Elevated Liver Function Tests (LFT’s)

Specific Liver Function Tests (LFT’s) (see Liver Function Tests, [[Liver Function Tests]])

Transaminases (Aminotransferases) (see Serum Transaminases, [[Serum Transaminases]])

Transaminases (Aminotransferases)
- Aspartate Aminotransferase (AST) (see Serum Transaminases, [[Serum Transaminases]])
  - Formerly Called Serum Glutamate-Oxaloacetate Transaminase (SGOT)
- Alanine Aminotransferase (ALT) (see Serum Transaminases, [[Serum Transaminases]])
  - Formerly Called Serum Glutamate-Pyruvate Transaminase (SGPT)
Origin of Transaminases (Aminotransferases)
- Liver: AST and ALT
- Cardiac and Skeletal Muscle: AST only
- Thyroid: AST only
Sensitivity/Specificity of Transaminases (Especially ALT) for the Differentiation of Liver Disease from Other Disorders Depends on the Cutoff Value Chosen to Define an Abnormal Result
- ALT Levels Correlate with the Degree of Abdominal Adiposity Vary Between the Sexes
- AST and ALT Upper Limits of Normal Vary Between Laboratories: due to differing reference standards used
- Optimal ALT Cutoff Value (Male): 29 IU/L (Hepatology, 2012) [MEDLINE]
- Optimal ALT Cutoff Value (Female): 22 IU/L (Hepatology, 2012) [MEDLINE]

Alkaline Phosphatase (see Serum Alkaline Phosphatase, [[Serum Alkaline Phosphatase]])

Origin of Alkaline Phosphatase
- Bone
- Intestine
- Kidney
- Liver
- Third Trimester Placenta
Determination of Origin
- Elevated Alkaline Phosphatase Associated with a Normal Gamma-Glutamyl Transpeptidase or 5′-Nucleotidase Suggests a Non-Hepatic Source of the Alkaline Phosphatase
- Fractionation of Alkaline Phosphatase: may also be used to determine origin
  - Heat-Labile Alkaline Phosphatase: suggests bone origin (“bone burns”)
  - Heat-Stable Alkaline Phosphatase: suggests liver origin
Alkaline Phosphatase Levels are Age-Dependent
- Alkaline Phosphatase Levels are Higher (Up to 3x Adult Levels) in Children and Adolescents: due to physiologic osteoblastic activity
- Normal Alkaline Phosphatase Level Increases from 40 to 65 y/o: especially in women

Bilirubin (see Serum Bilirubin, [[Serum Bilirubin]])

Bilirubin Species
- Unconjugated (Indirect) Bilirubin (see Serum Bilirubin, [[Serum Bilirubin]])
- Conjugated (Direct) Bilirubin (see Serum Bilirubin, [[Serum Bilirubin]])

Gamma-Glutamyl Transpeptidase (GGT) (see Serum Gamma-Glutamyl Transpeptidase, [[Serum Gamma-Glutamyl Transpeptidase]])

General Comments
- Gamma-Glutamyl Transpeptidase is Elevated in Normal Neonates: levels decrease and reach adult levels by 5-7 mo of age
- Although GGT Has High Sensitivity for Liver Disease, Due to its Low Specificity, it Should Only Be Used to Evaluate Other LFT Abnormalities
Origin of Gamma-Glutamyl Transpeptidase
- Biliary Epithelial Cells
- Brain
- Heart
- Hepatocytes
- Kidney
- Pancreas
- Seminal Vesicle
- Spleen

5′-Nucleotidase (see Serum 5′-Nucleotidase, [[Serum 5-Nucleotidase]])

General Comments
- Physiologic Function of 5′-Nucleotidase is Unknown
Origin of 5′-Nucleotidase
- Blood Vessels
- Brain
- Endocrine Pancreas
- Heart
- Liver: liver is the only organ which releases 5′-nucleotidase into the serum

Lactate Dehydrogenase (LDH) (see Serum Lactate Dehydrogenase, [[Serum Lactate Dehydrogenase]])

General Comments
- LDH is a Cytoplasmic Enzyme Found in Many Organs
- There are 5 LDH Isoenzymes of LDH Present in the Serum: isoenzymes can be separated by electrophoresis
- Slowest Migrating Isoenzyme is the Predominant Form Present in the Liver
Origin of Lactate Dehydrogenase Isoenzymes
- LDH-1 (4H) Isoenzyme
  - Brain
  - Heart
  - Red Blood Cell (RBC)
- LDH-2 (3H1M) Isoenzyme
  - Reticuloendothelial System
- LDH-3 (2H2M) Isoenzyme
  - Lung
- LDH-4 (1H3M) Isoenzyme
  - Kidney
  - Pancreas
  - Placenta
- LDH-5 (4M) Isoenzyme
  - Liver
  - Striated Muscle

Patterns of Liver Function Test Abnormalities

General Patterns

Hepatocellular Pattern
- Disproportionate Transaminitis, Compared to Elevation of Alkaline Phosphatase
- Total Bilirubin May Be Elevated
- Tests of Hepatic Synthetic Function (Serum Albumin, Prothrombin Time/International Normalized Ratio) May Be Abnormal
Cholestatic Pattern
- Disproportionate Elevation in Alkaline Phosphatase, as Compared to Transaminitis
- Total Bilirubin May Be Elevated
- Tests of Hepatic Synthetic Function (Serum Albumin, Prothrombin Time/International Normalized Ratio) May Be Abnormal
Isolated Hyperbilirubinemia
- Hyperbilirubinemia with Normal Transaminases and Alkaline Phosphatase

Magnitude of AST and ALT Elevation

General Comments: magnitude of AST and ALT elevations vary depending on the etiology of the hepatocellular injury
Non-Alcoholic Fatty Liver Disease (NAFLD) (see Non-Alcoholic Fatty Liver Disease, [[Non-Alcoholic Fatty Liver Disease]])
- AST: <4x upper limit of normal
- ALT: <4x upper limit of normal
Alcoholic Fatty Liver Disease
- AST: <8x upper limit of normal
- ALT: <5x upper limit of normal
Chronic Hepatitis B Virus Infection (see Hepatitis B Virus, [[Hepatitis B Virus]]):
- AST: may be normal-2x upper limit of normal (may increase to >10x upper limit of normal during exacerbation)
- ALT: may be normal-2x upper limit of normal (may increase to >10x upper limit of normal during exacerbation)
Chronic Hepatitis C Virus Infection (see Hepatitis C Virus, [[Hepatitis C Virus]]):
- AST: wide variability, but usually <2x upper limit of normal (rarely >10x upper limit of normal)
- ALT: wide variability, but usually <2x upper limit of normal (rarely >10x upper limit of normal)
Acute Viral/Toxic Hepatitis with Associated Hyperbilirubinemia
- AST: >25x upper limit of normal
- ALT: >25x upper limit of normal
Hypoxic Hepatitis (see Hypoxic Hepatitis, [[Hypoxic Hepatitis]])
- AST: >50x upper limit of normal
- ALT: >50x upper limit of normal
- LDH: markedly elevated (usually)

Etiology of Mildly-Moderately Elevated Transaminases (Transaminitis <15x Upper Limit of Normal)

Hepatic Disease

ALT-Predominant (AST/ALT Ratio <1)

General Comments: AST/ALT Ratio <1 in most cases of hepatocellular injury
Alpha-1 Antitrypsin Deficiency (see Alpha-1 Antitrypsin Deficiency, [[Alpha-1 Antitrypsin Deficiency]])
Autoimmune Hepatitis (see Autoimmune Hepatitis, [[Autoimmune Hepatitis]])
Chronic Viral Hepatitis
- Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
Congestive Hepatopathy (see Congestive Hepatopathy, [[Congestive Hepatopathy]])
Drug/Toxin
- Acetaminophen Intoxication (see Acetaminophen Intoxication, [[Acetaminophen Intoxication]])
- Drug-Induced Hepatotoxicity (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])
- Toxic Mushrooms (see Toxic Mushrooms, [[Toxic Mushrooms]])
Hemochromatosis (see Hemochromatosis, [[Hemochromatosis]])
Hepatic Metastases
- Breast Cancer (see Breast Cancer, [[Breast Cancer]])
- Lymphoma (see Lymphoma, [[Lymphoma]])
- Melanoma (see Melanoma, [[Melanoma]])
- Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
- Small Cell Lung Cancer (see Lung Cancer, [[Lung Cancer]])
Non-Alcoholic Fatty Liver Disease (NAFLD) (see Non-Alcoholic Fatty Liver Disease, [[Non-Alcoholic Fatty Liver Disease]])
Wilson Disease (see Wilson Disease, [[Wilson Disease]])

AST-Predominant (AST/ALT Ratio ≥1)

Alcohol-Related Liver Disease
- General Comments
  - AST/ALT Ratio >2: Suggestive of Alcoholic Liver Disease (Especially in the Setting of Elevated Gamma-Glutamyl Transpeptidase) (Dig Dis Sci, 1985) [MEDLINE]
  - AST/ALT Ratio >3: Even More Strongly Suggests Alcoholic Liver Disease (Dig Dis Sci, 1979) [MEDLINE]
- Alcoholic Hepatitis (see Alcoholic Hepatitis, [[Alcoholic Hepatitis]])
- Alcoholic Liver Disease (see Alcoholic Liver Disease, [[Alcoholic Liver Disease]])
Cirrhosis Due to Viral Hepatitis (see Cirrhosis, [[Cirrhosis]]): AST/ALT ratio is frequently >1 (but is usually <2)
Non-Alcoholic Fatty Liver Disease (NAFLD) (see Non-Alcoholic Fatty Liver Disease, [[Non-Alcoholic Fatty Liver Disease]]): AST/ALT ratio may be >1 in some cases
Wilson Disease (see Wilson Disease, [[Wilson Disease]]): AST/ALT ratio may be >1
- Fuliminant Wilson Disease Cases Frequently Present with AST/ALT Ratio >2.2 and Alkaline Phosphatase/Total Bilirubin Ratio <4

Non-Hepatic Disease

Adrenal Insufficiency (see Adrenal Insufficiency, [[Adrenal Insufficiency]])
Anorexia Nervosa (see Anorexia Nervosa, [[Anorexia Nervosa]])
Celiac Disease (see Celiac Disease, [[Celiac Disease]])
Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
Macro AST: moderate elevations in plasma AST due to the presence of AST-immunoglobulin complexes (usually IgG)
Muscle Disorders
- Inborn Errors of Muscle Metabolism
- Polydermatomyositis (see Polydermatomyositis, [[Polydermatomyositis]])
- Seizures (see Seizures, [[Seizures]])
- Heavy Exercise
  - Marathon Running
Myocardial Infarction (MI) (see Coronary Artery Disease, [[Coronary Artery Disease]])
Thyroid Disease

Clinical Evaluation of Mildly-Moderately Elevated Transaminases (Transaminitis <15x Upper Limit of Normal)

Abdominal CT (see Abdominal-Pelvic Computed Tomography, [[Abdominal-Pelvic Computed Tomography]])
- Abdominal CT is Useful to Diagnose Hepatic Steatosis (see Hepatic Steatosis, [[Hepatic Steatosis]])
Abdominal MRI (see Abdominal Magnetic Resonance Imaging, [[Abdominal Magnetic Resonance Imaging]])
- Abdominal MRI is Useful to Diagnose Hepatic Steatosis (see Hepatic Steatosis, [[Hepatic Steatosis]])
Autoimmune Serologies/Studies: useful to diagnose autoimmune hepatitis (see Autoimmune Hepatitis, [[Autoimmune Hepatitis]])
- Anti-Nuclear Antibody (ANA) (see Anti-Nuclear Antibody, [[Anti-Nuclear Antibody]])
- Anti-Smooth Muscle Antibody (see Anti-Smooth Muscle Antibody, [[Anti-Smooth Muscle Antibody]])
- Anti-Liver/Kidney Microsomal Antibody Type 1 (see Anti-Microsomal Antibody, [[Anti-Microsomal Antibody]])
Cortrosyn Stimulation Test (ACTH Stimulation Test) (see Cortrosyn Stimulation Test, [[Cortrosyn Stimulation Test]]): in appropriate patients with relevant symptoms/signs, this is useful to diagnose adrenal insufficiency (see Adrenal Insufficiency, [[Adrenal Insufficiency]])
Evaluation for Kaiser-Fleisher Rings: useful to diagnose Wilson disease (see Wilson Disease, [[Wilson Disease]])
Hepatobiliary Ultrasound with Dopplers (see Abdominal-Pelvic Ultrasound, [[Abdominal-Pelvic Ultrasound]])
- Hepatic Ultrasound is Useful to Diagnose Hepatic Steatosis (see Hepatic Steatosis, [[Hepatic Steatosis]])
- Doppler Studies are Required to Exclude Hepatic Vein Thrombosis (Budd-Chiari Syndrome)
Liver Biopsy (see Liver Biopsy, [[Liver Biopsy]]): may be required if remaining work-up is non-diagnostic
- Utility of Liver Biopsy in the Setting of Chronic LFT Abnormalities (Am J Gastroenterol, 2000) [MEDLINE]
  - Liver Biopsy May Aid in a Diagnosis, But the Results Infrequently Alter the Presumptive Pre-Biopsy Diagnosis and No Proven Therapy Exists for the Vast Majority of Patients
  - Risks and Benefits of Liver Biopsy Should Be Carefully Considered, Especially in Settings Where Investigational Therapies are Not Available
- Liver Biopsy is Probably Indicated in Patients with Undiagnosed Persistent Transaminitis >2 Upper Limit of Normal
Serum Aldolase (see Serum Aldolase, [[Serum Aldolase]]): in patients with suspected muscle disorder
Serum Alpha-1 Antitrypsin Level (see Serum Alpha-1 Antitrypsin, [[Serum Alpha-1 Antitrypsin]]): useful to diagnose alpha-1 antitrypsin deficiecy
Serum Ceruloplasmin (see Serum Ceruloplasmin, [[Serum Ceruloplasmin]]): useful to diagnose Wilson disease (see Wilson Disease, [[Wilson Disease]])
Serum Creatine Kinase (CK) (see Serum Creatine Kinase, [[Serum Creatine Kinase]]): in patients with suspected muscle disorder
Serum Iron and Total Iron Binding Capacity (Transferrin Saturation) (see xxxx, [[xxxx]])
- Transferrin Saturation >45% Warrants Obtaining a Serum Ferritin (see Serum Ferritin, [[Serum Ferritin]])
- Serum Ferritin Should Not Be Obtained as an Initial Test Since it is an Acute Phase Reactant and is Less Specific than the Transferrin Saturation
- Serum Ferritin >400 ng/mL (>900 pmol/L) in Male and >300 ng/mL (<675 pmol/L) in Female Supports (But Does Not Confirm) the Diagnosis of Hemochromatosis (see Hemochromatosis, [[Hemochromatosis]])
Serum Protein Electrophoresis (SPEP) (see Serum Protein Electrophoresis, [[Serum Protein Electrophoresis]])
- SPEP is Useful to Diagnose Autoimmune Hepatitis (see Autoimmune Hepatitis, [[Autoimmune Hepatitis]])
Serum Transglutaminase Antibody (see Serum Transglutaminase Antibody, [[Serum Transglutaminase Antibody]]): useful to diagnose celiac disease (see Celiac Disease, [[Celiac Disease]])
Thyroid Function Tests (TFT’s) (see Thyroid Function Tests, [[Thyroid Function Tests]])
- Serum Thyroid Stimulating Hormone (TSH)
- Free T4
- Free T3
Urinary Copper Excretion: useful to diagnose Wilson disease (see Wilson Disease, [[Wilson Disease]])
Viral Serologies/Studies
- Hepatitis B Surface Antigen (HBsAg)
- Anti-Hepatitis B Core Antigen IgM Antibody (Anti-HBc)
- Anti-Hepatitis C Antibody

Etiology of Markedly Elevated Transaminases (Transaminitis >15x Upper Limit of Normal)

Fulminant Hepatic Failure (Acute Liver Failure) (see Fulminant Hepatic Failure, [[Fulminant Hepatic Failure]])

Physiology: acute hepatocellular injury
Clinical
- Hepatic Encephalopathy
- Liver Function Tests >10x Upper Limit of Normal
- Prolonged Prothrombin Time (International Normalized Ratio)

Other Liver Disease (without Fulminant Hepatic Failure)

Acute Viral Hepatitis
- Cytomegalovirus (CMV) (see Cytomegalovirus, [[Cytomegalovirus]])
- Epstein-Barr Virus (EBV) (see Epstein-Barr Virus, [[Epstein-Barr Virus]])
- Hepatitis A Virus (see Hepatitis A Virus, [[Hepatitis A Virus]])
- Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
Alcoholic Hepatitis (see Alcoholic Hepatitis, [[Alcoholic Hepatitis]])
Autoimmune Hepatitis (see Autoimmune Hepatitis, [[Autoimmune Hepatitis]])
Heat Stroke (see Heat Stroke, [[Heat Stroke]])
HELLP Syndrome (see HELLP Syndrome, [[HELLP Syndrome]])
Hepatic Metastases
- Breast Cancer (see Breast Cancer, [[Breast Cancer]])
- Lymphoma (see Lymphoma, [[Lymphoma]])
- Melanoma (see Melanoma, [[Melanoma]])
- Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
- Small Cell Lung Cancer (see Lung Cancer, [[Lung Cancer]])
Hepatic Vein Thrombosis (Budd-Chiari Syndrome) (see Hepatic Vein Thrombosis, [[Hepatic Vein Thrombosis]])
Hepatic Veno-Occlusive Disease (VOD) (see Hepatic Veno-Occlusive Disease, [[Hepatic Veno-Occlusive Disease]])
Hypoxic Hepatitis (Ischemic Hepatopathy) (see Hypoxic Hepatitis, [[Hypoxic Hepatitis]])
Drug/Toxin-Associated Hepatoxicity
- Acetaminophen Intoxication (see Acetaminophen Intoxication, [[Acetaminophen Intoxication]])
- Drug-Induced Hepatotoxicity (see Drug-Induced Hepatotoxicity, [[Drug-Induced Hepatotoxicity]])
- Toxic Mushrooms (see Toxic Mushrooms, [[Toxic Mushrooms]])
Partial Hepatectomy (see Hepatectomy, [[Hepatectomy]])
Sepsis (see Sepsis, [[Sepsis]])
Wilson Disease (see Wilson Disease, [[Wilson Disease]])

Other Disorders

Muscle Disorders
- Polydermatomyositis (see Polydermatomyositis, [[Polydermatomyositis]])
- Seizures (see Seizures, [[Seizures]])
- Heavy Exercise
  - Marathon Running

Clinical Evaluation of Markedly Elevated Transaminases (Transaminitis >15x Upper Limit of Normal)

Acetaminophen Level (see Acetaminophen Level, [[Acetaminophen Level]])
Autoimmune Serologies/Studies: useful to diagnose autoimmune hepatitis (see Autoimmune Hepatitis, [[Autoimmune Hepatitis]])
- Anti-Nuclear Antibody (ANA) (see Anti-Nuclear Antibody, [[Anti-Nuclear Antibody]])
- Anti-Smooth Muscle Antibody (see Anti-Smooth Muscle Antibody, [[Anti-Smooth Muscle Antibody]])
- Anti-Liver/Kidney Microsomal Antibody Type 1 (see Anti-Microsomal Antibody, [[Anti-Microsomal Antibody]])
- Serum Immunoglobulins (see Serum Immunoglobulins, [[Serum Immunoglobulins]])
Evaluation for Kaiser-Fleisher Rings: useful to diagnose Wilson disease (see Wilson Disease, [[Wilson Disease]])
Hepatobiliary Ultrasound with Dopplers (see Abdominal-Pelvic Ultrasound, [[Abdominal-Pelvic Ultrasound]])
- Doppler Studies are Required to Exclude Hepatic Vein Thrombosis (Budd-Chiari Syndrome)
Liver Biopsy (see Liver Biopsy, [[Liver Biopsy]]): may be required if remaining work-up is non-diagnostic
Pregnancy Test (see Pregnancy Test, [[Pregnancy Test]]): in women of childbearing potential
Serum Aldolase (see Serum Aldolase, [[Serum Aldolase]]): in patients with suspected muscle disorder
Serum Ceruloplasmin (see Serum Ceruloplasmin, [[Serum Ceruloplasmin]]): useful to diagnose Wilson disease (see Wilson Disease, [[Wilson Disease]])
Serum Creatine Kinase (CK) (see Serum Creatine Kinase, [[Serum Creatine Kinase]]): in patients with suspected muscle disorder
Toxicology Screen (see xxxx, [[xxxx]])
Urinalysis (see Urinalysis, [[Urinalysis]]): to diagnose proteinuria in pregnant patients
Urinary Copper Excretion: useful to diagnose Wilson disease (see Wilson Disease, [[Wilson Disease]])
Viral Serologies/Studies
- Anti-Hepatitis A IgM Antibody
- Hepatitis B Surface Antigen (HBsAg)
- Anti-Hepatitis B Core Antigen IgM Antibody (Anti-HBc)
- Anti-Hepatitis C Antibody
- Hepatitis C Viral RNA
- Anti-Hepatitis D Antibody: in patient with acute or chronic hepatitis B (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Anti-Hepatitis E Antibody: in patients with residence in or travel to hepatitis E endemic regions (Asia, Africa, Middle East, Central America) or in pregnant patients (due to the high rates of acute liver failure in pregnant women with hepatitis E vural infection)
  - Cases of Hepatitis E Have Also Been Reported in Developed Countries without a History of Foreign Travel
- Anti-Herpes Simplex Virus (HSV) Antibody: optional
- Anti-Varicella-Zoster Antibody: optional
- Anti-CMV Antibody: optional
- CMV Antigen: optional
- Heterophile Antibody (for Epstein-Barr Virus): optional

Etiology of Moderately Elevated Alkaline Phosphatase Elevation (<4x Upper Limit of Normal) (see Serum Alkaline Phosphatase, [[Serum Alkaline Phosphatase]])

Hepatic

Acute Viral Hepatitis
- Cytomegalovirus (CMV) (see Cytomegalovirus, [[Cytomegalovirus]])
- Epstein-Barr Virus (EBV) (see Epstein-Barr Virus, [[Epstein-Barr Virus]])
- Hepatitis A Virus (see Hepatitis A Virus, [[Hepatitis A Virus]])
- Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
Alcoholic Hepatitis (see Alcoholic Hepatitis, [[Alcoholic Hepatitis]])
Chronic Viral Hepatitis
- Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
Cirrhosis (see Cirrhosis, [[Cirrhosis]])
Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
- Physiology: hepatic hypoperfusion
Hepatic Infiltration
- Amyloidosis (see Amyloidosis, [[Amyloidosis]])
- Liver Abscess (see Pyogenic Liver Abscess, [[Pyogenic Liver Abscess]])
- Lymphoma (see Lymphoma, [[Lymphoma]])
- Sarcoidosis (see Sarcoidosis, [[Sarcoidosis]])
- Tuberculosis (see Tuberculosis, [[Tuberculosis]])
Sepsis (see Sepsis, [[Sepsis]])
- Physiology: hepatic hypoperfusion

Non-Hepatic

Benign Familial Elevation of Alkaline Phosphatase
- Physiology: intestinal source
High Bone Turnover
- Bone Metastases
- Growth
- Healing Fracture
- Hyperparathyroidism (see Hyperparathyroidism, [[Hyperparathyroidism]])
- Hyperthyroidism (see Hyperthyroidism, [[Hyperthyroidism]])
- Osteosarcoma (see Osteosarcoma, [[Osteosarcoma]])
- Osteomalacia (see Osteomalacia, [[Osteomalacia]])
- Paget Disease of Bone (see Paget Disease of Bone, [[Paget Disease of Bone]])
Influx of Intestinal Alkaline Phosphatase After Eating a Fatty Meal
- Epidemiology: occurs in patients with blood type O or B
Malignancy
- Gastric Cancer (see Gastric Cancer, [[Gastric Cancer]])
- Head and Neck Cancer (see Head and Neck Cancer, [[Head and Neck Cancer]])
- Hodgkin’s Disease (see Hodgkin’s Disease, [[Hodgkins Disease]])
- Lung Cancer (see Lung Cancer, [[Lung Cancer]])
- Osteosarcoma (see Osteosarcoma, [[Osteosarcoma]])
- Ovarian Cancer (see Ovarian Cancer, [[Ovarian Cancer]])
- Renal Cell Carcinoma (see Renal Cancer, [[Renal Cancer]])
- Uterine Cancer (see Uterine Cancer, [[Uterine Cancer]])
Physiologic Elevation of Alkaline Phosphatase: occurs in children and adolescents
Third Trimester of Pregnancy (see Pregnancy, [[Pregnancy]])
Other
- Myeloid Metaplasia
- Peritonitis (see Peritonitis, [[Peritonitis]])
- Diabetes Mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])
- Subacute Thyroiditis (see Subacute Thyroiditis, [[Subacute Thyroiditis]])
- Gastric Ulcer (see Peptic Ulcer Disease, [[Peptic Ulcer Disease]])

Clinical Evaluation of Elevated Alkaline Phosphatase (of Hepatic Origin) (see Serum Alkaline Phosphatase, [[Serum Alkaline Phosphatase]])

Hepatobiliary Ultrasound (see Abdominal-Pelvic Ultrasound, [[Abdominal-Pelvic Ultrasound]])
- Hepatic Ultrasound is Useful to Biliary Ductal Dilation (Consistent with the Diagnosis of Extrahepatic Cholestasis): however, biliary ultrasound may fail to show biliary ductal dilation in cases with partial bile duct obstruction, as well as cirrhosis and primary sclerosing cholangitis (where scarring prevents the intrahepatic ducts from dilating)
- In General, Absence of Biliary Ductal Dilation Indicates Intrahepatic Cholestasis

Etiology of Markedly Elevated Alkaline Phosphatase Elevation (≥4x Upper Limit of Normal) (see Serum Alkaline Phosphatase, [[Serum Alkaline Phosphatase]])

Intrahepatic Cholestasis

Alcoholic Hepatitis (see Alcoholic Hepatitis, [[Alcoholic Hepatitis]])
Benign Postoperative Cholestasis
Hepatic Infiltration
- Amyloidosis (see Amyloidosis, [[Amyloidosis]])
- Liver Abscess (see Pyogenic Liver Abscess, [[Pyogenic Liver Abscess]])
- Lymphoma (see Lymphoma, [[Lymphoma]])
- Sarcoidosis (see Sarcoidosis, [[Sarcoidosis]])
- Tuberculosis (see Tuberculosis, [[Tuberculosis]])
- Wegener’s Granulomatosis (see Wegener’s Granulomatosis, [[Wegeners Granulomatosis]])
Hepatic Metastases
- Breast Cancer (see Breast Cancer, [[Breast Cancer]])
- Lymphoma (see Lymphoma, [[Lymphoma]])
- Melanoma (see Melanoma, [[Melanoma]])
- Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]])
- Small Cell Lung Cancer (see Lung Cancer, [[Lung Cancer]])
Intrahepatic Cholestasis of Pregnancy (see Pregnancy, [[Pregnancy]])
Ischemic Cholangiopathy (see Ischemic Cholangiopathy, [[Ischemic Cholangiopathy]])
Liver Transplant Rejection (see Liver Transplant, [[Liver Transplant]])
Primary Biliary Cirrhosis (PBC) (see Primary Biliary Cirrhosis, [[Primary Biliary Cirrhosis]])
Primary Sclerosing Cholangitis (PSC) (see Primary Sclerosing Cholangitis, [[Primary Sclerosing Cholangitis]])
Sickle Cell Disease (Hepatic Crisis) (see Sickle Cell Disease, [[Sickle Cell Disease]])
Drugs/Toxins
- Alkylated Steroids
- Arsenic (see Arsenic, [[Arsenic]])
- Chlorpromazine (Largactil, Thorazine) (see Chlorpromazine, [[Chlorpromazine]])
- Jamaican Bush Tea (see Jamaican Bush Tea, [[Jamaican Bush Tea]])
- Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition, [[Total Parenteral Nutrition]])

Extrahepatic Cholestasis (Biliary Obstruction)

Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])
Biliary Infection
- AIDS Cholangiopathy (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
- Ascaris Lumbricoides (see Ascariasis, [[Ascariasis]])
- Liver Flukes (Trematodes)
  - Clonorchis (see Clonorchiasis, [[Clonorchiasis]])
  - Fasciola (see Fascioliasis, [[Fascioliasis]])
  - Metorchis (see Metorchiasis, [[Metorchiasis]])
  - Opisthorchis (see Opisthorchiasis, [[Opisthorchiasis]])
Biliary Stricture
- Chronic Pancreatitis with Stricture of Distal Bile Duct (see Chronic Pancreatitis, [[Chronic Pancreatitis]])
- Post-Liver Transplant Biliary Anastomotic Stricture (see Liver Transplant, [[Liver Transplant]])
- Post-Procedure
- Primary Sclerosing Cholangitis (PSC) with Extrahepatic Bile Duct Stricture (see Primary Sclerosing Cholangitis, [[Primary Sclerosing Cholangitis]])
Choledocholithiasis (see Cholelithiasis, [[Cholelithiasis]])
- Epidemiology: most common etiology of extrahepatic biliary obstruction
Malignant Biliary Obstruction
- Ampullary Carcinoma (see Ampullary Carcinoma, [[Ampullary Carcinoma]])
- Cholangiocarcinoma (see Cholangiocarcinoma, [[Cholangiocarcinoma]])
- Gallbladder Cancer (see Gallbladder Cancer, [[Gallbladder Cancer]])
- Pancreatic Cancer (see Pancreatic Cancer, [[Pancreatic Cancer]])

Non-Hepatic

Transient Hyperphosphatemia of Infancy and Childhood

Clinical Evaluation of Elevated Alkaline Phosphatase (of Hepatic Origin) (see Serum Alkaline Phosphatase, [[Serum Alkaline Phosphatase]])

Hepatobiliary Ultrasound (see Abdominal-Pelvic Ultrasound, [[Abdominal-Pelvic Ultrasound]])
- Hepatic Ultrasound is Useful to Biliary Ductal Dilation (Consistent with the Diagnosis of Extrahepatic Cholestasis): however, biliary ultrasound may fail to show biliary ductal dilation in cases with partial bile duct obstruction, as well as cirrhosis and primary sclerosing cholangitis (where scarring prevents the intrahepatic ducts from dilating)
- In General, Absence of Biliary Ductal Dilation Indicates Intrahepatic Cholestasis

Etiology of Isolated Gamma-Glutamyl Transpeptidase Elevation (see Serum Gamma-Glutamyl Transpeptidase, [[Serum Gamma-Glutamyl Transpeptidase]])

Barbiturates (see Barbiturates, [[Barbiturates]])
Chronic Obstructive Pulmonary Disease (COPD) (see Chronic Obstructive Pulmonary Disease, [[Chronic Obstructive Pulmonary Disease]])
Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
Ethanol Abuse (see Ethanol, [[Ethanol]])
Hepatobiliary Disease: serum GGT is sensitive (but not specific) for the presence of hepatobiliary disease
Myocardial Infarction (M) (see Coronary Artery Disease, [[Coronary Artery Disease]])
Pancreatic Disease
Phenytoin (Dilantin) (see Phenytoin, [[Phenytoin]])
Renal Failure
- Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
- Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])

Etiology of Isolated Hyperbilirubinemia (see Hyperbilirubinemia, [[Hyperbilirubinemia]])

Unconjugated (Indirect) Hyperbilirubinemia

Increased Bilirubin Production

Dyserthropoiesis
- Primary Shunt Hyperbilirubinemia (Idiopathic Dyserythropoietic Jaundice)
Hematoma
Hemolytic Anemia (Extravascular/Intravascular) (see Hemolytic Anemia, [[Hemolytic Anemia]])
- Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria, [[Paroxysmal Nocturnal Hemoglobinuria]])
- Sickle Cell Disease (see Sickle Cell Disease, [[Sickle Cell Disease]])
- Wilson Disease (see Wilson Disease, [[Wilson Disease]])
  - Physiology
    - Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]]): may occur in some cases
    - Decreased Hepatic Bilirubin Uptake and Conjugation

Impaired Hepatic Bilirubin Uptake

Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy, [[Congestive Hepatopathy]])
- Epidemiology: due to congestive heart failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
Drugs: hyperbilirubinemia due to these drugs usually resolves within 48 hrs after discontinuation
- Bunamiodyl Cholecystographic Contrast Agent
- Flavaspidic Acid
- Probenecid (see Probenecid, [[Probenecid]])
- Rifamycins (see Rifamycins, [[Rifamycins]])
  - Rifabutin (see Rifabutin, [[Rifabutin]])
  - Rifampin (Rifampicin, Rifadin) (see Rifampin, [[Rifampin]])
  - Rifapentine (Priftin) (see Rifapentine, [[Rifapentine]])
Gilbert Syndrome (see Gilbert Syndrome, [[Gilbert Syndrome]])
- Physiology: impaired hepatic bilirubin uptake occurs in some cases
Portosystemic Shunt
- Naturally-Occurring Portosystemic Shunt
- Transjugular Intrahepatic Portosystemic Shunt (TIPS) (see Transjugular Intrahepatic Portosystemic Shunt, [[Transjugular Intrahepatic Portosystemic Shunt]])
Wilson Disease (see Wilson Disease, [[Wilson Disease]])
- Physiology
  - Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]]): may occur in some cases
  - Decreased Hepatic Bilirubin Uptake and Conjugation

Impaired Bilirubin Conjugation

Breast Milk Jaundice
Crigler-Najjar Syndrome (Types I and II) (see Crigler-Najjar Syndrome, [[Crigler-Najjar Syndrome]])
Ethinyl Estradiol (see Estrogen, [[Estrogen]]): found in almost all oral contraceptives (see Oral Contraceptives, [[Oral Contraceptives]])
Gilbert Syndrome (see Gilbert Syndrome, [[Gilbert Syndrome]]): decreased hepatic bilirubin uptake and/or decreased conjugation
Hyperthyroidism (see Hyperthyroidism, [[Hyperthyroidism]])
Hypothyroidism (see Hypothyroidism, [[Hypothyroidism]])
Liver Disease
- Chronic Hepatitis
  - Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
  - Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
- Cirrhosis (see Cirrhosis, [[Cirrhosis]])
- Wilson Disease (see Wilson Disease, [[Wilson Disease]])
  - Physiology
    - Coombs-Negative Hemolytic Anemia (see Hemolytic Anemia, [[Hemolytic Anemia]]): may occur in some cases
    - Decreased Hepatic Bilirubin Uptake and Conjugation
Maternal Serum Jaundice
Neonatal Physiologic Jaundice

Conjugated (Direct) Hyperbilirubinemia

Inherited Disorders

Rotor Syndrome (see Rotor Syndrome, [[Rotor Syndrome]])
- Physiology: defective sinusoidal reuptake of conjugated bilirubin
Dubin-Johnson Syndrome (see Dubin-Johnson Syndrome, [[Dubin-Johnson Syndrome]])
- Physiology: defective canalicular organic anion transport

Intrahepatic Cholestasis

Acute Fatty Liver of Pregnancy (see Acute Fatty Liver of Pregnancy, [[Acute Fatty Liver of Pregnancy]])
Acute Viral Hepatitis
- Cytomegalovirus (CMV) (see Cytomegalovirus, [[Cytomegalovirus]])
- Epstein-Barr Virus (EBV) (see Epstein-Barr Virus, [[Epstein-Barr Virus]])
- Hepatitis A Virus (see Hepatitis A Virus, [[Hepatitis A Virus]])
- Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
Alcoholic Hepatitis (see Alcoholic Hepatitis, [[Alcoholic Hepatitis]])
Alpha-1 Antitrypsin Deficiency (see Alpha-1 Antitrypsin Deficiency, [[Alpha-1 Antitrypsin Deficiency]])
Autoimmune Hepatitis (see Autoimmune Hepatitis, [[Autoimmune Hepatitis]])
Benign Postoperative Cholestasis
Caroli Disease (see Caroli Disease, [[Caroli Disease]])
Chronic Viral Hepatitis
- Hepatitis B Virus (HBV) (see Hepatitis B Virus, [[Hepatitis B Virus]])
- Hepatitis C Virus (HCV) (see Hepatitis C Virus, [[Hepatitis C Virus]])
Cirrhosis (see Cirrhosis, [[Cirrhosis]])
Congestive Hepatopathy (Passive Hepatic Congestion) (see Congestive Hepatopathy, [[Congestive Hepatopathy]])
- Epidemiology: due to congestive heart failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
Drugs/Toxins
- Acetaminophen (Tylenol) (see Acetaminophen, [[Acetaminophen]])
- Alkylated Steroids
- Arsenic (see Arsenic, [[Arsenic]])
- Chlorpromazine (Largactil, Thorazine) (see Chlorpromazine, [[Chlorpromazine]])
- Erythromycin (see Erythromycin, [[Erythromycin]])
- Jamaican Bush Tea (see Jamaican Bush Tea, [[Jamaican Bush Tea]])
- Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition, [[Total Parenteral Nutrition]])
Hemochromatosis (see Hemochromatosis, [[Hemochromatosis]])
Hepatic Graft vs Host Disease (GVHD) (see Graft vs Host Disease, [[Graft vs Host Disease]])
Hepatic Infiltration
- Amyloidosis (see Amyloidosis, [[Amyloidosis]])
- Liver Abscess (see Pyogenic Liver Abscess, [[Pyogenic Liver Abscess]])
- Liver Metastases
- Lymphoma (see Lymphoma, [[Lymphoma]])
- Sarcoidosis (see Sarcoidosis, [[Sarcoidosis]])
- Tuberculosis (see Tuberculosis, [[Tuberculosis]])
- Wegener’s Granulomatosis (see Wegener’s Granulomatosis, [[Wegeners Granulomatosis]])
Hepatic Veno-Occlusive Disease (VOD) (see Hepatic Veno-Occlusive Disease, [[Hepatic Veno-Occlusive Disease]])
Hypoxic Hepatitis (Ischemic Hepatopathy) (see Hypoxic Hepatitis, [[Hypoxic Hepatitis]])
- Physiology: hepatic hypoperfusion
Intrahepatic Cholestasis of Pregnancy (see Pregnancy, [[Pregnancy]])
Non-Alcoholic Fatty Liver Disease (NAFLD) (see Non-Alcoholic Fatty Liver Disease, [[Non-Alcoholic Fatty Liver Disease]])
Post-Liver Transplant (see Liver Transplant, [[Liver Transplant]])
Pre-Eclampsia (see Pre-Eclampsia, Eclampsia, [[Pre-Eclampsia, Eclampsia]])
Primary Biliary Cirrhosis (PBC) (see Primary Biliary Cirrhosis, [[Primary Biliary Cirrhosis]])
Reye Syndrome (see Reye Syndrome, [[Reye Syndrome]])
Sepsis (see Sepsis, [[Sepsis]])
- Physiology: hepatic hypoperfusion
Sickle Cell Disease (Hepatic Crisis) (see Sickle Cell Disease, [[Sickle Cell Disease]])

Extrahepatic Cholestasis (Biliary Obstruction)

Acute Pancreatitis (see Acute Pancreatitis, [[Acute Pancreatitis]])
Biliary Infection
- AIDS Cholangiopathy (see Human Immunodeficiency Virus, [[Human Immunodeficiency Virus]])
- Ascaris Lumbricoides (see Ascariasis, [[Ascariasis]])
- Liver Flukes (Trematodes)
  - Clonorchis (see Clonorchiasis, [[Clonorchiasis]])
  - Fasciola (see Fascioliasis, [[Fascioliasis]])
  - Metorchis (see Metorchiasis, [[Metorchiasis]])
  - Opisthorchis (see Opisthorchiasis, [[Opisthorchiasis]])
Biliary Stricture
- Chronic Pancreatitis with Stricture of Distal Bile Duct (see Chronic Pancreatitis, [[Chronic Pancreatitis]])
- Post-Liver Transplant Biliary Anastomotic Stricture (see Liver Transplant, [[Liver Transplant]])
- Post-Procedure
- Primary Sclerosing Cholangitis (PSC) with Extrahepatic Bile Duct Stricture (see Primary Sclerosing Cholangitis, [[Primary Sclerosing Cholangitis]])
Choledocholithiasis (see Cholelithiasis, [[Cholelithiasis]])
- Epidemiology: most common etiology of extrahepatic biliary obstruction
Malignant Biliary Obstruction
- Ampullary Carcinoma (see Ampullary Carcinoma, [[Ampullary Carcinoma]])
- Cholangiocarcinoma (see Cholangiocarcinoma, [[Cholangiocarcinoma]])
- Gallbladder Cancer (see Gallbladder Cancer, [[Gallbladder Cancer]])
- Pancreatic Cancer (see Pancreatic Cancer, [[Pancreatic Cancer]])

References

Heat stability of human serum alkaline phosphatase in bone and liver diseases. Clin Chim Acta. 1972 Oct;41:329-34 [MEDLINE]
The SGOT/SGPT ratio–an indicator of alcoholic liver disease. Dig Dis Sci. 1979;24(11):835 [MEDLINE]
Serum gamma-glutamyl transpeptidase and chronic alcoholism. Influence of alcohol ingestion and liver disease. Dig Dis Sci. 1985;30(3):211 [MEDLINE]
An assessment of the role of liver biopsies in asymptomatic patients with chronic liver test abnormalities. Am J Gastroenterol. 2000;95(11):3206 [MEDLINE]
Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology. 2012;55(2):447 [MEDLINE]