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IRON BINDING IN HÆMOCHROMATOSIS
724 GASTRIC FUNCTION IN PRIMARY ADRENAL INSUFFICIENCY
IRON BINDING IN HÆMOCHROMATOSIS
SIR,-Dr. Pollack in his letter (Feb. 11, p. 329) asks in effect whether the absence of the gastric iron-binding protein, gastroferrin, we reported in patients with haemochromatosismight rather be a saturation of this protein with iron. The simplest
disease was probably idiopathic, but P.A. was not recorded in the tuberculous group. All 3 patients with P.A. were diagnosed by the standard methods referred to above; in 1 the intrinsic factor (I. F.) content of the gastric juice was assayed by radioimmunoassay,2 giving a result of 8 ng. units in the basal hour and 6 ng. units in the post-histamine hour, which is well within the P.A. range. All 3 patients had antibody to Of. in the serum but only 1 had parietal-cell antibody. 4 other patients in the combined idiopathic and probable idiopathic groups, but none of the patients with tuberculous Addison’s disease, had antibody to l.F. in the serum. These 4 all had parietalcell antibody in the serum and gastric analysis in 2 showed histamine-fast achlorhydria. 3 of the 4 are known to have maintained normal vitamin-B12 absorption for the period of follow-up (1-3 years) despite the presence of Of. antibody in the serum. The incidence of gastric parietal-cell antibody was 50% in the idiopathic group, 35% in the probable idiopathic group, and 6% in the tuberculous group. The incidence of achlorhydria and hypochlorhydria (see accompanying table) was found to be significantly higher in the patients with idiopathic or probable idiopathic adrenal insufficiency than in the tuberculous group. The 3 patients with P.A. are included among the 11 patients in the idiopathic groups shown to have achlorhydria. The 8 patients with hypochlorhydria have normal vitamin B12 levels in the serum, and in the 4 instances that a Schilling test was done the result was normal. Gastric-biopsy results correlated well with the figures obtained for gastric-acid secretion. The concentration of parietal cells varied inversely with the acid-secretion in response to histamine, and the degree of lymphocytic infiltration was noted to be higher in patients with achlorhydria and hypochlorhydria than in those with normal acid secretion. Antibodies to adrenal cortex were detected by immunofluorescence and complement fixation. They were detected in the serum of 80% (20/25) of the females with idiopathic or probable idiopathic adrenal insufficiency, and in only 10% (1/10) of the males. No antibody to adrenal cortex was detected in 54 patients with P.A. Serological evidence of adrenalitis is rare in patients with P.A., but gastritis is common in those with adrenalitis. The association of Addison’s disease and addisonian ansemia is being recognised more readily. P.A. has been reported in 7 of a group of 118 patients with Addison’s disease 7: 6 of the 7 were children. As to subclinical disease, atrophic gastritis associated with hypochlorhydria or achlorhydria has been described in Addison’s disease.8 Dr. Meecham and Dr. Wyn Jones suggest that cortisone treatment of their patient explained the apparent ten-year remission in his P.A., perhaps by encouraging some regeneration of gastric mucosa and improved vitamin-B12 absorption. Our study indicates that, at least in some cases, gastric atrophy with achlorhydria is commonly present many years after steroid replacement dosage has been instituted and maintained in patients with idiopathic adrenal insufficiency. It is also evident that normal vitamin-B12 absorption can continue in the presence of circulating antibodies to I.F. M.R.C. Clinical Endocrinology Research Unit, W. J. IRVINE Endocrine Clinic, Royal Infirmary, A. G. STEWART and Department of Therapeutics, LAURA SCARTH. University, Edinburgh. 7. 8.
Blizzard, R. M., Chee, D., Davis, W. Clin. exp. Immun. 1967, 2, 19. Smith, A. W. M., Delamore, I. W., Wynn Williams, A. Gut, 1961, 2, 163.
evidence in answer to Dr. Pollack’s speculation is afforded by the colour of fasting gastric juice. In neither normal subjects nor patients with haemochromatosis has the fasting gastric juice any noticeable colour. When iron is then added to the gastric juice and the excess unbound iron removed, as in the solubility test described in our papery normal gastric juice takes on a pronounced yellow-brown colour; gastric juice from patients with haemochromatosis remains uncoloured. Taking this simple observation a step further, when iron-labelled gastric juice is resolved by molecular sieving on ’SephadexG200 ’ a band of yellow colour is seen, and is restricted to the high-molecular-weight gastroferrin fraction. No such band is to be seen when the experiment is repeated with gastric juice from patients with haemochromatosis. Evidence of a different sort will be presented in a paper shortly to be published which reports that in iron-deficiency anaemia gastroferrin levels are decreased and return to normal only on correction of the anaemia. Dr. Pollack’s suggestion about haxmochromatosis would require that in the anaemic state the iron-binding capacity of gastric juice be enhanced because of increased sites of ironbinding in the gastric protein. However, the reverse situation exists in iron deficiency, adding further support to the concept that gastroferrin plays a physiological role in iron absorption, and that hsemochromatosis might be considered an example of a genetic breakdown in this mechanism. P. S. DAVIS Department of Medicine, C. G. LUKE Royal Adelaide Hospital, D. J. DELLER. Adelaide, South Australia
TREATMENT OF CLASSICAL HÆMOPHILIA SIR,-We have read with interest the communication by Dr. Prentice and his colleagues (March 4, p. 457). Although we agree that the antihxmophilic factor (A.H.F.) concentrate prepared by the method of Pool and Shannon is very useful in the treatment of classical haemophilia, we do not agree that this is the only useful or practical method. Dr. Prentice and his colleagues imply that when A.H.F. concentrates are prepared by other methods the supernatant plasma is discarded. This is erroneous. Human A.H.F. preparations have been produced for the American National Red Cross for the past four years (three different methods), by E. R. Squibb & Sons, from 40litre batches of plasma; fibrinogen, &ggr;-globulin, plasminogen, thrombin, and albumin are obtained from the supernatant plasma after the A.H.F. is removed. It is anticipated that a complex of prothrombin and factors vil, ix, and x will also be prepared from this supernatant in the future, for the treatment of patients with Christmas disease and bleeding due to liver
dysfunction. The Red Cross A.H.F. and other lyophilised concentrates have certain additional advantages: (1) samples from each batch can be assayed so that the A.H.F. activity of each bottle is known, permitting administration of exact doses; (2) bloodgroup specificity is not a problem; (3) allergic reactions are very rare, only one mild reaction having been encountered in over 80 persons who received our A.H.F. materials; (4) the concentrates are freeze-dried and remain stable for long periods at room temperature; (5) the unit cost is actually lower for a mass-produced lyophilised concentrate, because the overall cost includes the other valuable components removed subsequently, and because many units of plasma can be processed at one time; and (6) a regional or national blood-collection effort can supply local needs, because the lyophilised concentrates can be readily shipped and stored. We share Dr. Prentice and his colleagues’ satisfaction in 1.
Davis, P. S., Luke,
C.
G., Deller, D. J. Lancet, 1966, ii,
1431.
IRON BINDING IN HÆMOCHROMATOSIS
SIR,-Dr. Pollack in his letter (Feb. 11, p. 329) asks in effect whether the absence of the gastric iron-binding protein, gastroferrin, we reported in patients with haemochromatosismight rather be a saturation of this protein with iron. The simplest
disease was probably idiopathic, but P.A. was not recorded in the tuberculous group. All 3 patients with P.A. were diagnosed by the standard methods referred to above; in 1 the intrinsic factor (I. F.) content of the gastric juice was assayed by radioimmunoassay,2 giving a result of 8 ng. units in the basal hour and 6 ng. units in the post-histamine hour, which is well within the P.A. range. All 3 patients had antibody to Of. in the serum but only 1 had parietal-cell antibody. 4 other patients in the combined idiopathic and probable idiopathic groups, but none of the patients with tuberculous Addison’s disease, had antibody to l.F. in the serum. These 4 all had parietalcell antibody in the serum and gastric analysis in 2 showed histamine-fast achlorhydria. 3 of the 4 are known to have maintained normal vitamin-B12 absorption for the period of follow-up (1-3 years) despite the presence of Of. antibody in the serum. The incidence of gastric parietal-cell antibody was 50% in the idiopathic group, 35% in the probable idiopathic group, and 6% in the tuberculous group. The incidence of achlorhydria and hypochlorhydria (see accompanying table) was found to be significantly higher in the patients with idiopathic or probable idiopathic adrenal insufficiency than in the tuberculous group. The 3 patients with P.A. are included among the 11 patients in the idiopathic groups shown to have achlorhydria. The 8 patients with hypochlorhydria have normal vitamin B12 levels in the serum, and in the 4 instances that a Schilling test was done the result was normal. Gastric-biopsy results correlated well with the figures obtained for gastric-acid secretion. The concentration of parietal cells varied inversely with the acid-secretion in response to histamine, and the degree of lymphocytic infiltration was noted to be higher in patients with achlorhydria and hypochlorhydria than in those with normal acid secretion. Antibodies to adrenal cortex were detected by immunofluorescence and complement fixation. They were detected in the serum of 80% (20/25) of the females with idiopathic or probable idiopathic adrenal insufficiency, and in only 10% (1/10) of the males. No antibody to adrenal cortex was detected in 54 patients with P.A. Serological evidence of adrenalitis is rare in patients with P.A., but gastritis is common in those with adrenalitis. The association of Addison’s disease and addisonian ansemia is being recognised more readily. P.A. has been reported in 7 of a group of 118 patients with Addison’s disease 7: 6 of the 7 were children. As to subclinical disease, atrophic gastritis associated with hypochlorhydria or achlorhydria has been described in Addison’s disease.8 Dr. Meecham and Dr. Wyn Jones suggest that cortisone treatment of their patient explained the apparent ten-year remission in his P.A., perhaps by encouraging some regeneration of gastric mucosa and improved vitamin-B12 absorption. Our study indicates that, at least in some cases, gastric atrophy with achlorhydria is commonly present many years after steroid replacement dosage has been instituted and maintained in patients with idiopathic adrenal insufficiency. It is also evident that normal vitamin-B12 absorption can continue in the presence of circulating antibodies to I.F. M.R.C. Clinical Endocrinology Research Unit, W. J. IRVINE Endocrine Clinic, Royal Infirmary, A. G. STEWART and Department of Therapeutics, LAURA SCARTH. University, Edinburgh. 7. 8.
Blizzard, R. M., Chee, D., Davis, W. Clin. exp. Immun. 1967, 2, 19. Smith, A. W. M., Delamore, I. W., Wynn Williams, A. Gut, 1961, 2, 163.
evidence in answer to Dr. Pollack’s speculation is afforded by the colour of fasting gastric juice. In neither normal subjects nor patients with haemochromatosis has the fasting gastric juice any noticeable colour. When iron is then added to the gastric juice and the excess unbound iron removed, as in the solubility test described in our papery normal gastric juice takes on a pronounced yellow-brown colour; gastric juice from patients with haemochromatosis remains uncoloured. Taking this simple observation a step further, when iron-labelled gastric juice is resolved by molecular sieving on ’SephadexG200 ’ a band of yellow colour is seen, and is restricted to the high-molecular-weight gastroferrin fraction. No such band is to be seen when the experiment is repeated with gastric juice from patients with haemochromatosis. Evidence of a different sort will be presented in a paper shortly to be published which reports that in iron-deficiency anaemia gastroferrin levels are decreased and return to normal only on correction of the anaemia. Dr. Pollack’s suggestion about haxmochromatosis would require that in the anaemic state the iron-binding capacity of gastric juice be enhanced because of increased sites of ironbinding in the gastric protein. However, the reverse situation exists in iron deficiency, adding further support to the concept that gastroferrin plays a physiological role in iron absorption, and that hsemochromatosis might be considered an example of a genetic breakdown in this mechanism. P. S. DAVIS Department of Medicine, C. G. LUKE Royal Adelaide Hospital, D. J. DELLER. Adelaide, South Australia
TREATMENT OF CLASSICAL HÆMOPHILIA SIR,-We have read with interest the communication by Dr. Prentice and his colleagues (March 4, p. 457). Although we agree that the antihxmophilic factor (A.H.F.) concentrate prepared by the method of Pool and Shannon is very useful in the treatment of classical haemophilia, we do not agree that this is the only useful or practical method. Dr. Prentice and his colleagues imply that when A.H.F. concentrates are prepared by other methods the supernatant plasma is discarded. This is erroneous. Human A.H.F. preparations have been produced for the American National Red Cross for the past four years (three different methods), by E. R. Squibb & Sons, from 40litre batches of plasma; fibrinogen, &ggr;-globulin, plasminogen, thrombin, and albumin are obtained from the supernatant plasma after the A.H.F. is removed. It is anticipated that a complex of prothrombin and factors vil, ix, and x will also be prepared from this supernatant in the future, for the treatment of patients with Christmas disease and bleeding due to liver
dysfunction. The Red Cross A.H.F. and other lyophilised concentrates have certain additional advantages: (1) samples from each batch can be assayed so that the A.H.F. activity of each bottle is known, permitting administration of exact doses; (2) bloodgroup specificity is not a problem; (3) allergic reactions are very rare, only one mild reaction having been encountered in over 80 persons who received our A.H.F. materials; (4) the concentrates are freeze-dried and remain stable for long periods at room temperature; (5) the unit cost is actually lower for a mass-produced lyophilised concentrate, because the overall cost includes the other valuable components removed subsequently, and because many units of plasma can be processed at one time; and (6) a regional or national blood-collection effort can supply local needs, because the lyophilised concentrates can be readily shipped and stored. We share Dr. Prentice and his colleagues’ satisfaction in 1.
Davis, P. S., Luke,
C.
G., Deller, D. J. Lancet, 1966, ii,
1431.