CHOLESTYRAMINE FOR LONG TERM RELIEF OF THE PRURITUS COMPLICATING INTRAHEPATIC CHOLESTASIS

Transcription

1 GASTROENTEROLOGY Copyright 1966 by The Williams & Wilkins Co. CHOLESTYRAMINE FOR LONG TERM RELIEF OF THE PRURITUS COMPLICATING INTRAHEPATIC CHOLESTASIS Vol. 50, No.3 Printed in U.S.A. DHARAM V. DATTA, M.D., PH.D., AND SHEILA SHERLOCK, M.D. Department of Medicine, Royal Free Hospital School of Medicine, University of London, London, England The cause of the pruritus suffered by patients with obstructive jaundice is not known. Although bile salts have often been incriminated,! patients can be relieved by methyl testosterone,2 or norethandrolone (Nilevar)3 without any fall in serum bile acid levels. Such agents relieve pruritus at the expense of deepening jaundice and hirsutism. 4 Cholestyramine is a basic anion exchange resin which has been shown to relieve pruritus, perhaps secondarily to fecal removal of bile salts and to the interruption of their enterohepatic circulation. 5-8 The present paper reports the long term effects of cholestyramine therapy in patients with chronic intrahepatic cholestasis. Their clinical progress is compared with that of groups of patients with primary biliary cirrhosis receiving norethandrolone or untreated. Materials and Methods Twenty-seven patients suffering from chronic intrahepatic cholestasis were treated with cholestyramine, 23 of these for periods of 6 to 32 months (table 1). In each case the diagnosis was confirmed by the hepatic histological picture and by surgical exploration of the biliary system to exclude main bile duct obstruction. Seventeen patients had primary biliary Received March 8, Accepted October 29, Address requests for reprints to: Dr. Sheila Sherlock, Department of Medicine, Royal Free Hospital, Gray's Inn Road, London, W.C.I., England. One of the authors (D. V. D.) was supported by a grant from the Prudential Life Assurance Company. The authors are indebted to Merck Sharp & Dohme for generous gifts of cholestyramine. Dr. Datta's present address is: Department of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts. 323 cirrhosis; three, postnecrotic cirrhosis with cholestatic features; and three, congenital intrahepatic biliary atresia (table 1). In four patients, three with primary biliary cirrhosis and one with postnecrotic cirrhosis, cholestyramine was used for only a short time because it did not relieve the pruritus (table 2). All the patients had a severe degree of pruritus with scratch marks over the body and, in many instances, hemorrhages into the skin. No patient had received any treatment for itching for at least 2 months. A placebo of 10 g of bland potato powder flavored with lemon or orange juice was given in three doses daily for 2 to 6 weeks and then replaced by cholestyramine powder flavored similarly in a dose of 6.6 to 10 g per day. In some patients multivitamin tablets were used as a placebo and then replaced by cholestyramine tablets. Sixteen patients (nos. 1 to 6, 8, 10, 12, 15 to 19, and 21) received 10 g of the resin per day for 1 to 2 months followed by 6.6 g per day for 1 month and then 3.3 g per day. In two patients (nos. 22 and 23) the initial dose was 6.6 g per day and then similarly reduced to 3.3 g after a month. Four patients (nos. 7, 11, 13, and 14) received 10 g per day throughout. In five patients (nos. 20, 24 through 27) the dose of resin was increased to 12 g per day after a month. All patients except one (no. 22) received regular intramuscular injections of vitamin A, 100,000 IV; vitamin D, 200,000 IV; and vitamin K, 10 mg every 30 to 60 days. Patient no. 22 received vitamins A, D, and K orally. They also received 6 to 12 effervescent calcium tablets daily (one tablet contains 1 g of calcium gluconate). Routine clinical examination, including weighing and radiological bone survey of hands and spine, were performed prior to and at the end of therapy. Patients were free of edema and ascites at all weighings. Total body fat was also estimated with skin fold calipers.'o The mean levels of serum cholesterol" and bilirubin'" measured at weekly intervals for 2 to 6 weeks, were taken as the control values. The measurements were repeated after 7 and 30

2 TABLE 1. Effect of cholestyramine therapy on the pruritus of patients with chronic intrahepatic cholestasis -- ND. Patient Duration Dura- Diag- Age Sex Dose of Effect on pruritus Day of tion of nosis a pruritus relief treatment ide effects Effects of withdrawal b Fate g/day yr mo 1 J. B. PBC 50 F Relieved 8 27 Nil Recurrence (8) Living, liver failure 2 D. J. PBC 42 F Relieved but re- 5 8 Nil Living, well curred after 8 mo 3 M. S. PBC 53 F Relieved 5 26 Constipation Recurrence (15) Living, well 4 E. R. PBC 39 F Partially relieved Diarrhea Recurrence (3) Living, liver failure 5 M.M. PBC 53 F Relieved 6 6 Nil No recurrence Died, liver failure 6 R. C. PBC 58 F Relieved Nil Recurrence (10) Living, well 7 1. R. PBC 47 F Relieved Nil Recurrence (4) Living, well 8 R. L. PBC 39 F Relieved 8 20 Diarrhea Recurrence (6) Living, well 9 R.F. PBC 42 F Relieved 8 18 Diarrhea Recurrence (4) Living, well 10 A. T. PBC 33 F Partially relieved Nil Living, liver failure 11 E. J. PBC 59 F Relieved Nil Living, well 12 R.M. PBC 38 F Relieved Diarrhea Living, well 13 H.F. PBC 54 F Relieved 4 6 Nil No recurrence Died, liver failure 14 E. F. PBC 56 F Relieved 7 10 Nil No recurrence Died, liver failure 15 E.H. PBC 46 F Relieved Diarrhea Recurrence (7) Living, well 16 E. D. PBC 59 F Partially relieved 7 6 Nil Living, well 17 D.W. PBC 42 F Relieved 8 6 Nil Living, well 18 M.W. PNC 62 F Relieved 8 7 Abdominal No recurrence Died, liver hilure upset 19 H.E. PNC 42 F Relieved 4 21 Nil Recurrence (10) Living, liver failure 20 R.M. PNC 45 M Partially relieved 30 8 Diarrhea Recurrence (10) Living, well 21 G. J. CBA 9 M Relieved Diarrhea Recurrence (8) Living, well 22 A. W. CBA 3 M Relieved Nil Recurrence (14) Died, subarachnoid hemorrhage 23 C. B. CBA 7 F Relieved 7 20 Nil Recurrence (4) Living, well a PBC = Primary biliary cirrhosis; PNC = postnecrotic cirrhosis with chronic cholestasis; CBA congenital intrahepatic biliary atresia. b Day of recurrence of pruritus is shown in parentheses. - - >+b '"-3 >- b t-< a Q -g: c "'"

3 March 1966 LUNG TERM CHOLESTYRAMINE THERAPY 325 TABLE 2. Patients with chronic intrahepatic cholestasis and pruritus not responding to cholestyramine (10 to 12 g daily) No. Patient Diagnosisfl. Age Sex Duration of pruritus Days treated Serum bilirubin Cholesterol Before I After Before I After therapy therapy therapy therapy yr yr mg/100ml 1IIg/ A. G. PBC 41 F P. K. PBC 52 F W. R. PBC 49 F N. C. PNC 49 F a PBC = primary biliary cirrhosis; PNC = postnecrotic cirrhosis. days and at the end of 6 to 32 months of therapy. In some patients plasma free fatty acids,13 serum phospholipids," and triglycerides' 5 were measured prior to and at the end of long term therapy. Serum alkaline phosphatase, aspartate transaminase, albumin, globulin, protein electrophoresis, calcium, phosphorus, and prothrombin determinations, by standard methods' ' 17 were performed prior to and at the end of therapy. Fat was measured" in 3-day collections of feces for 6 to 27 days, 15 to 30 days, and 6 to 9 days during the control period, after 1 month, and again after 6 to 32 months of resin treatment. The mean fecal fat excreted per day was then calculated. All patients had the same, constant, intake of fat during each of the collection periods. Patients with primary biliary cirrhosis were treated with cholestyramine (nos. 1 to 17) antihistaminics, and calamine lotions (nos. 28 to 37) or norethandrolone (Nilevar) (nos. 38 to 50). Results Side Effects (Table 1) The cholestyramine powder usually caused minor degrees of nausea and reluctance to take it. Adults preferred the tablets although children found them difficult to swallow. Oue patient complained of constipation and seven patients of diarrhea for as long as the treatment was continued. One patient suffered abdominal discomfort. Pruritus Unrelieved (Table 2) Four patients were treated for 42 to 84 days in doses of 10 to 12 g daily but were not relieved of their pruritus (table 2). Serum bilirubin and total cholesterol were unchanged (table 2). Three patients (nos. 24 to 26) did not have urobilinogen in the urine and feces when continually measured over 6 days. Patient no. 27 showed urobilinogen in the urine. Patient nos. 24, 25, and 26 were then given norethandrolone, 10 mg twice daily, and within 13 days the pruritus was relieved although the serum bilirubin levels rose to 44, 35, and 37 mg per 100 ml. Hirsutism also developed. Patient no. 27 was unrelieved both by norethandrolone or by antihistiminic tablets. A second surgical exploration was performed and the biliary system was found to be normal. Postoperatively, continuous bile drainage through a T -tube in the common bile duct relieved both her pruritus and jaundice and these returned when the T-tube was clamped. Pruritus Relieved (Table 1) In 19 patients relief started after 4 to 11 days therapy and was usually complete in 4 to 30 days. In four patients (nos. 4, 10, 16, and 20) relief was partial, and mild pruritus persisted after 6 to 24 months of therapy and after increasing the dose to 10 to 12 g per day. Relief was unrelated to the previous duration of pruritus, the age of the patient, or the degree of liver cell dysfunction. Pruritus was controlled as long as the resin was continued. Patient no. 21 has been relieved for 32 months by 3.3 g per day. Ten grams of resin per day were usually sufficient initially. The dose was gradually

4 326 DATTA AND SHERLOCK Vol. 50, No.8 reduced and 3.3 g of cholestyramine was usually adequate for maintenance. In two patients (nos. 21 and 22) an attempt was made to find out the minimum effective dose; 1.7 g per day proved too small but 3.3 g proved sufficient. In two instance.s (nos. 10 and 18) 3.3 g was not enough and 6.6 g daily was necessary. In 17 patients after 6 to 32 months therapy the resin was withdrawn and replaced by a placebo. In three patients (nos. 1, 6, and 21) this was done two or three times. In every case pruritus returned after 3 to 15 days, but the resin again proved effective. Four patients (nos. 5, 13, 14, and 18), within a month of death, voluntarily discontinued taking the resin and pruritus did not return. Patient no. 19, who developed liver cell failure following a hematemesis, had pruritus when the resin was stopped but relief followed on recommencing treatment. Five (nos. 1, 6, 7, 20, and 21) of the 23 patients showed an increased body weight of more than 2 kg and four (nos. 3, 4, 5, and 10) a decrease of more than 2 kg following long term treatment. One of those who showed an increase (no. 1) later developed edema and ascites. Total body fat showed variable changes. Two of eight patients showed an increase of more than 1 kg and two a decrease of more than 1 kg. Prior to therapy, nine patients (nos. 1, 2, 4, 7, 9, 10, 13, 14, and 22) showed extensive skin xanthomata. After 6 months treatment four patients (nos. 1, 4, 7, and 22) showed a marked regression and xanthomata decreased further as treatment was continued. Three (nos. 9, 13, and 14) showed a moderate lessening and one (no. 2) no change. Xanthomata around the elbow, groin, and hand creases were the first to diminish and patients noted improvement in previously limited finger mobility. Xanthomata around the eyelids decreased very slowly and were the last to disappear. Patient no. 10, treated for 18 months with only partial relief of pruritus, showed a marked increase in the size of xanthomata and many new xanthomata appeared. Before treatment ascites was demonstrable in only one patient (no. 22). After 6 to 32 months of therapy ascites was present in 7 patients (nos. 1, 4, 5, 10, 13, 18, and 22). Five patients (nos. 5, 13, 14, 18, and 22) died of liver failure and one of these (no. 22) also had a subarachnoid hemorrhage. The duration of life in the fatal cases was 34, 43, 79, 105, and 54 months from diagnosis. Fourteen patients treated for 6 to 32 months have shown no clinical deterioration (table 1). Bone changes. Long term therapy did not result in any obvious clinical deterioration in the state of the bones and no fractures were seen. Two patients (nos. 4 and 19) had persistent bone changes. Radiologically, seven patients (nos. 1, 9, 10, 11, 16, 17, and 22) had bone thinning which persisted during the 6 to 32 months of therapy. In one patient (no. 19) the thinning increased. One patient (no. 6) developed osteoporosis after 21 months of therapy. Bleeding tendency. After 18 months one patient bled per vaginum. This ceased when the resin was stopped. The prothrombin time was not measured at that time. One patient (no. 22) was receiving synthetic vitamin K therapy only by mouth and had a terminal subarachnoid hemorrhage. Serum Biochemical Changes (Table 3) Serum total bilirubin, alkaline phosphatase, albumin, globulin, calcium, phosphorus, and prothrombin concentrations showed variable changes (table 3). Electrophoretic analysis of the serum proteins showed increases in the proportion of a2- and,b-globulin in 19 of 20 patients and in seven of these y-globulin was also increased. In three of these patients therapy was followed by reversion of the pattern to normal. In all the other 17 patients the height of the a2- and,b-peaks diminished considerably and in eight the height of the y-peak increased. Serum total cholesterol showed a fall of more than 20% in 17 of 19 patients at the end of therapy. The two other patients (nos. 12 and 13) with initially lower values, showed no change. Serum free choles-

5 March 1966 LONG TERM CHOLESTYRAMINE THERAPY 327 TABLE 3. Summary of serum biochemical changes following long term cholestyramine therapy" Estimation Mean (:I: SEM) serum levels No. of patients b Before therapy After therapy Increased Decreased No change Total bilirubin (mg/loo 9.8 ± ± ml) Alkaline phosphatase (K-A 85.3 ± ± units/loo ml) Aspartate transaminase ± ± (IU/liter) Albumin (g/loo ml) 3.8 ± ± Globulin (g/loo ml) 3.6 ± ± Calcium (mg/loo ml) 9.5 ± ± Phosphorus (mg/loo ml) 4.0 ± ± Prothrombin concentration 93.1 ± ± Cholesterol (mg/loo ml) Total ± ± Free ± ± Ester ± ± Triglycerides (mg/loo ml) ± ± Phospholipids (mg/loo ml) ± ± Free fatty acids (meq/ml) 1.25 ± ± a Differences were statistically significant (P < 0.05) only for total cholesterol, phospholipids, and free fatty acid. b Changes over 20% of the initial values. terol paralleled the changes observed in total cholesterol. Ester cholesterol showed variable changes (table 3). Plasma free fatty acid, serum triglyceride, and phospholipid concentrations usually fell after treatment with the resin (table 3). Fecal fat changes. In nine patients, fecal fat excretion, measured over 6 to 27 days, was 5.7 to 12.1 g per day. Ten grams of cholestyramine daily were then given, and in seven of these patients after 1 month and in eight after 6 to 32 months, daily fecal fat excretion had increased more than 4 g (fig. 1). Untreated Patients The clinical feature and course of patients with primary biliary cirrhosis receiving neither norethandrolone nor cholestyramine therapy has been summarized in table 4. They had a moderate to severe degree of pruritus, only partially relieved by oral antihistaminics or by local applications. The itching persisted until the terminal stages. Xanthomata were present in five patients -8' <!) CONTROL VALUES I MONTH 6-32 MONTHS FIG. 1. The effect of cholestyramine on fecal fat excretion before, 1 month, and 6 to 32 months after treatment. at the beginning of the study and seven at the end. They increased in two patients. Ascites developed in two patients. Patients Treated with N orethandrolone The 13 patients with primary biliary cirrhosis had been ill for 1 to 4 years (mean, 2 years, 1 month) (table 4). All

6 328 DATTA A N D SHERLOCK Vol. 50, No. S TABLE 4 Clinical course oj patients with primary biliary cirrhosis receiving no treatment or Nilevar No. Patient Age Sex Duration of Duration of illness follow-up Tleatment Fate a yr yr mo 28 J.H. 53 M 2 6 Nil Living, well 29 M. D. 49 F 2 18 Nil Living, hematemesis 30 J. T. 62 F 3 24 Nil Died following laparotomy 31 J. T. 43 F 7 12 Nil Living, ascites 32 M.F. 49 F 4 12 Nil Died, liver failure 33 M. F. 46 F 6 8 Nil Died, liver failure 34 M. M. 52 F 1 12 N il Living, well 35 A. H. 50 F 3 16 Nil Living, well 36 B.L. 32 F 2 7 Nil Died, liver failure 37 C.A. 37 F 2 8 Nil Living, well 38 A.A. 53 F 4 24 Nilevar Died, liver failure 39 J. F. 35 F 2 30 Nilevar Living, jaundice deepened 40 J. L. 43 F 1 20 Nilevar Living, well 41 H.R. 48 F 1 33 Nilevar Died, liver failure 42 M.R. 37 F 1 24 Nilevar Living, jaundice deepened 43 J. G. 43 F 1 6 Nilevar Living, well 44 M F 3 12 Nilevar Living, jaundice deepened 45 J. G. 46 F 3 9 Nilevar Living, jaundice deepened 46 R.W. 54 F 2 30 Nilevar Died, liver failure 47 F. P. 30 F 2 14 Nilevar Living, jaundice deepened liver failure 48 J. H. 40 F 2 9 Nilevar Died, liver failure 49 T.L. 39 F 3 20 Nilevar Living, well 50 E. E. 54 F 2 14 Nilevar Living, jaundice deepened a Well = No evidence of fluid retention or precoma or coma duflng course of Illness. patients were relieved of pruritus within 7 days. Xanthomata were present in six patients when first seen and in 10 at the end of 6 to 32 months of treatment. In two patients xanthomata increased in size. In four patients ascites had developed by the end of treatment. Four patients died of liver failure, the mean duration of illness being 4 years, 3 months. Seven patients were well and two had had an episode of liver failure. The serum total bilirubin rose more than 50% in 10 patients. The other biochemical changes are summarized in table 5. Comparison of results. The results of treatment of primary biliary cirrhosis with cholestyramine, norethandrolone, or neither have been compared. The mean duration of life in fatal cases was 52 months in the cholestyramine group, 51 months in the norethandrolone group, and 58 months in those treated with neither. Discussion Cholestyramine was effective in relieving the pruritus for 6 to 32 months in 23 of 27 patients with chronic intrahepatic cholestasis. The long term effects of any therapy for pruritus in patients with liver disease are difficult to assess because this symptom remits spontaneously in the terminal phase of hepatocellular failure. 19 In four of our patients withdrawal of the resin before death did not result in any recurrence of pruritus. In the other 19 patients substitution of placebo was followed by pruritus and readministration of resin provided relief, suggesting that cholestyramine was continuing to be effective. Four deeply jaundiced patients did not respond to cholestyramine therapy, and probably had little bile in the intestinal contents on which the resin might act. In the fourth patient there was no explanation for the failure.

7 March 1966 LONG TERM CH(JLESTYRAMINE THERAPY TABLE 5. Serum biochemical changes in patients with primary biliary cirrhosis receiving no treatment or N ilevar" Estimation Mean (± SEM) serum levels No. patientsb Before therapy After therapy Increased Decreased No change No treatment Total bilirubin (mg/ioo m!) 3.9 ± ± Cholesterol (mg/ioo ml) ± ± Albumin (g/ioo ml) 3.6 ± ± Globulin (g/ioo ml) 4.5 ± ± Alkaline phosphatase (K-A units/ 54.9 ± ± m!) Nilevar treatment Total bilirubin (mg/ioo ml) 4.7 ± ± Total cholesterol (mg/ioo ml) ± ± Albumin (g/ioo ml) 3.8 ± ± Globulin (g/ioo ml) 4.1 ± ± Alkaline phosphatase (K-A units/ 66.3 ± ± ml) a There was a statistically significant difference (P < 0.05) in total bilirubin for both groups and a more significant difference (P < 0.051) in alkaline phosphatase for those receiving no treatment. b Changes over 20% of the initial values. The effective maintenance dose of cholestyramine seems to be 3.3 g per day rather than the 10 to 15 g previously recommended,6, 1 although 6.6 g might be necessary in some cases. Cholestyramine powder is difficult to take, even when heavily flavored, although patients usually accept the discomfort in return for the remarkable relief. Chocolate-flavored cholestyramine tablets are more palatable although, as each contains only 750 mg, four to eight tablets have to be taken for an effective maintenance dose. Children found it difficult to swallow the tablets and they preferred to take the powder flavored with orange or tomato juice. Since cholestyramine is not absorbed, systemic effects are absent. Diarrhea in seven patients was presumably related to steatorrhea. s One patient complained of constipation, as reported previously.6 In one patient an acute abdominal disturbance was probably due to the bulk and unpleasant taste of the powder; this has also been described. s Increased losses of fat are not surprising in view of the loss of bile salts in the feces. In normal men a high dose of cholestyramine causes steatorrhea. 20 Malabsorption of fat soluble vitamins and of calcium might be expected and hypoprothrombinemia due to lack of vitamin K has been reported. 21 Vaginal bleeding was noted by one of our patients. Signs of deficiency of other fat-soluble vitamins were not observed but our patients received intramuscular supplements. One child who was given only oral vitamins A, D, and K did in fact develop a prolonged prothrombin time and died of a subarachnoid hemorrhage. Bile salts are probably needed for the absorption of calcium from the intestine. 22 Calcium supplements are therefore necessary and resin therapy did not seem to hasten bone thinning. In spite of the fecal fat losses, weight losses were no greater than those expected in a natural course of the disease.19 Some patients showed a rise in total body weight which did not seem to be due to fluid retention. Total body fat measurement did not show gross changes. In one patient with intrahepatic biliary atresia, cholestyramine seemed to improve liver function. 23 In the present study the effect on liver function was not clear-cut. Pri-

8 330 DATTA AND SHERLOCK Vol. 50, No.3 mary biliary cirrhosis has so many spontaneous fluctuations it would be unwise to ascribe any beneficial or deleterious effect on hepatic function to cholestyramine. A fall in serum bilirubin level following resin therapy has been described in congenital biliary atresia 23 and primary biliary cirrhosis. 21 Biliary drainage in primary biliary cirrhosis is known to lower serum bilirubin.19 It is possible that cholestyramine can bind bilirubin. The fall in serum bilirubin observed in some of the patients might be partly attributed to interruption of the enterohepatic circulation of bilirubin. Bile acid synthesis seems to be regulated by the amount of bile acid in the enterohepatic circulation Bile acids that escape reabsorption and are lost in the feces are replaced by those produced by oxidation of cholestero1. 25 Cholestyramine, which impairs the absorption of bile salts from the intestine and promotes fecal excretions. 27 should increase the rate of cholesterol oxidation and so lower serum cholesterol levels. This effect has been shown in normal and hypercholesterolemic patients. 25 Impaired absorption of cholesterol which follows resin administrations. 27 might be contributory. All the present patients showed a decrease in serum total cholesterol values. The major decrease was usually in the free cholesterol fraction and the disappearance of xanthomata is probably related to this. The fall in other plasma lipid fractions confirms a previous report. 21 The mechanism of this change is not certain. Intravenous injection of bile salts in animals increases 29 and external biliary drainage decreases.plasma lipids. The fall in initially raised plasma lipid levels following resin therapy might be secondary to the effect on bile acid metabolism. The prominent a2- and p-peaks in the serum protein electrophoretic pattern in these patients is attributed to an increase in the various plasma lipid fractions 30 and the fall in the height of the peaks might be related to the decrease in the various lipid fractions. A spontaneous fall in serum lipid levels is noted in patients with primary biliary cirrhosis reaching the terminal stage of hepatocellular failure and this might be contributory. However, these changes were observed within 7 to 30 days of starting treatment and cannot solely be due to the natural course of the disease. Primary biliary cirrhosis is a progressive fatal disease and cholestyramine probably does not affect the course. The groups treated with norethandrolone, cholestyramine, or neither were not studied coincidentally but otherwise were reasonably well matched. Patients in all groups can show a clinical and biochemical deterioration. No difference was seen in the mean duration of illness of the patients who died in the various groups. At the end of the study, patients were either well or showed clinical deterioration in a roughly equal proportion of cases. Cholestyramine-treated patients usually showed a fall in serum bilirubin and cholesterol values and skin xanthomata usually decreased. These findings are in contrast to the observations in the other two groups of a rise in serum bilirubin, a rise or no change in serum cholesterol, and the appearance or increase in size of xanthomata. The increase in icterus was particularly marked in those receiving norethandrolone and this, with the development of hirsuties, made this treatment undesirable. However, norethandrolone (or methyl testosterone) remains the only method of controlling pruritus in patients with cholestatic jaundice who are unresponsive to cholestyramine. Patients with intrahepatic cholestasis can tolerate resin administration for as iong as 6 to 32 months without developing the expected complications of malabsorption. This may have been prevented by parenteral fat-soluble vitamin and oral calcium supplements. Relief of pruritus continues while the resin is given. Summary Twenty-seven patients with pruritus due to chronic intrahepatic cholestasis (usually due to primary biliary cirrhosis) were treated with cholestyramine. Relief was complete in 19 and partial in

9 March 1966 LONG TERM CHOLESTYRAMINE THERAPY 331 four patients and this was maintained for 6 to 32 months. Four patients were not relieved. The initial dose was 6.6 to 10 g daily and maintenance was usually 3.3 g per day. Intramuscular fat-soluble vitamins and oral calcium were given routinely. After 6 to 32 months therapy, malnutrition was not observed. Skin xanthomata decreased in seven of nine patients. Fourteen patients showed no clinical deterioration, whereas nine developed hepatocellular failure. Serum bilirubin values fell in 10, rose in three, and did not change in nine patients. Protein electrophoretic patterns showed a decrease in a2- and,b-globulins, total and free serum cholesterol levels usually fell. Plasma free fatty acids and triglycerides fell or were unchanged. Fecal fat excretion increased. Long term resin therapy did not produce any obvious deleterious effects on the bones. Patients can tolerate this therapy for as long as 32 months and control of pruritus is maintained. A comparison was made of three groups of patients with primary biliary cirrhosis treated for many months with cholestyramine, with norethandrolone (Nilevar), or with neither. The duration of illness in the fatal cases was similar. Norethandrolone relieved the itching but jaundice deepened, xanthomata increased, and hirsuties appeared. The control group had no relief from pruritus, serum bilirubin increased slightly and xanthomata increased also. The ultimate prognosis of the underlying disease is probably not affected by cholestyramine therapy. REFERENCES 1. Carey, J. B., Jr Serum trihydroxyldihydroxy bile acid ratio in liver and biliary tract disease. J. Clin. Invest. 37: Lloyd-Thomas, H. G. L., and S. Sherlock Testosterone therapy for the pruritus of obstructive jaundice. Brit. Med. J. 2: Osborn, E. C., 1. D. P. Wootton, L. C. Da Silva, and S. Sherlock Serum bile acid levels in liver disease. Lancet 2: Datta, D. V., and S. Sherlock Treatment of pruritus in obstructive jaundice with methyltestosterone, norethandrolone, cholestyramine and corn oi!. Second W orid Congress of Gastroenterology III: Van!tallie, T. B., S. A. Hashim, and R. S. Crampton Enteric sequestration of bile acids in the management of patients with primary biliary cirrhosis. Trans. ArneI'. Clin. Climato!. Ass. 72 : Van!tallie, T. B., S. A. Hashim, R. S. Crampton, and D. M. Tennent The treatment of pruritus and hypercholesteraemia of primary biliary cirrhosis with cholestyramine. New Eng. J. Med. 265: Carey, J. B., Jr., and G. William Relief of pruritus of jaundice with a bile acid sequestering resin. J. A. M. A. 176: Datta, D. V., and S. Sherlock Treatment of pruritus of obstructive jaundice with cholestyramine. Brit. Med. J. 1: Datta, D. V., S. Sherlock, and P. J. Scheuer Postnecrotic cirrhosis with chronic cholestasis. Gut 4: Fletcher, R. F The measurement of total body fat with skin fold calipers. Clin. Sci. 22: Sperry, W. M., and M. A. Webb A revision of Schoenheimer-Sperry method for cholesterol determination. J. BioI. Chern. 187: Malloy, H. T., and K. A. Evelyn The determination of bilirubin with the photoelecrtic colorimeter. J. Bio!. Chern. 119: Dole, 'I. P A relation between nonesterified fatty acids in plasma and metabolism of glucose. J. Clin. Invest. 35: Allen, R. J. L The estimation of phosphorus. Biochem. J. 34: Van Handel, E., and D. B. Zilversmit Micromethod for the direct determination of serum triglyceride. J. Lab. Clin. Med. 50: King, E. J., and 1. D. P. Wootton Microanalysis in medical biochemistry, Ed. 3. J. & A. Churchill, Ltd., London. 17. Kohn, J A microelectrophoretic method. Nature (London) 181: Van De Kamer, J. H., H. B. Huinink, and H. A. Weyers Rapid method for the determination of fat in feces. J. Biol. Chern. 177: Sherlock, S Primary biliary cirrhosis (Chronic intrahepatic obstructive jaundice). Gastroenterology 37:

10 332 DATTA AND SHERLOCK Vol. 50, No Hashim, S. A., S. S. Bergen, and T. B. Van!tallie Experimental steatorrhoea induced in man by bile acid sequesterant. Proc. Soc. Exp. BioI. Med.106: Visintine, R. E., G. D. Michaels, G. Fukayama, J. Conklin, and L. W. Kinsell Xanthomatous biliary cirrhosis treated with cholestyramine. A bile acid-adsorbing resin. Lancet 2: Lengemann, F. W., and J. W. Dobbins The role of bile in calcium absorption. J. Nutr. 66: Lottsfeldt, F. 1., W. Krivit, J. W. Aust, and J. B. Carey Cholestyramine therapy in intrahepatic biliary atresia. New Eng. J. Med. 269: Bergstrom, S., and B. Borgstrom Metabolism of lipids. Ann. Rev. Biochem. 25: Bergstrom, S Metabolism of bile acids. Fed. Proc. 20: Josephson, B The circulation of bile acids in connection with their production, conjugation and excretion. Physiol. Rev. 21: Tennent, D. M., H. Siegel, M. E. Zanetti, G. W. Kuron, W. H. Ott, and F. J. Wolf Plasma cholesterol lowering action of bile acid binding polymers in experimental animals. J. Lipid Res. 1: Bergen, S. S., T. B. Van!tallie, D. M. Tennent, and W. H. Sebrell Effect of an ion exchange resin on serum cholesterol in man. Proc. Soc. Exp. BioI. Med. 102: Byers, S. 0., and M. Friedman Cholic acid: Adequate stimulus for hyperlipaemia in normal fasting rats. Proc. Soc. Exp. BioI. Med. 82: Kunkel, H. G., and R. J. Slater Lipoprotein patterns of serum obtained by zone electrophoresis. J. Clin. Invest. 31: Ahrens, E. H., Jr., M. A. Payne, H. G. Kunkel, W. J. Eisenmenger, and S. H. Blondheim Primary biliary cirrhosis. Medicine 29: