Abnormal LFTs can indicate a spectrum of conditions, from benign and reversible to significant underlying pathology.

Whether it’s incidental transaminitis in someone with metabolic risk factors, an isolated ALP elevation in an otherwise well patient, a cholestatic picture that ultimately reveals malignancy, or a delayed drug‑induced liver injury, the key to diagnosing and managing these conditions lies in recognising the pattern of derangement.

Liver function tests are a misnomer

The term liver function test (LFT) is misleading, because most tests included in a standard LFT panel do not actually measure liver function. They are valuable for detecting hepatobiliary pathology and identifying whether the issue lies in the hepatocytes or the biliary tree, but true markers of liver function are limited to bilirubin, albumin, INR and platelets. Platelets also act as a surrogate marker for portal hypertension, reflecting splenic sequestration as well as reduced thrombopoietin production by the liver.

Recognising the pattern of LFT derangement

When LFTs are abnormal, the first step is to recognise the pattern:

• A hepatocellular pattern, where ALT is typically more than three times higher than ALP
• A cholestatic pattern, where ALP is higher than ALT
• A mixed pattern
• Isolated hyperbilirubinaemia

Patterns can change over time. For example, a hepatocellular pattern may evolve into cholestasis during recovery. It is also important to determine whether the abnormality is acute, chronic, or acute on chronic, which requires more than one set of LFTs.

Causes of abnormal LFTs

Hepatocellular abnormalities

ALT is the most specific marker of hepatocyte damage. The most common causes include:

• Metabolic dysfunction–associated fatty liver disease (MAFLD); typically causes chronic elevation of transaminases and GGT rather than acute changes.
• Alcohol usually produces an AST that is twice the ALT.
• Drug‑induced liver injury (DILI)
• Viral hepatitis

Less common but important causes include autoimmune hepatitis, haemochromatosis, Wilson’s disease, alpha‑1 antitrypsin deficiency, coeliac disease, liver lesions, ischemia and muscle breakdown. Ischemia from any cause, such as hypoperfusion or shock, produces very high transaminases that recover rapidly. Muscle injury, including rhabdomyolysis, myositis or intense exercise, can also elevate AST and ALT; pairing results with creatine kinase (CK) or repeating tests after 3–7 days of rest can help clarify that diagnosis.

When transaminases exceed 10 times the upper limit of normal, consider ischemia, acute viral hepatitis or drugs, especially paracetamol which can cause massive hepatic necrosis. Less common causes include acute Budd–Chiari syndrome, fulminant Wilson’s disease and haemophagocytic lymphohistiocytosis (HLH).

Cholestatic abnormalities

ALP is the most specific marker of cholestasis or biliary damage, often accompanied by elevated GGT and bilirubin. Causes include biliary obstruction (stones, strictures, malignancy), cholestatic liver diseases such as PBC and PSC, and infiltrative conditions including primary or secondary malignancy, lymphoma, sarcoidosis, amyloidosis and TB. Medications and hepatic congestion are also important causes.

ALP is also found in bone, and to a lesser extent, kidney, intestine, and placenta. An isolated elevated ALP may reflect vitamin D deficiency (due to stimulation of parathyroid hormone and release of calcium from bone), bony metastases or Paget’s disease. If isolated elevated ALP < 200, retest in 3 months, but if > 200, check bone isoenzyme and vitamin D level.

Mixed and isolated abnormalities

A mixed picture is typically seen with alcohol or DILI.

Isolated elevated bilirubin can reflect either conjugated or unconjugated fractions, and this distinction shapes the differential diagnosis. Unconjugated hyperbilirubinaemia is most commonly due to Gilbert syndrome, a benign condition affecting around 5–8% of the population, where bilirubin rises in response to concurrent illness, fasting or physiological stress. It’s still important to exclude haemolysis by checking lactate dehydrogenase, reticulocytes and haptoglobin, and to consider biliary obstruction as a less common cause. When the isolated bilirubin elevation is predominantly conjugated (>50% of total bilirubin), it points toward cholestasis or hepatocellular disease.

Quick pattern-recognition guide:

• ↑AST > ALT → alcohol
• ↑ALT > AST → viral or metabolic causes
• ↑ALP + ↑GGT → liver or biliary pathology
• Isolated ↑ALP → bone-related
• Isolated ↑GGT → liver/biliary, alcohol or drugs including OCP and anticonvulsants

Metabolic dysfunction-associated fatty liver disease

MAFLD is becoming increasingly prevalent and typically causes chronic elevation of transaminases and GGT. Diagnosis requires evidence of both metabolic dysfunction and hepatic steatosis, with alternative causes excluded.

In Australia, metabolic dysfunction is defined as type 2 diabetes, BMI ≥25, or two of central obesity, hypertension, high triglycerides, low HDL or prediabetes. The recommended first-line investigation to diagnose steatosis is a liver ultrasound given its reasonable sensitivity and specificity, wide availability, and low cost. But the diagnosis of steatosis can also be made with CT, MRI, FibroScan, or less commonly, liver biopsy.

It’s also important to exclude alternative causes of elevated transaminases, such as viral hepatitis, excess alcohol and haemochromatosis, as well as other causes of steatosis, such as medications including steroids, methotrexate, antipsychotics, valproate, amiodarone and tamoxifen, or hepatitis C genotype 3.

Once MAFLD is diagnosed, fibrosis staging is essential. This consensus statement includes flow chart showing the pathways when assessing patients with MAFLD.

FIB‑4 is a simple tool based on age, platelets and transaminases:

• <1.3 rules out advanced fibrosis; repeat in 2–3 years
• 1.3–2.7 requires second line confirmatory testing with elastography (FibroScan or shear wave) or a blood‑based test such as ELF or Hepascore
• >2.7 or elastography showing advanced fibrosis warrants hepatology referral

There is currently no MBS reimbursement for second line tests, and evidence for shear wave elastography in MAFLD is more limited than for FibroScan, although availability may guide choice.

Alcohol‑associated liver disease

Alcohol is a common cause of liver disease and presents across a spectrum of severity, from steatosis, to fibrosis, and cirrhosis. Assessing the level of fibrosis helps determine where a patient sits on that spectrum. Signs include AST predominance, elevated GGT, elevated MCV and pancytopenia from marrow suppression.

Acute alcohol‑related inflammation can falsely elevate fibrosis scores, including elastography results, so ultrasound is useful for identifying cirrhosis and portal hypertension. Alcohol‑associated hepatitis is a distinct condition that requires consideration of hospitalisation and specific treatments such as corticosteroids if the presentation is severe, determined by MELD score >21 or Maddrey’s discriminant function >32.

Viral hepatitis

Viral hepatitis can present acutely with malaise, right upper quadrant pain, nausea, vomiting and fevers. Viruses that can cause acute hepatitis include hepatitis A–E, CMV, EBV, HSV, varicella, HIV and syphilis. Adenovirus and dengue are also possible causes.

Chronic hepatitis occurs only with hepatitis B, hepatitis C, and hepatitis D (which occurs exclusively in those already infected with hepatitis B).

Drug‑induced liver injury (DILI)

DILI can be divided into two broad categories:

• Idiosyncratic: unpredictable, not dose-related, and can occur with a wide range of medications such as antibiotics
• Intrinsic: more predictable and related to hepatotoxicity of a medication such as paracetamol overdose

Common culprits can cause either hepatocellular or cholestatic injury depending on the agent. Livertox is a useful resource summarising recognised patterns of DILI for different medications.

Patterns of DILI:

• Hepatocellular: paracetamol, allopurinol, anti-tuberculosis medications (e.g. isoniazid), antifungals (e.g. ketoconazole), antibiotics (tetracyclines), anti-seizure drugs (e.g. valproate and phenytoin), antidepressants (e.g. fluoxetine), pyrazinamide, rifampicin, statins, antipsychotics (e.g. risperidone), antivirals (e.g. valaciclovir, ritonavir)​
• Cholestatic: anabolic steroids, NSAIDs, tricyclic antidepressants, antibiotics (e.g. azithromycin, amoxicillin, rifampicin, trimethoprim-sulfamethoxazole)

Autoimmune hepatitis

Autoimmune hepatitis requires consideration because immunosuppression is needed to prevent progression. Typical autoimmune panel findings include elevated ANA, liver kidney microsomal antibody, smooth muscle antibody and IgG. It is more common in females than males, in people with other autoimmune conditions and in those with a family history. It can also be triggered by drugs such as statins.

Hereditary haemochromatosis

Hereditary haemochromatosis is an iron overload syndrome that requires venesection for treatment. A transferrin saturation above 45% on two occasions warrants HFE gene testing with C282Y homozygosity confirming diagnosis. Compound heterozygotes (C282Y/H63D) and those with H63D alone are at low risk of iron overload unless cofactors such as fatty liver or viral hepatitis are present. Secondary haemochromatosis may occur due to high iron intake or frequent blood transfusions.

Wilson’s disease

Wilson’s disease is an autosomal recessive disorder causing copper deposition in the liver, brain and other tissues. It is fatal if not recognised and treated early. Diagnostic features include a low serum caeruloplasmin, elevated urinary copper, and Kayser-Fleischer rings on slit-lamp examination (though these may be absent). Liver biopsy demonstrating hepatic copper excess is confirmatory.

Diagnostic approach

The first step is to repeat the LFTs to confirm the abnormality and assess whether values are rising or falling. Then determine the pattern (hepatocellular, cholestatic, mixed, or an isolated elevated bilirubin), medication timeline, and chronicity (acute, chronic, or acute on chronic).

Medical history

When taking the patient history, key areas for inquiry include alcohol consumption, personal and family history of metabolic risk factors, inherited conditions, and autoimmune conditions (including type 1 diabetes, rheumatoid arthritis, and coeliac disease). Establish risk factors for viral hepatitis, ​particularly birth in an endemic country, as well as vaccination status​, travel history​, sexual contact​, injecting drug use​, tattoos ​and incarceration.

It’s important that discussions of drug history go beyond prescribed medications to include any drugs given during hospitalisation or at discharge, periprocedural antibiotics, over-the-counter medicines, herbal preparations, traditional medicines, supplements, vitamins, and illicit substances.

Examination

Examination findings may point to the underlying aetiology, such as features of metabolic risk, or injecting sites or tattoos suggesting viral hepatitis risk. Charcot’s triad (fever, right upper quadrant pain and jaundice) suggests cholangitis but may also occur in hepatitis, cholecystitis or hepatic abscess. Peripheral stigmata of chronic liver disease include muscle wasting, spider naevi, palmar erythema, and gynaecomastia. Signs of decompensation include jaundice, ascites, peripheral oedema, and hepatic flap.

Investigations

Initial investigations include a liver screen, which is tailored to the clinical picture. This typically includes:

• Metabolic assessment should include fasting glucose, lipids, and HbA1c
• Viral hepatitis serology selected based on whether the patients’ condition is acute or chronic
• PEth (phosphatidylethanol) indicates the amount of alcohol consumption over the preceding 30 days (although access to this test is limited in some states)
• Autoimmune serology may be considered where clinically relevant
• Iron studies ± HFE gene testing if transferrin saturation is persistently 45% or above.

In the context of a persistent unexplained abnormality or high pre-test probability, also consider copper, caeruloplasmin, alpha-1 antitrypsin level, and coeliac serology.

Imaging

Abdominal ultrasound is the standard first-line imaging modality. Contrast enhanced CT or MRI should be considered if liver lesions are identified. MRCP may be appropriate if ductal dilatation or unexplained cholestasis is present, and referral to a specialist may be considered to access the MBS rebate for this imaging.

Biopsy

Consider liver biopsy when non-invasive investigations have not yielded a clear diagnosis and the result would change management, for example to confirm or exclude specific conditions such as autoimmune hepatitis.

Referral

Refer to specialist if any of the following are present:

• Evidence of liver failure (encephalopathy, elevated INR, or significantly elevated bilirubin); these patients typically require hospital admission)
• Rapidly rising transaminases
• Abnormal LFTs with new systemic symptoms such as weight loss, nausea, or anorexia
• Abnormal LFTs in pregnancy
• Established or suspected cirrhosis

Any diagnosis that requires management beyond primary care scope, or cases with an unknown aetiology where further diagnostic clarification is needed, should also prompt specialist referral.

Key takeaways

• Most LFTs do not measure liver function; bilirubin, albumin, INR and platelets do
• Pattern recognition (hepatocellular, cholestatic, mixed, isolated elevated bilirubin) guides the differential
• MAFLD and alcohol are the most common causes of chronic abnormal LFTs
• Very high transaminases (>10× ULN) narrow the differential to a small group of serious conditions such as ischemia, acute viral hepatitis or drug-related hepatic necrosis
• Always repeat abnormal LFTs and assess the trend before extensive investigation
• Refer early when there is liver failure, rapid progression, pregnancy‑related abnormalities or suspected advanced fibrosis