CASE REPORT

Gastrointestinal Amyloidosis Secondary to

Hypersensitivity Vasculitis Presenting with

Intestinal Pseudoobstruction

KATSUSHI HIRAMATSU, MD, SHUICHI KANEKO, MD, YUKIHIRO SHIROTA, MD,

MITSURU MATSUDA, MD, KYOSUKE KAJI, MD, YOSIO KITANO, MD, NAOKI IKEDA, MD,

SHUICHI TERASAKI, MD, HIROSHI KAWAI, MD, ATSUSHI SHIMODA, MD,

HITOSHI YOKOYAMA, MD, EIKI MATSUSHITA, MD, TAKESHI URABE, MD,

and KENICHI KOBAYASHI, MD

KEY WORDS: gastrointestinal amyloidosis; hypersensitivity vasculitis; intestinal pseudoobstruction; amyloid A.

Hypersensitivity vasculitis is characte rized by in¯ am-

mation and necrosis of small blood vessels secondary

to allergic or hypersensitivity mechanisms (1, 2). Gas-

trointe stinal involve ment with edema and bleeding

also has been reported (3± 5).

Long-standing in¯ ammation, such as rheumatic

disease, infectious disease , in¯ ammatory bowe l dis-

ease , familial Mediterranean fever, and malignancy,

may lead to systemic amyloidosis (6). Gastrointe stinal

involve ment may induce anorexia, nausea and vomit-

ing, diarrhe a, constipation, bleeding, malabsorption,

and pseudoobstruction (6, 10 ± 12) .

In this report we discuss a patient with hypersensi-

tivity vasculitis with severe inte stinal bleeding who

deve lope d systemic amyloido sis with inte stinal

pseudoobstruction 29 months after onset. Secondary

amyloidosis due to hype rsensitivity vasculitis has not

been previously reported, and the causal relationship

is discussed in this report.

CASE REPORT

In August 1993, a 22-ye ar-old woman presented withlower abdominal pain. She was given antibiotic and anti-fungal drugs, based on working diagnosis of salpingitis. Thelower abdominal pain persisted, and fever and melenaoccurred. She was transferred to our hospital. The results ofthe laboratory examinations and abdominal computed to-mography (CT) indicated acute fatty liver with severe he-

patic cell dysfunction, and soon she manifested hepatic

encephalopathy. Afte r three whole plasma exchanges, her

liver function improved remarkably. However, her lower

abdominal pain, melena, and in¯ ammatory reaction per-

sisted. A vasculitis syndrome was suspected, and two

courses of methylprednisolone pulse therapy, each courseconsisting of a daily dose of 1000 mg for four days, were

administered. Abdominal angiography revealed bleeding

spots at the branch of the superior mesenteric artery, and a

selective transcatheter arterial embolization was per-formed, with improvement in the melena. After recovery,

hypersensitivity vasculitis was con® rmed by renal biopsy

(Figure 1). The liver biopsy specimens revealed macrove-sicular steatosis and hyalinosis of arterioles in the portal

tracts, representing organization of the vasculitis. Biopsy

specimens from the liver, kidney, stomach, and colon didnot show amyloid deposition. She was discharged in Janu-

ary 1994 on oral prednisolone (5± 10 mg/day) and was

followed for 27 months without any symptoms or in¯ am-

matory reaction.In January 1996, she began complaining of lower abdom-

inal fullness, tenderness, and nausea and vomiting. On

admission, she was normotensive without orthostasis. Thecardiac size was normal, and no heart murmurs were heard.

The abdomen was soft and ¯ at with lower abdominal ten-

derness and minimal bowel sounds. There was no palpable

liver, spleen, kidney, or masses. Stool examination wasnegative for blood. The laboratory examination on admis-

sion showed a red blood cell count of 4.2 3 106

cells/mm3,

a white blood cell count (WBC) of 7000 cells/mm3

with aleft shift, and a normal platelet count. Electrolytes, blood

glucose, liver, and renal function tests were normal. The

C-reactive protein (CRP) was positive (8.5 mg/dl), and the

erythrocyte sedimentation rate afte r 1 hr was 65 mm. Thetotal protein was 5.2 g/dl, and the albumin was 2.6 g/dl.

Anti-nuclear antibody, anti-DNA antibody, cytoplasmic

pattern anti-neutrophil cytoplasmic antibodies, perinuclearpattern anti-neutrophil cytoplasmic antibodies, and cryo-

Manuscript receive d July 31, 1997; accepte d February 25, 1998.From the First Department of Internal Medicine, Kanazawa

Unive rsity School of Medicine , Kanazawa, Japan.Address for reprint requests: Katsushi Hiramatsu, First Depart-

ment of Internal Medicine, Kanazawa Unive rsity School of Medi-cine , 13-1, Takaramachi, Kanazawa, Ishikawa 920, Japan.

Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998), pp. 1824 ± 1830

1824 Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998)

0163-2116/98/0800-1824$15.00/0 Ñ 1998 Plenum Publishing Corporation

Fig 2. A plain abdominal radiograph showing gase ous distension ofthe colon.

Fig 3. Gastrographin small intestine and colon series showing noobvious obstruction.

Fig 1. Renal biopsy specime n on ® rst admission, demonstrating the granulocytic in® ltration around the wall

of the arteriole. Hyalinizatoin is also seen in those areas and in the vascular pole of the glomerulus. H& Estain, magni® cation ( 3 100).

SECONDARY GASTROINTESTINAL AMYLOIDOSIS

globulin were all negative , and the complement leve l wasnormal. The urinalysis revealed mild proteinuria.

A plain abdominal radiograph showed gaseous distensionof the colon (Figure 2). Obvious obstruction was not de-tected in the gastrographin small intestine and colon series(Figure 3). The abdominal CT showed marked wall thick-ening of the small intestine. Endoscopic study showededematous changes of the gastric mucosa. Amyloid depositswere histologically demonstrated in the stomach (Figure 4Aand B) and rectum (Figure 5A and B). A renal biopsyrevealed amyloid deposits in the glomeruli, interstitium,

and vessels. Immunohistochemical study with anti-amyloidA ¯ uorescent antibody con® rmed that these systemic amy-loid deposits were secondary to an underlying disease (Fig-ure 6A± C). The clinical course and the histologic ® ndingsindicated that the hypersensitivity vasculitis resulted in sys-temic amyloid deposits and that gastrointestinal involve-ment led to pseudoobstruction.

The patient was treated with intravenous hyperalimenta-tion. The lower abdominal fullness, tenderness, and nauseaand vomiting continued, and three courses of methylpred-nisolone pulse therapy (1000 mg/day for three days) were

Fig 4. Gastric biopsy specime ns show amyloid deposits in the lamina propria mucosae . (A) H& E stain

( 3 100) ; (B) Congo red stain with polarized light ( 3 100) .

HIRAMATSU ET AL

1826 Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998)

administered successively with two courses of 500 mg forthree days. The parameters of in¯ ammatory reaction suchas CRP and WBC ¯ uctuated until two months afte r admis-sion, afte r which oral intake was started. No gastrointestinal

bleeding or pseudoobstruction occurred. The wall thicken-

ing of the small intestine, demonstrated by abdominal CT,

improved gradually.

DISCUSSION

Calabre se (7) propose d ® ve criteria for the diagno-sis of hypersensitivity vasculitis: age greater than 16

years at onse t, history of causative medication, pres-

ence of palpable purpura, presence of a maculopap-

ular rash, and a biopsy demonstrating granulocyte s

Fig 5. Rectal biopsy specime ns show amyloid deposits in the lamina propria mucosae . (A) H& E stain

( 3 100) ; (B) Congo red stain with polarized light ( 3 100).

SECONDARY GASTROINTESTINAL AMYLOIDOSIS

1827Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998)

around an arteriole or venule . Skin involve ment is

very common, and the disease may be limited to the

skin or there may be systemic involve ment of joints,

kidne ys, lungs, and gastrointe stinal tract (7). Abdom-

inal pain, nausea and vomiting, diarrhe a, and bleed-

ing have been reported as symptoms associate d with

gastrointe stinal tract involve ment.

It is often dif® cult to differentiate hype rsensitivity

vasculitis from other vascular diseases that affect

small blood vessels, such as Henoch-ShoÈ nle in pur-

pura, cryoglobuline mia, polyarte ritis nodosa, Churg-

Strauss syndrome , or Wegener’s granulomatosis (3, 5,

7). Although there were no skin manife stations, this

patient was diagnose d with hype rsensitivity vasculitis

Fig 6. Immunohistochemical study using anti-amyloid A ¯ uorescent antibody ( 3 400) showing positive stainin the glomerulus (A), the lamina propria mucosae of stomach (B), and the rectum (C).

HIRAMATSU ET AL

1828 Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998)

because of her age, history of antibiotic and antifun-

gal drug usage , pathologic ® ndings on renal biopsy,

and the absence of ® ndings that supported an alte r-native diagnosis. The presence of renal insuf® ciency

and gastrointe stinal bleeding were sugge stive of sys-

temic involve ment.

Systemic amyloidosis frequently involve s the gas-

trointe stinal tract and may cause anorexia, nausea

and vomiting, diarrhe a, constipation, bleeding, mal-

absorption, and pseudoobstruction (6, 10 ± 12) . Amy-

loid in® ltration in muscle and autonomic nerves has

been proposed as a factor that induces gastrointe sti-

nal motility dysfunction (13± 15) .

There are few reports of patients with amyloidosis

complicated by gastrointe stinal pseudoobstruction,that have include d pathologic ® ndings (16 ± 19) . Tada

et al (18) have shown that extensive in® ltration and

replacement of the muscularis propria by amyloid

deposits throughout the gastrointe stinal tract, espe-

cially the small inte stine, were found in amyloid L

(primary or myeloma-associated) and amyloid H (he-

modialysis-associat ed) cases; obstructive symptoms

were irreversible . However, amyloid deposits in the

myenteric plexus, without appre ciable muscle in® ltra-

tion, were shown in amyloid A (secondary) cases with

reversible symptoms. In our case , systemic amyloid A

deposition was found, and pseudoobstruction gradu-ally diminishe d after treatment with intrave nous hy-

peralimentation. These ® ndings suggest that amyloid

A deposits affect autonomic nerves in the gastrointe s-

tinal tract rather than the muscularis propria. Thus,

our case may support the sugge stion of Tada et al (18)

that the neuronal disorde r may be compensated to

some degree because the inte stines are richly inne r-

vated.

Amyloidosis secondary to hypersensitivity vasculitis

has not been previously reported. Tinaztepe et al (9)

have reported three cases of renal amyloidosis asso-

ciated with Henoch-SchoÈ nle in syndrome . Henoch-

SchoÈ nle in syndrome is dif® cult to differentiate from

hypersensitivity vasculitis (9) and is similar to our

case .

Secondary systemic amyloidosis can occur after

long-standing in¯ ammatory diseases such as rheu-

matic disease, infectious disease, and malignancy.

However, this patient did not show any clinical man-

ifestation of in¯ ammation after treatment for 29

months. There are two possible explanations for the

secondary amyloidosis in this patient. The patient

may have had a subclinical level of chronic in¯ amma-

tion. However, her blood tests were repeatedly neg-

ative for C-reactive prote in and leukocytosis. Anothe r

possibility is that an allergic reaction, often found in

patients with hype rsensitivity vasculitis, produce d

amyloid prote ins. In fact, Orriols et al (20) have

reported that alle rgic reactions provoke secondary

amyloidosis. Clearly, further study is necessary to

con® rm the causal relation between hype rsensitivity

vasculitis and secondary amyloidosis. Patients with

Fig 6. Continued.

SECONDARY GASTROINTESTINAL AMYLOIDOSIS

1829Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998)

hypersensitivity vasculitis should be carefully exam-

ined for the presence of systemic amyloidosis.

SUMMARY

A 22-ye ar-old woman developed sudden hepatic

encephalopathy and severe intestinal bleeding. She

was diagnose d with acute fatty liver and hypersensi-

tivity vasculitis and was successfully treated with

whole plasma exchange , methylpre dnisolone pulse

therapy, and transcathe ter arterial embolization.

Twenty-seven months later, she began complaining

of lower abdominal fullne ss, tenderness, and nausea

and vomiting. Histologic examination showed that

she had developed gastrointe stinal and renal amyloid-

osis with inte stinal pseudoobstruction and prote in-

uria. The immunohistochemical study of the stomach,

rectum, and kidne y with anti-amyloid A ¯ uorescent

antibody showed that the systemic amyloid deposit

was secondary to her unde rlying disease. This is the

® rst report of amyloidosis occurring secondary to

hypersensitivity vasculitis.

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1830 Digestive Diseases and Sciences, Vol. 43, No. 8 (August 1998)