10.18.35.54.html.doc,Gastrointestinal Manifestations of Amyloidosis

American Journal of Gastroenterology ISSN0002-9270 C 2008by Am.Coll.of Gastroenterology doi:10.1111/j.1572-0241.2007.01669.x Published by Blackwell Publishing

Gastrointestinal Manifestations of Amyloidosis

Ellen C.Ebert,M.D.,1and Michael Nagar,M.D.2

Departments of1Medicine and2Pathology,UMDNJ-Robert W ood Johnson Medical School,

New Brunswick,New Jersey

Amyloidosis is characterized by extracellular deposition of abnormal protein.There are six types:primary,

secondary,hemodialysis-related,hereditary,senile,and localized.Primary(AL)amyloidosis is associated with

monoclonal light chains in serum and/or urine with15%of patients having multiple myeloma.Secondary(AA) amyloidosis is associated with in?ammatory,infectious,and neoplastic diseases.The presentation is protean, including macroglossia,a dilated and atonic esophagus,gastric polyps or enlarged folds,and luminal narrowing or ulceration of the colon.Amyloid deposition in the gastrointestinal(GI)tract is greatest in the small intestine.The symptoms include diarrhea,steatorrhea,or constipation.Pseudo-obstruction carries a particularly grave prognosis, often not responding to promotility agents.Hepatic involvement is common,but the clinical manifestations are usually mild with hepatomegaly and an elevated alkaline phosphatase level.Biopsies to diagnose amyloidosis can be taken from the fat,kidney,intestine,or bone marrow.The safety of liver biopsies is controversial.With Congo Red stain,amyloid appears red in normal light and apple-green in polarized light.Treatment for AL amyloidosis is chemotherapy and stem cell transplantation;treatment for AA amyloidosis is control of the underlying disease.

Amyloidosis should be considered in patients with proteinuria,cardiomyopathy,hepatomegaly(with mildly

abnormal liver tests),peripheral and autonomic neuropathy,weight loss,and GI symptoms.

(Am J Gastroenterol2008;103:776–787)

INTRODUCTION

This review is based upon450articles found in the English lit-erature identi?ed by a MEDLINE search.The term“amyloi-dosis”was combined with each of the key words,“gastroin-testinal,”“esophagus,”“stomach,”“intestine,”“colon,”or “liver.”Additional relevant publications were selected from the reference lists of the retrieved papers.

TYPES OF AMYLOIDOSIS

Amyloidosis is de?ned as an extracellular deposit of pro-tein?brils with aβ-sheet?brillar structure and characteristic properties after staining with Congo Red dye(1,2).The cur-rent nomenclature consists of the?rst letter,A(for amyloid), followed by a description of the precursor protein. Primary(AL)or light chain(L)-associated AL amyloidosis is the most common form,with generalized deposition of excess light chains.It is associated with plasma cell dyscrasia and has the maximum GI involvement.Fifteen percent of patients have multiple myeloma(3),although symptomatic myeloma is unusual.

Secondary(AA)amyloidosis with acute-phase reactant serum amyloid A protein(A)is associated with infec-tious,in?ammatory,or,less commonly,neoplastic disorders. Rheumatoid arthritis is found in48%of such patients(4). In contrast,the incidence of amyloidosis in patients with rheumatoid arthritis ranges from7to21%,with the highest number derived from an autopsy study(5–8).Of the patients with rheumatoid arthritis and diarrhea,62%had amyloido-

sis(9).Also associated with AA amyloidosis(4)are other in?ammatory disorders such as Crohn’s disease(CD),anky-losing spondylitis,Reiter’s syndrome,psoriasis,progressive systemic sclerosis(10),primary biliary cirrhosis(11),and serum lupus erythematosus.Other associations include infec-tious processes such as leprosy,tuberculosis,osteomyelitis, and bronchiectasis;tumors such as renal cell carcinoma,GI stromal tumors(12,13),and intestinal carcinomas;and other disorders,such as idiopathic retroperitoneal?brosis(14).

Patients undergoing long-term hemodialysis depositβ2-microglobulin(β2MG),resulting in amyloidosis called Aβ2MG.β2MG is the nonvariable light chain of the HLA

I class complex that is excreted by the kidneys.With renal

failure,it deposits throughout the body and can be detected immunohistochemically.The disease occurs after14–15yr of dialysis(15–17),although the incidence has declined with the use of high-?ux hemodialysis(15–19).

Hereditary amyloidosis,an autosomal dominant inheri-tance of amyloidogenic proteins,is rare.The most common form is variant transthyretin(TTR),which is produced by the liver.The resulting amyloidosis(ATTR)is called familial amyloidotic polyneuropathy(FAP).Besides FAP,there are hereditary nonneuropathic systemic amyloidoses associated with mutations in genes for apolipoprotein AI,lysozyme,and ?brinogenα-chain(20–22).

Senile amyloidosis is found in10–36%of patients over80 yr old and mainly involves the heart,but can also be seen throughout the GI tract(23).GI amyloid was observed in the subserosal veins of41–44%of elderly patients,mainly in the large and small bowel(23,24).

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