Conclusions
AIH is a relatively rare liver disease of unknown aetiology characterised by interface hepatitis, hypergammaglobulinaemia, circulating autoantibodies and a favourable response to immunosuppression. Due to a large heterogeneity of the genetic, clinical, laboratory, histological and serological features of the disease, AIH might be underestimated or unrecognised. It should be clear that the disease has global distribution affecting any age, both sexes and all ethnic groups.
AIH is developed in genetically predisposed individuals, who are also exposed to diverse triggering factors. Thereafter, the autoimmune attack is perpetuated, possibly via 'molecular mimicry', and is favoured by the impaired control of regulatory T-cells.
Clinical manifestations are variable, ranging from no symptoms to severe acute hepatitis and even fulminant hepatic failure; almost one-third of patients have already cirrhosis at diagnosis, perhaps due to the indolent course of the disease and underestimation of the clinician. Therefore, high clinical suspicion for AIH diagnosis should be raised in every case of unexplained acute or chronic hepatitis. AIH may first be diagnosed during pregnancy or in the early postpartum period, after viral infections or after the administration of several drugs as well as de novo after liver transplantation for other reason; a common clinical feature is the presence of a wide spectrum of other autoimmune or immune-mediated diseases in the patient or in first-degree relatives.
Biochemical indices are not characteristic with bilirubin and aminotransferases from just above the upper normal limits to more than 50 times these levels, with normal or only moderately elevated cholestasis; these findings do not reliably reflect severity of the disease at the histological level. Biochemistry may even spontaneously normalise (spontaneous biochemical remission), despite histological evidence of continuing activity; this is a critical issue, which may result in delay and/or underestimation of diagnosis as the subsequent hit can be obvious after several months or years and may be completely asymptomatic. In most patients, the typical laboratory feature is polyclonal hypergammaglobulinaemia with selective elevation of serum IgG; however, almost 15–25% of patients, particularly the children and the elderly, and also those with a severe/acute onset, have normal IgG at presentation; therefore, the diagnosis of AIH should never be ruled out only on the basis of normal IgG.
The detection of non-organ and liver-related autoantibodies, although not pathognomonic, still remains the hallmark of the diagnosis, in the absence of viral, metabolic, genetic and toxic aetiology of chronic or acute hepatitis; the IAIHG has published detailed guidelines on how to test for autoantibodies relevant to AIH; both the laboratory personnel and the clinician need to become more familiar with the disease expressions and the interpretation of liver autoimmune serology to derive maximum benefit for the patient.
Liver histology is mandatory for AIH diagnosis, although no findings are specific for AIH; typical findings include interface hepatitis consisting of lymphocytes and abundant plasma cells; however, one-third of patients have few or no portal or acinar plasma cells and therefore, the absence of portal tract plasma cell infiltration does not preclude diagnosis. Emperipolesis and hepatic rosette formation were also regarded as typical for AIH diagnosis; the histological features in patients with severe-acute to fulminant AIH differs as the lesions predominate in the centrilobular zone, including distinctive patterns of massive hepatic necrosis, presence of lymphoid follicles, a plasma cell-enriched inflammatory infiltrate and central zonal necrosis/perivenulitis.
Because of the low prevalence of 'overlap syndromes', and on the basis of the current, very limited knowledge about the aetiopathogenesis of AIH, PBC and PSC, definition of diagnostic criteria for 'overlap conditions' can only be arbitrary and therefore, patients with autoimmune liver diseases should be categorised as AIH, PBC and PSC, including its small duct variant, respectively, based on the predominating disease; those with 'overlapping features' should not be considered distinct diagnostic entities.
Reliable scores for AIH diagnosis carrying high sensitivity and specificity do exist and the latest simplified score taking into account only four parameters seems easier for everyday use in clinical practice; the absence, however, of a definite gold standard for AIH diagnosis makes impossible the performance of precise studies on sensitivity and specificity and therefore, clinicians must regard diagnostic scores only as an aid to AIH diagnosis.
Treatment is mandatory and usually life-saving in patients who have clinical, laboratory or histological features of active liver inflammation; treatment can be divided into induction of remission, and remission maintenance either by monotherapy with high-dose corticosteroids or a reduced initial steroid dose in combination with azathioprine. An individualised dosage of prednisolone (or prednisone) of 1 mg/kg/day plus azathioprine has been proposed as first-line treatment of patients with AIH; today, there is an internationally agreed consensus on the definition of disease remission as complete normalisation of transaminases, along with normal IgG levels. Recent systematic review of all published RCTs has shown that treatment of AIH with prednisolone in combination or not with azathioprine is far from ideal; in parallel, a recent large study showed that relapse occurs in virtually all patients with AIH in long-term remission when immunosuppression with azathioprine was discontinued. Therefore, the search for alternative drugs with a favourable risk–benefit ratio seems mandatory. The application of the 2010 AASLD practice guidelines regarding the definition of response is expected to result in increased number of nonresponders to conventional treatment with corticosteroids and azathioprine.
Alternative therapies, such as ciclosporin, tacrolimus, MMF, budesonide, rapamycin, or other new drugs, including biological agents, are very promising and ideally should be tested in the next years, especially for the difficult-to-treat or nonresponder patient. To this endpoint, a network of committed clinical investigators must be generated to evaluate new therapies in multicentre studies.