Cirrhosis in PBC
PBC progresses through a number of stages: Preclinical, asymptomatic, symptomatic, and liver failure. The preclinical phase is symptom-free and is associated with AMA positivity in the absence of biochemical indications of liver disease[6,97]. Biochemical abnormalities eventually appear after a median time of 5.6 years (range, 1-20 years), but this phase is not yet associated with the presence of symptoms. When symptoms eventually develop, they are most commonly fatigue and pruritus, and later varices, oedema or ascites.
Liver failure is characterised by the accelerated development of jaundice, and is associated with poor prognosis. Mean survival for patients with a bilirubin of 2.0 mg/dL is 4 years, while for those with bilirubin of 6.0 mg/dL is only 2 years. PBC prognosis has dramatically improved in the last 20 years thanks to earlier diagnosis and the introduction of UDCA as the mainstay of treatment[99,100].
UDCA slows fibrosis progression and delays cirrhosis development. In clinical trials, UDCA treatment of PBC patients decreased the development of oesophageal varices and prolonged survival[102-106]. Cirrhosis does, however, still develop in UDCA-treated PBC patients. Indeed, the development of cirrhosis under UDCA treatment is an independent predictor of negative outcome[101,107].
Histologically, PBC can be divided according to the presence of fibrosis/cirrhosis into four stages[108,109]. Stage one is characterised by portal inflammatory cell infiltrate, which, in stage two, invades the liver parenchyma. In stage three, bridging fibrosis, in which fibrotic septa extend from and link the portal tracts, can be seen. Stage four is characterised by progression to cirrhosis. The development of cirrhosis does not occur uniformly throughout the liver, thus features of all four stages can ocur simultaneously in a single biopsy specimen. Histological staging should depend upon the most advanced histological features.
Histological stages can predict survival of PBC patients. In untreated PBC patients, the median time to the development of extensive fibrosis is 2 years. The probability of remaining in early stages after 4 years is 29%, whereas development of cirrhosis occurs in 50% of patients originally demonstrating histological evidence of interface hepatitis without ﬁbrosis. In two studies the proportion of patients developing liver failure during a follow-up time of 5 years was found to be 15% and 25%. The development of oesophageal varices, and the associated impact on survival, has been examined in a prospective study over the course of 5.6 years, which included 256 patients. Twenty-eight percent of patients were cirrhotic. Nearly one-third of patients developed oesophageal varices, after which the 3-year survival was 59%. Survival after the first bleeding episode was 46%.
The introduction of UDCA as first line treatment for PBC patients has changed the natural history of the disease[25,100,115,116]. Indeed, the number of PBC patients requiring liver transplantation (LT) decreased by 20% in between 1996 and 2006. Additionally, PBC has fallen in the ranking of the most common indications for LT from the first to the sixth place LT over a period of 20 years.
Several papers have also assessed the impact of UDCA therapy on the progression rate of cirrhosis in PBC patients. Corpechot et al examined progression to cirrhosis in 183 UDCA-treated PBC patients. In this study, 21% of patients developed cirrhosis during follow-up. The incidence of cirrhosis in patients followed up from stages 1, 2 and 3 was 4%, 12% and 59% respectively and the median length of times to cirrhosis development was 25, 20 and 4 years respectively. Albumin and bilirubin levels, and the histological severity of interface hepatitis were independently associated with progression to cirrhosis; cirrhosis was most likely to develop in patients with serum bilirubin over 17 μmol/L, serum albumin below 38 g/L and in patients with moderate to severe interface hepatitis. The impact of UDCA treatment oesophageal varices development has been examined in a 4-year prospective study including patients who received UDCA vs patients who received placebo. In the UDCA arm, the risk of varices development was 16%, while for those in the placebo group was 58%.
Cirrhosis in PSC
Typical symptoms of PSC, occurring in a variable number of patients include pruritus, abdominal pain, malaise, weight loss, and episodes of fever and chills. About 50% of PSC patients will present symptomatically[118,119]. Similarly to PBC, PSC progresses through four histological stages. In stage 1, which is known as the portal stage, changes are restricted to the portal tracts with features of mild hepatitis and cholangitis. Stage 2, known as the periportal stage, is characterised by extension of the lesion to include periportal fibrosis and occasionally interphase hepatitis. In this phase, the portal tracts are often notably enlarged. By stage 3, the septal stage, bridging ﬁbrous septa have developed and the bile ducts have begun to degenerate and disappear. Stage 4 is characterised by cirrhosis. The rate of progression through these stages has been investigated. Of PSC patients in the periportal stage, 42%, 66% and 93% progressed over 1, 2 and 5 years respectively. Of patients in the septal stage, 14%, 25% and 52% progressed over 1, 2 and 5 years respectively. In 15% of total observations, regression of histologic stage could be observed, highlighting the problem of sample variability when serial liver biopsies are used during the period of follow-up.
PSC can present at later stages of disease development, with complications of cirrhosis and portal hypertension. Similarly to other causes of cirrhosis, portal hypertension gradually develops in cirrhotic PSC patients. In one study, 36% of 283 newly diagnosed PSC patients had varices.
Cirrhosis in AIH
In a cohort of over 450 AIH patients, 30% had evidence of cirrhosis at diagnosis, with a further 10% developing cirrhosis during a median follow-up time of 7.2 years. The presence of cirrhosis at diagnosis correlated with negative outcome (LT or death). In another study, including 126 AIH patients, Feld et al (2005) reported that 33% of patients had histological evidence of cirrhosis at diagnosis. With the exception of platelet count, which was lower in patients with cirrhosis, laboratory parameters, patient demographics and AIH scores did not differ between cirrhotic and non-cirrhotic patients. A similar frequency of patients from each group were symptomatic at diagnosis and an equivalent proportion had good response to treatment. Importantly, similar response to treatment has also been reported elsewhere. Feld et al (2005) also found, however, that the presence of cirrhosis significantly increased risk of progression to LT or death. Consistent with the above studies, Verma et al (2004) reported that 28% of AIH patients were cirrhotic at diagnosis. In this study, a further 20% of patients developed cirrhosis during 52 mo of follow-up. Again, cirrhosis was an independent predictor of poor outcome in this cohort. On the other hand, studies in the adult[126,128] and paediatric settings, of comparable size and methodology to those described above, have not found associations between the presence of cirrhosis at diagnosis and the likelihood of poor outcome.
In one study, patients diagnosed between the ages of 21 and 60 years of age were more likely to present with cirrhosis than those outside of this range. Male patients were also more likely to have cirrhosis compared to their female counterparts. Low serum albumin concentrations, prolonged INR and low platelet count were all more frequently associated with the cirrhotic group of AIH patients.
There are indications that cirrhosis is more common among AIH type-1 patients compared to patients with type-2 AIH. In a paediatric study, 69% of ANA/SMA positive patients had evidence of “definite cirrhosis” on initial biopsy, whereas only 38% of patients positive for anti-LKM-1 were cirrhotic. On follow-up these values increased to 74% and 44% respectively.