Difficult treatment decisions in autoimmune hepatitis

Table 1 Conventional corticosteroid treatment regimens for autoimmune hepatitis[19,54,55]

Schedule	Monotherapy	Combination therapy
	Prednisone only1 (mg/d)	Prednisone1 (mg/d)	Azathioprine (mg/d)
Induction period
Week 1	60	30	50
Week 2	40	20	50
Week 3	30	15	50
Week 4	30	15	50
Maintenance period
Fixed doses until end point	20	10	50
Conditions that favor each regimen	Cytopenia (severe) Absent thiopurine methyltransferase activity Pregnancy Malignancy (active) Short trial ( ≤ 6 mo) Acute severe onset	Elderly/postmenopausal state Osteoporosis Brittle diabetes Obesity Acne Emotional instability/psychosis Hypertension Prolonged therapy (≥ 6 mo)

¹Prednisolone can be used in place of prednisone in equivalent doses.

Table 2 Difficult treatment decisions before starting conventional corticosteroid therapy

Problem	Response
Acute severe (fulminant) presentation	Prompt institution of conventional corticosteroid therapy with prednisone monotherapy[44,51-53]
	Azathioprine, 50 mg/d, can be added later if treatment is to be continued for ≥ 3 mo[55]
	Liver transplantation evaluation if laboratory indices worsen at any time during treatment, especially progressive hyperbilirubinemia, or no improvement after 2 wk[56]
Asymptomatic mild or mild disease	Institute conventional corticosteroid therapy with prednisone in combination with azathioprine[58,55]
	Consider empirical treatment with budesonide, 3 mg tid, in conjunction with azathioprine, 50 mg/d, if preexistent osteopenia, diabetes, hypertension, obesity, or emotional instability[25,26]
Autoantibody-negativity	Exclude viral, drug, toxic, metabolic causes and celiac disease[31,43]
	Apply codified scoring criteria of IAIHG for probable or definite diagnosis[31,46]
	Institute conventional corticosteroid therapy with prednisone in combination with azathioprine or a higher dose of prednisone alone[19,47-50]
Overlap syndromes	Conventional corticosteroid therapy alone or in combination with azathioprine if serum alkaline phosphatase level < 2 times ULN[59-62]
	Add ursodeoxycholic acid, 13-15 mg/kg per day, to corticosteroid regimen if serum alkaline phosphatase level ≥ 2 times ULN[60,63]
	Consider ursodeoxycholic acid alone, 13-15 mg/kg per day, if predominant features of PBC with minimal features of autoimmune hepatitis[64,65]

IAIHG: International Autoimmune Hepatitis Group; ULN: Upper limit of the normal.

Table 3 Difficult treatment decisions during conventional corticosteroid therapy

Problem	Response
Determining treatment end point	Continue conventional therapy until normal serum AST, ALT, bilirubin and γ-globulin levels and normal liver tissue or inactive cirrhosis (ideal end point)[119-121]
	Continue conventional therapy until serum AST ≤ 2 times ULN, bilirubin and γ-globulin levels normal, and portal hepatitis or minimally active cirrhosis (satisfactory end point)[11,54,55]
	Decrease dose of culprit drug or discontinue its use if side effects emerge (drug toxicity end point)[13,55]
	Limit conventional corticosteroid treatment of patients aged ≥ 60 yr if an ideal or satisfactory end point has not been achieved ≤ 24 mo (incomplete response end point)[11,19,124,125]
Relapse after drug withdrawal	Institute original therapy until clinical and laboratory resolution, then increase azathioprine dose to 2 mg/kg per day as dose of prednisone is withdrawn[126,127]
	Continue daily azathioprine in fixed dose indefinitely[126,127]
	Use low dose prednisone ( ≤ 10 mg/d) if severe cytopenia (leukocyte counts < 2.5 × 109/L or platelet counts < 50 × 109/L) or other azathioprine intolerances[13,55]
	Use low dose prednisone (2.5-5 mg/d) to supplement azathioprine maintenance if abnormal serum AST level[55,128]
Treatment failure	Prednisone, 60 mg/d, or prednisone, 30 mg/d, in combination with azathioprine, 150 mg/d, for at least 1 mo, then dose reductions by 10 mg for prednisone and 50 mg for azathioprine each month of laboratory improvement until conventional doses reached[54,55,129]
	Evaluate for liver transplantation if minimal criteria for listing (MELD ≥ 15 points) are met[130-132]
Incomplete response	Azathioprine (2 mg/kg per day) indefinitely after corticosteroid withdrawal[54,55,127]
	Low-dose prednisone ( ≤ 10 mg/d) if azathioprine intolerance[54,55,128]
	Adjustments to maintain serum AST level ≤ 3 times ULN[55,133]

MELD: Model of end stage liver disease; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 4 Difficult treatment decisions after conventional corticosteroid therapy

Problem	Response
Empirical salvage drugs	Consider cyclosporine (5-6 mg/kg per day)[144-150] or tacrolimus (4 mg bid)[21,22,151,152] if progressive disease on conventional treatment
	Consider mycophenolate mofetil (1 g bid) if corticosteroid or azathioprine intolerance[23,24,153-159]
	Consider budesonide (3 mg tid) as frontline therapy if mild disease or if azathioprine maintenance insufficient after relapse or incomplete response[25,26]
	Complete benefit-risk and cost analyses before use[160,161]
	Empirical trial must not supersede liver transplantation[55,130,131]
Liver transplantation	Consider if acute severe (fulminant) presentation unresponsive or worse within 2 wk of conventional treatment[52,53,56,57]
	Consider if treatment dependent ≥ 3 yr and features of decompensation develop (ascites, encephalopathy or variceal bleeding)[130]
	Consider if failure to conventional therapy and MELD score ≥ 15 points[52,131,132]
Elderly patients (aged ≥ 60 yr)	Restrict conventional therapy to combination regimen[124]
	Limit initial treatment to ≤ 24 mo[125]
	Institute azathioprine maintenance therapy (2 mg/kg per day) if initial response is incomplete at 24 mo[124]
	Consider liver transplantation if features of decompensation emerge[132]
Pregnant patients	Counsel regarding risks of prematurity and infant mortality[162-167]
	Institute high-risk obstetrical care[30,162]
	Avoid azathioprine if possible[165,168]
	Reduce doses of prednisone to lowest levels to stabilize if not resolve laboratory indices[169]
	Reestablish conventional prednisone doses prior to delivery[169]
	Be alert to post-partum flares[163,164,169]