Congenital hepatic fibrosis

222

JounlaloJ'Hepatology. 1988; 6:222-228 Elscvtct

HEP 00396

Congenital hepatic fibrosis M. D e Vos 1, F. B a r b i e r I and C. C u v e l i e r 2 Departments of 1Gastroenterology and "Pathology, Academic Hospttal, UniversiO' of Ghent, Ghent (Belgium) (Received 12 May 1987) (Accepted 11 December 1987)

Summary We report the clinical features of 7 men (mean age 22 years, range 7-53 years) with congenital hepatic fibrosis (CHF). Five patients presented with variceal bleeding and/or hepatosplenomegaly due to portal hypertension Cholangitis was the presenting symptom in the other 2 cases. Diagnosis was established by histological examination of a surgical wedge biopsy (4 patients) or needle biopsy (3 patients). A portal-systemic shunting was performed in 6 patients, three times prophylactically. None of the 5 survivors developed chronic hepatic encephalopathy. Recurrent bouts of cholangitis with septicemia and hepatic abscesses were a major complication in 5 patients with a fatal outcome in 2 cases. Six patients had associated small and large cysts in the cortex of both kidneys, compatible with adult-type polycystic disease. Onepatient developed terminal renal insufficiency. In 3 patients kidney function remained normal at a mean follow-up time~of 7.5 years (range 1-18 years). In 2 families (4 cases) an autosomal dominant inheritance of renal disease was suggested. This study demonstrates that CHF is a rare cause of portal hypertension in late childhood and in adults. Cholangitis is a severe and frequently fatal complication. Association with a variety of congenital renal abnormalities is very frequent. However, the association with adult-type polycystic disease as reported in 4 cases is very rare.

Introduction Congenital hepatic fibrosis (CHF) is an uncommon disease characterized by periportal fibrosis with irregularly shaped proliferating bile ducts. The portal areas are linked by broad bands of connective tissue which divide the parenchyma into irregular islands.

The Iobular architecture is intact. The hepatocytes are normal. Regeneration noduli and inflammatory signs are absent [1] (Fig. 1). In 1981, 200 patients with CHF were reported in the literature, 56% with sporadic and 44% with familial forms [2]. An autosomal recessive mode of inheritance has been postulated.

Correspondence: Martine De Vos, M.D., Department of Gastroenterology, Akademisch Zlekenhuis, University of Ghent, De Pintclaan 185, B-9000Ghent, Belgium. 0168-8278/88/$03.50 © 1988 Elsevier Science Publishers B.V. (B,omedical Division)

CONGENITAL HEPATIC FIBROSIS

Fig. 1. Congenital hepatic fibrosis. The liver parenchyma is intersected by broad bands consisting of mature connectivet:ssue containing cystic bile ducts. There is no necrosis or inflammat:on (haematoxylin-eosin.x 120).

We report 7 cases of CHF with particular emphasis t~n the variable clinical expression and the association with hereditary polycystic kidney disease.

Case reports Case 1 This 13-year-old boy presented in 1967 with bleedmg esophageal varices. Hepatosplenomegaly was palpated. At that time laboratory tests included leukocytes 3000/mm 3 and platelets 70 000/mm 3. Liver and kidney functions were normal. Splenoportography demonstrated a collateral circulation and distorted intrahepatic portal tree. An end-to-side portacaval shunt was performed. Wedge biopsy of the hver showed typical CHF. Postoperatively, cholangitis developed and the patient died in septicemia. An autopsy revealed CHF with purulent cholangitis, dilated intrahepatic bile ducts and sclerosing cholecystitis. Small and large cysts were found in the cortex and medulla of both kidneys. No family data are available.

223 hepatosplenomegaly, ecchymoses, thrombocytopenia and portal hypertension. A portacaval shunt and splenectomy were performed. A surgical wedge biopsy of the liver showed typical CHF. An excretory urogram revealed normal-sized kidneys without evidence of polycystic disease. Seventeen years later the patient is still in good condition and refuses any investigation. His mother (I18), born in 1932, suffered from longstanding arterial hypertension and terminal renal insufficiency. Ultrasonography and CT-scan revealed adult-type polycystic kidney disease and a few small cysts in the left liver lobe. Liver needle biopsy was normal. In 1982 and 1984 a cerebral artery aneurysm ruptured. At that moment, she also developed a severe hemorrhagic pancreatitis. Recent CAT-scan reveals persistent changes in the tail compatible with a polycystic pancreas. In 1984 she was admitted into a chronic ambulant peritoneal dialysis program. Case 3 The younger brother (III3) of patient III t was born in 1962 (Fig. 2). At familial screening an enormous hepatosplenomegaly was palpated. Ultrasonography revealed an enlarged liver with irregular density of echoes. Renal cysts of different sizes were also detected. Very prominent esophageal varices were demonstrated by endoscopy. Laboratory tests in-

1

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Case 2 This 7-year-old boy (lilt) presented in 1965 with

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Fig. 2. Pedigree of family 1.

224 cluded leucocytes 2800/mm 3, platelets 43 000/mm 3 and a slight elevation of aminotransferases. At laparoscopy the liver was hard and covered by fibrous formations. No tumoral mass was seen. Histologic examination of the needle biopsy confirmed the diagnosis of CHF. A prophylactic portacaval shunt was performed. One year later the patient is working normally as a lawyer. Although a high ammonium level persists, no signs of hepatic encephalopathy are present. The second brother of the patient had a normal ultrasonography of liver and kidney. Family 2 Case 4 This man (113), born in 1954, was first admitted in

Fig. 3. ERCP obtained at second admission. Fusiform dilatation of the common bile duct is shown,

M. DE VOS et al 1966 because of bleeding esophageal varices. Hepatosplenomegaly had first been noticed 2 years earlier. All liver tests were normal. A side-to-side portacaval shunt was performed. Wedge liver biopsy revealed CHF. In 1976 a first cholangitis episode recovered spontaneously. Endoscopic retrograde cholangiopancreatography (ERCP) demonstrated a fusiform dilatation of the common bile duct (Fig. 3) and some small intrahepatic cystic lesions communicating with the biliary tree. Two years later an insulin-dependent diabetes developed. In December 1981 recurrent cholangitis was complicated by multiple hepatic abscesses demonstrated by ultrasonography and CT-scan. Adult-type polycystic kidney disease was also noted (Fig. 4). Laboratory investigations showed thrombocytes 21 00(), mm 3, SGOT 1070 IU/I, SGPT 850 IU/I, bilirubin 35. ~) mol/l, alkaline phosphatase 1281 IU/I and albumin 2t) g/l. Upper digestive tract endoscopy showed no varices. Co-trimoxazole, metronidazole and gentamycin were started because of the detection of a culture ol E. coli in liver aspirate. Three weeks later liver test~ were normal but multiple cavities were still present on ultrasonography. Co-trimoxazole was prescribed for 3 months. Within 2 weeks after antibiotics were stopped the patient again became febrile. Over the following 2 years the patient was repeatedly admitted to hospital with similar febrile episodes and E. colt

Fig. 4. CAT-scanning of the upper abdomen showing multiple hepatic abcesses and large medullary cysts in both kidneys

('(}NGENITAL HEPATIC FIBROSIS

225

,cpticemia. He was treated by prolonged courses of co-trimoxazole, gentamycin and amoxicillin. On ultrasonography two cystic lesions persisted in the hver. Severe hypoalbuminemia of 10 g/I resulted from proteinuria up to 5.5 g/24 h. Kidney function deteriorated slowly. In December 1985 the patient was admitted with a ~aew E. coil urosepsis, deterioration of kidney function and severe thrombopenia, and began chronic hemodialysis. ('ase 5 The younger brother (115) of patient 113 was born in I%1 (Fig. 5). In 1968 he presented with hepatosple~omegaly. Liver needle biopsy showed extensive hver fibrosis. In 1981 an enlarged and hard left lobe ~tnd splenomegaly were the only clinical findings. l,aboratory tests showed thrombocytes 97 000/ram 3 ,rod normal liver tests. Ultrasonography, CT-scan ~md selective angiography showed the existence of multiple small liver cysts, signs of portal hypertension and polycystic kidneys with large and small cysts. Because of extensive esophageal varices, an elective distal splenorenal shunt was performed. A wedge liver biopsy revealed CHF. Six months later he was admitted because of cholangitis. Relevant laboratory tests included: serum bilirubin 125.5 tool/I, SGOT 284 1U/l, SGPT 91 IU/1 and alkaline phosphatase 312 IU/1. Blood cultures grew E. coll. Ultrasonography revealed an abscess 3 cm in diameter in the left liver lobe. This was successfully treated with antibiotics, At follow-up examination in 1984 the patient felt well. There was no laboratory evi-

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2

3

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4

5

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7

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Fig. 5. Pedigree of family 2

8

dence of significant hepatic or kidney impairment. No consanguinity is present in the parents of patients 1I3 and 115 (Fig. 5). In this family the adult-type polycystic kidney disease is probably an autosomal dominant trait. On ultrasonography the mother and 5 of her 7 children have the adult-type polycystic disease with small and large cysts in medulla and cortex. CHF, on the other hand, is probably inherited as an autosomal recessive trait with 2 and perhaps 3 of the 7 children affected, Indeed, the sister (I1 a) of patients I13 and 1I5 presents with splenomegaly without hepatomegaly or clinical signs of portal hypertension. Family 3 Case 6 At 21 years of age a transient ~cterus of unknown origin was noted in this young man, who refused further examination. Two years later the patient was admitted because of cholangitis. Hepatosplenomegaly was palpated. E. coil was cultured from the blood and urine. Needle biopsy of the liver revealed CHF with cholangitis. Despite antibiotic treatment cholangitis persisted. During the next 2 months E. coil was repeatedly isolated from the blood. Ultimately the patient died of septicemia. Autopsy confirmed the diagnosis of CHF. Both kidneys were enlarged with small cysts in the cortex. Case 7 His 53-year-old brother resided from 1957 to 1960 in Rwanda. Relapsing febrile episodes with jaundice and shaking chills were treated as malaria. At 53 years of age another episode with high fever and jaundice occurred. Hepatosplenomegaly was palpated, He became stuporous and was admitted to hospital. At that time laboratory resuls were as follows: platelets 95 0C)0/mm3. urea nitrogen 44.4 mmol/l, bilirubin 8.55 mol/l, SGOT 398 IU/l, SGPT 241 IU/I, alkaline phosphatase 744 IU/I and ammonia 52.63 mol/l. Ultrasonography of the abdomen revealed a very enlarged liver of diffuse irregular density and with one hypodense area in the right lobe. Both kidneys were enlarged with several cysts. The patient was treated with ampicillin, gentamycin and

226 metronidazole. Three days later a Sengstaken-Blakemore tube was inserted because of bleeding esophageal varices. Two weeks later the patient was dramatically improved. At that time platelets were 135 000/ mm 3, urea nitrogen 9.1 mmol/l, bilirubin 34.2 mold, SGOT 77 IU/l and SGPT 31 IU/l. A portacaval shunt was performed. Wedge liver biopsy revealed the diagnosis of CHF with cholangitis. The postoperative course was uneventful. CT-scan was normal except for hepatosplenomegaly and small cysts in both kidneys. More than 3 years after the operation he was doing well except for thrombocytopenia. He is working as a medical doctor but refuses any examination. Consanguinity is present in the parents of cases 6 and 7. A sister and a brother are healthy and refused examination. Ultrasonography in another sister showed no liver or kidney abnormalities. The six children of patient 7 refused ultrasonographic examination.

Discussion

The diagnosis of CHF was established in 4 patients by a surgical wedge biopsy and in 3 patients by needle biopsy. Classically affected patients are asymptomatic until the age of 5 or 7 years when portal hypertension or cholangitis leads to the diagnosis. In some patients the disease remains latent until the third or fourth decade, although in some cases symptoms are described in early infancy. In our series the mean age of 22 years at diagnosis is elevated. Several clinical forms are recognized [3] which are dependent on the variable predominance of portal hypertension and cholangitis. Our patients, as well as those described in the literature, illustrate that clinical expression of the disease, or the sequence of the major symptoms, can be different [4,5]. Gastrointestinal bleeding with portal hypertension was the first clinical sign of the disease in cases 1 and 4. Cases 1-5 and 7 had thrombocytopenia consistent with hypersplenism. The cholangitis form of CHF as seen in families 2 and 3 is more severe and usually occurs in late childhood and adult life. Recurrent cholangitis is the presenting symptom in

M. DE VOS et z~l those forms of CHF with cystic dilated intrahepatlc ducts [6] and exceptionally in patients with major dilatation of the extrahepatic bile ducts. Case 4 is a rare example of a fusiform choledochal cyst associated with CHF [7,8]. Cholangitis is precipitated or worsened by instrumentation of the biliary tree such as n~ transparietal, endoscopic or operative cholangiography and cholecystectomy. The cholangitis form ol CHF, however, is difficult to differentiate from Caroli's disease characterized by nonobstructive dilat~tion of intrahepatic bile ducts occurring as an isolated abnormality without portal fibrosis. This suggests z~ spectrum of congenital biliary tree diseases with portal fibrosis and normal-caliber ducts at one end anti multiple intrahepatic, even extrahepatic, dilatation~ without fibrosis at the other end [9]. Overlapping ol CHF and Caroli's disease has been confirmed by histological studies [10,11]. Most cases of CHF have been associated with a w~riety of congenital renal abnormalities, varying in scope from the more radiologic image of medulla tubular ectasia with minimal cortical involvement (childhood-type) to a major form of polycystic kidney disease characterized by both cortical and medullary localization (adult-type). Most reports associate CHF with childhood-type polycystic disease. Blyth and Ockenden [12] divided their patients into four groups called perinatal, neonatal, infantile and juvenile in accordance with the age at clinical presentation. Renal involvement is maximal in the perinatal group and minimal in the juvenile group, the neonatal and perinatal groups being intermediate between the other two. Autosomal recessive inheritance was indicated for each group Apparently some patients with childhood-type polycystic disease may later develop large medullary anti cortical cysts resembling those found in the adulttype [13,14]. Family members seen at different age~ may have lesions of differing appearance [15,16]. In this regard it is almost impossible to assign every patient to a single type of cystic renal disease. Nevertheless some reports document clear evidence for an association between CHF and adult-type polycystie disease. This type can be present in infancy and childhood [1] and is characterized by the late onset of re-

CONGENITAL HEPATIC FIBROSIS hal s y m p t o m s a n d a u t o s o m a l d o m i n a n t inheritance. Only eight reports associate C H F with adult-type of polycystic k i d n e y disease with a u t o s o m a l d o m i n a n t inheritance [1,14,17-22]. A positive family history is [,tcking in over half the cases r e p o r t i n g the association [1,14,17-19]. Families 2 and 3 r e p r e s e n t f u r t h e r evidence for the a~sociation b e t w e e n the a u t o s o m a l d o m i n a n t adulttype polycystic k i d n e y disease a n d the a u t o s o m a l recessive i n h e r i t a n c e of C H F . This emphasizes the genetic complexity of the disease. Portal h y p e r t e n s i o n with u p p e r gastrointestinal Needing mostly occurs in childhood and y o u n g adult hic. The operative mortality of portal-systemic ~hunting in this group of patients is low. T h e fairly good liver function explains the good t o l e r a n c e a n d the low f r e q u e n c y of p o s t - s h u n t i n g e n c e p h a l o p a t h y [5,161. Early s h u n t i n g a n d s p l e n e c t o m y can therefore be

227 proposed in patients with C H F and portal h y p e r t e n sion in o r d e r to p r e v e n t b l e e d i n g and so improve life expectancy [ 1,5,15,23]. In our study an operative s h u n t was p e r f o r m e d in 6 patients, three times prophylactically. In 2 patients a s p l e n e c t o m y was also p e r f o r m e d . O u r report confirms that s h u n t surgery is relatively well tolerated even in adults. N o n e of the 5 survivors d e v e l o p e d manifest chronic e n c e p h a l o p a t h y over the years. H o w e v e r , because e n c e p h a l o p a t h y is an i m p o r t a n t risk factor, a long-term controlled study is necessary to evaluate w h e t h e r early sclerotherapy is an effective alternative in p r e v e n t i n g variceal bleeding. R e c u r r e n t bouts of cholangitis, complicated by hepatic abscesses or septicemia, are a m a j o r complication in a d u l t h o o d , with a fatal e v o l u t i o n in two of o u r cases. In patients with C H F complicated by rec u r r e n t u n c o n t r o l l e d cholangitis, liver t r a n s p l a n t a tion should be considered.

References

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