What does a positive antinuclear antibody (ANA) with negative smooth‑muscle antibody (SMA), negative viral hepatitis panel, normal prothrombin time (PT), normal iron studies, elevated total and direct bilirubin, and a history of childhood hepatitis indicate?

Diagnostic Interpretation: Positive ANA with Negative SMA and Elevated Bilirubin

This serological and biochemical pattern strongly suggests autoimmune hepatitis (AIH), specifically seronegative or atypical type 1 AIH, and requires immediate liver biopsy and expanded autoantibody testing (anti-SLA, atypical p-ANCA, anti-LKM1) to confirm the diagnosis before initiating immunosuppression. 1

Primary Diagnostic Consideration: Autoimmune Hepatitis

Why AIH is the Leading Diagnosis

• Positive ANA alone is sufficient to raise suspicion for type 1 AIH, as ANA is detected in 80% of white North American adults with AIH at presentation, and 49% of AIH patients have ANA as an isolated serological finding. 1

• Negative SMA does not exclude AIH—approximately 20% of type 1 AIH patients are negative for conventional autoantibodies (ANA, SMA, anti-LKM1) despite having characteristic clinical features, a condition termed "seronegative AIH." 1

• The elevated direct (conjugated) bilirubin with normal PT indicates hepatocellular injury rather than synthetic dysfunction, which is consistent with active AIH. 2

• The childhood hepatitis history is particularly relevant: patients with prior hepatitis may have developed chronic autoimmune liver disease that remained subclinical until now. 1

Critical Next Steps in Evaluation

Expanded autoantibody panel:

• Anti-SLA testing is mandatory because it has 99% specificity for AIH, is present in 7-22% of type 1 AIH patients, and can be the sole serological marker in 14-20% of cases. 1, 3

• Atypical p-ANCA should be measured as it is detected in 50-92% of type 1 AIH patients and may be the only positive marker when conventional antibodies are negative or low-titer. 1, 3

• Anti-LKM1 and anti-LC1 testing is required to exclude type 2 AIH, which is characterized by these antibodies in the absence of ANA/SMA. 1

Biochemical markers:

• Measure serum IgG or γ-globulin levels immediately—elevated IgG is characteristic of AIH, though it is normal in approximately 10% of European patients and 25-39% of acute presentations. 1, 3

• Calculate the alkaline phosphatase to AST ratio: a ratio <1.5 supports AIH diagnosis, while a ratio >3 argues against it. 3

Liver biopsy is mandatory:

• Biopsy cannot be omitted (except in highly typical acute presentations) because serology alone may be misleading. Interface hepatitis is the hallmark finding; plasma cell infiltration is typical but not required. 1, 3

• Histology will distinguish AIH from other causes of elevated bilirubin, including drug-induced liver injury, viral hepatitis sequelae, or overlap syndromes. 1

Essential Exclusions Before Confirming AIH

The following must be ruled out systematically:

• Viral hepatitis E serology should be obtained because acute hepatitis E can mimic AIH and must be excluded. 3

• Wilson disease must be excluded in any patient with a history of childhood hepatitis—measure ceruloplasmin and 24-hour urinary copper, especially given the normal iron studies already documented. 3

• Alpha-1-antitrypsin level is required to exclude alpha-1-antitrypsin deficiency. 3

• Thorough medication history (including over-the-counter, herbal, and illicit agents) is essential to exclude drug-induced liver injury. 3

• Alcohol use assessment using a validated tool (e.g., AUDIT-C) is recommended. 3

• Abdominal ultrasound with Doppler to evaluate liver morphology, exclude biliary obstruction, and assess for cirrhotic changes (surface nodularity, splenomegaly, caudate lobe hypertrophy). 3

Seronegative AIH: A Common Pitfall

• Seronegative AIH accounts for 19-34% of all AIH patients and is defined as clinically and pathologically compatible AIH without ANA, SMA, or anti-LKM1. 1

• Seroconversion occurs in 60% of seronegative patients within 5 years of follow-up, so repeat autoantibody testing during the disease course is valuable. 1

• Seronegative AIH is particularly common (29-39%) in acute presentations and in patients with acute-on-chronic liver failure, making it easily misdiagnosed as "hepatitis of unknown etiology." 1

• ANA-negative patients more frequently show acute presentation with higher serum bilirubin and transaminase levels at presentation, which matches this clinical scenario. 4

Diagnostic Scoring and Management

Apply the International Autoimmune Hepatitis Group scoring system:

• A pretreatment score ≥15 indicates "definite" AIH, while a score of 10-14 indicates "probable" AIH. The score incorporates female sex, ALP:AST ratio, IgG levels, autoantibody titers, absence of viral markers, and histology. 3

If AIH is confirmed:

• Standard induction therapy is prednisone 15-20 mg/day plus azathioprine 1-2 mg/kg/day for moderate-to-severe AIH. 3, 2

• In acute presentations with high bilirubin, high-dose prednisolone should be started promptly after exclusion of other causes, even if serology remains atypical. 3

Alternative Diagnoses to Consider

If biopsy and expanded serology do not support AIH:

• Primary biliary cholangitis (PBC) should be considered—test for anti-mitochondrial antibodies (AMA), though the negative hepatitis panel and normal PT make this less likely. 1

• Overlap syndrome (AIH-PBC or AIH-PSC) can present with positive ANA and cholestatic features; cholangiography may be needed if alkaline phosphatase is disproportionately elevated. 1

• Sequelae of childhood hepatitis leading to chronic liver disease with secondary autoimmune phenomena is possible, but this would typically show more advanced fibrosis and lower inflammatory markers. 1