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Kasuistik 977

Excessive Bilirubin Elevation in a Patient with


Hereditary Spherocytosis and Intrahepatic Cholestasis
Ausgeprägte Bilirubinerhöhung eines Patienten mit hereditärer Sphärozytose
und intrahepatischer Cholestase

Authors A. Wree1, A. Canbay1, H. Müller-Beißenhirtz2, A. Dechêne1, G. Gerken1, U. Dührsen2, F. Lammert3, H. Nückel2

1
Affiliations Dept. Gastroenterology and Hepatology, University Hospital Essen
2
Department of Hermatology, University Hospital Duisburg-Essen
3
Department of Medicine II, Saarland University Hospital, Homburg

Schlüsselwörter Zusammenfassung Abstract



▶ hereditäre Sphärozytose
! !

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▶ benigne rekurrierende intra-
Mit einer Inzidenz von 1 Fall auf 2500 Geburten Hereditary spherocytosis is a common hemoly-
hepatische Cholestase
ist die hereditäre Sphärozytose eine der häufigs- tic anemia with an estimated incidence of 1/

▶ ABCB11

▶ Gallensalz-Exporter-Pumpe ten hämolytischen Anämien, sie wird durch De- 2500 births. It is caused by a molecular defect

▶ BSEP fekte des Zystoskeletts von Erythrozyten verur- in one or more of the proteins of the red blood
sacht. Mutationen in Gallensäuretransportern cell cytoskeleton. Mutations in the ABCB11
Key words
und dem kodierenden ABCB11-Gen können zur gene, encoding the bile salt export pump, can

▶ hereditary spherocytosis


▶ benign recurrent intrahepatic
progressiven familiären intrahepatischen Chole- entail progressive familial intrahepatic cholesta-
cholestasis stase oder benignen rekurrierenden intrahepa- sis and benign recurred intrahepatic cholestasis.

▶ ABCB11 tischen Cholestase führen. Ein 18-jähriger türki- A 18 year old Turkish patient with hereditary

▶ bile salt export pump scher Patient wurde bei Juckreiz und ausge- spherocytosis was admitted to hospital with

▶ BSEP
prägtem Ikterus ins Krankenhaus eingewiesen. pruritus and severe jaundice. Ultrasound exam-
In der Sonografie des Abdomens zeigten sich ination presented stones in gallbladder and bile
Konkremente in der Gallenblase und im -gang. duct. After endoscopic retrograde cholangiogra-
Nach endoskopischer retrograder Cholangiogra- phy with extraction of small bile duct stones
fie mit Extraktion der Konkremente besserten abdominal pain resolved and liver enzymes nor-
sich die Oberbauchschmerzen und normalisier- malized within a few days, but bilirubin and
ten sich die Leberwerte zügig, jedoch blieben bile acids remained highly elevated. Liver biop-
Bilirubin und die Gallensäuren im Serum wei- sy revealed a severe canalicular cholestasis. Ge-
terhin deutlich erhöht. In einer Leberbiopsie netic analysis showed the compound heterozy-
wurde eine schwere intrahepatische Cholestase gous variants ABCB11 A 444V and 3084A > G.
diagnostiziert. Die genetische Analyse der Gal- Treatment with ursodesoxycholic acid and in-
received 16.11.2010 lensäuretransporter zeigten einen compound- termittent therapy with prednisone reduced
accepted 6.4.2011 heterozygoten Variationsstatus im ABCB11-Gen pruritus and jaundice with concomitant im-
(A444V und 3084A > G). Durch eine Therapie provement of blood test. Here we report the
Bibliography
mit Ursodesoxycholsäure und die intermittier- first case of a patient with combined hereditary
DOI http://dx.doi.org/10.1055/
s-0031-1273368 ender Gabe von Prednison konnten die Besch- spherocytosis and compound heterozygous
Z Gastroenterol 2011; 49: werden und die Laborparameter des Patienten ABCB11 gene variants predisposing to intrahe-
977 – 980 © Georg Thieme deutlich verbessert werden. Dies ist der erste patic cholestasis. Therefore, patients with he-
Verlag KG Stuttgart ∙ New York ∙ Fallbericht eines Patienten mit hereditärer molytic disorders should be investigated for
ISSN 0044-2771 Sphärozytose und Varianten im ABCB11-Gen, bile acid transporter diseases in case of hyper-
Correspondence die eine intrahepatische Cholestase begünsti- bilirubinemia and severe cholestasis.
Prof. Dr. Ali Canbay gen. Es sollten folglich Patienten mit hämolyti-
Clinic for Gastroenterology and schen Erkrankungen, erhöhten Bilirubinwerten
Hepatology, University Hospital und fortgeschrittener Cholestase auf entspre-
Essen chende Varianten und Mutationen untersucht
Hufelandstraße 55
werden.
45130 Essen
Germany
Tel.: ++ 49/2 01/72 38 47 13
Fax: ++ 49/2 01/7 23 57 19
ali.canbay@uni-due.de

Wree A, Canbay A. Excessive Bilirubin Elevation… Z Gastroenterol 2011; 49: 977 – 980
978 Kasuistik

Fig. 1 18 year old Turkish patient with severe


jaundice, total bilirubin 37,3 mg/dl (normal range
0,3 – 1,2 mg/dl) A; endoscopic retrograde cholan-
giograhy with multiple stones in gallblader and
common bile duct (black arrow) B; endoscopic view
of major papilla with bilirubin stone (white arrow) C.

Introduction Blood analysis identified highly elevated total bilirubin (37.3 mg/
! dl; norm 0.3 – 1.2 mg/dl) with a direct bilirubin fraction of
Deficient bile secretion without anatomic obstruction can be 18 mg/dl, increased bile acids (200 µmol/l; norm < 6 µmol/l), ele-
caused by a group of several clinically and genetically hetero- vated liver enzymes (AST 131 U/l, norm 0 – 35 U/l; ALT 256 U/l,
geneous hereditary disorders, known as familial intrahepatic norm < 40 U/l; AP 173 U/l, norm 25 – 124 U/l; GLDH 46,4 U/l,
cholestasis syndromes [1]. The human bile salt export pump norm < 7 U/l), mild anemia (hemoglobin 10.3 g/dl), elevated reti-
(BSEP) is situated exclusively in the canalicular membrane of culocytes (17.44%, norm 0.4 – 1.6%) and reduced haptoglobin
hepatocytes. Mutations in the ABCB11 gene, encoding BSEP, (< 0.06 g/dl). However, LDH was only slightly abnormal (378 U/l)
have been linked to progressive familial intrahepatic cholesta- arguing against a hemolytic crisis in hereditary spherocytosis.
sis (PFIC), leading to severe progressive liver disease and be- Extented serological tests for liver disease produced negative

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nign recurrent intrahepatic cholestasis (BRIC) with intermit- results for autoimmune hepatitis (ANA, c-ANCA, p-ANCA,
tent attacks of cholestasis but no permanent liver damage [2, LKM1-antibody, SLA, AMA-M2-antibody), viral hepatitis (HAV,
3]. HBV, and HCV), adenovirus and Ebstein-Barr-Virus. Parvovirus
Hereditary spherocytosis (HS) is a common hemolytic anemia B 19 IgM was negative and IgG positive. Human leukocyte an-
with an estimated incidence of 1 /2500 births. It is caused by a tigen typing was not suspicious (HLA-A 03, 30; HLA-B 13, 51;
variety of molecular defects in genes that code for erythrocyte HLA-DRB1 07, 14; HLA-DQB1 02, 05).
membrane and cell cytoskeleton proteins [4]. In HS the ery- Ultrasound examination revealed splenomegaly (200 × 100 mm)
throcytes are degraded in the spleen, leading to varying de- as well as several stones in the gallbladder and the common
grees of anemia and hyperbilirubinemia, which in turn result bile duct. Ascites was absent. Endoscopic retrograde cholangio-
in symptoms of fatigue, pallor and jaundice. Chronic symptoms graphy identified several small bile duct stones (● ▶ Fig. 1). After

of HS include anemia, splenomegaly and often pigmented bili- extraction of the bile duct stones abdominal pain resolved and
rubin gallstones. liver enzymes normalized within a few days. Bilirubin and bile
In hemolytic disorders impaired bile secretion can lead to ex- acids remained markedly elevated (total bilirubin 70 mg/dl; di-
cessive accumulation of bile constituents, which may be diffi- rect bilirubin 44.5 mg/dl; bile acids 196 µmol/l) (● ▶ Fig. 2). To

cult to distinguish from a hemolytic crisis. Here we describe a distinguish between different causes of intrahepatic cholestasis
young male with known hereditary spherocytosis and severe a liver biopsy was performed, which revealed severe hepatic
jaundice. and mild canalicular cholestasis (●▶ Fig. 3).

Genetic analysis for intrahepatic cholestasis included common


mutations of the hepatocanalicular bile acid transporter
Case Report (ABCB11), the hepatic bile salt sensor (nuclear receptor FXR),
! the hepatocanalicular phosphatidylcholine transporter (ABCB4)
A 18 year old Turkish patient, suffering from intense pain in as well as UDP glucuronyl transferase (UGT1A1) and identified
the upper abdomen and jaundice over 72 hours, was admitted heterozygosity for the ABCB11 variants 1331C > T (A444V) and
to the emergency room. Milder self-limiting courses of jaun- 3084A > G (A1082A, splice variant).
dice occurred several times in his childhood. Hereditary spher- The patient was initially treated with ursodesoxycholic acid
ocytosis was diagnosed at the age of 10 with mild course. Five (500 mg three times per day) and prednisone (starting dose:
months before admittance to our hospital he had an aplastic 1 mg/kg body weight). Symptoms improved and abnormal la-
crisis based on a parvovirus B 19 infection with severe anemia. boratory parameters started to normalize. Prednisone therapy
At that time he was treated in the intensive care unit and re- was reduced weekly and stopped on day 28 at bilirubin of
ceived several packed red blood cells. 17.7 mg/dl and next to normal liver values (AST 56 U/l, ALT
The patient did not suffer from prolonged icterus neonatorum. 59 U/l). Six months later, the patient was free of symptoms
In his family recurrent jaundice was not present and his mo- and showed further improvement of laboratory results (biliru-
ther had no history of cholestasis in pregnancy. bin 6.6 mg/dl and normal serum transaminases).
Clinical investigation at presentation showed a young man
with severe jaundice (● ▶ Fig. 1) and splenomegaly, moaning

about strong pain in the upper right abdomen. He did not Discussion
show signs of muscular defense or ileus and had normal bowel !
sound. Urine color was dark brown and stool was loose and With an incidence of 200 to 300 per million in northern Eu-
discolored. ropean populations, hereditary spherocytosis is a common he-
molytic disease. In the case of severe HS, unconjugated biliru-

Wree A, Canbay A. Excessive Bilirubin Elevation… Z Gastroenterol 2011; 49: 977 – 980
Kasuistik 979

normal liver function [5]. In patients with mild hepatic disease


hemolysis can lead to severe hyperbilirubinemia and accumu-
lation of a disproportionate amount of conjugated bilirubin.
Benign recurrent intrahepatic cholestasis (BRIC) was first de-
scribed in 1959 [6]. Clinical presentation normally begins in
adolescence or early adulthood with recurrent episodes of
conjugated hyperbilirubinemia associated with malaise, anor-
exia, pruritus, weight loss, and malabsorption. Laboratory tests
reveal biochemical evidence of cholestasis without severe he-
patocellular injury [7]. Episodes with clinical manifestation
last for weeks to months followed by a complete clinical, bio-
chemical, and histologic normalization in patients. Liver histol-
ogy reveals, like in our patient, non-inflammatory intrahepatic
cholestasis without fibrosis, regardless of the number and se-
verity of attacks [8].
The “classical” form of BRIC results from mutations of the famil-
ial intrahepatic cholestasis (ATP8B1) gene. More recent studies
identified that ABCB11 mutations can also cause a BRIC pheno-
type, termed BRIC type 2 [3]. As an example, a patient with
clinical features of BRIC was found to carry the two different
mutations 556A > G and 1331C > T, and compound heterozygos-
ity led to the absence of BSEP in bile canaliculi of hepatocytes

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[9]. In our case, we identified two ABCB11 variants that are
known to predispose to intrahepatic cholestasis [10 – 13]. The
1331C > T variant is localized in exon 13 and leads to substitu-
tion of valine by alanine as well as decreased levels of mature
BSEP protein [11 – 13]. It is one of the most common poly-
morphisms with a prevalence of 43 to 60%. In addition, we de-
tected another common nucleotide change (3084A > G) that is
Fig. 2 Development of liver enzymes A and hemoglobin, reticulocyte, to- localized in exon 24 and causes severe exon skipping [10].
tal bilirubin level B after endoscopic retrograde cholangiograhy (ERC) and Treatment of most hepatocanalicular transporter diseases still
initiation of ursodesoxycholic acid (UDCA) (3 × 500 mg/day) and intermit- represents a clinical and scientific challenge. Current evidence
tent prednisone (1 mg/kg body weight/day) therapy (AST, aspartat amino- indicates that ursodesoxycholic acid (UDCA) can be effective in
transferase; ALT, alanine aminotransferase; GGT, gamma glytamyl trans-
selected patients with progressive familial intrahepatic choles-
ferase; ERC, endoscopic retrograde cholangiography, UDCA,
tasis typ 3 (PFIC3), while rifampicin reduces pruritus in pa-
ursodeoxycholic acid).
tients with PFIC1 (ATP8B1 deficiency) and PFIC2 (ABCB11 defi-
ciency), and might abort cholestatic episodes in BRIC (mild
ATP8B1 or ABCB11 deficiency). Most patients with PFIC1 and
PFIC2 and some patients with BRIC showed benefits after inva-
sive therapy such as nasobiliary drainage, extracorporal albu-
min dialysis or biliary diversion [14]. Targeting nuclear recep-
tors, enhancing the stability of the mutated transporter
protein by employing chaperones, or by mutation specific
therapy are promising new approaches in the treatment of ca-
nalicular transport defects [14].
As gallstones have been linked to both, HS and BRIC, operative
treatment including cholecystectomy and splenectomy was
discussed for our patient, but due to the rare episodes of he-
molytic crisis not considered appropriate.
Here, we report the first case of a patient with combined he-
reditary spherocytosis and intrahepatic cholestasis associated
with compound heterozygous ABCB11 gene variants. There-
Fig. 3 Diagnostic work-up. fore, patients with haemolytic disorders and severe cholestasis
should be investigated for bile acid transporter diseases.

bin production can increase up to 10-fold. The canalicular ex- Abbreviations


cretion of bilirubin is rate-limiting since hepatic conjugating !
capacity normally exceeds maximum bilirubin production. Bi- BRIC, benign recurrent intrahepatic cholestasis
lirubin concentration will therefore not exceed 4 mg/dl and BSEP, bile salt export pump
the proportion of conjugated bilirubin in plasma (approxi- PFIC, progressive familial intrahepatic cholestasis
mately 3 to 5 % of the total) remains normal in patients with UDCA, ursodeoxycholic acid

Wree A, Canbay A. Excessive Bilirubin Elevation… Z Gastroenterol 2011; 49: 977 – 980
980 Kasuistik

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Wree A, Canbay A. Excessive Bilirubin Elevation… Z Gastroenterol 2011; 49: 977 – 980