Renal amyloidosis as a late complication of Crohn's disease: a case report and review of the literature from Japan

Abstract

Key Words: Crohn's disease/complication; renal amyloidosis; amyloid deposits

INTRODUCTION

Secondary amyloidosis is a rare but serious complication of Crohn's disease (CD). The incidence of the association of secondary amyloidosis in patients with CD has been reported to be 0.5%-8% in Western countries[1-6]. However, in Japan, the number of patients with CD complicated by amyloidosis is limited. The characteristics of their clinical manifestations and the incidence of association are uncertain. Therefore, we report herein a patient with Crohn's disease who developed amyloidosis 13 years after the onset of CD. The diagnosis of renal amyloidosis was confirmed by renal biopsy. We also reviewed the literature concerning amyloidosis associated with CD in Japan.

CASE REPORT

The patient was a 29-year-old Japanese female. In May 1985, at the age of 14, she developed diarrhea. In March 1986, she developed fever and arthralgia. A diagnosis of CD was made by endoscopic and radiographic examinations. Thereafter, she received corticosteroids and sulfasalazine. However, hospitaliz ation was required several times. In May 1993, severe stenosis of the ascending colon was found as shown in Figure 1. Therefore, subtotal colectomy, ileocecal resection, and ileosigmoid anastomosis were performed. As shown in Figure 2, surgical specimen of the terminal ileum, cecum, and ascending colon (May 26, 1993) showed thickening of the bowel wall, cobblestone appearance, and longitudinal ulceration. Histological findings showed transmural inflammation and noncaseating epithelioid cell granuloma. In February. 1997, the patient was admitted because of fever, anemia, and hypoproteinemia. As shown in Figure 3, gastrografin enema examination performed on May 8, 1997 showed a stricture around the ileosigmoid anastomosis. The anastomosis and part of the remaining ileum were resected because of the stenosis. Cholecystectomy was also performed because of gallstones (the biggest stone measured 11 mm ± 5 mm, five stones in total, pigmented). Immediately after surgery, right ureteral stricture due to retroperitoneal involvement was found and indwelling double J-catheter was placed. In August 1998, she was admitted because of anemia and hypoproteinemia. Her family history was unremarkable. Her height was 158 cm and body weight was 39.5 kg. Physical examination revealed marked pretibial edema. Laboratory findings included the followings: WBC 7.9 × 10⁹/L, RBC 2.25 × 10¹²/L, Hb-69 g/L, Ht 0.216, platelet 360 × 10⁹/L, total protein 53 g/L, albumin 11 g/L, CRP 8.9 mg/dL (normal: less than 0.25 mg/dL), serum amyloid A protein (SAA) 235 μg/dL (normal: less than 8 μg/dL), BUN 7.5 mmol/L, creatinine 145 μmol/L, creatinine clearance 0.38 mL/s, and urinary protein 9.3 g/d. Renal biopsy was performed in November 1998. As shown in Figure 4, amyloid deposition was found in the mesangial areas and blood vessels. The deposits were Congo red positive. The positive staining disappeared after pretreatment with potassium permanganate. The deposits immunoreacted with the antibody directed against amyloid A (AA)-amyloid. Colonoscopy revealed small discrete ulcerations around J-pouch. The amyloid deposition was not observed in the digestive tract. The electrocardiogram was normal. Ultrasonography did not show any abnormal findings in the heart. Thyroid was not swollen. Thyroid function tests were normal. Administration of prednisolone (40 mg/d) and 5-aminosalicylate (5-ASA) (2.25 g/d) normalized serum levels of acute phase protein such as CRP and SAA. However, massive proteinuria and hypoalbuminemia persisted. Then, when the dosage of prednisolone was reduced to 10 mg/d, serum CRP and amyloid A protein became positive. Thereafter, azathiopurine (50 mg/d) was administered in addition to 5-ASA (2.25 g/d) and prednisolone (10 mg/d).

Figure 1 Barium enema examination perfoemed on March 18, 1993. Stricture associated with cobblestone appearance was seen in the ascending colon. Small inflammatory polyps were observed in the transverse colon and descending colon.

Figure 2 Surgical specimen of the terminal ileum, cecum, and ascending colon (May 26, 1993). Thickening of the bowel wall, cobblestone appearance, and longitudinal ulceration were found, Histologically, transmur al inflammation and noncaseating epithelioid cell granuloma were found.

Figure 3 Gastrografin enema examination performed on May 8, 1997. A stricture was seen around the ileosigmoid anastomosis.

Figure 4 Findings of the renal biopsy. A: Histological findings (hematocylin and eosin). Amorphous, eosin-stained deposits were seen in the mesangial areas. B: Histological findings (Congo red stain). The deposits were Congo red positive. Congo red stain showed reddish pink deposits that demonstrated apple-green birefringence when examined under polarized light. C: Electron microscopic findings. Fine fibrils (8 to 10 nm in diameter) arranged randomly or in bundles were found in the mesangium.

The onset of CD in this patient was May 1985. Diagnosis was made in March 1986. Proteinuria developed in July 1997. Massive proteinuria developed in April 1998. Creatinine clearance was decreased in July 1997. Amyloid deposits were supposed to have already been present in mid 1997.

DISCUSSION

There is wide geographic variation in the incidence of secondary amyloidosis, occurring in 6%-8% of patients with CD in Northern Europe[2,4,5], 2% in England[3], but only 0.5%-0.9% in the United States[1,6]. However, in Japan, the incidence of secondary amyloidosis in patients with CD remains uncertain. Only 18 Japanese patients with CD complicated by secondary amyloidosis have been reported in the literature from Japan (Table 1)[7-22].

Table 1 Japanese Crohn's disease patients complicated by secondary amyloidosis.

Case	Age	Sex	Sites of CD	Duration of CD prior to amyloidosis diagnosis	Clinical course of CD before amyloidosis diagnosis	Major clinical manifestation of amyloidosis	type of amyloid	Proteinuria	Author (year)
1	23	M	I,C	6 year	Not well controlled	Intestinal	AA	Present	Oshima T et al[7] (1988)
2	28	M	I,C	9 year	Not well controlled	Renal	AA	Present	Tsutsui R et al[8] (1988)
3	37	M	I,C,R	11 year	Not well controlled	Renal	AA	Present	Araki T et al[9] (1989)
4	20	F	C	4 year	Not well controlled	Renal	AA	Present	Kikuchi H et al[10] (1989)
5	25	M	I	0#		Renal	AA	Present	Momiyama Y et al[11] (1989)
6	28	M	J,C	0		Renal	AA	Present	Takashima H et al[12] (1990)
7	24	M	I	0		Intestinal	AA	None	Itoh T et al[13] (1991)
8	44	M	I	8 year	Not well controlled	Intestinal	AA	None	Sakai Y et al[14] (1992)
9	26	M	I,C	13 year	Not well controlled	Renal	AA	Present	Ohwan T et al[15] (1994)
10	34	M	I,C	15 year	Unknown	Intestinal	AA	None	Yamamoto J et al[16] (1994)
11	28	M	I	12 year	Not well controlled	Renal	AA	Present	Itoh F et al[17] (1996)
12	28	M	I	7 year	Not well controlled	Renal	AA	Present	Itoh F et al[17] (1996)
13	26	M	C	4.5 year	Not well controlled	Renal	AA	Present	Yoshinaga Y et al[18] (1996)
14	43	M	C,R	15 year	Not well controlled	Renal	AA	Present	Yoshinaga Y et al[18] (1996)
15	21	M	I,C	3.5 year	Not well controlled	Renal	AA	Present	Horie Y et al[19] (1997)
16	43	M	C,R	18 year	Not well controlled	Renal	AA	Present	Muro K et al[20] (1998)
17	35	F	C	0#		Renal	AA	Present	Taki F et al[21] (1998)
18	26	M	C	11 year	Unknown	Thyroid	AA	Present	Habu S et al[22] (1999)
19	29	F	I,C,R	13 year	Not well controlled	Renal	AA	Present	Present case (1999)

^#:The diagnosis of amyloidosis preceded that of Crohn's disease. CD: Crohn's disease, J: Jejunum, I: Ileum, C:colon, R: Rectum, AA: Amyloid A

Secondary amyloidosis is caused by extracellular deposition of the N-terminal AA fragment of the circulating acute phase plasma protein SAA. Secondary amyloidosis can complicate any inflammatory condition in which there is a sustained ac ute-phase response including CD, rheumatoid arthritis, and chronic sepsis. It h as been reported that the activity of the underlying inflammation is an important factor in the development and progression of secondary amyloidosis. In the 18 Japanese patients with CD complicated by amyloidosis, there were no patients who maintained prolonged remission. Therefore, in CD as well, the disease activity is considered an important factor in the development of secondary amyloidosis. In the present patient, surgery had already been performed two times as the disease activity could not be controlled by medical treatment. Nevertheless, serum CRP remained positive. Moreover, in the present patient, the involvement of the retroperitoneum caused right ureteral stricture.

Inflammation is thought to precede the development of secondary amyloidosis. However, the time-course and progression of secondary amyloidosis are not under stood well. In animal experiments, amyloid deposits were found 18 h or a few weeks after inflammatory stimuli[23-25]. Various factors have been reported to influence the susceptibility, onset, and progression of murine amyloidosis[26,27]. It remains controversial whether amyloidosis is a late complication of CD. In the present patient, nephrotic syndrome developed and the diagnosis of secondary amyloidosis was made 13 years after the onset of CD. When proteinuria was initially detected, it had already been 12 years since the onset of CD. In the literature, the time lapse between the onset of CD and the diagnosis of amyloidosis has been reported to range from 3 to 15 years or from 1 to 21 years[28,29]. In 11 of the 18 Japanese patients, more than 5 years had passed after the onset of CD. The longest period was 18 years. Conversely, in 2 patients, the diagnosis of amyloidosis preceded that of CD. When CD was diagnosed in these 2 patients, the lesion of CD had already become typical. These finding suggest that secondary amyloidosis usually occurs as a late complication of CD. However, as the onset of CD is usually gradual, CD and secondary amyloidosis may be diagnosed almost simultaneously.

The kidney is involved in the majority of patients with secondary amyloidosis. The resulting renal insufficiency caused a deterioration in the prognosis of the patient. Azathiopurine[30], colchicine[31,32], dimethylsulfoxide[33], and elemental diet[19] have been proposed as the treatment for secondary amyloidosis. However, the effectiveness of this regimen has not been established. Therefore, prevention or early diagnosis and treatment are important. In 15 of the 18 Japanese patients, the kidney was involved by amyloidosis. And in 13 of the 15 patients, renal involvement was t he main clinical manifestation of amyloidosis. In only one of the 15 patients[19], the amount of urinary protein decreased to less than 0.3 g/d since the initiation elemental diet therapy. In the remaining 14 patients, however, neither proteinuria nor impaired renal function improved after various therapeutic attempts.

Therefore, regular urine test for proteinuria would be useful for early diagnosis of amyloidosis regardless of the interval since onset of CD. To prevent the development and progression of secondary amyloidosis, it is probably important to maintain CD in the remission.

ACKNOWLEDGEMENTS

The authors thank the doctors of Osaka Medical College Hospital for their invaluable contributions to the study of this case.