- Email: [email protected]
GASTRIC IRON BINDING IN HÆMOCHROMATOSIS, SECONDARY IRON OVERLOAD, CIRRHOSIS, AND DIABETES
844
centration was only increased postoperatively and the degree of increase was never significant. Protein excretion was increased postoperatively, reached a peak in the second postoperative 24-hour collection period, and had returned to within normal limits by the fourth or fifth postoperative day. The increase in protein excretion only reached a significant level in the second This pattern postoperative 24-hour collection (P<0-005). of response contrasts with series A where peak protein excretion was reached on the fourth or fifth postoperative day only to return to within normal limits at the time of discharge from hospital, usually the tenth postoperative
day. The mean urine protein concentration was significantly lower in those patients infused preoperatively compared with the earlier series for the " operative " specimen and for the first two postoperative periods (P<0.05, P<0-02, P<0-05, respectively) despite protein concentration being significantly higher in the preoperative phase. After operation mean protein excretion was less in the first and third and greater in the second 24-hour collection periods for series B. These differences were not, however,
significant. The mean urine volume was significantly greater in and day 2 (P<0-02). The series B on day 1 (P<0-01) mean urinary sodium excretion was appreciably greater postoperatively, but this difference was significant only on day 1 (P<0-05). Postoperatively, the mean creatinine clearances were not significantly different in the two groups.
more commonly than clinical tests would indicate. The pattern of electrophoretic separations of proteins appearing in the urine after operation, in our experience (Macbeth 1968), is remarkably similar to that described by others as characteristic of tubular proteinuria (Butler and
surgery,
Flynn 1958, 1961). Although the theory behind preoperative and operative hydration may remain contested, the preoperative infusion of saline solution in patients submitted to elective abdominal surgery seems to have a direct, beneficial effect upon renal tubular function in the postoperative period. It would, however, be highly contentious, at this stage, to expound on the possible mechanisms for these changes. This work was supported by the Medical Research Council of New Zealand. We thank our colleagues for letting us investigate their patients. Requests for reprints should be addressed to W. A. A. G. M. REFERENCES
Beall, A. C., Hall, C. W., Morris, G. C., DeBakey, M. E. (1965) Ann. Surg. 161, 46. Holman, M. R., Morris, G. C., DeBakey, M. E. (1963) Archs Surg., Chicago, 86, 34. Butler, E. A., Flynn, F. V. (1958) Lancet, ii, 978. (1961) J. clin. Path. 14, 172. Furneaux, R. W. (1968) Aust. N.Z.Jl Surg. 37, 315. Luck, R. J., Irvine, W. T. (1965) Lancet, ii, 409. Ludbrook, J. (1968) Personal communication. Macbeth, W. A. A. G. (1968) Aust. N.Z. Jl Surg. (in the press). Pope, G. R. (1968) Lancet, i, 215. Nanson, E. M., Noble, J. G. (1959) Surgery, St. Louis, 46, 388. Powers, S. R., Boba, A., Stem, A. (1957) ibid. 42, 156. Pruitt, B. A., Moncrieff, J. A., Mason, A. D. (1967) J. Trauma, 7, 767. Shires, T., Coln, D., Carrico, J., Lightfoot, S. (1964) Archs Surg., Chicago, 88, 688. Jackson, D. E. (1962) ibid. 84, 703. Williams, J., Brown, F. (1960) J. Lab. clin. Med. 55, 776. (1961) Ann. Surg. 154, 803. -
-
-
-
-
Discussion
We believe that the two series are very different in respect of urinary biochemical findings. In the series B protein excretion in the urine reached a peak appreciably earlier and returned to within normal limits at a time when, in series A, the peak of protein excretion had been reached. Furthermore, electrophoretic separation of urinary concentrates and immunoelectrophoresis reveal a reduction in the number and density of protein bands appearing in the urine in the postoperative phase of series B. The lower preoperative creatinine clearance, higher preoperative protein concentration and excretion in the urine, and the significant increase in urine volume postoperatively probably combine to account for the failure to demonstrate a statistically significant difference in the postoperative excretion of protein in the urine between the two series when the individual postoperative days are
compared. It is, however, significant that in series B protein concentration in the urine was never significantly raised and that protein excretion was raised significantly only on the second postoperative day. The preoperative administration of fluid has increasingly gained favour in clinical practice, especially in aortic surgery (Beall et al. 1963, Beall et al. 1965) which has, in the past, been recognised to be associated with a high incidence of renal functional impairment (Powers et al. 1957, Nanson and Noble 1959). This practice has been based largely on the work of Shires and colleagues (Shires et al. 1961, Shires and Jackson 1962, Shires et al. 1964) and others (Pruitt et al. 1967). However, other workers have been unable to reproduce Shires’ results (Furneaux 1968, Ludbrook 1968) and consider the observed changes in the extracellular space to be a reflection of some of the inherent fallacies in the isotopic markers used (Shires et al. 1960). Luck and Irvine (1965) observed microscopic tubular changes in renal-biopsy specimens, obtained during aortic
—
—
—
—
GASTRIC IRON BINDING IN HÆMOCHROMATOSIS, SECONDARY IRON OVERLOAD, CIRRHOSIS, AND DIABETES C. G. LUKE M.B. Adel. NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL
POSTGRADUATE MEDICAL SCHOLAR
P. S. DAVIS M.Sc. New South Wales, Ph.D. Adel. SENIOR LECTURER IN CLINICAL BIOLOGY
D. J. DELLER M.D. Adel., D.Phil. Oxon., F.R.A.C.P., M.R.C.P. MORTLOCK PROFESSOR OF MEDICINE
From the
Department of Medicine, University of Adelaide, Royal Adelaide Hospital, South Australia
iron-binding ability of fasting gastric juice was studied in normal subjects and in patients with hæmochromatosis, iron overload due to a variety of causes, hepatic cirrhosis, and diabetes mellitus. In patients with hæmochromatosis, negligible amounts of iron were bound, whereas in the other patients values were similar to those found in normal subjects. This absence of iron binding appears to be peculiar to idiopathic hæmochromatosis, and may account for the excessive absorption of dietary iron. Summary
The
Introduction
THE iron-binding substance present in the gastric juice of normal subjects (gastroferrin) has been found to be absent, or present in only negligible amounts, in patients with idiopathic hsemochromatosis (Davis et al. 1966).
845
physicochemical nature of this substance (Luke et al. 1967), its inhibitory effect on the transfer of radio-iron across a semipermeable membrane, as well as clinical evidence (Davis 1965, Davis et al. 1966, Luke et al. 1967), suggest an inhibitory role in iron absorption. In the absence of gastroferrin uncontrolled absorption of the metal might occur, and be of significance in the pathogenesis of hxmochromatosis (Davis et al. 1966, Pollack The
1967). We have shown (Davis et al. 1967) that the failure of gastric juice to bind iron in haemochromatosis is not caused by previous saturation of the iron-binding protein; but it is still possible that either the biochemical defect is a paraphenomenon of the disease or it is related to one or more of the separate components of the hxmochromatosis syndrome-iron overload, cirrhosis, and diabetes mellitus. We have therefore measured the iron-binding ability of gastric juice in hsemochromatosis and in each of these
conditions. Patients and Methods Patients Studies were carried out on the fasting gastric juice of 108 subjects: 50 normal people, 12 patients with hsemochromatosis, 6 padents with iron overload due to other causes, 20 patients with cirrhosis of the liver, and 20 patients with diabetes mellitus. The patients with hasmochromatosis satisfied the usual clinical criteria of the disease. The diagnosis was confirmed by serum-iron estimations in all cases and by liver biopsy in 9. Of the 6 patients with iron overload, each had received more than 150 blood-transfusions in the past 10 years. The causes were sideroblastic anaemia in 4 patients, aplasia of the bonemarrow in 1 patient, and chronic hasmolytic anaemia of obscure aetiology in 1 patient. The serum-iron levels were elevated in
all
cases
and liver
biopsy
showed
pronounced siderosis in 4
(table I). The cause of cirrhosis of the liver was alcoholism in 19 of the 20 patients studied, the remaining patient having juvenile cirrhosis. The diagnosis was established clinically and by liver-function tests in all patients, and was confirmed by liver biopsy in 10. Mild to moderate ansmia was present in 10 patients and mild siderosis of the liver was demonstrated in 2
(table II). The diagnosis of diabetes mellitus was confirmed by glucosetolerance tests, and in no case was there clinical or laboratory evidence of a secondary cause for the condition. Collection of Gastric Juice Gastric juice was collected after a 12-hour fast by intermittent suction through a stomach tube (Davis et al. 1966). Particular care secretions.
was
taken to exclude saliva and
Measurements of Iron-chelating Ability Chelating ability was measured by means of a radio-iron solubility test (Davis 1965, Davis et al. 1966, Davis and Deller 1966) and was expressed as mg. ferric iron bound per ml.
gastric juice. Results
The iron-binding ability of fasting gastric juice from normal subjects ranged from 0-04 to 0-24 mg. of ferric iron per ml. of gastric juice (mean 0-171 mg.) (see figure). Iron binding was negligible in the 12 cases of haemochromatosis, less than 0-008 mg. of ferric iron being bound per ml. (range 0-004-0-008 mg.). In contrast, normal to high levels of iron binding were found in the 6 patients with secondary iron overload. The chelating ability ranged from 0-126 to 0-248 mg. ferric iron per ml., with a mean of 0-176 mg. In the 20 cases of alcoholic cirrhosis, values fell within the normal range, the mean being 0-145 mg. per
TABLE I-CLINICAL AND LABORATORY DATA OF PATIENTS WITH SECONDARY IRON OVERLOAD
..
=
Not done.
TABLE II-CLINICAL AND LABORATORY DATA OF PATIENTS WITH CIRRHOSIS
..
=
nasopharyngeal
Not done.
846
chromatosis bound about the same amount of iron as gastric juice from normal subjects. We also have found that stimulation of gastric secretion by histamine, pentagastrin, and 2-deoxyglucose substantially increases the iron-binding ability of gastric juice in normal people. In heemochromatosis, however, we have found that although histamine stimulation produces a gastric juice with the ability to bind iron, this ability is considerably less than in normal subjects. Whether this binding is due to gastroferrin, or to the blood or plasma proteins frequently found in such samples, has yet to be determined. It is precisely for this reason that in all our reports on gastric iron binding, we have stated the findings in resting gastric
binding in normal people and in patients with heemochromatosis, secondary iron overload, cirrhosis, and diabetes.
Gastric iron
ml. There was no significant difference in iron binding between the patients in whom liver biopsy showed siderosis, and those in whom it did not. Iron binding in the 20 patients with diabetes mellitus was within the normal range. Discussion
This study has shown that reduction of gastroferrin levels is specifically related to idiopathic hxmochromatosis rather than to the separate conditions of iron overload, cirrhosis of the liver, and diabetes, in which gastroferrin levels were normal. Pollack (1967) has suggested that iron binding in haemochromatosis might be impaired because the iron-binding sites were already saturated by the excess of iron in the stomachs of patients with this condition. A similar situation might be expected in the patients with secondary iron overload. However, we found that the iron-binding ability, as measured by the radio-ironsolubility test, was normal or elevated in this condition. The estimation of the iron-binding ability of gastric juice is therefore useful in determining the cause of siderosis, since a low level is characteristic of hoemochromatosis. The present study and our previous reports have given evidence of a control of iron absorption mediated by the stomach, the influence being inhibitory. Increased iron absorption in haemochromatosis (Davis et al. 1966) and iron deficiency (Luke et al. 1967), according to this concept, is caused by a reduction in the levels of gastric inhibitory factor. Murray and Stein (1968), however, have suggested that the gastric control is active, a gastric iron-absorption-promoting factor being increased in iron deficiency and hoemochromatosis. Their concept is based on in-vivo studies of iron absorption in normal rats and in gastrectomised anaemic rats. At present it is impossible to reconcile these views. Both groups, however, agree that the stomach exerts an influence on iron absorption not dependent solely on its acid-peptic function, and that the gastric juice of patients with hxmochromatosis and irondeficiency anaemia is altered in a way that might enhance iron absorption. Wynter and Williams (1968) have studied the iron binding of gastric juice, secreted after maximum histamine stimulation and collected on ice to inhibit pepsin activity. They found that the gastric juice of patients with hsemo-
juice. Wynter and Williams reject our finding of iron chelation by gastric juice in normal subjects, and suggest instead that gastric juice forms a loose association with iron. In support of this they cite an experiment in which increasing amounts of iron are offered to gastric juice, and the excess iron is precipitated out of the system as ferric hydroxide, by raising the pH to 8-3. When a sufficient excess of iron is present, the amount of iron maintained in solution by the gastric juice decreases, and at higher concentrations becomes zero. These workers conclude that this is evidence against iron chelation by gastric juice. On the contrary, it appears to us to be quite compatible with the well-known use of ferric hydroxide as a scavenging agent in inorganic chemistry and radiochemistry. We have illustrated this by repeating the experiment of Wynter and Williams, using two well-known iron-chelating agents, salicylic acid and fructose, instead of gastric juice. In each case the curve obtained is identical to that published by Wynter and Williams. Their results, thus, give no evidence against the true chelation of iron by gastric juice. Requests for reprints should be addressed
to
D. J. D.
REFERENCES P. S. (1965) Proc. Aust. Ass. clin. Biochem. 1, 190. Deller, D. J. (1966) Nature, Lond. 212, 404. Luke, C. G., Deller, D. J. (1966) Lancet, ii, 1431. (1967) ibid. i, 724. Luke, C. G., Davies, P. S., Deller, D. J. (1967) ibid. p. 926. Murray, M. J., Stein, N. (1968) ibid. i, 614. Pollack, S. (1967) ibid. i, 329. Wynter, C. V. A., Williams, R. (1968) ibid. ii, 534.
Davis, -
-
-
-
-
ABNORMALITIES IN IgA-CONTAINING MONONUCLEAR CELLS IN THE GASTRIC LESION OF PERNICIOUS ANÆMIA R.
J. ODGERS
M.B. Adel. RESEARCH FELLOW
M.D.
A. G. WANGEL Adel., D.Phil. Oxon., M.R.C.P., M.R.A.C.P. MICHELL PROFESSOR OF MEDICINE
DEPARTMENT OF
MEDICINE,
UNIVERSITY OF
ADELAIDE,
SOUTH AUSTRALIA
The levels of serum and gastric-juice IgA, IgG, and IgM and the numbers of immunoglobulin-containing mononuclear cells in the gastric mucosa were measured in a study of gastritis. 20 patients with pernicious anaemia, 6 patients with duodenal ulceration, and 4 healthy volunteers were investigated, 15 of the 20 patients with pernicious anæmia had an atypical distribution of immunoglobulin-containing mononuclear cells in the gastric mucosa: IgA-containing cells Summary
centration was only increased postoperatively and the degree of increase was never significant. Protein excretion was increased postoperatively, reached a peak in the second postoperative 24-hour collection period, and had returned to within normal limits by the fourth or fifth postoperative day. The increase in protein excretion only reached a significant level in the second This pattern postoperative 24-hour collection (P<0-005). of response contrasts with series A where peak protein excretion was reached on the fourth or fifth postoperative day only to return to within normal limits at the time of discharge from hospital, usually the tenth postoperative
day. The mean urine protein concentration was significantly lower in those patients infused preoperatively compared with the earlier series for the " operative " specimen and for the first two postoperative periods (P<0.05, P<0-02, P<0-05, respectively) despite protein concentration being significantly higher in the preoperative phase. After operation mean protein excretion was less in the first and third and greater in the second 24-hour collection periods for series B. These differences were not, however,
significant. The mean urine volume was significantly greater in and day 2 (P<0-02). The series B on day 1 (P<0-01) mean urinary sodium excretion was appreciably greater postoperatively, but this difference was significant only on day 1 (P<0-05). Postoperatively, the mean creatinine clearances were not significantly different in the two groups.
more commonly than clinical tests would indicate. The pattern of electrophoretic separations of proteins appearing in the urine after operation, in our experience (Macbeth 1968), is remarkably similar to that described by others as characteristic of tubular proteinuria (Butler and
surgery,
Flynn 1958, 1961). Although the theory behind preoperative and operative hydration may remain contested, the preoperative infusion of saline solution in patients submitted to elective abdominal surgery seems to have a direct, beneficial effect upon renal tubular function in the postoperative period. It would, however, be highly contentious, at this stage, to expound on the possible mechanisms for these changes. This work was supported by the Medical Research Council of New Zealand. We thank our colleagues for letting us investigate their patients. Requests for reprints should be addressed to W. A. A. G. M. REFERENCES
Beall, A. C., Hall, C. W., Morris, G. C., DeBakey, M. E. (1965) Ann. Surg. 161, 46. Holman, M. R., Morris, G. C., DeBakey, M. E. (1963) Archs Surg., Chicago, 86, 34. Butler, E. A., Flynn, F. V. (1958) Lancet, ii, 978. (1961) J. clin. Path. 14, 172. Furneaux, R. W. (1968) Aust. N.Z.Jl Surg. 37, 315. Luck, R. J., Irvine, W. T. (1965) Lancet, ii, 409. Ludbrook, J. (1968) Personal communication. Macbeth, W. A. A. G. (1968) Aust. N.Z. Jl Surg. (in the press). Pope, G. R. (1968) Lancet, i, 215. Nanson, E. M., Noble, J. G. (1959) Surgery, St. Louis, 46, 388. Powers, S. R., Boba, A., Stem, A. (1957) ibid. 42, 156. Pruitt, B. A., Moncrieff, J. A., Mason, A. D. (1967) J. Trauma, 7, 767. Shires, T., Coln, D., Carrico, J., Lightfoot, S. (1964) Archs Surg., Chicago, 88, 688. Jackson, D. E. (1962) ibid. 84, 703. Williams, J., Brown, F. (1960) J. Lab. clin. Med. 55, 776. (1961) Ann. Surg. 154, 803. -
-
-
-
-
Discussion
We believe that the two series are very different in respect of urinary biochemical findings. In the series B protein excretion in the urine reached a peak appreciably earlier and returned to within normal limits at a time when, in series A, the peak of protein excretion had been reached. Furthermore, electrophoretic separation of urinary concentrates and immunoelectrophoresis reveal a reduction in the number and density of protein bands appearing in the urine in the postoperative phase of series B. The lower preoperative creatinine clearance, higher preoperative protein concentration and excretion in the urine, and the significant increase in urine volume postoperatively probably combine to account for the failure to demonstrate a statistically significant difference in the postoperative excretion of protein in the urine between the two series when the individual postoperative days are
compared. It is, however, significant that in series B protein concentration in the urine was never significantly raised and that protein excretion was raised significantly only on the second postoperative day. The preoperative administration of fluid has increasingly gained favour in clinical practice, especially in aortic surgery (Beall et al. 1963, Beall et al. 1965) which has, in the past, been recognised to be associated with a high incidence of renal functional impairment (Powers et al. 1957, Nanson and Noble 1959). This practice has been based largely on the work of Shires and colleagues (Shires et al. 1961, Shires and Jackson 1962, Shires et al. 1964) and others (Pruitt et al. 1967). However, other workers have been unable to reproduce Shires’ results (Furneaux 1968, Ludbrook 1968) and consider the observed changes in the extracellular space to be a reflection of some of the inherent fallacies in the isotopic markers used (Shires et al. 1960). Luck and Irvine (1965) observed microscopic tubular changes in renal-biopsy specimens, obtained during aortic
—
—
—
—
GASTRIC IRON BINDING IN HÆMOCHROMATOSIS, SECONDARY IRON OVERLOAD, CIRRHOSIS, AND DIABETES C. G. LUKE M.B. Adel. NATIONAL HEALTH AND MEDICAL RESEARCH COUNCIL
POSTGRADUATE MEDICAL SCHOLAR
P. S. DAVIS M.Sc. New South Wales, Ph.D. Adel. SENIOR LECTURER IN CLINICAL BIOLOGY
D. J. DELLER M.D. Adel., D.Phil. Oxon., F.R.A.C.P., M.R.C.P. MORTLOCK PROFESSOR OF MEDICINE
From the
Department of Medicine, University of Adelaide, Royal Adelaide Hospital, South Australia
iron-binding ability of fasting gastric juice was studied in normal subjects and in patients with hæmochromatosis, iron overload due to a variety of causes, hepatic cirrhosis, and diabetes mellitus. In patients with hæmochromatosis, negligible amounts of iron were bound, whereas in the other patients values were similar to those found in normal subjects. This absence of iron binding appears to be peculiar to idiopathic hæmochromatosis, and may account for the excessive absorption of dietary iron. Summary
The
Introduction
THE iron-binding substance present in the gastric juice of normal subjects (gastroferrin) has been found to be absent, or present in only negligible amounts, in patients with idiopathic hsemochromatosis (Davis et al. 1966).
845
physicochemical nature of this substance (Luke et al. 1967), its inhibitory effect on the transfer of radio-iron across a semipermeable membrane, as well as clinical evidence (Davis 1965, Davis et al. 1966, Luke et al. 1967), suggest an inhibitory role in iron absorption. In the absence of gastroferrin uncontrolled absorption of the metal might occur, and be of significance in the pathogenesis of hxmochromatosis (Davis et al. 1966, Pollack The
1967). We have shown (Davis et al. 1967) that the failure of gastric juice to bind iron in haemochromatosis is not caused by previous saturation of the iron-binding protein; but it is still possible that either the biochemical defect is a paraphenomenon of the disease or it is related to one or more of the separate components of the hxmochromatosis syndrome-iron overload, cirrhosis, and diabetes mellitus. We have therefore measured the iron-binding ability of gastric juice in hsemochromatosis and in each of these
conditions. Patients and Methods Patients Studies were carried out on the fasting gastric juice of 108 subjects: 50 normal people, 12 patients with hsemochromatosis, 6 padents with iron overload due to other causes, 20 patients with cirrhosis of the liver, and 20 patients with diabetes mellitus. The patients with hasmochromatosis satisfied the usual clinical criteria of the disease. The diagnosis was confirmed by serum-iron estimations in all cases and by liver biopsy in 9. Of the 6 patients with iron overload, each had received more than 150 blood-transfusions in the past 10 years. The causes were sideroblastic anaemia in 4 patients, aplasia of the bonemarrow in 1 patient, and chronic hasmolytic anaemia of obscure aetiology in 1 patient. The serum-iron levels were elevated in
all
cases
and liver
biopsy
showed
pronounced siderosis in 4
(table I). The cause of cirrhosis of the liver was alcoholism in 19 of the 20 patients studied, the remaining patient having juvenile cirrhosis. The diagnosis was established clinically and by liver-function tests in all patients, and was confirmed by liver biopsy in 10. Mild to moderate ansmia was present in 10 patients and mild siderosis of the liver was demonstrated in 2
(table II). The diagnosis of diabetes mellitus was confirmed by glucosetolerance tests, and in no case was there clinical or laboratory evidence of a secondary cause for the condition. Collection of Gastric Juice Gastric juice was collected after a 12-hour fast by intermittent suction through a stomach tube (Davis et al. 1966). Particular care secretions.
was
taken to exclude saliva and
Measurements of Iron-chelating Ability Chelating ability was measured by means of a radio-iron solubility test (Davis 1965, Davis et al. 1966, Davis and Deller 1966) and was expressed as mg. ferric iron bound per ml.
gastric juice. Results
The iron-binding ability of fasting gastric juice from normal subjects ranged from 0-04 to 0-24 mg. of ferric iron per ml. of gastric juice (mean 0-171 mg.) (see figure). Iron binding was negligible in the 12 cases of haemochromatosis, less than 0-008 mg. of ferric iron being bound per ml. (range 0-004-0-008 mg.). In contrast, normal to high levels of iron binding were found in the 6 patients with secondary iron overload. The chelating ability ranged from 0-126 to 0-248 mg. ferric iron per ml., with a mean of 0-176 mg. In the 20 cases of alcoholic cirrhosis, values fell within the normal range, the mean being 0-145 mg. per
TABLE I-CLINICAL AND LABORATORY DATA OF PATIENTS WITH SECONDARY IRON OVERLOAD
..
=
Not done.
TABLE II-CLINICAL AND LABORATORY DATA OF PATIENTS WITH CIRRHOSIS
..
=
nasopharyngeal
Not done.
846
chromatosis bound about the same amount of iron as gastric juice from normal subjects. We also have found that stimulation of gastric secretion by histamine, pentagastrin, and 2-deoxyglucose substantially increases the iron-binding ability of gastric juice in normal people. In heemochromatosis, however, we have found that although histamine stimulation produces a gastric juice with the ability to bind iron, this ability is considerably less than in normal subjects. Whether this binding is due to gastroferrin, or to the blood or plasma proteins frequently found in such samples, has yet to be determined. It is precisely for this reason that in all our reports on gastric iron binding, we have stated the findings in resting gastric
binding in normal people and in patients with heemochromatosis, secondary iron overload, cirrhosis, and diabetes.
Gastric iron
ml. There was no significant difference in iron binding between the patients in whom liver biopsy showed siderosis, and those in whom it did not. Iron binding in the 20 patients with diabetes mellitus was within the normal range. Discussion
This study has shown that reduction of gastroferrin levels is specifically related to idiopathic hxmochromatosis rather than to the separate conditions of iron overload, cirrhosis of the liver, and diabetes, in which gastroferrin levels were normal. Pollack (1967) has suggested that iron binding in haemochromatosis might be impaired because the iron-binding sites were already saturated by the excess of iron in the stomachs of patients with this condition. A similar situation might be expected in the patients with secondary iron overload. However, we found that the iron-binding ability, as measured by the radio-ironsolubility test, was normal or elevated in this condition. The estimation of the iron-binding ability of gastric juice is therefore useful in determining the cause of siderosis, since a low level is characteristic of hoemochromatosis. The present study and our previous reports have given evidence of a control of iron absorption mediated by the stomach, the influence being inhibitory. Increased iron absorption in haemochromatosis (Davis et al. 1966) and iron deficiency (Luke et al. 1967), according to this concept, is caused by a reduction in the levels of gastric inhibitory factor. Murray and Stein (1968), however, have suggested that the gastric control is active, a gastric iron-absorption-promoting factor being increased in iron deficiency and hoemochromatosis. Their concept is based on in-vivo studies of iron absorption in normal rats and in gastrectomised anaemic rats. At present it is impossible to reconcile these views. Both groups, however, agree that the stomach exerts an influence on iron absorption not dependent solely on its acid-peptic function, and that the gastric juice of patients with hxmochromatosis and irondeficiency anaemia is altered in a way that might enhance iron absorption. Wynter and Williams (1968) have studied the iron binding of gastric juice, secreted after maximum histamine stimulation and collected on ice to inhibit pepsin activity. They found that the gastric juice of patients with hsemo-
juice. Wynter and Williams reject our finding of iron chelation by gastric juice in normal subjects, and suggest instead that gastric juice forms a loose association with iron. In support of this they cite an experiment in which increasing amounts of iron are offered to gastric juice, and the excess iron is precipitated out of the system as ferric hydroxide, by raising the pH to 8-3. When a sufficient excess of iron is present, the amount of iron maintained in solution by the gastric juice decreases, and at higher concentrations becomes zero. These workers conclude that this is evidence against iron chelation by gastric juice. On the contrary, it appears to us to be quite compatible with the well-known use of ferric hydroxide as a scavenging agent in inorganic chemistry and radiochemistry. We have illustrated this by repeating the experiment of Wynter and Williams, using two well-known iron-chelating agents, salicylic acid and fructose, instead of gastric juice. In each case the curve obtained is identical to that published by Wynter and Williams. Their results, thus, give no evidence against the true chelation of iron by gastric juice. Requests for reprints should be addressed
to
D. J. D.
REFERENCES P. S. (1965) Proc. Aust. Ass. clin. Biochem. 1, 190. Deller, D. J. (1966) Nature, Lond. 212, 404. Luke, C. G., Deller, D. J. (1966) Lancet, ii, 1431. (1967) ibid. i, 724. Luke, C. G., Davies, P. S., Deller, D. J. (1967) ibid. p. 926. Murray, M. J., Stein, N. (1968) ibid. i, 614. Pollack, S. (1967) ibid. i, 329. Wynter, C. V. A., Williams, R. (1968) ibid. ii, 534.
Davis, -
-
-
-
-
ABNORMALITIES IN IgA-CONTAINING MONONUCLEAR CELLS IN THE GASTRIC LESION OF PERNICIOUS ANÆMIA R.
J. ODGERS
M.B. Adel. RESEARCH FELLOW
M.D.
A. G. WANGEL Adel., D.Phil. Oxon., M.R.C.P., M.R.A.C.P. MICHELL PROFESSOR OF MEDICINE
DEPARTMENT OF
MEDICINE,
UNIVERSITY OF
ADELAIDE,
SOUTH AUSTRALIA
The levels of serum and gastric-juice IgA, IgG, and IgM and the numbers of immunoglobulin-containing mononuclear cells in the gastric mucosa were measured in a study of gastritis. 20 patients with pernicious anaemia, 6 patients with duodenal ulceration, and 4 healthy volunteers were investigated, 15 of the 20 patients with pernicious anæmia had an atypical distribution of immunoglobulin-containing mononuclear cells in the gastric mucosa: IgA-containing cells Summary