Disclaimer

Educational overview for clinicians and informed readers; not individual medical advice.

Following my recent entry regarding LFT’s I though I follow this up with this blog entry:

Why these three markers matter

“Liver function tests” (LFTs) are misnamed: ALT and ALP are primarily injury/excretory markers, while bilirubin reports excretory capacity and, when high, overall severity; synthetic function is better reflected by albumin and INR.

UK practice follows the British Society of Gastroenterology (BSG) guideline on abnormal liver blood tests: classify the pattern as hepatocellular, cholestatic, or mixed (often via the R-ratio) and then investigate accordingly (Newsome et al., 2018).

The core physiology and why levels rise

ALT (alanine aminotransferase)

A cytosolic hepatocyte enzyme catalysing transamination; serum ALT rises when hepatocyte membranes are disrupted by necrosis/apoptosis or significant inflammatory injury. ALT can reach thousands in acute viral, ischaemic or drug‑induced injury; in chronic disease ALT may be modest, and in advanced cirrhosis it may fall as hepatocyte mass declines (Newsome et al., 2018).

ALP (alkaline phosphatase)

Hepatic ALP is concentrated on canalicular membranes and cholangiocytes. Impaired bile formation/flow (cholestasis) increases gene expression and regurgitation of ALP into blood; parallel GGT elevation supports hepatobiliary origin rather than bone (Newsome et al., 2018).

Bilirubin

Heme catabolite trafficked to liver as unconjugated bilirubin (albumin‑bound), conjugated by UGT1A1, and excreted into bile as conjugated bilirubin. Elevations reflect increased production (pre‑hepatic), impaired conjugation (hepatic), or impaired canalicular excretion/obstruction (intra/post‑hepatic). Conjugated bilirubin is water‑soluble and appears in urine (bilirubinuria) (Newsome et al., 2018).

Disease‑specific patterns you will actually see in UK clinics

NAFLD and NASH (UK – NICE NG49/NG50)

Pattern: Classically hepatocellular with ALT ≥ AST and only mild–moderate elevations (often <3× ULN). As fibrosis progresses, ALT may “normalise” and AST can overtake ALT; platelets fall with portal hypertension. Bilirubin is usually normal until advanced disease; ALP is typically normal or only mildly raised unless there is overlap cholestasis (Newsome et al., 2018).

Mechanisms: Lipotoxicity, oxidative stress, mitochondrial dysfunction and innate immune signalling drive hepatocellular injury and hence ALT rise; GGT often increases from microsomal induction.

UK pathway: NICE NG49 mandates non‑invasive fibrosis risk‑stratification: start with FIB‑4; if indeterminate/high‑risk, do ELF (Enhanced Liver Fibrosis). ELF ≥10.51 supports advanced fibrosis and prompts elastography/secondary care. Normal LFTs do not exclude NAFLD and must not be used to rule it out. NICE NG50 then governs confirmation of cirrhosis, surveillance and complication prevention (NICE, 2016a; NICE, 2016b).

Somerset/BNSSG: Somerset FT’s Abnormal LFT Algorithm (Sept 2025) operationalises FIB‑4 → ELF → elastography/referral locally; BNSSG ICB’s early‑2025 updates (now using MASLD terminology) mirror the same logic and remind that normal LBTs do not rule out liver disease.

ARLD (Alcohol‑related liver disease)

Pattern: AST:ALT >2:1 (often AST/ALT <300), high GGT; macrocytosis is common. Bilirubin rises in alcoholic hepatitis or decompensation; ALP may be modestly raised, but a markedly cholestatic picture warrants imaging for obstruction or alcoholic cholestasis (Parker et al., 2023).

Mechanisms: Acetaldehyde adducts, oxidative stress and mitochondrial injury preferentially elevate AST and induce GGT; severe alcoholic hepatitis causes conjugated hyperbilirubinaemia and coagulopathy.

UK pathway: BSG and UK quality standards advise non‑invasive fibrosis assessment in hazardous drinkers (≥50 units/week men, ≥35 units/week women) regardless of modest enzyme elevations; jaundiced/unwell patients need admission, severity scoring (e.g., mDF, MELD) and protocolised care. Once cirrhosis is diagnosed, follow NICE NG50.

Somerset/BNSSG: Local algorithms direct elastography/fibrosis staging in hazardous drinkers and advise using the Abnormal Liver Blood Test Algorithm alongside ARLD/MASLD pages.

Gallstone disease (cholelithiasis, choledocholithiasis, acute biliary obstruction)

Pattern: Cholestatic—ALP and GGT rise prominently; conjugated bilirubin increases if obstruction is sustained. Transaminases (particularly ALT) may transiently spike early in acute obstruction or gallstone pancreatitis, sometimes creating a mixed picture before settling into a cholestatic pattern. Marked cholestasis with pain/jaundice mandates urgent evaluation for common bile duct (CBD) stones (NICE CG188; Williams et al., 2017).

Mechanisms: Mechanical obstruction raises canalicular pressure, injures cholangiocytes and impairs excretion of conjugated bilirubin; ALP expression is upregulated and regurgitates into blood. If obstruction clears (stone passes), bilirubin/ALP fall; persistent obstruction risks ascending cholangitis.

UK diagnosis & treatment: Initial imaging is abdominal ultrasound to assess stones and duct dilatation; MRCP or EUS if suspicion persists without clear ultrasound findings.

Definitive therapy for CBD stones is stone extraction—most commonly ERCP with sphincterotomy—per BSG guidance; laparoscopic bile duct exploration is an alternative in surgical pathways.

Gallbladder management is laparoscopic cholecystectomy for symptomatic stones (timing expedited after biliary colic/cholecystitis or post‑ERCP). Cholangitis requires urgent antibiotics and biliary decompression (ERCP).

Red flags and when to escalate now

ALT >1000 U/L, bilirubin >100 µmol/L, rising INR, encephalopathy, or a cholestatic pattern with duct dilatation → urgent hepatology/surgical assessment (Newsome et al., 2018; NICE CG188).

In suspected alcoholic hepatitis (jaundice/systemic inflammation), admit for severity scoring (e.g., mDF, MELD) and follow UK quality‑standard protocols (Parker et al., 2023).

Suspected cholangitis (Charcot triad ± hypotension/confusion) requires antibiotics and urgent biliary drainage (ERCP).

Practical UK workflow (with Somerset specifics)

1) Confirm persistence/pattern: repeat LFTs, compute R‑ratio (Newsome et al., 2018).

2) History/exam: alcohol (units/week), metabolic syndrome, drugs/herbals, red flags.

3) Baseline “chronic liver screen” per BSG: hepatitis serology, autoimmune markers, ferritin/transferrin saturation ± coeliac/thyroid where indicated.

4) Imaging: ultrasound first‑line; MRCP/EUS if obstruction suspected but US equivocal (NICE CG188).

5) NAFLD/NASH route: FIB‑4 in primary care → ELF if indeterminate/high → elastography or specialist referral. Somerset FT (Sept 2025) and BNSSG (Feb/Mar 2025) PDFs provide thresholds/ordering details (NICE NG49/NG50).

6) ARLD route: hazardous drinkers get fibrosis assessment (transient elastography) even with modest enzyme rises; if jaundiced/unwell, admit for protocolised care.

7) Gallstones: RUQ pain + cholestatic LFTs → US; if CBD stone likely/confirmed, ERCP stone extraction then cholecystectomy to prevent recurrence.

Take‑home messages

ALT tracks hepatocellular injury; ALP/GGT signal cholestasis; bilirubin reflects excretory failure and severity. Pattern recognition is step one (Newsome et al., 2018).

NAFLD/NASH usually give mild hepatocellular derangement (ALT≥AST) and can have normal LFTs despite fibrosis; risk‑stratify with FIB‑4 → ELF → elastography (NICE NG49/NG50; Somerset/BNSSG).

ARLD shows AST>ALT with high GGT; assess fibrosis in hazardous drinkers and admit jaundiced/unwell for severity‑driven care (Parker et al., 2023).

Gallstones/CBD stones cause cholestatic LFTs (ALP/GGT, conjugated bilirubin), with possible early ALT spike; manage with ERCP extraction and cholecystectomy per NICE/BSG (NICE CG188; Williams et al., 2017).

References

BNSSG ICB (2025) Liver disease (Hepatology) primary‑care resource. Updated 27 Feb 2025. Available at: BNSSG Remedy (accessed 9 Oct 2025).

NICE (2016a) Non‑alcoholic fatty liver disease (NAFLD): assessment and management (NG49). Last reviewed 24 Oct 2024. London: National Institute for Health and Care Excellence. Available at: NICE NG49 (accessed 8 Oct 2025).

NICE (2016b; updates 2023) Cirrhosis in over 16s: assessment and management (NG50). London: National Institute for Health and Care Excellence. Available at: NICE NG50 (accessed 5 Oct 2025).

NICE (2014) Gallstone disease: diagnosis and management (CG188). London: National Institute for Health and Care Excellence. Available at: NICE CG188 (accessed 10. Oct 2025).

Newsome, P.N. et al. (2018) Guidelines on the management of abnormal liver blood tests, Gut, 67(1), 6–19.

Parker, R. et al. (2023) Quality standards for the management of alcohol‑related liver disease, BMJ Open Gastroenterology, 10(1), e001221.

Somerset NHS Foundation Trust (2025) Somerset Algorithm for Abnormal LFTs (Sept 2025). Taunton: Somerset FT Gastroenterology.

Williams, E. et al. (2017) Updated guideline on the management of common bile duct stones (CBDS), Gut, 66(5), 765–782.