AIH Flashcards
disease of unknown cause that
is characterized by the presence of autoantibodies, hypergammaglobulinemia, and histologic features of interface hepatitis and lymphoplastic infiltration.
AIH
mainly affects females, regardless of age or ethnicity
mainly a disease of mid-to-late life and that its peak age of onset varies among countries.
The median age of onset in the Netherlands is 43 years in men and 48 years in women.
Histopathology of interface hepatitis.
The limiting plate of the portal tract is disrupted by a lymphoplasmacytic infiltrate. This histologic pattern is the hallmark of autoimmune hepatitis, but it is not disease specific.
Histopathology of lymphoplasmacytic infiltration.
Plasma cells denoted by perinuclear halos are present in the portal tract and extend into the liver parenchyma with the interface hepatitis
Pathophysiology
AIH is a consequence of perturbations in homeostatic mechanisms that maintain immune tolerance of self-antigens
Genetic Predosposition
The susceptibility alleles of AIH in white North Americans and northern Europeans are DRB103:01 and DRB104:01.55,56 DRB104:04 and DRB104:05 are the susceptibility alleles in Mexican, Japanese mainland Chinese, and Argentinian adults, and DRB104:05 and DQB104:01 are the susceptibility alleles in South Korea
The principal autoantigen of AIH
that is targeted by anti-LKM1 is cytochrome P450 2D6 (CYP2D6).
CLINICAL FEATURES
An acute severe (fulminant) presentation, defined by the onset of hepatic encephalopathy within 26 weeks of the discovery of the disease
predominant laboratory features for AIH
Serum AST, ALT, and γ-globulin elevations reflect the severity of liver inflammation
laboratory hallmark of the disease
increased serum immunoglobulin G (IgG)
an independent predictor of treatment
respons
serum GGTP level can be increased, and its improvement during
glucocorticoid therapy
Laboratory parameters
Hyperferritinemia is commonly present in conjunction with other disturbances in iron homeostasis, including a high serum iron concentration and increased transferrin saturation.
The conventional autoantibodies for the diagnosis of AIH
ANA, smooth muscle antibodies (SMA), and anti-LKM1
Autoantibodies
SMA, ANA, and anti-LKM1 can be detected by IIF using rodent tissues or Hep-2 cell lines or by enzyme immunoassay (ELISA) using adsorbed recombinant or highly purified anti- gens.
preferred method for diagnosing AIH
IIF has been the preferred method for diagnosing AIH because the recombinant antigens used in ELISAs may not be the same antigens detected by IIF.
Other serologic markers of AIH
atypical perinuclear anti-neutrophil cytoplasmic anti- bodies (pANCA), antibodies to soluble liver antigen (anti-SLA), antibodies to actin (anti-actin), and anti-LC1
Present in 80% of patients with type 1 AIH
Concurrent with SMA in 43% of patients with type 1 AIH Diagnostic accuracy is 56% as sole marker
ANA
Present in 63% of patients with type 1 AIH Diagnostic accuracy is 61% as sole marker Diagnostic accuracy is 74% if ANA present
SMA
Hallmark of type 2 AIH
ANA and SMA usually absent
Concurrent with anti-LC1 in 32% of patients with AIH Mainly present in children
Associated with HLA DRB1*07
Anti-LKM1
High diagnostic specificity for AIH (99%) Associated with HLA DRB1*0301
Commonly concurrent with anti-Ro/SSA (96%) Associated with severe disease and relapse May be sole marker of AIH
Anti-SLA
Present in 50%-92% of patients with type 1 AIH Absent in type 2 AIH
Associated with PSC and UC
May be the sole marker of AIH
May be the result of gut-derived reactivity
Atypical pANCA
Present in 86% of SMA-positive patients with AIH
Does not detect non–actin-associated SMA
Concurrence with anti–α-actinin is associated with severe disease
Anti-actin
Frequently concurrent with anti-LKM1 (32%)
Mainly present in young patients (age ≤ 20 yr) Associated with same clinical phenotype as anti-LKM1 Rare in North American patients
Anti-LC1
Histology
Interface hepatitis is required for the diagnosis of AIH
Lymphocytic or lymphoplasmacytic inflammation, hepatocyte rosetting, emperipolesis (penetration of one cell into and through a larger cell), and hepatocyte swelling are other common findings
The histologic features of acute severe (fulminant) AIH
centrilobular necrosis with hemorrhage, severe interface hepatitis, lymphoplasmacytic infiltration around the central vein with hepatocyte drop-out or necrosis (“centrilobular perivenuli- tis”), lymphoid aggregates (in 50%), and plasma cell infiltration (in 90%).
prognostic biomarkers
Serum
levels of ferritin, vitamin D, and angiotensin converting enzyme and circulating levels of miR-21 and miR-122, PD-1 and its ligands (PD- L1 and PD-L2), macrophage migration inhibitory factor, soluble CD163, and BAFF are being assessed as therapeutic biomarkers.
The definite diagnosis
requires the presence of ANA, SMA, or anti-LKM1 alone or in various combinations, hypergammaglobulinemia manifested mainly as an increased serum IgG level, histologic features of interface hepatitis, and exclusion of other similar diseases.
Transient elastography
Transient elastography does not become an accurate assessment of cirrhosis until glucocorticoid treatment has been administered for 6 months or longer.
Type 1 AIH
characterized by the presence of SMA, ANA, or both
Diagnostic Type 1
MRCP or ERCP is warranted to exclude PSC in all patients
who have concurrent IBD or prominent features of cholestasis (serum alkaline phosphatase level ≥2-fold ULN or serum
GGTP level ≥5-fold ULN), especially if the features do not
improve during glucocorticoid therapy.
Type 2 AIH
Type 2 AIH is characterized by the presence of anti-LKM1.
Acute or Acute Severe (Fulminant)
AIH can have an acute or an acute severe (fulminant) presentation that can be mistaken for a viral or drug-induced hepatitis
The acute severe presentation is characterized by marked serum AST and ALT elevations, hepatic encephalopathy, and histologic changes that commonly include centrilobular necrosis with hemorrhage, lymphoid follicles, and plasma cell infiltration
Acute or Acute Severe (Fulminant)
The serum IgG level is normal in 25% to 39% of patients, and ANA are absent or weakly positive (titers ≤1:40) in 29% to 39%
Acute or Acute Severe (Fulminant)
Acute or Acute Severe (Fulminant) treatment
Prednisone or prednisolone alone, 0.5-1 mg/kg daily in adults
and up to 2 mg/kg in children,
AIH with AMA and bile duct injury or loss similar to PBC
AIH components:
Interface hepatitis plus 1 of 2 features: ALT ≥ 5 x ULN
IgG ≥ 2 x ULN or SMA present
PBC components (2 of 3 features):
Alk phos ≥ 2 x ULN or GGTP ≥ 5 x ULN AMA present
Florid duct lesions
AIH with AMA and bile duct injury or loss similar to PBC treatment
Combination therapy (endorsed by the EASL):
Prednisone or prednisolone (30 mg daily tapered to 10 mg daily) and
azathioprine (50 mg daily) plus UDCA (13-15 mg/kg daily) Individualized empiric therapies:
Budesonide (9 mg daily) and azathioprine (50 mg daily) plus UDCA (13-15 mg/kg daily)
Budesonide (6 mg daily) plus UDCA (10-15 mg/kg daily) Cyclosporine (3 mg/kg daily)
Mycophenolate mofetil (1-3 g daily)
UDCA only (13-15 mg/kg daily)
Prednisone (10 mg daily) plus azathioprine (50 mg daily)
AIH with cholangiographic changes of PSC
Typical AIH features:
AMA absent
Focal bile duct strictures and dilations by
cholangiography
Bile duct loss or damage, portal edema, and fibrous
obliterative cholangitis possible on histologic examination
AIH with cholangiographic changes of PSC treatment
Combination therapy (endorsed by the EASL, AASLD):
UDCA (13-15 mg/kg daily) and prednisone or prednisolone (0.5 mg/kg
daily tapered to 10-15 mg daily) plus azathioprine (50-75 mg daily) Avoid high-dose UDCA (28-30 mg/kg daily)
Individualized empiric therapies:
Prednisolone (20-80 mg daily, tapered to 7.5-10- mg daily) plus
azathioprine (75-150 mg daily)
AIH with unexplained cholestatic features
Typical AIH features
AMA absent
Normal cholangiography
Bile duct injury or loss on histologic examination Probably small-duct PSC or AMA-negative PBC
AIH with unexplained cholestatic features treatment
Individualized empiric therapies:
Prednisone or prednisolone (10 mg daily) and azathioprine (50 mg
daily) plus UDCA (13-15 mg/kg daily)
Prednisone or prednisolone (10 mg daily) plus azathioprine (50 mg
daily)
UDCA (13-15 mg/kg daily)
Caveats:
No regimens have been endorsed
Treatment must be modified according to response
TREATMENT Indications
Fragile patients, especially older adults and
pregnant women, require individualized treatment regimens with
close monitoring, and asymptomatic patients with mild
disease may be observed initially to document disease behavior.
First-line Treatment Regimens Endorsed
AASLD-Endorsed Combination Regimen
by AASLD, BSG, and EASL
Induction phase × 4 wk:
Prednisone or prednisolone: 30 mg daily × 1 wk
20 mg daily × 1 wk
15 mg daily × 2 wk Azathioprine: 50 mg daily
First-line Treatment Regimens Endorsed
AASLD-Endorsed Combination Regimen
by AASLD, BSG, and EASL
Preferred in all patients with thiopurine methyltransferase activity and azathioprine tolerance, especially those with obesity, diabetes mellitus, osteopenia, or emotional instability
Maintenance phase: Prednisone or prednisolone: 10 mg daily
Azathioprine: 50 mg daily
Doses may be adjusted to response and tolerance
AASLD-Endorsed Monotherapy Regimen
Induction phase × 4 wk: Prednisone or prednisolone: 60 mg daily × 1 wk
40 mg daily × 1 wk
30 mg daily × 2 wk
AASLD-Endorsed Monotherapy Regimen
Preferred in patients with severe cytopenia, absent thiopurine methyltransferase activity, azathioprine intolerance, or reluctance to use during pregnancy
Maintenance phase: Prednisone or prednisolone: 20 mg daily
Doses may be adjusted to response and tolerance
BSG/EASL-Endorsed Combination Regimen
Induction phase × 10 wk: Prednisolone: 0.5-1 mg/kg daily (e.g., patient weighing 60 kg) 60 mg daily × 1 wk 50 mg daily × 1 wk 40 mg daily × 1 wk 30 mg daily × 1 wk 25 mg daily × 1 wk 20 mg daily × 1 wk 15 mg daily × 2 wk 12.5 mg daily × 2 wk Azathioprine: 1-2 mg/kg daily started 2 wk after prednisolone 50 mg daily × 2 wk 100 mg daily thereafter
BSG/EASL-Endorsed Combination Regimen
Preferred in all patients with thiopurine methyltransferase activity and azathioprine tolerance
Maintenance phase: Prednisolone: 10 mg daily Azathioprine: 100 mg daily
Doses may be adjusted to response and tolerance
Budesonide
is a synthetic glucocorticoid with greater than or equal to 90% first-pass hepatic clearance and metabolites devoid of glucocorticoid activity.
Budesonide reduces the production of cytokines, including IL-1β, IL-2, IL-6, IL-8, TNF-α, and interferon (IFN)-γ, and it inhibits the activation and proliferation of T lymphocytes and monocytes.
Budesonide administration
Budesonide (3 mg 3 times daily) in combination with azathioprine (1 to 2 mg/ kg daily) has normalized serum AST and ALT levels more frequently (47% vs. 18%) and with fewer side effects (28% vs. 53%) than the combination of prednisone (40 mg daily, tapered to 10 mg daily) and azathioprine (1-2 mg/kg daily) when administered as first-line therapy for 6 months in a large, randomized clinical trial.
Azathioprine Therapy and Pregnancy
Azathioprine has been associated with congenital malformations (cleft palate, skeletal anomalies, hydrops fetalis, reduced thymic size, anemia, and bone marrow depression) in pregnant mice. the placenta is only a partial barrier to the metabolites of azathioprine
Pregnancy
These clinical experiences have supported the recommendation
by EASL that the management of AIH during pregnancy must
be individualized and that azathioprine therapy may be continued
in pregnant women with AIH.
An alternative strategy during
pregnancy is to discontinue azathioprine and maintain suppression
of inflammatory activity with dose-adjusted prednisone or prednisolone.
The inflammatory activity of AIH commonly subsides
during pregnancy and exacerbates after delivery, and the treatment regimen must be monitored and adjusted accordingly.
Responses
Remission
Remission connotes absence of symptoms, resolution of all laboratory indices of liver inflammation, and histologic improvement to normal hepatic architecture or inactive cirrhosis
Serum aminotransferase levels improve promptly in 80% to 90% of patients but histologic improvement lags behind laboratory improvement by 3 to 8 months.
Normal laboratory test results do not preclude histologic activity, disease progression, or reduced survival and treatment must be maintained beyond laboratory resolution.
Remission
is currently defined as normalization of serum AST, ALT, and IgG levels.
Treatment should be continued for at least 3 years and for at least 24 months after complete laboratory resolution before discontinuation is considered.110 Prompt normalization of serum AST, ALT, and IgG levels that is sustained for at least 6 months is predictive of histologic resolution. Follow-up liver tissue examination is preferred but not required to document the histologic response
Remission
Ultrasound elastography performed within 3 months after the start of treatment can demonstrate a reduction in liver stiffness that correlates with histologic grade
Treatment Failure
Laboratory tests of liver inflammation (serum AST, ALT,
or IgG level) or function (serum bilirubin level) that worsen
despite compliance with the first-line treatment regimen
The lack of laboratory improvement within 3 months of continuous therapy is another indication of a poor response.
Treatment response
Determination of the 6-TGN level has been associated with treatment response (>220 pmol/8 × 108 red blood cells), and low levels may indicate inadequate immunosuppression or poor compliance
the 6-TGN level may be useful in assess- ing compliance with treatment,369 its value in monitoring therapy or predicting azathioprine toxicity has not been established
Incomplete Response
connotes improvement in the laboratory indices of liver inflammation but the response is insufficient to satisfy remission criteria
Incomplete Response
patients who achieve laboratory and histologic remission within 6 months of treatment have a lower frequency of cirrhosis and liver failure than patients who require longer durations of treatment to the same endpoint.
Patients with an incomplete response after 6 months of therapy should be evaluated for remediable causes for the incomplete response (misdiagnosis, poor adherence, drug toxicity) and considered for a second-line therapy
Treatment Withdrawal
Patients who have normalized their serum AST, ALT, and IgG
levels are candidates for treatment withdrawal if they have maintained the improvement for at least 24 months.
Improvement in the serum ALT level to less than half the normal laboratory range and serum IgG level to less than 12 g/L has characterized individuals who have sustained their remission during a median follow-up of 28 months (range, 17 to 57 months) after treatment withdrawal.
Treatment Withdrawal
Glucocorticoid withdrawal should be gradual and monitored closely over a period of at least 6 weeks. The azathioprine dose is usually maintained over the first half of the withdrawal period and then reduced in dose by half until discontinuation in concert with the glucocorticoid.
Relapse
reappearance of laboratory and histologic features of disease activity after discontinuation of drug therapy.
Relapse
An increase in the serum AST level to more than 3-fold the ULN after discontinuation of medication is invariably associated with interface hepatitis on histologic examination and is sufficient to diagnose relapse without examination of liver tissue
Relapse treatment
Patients who relapse are re-treated with prednisone or prednisolone, in combination with azathioprine, until laboratory resolution is again achieved (mean duration, 4 ± 1 months).
The dose of azathioprine is then increased to 2 mg/kg daily,and the drug is continued indefinitely as the dose of prednisone or prednisolone is gradually reduced to the lowest levels possible to maintain normal liver biochemical test levels
Second-Line Treatments
These second-line regimens include high-dose glucocorticoids in combination with high-dose azathioprine, mycophenolate mofetil, calcineurin inhibitors, budesonide, and 6-mercaptopurine (6-MP).
Failure of second-line regimens may lead to LT363 and has justified the investigation of alternative agents, including cyclophosphamide (1 to 1.5 mg/kg daily), methotrexate (7.5 mg weekly),rapamycin (2 mg daily adjusted to achieve serum levels of 10 to 20 ng/dL),monoclonal anti- bodies to TNF-α (infliximab),monoclonal antibodies to CD20 (rituximab),and inhibitors of BAFF.
Second-Line Treatments
Prednisone or prednisolone (30 mg daily) in combination with azathioprine (150 mg daily) is appropriate for patients who worsen (treatment failure) or who fail to improve (nonresponse) during first-line therapy
High-dose prednisone or prednisolone plus azathioprine
Mainly for treatment failure or nonresponse
Induction phase: prednisone or prednisolone, 30 mg daily, and
azathioprine, 150 mg daily, × 1 mo
Maintenance phase: dose reduction of prednisone or
prednisolone by 10 mg each month of improvement until maintenance dose of prednisone or prednisolone, 10 mg daily.
Dose reduction of azathioprine by 50 mg each month of improvement until a maintenance dose of 50 mg daily
High-dose prednisone or prednisolone
Mainly for treatment failure with severe cytopenia, absent TPMT activity, or azathioprine intolerance
Induction phase: prednisone or prednisolone, 60 mg daily, ×1 mo
Maintenance phase: dose reduction by 10 mg each month of improvement until maintenance dose of prednisone or prednisolone of 20 mg daily
Mycophenolate mofetil plus glucocorticoid or other agent
Mainly for azathioprine intolerance and nonresponse Mycophenolate mofetil, 0.5-3 g daily, plus prednisone or
prednisolone or other agent (calcineurin inhibitor or budesonide)
6-MP
Mainly for azathioprine intolerance
6-MP, 1.5 mg/kg daily or 25 mg daily increased to 50 mg daily,
as a replacement for azathioprine
Cyclosporine or tacrolimus with or without prednisone or prednisolone
Mainly for treatment failure or nonresponse
Cyclosporine (Neoral): 2-5 mg/kg daily; dose adjustments for
trough levels of 100-300 ng/mL
Tacrolimus: 0.5-1 mg daily adjusted to 1 mg daily-3 mg twice
daily to achieve a serum level of 3 ng/mL (range, 1.7-10.7 ng/ mL)
Budesonide
Mainly for glucocorticoid intolerance or dependence Budesonide, 9 mg daily, plus azathioprine or other agent
