Rudolph's Pediatrics, 22nd Ed.

CHAPTER 420. Autoimmune Disorders of the Liver

Nada Yazigi

Autoimmune liver disorders result from a spectrum of immune dysregulation where the liver can be the only organ affected or may be part of a systemic multiorgan disorder with the inflammatory response being mediated by systemic or locally produced (portal system) cytokines. The immunogenic target varies and may include the liver parenchyma, bile duct epithelium or vasculature, with “overlap” syndromes that include both biliary and parenchymal involvement being increasingly recognized among children. Clinical manifestations vary depending upon the pattern of involvement.

AUTOIMMUNE HEPATITIS (AIH)

There are two types of AIH that are categorized based on the autoantibody profile. Type I AIH accounts for two-thirds of all cases, and is characterized by positivity for antinuclear antibody (ANA), antismooth muscle antibody (SMA), or anti–F-Actin antibodies. Type II AIH accounts for one-third of all cases, and is characterized by positivity for anti-liver-kidney-microsomal type 1 (LKM-1) antibody and/or anti-liver cytosol-1. This group tends to be younger, and to have a higher incidence of partial IgA deficiency and acute liver failure at presentation.^1-4

EPIDEMIOLOGY

Both types of autoimmune hepatitis (AIH) are more predominant in females.¹ Twenty percent of patients have associated autoimmunity upon presentation, and 40% report a positive family history of autoimmune disorders. AIH is more frequent in women than men. Untreated mortality can approach 50% within 5 years of diagnosis, and 90% after 10 years. Its prevalence in the pediatric age group is unknown but it is estimated to account for 10% of all new referrals for liver disease in large pediatric hepatology centers in North America and Europe. Some patients are positive for the atypical perinuclear antibody pANNA. Close to 50% of these patients have an overlap syndrome (with primary sclerosing cholangitis) affecting their ultimate outcome and response to medical therapy. A higher proportion of patients in this group tend to have advanced fibrosis upon presentation and a higher association with autoimmune polyendocrinopathy.

PATHOPHYSIOLOGY AND GENETICS

Autoimmune hepatitis (AIH) is a multifactorial polygenetic disease. As with many autoimmune disorders, individuals with certain HLA backgrounds (DR3, DR7, DR13) are at increased risk for AIH. The mechanism of liver injury includes involvement of T cells, NK cells, Macrophages, B cells, and NKT cells. Patients reported in 2 different series show evidence of decreased CD8 lymphocytes, impaired suppressor cells function² and T regulatory cell function.³ Autoreactive reactive T cells also are reported to induce autoantibody production by autologus B cells. In Type II AIH, the target of this humoral response is the cytochrome P450 2D6 (CYP2D6).

CLINICAL FEATURES

Patients often present with an acute hepatitis, accompanied by jaundice and fatigue. The clinical exam can reveal evidence of chronic liver disease. Occasionally, hepatomegaly, splenomegaly, complications of portal hypertension, and skin stigmata of chronic liver disease such as spider angioma can be the presenting feature. Autoimmune hepatitis (AIH) can have a similar clinical presentation to viral hepatitis, drug-induced hepatitis and Wilson disease.

DIAGNOSIS

The diagnostic criteria for autoimmune hepatitis (AIH) are shown in Table 420-1. Autoantibody titers greater than 1/40 are designated as being positive in adults, but in children lower titers of 1/10 to 1/20 are usually considered as being suggestive of a diagnosis. These lower titers fall below the level detected by most commercially available assays, which may explain the frequency of negative antibody titers in children with apparent AIH. Even with more sensitive assays 20% of children are seronegative. Antinuclear antibody (ANA) is nonspecific because it may be present in a wide variety of conditions. Anti-smooth muscle antibody (anti-SMA) is not only more specific but its presence portends a more severe disease progression and an increased risk of relapse. The clinical characteristics of seronegative patients are poorly defined. Liver biopsy is required to make a diagnosis of AIH. Typical findings include a chronic inflammatory infiltrate, with a predominance of plasma cells. Interface hepatitis (piecemeal necrosis), bridging necrosis and lobular collapse are common (Fig. 420-1).

FIGURE 420-1. Autoimmune hepatitis with portal and lobular inflammation, interface hepatitis, and cholestasis (H&E, 10x). (From Fauci AS, Braunwald E, Kasper DL et al (eds). Harrison’s Principles of Internal Medicine. 17th ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies. All rights reserved.)

Table 420-1. Diagnostic Criteria for Autoimmune Hepatitis (AIH)

MEDICAL THERAPY

Autoimmune hepatitis responds exquisitely well to immunosuppressors. Nearly all patients respond except for those with acute liver failure complicated by encephalopathy. Standard treatment consists of 2mg/kg of Prednisone per day (max 60 mg/day). Once the transaminases drop below 100, this steroid dose is weaned down progressively over 4 to 8 weeks to 0.1 to 0.2 mg/kg/day. The patient should be maintained on this very low doses of Prednisone to maintain normal liver chemistries.^1,4

Azathioprine therapy may be required if the liver chemistries do not normalize with steroids therapy. The maximal dose is 2.5 mg/kg/day. It is preferable to delay initiation of azathioprine until the bilirubin levels have either improved substantially or normalized. Azathioprine serves as a corticosteroid-sparing agent allowing a more rapid steroid wean and provides adequate maintenance therapy in 85% of patients with type I autoimmune hepatitis (AIH). Achievement of complete normalization of the liver chemistries often takes 6 to 9 months. Relapse on treatment is seen in up to 40% of patients, but is less frequent if a daily steroids regimen is adopted (highly advisable). Liver chemistries should be monitored at least every 3 months. Treatment cessation should only be considered if: (1) liver chemistries are normal for at least a year, (2) the IgG level is normal, (3) autoantibody titers are very low, and (4) a liver biopsy shows no inflammation (King College Hospital Criteria). Azathioprine is weaned first, then the corticosteroid.⁵

Despite such criteria, the risk of recurrence off immunomodulation is substantial in pediatric-age patients. In a patients series from Kings College’s group, 80% of Type I and 100% of type II patients with AIH recurred following cessation of immunomodulation.¹ Factors identified as putting a patient at high risk for recurrence when immunomodulators are discontinued include being pediatric age at presentation, less than 2 years of treatment, and puberty.

Trials of cyclosporine have shown no advantage compared to prednisone therapy but calcineurin inhibitors (cyclosporine and tacrolimus), or mycophenolate can be considered as alternative treatment approaches in the 10% of patients who are intolerant of both corticosteroids and/or azathioprine. Hepato-carcinoma is rarely reported in patients with AIH. Therefore, yearly screening with liver ultrasound and serum alpha-fetoprotein measurement should be considered.

LIVER TRANSPLANTATION

Despite treatment severe liver dysfunction requiring liver transplantation occurs in 10% of patients within 5 to 15 years of diagnosis. Liver transplantation should also be considered in patients presenting with encephalopathy since these patients have a poor response to medical therapy (suggesting that the liver is irreversibly damaged). Although liver transplantation has improved survival in those patients who progress despite medical therapy, recurrent disease in the graft is common, and can be evident within a few months after transplantation. Weaning from steroids might increase this risk. Diagnostic criteria in the liver transplant patient are similar to those of primary autoimmune hepatitis (AIH), with a liver biopsy showing chronic hepatitis, high IgG level, and positive autoantibody titers. Usually, medical treatment with prednisone and azathioprine is effective at preventing further graft damage or failure.^6,7Some patients who undergo liver transplantation for other indications develop what appears to be a histologic and serologic “classic” AIH. A propensity for this disorder may be related to immune dysregulation caused by the immunomodulators used to prevent graft rejection. In these situations, standard therapy for AIH appears to be effective.⁸

OVERLAP SYNDROME

Half of children initially diagnosed with type I autoimmune hepatitis (AIH) have what is now termed “overlap syndrome” characterized by a histological picture of chronic hepatitis with more prominent biliary inflammation and an abnormal cholangiograms at presentation. Alkaline phosphatase/AST ratio is over 3.⁶ Although patients with overlap syndrome usually respond to immunomodulation as do those with typical AIH, they seem to have more frequent relapses and a higher risk of progression to end-stage liver disease despite therapy. Some patients develop a bile duct paucity or frank sclerosing cholangitis. As a subgroup patients with overlap syndrome have a higher incidence of associated inflammatory bowel disorders (45% vs 20% incidence), and are twice as likely to be pANNA positive (74%). In end-stage liver disease owing to overlap syndrome, liver transplantation is indicated.

PRIMARY SCLEROSING CHOLANGITIS (PSC)

EPIDEMIOLOGY

Primary sclerosing cholangitis (PSC) is a chronic inflammatory condition targeting primarily the extrahepatic bile ducts. In children it is a rare disorder that is most often associated with inflammatory bowel disease (ulcerative colitis > Crohn). Although a fraction of patients with inflammatory bowel disease (IBD) develop overt PSC (2.5% of a series of 555 children with IBD),⁹ virtually all patients with PSC have chronic colitis, often not clinically symptomatic at the time of PSC diagnosis. The median age at diagnosis is 13 years.¹⁰ A positive family history is seen in approximately one-third of patients, and a personal history of other immune disorders (thyroiditis, positive pANCA) is higher than in the average population.

PATHOPHYSIOLOGY AND GENETICS

The underlying cause of primary sclerosing cholangitis (PSC) is unknown, although it is presumed to be an autoimmune disorder. The association with colitis in pediatric patients is unexplained.

CLINICAL FEATURES

Hepatomegaly, splenomegaly, and pruritus are the most common presenting signs.¹¹ Jaundice and fever occur but may be due to cholangitis in patients with primary sclerosing cholangitis (PSC). Cytopenias and ascites may occur due to portal hypertension and splenomegaly. Rarely the presenting feature can be a portal hypertensive complication like variceal bleeding or intractable ascites. With progression, malnutrition, hypoalbuminemia, anemia, recurrent cholangitis, and portal hypertensive complications are common. Persistent jaundice and coagulopathy are usually markers of end-stage disease.

The differential diagnosis of PSC includes cystic fibrosis, overlap autoimmune hepatitis, biliary atresia, neonatal sclerosing cholangitis, langerhans cell histiocytosis, other immunodeficiencies (eg, CD40 ligand deficiency/Hyper IgM syndrome), sometimes associated with cryptosporidiosis, and peri-ductal fibrotic disorders such as autosomal recessive polycystic kidney disease and nephronophthisis. Such disorders should be considered in any child with sclerosing cholangitis.

DIAGNOSIS

Increased liver transaminases are often the first biochemical signature of PSC in children. The cholestatic enzyme markers (alkaline phosphatase and gamma-glutaric transglutaminase) tend to increase with disease progression and eventually become the predominant biochemical abnormalities. Patients with primary sclerosing cholangitis (PSC) usually have negative autoimmune markers (ANA, SMA, LKM-1). Those with positive markers are likely to have overlap syndrome as evidenced by high IgG, and often a chronic hepatitis picture on the liver biopsy. These patients respond to immunomodualtors and therefore it is important to differentiate these patients from those with classical PSC.

Diagnosis of PSC rests on having evidence of liver disease with biochemical markers pointing toward a cholestatic process (AlkP/AST > 5, and ALT < 10× normal) in a child with no known immunodeficiency. The diagnosis is confirmed by an ERCP or MRCP showing beading of the extrahepatic and intrahepatic ducts. A liver biopsy is often required for diagnosis in the early stages of disease. It shows chronic pericholangitis and periductular fibrosis, with different degrees of liver fibrosis.

TREATMENT

There is currently no known curative treatment for primary sclerosing cholangitis (PSC). The disease typically does not respond to immunomodulators including corticoteroids and azathioprine. Trials of bile acids therapy (UDCA) in adults show improved biochemical profiles but continued disease progression, Unfortunately, treatment only focuses on management of complications of PSC, and supportive care. Complications are mostly related to portal hypertension, bacterial cholangitis, and hepato-cellular carcinoma. When complications lead to end-stage liver disease it is reasonable to consider liver transplantation but recurrent disease in the liver graft is frequent. All patients with PSC require close monitoring for colonic carcinoma after transplantation (yearly colonoscopy) since an incidence of up to 50% is reported in some adult series regardless of the presence of clinical colitis.