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Idiopathic Recurrent Cholestasis
GASTROENTEROLOGY
Vol. 52. No.3 Printed in U.S.A.
Copyright © 1967 by The Williams & Wilkins Co.
IDIOPATHIC RECURRENT CHOLESTASIS G. STATHERS, M.B., B.S., M.R.A.C.P., C. S. H. REED, M.B., B.S., F.R.A.C.P., AND E. HIRST, M.B., D.C.P., M.C.P.A. Departments of Medicine and Pathology, Sydney Hospital, Sydney, Australia
In 1959 Summerskill and Walshe 1 described 2 cases of obstructive jaundice which they called "benign recurrent intrahepatic obstructive jaundice." Subsequently, Tygstrup2 described this syndrome in two boys from the Faroe Islands and suggested that there was a famliial factor. Recently he has found 7 more cases, including two sets of brothers.s.4 Kuhn 5 also described the syndrome in two brothers. De Groote et a1 6 and Kuhn 5 suggested that the disease was more akin to a hepatitis than to a congenital hyperbilirubinemia. Schapiro and Isselbacher 7 described a patient who had 26 attacks of obstructive jaundice over 37 years. Williams et a1. 4 and Summerskill 8 reported further cases. The purpose of this case report is to record a patient with a similar syndrome but with features not previously recorded. Case History The patient, a 32-year-old housewife, was first seen at the age of 19 years (January 1951) with jaundice which had been preceded by 4 days of vomiting and diarrhea. She did not complain of anorexia or abdominal pain but noticed dark urine and clay colored stools. When seen in the hospital (March 1951), she was deeply jaundiced and her liver was palpable 3 cm below the costal margin. Bile was present in her urine and her stools were clay colored, but there were no other signs of liver disease. The results of initial and serial investigations are seen in table 1. No disorder of the serum proteins was found. Received June 20, 1966. Accepted October 13, 1966. Address requests for reprints to: Dr. G. Stathers, Department of Medicine, University of Sydney, Sydney, N.S.W., Australia. The authors thank Dr. N. Rose, the superintendent of Sydney Hospital, for permission to publish this case. 536
Treatment consisted of 250 mg of tetracycline orally every 6 hr for 7 days. This episode lasted for 6 months. Laparotomy, performed soon after the jaundice had resolved, demonstrated a macroscopically normal liver. There were no calculi in the common bile duct or gall bladder. Some recent adhesions were noted around the gall bladder. A wedge liver biopsy was taken. For 8 years she was well until, at 27 years of age (April 1959), in the last 10 days of her first pregnancy, she experienced generalized pruritus and noted dark urine and pale feces. The child was born with jaundice, which was transitory (April 28). Three days after delivery, the patient was observed to be jaundiced, but she did not experience nausea, malaise, or abdominal pain. Her liver, palpable 3 cm below the costal margin, was not tender. One spider nevus was found on her arm. Table 1 shows the investigations performed. Oral tetracycline, 250 mg every 6 hr, was prescribed for 3 weeks. On June 24, a laparotomy was performed. The common bile duct and gall bladder were opened and found to be empty and free from obstruction. Operative cholangiography was not performed. The liver was said to appear cirrhotic, and a liver biopsy was taken. There were some enlarged lymph nodes at the hilum of the liver, and some adhesions were present around the common bile duct. The pancreas, stomach, and duodenum were normal. Two days postoperatively the jaundice became deeper, spider nevi appeared on her chest and arms, and intravenous hydrocortisone (unspecified dose) was started. There was no immediate fall in the serum bilirubin (table 1). Following the institution of hydrocortisone in the immediate postoperative period, prednisone, 60 mg per day, was started, and on discharge from the hospital (September 9) the dosage was reduced to 30 mg per day. It was further decreased until a maintenance level of 5 mg per day was reached in February 1960. It was continued at this level until June 1961, when it was stopped. Table 1 shows the results of investigations in this period.
TABLE
Date
Second episode of jaundice 5/13/1959 6/18/1959 6/24/1959 6/30/1959 7/9/1959 9/9/1959 May 1960 November 1960 February 1961 May 1961 June 1961 Augu!lt 1961 February 1962 Julyi1962 Third episode of jaundice 10/6/1964 10/14/1964 11/4/1964 12/18/1964 3/24/1965 5/4/1965
1. Results of serial investigations
Serum Serum Serum Brom- glutamic glutamic Serum oxalo- pyruvic cholesSerum alkaline sulphacetic bilirubin phos· alien terol phatase retention trans- ~i::;~b aminaseG mg/loo ml
First episode of jaundice 3/29/1951 6/6/1951 7/17/1951 8/5/1951
537
IDIOPATHIC RECURRENT CHOLESTASIS
March 1967
--- --- --- --- --KAC % a! 45 units/lOO unils/lOO mg/loo units/ 100 ml
37.6 8.8 0.8
25
7.4 6.8
33 18
14.2 4.2
33 17
3.7 2.2 1.9 1.4
10 15 14
0.4
7
m.n
ml
ml
Prednisone
mg/day
ml
8
Laparotomy, liver biopsy
Laparotomy, liver biopsy
60 30 (reduced slowly to 5)
830 2625 240 170 1
7.5 12 16 24 16 15
340 280 Ceased
25 40 55
0.4
3.2 4.3 4.3 20.0 2.6 0.9
Operative procedures
Tubal ligation, liver biopsy
400 90 54
239
Liver biopsy
46
Normal range of investigations, 20 to 40. Normal range of investigations, 20 to 95. C King Armstrong.
G
b
In February 1962, the Bromsulphalein retention was 1% at 45 min. In July 1962, 11 months after cessation of the previous episode of jaundice, she again became pregnant. The pregnancy was terminated, and tubal ligation was performed through fear of precipitation of jaundice. A liver biopsy was performed. Liver function tests were normal.
She was then well until August 1964, when she developed an upper respiratory tract infection associated with malaise, anorexia, and myalgia. Pruritis developed and she was admitted to the hospital and found to be jaundiced. On November 4, 1964, a percutaneous liver biopsy was performed. The liver function tests gradually returned to normal (table 1), and the
STATHERS ET AL.
538
whole episode lasted 9 months. In the ensuing 12 months, she has been well and liver function tests have remained within normal limits.
Histology The material available for histological examination was four biopsies, two of which were recovered at open operation. The most striking changes were present in the first biopsy taken at laparotomy 7 months after the onset of the illness. Although it was a subcapsular biopsy, it was devoid of the subcapsular fibrous changes sometimes found in biopsies from this area. The section showed numerous scattered foci of inflammatory and reparative cells in portal tracts, near veins, and in the lobules. The cellular infiltrate was pleomorphic and consisted of neutrophils, a few eosinophils, and numerous lymphocytes and other mononuclear cells (fig. 1). In some areas, especially in the walls of large veins and in portal tracts, the appearance resembled those of inflammatory granulation tissue with proliferation of fibroblasts and lumenless, or narrow, vessels (figs. 2 and 3) . There was no cholestasis, and degenerative changes in the liver cells, such as ballooning and necrosis, were not found. Portal and hepatic veins and sinusoids were dilated. The second biopsy (1959) was also recovered at operation. The patient was jaundiced, and sections showed cholestasis. The histological appearances were similar to, but very much less severe than, those in the previous biopsy. A few portal tracts and hepatic vein radicles showed fibrosis with a little lymphocytic infiltrate. Very rare degenerating liver cells were found, but ballooning was again absent. A section stained for reticulin showed a coarsening and patchy matting of the reticulin fibers (fig. 4). Subsequent biopsies (1962 and 1964) were recovered by needle. The first, taken when jaundice was absent, showed no significant abnormality. The last biopsy, taken when jaundice had reappeared, showed cholestasis, accumulation of bile pigment in Kupffer cells, and scattered small pleomorphic inflammatory foci in portal tracts and near the walls of hepatic vein radicles (fig. 5). Reticulin arrangement in both of the latter biopsies was normal (fig. 6). Discussion This patient presents many of the features of idiopathic recurrent cholestasis. 4 In this syndrome, there are numerous attacks of cholestatic jaundice recurring over a number of years. Onset usually occurs before the age of 30 years, and it
Vol. 52, No.3
can present at a very early age. 2 Prodromal symptoms consist mainly of severe pruritus and occasionally of mild anorexia, lethargy, and vomiting for 1 to 2 weeks. There appears to be no constant precipitating factor leading to an attack. Influenza-like illnesses,2 pregnancy,! and dermatographism4 have been associated with the onset of jaundice. The attacks of jaundice usually last from a few months to 2 years. The time between attacks may be from a few months to many years. During attacks, weight loss is often severe and sometimes there is severe steatorrhea. The striking feature of our patient's attacks was the severe pruritus which heralded the onset of the last two episodes. Anorexia was not a marked feature. The onset of the second attack was during the third trimester of pregnancy, but the attack did not remit after delivery. In the third episode, the onset of jaundice was preceded by an influenza-like illness. The attacks of jaundice lasted from 6 to 24 months, and they occurred at intervals of 9 years, and 3 years, 2 months, respectively. In the reported cases, there appears to be almost a complete absence of signs of severe hepatocellular disease. The liver has often been reported as palpable,4, 7 but splenomegaly is absent. Our patient showed spider nevi during the second attack, when she was pregnant, and later when she was being treated with corticosteroids. Investigations usually disclose an elevated serum bilirubin and alkaline phosphatase, with mild to moderate elevation of the serum transaminase from 2 to 6 times normal during an attack of jaundice. The very high serum transaminase levels in our patient would seem to indicate active hepatic damage. These are the highest levels that we have found in this syndrome. However, there did not appear to be residual hepatic damage following this episode, as all parameters of liver function returned to normal. At no stage was there depression of the serum albumin or abnormal elevation of the serum globulins. Exploration of bile ducts has been made in all of the quoted cases, and no evidence of extrahepatic obstruction has been
March 1967
IDIOPATHIC RECURRENT CHOLESTASIS
FIG. 1. First biopsy. Inflammation in portal tracts and hepatic lobules (H & E, X 180). FIG. 2. First biopsy. Wall of vein with inflammatory granulation tissue (H & E, X 180).
539
FIG. 3. First biopsy. Granulation tissue-like proliferation and cellular infiltrate (H & E, X 650). X
FIG. 4. Second biopsy. Region of matted reticular fib ers (reticulin stain, method unstated, 180). 540
March 1967
IDIOPATHIC RECURRENT CHOLESTASIS
FIG. 5. Fourth biopsy. A few neutrophils in the wall of hepatic vein radicle (H & E, X 650). FIG. 6. Fourth biopsy. Normal reticular pattern (Lendrin's stain, X 180).
541
542
Vol. 52, No.3
STATHERS ET AL.
found. Operative cholangiograms, when performed, have been normal. Our patient had two explorations which demonstrated absence of extrahepatic biliary obstruction. When jaundice is present, there is cholestasis mainly in the centrilobular areas, accompanied by infiltration of the portal tracts with round cells. l -s Also described is pleomorphic inflammatory infiltrate of portal tracts and parenchyma. 4 Areas of cell necrosis/' 4-6 usually patchy in distribution, are described. Often these areas were not related to the areas of cholestasis. 4 Increase in fibrous tissue is usually slight and inconstant. 2, 4, 7 Ductular proliferation has been reported in 1 case. 4 Biopsies taken when the attack was subsiding have shown cholestasis with cellular infiltration.4, 7 There are only two previous reports of biopsies taken in complete remission,s, 9 and these showed normal liver. In our patient, a biopsy early in the disease but during remission showed inflammation in venous radicles. Later, during jaundice, the inflammatory changes were slight. Later biopsies, both during an attack and in remission, showed normal architecture. Corticosteroids have been used for therapy with varying success. Prednisone has been reported as being of benefit,2, 4 of uncertain value,7 and, in our patient, of having no effect. Cortisone and adrenocorticotropin in combination were said to clear the jaundice slowly in 1 case. l Recently, cholestyramine was reported to relieve the severe pruritus. 9 This syndrome in our patient, where liver damage appeared to be associated with cholestasis and parenchymal cellular infiltrates, appears to be an atypical recurring form of hepatitis, as previously suggested. 6 This syndrome also appears to be very similar to recurrent jaundice of pregnancy,lO in which jaundice occurs in the last few months of pregnancy and disappears soon after delivery. Liver function tests show obstruction without parenchymal liver damage, and liver biopsies demonstrate accumulation of bile pigment in the bile capillaries. Associated with some of these bile plugs there may be isolated
hepatic cell degeneration. However, in our patient there was no remission after delivery of the baby. The differential diagnosis should include the syndromes described by Dubin and Johnson 11 and Rotor et al. l2 However, pruritus is not a feature in these syndromes, and cholestasis is not seen histologically. In the Dubin-Johnson syndrome, lipochrome pigment is seen characteristically in the liver biopsy. Drug causes of intrahepatic cholestasis should also be searched for,13 In our patient, Cl7- a - alkyl substituted testosterones were not used for the prevention of lactation. Tetracyclines have been reported as causing hepatic injury,13 but in our patient the drug was given after the onset of jaundice in the first two episodes and not at all in the third. Summary
A female had obstructive jaundice at 19 years, with further attacks at intervals of 9 years and 3 years. They were heralded by severe pruritus and lasted from 6 to 24 months. Marked elevation of the serum transaminases occurred. Laparotomy on two occasions showed normal extrahepatic biliary system. Inflammatory changes were found in hepatic venous radicles. Treatment, including corticosteroids, was of no avail, and later biopsy showed the liver to be normal. The syndrome is preferably named "idiopathic recurrent cholestasis," 4 and features in our case suggest an atypical recurring hepatitis. REFERENCES 1. Summerskill, W. H. J., and J. M. Walshe. 1959. Benign recurrent intrahepatic "obstructive" jaundice. Lancet 2: 686-690. 2. Tygstrup, N. 1960. Intermittent possibly familial intrahepatic cholestatic jaundice. Lancet 1: 1171-1172. 3. Tygstrup, N. Quoted by Williams et al. in reference 4. 4. Williams, R., M. A. Cartter, S. Sherlock, P. J. Schever, and R. Hill. 1964. Idiopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases. Quart. J. Med. 33: 387-399. 5. Kuhn, H. A. 1963. Intrahepatic cholestasis in
March 1967
6. 7.
8.
9.
10.
IDIOPATHIC RECURRENT CHOLESTASIS
two brothers. German Med. Monthly 8: 185-188. De Groote, J., P. Goubeau, and J. Vandenbroucke. 1960. Ictere cholostatique recidivant. Acta Gastroent. Belg. 23: 747-755. Schapiro, R. H., and K. J. Isselbacher. 1963. Benign recurrent intrahepatic cholestasis. New Eng. J. Med. 268: 708-711. Summerskill, W. H. J. 1965. The syndrome of benign recurrent cholestasis. Amer. J. Med. 38: 298-305. Spiegel, E. L., W. Schubert, E. Perrin, and L. Schiff. 1965. Benign recurrent intrahepatic cholestasis, with response to cholestyramine. Amer. J. Med. 39: 682-688. Svanborg, A., and S. Ohlsson. 1959. Recur-
543
rent jaundice of pregnancy: clinical study of twenty-two cases. Amer. J. Med. 27: 40-49. 11. Dubin, 1. N., and F. B. Johnson. 1954. Chronic idiopathic jaundice with unidentified pigment in liver cells: new clinico-pathologic entity with report of 12 cases. Medicine (BaIt.) 33: 155-195. 12. Rotor, A. B., Manahan, L., and A. Florentin. 1948. Familial non-hemolytic jaundice with direct van den Bergh reaction. Acta Med. Philipp. 5: part 2, 37-49. 13. Popper, H., F. Schaffner, E. Rubin, T. Barka, and F. Paronetto. 1963. Mechanisms of intrahepatic cholestasis in drug-induced hepatic injury. Ann. N. Y. Acad. Sci. 104: 988-1013.
Vol. 52. No.3 Printed in U.S.A.
Copyright © 1967 by The Williams & Wilkins Co.
IDIOPATHIC RECURRENT CHOLESTASIS G. STATHERS, M.B., B.S., M.R.A.C.P., C. S. H. REED, M.B., B.S., F.R.A.C.P., AND E. HIRST, M.B., D.C.P., M.C.P.A. Departments of Medicine and Pathology, Sydney Hospital, Sydney, Australia
In 1959 Summerskill and Walshe 1 described 2 cases of obstructive jaundice which they called "benign recurrent intrahepatic obstructive jaundice." Subsequently, Tygstrup2 described this syndrome in two boys from the Faroe Islands and suggested that there was a famliial factor. Recently he has found 7 more cases, including two sets of brothers.s.4 Kuhn 5 also described the syndrome in two brothers. De Groote et a1 6 and Kuhn 5 suggested that the disease was more akin to a hepatitis than to a congenital hyperbilirubinemia. Schapiro and Isselbacher 7 described a patient who had 26 attacks of obstructive jaundice over 37 years. Williams et a1. 4 and Summerskill 8 reported further cases. The purpose of this case report is to record a patient with a similar syndrome but with features not previously recorded. Case History The patient, a 32-year-old housewife, was first seen at the age of 19 years (January 1951) with jaundice which had been preceded by 4 days of vomiting and diarrhea. She did not complain of anorexia or abdominal pain but noticed dark urine and clay colored stools. When seen in the hospital (March 1951), she was deeply jaundiced and her liver was palpable 3 cm below the costal margin. Bile was present in her urine and her stools were clay colored, but there were no other signs of liver disease. The results of initial and serial investigations are seen in table 1. No disorder of the serum proteins was found. Received June 20, 1966. Accepted October 13, 1966. Address requests for reprints to: Dr. G. Stathers, Department of Medicine, University of Sydney, Sydney, N.S.W., Australia. The authors thank Dr. N. Rose, the superintendent of Sydney Hospital, for permission to publish this case. 536
Treatment consisted of 250 mg of tetracycline orally every 6 hr for 7 days. This episode lasted for 6 months. Laparotomy, performed soon after the jaundice had resolved, demonstrated a macroscopically normal liver. There were no calculi in the common bile duct or gall bladder. Some recent adhesions were noted around the gall bladder. A wedge liver biopsy was taken. For 8 years she was well until, at 27 years of age (April 1959), in the last 10 days of her first pregnancy, she experienced generalized pruritus and noted dark urine and pale feces. The child was born with jaundice, which was transitory (April 28). Three days after delivery, the patient was observed to be jaundiced, but she did not experience nausea, malaise, or abdominal pain. Her liver, palpable 3 cm below the costal margin, was not tender. One spider nevus was found on her arm. Table 1 shows the investigations performed. Oral tetracycline, 250 mg every 6 hr, was prescribed for 3 weeks. On June 24, a laparotomy was performed. The common bile duct and gall bladder were opened and found to be empty and free from obstruction. Operative cholangiography was not performed. The liver was said to appear cirrhotic, and a liver biopsy was taken. There were some enlarged lymph nodes at the hilum of the liver, and some adhesions were present around the common bile duct. The pancreas, stomach, and duodenum were normal. Two days postoperatively the jaundice became deeper, spider nevi appeared on her chest and arms, and intravenous hydrocortisone (unspecified dose) was started. There was no immediate fall in the serum bilirubin (table 1). Following the institution of hydrocortisone in the immediate postoperative period, prednisone, 60 mg per day, was started, and on discharge from the hospital (September 9) the dosage was reduced to 30 mg per day. It was further decreased until a maintenance level of 5 mg per day was reached in February 1960. It was continued at this level until June 1961, when it was stopped. Table 1 shows the results of investigations in this period.
TABLE
Date
Second episode of jaundice 5/13/1959 6/18/1959 6/24/1959 6/30/1959 7/9/1959 9/9/1959 May 1960 November 1960 February 1961 May 1961 June 1961 Augu!lt 1961 February 1962 Julyi1962 Third episode of jaundice 10/6/1964 10/14/1964 11/4/1964 12/18/1964 3/24/1965 5/4/1965
1. Results of serial investigations
Serum Serum Serum Brom- glutamic glutamic Serum oxalo- pyruvic cholesSerum alkaline sulphacetic bilirubin phos· alien terol phatase retention trans- ~i::;~b aminaseG mg/loo ml
First episode of jaundice 3/29/1951 6/6/1951 7/17/1951 8/5/1951
537
IDIOPATHIC RECURRENT CHOLESTASIS
March 1967
--- --- --- --- --KAC % a! 45 units/lOO unils/lOO mg/loo units/ 100 ml
37.6 8.8 0.8
25
7.4 6.8
33 18
14.2 4.2
33 17
3.7 2.2 1.9 1.4
10 15 14
0.4
7
m.n
ml
ml
Prednisone
mg/day
ml
8
Laparotomy, liver biopsy
Laparotomy, liver biopsy
60 30 (reduced slowly to 5)
830 2625 240 170 1
7.5 12 16 24 16 15
340 280 Ceased
25 40 55
0.4
3.2 4.3 4.3 20.0 2.6 0.9
Operative procedures
Tubal ligation, liver biopsy
400 90 54
239
Liver biopsy
46
Normal range of investigations, 20 to 40. Normal range of investigations, 20 to 95. C King Armstrong.
G
b
In February 1962, the Bromsulphalein retention was 1% at 45 min. In July 1962, 11 months after cessation of the previous episode of jaundice, she again became pregnant. The pregnancy was terminated, and tubal ligation was performed through fear of precipitation of jaundice. A liver biopsy was performed. Liver function tests were normal.
She was then well until August 1964, when she developed an upper respiratory tract infection associated with malaise, anorexia, and myalgia. Pruritis developed and she was admitted to the hospital and found to be jaundiced. On November 4, 1964, a percutaneous liver biopsy was performed. The liver function tests gradually returned to normal (table 1), and the
STATHERS ET AL.
538
whole episode lasted 9 months. In the ensuing 12 months, she has been well and liver function tests have remained within normal limits.
Histology The material available for histological examination was four biopsies, two of which were recovered at open operation. The most striking changes were present in the first biopsy taken at laparotomy 7 months after the onset of the illness. Although it was a subcapsular biopsy, it was devoid of the subcapsular fibrous changes sometimes found in biopsies from this area. The section showed numerous scattered foci of inflammatory and reparative cells in portal tracts, near veins, and in the lobules. The cellular infiltrate was pleomorphic and consisted of neutrophils, a few eosinophils, and numerous lymphocytes and other mononuclear cells (fig. 1). In some areas, especially in the walls of large veins and in portal tracts, the appearance resembled those of inflammatory granulation tissue with proliferation of fibroblasts and lumenless, or narrow, vessels (figs. 2 and 3) . There was no cholestasis, and degenerative changes in the liver cells, such as ballooning and necrosis, were not found. Portal and hepatic veins and sinusoids were dilated. The second biopsy (1959) was also recovered at operation. The patient was jaundiced, and sections showed cholestasis. The histological appearances were similar to, but very much less severe than, those in the previous biopsy. A few portal tracts and hepatic vein radicles showed fibrosis with a little lymphocytic infiltrate. Very rare degenerating liver cells were found, but ballooning was again absent. A section stained for reticulin showed a coarsening and patchy matting of the reticulin fibers (fig. 4). Subsequent biopsies (1962 and 1964) were recovered by needle. The first, taken when jaundice was absent, showed no significant abnormality. The last biopsy, taken when jaundice had reappeared, showed cholestasis, accumulation of bile pigment in Kupffer cells, and scattered small pleomorphic inflammatory foci in portal tracts and near the walls of hepatic vein radicles (fig. 5). Reticulin arrangement in both of the latter biopsies was normal (fig. 6). Discussion This patient presents many of the features of idiopathic recurrent cholestasis. 4 In this syndrome, there are numerous attacks of cholestatic jaundice recurring over a number of years. Onset usually occurs before the age of 30 years, and it
Vol. 52, No.3
can present at a very early age. 2 Prodromal symptoms consist mainly of severe pruritus and occasionally of mild anorexia, lethargy, and vomiting for 1 to 2 weeks. There appears to be no constant precipitating factor leading to an attack. Influenza-like illnesses,2 pregnancy,! and dermatographism4 have been associated with the onset of jaundice. The attacks of jaundice usually last from a few months to 2 years. The time between attacks may be from a few months to many years. During attacks, weight loss is often severe and sometimes there is severe steatorrhea. The striking feature of our patient's attacks was the severe pruritus which heralded the onset of the last two episodes. Anorexia was not a marked feature. The onset of the second attack was during the third trimester of pregnancy, but the attack did not remit after delivery. In the third episode, the onset of jaundice was preceded by an influenza-like illness. The attacks of jaundice lasted from 6 to 24 months, and they occurred at intervals of 9 years, and 3 years, 2 months, respectively. In the reported cases, there appears to be almost a complete absence of signs of severe hepatocellular disease. The liver has often been reported as palpable,4, 7 but splenomegaly is absent. Our patient showed spider nevi during the second attack, when she was pregnant, and later when she was being treated with corticosteroids. Investigations usually disclose an elevated serum bilirubin and alkaline phosphatase, with mild to moderate elevation of the serum transaminase from 2 to 6 times normal during an attack of jaundice. The very high serum transaminase levels in our patient would seem to indicate active hepatic damage. These are the highest levels that we have found in this syndrome. However, there did not appear to be residual hepatic damage following this episode, as all parameters of liver function returned to normal. At no stage was there depression of the serum albumin or abnormal elevation of the serum globulins. Exploration of bile ducts has been made in all of the quoted cases, and no evidence of extrahepatic obstruction has been
March 1967
IDIOPATHIC RECURRENT CHOLESTASIS
FIG. 1. First biopsy. Inflammation in portal tracts and hepatic lobules (H & E, X 180). FIG. 2. First biopsy. Wall of vein with inflammatory granulation tissue (H & E, X 180).
539
FIG. 3. First biopsy. Granulation tissue-like proliferation and cellular infiltrate (H & E, X 650). X
FIG. 4. Second biopsy. Region of matted reticular fib ers (reticulin stain, method unstated, 180). 540
March 1967
IDIOPATHIC RECURRENT CHOLESTASIS
FIG. 5. Fourth biopsy. A few neutrophils in the wall of hepatic vein radicle (H & E, X 650). FIG. 6. Fourth biopsy. Normal reticular pattern (Lendrin's stain, X 180).
541
542
Vol. 52, No.3
STATHERS ET AL.
found. Operative cholangiograms, when performed, have been normal. Our patient had two explorations which demonstrated absence of extrahepatic biliary obstruction. When jaundice is present, there is cholestasis mainly in the centrilobular areas, accompanied by infiltration of the portal tracts with round cells. l -s Also described is pleomorphic inflammatory infiltrate of portal tracts and parenchyma. 4 Areas of cell necrosis/' 4-6 usually patchy in distribution, are described. Often these areas were not related to the areas of cholestasis. 4 Increase in fibrous tissue is usually slight and inconstant. 2, 4, 7 Ductular proliferation has been reported in 1 case. 4 Biopsies taken when the attack was subsiding have shown cholestasis with cellular infiltration.4, 7 There are only two previous reports of biopsies taken in complete remission,s, 9 and these showed normal liver. In our patient, a biopsy early in the disease but during remission showed inflammation in venous radicles. Later, during jaundice, the inflammatory changes were slight. Later biopsies, both during an attack and in remission, showed normal architecture. Corticosteroids have been used for therapy with varying success. Prednisone has been reported as being of benefit,2, 4 of uncertain value,7 and, in our patient, of having no effect. Cortisone and adrenocorticotropin in combination were said to clear the jaundice slowly in 1 case. l Recently, cholestyramine was reported to relieve the severe pruritus. 9 This syndrome in our patient, where liver damage appeared to be associated with cholestasis and parenchymal cellular infiltrates, appears to be an atypical recurring form of hepatitis, as previously suggested. 6 This syndrome also appears to be very similar to recurrent jaundice of pregnancy,lO in which jaundice occurs in the last few months of pregnancy and disappears soon after delivery. Liver function tests show obstruction without parenchymal liver damage, and liver biopsies demonstrate accumulation of bile pigment in the bile capillaries. Associated with some of these bile plugs there may be isolated
hepatic cell degeneration. However, in our patient there was no remission after delivery of the baby. The differential diagnosis should include the syndromes described by Dubin and Johnson 11 and Rotor et al. l2 However, pruritus is not a feature in these syndromes, and cholestasis is not seen histologically. In the Dubin-Johnson syndrome, lipochrome pigment is seen characteristically in the liver biopsy. Drug causes of intrahepatic cholestasis should also be searched for,13 In our patient, Cl7- a - alkyl substituted testosterones were not used for the prevention of lactation. Tetracyclines have been reported as causing hepatic injury,13 but in our patient the drug was given after the onset of jaundice in the first two episodes and not at all in the third. Summary
A female had obstructive jaundice at 19 years, with further attacks at intervals of 9 years and 3 years. They were heralded by severe pruritus and lasted from 6 to 24 months. Marked elevation of the serum transaminases occurred. Laparotomy on two occasions showed normal extrahepatic biliary system. Inflammatory changes were found in hepatic venous radicles. Treatment, including corticosteroids, was of no avail, and later biopsy showed the liver to be normal. The syndrome is preferably named "idiopathic recurrent cholestasis," 4 and features in our case suggest an atypical recurring hepatitis. REFERENCES 1. Summerskill, W. H. J., and J. M. Walshe. 1959. Benign recurrent intrahepatic "obstructive" jaundice. Lancet 2: 686-690. 2. Tygstrup, N. 1960. Intermittent possibly familial intrahepatic cholestatic jaundice. Lancet 1: 1171-1172. 3. Tygstrup, N. Quoted by Williams et al. in reference 4. 4. Williams, R., M. A. Cartter, S. Sherlock, P. J. Schever, and R. Hill. 1964. Idiopathic recurrent cholestasis: a study of the functional and pathological lesions in four cases. Quart. J. Med. 33: 387-399. 5. Kuhn, H. A. 1963. Intrahepatic cholestasis in
March 1967
6. 7.
8.
9.
10.
IDIOPATHIC RECURRENT CHOLESTASIS
two brothers. German Med. Monthly 8: 185-188. De Groote, J., P. Goubeau, and J. Vandenbroucke. 1960. Ictere cholostatique recidivant. Acta Gastroent. Belg. 23: 747-755. Schapiro, R. H., and K. J. Isselbacher. 1963. Benign recurrent intrahepatic cholestasis. New Eng. J. Med. 268: 708-711. Summerskill, W. H. J. 1965. The syndrome of benign recurrent cholestasis. Amer. J. Med. 38: 298-305. Spiegel, E. L., W. Schubert, E. Perrin, and L. Schiff. 1965. Benign recurrent intrahepatic cholestasis, with response to cholestyramine. Amer. J. Med. 39: 682-688. Svanborg, A., and S. Ohlsson. 1959. Recur-
543
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