Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum

Journal of Hepatology 36 (2002) 439–443 www.elsevier.com/locate/jhep

Case report

Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum Nancy A.M. van Ooteghem 1,*, Leo W.J. Klomp 2,3, Gerard P. van Berge-Henegouwen 1, Roderick H.J. Houwen 2 1

Department of Gastroenterology, Gastrointestinal Research Unit, University Medical Center, PO Box 85500, 3508 Utrecht GA, The Netherlands 2 Department of Pediatric Gastroenterology, University Medical Center, PO Box 85500, 3508 Utrecht GA, The Netherlands 3 Department of Metabolic Diseases, University Medical Center, PO Box 85500, 3508 Utrecht GA, The Netherlands

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease, characterised by intermittent attacks of cholestasis, which can start at any age and last for several weeks to months. Characteristically serum GGT activity is low and normal liver structure is preserved. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease, characterised by severe cholestasis, starting almost invariably before 6 months of age. All patients progress to cirrhosis, liver failure and death, unless a liver transplantation is performed. We now identified four patients who presented in childhood with recurrent attacks of cholestasis, while in the course of the disease the cholestasis gradually became permanent. Although liver biopsies performed in the early stages of the disease showed normal liver architecture, late stage biopsies revealed evident fibrosis with porto-portal septa formation. In conclusion, the disease of these patients started with the clinical and histopathological characteristics of BRIC but progressed to PFIC. q 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved. Keywords: Autosomal recessive; Benign recurrent intrahepatic cholestasis; Cholestasis; Progressive familial intrahepatic cholestasis; Progression

1. Introduction BRIC, an autosomal recessively inherited liver disease, is characterised by intermittent attacks of cholestasis. It was first described in 1959 by Summerskill and Walshe [1]. The bouts of cholestasis in benign recurrent intrahepatic cholestasis (BRIC) can start at any age (usually before the second decade) and attacks can last for several weeks to months [2– 5]. During an attack serum bile salt concentrations and bilirubin values are elevated but gamma glutamyl transpeptidase (GGT) and cholesterol values remain in the normal range. During symptom-free intervals, lasting several months to Received 22 June 2001; received in revised form 8 November 2001; accepted 23 November 2001 * Corresponding author. Tel.: 131-30-250-7004; fax: 131-30-250-5533. E-mail address: [email protected] (N.A.M. van Ooteghem). Abbreviations: BRIC, benign recurrent intrahepatic cholestasis; GGT, gamma glutamyl transpeptidase; PFIC, progressive familial intrahepatic cholestasis.

years, serum biochemistry is normal. Liver biopsies are characterised histologically by intrahepatic cholestasis with preservation of normal liver structure. There is no progression to liver cirrhosis. Mutations in a single gene, FIC1 (recently renamed ATP8B1) were found to be responsible for this disease in most families described to date [6– 8], although genetic heterogeneity is present [9,10]. PFIC is another autosomal recessive liver disease, which is characterised by unremitting cholestasis that starts almost invariably before the age of 1 year and progresses to cirrhosis and liver failure [11]. Two clinically indistinguishable subtypes with a normal serum GGT activity are recognised: PFIC1, which is caused by mutations in the ATP8B1 gene [6,8,12], and PFIC2, which is caused by mutations in the ABCB11 gene (formerly called BSEP) [13]. In both subtypes cholestasis starts early and patients suffer from severe pruritis and, due to conjugated hyperbilirubinaemia, from jaundice [14–17]. Liver biopsies show severe choles-

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tasis with fibrosis and eventually cirrhosis [18–21]. Death due to hepatic failure occurs in the first or second decade unless a liver transplantation is performed [15,22–24]. In contrast to these two PFIC subtypes, MDR3 deficiency, sometimes referred to as PFIC3, is characterised by a markedly elevated serum GGT activity [25]. It is customary to see low GGT, PFIC and BRIC as sharply delineated entities (progressive versus remitting). However, some patients from the original Byler kindred, which we now know to have mutations in the ATP8B1 gene, had intermittent cholestasis in the first few years of life, before they developed progressive liver disease. Here we report four patients with classical BRIC (attacks of cholestasis and no liver damage) in the first decades of life, who developed permanent liver damage subsequently. 2. Methods During our FIC1 cloning project [6,9,26,27] we included a total of 63 patients with BRIC. This clinical diagnosis was made in any patient with at least two attacks of cholestasis, a normal anatomy of the biliary tree, and a normal serum GGT activity. In four patients in this group, all described in detail later in this section, we noticed progression of the disease (Table 1). In these four patients no evidence for autoimmune disease was present, virological studies were negative and serum alpha-1-antitrypsin concentrations were normal.

3. Case reports Case 1 is a man born in 1973. He had his first episode of cholestasis at the age of 15 months, when he presented with jaundice, acholic stools and scratching effects. Cholestyramine therapy (1.5 g four times a day) was started. This episode lasted for several weeks. He had similar attacks of cholestasis when he was 4 and 11 years old. At the age of 16 years relapses became more frequent, for which changing the cholestyramine treatment to ursodeoxycholic acid seemed to have no effect. At that time a liver biopsy showed preserved liver architecture with intrahepatic cholestasis and some inflammation of the portal tracts. However, since age 21 bile salt levels remained elevated, causing severe itching. A combination of simvastatin, ursodeoxycholic acid and cholestyramine gave only little relief of these symptoms. A subsequent liver biopsy showed intrahepatic cholestasis and fibrosis in the portal tracts with the

beginning of porto-portal bridging. In this patient DNA analysis of the ATP8B1 gene showed the same splice site mutation on both chromosomes, resulting in skipping of exon 24. This mutation is not found in any other BRIC or PFIC1 patient (LWJ Klomp et al. in preparation). Case 2, a female, was born in 1967. She presented with itching at the age of 6 months and subsequently developed jaundice. Laboratory investigations revealed cholestasis with a normal serum GGT activity. A liver biopsy showed intrahepatic cholestasis without any other abnormalities. Therapy with cholestyramine was started and after 2 months the icterus subsided. At the age of 2 years, after discontinuation of cholestyramine therapy, another attack of cholestasis started. A laparotomy was performed and a drain was left in the common bile duct to ensure optimal bile flow. Jaundice and itching vanished shortly after this procedure. Because its function was thought to be disputable, the drain was removed after 6 weeks. Subsequently the cholestasis remitted. As the bile drainage seemed to have reduced the cholestasis, it was decided to perform ileal bypass surgery. After this intervention the patient had three other short attacks (weeks) in almost 20 years. However in 1989 the effect of the jejuno-transversostomy was questioned and it was decided to reverse it. A total of 4 months after this operation she became permanently cholestatic. Simvastatin was added to the cholestyramine therapy, but liver biochemistry failed to return to normal. In 1994 a liver biopsy was performed which showed intra-acinar cholestasis and portal fibrosis, but otherwise preservation of normal liver architecture. In 1996 her symptoms of itching and fatigue compromised her daily functioning so severely that a liver transplantation was done. She stayed symptom-free since then, without any signs of cholestasis. Case 3 is a man born in 1962. He had his first episode of cholestatis when he was 14 months of age, and subsequent attacks every 3–5 years. A liver biopsy at age 11 showed mild cholestasis and a normal liver structure, without fibrosis. Serum GGT activity always was in the normal range, so the diagnosis of BRIC was made. Cholestyramine seemed to have some effect on the itching during attacks, but did not prevent recurrence. Since the age of 30 years the attacks seemed to appear more frequent and at the age of 35 years the cholestasis became permanent, with elevated serum bilirubin (approximately 80 mmol/l). A percutaneous liver biopsy was performed that showed a preserved liver archi-

Table 1 Four patients starting with BRIC, progressing to permanent cholestasis and liver damage Patients

First cholestatic attack at

Permanent cholestasis

First liver biopsy in early stage (age)

Liver biopsy in late stage (age)

1 2 3

15 months 6 months 14 months

Third decade Third decade Fourth decade

Characteristic for BRIC (16 years) Normal liver structure (1/2 year) Normal liver structure, no fibrosis (11 years)

4

6 months

Second decade

Normal liver structure, no fibrosis (1/2 year)

Porto-portal fibrotic septa (22 years) Intra-acinar cholestasis, porto-portal fibrosis (27 years) Preserved liver structure with steatosis and the beginning of formation of porto-portal septa (35 years) Canalicular cholestasis, severe fibrosis (10 years)

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tecture with some steatosis and normal portal bile duct count, but with formation of porto-portal fibrous septa. Simvastatin, ursodeoxycholic acid and rifampicin were temporarily added to the medication, but without much effect. Case 4, female, and a distant relative of patient 1, was born in 1988. Her first cholestatic episode started at the age of 6 months. At that time a liver biopsy showed intrahepatic cholestasis, but a preserved liver architecture. Therapy with cholestyramine was started and the icterus subsided. Her second attack of icterus and itching started when she was 3 years old. Despite cholestyramine and simvastatine therapy the patient remained cholestatic for almost 2 years. The attack only subsided 1 week after starting therapy with rifampicin. Despite the permanent use of simvastatin, she developed her next attack of cholestasis when she was 8 years old. This time, adding cholestyramine and rifampicin to her medication had no sufficient effect on the cholestasis. When this attack lasted for 1.5 years, a partial biliary diversion, using the appendix, was performed. A liver biopsy obtained in the same session showed canalicular cholestasis and severe fibrosis. As the partial diversion did not result in sufficient bile flow, subsequently a total biliary diversion was done, and within 2 days the cholestasis disappeared completely. However, 2 years after the diversion procedure a new cholestatic attack ensued. Again simvastatin and rifampicin were started, after which the pruritis gradually subsided. In this patient the DNA analysis of the ATP8B1 gene showed the same splice site mutation on both chromosomes, resulting in skipping of exon 24 (LWJ Klomp et al. in preparation).

4. Discussion Here we describe four patients who presented with typical BRIC: attacks of cholestasis, low GGT activity, no obstruction of extrahepatic bile ducts and initially no signs of liver damage. Nevertheless, these patients subsequently developed permanent cholestasis and porto-portal fibrosis (Table 1). These latter clinical and histopathological features are generally considered diagnostic for PFIC rather than BRIC. Although some patients have been described previously with intermittent cholestasis that subsequently progressed (notably some patients from the original Byler kindred), these patients all developed permanent cholestasis within the first years of life [19,20,23,28–30]. We now show that some patients with intermittent cholestasis can develop progressive liver disease even after several decades. However, this does not imply that all patients with BRIC will show progression. Until now in our population of 63 BRIC patients only four developed permanent cholestasis. In addition numerous additional patients have been described, who, after a long life with numerous attacks, still were totally free of symptoms in between attacks,

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both clinically, biochemically and histopathologically [2,7,31–34]. The genetic background of BRIC and PFIC1 seemed to be solved when the gene mutated in these disorders, ATP8B1, at chromosome 18q21, was cloned [6]. However in some patients with recurrent attacks of cholestasis, a low serum GGT activity and no anatomical obstruction (i.e. BRIC) the disease is clearly not linked to 18q21 [9,10], indicating that mutations in at least one other gene can cause the BRIC phenotype. In the current patients a mutation in the ATP8B1 gene was only found in two out of the four patients. Either an ATP8B1 mutation remained undetected in the other two, or in these patients the disease is unlinked to chromosome 18q21. Further studies are underway to test this possibility. Effective medical intervention to interrupt the cholestatic attacks in BRIC is not available to date. Several treatment modalities have been described, such as cholestyramine [35], ursodeoxycholic acid [36,37] and rifampicin [38– 40]. Simvastatin was used in some of our patients as this reduces the synthesis of cholesterol ‘the precursor for bile acid synthesis’ and thus might lower serum bile acid levels. However this intervention did not have a consistent effect on preventing or terminating cholestatic attacks in our patients, nor did cholestyramine or ursodeoxycholic acid. In contrast, rifampicin completely stopped a cholestatic episode in one of our patients (case 4) on two separate occasions, although it failed to do so in patient 3. Rifampicin also has been effective in interrupting attacks in four other patients with low GGT recurrent cholestasis [38,40]. As rifampicin promotes the elimination of bile salts by inducing the 6hydroxylation of secondary bile salts, this intervention warrants further investigation [41]. In patients with PFIC a partial biliary diversion [42,43] or an ileal bypass [44], might have a beneficial effect on the course of the disease, especially in patients without established cirrhosis. In two of our patients a similar effect was observed. In case 4 a total biliary diversion reverted a longlasting cholestatic episode within days, while ileal bypass surgery stopped an attack in case 2. Although subsequently short and transient episodes of cholestasis did occur, these patients further remained free of cholestasis. Interestingly, reversing the ileal bypass in case 2 resulted in the development of permanent cholestasis, for which ultimately a liver transplantation was needed. Although careful analysis of more patients will be necessary before firm conclusions can be drawn, we suggest that diversion surgery might be considered in some patients with recurrent low GGT cholestasis, e.g. when exhibiting frequent debilitating attacks, or when progressing to permanent cholestasis. Historically BRIC and low GGT PFIC were considered to be separate entities clinically, with BRIC being characterised by recurrent attacks of cholestasis without the development of permanent liver damage, and PFIC characterised by permanent cholestasis. Our current data now support the hypothesis that these entities are part of a clinical conti-

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nuum. Progression, although a rare event, can develop at any age, both early and later on in life.

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