Investigations
1st investigations to order
serum aspartate aminotransferase (AST), alanine aminotransferase (ALT)
Test
AST (sensitivity 50%, specificity 82%) and ALT (sensitivity 35%, specificity 86%) are elevated in ARLD when alcohol use >50 g/day.[69]
True upper limits of normal for AST and ALT are considered to be 30 units/L for men and 19 units/L for women.[70] AST and ALT can be normal either in the absence of significant liver inflammation or in advanced cirrhosis with few viable hepatocytes to produce AST or ALT.[43]
AST and ALT both elevated to <300 units/L, unless associated with misuse of paracetamol or certain other complicating liver diseases.[71]
Result
men: >30 units/L; women: >19 units/L
serum AST/ALT ratio
Test
In patients with ARLD, AST level is almost always elevated (usually above ALT level). The classic ratio of AST/ALT >2 is seen in about 70% of cases.[44]
Reversal of the ratio, ALT > AST, suggests concomitant presence of viral hepatitis or possibly metabolic dysfunction-associated steatotic liver disease, previously known as non-alcoholic fatty liver disease, as the major cause of liver injury in patients who misuse alcohol.
Result
ratio >2
serum alkaline phosphatase
Test
If elevated may represent cholestasis associated with ARLD.
Result
normal or elevated
serum bilirubin
Test
Elevated bilirubin reflects impaired metabolic function of the liver in the absence of biliary obstruction.
Elevated bilirubin has prognostic utility in patients with ARLD in the absence of biliary obstruction.
Both conjugated and unconjugated bilirubin are increased in varying proportions.
Result
elevated
serum albumin, protein
Test
Low albumin reflects impaired synthetic function of the liver.
Result
low
serum gamma glutamyl transferase (gamma-GT)
Test
Increase in this liver microsomal enzyme represents enzyme activation, which can be induced by alcohol and certain drugs.
Increased in cholestasis along with alkaline phosphatase (ALP).
GGT is not significantly present in bone, such that concomitant elevated GGT and ALP indicates the liver as the source of the ALP.
Gamma-GT is more sensitive (sensitivity 69% to 73%) than AST or ALT for heavy alcohol use and liver injury.[49]
Result
elevated
FBC
Test
Anaemia in ARLD is likely to be due to multiple causes such as iron deficiency, gastrointestinal bleeding, folate deficiency, haemolysis, and hypersplenism.
Leukocytosis is likely from alcohol-related hepatitis-related leukaemoid reaction or associated infection.
Thrombocytopenia may be secondary to alcohol-induced bone marrow suppression, folate deficiency, or hypersplenism.
MCV, as a diagnostic tool for alcohol misuse, lacks sensitivity (27% to 52%) but is reasonably specific (85% to 91%) for alcohol use >50 g/day in the absence of vitamin B12 or folic acid deficiency.[49]
Result
anaemia, leukocytosis, thrombocytopenia, high mean corpuscular volume (MCV)
serum electrolytes, magnesium, phosphorus
Test
Hyponatraemia is frequently present in patients with advanced cirrhosis.
Hypokalaemia and hypophosphataemia are common causes of muscle weakness in ARLD.
Hypomagnesaemia can cause persistent hypokalaemia and may predispose patients to seizures during alcohol withdrawal.
Result
normal or low sodium, potassium, magnesium, phosphorus
serum urea and creatinine
Test
Elevated urea in the presence of normal creatinine suggests active gastrointestinal bleeding; elevated urea and creatinine is present in hepatorenal syndrome.
Result
normal or elevated
serum prothrombin time (PT), INR
Test
Useful to evaluate synthetic function of the liver. An elevated PT/INR indicates advanced cirrhosis or liver failure in patients with ARLD. Elevated PT has prognostic utility in patients with ARLD.
Result
normal or prolonged
hepatic ultrasound
Test
Ultrasound should be performed among patients with harmful alcohol use.[53]
It is also used to screen for hepatocellular carcinoma (HCC) every 6-12 months in patients with ARLD with cirrhosis.
Sensitivity of ultrasound for HCC detection is about 70% to >90% and specificity is >90%.[72]
Result
may show hepatomegaly, fatty liver, cirrhosis, liver mass, splenomegaly, ascites, evidence of portal hypertension
Investigations to consider
viral hepatitis serology
Test
HBV surface antigen, IgM anti-HBc, IgM anti-HAV, IgG anti-HCV, and PCR for HCV RNA are used to exclude concomitant hepatitis A, B, and C infection.
Anti-hepatitis surface and core antigens, total anti-HBc, and total anti-HAV are used to detect previous exposure to hepatitis B (natural or immunisation mediated) and hepatitis A, in order to plan immunisations.
Result
absence of hepatitis B virus (HBV) surface antigen, immunoglobulin M (IgM) anti-hepatitis B core (anti-HBc), IgM anti-hepatitis A virus (anti-HAV), IgG anti-hepatitis C virus (anti-HCV), and HCV-RNA PCR
serum iron, ferritin, transferrin
Test
Used to rule out the presence of associated haemochromatosis.
Elevated ferritin is common because it is an acute-phase reactant, and sometimes due to secondary iron overload.[46]
Iron distribution in tissue, hepatic iron index, and genetic studies for HFE can help clarify the co-existence of ARLD with haemochromatosis.
Result
normal or elevated serum iron, ferritin
urine copper (24-hour collection)
Test
Samples should be collected in trace element-free containers.
Levels >40 micrograms/24 hours raise the possibility of Wilson's disease.
Result
normal
serum ceruloplasmin
Test
In ARLD, the ceruloplasmin level is usually normal (20-35 mg/dL [200-350 mg/L]) or elevated due to acute injury.
With low or low-normal ceruloplasmin, liver biopsy with copper quantitation is needed to differentiate ARLD from Wilson's disease.
Result
normal or elevated
serum anti-mitochondrial antibody (AMA)
Test
Normal AMA will help to exclude presence of primary biliary cirrhosis.
Result
normal
serum anti-nuclear antibody (ANA) and anti-smooth muscle antibody (ASMA)
Test
Used to rule out the presence of associated autoimmune hepatitis.
Liver biopsy is needed to establish the diagnosis of autoimmune hepatitis.
Result
absent ANA and ASMA
serum alpha-1 antitrypsin level
Test
Used to screen for the presence of alpha-1 antitrypsin deficiency.
Result
normal
serum ammonia
Test
Elevated ammonia level does not correlate with presence or severity of hepatic encephalopathy, unless it is extremely high. Therefore, its routine use in diagnosis of hepatic encephalopathy or ARLD is not necessary.
Result
normal or elevated
serum folate
Test
Increased requirements for folate in hepatic disease, and decreased intake, may lead to folate deficiency.
Result
normal or low
non-invasive tests of liver elasticity
Test
Liver stiffness is the leading biomarker for the detection of advanced fibrosis. Ultrasound shear wave elastography is a non-invasive technique for assessing liver stiffness. Tissue stiffness is deduced from analysis of shear waves that are generated by high-intensity ultrasound pulses.[56] Transient elastography may help to rule out severe fibrosis (F3 or worse) in patients with ARLD.[1][57] Recent alcohol consumption may exaggerate the estimated severity of the fibrosis; thus, it is better to have 2 weeks of alcohol abstinence to increase the reliability of the test.[58]
Magnetic resonance elastography is an alternative technique for assessing liver stiffness. It is more accurate than ultrasound shear wave elastography for identifying fibrosis and cirrhosis, and performs better in people with obesity.[56][59]
The American Association for the Study of Liver Diseases (AASLD) suggests using imaging-based non-invasive testing to detect advanced fibrosis and cirrhosis in adults with ARLD.[60] Either ultrasound-based transient elastography or magnetic resonance elastography is recommended to stage fibrosis.[60] The AASLD advises against using imaging-based tests as a standalone test to assess regression or progression of liver fibrosis.[60]
The French Association for the Study of the Liver recommends that the results of FibroScan®, an elastography device, must be interpreted by considering specific diagnostic thresholds based on AST and bilirubin levels.[61] For the diagnosis of cirrhosis, the threshold is 12.1 kPa (area under receiver operating characteristic curve [AUROC] 0.92, sensitivity 85%, specificity 84%) with levels of AST <38.7 IU/L and bilirubin <9 micromol/L, compared with 25.9 kPa (AUROC 0.90, sensitivity 81%, specificity 80%) with levels of AST> 75 IU/L and bilirubin >16 micromol/L. For advanced fibrosis, the thresholds are 8.8 kPa (AUROC 0.92, sensitivity 80%, specificity 75%) and 16.1 kPa (AUROC 0.92, sensitivity 83%, specificity 80%) at the same aforementioned AST and bilirubin levels. Stopping alcohol consumption has an effect on liver elasticity level, with one study showing a decrease in median liver elasticity from 7.2 to 6.1 kPa on day 7. Two weeks of alcohol abstinence will increase the reliability of the test, especially if AST is >100 IU/L.[58]
A number of non-invasive laboratory tests are used to assess liver fibrosis in patients with ARLD, including enhanced liver fibrosis (ELF), fibrosis-4 (FIB-4), and AST to platelet ratio index (APRI).[11][54][55]
The ELF test uses specific molecular markers of fibrogenesis, while other tests use combinations of routinely collected blood tests (e.g., FIB-4, APRI).
The utility of these markers is predominantly for excluding severe fibrosis, with normal values being reassuring.
Result
serological marker and ultrasound-based elastography evidence of fibrosis.
CT abdomen, MRI abdomen
Test
Non-contrast plus triphasic contrast CT scan (four phase study) or four-dimensional phase contrast MRI of the abdomen are useful further investigations to evaluate a liver mass detected by ultrasound.
The choice between CT scan and MRI depends on factors such as availability, expertise, quality of equipment, and previous radiation exposure.
Result
may show hepatomegaly, splenomegaly, ascites, portal vein engorgement
liver biopsy
Test
Sensitivity is 91%, positive predictive value is 88%, specificity is 96%, and negative predictive value is 97% in diagnosis of ARLD and/or alcohol-related cirrhosis.[62]
Result
steatosis, inflammation-neutrophil infiltrate, ballooning hepatocytes, Mallory hyaline bodies, pericellular fibrosis
Emerging tests
serum carbohydrate-deficient transferrin test
Test
Relatively specific (82% to 92%) but not sensitive (58% to 69%) test to detect current alcohol misuse.[69]
When a patient denies alcohol use and clinical suspicion is high, a positive test may be helpful to establish alcohol misuse, particularly in young men with alcohol ingestion >60 g/day.[49][50] Serum CDT has a half-life of approximately 15 days and can detect excessive alcohol use for up to 4 weeks before analysis.[51] Alcohol biomarkers should not be used on their own to confirm or refute alcohol use but should be combined with other laboratory tests (including other alcohol biomarkers), physical examination, and the clinical interview.
Result
elevated
serum mitochondrial AST
Test
A specific mitochondrial isoform of the AST enzyme released from hepatocytes at high levels is associated with alcohol misuse.[52] Alcohol biomarkers should not be used on their own to confirm or refute alcohol use but should be combined with other laboratory tests (including other alcohol biomarkers), physical examination, and the clinical interview.
Result
elevated
Phosphatidylethanol (PEth)
Test
PEths are a group of aberrant phospholipids that are formed in the cell membrane, only in the presence of ethanol. PEths are formed by a reaction between ethanol and phosphatidylcholine, which is catalyzed by phospholipase D.[73] PEth has a half-life of 4 ± 0.7 days and may be detected until 28 days after sobriety.[74] Alcohol biomarkers should not be used on their own to confirm or refute alcohol use but should be combined with other laboratory tests (including other alcohol biomarkers), physical examination, and the clinical interview.
Result
levels above 20 ng/mL indicate 'social drinking', while concentrations above 200 ng/mL may be suggestive for chronic and excessive alcohol consumption. A cutoff of 80 ng/mL identifies intake of four drinks per day or more with a sensitivity of 91% (95% confidence interval [CI], 82% to 100%) and specificity of 77% (95% CI, 70% to 83%).
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