Autoimmune liver disease in children has a wide spectrum, including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and the overlap syndrome of AIH/PSC, also known as autoimmune sclerosing cholangitis (ASC).1 These liver disorders are immune-mediated and progressive in nature, and they are not secondary to inherited or acquired metabolic disease, viral infection, or drugs. Extrahepatic autoimmune disease, such as inflammatory bowel disease (IBD), may also be present. As there is considerable overlap in the clinical presentation of these diseases, confusion may arise when clinicians attempt to distinguish them (Table 1). This article reviews the epidemiology, etiology, presentation, diagnosis, and management of AIH, PSC, and ASC.
Autoimmune hepatitis is rare, chronic, and progressive. It was first described as being immune-mediated in 1950 by Waldenstrom.2 It is a diagnosis of exclusion in that it is not secondary to inherited or acquired metabolic disease, viral infection, or drugs. There are two types of AIH that affect children: type 1 and type 2. AIH type 1 is typically antinuclear antibody (ANA) and/or anti-smooth muscle antibody (anti-SMA) positive, whereas AIH type 2 is anti-liver kidney microsomal type 1 antibody (anti-LKM-1) positive and/or anti-liver cytosol type 1 antibody (anti-LC-1) positive.3 Both can also be anti-soluble liver antigen antibody (anti-SLA) positive.
Prior to 1999, there were no standard criteria for the diagnosis of AIH, so examining the characteristics and demographics of children with AIH was difficult. Based on the literature, the prevalence of AIH ranges from 5 to 20 per 100,000.4 Its peak incidence is in the second and third decades of life.5 It more commonly affects women and is strongly associated with other autoimmune diseases in the patients themselves or in first-degree relatives.3,6 Multiple studies have described the frequency of AIH in patients with IBD as ranging from 0.6% to 1.6%.7 AIH type 1 more commonly affects adolescents, whereas AIH type 2 more frequently affects younger children.
Although the initial insult is unknown, AIH is thought to be multifactorial in nature, with environmental, genetic, and immune contributions. The immune-mediated inflammation in AIH is thought to derive from decreased regulatory T-cell function, leading to the loss of self-tolerance to specific liver antigens by the patient's immune system.8,9
Patients with AIH often present with generalized symptoms, including fatigue, fever, nausea, and vomiting. They may also present with symptoms of cholestasis, including jaundice, pale stools, dark urine, and itching.3 Based on a 20-year retrospective review of children with AIH, about 55% of patients present acutely, over a period of days to weeks, which can lead to a misdiagnosis of a viral or toxic hepatitis.3 About 35% of patients can have a more gradual progression of symptoms over a period of months.3 These children present with signs and symptoms of advanced liver disease, including hepatosplenomegaly, spider veins, ascites, and coagulopathy. Finally, about 10% of patients are asymptomatic and are diagnosed based on an incidental finding of elevated transaminases on routine laboratory testing.3
The diagnosis of AIH is defined by (1) elevated transaminases, (2) elevated immunoglobulin G (IgG) levels, (3) presence of autoantibodies (ANA, anti-SMA, anti-LKM1, and/or anti-LC1), (4) periportal hepatitis on histology, and (5) absence of known etiology for hepatitis. As AIH is rare, it is considered a diagnosis of exclusion; therefore, the more common causes of hepatitis must be ruled out first. These include the viral hepatidities (A, B, and C), Wilson's disease, drugs, alpha-1 antitrypsin deficiency, and nonalcoholic fatty liver disease.
The diagnostic criteria for AIH were defined by the International Group for the Study of AIH in 19996 and later simplified for clinical use by Hennes et al.10 in 2008. These simplified criteria can be found in Table 2. Further study of both these criteria by Hiejima et al.9 showed that neither were able to differentiate between AIH and PSC; therefore, a negative cholangiogram is needed to rule out PSC.9
Diagnostic Criteria for Autoimmune Hepatitis
Prior to the use of immunosuppression, untreated AIH had a poor prognosis, with 5- and 10-year survival rates of 50% and 10% respectively.11 Immunosuppressants have been found to achieve remission rates of more than 80%.12 Prednisone is usually initiated first, then azathioprine is added with the goal of weaning the patient off the steroids. Transaminases and IgG levels are monitored throughout treatment, and remission is defined when both of them have normalized and there are none or only low-level autoantibodies detected. Biochemical remission is defined as normalization of laboratory values, whereas complete remission requires histologic normalization. As histological normalization can lag significantly behind (as much as 12–18 months), the goal of treatment is biochemical remission.13
In a study of 33 children and adolescents with AIH over a 25-year period, rates of overall survival without liver transplantation did not differ between those who had cirrhosis at the time of diagnosis and those who did not.12 This signifies that immunosuppressive treatment can be successful in reversing end-stage liver disease in AIH. About 10% of AIH patients do not achieve remission and continue to progress toward liver failure.12 Liver transplantation remains a viable option for these patients, but disease recurrence in the transplanted liver has been documented.10
Primary Sclerosing Cholangitis
PSC is a rare biliary disease that presents as chronic cholestasis and results in destruction of the intra- and/or extra-hepatic biliary tree, leading to multifocal biliary strictures. A variety of sclerosing cholangitis diseases are secondary to lesions in the bile duct or systemic disease. A pediatric patient can only receive a diagnosis of PSC in the absence of positive genetic markers or associations with diseases that are known to include biliary structuring as a manifestation, such as autoimmune disorders, immunodeficiencies, cystic fibrosis, and sickle cell anemia.14,15
The incidence rate in children, predicted by a study conducted in 2007, was reported to be 0.23 per 100,000 person-years compared to 1.11 in adults.16 Its incidence is felt to be rising due to increased screening of patients with IBD. PSC is associated with IBD, mostly ulcerative colitis, in 33% to 81% of children.17 Multiple case series have found that PSC is more common in boys and men (62%), with the average age of onset between ages 10 and 16 years.14,17,18
The etiology of PSC is not well understood. It is likely triggered by an alteration of the immune system, but it is not an autoimmune disease.19 The pathogenesis of PSC seems to be due to chronic portal tract bacterial colonization, toxic bile acid metabolites produced by the intestinal flora, chronic infections, and ischemic vascular damage. These processes start an immune-related destruction of the biliary tree.17 The successful use of oral vancomycin (described later in the article) also favors this theory. However, given that vancomycin is also an immunomodulator, its successful use may support the theory that there may be an autoimmune disorder of lymphocytes. The recurrence of PSC after liver transplantation suggests a T cell-mediated process.
Most patients with PSC are asymptomatic at diagnosis; those who are symptomatic present with fatigue, right upper quadrant abdominal pain, and hepatomegaly. A history of IBD is also common. Although a benign physical examination is more common on presentation, jaundice, hepatomegaly, and splenomegaly are frequent findings in patients with advanced disease.17 Persistently elevated cholestatic markers such as total bilirubin, alkaline phosphatase, and gamma-glutamyl transferase (GGT) are often an indication to further investigate.
PSC may be seen concomitantly associated with autoimmune hepatitis. If autoimmune markers of ANA or anti-SMA are found in a patient with confirmed PSC, then the patient is diagnosed with overlap syndrome and not solely PSC. Overlap syndrome occurs more than 50% of the time with PSC (see the following section on ASC).
Endoscopic retrograde cholangio-pancreatography (ERCP) is considered the gold standard for diagnosis of large duct PSC, but magnetic resonance cholangio-pancreatography (MRCP) is becoming more favored. MRCP is noninvasive, does not involve radiation, and poses no risk of pancreatitis (which can occur with use of ERCP). MRCP has been found to be 84% sensitive in diagnosing PSC in children.20 It does not reliably predict early disease, as does ERCP. Imaging rarely leads to diagnosis, but evidence of disease can be seen. Radiographic findings of a “beaded appearance” due to multifocal strictures and dilation of the intra- and extrahepatic biliary tract of the liver may suggest PSC. Abdominal ultrasound is usually normal, but bile duct wall-thickening and/or focal bile duct dilations may be seen.
Liver biopsy is necessary when small duct PSC is suspected and MRCP fails to demonstrate large duct abnormalities suggestive of PSC. The histological finding of this “onion skin” type of periductal fibrosis is the diagnostic feature of this disease, although it is not seen in all cases.19 Also, the possibility of concurrent ASC (ie, the overlap syndrome of AIH/PSC) must be ruled out, especially if certain laboratory markers (liver transaminases, ANA, smooth muscle antibody, or IgG) that are not usually found in isolated PSC are elevated.
One case series19 looked at 11 cases of PSC, and histopathology showed that patients had chronic hepatitis (82%), bile duct damage (73%) and proliferation (80%), and fibrosis (55% stage 4). Although these numbers are not statistically significant, they can help with suggestion of disease. Concentric fibrosis was only found in 44% of patients; therefore, it may not be as reliable of a marker as in adults. Histologic findings at diagnosis are not predictive of disease progression.
Unlike AIH and ASC, PSC does not require or improve with immunosuppression. Ursodeoxycholic acid is considered the mainstay treatment for PSC, but after it was shown to not slow disease progression or prolong survival, other classes of medications have been researched.17 Antibiotics, notably vancomycin, have shown promise.
Ursodeoxycholic acid is a hydrophilic dihydroxy bile acid that increases hepatocellular bile-acid excretion, bile flow, and micelle formation. It modifies the bile-acid pool by decreasing the level of hydrophobic bile acids, which increases the proportion of hydrophilic bile acids that are less toxic. This helps stabilize liver membranes and decrease apoptosis of hepatocytes. It has been proven to reduce biochemical markers for up to 20 months, but data on more long-term use still need to be published.17 A trial was conducted in adults using high-dose ursodeoxycholic acid, which was found to lead to increased morbidity;21 therefore, it is recommended that doses >20 mg/kg per day not be used in the pediatric population.17
Several antibiotics have been studied in the treatment of PSC. A long-term study on tetracyclines showed no benefit in adults.22 However, a pilot study of 16 adult patients with PSC given minocycline as treatment has shown significant results in reduction in alkaline phosphatase levels.23 Further clinical investigation is warranted prior to trying this antibiotic for children older than age 8 years old. A recent randomized, placebo-controlled trial using metronidazole with or without ursodeoxycholic acid showed improvement in alkaline phosphatase levels but no statistically significant effect on disease progression.24 Increasing evidence for oral vancomycin has been published. Oral vancomycin has been studied in two randomized clinical trials, multiple case series, and case reports and has been found to successfully reduced patients' risk score.24 Starting with an initial dose of 50 mg/kg per day, oral vancomycin reduces inflammatory markers and liver enzymes significantly. One study by Abarbanel et al.25 also found improvements on MRCP and liver biopsy within 12 weeks of starting oral vancomycin therapy.
Endoscopic therapies include balloon dilation and stent placement, which significantly improve symptoms and defer the need for transplantation. Multiple therapy sessions are needed to successfully reopen strictures, which can lead to the common complications of cholangitis and pancreatitis. Intravenous antibiotic can successfully treat these complications.
Liver transplant is the definitive treatment for advanced stage PSC. One case series found that 12% of children diagnosed with PSC from 1993 to 2011 underwent liver transplant, on average 7.5 years after diagnosis.18 Indications for liver transplantation include cirrhosis with impaired liver function, hemorrhage due to esophageal varices or portal gastropathy refractory to medical therapy, intractable ascites (with or without spontaneous bacterial peritonitis), recurrent episodes of bacterial cholangitis, growth failure, and hepatic encephalopathy.17 In the Studies of Pediatric Liver Transplantation registry, which looked at causes of liver transplant in children between 1995 and 2003, PSC accounted for 70 of 2,139 (3.3%) children listed.17 Unfortunately, recurrence has been reported to be 20% to 37%, with increased risk factors including male sex and absence of the colon.17
Antihistamines are first-line management of pruritis. Bile-acid binding resins work well; colestipol and colesevelam are reportedly better tolerated than cholestyramine.17 Ursodeoxycholic acid, phenobarbital, and rifampin can also lead to improvement in cholestatic pruritis. Opioid antagonists (such as naloxone, naltrexone) can be used successfully in adults.
Autoimmune Sclerosing Cholangitis
In 2001, Gregorio et al.26 defined an overlap syndrome of AIH and PSC. It consists of clinical, biochemical, and histological manifestations of typical AIH plus radiographic features suggestive of sclerosing cholangitis. Their study showed that 52% of children with AIH also showed bile duct abnormalities diagnostic of sclerosing cholangitis. They proposed calling this overlap syndrome “autoimmune sclerosing cholangitis,” due to the fact that it responds favorably to immunosuppression.
ASC is rare, with a prevalence of 0.6 per 100,000.27 The female preponderance that is present in AIH and PSC is still present, but less strongly in ASC (79% vs 55%).27 Patients with concomitant IBD (ulcerative colitis, Crohn's disease, or indeterminate colitis) are more likely to have ASC than isolated AIH. In contrast to adults, this overlap syndrome of AIH/PSC (ASC) is more common in children than isolated PSC.26
ASC as an overlap syndrome between AIH and PSC is a clinical description, not a defined pathological entity. There are many pathogenic hypotheses for ASC: as a variant of classical AIH, as a transitional stage between AIH and PSC, as concurrent diseases, or as distinct diseases.28 If ASC and AIH are both part of the same autoimmune liver disease process, it is unclear why the inflammatory process is confined to the liver parenchyma in some patients, whereas in others it involves the biliary tree. In patients with PSC and IBD, it has been suggested that bile duct damage is secondary to portal bacteremia or absorption of colonic toxins in those who are genetically predisposed.29 This may also be true in patients with ASC with IBD, which included 44% of ASC patients in the study by Gregorio et al.26
Patients with ASC present similarly to patients with PSC and AIH, with vomiting, diarrhea, abdominal pain, anorexia, fatigue, and less commonly with pruritis and weight loss. Signs on physical examination include jaundice, hepatomegaly, and splenomegaly. Laboratory features include elevated total bilirubin, elevated GGT, mildly elevated aspartate aminotransferase (AST), and positive autoimmune titers (ANA, SMA, LKM, and antineutrophil cytoplasmic autoantibodies). Cholangiography reveals irregularity, stricturing, and/or focal dilation in the intra- and/or extrahepatic bile ducts.
Diagnostic criteria for the overlap syndrome of AIH, including ASC, were proposed by Czaja in 2013.28 The diagnosis of the AIH component in ASC may be established with the original or simplified criteria, as discussed previously.6,10 A “probable” or “definite” diagnosis of AIH per these criteria is required for the diagnosis of ASC. To diagnose the sclerosing cholangitis component of ASC, cholangiography must show focal strictures and dilations of the biliary tree.28,30 Because ASC is much more common in children than adults, even without concomitant IBD, the threshold for performing cholangiography in children newly diagnosed with AIH is much lower.26,30
Like AIH, the cornerstone of treatment in ASC is immunosuppression. If histological changes are mild and there is minimal transaminase elevation on diagnosis, treatment may be commenced with ursodeoxycholic acid alone; however, most patients will require immunosuppressive medications at some point during their course of treatment. In patients with elevated transaminases, steroids and azathioprine are commonly used (as in AIH). Although these treatments are effective in reducing liver parenchymal damage in ASC, they may not be as efficacious in preventing progression of bile duct disease.26 On the other hand, some studies show that there is no difference in response to treatment between AIH and ASC.30 Penicillamine, cyclosporin, and colchicine are sometimes added to the treatment regimen for resistant cases.
Biochemical markers such as AST, alkaline phosphatase, and GGT are inadequate prognostic markers for bile duct disease in ASC; therefore, cholangiographies performed at regular intervals are essential to monitor these patients. The presence of sclerosing cholangitis in ASC predisposes these patients to cholangiocarcinoma, as in PSC. In addition, transplant-free survival at 10 years is significantly lower in patients with ASC than in patients with AIH.26