Autoimmune liver disease overlap syndromes

Autoimmune liver disease overlap syndromes are conditions that manifest with features of more than one autoimmune liver disease, most commonly autoimmune hepatitis (AIH) with primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC). These syndromes are considered clinical descriptions rather than distinct pathological entities. The AIH-PBC overlap syndrome is more common in women, while the AIH-PSC overlap syndrome is more common in younger men and is strongly associated with inflammatory bowel disease (IBD). Diagnosis of AIH-PBC overlap requires features of both conditions, including elevated transaminases and cholestatic liver injury, specific autoantibodies, and histology findings of interface hepatitis and florid bile duct lesions. Diagnosis of AIH-PSC overlap requires probable or definite AIH, negative antimitochondrial antibodies (AMA), and cholangiographic evidence of PSC. AIH-cholestatic syndrome is an autoimmune liver disease characterized by AIH with cholestatic liver injury that does not meet the diagnostic criteria for PBC or PSC. Treatment is directed at the predominant disease, typically involving combination therapy with ursodeoxycholic acid and immunosuppressants (e.g., glucocorticoids). Overlap syndromes are associated with an increased risk of cirrhosis, treatment failure, and a need for liver transplant.

General principles ^[1]

• Consider overlap syndromes in patients with confirmed or suspected AIH and features of PBC or PSC.
• Assess for elevated transaminases and cholestatic enzymes.
• Evaluate for IBD.
• Confirmatory criteria or liver biopsy are often required.

Initial studies ^[1]

• Liver chemistries
• MRCP or ERCP
• AMA
• Anti-smooth muscle antibody (ASMA)

Interpretation ^[1]

Overlap syndromes are identified based on serology (AMA, ASMA) and cholangiography (MRCP or ERCP) findings.

Definition

AIH-PBC overlap syndrome is an autoimmune liver disease characterized by clinical, serological, and histopathological features of both AIH and PBC.

Epidemiology

• Prevalence
  • Occurs in 1–3% of patients with PBC ^[2]
  • Occurs in 7% of patients with AIH ^[2]
• ♀ > ♂ ^[1]

Etiology

The exact cause is unknown but likely involves a combination of environmental triggers, genetic predisposition, and/or defects in immune tolerance mechanisms. ^[1]

Clinical features ^[1][2]

Features of both conditions may manifest simultaneously or sequentially.

• Fatigue
• Pruritus
• Jaundice
• Diarrhea
• Abdominal pain
• Weight loss
• Arthralgia

Diagnosis ^[1][2][3]

• Suspect AIH-PBC overlap syndrome in patients with features of both diseases, particularly those with an inadequate response to treatment. ^[1][3]
• Refer to hepatology or gastroenterology for diagnostic confirmation.
• Diagnostic confirmation requires meeting criteria for both PBC and AIH. ^[1][2]
  • PBC criteria (≥ 2 of the following) ^[1][3]
    • ALP ≥ 2× ULN or GGT ≥ 5× ULN
    • Positive antimitochondrial antibodies
    • Liver biopsy showing florid bile duct lesions
  • AIH criteria (≥ 2 of the following) ^[1][3]
    • ALT ≥ 5× ULN
    • IgG ≥ 2× ULN or positive anti-smooth muscle antibodies
    • Liver biopsy showing moderate to severe interface hepatitis
• Antibodies to soluble liver antigen/liver pancreas and double-stranded DNA may also be positive. ^[1]

Differential diagnoses ^[1]

• AIH
• PBC
• AIH with incidental AMA positivity
• AIH-cholestatic syndrome
• AMA-negative PBC

Management ^[1][2][3]

Refer to hepatology or gastroenterology for management.

Pharmacotherapy ^[1][3]

• Preferred: combination therapy with ursodeoxycholic acid plus and an immunosuppressant (e.g., prednisone ) ^[1][3]
  • Azathioprine may be added as a steroid-sparing agent. ^[1][2]
  • Immunosuppression is particularly recommended for patients with moderate to severe interface hepatitis on biopsy. ^[1]
• Alternate agents: for patients who can not tolerate or are unresponsive to glucocorticoids and/or azathioprine ^[2]
  • Mycophenolate mofetil
  • Tacrolimus
  • Cyclosporine

For patients who do not fully meet the diagnostic criteria, treatment should be directed at the predominant disease. ^[1][3]

Prognosis ^[2]

• Patients with AIH-PBC overlap syndrome typically have a worse prognosis than those with either PBC or AIH alone.
• Nearly 50% of patients develop cirrhosis within 10 years. ^[2]
• 10-year transplant-free survival rate ranges from 52–92%. ^[2]

Definition

AIH-PSC overlap syndrome is an autoimmune liver disease characterized by clinical, serological, and cholangiographic features of both AIH and PSC.

Epidemiology

• Prevalence among patients with PSC ^[1][4]
  • Adults: 5–14% ^[1][4]
  • Children: up to 35% ^[4]
• Prevalence among patients with AIH ^[1][2]
  • Adults: 2–10% ^[1]
  • 41% in patients with concurrent ulcerative colitis ^[1]
  • Children: up to 50% ^[1][2]
• Typically affects younger populations (mean age of 25 years) ^[1]
• ♂ > ♀

Etiology ^[1]

• The exact etiology is unknown but likely involves genetic predisposition, environmental triggers, and/or altered immune regulation.
• Strongly associated with IBD, especially ulcerative colitis

Clinical features ^[1]

• Patients are typically asymptomatic at diagnosis.
• When present, symptoms may include:
  • Fatigue
  • Jaundice
  • Pruritus
  • Diarrhea

Diagnosis

General principles ^[1][4]

• Suspect AIH-PSC overlap syndrome in patients with AIH who have concurrent IBD, unexplained elevated cholestatic liver enzymes, and/or inadequate response to glucocorticoid therapy.
• Refer to hepatology or gastroenterology for diagnosis.
• Diagnostic confirmation requires:
  • Probable or definite AIH
  • Negative AMA
  • MRCP findings of multifocal bile duct strictures
• Concurrent IBD is common but not required for diagnosis.

Laboratory studies ^[1][4]

• ↑ ALK and GGT
• ↑ AST and ALT
• ↑ IgG and IgM
• Positive ANA and/or anti-smooth muscle antibodies (characteristic of AIH) ^[3]
• p-ANCA may be present.
• Negative AMA

Imaging ^[4]

• First line: MRI with MRCP
• Findings: multifocal intrahepatic and/or extrahepatic strictures alternating with normal or slightly dilated segments

Liver biopsy ^[4]

• Indication: concern for overlap syndrome
• Findings include features of both conditions:
  • PSC: periductal fibrosis (e.g., "onion skinning"), fibro-obliterative duct lesions, ductular reaction, bile duct loss
  • AIH: lymphoplasmacytic interface hepatitis

Differential diagnoses ^[1][4]

• AIH without PSC
• PSC without AIH
• IgG4–related sclerosing cholangitis
• Secondary sclerosing cholangitis (e.g., infectious, ischemic, malignant)

Management ^[2][3][4]

• Refer to hepatology or gastroenterology for management.
• Combination therapy with immunosuppression (e.g., prednisone ± azathioprine) plus ursodeoxycholic acid is often used.
• Liver transplant is the definitive treatment for patients with advanced liver disease. ^[1]

Treatment is directed at the predominant disease. ^[3]

Prognosis

• Patients with AIH-PSC overlap have a poorer long-term survival than patients with AIH alone. ^[1]
• Patients with AIH-PSC overlap may have better survival outcomes compared to patients with PSC alone. ^[1]
• Overall 10-year survival rate ^[2]
  • Children: 89%
  • Adults: ∼ 67%