Iron metabolism in diseases of the liver

The purpose of this study has been to investigate the absorption of iron in various kinds of liver disease and to determine the influence of some of the factors which might affect absorption. Especial attention has bean paid to the possible role of the pancreas in influencing the absorption of iron in these conditions.
The absorption of iron was studied in a total of 39 patients with liver disease. Twenty patients with iron-deficiency anaemia went also given iron absorption tests. Data from 61 normal control subjects and 46 patients with iron-deficiency anaemia was used in defining a range of absorption in normal and iron-deficient subjects.
The absorption of iron was studied using the radio-isotope balance technique introduced by Dubach, Callender and Moore (1948). The principle of the method is that a known amount of activity is administered by mouth sad the amount of activity appearing in the faeces is determined. The amount of iron retained can then be calculated and equated to the amount absorbed.
Using this method the absorption of labelled inorganic iron and food iron as represented by labelled haemoglobin was determined. The doses of iron were prepared so that 5 mg. of elemental iron was present in each dose of labelled ferrous sulphate or haemoglobin. The amount of radioactivity in each dose was also comparable and varied from 3 to 5 microcuries.
The percentage of the dose given by mouth which was used for haemoglobin formation was determined from a blood sample taken 11 to 15 days after administration of the dose.
Haematological investigations and biochemical tests were done by standard procedures.
The results of iron absorption studies in normal control subjects given labelled ferrous sulphate showed in 45 observations on 37 subjects a mean absorption of 30 per cent. with a range of 7 to 70 per cent. The mean percentage appearing in the blood was 23 per cent. and the range 1 to 58 per cent.
Iron absorption studies using labelled haemoglobin in normal control subjects showed in 24 subjects a mean absorption of 11 per cent. with a range of 0 to 32 per cent. The mean percentage of the dose which appeared in the blood was 6 per cent. and the range 0 to 21 per cent.
In iron-deficient subjects absorption was increased. In 19 iron-deficient subjects given labelled ferrous sulphate the moan absorption was 54 per cent. with a range of 14 to 54 per cent. the mean percentage of the dose appearing in the blood was 53 per cent. with a range of 8 to 90 per cent.
The absorption of labelled haemoglobin in 27 patients showed a mean value of 20 per cent. with a range of 1 to 56 per cent. The mean percentage appearing in the blood was 18 per cent. with a range from 0 to 40 per cent.
Eight patients with haemochromatosis were investigated. Seven were untreated. They were ail tested with labelled haemoglobin. One patient had completed a full course of venesection end was not iron-laden. In the seven iron-laden patients the mean absorption of labelled haemoglobin was 12 per cent. with a range of 5 to 20 per cent. The amount of the dose utilised for red-cell formation showed a mean of 4 per cent. with a range of 1.5 to 7 per cent. In the patient who had been venesected absorption was 47 per cent. and the patient utilised 13 per cent. of the dose for red-cell formation. The absorption of iron in these patients was comparable to that seen in normal control subjects, but iron overload usually reduces absorption. Therefore this in fact represents a high absorption when the state of the increased tissue iron is taken into consideration.
Seventeen patients with cirrhosis of the liver were studied using either labelled ferrous sulphate or labelled haemoglobin iron. In seven patients with cirrhosis of the liver given labelled ferrous sulphate the mean absorption was 63 per cent. with a range of 17 to 100 per cent., an increase in absorption which is statistically significant when compared with a group of normal control subjects. In 10 patients with cirrhosis given labelled haemoglobin the mean absorption was 37 per cent. with a range of 3 to 64 per cent. This increase in absorption was also statistically significant.
Examination of this group of cirrhotic patients shows that nine had anaemia or recent bleeding which might be expected to increase absorption. However in the eight others no such complicating factor was present and in addition the saturation of the iron-binding capacity was increased. This group is noteworthy in that it contained patients with cryptogenic cirrhosis and also patients in whom cirrhosis was associated with alcoholism. Previous workers have suggested that increased absorption is specifically associated with alcoholic cirrhosis, but this was not confirmed.
The utilisation of the absorbed iron was remarkably low in nearly all patients with cirrhosis of the liver.
The levels of absorption seen in the cirrhotic patients frequently exceeded the upper limits seen in patients who were iron-deficient. The only other group who showed such high levels of absorption in this study were two chronic alcoholic subjects with little or no evidence of liver damage who absorbed 46 and 50 per cent. respectively of a dose of labelled haemoglobin.
The low levels of absorption found in general in patients with acute liver disease and transfusion siderosis are in marked contrast to the findings in cirrhosis. In eight patients with acute liver disease the absorption of labelled ferrous sulphate varied markedly during the course of the illness. It is not possible to state a range of absorption but with the exception of lupoid hepatitis other acute forms of liver disease tended to show a low absorption at the beginning of the disease which rose with clinical Improvement or administration of steroid hormones.
The mean absorption in four patients with transfusion siderosis given labelled haemoglobin was 5 per cent. with a range of 1 to 11 per cent. Utilisation of the dose of iron in these patieatft was extremely low.
The findings by previous workers (Davis and Badenoch, 1962) that patients with primary pancreatic disease show an increased absorption of iron and the high incidence of pancreatic fibrosis reported in post-mortem studies on patients with cirrhosis of the liver and haemochromatosis prompted an investigation into the effect of pancreatin on the absorption of iron.
This was studied using sequential iron absorption tests. Either the first or second dose of radioactive iron was accompanied by pancreatin; the order was determined randomly.
In eight patients with haemochromatosis the mean absorption of labelled haemoglobin was reduced by the pancreatin from 17 to 9.7 per cent. In one treated patient with haemochromatosis absorption was reduced from 47 to 16 per cent. Although the reduction in absorption in the group as a whole was not statistically significant a definite trend is evident and further investigation with patients whose haemochromatosis has been treated is warranted.
In six patients with cirrhosis of the liver the absorption of labelled ferrous sulphate was reduced from a mean level of 60 per cent. to 26 per cent. by pancreatin. The absorption of labelled haemoglobin was reduced from 56 to 32 per cent. in four patients.
Thus pancreatin was effective in reducing the absorption of iron in both haemochromatosis and in cirrhosis of the liver, conditions known to be associated with pancreatic fibrosis.
When pancreatin was given to patients with acute liver disease, a condition in which pancreatic fibrosis would not be expected to occur, there was no effect. There was a remarkably variable effect when pancreatin was given to iron-deficient subjects and the results in this particular group are without explanation at the moment.
The findings in patients with liver disease suggest that the pancreas is normally responsible for producing some agent that has an inhibitory effect on iron absorption.
In preliminary studies it has been shown that this inhibitory factor in pancreatic extract is heat labile and partly resistant to an acid medium. One of the constituents of pancreatin, the enzyme trypsin, has been shown to have an effect, though less marked than pancreatin, in reducing the absorption of iron, which suggests that enzymes are probably involved at some stage in the inhibition of iron absorption.
The increase in the absorption of iron in patients with cirrhosis of the liver affords an explanation for the siderosis sometimes seen in cirrhosis. Although no patients in the present study showed florid manifestations of secondary siderosis, eight showed increased saturation of their iron-binding protein and some excess stainable iron was seen either in liver biopsy of bone-marrow biopsy in some patients. If these patients survive it is likely that they will show the features of the patients with cirrhosis and secondary haemosiderosis described by Caroli et al. (1964).
The implications of the finding of increased iron absorption in some patients with cirrhosis of the liver are discussed with particular reference to the treatment of these patients with iron.
The present study lends no support to the 'mucosal block' theory of the control of iron absorption but emphasises the rôle of factors acting within the lumen of the intestine which enhance or inhibit the absorption of iron.