Clinical Biochemistry: How Laboratory Tests Reveal Disease

Enzyme Tests and Organ Damage

When cells are damaged or destroyed, their intracellular enzymes leak into the bloodstream, where they can be measured. The specific enzymes elevated in the blood point to the organ that is injured, because different tissues contain different enzyme profiles.

Liver damage is assessed using a panel of enzymes. Alanine aminotransferase (ALT) is relatively specific to the liver and is elevated in hepatitis, drug-induced liver injury, and fatty liver disease. Aspartate aminotransferase (AST) is found in both liver and muscle, so an elevated AST with a normal ALT suggests muscle damage rather than liver disease. Alkaline phosphatase (ALP) is elevated in conditions affecting the bile ducts (cholestasis) and in bone diseases. Gamma-glutamyl transferase (GGT) is elevated in biliary disease and is particularly sensitive to alcohol-related liver damage. The pattern of enzyme elevations, combined with other tests like bilirubin, helps clinicians distinguish between hepatocellular injury (primarily ALT and AST elevation) and cholestatic disease (primarily ALP and GGT elevation).

Heart muscle damage, as occurs during a myocardial infarction (heart attack), releases cardiac-specific biomarkers into the blood. Cardiac troponins (troponin I and troponin T) are highly specific to heart muscle and are the gold standard for diagnosing acute myocardial infarction. They begin to rise 3 to 6 hours after cardiac injury, peak at 12 to 24 hours, and remain elevated for up to 10 to 14 days. Creatine kinase MB (CK-MB), an isoform of creatine kinase found predominantly in heart muscle, was the standard cardiac marker before troponins became available and is still used in some clinical settings.

Pancreatic damage, particularly acute pancreatitis, is diagnosed by elevated serum amylase and lipase. Lipase is more specific to the pancreas than amylase and remains elevated longer, making it the preferred diagnostic test. Amylase is also produced by the salivary glands, so elevated amylase alone is not sufficient to diagnose pancreatitis.

Metabolic Panels

The basic metabolic panel (BMP) and comprehensive metabolic panel (CMP) are among the most commonly ordered laboratory tests. They measure a standard set of metabolites and electrolytes that reflect the function of several organ systems.

Blood glucose is the most frequently measured metabolite in clinical biochemistry. Fasting glucose levels above 126 mg/dL on two separate occasions indicate diabetes mellitus. The hemoglobin A1c (HbA1c) test measures the percentage of hemoglobin that has been glycated (non-enzymatically bound to glucose) and reflects average blood glucose over the preceding two to three months. An HbA1c of 6.5% or higher indicates diabetes. This test is especially useful for monitoring long-term glucose control in diabetic patients.

Kidney function is assessed primarily through serum creatinine and blood urea nitrogen (BUN). Creatinine is a breakdown product of creatine phosphate in muscle and is filtered by the kidneys at a relatively constant rate. When kidney function declines, creatinine accumulates in the blood. The estimated glomerular filtration rate (eGFR), calculated from creatinine, age, sex, and body size, is the standard clinical measure of kidney function. BUN rises when the kidneys cannot adequately excrete urea, a waste product of protein metabolism, and also increases with dehydration, high-protein diets, and gastrointestinal bleeding.

Electrolyte measurements (sodium, potassium, chloride, bicarbonate) reveal fluid balance and acid-base status. Sodium abnormalities reflect water balance disorders rather than sodium intake. Potassium abnormalities can cause life-threatening cardiac arrhythmias and require urgent correction. Bicarbonate levels, combined with blood pH and partial pressures of oxygen and carbon dioxide (from an arterial blood gas), are used to diagnose and classify acid-base disturbances such as metabolic acidosis, metabolic alkalosis, respiratory acidosis, and respiratory alkalosis.

Lipid Profiles and Cardiovascular Risk

A lipid panel measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. These measurements are central to assessing cardiovascular disease risk. Elevated LDL cholesterol promotes the development of atherosclerotic plaques in arterial walls, while HDL cholesterol is associated with reverse cholesterol transport and a reduced risk of atherosclerosis.

Current clinical guidelines target LDL cholesterol reduction as the primary strategy for preventing cardiovascular events. Statin drugs, which inhibit HMG-CoA reductase and reduce hepatic cholesterol synthesis, are the most widely prescribed treatment. The liver compensates for reduced cholesterol synthesis by increasing the expression of LDL receptors, which clear more LDL from the blood and lower serum LDL levels. Newer drugs, including PCSK9 inhibitors, further lower LDL by preventing the degradation of LDL receptors.

Elevated triglycerides are associated with insulin resistance, obesity, and increased cardiovascular risk, particularly when combined with low HDL cholesterol and high LDL cholesterol. Very high triglyceride levels (above 500 mg/dL) increase the risk of acute pancreatitis and require treatment to reduce levels.

Newborn Screening and Inborn Errors of Metabolism

Newborn screening programs test infants shortly after birth for a panel of inherited metabolic disorders. Most screening uses tandem mass spectrometry (MS/MS) to measure the levels of amino acids and acylcarnitines in a dried blood spot collected from a heel prick. Abnormal patterns identify infants at risk for conditions like phenylketonuria (PKU), medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, maple syrup urine disease, and galactosemia.

Early detection is critical because many inborn errors of metabolism can be effectively managed with dietary modifications or enzyme replacement therapy if treatment begins before symptoms develop. PKU, for example, is managed by restricting dietary phenylalanine, which prevents the intellectual disability that would otherwise result from toxic accumulation of phenylalanine in the brain. Without newborn screening, the diagnosis would typically not be made until irreversible neurological damage had already occurred.

Tumor Markers

Tumor markers are molecules produced by cancer cells or by the body in response to cancer. While no tumor marker is perfectly specific or sensitive, they are valuable tools for monitoring treatment response and detecting recurrence.

Prostate-specific antigen (PSA) is produced by both normal and malignant prostate tissue. Elevated PSA levels prompt further investigation for prostate cancer, although false positives can occur from benign prostatic hyperplasia or prostatitis. CA-125 is used to monitor ovarian cancer treatment response. Carcinoembryonic antigen (CEA) is used to monitor colorectal cancer. Alpha-fetoprotein (AFP) is elevated in hepatocellular carcinoma and certain germ cell tumors. Human chorionic gonadotropin (hCG) is the marker for gestational trophoblastic disease and testicular germ cell tumors.

Tumor markers are generally more useful for monitoring known cancers than for screening healthy populations, because their limited specificity can lead to false positives that cause unnecessary anxiety and invasive follow-up procedures. Clinical guidelines carefully balance the benefits of early detection against the harms of overdiagnosis when recommending tumor marker screening.

Hormones and Endocrine Function

Hormone measurements are essential for diagnosing endocrine disorders. Thyroid function is assessed by measuring thyroid-stimulating hormone (TSH), free T4, and free T3. An elevated TSH with low free T4 indicates primary hypothyroidism (the thyroid gland is underactive). A suppressed TSH with elevated free T4 indicates hyperthyroidism (the thyroid gland is overactive). TSH is the single most useful screening test for thyroid dysfunction because the pituitary gland amplifies small changes in thyroid hormone levels into large changes in TSH secretion.

Adrenal function is evaluated using cortisol measurements. A morning cortisol level below 3 micrograms per deciliter suggests adrenal insufficiency, while failure to suppress cortisol after dexamethasone administration suggests Cushing's syndrome (cortisol excess). Parathyroid hormone (PTH) and calcium levels are measured together to diagnose disorders of calcium metabolism, including hyperparathyroidism (elevated PTH and calcium) and hypoparathyroidism (low PTH and calcium).