Light chain deposition disease of the liver associated with AL-type amyloidosis and severe cholestasis

75

Light chain deposition disease of the liver associated with AL-type amyloidojis and seveis &&stasis A case report Gavino

Faa’,

Boudewiin

Peter

Van

A 67-year-old man with a 3.month

Eyken’,

Rita

Renal

function

review

De Vos’.

Jan De Groote?

history of jaundice prrrented

mal liver tests with raised biliruhin.

vealed normal extrahepatic bile ducts. Liver globular deposits of PAS-positive

Van

Dammet,

and literature

Johan

and Valeer

with hcpatomegaly. Laboratory

was normal

Endoscopic

non-congophilir

and a typical bile infarct.

creased in the peririnusoidal posed of fibrils

indistinguishable

chain deposition

disease (LCDD)

disorder first described by Randall actuized

by the deposition

red-wpative

material.

chain antiserum ultrastruclore

in various

reactive

is a systemic

et al. in 1976 (1). charwith

organs of Congo monotypic

and lacking rhe characteristic

fibrdlar

9s both intact and fragmented

pnrtcd,

ligbr

manly

(5.1 I-!6) wntation

chronic

between LCDD

type is not entirely

and amyiotdosio of the

and the bver (2.22).

that thz depobitrd material in LCDD

light chain deposition (8), pulmonary

Recently,

however.

disease presentmg with skin lesions

nodules (9) and even with faral varculopa-

Liver

involvement

in LCUD

brillar

has been occasionally re-

wuctwe

go&able

exammalions

(U.24)

More-

have revealed

may also have a fi-

like amyloid. and may even be indiron-

From amyloid fib&

(21.25.26)

We now report on a paoent with combined LCDD AL-type ear

thy (10) has been reported.

cases

have been reported of an association of both diseases tovalving the kxdney (2.19-21) over, ultrastructural

acute or chronic onset (S-7).

disease

clear (9). In recent yeas,

(3). The disease is known to mainly affect the ktdney (4).

renal

(15.17.18).

The distmc:ion AL

in eublects with

and rarely as a .na,or feature m the clinical prr-

chains, while the amyloid P component was not detected

with

in-

are discussed.

light

of amyloid (2). The deposits have been re-

cently charactenzeo

appeared markedly

the deposited material in the Disre spacer was mamty cam-

from amyloid, admixed with small amounts of granular elecwon-dense material. The simv

larities of light chain deposition disease and AL amyloidosis

light

and

revealed the presence of d-light chain

and in the portal tracts. Collagens type I and I\’ and fibroneuin space. On electron microxopy,

re-

Lammar

matenal were observed a the sinusoIdal WBUF. In ad-

dition, congophilic material was detected in the portal tracts. bmnunohtstochem~stry deposits both in the xnusoids

studtes revealed abnor-

retrograde Fholangiopancreatography

biopsy showed ~evrre bilirubinostasis

diastase-resistant

Fevery*, J. Desmet’

smylnidosis

presenting with cholc~atnc liar

A liver biopsy bbowrd wverr

Infarct.

and dir-

chulcatasis with a bile

76

C8SE

report

dilion

improved

mouths

markedly.

However.

after prcscntation.

when last seen, 6

protrinuria

(1.7 g/24 h) be-

cane appsrcnt. A 6%war-old

mate wns referred

dye to progressive

puinlcas jnundwz.

Five years earlier,

he hnd experienced

n myoocardiut infarction.

At thui lime hypcrchotcstcrol:-

mia (350 mg/dl) and mild late-onset diabetes meltitus

had

hcen discovered and treated with an appropriate diet. On odmasion.

he was markedly jaundiced. Cardiopul-

monary and \~~scuIur cxemination

was Norman The liver

Methods The liver needle hiopqy was divided into three fragments

for lig!~t microscopic,

ultrastructu~al

study.

immunohietochemical

A fragment

drated and paraffin embedded. Five micron thick sections were stained with hematoxylin

and eosin. periodic acid

u’as enlarged to 7 cm below the costal margin. The spleen

Schiff (PAS)

wus not pulpuble. hut slightly

Perl’s prussian blue, Congo red with and without

enlarged lymphnodes were

present m ttte cervical. sxillary laboratory

and inguinal

results arc summarized

to Ihe fe8:wcs

in Table

of marked cholcstosP

areas. The

I. In addition

u mild anemia. hy-

after diastase digestion.

pretreatment

and Hall’s

bilirubin

sections were also stained with and I-light

chains (Dako).

poalbumincm!a and a small M peah in the y-globulin frac-

frozen in liquid nitrogen-cooled this

rcvmisd

~8s normal.

bcparomegz!y:

mu seemed normal and the bile dur:s Cho!rcystolithiasi\ (CT)

was presrst.

Uttrasour.d

!he liver parenchy were not dilated.

Computed

rcvcalcd alightly enlargr 1 l?mphnodes

in the hitum

antisera

beiwern

the aorta and cavat vein,

liniment

and in the media&mm.

IC retrograde chalangiopallcreatography ruther fiue intrshepa!ic

in the

Endoscop-

(ERCP)

showed

bile ducts, with a normal :ommou

bile duct and main psncreabc duct. Bone marrow

examination

6” immunncytoma

IgD

KMnO,

Deparatfinized

antibodies

to K- (Dako)

isopentane.

III

Dickinson).

(Chemicon)

fDako).

Five micron

(Dako),

Protein

IgG (Becton

(Da~o).

IgA

(Dako).

!3ickinson)

an4 with

JgM (iLko),

and Amyloid

A

The third part of the specimen WBS fixed

in 2.5%

glutaraldehyde

troxide.

Ultrathin

l06A

(Eurodiagnostics),

(El-*..,disgnos!ics)

specific for human

to K-

collagen type I

and IV

taminin

and postfixed

in 1% osmium

sections were counterstained

nyl acetate and lead L.tmie

revealed a lymphopkama-

cylobis of 35% (control below 25%)

chains (Becton

(Chemicon), iibronectin

of the liwr.

stain.

red, reticulin,

cryostat sections were stained with antibodies

and I-light

tomogrqhy

gostrohcpatir

Sirius

Part of the biopsy wm snap-

tion were noted. Renal function exsmmation

and

was fixed in 85. dehy-

tnnsmission

te-

with urn-

and examineC with

a Zeiss

ele*‘ron microscope.

and the presence of

was suspected. An axillary lymph node

was cxciscd and a liv:?r biopsy taken. chemotherapy,

the patient

WC treated with 32 mg mc~bylprcdnisolone.

Before

eventually

starting

decreasing

to !2 mg. Jaundice subsided and rhe patient’s general con-

The

lobular

nrchitectorc

was preserved.

appeared enlarged and somewhat to peripheral

fibrous

extensions.

irregular

Portal

tracts

in shape due

In the periphery

portal areas, ductular proliferation

of the

and ductular metapla-

sia of hepatocyies was observed. There was a mild degree

oicholangiolitis and even ductular cholestasis.The parenchyw

showed severe cholestasis,

atoceltular.

characterized by hep-

canalicular and Kupffer

In addition,

a periportat

the periphery

crotic hepatucyws,

cell bilirubinostasis.

bite infarct,

and central bilintbin

with foamy cells at impregnation

was dctccted (Fig.

of ne-

1). The sinusoidal

wails appeared thickened due to the deposition of an eosinophilic The

homogcneow

deposits

uutterial

were both

evenly distributed

iinca:

throughout

rial WBE PAS-positive

in the spices of Disse. and globular

and were

all acinar zones. The mate-

after d&tare

digestion,

congophilic and did not exhibit bwefringence.

but not

Lo the por-

tal tracts, Congo red-positive

deposits,

tam to KMnO,

and were birefrigent,

werr

wall and in the comxctwe

tissue

pretreatment

present iu the arterial

which were r&s-

LCDD

Fig.

AND AMYLOIUOSK

2

WI’H

CHOLESTASIS

71

78

(Fig. 2). ln wmc nrcas. tt mild dcgrcc of sinusoidal pcri-

hihited a strong perisinusoidal

cellularf~brns~sw.lz

ing fx AA protein was negative.

nlsoahscrved.

The hiatologicnl study of the lyepn deporitton

node revealed the

of nhundnnt homogeneous

cosinophilic

rial. ill the sinuses and in the arterial were strongly PASpositive refring

mate-

wall. The deposits

and Congo red-negative.

nt material was found m ths dttrrial

In the lymph

node,

and portal staining. Stain-

the deposited

strongly with anti.,? antiserum.

material

reacted

No significant staining was

ohservrd with anti-K antiserum.

Bi-

wall on’y. On electron microscopy.

large globular

deposits were

found in :he space of Dissc (Fig. 4). They were composed lmmunohistochemical yielded comparable tions.

lncuhntion

staining

for

K-

results on paraffin with

anti-l.

and

i-chains

and cryostat sec-

light chain

antiserum

re-

of randomly

oriented

unhranched.

usually straight

about

filaments.

10 nm itt diameter

forming

or slightly

(Fig.

granular

walls (Fig. 3). A slight staining was found in the cannec-

the portal tracts,the same fihrillar

live tissue of the portal tracts and in the wall of the hepatic

Disse spaces was observed.

artery.

were lying in a nmre pnrallel orier.tarton.

Sections stained

with

anti-x

light

chain

rum showed nu specific staining. lmmunostaining munoglohulins I and IV

spaces of Disrr

was found on some collagen fibers, In material as found in the

The fibrils were longer and

for im-

revealed a strong positivity for IgM in the

sinusoidal ws!!s: I@, Type

ontise-

of

5). Fine electron-dense

sulted in an intense staining of deposits in the sinusoidal

nnterial

a meshwork

bent structures

IgA

rolkgcns

and IgD

were not detected.

were diffusely

positive

in the

ar well as in the portal areas. Immunore-

Liver

involvement

in light

chain

deposition

disease

aclivity for type 111collagen snd laminin was comparable

osuatiy orcurs in association with renal lesions and is only

to the pattern

rarely a major

observed m normal

liver. Fibronectin

ex-

feature

of the clinical presentation.

The

case reported

here differs from previous observatmns

in

that, to the best of our knowledge, it is the first observadon of LCDD presenting with jaundice and severe cholestasis, in the absena of clinical and laboratory evidence oiswious kidney invoivemenr. The histological picrure WIS quite unusual. In addition !o the typical features of LCDD, severe hepa!nrellular,

canabc~lar

and Kupffer 41 bdirubi~.~x~stas~s;and a typical

bllr infarc! wre observed. Bile infarct, or Cbarcot-Gombault necrosis. is considered ~;-aally diagnostic for extrabrpatic -b&stasis (27). However. in our patient the absenw ot any ewdcnce of eatrahepatic hdiary obrrruction confirms occasional observations (27) that typical bdc infarcts may be observed in inrrahepatic cholentasi?. The

cause of the sewrc cholestasis in our patient was not readily apparent. In amyloidosis. occur in 510% hepatic

~

(30-38).

of subjects

cholestaris

,

in which mild jaundice may

has

(28.29)

and severe intra-

occasionally

beat

reported

_”

it has been sueeested that bilirubinostasis

could

In adslitmn to light chain deposits along the sinusoids, our patient also had amyloid deposition in the portal tracts and combined

LCDD

nodes. Recently amyloidosis

and amyloidosis

the association

in the

of LUDD

the liver

portal deposits (38.39).

finding was not confirmed in

pathophysiology

amyloidosis

nostic feature is the presence of a single light chain isotype

other reports

of chotzstatic

loid had a pericentral

localization

(40).

where the amyIn the present

in the deposited

case. light chain deposits were preferentially

located in-

confirmed

side the lobule

only small

LCDD

in the Disse

spaces. while

amounts of congophitic amyloid material portal trots.

were found in

mainly in the hepatic artery watt and never

These

and in

be caused by the compression 01 tntrel~epatic bile ducts by This

(Z&22).

lymph

and AL-type

WBS reported in the kidney (2.19-21) cases suggest similarities

material.

Similarity

by the finding

deposits

in the

of both diseases, whose common diag-

that,

menfed tight chains (3).

has been recently

similar

are derived fmm

to AL

amyloid,

both intact and frag-

In the present case, the ultra-

structural

in close association with bilz ducts. The pathogenesis of

finding of fib:iltar deposits which were indistinguishable from amyi& fib&, further underscorer simi-

the cholestasir thus remains unclear.

laaities betwcen AL-amyloidosis

The

sinusoidal

deposits were not only reactive for .I-

light chains. but were also positive reactivity

of the deposits with

for IgM.

Significant

anti-heavy chain antisera

has occasionally heen reported (1.2.17.23.41)

It has been

tion disesse as previously The different

and light chain deposi-

suggested (26).

distribution

of amyloid and non-amylai-

dotic material in the liver, i.e., light chain deposits in the sinusoids

and smyloid

in the portal tracts, indicates that

suggested that. in these cases, the term light chain depomi-

local factors may be inzortant

lion disease should be wplaced by ‘light and heavy chain

which light chains are being deposited: as light chain de-

deposition discare’ (41). The observation brow

type I and ty+ sinusoidal position

IV

collagen and for fihronectin

wall confirms

previous

in the

disease (13,16).

of the sinusoidal

cats aid ruggeu tnat ai, iiltcraLti.o,, cells and me dcposnru

for

reports of collagen de-

m hepatic light chain deposition

These dais mdicate an actiwtion

kreni

of sinusoidal fi-

and sf B markedly increased immunoreactivity

lining

betwee,, the rebiden,

hght chams cuutd rxptam the dif

r,?orphological appcamncc of light chain deposits in

the l&r.

as in other organs (42).

in determining

the form in

position disease deposits or as amyloid (43). The different patterns

of PAS

positivity.

fringertce and ultrasttuctural

Congo red posilivity,

phasized

by numerous

Congo red-negative

recent

Slomerulx

suggest rhat these varisotc

biie-

granular and/or fibrillar

pearance of deposits in light chain deposition reports deposits

feawres

ap

dtsease, em-

of amyloid-like (25.26,4&!7),

could represent

dif-

ferent stages in the deposition of tight chains. Apparently, there is a spectrum ranging from easily recognized Congo red-negative granular

deposits to Congo red-positive

ti-

LCDD

AND AMYLDlDOSlS

brillar material.

Wll”

Perhaps au, case represents an mterme-

dlafe stage in the transifwn dixase

Xl

C”O!_EST*S,S

10 AL-type

The autbws

It appears from this report that li@, disease should be considered

Acknow!edgements

from light chain depositmn

amyioidoris. chain deposirion

in the differential

diagnosis

ca! asis,a”cc

gra,efully

acknowledge

of Ria Gillard.

for ,be prepvrvtinn of the micrographs.

possible extrabrpatie

chtilnce uf Marja”

hiliary obctmction.

afie light chain deposition sis (20.22).

Finillly,

rbe case

cases of combined bep-

disease and AL-,ypc

amyloido-

indicate rhat both diseases may represent ,wo

extremes of a spectrum.

6 cnnfalonicri R, B.rbia&di Belgiolosa G. Badi G, et a,. Qhl chain“ephropatby: bisrologicsl and clinical sspccts in IS w~eb. Nsphrol DialTranspk?“, L988;I 150-6. 7 “enkacarcrba” YS, Fala&“O T. Hughron MD. Bucbulald D, Oleanicky L. Goldrier” MH. Marpbalo& varia”6 af bgb, ehai” depositian diseasein rbc kidney. Am J Nepbml 19.58:8: 272-9 8 Mawy CPJ, -rep&w AM. Massive NIa”IIZO”, byatinoris. Am J Cli” Patho, ,984: 81: 543-5,. 9 Kijner CH, Yourem SY. Syslcmiclight chain deparitia” disease ,neren,iw. aI “l”bi8,S D”l”m”an nodules. Am J Sure Paillo!

i9m:n405-13.

IO Srone GC. Wall BA. Oppliger IR, et a’. A vanculopxbywith depxirion of lambda light chain ws,als. A”” I”, Med 1989: 110: 175-8. 1, Ganevs, D. Noel L”. Droz D, Leibowitcb J. Sys,c”“c lambda light chain dep&,io” in a palie”, wb my&ma. Br Med J ,981: 182: 681-3. 12 Case records Of ,hP Ma.rrrcbure,,s Orncra, “o,p,tal. Carr 1. 19111.N Engl J Med ,981: 301: 33-40. 13 Dra D, Noel L‘i, Cxnot F, DeSur F. Ganeval D, Grunfeld JP. Liver ln”ol”eme.nrill i.J”all”,“id beh, ihhl” lIeDmill deeale Lab invest 1984: 1‘0: 683-9. . 14 Le “eiger JL, Toule, R, Deug”er Y. Ra,“rr MP. A”om”,ir\ biologiqvcr bepa,lq”cr a” cows d‘une m&die der qJ,r de cbatncr Q&lea. Cast:~en,cro, Cli” ma, 198.5:9: 184-91. !5 “aff”lan.G”ilai”e C, Nocby D. facquot C. et a,. !_a mriad~r der iqi”,Z di c:l.meE,egcra- J”Scm,,? a”.,omopa,ba,“gique. A”” Parho, ,984: 4: w-13 55 Bcdoaa P. Fabre. M. Z’amf F, Martin E. irmaagre G. L,gh, chain deporiri”” disease wil.1 Iivcr dyrfwctio”. Hum P&s! ,988; 19: 3008-34

”

Aarscho,

VeulemanrWeckx

is gratefully acknowledged. Onderzoek’.

Roos
The xcrerw and Mariene

al asVan

Peter Van Eyktn

;I rewearch aes~sinn, of the Belgian ‘Nrtionaal Wrfrnrchappeli,k

techni-

Smets and Chns-

tel Van den Rrocck. They also thank Michel

of severe cholestasis even when hver hisrology suggests a presented hem and two pm:wus

the expx,

Bernadette

is

Fends vow

43 44

45 46 47