Possible Hepatotoxicity of Doxidan® KEITH G. TOLMAN, M.D., SAMUEL HAMMAR, M.D., and JOSEPH J. SANNELLA, M.D., Salt Lake City, Utah
A patient with chronic constipation developed liver injury and leukopenia following the ingestion of Doxidan®, a combination drug consisting of danthron and dioctyl calcium sulfosuccinate. Evidence is presented that dioctyl calcium sulfosuccinate may have potentiated the toxicity. The liver injury was associated with deposition of IgE in the Kupffer cells. The mechanism of toxicity remains unclear.
DOXIDAN®*, a widely used laxative, is a combination drug consisting of danthron (1,8 hydroxyanthraquinone) and dioctyl calcium sulfosuccinate. Danthron is an anthraquinone derivative, which is classified as a stimulant laxative but acts by an unknown mechanism to produce laxation. To date no untoward effects of its use other than an excessive cathartic effect and pinkish discoloration of the urine have been noted. Dioctyl calcium sulfosuccinate is a detergent that enhances hydration of stools. Dioctyl calcium sulfosuccinate and a similar agent, dioctyl sodium sulfosuccinate, have not been reported to cause serious adverse reactions, although dioctyl sodium sulfosuccinate when used with oxyphenisatin, a stimulant laxative, has been associated with the development of chronic active hepatitis (1-3). This report deals with a patient who developed leukopenia and liver disease while taking Doxidan. Deposits of IgE were found in the liver. Evidence is presented that dioctyl calcium sulfosuccinate may have potentiated the toxicity. Case Report
The patient is a 24-year-old housewife who had chronic constipation for several years. One year before admission she started taking Doxidan, one capsule per day. Her urine had a pinkish color almost constantly thereafter. Six months prior to admission she developed brownish urine and noted some sense of ill-being and easy fatigability but did not consult her physician. Three weeks before admission she increased the dose of Doxidan to one capsule four times per day. Two days before admission she developed anorexia, nausea, vomiting, and intermittent bilateral throbbing headaches. On the day of admission the patient had an unobserved syncopal episode that led to her admission to a local hospital. At the time of admission she was experiencing right and left upper-quadrant pain. The blood pressure was 110/72 mm Hg; heart rate, 84/min; respiratory rate, 16/min; and temperature, 37.0 °C orally. The epigastrium was tender to palpation. The * Hoechst Pharmaceutical, Inc., Somcrvillc, New Jersey. • From the Department of Medicine and Pathology, University of Utah College of Medicine, Salt Lake City, Utah.
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vertical diameter of the liver was 11 cm in the midclavicular line with a barely palpable sharp nontender edge. The spleen was not palpable. There was no lymphadenopathy. The remainder of the physical examination was normal. Laboratory examination at the time of admission showed a leukocyte count of 1500/mm3 with a differential cell count of 33% polymorphonuclear leukocytes, 42% lymphocytes, 17% monocytes, and 8% eosinophils. Hematocrit was 38.8% and platelet count, 259 + lOVmm8. Urinalysis was normal. Serum electrolytes were normal. A 12-channel serum analysis showed calcium, 8.1 mg/dl; phosphorus, 3.4 mg/dl; glucose, 86 mg/dl; creatinine, 0.6 mg/dl; uric acid, 2.9 mg/dl; cholesterol, 159 mg/dl; total protein, 6.0 gm/dl; albumin, 3.5 gm/dl; bilirubin, 0.8 mg/dl; alkaline phosphatase, 339 IU (normal, < 89); lactic dehydrogenase, 1112 IU; serum glutamic oxalacetic transaminase (SGOT), 560 IU. Hepatitis B surface antigen was not present as measured by radioimmunoassay. A lupus erythematosus cell preparation did not show lupus erythematosus cells. Nuclear-binding antibody was not present. The heterophile test was negative. A bonemarrow aspirate and biopsy were normal except for absent iron stores. A serum immunoelectrophoresis showed a polyclonal elevation in IgM. A chest X ray and electrocardiogram were normal. Doxidan, the only medication taken, was withdrawn the day of admission. The patient improved rapidly in sense of wellbeing. Three days after discontinuing the drug, the leukocyte count was 4600/mm8 with no eosinophils; the SGOT was 261 IU; and the alkaline phosphatase, 372 IU. A liver biopsy was done on the third day after admission and showed disruption of the limiting plate by a predominantly chronic inflammatory cell infiltrate (piecemeal necrosis). The infiltrate invaded the adjacent hepatic parenchyma and was associated with focal hepatocellular degeneration and necrosis. Architectural disruption was manifested by bridging necrosis and creeping fibrosis. The histologic pattern was typical of chronic aggressive hepatitis (Figure 1). The patient was discharged from the hospital without treatment and during the next month all of her abnormal serum chemistries returned to normal. Results of Rechallenge
The patient wished to continue taking Doxidan for constipation. Because of the uncertainty of its toxicity it was decided with the patient's informed consent to rechallenge the patient under controlled circumstances. The patient was admitted to the Clinical Research Center at the University of Utah Hospital. The repeat liver biopsy was normal as were the serum bilirubin, SGOT, and alkaline phosphatase. The leukocyte count was 5700/mm 3 with normal differential. The patient was initially given dioctyl calcium sulfosuccinate 60 mg/day as Surfak®*. After 1 week of therapy no change in bilirubin, SGOT, or alkaline phosphatase occurred. The patient was then given danAnnals of Internal Medicine 84:290-292, 1976
thron, 75 mg/day for 7 days. Again no change in bilirubin, SGOT, alkaline phosphatase, or leukocyte occurred. Finally the patient was rechallenged with Doxidan (50 mg danthron plus 60 mg dioctyl calcium sulfosuccinate) one capsule per day. On the second day the alkaline phosphatase rose from 64 to 139 IU. Heat fractionation showed that the alkaline phosphatase was 85% hepatobiliary. The leukocyte count fell from 8100 to 3800/mm3. No eosinophils were present. The drug was withdrawn and during the next few days the alkaline phosphatase returned to 47 IU and remained normal. The leukocyte count rose to 5000/mm3. A liver biopsy was not repeated at the patient's request. Special Microscopic Studies
At the time of the initial biopsy, a section of liver was fixed in cacodylate buffered 3% glutaraldehyde, postfixed in 2% osmium tetroxide, dehydrated in graded alcohols and propylene oxide, and embedded in Epon 812®* according to the method of Luft (4). Sections were examined with a RCA EM U4t electron microscope. Several degenerating hepatocytes were seen in association with normal hepatocytes and within hepatic sinusoids. Most of the hepatocytes in sinusoids had been phagocytosed by hypertrophied Kupffer cells. Lymphocytes and polymorphonuclear leukocytes were present within the sinusoids and in close association with degenerating and necrotic liver cells. The biopsy obtained after the patient recovered was normal except for an occasional fat droplet within hepatocytes. Sections of liver tissue from both biopsies were snapfrozen in isopentane by immersion in an acetone-dry ice bath. The tissues were stored at — 70 °C until examined. Frozen sections were cut and mounted on glass slides. After acetone fixation and air-drying, the fixed materials were immersed in phosphate-buffered saline for 10 min and overlayed with monospecific fluorescein conjugated antiserums:!: directed against human IgG, IgA, IgM, IgD, IgE, /J-1-C//3-1-A complement, fibrinogen, and albumin (5). Duplicate slides were overlayed with unconjugated antiserums. The liver biopsy taken during the active phase of hepatitis contained a granular deposit of IgE that was heaviest within Kupffer cell cytoplasm. These deposits were focal in contiguous groups of Kupffer cells and the sinusoidal margins of some adjacent hepatocytes. The nuclear material of Kupffer cells did notfluoresce.No other immunoproteins were seen. Pretreatment of the secretions with unconjugated antiserums blocked the attachment of fluoroscein-labeled antibody. A fine lacy deposit of fibrinogen within portal tracts but outside of vessels was also seen. An identical study done on the second biopsy failed to show deposits. • Fisher Scientific Co., Fairlawn, New Jersey. t RCA, Harrison, New Jersey. t Obtained commercially from Hyland Division, Travenol Laboratories (the antiserums were tested for monospecificity by double-gel diffusion and Immunoelectrophoresis).
Figure 1 . Region of liver showing portal and periportal mononuclear inflammatory cell infiltrate. The infiltrate is seen extending into the lobular parenchyma with associated hepatocellular necrosis. (Hematoxylin and eosin; magnification, x 125.)
Discussion
The association of chronic aggressive hepatitis and leukopenia in association with ingestion of Doxidan does not alone prove a cause-and-effect relation. Thefindingsin this case are not explained by any other cause, however, and the elevation of alkaline phosphatase and return of leukopenia on rechallenge with small doses of drug indicates that Doxidan was the likely cause of the initial abnormalities. It cannot be stated with certainty that the elevation of alkaline phosphatase on rechallenge represented hepatobiliary injury. It is conceivable that leukocyte injury or bowel injury could have caused the abnormality. However the increase in alkaline phosphatase was hepatobiliary by heat fractionation. The observation that the combination of danthron and dioctyl calcium sulfosuccinate was required to reproduce toxicity is interesting in view of the indictment of surface active agents in other hepatotoxicities when given in combination with oxyphenisatin. Chronic active hepatitis due to Dialose-plus®§ (oxyphenisatin and dioctyl sodium sulfosuccinate) is well established (1, 2). Rechallenge studies with oxyphenisatin resulted in signs of hepatotoxicity and this ingredient was then removed from the Dialose-plus product. However, there is evidence that dioctyl sodium sulfosuccinate itself may have contributed to the hepatotoxicity attributed to oxyphenisatin when given in combination with oxyphenisatin. Goldstein, Lam, and Mistilis (3) were able to identify only a single case of chronic active hepatitis in chronic users of oxyphenisatin alone but found that dioctyl sodium sulfosuccinate plus oxyphenisatin caused the disease in eight patients. Dujovne and Shoeman (6) have shown in man that dioctyl sodium sulfosuccinate, after oral ingestion of usual doses, is present in bile in concentrations that are hepatotoxic to Chang liver cells in culture and may potentiate the hepatotoxicity of oxyphenisatin in this system. These investigators also showed that erythromycin estolate, another surface-acting agent, injured liver cells in culture. It was postulated by Dujovne § Stuart Pharmaceuticals, Wilmington, Delaware. To/man at a/. • Doxldan and Hepatotoxlcity
Downloaded from https://annals.org by Karolinska Institute user on 01/23/2019
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and associates (7) that the detergent properties of dioctyl sodium sulfosuccinate and lauryl sulfate (a moiety in erythromycin estolate) facilitated transport of these agents and associated drugs such as oxyphenisatin and erythromycin across cell membranes. This view is supported by the observation that dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate enhance intestinal absorption of mineral oil (8). It has also been shown recently that dioctyl sodium sulfosuccinate stimulates adenyl cyclase activity in rat intestinal epithelium (9) and causes histologic damage to rat colon cells (10). The so-called stool softeners clearly have biological effects in addition to stool softening properties. This realization recently prompted an FDA-sponsored Panel on the Safety and Efficacy of Laxatives to recommend more intensive surveillance of dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate use to detect adverse reactions which might be associated with the use of these biologically active agents (8). The findings of hepatic IgE deposition is of particular interest: IgE is normally present in the serum only in minute amounts (5 X 10~4 mg/ml) and its demonstration in tissues other than skin is uncommon (11-13). Although IgE is often assumed to be involved only in allergic reactions, elevated serum levels have also been found in diseases not assumed to be related to atopy such as cirrhosis and pulmonary hemosiderosis (14). Gamma E immunoglobulin is known to sensitize mast cells, basophils, and other leukocytes. The union of antigen with glycoprotein results in release of histamine and other vasoactive substances from these cells (15). Cell degeneration necrosis and complement activation, however, are not thought to be involved in this type of immunologic reaction (16). In this case the deposition of IgE was found predominantly in Kupffer cells, a location shown by electron microscopy to be a site of numerous degenerating and necrotic hepatocytes. Likewise IgE was only found during the acute injury and was absent after resolution of the hepatic process. These findings suggest a causal relation between IgE and the hepatocellular necrosis despite the absence of a patho-
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March 1976 • Annals of Internal Medicine • Volume 84 • Number 3
Downloaded from https://annals.org by Karolinska Institute user on 01/23/2019
genetic mechanism to explain such an event. ACKNOWLEDGMENTS: Grant support: by Public Health Services grant no. RR-64 from the Division of Research Resources. Received 14 August 1975; revision accepted 17 December 1975. • Requests for reprints should be addressed to Keith G. Tolman, M.D., Division of Gastroenterology, University of Utah College of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132. References 1. REYNOLDS TB, PETERS RL, YAMADA S:
Chronic active and
lupoid hepatitis caused by a laxative, oxyphenisatin. N Engl J Med 285:813-820, 1971 2. MALLORY A,
FRANK
BW,
KERN
F
JR: Oxyphenisatin
and
chronic active hepatitis. N Engl J Med 285:1266, 1971 3. GOLDSTEIN GB, LAM MB, MISTILIS SP: Drug-induced active
chronic hepatitis. Am J Dig Dis 18:177-184, 1973 4. LUFT J: Improvements in epoxyresin embedding methods. J Biophys Biochem Cytol 9:409, 1961 5. COONS AH: Histochemistry with labelled antibody. Int Rev Cytol 5:1, 1956 6. DUJOVNE CA, SHOEMAN DW: Toxicity of a hepatotoxic laxative preparation in tissue culture and excretion in bile in man. Clin Pharmacol Ther 13:602-608, 1972 7. DUJOVNE CA, SHOEMAN D, BIANCHINE J, et al: Experimental
bases for the different hepatotoxicity of erythromycin preparations in man. J Lab Clin Med 79:832-844, 1972 8. Proposed monograph of the Panel on the Safety and Efficacy of Laxatives, Antidiarrheals, Antiemetics and Emetics. Fed Regis 40: no. 56, part II, 1975 9. DONOWITZ M, BINDER HJ: Dioctyl sodium sulfosuccinate (DSS) stimulates large intestinal water and electrolyte secretion: mechanism of laxative action? (abstract). Gastroenterology 66:184, 1974 10. SAUNDERS DR, SILLERY J: Effect of dioctyl sodium sulfosuccinate (DSS) on structure and function of the intestine (abstract). Clin Res 23:131, 1975 11. GERBER MA, PARONETTO F, KOCHEVA S: Immunohistochemical
localization of IgE in asthmatic lungs. Am J Pathol 62:339-348, 1971 12. GERBER MA, PARONETTO F: IgE in glomeruli of patients with nephrotic syndrome. Lancet 1:1097-1099, 1971 13. NISENGAID RJ, BEUTNER EH,
GAUTO M:
Immunofluorescent
studies of IgE in peridontal tissue. Ann NY Acad Sci 177:39-47, 1971 14. HEINER DC, ROSE B: Elevated levels of gamma E (IgE) in conditions other than classical allergy. / Allergy 45:30-42, 1970 15. EISEN HN: An introduction to molecular and cellular principles of the immune response, in Immunology. Hagerstown, Maryland, Harper and Row Publishers, Inc., 1974, pp. 532-544 16. TOMASI TB JR: Secretory immunoglobin. N Engl J Med 287: 500-506, 1972
A patient with chronic constipation developed liver injury and leukopenia following the ingestion of Doxidan®, a combination drug consisting of danthron and dioctyl calcium sulfosuccinate. Evidence is presented that dioctyl calcium sulfosuccinate may have potentiated the toxicity. The liver injury was associated with deposition of IgE in the Kupffer cells. The mechanism of toxicity remains unclear.
DOXIDAN®*, a widely used laxative, is a combination drug consisting of danthron (1,8 hydroxyanthraquinone) and dioctyl calcium sulfosuccinate. Danthron is an anthraquinone derivative, which is classified as a stimulant laxative but acts by an unknown mechanism to produce laxation. To date no untoward effects of its use other than an excessive cathartic effect and pinkish discoloration of the urine have been noted. Dioctyl calcium sulfosuccinate is a detergent that enhances hydration of stools. Dioctyl calcium sulfosuccinate and a similar agent, dioctyl sodium sulfosuccinate, have not been reported to cause serious adverse reactions, although dioctyl sodium sulfosuccinate when used with oxyphenisatin, a stimulant laxative, has been associated with the development of chronic active hepatitis (1-3). This report deals with a patient who developed leukopenia and liver disease while taking Doxidan. Deposits of IgE were found in the liver. Evidence is presented that dioctyl calcium sulfosuccinate may have potentiated the toxicity. Case Report
The patient is a 24-year-old housewife who had chronic constipation for several years. One year before admission she started taking Doxidan, one capsule per day. Her urine had a pinkish color almost constantly thereafter. Six months prior to admission she developed brownish urine and noted some sense of ill-being and easy fatigability but did not consult her physician. Three weeks before admission she increased the dose of Doxidan to one capsule four times per day. Two days before admission she developed anorexia, nausea, vomiting, and intermittent bilateral throbbing headaches. On the day of admission the patient had an unobserved syncopal episode that led to her admission to a local hospital. At the time of admission she was experiencing right and left upper-quadrant pain. The blood pressure was 110/72 mm Hg; heart rate, 84/min; respiratory rate, 16/min; and temperature, 37.0 °C orally. The epigastrium was tender to palpation. The * Hoechst Pharmaceutical, Inc., Somcrvillc, New Jersey. • From the Department of Medicine and Pathology, University of Utah College of Medicine, Salt Lake City, Utah.
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Downloaded from https://annals.org by Karolinska Institute user on 01/23/2019
vertical diameter of the liver was 11 cm in the midclavicular line with a barely palpable sharp nontender edge. The spleen was not palpable. There was no lymphadenopathy. The remainder of the physical examination was normal. Laboratory examination at the time of admission showed a leukocyte count of 1500/mm3 with a differential cell count of 33% polymorphonuclear leukocytes, 42% lymphocytes, 17% monocytes, and 8% eosinophils. Hematocrit was 38.8% and platelet count, 259 + lOVmm8. Urinalysis was normal. Serum electrolytes were normal. A 12-channel serum analysis showed calcium, 8.1 mg/dl; phosphorus, 3.4 mg/dl; glucose, 86 mg/dl; creatinine, 0.6 mg/dl; uric acid, 2.9 mg/dl; cholesterol, 159 mg/dl; total protein, 6.0 gm/dl; albumin, 3.5 gm/dl; bilirubin, 0.8 mg/dl; alkaline phosphatase, 339 IU (normal, < 89); lactic dehydrogenase, 1112 IU; serum glutamic oxalacetic transaminase (SGOT), 560 IU. Hepatitis B surface antigen was not present as measured by radioimmunoassay. A lupus erythematosus cell preparation did not show lupus erythematosus cells. Nuclear-binding antibody was not present. The heterophile test was negative. A bonemarrow aspirate and biopsy were normal except for absent iron stores. A serum immunoelectrophoresis showed a polyclonal elevation in IgM. A chest X ray and electrocardiogram were normal. Doxidan, the only medication taken, was withdrawn the day of admission. The patient improved rapidly in sense of wellbeing. Three days after discontinuing the drug, the leukocyte count was 4600/mm8 with no eosinophils; the SGOT was 261 IU; and the alkaline phosphatase, 372 IU. A liver biopsy was done on the third day after admission and showed disruption of the limiting plate by a predominantly chronic inflammatory cell infiltrate (piecemeal necrosis). The infiltrate invaded the adjacent hepatic parenchyma and was associated with focal hepatocellular degeneration and necrosis. Architectural disruption was manifested by bridging necrosis and creeping fibrosis. The histologic pattern was typical of chronic aggressive hepatitis (Figure 1). The patient was discharged from the hospital without treatment and during the next month all of her abnormal serum chemistries returned to normal. Results of Rechallenge
The patient wished to continue taking Doxidan for constipation. Because of the uncertainty of its toxicity it was decided with the patient's informed consent to rechallenge the patient under controlled circumstances. The patient was admitted to the Clinical Research Center at the University of Utah Hospital. The repeat liver biopsy was normal as were the serum bilirubin, SGOT, and alkaline phosphatase. The leukocyte count was 5700/mm 3 with normal differential. The patient was initially given dioctyl calcium sulfosuccinate 60 mg/day as Surfak®*. After 1 week of therapy no change in bilirubin, SGOT, or alkaline phosphatase occurred. The patient was then given danAnnals of Internal Medicine 84:290-292, 1976
thron, 75 mg/day for 7 days. Again no change in bilirubin, SGOT, alkaline phosphatase, or leukocyte occurred. Finally the patient was rechallenged with Doxidan (50 mg danthron plus 60 mg dioctyl calcium sulfosuccinate) one capsule per day. On the second day the alkaline phosphatase rose from 64 to 139 IU. Heat fractionation showed that the alkaline phosphatase was 85% hepatobiliary. The leukocyte count fell from 8100 to 3800/mm3. No eosinophils were present. The drug was withdrawn and during the next few days the alkaline phosphatase returned to 47 IU and remained normal. The leukocyte count rose to 5000/mm3. A liver biopsy was not repeated at the patient's request. Special Microscopic Studies
At the time of the initial biopsy, a section of liver was fixed in cacodylate buffered 3% glutaraldehyde, postfixed in 2% osmium tetroxide, dehydrated in graded alcohols and propylene oxide, and embedded in Epon 812®* according to the method of Luft (4). Sections were examined with a RCA EM U4t electron microscope. Several degenerating hepatocytes were seen in association with normal hepatocytes and within hepatic sinusoids. Most of the hepatocytes in sinusoids had been phagocytosed by hypertrophied Kupffer cells. Lymphocytes and polymorphonuclear leukocytes were present within the sinusoids and in close association with degenerating and necrotic liver cells. The biopsy obtained after the patient recovered was normal except for an occasional fat droplet within hepatocytes. Sections of liver tissue from both biopsies were snapfrozen in isopentane by immersion in an acetone-dry ice bath. The tissues were stored at — 70 °C until examined. Frozen sections were cut and mounted on glass slides. After acetone fixation and air-drying, the fixed materials were immersed in phosphate-buffered saline for 10 min and overlayed with monospecific fluorescein conjugated antiserums:!: directed against human IgG, IgA, IgM, IgD, IgE, /J-1-C//3-1-A complement, fibrinogen, and albumin (5). Duplicate slides were overlayed with unconjugated antiserums. The liver biopsy taken during the active phase of hepatitis contained a granular deposit of IgE that was heaviest within Kupffer cell cytoplasm. These deposits were focal in contiguous groups of Kupffer cells and the sinusoidal margins of some adjacent hepatocytes. The nuclear material of Kupffer cells did notfluoresce.No other immunoproteins were seen. Pretreatment of the secretions with unconjugated antiserums blocked the attachment of fluoroscein-labeled antibody. A fine lacy deposit of fibrinogen within portal tracts but outside of vessels was also seen. An identical study done on the second biopsy failed to show deposits. • Fisher Scientific Co., Fairlawn, New Jersey. t RCA, Harrison, New Jersey. t Obtained commercially from Hyland Division, Travenol Laboratories (the antiserums were tested for monospecificity by double-gel diffusion and Immunoelectrophoresis).
Figure 1 . Region of liver showing portal and periportal mononuclear inflammatory cell infiltrate. The infiltrate is seen extending into the lobular parenchyma with associated hepatocellular necrosis. (Hematoxylin and eosin; magnification, x 125.)
Discussion
The association of chronic aggressive hepatitis and leukopenia in association with ingestion of Doxidan does not alone prove a cause-and-effect relation. Thefindingsin this case are not explained by any other cause, however, and the elevation of alkaline phosphatase and return of leukopenia on rechallenge with small doses of drug indicates that Doxidan was the likely cause of the initial abnormalities. It cannot be stated with certainty that the elevation of alkaline phosphatase on rechallenge represented hepatobiliary injury. It is conceivable that leukocyte injury or bowel injury could have caused the abnormality. However the increase in alkaline phosphatase was hepatobiliary by heat fractionation. The observation that the combination of danthron and dioctyl calcium sulfosuccinate was required to reproduce toxicity is interesting in view of the indictment of surface active agents in other hepatotoxicities when given in combination with oxyphenisatin. Chronic active hepatitis due to Dialose-plus®§ (oxyphenisatin and dioctyl sodium sulfosuccinate) is well established (1, 2). Rechallenge studies with oxyphenisatin resulted in signs of hepatotoxicity and this ingredient was then removed from the Dialose-plus product. However, there is evidence that dioctyl sodium sulfosuccinate itself may have contributed to the hepatotoxicity attributed to oxyphenisatin when given in combination with oxyphenisatin. Goldstein, Lam, and Mistilis (3) were able to identify only a single case of chronic active hepatitis in chronic users of oxyphenisatin alone but found that dioctyl sodium sulfosuccinate plus oxyphenisatin caused the disease in eight patients. Dujovne and Shoeman (6) have shown in man that dioctyl sodium sulfosuccinate, after oral ingestion of usual doses, is present in bile in concentrations that are hepatotoxic to Chang liver cells in culture and may potentiate the hepatotoxicity of oxyphenisatin in this system. These investigators also showed that erythromycin estolate, another surface-acting agent, injured liver cells in culture. It was postulated by Dujovne § Stuart Pharmaceuticals, Wilmington, Delaware. To/man at a/. • Doxldan and Hepatotoxlcity
Downloaded from https://annals.org by Karolinska Institute user on 01/23/2019
291
and associates (7) that the detergent properties of dioctyl sodium sulfosuccinate and lauryl sulfate (a moiety in erythromycin estolate) facilitated transport of these agents and associated drugs such as oxyphenisatin and erythromycin across cell membranes. This view is supported by the observation that dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate enhance intestinal absorption of mineral oil (8). It has also been shown recently that dioctyl sodium sulfosuccinate stimulates adenyl cyclase activity in rat intestinal epithelium (9) and causes histologic damage to rat colon cells (10). The so-called stool softeners clearly have biological effects in addition to stool softening properties. This realization recently prompted an FDA-sponsored Panel on the Safety and Efficacy of Laxatives to recommend more intensive surveillance of dioctyl sodium sulfosuccinate and dioctyl calcium sulfosuccinate use to detect adverse reactions which might be associated with the use of these biologically active agents (8). The findings of hepatic IgE deposition is of particular interest: IgE is normally present in the serum only in minute amounts (5 X 10~4 mg/ml) and its demonstration in tissues other than skin is uncommon (11-13). Although IgE is often assumed to be involved only in allergic reactions, elevated serum levels have also been found in diseases not assumed to be related to atopy such as cirrhosis and pulmonary hemosiderosis (14). Gamma E immunoglobulin is known to sensitize mast cells, basophils, and other leukocytes. The union of antigen with glycoprotein results in release of histamine and other vasoactive substances from these cells (15). Cell degeneration necrosis and complement activation, however, are not thought to be involved in this type of immunologic reaction (16). In this case the deposition of IgE was found predominantly in Kupffer cells, a location shown by electron microscopy to be a site of numerous degenerating and necrotic hepatocytes. Likewise IgE was only found during the acute injury and was absent after resolution of the hepatic process. These findings suggest a causal relation between IgE and the hepatocellular necrosis despite the absence of a patho-
292
March 1976 • Annals of Internal Medicine • Volume 84 • Number 3
Downloaded from https://annals.org by Karolinska Institute user on 01/23/2019
genetic mechanism to explain such an event. ACKNOWLEDGMENTS: Grant support: by Public Health Services grant no. RR-64 from the Division of Research Resources. Received 14 August 1975; revision accepted 17 December 1975. • Requests for reprints should be addressed to Keith G. Tolman, M.D., Division of Gastroenterology, University of Utah College of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132. References 1. REYNOLDS TB, PETERS RL, YAMADA S:
Chronic active and
lupoid hepatitis caused by a laxative, oxyphenisatin. N Engl J Med 285:813-820, 1971 2. MALLORY A,
FRANK
BW,
KERN
F
JR: Oxyphenisatin
and
chronic active hepatitis. N Engl J Med 285:1266, 1971 3. GOLDSTEIN GB, LAM MB, MISTILIS SP: Drug-induced active
chronic hepatitis. Am J Dig Dis 18:177-184, 1973 4. LUFT J: Improvements in epoxyresin embedding methods. J Biophys Biochem Cytol 9:409, 1961 5. COONS AH: Histochemistry with labelled antibody. Int Rev Cytol 5:1, 1956 6. DUJOVNE CA, SHOEMAN DW: Toxicity of a hepatotoxic laxative preparation in tissue culture and excretion in bile in man. Clin Pharmacol Ther 13:602-608, 1972 7. DUJOVNE CA, SHOEMAN D, BIANCHINE J, et al: Experimental
bases for the different hepatotoxicity of erythromycin preparations in man. J Lab Clin Med 79:832-844, 1972 8. Proposed monograph of the Panel on the Safety and Efficacy of Laxatives, Antidiarrheals, Antiemetics and Emetics. Fed Regis 40: no. 56, part II, 1975 9. DONOWITZ M, BINDER HJ: Dioctyl sodium sulfosuccinate (DSS) stimulates large intestinal water and electrolyte secretion: mechanism of laxative action? (abstract). Gastroenterology 66:184, 1974 10. SAUNDERS DR, SILLERY J: Effect of dioctyl sodium sulfosuccinate (DSS) on structure and function of the intestine (abstract). Clin Res 23:131, 1975 11. GERBER MA, PARONETTO F, KOCHEVA S: Immunohistochemical
localization of IgE in asthmatic lungs. Am J Pathol 62:339-348, 1971 12. GERBER MA, PARONETTO F: IgE in glomeruli of patients with nephrotic syndrome. Lancet 1:1097-1099, 1971 13. NISENGAID RJ, BEUTNER EH,
GAUTO M:
Immunofluorescent
studies of IgE in peridontal tissue. Ann NY Acad Sci 177:39-47, 1971 14. HEINER DC, ROSE B: Elevated levels of gamma E (IgE) in conditions other than classical allergy. / Allergy 45:30-42, 1970 15. EISEN HN: An introduction to molecular and cellular principles of the immune response, in Immunology. Hagerstown, Maryland, Harper and Row Publishers, Inc., 1974, pp. 532-544 16. TOMASI TB JR: Secretory immunoglobin. N Engl J Med 287: 500-506, 1972
