Gastric histology and its relation to anaemia in the elderly.

Clinical Section Gerontology 23: 309-321 (1977)

Gastric Histology and Its Relation to Anaemia in the Elderly T. Bird, M.R.P. Hall and R.O.K. Schade1 Newcastle General Hospital, Newcastle upon Tyne, and University of Southampton, Southampton

Key Words. Geriatrics • Gastric histology • Gastric achlorhydria • Vitamin B13 absorp tion Abstract. During 1 year 725 consecutive patients admitted to a geriatric unit were investigated for anaemia. 51 % of men had haemoglobin levels below 13.5 g/dl and 41 % of women had levels below 12 g/dl. 657 patients had an azuresin tubeless test meal following an augmented dose of histamine acid phosphate and 450 (68 %) had achlorhydria. Gastric biopsies were performed on 240 of the patients with achlorhydria and 201 satisfactory biopsies were obtained. These were graded into five categories: (1) normal; (2) surface gastritis; (3) diffuse gastritis; (4) chronic atrophic gastritis, and (5) chronic atrophic gastritis with intestinal metaplasia. The grades of mucosal change could not be correlated with the presence or absence of anaemia, the state of gastric function as measured by the Schilling test for absorption of vitamin B, 3, or the level of vitamin Bt! in the serum.

The introduction of a flexible gastric biopsy tube ( Wood et al., 1949) has made it relatively easy to sample the gastric mucosa. The procedure is safe, not too unpleasant for the patient and can, if necessary, be undertaken in the out patient department. It is well recognised that chronic atrophic gastritis is more common with increasing age, though by no means all elderly subjects have an abnormal gastric mucosa (Palmer, 1954\Joske et al., 1955, Williams et al., 1957; Siitrala and Vuorinen, 1963; Edwards and Coghill, 1966). Wood and Taft (1958) suggest that chronic gastritis is most probably the cause of achlorhydria in the

Received: February 6, 1976.

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1 Wc would like to thank the nursing staff of the geriatric wards for all their help, and Miss Sonia Humphries for secretarial assistance.

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elderly and that this condition 'should not be considered a normal finding any more than chronic nephritis or chronic bronchitis is considered to be normal’. The relation between chronic atrophic gastritis, gastric atrophy and pernicious anaemia is well known. It is likely, in the majority of cases, that the atrophy is the sequel to an inflammatory process of the mucosa. A close association be tween gastritis and carcinoma of the stomach was suggested by Hurst (1929) on clinical grounds and by Konjetzny (1938) on a morphological basis. Morson (1955) has related intestinal metaplasia of the gastric mucosa to gastric carci noma. As the majority of gastric cancers are of intestinal cell type, Konjetzny's and Morson's suggestions that intestinal metaplasia is closely related to neoplasia seems justified but has so far not been proven conclusively. The relation between iron deficiency anaemia and gastric mucosal change is less certain, though Delamore and Shearman (1965) have suggested that there are two groups of patients; one group in whom the iron deficiency is primary and the gastritis is secondary, the other in whom the gastric change is primary and the iron defi ciency secondary. In the first group, correction of the iron deficiency may result in improved gastric secretory function, though reversal of the gastric mucosal change as described by Badenoch et al. (1957) is probably very rare. Further work by Wright et al. (1966) supports this hypothesis of two groups of patients. Our work in this very large and complicated field has developed out of a general survey of the incidence and causes of anaemia in elderly patients. Anaemia is a common finding in patients admitted to hospital geriatric wards and it probably attracts the investigator for three main reasons. Haemoglobin levels are estimated on nearly all patients and anaemia is relatively easy to investigate; anaemia is regarded by many as a sensitive index of ill health in the elderly and the correction of anaemia is thought to be one of the more encourag ing aspects of geriatric medicine. The incidence varies greatly, depending on what level of haemoglobin is accepted as the lower limit of normal and levels of 12-13.5 g/dl have been variously used. Myers et al. (1968), in a survey of fit elderly people, found that 32 % of men and 38 % of women had haemoglobin levels below 13 g/dl, though only 12% of women had levels below 12 g/dl. Batata et al (1967), investigating 100 consecutive admissions to a geriatric unit, found that 33 % had levels below 11.7 g/dl. While accepting that iron deficiency is probably the most important single factor, it is well recognised that the majority of patients have multiple causes — these include acute and chronic infections, chronic renal disease, neoplasms, subnutrition and mental impair ment, both affective and organic. We decided to investigate as fully as possible all patients over the age of 65 years admitted to the geriatric wards in a single year, and from these investigations we have extracted our findings on gastric function and histology and their relation to the presence or absence of anaemia. It is hoped to publish later the more extensive findings on the causation of anaemia in the elderly.

Gastric Histology and Anaemia

311

Patients and Methods 725 consecutive new patients, over the age of 65 years, admitted to the geriatric wards of the Newcastle General Hospital were investigated for anaemia after full clinical, dietary and social assessment. Standard haematological methods on venous specimens of blood were used, with further investigations as indicated. There were 340 men and 385 women. Gastric Acidity This was assessed by carrying out a tubeless azuresin test meal after giving an ‘aug mented' dose of 40 Mg/kg body weight of histamine acid phosphate with antihistamine cover for side effects (Kay, 1953). In this way a double stimulus was given to the gastric mucosa. A urinary excretion of less than 0.3 mg standard was regarded as indicative of achlorhydria, results between 0.3 and 0.6 mg indicated hypochlorhydria and results above 0.6 mg were regarded as normal. Satisfactory tests were obtained in 657 patients. Gastric Biopsy Those patients with achlorhydria, who had no current history of indigestion or gastro intestinal disturbance and whose clinical condition was good, were asked if they would agree to gastric biopsy after the nature of the investigation had been carefully explained to them. The gastric biopsies were performed using a flexible suction biopsy tube (Wood et at., 1949) and the mucosa obtained was fixed in 10% formol-saline, stained with haematoxylin and eosin and other stains when indicated and examined independently. Serum Vitamin B , 2 Estimations These were done by the method of Anderson (1964) using Euglena gracilis, var. Z. The normal range in our laboratory is 140 1,000 ng/1. Schilling Test (Schilling, 1953) The fasting patient was given 0.5 Mg of vitamin B12 containing 0.5 MCi of 58Co labelled vitamin B12. This was followed within 1 h by a 'flushing' dose of 1,000 Mg of cyanocobalamin (Cytamen) intramuscularly and the urine was collected for 24 h. Excretion of more than 7 % of the dose was regarded as normal while levels below 2.3 % indicated malabsorp tion as seen in pernicious anaemia. When subnormal results were obtained, the test was repeated with the addition of intrinsic factor.

Gastric Acidity Azuresin tests consistent with achlorhydria were obtained in 209 men (66%) and 241 women (70%). Hypochlorhydria was demonstrated in 14% of both sexes while normal results were obtained in 20 % of the men and 16 % of the women. The presence of hydrochloric acid is probably best assessed in the gastric juice obtained after stimulation of the mucosa with histamine or pentagastrin. We have found, however, over a period of some 2 years, a good correla tion between the standard technique and the tubeless azuresin test when the latter is preceded by an augmented dose of histamine, with antihistamine cover.


Results

312

Bird /Hall/Schade

This correlation was also seen in 20 cases in the present series where the gastric acidity was directly measured following intubation. It is true to say that, gener ally, there is some over-diagnosis of achlorhydria with the azuresin method. It was shown in these investigations that achlorhydria had very little relation to the presence or absence of anaemia and this is demonstrated in table I. Re ports in the literature of the incidence of anaemia in the elderly vary consider ably, depending on the level of haemoglobin below which anaemia is said to be present, and whether the population examined consists of patients in geriatric hospitals or healthy, elderly people at home. In a survey of one practice in Newcastle upon Tyne which we have recently completed, we examined 736 people over the age of 65 years who were living at home. 9.5 % of men and 22.5 % of women had levels o f haemoglobin below 13.5 g/dl, but only 5 % of men and 7.6 % of women had levels below 12 g/dl. In the present hospital series there was a much higher incidence of anaemia, 51 % of the men having haemo globin levels below 13.5 g/dl and 41 % of women having levels below 12 g/dl, presumably reflecting the various illnesses which had caused admission to hospi tal. Whether one takes 13.5 or 12 g/dl as the ‘critical’ level, and the lower level is commonly used in geriatric medicine, it can be seen that achlorhydria had no correlation with the presence or absence of anaemia. Approximately half of the males with achlorhydria had normal levels of haemoglobin above 13.5 g/dl with

Table I. Relation of tubeless test meal to haemoglobin (g/dl) Under 7.5

7.69.0

Males 0.3 mg standard 0.3-0.6 mg 0.6 mg standard

2 1 -

6

Total

3

9 .1 10.5

10.612.0

12.1 — 13.5

13.615.0

Over 15.1

Total

15

53 11 13

67 16 16

31 10 15

209 46 60

77

99

56

315

-

-

-

4

35 8 12

6

19

55

155 (49%)

160(51 %) Females 0.3 mg standard 0.3-0.6 mg 0.6 mg standard Total

8

2

61 7 11

68 13 11

43 14 21

17 7 7

241 46 56

35

79

92

78

31

343

33

2

11 5 2

10

18

-

142 (41 %)

-

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Diagnex result


313

Fig. 1. Grade I. Fundal mucosa from patient aged 87 years, showing thinning of mu cosa but normal pattern. HE. X 20. Fig. 2. Normal fundal mucosa from young adult (30 years old). HE. X 20.

the same proportion in those with hypochlorhydria and normal secretion of acid. The pattern was much the same in the females, if 12 g/dl is accepted as the lower limit of normal, though the incidence of anaemia in achlorhydria is in creased if the higher level of 13.5 g/dl is regarded as normal.


Gastric Biopsy The biopsies showed a wide range of histological appearances. In accordance with the biopsy technique used they showed throughout fundal mucosa modi fied by varying intensity of inflammatory changes. We graded the biopsies into five groups. Grade I (normal). The surface epithelium was composed of normal colum nar cells, with shallow gastric pits, overlying tubules of regularly arranged cells containing normal numbers of mucus-secreting, parietal and chief cells. Only occasional lymphoid and plasma cells were found in the lamina propria (fig. 1). When, however, this mucosa was compared with biopsies from young individuals (fig. 2) it could be shown that the mucosa of many of the older patients was thinner, and in fact showed a true atrophy with preservation of the normal

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pattern. This is an interesting observation, particularly as all other forms of gastric atrophy are the result of a preceding inflammatory process. Grade II (superficial gastritis). This showed a normal cellular and glandular pattern but there was a mild chronic inflammatory cell infiltration just below the surface epithelium. There was usually only slight loss of specialised cells (fig- 3). Grade III (diffuse gastritis). There was diffuse chronic inflammatory cell infiltration throughout the thickness of the mucosa, often accompanied by hyperplasia of lymphoid tissue and partial destruction of glandular tissue (fig. 4). This might be labelled moderate atrophic gastritis. Grade IV (chronic atrophic gastritis). This showed classical appearances with variable cell infiltration and marked destruction of specialised glandular tissue, often with change of epithelium to simple mucus-secreting cells (fig. 5). Grade V (chronic atrophic gastritis with intestinal metaplasia). This showed almost complete loss of specialised glandular tissue and could also be labelled gastric atrophy (fig. 6).


Fig. 3. Grade II. Normal pattern with mild surface gastritis. HE. X 16.5. Fig. 4. Grade III. Diffuse chronic gastritis with lymphoid hyperplasia and glandular destruction. HE. X 16.5. Fig. 5. Grade IV. Chronic atrophic gastritis. HE. X 16.5. Fig. 6. Grade V. Atrophic gastritis with intestinal metaplasia. HE. X 16.5.


315

Relation o f Gastric Biopsy Grading to Age Biopsies were obtained from 133 male patients but only 121 were satisfac tory. Table 11 shows the relation of the biopsy grading to age. Although the method of selection for biopsy would favour the finding of histological appear ances in grade IV and V, it is interesting to note that 26 % of the patients had gastric mucosa which was essentially normal, and that such a mucosa was found in nonagenarians. This is different from the findings of Joske et al. (1955) who demonstrated the increasing incidence of abnormal findings with increasing age, and is also contrary to the belief that chronic gastritis in all its forms is simply an aging phenomenon. Among the female patients 102 biopsies were performed and 80 were regarded as satisfactory. The relation of biopsy grading to age is shown in table 111 and there is a similar pattern to that seen in the men, 25 % having normal, or practically normal, mucosa, A closer study of the grade I biopsies in

Table II. Gastric histology in relation to age in males Age, years

Grade I

Total 11

III

IV

V

65 69 70 74 75 79 80-84 85 89 Over 90

3 5 7 11 3 2

3 5 4 5 3 1

3 2 3 2 2 0

5 10 8 5 4 1

5 4 5 5 4 0

19 27 27 28 16 4

(70) (67) (77) (66) (50) GO)

Total

32

21

12

33

23

121

(340)

Table III. Gastric histology in relation to age in females Grade i 65-69 70-74 75-79 80-84 85 89 Over 90 Total

Total 11

111

IV

V

2 2 8 3 3 2

1 3 7 5 0 0

0 1 3 2 0 0

2 8 8 4 2 1

1 3 4 4 1 0

6 17 30 18 6 3

(38) (61) (108) (103) (23) (23)

20

16

6

25

13

80

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Age, years

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Fig. 7. Relation of gastric biopsy to haemoglobin level. • = Males; o = females.

Relation o f Gastric Biopsy Grading to Degree o f Anaemia The results are shown in figure 7. Whether one again takes 13.5 or 12 g/dl as a ‘critical’ level, it would seem that the state of the gastric mucosa could not be correlated with the presence or absence of anaemia. Almost as many subjects have normal haemoglobin levels with grade IV-Vchanges as have anaemia. This is seen in both men and women and in both samples the patients who had biopsies performed were representative of the total number in the group studied during the year, having a similar proportion of anaemic patients.


both sexes did show that only approximately two-fifths of them had gastric mucosa of the same thickness and structure as that of a young individual. The remainder showed a variable reduction of thickness (true atrophy) and. although the pattern was normal, a slight increase of interglandular fibrous tissue was sometimes demonstrated with special stains. In addition there was a variable but always slight loss of chief and parietal cells, the loss of the latter usually being the more obvious. It should be added that there was no cellular infiltration in the mucosa or lamina propria of these patients.

317


Relation o f Gastric Mucosal Change to Vitamin B n Absorption Since it is well known that gastric mucosal changes are the rule in Addi sonian (pernicious) anaemia and are associated with malabsorption of vita min B12 due to lack of intrinsic factor, it was decided to check absorption in some of our patients, using the Schilling test (Schilling, 1953). Only patients without evidence of renal disease were studied and the results are shown in figure 8. The abnormal results in patients with a normal mucosa (grade I) coincided with the patients who produced very small specimens of urine and can probably be ignored. 46 men had normal results; 60 % of these had grades IV and V mucosal changes, and of them only half were anaemic. In addition 5 of the 8 men with doubtful results and grade IV or V changes were not anaemic, while the remaining 3 were all anaemic but only 1 showed an obvious cause. Of the 2 patients with very low results and grade V mucosal changes, 1 had treated pernicious anaemia while the other had a gluten-induced enteropathy.

26 I- • • 24 22

o

• 20 - •

•

o

o

•

o • • •• ° • •

•

• •• o X o • oo •

• • • • o •

o • • o

2 14 a« ' 12 S H

Ui

• •

• o

o o

• Q - •

• o o

0— •

• o • O •

:

8

•

•

2

6 1

Norm al

73

7

5

• • o 9 ^16 16 4 3 5 Grade of Gastric Biopsy

2

7

D o u b tfu l

20

• O o o

•

0 .1 2

o • o

• O o

• 4

o

•

•

S’ to

!£

• o o

4

21

L ow

9

Fig. 8. Relation of gastric biopsy to Schilling test. • = Males; o = females.


o 16 - • § • o

o

.1 o

18

Bird IHallISchade

318

A normal Schilling test was found in 27 women and almost half of these had grade IV or V mucosal changes. 14 of these women were not anaemic, 11 had an obvious cause for their anaemia of iron deficiency type and 2 had no obvious cause for their anaemia. Seven women with doubtful Schilling tests had grade IV and V changes and all but 2 were anaemic, although 4 of them had normal levels of serum vitamin B12 and had no apparent cause for the anaemia. There were 4 women with abnormally low excretion of BI2 and all had grade IV or V biopsies. Three were shown to have Addisonian (pernicious) anaemia, with megaloblastic changes in the bone marrow, return of Schilling test to normal by addition of intrinsic factor and response of the anaemia to B12 therapy, but the fourth was not anaemic. In general it can be said that there was an increase of low and doubtful Schilling tests in patients with severe atrophic gastritis, but this is less significant when the patients with pernicious anaemia are excluded. More than half of all the patients with normal Schilling tests had excretion rates above 15 %, and the range was 8 -2 6 %. The higher levels were more common in those with grade I and II biopsies but equally high levels were seen in some with grade III—V biopsies. Serum vitamin Bl2 levels were available in all of these patients. The range in the 73 patients with a normal Schilling test was from 75—500 ng/1 with a mean of 280 ng/1, and there were 8 patients with levels below our normal lower limit of 140 ng/1. Of the 20 patients with a Schilling test in the ‘doubtful" range, 4 had serum vitamin B,2 levels of 50-127 ng/1. There were 9 patients with abnormal low Schilling tests and of these 4 had levels of 25-80 ng/1 with other evidence of pernicious anaemia, while the remaining 5 patients had values of 160—250 ng/1. With the exception of 2 patients with grade I biopsies (and very low excretion of urine in the Schilling test) all of the patients in this last group had grade III—V biopsies, demonstrating the poor correlation between gastric mucosal change and serum B12 levels except in those patients shown to have pernicious anaemia. This lack of correlation can be demonstrated in all the grades of gastric mucosal change. Serum vitamin B12 values in patients with grade IV and V biopsies varied from 125—360 ng/1 (mean 270) and in grade I and II biopsies from 70—500 ng/1 (mean 290), while individual levels above 350 ng/1 were found with all grades. When making all these correlations it is necessary to add that a small biopsy may not truly represent all of the gastric mucosa.

Discussion


The patients selected for biopsy all had histamine-fast achlorhydria by the method used and would have been expected to have varying degrees of atrophic gastritis. Joske et al. (1955) have described the increasing incidence of achlor

319

hydria and atrophic gastritis after the age of 30, but they did find a normal biopsy in 12 % of patients with histamine-fast achlorhydria, while 33 % had only a superficial gastritis. In spite of this and other series Chanarin (1969) states that the quantity of hydrochloric acid, after histamine stimulation, correlates well with the state of the gastric mucosa. This is hardly reflected in our series, where 26 % of the patients with achlorhydria had a normal, if sometimes slightly thinned, mucosa and another 19 %had only mild superficial changes. Although it might be thought that severe atrophic gastritis would commonly cause impaired absorption of Bi2, this has been shown in only about one half of the cases in published series (Chanarin, 1969). It is known that intrinsic factor production decreases with the loss of parietal cells, but this loss is not the only factor affecting the state of gastric secretions and indeed many patients with achlorhydria and less than 1 % of intrinsic factor production may have normal absorption of B12, and normal serum B12 levels (Ardeman and Chanarin, 1965). This suggests that histological examination alone will not tell how many parietal cells are present, whether they are functioning or not, and how much intrinsic factor they are producing. Whilst the normal stomach will produce 2,000-18,00011 of intrinsic factor per hour after histamine, it would seem that normal absorption of B)2 and normal serum levels can be obtained with levels as low as 200 U/h (Chanarin, 1969). It is at these levels that the difficulty of separating atrophic gastritis and pernicious anaemia becomes apparent. Presence of serum antibodies will help, but intrinsic factor antibodies are said to be present in only 40 % of cases of pernicious anaemia and parietal cell antibodies can be found in up to 11 % of elderly patients, without any evidence of pernicious anaemia, in the Newcastle region (Bird and Stephenson, unpublished results). The histology of the gastric mucosa is not pathognomonic of pernicious anaemia and there are patients with identical lesions who absorb B12 normally. Although the serum vitamin B12 is said to be low in severe atrophic gastritis, it is rarely in the levels associated with pernicious anaemia ( Whiteside et al., 1964). In our series it was below normal in only 4 of the patients with grade IV and V biopsies (apart from those shown to have pernicious anaemia) and all had normal absorption of vitamin B,2 levels well within the normal range, although it is true that the highest levels were seen in those with grade l and II biopsies. There is no adequate explanation for the fact that patients with gastric mucosal changes, apparently every bit as severe as those seen in pernicious anaemia, can absorb B |2 normally and have normal serum levels. Chanarin (1969) has sug gested that, in such cases, either the serum B12 does not reflect accurately the B1: stores or that B12 absorption tests, as carried out and interpreted at present, do not detect less severe degrees of B,2 deficiency. At the moment it has become clear that the diagnosis of ‘pernicious anaemia’, usually defined by tests for serum Bi2, absorption of B,. with and without intrinsic factor, histamine-fast



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320

achlorhydria, gastric atrophy, antibodies to intrinsic factor and parietal cells and defective or absent secretion of intrinsic factor, may be difficult to separate from severe atrophic gastritis in the absence of megaloblastic anaemia. Our own findings have not enabled us to draw any definite conclusion as to the role of the gastric mucosa in the production of anaemia, other than its association with Addisonian (pernicious) anaemia. No obvious correlation has been shown between the presence of achlorhydria, abnormalities of gastric mu cosa, absorption of vitamin Bt2 serum B 12 levels and the presence or absence of anaemia. We were, indeed, surprised when comparing our series with others in the literature, at the number of our patients with achlorhydria, who had normal, or almost normal, mucosa, even over the age of 90, and the large number who had normal levels of serum vitamin B12 and normal absorption of vitamin B12 with every grade of gastric biopsy. It was unfortunate that, at the time, it was not possible to measure intrinsic factor in the gastric juice in order to estimate its relation to the gastric histology and absorption of B)2. Even this, however, although regarded as perhaps the key test at present in the diagnosis of perni cious anaemia, has been shown to be by no means infallible (Ardeman and Chanarin, 1966). There may exist a group of patients who have iron deficiency anaemia as a result of gastric mucosal changes. These changes may be due to autoimmune mechanisms. While this group is comparatively small, they are perhaps worthy of further consideration and study, since correction of the iron deficiency may not produce improvement in gastric function and it may be necessary to give them larger doses of supplementary iron indefinitely in order to correct and prevent recurrence of anaemia. The diagnosis may be suggested by the presence of idio pathic iron deficiency anaemia and may be confirmed by the finding of an abnormal gastric mucosa, a low Schilling test result and the presence of gastric parietal cell antibodies.

Anderson, B.B.: Investigation into the Euglena method for the assay of vitamin B,, in serum. J. clin. Path. 17: 14 (1964). Ardeman, S. and Chanarin, 1.: Assay of gastric intrinsic factor in the diagnosis of Addisonian pernicious anaemia. Br. J. Haemat. 11: 305 (1965). Ardeman, S. and Chanarin, I.: Intrinsic factor secretion in gastric atrophy. Gut 7: 99 (1966). Badenoch, J.; Evans, J., and Richards, W.D.C.: The stomach in hypochromic anaemia. Br. J. Haemat. 3: 175-185 (1957). Batata, N.: Spray, G.H.; Boldon, F.G.; Higgins, G., and Wollner, L : Blood and bone marrow changes in elderly patients. Br. med. J. i: 667 (1967). Chanarin, I.: The megaloblastic anaemias, pp. 605-616 (Blackwell, Oxford 1969).


References


321

Delamore, E.W. and Shearman, D.J.C.: Chronic iron deficiency anaemia and atrophic gastri tis. Lancet/.' 889 (1965). Edwards, F. and Coghill, N.F.: Aetiological factors in chronic gastritis. Br. med. J. //: 1409 (1966). Hurst, A.F.: Schlorstein lecture on precursors of carcinoma of stomach. Lancet //: 1023 1028 (1929). Joske, R.A.; Finckh, E.S., and Wood, I.J.: Gastric biopsy: a study of 1,000 consecutive successful gastric biopsies. Q. J1 Med. 24: 269 (1955). Kay, A.W.: Effect of large doses of histamine on gastric secretion of HC1, an augmented histamine test. Br. med. J. ii: 77 (1953). Konjetzny, G.: Der Magenkrebs, pp. 21-25 (Enke Vcrlag, Stuttgart 1938). Morson, B.C.: Intestinal metaplasia of the gastric mucosa. Br. J. Cancer 9: 365-376 (1955). Myers, A.M.: Saunders, G.R.G., and Chalmers, D.G.: The haemoglobin level of fit elderly people. Lancet//: 261 (1968). Palmer, E.D.: State of gastric mucosa of elderly persons without gastro-intestinal symptoms. J. Am. Geriat. Soc. 2: 171 (1954). Schilling, R.F.: Intrinsic factor studies. 11. The effect of gastric juice on the urinary excre tion of radio-activity after oral administration of radio-active vitamin B,,. J. Lab. clin. Med. 42: 860 (1953). Siurala, M. and Vuorinen, Y.: Follow-up studies of patients with superficial gastritis and patients with a normal gastric mucosa. Acta med. scand. 173: 45 (1963). Whiteside, M.G.; Mollin, D.L.; Coghill, N.F.; Williams, A.W., and Anderson, B.: Absorption of radio-active vitamin B,2 and secretion of hydrochloric acid in patients with atrophic gastritis. Gut 5: 385 (1964). Williams, A.W.: Edwards, F.. Lewis, T.H.C., and Coghill, N.G.: Investigation of non-ulcer dyspepsia by gastric biopsy. Br. med. J. i: 372- 377 (1957). Wood, l.J.: Doig, R.K.; Motteram, R., and Hughes, A.: Gastric biopsy: report of fifty-five biopsies using a new flexible gastric biopsy tube. Lancet /: 18 (1949). Wood, l.J. and Taft, Diffuse lesions of the stomach, pp. 24 25 (Arnold, London 1958). Wright, R.; Whitehead, R.; Salem, S.: Wangel, A.G., and Schiller, K.F.R.: Auto-antibodies and microscopic appearances of the gastric mucosa. Lancet /: 618 (1966).


Dr. T. Bird, Department of Pathology, Newcastle General Hospital, Westgate Road, New castle upon Tyne NE4 6BE (Great Britain)

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