What is the differential diagnosis and recommended work‑up for an adult with low‑normal serum calcium, mildly elevated alkaline phosphatase, and markedly elevated erythrocyte sedimentation rate (ESR) and C‑reactive protein (CRP)?

Differential Diagnosis and Work-Up for Low-Normal Calcium, Elevated Alkaline Phosphatase, and Markedly Elevated Inflammatory Markers

The combination of calcium 8.7 mg/dL, alkaline phosphatase 140 U/L, and markedly elevated ESR/CRP most strongly suggests chronic non-bacterial osteitis (CNO), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), or an infiltrative process such as malignancy or sarcoidosis—and you must immediately order GGT, complete metabolic panel, PTH, 25-hydroxy-vitamin D, CBC with differential, and abdominal ultrasound to differentiate hepatobiliary from bone disease. 1, 2, 3

Immediate Laboratory Testing Required

Confirm the Source of Alkaline Phosphatase

• Measure gamma-glutamyl transferase (GGT) concurrently with repeat ALP to confirm whether the elevation originates from liver or bone; elevated GGT indicates hepatobiliary disease, while normal GGT strongly suggests bone or other non-hepatic sources. 2, 3
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to quantify the percentage derived from liver versus bone. 2, 3

Assess Metabolic Bone Disease and Mineral Homeostasis

• Obtain serum calcium, phosphate, parathyroid hormone (PTH), and 25-hydroxy-vitamin D to exclude metabolic bone disorders (osteomalacia, Paget's disease, hypophosphatasia), secondary hyperparathyroidism from renal impairment, or vitamin D deficiency—all of which can elevate ALP and are common in patients with chronic inflammation. 1, 4
• Measure serum creatinine and calculate estimated GFR to assess renal function, as chronic kidney disease with secondary hyperparathyroidism is a frequent cause of isolated ALP elevation and can coexist with inflammatory conditions. 1, 3

Evaluate for Systemic Inflammation and Infection

• Order complete blood count with differential to detect anemia of chronic disease (common with malignancy, chronic infections, or inflammatory disorders such as sarcoidosis), leukocytosis (suggesting infection or malignancy), or cytopenias (indicating bone marrow infiltration). 2, 3
• The combination of elevated ESR and CRP indicates active systemic inflammation; however, ESR can remain elevated in resolving inflammatory disorders or be falsely elevated by anemia, renal impairment, or advanced age, whereas CRP rises and falls more rapidly with acute inflammation. 5, 6, 7
• CRP is more sensitive than ESR for detecting current inflammatory activity and should be prioritized when monitoring disease progression or response to therapy. 5, 6, 8

Screen for Autoimmune and Cholestatic Liver Disease

• If GGT is elevated (confirming hepatobiliary origin), immediately order antimitochondrial antibody (AMA), antinuclear antibody (ANA) with sp100/gp210 subtyping, anti-smooth muscle antibody (ASMA), and quantitative IgG to screen for primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis. 3
• Positive AMA plus elevated ALP essentially confirms primary biliary cholangitis (PBC), while ANA subtypes sp100 or gp210 support PBC variants when AMA is negative. 3
• Approximately 50–80% of PSC patients have concomitant inflammatory bowel disease; specifically inquire about chronic diarrhea, abdominal pain, or bloody stools. 3

Additional Markers for Specific Conditions

• Measure bone-specific alkaline phosphatase (B-ALP) if GGT is normal and bone disease is suspected, as B-ALP is a sensitive marker for bone turnover, rickets, osteomalacia, and bone metastases. 2, 3
• Consider intact FGF23 levels if hypophosphatemia is present or if X-linked hypophosphatemia or tumor-induced osteomalacia is suspected, especially in patients with bone pain and low-normal calcium. 1, 4
• In patients with suspected chronic non-bacterial osteitis, consider anti-CCP, rheumatoid factor (RF), and HLA-B27 on a case-by-case basis to evaluate for axial spondyloarthritis or psoriatic arthritis. 1

Imaging Studies Needed

First-Line Imaging: Abdominal Ultrasound

• Obtain abdominal ultrasound as the initial imaging modality to assess for dilated intra- or extra-hepatic bile ducts, gallstones, infiltrative liver lesions, masses, hepatosplenomegaly, and nephrocalcinosis. 2, 3
• Ultrasound demonstrates 84.8% sensitivity and 93.6% specificity for detecting moderate-to-severe hepatic steatosis and reliably identifies biliary obstruction and focal lesions. 3

Advanced Imaging: MRI with MRCP

• If ultrasound is negative but ALP and inflammatory markers remain elevated, proceed to MRI with magnetic resonance cholangiopancreatography (MRCP), which is superior to CT for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, small-duct disease, partial bile-duct obstruction, and infiltrative diseases such as sarcoidosis or hepatic metastases. 2, 3
• MRCP demonstrates 86% sensitivity and 94% specificity for diagnosing PSC, reliably visualizing multifocal strictures, dilatations, ductal thickening, and "beading" of the biliary tree. 3
• In elderly patients, MRCP can also identify cholangiocarcinoma, which frequently presents with progressive cholestasis and elevated inflammatory markers. 3

Bone Imaging

• Order a bone scan (bone scintigraphy) if GGT is normal and bone pain, localized symptoms, or radiographic findings suggestive of bone pathology are present, as 57% of isolated elevated ALP cases are due to underlying malignancy (bone metastases or infiltrative liver disease). 2, 3
• Whole-body MRI (with sagittal spinal images) should be preferred for suspected chronic non-bacterial osteitis, but technetium-labeled bone scintigraphy or PET/CT with a bone-seeking radiotracer are reasonable alternatives to map clinically silent but radiologically active lesions. 1
• Do not perform routine bone biopsies; reserve them for cases with inconclusive imaging and/or suspicion of malignancy or infectious osteomyelitis. 1

Chest X-Ray

• Obtain a chest X-ray to evaluate for pulmonary infection, sarcoidosis, or primary malignancy, especially in patients with elevated inflammatory markers and unexplained ALP elevation. 2

Critical Clinical Considerations

Prioritize Malignancy Evaluation

• Malignancy is the most common cause of isolated elevated ALP, accounting for 57% of cases due to infiltrative liver disease, bone metastases, or both; therefore, urgent evaluation is mandatory when ALP is markedly elevated (>10× ULN) or accompanied by constitutional symptoms, weight loss, or localized bone pain. 2, 3
• If imaging reveals malignancy, urgent oncology referral is recommended for comprehensive staging and treatment planning. 2

Assess for Chronic Non-Bacterial Osteitis (CNO)

• Atraumatic bone pain persisting for over 6 weeks, with inflammatory properties such as pain irrespective of motion or during the night, is suggestive of CNO, especially when accompanied by elevated inflammatory markers and normal or low-normal calcium. 1
• CNO is a diagnosis of exclusion; perform thorough clinical evaluation including history of initial and presenting complaints, full medical history, and family history of autoinflammatory or autoimmune diseases in first-degree relatives. 1
• Assess for additional inflammatory features such as psoriasis, inflammatory bowel disease, uveitis, or enthesitis, and consider diagnostic involvement of dermatology, ophthalmology, or gastroenterology. 1

Evaluate for Primary Sclerosing Cholangitis (PSC)

• PSC typically presents with ALP ≥1.5× ULN, mild transaminase elevation (2–3× normal), and normal bilirubin in up to 70% of patients at diagnosis, often accompanied by elevated ESR and CRP. 3
• The classic PSC patient is a young-to-middle-aged individual with inflammatory bowel disease who presents with biochemical cholestasis; up to 80% of PSC patients have concomitant ulcerative colitis. 3
• If inflammatory bowel disease is present, high-quality MRCP should be obtained to evaluate for PSC, as a normal ultrasound does not exclude intrahepatic cholestasis or small-duct disease. 3

Evaluate for Primary Biliary Cholangitis (PBC)

• PBC diagnosis requires elevated ALP plus positive AMA (or ANA sp100/gp210 if AMA-negative); elevated IgG is observed in 61% of PBC patients, most often reaching about 1.5× the upper limit of normal. 3
• First-line treatment is ursodeoxycholic acid (UDCA) 13–15 mg/kg/day, with up to 40% of UDCA-treated patients having persistently elevated ALP levels, which are associated with reduced transplant-free survival. 3

Consider Infiltrative Diseases

• Infiltrative non-malignant diseases such as sarcoidosis and amyloidosis can cause isolated ALP elevation with elevated inflammatory markers; consider these diagnoses in patients with unexplained elevation, especially when accompanied by organomegaly or systemic symptoms. 3
• Serum protein electrophoresis and immunofixation should be performed to screen for plasma-cell dyscrasias that may cause infiltrative liver disease. 3

Assess for Vitamin D Deficiency and Secondary Hyperparathyroidism

• Vitamin D deficiency is common in patients with chronic inflammation and can contribute to elevated ALP; when 25-hydroxyvitamin D is <10 ng/mL, approximately two-thirds of patients exhibit elevated PTH, while only about one-fifth show a concurrent rise in ALP. 3
• Vitamin D supplementation (e.g., 50,000 IU weekly for 8 weeks followed by maintenance dosing) can be initiated regardless of liver-enzyme abnormalities, as it does not worsen hepatic enzymes and is unlikely to improve them. 3
• Re-assess 25-hydroxyvitamin D and PTH 8–12 weeks after initiating supplementation to confirm biochemical repletion. 3

Follow-Up Plan

If GGT is Normal (Bone Origin Suspected)

• Measure bone-specific alkaline phosphatase (B-ALP) to confirm bone origin and evaluate for Paget's disease, osteomalacia, or benign bone conditions. 2, 3
• If bone scan is negative and B-ALP is elevated, consider X-linked hypophosphatemia, tumor-induced osteomalacia, or chronic non-bacterial osteitis and measure intact FGF23 levels. 1, 4
• If bone imaging reveals metastases, urgent oncology referral is recommended for comprehensive staging and treatment planning. 2

If GGT is Elevated (Hepatobiliary Origin Confirmed)

• Proceed with MRCP if ultrasound is negative or shows only fatty liver, as it is superior to CT for detecting intrahepatic biliary abnormalities and early primary sclerosing cholangitis. 2, 3
• If MRCP shows PSC features (multifocal strictures, dilatations, ductal thickening), refer to hepatology for disease-specific management and surveillance. 3
• If AMA is positive, diagnose PBC and initiate ursodeoxycholic acid therapy (13–15 mg/kg/day). 3
• If both serology and MRCP are negative, consider liver biopsy to assess for small-duct PSC, infiltrative disease, or drug-induced injury. 3

If Initial Workup is Unrevealing

• Recheck ALP, GGT, ESR, and CRP in 1–3 months; persistent or rising ALP warrants further investigation, including possible MRI with MRCP if hepatobiliary disease is suspected. 2, 3
• Repeat blood tests within 7–10 days to confirm reproducibility and direction of change in patients with unclear etiology and normal initial workup. 3

If Sepsis or Acute Infection is Identified

• Immediate hospitalization is necessary for IV antibiotics and supportive care, as sepsis carries a high risk of mortality if left untreated. 2

Common Pitfalls to Avoid

• Do not assume liver disease when GGT is normal, as this strongly indicates non-hepatic ALP elevation; extensive hepatobiliary workup should be avoided as the first step. 2, 3
• Do not delay bone imaging when GGT is normal and bone pain or localized symptoms are present, as bone metastases are a common cause of isolated elevated ALP and early detection impacts treatment options. 2, 3
• Do not rely solely on abdominal ultrasound; a normal ultrasound does not rule out PSC, PBC, or intrahepatic cholestasis, and MRCP is essential for definitive evaluation. 3
• Do not attribute isolated ALP elevation to non-alcoholic steatohepatitis (NASH), as elevation of ALP ≥2× ULN is atypical in NASH; NASH typically causes ALT elevation more than ALP. 3
• Do not underestimate the importance of ESR/CRP discordance; elevated ESR with normal CRP can occur in resolving inflammatory disorders, false-positive ESR due to anemia or renal impairment, or chronic conditions such as lupus nephritis or osteomyelitis. 5, 7, 9
• Patients aged ≥60 years are especially vulnerable to cholestatic drug-induced liver injury, which accounts for up to 61% of such cases in this age group; perform a thorough medication review including over-the-counter and supplement medications. 3