Physiology and Pharmacology of Iodized Oil in Goiter Prophylaxis

Introduction Millions of people living in iodine-deficient areas and suffering from goiter, growth and mental retardation, or cretinism have benefited from iodine supplementation with iodized oils. Except for long-standing fibrous multinodular glands, goiters diminish in size or disappear, hypothyroidism is reversed, mental retardation is arrested, and the incidence of new cretinism is reduced. More importantly, prophylactic use of iodized oil (mostly Lipiodol) prevents nearly all of these complications (4, 7, 9, 13, 16, 19, 20, 25, 30, 32, 33, 43, 46, 53, 60, 67, 70, 73, 86, 88, 89, 112, 113, 115, 120). Nevertheless, many more millions remain untreated; it is estimated that currently only about half the population in 83 developing countries receive an adequate iodine supply (44). Hence it is pertinent to look at the physiologic and pharmacologic aspects of iodized oil administration to understand better the mechanism of action and the risks involved in its future use. In addition to its widespread use in the treatment and prophylaxis of endemic goiter, there is a vast literature describing the use of Lipiodol (also called Ethiodol) in larger dosage: 1) As contrast medium for hysterosalpingo-graphy, lymphography, amniography, and myelography in the past; and 2) For detection and treatment of hepatocellular carcinoma by intraarterial (hepatic artery) injection. Lipiodol is preferentially accumulated in vascular hepatomas relative to adjacent liver tissue, approaching a concentration ratio of ∼3– 10 (6, 62, 93). There is also a 20%–30% longer effective half-life in the tumor versus normal liver. To what extent this is due to local embolization is not clear. This localization can be used for 4 different purposes: a) detection of small lesions; b) embolization of the tumor, alone or with gelfoam or other particulate matter; c) localized delivery of chemotherapeutic agents such as cisplatin, adriamycin, neocarzinostatin, etc; and d) reasonably localized internal radiation by use of [131I]Lipiodol. The latter can be readily produced by iodination of unsaturated oils with labeled iodine or by 1 of several exchange methods using previously iodized oil and an oxidized form of the radioisotope; this yields material of high radiochemical purity. Certain lessons learned from these uses are instructive for studies relating to goiter prophylaxis. Chemistry Lipiodol and related compounds are products of the addition (not substitution) of iodine to double bonds of the unsaturated fatty acids of certain plant oils, most of which have a very high percentage of unsaturated fatty acids. Historically this procedure stems from the determination of the “iodine number” used to estimate the number of double bonds in such oils (grams of iodine incorporated per 100 grams of oil). Recently more reactive iodinating agents such as IBr, ICl or HI (38, 52) have been used to speed the reaction, but adding only 1 iodine atom per double bond:EQUATION When the double bond is near the center of a long-chain fatty acid, as in the case of oleic acid, the location of the iodine atom is random between the 2 unsaturated carbons. Assuming the reaction goes to completion, the degree of iodination will depend on the number of double bonds present in the substrate oil. The predominant products are, therefore, mono-, di-, and tri-iodostearic acids, being derived from oleic (C18:1), linoleic(C18:2), and linolenic(C18:3) acids present as triglycerides in the plant oil. Shorter and longer chain unsaturated fatty acids will, of course, also be iodinated, but their abundance in the oils usually employed is low. Iodinated triglycerides tend to be too viscous for easy parenteral use but are satisfactory for oral use. By contrast, the singly esterified fatty acids (as ethyl esters) derived from the iodinated triglycerides, for example, Lipiodol or Ethiodol, are much less viscous. These are derived from poppy seed oil whose fatty acids are 98% unsaturated. Oriodol is the more viscous, iodinated triglyceride from poppy seed oil for oral use. The composition of various iodinated oils is listed in Table 1. It should be emphasized that there are many oils with abundant mono-, di-, and tri-unsaturated fatty acids that iodinate well and yield a useful iodine content. Their use in countries where such oils are available and cheap should be encouraged, especially for oral use.TABLE 1: Composition of iodized oilsLipiodol/Ethiodol is stabilized with 1% poppy seed oil, contains 37%-38% iodine, and with a specific gravity of + 1.25–1.28 g/mL contains ∼475 mg iodine per mL; it has a viscosity of 0.5–1.0 poise and is soluble in various organic solvents but not water. It is available under the names Lipiodol UF (ultrafluide) or Ethiodol, and is supplied by Guerbet Laboratoires, Aulnay sous Bois, (also listed as Roissy), France, and in the United States through Savage Laboratories, Melville, NY (see Table 1). Biologic Behavior of Lipiodol As mentioned above, Lipiodol has been highly successful as long-term replacement therapy for iodine deficiency disease, and by 1 estimate (97) more than 60 million doses have been administered (see references 20, 35, 43). Usually 1–2 mg of are to The per can be to well The of treatment with iodized oils on the of from the of from various but not The mechanism by which Lipiodol its iodine is not The have been with or as are for it is not by such as in the for be involved By contrast, or fatty are well to compounds and on These are of the a that in from a of organic compounds as be from the bond The the of with various compounds that an of this are also present in various with different and substrate can by of the most with an by or not these can use acids to be has by that can at for This has not been that are present in as a of of that Lipiodol are certain that can but for long-chain iodinated fatty acids It is where Lipiodol As will be Lipiodol a longer half-life than oral Lipiodol in but not studies The of oral Lipiodol be in to in the or not the their to this to be of is of [131I]Lipiodol. This to a liver effective half-life of and a half-life of these tend to be very it is the there are only a of There is not a of in the of the the per a of These by a and nearly of in the to of the at more of the in is in of labeled Lipiodol for This from the with Lipiodol administration for iodine it has not been that this is present as the the has been to be the iodine in Ethiodol, but a can be by organic to be half-life As mentioned above, Lipiodol administration by oral or has much longer and more of iodine than These have to be on determination of is not It be that only has it been in that iodine in the and not organic The and the of in different In several studies the half-life of from Lipiodol (as by to be of the administered it for 1). half-life of for a 10 of Lipiodol This is a larger than for prophylaxis. that at but small doses of Lipiodol to have a half-life in most there are too for half-life to yield a half-life for of The half-life of of labeled Lipiodol from the much than the half-life of that in the the other iodized oil be at the to and readily at the at 1: The of derived from iodized oils. Lipiodol from references 32, of 2 of Lipiodol from Lipiodol from iodine in of to iodine by is the that is a The in is at with an with the to iodine by of and a with a of or more In a of different iodized oils, that have The is the for the 2 oils, the is for than for and is as the more oil to use. The of not by a at In the oral iodized oil, there of this on the and in to and also to which not administration in the where the half-life from to from oral to and in where the half-life from to for the of This in the of administration has also been by Lipiodol to of the high oral the other at the has been this is due to local embolization as in the liver (see has not been of the relative of oral versus Lipiodol is available are also administration have 4 in their is by only 2 from these and other studies are in Table It should be emphasized that these are of the in the and the of of iodine Lipiodol administration to iodine-deficient is not of the in the administered Lipiodol 37%-38% iodine is present as different iodinated fatty The of iodinated products in Lipiodol present as to the tri-iodostearic acids (see Table 1). This well be in different of have that fatty acids are more in the than and will, for longer For example, that the longer half-life of be due to the of iodine as iodinated which has a from more are In iodized oil to have a longer than Lipiodol Hence the composition of the oil its in the (see Table should also be to the of or not iodized oil as oral triglyceride versus fatty have a longer half-life in the This has not been different the of different in different different Lipiodol at different for example, with a in as well as to should be the that Lipiodol have a on not on its the on embolization administration mentioned above, has been to and and in and in the has been It is that these have for prophylactic oral or Lipiodol administration at the and in the of Lipiodol treatment The the to Lipiodol 1) that in and the half-life of iodine in the only about that of the well This by of in the This is to be due to of iodine from Lipiodol and 2) in the to Lipiodol is the widespread of many iodine-deficient with These to diminish or of Lipiodol as by This is readily by treatment of the deficiency the of iodized oil with that in the and the in iodized oil with the with the to Lipiodol to Lipiodol also in with long-standing goiters that This is by a and the ratio a of the of the to to use or as a of this which to the of and of the produced from to of This will be on a of deficiency will be a more effective It has been for that is for normal this to the in a that in to the More it by and that 1 contains in the the is the reactive in most the better of as to in be to the much of of the of to + in the the is nearly at This to the more and deficiency therefore, be to iodine deficiency In these 2 in many of the and It as therefore, that the of Lipiodol in goiter size is as a of concentration in for example, in the It to be that supplementation will the of to the of the are than for the is the more Recently it has been that all are and also be involved in but the 1 at to be the more 1 in iodine deficiency of the of and iodine is the of as in iodine with high and deficiency are with for this with supplementation with or iodine alone will be to this is this has not been from where are other be The and of a number of soluble iodinated in the have been to with and be to be with a number of in the is an where such have been in that 60 million doses of Lipiodol have been the relative of that have been Lipiodol is and This be in to the in to the in between iodinated and in Lipiodol is administered under where is to be less than and be The is an to this In will a of 1–2 of Lipiodol (as for endemic goiter of to the population on the 1 and to the and on the Recently it has been that doses to mg of adequate for and it that at the but supplied in it is to larger doses of the longer of of to can be as a) as or such as and by not well b) as substrate for to and c) as hypothyroidism or goiter for which can be It that by by for the oxidized iodinating it that a number of other not also These growth of in and and and in 25, More it has been that the of the by This an for the of by The is that this is by iodinated It that these are by of of compounds have been and to be and of the of The of of to a reactive as is the case for iodination of such not in the of agents such as The compounds to be addition products to fatty acids such as as in these in an the products are that 1 of the double bond iodine the other an of this the iodinated can with the of the fatty and form internal of different (see double and due to the location of the and (as well as of of are, in only a have been There to be as to which is most for which of the The of iodinated from and from from the The are called in the are the 2 in most by and derived from iodinated acid, for example, and are also The for of and The iodination of the double bond of and of the are The is from and iodinated from present in (see It also a number of in the in other from its by the the of to the the between and there is there different of for the 2 that the concentration for about for iodination than for This with a of by and under normal It is also that this for iodination be due to a of addition to an double bond in solvents than for areas that are the of the people the goiter not most to the For example, can this be with the in the of in with iodine not from Lipiodol but to iodized prophylaxis for Lipiodol the are to more the in the from Lipiodol is to be of prophylaxis. this is due to the high of the of from or other to be the Lipiodol administration in In a the Lipiodol with to also a This in of with Lipiodol for endemic goiter, less than an have been in larger studies in studies with than are not listed the only and in with or and of have been (4, In a of previously the of an incidence much than in other a number of these it that the incidence by the of by the new this is due to the high of a highly the use of or other is not clear. In high 1 administration of 2 of iodized oil but it is not of the by Lipiodol have be by in the of This has not been but have been under are complications to be more supplementation of use of iodized are the many studies for which example, 13, 16, 20, and which the of the It is not or have been under the less than especially the to be in studies there a degree of for example, of with very Hence an incidence be Nevertheless, on the of the vast number of doses it to that the incidence of is to be It should also be that the incidence of from all as an of the size have previously on the mechanism by which In addition to the in multinodular goiters which are to for of in an that is is The normal the of and by through of the the of other in the this from the of iodinated The for such be much in will a in is but not It is well that multinodular goiters to more to number of have such from Lipiodol administration (see Table This has been to that to The be by the in the This to as as is this is the only for is not be there are, of the latter on The of to Lipiodol prevents an of all of the aspects of the that have been it that the not from that with other of The from the the ratio of is there are there are iodine is usually are are high on the Lipiodol The is usually with but a In the case of Lipiodol the half-life of the oil the but it is to be as as therapy from that are to with or a should be To what extent this is in areas to be these agents have their It has been for a that other than the such as tissue, glands, by a mechanism to that of example, The for is the but the in or tissue, for example, is in these have an the be a with These have been to have the or very whose has a on all as be from the and or It is in and glands, but is iodized oil. In 1 with and a a incidence of administration of 2 of Lipiodol In of are to have such are in most other the that be with iodine the number of with Lipiodol in their example, 53, but have been from and 10 of Lipiodol) in There are also of high but this is For that has the to in these it much longer than have been used in are goiter hypothyroidism of the by is by of of the are but for the in the and the The of these is to the to The (not in the is that of to in to goiter or as for example, with goiter in the of to goiter is this larger doses of and longer than for of from the that iodine-deficient to the are more to are to goiter To the is more with a of Lipiodol than iodine for of to goiter or hypothyroidism (see this with the estimate by that in a 10 than normal to in of the that these as a for to Lipiodol therapy and are in of goiter to in most of these the to be or used as a contrast medium larger doses the or can goiter case using only 4 of Lipiodol for the for complications with 4 of Lipiodol to from a but the with normal and By the a goiter with a in the with a of of and normal iodine with not for to normal and the goiter and and normal high of at The case for long-term is well By contrast, as used for has not to the of and hypothyroidism is iodized oil administration very high In and of this a of and have been in should the of goiter under in areas of highly iodine-deficient and The of the to is well by the of goiter of the with administration of to a of mg for radiation to in the to of in and The by a of These a of this population to several about the mechanism of to these in the or 1) of are in the and what is the which are in the 2) the to that of the there the of the or is there from to is goiter are there other and is there a what of about the of and in the is the concentration in the are the iodine from to most of these are or and what at a for in normal but to from a not by the in areas that are iodine these will be in iodine-deficient As mentioned above, Lipiodol in a mg of iodine to the the of this iodine its or other where it a very and for a or with to the in not to have been for replacement therapy with iodized oil. a but not between and at such that for in there is an of in at the be 10 or under in the a at the for and well at which of on the are the between and the at the Lipiodol administration to be of that concentration as a of at high The of for on the of the in the it is or but is in the iodine-deficient be to be very this to be a to use in the effective of that the Lipiodol to the The is to be in of a high of the is in can the of The Lipiodol administration be to such the of (see that or that there is an mechanism in these for the the of the of to the there are that that the of and of from the to the that and with from in of the of with be for the and are of the it be reasonably that of the can in this is the that of the have been to the is highly to the delivery to the will the The will the have in the In a in using iodized oils incorporated by the and oral Oriodol oral Lipiodol Lipiodol (see Table 1) a of the concentration Assuming a concentration of the be to the at the that of the that the normal concentration is this concentration of the has iodinated contrast but on is such an of these is the of from which with at the and of When is the at for The of in the at of as the It is not certain at present the of that at about the of but this has not been This is also the the the ratio of to The to a per is not through or It has been that the more than its The of the 10 as much per of from the as the This is not to be the case for the but the for by in the be in to be is the of of in the As above, this mechanism for the of an is very in the and be to be in the studies by are The and a mechanism for a to to iodine at the of delivery their the (as by and are of In to to It will be to the of by of that is in the This in the of the and the of an in the of all be to in the The be to high of the to and therefore, the to It to in and such be to In this have been by the of which not only for but also iodination In the such an be more goiter The other reaction, goiter, is not Lipiodol is for case that goiters are not with Lipiodol amniography, where much larger doses of Lipiodol are used than for iodine supplementation (see The the iodinated and the Lipiodol its of Lipiodol hypothyroidism and at delivery due to goiter to be In a by of that with Lipiodol with where of the iodine in these in a number of the can of the used and the of Lipiodol to the these have to with the doses of Lipiodol to the for endemic about the of the to Lipiodol to the for or and goiter have been the used for iodine the other treatment of with mg of hypothyroidism in at delivery the than their treatment has been to and complications in the or by Lipiodol there or goiter 1–2 of Lipiodol to the As mentioned above, in a of mg for radiation the of hypothyroidism that a and at 2 to Lipiodol the the goiter or hypothyroidism in of there 2 goiters in In example, goiters in whose Lipiodol example, 16, 20, also that in a of Lipiodol administration to for iodine of As such treatment hypothyroidism and a high incidence of hypothyroidism Lipiodol has been on the that the incidence of hypothyroidism in the of The vast of studies not this of long-term of or of Lipiodol in or with from To a better of the of goiter the that 1 million have been half of these will be and that at the of Lipiodol are with a population of for the of that there will be of goiter of the has been that be from iodine deficiency goiter a very of Lipiodol treatment for deficiency to the from this highly for better for are the available that the to Lipiodol not its use. the of iodine from in have In the by in iodine the iodized oil with Oriodol oral Lipiodol of iodine from Lipiodol in has been to for administration the of the iodine not it is to that contains which is involved in the delivery of the It that the will be to from The iodine of from at per 100 at the of This is more than than in this is for the or is to it be to It is also to that by prevents goiter in the which of in from is not to to but is to be 1) The at by many is that the from the use of Lipiodol or related iodized oils for iodine deficiency are to the number of doses as to to its use. and in the and of are that be in of iodized oils, and should be where with iodized oil are less than with the such as high doses of iodine, and certain iodinated contrast 2) of to or the of are in and in The is well supplied with from the and it well the but very in As a the is at for the of Nevertheless, these complications are and have not been with Lipiodol treatment or will be and reaction in the of Lipiodol not related to its not from embolization at the When multinodular goiters are in a a of be should be but this should not all of the by It to about 10 as high an to iodinate unsaturated fatty acids than to hypothyroidism of of are than to hypothyroidism is to in the administration from for the hypothyroidism from Lipiodol is more to be goiter is not in from iodine-deficient with this not Lipiodol is used as contrast medium at Lipiodol or Oriodol are most iodination of available unsaturated plant oils, especially for oral should be of on a and local is for a and easy for iodine oils have different such as iodine and effective half-life in the but use is easy to is very is more of the is not and in areas this is not at this procedure have to due to the high replacement it be to iodine deficiency with iodized oil, by which can be in and use. complications from such as or hypothyroidism are much iodine supplementation with Lipiodol than with not its widespread use in endemic goiter especially in with multinodular goiter should not be or should be only under When it to be or and treatment is with or is goiter has not been Lipiodol has derived from Lipiodol readily the by and the of the the in goiter from deficiency goiter of the of goiter have been of by are The use of produced iodized plant oils is for as well as for the derived from local