LIVER TESTS AND DISEASES










  • Reference [1]
Normal ALT ranges
Sex ALT value (U/L)
Male 29 - 33
Female 19 - 25





  • Reference [3]
Normal AST ranges
Sex AST value (U/L)
Male 9 - 50
Female 9 - 40





  • Reference [3]
Normal ALP ranges
Age (years) Male (U/L) Female (U/L)
13 - 14 126 - 499 90 - 306
30 - 35 40 - 112 40 - 114
52 - 55 40 - 120 40 - 133
≥ 66 40 - 125 40 - 142




  • Reference [3]
Normal GGT range
Sex GGT value (U/L)
Male < 60
Female < 40





















ACG 2017 Recommendations for Evaluating Elevated ALT / AST
Borderline / Mild Elevations (<5 X ULN)
Step 1 - assess patient
  • Assess for hepatotoxic medications (including OTC meds), supplements, and alcohol use
  • Assess risk factors for fatty liver (obesity, diabetes, dyslipidemia, hypertension)
  • Assess risk factors for viral hepatitis

  • In patients without overt signs of liver disease:
    • If a hepatotoxic drug or supplement is identified, consider discontinuing the drug/supplement and rechecking enzymes in 6 weeks
    • If patient consumes regular alcohol, recommend alcohol cessation and recheck enzymes in 6 weeks
    • If patient is overweight, recommend weight loss and recheck at later date, keeping in mind that significant weight loss is difficult for most people to achieve
Step 2 - initial workup
  • CBC with platelets
  • Liver testing including ALP, bilirubin, and albumin
  • PT/INR
  • Hepatitis panel (should include HBsAg, HBcAb, HBsAb, HCV Ab)
  • Iron studies - see hemochromatosis
  • Abdominal ultrasound

  • Negative findings
    • If above workup does not reveal a source, consider observation for 3 - 6 months and then repeat liver tests
    • If repeat testing is still elevated or concern for less common etiologies is high, proceed to next step
Step 3 - extended workup

  • Other labs to consider based on individual history
    • Celiac disease testing - see celiac labs
    • Thyroid testing
    • Muscle disorders
    • Tick-borne diseases - Lyme disease, babesiosis, and ehrlichiosis

  • Negative findings
    • If no etiology is found, final step is liver biopsy
Moderate to Severe Elevation (≥ 5 X ULN)
History and physical
  • Patients with moderate to severe elevations require immediate assessment
  • Assess for hepatotoxic medications (including OTC meds), supplements, and alcohol use and discontinue all
  • Assess for signs and symptoms of acute liver failure (e.g. jaundice, ascites, hepatomegaly, right upper quadrant pain, nausea and vomiting, mental status changes)

Testing (all patients)
  • CBC with platelets
  • Liver testing including ALP, bilirubin, and albumin
  • PT/INR
  • Viral hepatitis testing (should include HAV IgM, HAV IgG, HBsAg, HBcAb IgM, HBcAb IgG, HBsAb, HCV Ab)
  • Iron studies - see hemochromatosis
  • ANA, ASMA, IgG levels - see autoimmune hepatitis
  • Ceruloplasmin - see Wilson disease
  • Abdominal ultrasound

Extended testing for ALT > 15 X ULN
  • Herpes simplex virus (HSV)
  • Cytomegalovirus testing (CMV)
  • Epstein–Barr virus (EBV)
  • CK (to look for rhabdomyolysis)
  • Anti-liver kidney microsomal antibody (LKM antibody) - see autoimmune hepatitis
  • Serum and urine drug panel
  • Consider n-acetyl cysteine level if any evidence of acetaminophen ingestion

If there are signs of acute liver failure
  • Urgent hepatology consult and consider referral to liver transplant center

Negative testing
  • If testing is negative, proceed to liver biopsy if stable




ACG 2017 Recommendations for Evaluating Elevated Alkaline Phosphatase (ALK)
Isolated elevated ALP (normal ALT, AST, and bilirubin)
Step 1 - check a GGT
  • If GGT is normal

  • If GGT is elevated, perform the following:
Step 2 - further evaluation based on results from above
  • Evaluation negative and ALP > 2 X ULN
    • Consider liver biopsy

  • Evaluation negative and ALP 1 - 2 X ULN
    • Consider observation for 6 months. If still elevated after 6 months, consider liver biopsy.

  • If ductal dilation is present

  • If AMA is positive
Elevated ALP with Elevated ALT/AST +/- Bilirubin
Step 1 - order abdominal ultrasound
Step 2 - extended testing based on above results
  • If AMA positive

  • If AMA negative and ALP > 2 X ULN
    • Consider liver biopsy or MRCP

  • If AMA negative and ALP 1 - 2 X ULN
    • Consider observation for 6 months. If still elevated after 6 months, consider liver biopsy or MRCP.






ACG 2017 Recommendations for Evaluating Elevated Bilirubin
Elevated Unconjugated (indirect) Bilirubin
Step 1 - initial testing and assessment
Step 2 - further evaluation if above is negative

  • If no cause is found and elevations persist and/or AST/ALT elevations are present
    • Consider liver biopsy
Elevated Conjugated (direct) Bilirubin
Step 1 - initial testing and assessment
  • Evaluate other liver tests (ALT, AST, ALP)
  • Evaluate for medications that can increase bilirubin (see medications below)
  • Look for clinically overt etiologies: sepsis, TPN, cirrhosis, and biliary obstruction
  • Perform abdominal ultrasound
Step 2 - further evaluation based on results from above











  • Reference [1,2,8]
Risk factors for NAFLD
Risk factor Comment
Obesity
  • Obesity is the most important risk factor for NAFLD
  • Any degree of being overweight increases the risk of NAFLD
  • 80% of patients with NAFLD are overweight or obese
Type 2 diabetes
  • In studies, NAFLD is present in up to 66% of diabetics
Dyslipidemia
  • High triglycerides and low HDL are strongly associated with NAFLD
  • 72% of patients with NAFLD have dyslipidemia
Metabolic syndrome
  • More than 40% of patients with NAFLD meet the definition of the metabolic syndrome
  • Metabolic syndrome is defined as ≥ 3 of the following:
    • Waist circumference > 102 cm (men) | > 88 cm (women)
    • Triglycerides ≥ 150 mg/dl
    • HDL < 40 mg/dl (men) | < 50 mg/dl (women)
    • SBP ≥ 130 mmHg or DBP ≥ 85 mmHg
    • Fasting blood sugar ≥ 110 mg/dl
Polycystic ovary disease (PCOS)
  • Women with PCOS have a higher prevalence of NAFLD
Male sex
  • Men are affected twice as much as women
Race
  • Hispanics are affected more than other races
  • Blacks appear to have the lowest prevalence




  • References [6,7,8]
Diagnostic Modalities for NASH
Modality Comments
Liver biopsy
  • Gold standard
  • Invasive and expensive
NAFLD fibrosis score
  • Predicts presence of NASH based on patient's age, BMI, hyperglycemia, platelet count, albumin, and AST/ALT ratio
  • Online calculator available here - NAFLD fibrosis score calculator
  • In a meta-analysis that included 3,064 patients, a score < -1.455 had 90% sensitivity and 60% specificity to exclude advanced fibrosis, whereas a score > 0.676 had 67% sensitivity and 97% specificity to identify the presence of advanced fibrosis
Fibrosis 4 score
  • Predicts presence of NASH based on patient's age, platelet count, ALT, and AST values
  • Online calculator available here - Fibrosis 4 score calculator
  • Patients with score < 1.45 are unlikely to have NASH, whereas patients with score > 3.25 are likely to have advanced fibrosis
Vibration controlled transient elastography (Fibroscan)
  • Specialized ultrasound machine that uses a transducer to measure the velocity of a sound wave passing through the liver. The velocity is then used to calculate "liver stiffness" which is a marker of fibrosis.
  • Fibroscan has a sensitivity of 85% for detecting advanced fibrosis and 92% for detecting cirrhosis
MR elastography
  • Specialized MRI where sound waves are passed through the liver and images are produced using a special MRI technique. The images are then used to quantify "liver stiffness" which is a marker for fibrosis.
  • MRE has a sensitivity of 86% for identifying patients with advanced fibrosis. In some studies, it has performed better than Fibroscan. It is expensive and not widely available.


  • Average baseline body weight 183 lbs (83.4 kg)
  • Average baseline BMI - 31
  • Reference [9]
Effects of Weight Loss on NASH
Average % weight loss over 52 weeks
Measure 1.8% 5.9% 8.2% 13%
Resolution of steatohepatitis 10% 26% 64% 90%
Steatosis improvement 35% 65% 76% 100%
Fibrosis regression 16% 18% 16% 45%
Fibrosis stabilized 63% 74% 84% 55%
Fibrosis worsened 21% 8% 0% 0%
































  • Check and monitor HBV viral load as indicated
  • Reference [3,14]
HBV Screening
Test result Interpretation
+ HBsAg
- Anti-HBs
+ Anti-HBc (+IgG, -IgM)
Chronic infection
+ HBsAg
- Anti-HBs
+ Anti-HBc (+IgM)
Acute infection
(within 6 months)
- HBsAg
+ Anti-HBs
+ Anti-HBc (IgM/IgG)
Resolution of HBV infection
(natural immunity)
- HBsAg
+ Anti-HBs
- Anti-HBc (IgM/IgG)
Past vaccination
- HBsAg
- Anti-HBs
+ Anti-HBc (IgM/IgG)
One of the following:
  • Possible occult infection
  • Resolving acute infection
  • Resolved infection (most common)
  • False positive Anti-HBc
- HBsAg
- Anti-HBs
- Anti-HBc (IgM/IgG)
Never infected and no evidence of vaccination


  • ULN of ALT is 35 IU/L for men and 25 IU/L for women
  • *See Metavir scoring for liver fibrosis assessment. Noninvasive testing (e.g. Fibroscan) may also be used.
  • Reference [16]
AASLD 2018 Treatment Recommendations for HBV
Patients with cirrhosis
  • Patients with cirrhosis and detectable HBV DNA levels should be treated regardless of ALT level
HBeAg positive
ALT HBV DNA (IU/ml) Liver disease * Recommendation
≤ ULN > 20,000 < F2 and < A3
  • Do not treat
  • Monitor ALT and HBV DNA every 3 - 6 months
  • Monitor HBeAg every 6 - 12 months
> ULN but < 2 X ULN 2000 - 20,000 < F2 and < A3
  • Monitor ALT and HBV DNA every 1 - 3 months
  • If ALT elevation persists for > 6 months, treat
> ULN but < 2 X ULN > 20,000 < F2 and < A3
  • Monitor ALT and HBV DNA every 1 - 3 months
  • If ALT elevation persists for > 6 months, treat
> ULN but < 2 X ULN > 20,000 ≥ F2 or ≥ A3
  • Treat, especially if age > 40 years
≥ 2 X ULN 2000 - 20,000 < F2 and < A3
  • Monitor ALT and HBV DNA every 1 - 3 months
  • If ALT elevation persists for > 6 months, treat
≥ 2 X ULN > 20,000 Any or none
  • Treat
HBeAg negative
≤ ULN < 2000 < F2 and < A3
  • Do not treat
  • Monitor ALT and HBV DNA every 3 - 6 months
  • Monitor HBsAg annually
≤ ULN ≥ 2000 < F2 and < A3
  • Monitor ALT and HBV DNA every 3 months for 1 year, then every 6 months
> ULN but < 2 X ULN Detectable < F2 or < A3
  • Monitor ALT and HBV DNA every 1 - 3 months
  • If ALT elevation persists with HBV DNA ≥ 2000 IU/ml for > 6 months, treat
> ULN but < 2 X ULN Detectable ≥ F2 or ≥ A3
  • Treat, especially if age > 40 years
≥ 2 X ULN < 2000 < F2 or < A3
  • Monitor ALT and HBV DNA every 1 - 3 months
  • If ALT elevation persists with HBV DNA ≥ 2000 IU/ml for > 6 months, treat
≥ 2 X ULN < 2000 ≥ F2 or ≥ A3
  • Treat, especially if > 40 years old
≥ 2 X ULN ≥ 2000 Any or none
  • Treat



  • Reference [16, 17, Manufacturer's PI]
Nucleoside Analogues to Treat HBV
Medications Comments
Entecavir (Baraclude®)
  • Dosing: 0.5 mg once daily
  • Should not be used in pregnancy
  • Suitable for decompensated liver disease
  • Cases of lactic acidosis and severe hepatomegaly has been reported, especially in patients with hepatic decompensation
  • Generic available. Cost of 30 tablets is < $50.
Tenofovir disoproxil fumarate (Viread®)
  • Dosing: 300 mg once daily
  • Okay to use in pregnancy
  • Suitable for decompensated liver disease
  • Can cause renal impairment and hypophosphatemia. Check creatinine at baseline. If patient is at risk for renal impairment, check creatinine clearance, serum phosphate, urine glucose, and protein at least annually.
  • May cause bone loss. Consider a bone density study at baseline and during treatment in patients with a history of fracture(s) or other risks for osteopenia.
  • Cases of lactic acidosis and severe hepatomegaly has been reported, especially in patients with hepatic decompensation
  • Generic available. Cost of 30 tablets is < $50.
Tenofovir alafenamide (Vemlidy®)
  • Dosing: 25 mg once daily
  • No data on pregnancy use or use in decompensated liver disease
  • Tenofovir alafenamide achieves much higher intracellular concentrations than tenofovir disoproxil fumarate. Because of this, it has a much lower dose which leads to lower systemic exposure and lower risk of renal and bone toxicity.
  • No generic available. Cost of 30 tablets is > $1000.











  • Reference [3,21]
Lab Findings in Hereditary Hemochromatosis
Study Comments
Transferrin saturation
  • A transferrin saturation > 45% is 98% sensitive for C282Y homozygous HH
Ferritin
  • Elevated ferritin levels are common in HH, but ferritin is an acute phase reactant and is nonspecific for HH
  • A normal ferritin level (< 200 ng/ml in premenopausal women | < 300 ng/ml in men) in combination with a transferrin saturation < 45% has a negative predictive value of 97% for iron overload.
  • Ferritin is useful in predicting the presence of cirrhosis in HH. In C282Y homozygotes, a ferritin level > 1000 ng/ml in combination with elevated ALT/AST and low platelets indicates cirrhosis in > 80% of patients.
HFE Genotyping
C282Y / C282Y
  • Homozygous C282Y is diagnostic for HH
  • Present in 80 - 90% of patients with clinical HH
C282Y / H63D
  • This genotype has a low likelihood of clinically relevant HH
  • Only 0.5 - 2% of affected individuals will have significant iron overload
  • Affected patients may have increased ferritin and transferrin saturation
  • This genotype is present in 2 - 5% of cases of clinical HH
C282Y / S65C
  • Very low risk of clinically relevant HH
H63D / H63D
  • Not at increased risk of iron overload














  • Reference [24]
Diagnostic Studies in Wilson Disease
Study Comments
Ceruloplasmin
  • In Wilson disease, copper is not incorporated into ceruloplasmin correctly and this reduces its half-life
  • Ceruloplasmin levels ≤ 20 mg/dl are considered consistent with Wilson disease
  • Normal levels do not rule out Wilson disease
  • Ceruloplasmin ≤ 20 mg/dl in the presence of Kayser-Fleischer rings is diagnostic for Wilson disease
Kayser-Fleischer rings
  • Kayser-Fleischer rings are a band of gold-brown pigments that encircle the iris. They form secondary to copper deposition in the cornea.
  • Kayser-Fleischer rings are present in almost all patients who present with neurologic symptoms. They are seen in 44 - 62% of patients who present with liver abnormalities.
  • Ceruloplasmin ≤ 20 mg/dl in the presence of Kayser-Fleischer rings is diagnostic for Wilson disease
24-hour urine copper
  • Non-ceruloplasmin bound copper is excreted in the urine
  • 24-hour excretion > 40 mcg is consistent with Wilson disease
Hepatic copper concentration
  • Hepatic copper concentration can be measured from a liver biopsy specimen
  • Copper concentration > 250 mcg/g are considered consistent with Wilson disease. Concentrations < 50 mcg/g exclude Wilson disease and concentrations between 50 - 250 mcg/g are indeterminate.
ATP7B genotyping
  • ATP7B codes for ATPase, and ATP7B genotyping can identify alleles that are associated with Wilson disease




  • Reference [27]
Metavir fibrosis score (F) Finding
0 No scarring
1 Minimal scarring
2 Scarring has occurred and extends outside the areas in the liver that contains blood vessels
3 Bridging fibrosis is spreading and connecting to other areas that contain fibrosis
4 Cirrhosis or advanced scarring of the liver

  • Reference [27]
Metavir activity
score (A)
Finding
0 No activity
1 Mild activity
2 Moderate activity
3 Severe activity




Child-Pugh Score
Finding 1 2 3
Encephalopathy
(see encephalopathy staging below)
None 1 and 2 3 and 4
Ascites Absent Slight Moderate
Bilirubin(mg/dl) < 2 2 - 3 > 3
Albumin (g/dl) > 3.5 2.8 - 3.5 < 2.8
Prothrombin time (PT)
(seconds prolonged)

OR
< 4 4 - 6 > 6
INR < 1.7 1.7 - 2.3 > 2.3


Bilirubin (mg/dl) Child-Pugh score
< 4 1
4 - 10 2
> 10 3


  • Surgical mortality based on 12-year study published in 1997 involving abdominal surgery [31]
  • Reference [28]
Total score Child-pugh class Expected mortality
5 - 6 A 5-year survival 90%
Surgical mortality 10%
7 - 9 B 5-year survival 80%
Surgical mortality 32%
≥ 10 C More than 33% die within one year
Surgical mortality 82%


  • Reference [29,30]
Stage Mental status Neuro exam EEG findings
0 normal normal none
1 mild confusion sleep disturbance slight tremor normal to slightly normal
2 disoriented abnormal behavior significant tremor coordination problems abnormal
3 confused, incoherent excessive sleep muscle rigidity positive Babinski abnormal
4 coma none abnormal