Focal Biliary Cirrhosis Research Articles

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Chinese experts consensus statement: diagnosis and treatment of cystic fibrosis (2023)

Cystic fibrosis related liver disease and endocrine considerations

Cystic fibrosis-liver disease (CFLD) is one of the most common non-pulmonary complications in the CF population, is associated with significant morbidity and represents the third leading cause of mortality in those with CF. CFLD encompasses a broad spectrum of hepatobiliary manifestations ranging from mild transaminitis, biliary disease, hepatic steatosis, focal biliary cirrhosis and multilobular biliary cirrhosis. The diagnosis of CFLD and prediction of disease progression remains a clinical challenge. The identification of novel CFLD biomarkers as well as the role of newer imaging techniques such as elastography to allow for early detection and intervention are active areas of research focus. Biliary cirrhosis with portal hypertension represents the most severe spectrum of CFLD, almost exclusively develops in the pediatric population, and is associated with a decline in pulmonary function, poor nutritional status, and greater risk of hospitalization. Furthermore, those with CFLD are at increased risk for vitamin deficiencies and endocrinopathies including CF-related diabetes, CF-related bone disease and hypogonadism, which can have further implications on disease outcomes and management. Effective treatment for CFLD remains limited and current interventions focus on optimization of nutritional status, identification and treatment of comorbid conditions, as well as early detection and management of CFLD specific sequelae such as portal hypertension or variceal bleeding. The extent to which highly effective modulator therapies may prevent the development or modify the progression of CFLD remains an active area of research. In this review, we discuss the challenges with defining and evaluating CFLD and the endocrine considerations and current management of CFLD.

Experimental Model of Cirrhosis of the Liver.

A new model of cirrhosis of the liver was created in experiment on 30 rats. Over 3 weeks, experimental animals in addition to the standard diet daily intragastrically received corn oil in combination with intragastric administration of acetaminophen in a dose of 500 mg/day. High-fat load in combination with acetaminophen over 3 weeks led to the development of focal biliary cirrhosis.

A135 HEPATOLITHIASIS AND CHOLANGIOPATHY IN PEDIATRIC CYSTIC FIBROSIS: A CASE REPORT

Abstract Background Liver disease has emerged as an important cause of cystic fibrosis (CF)-associated morbidity due to recent advancements in management and a resultant increase in life expectancy. Although focal biliary cirrhosis remains the pathognomonic finding in CF, other hepatic manifestations exist but are not as well described, particularly in the pediatric population. Aims Present two rare manifestations of pediatric CF-associated liver disease. Methods In this report, we present a pediatric CF patient with chronic abdominal pain who was found to have hepatolithiasis, cholangitis and secondary sclerosing cholangitis. Results A 12-year-old boy with CF was seen for abdominal pain with functional impairment. He had prior evidence of calculi in the common bile duct (CBD) and right intrahepatic (IH) duct, and had undergone endoscopic retrograde cholangiopancreatography (ERCP) twice with sphincterotomy once. Magnetic resonance cholangiopancreatography (MRCP) at presentation showed dilated CBD and bilateral IH ducts with calculi, evidence of acute cholecystitis and early cholangitis. He subsequently underwent a third ERCP with stone retrieval, stent placement and a laparoscopic cholecystectomy. Ursodiol dose was optimized and antibiotics were initiated. Follow-up MRCP showed improvement in CBD and IH duct dilation; the stent was removed. One month later, a fifth ERCP was performed for worsening symptoms associated with a distal filling defect in the left IH duct. Sludge was removed from the CBD and another stent was placed. A sixth ERCP with stent removal showed no stones. Interval MRCP showed resolution of IH calculi, a CBD filling defect suggestive of sludge, and thickening and enhancement of IH bile ducts with focal areas of alternating narrowing and dilation. He was maintained on antibiotics, and his symptoms persisted over the following months despite resolution of sludge, peri-portal edema and duct-wall enhancement. There was a background of increased IH ductal dilation with “beaded appearance”. Interval imaging has demonstrated persistence of these findings with recurrence of hepatolithiasis in both IH ducts, despite improved symptoms. Conclusions This case describes two rare manifestations of pediatric CF-associated liver disease: hepatolithiasis and secondary sclerosing cholangitis. While CFTR dysfunction alone predisposes to gallstone formation, the patient’s clinical course supports a theory for the development of hepatolithiasis resembling that of recurrent pyogenic cholangitis, whereby bacteriobilia from chronic or recurrent infection may promote lithogenesis in the presence of inflammatory bile duct damage. In this patient, secondary sclerosing cholangitis may have resulted from cycles of cholangitis and hepatolithiasis; alternatively, it may represent under-recognized cholangiopathy in the pediatric CF population. Funding Agencies None

Cystic Fibrosis–Related Liver Disease in a 12-Year-Old: Important Questions of Portal Hypertension Etiology That Start With Pathology: A Case Presentation

Abstract Introduction Cystic fibrosis liver disease (CFLD) has long been postulated to be secondary to dysfunctional cystic fibrosis transmembrane conductance regulator in the apical biliary epithelium, leading to bile stasis and eventually cirrhosis with portal hypertension (PH). We present a considerably young patient with signs of esophageal varices and liver biopsy indicating CFLD with significant obliterative portal venopathy as a result of long-standing portal hypertension. Case Presentation A 12-year-old with CF (diagnosed at 1 year) and pancreatic insufficiency was noted to have chronically elevated liver enzymes with decreasing platelet counts (130,000 K/ µL). These findings prompted an ultrasound, which showed splenomegaly. Upper endoscopy showed grade 1 esophageal varices, and liver needle biopsy performed at this time demonstrated focal neutrophilic lobular inflammation with marked pseudoacinar transformation and biliary metaplasia. Noted was grade 1 macrovesicular steatosis, focal dense fibrosis also known as “focal biliary cirrhosis,” and obliterative portal venopathy. Discussion CF patients with liver fibrosis have significant risk of future morbidity. Of specific interest is identification of PH, and obliterative portal venopathy is a very important feature to distinguish on biopsy as it predicts clinical course. Two recent studies in young adults described obliterative portal venopathy (OPV) and noncirrhotic portal hypertension (NCPH) as the predominant pathophysiology in young adults (median, 22 years) with CFLD. One study found cirrhosis present in only 27% of patients with portal hypertension. In addition, it appears that portal hypertension can precede cirrhotic changes. This unique case in a very young patient with CFLD demonstrates that the underlying pathogenesis of noncirrhotic portal hypertension and CFLD remains to be fully solved. These observations may have important consequences for CFLD management, including opting away from “cholestasis-targeted” treatments and more often considering portosystemic shunting procedures instead of transplant, as liver function remains preserved in numerous CFLD cases.

WS16.5 Pathological analysis of native liver in cystic fibrosis (CF) with severe portal hypertension reveals a vascular liver disease without cirrhosis

The prevalence of CF related liver disease (CFLD) ranges from 26% to 45%. The pathogenesis is allegedly related to small bile duct obstruction leading to focal biliary cirrhosis and cirrhosis. Portal hypertension (PHT) without hepatocellular insufficiency is the main presentation of CFLD. The aim of this study was to establish the pathologic pattern in CFLD patients with severe PHT. Patients and Methods In 2 CF centers, all consecutive patients who underwent liver transplantation were retrospectively analysed. Results Eight patients (7 males; 14–32 y) were analysed. All presented with severe PHT: esophageal varices more than grade 2 (bleeding in 2 patients), splenomegaly 18–30 cm, collaterals or ascites. None had signs of hepatocellular insufficiency. Liver tests were less than 1.5 times elevated. Macroscopically, all explants (mean weight 1.6 kg) were dysmorphic with left atrophy and irregular macronodular aspect. There was no thrombosis of the large veins and large bile ducts were normal. Microscopically, all explants showed septal fibrosis without cirrhosis (F2 or F3 Metavir Score, n = 4 each). Diffuse obliterative portal venopathy with sinusoidal dilatation and regenerative nodular hyperplasia was observed in all, associated with frequent ductopenia in small portal tracts, without cholestasis or inflammation. Biliary plugs with ductular reaction were scarce, medium or large biliary ducts were normal. Conclusion According to histological examination of the native livers, CFLD with PHT is not related to biliary cirrhosis but responds to vascular damages as observed in idiopathic non-cirrhotic PHT. The mechanism leading to vascular lesion in CF is unknown.

Cystic Fibrosis below the Diaphragm: Abdominal Findings in Adult Patients.

Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in the white population. Mutation of the CF transmembrane conductance regulator gene on chromosome 7 results in production of abnormally viscous mucus and secretions in the lungs of patients with CF. A similar pathologic process occurs in the gastrointestinal tract, pancreas, and hepatobiliary system. Inspissated mucus causes luminal obstruction and resultant clinical and radiologic complications associated with the disease process. Pancreatic involvement can result in exocrine and endocrine insufficiency, pancreatic atrophy, fatty replacement, or lipomatous pseudohypertrophy. Acute and chronic pancreatitis, pancreatic calcification, cysts, and cystosis also occur. Hepatic manifestations include hepatic steatosis, focal biliary and multilobular cirrhosis, and portal hypertension. Biliary complications include cholelithiasis, microgallbladder, and sclerosing cholangitis. The entire digestive tract can be involved. Distal ileal obstruction syndrome, intussusception, appendicitis, chronic constipation, colonic wall thickening, fibrosing colonopathy, pneumatosis intestinalis, gastroesophageal reflux, and peptic ulcer disease have been described. Renal manifestations include nephrolithiasis and secondary amyloidosis. The educational objectives of this review are to reveal the abdominal manifestations of CF to facilitate focused analysis of cross-sectional imaging in adult patients. Life expectancy in patients with CF continues to improve because of a combination of aggressive antibiotic treatment, improved emphasis on nutrition and physiotherapy, and development of promising new CF transmembrane conductance regulator modulators. As lung function and survival improve, extrapulmonary conditions, including hepatic and gastrointestinal malignancy, will be an increasing cause of morbidity and mortality. Awareness of the expected abdominal manifestations of CF may assist radiologists in identifying acute inflammatory or neoplastic conditions. (©)RSNA, 2015.

Gastrointestinal Manifestations of Cystic Fibrosis.

Gastrointestinal symptoms of cystic fibrosis are the most important non-pulmonary manifestations of this genetic illness. Pancreatic manifestations include acute and chronic pancreatitis as well as pancreas insufficiency resulting in malnutrition. Complications in the gastrointestinal lumen are diverse and include distal intestinal obstruction syndrome (DIOS), meconium ileus, intussusception, and constipation; biliary tract complications include focal biliary cirrhosis and cholangiectasis. The common pathophysiology is the inspissation of secretions in the hollow structures of the gastrointestinal tract. Improved survival of CF patients mandates that the adult gastroenterologist be aware of the presentation and treatment of pancreatic, luminal, and hepatobiliary CF complications.

Multidisciplinary Treatment of Cystic Fibrosis-Related Recurrent Pyogenic Cholangitis (CF-RPC).

As the survival of cystic fibrosis patients improves due to better treatment of its pulmonary manifestations, the management of hepatobiliary complications becomes increasingly vital. While focal biliary cirrhosis is common, large duct manifestations are less frequently encountered. We prospectively evaluated cases of large bile duct disease in a large adult cystic fibrosis practice at the Keck Hospital of the University of Southern California. Over a 5-year period, six patients presented with cholangiectasia, hepatolithiasis, and strictures. Their clinical presentation and course closely resembled recurrent pyogenic cholangitis (RPC). Treatment of cholangitis and strictures was primarily by endoscopic retrograde cholangiopancreatography, but major hepatobiliary surgery following pulmonary optimization was required in 33 %. In adult populations, CF-RPC may not be as unusual as previously reported and recognition allows optimal endoscopic, medical, and surgical management.

Liver disease in children with cystic fibrosis

Liver disease is an early complication in children with cystic fibrosis (CF).The clinical manifestations in hepatobiliary disease of CF include neonatal cholestasis, liver steatosis, liver fibrosis, biliary lithiasis, focal biliary cirrhosis and multilobular cirrhosis, with or without portal hypertension. Changes in the tests evaluating the liver function are inconsistent and are not correlated with the severity of the liver lesions. The diagnosis of liver disease in CF requires the presence of at least two of the following four diagnosis criteria: clinical manifestations, pathologic liver function tests, ultrasound and histologic changes. The annual follow-up to evaluate the liver function is s recommended for diagnosis of asymptomatic liver disease and early initiation of treatment with ursodeoxycholic acid. The improvement of the liver function influences life quality and increases the survival rate in patients with CF.

Liver disease in cystic fibrosis.

Cystic fibrosis-associated liver disease (CFLD) affects ca. 30% of patients. The CFLD is now considered the third cause of death, after lung disease and transplantation complications, in CF patients. Diagnostics, clinical assessment and treatment of CFLD have become a real challenge since a striking increase of life expectancy in CF patients has recently been observed. There is no elaborated “gold standard” in the diagnostic process of CFLD; clinical evaluation, laboratory tests, ultrasonography and liver biopsy are used. Clinical forms of CFLD are elevation of serum liver enzymes, hepatic steatosis, focal biliary cirrhosis, multilobular biliary cirrhosis, neonatal cholestasis, cholelithiasis, cholecystitis and micro-gallbladder. In children, CFLD symptoms mostly occur in puberty. Clinical symptoms appear late, when damage of the hepatobiliary system is already advanced. The CFLD is more common in patients with severe mutations of CFTR gene, in whom a complete loss of CFTR protein function is observed. CFLD, together with exocrine pancreatic insufficiency and meconium ileus, is considered a component of the severe CF phenotype. Treatment of CFLD should be complex and conducted by a multispecialist team (gastroenterologist, hepatologist, dietician, radiologist, surgeon). The main aim of the treatment is to prevent liver damage and complications associated with portal hypertension and liver cirrhosis. Ursodeoxycholic acid is used in the treatment of CFLD. There is no treatment of proven long-term efficacy in CFLD. Liver transplantation is a treatment of choice in end-stage liver disease.

Combined heterotopic liver–pancreas transplantation as a curative treatment for liver cirrhosis and diabetes mellitus in cystic fibrosis

Cystic fibrosis (CF) is an inherited disease with a defect in epithelial chloride transport that results in a multisystem disease. Although pulmonary disease remains the primary cause of morbidity and mortality, focal biliary cirrhosis and portal hypertension may develop in up to 8% of these patients. Liver transplantation (TX) is an accepted therapy and shows good results. We report on a patient with cystic fibrosis homozygous for the most common CFTR mutation delta F 508 who received a combined heterotopic liver and pancreas transplantation at the age of 18 yr. He suffered from CFRD, which untypically required high doses of insulin. In addition, the patient had pulmonary complications, was chronically colonized with multiresistant Pseudomonas aeruginosa (MBL) and had an allergic bronchopulmonary aspergillosis (ABPA). The patient remained in stable health for 54 months post-TX and was able to live a nearly normal life. With a follow-up of five yr, the function of the liver and pancreas allografts was excellent. However, and sadly, his pulmonary function continued to deteriorate from progression of his CF, and he died of respiratory failure due to a severe pneumonia and septicemia at the age of 23 yr and five months.

Intestinal CFTR expression alleviates meconium ileus in cystic fibrosis pigs

Cystic fibrosis (CF) pigs develop disease with features remarkably similar to those in people with CF, including exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens loss, airway disease, and meconium ileus. Whereas meconium ileus occurs in 15% of babies with CF, the penetrance is 100% in newborn CF pigs. We hypothesized that transgenic expression of porcine CF transmembrane conductance regulator (pCFTR) cDNA under control of the intestinal fatty acid-binding protein (iFABP) promoter would alleviate the meconium ileus. We produced 5 CFTR-/-;TgFABP>pCFTR lines. In 3 lines, intestinal expression of CFTR at least partially restored CFTR-mediated anion transport and improved the intestinal phenotype. In contrast, these pigs still had pancreatic destruction, liver disease, and reduced weight gain, and within weeks of birth, they developed sinus and lung disease, the severity of which varied over time. These data indicate that expressing CFTR in intestine without pancreatic or hepatic correction is sufficient to rescue meconium ileus. Comparing CFTR expression in different lines revealed that approximately 20% of wild-type CFTR mRNA largely prevented meconium ileus. This model may be of value for understanding CF pathophysiology and testing new preventions and therapies.

Cystic Fibrosis-Related Liver Disease: A Single-Center Experience

Prospective studies concerning liver disease in pediatric cystic fibrosis patients are scarce. The present study aimed to describe the prevalence and clinical expression of cystic fibrosis - related liver disease, in a cohort of 62 pediatric patients. Descriptive study, resulting from the prospective evaluation, between 1994 and 2009, of 62 pediatric patients (age <18 years) with cystic fibrosis. The follow-up protocol included a clinical assessment every 2 months, liver function tests every 6 months and annual liver ultrasonography. The cumulative prevalence of liver disease was 11.2% (7/62 cases). All patients had ΔF508 mutation and pancreatic insufficiency, none had meconium ileus. The liver involvement became clinically evident at a mean age of 8 years (3–15 years), revealed by hepatomegaly or hepatosplenomegaly (3 cases) and/ or abnormalities of liver function tests (3 cases) changes of liver ultrasound (7 cases) with evidence of portal hypertension (2 cases). Four patients were submitted to liver biopsy; biliary fibrosis was documented in one case, focal biliary cirrhosis in 2 cases and multilobular cirrhosis in another case. Within a median 11.6 years follow-up period (all patients under UDCA therapy after liver disease diagnosis), progression of liver disease was observed in 2 patients; one patient developed refractory variceal bleeding and progressive hepatic failure, requiring liver transplant. The results of the present study agree with those of previous pediatric studies, further documenting clinical expression of liver disease in CF patients, which is usually detected in the first decade of life and emphasize the contribution of ultrasound to early diagnosis of liver involvement. Moreover, although advanced liver disease is a relatively rare event, early isolated liver transplantation may have to be considered at this age group.

Transient elastography in patients with cystic fibrosis

Hepatic involvement is frequent in patients with cystic fibrosis (CF), with focal biliary cirrhosis being the pathognomonic hepatic manifestation. In around one-quarter of CF patients, it results in CF-associated liver disease (CFLD). This occurs as a relatively early complication with the majority of patients presenting in childhood or their early teens. However, a normal US does not preclude significant liver fibrosis and liver biopsy is an invasive procedure that is hampered by potential sampling errors. Transient elastography (TE) (Fibroscan) is a non-invasive, user-friendly and quick technique that provides an objective and reproducible measure of liver stiffness. This is accomplished with a device using an US probe mounted in the axis of a vibrator. Vibrations are transmitted by the transducer, inducing an electronic shear wave that propagates through the underlying tissue. We aimed to prospectively compare TE and transabdominal US scanning in children and adults attending a CF clinic. A total of 134 consecutive patients with documented CF were prospectively studied. In each case, transient elastography measurement was performed immediately after the routine annual US evaluation of the liver. Sonographic appearance of the liver was classified from 1 to 5. Ten validated TE measurements were performed in each patient with the result expressed in kilopascals (kPa). The median value was considered representative of the elastic modulus of the liver. Measurements were performed in 59 CF adults, 75 CF children and 31 control children. There was no relationship between age and liver stiffness in either the control group or CF patients. Elasticity values of controls, CF pancreatic sufficient (PS) patients and pancreatic insufficient (PI) CF patients with a US score <3 were comparable and significantly lower than in CF patients with a US score > or = 3 (all PI) (P < 0.002). Median elasticity in CF patients was significantly higher in males (4.7 kPa) than in females (3.9 kPa) (P = 0.0013). Considering the limitations of US and the low risk-benefit rate of liver biopsy in most CF patients, this preliminary study suggests that TE is an attractive non-invasive way to assess and follow-up liver disease in these patients.

Hepatobiliary disease in patients with cystic fibrosis

This review explores the recent advances in knowledge regarding hepatobiliary disease in patients with cystic fibrosis. Hepatobiliary abnormalities associated with cystic fibrosis are varied in nature and range from defects attributable to the underlying genetic defect to those related to systemic disease and malnutrition. Novel research into the underlying pathogenesis of cystic fibrosis liver disease and the primary role of cystic fibrosis transmembrane conductance regulator in biliary secretory epithelium is presented. This work has been fostered by the development of new animal models of cystic fibrosis transmembrane conductance regulator dysfunction. Of the wide range of hepatobiliary complications associated with cystic fibrosis the most clinically relevant problem is progression of focal biliary cirrhosis to multilobular cirrhosis with its attendant complications of portal hypertension and potentially end-stage liver disease. However, recent studies suggest that liver transplantation may not improve survival in patients with cystic fibrosis and significant portal hypertension. Hepatobiliary disease is a common finding in patients with cystic fibrosis; the pathogenesis is multifactorial in nature. As new therapeutic strategies emerge, life expectancy will continue to increase as will the impact of liver disease on quality of life and survival of patients with cystic fibrosis. This review will discuss novel insights into pathogenesis as well as diagnostic and management options.

Are pigs more human than mice?

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel AC, Wohlford-Lenane CL, Davis GJ, Hanfland RA, Smith TL, Samuel M, Wax D, Murphy CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ. Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment. [Abstract reproduced by permission of Science 2008;321:1837–1841].

Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs.

Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles. Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment.

Liver disease in cystic fibrosis

This review highlights recent developments in liver disease associated with cystic fibrosis. The broad spectrum of hepatobiliary problems in cystic fibrosis includes specific alterations ascribable to the underlying defect as well as lesions of iatrogenic origin or that reflect the effects of a disease process occurring outside the liver. Focal biliary cirrhosis, resulting from biliary obstruction and progressive periportal fibrosis, is the most clinically relevant problem, because extension of the initially focal fibrogenic process may lead to multilobular biliary cirrhosis, portal hypertension and eventually liver failure. Cystic fibrosis associated liver disease is presently classified among genetic cholangiopathies and results from lack or dysfunction of the cystic fibrosis transmembrane regulator at the apical membrane of bile duct cells. Major advances have been achieved regarding characterization of natural history, risk factors, diagnostic modalities and treatment options. Liver disease is a relatively frequent and early complication of cystic fibrosis. The pathogenesis is apparently multifactorial, with contributions from environmental and genetic determinants. Its impact on quality of life and survival will increase in future years, and its early detection and treatment will become increasingly important issues. Ursodeoxycholic acid is the only treatment currently available, but novel therapeutic options are being evaluated.

Unexpected diagnosis of cystic fibrosis at liver biopsy: a report of four pediatric cases

We report here four cases of pediatric patients in whom the diagnosis of cystic fibrosis was made only after the histological examination of a liver specimen obtained by biopsy (three cases) or at autopsy (one case). There were two boys and two girls, aged 13 months to 7.5 years. None had a personal or familial history suggestive of cystic fibrosis. One patient, presenting with myocardial lesion and hepatomegaly, died of heart failure; at autopsy, the liver showed a typical aspect of focal biliary cirrhosis. In the three other cases, liver disease was the only manifestation of cystic fibrosis at the time of diagnosis. Liver biopsy examination showed focal biliary cirrhosis in one case and massive steatosis in two. In all four cases, the diagnosis was confirmed by the existence of known pathogenic mutations in the CFTR gene. The evolution was variable; one patient had progressive liver disease with severe portal hypertension after 7 years; another one had lung complications after 1 year. In conclusion, our experience recalls that the diagnosis of cystic fibrosis must be considered in children presenting with unexplained liver disease; its confirmation by molecular techniques makes it possible to set up an appropriate follow-up.