Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant

Abstract

The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant fibrosis or cirrhosis. Further diagnostic studies and repeat biopsies confirmed the absence of liver cirrhosis as well as other potential causes of hyperbilirubinaemia. Comparison of the fibrosis-ductopenia relationship for our cases with that for a group of 101 non-cirrhotic PBC patients indicated that in the former the severity of bile duct loss relative to the amount of fibrosis was significantly higher. The proportion of portal triads containing an interlobular bile duct was 3%, 4%, 6%, and 10% compared with 45% (median; range 8.3--100%) for controls (p<0.001). Three patients received a liver transplant 6--7 years after the first manifestation of PBC because of progressive cholestasis, refractory pruritus, and weight loss, while the fourth patient is considering this option. In one case cirrhosis had developed at the time of transplantation while the others still had non-cirrhotic disease. These cases suggest that cholestatic jaundice in non-cirrhotic PBC may be secondary to extensive "premature" or accelerated intrahepatic bile duct loss. Although the extent of fibrosis may be limited initially, progression to cirrhosis appears to be inevitable in the long run. Despite intact protein synthesis and absence of cirrhotic complications, liver transplantation in the pre-cirrhotic stage for preventing malnutrition and to improve quality of life should be considered for these patients.

Figure 1

Scatterplot showing the relationship between biopsy length and number of portal tracts.

Figure 2

Scatterplot showing the relationship between the ductopenic index (ratio of portal tracts (n) to ducts (n)) and fibrosis score. A high index indicates severe ductopenia. The central line indicates the least squares regression line. The upper line represents the 97.5 percentile and the lower line the 2.5 percentile. Note the logarithmically scaled horizontal axis. Three of four cases fell outside the 95% reference interval of the control biopsy specimens.

Figure 3

Plot showing the difference in length (mm)/ducts (n) ratio between the controls and cases. A high ratio indicates severe ductopenia.

Figure 4

(A) Haematoxylin-eosin coloured liver biopsy from patient No 2 showing at least four portal tracts. The amount of fibrosis is very limited and there are no portoportal or portoseptal connections. (B) Anticytokeratin 19 (keratin 19) stained liver biopsy from patient No 2 showing the same portal tracts as in (A) with total absence of pre-existent interlobular bile ducts and only very moderate ductular proliferation (darkish brown coloured cells).