Chronic Liver Disease

NAFLD

Definition, epidemiology and terminology

Non-alcoholic fatty liver disease is defined by hepatic steatosis in ≥5% of hepatocytes, demonstrated by imaging or histology, in the absence of secondary causes and without harmful alcohol intake, conventionally <30 g/day in men and <20 g/day in women. It spans simple steatosis, non-alcoholic steatohepatitis and progressive fibrosis/cirrhosis. Contemporary nomenclature increasingly uses metabolic dysfunction-associated steatotic liver disease, but MRCP questions commonly retain NAFLD.

NAFLD is the commonest cause of abnormal liver biochemistry in the UK, affecting approximately 25–30% of adults and up to 70–90% of patients with obesity or type 2 diabetes. The major prognostic determinant is fibrosis stage, not aminotransferase level or degree of steatosis. Cardiovascular disease is the leading cause of death; liver-related mortality rises steeply with advanced fibrosis.

Pathophysiology and histological classification

NAFLD reflects insulin resistance-driven lipid flux to the liver: increased adipose lipolysis, de novo lipogenesis via SREBP-1c and ChREBP, impaired mitochondrial β-oxidation, and reduced very-low-density lipoprotein export. Lipotoxic intermediates, particularly free cholesterol, diacylglycerols and ceramides, trigger oxidative stress, endoplasmic reticulum stress, inflammasome activation, hepatocyte ballooning and stellate-cell fibrogenesis through TGF-β and platelet-derived growth factor signalling. Gut dysbiosis, endotoxin-mediated TLR4 activation and genetic variants such as PNPLA3 I148M and TM6SF2 E167K modify susceptibility.

Entity	Key feature	Clinical implication
NAFL/simple steatosis	Steatosis without ballooning injury or lobular inflammation	Lower short-term liver risk, but may progress with metabolic injury
NASH	Steatosis plus hepatocyte ballooning and lobular inflammation, with or without fibrosis	Greater risk of fibrosis progression and hepatocellular carcinoma
Fibrotic NASH	NASH with stage F2–F4 fibrosis	High-risk group targeted in trials and specialist pathways

Assessment and exclusion of competing diagnoses

Biochemistry is insensitive: ALT may be normal even with advanced fibrosis. Typical pattern is mild ALT-predominant transaminitis, though AST may exceed ALT once cirrhosis develops. GGT is often raised. Initial assessment should exclude alcohol-related disease, viral hepatitis B/C, autoimmune hepatitis, haemochromatosis, Wilson disease in younger patients, α1-antitrypsin deficiency where appropriate, coeliac disease, hypothyroidism, and steatogenic drugs such as amiodarone, methotrexate, tamoxifen, corticosteroids and valproate.

Ultrasound detects moderate steatosis with reasonable performance but loses sensitivity when hepatic fat is <20% or BMI is high; it cannot stage fibrosis. MRI-proton density fat fraction quantifies steatosis accurately but is not first-line. Transient elastography estimates liver stiffness; values are method- and population-dependent, but in NAFLD <8 kPa generally suggests low risk of advanced fibrosis, 8–12 kPa indeterminate, and >12–15 kPa suggests advanced fibrosis/cirrhosis. Reliability requires ≥10 valid measurements, success rate >60% and IQR/median <30%.

Risk stratification: exam-relevant scores

Guidelines recommend non-invasive fibrosis stratification in patients with metabolic risk factors or incidentally detected steatosis. FIB-4 is favoured for first-line triage because it uses age, AST, ALT and platelet count. In patients aged 35–65 years, FIB-4 <1.3 has high negative predictive value for advanced fibrosis; ≥1.3 warrants second-line testing such as ELF or transient elastography. In patients aged >65 years, a higher threshold, commonly <2.0 for low risk, reduces false positives.

Test	Components / cut-offs	Use
FIB-4	Age × AST / platelet count × √ALT; low risk <1.3, high risk often >2.67	Primary-care and clinic triage; high NPV, modest PPV
NAFLD fibrosis score	Age, BMI, diabetes/IFG, AST/ALT ratio, platelets, albumin; low risk <−1.455, high risk >0.676	Older validated tool; age confounding
ELF test	Hyaluronic acid, TIMP-1, PIIINP; ≥10.51 suggests advanced fibrosis in NICE pathways	Second-line fibrosis assessment

Management

The core intervention is weight loss and cardiometabolic risk reduction. A sustained ≥5% weight loss improves steatosis, ≥7–10% improves NASH activity, and ≥10% is associated with fibrosis regression. Recommend hypocaloric diet, Mediterranean dietary pattern, avoidance of sugar-sweetened beverages, and aerobic plus resistance exercise; exercise reduces hepatic fat even without major weight loss. Bariatric surgery may be considered according to obesity criteria and can improve NASH, but is not a primary treatment for decompensated cirrhosis.

Pharmacotherapy is targeted to selected patients, especially biopsy-proven NASH with significant fibrosis or coexistent diabetes/obesity. Pioglitazone 30–45 mg once daily improves steatohepatitis and insulin sensitivity; adverse effects include weight gain, oedema, heart failure exacerbation and fracture risk. Vitamin E 800 IU/day improved histological NASH resolution in non-diabetic adults in the PIVENS trial, but concerns include haemorrhagic stroke and possible prostate cancer signal; avoid routine use in diabetes or cirrhosis. GLP-1 receptor agonists are increasingly important: liraglutide in LEAN improved NASH resolution, and semaglutide 0.4 mg daily achieved NASH resolution in 59% versus 17% with placebo in a phase 2 trial, though fibrosis improvement was not statistically significant. SGLT2 inhibitors reduce hepatic fat and improve metabolic outcomes but are not yet licensed specifically for NASH.

Statins are safe in NAFLD, including compensated cirrhosis, and should be prescribed for standard cardiovascular indications; mild transaminase elevation is not a contraindication. Patients with cirrhosis require surveillance for hepatocellular carcinoma and varices, but uncomplicated NAFLD without advanced fibrosis does not.

Alcohol-Related Liver Disease

Pathobiology and Clinicopathological Spectrum

Alcohol-related liver disease (ARLD) is a dose- and susceptibility-dependent continuum comprising simple steatosis, alcohol-related steatohepatitis, progressive fibrosis, cirrhosis and acute alcohol-related hepatitis. A UK alcohol unit contains 8 g ethanol; harmful drinking is commonly defined as >50 units/week in men or >35 units/week in women, although cirrhosis risk rises continuously above approximately 30 g/day. Women develop ARLD at lower cumulative exposure because of lower gastric alcohol dehydrogenase activity, higher body fat proportion and hormonal effects on endotoxin-mediated inflammation.

Ethanol is metabolised predominantly by hepatic alcohol dehydrogenase to acetaldehyde, then by mitochondrial aldehyde dehydrogenase to acetate. Chronic excess also induces CYP2E1, generating reactive oxygen species and increasing susceptibility to paracetamol hepatotoxicity. The increased hepatic NADH:NAD⁺ ratio inhibits β-oxidation and promotes triglyceride synthesis, explaining macrovesicular steatosis. Acetaldehyde forms protein adducts, impairs microtubules, activates stellate cells and promotes collagen deposition. Gut permeability and portal lipopolysaccharide activate Kupffer cells via TLR4, producing TNF-α, IL-1β and IL-8; histology therefore shows hepatocyte ballooning, Mallory-Denk bodies, pericellular “chicken-wire” fibrosis and neutrophilic lobular inflammation.

Diagnosis and Risk Stratification

Typical biochemistry shows AST > ALT, often with an AST:ALT ratio >2, but absolute aminotransferases are usually modest, commonly <300 IU/L; ALT is limited by pyridoxal phosphate deficiency. GGT and MCV are sensitive but non-specific. Synthetic dysfunction, rising bilirubin and thrombocytopenia indicate advanced disease. Biomarkers of recent intake include carbohydrate-deficient transferrin, ethyl glucuronide and phosphatidylethanol; PEth is highly specific and may remain positive for approximately 2–4 weeks.

Clinical entity	Key features	Exam-relevant points
Alcohol-related steatosis	Often asymptomatic; reversible within weeks of abstinence	May occur after short binge exposure; ultrasound detects steatosis poorly below 20–30% fat
Alcohol-related steatohepatitis	Inflammatory injury with ballooning and neutrophils	Can progress despite only modest transaminase elevation
Severe alcohol-related hepatitis	Acute jaundice, systemic inflammation, tender hepatomegaly, decompensation	Clinical diagnosis supported by recent heavy alcohol use, bilirubin >50 μmol/L and AST/ALT usually <400 IU/L

The NIAAA clinical definition of alcohol-related hepatitis requires jaundice developing within the preceding 8 weeks, heavy alcohol use for >6 months with <60 days abstinence before jaundice, typically >40 g/day in women or >60 g/day in men, AST >50 IU/L, AST:ALT >1.5 and both aminotransferases <400 IU/L. Liver biopsy is reserved for diagnostic uncertainty, especially where sepsis, drug-induced liver injury, biliary obstruction or autoimmune hepatitis would alter management.

Severity Scores and Prognosis

Score	Variables	Threshold and interpretation
Maddrey discriminant function	Prothrombin time prolongation and bilirubin	≥32 defines severe disease; historical 28-day mortality approximately 30–50%
Glasgow Alcoholic Hepatitis Score	Age, WCC, urea, PT ratio, bilirubin	≥9 identifies high mortality and potential steroid benefit
MELD	Bilirubin, INR, creatinine, sodium in MELD-Na	≥20–21 commonly denotes severe alcohol-related hepatitis
Lille score	Age, albumin, creatinine, PT, baseline and day-7 bilirubin	>0.45 indicates steroid non-response; stop corticosteroids

Management

The central disease-modifying intervention is complete abstinence, supported by addiction medicine input, motivational interviewing and relapse-prevention pharmacotherapy. In decompensated liver disease, acamprosate is preferred because it is renally excreted; usual dosing is 666 mg three times daily, reduced when eGFR is 30–50 mL/min/1.73 m² and avoided below 30. Disulfiram is generally avoided in liver disease because of hepatotoxicity. Naltrexone may worsen hepatic injury and is avoided in acute hepatitis or decompensated cirrhosis. Baclofen, often 5 mg three times daily titrated to 10 mg three times daily, has trial evidence in cirrhosis but requires caution with encephalopathy and renal dysfunction.

All patients require screening and treatment for alcohol withdrawal, thiamine replacement before carbohydrate administration, and nutritional rehabilitation. Severe ARLD is commonly protein-calorie malnutrition; targets are approximately 35–40 kcal/kg/day and 1.2–1.5 g/kg/day protein, with enteral feeding preferred if oral intake is inadequate. Give parenteral thiamine when Wernicke risk is present, for example Pabrinex according to local protocols, before glucose-containing fluids.

For severe alcohol-related hepatitis without contraindications, use prednisolone 40 mg orally daily for 28 days. Contraindications include uncontrolled sepsis, active gastrointestinal bleeding, acute pancreatitis, uncontrolled diabetes and severe renal failure. Assess response with Lille score at day 7; continuing steroids in non-responders increases infection risk without survival benefit. The STOPAH trial showed prednisolone produced a non-significant trend to reduced 28-day mortality but no benefit at 90 days or 1 year; pentoxifylline showed no survival benefit and is not recommended. N-acetylcysteine combined with prednisolone improved 1-month survival in a French trial but not 6-month survival; it is not universal standard therapy.

Manage complications as for decompensated cirrhosis: ascites, spontaneous bacterial peritonitis, variceal bleeding, encephalopathy, hepatorenal syndrome and hepatocellular carcinoma surveillance. Early liver transplantation may be considered in highly selected steroid non-responders with first presentation, severe disease and robust psychosocial assessment; a fixed 6-month abstinence rule is no longer an absolute requirement in many transplant programmes, although sustained abstinence remains prognostically critical.

Cirrhosis

Cirrhosis is the final common histological pathway of chronic hepatic injury, defined by diffuse bridging fibrosis with regenerative nodules and architectural distortion. The key pathobiology is activation of hepatic stellate cells by inflammatory cytokines, oxidative stress and gut-derived endotoxin, causing excess type I/III collagen deposition, sinusoidal capillarisation, intrahepatic vasoconstriction and increased portal resistance. Portal hypertension then drives splanchnic vasodilatation via nitric oxide, effective arterial underfilling, neurohumoral activation, sodium retention and the complications of decompensation.

Classification and staging

Clinically, cirrhosis is classified as compensated or decompensated. Decompensation is defined by ascites, variceal haemorrhage, hepatic encephalopathy or jaundice, and marks a major prognostic transition: median survival is often >10 years in compensated disease but approximately 2 years after decompensation without transplantation. Portal hypertension becomes clinically significant at a hepatic venous pressure gradient HVPG ≥10 mmHg; variceal bleeding risk rises substantially at HVPG ≥12 mmHg. Normal HVPG is approximately 1–5 mmHg.

Score	Components	Interpretation/exam relevance
Child–Pugh	Bilirubin, albumin, INR/prothrombin time, ascites, encephalopathy	A 5–6, B 7–9, C 10–15. Used for prognosis, operative risk and some drug decisions; 1-year survival roughly 100%, 80%, 45% for A, B, C respectively.
MELD-Na	Bilirubin, INR, creatinine, sodium	Predicts 3-month mortality and prioritises transplant listing. Referral is generally appropriate with decompensation or MELD-Na ≥15.
UKELD	Bilirubin, INR, creatinine, sodium	UK transplant allocation; UKELD ≥49 predicts survival benefit from transplantation.

Diagnosis and assessment

Cirrhosis should be suspected with thrombocytopenia, splenomegaly, low albumin, prolonged INR, nodular liver contour, ascites or stigmata such as spider naevi and palmar erythema. Platelet count is an early surrogate of portal hypertension. Transient elastography is central: liver stiffness >15 kPa strongly suggests compensated advanced chronic liver disease, while >20–25 kPa plus platelets <150 × 10⁹/L identifies patients needing variceal assessment in many pathways. Ultrasound assesses morphology, ascites, splenomegaly and portal vein patency; CT/MRI is used when malignancy, vascular thrombosis or uncertain anatomy is suspected. Liver biopsy is reserved for diagnostic uncertainty or overlapping aetiologies.

Portal hypertension and varices

All patients with cirrhosis should be assessed for varices at diagnosis unless non-invasive Baveno criteria exclude clinically significant risk: liver stiffness <20 kPa and platelets >150 × 10⁹/L allow endoscopy to be deferred. Primary prophylaxis is indicated for medium/large varices or high-risk small varices.

Intervention	Typical regimen	Key points
Propranolol	20–40 mg orally twice daily, titrate to HR 55–60/min if tolerated	Non-selective beta-blockade reduces portal inflow via β1 blockade and splanchnic vasoconstriction via unopposed α activity.
Carvedilol	6.25 mg daily, increase to 12.5 mg/day	Additional α1 blockade lowers intrahepatic resistance; avoid in severe hypotension, refractory ascites or AKI.
Endoscopic band ligation	Repeat every 2–4 weeks until eradication	Alternative when beta-blockers contraindicated or not tolerated.

Acute variceal bleeding requires resuscitation, restrictive transfusion aiming haemoglobin 70–80 g/L unless cardiovascular disease, antibiotics such as ceftriaxone 1 g IV daily for up to 7 days, vasoactive therapy such as terlipressin 2 mg IV every 4–6 h initially, and endoscopy within 12 hours. Early TIPS within 72 hours is considered in Child–Pugh C 10–13 or Child–Pugh B with active bleeding.

Ascites, SBP and renal dysfunction

New ascites mandates diagnostic paracentesis. Serum–ascites albumin gradient SAAG ≥11 g/L indicates portal hypertension. First-line therapy is sodium restriction to approximately <2 g/day sodium and spironolactone 100 mg/day, titrated to 400 mg/day; add furosemide 40 mg/day, titrated to 160 mg/day, maintaining a 100:40 ratio. Safe weight loss is ≤0.5 kg/day without oedema or ≤1 kg/day with oedema. Large-volume paracentesis requires albumin 8 g per litre removed when >5 L is drained.

Spontaneous bacterial peritonitis is diagnosed by ascitic neutrophils ≥250 cells/mm³, irrespective of culture. Treat with cefotaxime 2 g IV every 8 h or ceftriaxone, plus albumin 1.5 g/kg day 1 and 1 g/kg day 3 in high-risk patients, reducing renal failure and mortality. Secondary prophylaxis is norfloxacin 400 mg daily or ciprofloxacin 500 mg daily, depending on local resistance policy. Hepatorenal syndrome is functional renal failure in advanced cirrhosis; management includes stopping diuretics/nephrotoxins, albumin expansion and vasoconstrictors, with transplantation definitive.

Hepatic encephalopathy, surveillance and prognosis

Hepatic encephalopathy results from impaired ammonia detoxification, portosystemic shunting, astrocyte glutamine accumulation and neuroinflammation. Precipitants include infection, gastrointestinal bleeding, constipation, sedatives, hypokalaemia, renal failure and excess diuresis. Lactulose is titrated to 2–3 soft stools/day; rifaximin 550 mg twice daily reduces recurrence when added after at least one overt episode. Avoid benzodiazepines and unnecessary opioids.

Cirrhosis requires structured surveillance: ultrasound for hepatocellular carcinoma every 6 months, with or without alpha-fetoprotein depending on local guidance; AFP alone is insufficient. Vaccinate against hepatitis A/B if non-immune, pneumococcus and influenza; assess osteoporosis, malnutrition and sarcopenia. Decompensation, MELD-Na ≥15, recurrent variceal bleeding, refractory ascites, SBP, hepatorenal syndrome or HCC within transplant criteria should prompt early transplant referral. In exams, never regard “normal transaminases” as excluding cirrhosis: synthetic function, platelets, imaging and portal hypertensive complications are more prognostically important.