What are the causes of elevated Alanine Transaminase (ALT) and Alkaline Phosphatase (ALK Phosphatase) in a patient?

Causes of Elevated ALT and Alkaline Phosphatase

Hepatobiliary Causes of Combined ALT and ALP Elevation

The most common causes of combined ALT and alkaline phosphatase elevation include cholestatic liver diseases (primary biliary cholangitis, primary sclerosing cholangitis, drug-induced cholestasis), biliary obstruction (choledocholithiasis, malignant obstruction, biliary strictures), infiltrative liver diseases (hepatic metastases, amyloidosis), and sepsis. 1

Cholestatic Liver Diseases

• Primary biliary cholangitis (PBC) typically presents with ALP elevation (2-10× ULN) and is diagnosed when two of the following are present: elevated ALP, positive antimitochondrial antibody, or consistent liver histology 1
• Primary sclerosing cholangitis (PSC) shows a cholestatic pattern with raised ALP and γ-glutamyl transpeptidase (GGT), while ALT is often only mildly raised in approximately 75% of PSC patients 1
• PSC is strongly associated with inflammatory bowel disease, and if IBD is present, high-quality MRCP should be obtained to evaluate for PSC 1

Biliary Obstruction

• Choledocholithiasis (common bile duct stones) causes partial or complete biliary obstruction, leading to cholestasis and elevated ALP, with approximately 18% of adults undergoing cholecystectomy having this condition 1
• Malignant biliary obstruction from cholangiocarcinoma, pancreatic cancer, or other malignancies commonly presents with markedly elevated ALP 2, 3
• Sustained elevation of ALP is significantly correlated with choledocholithiasis on MRCP and may help triage patients for endoscopic retrograde cholangiopancreatography (ERCP) 1

Infiltrative Liver Diseases

• Hepatic metastases are a leading cause of isolated elevated ALP, with 57% of unexplained isolated ALP elevations due to cancer, including 61 patients with infiltrative intrahepatic malignancy in one cohort 1, 4
• The prevalence of ALP ≥2× ULN is 30% in patients with liver metastases, and this is linked to poor prognosis 1
• Amyloidosis and sarcoidosis can cause isolated alkaline phosphatase elevation and should be considered in patients with unexplained elevation 1

Drug-Induced Liver Injury

• Medication-induced liver injury causes 8-11% of cases with mildly elevated liver enzymes, with cholestatic drug-induced injury comprising up to 61% of cases in patients ≥60 years 5
• Older patients are more prone to cholestatic drug-induced liver injury, highlighting the need for careful medication review 1
• All medications should be checked against the LiverTox® database for hepatotoxic potential, including prescription drugs, over-the-counter products, herbal supplements, and dietary supplements 5

Sepsis and Systemic Infections

• Sepsis is one of the most frequent causes of extremely high elevations of alkaline phosphatase (>1000 U/L), and patients with sepsis can have an extremely high alkaline phosphatase level with a normal bilirubin 3
• Sepsis from gram-negative organisms, gram-positive organisms, and fungal infections can all cause marked ALP elevation 3
• In patients with AIDS, causes of elevated ALP include sepsis, mycobacterium avium intracellulare (MAI) infection, and cytomegalovirus infection 3

Hepatocellular Causes of Elevated ALT

Nonalcoholic Fatty Liver Disease (NAFLD)

• NAFLD is the most common cause of persistently elevated ALT in patients with metabolic risk factors (obesity, diabetes, hypertension), typically presenting with AST:ALT ratio <1 and mild to moderate transaminase elevations 5
• ALT elevation of ≥5× ULN is rare in NAFLD/NASH and usually should not be attributed to these conditions alone 5
• Metabolic syndrome components, including obesity, diabetes, and hypertension, are key risk factors for NAFLD 5

Viral Hepatitis

• Viral hepatitis (acute or chronic) can present with ALT >3× ULN, and hepatitis B, C, and E should be considered 5
• Chronic hepatitis B reactivation presents with elevated, often fluctuating ALT levels and moderate fluctuating HBV DNA levels >2000 IU/mL 5
• Chronic hepatitis C commonly presents with fluctuating transaminase elevations over months 5

Alcoholic Liver Disease

• Alcoholic liver disease typically shows an AST/ALT ratio >2 in 70% of patients, with AST elevation 2-6 times ULN 5
• An AST/ALT ratio ≥2 is highly suggestive of alcoholic liver disease, with ratios >3 being particularly specific for this diagnosis 5
• Alcohol consumption of ≥14-21 drinks/week in men or ≥7-14 drinks/week in women may indicate alcoholic liver disease 5

Autoimmune Hepatitis

• Autoimmune hepatitis typically presents with higher ALT elevations and elevated autoantibodies (ANA, ASMA), with elevated immunoglobulin G levels 5
• Overlap syndromes (AIH/PBC or AIH/PSC) should be considered when serum alkaline phosphatase is more than mildly elevated and does not normalize rapidly with immunosuppressive treatment 1

Non-Hepatic Causes of Elevated ALP

Bone Disorders

• Bone disorders, including Paget's disease, bony metastases, and fractures, are significant sources of ALP elevation 1
• Bone metastases accounted for 52 patients in one cohort of isolated elevated ALP, with 34 patients having both hepatic and bone metastasis 4
• Bone-specific alkaline phosphatase (B-ALP) measurement can be useful for suspected bone origin, with B-ALP a sensitive marker for bone turnover and bone metastases 1

Physiologic Causes

• Childhood and pregnancy can lead to elevated ALP levels, with ALP levels physiologically 2-3× adult values in children due to bone growth 1
• In pregnancy, ALP can be elevated due to placental production 1

Other Non-Hepatic Causes

• Intestinal ALP can be elevated in benign familial intestinal hyperphosphatemia (BFIH), a rare but benign condition 6
• Alkaline phosphatase is found in multiple tissues including intestines, placenta, kidneys, and leukocytes, which can contribute to elevations 2, 7

Diagnostic Approach Algorithm

Step 1: Confirm Hepatic Origin of ALP

• Measure GGT concurrently with ALP to confirm hepatobiliary origin; elevated GGT confirms hepatic origin, while normal GGT suggests bone or other non-hepatic sources 1
• If GGT is unavailable or equivocal, obtain ALP isoenzyme fractionation to determine the percentage derived from liver versus bone 1

Step 2: Calculate R Value to Classify Injury Pattern

• Calculate the R value [(ALT/ULN)/(ALP/ULN)] to classify liver injury patterns: cholestatic (R ≤2), mixed (R >2 and <5), or hepatocellular (R ≥5) 1, 5
• This classification guides the differential diagnosis and subsequent workup 1

Step 3: Obtain Complete Liver Panel and Initial Testing

• Perform a complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR 8, 5
• Obtain viral hepatitis serologies (HBsAg, anti-HBc IgM, anti-HCV) if risk factors are present 8, 5
• Check autoimmune markers (ANA, ASMA, AMA) if autoimmune disease is suspected 8, 1
• Measure creatine kinase (CK) to exclude muscle injury as a source of transaminase elevation 8, 5

Step 4: Imaging Evaluation

• Abdominal ultrasound is the first-line imaging modality to assess for dilated intra/extrahepatic ducts, gallstones, infiltrative lesions, or masses, with 84.8% sensitivity and 93.6% specificity for detecting moderate-severe hepatic steatosis 1, 5
• If ultrasound is negative but ALP remains elevated, proceed to MRI with MRCP, which is superior to CT for detecting intrahepatic biliary abnormalities, primary sclerosing cholangitis, and small duct disease 1
• If common bile duct stones are demonstrated on ultrasound, proceed directly to ERCP for both diagnosis and therapeutic intervention 1

Step 5: Severity-Based Approach

• Mild elevation (<5× ULN): Repeat testing in 2-4 weeks to establish trend, complete initial workup, and monitor 1, 5
• Moderate elevation (5-10× ULN): Expedite workup with imaging and laboratory evaluation 1
• Severe elevation (>10× ULN): Requires expedited workup given high association with serious pathology including malignancy, sepsis, and biliary obstruction 1, 3

Critical Pitfalls to Avoid

• Do not assume NAFLD is the cause of ALP elevation ≥2× ULN, as NASH typically causes ALT elevation more than ALP 1
• Do not overlook sepsis as a cause of extremely high ALP, as patients with sepsis can have an extremely high alkaline phosphatase level with a normal bilirubin 3
• Do not delay ERCP when choledocholithiasis is identified, as conservative management carries a 25.3% risk of unfavorable outcomes compared to 12.7% with active extraction 1
• Do not ignore malignancy as a cause of isolated elevated ALP, as 57% of unexplained isolated ALP elevations are due to cancer 4
• In patients with inflammatory bowel disease and elevated ALP, always evaluate for primary sclerosing cholangitis with high-quality MRCP 1