Delayed Effect of Thorotrast Deposition in Humans: Carcino- Genesis and Suppression of the Reticuloendothelial System

Home , Thorotrast

Review Bioscience Microflora Vol. 19 (2), 107-116,2000 Delayed Effect of Thorotrast Deposition in Humans: Carcino- genesis and Suppression of the Reticuloendothelial System Hiroshi IRIE* Department of Pathology, TeikyoUniversity School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan Received for publication, July 26, 2000

Thorotrast is a colloidal solution containing 20% thorium (232Th),and used to be used primarily in diagnostic radiology for visualization. Once thorotrast is infused into the body, it is not eliminated easily. Over 90% of thorotrast forms deposits. It emits a-rays, and thorotrast-injected patients are semipermanently irradiated from a-particles deposited in the body. Thorotrast gives rise to malignant tumors by delayed effect of deposition, and especially liver cancer is highly associated with thorotrastosis. Deposition of thorotrast as an exogenous substance inhibits phagocytosis by suppressing the reticuloendothelial system (RES) as well and bringing about a Shwartzman preparatory state (pre- shock state) in patients. A majority of thorotrast-injected patients died abruptly. This short natural history of thorotrastosis is thought to have some relation to RES suppression by long-term thorotrast deposition resulting in vulnerability to shock and infection. Key words: thorotrast, a-ray emitter; carcinogenesis; reticuloendothelial system

German firm Heyden and exported and used widely at INTRODUCTION military hospitals and other medical institutions, mainly With the use of radioactive imaging materials, the for angio- and hepatolienography. Thorotrast provided potential for internal injury, (i.e., internal irradiation) good contrast with relatively low risk of allergic reac- is always of concern. A radioactive substance known tion and was widely utilized in western countries until as thorotrast was used widely in Japan, Portugal, Ger- 1955. This contrast agent remained in certain body tis- many, France and the United States from 1930 to 1955 sues indefinitely and continued to emit a-rays. as a contrast medium for X-ray photography, but was Use of thorotrast continued in Japan until about 1954, discontinued when it was discovered that it is difficult and the number of persons injected with it is estimated to excrete and that it forms long-term deposits in the at somewhere between 20,000 and 33,000. Thorotrast body. There are two primary concerns for patients hav- was used mainly in angiographies for wounded Japa- ing undergone X-ray studies with thorotrast: one is the nese soldiers, most of whom were not suffering from long-term deposition of exogenous substance and the disease (35, 38, 39). other is chronic internal irradiation by an a-emitter. Malignant tumors, especially liver cancer, are highly DISTRIBUTION OF THOROTRASTIN THE associated with thorotrastosis. Most patients given BODYAFTER INFUSION thorotrast in the past, have died, and its effects have Once thorotrast is infused into the blood, it is not been virtually forgotten. It is important, however, to eliminated easily from the body; over 90% of thorotrast remember cases wherein accepted medical treatments forms deposits (6, 15, 30, 32, 55). After injection as a have long-term adverse affects. This paper treats the contrast material into the blood, it circulates to the sys- character and process of thorotrastosis and its implica- temic organs, soon accumulating in the liver, spleen tions with regard to exogenous substances. and lymph nodes (8, 18, 29, 32, 56, 57). Figure 1 is a HISTORY OF THOROTRAST plain abdominal X-ray photo showing numerous spots of a radiopaque substance on the liver, spleen and ab- Oka and Radt first used colloidal thorium dioxide dominal lymph nodes. This substance is thorotrast that (ThO2) as a radiologic contrast medium for hepato- distributed in the body 24 years after injection. lienography in 1928 (43, 47). In 1930, another thorium Autoradiography (Fig. 2) is the only method tradi- dioxide preparation, thorotrast, was developed by the tionally used to detect thorium dioxide in conventional histological specimens, but more recently it has been *Corresponding author . Mailing address: Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, detected by X-ray analysis, which is quicker and more Japan. Phone: +81-3-3964-1211. Fax: +81-3-3964-9622. easily performed. We examined distribution of

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Fig. 4. Thorotrast particles present in the Disse space of sinu-

soid and in hepatocytes (arrows) (U-Pb staining •~ 6,000). Fig. 1. Plain abdominal X-ray photo of a thorotrast-injected patient.

Fig. 2. Autoradiogram of human liver 20 years after thorotrast injection. Thorotrast deposit in liver tissue is demonstrated by a-tracks (HE staining •~ 400). thorotrast particles in the liver of two biopsy materials by electron microscope with an energy-dispersion X- ray spectrometer (Fig. 3). Fig. 5. Microscopic findings of thorotrast liver fibrosis (HE

We found that 70A thorotrast particles that enter the staining •~ 400) (a), and the small amount of thorotrast particles present in hepatocytes (arrows) (HE staining x 400) (b) sinusoid of the liver are taken up by endocytosis of the . hepatocyte and macrophage phagocytosis (Fig . 4). Par- ticles ingested by hepatocytes are excreted into bile 17%), and bone marrow (6-10%) (16). Although the canaliculi through the phagosomes. Circulating particles term RES has been replaced by the term mononuclear aggregate, increasing in size to 150-200A or more, phagocytic system (MPS), the former will he used here which is too large for endocytosis and subsequent elimi- since it is the most familiar and has been used in previ- nation via hepatocytes (13, 14, 19, 52). Though very ous thorotrast papers. Both refer to cells in the bone little excretion is found in urine and the air passage (12 , marrow, peripheral blood, and tissues that are highly 51), more than 90% of 232Th introduced into the body specialized for endocytosis (pinicytosis, phagocytosis is deposited in the reticuloendothelial system (RES) , and intracellular digestion). thus accumulating in the liver (71 to 73%), spleen (7— Thorotrast particles are phagocytosed by macro- DELAYED EFFECT OF THOROTRAST DEPOSITION IN HUMANS 109

Fig. 7. Thorotrast liver with cholangiocellular carcinoma (a) and its soft X-ray photograph (b). Arrowheads on Fig. 7a indicate the border of cholangiocellular carcinoma.

Fig. 3. Thorotrast particles in the human liver 25 years after injection. Numerous and aggregated thorotrast particles are present mainly in the portal triad (a) (U-Pb staining x 3,000); energy dispersion X-ray spectrum of thorium and X-ray mapping of thorium (a window to X-ray of 2.996 peak of thorium) in the same visual field (b); and energy disperse X-ray spectrum (lower).

Fig. 6. Thorotrast particles in a human spleen 20 years after

injection (HE staining •~ 20). Fig. 8. Thorotrast liver with angiosarcoma (a), and its soft X- Inset is soft X-ray photograph. The spleen weighs 4 g. ray photograph (b). 110 H.IRHE phages or Kupffer cells and deposited in the portal area, genesis in mice, hamsters, rabbits, guinea pigs and other sinusoid and subcapsular region of the liver several animals (44, 49, 58). Bauer estimated the term required decades after injection. Hepatocytes have been general- for carcinogenesis by thorotrast to be 12 to18 years af- ly thought to be free from thorotrast particles in the late ter infusion, based on research into human 226Raexpo- period. However, small thorium particles have been sure (3). found in the hepatocytes. Fibrosis of the liver is manifes- In 1947, MacMahon reported the first case of liver tated several decades after the ingestion of thorotrast hemingiosarcoma 12 years after the ingestion of (Fig. 5). In the spleen, it deposits around the lymphatic thorotrast (33). Subsequently, reports of hepatic carci- duct, resulting in fibrosis and eventual shrinkage of the noma, leukemia, and liver cirrhosis related to cases of spleen due to repeated infarction or hemorrhage induced thorotrastosis appeared all over the world. by circulatory disturbance. Marked atrophy of the spleen The author examined 300 autopsied cases, carried is one of the characteristics of thorotrastosis (24 , 32, out during the 43 years from 1945 to 1987, listed by 53); a spleen weighing even less than 5 g was observed the Ministry of Education, Science and Culture. The in an extreme case (Fig. 6) (45). autopsy cases consisted of 260 males and 40 females . Thorotrast also deposits in the lymph nodes of the The population study included civilians, though the ma- paraaortic region and mesenterium, causing the jority were wounded soldiers. Thorotrast was injected lymphofollicles to shrink. Thorotrast deposits in the intravascularly for diagnosis and the amount of bone marrow as well, but the extent of deposition is thorotrast injected ranged from 5 to 182 ml (0 .1-3.6 less severe than in other organs. After macrophages Ci). Table 1 shows the carcinomas that occurred in as- phagocytose thorotrast particles, their function, espe- sociation with the 300 cases of thorotrastosis . The pe- cially phagocytotic activity, is thought to be suppressed. riod between ingestion of thorotrast and death was a It may be that a compensatory mechanism such as in- mean of 35 years. The total incidence of malignant he- crease of NK cells plays a role in immunity in place of patic tumors was approximately 87% (Figs. 7-9). Liver compromized macrophage (1), and that aging and can- cancer, leukemia and lung cancer were observed quite cer development accelerate RES suppression over time . frequently, but only a few cases of gastric cancer and Patients are then more vulnerable to infection and de- colon cancer were found. Cholangiocellular carcinoma velop malignant tumors more easily than do normal per- accounted for the greatest number (n = 102) of malig- sons. nant tumors, but hepatic angiosarcoma (n=48) was considered the most specific to thorotrastosis since angio- CARCINOGENESIS CAUSED BY sarcomas are very rare in the normal population (1 THOROTRAST INJECTION in 4,000,000 population) (5, 25, 46). Hematologic dis- Thorium-232 belongs to the thorium chloric series , orders such as leukemia and idiopathic acquired so if the ƒ¿ nuclear species is released, there is no sideroblastic anemia were seen, but many were atypi- influence unless it is taken into the body because the cal (2, 26). It is thought that fibrosis of microhemato- range of the ƒ¿ track is less than 100 ƒÊm . Once it is genic circumstance in addition to damage to multipotent infused into the body, however, very little is excreted stem cells by thorotrast deposition and a-ray emission (its biological half-life is 200-400 years) (17). Thoro- complicated the pattern of disease . The development trast-injected patients are semipermanently irradiated of cancer accelerated over about 20 years after thorotrast from a-particles deposited in the body (total doses were injection as shown in Fig. 10, and the incidence of mul- 10-100 ml, 0.2-2 ƒÊCi, with a physiological half-life of tiple cancers (double cancers were 28 cases and triple 1.4 •~ 1010 years) (27). cancers were 2 cases) increased with time (Table 1) The relation between internal radiation exposure from (36-38). a-particles and carcinogenesis came into question very Now cancer is known to result from DNA mutated early, especially in the U.S., when it was found that in the course of DNA repair (54). When a-ray emis- watchmakers exposed to the radium in luminous dials sion injures the chromosome, the cell dies if the dam- developed osteogenic sarcoma at a high rate. age is severe and cancer develops if the damage is not Twice, in 1932 and 1937, a warning was issued by so severe and the cell lives on. Thorotrast has been the American Medical Association to restrict the use clarified as carcinogenic to humans. This has become of thorotrast (8, 9). A link between thorotrast and car- clear pathologically as well as epidemiologically . The cinogenesis was established in a rate study by Oberling total irradiation dose of thorotrast is a mean of 800 to and Guerin (42), followed by many reports of carcino- 1,000 rads, much less than the two to several thousand DELAYED EFFECT OF THOROTRAST DEPOSITION IN HUMANS 111

Table 1. Carcinomas associated with thorotrastosis.

Numbers shown are number of cancers out of 300 cases examined . * Included one case of triple cancers (CCC+AS+HCC) . ** Included one case of triple cancers (AS+HCC+Re nal). Abbreviations: CCC, cholangiocellular carcinoma; HCC , hepatocellular carcinoma; AS, angiosarcoma; MH, mul- tiple myeloma; Gastric, gastric cancer; Lung, lung cancer; Colon , colon cancer; Renal, renal cancer. rads that the workers exposed to luminous paint expe- rienced, which caused the development of osteogenic sarcoma. Though the irradiation dose is considered small, thorotrast injected as it has been in the past has proven to be very harmful. Decreased immune response with age may also influence the long-term potential for carcinogenesis in cases of thorotrastosis . Although the carcinogenic effects of thorotrast appear to be due to chronic internal irradiation, we must not neglect the potential effect of long-term deposition of thorotrast particles as an exogenous substance. There is the example of zerconium hydroxide sol , a non- radioactive contrast media, causing cancer in animal experiments (4).

THOROTRAST LIVER FIBROSIS AND PORTAL HYPERTENSION Some human diseases involve metals deposits in organs such as the liver, spleen and bone marrow; hemo- siderosis (excessive iron deposition) and Wilson's disease (excessive copper deposition) for example. These diseases lead to liver cirrhosis and, less commonly, are associated with liver cancer. The clinical symptoms and Fig. 10. Cumulativeincidences of malignanthepatic tumors, laboratory data for thorotrastosis several dacades after liver cirrhosisand blood diseasesin thorotrastosis. injection of thorotrast look like those of post-necrotic liver cirrhosis. Pathohistologically, the liver shows sidered thorotrast fibrosis (Fig. 11) (23). The macroph- fibrosis around the thorotrast particles in the portal triad, ages laden with thorotrast form thrombi in the sinusoid sinusoid and subcapsular region. The convex surface that disturb the intrahepatic circulation and accelerate of the liver recalls post-necrotic liver cirrhosis by sub- liver damage by ischemia (Fig. 12) (20). Splenic atro- capsular fibrosis, but nodular regeneration on the cut phy is one of the characteristics of thorotrastosis, but surface is not conspicuous, thus, the condition is con- there are a few cases of splenomegaly. Histologically , 112 H. IRIE

Fig. 12. Thorotrast-laden macrophage thrombus in liver sinusoid (scan-

ning of electron micrograph) and X-ray mapping of thorium in the

same visual field.

Inset is light microscopy findings (HE staining •~ 40).

Fig. 9. Thorotrast liver with hepatocellular carcinoma (a), and its soft X-ray photograph (b).

Fig. 13. Esophageal varices of two thorotrast-injected patients (arrows) (left is fixed state, right is unfixed). These two cases were associated with splenomegaly.

the liver change resembles that in Banti's disease (idiopathic portal hypertension) in which liver fibrosis, splenomegaly and esophageal varices are seen, except that esophageal varices of thorotrastosis are relatively few in comparison. Portal blood flow is disturbed in the liver by post- necrotic liver cirrhosis or liver fibrosis, as in Banti's disease, and the overflowing blood that cannot flow into Fig. 11. Gross findings of thorotrast liver fibrosis (a), the liver bypasses via the esophageal venous plexus to and its soft X-ray photograph (b). the superior caval vein. Thus, esophageal varices are DELAYED EFFECT OF THOROTRAST DEPOSITION IN HUMANS 113

Table 2. Frequency of varices in thorotrast-injected autopsied cases.

* A, B, C, D groups are thorotast-injected autopsied cases divided by spleen weight. formed as collateral circulation (Fig. 13). The severity nisms are activated as a result of thrombotic diathesis, of esophageal varices is relatively mild compared with and hemorrhagic diathesis results. the degree of fibrosis in the thorotrastosis of the 300 The Shwartzman reaction that develops in animals autopsy cases. We examined 211 thorotrast-injected au- has its counterpart in human DIC (48). When an ani- topsy cases whose spleen weights were recorded and mal is sensitized by a subcutaneous injection of endo- divided into four groups (A, B, C, D) according to spleen toxin, intravenous injection of the same antigen 24 hr weight (Table 2). Group A (below 20 g of spleen later will induce minute thromboses at the site of the weight) was frequently accompanied by marked liver prior sensitization. When both sensitizing and challenge atrophy (severe fibrosis). Approximately 10% showed doses are given intravenously, a systemic Shwartzman splenomegaly. Particularly, splenomegaly exceeding reaction develops and generalized microthromboses over 200 g (Group D) was seen in 13 cases, 9 of which appear, which cause various infarctions, particularly had marked esophageal varices. It may be that portal renal cortical necrosis (48, 50). The Shwartzman reac- blood pressure was accelerated in cases of spleno- tion follows a two-step process, first sensitization and megaly exceeding 200 g. Though the specific mecha- then provocation. The first step is thought to cause sup- nism by which portal blood pressure is increased is pression of the RES, and thorotrast injection has been unclear, it may result in part from increased flow from shown in animals to suppress the RES and bring about the splenic artery as well as increased intrahepatic vas- the preparatory sensitization needed for the Shwartzman cular resistance in the portal vein. reaction (7, 10, 11, 28). Thorotrast-injected patients are Rupture of esophageal varices associated with por- thought to be in a kind of Shwartzman preparatory state tal hypertension is lethal in most cases. Most thorotrast- due to chronic suppression of the RES following injected patients with splenomegaly died by rupture of thorotrast administration. the esophageal varices; in the cases studied, the time Pseudomembranous colitis, fulminant hepatitis, and until death was 10 years shorter than in cases without renal cortical necrosis have been attributed to the DIC splenomegaly (Table 2) (24). or Shwartzman reaction (22, 34, 40, 41, 48). Phago- Splenectomy decreases the portal pressure, which cytes make a major contribution to the first line of host implies decreased blood flow into the esophageal defense, but RES suppression disturbs the phagocyte varices. Splenic atrophy is a pathologic change associ- function, making it difficult to engulf and destroy or- ated with thorotrastosis, but it is possible that such at- ganisms. In thorotrast autopsy cases, petichiae, mas- rophy works to prevent increased variceal blood flow sive hemorrhage, microthrombosis, and necrosis of or- as does splenectomy (24). On the other hand, hepatic gans are frequently observed, and in the liver of thoro- failure was conspicuous in Group A. trast-injected patients, disruption of the sinusoidal lining is less frequently observed, as shown in Fig. 14. These THOROTRASTOSISAND DISSEMINATED findings, which were not observed in the liver biopsy INTRAVASCULARCOAGULATION specimens of living thorotrast-injected patients, suggest Disseminated intravascular coagulation (DIC) is an that severe circulatory disturbance like DIC or shock is acquired thrombohemorrhagic disorder that occurs as provoked at the end stage of thorotrastosis (21, 59). a complication in a variety of diseases. It is character- We observed 9 cases of clinically diagnosed fulmi- ized by activation of a coagulation sequence that leads nant hepatitis out of the 300 thorotrast autopsy cases to the formation of microthrombi. Fibrinolytic mecha- (Table 3). Eight cases were associated with malignancy, 114 H. IRIE

Table 3. Massive hepatic necrosis in thorotrast-injected autopsied cases.

* Period: Duration of life between injection of thorotrast and death . NH; Natural history (period between onset of symptoms and death). Abbreviations: Clin diag, clinical diagnosis; Path diag, pathological diagnosis; FH, fulminant hepatitis; AHF, acute hepatic failure; DIC, disseminated intravascular coagulation; MHN, massive hepatic necrosis; Malig, malignancy; CCC, cholangiocellular carcinoma; HCC, hepatocellular carcinoma; AS, angiosarcoma; TCC, transitional cell carcinoma.

Fig. 14. Rupture of the sinusoidal lining (arrows) of the liver of a thorotrast-injected patient (HE staining •~ 400). Fig. 15. Natural history of thorotrast-injected patients (upper) and control patients (lower). especially angiosarcoma (5 cases). In pathohistological findings, the liver was swollen and centrilobular pa- history of the disease (period between the onset of clini- renchymal necrosis was observed. It is thought that cal symptoms and death). The initial symptoms were massive hepatic necrosis is provoked by endotoxin at nonspecific, such as general malaise, abdominal full- the end stage of thorotrastosis due to RES suppression ness and appetite loss. The main direct causes of death after long-term thorotrast deposition (22). The possi- in cases of thorotrastosis were renal failure, hepatic fail- bility exists that these hepatic necroses were produced ure, and gastrointestinal bleeding or DIC. Figure 15 by severe circulatory disturbance related to Shwartzman shows the natural history. One-hundred-and-fifty of the reaction in addition to chronic liver disease, so-called 300 autopsy cases were selected and the time to death "thorotrast liver ." was calculated and compared with that of 100 persons

who died from causes other than thorotrastosis; serial NATURAL HISTORY OF THOROTRASTOSIS autopsy cases. Mean (•} SD) time to death was signifi- To study the effect of RES suppression by deposi- cantly shorter in the thorotrast cases than in the serial tion of exogenous substance, we observed the natural autopsy cases (252 •} 407 days, 1,439 •} 2,415 days, re- DELAYED EFFECT OF THOROTRAST DEPOSITION IN HUMANS 115 spectively). A majority of the thorotrast-injected pa- (7) Easton TW. 1952. The role of macrophage movement in tients died abruptly. The short natural history of the transport and elimination of the intravenous thorium thorotrastosis is thought have some relation to RES dioxide in mice. Am J Anat 90: 1-33. suppression by long-term thorotrast deposition (31) (8) Editorial. 1932. Thorotrast, report of council on pharmacy and chemistry. JAMA 99: 2183-2185. resulting in vulnerability to shock and infection. (9) Editorial. 1937. Potential hazard of diagnostic use of tho- CONCLUSION rium dioxide (Editorial). JAMA 108: 1656-1657. (10) Frankel HH, Patek PR, Bernick S. 1962. Long term studies The author worked in a certain hospital of Ibaraki of the rat reticulendothelial system and endocrine gland re- Prefecture between 1977 and 1979, and encountered sponses to foreign particles. Anat Rec 145: 359-373. four thorotrast-injected patients (one woman and three (11) Good RA, Thomas L. 1952. Studies of the generalized men) from the same village. These patients were origi- Shwartzman Reaction. II. The production of bilateral cor- nally from Nagano Prefecture and emigrated in a group tical necrosis of the kidneys by a single injection of bacterial toxin in rabbits previously treated with thorotrast or to the same settlement in Manchuria before World War trypan blue. J Exp Med 96: 625-641. II, where they were injected with thorotrast. The de- (12) Hall AR, baillif RH. 1954. The retention and elimination tailed history of the thorotrast injection in these cases of colloidal thorium dioxide in albino rat following pro- was unclear. After the war, they returned to Japan and tracted administration. Anat Rec 117: 163-174. immigrated to the same village in Ibaraki Prefecture. (13) Hampton JC, Rosario B. 1967. The distribution of colloi- Unfortunately, it is unclear how many persons injected dal thorium dioxide in mouse liver after intravenous injec- with thorotrast were there in that village, because we tion. Ann N Y Acad Sci 145: 533-544. ( 14) Hampton JC. 1976. An electron microscopic study of the have had no chance to check the total number of hepatic uptake and execution of submicroscopic particles thorotrast-injected patients. If it was done, we would injected into the blood stream and into the bile duct. Acta have some knowledge of thorotrast usage in Manchu- Anat 32: 262-291. ria. 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