Elevated Total Protein and Globulin: Differential Diagnosis

Introduction to Causes

The American College of Cardiology and other guideline societies consider infection/inflammation, statin-induced muscle injury with acute phase response, autoimmune conditions, and chronic liver disease as primary considerations in patients with hyperlipidemia on statin therapy presenting with elevated total protein and globulin, with muscle injury being particularly relevant given the clinical context 1, 2

Intensive exercise or statin-related muscle injury can lead to acute elevation in muscle enzymes that may be mistaken for other pathology, with testing for creatine phosphokinase (CK), aldolase, or other muscle-related enzymes confirming the nonhepatic origin of transaminase elevations 1
Risk factors for statin-induced myositis include advanced age, female sex, small body frame, chronic renal insufficiency, and polypharmacy, with severe myopathy occurring in approximately 0.08% of patients on lovastatin/simvastatin 2, 3

The American Association of Clinical Endocrinologists notes that statin-associated autoimmune myopathy is rare but causes persistent CK elevation and requires immunosuppressive therapy, not just statin cessation, with hypergammaglobulinemia potentially present and confounding the clinical picture 1, 2

The European Association for the Study of the Liver states that in patients with metabolic syndrome and NASH, positive ANA or ASMA with low titers are epiphenomena and do not indicate autoimmune hepatitis, with elevated serum autoantibodies occurring in 21% of patients with biopsy-proven NAFLD without AIH 1
Concomitant hypergammaglobulinemia or other clinical features suggesting AIH may warrant liver biopsy to rule out idiopathic AIH, with these autoantibodies contributing to elevated globulin fractions but being clinically insignificant in NASH 1

The American Heart Association recommends checking CK, aldolase, inflammatory markers, serum protein electrophoresis, and TSH to differentiate between muscle injury, infection/inflammation, and other causes, with serum protein electrophoresis distinguishing polyclonal from monoclonal gammopathy 1, 2
If CK is markedly elevated, discontinue statin immediately and evaluate for rhabdomyolysis, with consideration of other causes including hypothyroidism, autoimmune myopathy, or chronic infection if muscle symptoms persist after 2 months without statin treatment 2, 4

The American College of Cardiology advises against attributing neutrophilia to statin therapy, as statins cause muscle injury but not leukocytosis, with neutrophilia indicating infection or inflammation requiring separate evaluation 5