Page 1060 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 76 Inflammatory Hepatobiliary Diseases 1023

Serum autoantibodies against LKM-1 are the main serological
markers of AIH-2 and recognize the proximal renal tubule and Therapy
hepatocellular cytoplasm. The 50-kDa autoantigen was identified In contrast to other autoimmune liver diseases, immunosup-
as the cytochrome P450 2D6 (CYP2D6). Interestingly, the sequence pressants are the treatment of choice for AIH, based on the good
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between amino acids 316 and 327, which is most likely exposed response in terms of biochemistry, histology, and survival.
on the surface of the molecule, appears to be a region capable Corticosteroids, in particular prednisone, represent the first-line
of differentiating LKM-1 activity in AIH and HCV and may of treatment in monotherapy or in combination with azathioprine,
represent a key target for autoimmunity. The mechanisms of inducing remission (i.e., normal transaminases and IgG levels)
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onset remain enigmatic, and solid evidence of a causative role in over 80% of patients, regardless of the presence of cirrhosis.
of hepatitis C virus cross-reactivity is still awaited. Similarly, the Once achieved, remission can be maintained with azathioprine
pathogenic role of anti-LKM-1 antibodies and their prognostic alone. Relapses after therapy discontinuation are common since
significance are debated, despite the development of AIH-2 in only 20% of patients remain in sustained remission. It should
animal models after immunization with human CYP2D6 or with be noted, however, that subgroups of patients manifest disease
adenoviruses in mice transgenic for human CYP2D6. Finally, two progression (approximately 10%) or are intolerant to standard
other types of serum anti-LKM have been described in patients therapy (13%). In such patients, other drugs have been anecdotally
with ticrynafen-associated hepatitis (anti-LKM-2, directed against tried, including methotrexate, cyclophosphamide, tacrolimus,
CYP2C9) and in 10% of patients with type 2 AIH (anti-LKM-3, ursodeoxycholic acid, cyclosporine, and mycophenolate mofetil,
directed against uridine-diphosphate glucuronosyl transferase 1A the latter two being those most frequently reported as alternative
[UGT1A]), either alone or in combination with LKM-1 antibodies. medications. Liver transplantation is the ultimate treatment for
Anti-SLA/LP antibodies are detectable by radioimmunoassay AIH patients presenting with acute liver failure or end-stage
and enzyme-linked immunosorbent assay, but not by immuno- chronic liver disease and for those with hepatocellular carcinoma
fluorescence, and are directed against various epitopes of a UGA that meet the transplant criteria. Although liver transplantation
tRNA suppressor. Serum anti-SLA/LP antibodies are occasionally for AIH is very successful, it should be noted that AIH may recur
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found in patients with AIH who are negative for ANA, SMA, after transplant. Patients with AIH undergoing liver transplant
and anti-LKM and are cumulatively detected in 10–30% of cases have overall 5- and 10-year survival rates of 90% and 75%,
of AIH-1 and -2. Recent data indicate that anti-SLA/LP antibodies respectively, although infectious complications and disease
are also detectable in subgroups of pediatric patients with recurrence are common. 15
autoimmune cholangitis or in adult patients with HCV infection
when tested with sensitive methods.
Anti-LC1 antibodies are detected by indirect immunofluo- KeY COnCePts
rescence in sera from up to 50% of patients with type 2 AIH
and less frequently in type 1 AIH or chronic hepatitis C. • Autoimmune hepatitis (AIH) is a severe autoimmune disease associated
Importantly, however, anti-LC1s are the only detectable markers with high morbidity and mortality, especially due to the development
in 10% of AIH cases. The LC1 autoantigen is the liver formimi- of cirrhosis and possibly hepatocellular carcinoma.
notransferase cyclodeaminase, an enzyme involved in folate • Autoantibodies represent a distinctive feature of AIH and can also aid
in the definition of AIH subsets.
metabolism. Interestingly, serum anti-LC1 antibodies correlate • Liver biopsy is helpful, and histology remains the gold standard for
with AIH severity and progression. grading and staging, particularly to determine the response to therapy.
Antibodies to the asialoglycoprotein receptor are observed
in up to 90% of all patients with AIH and often coexist with
other autoantibodies while lacking specificity for the disease.
Similar to anti-LC1, however, antiasialoglycoprotein titers are CLInICaL PearLs
associated with more florid inflammatory disease activity and
with less effective treatment responses. • Autoimmune hepatitis (AIH) may cause an increase in aminotrans-
Finally, antibodies to neutrophil cytoplasmic antigens (pANCA) aminases and in cholestatic markers.
can be detected by indirect immunofluorescence in sera from • Autoantibody testing is helpful. Antinuclear antibodies (ANAs), SMAs,
and antiliver/kidney microsomal (LKM) are the most important, but
patients with AIH-1; they also can be detected in a subgroup of other sets of autoantibodies also should be tested in suspected cases,
patients with PSC or chronic viral hepatitis. in particular anti-LC1, perinuclear antineutrophil cytoplasmic antibodies
(pANCA), soluble liver antigen/liver-pancreas antigen (SLA/LP), and
Histology the asialoglycoprotein receptor antibody.
The role of liver histology in the management of AIH remains • Diagnostic criteria are available and provide good sensitivity and
critical, and all patients with suspected cases should undergo a specificity.
liver biopsy. In fact, although no typical feature can prove the
diagnosis, histology remains the gold standard for grading and
staging, particularly to determine the response to therapy.
Common findings include periportal hepatitis with lymphocyte tHeraPeUtIC PrInCIPLes
and plasma cell infiltrate and piecemeal necrosis. Fibrosis usually • Glucocorticoids represent the cornerstone of autoimmune hepatitis
is observed, and bridging necrosis ultimately indicates advanced (AIH) therapy as monotherapy or in combination with azathioprine.
disease evolving into frank cirrhosis. Importantly, the presence • Other immunosuppressants, i.e., methotrexate, tacrolimus, cyclosporine,
of granulomas, bile duct damage, or iron or copper accumulation and mycophenolate mofetil, have been used in patients who are
should not be overlooked, since these signs point toward other intolerant or refractory to standard therapy.
diagnoses. On the other hand, steatosis is a nonspecific finding • Liver transplantation is very successful; however, AIH may recur after
transplant.
that does not rule out AIH. 9