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Ductal plate malformation and congenital hepatic fibrosis
Hepatology Research 35 (2006) 147–150
Case report
Ductal plate malformation and congenital hepatic fibrosis Clinical and histological findings in four patients Olga Giouleme a , Nikolaos Nikolaidis a , Konstantinos Tziomalos a,∗ , Kalliopi Patsiaoura b , Themistoklis Vassiliadis a , Nikolaos Grammatikos a , Vassilios Papanikolaou c , Nikolaos Eugenidis a a
Gastroenterology Section of 2nd Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, 63 Solonos Street, Thessaloniki 54248, Greece b Department of Pathology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece c Organ Transplant Unit, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece Received 7 September 2005; received in revised form 20 November 2005; accepted 8 February 2006 Available online 10 March 2006
Abstract Congenital hepatic fibrosis belongs to the fibrocystic diseases of the liver and represents ductal plate malformation of interlobular bile ducts, along with a destructive cholangiopathy associated with fibrosis. Four patients with congenital hepatic fibrosis are described. Their median age at presentation was 25 years; none of them had a family history of liver or renal disease. Variceal bleeding was the initial manifestation in three patients. All of them required frequent endoscopic variceal ligation sessions and distal splenorenal shunting was also performed in two, almost obviating the need for further variceal ligation. Variceal bleeding did not recur during follow-up. One of these three patients rarely exhibited acute cholangitis; administration of ursodeoxycholic acid resulted in complete remission. In contrast, the fourth patient showed frequent severe episodes of acute cholangitis but normal cholangiographic findings. He underwent liver transplantation but died 2 months later. Laboratory findings disclosed pancytopenia in all patients whereas hepatic synthetic capacity was well preserved. Renal function was unaffected despite the presence of polycystic kidneys in two patients. In summary, congenital hepatic fibrosis can also be diagnosed in older ages, might have strikingly different manifestations and is associated with prominent portal hypertension necessitating aggressive management in order to prevent variceal bleeding. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Congenital hepatic fibrosis; Fibrocystic diseases of the liver; Ductal plate malformation; Distal splenorenal shunting; Endoscopic variceal ligation; Portal hypertension
1. Introduction Fibrocystic diseases of the liver are a group of conditions originating from abnormal persistence or defects in the progressive remodeling of the ductal plate. Ductal plate malformation (DPM) is now considered to be the basic component of these diseases and DPM at different levels of the biliary tree give rise to the wide spectrum of these disorders [1,2]. Congenital hepatic fibrosis (CHF) belongs to this group, is an ∗
Corresponding author. Tel.: +30 2310823487; fax: +30 2310848354. E-mail address: [email protected] (K. Tziomalos).
1386-6346/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.hepres.2006.02.004
autosomal recessive inherited condition and represents DPM of interlobular bile ducts, along with a superimposed destructive type of cholangiopathy (of variable speed and duration) associated with scarring fibrosis [2,3]. We report the clinical and histological findings of four patients who were diagnosed with CHF in our department.
2. Case series Table 1 summarizes the main characteristics of the patients. Their median age at presentation was 25 years; none
148
O. Giouleme et al. / Hepatology Research 35 (2006) 147–150
Table 1 Characteristics of the patients No.
Gender
Age at presentation (years)
Family history of liver or renal disease
Initial manifestation
Magnetic resonance cholangiography
Renal involvement
Follow-up (months)
Remarks
1 2 3
Male Male Female
25 25 25
Negative Negative Negative
Variceal bleeding Variceal bleeding Variceal bleeding
Normal findings Normal findings Normal findings
Polycystic kidneys Polycystic kidneys No
26 70 72
4
Male
44
Negative
Acute cholangitis
Normal findings
No
86
Splenorenal shunting Splenorenal shunting Episodes of acute cholangitis Liver transplantation
of them had a family history of liver or renal disease. Variceal bleeding was the initial manifestation in three patients. All of them required frequent endoscopic variceal ligation (EVL) sessions, approximately every 3 months, in order to obliterate their gastroesophageal varices. Distal splenorenal shunting was performed uneventfully in patients 1 and 2 approximately 8 and 30 months after the diagnosis; the frequency of EVL sessions has fallen significantly after the operation, and was only required once every year. During a follow-up time of 26, 70 and 72 months, respectively, none of these patients experienced variceal bleeding. Patient 3 also exhibited rare episodes of acute cholangitis but hospitalization was never required; ursodeoxycholic acid was administered at a dosage of 15 mg/kg per day and resulted in complete clinical and biochemical remission. Magnetic resonance cholangiography (MRC) was performed in all patients and showed normal findings, thus excluding the coexistence of Caroli’s disease. Patient 4 showed a markedly different clinical course, characterized by frequent severe episodes of acute cholangitis that required prolonged hospitalizations. Both MRC and endoscopic retrograde cholangiography (ERC) were performed and showed normal findings, thus excluding the coexistence of Caroli’s disease. He underwent orthotopic liver transplantation 7 years after the initial presentation and died 2 months later due to hepatic artery thrombosis. He never exhibited variceal bleeding and prophylactic EVL was performed only once. Laboratory findings were within normal limits in all patients, except for thrombocytopenia and mild leukopenia and anaemia, consistent with the presence of portal hypertension-associated hypersplenism; hepatic synthetic capacity was well preserved (Table 2). It is noteworthy that renal function was also unaffected in all patients, despite the presence of polycystic kidneys in two of them (Table 2). Liver biopsy was performed in all patients and similar histological findings were observed in all of them (Figs. 1 and 2). The portal tracts were enlarged due to severe fibrosis which was developed in them; the fibrous tissue was mature and collagenized. The other characteristic feature was the numerous uniform and generally small bile ducts, scattered in the fibrous tissue. Bile duct morphology and arrangement (anastomosing biliary channels) was consistent with the diagnosis of DPM. The ducts were lined by cuboidal to low columnar epithelium and some of them contained bile. Broad fibrous bands encircled single hepatic acini or groups of them. In
Fig. 1. Enlarged portal tract with small bile ducts, some of which are dilated and contain bile. Haematoxylin and eosin, ×200.
Fig. 2. Appearance of ducts which suggests DPM. PAP (Keratin 7), ×200.
immunohistochemical staining, both peripheral and central bile ducts showed strong immunoreactivity for cytokeratin (CK) 7 and CK19 whereas positive staining for CK8 and CK18 was observed in the hepatocytes; we did not use antibodies against CD34 in our immunohistochemical analysis.
3. Discussion Our case series highlights several interesting aspects of CHF; this inherited fibrocystic disease of the liver might be diagnosed in older ages, family history of liver or renal
ALP, alkaline phosphatase; ␥GT, gamma-glutamyltransferase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time prolongation; Hb, haemoglobin; WBC, white blood cells; PLT, platelets.
1.1 1.0 0.8 0.6 0.8–1.2 45 33 30 19 17–43 60000 59000 98000 46000 150000–450000 3000 3500 4500 3200 5200–10500 9.9 11.6 12.6 12.2 14.0–18.0 13.0 13.9 12.6 13.0 12.0–14.0 5.9 8.0 7.1 8.1 3.8–5.1 1.3 0.6 1.2 0.5 0.1–1.1 27 31 86 41 7–33 23 38 55 25 10–34 22 60 92 160 10–49 31 100 198 165 30–125 1 2 3 4 Normal range
␥GT (IU/L) ALP (IU/L) No.
Table 2 Laboratory findings at diagnosis
AST (IU/L)
ALT (IU/L)
Total bilirubin (mg/dL)
Albumin (g/dL)
PT (s)
Hb (g/dL)
WBC (×106 /L)
PLT (×106 /L)
Urea (mg/dL)
Creatinine (mg/dL)
O. Giouleme et al. / Hepatology Research 35 (2006) 147–150
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diseases may be absent, its manifestations can be strikingly different and both hepatic synthetic capacity and renal function are often well preserved. But most importantly, CHF appears to be associated with prominent portal hypertension necessitating aggressive endoscopic and, frequently, surgical management in order to prevent potentially fatal variceal bleeding. Intrahepatic bile ducts develop from primitive hepatocyte precursor cells which ensheath the mesenchyme of the portal vein [2,4]. At around 9–10 weeks of gestation, these precursor cells become smaller and more condensed forming a sleeve around the portal tract. This sleeve-like condensation of hepatocyte precursor cells is known as the ductal plate [4]. During the development of the fetal liver, certain peripheral tubules that have developed in the ductal plates are selected by a process of remodeling to form mature tubular ducts while the redundant ones are deleted [3,5]. This process is regulated by factors influencing epithelial proliferation and apoptosis, by the surrounding mesenchymal tissue, as well as by the portal veins and various adhesion molecules [5–7]. Failure or arrest of this organized epithelial–mesenchymal interaction results in persistence of an excess of embryonic bile ducts in a ductal plate configuration. This abnormality has been termed DPM [2,4,8]. It has been proposed that virtually all congenital diseases of IHBDs represent examples of DPM [2]. Indeed, DPM may affect all levels of the intrahepatic biliary tree; segmental ducts, septal ducts, interlobular ducts and the smaller ducts of the more terminal portal tract ramifications. The DPMs at these different levels of the biliary tree determine the different anatomical–clinical entities known under the designations Caroli’s disease, “infantile polycystic disease” and “adult polycystic disease”. Furthermore, DPM seems to often be associated with a progressive destruction of these immature IHBDs by a non-specific necroinflammatory process, which gives rise to the anatomical–clinical entities known as CHF and Caroli’s syndrome. Finally, the liver lesions are also associated with kidney abnormalities, which may also affect some or all levels of the nephron and which also may be accompanied by slow destruction of the involved tubular segments in a non-specific inflammatory process [1]. Congenital hepatic fibrosis represents DPM of the interlobular bile ducts; the immature bile duct structures are subject to a destructive cholangitis resulting in gradual disappearance of bile duct profiles associated with increasing periportal fibrosis. The rate and duration of this cholangitis are variable in individual patients; in some cases it is rapidly progressive, in others it is slow and torpid and in still other patients it may burn out spontaneously [3]. This hypothesis on the pathogenesis of CHF explains the variability in the time of appearance of clinical symptoms, the cholestatic features observed in some patients and the association of CHF with kidney lesions of autosomal recessive polycystic kidney disease [3]. Congenital hepatic fibrosis does not correspond to a single clinical entity but to a broad, merging spectrum of conditions
150
O. Giouleme et al. / Hepatology Research 35 (2006) 147–150
[3,9]. Different forms of CHF have been recognized; portal hypertensive (which is the most common), cholangitic, mixed and latent CHF [9]. Our case series includes two patients with the portal hypertensive form (patients 1 and 2), one patient with the cholangitic form (patient 4) and one patient with the mixed form (patient 3). The cholangitic and mixed forms may be due to coexisting Caroli’s syndrome, although some authors have reported cases where no macroscopic dilatation of the bile ducts was evident [10]; this was the case in patients 3 and 4 of our report as well. Indeed, all our patients showed normal findings at MRC. Portal hypertension, a very common clinical feature of CHF, has been attributed to the compression of portal vein radicles in the fibrous bands and to an anomaly in the branching pattern of the portal vein, giving rise to hypoplastic and involutive branches [10]. Endoscopic sclerotherapy has been shown to be effective in preventing variceal bleed in patients with CHF [11]. Nowadays, ligation therapy is the gold standard since compared with sclerotherapy reduces rebleeding, bleeding-associated and overall mortality rates, requires fewer sessions to achieve variceal obliteration and is associated with a lower rate of complications [12]. Portal hypertension seems to be particularly prominent in CHF and frequent EVL sessions were required in this case series. Distal splenorenal shunting is both safe and effective for treating patients in whom EVL is inappropriate or has failed and was performed in two of our patients [13–16]. Postoperative encephalopathy is unusual in CHF and was not observed in this case series [9,10]. The prognosis of patients with CHF is universally good in the absence of renal disease; in the adult type of the disease only some 10% of renal tubules are involved [9,10]. Our results seem to strongly support this contention since all our patients had intact renal function. In conclusion, prevention of variceal bleeding with EVL and, if necessary, portosystemic shunting and prompt management of the episodes of acute cholangitis represent the cornerstone of treatment of patients with CHF. Liver transplantation is curative but should be limited only to cases of chronic cholangitis or progressive hepatic dysfunction [9].
References [1] Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”. Hepatology 1992;16:1069–83. [2] Kim WR, Ludwig J, Lindor KD. Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol 2000;95:1130–8. [3] Desmet VJ. What is congenital hepatic fibrosis? Histopathology 1992;20:465–77. [4] Awasthi A, Das A, Srinivasan R, Joshi K. Morphological and immunohistochemical analysis of ductal plate malformation: correlation with fetal liver. Histopathology 2004;45:260–7. [5] Terada T, Nakanuma Y. Detection of apoptosis and expression of apoptosis related proteins during human intrahepatic bile duct development. Am J Pathol 1995;146:67–74. [6] Terada T, Nakanuma Y. Expression of tenascin, type IV collagen and laminin during human intrahepatic bile duct development and in intrahepatic cholangiocarcinoma. Histopathology 1994;25:143–50. [7] Terada T, Ashida K, Kitamura Y, et al. Expression of epithelial cadherin, alpha catenin and beta catenin during human intrahepatic bile duct development: a possible role in bile duct morphogenesis. J Hepatol 1998;28:263–9. [8] Jorgensen MJ. The ductal plate malformation. Acta Pathol Microbiol Scand 1977;257(Suppl.):1–87. [9] D’Agata ID, Jonas MM, Perez-Atayde AR, Guay-Woodford LM. Combined cystic disease of the liver and kidney. Semin Liver Dis 1994;14:215–28. [10] Summerfield JA, Nagafuchi Y, Sherlock S, Cadafalch J, Scheuer PJ. Hepatobiliary fibropolycystic diseases. A clinical and histological review of 51 patients. J Hepatol 1986;2:141–56. [11] Poddar U, Thapa BR, Vashishta RK, Girish CS, Singh K. Congenital hepatic fibrosis in Indian children. J Gastroenterol Hepatol 1999;14:1192–6. [12] Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding: a meta-analysis. Ann Intern Med 1995;123:280–7. [13] Renard TH, Andrews WS, Rollins N, et al. Use of distal splenorenal shunt in children referred for liver transplant evaluation. J Pediatr Surg 1994;29:403–6. [14] Iannitti DA, Henderson JM. The role of surgery in the treatment of portal hypertension. Clin Liver Dis 1997;1:99–114. [15] Shun A, Delaney DP, Martin HC, Henry GM, Stephen M. Portosystemic shunting for paediatric portal hypertension. J Pediatr Surg 1997;32:489–93. [16] Shilyansky J, Roberts EA, Superina RA. Distal splenorenal shunts for the treatment of severe thrombocytopenia from portal hypertension in children. J Gastrointest Surg 1999;3:167–72.
Case report
Ductal plate malformation and congenital hepatic fibrosis Clinical and histological findings in four patients Olga Giouleme a , Nikolaos Nikolaidis a , Konstantinos Tziomalos a,∗ , Kalliopi Patsiaoura b , Themistoklis Vassiliadis a , Nikolaos Grammatikos a , Vassilios Papanikolaou c , Nikolaos Eugenidis a a
Gastroenterology Section of 2nd Propaedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital, 63 Solonos Street, Thessaloniki 54248, Greece b Department of Pathology, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece c Organ Transplant Unit, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece Received 7 September 2005; received in revised form 20 November 2005; accepted 8 February 2006 Available online 10 March 2006
Abstract Congenital hepatic fibrosis belongs to the fibrocystic diseases of the liver and represents ductal plate malformation of interlobular bile ducts, along with a destructive cholangiopathy associated with fibrosis. Four patients with congenital hepatic fibrosis are described. Their median age at presentation was 25 years; none of them had a family history of liver or renal disease. Variceal bleeding was the initial manifestation in three patients. All of them required frequent endoscopic variceal ligation sessions and distal splenorenal shunting was also performed in two, almost obviating the need for further variceal ligation. Variceal bleeding did not recur during follow-up. One of these three patients rarely exhibited acute cholangitis; administration of ursodeoxycholic acid resulted in complete remission. In contrast, the fourth patient showed frequent severe episodes of acute cholangitis but normal cholangiographic findings. He underwent liver transplantation but died 2 months later. Laboratory findings disclosed pancytopenia in all patients whereas hepatic synthetic capacity was well preserved. Renal function was unaffected despite the presence of polycystic kidneys in two patients. In summary, congenital hepatic fibrosis can also be diagnosed in older ages, might have strikingly different manifestations and is associated with prominent portal hypertension necessitating aggressive management in order to prevent variceal bleeding. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Congenital hepatic fibrosis; Fibrocystic diseases of the liver; Ductal plate malformation; Distal splenorenal shunting; Endoscopic variceal ligation; Portal hypertension
1. Introduction Fibrocystic diseases of the liver are a group of conditions originating from abnormal persistence or defects in the progressive remodeling of the ductal plate. Ductal plate malformation (DPM) is now considered to be the basic component of these diseases and DPM at different levels of the biliary tree give rise to the wide spectrum of these disorders [1,2]. Congenital hepatic fibrosis (CHF) belongs to this group, is an ∗
Corresponding author. Tel.: +30 2310823487; fax: +30 2310848354. E-mail address: [email protected] (K. Tziomalos).
1386-6346/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.hepres.2006.02.004
autosomal recessive inherited condition and represents DPM of interlobular bile ducts, along with a superimposed destructive type of cholangiopathy (of variable speed and duration) associated with scarring fibrosis [2,3]. We report the clinical and histological findings of four patients who were diagnosed with CHF in our department.
2. Case series Table 1 summarizes the main characteristics of the patients. Their median age at presentation was 25 years; none
148
O. Giouleme et al. / Hepatology Research 35 (2006) 147–150
Table 1 Characteristics of the patients No.
Gender
Age at presentation (years)
Family history of liver or renal disease
Initial manifestation
Magnetic resonance cholangiography
Renal involvement
Follow-up (months)
Remarks
1 2 3
Male Male Female
25 25 25
Negative Negative Negative
Variceal bleeding Variceal bleeding Variceal bleeding
Normal findings Normal findings Normal findings
Polycystic kidneys Polycystic kidneys No
26 70 72
4
Male
44
Negative
Acute cholangitis
Normal findings
No
86
Splenorenal shunting Splenorenal shunting Episodes of acute cholangitis Liver transplantation
of them had a family history of liver or renal disease. Variceal bleeding was the initial manifestation in three patients. All of them required frequent endoscopic variceal ligation (EVL) sessions, approximately every 3 months, in order to obliterate their gastroesophageal varices. Distal splenorenal shunting was performed uneventfully in patients 1 and 2 approximately 8 and 30 months after the diagnosis; the frequency of EVL sessions has fallen significantly after the operation, and was only required once every year. During a follow-up time of 26, 70 and 72 months, respectively, none of these patients experienced variceal bleeding. Patient 3 also exhibited rare episodes of acute cholangitis but hospitalization was never required; ursodeoxycholic acid was administered at a dosage of 15 mg/kg per day and resulted in complete clinical and biochemical remission. Magnetic resonance cholangiography (MRC) was performed in all patients and showed normal findings, thus excluding the coexistence of Caroli’s disease. Patient 4 showed a markedly different clinical course, characterized by frequent severe episodes of acute cholangitis that required prolonged hospitalizations. Both MRC and endoscopic retrograde cholangiography (ERC) were performed and showed normal findings, thus excluding the coexistence of Caroli’s disease. He underwent orthotopic liver transplantation 7 years after the initial presentation and died 2 months later due to hepatic artery thrombosis. He never exhibited variceal bleeding and prophylactic EVL was performed only once. Laboratory findings were within normal limits in all patients, except for thrombocytopenia and mild leukopenia and anaemia, consistent with the presence of portal hypertension-associated hypersplenism; hepatic synthetic capacity was well preserved (Table 2). It is noteworthy that renal function was also unaffected in all patients, despite the presence of polycystic kidneys in two of them (Table 2). Liver biopsy was performed in all patients and similar histological findings were observed in all of them (Figs. 1 and 2). The portal tracts were enlarged due to severe fibrosis which was developed in them; the fibrous tissue was mature and collagenized. The other characteristic feature was the numerous uniform and generally small bile ducts, scattered in the fibrous tissue. Bile duct morphology and arrangement (anastomosing biliary channels) was consistent with the diagnosis of DPM. The ducts were lined by cuboidal to low columnar epithelium and some of them contained bile. Broad fibrous bands encircled single hepatic acini or groups of them. In
Fig. 1. Enlarged portal tract with small bile ducts, some of which are dilated and contain bile. Haematoxylin and eosin, ×200.
Fig. 2. Appearance of ducts which suggests DPM. PAP (Keratin 7), ×200.
immunohistochemical staining, both peripheral and central bile ducts showed strong immunoreactivity for cytokeratin (CK) 7 and CK19 whereas positive staining for CK8 and CK18 was observed in the hepatocytes; we did not use antibodies against CD34 in our immunohistochemical analysis.
3. Discussion Our case series highlights several interesting aspects of CHF; this inherited fibrocystic disease of the liver might be diagnosed in older ages, family history of liver or renal
ALP, alkaline phosphatase; ␥GT, gamma-glutamyltransferase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time prolongation; Hb, haemoglobin; WBC, white blood cells; PLT, platelets.
1.1 1.0 0.8 0.6 0.8–1.2 45 33 30 19 17–43 60000 59000 98000 46000 150000–450000 3000 3500 4500 3200 5200–10500 9.9 11.6 12.6 12.2 14.0–18.0 13.0 13.9 12.6 13.0 12.0–14.0 5.9 8.0 7.1 8.1 3.8–5.1 1.3 0.6 1.2 0.5 0.1–1.1 27 31 86 41 7–33 23 38 55 25 10–34 22 60 92 160 10–49 31 100 198 165 30–125 1 2 3 4 Normal range
␥GT (IU/L) ALP (IU/L) No.
Table 2 Laboratory findings at diagnosis
AST (IU/L)
ALT (IU/L)
Total bilirubin (mg/dL)
Albumin (g/dL)
PT (s)
Hb (g/dL)
WBC (×106 /L)
PLT (×106 /L)
Urea (mg/dL)
Creatinine (mg/dL)
O. Giouleme et al. / Hepatology Research 35 (2006) 147–150
149
diseases may be absent, its manifestations can be strikingly different and both hepatic synthetic capacity and renal function are often well preserved. But most importantly, CHF appears to be associated with prominent portal hypertension necessitating aggressive endoscopic and, frequently, surgical management in order to prevent potentially fatal variceal bleeding. Intrahepatic bile ducts develop from primitive hepatocyte precursor cells which ensheath the mesenchyme of the portal vein [2,4]. At around 9–10 weeks of gestation, these precursor cells become smaller and more condensed forming a sleeve around the portal tract. This sleeve-like condensation of hepatocyte precursor cells is known as the ductal plate [4]. During the development of the fetal liver, certain peripheral tubules that have developed in the ductal plates are selected by a process of remodeling to form mature tubular ducts while the redundant ones are deleted [3,5]. This process is regulated by factors influencing epithelial proliferation and apoptosis, by the surrounding mesenchymal tissue, as well as by the portal veins and various adhesion molecules [5–7]. Failure or arrest of this organized epithelial–mesenchymal interaction results in persistence of an excess of embryonic bile ducts in a ductal plate configuration. This abnormality has been termed DPM [2,4,8]. It has been proposed that virtually all congenital diseases of IHBDs represent examples of DPM [2]. Indeed, DPM may affect all levels of the intrahepatic biliary tree; segmental ducts, septal ducts, interlobular ducts and the smaller ducts of the more terminal portal tract ramifications. The DPMs at these different levels of the biliary tree determine the different anatomical–clinical entities known under the designations Caroli’s disease, “infantile polycystic disease” and “adult polycystic disease”. Furthermore, DPM seems to often be associated with a progressive destruction of these immature IHBDs by a non-specific necroinflammatory process, which gives rise to the anatomical–clinical entities known as CHF and Caroli’s syndrome. Finally, the liver lesions are also associated with kidney abnormalities, which may also affect some or all levels of the nephron and which also may be accompanied by slow destruction of the involved tubular segments in a non-specific inflammatory process [1]. Congenital hepatic fibrosis represents DPM of the interlobular bile ducts; the immature bile duct structures are subject to a destructive cholangitis resulting in gradual disappearance of bile duct profiles associated with increasing periportal fibrosis. The rate and duration of this cholangitis are variable in individual patients; in some cases it is rapidly progressive, in others it is slow and torpid and in still other patients it may burn out spontaneously [3]. This hypothesis on the pathogenesis of CHF explains the variability in the time of appearance of clinical symptoms, the cholestatic features observed in some patients and the association of CHF with kidney lesions of autosomal recessive polycystic kidney disease [3]. Congenital hepatic fibrosis does not correspond to a single clinical entity but to a broad, merging spectrum of conditions
150
O. Giouleme et al. / Hepatology Research 35 (2006) 147–150
[3,9]. Different forms of CHF have been recognized; portal hypertensive (which is the most common), cholangitic, mixed and latent CHF [9]. Our case series includes two patients with the portal hypertensive form (patients 1 and 2), one patient with the cholangitic form (patient 4) and one patient with the mixed form (patient 3). The cholangitic and mixed forms may be due to coexisting Caroli’s syndrome, although some authors have reported cases where no macroscopic dilatation of the bile ducts was evident [10]; this was the case in patients 3 and 4 of our report as well. Indeed, all our patients showed normal findings at MRC. Portal hypertension, a very common clinical feature of CHF, has been attributed to the compression of portal vein radicles in the fibrous bands and to an anomaly in the branching pattern of the portal vein, giving rise to hypoplastic and involutive branches [10]. Endoscopic sclerotherapy has been shown to be effective in preventing variceal bleed in patients with CHF [11]. Nowadays, ligation therapy is the gold standard since compared with sclerotherapy reduces rebleeding, bleeding-associated and overall mortality rates, requires fewer sessions to achieve variceal obliteration and is associated with a lower rate of complications [12]. Portal hypertension seems to be particularly prominent in CHF and frequent EVL sessions were required in this case series. Distal splenorenal shunting is both safe and effective for treating patients in whom EVL is inappropriate or has failed and was performed in two of our patients [13–16]. Postoperative encephalopathy is unusual in CHF and was not observed in this case series [9,10]. The prognosis of patients with CHF is universally good in the absence of renal disease; in the adult type of the disease only some 10% of renal tubules are involved [9,10]. Our results seem to strongly support this contention since all our patients had intact renal function. In conclusion, prevention of variceal bleeding with EVL and, if necessary, portosystemic shunting and prompt management of the episodes of acute cholangitis represent the cornerstone of treatment of patients with CHF. Liver transplantation is curative but should be limited only to cases of chronic cholangitis or progressive hepatic dysfunction [9].
References [1] Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme “ductal plate malformation”. Hepatology 1992;16:1069–83. [2] Kim WR, Ludwig J, Lindor KD. Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol 2000;95:1130–8. [3] Desmet VJ. What is congenital hepatic fibrosis? Histopathology 1992;20:465–77. [4] Awasthi A, Das A, Srinivasan R, Joshi K. Morphological and immunohistochemical analysis of ductal plate malformation: correlation with fetal liver. Histopathology 2004;45:260–7. [5] Terada T, Nakanuma Y. Detection of apoptosis and expression of apoptosis related proteins during human intrahepatic bile duct development. Am J Pathol 1995;146:67–74. [6] Terada T, Nakanuma Y. Expression of tenascin, type IV collagen and laminin during human intrahepatic bile duct development and in intrahepatic cholangiocarcinoma. Histopathology 1994;25:143–50. [7] Terada T, Ashida K, Kitamura Y, et al. Expression of epithelial cadherin, alpha catenin and beta catenin during human intrahepatic bile duct development: a possible role in bile duct morphogenesis. J Hepatol 1998;28:263–9. [8] Jorgensen MJ. The ductal plate malformation. Acta Pathol Microbiol Scand 1977;257(Suppl.):1–87. [9] D’Agata ID, Jonas MM, Perez-Atayde AR, Guay-Woodford LM. Combined cystic disease of the liver and kidney. Semin Liver Dis 1994;14:215–28. [10] Summerfield JA, Nagafuchi Y, Sherlock S, Cadafalch J, Scheuer PJ. Hepatobiliary fibropolycystic diseases. A clinical and histological review of 51 patients. J Hepatol 1986;2:141–56. [11] Poddar U, Thapa BR, Vashishta RK, Girish CS, Singh K. Congenital hepatic fibrosis in Indian children. J Gastroenterol Hepatol 1999;14:1192–6. [12] Laine L, Cook D. Endoscopic ligation compared with sclerotherapy for treatment of esophageal variceal bleeding: a meta-analysis. Ann Intern Med 1995;123:280–7. [13] Renard TH, Andrews WS, Rollins N, et al. Use of distal splenorenal shunt in children referred for liver transplant evaluation. J Pediatr Surg 1994;29:403–6. [14] Iannitti DA, Henderson JM. The role of surgery in the treatment of portal hypertension. Clin Liver Dis 1997;1:99–114. [15] Shun A, Delaney DP, Martin HC, Henry GM, Stephen M. Portosystemic shunting for paediatric portal hypertension. J Pediatr Surg 1997;32:489–93. [16] Shilyansky J, Roberts EA, Superina RA. Distal splenorenal shunts for the treatment of severe thrombocytopenia from portal hypertension in children. J Gastrointest Surg 1999;3:167–72.