There are three liver diseases in which an autoimmune mechanism is primarily responsible for damage to the liver: autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC), and de novo AIH after liver transplant. This chapter will review each of these three topics.

Definitions and Epidemiology

This disorder has been alternately called a variety of terms, including active chronic hepatitis, chronic active hepatitis, chronic aggressive hepatitis, lupoid hepatitis, plasma cell hepatitis, and, most commonly, autoimmune chronic active hepatitis. In 1992, the International Autoimmune Hepatitis Group (IAIHG) recommended AIH as the most appropriate and least redundant term for this disease.1

AIH is characterized by inflammatory liver histology, circulating non-organ-specific autoantibodies, and elevated levels of IgG, all in the absence of a known etiology. Two types of AIH have been described, with the distinction made according to differing profiles of the circulating autoantibodies. Type 1 or classic AIH is characterized by the presence of smooth muscle antibody (SMA) and/or anti-nuclear antibody (ANA), whereas type 2 AIH is positive for anti-liver kidney microsomal type 1 antibody (anti-LKM-1). There are several other antibodies, discussed below, which can also be present (Table 27–1).

AIH affects both children and adults. Type 1 AIH, which accounts for roughly two-thirds of cases, has a bimodal age distribution. One incidence peak is between 10 and 20 years of age, with the second between 45 and 70 years of age.2 Type 2 AIH generally presents at a younger age, often between the ages of 2 and 14 years, though not infrequently in infancy.3,4 In both types 1 and 2 AIH, females represent roughly 75% of cases.4 The exact prevalence in children is unknown.

Pathogenesis

A paradigm for the pathogenesis of AIH centers upon the concept that in a genetically susceptible host, exposure to an environmental agent can trigger a cascade of events, ultimately resulting in a chronic hepatic necroinflammatory response, leading to fibrosis and cirrhosis.5

The search for genetic predisposing factors has focused to a large extent on the genes encoding human leukocyte antigens, located in the major histocompatibility complex. In Caucasians, type 1 AIH is strongly associated with the HLA-DR3 serotype and with HLA-DR4.6–8 HLA-DR3-associated disease is more commonly found in the early onset, severe form of disease, resulting more frequently in liver transplantation.9 HLA-DR4, in contrast, is more common in Caucasians with late-onset disease and appears to be associated with a higher incidence of extrahepatic manifestations and a better response to corticosteroids.7,8

Liver damage is believed to be orchestrated by CD4-positive T lymphocytes recognizing a self-antigenic peptide. To trigger an autoimmune response, this peptide must be presented to an uncommitted T helper (Th0) cell by an antigen-presenting cell via an HLA class II molecule. Depending on the microenvironment, this T helper cell then adapts either a Th1 or Th2 phenotype, initiating a series of immune reactions that culminates in an inflammatory attack on the liver. Impairment in the immunoregulatory system, described in AIH, allows this attack to be perpetuated. Recent evidence points to a reduction in the number of regulatory T cells (T-regs) in patients with AIH, and their reduction relates to the stage of disease, with a greater reduction at the time of diagnosis than during drug-induced remission.10

The autoantigens responsible for initiating this inflammatory response have not been definitively identified. Candidates include the asialoglycoprotein receptor (a liver-specific membrane protein highly expressed in periportal hepatocytes)11 and CYP2D6 (cytochrome P450IID6).12

The presumed environmental agent that triggers the immune system to react to an autoantigen is as of yet unknown. Several viruses have been implicated, including measles virus, hepatitis viruses, herpes simplex virus, cytomegalovirus, and Epstein–Barr.13 Drugs are another potential candidate, with reports of oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, minocycline, and possibly statins inducing liver damage that mimics AIH.14,15

Clinical Presentation

AIH can present with a variety of clinical manifestations, ranging from silent elevation of liver enzymes to fulminant hepatic failure. Asymptomatic patients may come to attention during routine blood screening for a variety of reasons, when an elevated aminotransferase level may be the only clue to the presence of underlying liver disease. At the other extreme, patients may present with acute liver failure, characterized by profound jaundice, an elevated prothrombin time, and aminotransferase levels in the thousands. Fortunately, such a presentation is somewhat infrequent.4 The most common presentation is that of acute hepatitis, with non-specific symptoms such as malaise, nausea/vomiting, anorexia, and abdominal pain progressing to include jaundice, dark urine, and pale stools. Many of these patients will have cirrhosis at the time of initial biopsy, indicating that subclinical disease had existed for some time. Second, patients may present with a more insidious onset, characterized by progressive fatigue, relapsing jaundice, headache, and anorexia, lasting from months to years. Third, as 40–80% of patients will have cirrhosis at the time of diagnosis,4,16,17 some patients may present with complications from unknown portal hypertension, such as bleeding from esophageal varices. Lastly, AIH patients may present with manifestations from other autoimmune disorders, including thyroid disease, diabetes mellitus, ulcerative colitis, celiac, and Behçet’s disease. Type 2 AIH can be part of the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome, an autosomal recessive genetic disorder in which the liver disease is reportedly present in roughly 20% of cases.18

Physical findings range from a normal physical examination to the presence of hepatomegaly, splenomegaly, stigmata of chronic liver disease, and/or jaundice.

Laboratory values vary, but aminotransferase values are typically more significantly elevated than bilirubin, γ-glutamyl transferase, and alkaline phosphatase. Occasionally, a more cholestatic picture is noted, though this should alert the clinician to the possibility of other conditions, including extrahepatic biliary obstruction, viral hepatitis, or primary sclerosing cholangitis. One characteristic laboratory feature of AIH, although not universally present, is an elevation in serum globulins, particularly IgG.

Table 27–2 summarizes the presenting characteristics for 52 pediatric AIH patients that presented to a single tertiary referral center over a 20-year period.4

Differential Diagnosis

The differential diagnosis for AIH depends on its mode of presentation. With the acute presentation, the clinical picture resembles that of acute viral hepatitis (e.g., hepatitis A–E, cytomegalovirus, and Epstein–Barr virus), Wilson disease, or drug-induced hepatitis if relevant. When AIH presents as chronic hepatitis or cirrhosis, the differential diagnosis again includes viral hepatitis (hepatitis B/D, or C), Wilson disease, and drug-induced liver disease, but additionally, one must consider alpha-1-antitrypsin deficiency, non-alcoholic steatohepatitis, primary sclerosing cholangitis, and iron overload syndromes (Table 27–3). Of note, distinguishing AIH from chronic hepatitis C requires the analysis for hepatitis C RNA, as some patients with AIH develop a non-specific antibody response, potentially leading to false-positive hepatitis C antibodies. Additionally, ANA, SMA, and LKM-1 autoantibodies are commonly elevated in those with chronic hepatitis C.

As the signs and symptoms of AIH are non-specific, it is important to consider this diagnosis in any child presenting with unexplained liver disease.

Diagnosis

The diagnosis of AIH requires both the presence of classic features and the absence of other conditions that can resemble AIH (Table 27–4).1,19 Elevated transaminases are a universal finding. Increased levels of IgG are typical, though not universal (Table 27–2). The presence of autoantibodies (ANA, SMA, and LKM-1) is characteristic. Liver biopsy is mandatory to establish the diagnosis. The typical histology includes a dense mononuclear and plasma cell infiltrate of the portal areas that expands into the liver lobule; destruction of the hepatocytes at the periphery of the lobule with erosion into the limiting plate (“interface hepatitis”); connective tissue collapse resulting from hepatocyte death and expanding from the portal area into the lobule (“bridging collapse”); and hepatic regeneration with “rosette” formation (Figure 27–1). Other potential disorders with similar presentations, as discussed in the preceding section “Differential Diagnosis” , must be ruled out prior to arriving on the diagnosis (Figure 27–2).