533
THE LANCET
Serum-ferritin
tiny quantity of ferritin normally present
in from the breakdown of cells in iron-containing tissues, particularly from macrophages of the reticuloendothelial system in the liver, spleen, and bone-marrow.I,2 Under most circumstances the amount of ferritin within these cells represents the amount of storage iron within the body so that the concentration of ferritin in serum indicates the body’s storage iron status. This will be increased if there is too much iron in the tissues and lowered if there is too little. Lately a radioimmunoassay for ferritin has become available for use in routine laboratories3 and this may now replace measurement of serum iron and total iron-binding capacity or transferrin, particularly since it is cheaper than these two investigations. When there is iron overload with hxmochromatosis or hsemosiderosis the serum-ferritin level may be very high indeed. After treatment by venesection or with iron-chelating agents, the serumferritin concentration may fluctuate quite widely, but as the iron status falls towards normal so does the serum-ferritin.4,5 Thus, serum-ferritin estimations can make an important contribution to the initial assessment of iron overload and can be used to follow the course of its treatment. Perhaps a more important use would be to screen relatives of patients with idiopathic hsemochromatosis and so diagnose early stages of iron overload which can be treated to prevent tissue damage. Unfortunately, THE
serum seems to come
1 Jacobs, A., Worwood, M.
New
Engl. J
Med. 1975,
292,
951.
2 Lipschitz, D. A., Cook, J. D., Finch, C. A. ibid. 1974, 290, 1213. 3 Luxton,
A. W.,
Walker, W. H. C., Gauldie, J.,
et
al. Clin. Chem.
1977, 23,
683.
J., Williams, R.
5
J.
27, 652.
6. Wands, J., et al. New Engl. J. Med. 1976, 294, 302. 7. Halliday, J. W., Russo, A. M., Cowhshaw, J. L., Powell, L. W. Lancet, 1977,
ii, 621.
4 Leyland,
M. J., Brown, P. J., Bomford, A., Walker, R. J Hœmat. 1977, 36, 441. Letsky, E. A., Miller, F., Worwood, M., Flynn, D. M.
there is some doubt about this, two families having been reported with proven iron overload and tissue damage but normal serum-ferritin levels.6 Measurement of transferrin saturation is no substitute since it may be high in normal people but not raised in people with early iron overload.7 Iron deficiency is far commoner than iron overload. Uncomplicated iron-deficiency anaemia can be diagnosed easily by examination of the blood film and from the red-cell indices which are printed out routinely by the automated equipment used in most laboratories. In such circumstances neither serumferritin nor serum-iron and transferrin need be measured. If there is any difficulty, then there is a very good correlation between serum-ferritin and iron depletion in uncomplicated cases.1 There continues to be some debate about the value of diagnosing latent iron deficiency.8 This is the condition when the body’s iron stores are depleted but the level of serum iron and the saturation of transferrin remain high enough to maintain sufficient iron supply to the bone-marrow to prevent anaemia.9 Theoretically, latent iron deficiency can be diagnosed easily, since lack of storage iron in the liver should result in increased transferrin synthesis and a raised total iron-binding capacity, even before there is any consistent lowering of the serum-iron level (which always fluctuates quite widely). Lack of storage iron also means that less ferritin leaks from the tissues, hence a low serumferritin. If the presence of iron in a bone-marrow aspirate is used as the criterion against which these two estimations are evaluated, then a low serumferritin is slightly more reliable than a raised total iron-binding capacity or transferring However, although iron deficiency can deplete cytochromes, myoglobin, and iron-containing enzymes and, thus, in theory, may cause symptoms, there is no evidence that these effects are important clinically and no evidence that any benefit is obtained from treatment unless the patient is also ana’mic.8 The most difficult area of clinical practice in which measurement of serum-ferritin may help is in the diagnosis of ansemia when it complicates other conditions such as infections, rheumatoid arthritis, and malignant disease. The so-called anaemia of chronic disorders is usually normochromic and normocytic. Occasionally, at least part of the population of circulating red cells are hypochromic and microcytic even though there is no iron deficiency as shown by an excess of storage iron in bone-marrow. Measurement of serum iron and transferrin is often unreliable in this situation.
Br.
clin. Path. 1974,
8. Dallman, P. R., Beutler, E., Finch, C. A. Br J Hœmat 1978, 40, 179. 9. Dagg, J. H., et al. Q.Jl Med 1967, 36, 600. 10. Mazza, J., Barr, R. M., McDonald, J. W. D, Valberg, L. S. Can. med. Ass.
J 1978, 119, 884.
534
The serum-iron level may fall sharply since in infections and inflammatory conditions iron is no longer released from the reticuloendothelial system. Transferrin synthesis in the liver may be depressed, causing the serum total iron-binding capacity to fall slowly over a period of weeks, and this should be diagnostically helpful as it contrasts with the raised transferrin level of uncomplicated iron deficiency, but there is often difficulty in its interpretation. Serum-ferritin is more reliable: a subnormal concentration correlates well with lack of iron in the bone-marrow .10 However, the serum-ferritin may be raised in acute or chronic liver disease," and occasionally in infections and malignant conditions.6 It is also increased if there is haemolysis leading to increased red-blood-cell turnover.2 Where doubt remains, the most reliable test of iron deficiency is still to stain a bone-marrow aspirate with prussian blue.
stantially different from the other or that, if it is, the possible side-effects might cancel out any benefits. But he may be sincerely mistaken, so that if he refuses to do a trial on these grounds his ethical behaviour-ethical, as he sees it-may not be in the best interests of the patient. The unreliability of doctors’ impressions is a powerful argument for the value of controlled trials. Secondly, a placebo should be used only if there is a good chance of a placebo response or a spontaneous remission, or if the active drug has important sideeffects. Thirdly, mutual trust between doctor and patient is maintained by a trial being double-blind. Both are in the same boat of ignorance and this, like informed consent, brings otherwise inherently unequal parties into a joint adventure or partner-
ship.3
of avoiding deception lies in the exact of the wording explanation given to the patient. This is well illustrated by a "placebo controlled double blind cross-over investigation of the side effects attributed to oral contraceptives" reported Controlled Trials: Planned in 1971.4 The women who had come expressly for Deception? contraception were advised that since the pill had not been proven to be completely reliable they IN the old days, placebos were a normal part of should use vaginal cream as well. Six pregnancies treatment for many self-limiting diseases. There in the group receiving dummy pills. This occurred were too few reliable drugs to satisfy the patients’ seems a clear case of inadequate explanation, if not demand for medicine. (A placebo has been defined deception; but most situations are not so clearcut. as "any therapy or component of therapy that is Undoubtedly consent should be sought for any deliberately or knowingly used for its non-specific drug trial, and where two active drugs are to be psychologic or psycho-physiologic effect".’) Then compared, the details should be explained. With the pharmaceutical industry burst into activity, placebo, the patient may be told that one drug is and it became accepted that the plethora of new active and the other a dummy or inactive, but, as drugs should be tested against placebos or wellwe have seen, this is not strictly true if a placebo tried remedies. So double-blind, randomised contrial is justified at all. Alternatively the investigator trolled trials have become the hallmark of theramay say that one tablet has a specific effect on the peutic respectability. But not everyone is happy illness and the other a general effect, or that two about them. tablets are being compared one of which contains The first main objection to controlled trials, and a new drug. Whatever formula is used, working out placebo trials in particular, is that the patient is the exact wording highlights the ethical issues and being deceived. SIMMONS2 weighs the benefits of this wording should be available to the institution’s placebo trials against "all the ethical costs of decepethical review committee. Particular problems tion and dishonesty" if the patient is not aware occur in psychiatry where full explanation may be that a placebo is being used. "Deception", she difficult; these are well discussed by PRYCE.5 writes, "is ethically degrading to both parties not The second main accusation against controlled only being a breach of trust, but denying the moral trials is that one group of patients will receive inautonomy of the patient or subject to make his own ferior treatment. A recent article from Germany6 choice". In drug trials the patient knows that the treatments are "experimental", but some investigaquotes FINCKE’s discussion of a hypothetical trial of a new anti-cancer drug. FINCKE concludes that, tors believe that to tell the patient that one of the if uncontrolled studies suggested that the drug was tablets is a dummy will either annul the placebo effect or put him off taking part in the trial. How highly effective, and more patients died in the control group, the doctors would be guilty of mancan a controlled trial be conducted without deceivthe the doctor must be conpatient? Firstly, ing vinced in his own mind that one drug is not sub3. Ramsay, P. The Patient As a Person; p.1 New Haven, 1970. 11. Prieto, J., Barry, M., Sherlock, S. Gastroenterology, 1975, 68, 525. 1. Shapiro, A. K. quoted by Bok, S. Scient. Am. 1974, 231, no. 5, p. 2. Simmons,B.J. med. Ethics, 1978, 4, 172.
17.
The
crux
4. Goldzieher, J. W., et al. Fert. Steril 1971, 22, 609. 5. Pryce, I. G. Br. JPsychiat. 1978, 132, 366 6. Burkhardt, R., Kienle, G. Lancet, 1978, ii, 1356. 7. Fincke, M. Arzneimittelprüfung: Strafbare Versuchsmethoden. Heidelberg Karlsruhe, 1977.
THE LANCET
Serum-ferritin
tiny quantity of ferritin normally present
in from the breakdown of cells in iron-containing tissues, particularly from macrophages of the reticuloendothelial system in the liver, spleen, and bone-marrow.I,2 Under most circumstances the amount of ferritin within these cells represents the amount of storage iron within the body so that the concentration of ferritin in serum indicates the body’s storage iron status. This will be increased if there is too much iron in the tissues and lowered if there is too little. Lately a radioimmunoassay for ferritin has become available for use in routine laboratories3 and this may now replace measurement of serum iron and total iron-binding capacity or transferrin, particularly since it is cheaper than these two investigations. When there is iron overload with hxmochromatosis or hsemosiderosis the serum-ferritin level may be very high indeed. After treatment by venesection or with iron-chelating agents, the serumferritin concentration may fluctuate quite widely, but as the iron status falls towards normal so does the serum-ferritin.4,5 Thus, serum-ferritin estimations can make an important contribution to the initial assessment of iron overload and can be used to follow the course of its treatment. Perhaps a more important use would be to screen relatives of patients with idiopathic hsemochromatosis and so diagnose early stages of iron overload which can be treated to prevent tissue damage. Unfortunately, THE
serum seems to come
1 Jacobs, A., Worwood, M.
New
Engl. J
Med. 1975,
292,
951.
2 Lipschitz, D. A., Cook, J. D., Finch, C. A. ibid. 1974, 290, 1213. 3 Luxton,
A. W.,
Walker, W. H. C., Gauldie, J.,
et
al. Clin. Chem.
1977, 23,
683.
J., Williams, R.
5
J.
27, 652.
6. Wands, J., et al. New Engl. J. Med. 1976, 294, 302. 7. Halliday, J. W., Russo, A. M., Cowhshaw, J. L., Powell, L. W. Lancet, 1977,
ii, 621.
4 Leyland,
M. J., Brown, P. J., Bomford, A., Walker, R. J Hœmat. 1977, 36, 441. Letsky, E. A., Miller, F., Worwood, M., Flynn, D. M.
there is some doubt about this, two families having been reported with proven iron overload and tissue damage but normal serum-ferritin levels.6 Measurement of transferrin saturation is no substitute since it may be high in normal people but not raised in people with early iron overload.7 Iron deficiency is far commoner than iron overload. Uncomplicated iron-deficiency anaemia can be diagnosed easily by examination of the blood film and from the red-cell indices which are printed out routinely by the automated equipment used in most laboratories. In such circumstances neither serumferritin nor serum-iron and transferrin need be measured. If there is any difficulty, then there is a very good correlation between serum-ferritin and iron depletion in uncomplicated cases.1 There continues to be some debate about the value of diagnosing latent iron deficiency.8 This is the condition when the body’s iron stores are depleted but the level of serum iron and the saturation of transferrin remain high enough to maintain sufficient iron supply to the bone-marrow to prevent anaemia.9 Theoretically, latent iron deficiency can be diagnosed easily, since lack of storage iron in the liver should result in increased transferrin synthesis and a raised total iron-binding capacity, even before there is any consistent lowering of the serum-iron level (which always fluctuates quite widely). Lack of storage iron also means that less ferritin leaks from the tissues, hence a low serumferritin. If the presence of iron in a bone-marrow aspirate is used as the criterion against which these two estimations are evaluated, then a low serumferritin is slightly more reliable than a raised total iron-binding capacity or transferring However, although iron deficiency can deplete cytochromes, myoglobin, and iron-containing enzymes and, thus, in theory, may cause symptoms, there is no evidence that these effects are important clinically and no evidence that any benefit is obtained from treatment unless the patient is also ana’mic.8 The most difficult area of clinical practice in which measurement of serum-ferritin may help is in the diagnosis of ansemia when it complicates other conditions such as infections, rheumatoid arthritis, and malignant disease. The so-called anaemia of chronic disorders is usually normochromic and normocytic. Occasionally, at least part of the population of circulating red cells are hypochromic and microcytic even though there is no iron deficiency as shown by an excess of storage iron in bone-marrow. Measurement of serum iron and transferrin is often unreliable in this situation.
Br.
clin. Path. 1974,
8. Dallman, P. R., Beutler, E., Finch, C. A. Br J Hœmat 1978, 40, 179. 9. Dagg, J. H., et al. Q.Jl Med 1967, 36, 600. 10. Mazza, J., Barr, R. M., McDonald, J. W. D, Valberg, L. S. Can. med. Ass.
J 1978, 119, 884.
534
The serum-iron level may fall sharply since in infections and inflammatory conditions iron is no longer released from the reticuloendothelial system. Transferrin synthesis in the liver may be depressed, causing the serum total iron-binding capacity to fall slowly over a period of weeks, and this should be diagnostically helpful as it contrasts with the raised transferrin level of uncomplicated iron deficiency, but there is often difficulty in its interpretation. Serum-ferritin is more reliable: a subnormal concentration correlates well with lack of iron in the bone-marrow .10 However, the serum-ferritin may be raised in acute or chronic liver disease," and occasionally in infections and malignant conditions.6 It is also increased if there is haemolysis leading to increased red-blood-cell turnover.2 Where doubt remains, the most reliable test of iron deficiency is still to stain a bone-marrow aspirate with prussian blue.
stantially different from the other or that, if it is, the possible side-effects might cancel out any benefits. But he may be sincerely mistaken, so that if he refuses to do a trial on these grounds his ethical behaviour-ethical, as he sees it-may not be in the best interests of the patient. The unreliability of doctors’ impressions is a powerful argument for the value of controlled trials. Secondly, a placebo should be used only if there is a good chance of a placebo response or a spontaneous remission, or if the active drug has important sideeffects. Thirdly, mutual trust between doctor and patient is maintained by a trial being double-blind. Both are in the same boat of ignorance and this, like informed consent, brings otherwise inherently unequal parties into a joint adventure or partner-
ship.3
of avoiding deception lies in the exact of the wording explanation given to the patient. This is well illustrated by a "placebo controlled double blind cross-over investigation of the side effects attributed to oral contraceptives" reported Controlled Trials: Planned in 1971.4 The women who had come expressly for Deception? contraception were advised that since the pill had not been proven to be completely reliable they IN the old days, placebos were a normal part of should use vaginal cream as well. Six pregnancies treatment for many self-limiting diseases. There in the group receiving dummy pills. This occurred were too few reliable drugs to satisfy the patients’ seems a clear case of inadequate explanation, if not demand for medicine. (A placebo has been defined deception; but most situations are not so clearcut. as "any therapy or component of therapy that is Undoubtedly consent should be sought for any deliberately or knowingly used for its non-specific drug trial, and where two active drugs are to be psychologic or psycho-physiologic effect".’) Then compared, the details should be explained. With the pharmaceutical industry burst into activity, placebo, the patient may be told that one drug is and it became accepted that the plethora of new active and the other a dummy or inactive, but, as drugs should be tested against placebos or wellwe have seen, this is not strictly true if a placebo tried remedies. So double-blind, randomised contrial is justified at all. Alternatively the investigator trolled trials have become the hallmark of theramay say that one tablet has a specific effect on the peutic respectability. But not everyone is happy illness and the other a general effect, or that two about them. tablets are being compared one of which contains The first main objection to controlled trials, and a new drug. Whatever formula is used, working out placebo trials in particular, is that the patient is the exact wording highlights the ethical issues and being deceived. SIMMONS2 weighs the benefits of this wording should be available to the institution’s placebo trials against "all the ethical costs of decepethical review committee. Particular problems tion and dishonesty" if the patient is not aware occur in psychiatry where full explanation may be that a placebo is being used. "Deception", she difficult; these are well discussed by PRYCE.5 writes, "is ethically degrading to both parties not The second main accusation against controlled only being a breach of trust, but denying the moral trials is that one group of patients will receive inautonomy of the patient or subject to make his own ferior treatment. A recent article from Germany6 choice". In drug trials the patient knows that the treatments are "experimental", but some investigaquotes FINCKE’s discussion of a hypothetical trial of a new anti-cancer drug. FINCKE concludes that, tors believe that to tell the patient that one of the if uncontrolled studies suggested that the drug was tablets is a dummy will either annul the placebo effect or put him off taking part in the trial. How highly effective, and more patients died in the control group, the doctors would be guilty of mancan a controlled trial be conducted without deceivthe the doctor must be conpatient? Firstly, ing vinced in his own mind that one drug is not sub3. Ramsay, P. The Patient As a Person; p.1 New Haven, 1970. 11. Prieto, J., Barry, M., Sherlock, S. Gastroenterology, 1975, 68, 525. 1. Shapiro, A. K. quoted by Bok, S. Scient. Am. 1974, 231, no. 5, p. 2. Simmons,B.J. med. Ethics, 1978, 4, 172.
17.
The
crux
4. Goldzieher, J. W., et al. Fert. Steril 1971, 22, 609. 5. Pryce, I. G. Br. JPsychiat. 1978, 132, 366 6. Burkhardt, R., Kienle, G. Lancet, 1978, ii, 1356. 7. Fincke, M. Arzneimittelprüfung: Strafbare Versuchsmethoden. Heidelberg Karlsruhe, 1977.
![[Serumferritin in patients with malignant lymphomas (author's transl)].](/assets/img/hold.png)
