Abnormal liver function tests and jaundice

• Routine "liver function tests" are not tests of function at all. They are injury markers: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) for hepatocellular injury, alkaline phosphatase and gamma-glutamyl transferase (GGT) for cholestasis, and bilirubin for both. True tests of liver function are albumin, prothrombin time (or international normalised ratio, INR), bilirubin and, rarely, clearance tests. ^[1]
• Hepatocellular injury shows a disproportionate rise in AST and ALT; cholestatic injury shows a disproportionate rise in alkaline phosphatase; a mixed picture raises both; an isolated rise in bilirubin with normal enzymes points to disorders of bilirubin itself. ^[1]
• The R ratio, (ALT divided by its upper limit of normal) divided by (alkaline phosphatase divided by its upper limit of normal), classifies the pattern: above 5 is hepatocellular, below 2 is cholestatic, and 2 to 5 is mixed. ^[1]
• Jaundice (yellow eyes or skin from hyperbilirubinaemia) usually becomes visible once serum bilirubin exceeds about 2 to 2.5 mg per dL (34 to 43 micromol per L) in the sclerae and about 2 to 3 mg per dL (34 to 51 micromol per L) in the skin. ^[2][4]
• The stepwise assessment begins with confirming that the result is real (repeat the panel, use GGT for an isolated alkaline phosphatase), then the history and examination, then a disease-specific laboratory screen, then imaging. The ACG 2017 guideline anchors these steps. ^[1]

By the end of this page you should be able to:

1. Explain what each routine liver blood test measures, why it is not a "function test", and what the true tests of hepatic function are.
2. Classify an abnormal liver panel into hepatocellular, cholestatic, mixed, or isolated hyperbilirubinaemia, using the R ratio, and name the usual causes of each.
3. Recognise the common benign causes of a mild ALT rise, the meaning of an AST to ALT ratio above 2, and why aminotransferases above 1000 IU per L are an emergency.
4. Decide whether an elevated alkaline phosphatase comes from liver or bone, and use GGT and 5-prime nucleotidase correctly.
5. Describe the clinical features of jaundice, distinguish prehepatic, hepatic and posthepatic mechanisms, and use dark urine, pale stools and pruritus as clues.
6. Walk through the algorithms for cholestasis and for raised transaminases, know when synthetic tests indicate liver failure, and adapt the approach to a low-resource setting.

A "liver function test" panel (ALT, AST, alkaline phosphatase, bilirubin and albumin, sometimes prothrombin time) contains mostly injury markers. ^[1] None of them measures how much functioning liver tissue remains. True tests of hepatic function are clearance of substances the liver takes up, metabolises or excretes, and of the proteins and clotting factors it synthesises. ^[1] In routine practice we use albumin, prothrombin time or INR and bilirubin as surrogates for synthetic function, plus a platelet count as a clue to advanced fibrosis. ^[3]

ALT is present mainly in the hepatocyte; AST is present in liver, cardiac muscle, skeletal muscle, kidney and brain. ALT is therefore the more specific marker of hepatocellular injury. ^[1] An isolated rise in AST without a rise in ALT should make you think of muscle or cardiac disease before liver disease. ^[1] As hepatocytes are injured or die, these enzymes leak into plasma, so the height of the rise reflects activity and extent of injury rather than the amount of permanent liver loss.

Alkaline phosphatase belongs to a family of zinc metalloenzymes attached to the hepatocyte canalicular membrane. Its activity rises when bile flow is impaired, even slightly, because bile acids induce its synthesis and translocation to the sinusoidal surface. ^[1][2] GGT is a canalicular enzyme too, but it is not bone-derived, so an elevated GGT suggests that an alkaline phosphatase rise is hepatic in origin. ^[1][2] Bilirubin rises in both hepatocellular and cholestatic disease because conjugated bilirubin leaks back into blood when excretion is impaired.

Albumin is synthesised only by the liver and has a circulating half-life of about three weeks. A low albumin (normal at least 3.5 g per dL) usually indicates liver disease of more than three weeks' duration, although sepsis, nephrotic syndrome, malnutrition and any serious systemic illness also lower it. ^[1][2] Prothrombin time is a far more sensitive early marker because it can be prolonged in severe liver disease of under 24 hours' duration. ^[1] Prothrombin time measures the extrinsic coagulation pathway and factors 1, 2, 5, 7, 9 and 10; factors 2, 7, 9 and 10 are vitamin K dependent. ^[1]

Both albumin and prothrombin time are influenced by extrahepatic factors, which is why the ACG guideline calls them markers of hepatocellular function rather than true function tests. ^[1]

Before initiating a work-up, repeat the panel and add a clarifying test, such as GGT if the alkaline phosphatase is raised. ^[1] A single borderline value in an asymptomatic person is often transient: elevated liver enzymes occur in roughly 8 percent of the general population, and up to 30 percent of asymptomatic elevations disappear within three weeks according to the cited literature.

A "true healthy" ALT is lower than many laboratory reference ranges. In prospectively studied populations without identifiable liver disease risk factors, normal ALT runs 29 to 33 IU per L in males and 19 to 25 IU per L in females, and values above this should be assessed. ^[1] Local reference ranges for ALT vary widely for methodological reasons, so clinicians should know their own laboratory's range and use clinical judgement. ^[1] Total serum bilirubin is usually under 1.1 mg per dL and an elevated direct (conjugated) bilirubin indicates hepatocellular disease or cholestasis. ^[1] Normal ALT does not exclude significant liver disease, which is important advice for patients with hepatitis C, haemochromatosis or fatty liver. ^[1]

The pattern, not just the height, of enzyme elevation guides the diagnosis. ^[1] Hepatocellular injury is a disproportionate rise in AST and ALT as compared with alkaline phosphatase. Cholestatic injury is a disproportionate rise in alkaline phosphatase as compared with AST and ALT. A mixed pattern raises both groups. Isolated hyperbilirubinaemia means a bilirubin rise with normal alkaline phosphatase and AST or ALT. ^[1] Even in these categories, the other tests may also be mildly raised; the word "predominant" matters. ^[1]

The R ratio formalises this for drug-induced and other injuries:

R = (ALT divided by ALT upper limit of normal) divided by (alkaline phosphatase divided by alkaline phosphatase upper limit of normal).

An R above 5 is hepatocellular, below 2 is cholestatic and 2 to 5 is mixed. ^[1]

The magnitude of aminotransferase elevation also narrows the differential: borderline is under 2 times the upper limit of normal, mild is 2 to 5 times, moderate is 5 to 15 times, severe is above 15 times and massive is above 10 000 IU per L. ^[1] Moderate to massive elevations generally come from acute hepatocellular insults, where sepsis, muscle injury and heatstroke must also be remembered. ^[1]

For most hepatocellular diseases, including chronic viral hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD), ALT is higher than AST. ^[1] In contrast, about 90 percent of patients with alcoholic liver disease have AST above ALT, and above 70 percent have an AST to ALT ratio above 2. ^[1] The ratio is usually below 2 in non-alcoholic disease, and cirrhosis of any cause can also raise it. ^[1][3] A helpful general screen of fibrosis in adults is an AST to ALT ratio above 1, which indicates advanced fibrosis or cirrhosis even when both values sit within the reference range. ^[3]

Alcohol is a very common and easily missed contributor. Significant consumption is more than 210 g of alcohol per week in men and more than 140 g per week in women. ^[1] Alcoholic liver disease classically produces the AST to ALT ratio of at least 2 to 1, with AST or ALT rarely above 300 IU per L. ^[1] Drugs and supplements are equally important: prescribed drugs, over-the-counter analgesics, herbal products and dietary supplements all cause acute and chronic injury. ^[1] Common examples include antibiotics, antiepileptics, non-steroidal anti-inflammatory drugs, statins, antituberculosis drugs, biologic agents and cancer chemotherapy. Statins have an extensive safety record even in chronic liver disease. ^[1] In anyone with high aminotransferase levels, above 1000 IU per L, a careful history of acetaminophen use, both as a single medicine and in combination products, is essential. ^[1]

Metabolic dysfunction-associated (non-alcoholic) fatty liver disease is a highly prevalent cause of mild transaminase elevations and should be strongly considered when the patient has obesity, diabetes, dyslipidaemia or hypertension. ^[1] Unlike alcoholic disease, there is no unique pattern, although in general ALT is higher than AST and levels are rarely above 300 IU per L. ^[1] Many people with fatty liver have entirely normal tests, but abnormal enzymes make non-alcoholic steatohepatitis with or without fibrosis more likely and warrant evaluation. ^[1] Imaging helps identify steatosis, and elastography (vibration-controlled transient elastography, acoustic radiation force impulse or shear-wave) can stratify fibrosis without biopsy. ^[1][3]

Very high aminotransferases, above 15 times the upper limit of normal, raise the specific differentials of acute viral hepatitis, ischaemic and shock liver, sepsis, acute Budd-Chiari syndrome or hepatic artery occlusion, toxin or drug injury, autoimmune hepatitis, acute biliary obstruction, infiltration with malignancy, liver trauma, veno-occlusive disease, HELLP syndrome and Wilson disease. ^[1] Massive elevations above 10 000 IU per L are generally only seen with ischaemic or shock liver (ischaemic hepatopathy) or drug or toxic hepatitis, and rhabdomyolysis and heatstroke can also produce very high AST values. ^[1] The highest aminotransferase levels are typically seen with acetaminophen overdose, ischaemic hepatopathy or toxin exposure such as Amanita phalloides. ^[1] Other possible causes of severe elevations include reactivation of chronic hepatitis B, herpes simplex, Epstein-Barr virus, cytomegalovirus and acute autoimmune hepatitis. ^[1]

When aminotransferases are above about 500 IU per L, hepatocellular dysfunction is likely (Merck Manual teaching threshold); when they are below about 200 IU per L in the presence of jaundice, cholestasis is more likely. ^[4] These thresholds are a guide, not an absolute rule, and aminotransferase levels can be normal even in cirrhosis. ^[3]

The approach is staged by the height of the rise and the clinical picture.

1. Take a structured history: risk factors for viral hepatitis and metabolic liver disease; prescribed, over-the-counter and herbal medicines; alcohol; associated conditions such as inflammatory bowel disease, haematologic, pulmonary or cardiac disease; and a family history of haemochromatosis, Wilson disease or alpha-1-antitrypsin deficiency. ^[1]
2. Examine for stigmata of chronic liver disease (jaundice, ascites, splenomegaly, spiders, palmar erythema, hepatic flap), hepatomegaly, a firm liver edge suggesting cirrhosis or infiltration, and signs pointing to a specific diagnosis such as Kayser-Fleischer rings in Wilson disease or bronzing in haemochromatosis. ^[1]
3. Repeat the panel, advise abstinence from alcohol and review possibly hepatotoxic medicines.
4. Screen for haemochromatosis with iron studies (transferrin saturation of 45 percent or higher, or raised ferritin), for viral hepatitis B and C, and for fatty liver. ^[1] If these are negative, consider autoimmune hepatitis, Wilson disease and alpha-1-antitrypsin deficiency. ^[1]

Investigate more promptly with serologic testing for hepatitis A, B and C; an iron panel; ceruloplasmin; alpha-1-antitrypsin phenotype; and autoimmune markers (antinuclear antibody, anti-smooth muscle antibody and sometimes anti-liver-kidney microsomal antibody and anti-soluble liver antigen). ^[1] Add thyroid function tests, coeliac serology (tissue transglutaminase IgA) and creatine kinase if the pattern or history suggest them. ^[1][3]

The specific disease work-up uses the following tests. ^[1][2]

• Viral hepatitis: hepatitis A and E in acute illness (hepatitis A and E are spread by the faecal-oral route); hepatitis B surface antigen, core antibody and surface antibody; hepatitis C antibody confirmed by highly sensitive RNA polymerase chain reaction; and hepatitis E serology in travellers to endemic areas or the immunosuppressed. ^[1]
• Autoimmune hepatitis: antinuclear antibody, anti-smooth muscle antibody, anti-liver-kidney microsomal antibody and, less often, anti-soluble liver antigen antibody, with raised IgG on protein electrophoresis. ^[1] Diagnosis needs histologic confirmation and it is commoner in women than men (about 4 to 1). ^[1]
• Haemochromatosis: homozygous C282Y mutation occurs in roughly 1 in 220 to 250 people in some populations, with low penetrance. ^[1] If transferrin saturation is at least 45 percent or ferritin is raised, consider HFE mutation analysis; the presence of cirrhosis or ferritin above 1000 microg per L should prompt biopsy for staging. ^[1]
• Wilson disease: an autosomal recessive disorder of biliary copper excretion at a prevalence of about 1 in 30 000. ^[1] Screen with serum ceruloplasmin, and if low, confirm with 24-hour urine copper, serum copper, slit-lamp examination for Kayser-Fleischer rings and, when needed, liver biopsy with quantitative copper and genetics. ^[1]
• Alpha-1-antitrypsin deficiency: prevalence around 1 in 2500 in some populations and the most common genetic cause of liver disease in children. ^[1] Screen with a quantitative level and PiZZ genotyping; heterozygotes such as PiMZ may also develop disease when steatosis or viral hepatitis coexists. ^[1]
• Coeliac disease, thyroid disease, muscle disease and tick-borne infections are uncommon causes worth considering in persistent, unexplained cases. ^[1]

Patients with moderate, severe or massive elevations require immediate evaluation for acute hepatitis from all causes, drug or toxin exposure and acute biliary obstruction. ^[1] If any signs of acute liver failure appear (rapid severe liver injury with prolonged prothrombin time and hepatic encephalopathy in someone without prior liver disease), urgent hepatology referral and assessment for transplantation is mandatory regardless of the enzyme height. ^[1]

Imaging follows the clinical picture: abdominal ultrasound for steatosis, structure and fibrosis, CT or MRI for focal lesions or biliary anatomy, and elastography (FibroScan, acoustic radiation force impulse or magnetic resonance elastography) to stage fibrosis without biopsy. ^[1][3] A liver biopsy is most often done to grade and stage disease (hepatitis B, hepatitis C, fatty liver disease) or to confirm a suspected diagnosis such as Wilson disease, haemochromatosis or alpha-1-antitrypsin deficiency. ^[1]

Referral to a gastroenterologist or hepatologist is appropriate when tests are unexplained, persistently more than 1.5 to 2 times the upper limit of normal on more than one occasion, or when an unexplained abnormality of synthetic function appears. ^[2][3] Further evaluation after a negative extended aetiology screen and risk assessment should also prompt specialist referral. ^[3]

The first task with a raised alkaline phosphatase is deciding where it comes from. Sources include bone (the most common extrahepatic source), liver canalicular membrane, placenta (pregnancy), intestine and kidney. ^[1][2] Physiologic elevation also occurs in children from rapid bone growth, in pregnancy and in elderly women, particularly over 50 years of age, from bone turnover. ^[1][4] After a fatty meal, people with blood groups O and B can show a rise from intestinal isoenzyme. ^[1] Serum alkaline phosphatase can also be low in Wilson disease, zinc deficiency, malnutrition, hypothyroidism and certain deficiency states. ^[2]

GGT is not found in bone. An elevated GGT therefore suggests that the alkaline phosphatase is hepatic in origin. ^[1][2] A normal GGT with a high alkaline phosphatase points towards bone, pregnancy or intestinal sources. ^[2] GGT is sensitive but non-specific: it can rise with alcohol use (it is raised in more than 50 percent of people with alcohol excess without obvious liver disease), pancreatic disease, myocardial infarction, renal failure, emphysema, diabetes and drugs such as phenytoin and barbiturates. ^[1][2] For this reason GGT should not be used as a routine screening test when there are no abnormal liver chemistries. ^[1]

When the GGT result is unhelpful, 5-prime nucleotidase or alkaline phosphatase isoenzyme electrophoresis can confirm a hepatic source. 5-prime nucleotidase is highly specific for hepatobiliary disease but insensitive; its sensitivity is around 47 percent and specificity around 86 percent when liver-derived alkaline phosphatase is the gold standard. ^[2] Fractionating the isoenzymes by electrophoresis separates liver, bone and intestinal components. ^[2]

If other liver tests are already abnormal, confirming hepatic origin is usually unnecessary. ^[1] Up to about 80 percent of isolated alkaline phosphatase elevations in hospitalised patients could be diagnosed from the history, examination, routine labs and chest radiograph alone. ^[1]

Jaundice is yellow discoloration of skin, mucous membranes and the whites of the eyes (scleral icterus) caused by hyperbilirubinaemia. ^[4] Clinical signs usually appear once serum bilirubin exceeds about 2.5 to 3 mg per dL (43 to 51 micromol per L), although in the sclerae it can be detected at around 2 to 2.5 mg per dL (34 to 43 micromol per L). ^[2][4] Scleral icterus occurs because sclerae have high elastin content with strong bilirubin affinity. ^[2] Dark urine from bilirubinuria can appear before visible jaundice in conjugated hyperbilirubinaemia, because conjugated bilirubin is water soluble and filtered by the kidney; unconjugated bilirubin, which is bound to albumin, is not. ^[1][4]

Bilirubin is formed from the breakdown of heme-containing proteins, mostly senescent red cells, and circulates mainly in an unconjugated form bound to albumin. The liver conjugates it, making it water soluble for biliary excretion. ^[1][2] Conjugated bilirubin in bile becomes urobilinogen in the colon, which gives stool its colour. Impaired bile flow (cholestasis) removes urobilinogen and produces pale or clay-coloured stools. ^[1]

Prehepatic (unconjugated) hyperbilirubinaemia is usually due to overproduction (haemolysis, haematoma resorption), decreased hepatic uptake (heart failure, fasting, drugs) or decreased conjugation (Gilbert syndrome, Crigler-Najjar syndrome). ^[4] In haemolysis, bilirubin is rarely pushed above 5 mg per dL unless liver or renal disease or severe acute haemolysis is present, and Gilbert syndrome usually keeps bilirubin under 3 mg per dL even during fasting or stress. ^[1][2] Isolated unconjugated rises under 4 mg per dL in an asymptomatic person with normal enzymes usually do not need investigation beyond excluding haemolysis and hepatotoxic medicines, and a presumptive diagnosis of Gilbert syndrome (prevalence about 3 to 7 percent) can be made. ^[1] Gilbert causes mild, fluctuating jaundice, often made worse by fasting, stress or illness, without liver disease. ^[2]

Hereditary conjugated hyperbilirubinaemias, Dubin-Johnson and Rotor syndromes, raise direct bilirubin to about half of the total while all other liver tests stay normal and the clinical course is benign. ^[1][2] Total bilirubin can exceed 30 mg per dL in severe liver damage (for example alcoholic hepatitis with cirrhosis, or advanced cirrhosis with sepsis and renal failure), while conjugated (delta) bilirubin bound to albumin with a half-life near that of albumin explains prolonged jaundice during recovery from hepatitis or obstruction. ^[1]

In cholestasis, stool loses its colour, urine darkens, pruritus (often worse at night and on the palms and soles) is common, and a prolonged, painless course with weight loss in an older patient suggests malignant obstruction. ^[2][4] Intrahepatic cholestasis can produce pruritus, fat-soluble vitamin (A, D, E, K) deficiencies and hyperlipidaemia. ^[2]

Onset of dark urine marks the start of conjugated (or mixed) hyperbilirubinaemia more accurately than the appearance of visible jaundice. ^[4] Itching from cholestasis can be treated with cholestyramine 2 to 8 g by mouth twice daily, but this is ineffective once there is complete biliary obstruction. ^[4]

When cholestasis is suspected, first confirm a hepatic source of alkaline phosphatase (GGT or 5-prime nucleotidase, or isoenzyme electrophoresis), then image. Right upper quadrant ultrasound should be performed for any alkaline phosphatase elevation; it is safe and has high specificity (95 to 100 percent) for common bile duct stones. ^[1][2] Biliary dilatation indicates an extrahepatic obstruction; a non-dilated system points to an intrahepatic cause. ^[1][2] Ultrasound can miss obstruction in obesity, with bowel gas, or with small lesions, so if it is unremarkable but suspicion remains, proceed to MRI cholangiopancreatography or, where needed, endoscopic ultrasound or endoscopic retrograde cholangiopancreatography. ^[2] CT is more accurate for the level and cause of obstruction (except small stones) but is less sensitive for choledocholithiasis. ^[2] Magnetic resonance cholangiopancreatography has comparable sensitivity and specificity to endoscopic retrograde cholangiopancreatography for diagnosing biliary obstruction and is non-invasive. ^[2]

Serologic leads for intrahepatic cholestasis include antimitochondrial antibody (positive in over 95 percent of primary biliary cholangitis), IgG and anti-neutrophil cytoplasmic antibody for primary sclerosing cholangitis, and IgG4 for the IgG4-related form. ^[1] Primary biliary cholangitis is most common in middle-aged women and presents with fatigue and pruritus; primary sclerosing cholangitis is strongly associated with inflammatory bowel disease and strictures of both intra and extrahepatic ducts. ^[1] Pregnancy testing, review of medicines and supplements, and abdominal imaging belong in every cholestasis work-up. ^[1][2]

Infiltrative and granulomatous disorders (sarcoidosis, tuberculosis, amyloidosis, lymphoma, metastatic or primary liver cancer) often raise alkaline phosphatase out of proportion to aminotransferases and may produce intrahepatic cholestasis, hepatomegaly and sometimes fever. ^[1][2] They enter the differential after obstruction and the common autoimmune diseases have been excluded, frequently requiring liver biopsy, cross-sectional imaging and tissue diagnosis.

Routine liver chemistries cannot tell you how much function remains. Estimating function needs albumin, prothrombin time or INR and, in some centres, individual coagulation factors. ^[1][2]

Albumin falls after processes lasting weeks: its half-life of 19 to 21 days means an acute hepatitis may have entirely normal albumin despite very high transaminases, while an albumin below 3.5 g per dL in the presence of chronic disease or ascites is ominous. ^[1][2] Interpret albumin cautiously, because sepsis, nephrotic syndrome, malnutrition and systemic inflammation also lower it. ^[2]

Prothrombin time is the acute marker: clotting factors II, V, VII, IX and X have short half-lives, so PT or INR prolongs once roughly 70 percent or more of synthetic function is lost. ^[3] Vitamin K deficiency and cholestasis itself prolong PT because factors 2, 7, 9 and 10 are vitamin K dependent; vitamin K deficiency (and steatorrhoea) is the usual explanation when there is no liver disease. ^[1][3] A trial of vitamin K, plus measurement of individual clotting factors (factor V is not vitamin K dependent), helps separate vitamin K deficiency from true hepatocellular failure. ^[1][2] Synthetic failure typically does not appear until clotting factor concentrations fall below about 10 percent of normal. ^[1] Platelet count is a useful marker of advanced fibrosis through portal hypertension. ^[3]

Acute liver failure is defined as rapid development of acute liver injury with severe impairment of synthetic function (prolonged prothrombin time and hepatic encephalopathy) in someone without obvious prior liver disease. ^[1][4] It requires immediate evaluation, whatever the aminotransferase level, and urgent referral to a transplant centre. ^[1] In chronic disease, synthetic failure combines with portal hypertension to produce decompensation (ascites, variceal bleeding, encephalopathy). ^[4] INR is a key component of the Model for End-Stage Liver Disease (MELD) score used to prioritise transplant candidates. ^[2]

The ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries (2017) is the framework used throughout this page, complemented by British Society of Gastroenterology 2018 guidance and the cited reviews. ^[1][3] Its key practical messages are: ^[1]

• Liver chemistries (ALT, AST, alkaline phosphatase and bilirubin) are markers of liver injury, not function, and should be called liver chemistries or liver tests.
• Albumin, bilirubin and prothrombin time are markers of hepatocellular function that extrahepatic factors influence.
• ALT is more specific for hepatic injury than AST.
• An elevated alkaline phosphatase of hepatic origin may be confirmed by GGT or by fractionation of alkaline phosphatase isoenzymes.
• A true healthy normal ALT is 29 to 33 IU per L in males and 19 to 25 IU per L in females.
• Clinicians may rely on local laboratory reference ranges for alkaline phosphatase and bilirubin.
• Borderline, mild, moderate, severe and massive elevations are defined as under 2, 2 to 5, 5 to 15, above 15 and above 10 000 IU per L times the upper limit of normal.
• GGT should not be used as a screening test without abnormal liver chemistries, because it is raised in many non-hepatic conditions.
• Where serology and imaging do not settle the diagnosis, or when staging or multiple diagnoses are possible, biopsy becomes a consideration, sometimes with urgent referral. ^[1]

The guideline also notes that no controlled trial has determined the optimal approach to abnormal liver chemistries, recommendations are graded by evidence strength, and higher or unexplained values demand investigation rather than watchful waiting. ^[1]

• Where abdominal ultrasound is unavailable, rely on the history, examination and basic tests, then refer for imaging patients with jaundice, suspected obstruction, synthetic failure or unexplained persistent enzyme elevation. ^[1][2]
• GGT (or, if possible, 5-prime nucleotidase) can confirm a hepatic origin of an alkaline phosphatase rise; without them, clinical clues (children, pregnancy, recent childbirth, suspected bone disease, blood group O or B after a fatty meal, rickets, fracture) help. ^[1][2]
• Empirical withdrawal of possible offending drugs and alcohol should be followed by repeat testing; treat likely causes such as viral hepatitis or sepsis according to locally available formularies.
• Devices for non-invasive fibrosis assessment may be unavailable; in adults the AST to ALT ratio above 1 still offers a crude clue to advanced fibrosis or cirrhosis. ^[3]
• Pruritus from cholestasis can be treated with cholestyramine 2 to 8 g by mouth twice a day where available, but it does not work in complete biliary obstruction. ^[4]
• Early referral for jaundice with pain, fever or cholangitis is essential, because biliary obstruction with infection needs urgent drainage regardless of available technology. ^[4]

A worthwhile early step is confirming persistence: repeat the panel after withdrawing suspect drugs and alcohol, since up to about 30 percent of asymptomatic elevations resolve within three weeks. Isolated, very mild, unchanged values in a well person can be observed while lifestyle factors are addressed. Persistent or unexplained values above 1.5 to 2 times the upper limit of normal on more than one occasion, unexplained synthetic abnormality, jaundice, symptoms (weight loss, pruritus, pale stools) or any suspicion of obstruction or liver failure warrant further investigation and often referral. ^[2][3]

• "LFTs" are mostly liver injury markers, not function tests; true function is reflected in albumin, prothrombin time or INR, bilirubin and platelet count. ^[1][3]
• Hepatocellular injury (R above 5) raises AST and ALT disproportionately; cholestatic injury (R below 2) raises alkaline phosphatase disproportionately; a mixed picture (2 to 5) raises both; isolated bilirubin with normal enzymes suggests a disorder of bilirubin. ^[1]
• ALT is more specific for liver injury than AST. A high AST with a normal ALT first suggests muscle or cardiac disease. ^[1]
• An AST to ALT ratio above 2 is characteristic of alcohol-associated liver disease, affecting about 90 percent of such patients, whereas in most other diseases ALT is higher than AST. ^[1]
• An AST to ALT ratio above 1 in an adult suggests advanced fibrosis or cirrhosis, even when both values are normal. ^[3]
• Aminotransferase levels above 1000 IU per L demand urgent cause-finding; the highest values suggest acetaminophen toxicity, ischaemic hepatopathy or toxin. ^[1]
• Fibrofatty liver (MASLD) usually produces mild ALT-predominant rises under 300 IU per L; many affected people have normal tests. ^[1]
• Alkaline phosphatase is produced by bone, liver, placenta, intestine and kidney. GGT is absent from bone; an elevated GGT suggests a hepatic source, but it is non-specific. ^[1][2]
• In children, pregnancy and osteoporotic older women, alkaline phosphatase can be raised from bone; in blood groups O and B it rises after a fatty meal. ^[1]
• 5-prime nucleotidase is specific but only about 47 percent sensitive for hepatobiliary disease. ^[2]
• Clinical jaundice appears once bilirubin exceeds about 2.5 to 3 mg per dL; scleral icterus may be visible at 2 to 2.5 mg per dL. ^[2][4]
• Dark urine from bilirubinuria can precede visible jaundice in conjugated hyperbilirubinaemia; pale stools suggest prolonged cholestasis. ^[1][4]
• Prehepatic jaundice is usually unconjugated with normal-coloured stools and no bilirubin in urine; bilirubin is often under 3.5 mg per dL, or under 3 mg per dL in Gilbert syndrome. ^[1][4]
• Ultrasound is the first investigation of cholestasis; dilated ducts mean obstruction (stone, stricture, tumour), non-dilated ducts point to intrahepatic disease (autoimmune, drug, pregnancy, infection, infiltration). ^[1][2]
• Albumin lags by two to three weeks and falls in several non-hepatic illnesses; prothrombin time prolongs once about 70 percent of synthetic function is lost. ^[1][2][3]
• Acute liver failure is severe injury with prolonged PT and encephalopathy in someone without prior liver disease, and requires urgent transplant assessment. ^[1][4]
• Persistence beyond 1.5 to 2 times the upper limit of normal on repeated testing, jaundice or abnormal synthetic tests should prompt specialist referral. ^[2][3]

Planned follow-ons you can look for include viral hepatitis, metabolic dysfunction-associated steatotic liver disease, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, haemochromatosis, Wilson disease, alpha-1-antitrypsin deficiency, gallstone disease and biliary obstruction, alcoholic liver disease, cirrhosis and portal hypertension, acute liver failure, pregnancy-related liver disorders, and hereditary unconjugated and conjugated hyperbilirubinaemias. Links are added once those topics are published.