In a 48‑year‑old woman with elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), leukocytosis with lymphocytosis, high follicle‑stimulating hormone (FSH) and modestly elevated prolactin, what is the likely cause and appropriate work‑up?

Diagnostic Evaluation and Management

Most Likely Diagnosis

This 48-year-old woman most likely has chronic lymphocytic leukemia (CLL) with hepatic involvement causing mild hepatocellular injury, combined with menopausal transition. The striking lymphocytosis (absolute lymphocyte count 10,263/µL, representing >56% of total WBC) is the key finding that drives this assessment, while the elevated FSH (142 IU/L) confirms menopause 1.

Critical Laboratory Interpretation

Lymphocytosis Pattern

• Absolute lymphocyte count >10,000/µL in an adult is highly specific for chronic lymphoproliferative disorder, most commonly CLL, and requires immediate hematologic evaluation 1, 2.
• The combination of marked lymphocytosis with mild transaminase elevation suggests leukemic infiltration of the liver, a well-documented phenomenon in acute and chronic leukemias 2.

Liver Enzyme Pattern

• ALT 127 U/L represents approximately 5× the upper limit of normal for women (normal range 19-25 IU/L), classifying this as moderate hepatocellular elevation requiring prompt evaluation 3, 4.
• The AST:ALT ratio of 0.51 (<1) argues strongly against alcoholic liver disease and is more consistent with non-alcoholic fatty liver disease, viral hepatitis, medication-induced injury, or infiltrative processes 3, 5.
• This degree of ALT elevation (≥5× ULN) is rare in NAFLD/NASH and should not be attributed to metabolic disease alone; it mandates investigation for viral hepatitis, autoimmune hepatitis, and infiltrative disorders 3.

Endocrine Findings

• FSH 142 IU/L confirms ovarian failure and menopause (normal postmenopausal FSH >35 IU/L) 1.
• Prolactin 57 µg/L is mildly elevated (normal <20 µg/L); this may reflect stress, medications, or hypothyroidism, but is not high enough to suggest prolactinoma 1.

Immediate Diagnostic Work-Up (Within 48-72 Hours)

Hematologic Evaluation (Priority #1)

• Obtain peripheral blood smear with manual differential immediately to characterize lymphocyte morphology and confirm absolute lymphocyte count 1, 2.
• Flow cytometry on peripheral blood to immunophenotype lymphocytes and establish diagnosis of CLL versus other lymphoproliferative disorders 1.
• Complete blood count with platelets to assess for thrombocytopenia (which may indicate bone marrow involvement or splenic sequestration) 1, 3.
• Lactate dehydrogenase (LDH) as a marker of tumor burden and cell turnover 1.

Hepatobiliary Evaluation (Priority #2)

• Complete liver panel: total and direct bilirubin, albumin, prothrombin time/INR to assess synthetic function 1, 3, 5.
• Viral hepatitis serologies: HBsAg, anti-HBc IgM, anti-HCV with reflex PCR 1, 3, 5.
• Autoimmune markers: ANA, anti-smooth muscle antibody, quantitative IgG to exclude autoimmune hepatitis 1, 3.
• Iron studies: ferritin and transferrin saturation to screen for hemochromatosis 3, 5.
• Creatine kinase (CK) to exclude muscle injury as source of transaminase elevation 1, 3.

Imaging

• Abdominal ultrasound (sensitivity 84.8%, specificity 93.6% for hepatic steatosis) to evaluate for hepatomegaly, splenomegaly, lymphadenopathy, hepatic steatosis, and biliary obstruction 3, 5, 4.

Additional Testing

• Thyroid-stimulating hormone (TSH) because hypothyroidism can elevate both transaminases and prolactin 1, 3, 5.
• Comprehensive metabolic panel if not already obtained to assess renal function and electrolytes 1.

Differential Diagnosis by Priority

1. Chronic Lymphocytic Leukemia with Hepatic Infiltration (Most Likely)

• Absolute lymphocytosis >10,000/µL is pathognomonic 1, 2.
• Hepatic infiltration by leukemic cells causes transaminase elevation in >30% of ALL/CLL cases at presentation 2.
• Urgent hematology referral within 24-48 hours is mandatory 1.

2. Viral Hepatitis (Hepatitis B, C, or E)

• Acute or chronic viral hepatitis commonly presents with fluctuating transaminase elevations and ALT >400 IU/L in acute infection 5, 6.
• Country of origin is the strongest predictor of viral hepatitis risk 5.
• Must be excluded with serologic testing 1, 3, 5.

3. Non-Alcoholic Fatty Liver Disease (NAFLD)

• NAFLD affects 20-30% of the general population, increasing to 70% with obesity 5.
• However, ALT ≥5× ULN is atypical for NAFLD and should not be attributed to this diagnosis without excluding other causes 3.
• Metabolic syndrome components (obesity, diabetes, hypertension) increase likelihood 3, 4.

4. Medication-Induced Liver Injury

• Medication-induced liver injury causes 8-11% of cases with mildly elevated transaminases 3, 5.
• Requires comprehensive review of all prescription medications, over-the-counter drugs, and herbal supplements 1, 3, 5.

5. Autoimmune Hepatitis

• Typically presents with higher ALT elevations, elevated immunoglobulins, and positive autoantibodies 3, 5.
• More common in women and can present at any age 3.

Management Algorithm

If Lymphocytosis Confirmed (CLL Diagnosis)

1. Immediate hematology referral for staging and treatment planning 1.
2. Monitor liver enzymes every 2-4 weeks during initial evaluation 3.
3. Defer hepatotoxic medications until hematologic diagnosis is established 1.
4. Consider liver biopsy only if diagnosis remains unclear after comprehensive evaluation 3, 5.

If Lymphocytosis Not Confirmed (Alternative Diagnosis)

1. If viral hepatitis positive: Refer to hepatology for antiviral therapy 3, 5.
2. If autoimmune hepatitis suspected: Check autoimmune markers and consider liver biopsy 3, 5.
3. If NAFLD suspected after exclusion of other causes:
   • Calculate FIB-4 score (age, ALT, AST, platelet count) to stratify fibrosis risk 3, 5.
   • FIB-4 >2.67 indicates high risk for advanced fibrosis and warrants hepatology referral 3.
   • Initiate lifestyle modifications: 7-10% weight loss, 150-300 minutes/week moderate-intensity exercise, low-carbohydrate/low-fructose diet 3, 5.

Prolactin Elevation Management

• Repeat prolactin measurement after 2-4 weeks (fasting, morning, non-stressed state) to confirm elevation 1.
• If persistently elevated >100 µg/L or symptomatic (galactorrhea): Obtain pituitary MRI to exclude prolactinoma 1.
• If mildly elevated (20-100 µg/L): Check TSH and review medications (antipsychotics, metoclopramide, SSRIs can elevate prolactin) 1.

Critical Pitfalls to Avoid

• Do not assume NAFLD is the cause of ALT ≥5× ULN without excluding viral hepatitis, autoimmune hepatitis, and infiltrative disease 3.
• Do not overlook the lymphocytosis—absolute lymphocyte count >10,000/µL demands immediate hematologic evaluation regardless of other findings 1, 2.
• Do not delay hepatology referral if ALT remains >5× ULN (>125 IU/L for women) or if evidence of synthetic dysfunction develops 3.
• Do not attribute mildly elevated prolactin to menopause alone—rule out hypothyroidism and medications first 1.
• Do not perform liver biopsy before establishing hematologic diagnosis, as thrombocytopenia or coagulopathy from leukemia increases bleeding risk 3, 2.

Monitoring Strategy

• Repeat CBC with differential and liver enzymes in 2-5 days to establish trend 3.
• If ALT increases to ≥3× baseline or doubles from current level, escalate monitoring to every 3-7 days 3.
• If bilirubin rises to >2× ULN, this suggests potential for acute liver failure and requires urgent hepatology consultation 1, 3.