Assessment and Significance of Albumin-Globulin (AG) Reversal from Liver Function Tests
How to Assess AG Reversal
AG reversal is identified when serum globulin concentration exceeds serum albumin concentration, calculated by subtracting globulin from albumin on a standard liver function test panel. 1
Calculation Method
- Total protein and albumin are directly measured on standard LFT panels 1
- Globulin is calculated as: Total Protein - Albumin 1
- Normal AG ratio is approximately 1.0-2.0 (albumin higher than globulin) 1
- AG reversal occurs when the ratio falls below 1.0, meaning globulin > albumin 1
Example Calculation
- If total protein = 7.0 g/dL and albumin = 2.5 g/dL
- Globulin = 7.0 - 2.5 = 4.5 g/dL
- AG ratio = 2.5/4.5 = 0.56 (reversed)
Clinical Significance of AG Reversal
AG reversal indicates advanced chronic liver disease with severe hepatic synthetic dysfunction and typically signals poor prognosis, particularly in the context of cirrhosis or chronic hepatitis. 1, 2
Primary Pathophysiologic Mechanisms
Decreased albumin production is the dominant factor, as the liver loses synthetic capacity in advanced disease 2. In chronic liver disease, albumin levels progressively decline as hepatocyte function deteriorates, while globulin levels remain normal or increase 1, 2.
Increased globulin levels occur through multiple mechanisms 1:
- Chronic immune stimulation from ongoing hepatic inflammation
- Polyclonal hypergammaglobulinemia in autoimmune hepatitis 3
- Impaired clearance of immunoglobulins by the diseased liver
- Portal-systemic shunting exposing the immune system to gut antigens
Specific Disease Contexts
In chronic hepatitis and cirrhosis, AG reversal correlates with disease severity and decompensation 1, 2. Albumin synthesis is increased 7-fold in acute liver failure and acute-on-chronic liver disease, yet levels remain severely reduced due to massive consumption and hepatocyte necrosis 2.
In autoimmune hepatitis, AG reversal is particularly common due to markedly elevated IgG levels (often >1.1× upper limit of normal) combined with reduced albumin synthesis 3. The American Association for the Study of Liver Diseases recommends measuring serum IgG levels immediately when autoimmune hepatitis is suspected 3.
In decompensated cirrhosis, hypoalbuminemia persists for weeks even after liver transplantation 4. The wait-list mortality remains elevated, and albumin <3 g/dL is associated with increased complications 5, 4.
Prognostic Implications
In acute liver failure, Gc-globulin (a specific globulin fraction) levels <100 mg/L predict mortality with accuracy equal to King's College Hospital criteria 2. Admission Gc-globulin was 26% of normal in nonsurvivors versus 46% in survivors (P<0.001) 2.
Post-transplant monitoring shows albumin continues to decrease while other liver proteins normalize, suggesting different regulatory mechanisms 2. After liver transplantation, Gc-globulin normalizes within two weeks, contrasting with continuous albumin decline 2.
Critical Clinical Pitfalls
Do not assume AG reversal alone defines the diagnosis - it is a nonspecific marker requiring comprehensive evaluation including viral hepatitis serology, autoimmune markers (ANA, ASMA, AMA), and imaging 3, 1. A panel of tests (AST, alkaline phosphatase, bilirubin, albumin) is preferable to single tests for superior sensitivity and specificity 1.
Do not use albumin supplementation as definitive treatment - postoperative albumin administration to maintain levels ≥3 g/dL does not improve outcomes in liver transplant recipients 4. However, long-term albumin administration in decompensated cirrhosis awaiting transplant may reduce life-threatening complications if given in sufficient amounts and duration 5.
In transplant recipients with AG reversal, deterioration in LFTs should not be presumed as disease flare or acute rejection without biopsy confirmation 6, 7. Allograft rejection is a diagnosis of exclusion requiring liver biopsy, and empirical treatment without biopsy is discouraged 7.
Monitoring Algorithm
For patients with AG reversal and chronic liver disease 3, 1:
- Complete autoimmune workup if not already done (ANA, ASMA, anti-LKM1, anti-SLA, IgG levels)
- Viral hepatitis panel (HBsAg, anti-HCV with reflex PCR)
- Abdominal ultrasound with Doppler to assess for cirrhosis and portal hypertension
- Consider liver biopsy if diagnosis uncertain or before initiating immunosuppression
For transplant candidates with MELD ≥25 and AG reversal 8:
- Urgent multidisciplinary evaluation including hepatology, transplant surgery, and nephrology
- Assessment for combined liver-kidney transplantation if GFR <30 ml/min
- Weekly monitoring of LFTs and clinical status while awaiting transplant