Xanthomatous biliary cirrhosis following chlorpromazine

Xanthomatous Biliary Cirrhosis Following Chlorpromazine* NORMAN N . KOHN, M .D_ and RALPH M . MYERSON, M .D . Philadelphia, Pennsylvania

test was 0 .8 units, the cephalin flocculation test negative . The serum alkaline phosphatase was 37 .8 units (Shinowara-.tones), serum transaminase 380 units ; serum albumin 3 .9 gm . per 100 ml . and globulin 4 .1 gm . per 100 ml . The prothrombin time was 100 per cent . After a period of three weeks of icterus the serum bilirubin level had risen to 41 mg . per 100 ml ., with 20 mg . direct reacting pigment . The serum alkaline phosphatase was 68 units and the serum total cholesterol 1,164 mg . per 100 ml . Serum protein electrophoresis was normal . 'The result of a heterophil antibody test was negative . Jaundice and laboratory evidence of hepatic dysfunction of an obstructive type persisted throughout the subsequent period of ten months of observation . The significant laboratory abnormalities during this time are summarized in fable t . Treatment initially consisted of bedrest and administration of a high caloric, high protein diet, low in fat content. A seven-day course of prednisone in 40 mg . daily dosage was begun on the twenty-eighth day of jaundice, without noticeable effect . The patient became progressively more depressed, anorexic and suffered a weight loss of 25 pounds during the first six weeks of hospitalization . Although the clinical picture was entirely compatible with chlorpromazine jaundice, a potentially correctable surgical lesion could not be ruled nut for certain. Accordingly, six weeks after the onset of jaundice, an exploratory laparotomy was performed . At surgery, the entire biliary system was normal to inspection and palpation . The liver was slightly enlarged . Exploration of the common duct revealed no abnormalities . A T-tube was inserted into the common duct and an operative cholangiogratn was performed ; a wedge of hepatic tissue was taken for biopsy purposes . The cholangiogram was reported to be within normal limits . Grossly, the liver biopsy specimen was mottled green in appearance . Microscopically, there was bile plugging and accumulation of bile in the parenchymal and Kupffer cells . (Fig . 1- 1) Increased numbers of lymphocytes, gramdocytes and plasma cells were present in the portal areas ; neca-

the vast majority of subjects chlorpromazine hepatitis is benign and of relatively short duration . In the patient to be described, however, jaundice has been extremely prolonged ; there has been a marked disturbance of lipid metabolism ; and a syndrome indistinguishable from xanthomatous biliary cirrhosis has resulted .

I

N

CASE REPORT

A forty-one year old white man (L . J .) was well until early 1958 when, following the death of his parents, vague generalized symptoms developed and he was admitted to another hospital . The physical examination and laboratory studies (including serum cholesterol determination) were within normal limits . the diagnosis of a depressive reaction with anxiety was made and the patient received psychotherapy . Because of an increase in his symptoms the patient was hospitalized on the psychiatric service of the Veterans Administration Hospital, Philadelphia, On October 5, 1959 . On admission, the physical examination and routine laboratory studies were within normal limits . The urine contained no bile . An electrocardiogram and roentgenogram of the chest revealed no abnormalities . There had been no recent injections or known exposure to hepatotoxins . Chlorpromazine therapy, 25 mg . given orally four times daily, was instituted . On the tenth hospital day, because of increasing anxiety, the dosage was increased to 50 mg . four times daily . On the seventeenth hospital day icterus, dark urine and light colored stools were noticed . The patient's symptoms were unchanged from those on admission . Physical examination at this time revealed the presence of an enlarged liver felt 2 inches below the right costal margin . Shortly after the onset of jaundice the leukocyte count was 11,700 per en . m m . with 9 per cent eosinophils . The hemoglobin was 15 .1 gm . per 100 ml ., hematocrit 48 per cent . The urine was positive for bile and negative for urobilinogen . The serum total bilirubin was 12 mg ., with .6 7 mg. per 100 ml . direct reacting pigment ; serum total cholesterol was 390 mg . per 100 of . The result of the thymol turbidity

From the Medical Service of the Philadelphia Veterans Administration Hospital, Philadelphia, Pennsylvania . Manuscript received September 7, 1960 . VOL . 31, OCTOBER 1961

665



666

Xanthomatous Biliary Cirrhosis After Chlorpromazine-Kohn, Myerson TABLE I SUMMARY OF LIVER FUNCTION STUDIES

Duration of Jaundice

I

Serum Alkaline

phospbatase.

Gephalin Flocculation

1 8G0'F

(Shinowara units) (omit) 24 Hr .

48 Hr.

2}

Serum Total Cbotestcrol (mg, %)

I

Serun Rilwttbin Others Total (mg. %)

Dlrc (mg . % )

7 .6 19,4 15 .0 8 .8 7,2 9 .2 6 .0 2 .6 5 .0

i days 37 . B 10 days . . 60 .0 30 days . . . . 82 .5 IMe 36 .1 tmo 96 .0 Sum 90 .0 imo 68 .3 ttno 38 .8 3m o, 60 .5

390

2+

110 . . . 270 440 130 90 180

. .. Negative Negative 3+ 1} Negative Negative

Negative 1} 4+ 1} Negative Negative

64 ,. . 1,022 1,048 1,236 1,560 1,728

12 .0 38 .8 40 .0 190 15_4 18 .0 14 .0 5 .4 9 .6

7m o

570

Negative

Negative

1,800

5 .9

65 .1

390 1

sional eosinophils were noted . The biopsy was considered to be compatible with chlorpromazine hepatitis . Following surgery, and with continuing "F-tube drainage of the common duct, an abrupt fall in serum alkaline phosphatase and serum bilirubin levels was noted . (Fig . 2 .) Over a period of four weeks, however, the serum alkaline phosphatase returned to its preoperative level . The serum bilirubin, however, never returned to the high preoperative level during the subsequent period of observation . Additional cholangiograms were performed one and two months postoperatively and were within normal limits . Further studies were precluded when the patient inadvertently pulled the 'I-tube out shortly after the second postoperative study . Postoperatively, the patient's course was character-

SGPT, 102.8 units ; serum leueine aminopeptidase, 818 units ; a e stage prothrombin time; greater than 100% ; true prothrombin assay, 400% ; proconvertin away, 400% ; proateelerit, assay, 300%

ized by continuing anorexia, profound depression and weight loss . Despite his poor medical condition, it was decided to attempt a course of electroshock therapy . Nine such treatments were administered in early March 1960 . The response was immediate and dramatic . The patient became aware of his surroundings for the first time and was amenable to psychotherapy . His appetite improved, and he regained 20 pounds during a six-week period after the shock therapy . Despite continuing icterus the patient was asymptomatic at this time . However in April 1960 the liver had increased in size to 3 inches below the right costal margin and for the first time the spleen was palpable, extending 1 inch below the left costal margin . A second liver biopsy was performed on March 22, 1960, on the 150th day of jaundice . (Fig. 3 .) Microscopic study of this tissue showed some patchy areas of prominent bile staining within liver cells, canaliculi and Kupffer cells . An occasional bile lake was noted . In a few areas, liver cell karyorrhexis, nuclear enlargement and binucleation were noted . The periportal spaces were slightly enlarged with edema and granulocytic infiltration . The findings were interTABLE 11 SERUM LIPID ABNORMALITIES OBSERVED AFTER EIGHT MONTHS OF JAUNDICE

Lipid Fraction

Fic . 1 . Biopsy specimen of the liver after six weeks of jaundice showing bile plugging and infiltration with lymphocytes, gTanulocytes and plasma cells in the portal areas . Hematoxylin and eosin stain, original magnification X 350 .

Total lipids (mg . %) Total cholesterol (mg . %) . . . , Cholesterol esters (%) Phospholipids (mg . %) . . . . Neutral fat (mg. %) Total fatty acids (mg . %) . . . .

Observed Upper Limit Value of Normal

6,800 1,765 17 3,450 1,390 3,820

950 275 50-75 275 350 625

AMERICAN JOURNAL OF MEDICINE

Xanthomatous Biliary Cirrhosis After Chlorpromazine -Kahn,

Myerson

667

lnemlnn .r r-wee

Is

Fin . 2 . Changes in hihrubin and alkaline phosphatase levels after insertion of T-tube into common bile duct .

Fin . 3 . Biopsy specimen of the liver after 150 days of jaundice showing prominent bile staining within liver cells, canaliculi and Kupfl'er cells . Occasional bile lakes are present . Hematoxylin and eosin stain, original magnification X 350 .

Fin . 4 . Biopsy specimen of the liver after 240 days of jaundice showing prominent bile staining with occasional bile granulomas . Scattered focal necrosis is present . Hematoxylin and eosin stain, original magnification X 350,

preted as compatible with prolonged bile stasis due to chlorpromazine therapy . A second course of prednisone therapy was administered during the sixth month of jaundice . The patient received 60 mg . daily over a thirty day period . During this time there was a slight fall in serum alkaline phosphatase and bilirubin levels . but the serum total cholesterol level remained high . Hepatosplenomegaly persisted and the stools were acholie in appearance . A third biopsy was performed after 240 days of jaundice . (Fig . 4 .) Again, intrahepatic bite stasis was noted . There was patchy necrosis of liver cells . Phagocytosis of bile and small bile granulomas were noted for the first time . A small amount of portal fibrous reaction was present. At this time a yellow popular eruption appeared suddenly, involving the chest and back principally, with fewer lesions on the

nose, eyelids and extremities . (Fig . 5 .) Biopsy specimen of one of these lesions showed typical xanthoma . (Fig . 6 .) The results of the patient's serum lipid pattern performed eight months after the onset of jaundice are shown in Table it_ * Lactescenee of the serum was not present. The addition of ether to the serum, however, produced a dense white floceulmn . The results of radioactive fat study employing oral triolein were within normal limits . As of this writing, the size of the liver has not clinically decreased and the spleen remains enlarged . There has been no roentgenographic evidence of esophageal varices and the electrocardiogram remains within normal limits . * Kindly performed by Dr . Harry Shay, Eels Research Institute, Temple University School of Medicine . Philadelphia, Pennsylvania .

vol . . 31, OCTOBER 1961

66 8

Xanthornatous Biliary Cirrhosis After Chlorpromazine-Kohn, Myerson

Fm . 6 . Biopsy specimen of the skin (chest) showing histocytes with foamy cytoplasm characteristic of

xanthoma .

In . 5

ppearance of back after onset of xanthomatosis .

Assays of certain coagulation factors were performed in the tenth month of jaundice, and at a time when all medication had been discontinued for several weeks. One-stage prothrombin determinations revealed values slightly greater than 100 per cent . The true prothrombin assay was slightly greater than 400 per cent, as was the assay for proconvertin (factor vu) . Assay for proaccelerin (factor v) was slightly over 300 per cent . At the present time, ten months after the onset of his illness, the patient is asymptomatic except for severe pruritus which began in the sixth month of icterus . This symptom has proved refractory to the following drugs administered in appropriate dosage and for periods of time sufficient to demonstrate their ineffectiveness : phenobarbital, secobarbital, ephedrine, diphenhydramine, nitroglycerine, sodium dehydrocholate, ergotamine, intravenous procaine and prednisone . Trimeprazine (Temaril ® ) and other phenothiazine derivatives were withheld because of their chemical similarity to chlorpromazine . Testosterone therapy has afforded slight relief for brief periods . In an attempt to lower the serum cholesterol, a course of triparanol (MER 29 0 ) was administered in dosage of 250 mg. daily for five weeks . There was no appreciable change in serum cholesterol . Currently, the patient is out of the hospital and is attempting to resume work . COMMENTS

It has been stated that in approximately 25 per cent of patients treated with chlorpromazine, some evidence of hepatic dysfunction appears [1] . This abnormality is most often asymptomatic

and may even disappear with continued administration of the drug . In such instances it is detectable only through the demonstration of abnormalities in liver function tests, usually in the form of bromsulphalein retention and elevation of serum alkaline phosphatase and cholesterol . In approximately 1 per cent of the patients, jaundice appears but is usually of short duration [2] . The long-term prognosis in these patients has been considered to be benign [3], but detailed clinical, laboratory and histologic follow-up in some of them has pointed out the need for reserved opinion in this regard [4] . A rare fatality during the acute phase of jaundice has been noted [5-7] . In approximately 10 per cent of the patients, chloropromazine hepatitis lasts longer than three months [8] and prolonged jaundice continuing over a period of many months has been reported [8-13] . More severe and prolonged reactions associated with lipid disturbances have been noted in very few instances . In a patient treated with chlorpromazine, Stacey and others [12] noted the appearance of xanthelasma which lasted 197 days, but was followed by full recovery . Read and Sherlock [11] described four patients with jaundice which lasted from seven to thirty months . The serum cholesterol values were over 1,000 mg . per 100 ml . in all of these patients . In one of the four generalized xanthomatosis developed and portal hypertensionn was thought to be developing . Beattie and co-workers [10] observed a patient with chlorpromazine jaundice for eight months . At the end of this time no indication of remission had appeared and the serum cholesterol was 2,200 mg . per 100 ml ., the serum alkaline phosphatase 59 .4 King-ArmAMERICAN JOURNAL . OF MEDICINE



Xarithomatous Biliary Cirrhosis After Chlorpromazine SUMMARY

Authors

OF

CASES

OF

-Kahn,

Myerson

TABLE Ill CHRONIC HEPATIC DYSFUNCTION WITH EANTHOMATOSIS TO CHLORPROMAZINE THERAPY

Duration of Jaundice

Sen~m Lipid Abnormalities

Stacey et al . [72] 197 days Not stated Beattie et al . [70] 240} days I Total cholesterol 2,200 mg . Read, Sherlock [11] 30 me . j'Iotal cholesterol 1,620 mg . Myers et al . 11 .31 1 23 mo . I Total lipids 9,000 mg. ,o ; total cholesterol 2,500 mg. q ; phospholipids 4,800 mg. Kohn, Myerson 300+ days Total lipids 6,800 mg . % ; total cholesterol 1,765 mg. % ; phospholipids 3,450 mg. °%

strong units. Cutaneous xanthomas were present . They employed the term "hepatohypercholesterolemic cirrhosis" in describing this syndrome . A well documented similar case was reported by Myers and his associates [13] . The duration of jaundice in their patient was twenty-three months ; hepatosplenomegaly was present and there was generalized xanthomatosis . A serum total lipid level of over 9,000 mg . per 100 ml. was found ; of this, the serum cholesterol accounted for 2 .500 mg . The presence of portal hypertension was proved in this case by catheterization of the hepatic vein . The outcome in this patient was still uncertain, but the prognosis was considered to be poor . As in the present patient, Mycrs and his associates demonstrated the presence of markedly elevated levels of circulating coagulation factors, including prothrombin, proconvertin and proaccelerin . In addition, studies with acetate-l-C"• indicated a greatly enhanced hepatic production of cholesterol and phospholipid, a finding possibly calling for revision of the concept that in xanthomatous liver disease the observed hyperlipemic state results from retention of substances secondary to inadequate flow of bile . A tabulation of cases characterized by chronic liver abnormalities with xanthomatosis following administration of chlorpromazine is given in Table uI . This group of cases is quite similar to the syndrome variously described as xanthomatous hiliary cirrhosis, primary biliary cirrhosis or hepatohyperc holesterolemic cirrhosis . Thannhauscr and Magendantz [74] delineated the five outstanding characteristics of this disorder . These included (1) the presence of skin xanthomas, (2) hepatosplenomegaly, (3) obstructive jaundice which lasts for years, (4) voi . . 3t, OCTOBER 1961

I

Evidence of Xanthomatosis Xanthclasma

669

DUE

Outcome

Complete recovery icteric after 8 mo . Portal hypertension Portal hypertension, biliary cirrhosis

SUB

+ + +

Persistent jaundice and hepatosplenomegaly

extremely high values for serum total cholesterol and lecithin, and (5) absence of a milky serum . Cinchophen and arsphenamine have been incriminated in the evolution of a picture indistinguishable from xanthomatous biliary cirOn the basis of the evidence rhosis presented in this report, it is likely that chlorpromazine should be added to this group of drugs . In speaking of chronic liver disorders following the use of certain drugs . Sherlock [19] recently pointed out certain similarities with and differences from the idiopathic type of xanthomatous biliary cirrhosis . Although obstructive jaundice, relative well-being, pruritus, very high serum cholesterol levels and xanthomas are common to both, certain clinical and histologic features distinguish one from the other . The outcome in the primary disorder is uniformly fatal, while in the drug-induced disorder recovery takes place . Although stressing these differences, Sherlock concedes that an unknown number of cases regarded as instances of primary hiliary cirrhosis may indeed be due to unsuspected drug injury. Although emphasis has been placed upon the effect of chlorpromazine upon the smaller biliary radicles, little has been noted of the possible hepatocellular effect . Recently, this has been reevaluated, with the conclusion that in certain cases there is significant hepatocellular necrosis [20] . The marked elevations in serum SGPT and SCOT noted in this case would tend to support this concept . 'I he prompt improvement in certain abnormalities of liver function observed following institution of T-tube drainage of the common duct has been noted before in cases of chlor-

670

Xanthomatous Biliary Cirrhosis After Chlorpromazine

promazine jaundice [21], as well as in a few cases of primary biliary cirrhosis [19] . The explanation for this interesting phenomenon is unknown . Menguy and his associates [22] in experimental work on dogs, demonstrated that chlorpromazine may have some extrahepatic effect upon the biliary tree, particularly upon the biliary sphincteric mechanism and upon intraductal pressure within the common duct . However, this effect is evanescent and would be inadequate to explain the improvement in itching and jaundice observed following surgery in subjects from whom chlorpromazine therapy had been withdrawn for some time . The prognosis in this disorder cannot be stated at this time . As in the four cases of xanthomatous liver disease reported in the literature, the ultimate outcome in the case described herein is unknown . Despite the view that complete recovery is the rule in this type of hepatic dysfunction [19], study of these cases does not seem to warrant this conclusion . Treatment for this condition is centered upon the only disturbing symptom, namely pruritus . This usually proves refractory to a wide variety of drugs . Recently, norcthandrolone has been noted to be effective [11,19] . Although the administration of corticosteroids and their variants has been suggested in the treatment of chlorpromazine jaundice [23], the use of these drugs in the protracted form of the disease described in this report has been uniformly unsuccessful . SUMMARY

A case of chlorpromazine-induced jaundice, progressing to a chronic hepatic disorder characterized by a marked disturbance of lipid metabolism, with formation of xanthomas and resembling xanthomatous biliary cirrhosis, is presented . Markedly elevated levels of prothrombin, proconvertin and proaccelerin were also present . REFERENCES

1 . SHAY, H . and StpI .ET, H . Study of chlorpromazine jaundice, its mechanism and prevention ; special reference to Serum alkaline phosphatase and glutamic oxalacetic transaminase. Gastroenterology, 32 : 571, 1957 . 2 . Douowrv, R . Incidence of jaundice associated with thorazine therapy . Philadelphia, 1955 . Science Information Dept., SKF Laboratories . 3 . WaanHER . J . L . and KORELITZ, B. I . Chlorpromazine jaundice ; analysis of twenty-two cases . Am . J. Med., 22 : 351, 1957 . 4. MELROSE, A . G . and Roy, J . R. Late prognosis of chlorpromazinejaundice . Brit . Al . J., 1 : 818, 1959 .

Kohn, Myerson

5 . RODIN, A. E . and ROBERTSON . D . M . Fatal toxic hepatitis following chlorpromazine therapy ; report of a case with autopsy findings . Arch . Path ., 66 :170, 1958 . 6 . ISAACS, B ., MAc ARTHUR, J . G . and TAYLOR, R . M . Jaundice in relation to chlorpromazine therapy . Brit . M. J., 2 : 1122, 1955 . 7 . BO.ARDMAN, R . H . Fatal case of toxic hepatitis implicating chlorpromazine . Brit . M . J., 2 : 579, 1954 . 8 . BRICK, 1 . B . and BUCKLEY, S. V . Prolonged jaundice (over three months) occurring during chlorpromazine administration . Gastroenterology, 33 :192. 1957 . 9 . MEYER, H . M . and COOK, J . E . Long continuing jaundice following minimal chlorpromazine (thorazine) medication . Ann . lot . Med., 48 : 199, 1958. 10 . BEATTIE . A . S ., FARRLS, J . M . and FREMPTER, G . R . Hepatohypcrcholesterulcmic cirrhosis ; report of a case implicating chlorpromazine as the etiologic agent . California Med., 91 : 154, 1959. 11 . READ, A . E . and SHERLOCK, S . Prolonged jaundice due to chlorpromazine. Gostroenterologia, 92 : 135, 1959 . 12 . STACEY G. IJ ., AZIMA, 11 ., IIUESTIS, D . W ., IIOWLETT, J . G . and HOFFMAN, M. M . Jaundice occurring during the administration of chlorpromazine. Canad. M . A . J., 73 : 386, 1955 . 13 . MYERS,J . D ., OLSON, R . E ., LEwis, J . H . and MORAN, T . J. Xanthomatous biliary cirrhosis following chlorpromazine, with observations indicating overproduction of cholesterol, hyperprothrombinemia, and the development of portal hypertension . Tr. A . Am . Physicians, 70 : 243, 1957 . 14 . THANNHAUSER, S . J . and MAGENDANTZ, H . Different clinical groups of xanthomatous diseases ; clinical physiological study of 22 cases . Ann . lot . Med., 11 : 1662, 1938 . 15 . SHAY, H . and HARRIS, C . Changing concepts of °xanthomatous biliary cirrhosis ." Am . J. A4. Se., 223 : 286, 1952 . 16 . BocKus . H . L . and MONAGHAN, J . F . Metabolic diseases of the liver . In : Gastroenterology, vol . 3, p. 401 . Edited by Bockus, H. L. Philadelphia, 1946 . W. B . Saunders Co . 17 . CHANUTIN, A . and LUDEwIG, S . Blood lipid studies in case of xanthomatosis associated with hepatic damage . J. Lab . & Clin. Med., 22 : 903, 1937. 18 . STOLZER, B. L ., MILLER, G ., WHITE, W. A ., JR . and ZUCKERBROD, M . Postarsenical obstructive jaundice complicated by xanthomatosis and diabetic mellitus . Am . J. hfed., 9 : 124, 1950 . 19 . SHERLOCK, S . Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice) . Gastroenterology, 37 : 574, 1959 . 20 . ZELMAN, S . Liver cell necrosis in chlorpromazine jaundice (allergic cholangiolitis) ; a serial study of twenty-six needle biopsy specimens in nine patients . Am. J. Afed., 27 : 708, 1959 . 21 . Case records of the Massachusetts General Hospital ; Case 43222 . New England J. Med., 256 : 1060, 1957 . 22 . MENGUY, R. B., GRINDLAY, J . H, and CAIN, J . C . Effects of chlorpromazine hydrochloride on dynamics of biliary tree ; experimental study . Gastroenterology, 30 : 752, 1956 . 23 . CUTTs, M. Chlorpromazine hepatitis treated with cortisone ; case report . Ann . lot. Med., 46 : 1160, 1957 . AMERICAN JOURNAL OF MEDICINE