Prolonged achlorhydria and gastric neoplasia: Is there a causal relationship?

1554

EDITORIALS

GASTROENTEROLOGY

Vol. 104,

No. 5

Prolonged Achlorhydria and Gastric Neoplasia: Is There a Causal Relationship?

T

o our knowledge,

the article

by Lamberts

this issue of GASTROENTEROLOGY

most

extensive

induced

experience

achlorhydria

with

et al.’ in

represents

prolonged

in humans.

medically

The insights

from this report, taken in the context of current edge on gastritis and gastric carcinogenesis, good deal of light into the issue of whether long-term creased

achlorhydria risk to acquire

noid tumor hydria

patients

on two fronts:

the endocrine

knowlshed a

Quincke

at an inachlor-

in the gastric

cells and the exo-

Achlorhydria

has been shown

to induce

antral

gas-

accompanied by (G) cell hyperplasia *p3As gastrin constitutes a powerful hypergastrinemia. trophic factor for the argyrophilic enterochromaffintrin-producing

like (ECL) cells of the oxyntic mucosa, XL-cell perplasia generally follows hypergastrinemia.3,4 plastic nicious drome,

gastric carcinoid ECL-cells

tumors

derived

hyIn

from hyper-

have been seen in patients

with per-

anemia5s6 or with the Zollinger-Ellison synonly when it is part of the multiple endocrine

neoplasia type I (MEN I) picture7; in both instances there is considerable hypergastrinemia. In experimental conditions,

mucosa

rats treated

for a long period

with hista-

mine-receptor H, blockers,3*s*9 gastric proton pump inhibitors,3*‘0 or the hypolipidemic agent ciprofibrate” or those subjected to partial fundectomy’* develop ECL-cell hyperplasias leading to carcinoid tumor for-

mucosa

had lost its function

egg white

failed to dissolve

after

12 hours

reported

mia and gastric

carcinoma,

tial pathogenetic gastritis, The

concept

mucosa

that

was supported

ane-

a potenatrophic

l6

pernicious

anemia

is carcinogenic

resulting

in

for the gastric

by a series of studies,

observation

of Quincke

confirm-

and stating

that the risk of gastric carcinoma is elevated in patients with pernicious anemia. “-19 Mosbech and Videbaek in 1950 postulated ach cancer

that both pernicious

link has been challenged ation

anemia

are caused by achlorhydria.”

between

the two conditions,

first by Strickland

and Mackay*’ and later by Schafer studied a well-documented mia patients representing years of follow-up.

and stom-

This apparent

on the basis of a lack of associ-

*’ The

and coworkers,

who

cohort of pernicious anemore than 1500 personresolution

of this apparent

discrepancy is important because it may help us gain insights into the mechanisms of gastric carcinogenesis and because cerning

it has practical

the surveillance

clinical

implications

of patients

with

con-

pernicious

anemia. Some valid reasons for the discrepant results are discussed by Schafer et al.,*r especially the poor reliability of many diagnoses some of the studies. Central

of pernicious to the proper

tion of such conflicting

that tion

ing of the gastric cancer precursor than the enigmatic entity chronic

range. Moreover, as already gleaned from past experience,13 unlike rats, humans show a limited ECL-cell response to omeprazole-induced hypergastrinemia, well short of dysplasia and carcinoid tumor formation. Therefore, it seems safe to conclude that in spite of earlier misgivings,14 this long-term drug-induced achlorhydria does not appear to pose a significant risk toward the acquisition of gastric carcinoid tumors. On the other hand, the role of achlorhydria and gastric atrophy in the pathogenesis of gastric adenocarcinema has been a matter of concern to the scientific community for more than a century. In 1870, Fenwick

1876,

achlorhydria,

malignancy.

achlorhydria

In

of pernicious

thus establishing

link between

and gastric

prolonged

of incubation.15

mation in up to 30% of the female population.3 From the present study, we learn that the hypergastrinemia results from prolonged omeprazole administrato humans is self-limiting and has a moderate

in

a cube of hard-boiled

the coexistence

ing the original

structures.

humans,

how the gastric

a patient who died of severe (later called “pernicious”) anemia. Unlike Fenwick’s other patients, this patient’s gastric

be it a carci-

Prolonged

to have consequences

showed

gained

iatrogenic

neoplasm,

or an adenocarcinoma.

is expected

mucosa crine

may place a gastric

the

evidence

anemia in interpreta-

is a clear understandlesion-none other atrophic gastritis.

There are two distinct types of atrophic gastritis. The so-called type A or autoimmune has been recognized and well described for decades.*’ Its primary lesion is the diffuse loss of parietal and chief cells in the oxyntic mucosa (atrophy), leading to the so-called pseudoantral metaplasia and followed by intestinal metaplasia. In advanced cases, the loss of peptic-oxyntic glands, related to anti-parietal cell and other autoantibodies, is total and leads to achlorhydria. This physiopathological entity is clearly a part of the pernicious anemia syndrome. As already pointed out, most of these patients develop ECL-cell hyperplasia,

May 1993

which

EDITORIALS

in some evolves

into

a carcinoid

stomach.“6,22*23 The intestinal associated

with

this

type

type I, characterized

tumor

metaplasia

of gastritis

of the

prominently

is the so-called

by lack of atypia

and by the pres-

ence of absorptive and Paneth cells as well as goblet cells containing sialomucins. Significant numbers of intermediate atypia

cells containing

are not encountered

metaplasia.2”26 conclusion “small non

sulphomucins in this

A number

that type I, also known

intestinal”

metaplasia,

populations.

It has virtually

with respect noma. :!6-29

lesion

or

phenomewith

no predictive of gastric

gastritis

age in value

adenocarci-

in the area of the inci-

and the antrum-corpus

foci appear

later, mostly

ture of the antrum

loss of glands.

along

and corpus.

junction.

Addi-

the lesser curva-

The independent

foci

being

almost

form

associated

duodenal

with

very prevalent tions

(diffuse

universally antral

peptic

present

gastritis

ulcer,4143

in MAG. 44,45However,

in

[DAG]) and

also

in some popula-

of Africa

and in the coastal lowlands of Costa are very prevalent, Rica, DAG and H. pylon’ infection but gastric cancer is not. 46-48 From accumulating evidence it appears that H. py/ori plays a prominent role in MAG

and gastric

must be involved

adenocarcinoma, in their

but other

causation.32’44

factors

In the report

by Lamberts et al., there is a slight decrease in the H. pylori infection of both antral and oxyntic mucosa after 5 years of omeprazole paralleled

is more contro-

is the focal

foci first appear

sura angularis tional

led to the

gastritis,

its nonatrophic

treatment.

by a similar

of gastritis type of atrophic

Its primary

The atrophic

increases

to the development

The second versial

have

as “complete”

is a common

of which

many

type of intestinal

of studies

tbe prevalence

and gland

chronic

1555

decrease

but not by atrophic

From a considerable ent that patients with gastric

This slight decrease in the general gastritis.

number of studies, pernicious anemia

adenocarcinomas

is

activity

it is appardeveloped

at a rate significantly

higher

than that expected from the rest of a comparable general population. 17-19,34*49 The classical type of tumors described

in patients

with pernicious

anemia

are well-

grow larger and coalesce and may cover extensive areas of the antrum and corpus.30 In this condition, the

differentiated and frequently

adenocarcinomas located in the corpus polypoid in nature.49,50 In contrast, the

gastric

glands

tumors

in patients

usually

there is hypochlorhydria

are almost

This manifestation

never

of chronic

completely

eliminated;

but not achlorhydria. gastritis

(predominantly

was first called

“multifocal” by Lambert in 1977.31 Multifocal atrophic gastritis (MAG) is the most appropriate name for this entity. This type of gastritis is generally associated with a high incidence it recognizes a variety as deficient NaCl,

intake

consumption,

of gastric adenocarcinoma, of environmental factors,

of fresh fruits

and such

and vegetables,

high

and Helicobacterpyiori infection,

found

in

differentiated, generally

around

the incisura),

and frequently

recognized

are often

with MAG

are mostly moderately

ulcerated.

is that the latter

seen in patients

antral well

What

is not

type of tumors

who also have family

history

of pernicious anemia, especially in Scandinavian countries. Elsborg and Mosbech4” clearly described the two

types

Siurala chronic

of carcinomas

in the

Danish

population.

and Seppala” pointed out the existence of atrophic gastritis in their patient population

its etiopathogenesis. 30.32The intestinal metaplasia associated with this type of gastritis is most often type I,

and presented convincing evidence that in many instances atrophic gastritis preceded, and probably was a

but in advanced

stages foci of type III make their

pearance.

foci are characterized

cause of, pernicious in the Scandinavian

These

ap-

by the presence

by several groups have led to the conclusion that type III intestinal metaplasia, also known as “incomplete”

gastritis and populations Europeans, tis observed. did not take

or “colonic”

studies by Sipponen

of significant amounts of sulphated mucins, particularly inside intermediate cells, as well as the development of glandular atypia. 26,27A series of studies carried

nificant

metaplasia,

marker

constitutes

for the development

a statistically of gastric

sigcarci-

noma and probably represents a precursor lesion for malignancy.28~33-35 Evidence has been presented recently indicating that infection with H. pylori increases the risk of gastric carcinoma because it has been noted that the combination of MAG and H. pyLoti infection is associated with high gastric cancer risk. 3Ho Indeed, the ubiquitous H. pylori plays a prominent role in the pathogenesis of

vian patients

anemia. It seems clear, then, that populations autoimmune (type A)

MAG frequently coincide. By contrast, in without major contingents of Northern MAG is practically the only type of gastriAlthough the earlier works predictably into account the H. pylon’ infection, recent et al. on a population

find abundant

of Scandina-

H. pylori in the gastric

mu-

cosa of patients with antral gastritis or pangastritis but, interestingly, none in patients with corpus gastritis and severe atrophy.45 The dynamics of the gastric cancer epidemic are characterized by declining age-adjusted rates, which were first clearly observed in the white U.S. populacountries, the tions around 1930. 52 In Scandinavian decline in rates was only clearly observed around

1556

EDITORIALS

1950-1960.53

GASTROENTEROLOGY Vol. 104, No. 5

In Japan,

the changes

in age-adjusted

cause of gastric cancer. If achlorhydria were a factor in its role would be subordinated

cancer rates took place after 1 970.33 The prevalence of intestinal mataplasia in autopsy specimens was already

gastric carcinogenesis,

very low in adult stomachs studied by Hebbel in Min-

ences, still incompletely

neapolis between 1937 and 1947.54 By contrast,

in Ja-

pan, the rates of such metaplasia as determined

at au-

topsy apparently started to decrease significantly

only

after around

1970.55 A direct comparison

vealed a prevalence

study re-

of more severe degrees of intes-

tinal metaplasia for the sixth decade of life of 17% in Minnesota

around 1940, as opposed to 79% in Japan

around 1960.56 From these data, it seems that the chronological

changes in cancer rates were preceded by a

decline in MAG several decades earlier. The studies of Schell et al. ‘* and of Kuster et al.” dealing with significant numbers of patients having pernicious anemia and gastric carcinoma

were carried out on populations

of Mayo Clinic patients seen between

1906 and 1950

and between 1947 and 196 1, respectively.

The work of

Schafer et al. ” finding no sign ificant association

be-

tween pernicious anemia and gastric adenocarcinoma, on the other hand, was performed using a cohort of residents of Rochester,

Minnesota,

between 1950 and

1979. Because the incidence of pernicious anemia has not declined, it would appear that the Scandinavian migrants to Minnesota brought their pernicious anemia genes but with time shed the environmental factors related to gastric carcinoma. remained

in Scandinavia

Their relatives who

continued

to be exposed to

the carcinogenic environment for several decades. Therefore, it is quite possible that Scandinavian patients who develop antral carcinomas are suffering the consequences of MAG. This line of reasoning would lead to the conclusion that pernicious anemia per se does not lead to excessive gastric cancer risk in the present environment of the United States and, probably, of present-day Northern Europe. The work of Lamberts et al.’ in this issue of GASleads to similar

TROENTEROLOGY

longed achlorhydria

conclusions:

did not induce chronic

gastritis over the duration

pro-

atrophic

of the study and did not

transform pre-existingtype I (small intestinal) metaplasia into the more ominous type III (colonic) metaplasia, in turn leading to dysplasia. The work of one of us in a Colombian population at high risk to acquire gastric cancer shows a rate of transition from nonatrophic to atrophic gastritis of 3.3 per hundred person-years,57 higher than the rate shown in Table 1 of the paper by Lamberts et al. The Colombian population has severe MAG and some degree of hypochlorhydria, but no achlorhydria. Therefore, it can be concluded that achlorhydria as an isolated factor is not a sufficient

WBS: Gastro

544

/i/j/wbs/‘a5194/0545/p1556

to

other,

largely environmental

carcinogenic

influ-

understood.32

JUAN LECHAGO Depatiment of Pathology Baylor College of Medicine and Methodist Hospita/ Houston, Texas PELAYO CORREA Department of Patboloag Louisiana State UniversityMedical Center New Orleans, Louisiana

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Address requests for reprints to: Juan Lechago. M.D., Ph.D., Department of Pathology (MS 205), Methodist Hospital, 6565 Fannin Street, Houston, Texas 77030. 0 1993 by the American Gastroenterological Association 0016-5085/93/$3.00