Acta Medica Scandinavica. Vol. 166, fasc. 3, 1960

From the Medical Department, Maria Hospital (Head: Guido Tottcrman, M. D.), Helsinki, Finland

Pernicious Anemia and Atrophic Gastritis

BY

M. SIURALA, E. ERAMAA and W. NYBERG

Atrophic changes of the gastric mucosa have been encountered in most cases of pernicious anemia (3, 5, 7, 8, 9, 15, 17, 21, 22, 23, 26, 31, 33, 38). These changes have been held responsible for the de- ficient secretion of intrinsic factor leading to pernicious anemia (9, 10, 16, 26, 27, 40). Recent studies with radiovitamin B,, seem to support this view ( 1 , 2, 4, 1 1 , 12, 13, 19, 20, 25, 36, 37). However, there have been reports of cases of pernicious anemia with deficient intrinsic factor secretion in spite of a histologically normal gastric mucosa and normal hydrochloric acid secretion (6, 14, 24, 28, 29, 30). Siurala and Nyberg (36)) who found by the Schilling test that vitamin B,, absorption was lowered in many cases with severe atrophic gastritis, suggested that a decrease of intrinsic factor produc- tion resulting in pernicious anemia may develop in a t least two ways: In some cases it may be due to specific lack of intrinsic factor independent of the patho- anatomical condition of the gastric mu- cosa; in others it may result from a chronic, atrophic gastritis.

This study was aided by a grant from Sigrid Just1 ius Stiftelse.

Submitted for publicatiuri August 21, 1959.

‘The aim of this investigation was to study from various aspects (family his- tory, age and sex distribution, case his- tory and functional and histological con- dition of the gastric mucosa) a large series of patients with pernicious anemia and gastritis not associated with perni- cious anemia, in order to discover the following. Firstly, whether there exist any significant differences between per- nicious anemia and advanced atrophic gastritis. Secondly whether atrophic gas- tritis predisposes to deficiency of in- trinsic factor, i. e. whether atrophic gas- tritis can be considered a pre-pernicious anemia state.

Material and methods In cases in which suction gastric biopsy wa.,

pcrforrned in Maria Hospital during 1956,, 1957 and 1958, the Schilling test was em- ployed almost as a matter of routinc ir- respective of the disease and the histological condition of the gastric mucosa. All the patients on whom both gastric biopsy and the Schilling test were performed were included in the present series. Cases with hcmatological signs of pernicious anemia, in which the Schilling test coilfirmed the dizgnosis, were dealt with as a separate group. The remaining

213

214 M. SIURALA, E. ERAMAA AND w. NYBERG

cases with no hematological signs of pernicious anemia were grouped according to the histo- logical condition of the gastric mucosa. The distribution of cases into various groups is as follows :

Prrnicious a n e m i a . . . . . . . . . . . 50 cases untreated . . . . . . . . . . . . . . . . 24 >> treated . . . . . . . . . . . . . . . . . . 26 )>

Severe atrophic gastritis (total loss of body glands, or only

Moderate atrophic gastritis (moderate loss of normal body glands) . . . . . . . . . . . . . . 40 n

Superficial gastritis (edema and inflammatory cells be- neath the surface without loss

remnants present) . . . . . . . . . 24 ))

of normal body glands). . . . . . 14 ))

Normal gastric mucosa . . . . . . . 35 >>

Total 163 cases

The loss of normal body glands was deter- mined from the amount of parietal and zymogenic cells present. The loss of mucous neck cells, considered by Glass (12) to be the site of intrinsic factor production, could not be used as the criterion since it was difficult to differentiate them from other mucous elements of the diseased gastric mucosa. The experiments of Keuning et al. (18), who found a selective uptake of radioactive vitamin B,, by zymogenic cells, suggest that intrinsic factor i5 produced by these cells.

Total loss of normal body glands was present in 88 ‘)A of patients with pernicious anemia and 80 ?{, of those with severe atrophic gastritis. Thus the degree of mucosal atrophy was approximately of the same order in these groups.

The ordinary Schilling test (36) uropepsin determination (39) and histamine test (samples were taken 30, 60 and 90 min. after adminis- tration of 0.1 mg of histalog or 0.2 mg of histamine phosphate per 10 kg of body weight) were performed in all cases. If the ordinary Schilling test (URT=urinary radio- activity test) revealed low (below 5 %) or low-normal (5-10 values the test was repeated and in addition, the U R T with carbachol (0.25 mg of carbamylcholine) and with intrinsic factor (Organon “intrinsic factor” two tablets) were performed. Before performing the URT, a blood sample was

Table I. The occurrence of pernicious anemia and gastric carcinoma in relatives of patients with gastritis and pernicious anemia

Patient groups

Pernicious anemia. . . . Severe atrophic gas-

tritis. . . . . . . . . . . . . . Moderate atrophic gas,

tritis. . . . . . . . . . . . . . Superficial gastritis . ,

. .

Total No. of cases

28

19

19 14

No. of patients with family history of

Perni- cious anemia

3

3

2 -

- Gas- tric carci- noma -

8

5

4 2 -

taken in 29 cases for drtermination of the serum vitamin B,, level (Euglaena gracilis, Z-strain). The serum iron level was deter- mined in cases of anemia and the blood urea was examined in a patient with low U R T and uropepsin values. A careful case history was taken. A special note was made of the possible occurrence of neurological and lingual changes characteristic of pernicious anemia in cases with atrophic gastritis.

Biopsy specimens were taken from the gas- tric body mucosa using a modification of Woods biopsy tube (32). 502 specimens were obtained from 163 patients, i. e. an average of 3 specimens per patirnt. The specimens were immediately fixed in 5 yo neutral formalin and stained with hematoxylin- eosin, Unna-Pappenheim and PAS.

All the patients were examined by the authors themselves.

Results

1. Family history, age and sex distribution and diseases o f patients wi th pernicious anemia and atrophic gas t r i t k l

Family history o f the patients. A family history of pernicious anemia and gastric carcinoma occurring in nearest relatives

Not associated with hematological signs of pernicious anemia.

PERNICIOUS ANEMIA AND ATROPHIC GASTRITIS

Toble I I . Diseases encountered in various grotifips qf gastritis

Gastric cancer . . . . . . . . . . . . Peptic rilcer . . . . . . . . . . . . . .

Iliiodcnal polyps C:olonic polyps . . . . . . . . . . . .

Tapeworm pern. ancmia. . . .

Other anemias . . . . . . . . . . . . GI ossi t is . . . . . . .

I liyrotoxicosis . . . . . . . . . . . .

Cardiovascular diseases . . . . rI '~~bercr~losis . . . . . . . . . . . . . . None of the abovc mentioncc

tliscascs . . . . . . . . . . . .

c zast1 . : IC polyps . . . . . . . . . . . .

Iron deficiency anemia . . . .

. . -. h'tphroplhy . . . . . . . . . . . . . .

Severe atrophic gastritis 24 cases

Diseases in the past

1 2 -

- -

2 3 7 2 -

- 2 2 2 G

2

Diseascs encount. a t prcscnt examinat.

4

1 1 1 2 I 5 1

I 2 1 2

-

r

-

5

(in sisters and tirothers and parents of the patient and in sisters and brothers of the patient's parents) was obtained from 52 patients with gastritis and 28 patients \vith pernicious anemia. The results are presented in table I. I t appears that the incidcncc of gastric carcinoma and per- nicious anemia in relatives of patients \vith pernicious anemia is largely the same as in patients with severe atrophic gastritis. However, the material is too small to permit any definite conclu- sions.

Sex and age distribution o f the patients is seen from table 111. All groups show a predominance of females, which seems to increase with the degree of severity of mucosal lesion. The percentage incidence of females in the various groups is as follows : pernicious anemia 80 yo, severe atrophic gastritis 76 yo, moderate atro-

Moderate atrophic gastritis 40 cascs

Diseases in the past

I h e a s r s cncount. at prcsent examinat.

215

Superficial gastritis 14 cases

Diseases in the past

liseases ncount. t prcscnt xaminat.

phic gastritis 60 superficial gastritis 57 yo and normal gastric mucosa 54 yo. These groups show a corresponding although lcss marked increase in the mean age also: pernicious anemia 62.4, severe atrophic gastritis 60.5, moderate atrophic gastritis 60.4, superficial gastritis 55.4 and normal gastric mucosa 41.7 years.

Present and previous diseases o f the patients. Diseases f?om which patients with gastritis had suffered in the past and diseases encountered a t the present examination are listed in table 11. Various anemias were encountered in the past history of 12 out of 24 (50 %) cases with severe atrophic, 11 out of 40 (28 yo) cases with moderate atrophic gastritis and 5 out of 14 (36 yo) cases with superficial gastritis. Iron deficiency anemia (hypochromic ane- mia with low serum iron values responding to iron treatment) was the most common

216 M. SIURALA, E. ERAMAA AND w. NYBERG

Table III. Sex and age distribution of the series and the results of the ordinary Schilling test, urobepsin

6 16 6

16

Pernicious anemia . . . . . . . . . . . .

Moderate atrophic gastritis . . . . Severe atrophic gastritis . . . . . . . .

Superficial gastritis . . . . . . . . . . . . Normal gastric mucosa . . . . . . . .

18 24

8 19

Total No. of cases

60.5 60.4 55.4 41.7

50 24 40 14 35

10 1 - -

type of anemia found, both in the past history and at examination of the pa- tients. Judging from previous investiga- tions, it is quite possible that the iron defi- ciency state as well as the vitamin B,, defi- ciency of pernicious tapeworm anemia noted in the past history of 3 patients with severe atrophic gastritis might have predisposed to the development of atro- phic gastritis (2, 33, 34). O n the other hand, it is also possible that atrophic gastritis in some way produced a predis- position to the iron deficiency and vita- min B,, deficiency in these cases.

Gastric cancer was present in four cases with severe and one case with moderate atrophic gastritis. I n addition, one patient with severe atrophic gastritis had under- gone partial gastrectomy for antral cancer 6 years previously without sign of recur- rence. Gastric polyps were encountered in 1 case with severe and 2 cases with moderate atrophic gastritis. These condi- tions were not represented in the groups with superficial gastritis and normal gastric mucosa. O n the other hand 5 out of 50 cases with pernicious anemia had gastric carcinoma and two had gastric polyps. Peptic ulcer was a common find- ing in the past history of patients with moderate atrophic gastritis, hut only two patients with severe atrophic gastritis had suffered from it in the past. The occur- rence of neurological and lingual changes

Sex

in patients with atrophic gastritis rvill he discussed later.

I t appears from the above that in this series the incidence of females and the mean age of the patients showed some increase as the degree of the gastric lesion progressed and that the groups of severe atrophic gastritis and pernicious anemia largely resembled each other both in familial history and in the occurrence of gastric tumours. However, the high incidence of gastric carcinoma in the group with severe atrophic gastritis permits of no far-reaching conclusions since in most cancer patients the diagnosis of cancer was made before gastric biopsy was done.

2 . Functional changes of lhe stomach in per- nicious anemia and atrophic gastritis.

The results of the ordinary Schilling test (URT), uropepsin determination and histamine test are presented in table I11 and fig. 1, and fig. 2 gives the results of the ordinary U R T and U R T with carbachol and intrinsic factor from patients with severe atrophic gastritis. I t appears that ordinary U R T was normal in all cases with normal gastric mucosa and superficial gastritis. Of 40 cases with moderate atrophic gastritis, 2 showed low or low-normal values (4.5 and 9.8 O0),

though normal values were obtained

PERNICIOUS ANEMlA AND ATROPHIC GASTRITIS

determination and histamine test in pernicious anemia and gastritis

Schilling test values yo 5-10 -1 0-5 15-10 I 10-30 I >30

Uropepsin excretion U P units/ hr

1 - 46 I 4 - - - 7 7 20 3 1

I 38 15 10 10 5 - 14 1 1 9 3

Histamine test Free HCI

present I absent

1 50 24

9 31 9 5

~-

-

-

with carbachol stimulation ( 1 9.2 and 12.0 yo). Of 24 cases with severe atrophic gastritis, 10 had low, 7 low-normal and 7 normal values. The values represent the highest ordinary U R T values obtained at different control examinations. U R T with carbachol was performed in 8 out of 10 cases with Iow values, without however obtaining any significant in- crease (fig. 2). U R T with intrinsic factor was performed in 7 out of 9 cases with low values. The result showed an in- crease of the urinary radioactivity, thus probably excluding the possibility of intestinal malabsorption in these cases. I t should be noted also that in all but one of the 10 cases with low U R T values, total loss of normal body glands was found on all specimens. O n the other hand, there was no clear correlation between the U R T values, the severity of the inflammatory changes and the type of inetaplasia in the histological picture.

Serum vitamin B,, level was determined before the performance of the U R T in 29 cases. Values above 150 ,u,ug/ml of serum were considered normal, 100-1 50 low- normal, and below 100 low. The results are depicted in table IV. I t appears that in the 14 cases with severe atrophic gastritis the values were normal in 5, low-normal in 3 and low in 6 cases (33, 34, 34, 63, 77, and 91 ppg/ml of serum, respectively). I n the 8 cases with mod-

- 35 1 - 3 20

..

. : -

12 1 34 1

.. .... . . .. .. . .

* .

..*a

Fig. 1. Distribution or ordinary URT values in various groups.

7 0

2 5

PO

15

10

5

0

Fig. 2. The effect of Carbachol stimulation and intrinsic factor upon low or low normal ordinary UKT values in severe atrophic gastritis.

218 M. SIURALA. E. ERAMAA AND w. NYBERG

Severe atrophic gastritis . . . . . .

Moderate atrophic gastritis . . . . . .

Superficial gastri- tis. . . . . . . . . . . .

Total

Table IV. Serum Vitamin BIZ determinations

14

8

7

29

No. of cases

I-- Serum vitamin B,, level

< l o ( 100-150

erate atrophic gastritis, t h e values were low-normal in one and normal in t h e rest, and in t h e 7 patients with superficial gastritis t h e values were normal in all b u t one case. The ord inary URT revealed normal values i n 17 o u t of 18 cases with a normal serum vi tamin B,l level. On t h e other hand, of 6 cases with a low serum vi tamin B,, level, 4 had low and two low-normal ord inary URT values.

In t h e g r o u p of severe at rophic gastritis there were two cases with l ingual changes and one case with lin- gua l and neurological changes character- istic of pernicious anemia , which respond- ed t o vi tamin B,, adminis t ra t ion i n con- nection with URT. S h o r t case histories of these patients a r e presented here.

Case S. S., female, aged 56. Admitted to hospital for epigastric distress. Roentgen examination of the stomach: negative. Gas- tric biopsy: total atrophy wtth slight inflam- matory changes and with intestinal and pseudopyloric metaplasia. Ordinary U R T : 0.6-1.5 '$6. U R T with intrinsic factor: 22.4 O O . Uropepsin excretion: 1.7 UP units/ hr. Histamine-fast achlorhydria. The tongue was reddish and slightly atrophic, though neither hematological nor neurological changes indicative of pernicious anemia were present. Serum Fe: 66 gamma O h . After the Schilling tests the lingual sings disappeared, returning, however, 6 months later.

Case E. K.: female, aged 76. The patient's mother had suffered from gastric carcinoma. The patient had been treated for many years for heart failure and rheumatoid arthritis and had ingested considerable amounts of anti- rheumatic drugs. Roentgen examination of the stomach : negative. Gastroscopy : atrophy. Gas- tric biopsy: total atrophy with marked in- testinal metaplasia and inflammatory changes almost absent. Ordinary U R T : 2.8 06. U R T with carvachol: 0.4 0;. U R T with intrinsic factor : 12.9 l b . Serum vitamin B12: 77 ppg/ ml. Uropepsin excretion: 1.5 U P units/hr. Histamine-fast achlorhydria. No neurological changes. The tongue was atropic and reddish. This change disappeared after the Schilling tests, but returned some months later.

Case E. P., male, aged 63. His father had achlorhydria and had suffered from tapeworm pernicious anemia. The patient was admitted to hospital for tapeworm infestation with ane- mia. The anemia was macrocytic and megal- oblastic. Marked lingual and neurological changes were present. Ordinary U R T : 1.5-2.0 96. U R T with carbachol: 3.6 yo. Gastric biopsy: almost total loss of normal body glands, intestinal metaplasia and slight inflammatory changes. The anemia and other manifestations disappeared after the Schilling tests and during peroral intrinsic factor ad- ministration. The tapeworm was expelled. Eight months later U R T with carbachol was only 1 yo and uropepsin excretion 2.1 U P units/hr.

In patients S. S. and E. K. there is assumed to be an early pernicious anemia present. In patient E. P. tapeworm infestation resulted in a clinical manifestation of, presumably, pre-existing vitamin B,, deficicncy.

Hydrochlor ic acid secretion and uropepsin secretion showed a distinct decrease with progression in the degree of t h e mucosal lesion ( table 111). Low uropepsin excretion (below 10 UP units/ hr) was noted in 8 yo of patients with a normal gastric mucosa, in 14 yo of patients wi th superficial gastritis, in 62 yo of patients with modera te atrophic gas- tritis, in 95 yo of patients wi th severe a t rophic gastritis and in 100 yo of those with pernicious anemia. The correspond-

PERNICIOUS ANEMIA AND ATROPHIC GASTRITIS 219

Tuble 1’. Histological characteristics of the gastric mticosa in pernicious anemia and atrophic gastritis

20

Pernicious anemia. . . Severe atrophic gastri

Moclcrarc atrophic t I S . . . . . . . . . . . . . . .

. . gastritis . . . . . . . . .

5 3

14

- Total No. of cases

__

50

24

40

I nflamtnatory changes I Intcstinal metaplasi;

sever

10

4

- 21

prcs- cnt

18

11

20 -

lomi- iant

14

10

6 -

I’seudopyloric metaplasia

%bSCIl

10

12

17 -

pres- cnt

19

2

23 -

- Iomi- iant

21

10

- -

1 d e m a and inflaminatorv cells bencath thc s~crfacc.

iiig mean valucs were: 33.1, 18.1, 13.0, 2.1 and 1.5 U P units/hr, respectively. Thc incidence of achlorhydria was as foIIo\\;s: normal gastric mucosa 3 yo, superficial gastritis 36 yo, moderate atrophic gastritis 78 yo, severe atrophic gastritis 100 %b and pernicious anemia

From the data prcsented above i t ap- pears that hydrochloric acid secretion and uropepsin excretion tend to decrease as thc mucosal lesion progresses, and that vitamin B,? absorption and serum vitamin 13,, level reveals the same tendency. I n patients with scverc atrophic gastritis the uropepsin excretion was low, free hydro- chloric acid was absent and in many cases the U l i T values werc of the same order as in pernicious anemia. Three cascs \\;ere presented \vhich might be considered intcrmediate stages between “nonspecific” atrophic gastritis and actual pernicious anemia. I t should be pointed out that even three biopsy specimens do not represent the whole body mucosa. Thus, arcas with normal tubules might

100 %,.

havc been overlooked bioptically, and this might explain thc finding of normal URT values in cases with total or almost total atrophy.

It was interesting to note that with progression of gastritis the hydrochloric acid secretion appearcd to fail first and the ability to secrete pepsin - if uropep- sis secretion reflects the ability of the stomach to secrete pepsin - was lost only later. The intrinsic factor secretion is maintained longest and is not lost until the end stages of atrophic gastritis. Poliner et al. (28) have recently drawn attcntion to the same phenomenon.

3. Histological characteristics of the gastric mzicosa in pernicious anemia and atrophic gastrits.

Of 50 patients with pernicious anemia 26 were treated and 24 new, untreated cases. In 6 cases some normal tubules or remnants of normal body glands were encountered. Remnants of normal body glands were seen in 5 cases of 24 with severe atrophic gastritis.

220 M. SIURALA, E. ERAMAA AND w. NYBERG

In the following pages attention will be paid to the occurrence of inflammatory changes and various types of metaplasia. Since biopsy specimens form only a minimal part of the whole body mucosa, the degree of inflammatory changes and the occurrence of metaplasia was only roughly noted. The results of histological examination are presented in table V and figs. 3-9.

Injammatory changes were most pro- nounced in cases with a mild degree of atrophy (moderate atrophic gastritis). Signs of superficial inflammation and severe inflammatory cell infiltration throughout the mucosa were present in 50 yo of these cases. In cases with severe atrophic gastritis the inflammatory changes were less marked and largely of the same order as in cases with pernicious anemia. Large numbers of granulocytes (chiefly eosinophils) were encountered in 13 yo of cases of pernicious anemia, in 28 of cases with severe atrophic gastritis and in 35 Yo of cases with moderate atrophic gastritis.

Total or almost total intestinali<atiotz (figs. 3 and 7) of the gastric mucosa has been said to be characteristic of perni- cious anemia. However, this type of atrophic mucosa was present in only 15 (30 ”/) cases of pernicious anemia. On the other hand, 10 (42 yo) cases with severe atrophic gastritis revealed total or almost total intestinalization of the gas- tric mucosa.

Mucosa with predominance of the antral type of glands - pseudopyloric meta- plasia (figs. 4, 5, 8) - was found almost equally often in pernicious anemia (42 yo) and severe atrophic gastritis (50 yo).

The Brunner ope of rnetaplasia (antral type of cells a t the bottom and intestinal cells in the superficial parts of the same tubule) was noted in 4 (14 %) cases with

severe atrophic gastritis and 7 (14 O o )

cases with pernicious anemia. Pseiidomefa- plasia (flattened mucus-forming cells ivith a round nucleus - CJ fig. 9--; various mucus-forming cells of undetermined type were included in this group) was encountered in approximately 50 of cases with pernicious anemia and severe atrophic gastritis. Cyst-formation was found in approximately 50 yo of the cases of these groups. Marked /zy@er@lasia of the superficial epithelium and ectopic glands was encountered rarely (10 resp. 8 O0) in pernicious anemia and equally often in severe atrophic gastritis.

I t appears, firstly, that the more pro- nounced the atrophy the less marked are the inflammatory signs, and, secondly, that the histological picture of severe atrophic gastritis does not essentially dif- fer from that of pernicious anemia. This is illustrated in figs. 3-9. A gastric mucosa of pernicious anemia with slight or absent inflammatory changes is presented in figs. 3 and 4 and one with considerable inflammatory changes in figs. 5 and 6. The histological picture of severe atrophic gastritis, as shown in figs. 7-9, is almost indistinguishable from that presented in figs. 1 and 2.

Discussion and conclusions

Pernicious anemia and gastritis, par- ticularly atrophic gastritis, not associated with hematological signs of pernicious anemia were studied from various as- pects.

’The family incidence of pernicious anemia and gastric carcinoma was largely the same in pernicious anemia and severe atrophic gastritis. The mean age of the patients and the percentage of females appeared to increase with the severity of the mucosal lesion, the highest mean age

Fig. 3. Pernicious ancinia in rcmission. Total intcstinalization. Slight inflammatory changes. Hcmatoxylin-cosin x 35.

n

Fig. 4. I’crnicious ancmia i n remission. Only pyloric typc of glancls. N o noteworthy inllamnia- tory changes. Cyst formation. Hcmatosylin-cosin x 35.

Fig. 5. Pci nicious anemia in remission. Only pyloi ic typc of glancls. PI onouncecl inflammatory changcs. Hcmatoxylin-eorin x 70.

M. SIURAIA, 1:. EK;im\..\ atid W. NYHEKG: Pcrnicious Ancrnia anel Atrophic Gastritis

Acta klcclica Scanclinav. Vol. IM, fasc. 3, 1960

Fig. 6. Pernicious anemia. Untreated. Groups of normal body glands a t the bottom. Some intestinal crypts. Inflam- matory ccll infiltration and edema be- neath the surfacc cpithelium. Hcma- toxylin-cosin x 70.

Fig. 7. Atrophic gastritis without pernicious anemia. Male, 51 years. Schilling test: 4 ”,; with intrinsic factor: 7.5 yo. Total intestinalization. Slight inflam- matory changes. Hcmatoxylin-eosin x 70.

Fig. 8. Atrophic gastritis without pernicious anemia. Femalr, 58 years. Schilling test 8.2 %; with intr. factor: 15.9 ”,). Only pscudopyloric metaplasia and pseudometaplasia. Prolikration of the pits. i\lmost absent inflammatory signs. Hematoxylin-eosin x 70.

Fig. 9. Atrophic gastritis without pernicious anemia. Female, 69 years. Schilling test: 0.9 o/u. Pseudometaplasia. Slight inflammatory changes. Hematoxylin-eosin x 70.

PERNICIOUS ANEMIA AND ATROPHIC GASTRITIS 22 1

and highest female incidence being noted in pernicious anemia. The Schilling test (UIIT) values, ability to secrete hydro- chloric acid and uropepsin excretion de- creased markedly as the degree of gas- tritis progressed. In 10 of 24 cases with scverc atrophic gastritis the U R T re- vealed lo\\ values which did not respond to carbachol stimulation and which ivere of approximately the same order as those in the cases of pernicious ane- mia. .-I significant increase in the URT values ivas obtained with intrinsic factor. i h e serum vitamin B,, content was

101v in 6 of 14 cases with severe atrophic gastritis but in none of 8 cases with moder- ate atrophic gastritis studied. The his- tological studies revealed a decrease in inflammatory changes and increase of metaplasia with progression of the atroph- ic process: there was no essential differ- ence lietween the histological picture of pernicious anemia and severe atrophic gastritis. Thus, it seems that the family history, the age and sex distribution and the functional and histological condition of the stomach was largely the same in cases \\;it11 pernicious anemia and severe atrophic gastritis.

The results presented above suggest that the nizicosal process (atrophic gastritis) rvhich proceeds wi th marked injiammatory changes arid disappearence o f normal body glands t-eszilts iti a conditiori almost indis- tinguishable f r o m pernicious anemia and Leads to deficient absorption o f vitamin B,, and thus possih4v to perriicious anemia. I t may be a long timc before the body stores of vita- min B,, are depleted enough to cause clinical manifestations of pernicious ane- mia. Thc increased loss of or increased need for vitamin B,, caused for instance liy severe infections or hemorrhage may promote the manifestation of the de- ficiency statc. It should be noted, how-

r -

ever, that deficiency of intrinsic factor is not necessarily the only cause of the mal- absorption of vitamin B,, leading to pernicious anemia. For instance, patho- logical bacterial flora in the upper intes- tine, commonly encountered in pernicious anemia, and lesion of the intestinal mu- cosa, also noted in pernicious anemia (38), might be of importance in this respect.

I t must be pointed out that atrophic gastritis is certainly not the sole cause of intrinsic factor deficiency in pernicious anemia. The occurrence of normal tu- bules in the gastric mucosa of patients with pernicious anemia (6, 14, 24, 28, 29, 30), noted also in this series, and the fact that in children and adults fullblown pernicious anemia due to intrinsic factor deficiency may be associated with a histologically normal gastric mucosa sug- gest that pernicious anemia in some cases may be caused b y a specific inherited functional anomaly - lack of intrinsic factor - irrespective of other functions and the histological condition of the gas- tric mucosa. Thus, it is also possible that the atrophic changes of pernicious ane- mia might in some cases be the result of the deficiency state and not the cause of it. Since the mucosal atrophy in most cases of untreated pernicious anemia is complete, it has been assumed that the atrophy is caused by prolonged subclini- cal deficiency of vitamin B,,. In fact vitamin B,, deficiency may have a dele- terious effect upon the gastric mucosa. Siurala (33, 34) noted that atrophic- superficial gastritis found in pernicious tapeworm anemia - a clear-cut vitamin B,, deficiency state - may subside after adequate treatment, i. e. tapeworm expulsion. However, the results of the present study do not seem to support this view. Low UlIT values were encoun-

222 M. SIURALA, E . ERAMAA AND w. NYBERG

tered chiefly in cases with total atrophic gastritis. In less advanced atrophic gas- tritis low or low-normal values were encountered in only 2 cases and normal values were obtained in both after car- hachol stimulation. The serum vitamin B,, level was normal in 6 of 14 cases with severe atrophic gastritis and normal in all but one case (low-normal value) with less severe atrophic gastritis. Thus, the deficient absorption of vitamin B,, iip- pears in the present cases to be the result rather than the cause of the atrophic changes of the gastric mucosa.

Gastric carcinoma, commonly associa- ted with atrophic gastritis, has been encountered relatively often in pernicious anemia. Recently, Siurala et al. (35) noted that the incidence of gastric car- cinoma was significantly higher in per- nicious anemia than in two control series of the same age distribution. I t is quite possible, therefore, that atrophic gastritis, which according to the present investigation did not in any respect stud- ied differ essentially from pernicious ane- mia, might also be considered to some degree a precancerous condition, as has been pointed out by many authors.

Summary

The family history, age and sex distri- bution, Schilling test (ordinary and with carbachol and intrinsic factor), hydro- chloric acid secretion, uropepsin excretion and histological condition of the gastric mucosa were studied in 50 cases with pernicious anemia, 24 with severe atrophic gastritis (unassociated with hematological signs of pernicious anemia), 40 cases with moderate atrophic gastritis, 14 with su- perficial gastritis and 35 with a normal gastric mucosa. The following observa- tions were made:

1. The incidence of pernicious anemia and gastric carcinoma in relatives \vas largely the same in pernicious anemia and severe atrophic gastritis.

2. The mean age of the patients and the percentage incidence of females in- creased somewhat with the severit! of the gastric mucosal lesion. The mean age and the incidence of females in the pernicious anemia group was only slightl) higher than in the severe atrophic gastritis group.

3. Gastric tumours were present in 7 cases with pernicious anemia, in 5 cases with severe and 3 with moderate atrophic gastritis. Iron deficiency anemia \ \as en- countered in 9 patients with atrophic gas- tritis and it was present in the past history of 1 1 patients with gastritis.

4. The ordinary Schilling test IUKT) revealed normal values in all cases tvith superficial gastritis and normal gastric mucosa. In moderate atrophic gastritis, a low value was encountered in one and a low-normal value in another rase. In both cases normal values were obtained after carbachol stimulation. In severe atrophic gastritis 10 had IOU, 7 low- normal and 7 normal values. Patients with low values did not respond to car- hachol stimulation, but the values \rere raised with intrinsic factor.

5. The serum vitamin B,, level I\ as low in 6 of 14 cases with severe atrophic gas- tritis and normal in 13 of 15 rases Lvith less advanced gastritis.

6. The mean uropepsin excretion values were : pernicious anemia 1.5, severe atrophic gastritis 2.1, moderate atrophic gastritis 13.0, superficial gastritis 18.1 and normal gastric mucosa 33.1 U P unitsihr. The incidence of achlorhydria in these groups was: 100 n/o, 100 "6, 78 "(,, 36 O , )

and 3 o/o, respectively. 7. Histological study of biops) speci-

mens taken from the body of the stomach

PERNICIOUS ANEMIA AND ATROPHIC GASTRITIS 223

by the suction method revealed a d.c- creasc of inflammatory signs with pro- gression of the mucosal atrophy. Therc were no significant differences between pernicious anemia and severe atrophic gastritis, either in the severity of the in- flammatory changes or in the occurrence of metaplasia or other characteristics of a diseased gastric mucosa.

The results suggest that chronic atrophic gastritis, the end sequel of which is almost indistinguishable from the gastric lesion of pernicious anemia, may lead to deficient secretion of intrinsic factor and thereby possibly to pernicious anemia.

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