Pathophysiology: jaundice is caused by excess circulating bilirubin, a breakdown product of haem with levels >50 μmol/L when it becomes detectable clinically (normal <17 μmol/L). Seen most easily in pale skin in good light or in the scleral part of the eye. It may be seen in 3% of population as Gilbert’s syndrome. It must be viewed in clinical context. It is included here as a sign of liver function. Is the patient toxic and unwell, is there pale stool and dark urine, wasting, cachexia and likely cancer? Bilirubin is conjugated with glucuronate within the liver so pre-hepatic is excess unconjugated form. Excreted in urine and faeces and gives them their distinctive yellow and brown colours, respectively. Look for IV drug use, alcohol, toxins, all drugs, history of gallstones, pregnancy. Most commonly the question is whether it is hepatic or post-hepatic and the most critical test is abdominal USS. Severe liver damage causes loss of synthetic function making procoagulant: fibrinogen, prothrombin, factors V, VII, IX, X and XIII. Anticoagulant proteins C and S. NOT gammaglobulins. Antithrombin, transferrin and caeruloplasmin. Albumin t1/2 about 20 days. Glucose homeostasis – controlling blood sugar.

About: Fulminant hepatic failure is where encephalopathy develops in under 2 weeks with a previously normal liver. Prothrombin time is a useful marker of synthetic function. Take an accurate drug history including over the counter and herbal remedies. Classification based on time from appearance of jaundice to developing encephalopathy. Hyperacute <1 week: usually paracetamol or viral. There is massive necrosis and loss of function. Acute <4 weeks: viral, drugs, others. Subacute 12 weeks: viral, drugs, others.

• Clinical: history of drug/toxin exposure key. Encephalopathy: flapping tremor, poor concentration. Reversal of day/night cycle, jaundice usually but not always – date when first appeared, bleeding and coagulopathy. Hypoglycaemia, fetor hepaticus, look for Kayser–Fleischer rings. RUQ tenderness, NO splenomegaly or ascites, exception is Budd–Chiari syndrome.
  
• Identify likely precipitants of acute on chronic decompensation: sepsis, spontaneous bacterial peritonitis, fluid overload, albumin. Transjugular intrahepatic porto-systemic shunt, renal failure, CNS suppressants. Electrolyte abnormalities, diuretic overuse, GI bleeding.
  
• Clinical: reversal of day/night sleeping, psychomotor dysfunction, impaired memory. Sensory abnormalities, poor concentration, disorientation, tremor, shuffling gait. Melena, haematemesis. Fetor hepaticus, flapping tremor, asterixis. See Encephalopathy Section 7.11.
  
• Investigations: FBC: ↑WCC, ↑ESR, ↑CRP, ↓platelets (alcohol, HELLP). Haemolysis in Wilson’s disease: ↓Hb, ↑reticulocytes, ↑LDH. ↑Prothrombin time. ↑Bilirubin: elevated unconjugated. LFT: ↑AST, ↑ALT often >1000 (transaminases fall eventually). U&E: ↑creatinine. Check paracetamol levels and salicylates. VBG: metabolic acidosis and ↑arterial lactate and arterial ammonia. Viral serology: anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV, EBV, CMV, HSV, HIV, anti-HCV( rare cause). Others: paracetamol level, caeruloplasmin and 24 h urine copper, ammonia levels. Autoimmune: ANA, anti-smooth muscle actin, anti-liver/kidney microsomal antibodies and immunoglobulins. USS doppler: liver size and pathology, and hepatic veins for Budd–Chiari syndrome. Miscellaneous: pregnancy test. ANA, anti-smooth muscle, immunoglobulin, HIV status. NB. Focal neurology not typical and suggests need for CT brain.
  
• Management: stop all potentially implicated drugs. Regard all as potentially hepatotoxic if no other evident cause. Consider N-acetyl cysteine (NAC) infusion – possibly useful in both paracetamol and non-paracetamol ALF. Supportive: ABCs and O2 to get and maintain sats >92% and admit to an HDU/ITU environment.
  
• Hypovolaemia/↓BP: cross-match blood and transfuse if bleeding or anaemia. 4.5% human albumin solution is the colloid of choice to elevate CVP to 10 cmH2O or until clinically euvolaemic. G5 if fluids needed (but can worsen hyponatraemia). Give 100 ml 20% human albumin solution per 2.5 L of ascites during paracentesis, or if SBP. Avoid NS (worsens fluid overload).
  
• Hypoglycaemia: stat dose 20 ml 50% IV GLUCOSE and then 10% GLUCOSE infusion as needed. GLUCAGON 1 mg has limited effectiveness if no liver glycogen. Section 5.2.
  
• Low K, phosphate, magnesium: replace as needed (Sections 5.4, 5.12, 5.14).
  
• Hyponatraemia: may need hypertonic 3% saline. Section 5.10.
  
• PABRINEX IV ×2 TDS for 1–2 days. Provide thiamine if alcoholic or malnourished. If suspected Wernicke’s syndrome give for 7 days to prevent Korsakoff psychosis. Give before any nutrition/IV glucose. Long term THIAMINE 100 mg TDS PO.
  
• Cerebral oedema: nurse at 20° head elevation. Consider intubation and hyperventilation to reduce PCO2. MANNITOL 200 ml of 20% (20 g/100 ml) IV over 20–30 min and can be repeated.
  
• Stress ulcer prevention: start IV PPI or RANITIDINE 150 mg BD PO.
  
• Antivirals: ACICLOVIR for HSV or VZV and GANCICLOVIR for CMV.
  
• Antibiotics: low threshold to treat any infection. Bacterial and fungal. Impaired immunity. Treat if encephalopathy. TAZOCIN IV is often first line.
  
• Coagulopathy: VITAMIN K 2–5 mg slow IV, 2–4 units FFP, platelets if <50 × 109/L and bleeding. VITAMIN K replaces any deficit so any resulting coagulopathy is entirely due to reduced liver function.
  
• Hepatic encephalopathy: avoid the use of FFP unless actively bleeding. FFP renders the PTT (a vital prognostic marker) less useful. Give LACTULOSE 20 ml BD +/− enemas to ensure three bowel movements per day. Use phosphate enemas if unsuccessful. Section 7.11.
  
• Ascites and spontaneous bacterial peritonitis, Section 7.9.
  
• Acidosis: take expert advice and consider IV NaHCO3. A pH <7.3 at >24 h after paracetamol overdose is a poor prognostic indicator.
  
• Renal failure and AKI common with ALF and may require haemofiltration or haemodialysis. Section 10.4.

• About: the aim of the liver clinician is to keep the patient alive long enough to allow them to benefit from alcohol cessation (Hazeldine, et al., 2015).
  
• Acute liver dysfunction with jaundice in known alcoholic. Poor prognosis. Discriminant function >32 implies >50% mortality at 1 month. Reversible if patients are non-cirrhotic. The term hepatitis is a misnomer as transaminases (AST and ALT) are marginally elevated.
  
• Causes: acute exacerbation in known alcohol abuser. Look out for SBP. Quantity of alcohol ingested is not always directly proportional to risk of liver disease. Steatohepatitis (fat + hepatocellular injury + inflammation +/− fibrosis). Loss of liver function.
  
• Clinical: pyrexia, ↑HR, jaundice, encephalopathy, anorexia. Hepatomegaly (tender), abdominal discomfort, nausea, worsening ascites. Alcoholic neuropathy, cerebellar degeneration, cardiomyopathy, AF. Evidence of hepatitis B/C/HIV infection.
  
• Aetiology: polymorphs + necrosis in zone 3. Mallory bodies seen but non-specific.
  
• Investigations: FBC, U&E, LFT: ↑WCC, ↑reticulocytes (haemolysis suggests Zieve’s syndrome), ↑CRP, ↑bilirubin, AST, ALT (usually <200 and rarely ever >400 U so not a severe biochemical ‘hepatitis’).
  
• Abdominal USS: hepatomegaly, coarse edge, increased echogenicity, free fluid.
  
• Ascitic tap: if spontaneous bacterial peritonitis suspected – neutrophil count >250 cells/mm3. Infection seen in 10%. Transudate total protein <30 g/L, e.g. cirrhosis, CCF/RHF, nephrotic syndrome. Exudate has a total protein >30 g/L, e.g. cancer, infection, TB.
  
• Specialist tests: ‘Hepatic screen’: immunoglobulins, anti-mitochondrial antibody, anti-smooth muscle antibody; ANA/dsDNA; ferritin (↑ in acute illness, check iron studies and transferrin saturation), caeruloplasmin (if <45 y); αFP; anti-HA IgM, HBsAg, anti-HCV ± EBV, CMV ± tumour markers (CA125, CA15-3, CA19-9, CEA, AFP) ± haptoglobin/LDH (haemolysis).
  
• Liver biopsy: histological confirmation is required where there is uncertainty about the diagnosis. 25% of presumed alcoholic hepatitis not confirmed on histology. Trans-jugular biopsy is required if coagulopathy.

Severity scorings to determine prognosis and need for abstention

• Several prognostic scores are available but the most practical one to assess severity is the Glasgow Alcoholic Hepatitis score (GAHS, see table below ). This predicts 28 day and 3 month mortality and can be used as a guide for treatment with corticosteroids or Pentoxifylline. It has an overall accuracy of 81% in predicting 28 day mortality.

• Management: supportive. Long-term abstinence from alcohol – refer to appropriate support on discharge. Management is supportive care to allow liver regeneration without additional ‘toxin’ exposure. Nutrition must be maintained with enteral feeding if required. Manage alcohol withdrawal, complications of portal hypertension, ascites, encephalopathy, variceal haemorrhage. PABRINEX IV paired vials TDS for 1–2 days + IV VITAMIN K. Commence and continue THIAMINE 200 mg PO OD. Signs of agitation of alcohol withdrawal consider CHLORDIAZEPOXIDE PO or DIAZEPAM PO.
  
• Active treatment: the role of steroids has been questioned by the STOPAH trial. However, some may consider in those with GAHS ≥9 (severe alcoholic hepatitis) either PREDNISOLONE 40 mg od for 28 days (reassess at 7 days) or PENTOXIFYLLINE 400 mg PO TDS for 28 days. Take local expert advice as some continue to use. If advice is to give steroids ensure all infection is excluded/treated. NAC has also failed to improve 6 month survival. Reassess at day 7 to decide on continuing steroid/Pentoxifylline therapy.
  
• Severe liver dysfunction: liver failure (INR >2, albumin <30, encephalopathy) discuss with local or regional liver centre. In those with decompensated cirrhosis or alcoholic hepatitis then any rise in creatinine by 50% must be met with stopping diuretics and nephrotoxins with plasma expansion with albumin (see Section 7.11 on hepatorenal syndrome) and renal advice. If signs of encephalopathy give LACTULOSE 20 ml 12 h +/− enemas to ensure two bowel movements per day. Section 7.11.
  
• Best supportive care involves access to 24 h endoscopy, expert fluid management, variceal banding and TERLIPRESSIN 2 mg 4 h for bleeding and early active management of sepsis – the commonest cause of death.
  
• Antibiotics: broad spectrum antibiotics indicated for variceal bleeding. Prophylactic antibiotics after SBP such as NORFLOXACIN or CIPROFLOXACIN should be considered.
  
• Early transplantation: consider with severe alcoholic hepatitis because it reduces mortality, though some will go back to alcohol.

References: European Association for the Study of the Liver (2010) EASL clinical practice guidelines. J Hepatol, 533:97. Hazeldine et al. (2015) Alcoholic liver disease – the extent of the problem and what you can do about it. Clinical Medicine, 15:179. O’Shea et al. (2010) Alcoholic Liver Disease. Am J Gastroenterol, 105:14.

• About: seen with severe alcoholic liver dysfunction + alcohol and/or starvation.
  
• Causes: acute exacerbation in known alcohol abuser due to sepsis, starvation. Look out for spontaneous bacterial peritonitis.
  
• Clinical: signs of advanced alcoholic liver disease, ↑HR, dehydration. Jaundice, alcoholic hepatitis, ascites, coagulopathy, encephalopathy. Anorexia, N&V may be prominent. May follow 2–3 days after a binge. Ketones detectable in breath, Kussmaul’s respiration.
  
• Investigations: FBC, U&E, LFT: low urea or AKI. ↑LFTs. Anaemia. Measure Mg, Ca, phosphate. Glucose: hypoglycaemia. Urine: ketones. Venous blood gas: ↑AG metabolic acidosis with ↑ketones (beta-hydroxybutyrate). Metabolic alkalosis if vomiting. Ascites: test as may have SBP – always aspirate.
  
• Management: supportive as for advanced alcoholic liver disease: IV fluids and IV GLUCOSE and IV PABRINEX paired vials TDS for 1–2 days. Replace electrolytes and phosphate and magnesium as needed. Long-term abstinence from alcohol and refer to appropriate support on discharge. Alcoholic hepatitis, Section 7.4.

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