Severe Hepatocellular Injury with Iron Deficiency Anemia in a 43-Year-Old Indian Woman

This patient most likely has acute-onset autoimmune hepatitis (AIH) with concurrent iron deficiency anemia from chronic blood loss; immediate management requires urgent hepatology referral, initiation of corticosteroid therapy (prednisolone 0.5–1 mg/kg/day), and iron replacement while excluding competing diagnoses.

Most Likely Diagnosis: Acute-Onset Autoimmune Hepatitis

The constellation of severe hepatocellular injury (AST 570, ALT 334), hyperbilirubinemia (total bilirubin 7.8 mg/dL with direct 3.8 mg/dL), hypoalbuminemia (2.8 g/dL), elevated INR (2.0), low-titer anti-smooth muscle antibody (1:40), and negative competing serologies strongly suggests acute-onset AIH. 1, 2

Key Diagnostic Features Supporting AIH

Hepatocellular injury pattern: The R-value [(ALT ÷ ULN) / (ALP ÷ ULN)] is approximately 8.8, confirming hepatocellular injury (R ≥ 5). 1
Synthetic dysfunction: Albumin 2.8 g/dL and INR 2.0 indicate impaired hepatic synthetic function, consistent with severe acute hepatitis. 1, 3
Autoimmune markers: Anti-smooth muscle antibody at 1:40 is positive, though low-titer; 39% of acute-onset AIH patients present with ANA ≤1:40, and seronegative AIH is highly possible early in the acute phase. 2
Negative competing serologies: Negative mitochondrial antibody excludes primary biliary cholangitis; negative LKM-1 excludes type 2 AIH; normal ceruloplasmin excludes Wilson disease. 1, 4
Hemolysis markers: Low haptoglobin (23.3 mg/dL) and modest reticulocytosis (1.76%) with negative DAT suggest mild hemolysis, which can occur in AIH as an acute-phase phenomenon but is insufficient to explain the anemia. 4, 2

Critical Diagnostic Pitfall: Seronegative Acute-Onset AIH

Do not exclude AIH based on low-titer or negative autoantibodies—seronegative AIH occurs in up to 39% of acute presentations, and the simplified AIH score is unreliable in acute liver failure. 1, 2 Liver biopsy is mandatory for definitive diagnosis in seronegative cases, but corticosteroid therapy should not be delayed pending biopsy if clinical suspicion is high and no alternative cause is identified. 1, 2

Concurrent Iron Deficiency Anemia

The microcytic anemia (low iron 22 µg/dL, low ferritin 24 ng/mL, elevated TIBC 440 µg/dL, elevated transferrin 351 mg/dL) with normal endoscopies indicates chronic occult blood loss, likely gynecologic or from a source not visualized on EGD/colonoscopy. 5

Interpretation of Iron Studies in the Context of Inflammation

Ferritin is an acute-phase reactant and can be falsely elevated in AIH; however, a ferritin of 24 ng/mL is unequivocally low even in the setting of severe inflammation, confirming true iron deficiency. 4, 6
Transferrin saturation is low (iron 22 ÷ TIBC 440 = 5%), consistent with iron deficiency rather than anemia of chronic disease. 5
The elevated transferrin (351 mg/dL) relative to albumin (2.8 g/dL) creates a pathologic DAT (difference albumin-transferrin) >28%, which has 67.4% sensitivity and 97.3% specificity for iron deficiency even in the presence of liver disease. 6

Target Cells and Polychromasia

Target cells on peripheral smear are consistent with both iron deficiency and liver disease (due to altered lipid metabolism and increased membrane surface area). 5
Polychromasia reflects the modest reticulocytosis (1.76%), indicating bone marrow response to anemia but insufficient to correct the deficit. 5

Immediate Management Algorithm

Step 1: Urgent Hepatology Referral and Transplant Center Transfer

Transfer the patient immediately to a liver transplant center without waiting for clinical deterioration—this patient meets criteria for acute liver failure (ALT >400 IU/mL, bilirubin >3 mg/dL, INR 2.0, hypoalbuminemia). 1, 3

Calculate the CLIF-SOFA score to assess organ dysfunction severity: Bilirubin 7.8 mg/dL (2 points), INR 2.0 (1 point), no encephalopathy documented (0 points), creatinine not provided but monitor closely. 3
Evaluate for King's College criteria for transplant listing: Non-acetaminophen ALF with INR >2.0 and any degree of encephalopathy, or INR >6.5 regardless of encephalopathy. 3

Step 2: Initiate Corticosteroid Therapy

Start prednisolone 0.5–1 mg/kg/day (approximately 40–60 mg/day for a 43-year-old woman) immediately if no contraindications exist and viral hepatitis is excluded. 1, 2

Do not delay corticosteroids pending liver biopsy if clinical suspicion for AIH is high and no alternative cause is identified—early treatment improves prognosis in acute-onset AIH. 1, 2
If no improvement occurs within 2–3 days, increase prednisolone to 2 mg/kg/day and consider adding mycophenolate mofetil 500–1000 mg twice daily. 1
Monitor liver enzymes every 2–3 days initially; expect ALT/AST to decline within 1–2 weeks if AIH is the correct diagnosis. 1, 2

Step 3: Transjugular Liver Biopsy

Arrange transjugular liver biopsy (not percutaneous, given INR 2.0) to confirm AIH and assess fibrosis stage. 1, 2

Histological features of acute-onset AIH include severe activity (interface hepatitis, piecemeal necrosis), centrizonal necrosis, and plasma cell accumulation—these findings are diagnostic even when serology is negative. 2
Biopsy is mandatory for seronegative cases and provides prognostic information (grade 2 fibrosis suggests early cirrhotic changes). 2, 7

Step 4: Iron Replacement Therapy

Initiate oral ferrous sulfate 325 mg (65 mg elemental iron) three times daily on an empty stomach to replenish iron stores. 5

Recheck hemoglobin in 1 month; expect a 1–2 g/dL increase if iron is absorbed and bleeding has stopped. 5
If hemoglobin does not rise, consider malabsorption (less likely given normal endoscopies) or ongoing occult bleeding requiring further investigation (e.g., capsule endoscopy, gynecologic evaluation). 5
Intravenous iron (e.g., iron sucrose 200 mg weekly) is an alternative if oral iron is not tolerated or malabsorption is suspected. 5

Step 5: Exclude Competing Diagnoses

Complete the etiologic workup to exclude drug-induced liver injury, viral hepatitis reactivation, and Wilson disease (already excluded by normal ceruloplasmin). 1, 4

Review all medications, supplements, and herbals against the LiverTox® database—drug-induced AIH (DIAIH) is a DILI phenotype that mimics idiopathic AIH and requires drug discontinuation. 7
Check HBsAg, anti-HBc IgM, HCV RNA, and HEV IgM/RNA to exclude viral hepatitis (already negative per history, but confirm). 1
Measure IgG levels (not provided)—hypergammaglobulinemia >1.5× ULN supports AIH, though 39% of acute-onset AIH patients have normal IgG. 2

Critical Pitfalls to Avoid

Pitfall 1: Delaying Corticosteroids Pending Biopsy

Do not wait for liver biopsy to initiate corticosteroids if clinical suspicion for AIH is high—acute-onset AIH can progress to fulminant hepatic failure within days, and early treatment is life-saving. 1, 2

Pitfall 2: Attributing Low Ferritin to Inflammation

Do not assume ferritin is falsely low due to liver disease—a ferritin of 24 ng/mL is unequivocally low even in the setting of severe inflammation, and the elevated TIBC/transferrin confirms true iron deficiency. 4, 6

Pitfall 3: Overlooking Seronegative AIH

Do not exclude AIH based on low-titer anti-smooth muscle antibody (1:40)—seronegative AIH occurs in 39% of acute presentations, and liver biopsy is the gold standard for diagnosis. 2

Pitfall 4: Assuming Normal Endoscopies Exclude Blood Loss

Normal EGD and colonoscopy do not exclude occult gastrointestinal bleeding (e.g., small bowel angiodysplasia, Cameron lesions) or gynecologic blood loss (e.g., menorrhagia, uterine fibroids)—further investigation is warranted if hemoglobin does not respond to iron replacement. 5

Pitfall 5: Failing to Transfer to a Transplant Center

Do not manage acute liver failure in a non-transplant center—this patient has synthetic dysfunction (INR 2.0, albumin 2.8 g/dL) and meets criteria for urgent transplant evaluation. 3

Monitoring and Follow-Up

Repeat liver enzymes, bilirubin, INR, and albumin every 2–3 days initially to assess response to corticosteroids. 1, 2
If ALT/AST decline by ≥50% within 1 week, continue prednisolone and taper slowly over 4–6 weeks once enzymes normalize. 1
If no improvement or worsening occurs, escalate to prednisolone 2 mg/kg/day and add mycophenolate mofetil 500–1000 mg twice daily. 1
Monitor for hepatic encephalopathy, ascites, and renal dysfunction (creatinine >1.5 mg/dL worsens prognosis). 3
Recheck hemoglobin and iron studies in 1 month; if hemoglobin does not rise by 1–2 g/dL, investigate for ongoing blood loss or malabsorption. 5

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