amyloid A and Creactive protein measurements in secondary amyloidosis. Int J Tissue React 1985;7:405–407. Mandelstam P, Simmons DE, Mitchell B. Regression of amyloid in Crohn’s disease after bowel resection. J Clin Gastroenterol 1989;11:324–326. Hawkins PN. Studies with radiolabelled serum amyloid P component provide evidence for turnover and regression of amyloid deposits in vivo. Clin Sci 1994;87:289–295. Hawkins PN, Vigushin DM, Richardson S, Seymour A, Pepys MB. Evaluation of 100 cases of systemic AL amyloidosis by serum amyloid P component (SAP) scintigraphy. In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle TJ, Young ID, eds. Amyloid and amyloidosis 1993. Pearl River, NY: Parthenon, 1994:209– 211. Tan SY, Irish A, Winearls CG, Brown EA, Gower PE, Clutterbuck EJ, Madhoo S, Lavender JP, Pepys MB, Hawkins PN. Long-term effect of renal transplantation on dialysis-related amyloid deposits and symptomatology. Kidney Int 1996;50:282–289. Holmgren G, Ericzon B-G, Groth C-G, Steen L, Suhr O, Andersen O, Wallin BG, Seymour A, Richardson S, Hawkins PN, Pepys MB. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993; 341:1113–1116. Holmgren G, Steen L, Ekstedt J, Groth C-G, Ericzon B-G, Eriksson S, Andersen O, Karlberg I, Norden G, Nakazato M, Hawkins P, Richardson S, Pepys M. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 1991;40:242–246. Wilkins J, Gallimore JR, Tennent GA, Hawkins PN, Limburg PC, van Rijswijk MH, Moore EG, Pepys MB. Rapid automated enzyme immunoassay of serum amyloid A. Clin Chem 1994;40:1284– 1290.
Received March 20, 1996. Accepted November 21, 1996. Address requests for reprints to: Philip N. Hawkins, M.D., Immunological Medicine Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 0NN, England. Fax: (44) 181-383-2118. Supported by the MRC Programme grant G7900510 (M.B.P. and P.N.H.) and MRC Research Training Fellowship (L.B.L.)
WBS-Gastro
CASE REPORTS Long-term Survival in Systemic Amyloid A Amyloidosis Complicating Crohn’s Disease LAURENCE B. LOVAT, SHERIL MADHOO, MARK B. PEPYS, and PHILIP N. HAWKINS Immunological Medicine Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England
Systemic AA amyloidosis is a serious and potentially fatal complication of Crohn’s disease. Proteinuria is the most common presentation, but the diagnosis can only be confirmed by showing amyloid in the tissues and is often delayed. Recently, scintigraphy has been developed using 123I–serum amyloid P component (SAP) as a noninvasive and quantitative alternative to histology in which this nuclear medicine tracer specifically targets amyloid deposits in vivo. This study investigates 4 patients with Crohn’s disease who, despite having only low-grade clinical activity, developed progressive AA amyloidosis and renal failure. One patient died while receiving hemodialysis, but in the other 3 cases, renal transplantation and standard antirejection therapy were associated with remission of inflammatory activity. Serial SAP scintigraphy showed regression of amyloid in 2 of these patients and absence of progression in the other. These case studies show the dynamic but variable behavior of AA deposits in different patients and show the use of radiolabeled SAP for diagnosis and monitoring of amyloidosis in Crohn’s disease.
S
ystemic AA amyloidosis occurs in up to 6% of patients with chronic inflammatory disorders such as Crohn’s disease or any condition that is associated with a sustained acute-phase response.1 The diagnosis can only be confirmed by showing amyloid deposits in the tissues and frequently remains unrecognized until a late stage. The prognosis is poor, but treatment that suppresses the acute-phase response can lead to regression of amyloid, preservation or improvement of function of affected organs, and long-term survival.2,3 Radiolabeled serum amyloid P component (SAP) has been developed as a diagnostic tracer in amyloidosis,4 and we report its use in this study for the diagnosis and quantitative monitoring of AA amyloid deposits in 4 patients with Crohn’s disease.
bowel movements and onset of a large joint arthropathy, histological confirmation of Crohn’s disease was obtained at appendectomy. Postoperative barium enema showed severe rightsided colitis necessitating right hemicolectomy 3 weeks later. Clinically, the disease was controlled for more than 10 years on low-dose prednisolone, which was withdrawn eventually. He required a further laparotomy for division of adhesions in 1972, at which time the terminal ileum was thickened. In 1983, he became hypertensive and developed proteinuria (Table 1); although amyloid was suspected, rectal biopsy specimen was reported as normal. The proteinuria persisted and amyloid was confirmed by the renal biopsy specimen 18 months later. End-stage renal failure supervened, and in 1990, he received a renal transplant from a live related donor. Antirejection treatment has comprised prednisolone, cyclosporine, and azathioprine. 123I-SAP scintigraphy performed soon after transplantation showed extensive amyloid deposits in the spleen and adrenal glands, but as is frequently the case in end-stage renal failure, the patient’s own kidneys were not visible. Subsequently, the Crohn’s disease has been inactive clinically, and serial plasma levels of C reactive protein and serum amyloid A (SAA) protein have been completely normal. Follow-up 123ISAP scans have shown regression of amyloid and no deposition in the transplanted kidney (Figure 1).
Patient 2 A 16-year-old boy presented in 1983 with acute watery diarrhea, anorexia, weight loss, aphthous ulceration, symmetrical peripheral arthropathy, and erythema nodosum. Barium enema and the rectal biopsy specimen were normal, but barium follow-through suggested terminal ileitis and a clinical diagnosis of Crohn’s disease was made. The gastrointestinal symptoms responded well to oral prednisolone and sulfasalazine during the next 4 years, but the arthropathy persisted and sedimentation rate remained elevated at between 40 and 100 mm in the first hour. In March 1990, the patient developed acute renal failure and the renal biopsy specimen showed amyloid (Table 1). He underwent cadaveric renal transplantation within 6
Case Reports Patient 1 A 9-year-old boy presented in 1962 with diarrhea and erythema nodosum. Seven years later, after persistently loose
/ 5e1b$$0021
03-14-97 01:31:02
gasa
Abbreviations used in this paper: AA, amyloid A; SAA, serum amyloid A; SAP, serum amyloid P component. q 1997 by the American Gastroenterological Association 0016-5085/97/$3.00
WBS-Gastro
April 1997
AA AMYLOIDOSIS IN CROHN’S DISEASE 1363
Table 1. Features in 4 Patients With Crohn’s Disease Who Developed Systemic AA Amyloidosis and Renal Failure Patient 1
Patient 2
Patient 3
Patient 4
Sex Age at diagnosis of Crohn’s disease ( yr ) Duration of Crohn’s disease when amyloid diagnosed ( yr ) Clinical presentation of systemic amyloidosis Time between diagnosis of amyloidosis and end-stage renal failure ( yr ) Site of amyloid deposition at initial SAP scintigraphy Acute-phase response after initial scintigraphy Evolution of deposits at serial SAP scintigraphy
M 15
M 16
M 25
F 37
24
7
1.5
21
Proteinuria (2.3 g/day)
Acute renal failure
Proteinuria (40 g/day)
Proteinuria (2.3 g/day)
5
0
10
1.5
S / Aa
S / Lb
S / Aa
S/K
None
Variable
None
Large
Substantial regression at 4 years
Substantial regression at 4 years
Progression at 1 yr
Follow-up postrenal transplantation ( yr )
6 (Still alive)
Regression at 2 years, reaccumulation at 4 years 6 (Still alive)
11 (Still alive)
Died while receiving hemodialysis
A, adrenals; K, kidneys; L, liver; S, spleen. a Kidneys not visible because patient already had end-stage renal failure. b Kidneys not visible because patient already had end-stage renal failure. Adrenals were obscured by massive uptake of tracer to deposits in liver and spleen.
months and received prednisolone and cyclosporine as antirejection therapy. 123I-SAP scanning after transplantation showed extensive amyloid deposition in the spleen and liver, obscuring evaluation of the native kidneys (Figure 2A). Subsequently, the Crohn’s disease has remained in clinical remission but plasma levels of SAA have remained moderately and variably elevated. Follow-up SAP scans initially showed regression of amyloid, but subsequently there has been some reaccumulation (Figure 2B and C). Data from 2 additional patients are summarized in Table 1.
Figure 1. Case 1, renal transplant 1990. (A) Anterior (left) and (B ) posterior (right) whole-body scintigraphy 24 hours after IV injection of 123 I-labeled SAP in 1990. There is massive abnormal uptake of tracer in the spleen and in the adrenal glands, indicating advanced amyloidosis. There is very little blood-pool background signal. (B) Followup scans in 1994 show much less specific uptake of tracer into the amyloidotic organs and much more unbound tracer in the circulation, indicating substantial regression of amyloid. The intensity of uptake into the transplanted kidney (seen in the left, anterior image) is the same as the blood-pool background, excluding graft amyloidosis.
/ 5e1b$$0021
03-14-97 01:31:02
gasa
Discussion Systemic AA amyloidosis is caused by extracellular deposition of the N-terminal AA fragment of the circulating acute-phase plasma protein SAA in an abnormal fibrillar form. AA amyloidosis can complicate any
Figure 2. Case 2, renal transplant 1990. Serial anterior whole-body 123 I-SAP scans performed in (A) 1991, (B) 1992, and (C) 1994. The initial study shows massive amounts of amyloid in the liver and spleen, which had regressed substantially (particularly that in the liver) at follow-up. Subsequently, there has been reaccumulation of both hepatic and splenic amyloid but no involvement of the transplanted kidney. Concurrently, the relative intensity of the blood-pool background initially increased and then decreased. The findings in this patient highlight the dynamic nature of amyloid deposition and regression, which, furthermore, also varies in different anatomic sites.
WBS-Gastro
1364 LOVAT ET AL.
GASTROENTEROLOGY Vol. 112, No. 4
inflammatory or infective condition in which there is a sustained acute-phase response including Crohn’s disease, rheumatoid arthritis, and chronic sepsis.1 In contrast, in inflammatory disorders characterized by modest or absent acute-phase responses, such as ulcerative colitis or systemic lupus erythematosus, amyloidosis is very rare.5 – 8 There is wide geographical variation in the incidence of AA amyloid, occurring in 6% of patients with Crohn’s disease in northern Europe,9,10 2% in England,11 but only 0.5% in the United States.8 The frequency of AA amyloidosis complicating other inflammatory illnesses shows a similar geographical variation, but the underlying mechanisms are not clear. In addition, little is known about the factors that determine the anatomic distribution and clinical effects of the amyloid deposits and the highly variable latency between onset of inflammatory disease and development of AA amyloidosis. All our patients presented with proteinuria or renal failure as do 95% of patients with AA amyloidosis.12,13 Therefore, regular urinary dipstick testing for proteinuria is an important aid to early diagnosis. Confirmation of amyloid has hitherto required histological proof, but although renal biopsy specimens are almost always diagnostic, rectal biopsy specimens and other screening tests may be negative in 50% of cases in routine practice. Rectal biopsy diagnostic sensitivity can be increased by obtaining adequate submucosa in the biopsy specimen, but inexperience in histochemical processing and interpretation causes many false-negative results. Furthermore, biopsy specimens can never show the quantity or distribution of amyloid deposits in the body. In contrast, 123 I-SAP scintigraphy has a diagnostic yield for amyloid of almost 100% in AA amyloidosis,14 and because of the specific reversible nature of the interaction between SAP and amyloid fibrils, it can be used repeatedly to monitor serially the amyloid regardless of whether the deposits are accumulating, in steady state, or regressing.15 Although SAP scintigraphy is currently available at only a few centers, we have lately succeeded in radiolabeling SAP with 99mTc, which should improve availability of the technique in due course.16 It has long been known that active inflammatory disease causing persistently high serum levels of SAA is associated with progressive AA amyloidosis,17 and, conversely, occasional cases of clinical improvement suggesting amyloid regression have been reported in patients in whom the underlying disease has remitted.18 With the introduction of SAP scintigraphy, net accumulation of amyloid has been shown in most patients whose underlying inflammatory disorder remains active, and substantial and fairly rapid regression of amyloid has been shown in about one half of patients whose underlying acute/ 5e1b$$0021
03-14-97 01:31:02
gasa
phase response is controlled.19 AA amyloidosis is evidently a dynamic process, but the natural history of the underlying diseases that cause it favors accumulation of the deposits. Also, serial SAP scintigraphy has shown regression of amyloid in other forms of systemic amyloidosis after treatments that correct the underlying metabolic abnormalities. These include systemic AL amyloidosis after chemotherapy that reduces production of monoclonal immunoglobulin light chains,3,20 dialysisrelated amyloidosis after renal transplantation,21 and familial amyloid polyneuropathy after orthotopic liver transplantation.22,23 However, there is a poor and inconsistent correlation between the quantity of amyloid and the degree of resulting organ dysfunction, and the rate of amyloid regression is highly variable. In the absence of any direct therapy that promotes mobilization of amyloid, a vital objective in AA amyloidosis is to reduce the supply of the amyloid fibril precursor SAA; frequent estimation of the plasma SAA is therefore highly desirable.24 In Crohn’s disease, suppression of the acute-phase response may require aggressive anti-inflammatory therapy or surgery to remove segments of diseased bowel. However, conservative management is best because of increased bleeding and poor healing of amyloidotic tissue and because amyloidotic kidneys are exquisitely sensitive to episodes of reduced perfusion. It is now clear that aggressive anti-inflammatory therapy can improve survival and preserve organ function in AA amyloidosis associated with many conditions.2,12 The acute-phase response was abolished completely in two of our renal transplant patients treated with immunosuppressive therapy and was associated with impressive regression of amyloid. Late reaccumulation of amyloid in the third case highlights the need to monitor serum SAA levels indefinitely in patients with AA amyloidosis and consider increasing anti-inflammatory therapy even when there is no clinical evidence of disease activity. However, even in this case, there has been no evidence of amyloid deposition in the transplanted kidney. Renal transplantation may offer the best prospect for patients with Crohn’s disease who develop amyloidosis and end-stage renal failure.
References 1. Pepys MB. Amyloidosis. In: Frank MM, Austen KF, Claman HN, Unanue ER, eds. Samter’s immunologic diseases. 5th ed. Boston: Little, Brown, 1994:637–655. 2. David J, Vouyiouka O, Ansell BM, Hall A, Woo P. Amyloidosis in juvenile chronic arthritis: a morbidity and mortality study. Clin Exp Rheumatol 1993;11:85–90. 3. Hawkins PN, Richardson S, MacSweeney JE, King AD, Vigushin DM, Lavender JP, Pepys MB. Scintigraphic quantification and serial monitoring of human visceral amyloid deposits provide
WBS-Gastro
April 1997
4.
5.
6.
7.
8.
9.
10. 11. 12. 13.
14.
15. 16.
AA AMYLOIDOSIS IN CROHN’S DISEASE 1365
evidence for turnover and regression. Q J Med 1993;86:365– 374. Hawkins PN, Lavender JP, Pepys MB. Evaluation of systemic amyloidosis by scintigraphy with 123I-labeled serum amyloid P component. N Engl J Med 1990;323:508–513. Fagan EA, Dyck RF, Maton PN, Hodgson HJF, Chadwick VS, Pepys MB. Serum levels of C-reactive protein in Crohn’s disease and ulcerative colitis. Eur J Clin Invest 1982;12:351–360. de Beer FC, Mallya RK, Fagan EA, Lanham JG, Hughes GRV, Pepys MB. Serum amyloid A protein (SAA) concentration in inflammatory diseases and its relationship to the incidence of reactive systemic amyloidosis. Lancet 1982;ii:231–234. Saverymuttu SH, Hodgson HJF, Chadwick VS, Pepys MB. Differing acute phase responses in Crohn’s disease and ulcerative colitis. Gut 1986;27:809–813. Greenstein AJ, Sachar DB, Panday AK, Dikman SH, Meyers S, Heimann T, Gumaste V, Werther JL, Janowitz HD. Amyloidosis and inflammatory bowel disease: a fifty year experience with 25 patients. Med Baltimore 1992;71:261–270. Weterman IT, Biemond I, Pena AS. Mortality and causes of death in Crohn’s disease. Review of 50 years’ experience in Leiden University Hospital. Gut 1990;31:1387–1390. Lind E, Fausa O, Elgjo K, Gjone E. Crohn’s disease. Clinical manifestations. Scand J Gastroenterol 1985;20:665–670. Cooke WT, Mallas E, Prior P. Crohn’s disease: course, treatment and long term prognosis. Q J Med 1980;49:363–384. Schnitzer TJ, Ansell BM. Amyloidosis in juvenile chronic polyarthritis. Arthritis Rheum 1977;20:245–252. Gertz MA, Kyle RA. Secondary systemic amyloidosis: response and survival in 64 patients. Med Baltimore 1991;70:246– 256. Hawkins PN, Richardson S, Vigushin DM, David J, Kelsey CR, Gray RES, Hall MA, Woo P, Lavender JP, Pepys MB. Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis. Arthritis Rheum 1993;36:842–851. Hawkins PN, Pepys MB. Imaging amyloidosis with radiolabelled SAP. Eur J Nucl Med 1995;22:595–599. Hutchinson WL, Mather SJ, Staltieri M, Noble GE, Vigushin DM, Tan SY, Seymour A, Pepys MB, Hawkins PN. Scintigraphic imaging of amyloid deposits with 99mTc-labelled serum amyloid P component. In: Kisilevsky R, Benson MD, Frangione B, Gauldie
/ 5e1b$$0021
03-14-97 01:31:02
gasa
17.
18.
19.
20.
21.
22.
23.
24.
J, Muckle TJ, Young ID, eds. Amyloid and amyloidosis 1993. Pearl River, NY: Parthenon, 1994:682–684. Maury CP, Wegelius O. Clinical value of serum amyloid A and Creactive protein measurements in secondary amyloidosis. Int J Tissue React 1985;7:405–407. Mandelstam P, Simmons DE, Mitchell B. Regression of amyloid in Crohn’s disease after bowel resection. J Clin Gastroenterol 1989;11:324–326. Hawkins PN. Studies with radiolabelled serum amyloid P component provide evidence for turnover and regression of amyloid deposits in vivo. Clin Sci 1994;87:289–295. Hawkins PN, Vigushin DM, Richardson S, Seymour A, Pepys MB. Evaluation of 100 cases of systemic AL amyloidosis by serum amyloid P component (SAP) scintigraphy. In: Kisilevsky R, Benson MD, Frangione B, Gauldie J, Muckle TJ, Young ID, eds. Amyloid and amyloidosis 1993. Pearl River, NY: Parthenon, 1994:209– 211. Tan SY, Irish A, Winearls CG, Brown EA, Gower PE, Clutterbuck EJ, Madhoo S, Lavender JP, Pepys MB, Hawkins PN. Long-term effect of renal transplantation on dialysis-related amyloid deposits and symptomatology. Kidney Int 1996;50:282–289. Holmgren G, Ericzon B-G, Groth C-G, Steen L, Suhr O, Andersen O, Wallin BG, Seymour A, Richardson S, Hawkins PN, Pepys MB. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993; 341:1113–1116. Holmgren G, Steen L, Ekstedt J, Groth C-G, Ericzon B-G, Eriksson S, Andersen O, Karlberg I, Norden G, Nakazato M, Hawkins P, Richardson S, Pepys M. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP-met30). Clin Genet 1991;40:242–246. Wilkins J, Gallimore JR, Tennent GA, Hawkins PN, Limburg PC, van Rijswijk MH, Moore EG, Pepys MB. Rapid automated enzyme immunoassay of serum amyloid A. Clin Chem 1994;40:1284– 1290.
Received March 20, 1996. Accepted November 21, 1996. Address requests for reprints to: Philip N. Hawkins, M.D., Immunological Medicine Unit, Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, Du Cane Road, London W12 0NN, England. Fax: (44) 181-383-2118. Supported by the MRC Programme grant G7900510 (M.B.P. and P.N.H.) and MRC Research Training Fellowship (L.B.L.)
WBS-Gastro