Autoimmune liver disease in gastrointestinal conditions : Clinical Liver Disease

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REVIEWS: New Innovations in Pediatric Autoimmune Liver Disease

Autoimmune liver disease in gastrointestinal conditions

Nassar, Raouf1,2; Waisbourd‐Zinman, Orith*,1,3

Editor(s): Lin, Henry Guest Editor

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Clinical Liver Disease 20(4):p 108-110, October 2022. | DOI: 10.1002/cld.v20.4
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Nassar R, Waisbourd‐Zinman O. Autoimmune liver disease in gastrointestinal conditions. Clin Liver Dis. 2022;20:108–110., Waisbourd‐ZinmanO. Autoimmune liver disease in gastrointestinal conditions. Clin Liver Dis. 2022;20:108–110.


Disorders of the hepatobiliary system are relatively common manifestations of gastrointestinal (GI) diseases, in part because of the close anatomical and physiological relations between the gut and the liver.1 Autoimmune liver diseases, characterized by elevated transaminase levels, inflammatory liver histology, and circulating autoantibodies,2 are associated with several GI conditions. In this review, we discuss the relationship between autoimmune liver disease (specifically autoimmune hepatitis [AIH], primary sclerosing cholangitis [PSC], and AIH/PSC overlap) and celiac disease, autoimmune enteropathy (AE), and inflammatory bowel diseases (IBDs).


Celiac disease is a systemic autoimmune disease due to a dysregulated mucosal immune response to gluten and related prolamins,3 resulting in intestinal and extraintestinal manifestations, including liver disorders.4 The prevalence of elevated liver enzymes in celiac disease is 15% to 61%; the presentation ranges from asymptomatic elevation of transaminases to chronic liver disease.4,5 Conversely, the prevalence rate of celiac disease in unexplained hypertransaminasemia is 10%.5

The pathogenesis of the above is unknown and thought to result from increased intestinal permeability, mucosal damage, inflammation, and malnutrition. Celiac hepatitis refers to isolated elevations of alanine transaminase and aspartate transaminase, which are often present at diagnosis of celiac disease and usually resolve within 6 to 12 months of a gluten‐free diet (GFD). However, although rare, deterioration to fibrosis and cirrhosis has been reported.1,3,4 Liver histology in celiac hepatitis is nonspecific hepatitis with mild periportal inflammation, focal ductular proliferation, minimal steatosis, and typically absence of chronic changes.4 Liver biopsy is not indicated unless suspicion arises of a concomitant liver disease (i.e. AIH) or if liver enzymes are not normalized within 6 to 12 months of initiating a GFD.5 AIH concomitant with celiac disease is less common than celiac hepatitis. Celiac disease has been reported in 6.3% of individuals with AIH, and 2% to 3% of those with PSC.6 The pathophysiology of AIH in patients with celiac disease is not driven by gluten because GFD alone does not improve the liver tests, and immunosuppressive therapy is required. It is unknown if the prognosis of AIH with celiac disease is different from that of AIH alone, and the impact of GFD on the progression of AIH remains uncertain.6 Notably, small studies have shown higher rates of treatment‐free remission among children with AIH and celiac disease on a GFD than among children with AIH alone. Moreover, several children with celiac disease and AIH experienced AIH relapse during spontaneous gluten challenges.3,6 We recommend checking liver enzymes yearly.


AE is a group of diseases caused by the abnormal intestinal immune‐mediated response, which presents as severe intractable diarrhea in early childhood.7 Patients with AE can have various GI manifestations and other autoimmune disorders, such as gastritis, pancreatitis, hepatitis, hypothyroidism, and arthritis.7,8

Individuals with AE may be affected by other autoimmune disorders, sometimes leading to particular forms such as autoimmune polyglandular syndrome type 1.8 This autosomal recessive disease caused by mutation in the AIRE gene is characterized by candidiasis, hypoparathyroidism, and adrenal insufficiency. Other manifestations include type 1 diabetes, thyroid disease, and AIH.7 Treatment of AE with or without AIH is the same and includes corticosteroids, immunomodulators (such as azathioprine), and biologic drugs (such as infliximab, adalimumab, and vedolizumab).7,9 Patients with AE usually get frequent laboratory workups; we recommend checking liver enzymes at least twice a year.


IBDs are a group of chronic inflammatory diseases of the GI tract that include Crohn's disease (CD), ulcerative colitis (UC), and unclassified bowel disease.10,11 Hepatic disorders are common in children with IBD, and abnormal liver enzymes are reported in 20% to 30% of patients.12 In the context of IBD, elevated liver enzymes can result from the disease itself, from complications of the medical therapy, or from an underlying primary liver immune disorder.1,12 Liver disorders in patients with IBD include AIH, PSC, and PSC/AIH overlap syndrome, nonalcoholic fatty liver disease, and venous thrombosis. In this review, we discuss autoimmune liver diseases associated with IBD. Although there are no specific guidelines, we recommend checking liver enzymes for patients with IBD biannually with other routine laboratory tests.


PSC is a chronic, progressive, cholestatic liver disease characterized by inflammation and fibrosis of the entire biliary tree, with multifocal bile duct strictures. The incidence of PSC is 0.2 per 100,000 children.12 PSC occurs mostly in individuals with IBD; about 70% of patients with PSC have IBD, mostly (75%) UC,13 and up to 4% of patients with UC have PSC.12 The term PSC‐IBD refers to the unique IBD phenotype with PSC, characterized by higher prevalence of pancolitis with rectal sparing and a more backwash ileitis compared with UC. Individuals with CD and PSC are more likely to have Crohn's colitis.12,14 Patients with PSC‐IBD exhibit a decreased rate of severe IBD, with a lower rate of colectomy. In contrast, they have a higher pouchitis rate after colectomy, and colorectal cancers are more common.12

Notably, liver involvement in PSC‐IBD is independent of the severity of the gut disease; the PSC course is not changed in patients after colectomy, and immunosuppressive therapy for IBD does not affect PSC progression.14 PSC adds significant morbidity and mortality to pediatric PSC‐IBD, because of cholangitis episodes, progression to end‐stage liver disease, and higher rates of cholangiocarcinoma development in up to 37% of adult patients within 5 years of PSC diagnosis. Immunosuppressive and immunomodulatory medications have not demonstrated benefit. In the pediatric population, data on ursodeoxycholic acid (UCDA) and vancomycin therapy are limited, and liver transplantation remains the treatment of choice for progressive PSC.15 Some case series and case reports showed biochemical improvement of PSC with vancomycin and UCDA treatment, including in children.16,17 However, in a recent large pediatric study, neither UCDA nor vancomycin showed improved outcomes compared with observation only.15 Moreover, some reports showed that high‐dose UCDA (28‐30 m/kg/day) could cause more adverse effects, including death, liver transplantation, cirrhosis, esophageal varices, and cholangiocarcinoma, compared with placebo.18


The frequency of AIH in individuals with IBD is 0.6% to 1.6%. The prevalence of AIH in the general pediatric population is unknown, with an estimated annual incidence of 0.26 per 100,000 children.2 The clinical presentation of AIH is wide and nonspecific, including fatigue, nausea, and abdominal pain. In patients with IBD, AIH is usually diagnosed after a persistent elevation of transaminases that prompts further workup. A liver biopsy is currently still necessary to rule out other causes, such as drug toxicity, and to provide information about liver damage.2,12,19 Treatment of AIH does not generally differ between patients with and without IBD, and it includes steroids and steroid‐sparing medication such as azathioprine.2 Data are currently insufficient to determine whether the disease course of AIH differs in patients with and without IBD.12

As noted earlier, elevated liver enzymes in patients with IBD may be caused by medications. Albeit rare, anti‐tumor necrosis factor‐α (TNF‐α)‐induced AIH has been described in a number of reports.20 In case reports of children with IBD, autoimmune features in liver biopsies normalized after discontinuation of anti‐TNF‐α therapy.21,22 In contrast, refractory AIH was reported to respond to infliximab therapy.2,23 Thus, large‐scale studies are needed to determine the role of anti‐TNF‐α therapy in both inducing and treating AIH.

AIH/PSC overlap

AIH/PSC overlap is more strongly associated with IBD than AIH, although the clinical presentation of the two diseases is similar.12 The main difference between AIH and AIH/PSC is the evidence of cholangiopathy. Children with IBD and apparent AIH must be routinely investigated for evidence of biliary disease with magnetic resonance cholangiopancreatography because γ‐glutamyl transferase can be normal in the early course of AIH/PSC. Correct identification of AIH/PSC is essential, because the prognostic implications differ from AIH and are more similar to PSC alone. Notably, AIH has been reported to evolve into AIH/PSC in association with IBD. The treatment of AIH/PSC includes steroids or azathioprine.2,12 The use of UCDA or vancomycin may be considered, and they are commonly in use; however, it should be noted that no benefits have been proved in clinical trials.16


Nothing to report.


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