Autoimmune hepatitis (AIH) is an uncommon, chronic, immune-mediated inflammatory liver disorder of unknown etiology, first recognized in the 1950s. It is characterized by elevated aminotransferases, hypergammaglobulinemia, circulating autoantibodies, and interface hepatitis on histology [1,2]. Left untreated, AIH may progress to cirrhosis and liver failure, with a six-month mortality of up to 40% [3]. With timely corticosteroid-based therapy, survival rates improve dramatically to 80–98% [4].

Epidemiologically, AIH is more frequent in women, with a female-to-male ratio of approximately 3.6:1 [5]. It is typically diagnosed in young and middle-aged women, though it can occur at any age. Two major types are recognized:

• Type 1 AIH: The classical form, associated with ANA and SMA, often in young to middle-aged females.
• Type 2 AIH: Seen in children and adolescents, associated with anti-LKM1 and anti-LC1 antibodies [6].

Seronegative AIH, where conventional autoantibodies are absent, accounts for 10–20% of cases [7]. Diagnosis in such cases is challenging and requires reliance on IgG elevation, histology, exclusion of other etiologies, and scoring systems proposed by the International Autoimmune Hepatitis Group (IAIHG) [8].

We present a rare case of seronegative AIH in a young male, emphasizing diagnostic difficulties and the crucial role of liver biopsy and scoring systems in establishing the diagnosis

A 28-year-old male IT professional presented with yellowish discoloration of eyes and urine for three weeks. He denied fever, abdominal pain, nausea, vomiting, diarrhea, pruritus, weight loss, or altered sensorium. There was no history of blood transfusion, high-risk behavior, or significant travel.

He reported taking ayurvedic medications after symptom onset, following which his jaundice worsened. His past history was notable for recently diagnosed diabetes mellitus, controlled with oral hypoglycemic agents. He consumed a mixed diet, had no addictions, and reported no family history of chronic liver disease.

Examination

On examination, the patient was icteric, obese (BMI 32.9, waist circumference 132 cm), and had acanthosis nigricans. There was no hepatosplenomegaly, ascites, pedal edema, or stigmata of chronic liver disease. Other systemic examinations were unremarkable.

Investigations

Key laboratory investigations are summarized in Table 1. The patient demonstrated markedly elevated aminotransferases (AST 770 U/L, ALT 592 U/L, >10× ULN) with conjugated hyperbilirubinemia (total bilirubin 8.0 mg/dL; direct fraction 5.3 mg/dL). Serum total protein was elevated (10 g/dL) with a reduced albumin-to-globulin ratio (0.6:1), reflecting hypergammaglobulinemia. Glycemic assessment revealed poorly controlled diabetes (HbA1c 10.3%). Viral serologies for hepatitis A, B, C, and E were negative. Autoimmune testing revealed a weakly positive ANA (1+ homogeneous), while ASMA and anti-LKM1 were negative. Notably, serum IgG was markedly elevated at 44 g/L (~3× upper limit of normal). Metabolic and genetic evaluations, including ceruloplasmin and iron studies, were within normal limits. Abdominal ultrasonography demonstrated grade I fatty liver with borderline hepatosplenomegaly.

Table 1- Key Laboratory and Imaging Findings

Liver Biopsy

 Histopathological examination of the liver biopsy revealed features of chronic active hepatitis with moderate to marked portal inflammation, interface hepatitis, and lobular necroinflammation. Bridging fibrosis with occasional nodule formation was observed, consistent with Ishak fibrosis stage 5. Representative photomicrographs are shown in Figures 1 and 2.

                                Figure 1 A                                                           Figure 1 B

Figure 1A- Hemotyxylin and Eosin staining of Hepatocytes showing focal ballooning degeneration and spotty necrosis. Figure 1B- Hemotyxylin and Eosin staining showing portal and lobular inflammation with dense inflammatory infiltrates composed of neutrophils, plasma cells and lymphocytes and interface activity.

Figure 2A                                          Figure 2 B

Figure 2 A and B: Trichrome stain of liver biopsy showing area of portal fibrosis with bridging and early nodule formation.

Diagnosis

Diagnostic scoring using the Simplified IAIHG criteria (2008) yielded a total of 7 points, consistent with definite autoimmune hepatitis. Application of the more detailed Revised IAIHG criteria (1999) produced a pre-treatment score of 16, also confirming definite autoimmune hepatitis (Table 2).

Together, these findings—marked hypergammaglobulinemia, exclusion of viral and metabolic etiologies, supportive histopathology, and convergent scoring on both diagnostic systems—established a definitive diagnosis of autoimmune hepatitis in this patient.

Table 2- Comparison of Simplified vs Revised IAIHG Diagnostic Scores in the Present Case

The revised IAIHG score was 16, consistent with definite AIH. Other differentials, including viral hepatitis, Wilson disease, and hemochromatosis, were excluded.

Treatment and Outcome

The patient was initiated on oral corticosteroids (prednisolone) with azathioprine. He demonstrated marked clinical improvement and normalization of liver function tests on follow-up. He remains under regular gastroenterology supervision

AIH is a complex interplay of genetic predisposition, immune dysregulation, and environmental triggers. HLA-DR3 and DR4 alleles confer increased susceptibility [9]. Viral infections and drugs have been proposed as possible triggers [10].

Diagnostic Challenges in Seronegative AIH

The absence of conventional autoantibodies complicates diagnosis. Seronegative AIH may result from:

1. Low titers below detection thresholds.
2. Presence of non-classical antibodies such as anti-SLA/LP or anti-LC1, not routinely tested [11].
3. A true immunological variant lacking detectable humoral markers [12].

In our patient, ANA was weakly positive, but absence of ASMA and anti-LKM1, along with markedly elevated IgG and characteristic biopsy findings, fulfilled the diagnostic criteria.

Role of Scoring Systems

The IAIHG revised scoring system remains vital in cases with atypical presentations. A pre-treatment score >15 indicates definite AIH [8]. The simplified criteria introduced in 2008 improve usability but may miss some seronegative cases [13]. In our patient, a score of 16 established the diagnosis.

Treatment Outcomes

First-line therapy includes prednisone with or without azathioprine. Immunosuppression achieves remission in most cases, with survival rates of 80–98% [14]. Our patient responded well to standard therapy, consistent with reported outcomes in seronegative AIH [15].

Literature Context

Liberal et al. described seronegative AIH as a diagnostic dilemma, stressing reliance on IgG and biopsy [7]. Czaja emphasized that treatment response supports diagnosis, as seronegative patients respond similarly to classical AIH [12]. Wang et al. highlighted that seronegative patients often present with more advanced fibrosis, as seen in our case (Ishak stage 5) [16].

Thus, this case reinforces the importance of maintaining high clinical suspicion and utilizing histology and scoring systems when serology is inconclusive.

Autoimmune hepatitis should be considered in the differential diagnosis of unexplained hepatitis in males, even in the absence of conventional autoantibodies. This case highlights the clinical significance of seronegative AIH, where elevated IgG, liver biopsy, and scoring systems are crucial for diagnosis. Early initiation of immunosuppressive therapy yields excellent outcomes and prevents disease progression.

Conflict of Interest: Nil

Funding: Nil

Acknowledgment: The authors used ChatGPT (GPT-5, OpenAI, San Francisco, CA, USA) for language refinement and grammar correction. The content and scientific interpretations were entirely prepared and verified by the authors.

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