Gut 1993; 34: 1412-1417

Intestinal pseudo-obstruction in patients withamyloidosis: clinicopathologic differences betweenchemical types of amyloid protein

S Tada, M lida, T Yao, T Kitamoto, T Yao, M Fujishima

AbstractA clinicopathologic study was made of 16patients with amyloidosis and with clinicalsigns of intestinal pseudo-obstruction.Amyloid deposits in the small intestine wereproved in all cases by endoscopic or intra-operative biopsies, and immunohistochemicalstudy identified the chemical types of amyloidprotein: amyloid A protein (AA) in 13 cases,light chain protein (AL) in two, and P32-micro-globulin (AH) in one. Clinically, an acute selflimiting obstructive condition was evident in 13cases with AA, and 12 of them returned tonormal bowel function after receiving totalparenteral nutrition. Two cases with AL andone with AH presented chronic, intermit-tent, obstructive symptoms, and medical treat-ment, including total parenteral nutrition, wasineffective with no recovery of intestinalpropulsion. Pathological examination of thenecropsy specimens in seven cases showedconsiderable differences in the preferentialsites of gastrointestinal deposits between thechemical types of amyloid; extensive infiltra-tion and replacement ofthe muscularis propriaby amyloid deposits throughout the gastro-intestinal tract, especially the small intestine,were found in the AL and the AH cases, whileamyloid deposits in the myenteric plexus with-out appreciable muscle infiltration were shownin the AA cases. These results show thatintestinal pseudo-obstruction in patients withamyloidosis is caused by either myopathy orneuropathy, and that chemical types ofamyloid may determine which of the twofactors has the dominant affect on the bowelfunction.(Gut 1993; 34: 1412-1417)

Intestinal pseudo-obstruction is a clinical syn-drome characterised by symptoms and signs ofintestinal obstruction despite the absence ofmechanical blockage of the intestinal lumen.'-3Systemic amyloidosis often affects the gastro-intestinal tract45 and may result in this condi-tion." It is unclear, however, whether theimpaired gastrointestinal motility is secondary tothe effects ofamyloid on the smooth muscle or onthe autonomic nervous system, because therehave been few reports assessing the clinicopatho-logic features in a considerable number ofamyloidosis patients with intestinal pseudo-obstruction.

Recently, biochemical analyses have shownthat several different types of amyloid fibrilprotein exist in systemic amyloidosis. Lightchain protein (AL) amyloid, which is of

immunoglobulin origin, is found in primary ormyeloma-associated amyloidosis.9 '° Secondaryamyloidosis associated with chronic inflamma-tory diseases consists of amyloid A (AA) pro-tein." 12 AH amyloid consisting of P2-micro-globulin is found in patients receiving longtermhaemodialysis. '3 ' It is now widely recognisedthat amyloidosis, rather than being a singledisease entity, represents a group of diseases thathave in common characteristic microscopicstaining properties and electron microscopicfibrillar configuration."' Correlations betweenthe chemical types, however, of amyloid andhistological or clinical features in amyloidosispatients with intestinal pseudo-obstruction havenever been determined.The aims of this study were: (a) to explore the

distinguishing clinical characteristics betweenthe patients with three types of amyloidosis whopresented with clinical signs ofintestinal pseudo-obstruction, and (b) to examine the relationsbetween the clinical features and pathologicalfindings.

Methods

PATIENTSBetween 1978 and 1992, we saw 17 patients withamyloidosis who presented with clinical signs ofintestinal obstruction. Of these, 11 patientsinitially came to the hospital complaining ofabdominal distension, cramping, anorexia,vomiting, constipation or diarrhoea, and wefound six in whom such clinical signs developedduring the follow up of illness. The abdominalplain films of these patients showed abnormalaccumulation of gastrointestinal gas, dilatedloops of the small and large bowel, with occa-sional air-fluid values. Two patients had emerg-ency laparotomy and no mechanical obstructionwas found. In the other 14 patients, bariumstudies of the small and large intestine did notshow any mechanical obstruction. The remain-ing patient showed a large mass in the jejunum,which was histopathologically diagnosed as anamyloid tumor. Excluding this exceptional case,we examined 16 patients showing clinical signs ofintestinal pseudo-obstruction.

IDENTIFICATION OF AMYLOID PROTEINOne patient had primary amyloidosis, twohad myeloma associated amyloidosis, one hadhaemodialysis associated amyloidosis, and 12had secondary amyloidosis (rheumatoid arthritisin eight, ankylosing spondylitis in one, adultStill's disease in one, polymyositis in one, and

Departments of InternalMedicine I, PathologyI, and Neuropathology,Faculty of Medicine,Kyushu University,Fukuoka, JapanS TadaM IidaT YaoT KitamotoM Fujishima

Department ofGastroenterology,Fukuoka University,Chikushi Hospital,Fukuoka, JapanT YaoCorrespondence to:Dr S Tada, SecondDepartment of InternalMedicine, Faculty ofMedicine, Kyushu University,Maidashi 3-1-1, Higashi-ku,Fukuoka 812, Japan.Accepted for publication16 February 1993

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Intestinal pseudo-obstruction in patients with amyloidosis: clinicopathologic differences between chemical types ofamyloid protein

TABLE I Summary ofthe clinical datafrom amyloidosis patients with intestinal pseudo-obstruction

Chemical Interval betveenCase Age (y) Underlying types of Onset ofobstructive Ileus the diagnosis andno and sex disease amyloid symptoms (duration) Treatment reversibility death or survival

1 77 M Multiple myeloma AL Chronic (2 y 3 mth) TPN, Ch, M Irreversible 1 mth died2 51 F Multiple myeloma AL Chronic (2 y) TPN, Ch, M Irreversible 2 mth died3 42 M Chronic haemodialysis AH Chronic (2 y 10 mth) M-A tube, TPN, Irreversible 2 y 3 mth died

Ch, M,Ci4 65 M Rheumatoid arthritis AA Acute (3 wk) TPN, Ci, M * 3 wk died5 60 F Rheumatoid arthritis AA Acute (6 wk) TPN, M Reversible 2 mth died6 42 F Rheumatoid arthritis AA Acute (4 wk) TPN Reversible 3 y 1 mth died7 24 F Polymyositis AA Subacute (10 wk) TPN, P Reversible 5 y 8 mth died8 62 F Rheumatoid arthritis AA Acute (8 wk) TPN Reversible 4 y 2 mth alive9 52 M Ankylosing spondylitis AA Acute (4 wk) TPN, M Reversible 8 y 10 mth alive10 47 F Rheumatoid arthritis AA Acute (5 wk) TPN Reversible 2 y 5 mth alive11 44M Rheumatoid arthritis AA Acute (3 wk) TPN Reversible 1 y 11 mth died12 42 M Adult Still's disease AA Subacute (14 wk) M-A tube, TPN Reversible 6y 10 mth alive13 36 M Rheumatoid arthritis AA Acute (8 wk) TPN Reversible 2 y 4 mth alive14 34 F Rheumatoid arthritis AA Acute (4 wk) TPN Reversible 4 y 3 mth alive15 30 F None AA Subacute (10 wk) TPN, M Reversible 10 y 7 mth alive16 23 M Crohn's disease AA Acute (9 wk) TPN, P Reversible 6 y 6 mth alive

TPN=total parenteral nutrition, Ch= cholinergic agents, M=metoclopramide, M-A=Miller-Abbott tube, Ci= cisapride,P=prednisolone. AA=anyloid A protein, AL=light chain protein, AH=,P2 - microglobulin protein.*We could not evaluate the ileus reversibility because this patient died of renal failure and sepsis shortly after admission to hospital.

Crohn's disease in one). Using a long duodeno-fibrescope,'6 endoscopic biopsy specimens of thejejunum showed amyloid deposits in 15 patients.In the remaining patient, amyloid deposits of thejejunum were confirmed by intraoperativebiopsy specimens. Using these specimens,chemical types of amyloid protein were identi-fied by the avidin-biotin complex (ABC) methodusing anti-AA'7, anti-P2-microglobulin (1:500,Dako), and anti-prealbumin (1:500, Dako)antibodies. For a comparative evaluation ofamyload protein, potassium permanganate(KMnO4) treatment was performed before stain-ing with Congo red.'8 AA protein was identifiedby positive staining with anti-AA antibody andsensitivity to KMnO4 reaction, while AL proteinfailed to stain with anti-AA, anti-(32-micro-

Figure 1: Plain abdominal radiograph ofpatient with 0j2-microglobulin protein (AH) amyloidosis (case 3) showedgaseous dilatation ofthe small and large intestine. The gaseousdilatation ofthe bowel was consistently seen until the patientdied ofcardiac failure.

globulin, and anti-prealbumin antibodies, andwas resistant to KMnO4 reaction. AH proteinwas shown by positive staining with anti-,32-microglobulin antibody and by negative stainingwith other antibodies.

NECROPSY EXAMINATIONOf the 16 patients, three died at the time of theirfirst hospital admission and five died subse-quently. Postmortem examination was carriedout in seven patients, and the gastrointestinaltract was fixed in 10% neutral buffered formalin.From each of the oesophagus (lower third),stomach (fundus and antrum), duodenum(second portion), jejunum (within 50 cm fromthe Treitz ligament), ileum (within 50 cm from

Figure 2: Plain abdominal radiograph ofpatient with anyloidA protein (AA) amyloidosis (case 9) showed gaseous distensionofthe stomach and small intestine. Thisfinding disappearedafter total parenteral nutrition treatment, and there was norecurrence during thefollow up period.

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Tada, Iida, Yao, Kitamoto, Yao, Fujishima

TABLE II Histologicalfindings ofthe small intestine in seven necropsy cases with intestinalpseudo-obstruction

Muscularis propria Myenteric plexuses VesselsChemicaltypes of Amyloid Muscle Amyloid Degeneration Amyloid

Case no amyloid deposits replacement deposits and reduction deposits

1 AL +++ +++ - +2 AL ++ to +++ ++ to +++ - ++ ++3 AH +++ +++ - +++ - to +4 AA - - ++ to +++ + to ++ +++5 AA -to + ++ + to ++ +++6 AA + + + to +++ + to ++ +++7 AA + + + to +++ + to ++ +++

absent, + mild, + + moderate, + + + severe. Other abbreviations as in Table I.

Figure 3: Light chain protein(AL) amyloidosis (case 1).Section ofjejunum showingextensive amyloid deposits inthe muscularis propria andmuscle tissue replaced byamyloid (top, haematoxylinand eosin (originalmagnification x45); bottom,Congo red stain withpolarised light (originalmagnification xSO)).

the ileocaecal valve), colon (mid-transverse), andrectum (lower part), three specimens, measuring3 or 4 cm long and 0 5 cm wide and includingall the layers of the wall, were obtained andembedded in paraffin wax. Sections of 5 iim

thickness were stained with haematoxylin andeosin, Congo red, and azan stain. Immunohisto-chemical studies were performed by the ABCmethod using S-100 protein, anti-AA, and anti-,P2-microglobulin antibodies. The extent ofamyloid deposits in the muscularis propria,

myenteric plexuses, and blood vessels wasgraded from - to +++: -, absent; +, mild;+ +, moderate; +++, severe. The smoothmuscle replacement and degeneration or reduc-tion of the myenteric plexuses were also gradedfrom - to +++.

Results

CHEMICAL TYPES OF AMYLOID PROTEINAccording to the results of immunohisto-chemistry and sensitivity to KMnO4 reaction,there were 13 patients with AA amyloidosis, twowith AL, and one with AH. Good correlationwas noted between clinical classification and theexpected amyloid type in 15 of 16 patients; the12 patients with secondary amyloidosis had AA,two with multiple myeloma had AL, one withlongterm haemodialysis had AH. An exceptionalcase, who was clinically classified as primaryamyloidosis because no predisposing diseasecould be recognised, showed deposits of AAprotein as evidenced by a positive stain for anti-AA antibody, which was sensitive to KMnO4reaction.

CLINICAL FEATURESAll 16 patients suffered from similar symptomssuch as nausea, vomiting, abdominal distension,and pain. The patients had either diarrhoea orconstipation. Malnutrition was evident in allpatients whose laboratory data showed hypo-albuminaemia (mean (SD) was 2.6 (0.6) mg/dl,ranging from 1-0 to 3.5 mg/dl). The duration ofobstructive symptoms varied widely with a rangefrom a few weeks to several years. Thirteen hadan acute or subacute self limiting condition, butthe remaining three had several years history ofrecurrent obstructive symptoms. Table I sum-marises the clinical features and chemical typesof amyloid protein.We found differences in the clinical signs

between amyloid types. The patients with ALand AH presented with chronic, intermittent,obstructive symptoms, which developed into asevere form that required admission to hospital.The patients with AA had no chronic obstructivesymptoms until they developed an acute condi-tion with apparent intestinal obstruction. In allpatients, plain films of the abdomen showedabnormal gastrointestinal gas. Considerablegaseous dilatation of the small and large bowelwas consistently seen in the AL and the AHpatients during their hospital stay (Fig 1),whereas the abnormal gas disappeared aftertreatment in 12 of 13 patients with AA (Fig 2).

All patients received total parenteral nutritiontreatment. The daily maintenance dose ofcalories was 2000 to 2400 kcal (40-60 kcal/kgbody weight). The average period of treatmentwas 10.3 (6.7) weeks, ranging from 2 to 28weeks. One patient with AA died shortly afterthe start of total parenteral nutrition because ofrenal failure and sepsis. In 12 patients, all ofwhom were AA, total parenteral nutrition waseffective in improving symptoms and signs, andthereafter, made it possible to maintain adequateoral intake again. In these AA patients, there was

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Intestinal pseudo-obstruction in patients with amyloidosis: clinicopathologic differences between chemical types ofamyloidprotein

Figure 4: AH amyloidosis(case 3). Jejunal specimensshowing massive amyloiddeposits in the muscularis poi,propria and slight deposits inthe submucosal vessels(arrow) (left, Congo redstain, right, avidin-biotincomplex method with anti-032-microglobulin antibody(brown reaction product)original magnification X80). w- A s i . e i

no recurrence of paralytic ileus or severe obstruc and blood vessels of the small intestine Intive symptoms during the follow up ranging comparing the AA, AL, and AH cases we foundfrom 19 to 10 6 years (average 5 1 years), an appreciable difference in the degree ofalthough minor symptoms occasionally occur amyloid deposits inthe muscularis propria Byred. In the remaining three patients (AL in two contrast with negative or slight smooth muscleand AH in one), however, the obstructive symp- infiltration in the AA cases, the muscularis wastoms were persistent and quite resistant to total quite extensively affected in the AL (Fig 3) andparenteral nutrition treatment. Medical treat- the AH cases (Fig 4). In cases with massivements such as cholinergic agents, metoclopra- deposits, there were degenerative changes inmide, and cisapride were also ineffective. All of muscle fibres, with muscle tissue being replacedthem eventually died of cardiac failure without by amyloid.the return to normal bowel function. Amyloid was found in the myenteric plexu'ses

in the AA cases (Fig 5). The degree of amyloidFigure 5 AA amylodoisat rn the muscularis propria, myenteric plexuses, deposition in the myenteric plexuses variedFigure: AAamyioidosisunu NECROPSY FINDINGS widely; some were free of amyloid in certainshowing massive amyloid In all seven necropsy cases, amyloid was found in areas, while massive amyloid deposits weredeposits in Auerbach's every site of the gastrointestinal tract including evident in others. In plexuses with amyloidplexus. The nerve bundles the oesophagus, stomach, small, and large deposits, some residual ganglion cells showedand ganglion cells arecompressed by amyloid and intesties. Table II shows the degree of amyloid degenerative changes. In the AL and AH cases,show atrophic changes deposition and destruction of organic structures we could not find any amyloid in the myenteric(haematoxylin and eosin in the muscularis propria, myenteric plexuses, plexuses. Many Auerbach's plexuses were com-stain original magnification pressed, however, by the surrounding abundant

x350). ~~~~~~~~~~~~~~amyloiddeposits, with a diminution in theirJ ~~~number and the presence of degenerative

ganglion cells.In all cases, vascular deposits of amyloid were

found most commonly in the submucosa.Massive vascular depositswerefound in theAA

*~~~~ ~cases., while the degree was moderate in the ALand slight in the AH.These histological findings were similar in all

parts of the gastrointestinal tract. The degree ofamyloid deposition, however, was greatest in thesmall intestine.

DiscussionThe main finding of this study is that if intestinalpseudo-obstruction develops in patients withayloidosis, the clinical features are consider-

ably different according to the chemical types ofamyloid protein. Acute or subacute self limiting

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1416 Tada, Iida, Yao, Kitamoto, Yao, Fujishima

intestinal pseudo-obstruction (so called paralyticileus) occurred in patients with AA amyloidosisand bowel function was usually restored byconservative treatment. Conversely, chronicintestinal pseudo-obstruction, which is mani-fested clinically by recurrent attacks of obstruc-tive conditions, occurred in the patients with ALand AH amyloidosis, with failure of intestinalpropulsion to return.

Abnormalities of gastrointestinal motility mayoccur in all forms of amyloidosis920 andintestinal pseudo-obstruction has been reportedin secondary7 12 or primary amyloidosis,'0 includ-ing amyloidosis associated with multiplemyeloma.6' Although the mechanisms ofimpaired motility have not been fully defined,infiltration of intestinal smooth muscle"' andgastrointestinal neuropathy with amyloidinvolvement of the autonomic nerves""'2 havebeen reported. It has not be concluded, however,which of the two factors dominantly affects thebowel motor function, and the relation betweenmotility disorders and chemical types of amyloidhas not been examined.

In this study, the most striking histologicalfinding was the presence of extensive amyloidinfiltration of the smooth muscle in the AL andthe AH cases, but such amyloid deposits werenot seen in the AA cases. If the amyloid almosttotally replaces smooth muscle, intestinal pro-pulsive activity disappears.7'8 Once massiveamyloid deposits occur in the muscularispropria, this myopathy is thought to be anirreversible change because of the difficulty ofelimination of this insoluble protein. This mayalso explain the finding that the AL and the AHcases in this study did not respond to anytreatment and had a poor prognosis when theypresented with severe intestinal obstruction.The possibility exists, however, that some treat-ments may be effective when the smooth muscleamyloid infiltration is not so extensive, as shownin a case of Fraser et al,23 which was responsive tocisapride.

Gilat et all studied 68 cases of systemicamyloidosis affecting the gastrointestinal tract,and showed that parenchymal deposition pre-dominated in the muscularis propria in primaryor myeloma associated amyloidosis, while insecondary amyloidosis it was mainly distributedin the lamina propria mucosa. In reviewingreports on amyloidosis patients with intestinalpseudo-obstruction, the patients with multiplemyeloma tend to have extensive smooth muscleinfiltration.6" These studies support our findingsthat clinically significant amyloid deposits in themuscularis propria are more likely in ALamyloidosis than in AA.

Recently, a new form of amyloid proteinassociated with longterm haemodialysis has beenidentified as ,32-microglobulin.'3 Gastrointestinalinvolvement by amyloid has been reported indialysis patients, and there have been cases ofintestinal infarction associated with massiveamyloid deposits in the muscle layers of thebowel.'424 Although only a few cases have beenstudied, it seems probable that extensive infiltra-tion and smooth muscle replacement by amyloiddeposits occur in patients with AH amyloidosis,as shown in our case.

Myenteric plexuses often participate infamilial amyloid polyneuropathy20 and in a fewcases with AL22 and AA.4 In this study, patho-logical examination of the necropsy specimensshowed that amyloid deposits in the myentericplexuses were seen only in the AA cases.Interestingly, 12 of our 13 patients with AAshowed a remarkable improvement in bowelfunction after receiving total parenteral nutritiontreatment. Although total parenteral nutritiondoes nothing to treat the primary diseasedirectly, it helps the patient receive enoughnutrition until bowel functions return to normalagain.25 Our clinical findings suggest that theneuronal disorder may be compensated to somedegree because the intestines are richly inner-vated.' If the muscularis propria escapes exten-sive damage, we assume that the impaired bowelpropulsion is allowed to recover to some extent.On the other hand, vascular insufficiency mightalso have contributed to the impaired peri-stalsis,6 because appreciable vascular depositswere seen m our AA cases. Further examinationsare required, however, to know the exact correla-tion between them.

In this study, differences in the histologicalsites of amyloid deposits between the chemicaltypes of amyloid affected the clinical signs ofintestinal pseudo-obstruction. Our findings sug-gest that this disease usually runs a more seriouscourse in AL andAH than in AA. Recent reportsshow that clinical and histological differences inthe preferential sites of amyloid depositionbetween the chemical types of amyloid exist inthe heart,' kidney,26 and spleen.27 In the heart,clinically significant cardiac amyloid with con-gestive heart failure is more likely in AL than inAA, because extensive amyloid interstitial infil-tration in the myocardium is more often seen inAL than in AA."' 1215 In patients with amyloido-sis, therefore, we believe that chemical typing ofthe amyloid protein is very important in predict-ing the clinical characteristics, course, and pro-gnosis of the disease.

We thank Mr Peter Flaherty for his assistance in preparation of themanuscript.

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