Jan, 2001. Liver disease [online]. Seacroft and St James's University Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com

With the mean age of survival of patients with CF improving significantly, diagnosis and treatment of liver disease has now become a very relevant clinical issue. It can cause significant problems and accounts for 2.2% of all deaths due to CF, second only to respiratory complications (Fitzsimmons, 1995). It is the initial diagnostic finding in 1.5% of patients, suggesting that all patients with unexplained cirrhosis should have a sweat test as part of their diagnostic evaluation. Liver disease has been shown to have a peak incidence in adolescence, affecting males twice as frequently as females (Scott-Jupp et al, 1991). There is no current explanation why liver disease develops in some patients and not in others. No specific genotype/phenotype connection has been identified (Duthie et al, 1992). Some studies have shown a four fold risk for the development of liver disease in patients with a history of meconium ileus (Colombo et al, 1994). CF associated liver disease is often difficult to define on a clinical basis as it is initially a purely histological disorder causing no symptoms and inconsistent abnormalities in serum liver function tests. Isolated hepatomegaly may be the only clinical finding. The pathogenesis of liver disease is due to a combination of several underlying mechanisms. CFTR has been found at the apical membrane of the bile duct epithelium (Cohn et al, 1993). Abnormal bile flow and inspissated secretions develop secondary to a primary defect in chloride transport. Bile duct obstruction and the development of mucus plugs may be precursors of focal biliary cirrhosis, the pathognomonic lesion in CF associated liver disease (Maraye et al, 1989). In addition bile acid malabsorption causes retention of hepatotoxic glycine conjugated bile acids which may be responsible for the progression of liver damage. The prevalence of focal biliary cirrhosis is difficult to determine. Autopsy studies have shown this lesion to be present in over 70% of patients over the age of 20 years (Vouter & Shwachman, 1979). The development of multilobar biliary cirrhosis occurs in 2 - 5% of patients (Colombo et al, 1994). When this deranged liver architecture is seen, major clinical problems occur, e.g. portal hypertension with the development of splenomegaly and oesophageal varices; massive enlargement of the spleen causing abnormal pain, dyspnoea and signs of hypersplenism and upper gastrointestinal bleeding secondary to oesophageal varices (Tanner, 1992). Once hepatocellular failure occurs with the development of jaundice, ascites and encephalopathy the only potentially curative treatment is liver transplantation. However, even in established cases of cirrhosis, serum liver enzymes may be completely normal. Early detection is thus of vital importance to allow treatment to prevent or delay its progression. One study has shown an impressive increase in biliary secretion following treatment highlighting the apparent reversible nature in the early stages (Colombo et al, 1992).

Screening for liver disease: In all patients attending the Leeds Unit, clinical examination for the presence of hepatosplenomegaly is carried out routinely at every visit. Abdominal ultrasound is carried out annually in all patients over 10 years of age in association with serum liver function tests. The latter tests do not always correlate with the severity of hepatic lesions. In addition transient elevation may be seen with hypoxaemia, antibiotic treatment and during a pulmonary exacerbation. Thus serial determinations should be performed. Of the different enzymes measured, those that originate from the biliary epithelium (a GT, 5-nucleotidase and the biliary isoenzyme of alkaline phosphatase) are more specific for CF associated liver disease. Abdominal ultrasound is the current technique of choice to look for hepatobiliary problems and for continuing long term follow up (Williams et al, 1995). Liver size and texture, presence of associated splenomegaly and gallbladder abnormalities can be assessed. The latter has been reported in up to 40% of patients, ranging from microgallbladder to gallstones (4 - 12%). For a better evaluation of portal hypertension ultrasound can be used in association with Doppler studies of the portal vein (Vergesslian et al, 1989). Hepatobiliary scintigraphy with the new technetium labelled isotope (DISIDA) represents another non-invasive means of assessing both liver function and biliary excretion (O'Connor et al, 1996). Recent studies have suggested that this may be more useful in assessing early liver involvement, however it is not available as routine.

Treatment of liver disease: Therapy is aimed at improving biliary excretion and bile acid composition. Ursodeoxycholic acid (UDCA) is a naturally occurring hydrophilic bile acid which has been shown to both increase bile flow and to improve biochemical indices of liver function (Colombo et al, 1990; O'Brien et al, 1992). It is commenced when early abnormalities on ultrasound are seen and/or persistent raised liver function tests are documented as 20 mg/kg/day in two or three divided doses. This dose is necessary to compensate for poor absorption. Its effect has been shown to be dose dependent. Although a randomised, double-blind trial showed no significant effect of taurine supplement on liver function test resutls (Colombo et al, 1996), taurine deficiency is common in patients with CF (Thompson, 1988) as a result of bile acid malabsorption (Weber & Roy, 1985). Longterm administration of unconjugated UDCA may critically increase the demand for taurine needed for bile acid conjunction, and depletion of taurine induced by large doses of exogenous bile acid has been demonstrated in patients with gallstones (Batta et al, 1982). Patients given taurine also show a significant improvement in serum prealbumin levels, a sensitive indicator of nutritional status, and a trend to less fat malabsorption (Colombo et al, 1996). Thus all our patients are also supplemented with taurine at a dose of 30 mg/kg/day again in two or three divided doses. Increasing information is available on the effect of UDCA treatment in CF associated liver disease from several randomised controlled trials. All studies have shown a consistent and sustained improvement in biochemical indices, confirmed by multicentre trials (Colombo et al, 1996). Improvements in hepatic excretory function and biliary composition have been documented. Only preliminary data on its effects on liver histology are available. One study in a limited number of patients showed a marginal improvement in inflammation and fibrosis following two years of treatment with UDCA (Lindblad et al, 1998). In another 22 patients, 8 of 10 rebiopsied after one year's treatment with UDCA showed histological improvement (Wong et al, 1997). The long term benefits of treatment in preventing events related to morbidity and mortality from CF related liver disease are under evaluation. However, the impressive improvement of biliary secretion, as assessed by scintigraphy (Colombo et al, 1992), suggests that all patients should be started on treatment at an early stage when the lesions may well be reversible. Symptomatic upper gastrointestinal bleeding secondary to variceal development is treated by injection sclerotherapy (Stringer et al, 1993). There is no evidence to suggest the use of prophylactic treatment for known varices. If not successful other measures include surgical portacaval anastomosis and selective distal spleno-renal shunting (Bern and Gand, 1996). Splenectomy has been successfully performed in patients with massive splenic enlargement (Moya et al, 1996). For patients with liver cirrhosis and decompensated end stage liver disease, liver transplantation has been shown to be an effective therapy (Mieles et al, 1989; Noble-Jamieson et al 1996). Medium term survival rates vary from 70 - 100% with a good quality of life. In addition a beneficial effect on lung function has been observed. One Leeds adult patient remains well 10 years following isolated liver transplantation.

However, for patients with moderate to severe pulmonary involvement combined heart/lung/liver transplant remains the only option. The experience of triple transplantation so far is too limited to allow any conclusions to be made. Recent case reports have suggested that TIPS procedure (transjugular intrahepatic portosystemic shunt) can be useful as a short term measure for portal decompression (Rossle et al, 1994). Further studies are awaited. Future therapies will likely be directed at gene transfer. A recent study showed delivery of adenoviral human CFTR gene to the biliary tree via ERCP with successful gene expression in bile duct cells. This would represent the ideal response to all liver problems in CF.

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