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Histological assessments continue to play an important role in the diagnosis and management of liver allograft rejection. The changes occurring in acute and chronic rejection are well recognized and liver biopsy remains the 'gold standard' for diagnosing these two conditions. Recent interest has focused on the diagnosis of late cellular rejection, which may have different histological appearances to early acute rejection and instead has features that overlap with so-called 'de novo autoimmune hepatitis' and 'idiopathic post-transplant chronic hepatitis'. There is increasing evidence to suggest that 'central perivenulitis' may be an important manifestation of late rejection, although other causes of centrilobular necro-inflammation need to be considered in the differential diagnosis. There are also important areas of overlap between rejection and recurrent hepatitis C infection and the distinction between these two conditions continues to be a problem in the assessment of liver allograft biopsies. Studies using immunohistochemical staining for C4d as a marker for antibody-mediated damage have found evidence of C4d deposition in liver allograft rejection, but the functional significance of these observations is currently uncertain. This review will focus on these difficult and controversial areas in the pathology of rejection, documenting what is currently known and identifying areas where further clarification is required.

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) may all recur after liver transplant. Diagnosis of rPBC is defined by histology; rAIH by serology, biochemistry and histology; rPSC by histology and/or imaging of the biliary tree and exclusion of other causes of nonanastomotic biliary strictures. Criteria for recurrent disease (RD) may differ from those used in similar disease in the native liver: frequent use of immunosuppressive therapy changes the pattern and natural history of RD and can co-exist with other transplant-related causes of graft damage. RD may occur in the presence of normal liver tests; the reported incidence will depend on the way in which diagnostic tests (especially protocol biopsies) are applied. The risk of RD increases with time, but does not correlate with the rate of graft loss. Treatment is largely unproven: ursodeoxycholic acid will improve serology and may slow progression of rPSC and rPBC; introduction or increased dose of corticosteroids may reduce progression of rAIH. Risk factors for rPBC include use of tacrolimus compared with cyclosporine; for rPSC include absence of colon peri-transplantation and for rAIH possible associations with some HLA haplotypes have been suggested.