Autoimmune Hepatitis

Clinical Snapshot

Autoimmune hepatitis (AIH) is a chronic, immune-mediated inflammatory liver disease of unknown trigger, characterized by elevated aminotransferases, circulating autoantibodies, elevated serum immunoglobulin G (IgG), and a characteristic histologic pattern — interface hepatitis — on liver biopsy. Unlike some other liver diseases covered elsewhere on this platform, biopsy remains a genuinely active part of both confirming the diagnosis and staging severity, not merely an optional confirmatory step.^[1]

AIH affects women disproportionately (roughly 70-80% of cases) and can present at any age. Two broad serologic/clinical subtypes are recognized: type 1 — positive antinuclear antibody (ANA) and/or anti-smooth-muscle antibody (ASMA), the large majority of cases, any age — and type 2 — positive anti-liver-kidney microsomal type 1 antibody (anti-LKM1), less common, more often affecting children and young adults, and generally following a more severe, relapsing course.^[1]^[2]

Clinically, AIH presents as one of two genuinely distinct phenotypes that this chapter treats as a central organizing concept: a more common indolent chronic presentation — often discovered incidentally on routine liver enzymes, sometimes only after cirrhosis has already developed — and a less common but clinically urgent acute severe presentation that can closely mimic, and without prompt recognition and treatment can evolve directly into, acute liver failure. The Acute Liver Failure chapter's King's College Criteria, hepatic encephalopathy grading, and general supportive-care principles all apply directly to a deteriorating acute severe AIH presentation and are cross-referenced rather than repeated here (see Red Flags & Refer and Choose Initial Treatment).

Recognize the Condition

Chronic, indolent presentation — the more common pattern

Many patients have no symptoms at all, or only nonspecific fatigue, mild right-upper-quadrant discomfort, arthralgias, or pruritus, with the diagnosis first suspected because of incidentally elevated transaminases on routine bloodwork. Because this presentation is so easy to miss, a meaningful proportion of patients — historically cited at around a quarter to a third — already have cirrhosis at the time AIH is first diagnosed, underscoring why unexplained transaminase elevation deserves a genuine diagnostic work-up rather than being dismissed as incidental.^[1] If cirrhosis has already developed, the usual stigmata of chronic liver disease may be present — see the Cirrhosis chapter for the full differential of spider angiomata, palmar erythema, splenomegaly, and related findings, not repeated here.

Acute severe presentation — the clinically urgent pattern

A meaningful minority of patients instead present acutely: rapid-onset jaundice, marked malaise, and, in the most severe cases, evolving coagulopathy and hepatic encephalopathy indistinguishable at the bedside from acute liver failure of any other cause. This is commonly described as an INR ≥1.5 without hepatic encephalopathy ("acute severe AIH") versus INR ≥1.5 with any degree of encephalopathy (frank acute liver failure) — see Red Flags & Refer for how urgently each requires escalation.^[1] Notably, biopsy in an apparently "acute" presentation not infrequently reveals pre-existing fibrosis, suggesting many of these cases are really an acute exacerbation of previously unrecognized chronic disease rather than a genuinely new process — a distinction that does not change acute management but is worth knowing.

Extrahepatic autoimmune associations

AIH commonly coexists with other autoimmune conditions — autoimmune thyroiditis, celiac disease, type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease among the most frequently reported — and can overlap with the other autoimmune liver diseases, primary biliary cholangitis and primary sclerosing cholangitis (see Special Populations).^[2]

Risk Factors

Female sex — women make up roughly 70-80% of cases, across both type 1 and type 2 disease.
A personal or family history of other autoimmune disease — autoimmune thyroiditis, type 1 diabetes, celiac disease, and others — increases suspicion when unexplained transaminase elevation is found.
Genetic susceptibility — specific HLA class II haplotypes (HLA-DRB1*03:01 and *04:01 in type 1 disease in North American and European populations; HLA-DRB1*07 more often in pediatric type 2 disease) are associated with increased risk, though genetic testing does not currently change management.
Drug- or checkpoint-inhibitor-triggered autoimmune-like hepatitis — nitrofurantoin and minocycline are the most consistently implicated conventional drugs; immune checkpoint inhibitors used in oncology can trigger a clinically and histologically similar immune-mediated hepatitis. These phenotypes often improve after stopping the causative agent, sometimes without needing the years-long immunosuppression that de novo AIH requires — see Special Populations, and the Acute Liver Failure chapter for a fuller drug-induced liver injury differential not repeated here.
Viral infection has long been postulated as a possible trigger in a genetically susceptible person, though no single virus has been established as causal.
Unlike alcohol-associated or metabolic liver disease, AIH is not driven by alcohol quantity, obesity, or metabolic syndrome — its risk factors are immunologic and genetic rather than exposure-based.

Red Flags & Refer

Escalate urgently for any of the following:

Any degree of hepatic encephalopathy in a patient with suspected or known AIH — this meets the definition of acute liver failure regardless of underlying cause and needs the same urgent management and transplant-centre contact detailed in the Acute Liver Failure chapter, including King's College Criteria and encephalopathy grading, which are not repeated here.^[1]
INR ≥1.5 without encephalopathy in a new or acutely worsening presentation ("acute severe AIH") — a genuine emergency requiring prompt high-dose corticosteroid initiation and close inpatient monitoring for evolution into frank acute liver failure (see Choose Initial Treatment).^[1]
Marked or rapidly rising jaundice, even without encephalopathy or coagulopathy yet — trend bilirubin and INR closely rather than assuming a benign course.
Severe cytopenias in a patient on azathioprine — hold the drug and investigate; do not attribute unexplained bruising, infection, or fatigue to the underlying liver disease without checking a CBC first.
Signs of decompensated cirrhosis at presentation or during treatment (new ascites, variceal hemorrhage, encephalopathy, or worsening jaundice in a patient with established AIH-related cirrhosis) — manage and refer per the Cirrhosis chapter's decompensation and transplant-referral triggers, including the MELD ≥15 threshold, not repeated here.
No meaningful biochemical improvement after an adequate trial of first-line induction therapy — see Treatment Failure / Next Step rather than continuing an ineffective regimen indefinitely.
A patient planning pregnancy or newly pregnant while on treatment — coordinate with hepatology and maternal-fetal medicine promptly rather than making a unilateral medication change (see Special Populations).

Assessment & Diagnosis

Core laboratory pattern

Aminotransferases (ALT, AST) are elevated, sometimes markedly so, and unlike alcoholic hepatitis there is no characteristic AST:ALT ratio pattern to lean on — ALT is often the more elevated of the two, as in most other non-alcohol-related hepatitis. Serum IgG (or total gamma-globulin where IgG is not directly measured) is elevated in the great majority of patients and, together with autoantibodies, is one of the core diagnostic and remission-monitoring markers used throughout this chapter.^[1]

Autoantibody profile and the two recognized subtypes

	Type 1 AIH	Type 2 AIH
Key autoantibodies	Antinuclear antibody (ANA) and/or anti-smooth-muscle antibody (ASMA)	Anti-liver-kidney microsomal type 1 antibody (anti-LKM1); sometimes anti-liver cytosol type 1 (anti-LC1)
Relative frequency	The large majority of AIH cases	A minority of cases
Typical age	Any age, including older adults	More often children and young adults
Typical course	Generally responsive to standard induction	Often more severe at presentation and more prone to relapse

A positive anti-soluble liver antigen/liver-pancreas antibody (anti-SLA/LP), found in a minority of type 1 patients, is highly specific for AIH and is associated with a more severe, relapsing course requiring closer long-term follow-up.^[2] Antimitochondrial antibody (AMA) should also be checked at baseline specifically to screen for primary biliary cholangitis overlap (see Special Populations); a low-titer ANA or ASMA alone, without the rest of the diagnostic picture, is not sufficient to diagnose AIH, since these autoantibodies are also found at low titer in the general population and in other liver diseases.^[1]

Liver biopsy

Liver biopsy remains an important, active part of confirming the diagnosis, not merely staging fibrosis — the histologic hallmark is interface hepatitis: a dense lymphoplasmacytic infiltrate crossing the limiting plate into the periportal parenchyma, often with hepatocyte "rosette" formation and, in some cases, emperipolesis. Biopsy also stages fibrosis at diagnosis (a meaningful minority already have bridging fibrosis or cirrhosis) and is the tool used later to help confirm histologic remission before attempting drug withdrawal (see Choose Initial Treatment and Monitoring & Follow-Up).^[1]^[2]

Simplified diagnostic criteria

The International Autoimmune Hepatitis Group's simplified scoring system combines four readily available elements into a point-based diagnostic aid; it does not replace clinical judgment but is a useful teaching and documentation tool.^[3]

Parameter	Finding	Points
ANA or ASMA titer	1:40 or higher	1
ANA or ASMA titer	1:80 or higher (ANA/ASMA), or anti-LKM1 1:40 or higher, or anti-SLA positive	2
IgG level	Above the upper limit of normal	1
IgG level	1.10 times the upper limit of normal or higher	2
Liver histology	Compatible with AIH	1
Liver histology	Typical of AIH (interface hepatitis, rosettes, emperipolesis)	2
Absence of viral hepatitis	Yes	2

A total score of 6 or more indicates "probable" AIH; a score of 7 or more indicates "definite" AIH.^[3]

Differential diagnosis

Viral hepatitis (A, B, C, and, where relevant, E) — check serologies in every new presentation before attributing hepatitis to AIH.
Drug-induced liver injury, including checkpoint-inhibitor hepatitis — a careful, specific medication/supplement history covering the preceding weeks to months is essential (see the Acute Liver Failure chapter for a fuller DILI differential, not repeated here).
Wilson disease — particularly in patients under 40; a low alkaline phosphatase relative to bilirubin and a Coombs-negative hemolytic anemia are supportive clues (see the Acute Liver Failure chapter).
MASLD/MASH and alcohol-associated liver disease — can coexist with AIH and confound the biochemical picture; consider especially when the response to immunosuppression is only partial.
Primary biliary cholangitis and primary sclerosing cholangitis, alone or as an overlap syndrome with AIH (see Special Populations).

Baseline evaluation before starting treatment

CBC, comprehensive metabolic panel, and INR at baseline, before the first dose of any therapy.
TPMT (and NUDT15, where available) activity or genotype testing before starting azathioprine, where accessible (see Choose Initial Treatment and Drug Tables).^[4]
Bone density (DEXA) at baseline if a substantial corticosteroid course is anticipated, particularly with other osteoporosis risk factors present.
Baseline glucose/HbA1c, given the hyperglycemic effect of induction corticosteroid therapy.
Pregnancy test in any patient of childbearing potential before starting or changing therapy.

Treatment Targets

Achieve and confirm biochemical remission — normalization of both aminotransferases and IgG, not aminotransferases alone.
Work toward histologic remission (resolution of interface hepatitis) as the deeper treatment goal, since biochemical normalization can occur while histologic activity persists.
Minimize cumulative corticosteroid exposure by transitioning to steroid-sparing azathioprine (or an alternative) as early as clinically appropriate.
Recognize and treat an acute severe presentation promptly enough to avoid progression to frank acute liver failure and transplantation.
Only attempt drug withdrawal after genuinely sustained remission, understanding and counselling on the high relapse risk.
Prevent progression to cirrhosis, and manage established cirrhosis and its complications per the Cirrhosis chapter once it develops.
Protect bone health and monitor metabolic effects throughout corticosteroid therapy.
Maintain the patient's engagement with regular monitoring — AIH is frequently asymptomatic even during a flare, so lab-based surveillance carries real diagnostic weight, not just confirmatory weight.

Choose Initial Treatment

Two induction options, chosen mainly by cirrhosis status, plus a distinct emergency pathway

Standard induction — any patient

Prednisone (or prednisolone) alone or combined with azathioprine; appropriate with or without cirrhosis.

Budesonide-based induction — non-cirrhotic patients only

Budesonide plus azathioprine; contraindicated once cirrhosis develops.

Acute severe presentation

Prompt high-dose corticosteroid therapy with very close monitoring for evolution into acute liver failure.

Direct treatment rule — first-line induction

Preferred Prednisone (or prednisolone) 40-60 mg/day (roughly 0.5-1 mg/kg/day) alone, or a reduced-dose prednisone (commonly 20-30 mg/day) started together with azathioprine.^[1]^[2]

Combination therapy is preferred over corticosteroid monotherapy in most patients able to tolerate azathioprine — it allows a substantially lower cumulative steroid dose and produces fewer steroid-specific adverse effects (weight gain, cushingoid features, hyperglycemia, bone loss, mood change) for an equivalent remission rate, a genuinely pharmacist-relevant counselling point when a patient asks why a second drug is being added rather than simply raising the steroid dose.^[1]

If azathioprine is started at the same time as corticosteroids, begin at a lower dose (e.g., 50 mg/day) for the first 1-2 weeks to confirm tolerance before increasing toward the target maintenance dose — early full-dose azathioprine in a patient with significant cholestasis or hyperbilirubinemia can worsen liver injury.^[1]

Taper the corticosteroid gradually — commonly over 4-6 weeks — toward the lowest dose that maintains biochemical response, or off entirely, once azathioprine has reached its full effect (azathioprine's onset is slow, typically 6-8 weeks) and the aminotransferase/IgG trend supports it. Guide every taper step by the biochemical trend, not by symptoms alone, since AIH is frequently asymptomatic even during a flare.^[2]

Before starting azathioprine

Check TPMT (and NUDT15, where available) activity or genotype before the first dose wherever testing is accessible — a patient with reduced or absent enzyme activity is at markedly increased risk of severe, early myelosuppression at a standard starting dose and needs either a substantially reduced dose or an alternative agent.^[4] Where testing is not available or the result is pending, start at a lower dose and monitor CBC closely over the first several weeks (see Monitoring & Follow-Up and Drug Tables).

Alternative induction — budesonide, non-cirrhotic patients only

Budesonide 3 mg PO three times daily (9 mg/day), combined with azathioprine from the outset, is an evidence-based alternative to prednisone in a patient without cirrhosis: a randomized controlled trial found a significantly higher complete biochemical response rate and a substantially lower rate of steroid-specific adverse effects with budesonide plus azathioprine than with prednisone plus azathioprine over 6 months.^[5]

Contraindicated once cirrhosis develops — budesonide undergoes roughly 90% first-pass hepatic metabolism when the portal circulation is intact, which is what gives it its favourable systemic side-effect profile; once cirrhosis produces portosystemic shunting, a substantial fraction of the dose bypasses the liver entirely and reaches the systemic circulation unmetabolized, converting budesonide into an unpredictably high-exposure systemic corticosteroid with all of prednisone's adverse-effect burden and none of its dosing predictability. Confirm the absence of cirrhosis before choosing budesonide, and switch to prednisone if cirrhosis is diagnosed at any point during treatment.^[1]

Acute severe presentation

Start corticosteroid therapy promptly — oral prednisone/prednisolone 40-60 mg/day, or IV methylprednisolone if oral intake or absorption is a concern — as soon as the diagnosis is reasonably confident and other causes have been reasonably excluded; do not delay treatment to complete every element of the diagnostic work-up in a patient who is deteriorating.^[1]

Unlike severe alcoholic hepatitis, there is no widely validated day-7 response score (analogous to the Lille score) for acute severe AIH. Judge response instead by the trend in bilirubin and INR, and by clinical status, over the first 1-2 weeks.^[1]

Any evolving encephalopathy or a worsening INR/bilirubin trend despite corticosteroids — this meets or is approaching the definition of acute liver failure; contact the liver transplant centre in parallel with continuing medical therapy, not only after steroids have clearly failed (see Red Flags & Refer and Treatment Failure / Next Step, and the Acute Liver Failure chapter for King's College Criteria and full supportive-care detail).^[1]

Maintenance therapy and the drug-withdrawal decision

Once biochemical remission is achieved (normal aminotransferases and normal IgG), continue azathioprine monotherapy at the target maintenance dose (roughly 1-2 mg/kg/day) with the corticosteroid tapered to the lowest effective dose or discontinued if tolerated. Maintain this for a prolonged period of confirmed, sustained remission — commonly cited as at least 2-3 years — before drug withdrawal is even considered.^[1]^[2]

Before attempting withdrawal, current guidance favours confirming histologic remission (repeat liver biopsy showing resolution of interface hepatitis), not biochemical remission alone — histologic activity can persist despite normal aminotransferases and IgG, and withdrawing therapy on biochemical grounds alone carries a higher relapse risk.^[2]

Relapse risk after withdrawal is genuinely high — commonly cited in the range of roughly half to the large majority of patients, depending on how long remission was sustained and whether histologic remission was confirmed before stopping — so withdrawal should be a carefully counselled, shared decision, not a default once biochemistry looks normal.^[1]^[2] Taper slowly rather than stopping abruptly, and monitor closely (frequent liver enzymes) for at least the first 12 months off therapy, since most relapses occur early (see Monitoring & Follow-Up).

Second- and third-line options

Mycophenolate mofetil is the usual second-line steroid-sparing agent for a patient who is intolerant of azathioprine; evidence for switching to it after a true (adherent, adequately dosed) azathioprine non-response is weaker than for intolerance.^[2]

Calcineurin inhibitors (tacrolimus or cyclosporine) are reserved, specialist-directed third-line options for patients refractory to or intolerant of both azathioprine and mycophenolate mofetil, requiring therapeutic drug monitoring and hepatology direction (see Treatment Failure / Next Step and Drug Tables).

Non-Pharmacologic Treatment

Bone health — calcium and vitamin D supplementation and weight-bearing exercise for the duration of meaningful corticosteroid exposure; baseline and periodic bone density (DEXA) monitoring given the cumulative steroid dose over what is often a multi-year course.
Glycemic and metabolic monitoring during induction corticosteroid therapy — proactive rather than reactive glucose management, the same principle applied in the Alcoholic Hepatitis chapter.
Vaccination review: hepatitis A and B (if non-immune) and standard age-based adult vaccines; avoid live vaccines during significant immunosuppression (high-dose corticosteroid, azathioprine, mycophenolate mofetil, or a calcineurin inhibitor) and resume once the regimen is tapered to a level generally considered non-significantly-immunosuppressive.
Avoid unregulated herbal and dietary supplement products and uncapped acetaminophen use — the same standing caution as every other chapter in this liver-disease group, given an already-inflamed liver.
Alcohol moderation/avoidance — AIH is not alcohol-driven, but ongoing heavy alcohol use adds an independent source of hepatic injury on top of the autoimmune process.
Nutrition, and hepatocellular carcinoma/variceal surveillance once cirrhosis has developed, follow the Cirrhosis chapter in full and are not repeated here.
Patient education on relapse recognition is a genuinely high-value counselling point, since AIH flares are frequently silent until relatively advanced — reinforce that stopping medication early or missing scheduled follow-up labs because "I feel fine" is one of the most common preventable causes of relapse.
Pregnancy planning counselling for anyone of childbearing potential on treatment — discussed in full in Special Populations.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Prednisone Preferred	First-line induction, alone or with azathioprine	40-60 mg/day alone, or 20-30 mg/day combined with azathioprine; taper over 4-6 weeks toward maintenance/off	Hyperglycemia, weight gain, bone loss, mood changes, cataracts, increased infection risk	Combining with azathioprine from the outset (or within about 2 weeks) allows a lower cumulative steroid dose and fewer steroid-specific adverse effects than monotherapy.
Prednisolone Alternative	Interchangeable with prednisone; preferred with significant hepatic synthetic impairment	Dosed the same as prednisone	Same as prednisone	Does not require hepatic activation — the same reasoning applied to severe alcoholic hepatitis; consider specifically in acute severe AIH or decompensated cirrhosis.
Azathioprine Preferred	Steroid-sparing induction and maintenance	Start 50 mg/day, increase over 2-6 weeks to 1-2 mg/kg/day; continued as maintenance monotherapy once the steroid is tapered	Myelosuppression, hepatotoxicity, GI upset, rare pancreatitis	Check TPMT/NUDT15 where available before starting; watch for the allopurinol/febuxostat interaction (see Drug Tables).
Budesonide Alternative	Non-cirrhotic induction only, combined with azathioprine	3 mg PO three times daily (9 mg/day)	Fewer systemic steroid effects than prednisone in the absence of cirrhosis; still causes some hyperglycemia/GI upset	Contraindicated once cirrhosis develops — portosystemic shunting removes its first-pass-metabolism advantage.
Mycophenolate mofetil Second-line	Azathioprine intolerance (preferred use) or non-response (weaker evidence)	1,000-1,500 mg PO twice daily	GI upset/diarrhea, myelosuppression, significant teratogenicity	Not preferred in pregnancy or a patient planning conception — unlike azathioprine, generally considered compatible (see Special Populations).
Tacrolimus Third-line	Specialist-directed, refractory to azathioprine and mycophenolate mofetil	Individualized, trough-level-guided	Nephrotoxicity, tremor, hyperglycemia, extensive CYP3A4 interactions	Reserved for hepatology-directed refractory disease; requires therapeutic drug monitoring.

Special Populations

Pregnancy

Azathioprine is generally considered compatible with pregnancy — a genuinely useful counselling point, since it stands apart from many other immunosuppressants used in autoimmune disease: current guidance supports continuing it through pregnancy in a patient who needs it for disease control, rather than stopping or switching preemptively.^[1]^[2] Mycophenolate mofetil, in contrast, is clearly teratogenic and should be stopped and switched (typically to azathioprine) well before conception is attempted, with reliable contraception used while on it. Corticosteroids (prednisone/prednisolone) are also generally continued through pregnancy at the effective dose. Postpartum flares are a recognized risk — monitor liver enzymes closely in the months after delivery rather than assuming the disease will remain quiet simply because pregnancy itself is often associated with relative immunologic quiescence. Breastfeeding is generally considered compatible with prednisone and azathioprine at usual therapeutic doses per current guidance. Manage jointly with maternal-fetal medicine and hepatology.^[2]

Cirrhosis at diagnosis or developing during treatment

Budesonide is contraindicated once cirrhosis is present (see Choose Initial Treatment); prednisone or prednisolone combined with azathioprine remains the induction approach. Manage cirrhosis complications, HCC/variceal surveillance, and transplant-referral triggers per the Cirrhosis chapter, not repeated here. Azathioprine-related cytopenias can be harder to distinguish from portal-hypertension-related cytopenias (splenic sequestration) in this population — a falling platelet count alone does not necessarily mean azathioprine toxicity, and both possibilities need to be considered.

Overlap syndromes

AIH-primary biliary cholangitis overlap — add ursodeoxycholic acid (ursodiol) under specialist direction, alongside AIH-directed immunosuppression. AIH-primary sclerosing cholangitis overlap — generally managed primarily as PSC with adjunctive immunosuppression, under specialist direction. Suspect either when the biochemical or serologic picture is atypical for straightforward AIH — a significant cholestatic pattern, or an unexpectedly positive AMA — see Assessment & Diagnosis.

Drug- and checkpoint-inhibitor-induced autoimmune-like hepatitis

Distinguish from de novo AIH where possible — stopping the causative drug is the first step, and many of these cases improve without needing the years-long immunosuppression that established AIH requires. Involve oncology and hepatology jointly when a checkpoint inhibitor is implicated, since resuming cancer therapy is a genuine competing consideration not present in de novo AIH.

Older adults

AIH in older adults can present, and often responds, similarly to younger patients, but corticosteroid-related risks (osteoporosis, diabetes, infection, falls) carry disproportionate consequences — monitor bone health and glucose more closely and favour an earlier transition to steroid-sparing therapy where tolerated.

Monitoring & Follow-Up

ALT, AST, and bilirubin every 1-2 weeks during induction; space to monthly once responding, then every 3-6 months once in confirmed sustained remission.
IgG alongside every significant liver-enzyme check — normalization of IgG, not aminotransferases alone, is required to call biochemical remission (see Treatment Targets).
CBC regularly on azathioprine — commonly weekly to every 2 weeks for the first 4-8 weeks, then spacing to every 1-3 months once a stable dose is established; more frequent monitoring if TPMT/NUDT15 status is unknown or indicates reduced activity.^[4]
Bone density (DEXA) periodically during a prolonged corticosteroid course.
Glucose monitoring during induction-dose corticosteroid therapy.
Consider repeat liver biopsy specifically before attempting drug withdrawal, to confirm histologic (not just biochemical) remission (see Choose Initial Treatment).
HCC surveillance (ultrasound ± AFP every 6 months) and variceal screening once cirrhosis has developed, per the Cirrhosis chapter, continued indefinitely regardless of how well-controlled the AIH itself appears.
Close monitoring — frequent liver enzymes — for at least the first 12 months after any significant dose reduction or a drug-withdrawal attempt, since most relapses happen early.

Treatment Failure / Next Step

Incomplete biochemical response after roughly 3-6 months of adequately dosed first-line therapy — confirm adherence first (a common and easily missed cause of apparent non-response, since AIH is often asymptomatic), then confirm azathioprine has actually reached its target weight-based dose before concluding true non-response.
Confirmed non-response despite adherent, adequately dosed prednisone plus azathioprine — switch to or add mycophenolate mofetil.^[2]
Azathioprine intolerance (significant GI upset, hepatotoxicity, pancreatitis, or cytopenias not attributable to another cause) — switch to mycophenolate mofetil rather than pushing through an intolerable regimen.
Refractory to both azathioprine and mycophenolate mofetil — refer to hepatology for a calcineurin inhibitor (tacrolimus or cyclosporine) or another specialist-directed option; this is not an ambulatory-initiated decision.
Relapse after a drug-withdrawal attempt — restart the previously effective induction regimen; most patients respond again, but a relapse after withdrawal generally establishes the need for indefinite maintenance therapy rather than a near-term repeat withdrawal attempt.^[1]
Progression to decompensated cirrhosis despite treatment — refer for transplant evaluation using the Cirrhosis chapter's triggers (a first decompensation event, or MELD ≥15), not a fixed AIH-specific threshold.
Deteriorating acute severe presentation despite prompt high-dose corticosteroids — do not wait for a clearly failed steroid trial; treat as evolving acute liver failure and contact the transplant centre in parallel with continuing medical therapy (see the Acute Liver Failure chapter).

Common Errors to Avoid

Diagnosing AIH from a positive autoantibody or an elevated IgG alone, without biopsy confirmation and a reasonable exclusion of other causes — autoantibodies are also found, often at low titer, in other liver diseases and in the general population.^[1]
Choosing budesonide for a patient who already has cirrhosis — portosystemic shunting removes its first-pass-metabolism advantage and produces unpredictable systemic corticosteroid exposure.^[1]
Starting azathioprine without any consideration of TPMT/NUDT15 status where testing is accessible, then discovering severe myelosuppression at what should have been a standard dose.^[4]
Treating a single normal set of liver enzymes as "cured" and stopping therapy without confirming sustained (and ideally histologic) remission over a genuinely prolonged period.^[2]
Abruptly stopping corticosteroids or azathioprine — for a mild side effect, a missed refill, or the patient's own decision once feeling well — rather than tapering and monitoring; abrupt discontinuation risks both adrenal insufficiency (corticosteroids) and a rebound flare.
Missing an evolving acute severe presentation by treating new jaundice and malaise as a routine flare rather than actively checking INR and mental status for signs approaching acute liver failure.
Prescribing or continuing mycophenolate mofetil in a patient who is pregnant or actively planning conception, rather than using azathioprine, which is generally considered the compatible option.
Not checking AMA or otherwise screening for an overlap syndrome when the biochemical or serologic picture is atypical for straightforward AIH.
Discontinuing HCC/variceal surveillance once cirrhosis has developed just because the AIH itself is now biochemically quiet — surveillance is time-based, not activity-based, the same point made in the Cirrhosis chapter.

Clinical Decision Algorithm

Algorithm A — Diagnosing suspected autoimmune hepatitis

Unexplained elevated aminotransferases, or acute jaundice with a compelling clinical picture

Check autoantibodies (ANA, ASMA, anti-LKM1, anti-SLA), IgG, and AMA; exclude viral hepatitis, DILI/checkpoint-inhibitor exposure, Wilson disease, and other competing causes

Liver biopsy to assess for interface hepatitis and stage fibrosis; apply the simplified IAIHG score

Score 6 or more (probable) or 7 or more (definite) AIH, other causes reasonably excluded

AIH confirmed — assess presentation severity and proceed to Algorithm B

Score below threshold, or an alternative diagnosis better fits

Reconsider the differential (viral, drug-induced, Wilson disease, MASLD/alcohol-related, or an overlap syndrome) before assuming AIH

Algorithm B — Choosing induction therapy

AIH confirmed — assess for hepatic encephalopathy and INR, and for pre-existing cirrhosis

Any hepatic encephalopathy present

Meets the definition of acute liver failure — manage per the Acute Liver Failure chapter (King's College Criteria, ICU-level care) in parallel with high-dose corticosteroids and immediate transplant-centre contact

INR 1.5 or higher, no encephalopathy — acute severe AIH

Start high-dose corticosteroids promptly; monitor the bilirubin/INR trend closely over 1-2 weeks

If not clearly improving, or any encephalopathy develops, escalate immediately to transplant-centre contact rather than waiting for a clear steroid failure

For the more common non-emergent presentation: is cirrhosis present?

No cirrhosis

Prednisone with or without azathioprine (preferred), or budesonide plus azathioprine (evidence-based alternative) — check TPMT/NUDT15 before starting azathioprine

Cirrhosis present

Prednisone (or prednisolone) with or without azathioprine — do not use budesonide

Algorithm C — Maintenance and the drug-withdrawal decision

Biochemical remission achieved — normal aminotransferases and normal IgG

Taper corticosteroid to the lowest effective dose or off; continue azathioprine maintenance

Sustained remission maintained for at least ~2-3 years

Consider repeat liver biopsy to confirm histologic remission before attempting withdrawal

Histologic remission confirmed (or accepted after informed discussion) — slow taper/withdrawal with close monitoring for at least 12 months

Relapse (biochemical or clinical)

Restart the previously effective induction regimen — plan for indefinite maintenance going forward rather than a near-term repeat withdrawal attempt

No relapse through 12 months

Continue periodic monitoring off therapy — relapse can still occur later, though risk falls substantially after the first year

Remission not yet sustained ~2-3 years, or histologic activity still present

Continue maintenance azathioprine, with or without low-dose corticosteroid; reassess withdrawal candidacy at future visits

Algorithm D — Inadequate response or intolerance

Inadequate response or intolerance to prednisone plus azathioprine

Apparent non-response

Confirm adherence and confirm azathioprine has reached its target weight-based dose before concluding true non-response

Genuine azathioprine intolerance

Switch to mycophenolate mofetil (steroid-sparing) — avoid in pregnancy/conception planning, unlike azathioprine

Still inadequate response or intolerant despite mycophenolate mofetil?

Refer to hepatology for a calcineurin inhibitor (tacrolimus or cyclosporine) or another specialist-directed option — not an ambulatory-initiated decision

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Corticosteroids — induction

Combine with azathioprine from the outset (or within about 2 weeks) in most patients able to tolerate it, to reduce cumulative steroid dose.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Prednisone	Induction, monotherapy: 40-60 mg PO once daily Induction, combined with azathioprine: 20-30 mg PO once daily Taper: Gradual reduction over 4-6 weeks toward maintenance or discontinuation	Hyperglycemia, weight gain/cushingoid features, bone loss, mood changes, cataracts, adrenal suppression with prolonged use, increased infection risk	Additive hyperglycemia with other diabetogenic drugs; reduced response to vaccines during therapy; numerous CYP3A4-mediated interactions — review the full profile before prescribing	First-line induction, alone or combined with azathioprine. Taper over 4-6 weeks toward the lowest effective maintenance dose or off, guided by the aminotransferase/IgG trend once azathioprine has reached full effect.^[1]
Prednisolone	Dosing: Interchangeable with prednisone at equivalent doses	Same as prednisone	Same as prednisone	Dosed the same as prednisone. Does not require hepatic activation — consider specifically in acute severe AIH or decompensated cirrhosis, the same reasoning applied to severe alcoholic hepatitis.^[1]

Budesonide — non-cirrhotic induction alternative

Drug	Dosage	Adverse effects	Drug interactions	Comments
Budesonide	Induction: 3 mg PO three times daily (9 mg/day)	Fewer systemic corticosteroid effects than prednisone in a non-cirrhotic patient (hyperglycemia, GI upset, headache); still causes some systemic effect	Strong CYP3A4 inhibitors (azole antifungals, some protease inhibitors, grapefruit) increase systemic exposure	Combined with azathioprine from the outset. Superior complete biochemical response and fewer steroid-specific adverse effects than prednisone plus azathioprine in a randomized trial restricted to non-cirrhotic patients. Contraindicated once cirrhosis develops — portosystemic shunting bypasses the first-pass hepatic metabolism this drug depends on for its favourable side-effect profile.^[5]

Azathioprine — steroid-sparing induction and maintenance

Drug	Dosage	Adverse effects	Drug interactions	Comments
Azathioprine	Starting dose: 50 mg PO once daily Target maintenance: 1-2 mg/kg/day, increased over 2-6 weeks as tolerated	Myelosuppression (leukopenia, thrombocytopenia), hepatotoxicity, GI intolerance/nausea, rare pancreatitis, long-term malignancy risk (lymphoma, non-melanoma skin cancer) with prolonged use	Allopurinol and febuxostat (xanthine oxidase inhibitors) markedly increase active thiopurine metabolite levels — reduce the azathioprine dose by roughly 50-75% if the combination is unavoidable, or avoid; may reduce warfarin's anticoagulant effect; avoid live vaccines during significant immunosuppression	Check TPMT (and NUDT15 where available) activity or genotype before starting where accessible — reduced-activity patients need a substantially lower starting dose or an alternative agent. Start at a lower dose for the first 1-2 weeks to confirm tolerance, especially with significant baseline hyperbilirubinemia. Continued as maintenance monotherapy once the corticosteroid is tapered off.^[4]

Second- and third-line steroid-sparing options

Reserved for azathioprine intolerance or non-response; calcineurin inhibitors require specialist direction and therapeutic drug monitoring.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Mycophenolate mofetil	Dosing: 1,000-1,500 mg PO twice daily	GI intolerance (diarrhea common), myelosuppression, significant teratogenicity, increased infection risk	Reduced absorption with antacids, iron, and cholestyramine — space administration	Preferred second-line option for azathioprine intolerance; weaker evidence for switching after a confirmed azathioprine non-response. Not preferred in pregnancy or active conception planning — unlike azathioprine, generally considered compatible (see Special Populations).^[2]
Tacrolimus	Dosing: Individualized, trough-level-guided	Nephrotoxicity, tremor, hyperglycemia, hypertension, infection risk	Extensive CYP3A4-mediated interaction profile; additive nephrotoxicity with other nephrotoxic agents	Third-line, hepatology-directed, for disease refractory to or intolerant of both azathioprine and mycophenolate mofetil. Requires therapeutic drug monitoring.^[2]
Cyclosporine	Dosing: Individualized, trough-level-guided	Nephrotoxicity, hypertension, hirsutism, gingival hyperplasia, tremor	Extensive CYP3A4-mediated interaction profile; additive nephrotoxicity with other nephrotoxic agents	Alternative calcineurin inhibitor to tacrolimus, same third-line, specialist-directed role.^[2]

Overlap syndrome — adjunctive therapy

Drug	Dosage	Adverse effects	Drug interactions	Comments
Ursodiol (ursodeoxycholic acid)	Dosing: 13-15 mg/kg/day PO, in divided doses	GI upset, diarrhea; generally well tolerated	None clinically significant at standard dosing	Added specifically for confirmed AIH-primary biliary cholangitis overlap, alongside AIH-directed immunosuppression, under specialist direction — not an AIH-alone therapy.

Medications and exposures requiring caution

Drug	Dosage	Adverse effects	Drug interactions	Comments
Ibuprofen, naproxen (NSAIDs)	—: Avoid routine use with corticosteroids	Additive GI bleeding/ulceration risk with corticosteroid therapy; renal injury; can blunt some antihypertensive effect	Additive GI bleeding risk with corticosteroids; additive nephrotoxicity with other nephrotoxic agents	Avoid routine use during corticosteroid therapy — prefer acetaminophen at a conservative dose for analgesia.
Live vaccines	—: Avoid during significant immunosuppression	Risk of vaccine-strain infection in an immunosuppressed host	None applicable	Avoid during high-dose corticosteroid therapy or while on azathioprine/mycophenolate mofetil/a calcineurin inhibitor; resume routine (non-live) vaccination review once immunosuppression is reduced and the patient is stable.

References

Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases — American Association for the Study of Liver Diseases (Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, Vierling JM, Alsawas M, Murad MH, Czaja AJ). Hepatology 2020;72(2):671-722
EASL Clinical Practice Guidelines on the management of autoimmune hepatitis — European Association for the Study of the Liver (Dalekos GN, Gatselis N, Drenth JPH, Heneghan M, Jørgensen MH, Lohse AW, Londoño MC, Muratori L, Papp M, Samyn M, Tiniakos D, Lleo A). J Hepatol 2025;83(2):453-501
Simplified criteria for the diagnosis of autoimmune hepatitis — International Autoimmune Hepatitis Group (Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, Bittencourt PL, Porta G, Boberg KM, Hofer H, et al.). Hepatology 2008;48(1):169-176
Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update — Clinical Pharmacology & Therapeutics (Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM, Moyer AM, Evans WE, Klein TE, et al.). Clin Pharmacol Ther 2019;105(5):1095-1105
Budesonide Induces Remission More Effectively Than Prednisone in a Controlled Trial of Patients With Autoimmune Hepatitis — Gastroenterology (Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, Bahr MJ, Beuers U, Kanzler S, et al.). Gastroenterology 2010;139(4):1198-1206

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.