What is the differential diagnosis for an elderly female with generalized pruritus, slightly elevated Gamma-Glutamyl Transferase (GGT), normal liver enzymes, and a long history of daily Reactine (Cetirizine) use?

Differential Diagnosis for Generalized Pruritus with Isolated GGT Elevation

In an elderly female with chronic generalized pruritus, normal liver enzymes except mildly elevated GGT (62), and long-term antihistamine use, the key differentials to investigate are iron deficiency (the most common systemic cause), cholestatic liver disease, hematological disorders including polycythemia vera and lymphoma, medication-induced pruritus from cetirizine itself, and senile pruritus with asteatotic eczema. 1, 2, 3

Primary Differentials to Investigate

Iron Deficiency (Most Common Systemic Cause)

• Iron deficiency is the most common cause of generalized pruritus with systemic disease, accounting for 25% of cases and often responding dramatically to iron replacement. 1, 4
• Check complete blood count, ferritin, serum iron, and total iron-binding capacity, as ferritin can be falsely "normal" when it's an acute-phase reactant in the presence of inflammation. 1, 2
• A therapeutic trial of iron replacement is warranted if ferritin is below the lower reference range (15-25 µg/L) or if there is unexplained anemia or microcytosis. 1, 2
• Consider tissue transglutaminase antibodies if iron deficiency is unexplained, as celiac disease can cause both iron deficiency and pruritus. 1

Cholestatic Liver Disease

• The isolated GGT elevation (62) with normal other liver enzymes suggests possible early cholestasis or biliary pathology. 3, 5
• GGT elevation can indicate dysfunction of bile canalicular transporters, particularly in cholestatic conditions. 5
• Check serum bile acids, antimitochondrial antibodies (for primary biliary cholangitis), and consider hepatitis serology (A, B, C). 3, 6
• Cholestatic pruritus typically has specific effective treatments once identified. 7

Hematological Disorders

• Polycythemia vera should be considered, especially if the patient reports water-induced (aquagenic) pruritus, which is highly characteristic. 2
• Check blood film, lactate dehydrogenase, erythrocyte sedimentation rate, and JAK2 V617F mutation if hemoglobin/hematocrit is elevated or if there's microcytosis with elevated leukocytes/platelets. 2, 3
• Hodgkin lymphoma must be excluded if there are nocturnal symptoms, weight loss, fever, night sweats, or palpable lymphadenopathy. 2
• Hematological causes account for approximately 2% of generalized pruritus cases but are critical not to miss. 2

Medication-Induced Pruritus (Cetirizine)

• Long-term daily cetirizine use itself can paradoxically cause or perpetuate pruritus as a drug-induced phenomenon. 1, 6
• A trial cessation of cetirizine should be considered if the risk-benefit analysis is acceptable, as drug-induced pruritus is a common and reversible cause. 1, 6
• Many patients develop tolerance or paradoxical reactions to chronic antihistamine use. 1

Senile Pruritus with Asteatotic Eczema

• In elderly patients, initiate a 2-week trial of high-lipid-content emollients and topical corticosteroids before extensive workup to exclude asteatotic eczema. 1, 6
• Age-related changes in nerve fiber bundles and skin barrier function contribute to pruritus in the elderly. 1
• If initial treatment fails, reassess and proceed with systemic workup. 1

Additional Differentials to Consider

Renal Disease

• Check urea, creatinine, and electrolytes to evaluate for uremic pruritus from chronic kidney disease. 3, 6
• Uremic pruritus is a significant cause of generalized pruritus with specific effective treatments. 7

Endocrine Disorders

• Diabetes mellitus and thyroid disease can cause pruritus, though thyroid testing should only be ordered if there are clinical features suggesting thyroid dysfunction. 6, 8, 4
• Check fasting glucose or HbA1c as part of the initial workup. 8

Occult Malignancy

• In elderly patients with persistent unexplained pruritus, consider evaluation for internal malignancy, particularly lung cancer. 8, 4
• However, extensive malignancy screening should not be pursued without specific clinical indicators. 6

HIV and Viral Hepatitis

• Consider HIV and hepatitis serology based on risk factors or relevant history. 3, 6

Critical Pitfalls to Avoid

• Do not overlook iron deficiency—ferritin must be checked in all cases of chronic generalized pruritus without rash. 1, 3
• Do not continue cetirizine indefinitely without considering it as a potential cause rather than treatment. 1, 6
• Do not use sedating antihistamines in elderly patients except in palliative care due to dementia risk. 1, 6
• Do not order routine thyroid function tests without clinical features suggesting endocrinopathy. 6
• Do not fail to follow up regularly when the cause is not immediately evident, as systemic causes may declare themselves over time. 1, 6

Recommended Initial Workup

• Complete blood count with peripheral smear and ferritin 1, 2, 3
• Serum iron and total iron-binding capacity (if ferritin equivocal) 1, 2
• Comprehensive metabolic panel (liver function tests, urea, creatinine, electrolytes, glucose) 3, 6
• Serum bile acids 6
• Lactate dehydrogenase and erythrocyte sedimentation rate 2, 3
• Consider JAK2 V617F mutation if polycythemia suspected 2, 3
• Consider hepatitis and HIV serology based on risk factors 3, 6