Anemia in Diphyllobothrium Latum

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1948 3: 91-102

BERTEL VON BONSDORFFLIGHT OF RECENT INVESTIGATIONSPERNICIOUS ANEMIA CAUSED BY DIPHYLLOBOTHRIUM LATUM, IN THE

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PERN IC IO U S A NEM IA CA U SED BY D IPHY LLO BO THR IUM LA TUM ,

IN TH E L IGH T OF RECEN T INV EST IGA TION S

By BER TEL VO N BON SDO RFF , M.D .

T H E M A CRO CY T IC anem ia cau sed by th e broad fish tapew orm , D iphy llob o-

th rium la tum , has been the sub jec t o f ex tens ive investiga tions in F in land , sta rt-

ing w ith the p ion ee r w ork ofJ . W . R unebe rg(1887) and 0 . S chaum an (1894) .

The fish tapew o rm is ex trao rd ina rily com m on in th e co un try . In certain p rov -

inces m o re th an 90 p er cen t o f th e p opu latio n is in fe sted w ith the p ara site . O f th e

to ta l p opu la tio n of th e cou n try , w h ich is ab ou t, 000 , 000 , one ha lf to o ne m illio n

can be con side red to be tap ew orm ca rrie rs . T he pa rasite is fo und in p erson s o f a ll

ages, ev en in ch ild ren und er i year o f age .

For m ost o f these carr ie rs , the w o rm is a re la tive ly inn ocen t paras ite , bu t

in som e , it causes a m ac rocy tic anem ia . A cco rd ing to ea rlie r in vestiga tions (R .

Ehrs trom , 192 .6 ) the f requency of anem ia w as estim ated to becase in 5 ,000 -10 ,000

w orm carr ie rs . B u t, if th e b lo od of w orm ca rr ie rs is exam in ed sy stem atica lly , a

fa r g rea te r num ber o f an em ia cases can be sh ow n . Am ong the con scrip ts o f.0

years o f ag e adm itted to a m ilitary hosp ita l in p eace tim e , S epp a192 . 7 ) found i case

o f an em ia in 65 9 w o rm carrie rs . G . T #{246 }tte rm an1944) , in a comm unity strong ly

in fested w ith tapew orm , no ted , in942 ., I case o f anem ia in136 carrie rs; and in

1943 , he fo und the freq uency to be case o f anem ia in 38 3 ca rr iers . In a w ar ho s-

p ital, from 1941 tO 1944 , I fo und 96 instances of tapew o rm anem ia in abou t I I,o oo

m edica l ca se s. Th e num ber o f w o rm ca rr ie rs in th is g roup , com posed of m en from

i8 to 40 yea rs o f ag e, is n o t know n .

T he abov e figu re s g ive a go od id ea o f th e im portance o f the p ro b lem o f tapew orm

anem ia in F in land . Th is anem ia is a typ ica l “p ern ic iou s anem ia” w ith a ch arac-

ter is tic b lo od p ic tu re and a m ega lob la stic bo ne m arrow , ag ree ing in a ll re spec ts

w ith tha t foun d in ‘c ry p tog en etic” A dd ison ian an em ia. A pe rn ic ious tap ew o rm

an em ia can also be brough t to rem ission w ith live r p repa ra tion s p e r os o r p aren -

tera lly , o r w ith stom ach prepa ra tion s pe r o s w ith ou t rem ova l o f th e w orm .

In con tra st to cryp togene tic pe rn ic ious anem ia , tapew o rm anem ia occu rs ev en in

p eo p le un de r 2.0 yea rs o f age . In m ost ca se s the re is an ach io rhyd ria a fte r the in -

jec tion of h istam in e; thou gh , e spec ia lly in younge r pa tien ts , th e gastr ic ju ice o ften

con tain s free h ydroch lo ric ac id and is secre ted in the u sua l q uan titie s . S ig ns o f

sp ina l co rd invo lvem en t a re le ss ap pa ren t th an in c ryp to gene tic pe rn icio us anem ia .

Th at th e illne ss is rea lly du e to the w orm in festa tion is p ro ved by the fact tha t

com ple te rem is sion takes p lacea fte r the w orm is expe lled w ithou t any fu rth er n eed

fo r an tianem ic trea tm en t.

S ince c ry p tog en etic pe rn icio us anem ia is n o t rare in F in land and w o rm in fe sta tion

is common, it is n a tu ra l th at now and then bo th ty pes o f anem ia sh ou ld o ccur

sim ultaneous ly in an in d iv id ua l. In such cases, o f co urse, the re is n o rem ission

a fte r th e w orm cure . In fac t, the anem ia o ften becom es m ore seve re.

From the U niv ersi ty of H e lsingfors , F in lan d .

91










92 . D IPH Y L L O B O T H R IUM L A T UM A N D A N E M IA

G . T #{ 24 6} tte rm an ( 1944 ) says tha t h e has en coun tered cases o f m ild m ac rocy tic an e-

m ia in tapew orm carrie rs tha t d id no t re spo nd to live r trea tm en t b u t show ed good

rem issio n a fter a w o rm cu re . H e assum es th a t th e p a thog en etic m echan ism fo r th is

fo rm of an em ia is d iffe ren t from tha t fo r th e tru e pe rn ic ious tapew o rm anem ia ,

w h ich d oes respond to liv er the rapy .

O n the o the r h an d , the re hav e been num erous repo rts in F in land of case s o f hy po-

chrom ic an em ia in tapew orm carriers w hich w ere no t cu red b y expe lling the w orm .

O n th is po in t, con flic ting in fo rm a tion is still foun d in the lite ratu re .

Th e q uestion w hich is o f sp ecia l in tere st fo r re search is : w hy do so few w orm

carrie rs have p ern ic iou s anem ia? O r fo rm ula ted in g rea ter de tail : w ha t are th e

fac to rs w hich lead to th e rise o f w orm anem ia and w hy are these fac to rs ac tive in

on ly a sm all num ber of cases?

H ithe rto , the se q uestions have n o t been sa tisfacto rily answ ered . Th e d iscussio n

of them and the tapew o rm anem ia prob lem as a w ho le has b een reported in d eta il

by B irke land ( 1931 ) .

T he presen t kn ow led ge of the genesis o f pe rn ic ious anem ia sug gests th at in som ew ay the w orm in te rfe red w ith the pro duc tion o r absorp tion o f th e an tianem ic fac -

to r o r w ith the produc tion o f th e com ponen ts inv o lved in its fo rm atio n . T h is

tho ug h t w as firs t ex p res sed b y S a ltzm an ( 1935) . O n the basis o f sim ilar reason ing

the pern ic io us anem ia in con nec tion w ith sp rue , v en tricu la r les ions, in tes tina l re -

sec tion s, e tc., can , a s is w e ll kn ow n , be exp lain ed .

A n investig atio n is h e re repo rted ca rr ied ou t on these line s w ith the o b jec t o f

e x pl a i n i n g t h e p a t h o g e n e s i s o f c a s e s o f p e r n i c i o u s a n e mi a , mo s t o fhem due to

tapew orm in fe sta tion . T he tes ts have been go in g on sin ce937.

1 . T H E IN T R I N S I C FA C T O R

a ) The course of rem ission after rem oval of the w orm .f the w orm is ex pe lled in the

u s ua l wa y (w ith 3 -4 .5 Gm . Ex tractio n filic is ) from hosp ita l p atien ts o n an un -

re str icted d iet, a b lood rem issio n beg ins sho rtly a fte rw ard s and co n tinu es un til the

b lood p ic tu re has becom e no rm al. In a g ro up of 7 cases, it w as obse rved th a t the

re ticu locy tos is began on the fo urth to the s ix th day afte r the w o rm w as expe lled in

6 of the pa tien ts and in case , no t un til th e e leven th day . Th e re ticu locy te m ax i-

m um was reached in th e firs t 6 cases m en tioned be tw een the seven th and the ten th

day afte r the w o rm cu re , and in the sev en th case on the th irteen th day . Th e m axi-

m um re ticu locy te va lues varied b e tw een 7 .4 an d 2.3 pe r cen t. In th ese case s, ex -

am ina tio n of th e b lood befo re E x trac tum filic is w as g iven show ed tha t the e ry th ro -

cy tes w ere b etw een ii a n d i.i m illion per cu . mm . of b lood .

A pparen tly , a fte r the w o rn i cu re , th e reticu lo cy tosis gene rally se ts in a few d ay s

la te r th an afte r a stro ng in itia l live r trea tm en t. T he m axim um fo r re ticu locy te

va lu es is on the average som ew hat low er than in cases o f pern ic iou s an em ia treated

w ith liv er , bu t on th e o the r hand , th e re ticu locy te c ris is la sts lo nge r . T he in crease

o f t h e e r y t h r o c y t e s i s g e n e r a l l y a b o u t ioo ,ooo pe r d ay , w h ich is ju st a s g rea t a s

wi t h a d e q u a t e l i v e r t he r a p y .

It ha s been fo und by m eans o f a ste rna l pun c tu re th at w ith in 48 hours a fte r the










BE R T E L VO N BO NSDO R F F 93

w orm cure , th e m egalob las to sis in th e b one m arrow g iv e s w ay to a n orm ob las tic

type o f re ge n er at io n .

T he m ost rational th erapy in p ern ic iou s tapew o rm anem ia is th e sim ple w orm

cure . O n ly in v ery sev ere anem ia ist n eces sary to start treatm en t w ith liv e r in -

jec tion s and no t ex pe l th e w orm until af ter th e b lood p ic ture has im prov ed . In

su ch cases, how ev er, it is d if f icu lt to d ec ide af terw ards w he ther the pern ic iou s

anem ia w as cau sed by the w orm or no t. O n ly if th e patien t is v e ry y oung and /o r

has f ree hy droch loric ac id in the gastric con ten ts can one be to som e ex ten t certain

that th e pern ic iou s anem ia w as caused by th e tapew o rm .

T he fac t th at th e pern icio us tapew o rm anem ia is com p le tely cu red af te r the w o rm

is ex pe lled can be ex p lain ed in no o ther w ay than that th e patien ts hav e access to

all th e substances requ ired f or the endogenous form ation o f the an tian em ic prin -

c ip le . E v iden tly , these subs tan ces are av ailab le d irectly af te r e lim in atio n o f th e

w o rm , as in d icated by the p rom p tness w ith w h ich the rem is sion beg in s the reaf te r.

If th e fo od con tain s the ex trin sic fac tor, th is m ust im ply abov e all th at th e in trins ic

fac tor becom es at once av ailab le.b) Castle’ s te st with ga stric juice from patients with pernic io us tapewo rm anemia .

Hernberg (1936-1941) has show n that the gastric ju ice in patien ts w ith p ern ic iou s

tap ew o rm anem ia, as w e ll as in perso ns w ho hav e hadt, con tain s in trinsic fac tor.

M ix ed w ith m eat, such gastric ju ices p roduce a ty p ical rem is sion w hen g iv en to

patien ts w ith cry p tog en etic pern ic ious anemia .

c) In vitro experiments. T he au th or has m ade som e in v estigation s o f the pro teo-

ly tic gastric enz ym e ac tiv e at neu tral reac tion acco rd ing to th e m ethod g iv en b y

T ay lo r e t al. (193 8 ), and has f ound1940) that th is en z ym e occurs in pern ic ious

tapew o rm anem ia as w e ll as in cry p togene tic pern ic ious anem ia, th ough in the

latter cases the to tal am oun t o f the gas tric secretio n is v ery m uch redu ced . It h as

been suggested th at th is enz ym e is iden tical w ith th e in trin sic f acto r. M y resu lts

h av e been con f irm ed by H elander (1945) . Hernberg (1939) w ith L asch’s reac tion

has ob tain ed s im ilar resu lts in the gastric ju ice f rom patien ts w ith pern ic io us tap e-

w o rm anem ia.

T h e in v estigation s h ere repo rted , all support the idea th at the gastric ju ice o f

patien ts w ith p ern ic iou s tapew o rm anem ia con tains in trinsic f ac tor. In sp ite o f

th is , an d in sp ite o f the f ac t that the am oun t o f gastric ju ice is o f ten norm al, an

anem ia has arisen . A pparen tly the pern icio us an em ia in tapew orm carriers is no t

caused b y cessatio n o f the secretio n o f the in trin sic f ac tor becau se o f the presen ce o f

the w orm . H ow ev er, it is ev iden t that som e inh ib ition o f the gastric ju ice secre -

tion m ay occur in connectio n w ith pern icio us tapew orm anem ia, f or in som e cases

f ree hy droch loric ac id reapp ears in th e gastric con ten ts af te r th e rem is sion in pa-

tien ts w ho show ed ach lorhy d ria w h ile the anem ia w as apparen t.

T he au thor has b een unab le to f in d an y d if f e rence in the sp eed o f rem ission af te r

a w orm cu re in patien ts w ith ach lorhy dria and those w ith norm al g as tric secre tion .

It seem s possib le that a d ecreased secretio n o f in trin sic fac tor m ay f acilitate the

occurrence o f a pern ic ious anem ia in connec tion w ith tapew o rm in f estatio n . I t is

w e ll k now n that som e p eop le w ho hav e had a pern ic ious tap ew orm anem ia w hen

y oung , h av e later f allen ill w ith a cry p togene tic f orm of th e d isease . In som e










94 D IPH Y L L O B O T H R IUM L A T UM A N D A N E M I A

fam ilie s m any cases o ccur o f bo th cryp to gene tic anem ia and p ern ic io us anem ia due

to w orm . T he cause of th is has b een con sidered a spec ial‘cons titu tion al d ispos i-

t ion ’ ‘ fo r th is type of anem ia . It m ay be tha t th is‘d ispos i t ion ’ ‘ con sists in a de-

fic ien t p rod uc tio n o f in trinsic facto r .

2.. T H E E x T R IN sI C FA C T O R

a) Clinica l observa tions . Experience in F in land show s th at w o rm carrie rs can

have p ern iciou s anem ia even thou gh the ir food con ta ins a su f fic ien t am oun t o f p ro -

tein o f d iffe ren t k inds . A pparen tly , lack ofex trins ic fac to r is no t essen tia l fo r the

occurrence o f pern ic ious tapew orm anem ia (in con tras t to som e other cond itions

such as , fo r ex am ple, th e nu tritiona l trop ica l pe rn ic ious anem ia). H ow ever, ce r-

tam fac ts do support the id ea tha t a re lativ e de ficiency in ex tr in sic fac to r

can con tr ib u te to th e r ise o f the d isease . G . T #{246}tte rm an fou nd in h is m ate rial a

h igh er frequen cy of pern ic ious tapew orm anem ia in942 . th an in 1943 . In th e

fo rm er year the food s itu ation in our coun try w as particu la rly se riou s; the re w s a

spec ia l lack of p ro te ins. Th e nex t y ear the situa tion had im p roved con siderab ly .

My ow n expe rience ag rees w ith th at o f T#{246}tte rm an’s . In som e cases o f w orm ane -

m ia , I have seen a sligh t re ticu lo cy tosis and ev en a cer ta in im provem ent o f the

ery th rocy te coun t during the adm in istra tion of m ea t. T h is w as the case w ith

so ld ie rs w ho cam e for trea tm en t d irec tly from the fron t. C ram er1911) observed

pern ic ious tap ew orm anem ia a t the sam e tim e in 3 s iste rs w ho , by reason of som e

m enta l pecu liar ity , lived like herm its and fed them se lves w ith an ex trem ely in -

sufficient d ie t .

b) The course o f remission a fter remova l o f the worm in the a bsence o f extrins ic fac tor.

It is log ica l to assum e th at the re w ill be no rem iss ion af te r th e w orm is exp elled if

the p a tien t, shortly befo re and afte r th e w orm cure , h as taken food co n ta in in g n o

ex trins ic fac to r. T he correc tness o f th is reaso n ing has been sh ow n in a se ries o f

tw elve tests. W hen the p atien ts w ere adm itted to the hosp ita l they w ere p laced

on a bas ic d ie t as f ree f rom ex trins ic fac to r as possib le . A fte r som e days , th ey w ereg iv en a w orm cu re . V ery ins ign ifican t s ig ns of b lood regenera tion , o r no ne a t a ll,

w ere o bserv ed even af te r tw e lv e to fifteen d ay s. O n the con tra ry , th e b loo d p ic tu re

o f t e n becam e p rogressive ly m o re abnorm al. A soon a s substan ce s know n or be-

liev ed to co n tain ex trinsic fac to r w ere ad ded to the d ie t, a m arked re ticu lo cy to sis

began and the b loo d p ic tu re im prov ed rap id ly . It has been p rovedha t th is is

tru e w hen m eat, m ilk , H amm arsten ’s case in , pep ton , b rew er’s yeast and concen-

tra ted yeast ex trac t and , to a lesse r d egree , so y bean pro tein w ere ad ded to the d ie t.

T h ese observa tion s con firm Cas tle ’s theory tha t b o th in trinsic and ex tr in sic fac to r

a re necessa ry .

T he m ethod fu rn ishes a m eans of tes tin g subs tan ces fo r the ir co n ten t o f ex trin sic

fac to r .

One practical conclusion is that, after worm cure, patients with worm anemia

m ust be g iven a d ie t rich in pro te ins if a rap id rem issio n is to be expec ted .

3. T H E IN T E R A C T IO N B E T W E E N T H E I N T R IN S IC A N D E X T R I N S IC FA C T O R S

Castle ’s test has no t been prev ious ly carried ou t on pa tien ts w ith pern ic ious tape-

w orm anem ia , ye t th is experim en t is o f g rea t im por tance . It is co nce iv ab le tha t










B E R T E L VO N BO NSDO R F F 95

th e w o rm in the in tes tinal canal p rev en ts th e in te rac tio n be tw een ex trin s ic an d

in trin s ic f ac to rs an d in th is w ay g iv e s rise to the pern ic iou s anem ia. If th is is true ,

it w ou ld be ex p ec ted th at no rem is sion w ou ld occur w hen a patien t is g iv en a m ix -

tu re o f m eat an d gas tric ju ice . T h is w ou ld ind icate th at the w orm h as been ab le

to des tro y the e f f ec t o f th e se subs tances supp lied f rom ou ts ide in the sam e w ay as it

p rev en ts the body ’s ow n in trin s ic f ac to r f rom in te rac ting w ith ex trin s ic f acto r in

the patien t’s o rd in ary f o od . If a f re sh m ix tu re o f gastric ju ice an d m eat p ro v es to

be ine f f ec tiv e w h ile the sam e m ix tu re incub ated f o r six h ours at 3 7#{ 1 76}. do es h av e an

an tianem ic e f f ec t, th e conc lu sion m ig h t be draw n th at b y m ean s o f the enz y m e ac -

tiv ity in v itro , som e new su bstance is f o rm ed w h ich the w orm is unab le to in ju re .

A series o f 14 te s ts w as carried ou t to clear up th is q uestion . M eat (iso Gm .

per day ), o r in som e te sts y east ex trac t, w as used as the sou rce o f th e ex trin sic f ac -

to r. T he daily am oun t o f gas tric ju ice w ith w h ich the m eat o r y eas t w as m ix ed

w as 150-175 m l. E ach te st pe riod lasted e igh t day s. D u rin g the f irst te st pe riod a

no n incubated m ix tu re w as g iv en .

In som e cases o f cry p togene tic p ern ic io u s anem ia these tes ts p rod uced a sp len d id

rem is sion . T he e f f ec t w as equally goo d w he ther the m ix tu re w as incub ated pre-

v io u sly o r no t. O n th e o ther hand , the te s t re su lts w ere c learly n eg ativ e in case s

of p ern ic iou s tapew o rm anem ia. N e ither f resh nor in cubated m ix tures o f m eat and

gas tric ju ice p ro duced any rem iss ion . In som e cases the id en tical gas tric ju ice w as

used as in paralle l te s ts w ith c ry p togene tic pern ic iou s anem ia. T he rem is sio n

occurred o n ly af ter the w o rm had b een ex pe lled .

In one case o f pern ic ious tapew orm anem ia,io o m l. o f g astric ju ice w as bro ugh t

up daily af te r in su lin s tim u lation , and w as incubated w ith io G m . o f m eat f o r six

h ours , af te r w h ich the m ix tu re w as adm in is te red to th e patien t. N o t ev en in th is

w ay cou ld any rem iss io n be prod uced .

T hese observ atio n s g iv e stro ng su pport to the idea that the w orm in the

in te s tin al canal is capab le o f p rev en tin g in te raction be tw een the ex trin s ic and in -

trin sic f ac to rs an d that such an in h ib ition can be deem ed to be th e reaso n f o r the

pern ic iou s anem ia.

T he f ac t th at incub ation does no t in v o lv e an im prov em en t o f th e an tian em ia

e f f ec t o f m eat an d gas tric ju ice co n f irm s the assum p tion that the an tian em ic prin -

c ip le cann o t be f o rm ed in v itro bu t on ly in v iv o . It is po ss ib le that the in te rac tion

be tw een ex trin s ic an d in trin s ic f ac to rs tak es p lace in the in te s tin al w all (Form ij-

n e x , 1940) . Perhap s th is in te rac tio n is no t a sim p le en z y m e reac tion .

4. T H E L IV E R F AC TO R

If th e w orm in pern ic iou s tapew o rm anem ia is ex pe lled and the f o rm ation o f new

an tianem ic f ac to r is p rev en ted by g iv ing a d ie t f ree f rom ex trin sic f ac to r, th en , as

already stated , th e re is no b lood rem is sion . T h is sh ow s that the liv e r m us t b e de -

p riv ed o f its stock o f an tianem ic f acto r, f o r if any w ere presen t, b lood reg en eration

shou ld tak e p lace af te r th e anem ia-p rod uc in g w orm had been rem ov ed , in -

depend en tly o f th e su pp ly o f in trin sic and ex trin sic f acto rs.

It is conce iv ab le th at the w o rm m ay des troy the an tianem ic f acto r at the p lace

w here it is assum ed to be f o rm ed , i.e . in the in te stin e . A n o ther possib ility is that










96 D IPH Y L L O B O T H R 1UM L A T UM A N D A N E M I A

the w o rm tox ins ab sorb ed from the in tes tin e m ay destroy the en tire q uan tity o f

an tianem ic live r fac to r ava ilab le in th e b ody , bu t th is is an im probab le theory .

It is a p rio ri som ew hat im pro bab le tha t the tapew orm can in ju re th e liv er facto r,

pa rtly becau se it is ra the r stab le an d partly becau se w e know tha t the adm in istra -

tio n of live r p repara tions bo th p aren tera lly an d per os qu ick ly cu res a pern ic ious

tap ew orm anem ia.

I have in cu ba ted o rd ina ry in jectab le live r ex trac ts tog eth e r w ith w orm in v itro

a t 37# {176 }. fo r som e d ay s and cou ld no t, a t least in th is w ay , p ro ve any decrease o f

the ir an tianem ic ef fect.

I t appea rs , then , tha t the lack of the liv er fac to r is no t the re su lt o f destruc tion

by the tapew o rm itself no r by tox in s from the w orm .

5 . F 0L I c A C ID

I have trea ted 4 cases o f pe rn icio us tapew orm anem ia w ith fo lic ac id p e r os. A n

exce llen t rem ission w as ob ta ined in a ll cases w ith do ses o f lo -30 m g. da ily fo r-10

day s, show ing tha t fo lic ac id a lso is n o t in ju red by the w orm .

6. T H E A B S O R PT IO N

The clin ica l p ic tu re in pe rn ic ious tapew o rm anem ia g ives no reaso n to be lieve

tha t the abso rp tion in th is d is ea se is im p a ired . C a rr ie rs o f D iph y llob o th rium

latum seldom suffe r from sev ere in tes tina l d istu rb an ces . W orm carrie rs w ith and

w itho u t anem ia do no t d if fe r from each o th er in th is resp ec t. In n o case are the

cond itions com parab le w ith those in sp rue , in tes tin a l an as tom oses, etc .

T he g lucose to le ran ce test has been car ried ou t in 4 cases o f pern ic io us tap ew orm

a n e mi a , b o t h b e f o r e t h e wo r m c u r e a n d a f t e r t h e b l o o d h a d b e c o me n o r ma l . I n a l l

cases the b lood sugar curve had a n orm al course b o th befo re and afte r the w o rm

cure ; thus i t w as no t possib le to sh ow tha t th ere w as any d is tu rbance in the g lucose

absorp t ion .

7. E X PE R IM E N T A L FE E D IN G W I T H T A PEW O R M PR E PA R A T IC N

The effec t on the b lood of g iv ing w orm p rep ara tion s per os o r p aren terally has , o f

course , been s tu d ied in bo th an im als and hum ans . T . W . T a llq v ist1907 ) exper i -

m en ted on h im se lf in th is w ay an d G . T#{246} tterm ani 8-1940) has pu b lished a la rge

se ries o f tes ts. B o th have tho ugh t th ey saw a cer ta in anem ising effec t f rom the

prepara tions they used . I am no t con v inced of the co rrectness o f the ir conc lus io ns

f o r r e a s o n s s t a t e d i n a n o t he r p u b l i c a t i o n .

The prob lem has b een a ttacked by a ttem ptin g to answ er th e fo llow ing questions :

(i) Is the an tianem ic effec t o f the m ix tu re o f g as tric ju ice and m ea t nu llif ied if

wo rm is add ed ? (i) Is th e rem ission a fter the w orm cure absen t in w orm anem ia pa -

tien ts if th e w orm prep aration is g iven per os?

Th e mi x t u r e s o f g a s t r i c j u i c e a n d me a t ( o reas t ex trac t) w ere prepared in th e

sam e w ay as d esc ribed earlie r. T he sub jec ts w ere pa tien ts w ith un trea ted cry p to -

gene tic pern ic iou s anem ia . F irst they w ere trea ted fo r e ig h t d ay s w ith g as tric ju ice

p lus m ea t (o r yeas t ex trac t) w ith the add ition of a con side rab le am ount o f fresh or

d r ied D iphy llobo th rium la tum . Th e rem ission w as a lw ays sp len d id . D uring the










B E R T E L VO N BO N SDO R F F 97

fo llow ing period w ith gastric juice plus meat (or yeast ex tract) w ithout the addi-

tion o f w orm , no new reticulocytos is w as o bserv ed and the blo od regeneration w as

no more rapid than during the first test period.

In one case of w orm anemia the patient, af ter the w orm cure , w as g iv en w orm

pow der per O s in increas ing amounts. In spite o f this the blo od impro ved in the

usual w ay .

In some tests the w orm anemia patients w ere kept on a die t free from ex trinsic

facto r, w ere g iv en w orm cure and then fo r e ight day s extrinsic factor in the form of

y east ex tract w ith the addition of w o rm pow der. In spite o f this addition the bloo d

im pro ved rapidly .

In connection w ith these tes ts, w orm pow der w as mixed w ith hog’s stom ach in

order to investigate the possibility o f loss o f antianemic effec t. In spite o f the addi-

tion of pow dered w o rms in tw o such tests the hog ’s stom ach still had a m arked

antianemic effec t.

It w as thus show n that additio n of w orm is unable to destro y the antianemic ef-

fee t o f m ix tures of g astric juice and extrinsic factor, or of stomach preparations.

M oreov er, the presence o f w orm does no t prevent the rem ission after the e lim ina-

tion o f the w orm in w orm anem ia. This fact has been interpreted to m ean that the

inhibition o f the interaction betw een the intrins ic and ex trins ic factors can be pro-

duced only by the liv ing w orm in its natural surrounding s at the place w here the

int er ac ti on o cc ur s.

8. IN H IB I T IoN IN V IT R O O F T H E P R O T E O L YT IC AC T IV I T Y O F G A ST R IC

J U IC E AT N E UT R AL R E AC T IO N

The gastric protease w hich is active at a pH rang e from 5O 9 is greatly inhibited

in its hydro ly tic capac ity in v itro after the additio n o f even re lative ly small

amounts of Diphyllobothrium latum. The inhibitory substance is destroyed by

heating to 8o#{ 176}. for tw enty m inutes . It is not dialyzable and is not so luble in

ether, nor in 98 per cent e thy l alco ho l. It cannot be prec ipitated w ith0 per cent

alcohol, but can be precipitated quantitatively in0 per cent alcoho l.

The gastric protease in question has been assumed to be identical w ith the in-

trins ic factor, and the hydro lysis o f case in in v itro has been cons idered as corres-

po nding to the interactio n betw een the intrins ic and extrinsic factors in v ivo . It

has no t y et been possible to pro ve this assumption. A s stated abo ve it seems

pro bable that such interactio n cannot occur in v itro but o nly in the intestinal canal.

There is thus a descrepancy as fo llow s: (a) The liv ing w orm in s itu seems to in-

hibit the interaction betw een the extrins ic and intrinsic facto rs, (b) the administra-

tio n per o s of w orm preparations does no t inhibit this interaction, w hile again (c )

the addition of w o rm in v itro inhibits the proteo ly tic activ ity of gastric juice at

neutral reaction. Itseems that this discrepancy cannot be explained until w e have

more detailed know ledge of the different substances here concerned. The ex act

chemical nature of the extrinsic factor, intrinsic factor and the tapeworm toxin

are as yet unknow n.










98 D IPH Y L L O BO T H R IUM L A T UM A N D A N E M IA

9. T H E L O C A L IZ A T IO N O F T H E T A PE W O R M IN T H E IN T E S T I N A L C A N A L

P resum ab ly the w o rm canno t inh ib it the reac tion be tw een ex tr in sic and in trins ic

fac to r un less the w orm is p resen t a t the p lace w here the in te rac tion occurs. N ow

the question ar ises: W here in the in tes tina l cana l is the w orm to be found? V ery

uncerta in in fo rm ation on th is po in t is ava ilab le . E xperience from opera tio ns an d

au to psy in genera l ind ica te tha t the w orm has been ch ie fly ob served in th e ileum ,

bu t the re a re no sys tem atic ob serva tions of th is fac t. S om etim est happ ens tha t

D iphy llobo th rium la tum is vom ited , w hich show s tha t a t leas t occas iona lly i t ca n

b e very h ig h up in the in tes tine . T o inves tig ate th is q uestion , the au tho r m ade a

se ries o f in testina l in tub a tion s. A s the D ip hy llobo th rium la tum p roduces la rge

quan titie s o f eggs it w as re la tive ly easy to de te rm ine a t w h at d istance from the

TABLE i-D istance from M outh (cm .) w here O va and/or Proglottids of D iphyl/obothrium Latum W ere Found

(;roupl

X o a n em ia

Cou

Nonpe rn i c iou

- G roup 3

s a n e m a Pe r n i c i o u s t a p e wo r ma n e m a , ma n i f e s t

G roup 4

P er n , i c i u s t aPe wo r m

a n e m a i n p ? n t a n e o u s

r e m s s i o n

2.35 3 3 4 ‘ 3 5 3 2 . 0

2 . 3 5 i 8 o 1 2 . 0 2 . 4 0

2 . 3 0 1 4 0 1 2 . 0 2 . 0 5

i 8 o 1 2 . 0

i 8 o 11 5

i 8 o ii

i6 iio

ISO 105

145 105

53 0 95

m outh the firs t eggs cou ld be asp ira ted . In m any cases sm all p ieces o f the w o rmt-

se lf w ere asp ira ted a t the sam e tim e . O f co urse,t is no t possib le to ca lcu la te in th is

w ay the h igh es t po in t in the in tes tine w here the w orm is attached . A lth ough no

eggs are p ro duced from the h ighes t segm en ts o f the w orm , ye t I have been con -

v inced tha t resu lts can b e ob ta ined w h ich allow com parison b etw een d iffe ren t

cases .

T he in tuba tions w ere carried ou t on 2 .6 w orm carrie rs w ho w ere d iv ided in to 4

grou ps as ap pears in tab le i, in w hich the resu lts a re a lso summ arized .

T he resu lts sh ow tha t in m an ifest pe rn ic iou s anem ia the w o rm is found h ig her

up in the in tes tin e th an o th erw ise. P erhaps o ne can im ag ine tha t in tha t reg io nt is

be tter ab le to in ter fe re w ith the in te rac tio n be tw een ex trin sic and in trins ic fac to rs .

Ho w h i g h u p i n t h e i n t e s t i n e t h e wo r m mu s t b e f o rt to inh ib it th is reaction isi f l i -

cu lt to de te rm ine . M y resu lts fav or the o p in ion tha t a “c ritica l lim it” lie s40-I 50

cm . from th e m ou th , w hich ough t to be abou t the borderline be tw een the je junum

and the ileum .

JO . AN A T T E M PT T O E X PL A I N T H E PA T H O G E N E S IS O F T H E PE R N I C IO U S

T A PE W O R M A N EM I A

A s described above , i t app ears to be po ss ib le tha t the D iphy llobo th rium la tum

causes pern ic io us anem ia by inh ib iting th e in te rac tio n be tw een ex trins ic and in trin -











sic f ac to rs , bu t that th is reac tion can occur on ly if th e w o rm is su f f ic ien tly h ig h in

the in te stin e . H ow ev er, as stated p rev iou s ly , th e re is reason to p resum e th at th e

am oun t o f ex trin sic f acto r in th e f ood an d o f in trin sic f acto r in the gas tro in tes tinal

canal is also o f som e im portance . T hus w h ether anem ia occurs o r n o t w ou ld d ep en d

on a d ef in ite co rre latio n am ong these th ree de term in an ts : th e am oun t o f ex trin s ic

f acto r, th e am ou n t o f in trin sic f ac to r, and the w orm ’s h igh o r low pos itio n in the

intestine.

Finally a tim e f ac to r m ust also be tak en in to cons id eration . T h e f o rm atio n o f

an tianem ic f acto r m us t hav e been inh ib ited f o r such a long tim e that the liv e r is

w ho lly depriv ed o f it. O n ly then is th ere reason to ex pec t that th e anem ia w ill

m an if e st its e lf .

It m us t be em phas iz ed that in the g reat m ajo rity o f case s o f pern ic iou s tapew o rm

an em ia, th e re is no basis f o r the assum p tion that e ith e r a de f ectiv e d iet o r a h ered i-

tary d ispos itio n are to be reck on ed w ith as co -o perating causes . M o st tap ew orm

anem ia patien ts dono t f all ill late r w ith a cry p togene tic anem ia. I can , th e re f o re ,

no t con f irm th e correc tnes s o f B irk e lan d ’s con clu s ion that‘ it seem s approp riate to

c lass if y su rv iv ing patien ts w ith D iphy llobo th rium anem ia as su f f e ring f rom abor-

tiv e f o rm s o f genu ine pern ic iou s anem ia. ‘ M y v iew o f the p rob lem is that in p rin -

c ip le an y w orm carrier w hosoev er can ge t a pern ic iou s tapew o rm anem ia if on ly

the w o rm -cete ris paribu s -is h igh eno ugh up in the in te stin e . I f th e w orm is ex -

pe lled a com p le te re stitu tio n can f o llow .

T h e th eo ry I hav e f o rm u lated ex p lain s -in m y o p in ion -the f o llow ing c ircum -

s tances w h ich hav e b een specially pu t f o rw ard by S altz m an1914 ) and w h ich hav e

h ithe rto b een d if f icu lt to in te rp re t.

a) A person can carry D iphyllobo thrium la tum fo r many years be fore he fa lls ill with

pernic ious anemia . T h e ex p lan ation o f th is can be that the w o rm , f o r one reaso n or

ano th er, has inv ad ed the upp er parts o f th e in te s tin e , som e tim es po ss ib ly as a re in -

festation.

b) A person who ha s had pernic ious worm anemia a nd becomes we ll a fter the wo rm is

expe lled does no t necessarily ge t anemia if he is aga in infe sted w ith worm.t th e re in f e sta-

tion it m ay happen that th e w orm is on ly in th e low es t parts o f th e in te stin e .

c) A worm expe lled from an anemia pa tient is o ften dis integra ting and disco lored.o m e -

tim es no w orm at all is seen in the f ece s . A cco rd ing to m y theory , th is d isin teg ra-

tion can b e due to the f ac t th at the w orm , be in g h igh er up in the in tes tin e has had

a lon ger d istance to go be f o re it w as ex p elled . D u ring its passage th ro ugh the in -

testine it has had to undergo a stron g au to ly tic decom pos ition and is also af f ec ted

m ore by th e d ig es tiv e en z y m es than if it had b een in the low er part o f th e sm all

in te stin e an d o n ly had to p ass th roug h the co lon , w here the en z y m es are le s s ac tiv e .

d) The amount o f worm is no t in corre la tion w ith the o ccurrence o f anemia .sma l l

am oun t o f w orm can cau se anem ia if it is su f f icien tly h igh up in th e in te s tin e, w h ile

a large amount does not necessarilydo so ifit is co llec ted in th e low er part o f th e

sm all in te stin e . Y et case s w ith v ery larg e am oun ts o f w orm ,o-ioo M . and more,

are o f ten accom p an ied by anem ia. In such cases it can b e im ag ined that the w orm ,

b ecause o f its g reat v o lum e , has been f o rced u pw ard s tow ard s the je ju num .

e) Spontaneous remiss ion with a return to normal blood values are not rare in worm










10 0 D I PH Y L L O B O T H R IUM L A T UM A N D A N E M IA

anem ia . T he exp lana tion of th is can be tha t the w orm had deserted the upp er parts

o f the sm all in tes tine and w andered dow n tow ards the ileum . In m y 3 cases o f th is

type the w o rm w as found ju st as low in the in testine as in non anem ic w orm carrie rs

(c f . table i).

f) Remiss io n a fter an incomplete worm cure can a lso occur. filic in cure can fa il in such

a w ay th at on ly a sm all am oun t o f th e w orm , or none at a ll is exp elled , and af te r

the cure w o rm egg s can still b e seen in the feces . In sp ite o f th is, the b lood im prov es .

A t a la te r w orm cure-af te r th e b loo d p ic tu re has becom e norm al-a con side rab le

am oun t o f w orm is o ften rem ov ed . In su ch cases-accord ing to m y idea-the w orm

at the firs t ‘ ‘unsuccess fu l ’ ‘ cure w as d riven from th e upper part o f the in testine bu t

rem ained in the low er part w hereit w as no long er ab le to exerc ise its anem ia-p ro -

duc ing effect.

T h is idea w as con firm ed by the fo llow ing test. In on e case of m an ifes t p ern iciou s

w orm anem ia the egg s w ere fou ndi i cm . from the m outh . T hrough the in testina l

tube 2. Gm . fih icin em uls io n w ere ins tilled . T he w orm w as no t expe lled and the feces

con tinued to con ta in w orm egg , bu t they cou ld no t b e dem onstra ted as presen t a t

the fo rm er dep th ( ii cm .). A few days afte r the filicin cure a m arked re ticu locy to -

s is b egan and the b lood p ictu re im prov ed rap id ly . T h e tube w as then a llow ed to

g lide fa rthe r in , and w orm eggs w ere no t foun d tillC O cm . from the m outh , th at

is , fa r dow n in the ileum . F o llow ing an o ther trea tm en t w ith filic in ,1 M . of or-

d ina ry lo ok ing D iphy llob o th rium latum w ere ex pe lled .

C O M M E N T

A cco rd ing to one earlie r th eory , th e occurrence of w orm anem ia m ay b e du e to a

chan ge in the charac te r o f the paras ite , possib ly an abnorm al d isin teg ra tion f the

w orm in the in tes tine , bu t I have been unab le to find any s ig ns of such a d isin te -

g ra tion . T he w orm segm ents w hich I som etim es asp ira ted a t in tuba tio n from w orm

anem ia p a tien ts h av e been v ery m otile and of o rd inary appearance . A ccord ing to

o th er theories, the cause of the anem ia lay in the ho st. T h ese theor ies hav e pre -

sum ed a vary ing perm eab ility o f th e in testina l w a ll to the w orm tox in , a spec ial,

ind iv id ua l su scep tib ility o f the hem opoie tic o rgans to it, o r an a lle rg ic p repared-

n ess; G . T #{246} tte rm an has c lassed the pernc ious tapew orm anem ia w ith the m alignan t

g ranu locy topen ia due to th e use of am idopy rin e . A part from the fac t tha t I find the

exp erim en ta l basis o f these theories d efective , none o f them seem to m e to exp la in

the w orm anem ia p rob lem satis facto r ily . It appears a rtif ic ia l to conce ive of the

m acrocy tic anem ia w ith its m ega lob lastos is as an a lle rg ic reaction . A no ther fac t

tha t tells aga ins t the tox ic an d alle rgo- to x ic th eories is tha t the anem ia can be cured

w ith live r o r stom ach prepara tions w itho u t exp u lsion o f the w orm . A ga in , on the

b as is o f them , it is d iff icu lt to ex p la in w hy no rem ission occu rs a fte r the w orm cure

un less ex trinsic fac to r is ava ilab le . T he c ircum stan ces lis ted under Sec tion JO

(a- f) abov e are a lso no t easy to exp la in .

T here is n o doub t tha t D iphy llobo th rium latum con ta in s a pow erfu l po iso n . If

one h and les fresh w orm w ith unpro tec ted hands , the sk in is g rea tly irrita ted . I f one

p laces a sm all am oun t o f d ried and pu lverized w orm on the tong ue , th ere is a fee ling

o f burn in g . Th e in ha lation of w orm pow der has been proved to produ ce n au sea ,











f e v e r, rh in itis , asthm atic co ugh an d eosino ph ilia in th e b loo d . A w orm carrie r

o f ten su f f e rs f rom g idd in ess , v ario u s nerv ou s m an if e station s and nausea, has eo sino -

ph ilia (w h ich m ay o r m ay n o t be absen t in anem ia cases ) an d show s sero log ical

changes . L ik e the m acro cy tic , n onpern ic iou s anem ia d esc ribed by G . T #{ 246} tte rm an ,

the se phenom ena can be co nsidered as the ex pres sion o f th e e f f ec ts o f to x ic ac tiv ity ,

re sem b ling tho se w h ich co nd itio n the rise o f pern ic iou s anem ia. T hus , accord ing to

m y idea, th e inh ib itio n o f the in terac tion be tw een ex trin sic and in trin s ic f ac to rs is

on ly on e ex pres sion o f the w o rm ’s to x icity .

T ests on an im als w ith w orm p reparatio n in jec tion s also bear w itn es s to the tox -

ic ity o f th e w orm . A m ong o th er th in g s, it appears to con tain a hem o ly tic tox in .

Y et it h as no t been possib le w ith the se te sts to p roduce an an em ia w h ich d irectly

co rre spond s to the A dd ison ian an em ia in m an .

M uch con f u s ion in the d iscu ssion s cou ld , I be liev e , be av o id ed if th e ab ility o f

th e w orm to prod uce p ern iciou s anem ia w as cons is ten tly k ep t sep arate f rom its

o ther to x ic p ropertie s.

C ertain d etails in the tap ew orm an em ia p rob lem still aw ait so lu tion . L ik e th e

cry p togene tic pern ic iou s anem ia, th e pern ic iou s tapew orm anem ia show s de f in ite

v ariation s in its seasonal d is trib u tion . I t is m os t u sual du ring the period f rom

M arch to A u gus t. I llu s trativ e cu rv es w ith w h ich m y ow n ex p erience agrees are to

b e f o und in B irk e lan d ’s m onograp h . It is at p re sen t im possib le to decide to w hat

ex ten t the se seasonal v ariation s depend on c ircum stances in the patien t h im self :

on ligh t co nd itio n s, on the con ten ts in the d ie t o f p ro te in , f o lic ac id (as sugges ted

b y W aldens tr# { 2 46} m ) , o r o ther su bstances. A rac ial f ac to r (in con nection w ith

p igm en t m e tabo lism ) m ust also be tak en in to con sideration in bo th f o rm s o f per-

n ic iou s anem ia.

T he chem ical n atu re o f the w orm ’s tox in is s till unk now n . If th at cou ld be de te r-

m i n e d , it m igh t be p oss ib le to ge t a be tte r idea o f the p rocess by w h ich the p o ison

in te rf eres w ith the in te rac tion b etw een the ex trin sic and the in trin s ic f ac to rs .

I hav e tried to sh ow here that the inv estigation o f pern ic iou s w orm anem ia h as

n o t o n ly a local in te re st bu t can also con trib u te to the e lu cidation o f the w ho le

g reat ques tio n o f the m acrocy tic and m egalob las tic anem ias w h ich re spond to liv e r

treatm en t and w h ich are te rm ed ‘p ern ic io u s.”

REFERENCES

R I R 1 C E L A ND , I. W .: “B o thriocephalu s an em ia.” M ed icine ii: I, 1932..

vo N BONSDORI’F, B .: L iv e r ex tract ex posed to the action of in tes tin al w orm s do es no t lo set s a nt i- an em i c

e f f e ct. A cta m ed. scand. 100 , 436, 5939 .

Th e inf luence of in testinal worms on the pro teo ly t ic activ ity in v itro o f try p sin , papain and pepsin

and e specially o f hum an gastric ju icet ne u tral re ac tion . A cta m ed. scand. io o , 459 , 1939 .

T he in hib itory ef f e ct o f D ip hy lloboth rium latum on the p roteoly tic ac tiv ity in v itro ofepcps in -

iz ed hum an gastric ju ice . A c ta m ed . scand.os, 502 ., 1940.

O n th e r et icu locy t e r esp on se a n d cou r sef rem ission af ter rem ov al o f th e orm in patien ts w i t h

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scand . 105 , 5 40 , 1940 .










1 02 . D IPH YL LOBO THR IUM LA TUM AND A NEM IA

: O n t h e r em iss ion a f t er r em ov a l o f t h e w orm in p e r n ic iou s ta p ew orm an em ia in p r esen c e an d a b -

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I n p r ess .

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m#{233}m.S o c . Me d d . h o p . d e Pa r i s 4 6 . ’ 5 4 7 5 ,192.2..

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m t. M ed . 6 6 : 1191 , 1940 .

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an aem ia . A cta m ed . scand . S upp .78: 582 . , 1936.

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me d . s e a n d . S u p p . 7 .’ 2 .6 8 , 192.4.

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rioc eph alu san #{228}m ie. Z tschr . f. k Im . M ed .6i: 42 . 7 , 1907.

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T #{ 24 6} TT ER MA N, G UI DO : U ber d ie Pa tho gen ese der W u rm anSm ie. A cta m ed . sc and .i6.’ 2 .68 , 1938.

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ii8.’ 410, ‘944 .

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Anemia in Diphyllobothrium Latum

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