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Chlorpromazine jaundice
Chlorpromazine
Jaundice
WILLIAM R. C. STEWART, M.D., Columbus, From tbe Deportment of Surgery, Tbe Obio State University College of Medicine, Columbus, Obio.
Peight
ATIENT J. B., a somewhat seniIe, seventyyear oId white man, was admitted directIy from a rest home, unaccompanied, with a history of progressive jaundice, Iight stooIs and dark urine for one and a haIf weeks. The patient’s present iIIness had a febriIe onset with inffuenza-Iike symptoms, vague abdomina1 pain and anorexia. He had lost approximately IO pounds over the past two weeks. The patient denied any coIicky pain, previous jaundice or intoIerance to fatty foods, but said that twenty-five years ago his famiIy physician had toId him that he had “gaIIbIadder troubIe.” There was a past history suggesting aIcohoIism but the patient denied drinking any aIcoho1 over the past two years. Six months prior to this admission he had been admitted via the emergency room to asther hospita1 and had undergone what was apparentIy a closure of a perforated gastric or duodena1 uIcer. Since then he had been taking various medications, the nature of which was unknown to him. PHYSICAL EXAMINATION On physica examination the patient was a seniIe, somewhat agitated man in no acute distress. There was marked icterus of the skin and scIera. No spider nevi or abnorma1 venous distention was evident. Examination of the chest and heart was within norma Iimits. The abdomen was sIightIy distended. The edge of the Iiver was paIpabIe approximately two fingers beIow the right Costa1 margin and was smooth, firm and sIightIy tender. No other masses or organs were paIpabIe. On recta1 examination the prostate was moderately enIarged, smooth and firm. CIay-coIored stoo1 was noted on the gloved fingertip.
J
Obio
bIood ceI1 count was 8,750 per cu. mm. with 60 per cent neutrophiIs, 14 per cent Iymphocytes, 2 per cent monocytes and 22 per cent eosinophiIs. UrinaIysis showed 5 to ro white bIoodceIIs per low power fieId, and 15 mg. per cent of protein. The foam test was positive for biIe. Urine urobiIinogen was absent in two twentyfour hour sampIes. Serum bilirubin (van den Bergh) was 14.2 mg. per cent total, 6.8 mg. per cent direct. AIkaIine phosphatase was rg units (Shinowara, Jones and Reinhart), cephaIin flocculation o, and thymo1 turbidity 5 units. The bromsuIphaIein test showed 18 per cent retention. The prothrombin time was 89 per cent of normaI, choIestero1 was 687 mg. per cent with 128 mg. per cent esters. The tota protein was 7.4 units with a normal albumin: gIobuIin ratio. BIood urea nitrogen was 27. Serum gIutamic 0xyIacetic transaminase IeveIs ranged between 18 and 20 units. On three occasions stools were negative for bIood by the guaiac method. The upper gastrointestina1 examination demonstrated a deformity of the duodena1 buIb without an active uIcer crater. The esophagus, stomach and duodena1 Ioop were normaI. The roentgenogram of the chest showed an oId, heaIed granulomatous process and moderate pulmonary emphysema. HOSPITAL COURSE FoIIowing the initia1 history and physica examination a tentative diagnosis of obstructive jaundice was made. It was believed that this was probabIy secondary to a pancreatic neopIasm. Soon after admission further detaiIs were obtained from the rest home to augment the patient’s rather confusing medical history. It was discovered that during his hospita1 admission six months previousIy he had undergone cIosure of a perforated benign gastric uIcer and had been foIIowing a strict medical ulcer regimen since. AIso, because of extreme agitation and a history of aIcohoIism, he was discharged on chIorpromazine, 50 mg. four times daily. The
LABORATORYDATA The admission hemogIobin was 14.3 gm. per cent with a 43 per cent hematocrit. The white
495
American
Journal
of Surgery.
Volume
IOO, September
1960
Stewart patient had discontinued this medication one month following discharge. However, chIorpromazine therapy was reinstituted because of severe agitation three weeks prior to admission. In view of this history and subsequent Iaboratory studies (i.e., eosinophiIia, eIevated aIkaIine phosphatase, norma hepatoceIIuIar function and elevated choIestero1 and tota esters), a Silverman needIe biopsy of the Iiver was performed to confirm the more recent cIinica1 impression of jaundice due to chIorpromazine. Microscopic section of the Iiver showed marked intracanaIicuIar biIe stasis and biIe thrombi. No Iarge biIe Iakes were noted and none of the Iarger ducts were fiIIed with biIe. There was a moderate periporta1 infiItration of Ieukocytes, histiocytes and eosinophiIs; however, the Iiver ceIIs were compIeteIy norma and showed no evidence of damage. His treatment in the hospita1 consisted of bed rest, a high caIoric, high protein diet and muItivitamins. He was discharged on his twentyfirst hospita1 day, compIeteIy anicteric, with instructions cautioning against the administration of chIorpromazine to him in the future. COMMENTS
The jaundiced patient continues to present the surgeon with an interesting chaIIenge in HemoIytic both diagnosis and treatment. jaundice may usuaIIy be ruIed out quickIy on the basis of cIinica1 findings and a few simpIe Iaboratory tests (i.e., hemotoIogica1 studies, van den Bergh, stool and urine urobiIinogen). The differentiation of hepatoceIIuIar from obstructive disease is a much more diffrcuh probIem and may be especiaIIy confusing if the former is seen earIy, or the Iatter is seen Iate during the course of the disease. It has been our experience that the initiaI cIinica1 impression foIlowing a carefu1 history and physica examination is most often correct despite subsequent contradictory Iaboratory resuIts. In the case presented, hepatoceIIuIar disease couId be excIuded on a11 counts-history, cIinica1 and Iaboratory findings. Despite the history of aIcohoIism, jaundice is a Iate and rather infrequent manifestation of cirrhosis. When,it does occur it is usuaIIy accompanied by other physical signs suggesting Iiver damage such as spider nevi, ascites, gynecomastia, etc. Furthermore, laboratory tests wouId support hepatic ceIluIar impairment.
The interva1 of six months since hospitaIization for perforated uIcer (and probabIy bIood transfusion) we11exceeds the incubation period for serum hepatitis. An active infectious hepatitis wouId be accompanied by aiterations in hepatoceIIuIar studies as we11as a markedIy elevated serum transaminase IeveI. In analysis, the case presented is a typica exampIe of Iiver disease due to chlorpromazine therapy and might we11have been diagnosed on admission had a better history been avaiIabIe. CertainIy, in this age of tranquiIization, one shouId suspect the possibiiity of previous administration of chIorpromazine in an eIderIy, agitated, onetime aIcohoIic patient who was under medica care in a rest home. Every patient with obstructive-Iike jaundice should be carefuIIy questioned about recent medication. If an accurate history is unavaiIabIe an attempt shouId be made to contact the referring physician or rest home and obtain this information. FrequentIy, a patient may recognize a chIorpromazine spansuIe or tabIet if it is shown to him. Of course it shouId be kept in mind that this drug may aIso be administered parenteraIIy. The incidence of jaundice foIIowing the administration of chIorpromazine is generaIIy recognized at about I per cent [I] and usuaIIy deveIops from two to four weeks folIowing its initia1 administration. There is no cIear-cut reIationship to age, sex, dose or duration of drug administration [2]. Jaundice has even been reported to occur foIIowing the administration of as IittIe as 50 mg. of chIorpromazine b]. The onset is often febriIe with associated symptoms Iike those of inffuenza, maIaise, anorexia and occasiona chiIIs. This progresses to an obstructive-Iike icterus with pruritis, dark urine and light stooIs. About three-fourths of the patients have a paIpabIe, tender Iiver [4]. The hepatic function studies in this case were, for the most part, consistent with obstructive jaundice: a high aIkaIine phosphatase, norma tota protein and aIbumin: gIobuIin ratio, thymo1 turbidity and cephaIin ffocculation tests. The bromsuIphaIein retention was eIevated; however, this test is based on a coIorimetric reading and is therefore inaccurate in the face of significant icterus. The two Iaboratory tests of greatest diagnostic significance were: (I) an eIevated tota pIasma choIestero1 and total choIestero1 esters (aIthough the actual percentage of esterified
ChIorpromazine cholesterol is decreased); this is a very consistent finding in jaundice due to chIorpromazine therapy and (2) periphera1 eosinophiIia; this is exhibited in 40 to 80 per cent of the cases reported; the higher percentage is usually found in that group of patients who come to the physician shortIy after icterus is noted. A needle biopsy was performed onIy after it had been we11 estabIished that the patient did not have surgica1 jaundice. GeneraIIy, needIe biopsies shouId be avoided in al1 patients suspected of having obstruction, as perforation of one of the engorged intrahepatic ducts couId easiIy Iead to a fata biIe peritonitis. A Iow prothrombin time aIso contraindicates needIe biopsy. PathoIogic changes in the Ever are simiIar to those seen occasionaIIy foIIowing the administration of arsphenamine, thiouraci1 and methy testosterone. The hepatic ceIIs appear normaI; however, there is intrahepatic obstruction to the fIow of biIe, especiaIIy in the smaIIer biIiary canaIicuIi. The Iarger ducts are not diIated, thus differing from extrahepatic obstruction. PeriportaI infiItration, frequentIy containing eosinophiIs, is present in varying degrees. Numerous theories on the mechanism of jaundice due to chIorpromazine therapy have been postulated. The most IogicaI expIanation appears to be that it represents an allergic manifestation leading to intrahepatic cholestasis and biIe plugging. Gebhart et a1. [4] are of the opinion that this concept is supported for the foIIowing reasons, a11 of which appIy to the case presented: (I) there is usuaIIy a Iatent period between the administration of the drug and cIinica1 signs, (2) there is apparentIy an accelerated reaction in patients resuming the drug in smaI1 doses, and (3) periphera1 and periporta1 eosinophiIia are frequentIy observed. Against this concept is the apparentIy inconsistent resuIt obtained with steroid therapy.
Jaundice Jaundice due to chIorpromazine therapy is generaIIy benign and seIf-Iimited, ordinarily having a duration of one week to two months. Treatment is supportive and consists of a hepatitis medica regimen incIuding bed rest, high protein and high caIoric diet and vitamin suppIements. The cIinica1 significance of this disease Iies in its recognition. The surgeon must constantly keep in mind the possibility of previous administration of chIorpromazine in every jaundiced patient, and must be aware of its various manifestations. FaiIure to do this might we11 resuIt in an unnecessary and possibIy fata Iaparotomy. SUMMARY
A case of jaundice due to the administration of chIorpromazine is presented and salient diagnostic features are discussed. A carefu1 attempt must be made to determine the type of medication previousIy administered to any patient with a cIinica1 picture of obstructive jaundice. If chIorpromazine has been taken recentIy, even in smaI1 amounts, surgery shouId be deferred unti1 an accurate diagnosis can be established. REFERENCES
I. DOUGHTY, R. Incidence of jaundice associated with Thorazine@ therapy. PhiIadeIphia, 1955. Science Information Department: Smith, KIein and French Laboratories. 4. KELSEY, J. R., JR., MOYER, J. H., BROWN, W. G. and BENNETT, H. D. Chlorpromazine iaundice. Gastroenterology, 29: 865, 1955. 3. SUSSMAN,R. M. and SUMNER, P. Jaundice foIIowing the administration of 1;o me. of chIororomazine. New England J. Med., 253: i99. 1955. * 4. GEBHART, W. F., VAN OMMEN, R. A., MCCORYACK, L. J. and BROWN, C. H. ChIorpromazine jaundice. Arch. Int. Med., IOK: 1085, 1958.
497
Jaundice
WILLIAM R. C. STEWART, M.D., Columbus, From tbe Deportment of Surgery, Tbe Obio State University College of Medicine, Columbus, Obio.
Peight
ATIENT J. B., a somewhat seniIe, seventyyear oId white man, was admitted directIy from a rest home, unaccompanied, with a history of progressive jaundice, Iight stooIs and dark urine for one and a haIf weeks. The patient’s present iIIness had a febriIe onset with inffuenza-Iike symptoms, vague abdomina1 pain and anorexia. He had lost approximately IO pounds over the past two weeks. The patient denied any coIicky pain, previous jaundice or intoIerance to fatty foods, but said that twenty-five years ago his famiIy physician had toId him that he had “gaIIbIadder troubIe.” There was a past history suggesting aIcohoIism but the patient denied drinking any aIcoho1 over the past two years. Six months prior to this admission he had been admitted via the emergency room to asther hospita1 and had undergone what was apparentIy a closure of a perforated gastric or duodena1 uIcer. Since then he had been taking various medications, the nature of which was unknown to him. PHYSICAL EXAMINATION On physica examination the patient was a seniIe, somewhat agitated man in no acute distress. There was marked icterus of the skin and scIera. No spider nevi or abnorma1 venous distention was evident. Examination of the chest and heart was within norma Iimits. The abdomen was sIightIy distended. The edge of the Iiver was paIpabIe approximately two fingers beIow the right Costa1 margin and was smooth, firm and sIightIy tender. No other masses or organs were paIpabIe. On recta1 examination the prostate was moderately enIarged, smooth and firm. CIay-coIored stoo1 was noted on the gloved fingertip.
J
Obio
bIood ceI1 count was 8,750 per cu. mm. with 60 per cent neutrophiIs, 14 per cent Iymphocytes, 2 per cent monocytes and 22 per cent eosinophiIs. UrinaIysis showed 5 to ro white bIoodceIIs per low power fieId, and 15 mg. per cent of protein. The foam test was positive for biIe. Urine urobiIinogen was absent in two twentyfour hour sampIes. Serum bilirubin (van den Bergh) was 14.2 mg. per cent total, 6.8 mg. per cent direct. AIkaIine phosphatase was rg units (Shinowara, Jones and Reinhart), cephaIin flocculation o, and thymo1 turbidity 5 units. The bromsuIphaIein test showed 18 per cent retention. The prothrombin time was 89 per cent of normaI, choIestero1 was 687 mg. per cent with 128 mg. per cent esters. The tota protein was 7.4 units with a normal albumin: gIobuIin ratio. BIood urea nitrogen was 27. Serum gIutamic 0xyIacetic transaminase IeveIs ranged between 18 and 20 units. On three occasions stools were negative for bIood by the guaiac method. The upper gastrointestina1 examination demonstrated a deformity of the duodena1 buIb without an active uIcer crater. The esophagus, stomach and duodena1 Ioop were normaI. The roentgenogram of the chest showed an oId, heaIed granulomatous process and moderate pulmonary emphysema. HOSPITAL COURSE FoIIowing the initia1 history and physica examination a tentative diagnosis of obstructive jaundice was made. It was believed that this was probabIy secondary to a pancreatic neopIasm. Soon after admission further detaiIs were obtained from the rest home to augment the patient’s rather confusing medical history. It was discovered that during his hospita1 admission six months previousIy he had undergone cIosure of a perforated benign gastric uIcer and had been foIIowing a strict medical ulcer regimen since. AIso, because of extreme agitation and a history of aIcohoIism, he was discharged on chIorpromazine, 50 mg. four times daily. The
LABORATORYDATA The admission hemogIobin was 14.3 gm. per cent with a 43 per cent hematocrit. The white
495
American
Journal
of Surgery.
Volume
IOO, September
1960
Stewart patient had discontinued this medication one month following discharge. However, chIorpromazine therapy was reinstituted because of severe agitation three weeks prior to admission. In view of this history and subsequent Iaboratory studies (i.e., eosinophiIia, eIevated aIkaIine phosphatase, norma hepatoceIIuIar function and elevated choIestero1 and tota esters), a Silverman needIe biopsy of the Iiver was performed to confirm the more recent cIinica1 impression of jaundice due to chIorpromazine. Microscopic section of the Iiver showed marked intracanaIicuIar biIe stasis and biIe thrombi. No Iarge biIe Iakes were noted and none of the Iarger ducts were fiIIed with biIe. There was a moderate periporta1 infiItration of Ieukocytes, histiocytes and eosinophiIs; however, the Iiver ceIIs were compIeteIy norma and showed no evidence of damage. His treatment in the hospita1 consisted of bed rest, a high caIoric, high protein diet and muItivitamins. He was discharged on his twentyfirst hospita1 day, compIeteIy anicteric, with instructions cautioning against the administration of chIorpromazine to him in the future. COMMENTS
The jaundiced patient continues to present the surgeon with an interesting chaIIenge in HemoIytic both diagnosis and treatment. jaundice may usuaIIy be ruIed out quickIy on the basis of cIinica1 findings and a few simpIe Iaboratory tests (i.e., hemotoIogica1 studies, van den Bergh, stool and urine urobiIinogen). The differentiation of hepatoceIIuIar from obstructive disease is a much more diffrcuh probIem and may be especiaIIy confusing if the former is seen earIy, or the Iatter is seen Iate during the course of the disease. It has been our experience that the initiaI cIinica1 impression foIlowing a carefu1 history and physica examination is most often correct despite subsequent contradictory Iaboratory resuIts. In the case presented, hepatoceIIuIar disease couId be excIuded on a11 counts-history, cIinica1 and Iaboratory findings. Despite the history of aIcohoIism, jaundice is a Iate and rather infrequent manifestation of cirrhosis. When,it does occur it is usuaIIy accompanied by other physical signs suggesting Iiver damage such as spider nevi, ascites, gynecomastia, etc. Furthermore, laboratory tests wouId support hepatic ceIluIar impairment.
The interva1 of six months since hospitaIization for perforated uIcer (and probabIy bIood transfusion) we11exceeds the incubation period for serum hepatitis. An active infectious hepatitis wouId be accompanied by aiterations in hepatoceIIuIar studies as we11as a markedIy elevated serum transaminase IeveI. In analysis, the case presented is a typica exampIe of Iiver disease due to chlorpromazine therapy and might we11have been diagnosed on admission had a better history been avaiIabIe. CertainIy, in this age of tranquiIization, one shouId suspect the possibiiity of previous administration of chIorpromazine in an eIderIy, agitated, onetime aIcohoIic patient who was under medica care in a rest home. Every patient with obstructive-Iike jaundice should be carefuIIy questioned about recent medication. If an accurate history is unavaiIabIe an attempt shouId be made to contact the referring physician or rest home and obtain this information. FrequentIy, a patient may recognize a chIorpromazine spansuIe or tabIet if it is shown to him. Of course it shouId be kept in mind that this drug may aIso be administered parenteraIIy. The incidence of jaundice foIIowing the administration of chIorpromazine is generaIIy recognized at about I per cent [I] and usuaIIy deveIops from two to four weeks folIowing its initia1 administration. There is no cIear-cut reIationship to age, sex, dose or duration of drug administration [2]. Jaundice has even been reported to occur foIIowing the administration of as IittIe as 50 mg. of chIorpromazine b]. The onset is often febriIe with associated symptoms Iike those of inffuenza, maIaise, anorexia and occasiona chiIIs. This progresses to an obstructive-Iike icterus with pruritis, dark urine and light stooIs. About three-fourths of the patients have a paIpabIe, tender Iiver [4]. The hepatic function studies in this case were, for the most part, consistent with obstructive jaundice: a high aIkaIine phosphatase, norma tota protein and aIbumin: gIobuIin ratio, thymo1 turbidity and cephaIin ffocculation tests. The bromsuIphaIein retention was eIevated; however, this test is based on a coIorimetric reading and is therefore inaccurate in the face of significant icterus. The two Iaboratory tests of greatest diagnostic significance were: (I) an eIevated tota pIasma choIestero1 and total choIestero1 esters (aIthough the actual percentage of esterified
ChIorpromazine cholesterol is decreased); this is a very consistent finding in jaundice due to chIorpromazine therapy and (2) periphera1 eosinophiIia; this is exhibited in 40 to 80 per cent of the cases reported; the higher percentage is usually found in that group of patients who come to the physician shortIy after icterus is noted. A needle biopsy was performed onIy after it had been we11 estabIished that the patient did not have surgica1 jaundice. GeneraIIy, needIe biopsies shouId be avoided in al1 patients suspected of having obstruction, as perforation of one of the engorged intrahepatic ducts couId easiIy Iead to a fata biIe peritonitis. A Iow prothrombin time aIso contraindicates needIe biopsy. PathoIogic changes in the Ever are simiIar to those seen occasionaIIy foIIowing the administration of arsphenamine, thiouraci1 and methy testosterone. The hepatic ceIIs appear normaI; however, there is intrahepatic obstruction to the fIow of biIe, especiaIIy in the smaIIer biIiary canaIicuIi. The Iarger ducts are not diIated, thus differing from extrahepatic obstruction. PeriportaI infiItration, frequentIy containing eosinophiIs, is present in varying degrees. Numerous theories on the mechanism of jaundice due to chIorpromazine therapy have been postulated. The most IogicaI expIanation appears to be that it represents an allergic manifestation leading to intrahepatic cholestasis and biIe plugging. Gebhart et a1. [4] are of the opinion that this concept is supported for the foIIowing reasons, a11 of which appIy to the case presented: (I) there is usuaIIy a Iatent period between the administration of the drug and cIinica1 signs, (2) there is apparentIy an accelerated reaction in patients resuming the drug in smaI1 doses, and (3) periphera1 and periporta1 eosinophiIia are frequentIy observed. Against this concept is the apparentIy inconsistent resuIt obtained with steroid therapy.
Jaundice Jaundice due to chIorpromazine therapy is generaIIy benign and seIf-Iimited, ordinarily having a duration of one week to two months. Treatment is supportive and consists of a hepatitis medica regimen incIuding bed rest, high protein and high caIoric diet and vitamin suppIements. The cIinica1 significance of this disease Iies in its recognition. The surgeon must constantly keep in mind the possibility of previous administration of chIorpromazine in every jaundiced patient, and must be aware of its various manifestations. FaiIure to do this might we11 resuIt in an unnecessary and possibIy fata Iaparotomy. SUMMARY
A case of jaundice due to the administration of chIorpromazine is presented and salient diagnostic features are discussed. A carefu1 attempt must be made to determine the type of medication previousIy administered to any patient with a cIinica1 picture of obstructive jaundice. If chIorpromazine has been taken recentIy, even in smaI1 amounts, surgery shouId be deferred unti1 an accurate diagnosis can be established. REFERENCES
I. DOUGHTY, R. Incidence of jaundice associated with Thorazine@ therapy. PhiIadeIphia, 1955. Science Information Department: Smith, KIein and French Laboratories. 4. KELSEY, J. R., JR., MOYER, J. H., BROWN, W. G. and BENNETT, H. D. Chlorpromazine iaundice. Gastroenterology, 29: 865, 1955. 3. SUSSMAN,R. M. and SUMNER, P. Jaundice foIIowing the administration of 1;o me. of chIororomazine. New England J. Med., 253: i99. 1955. * 4. GEBHART, W. F., VAN OMMEN, R. A., MCCORYACK, L. J. and BROWN, C. H. ChIorpromazine jaundice. Arch. Int. Med., IOK: 1085, 1958.
497