Hepatic Disease

Pathophysiology

• Central characteristics of liver failure
  • Loss of metabolic and synthetic function
  • Progressive development of portal hypertension
  • Ascites
  • Portosystemic shunting
• Synthetic functions
  • Coagulation and anticoagulation factor synthesis
    • Protein C/S, Factors II, VII, IX, X
• Ascites due to increased hydrostatic pressure in intraperitoneal veins, hypoalbuminaemia and poor renal management of sodium and water

Pathophysiology

• Encephalopathy
  • Pivotal characteristic of chronic liver disease and hallmark of liver failure
  • Ammonia formed by colonic bacteria enters general circulation through portosystemic shunting with large intestinal protein loads fueling this process
  • Levels of ammonia do not correlate with mental status but is a contributing factor nonetheless
  • In fulminant liver failure, cerebral oedema and raised ICP develop with loss of autoregulation and ammonia-related oedema
• Jaundice
  • Pre-hepatic – Raise unconjugated bilirubin
  • Hepatic – Raised unconjugated bilirubin
  • Post-hepatic – Raised conjugated bilirubin
• Coagulopathy
  • Platelets
    • Thrombocytopaenia is common through splenic sequestration, reduced marrow synthesis due to deficiency in hepatic thrombopoietin or bone marrow suppression (e.g. alcoholism)
    • Platelet function can be enhanced by both increased levels of platelet adhesion factor and von willebrand factor levels in cirrhosis
    • Sepsis or endotoxinaemia due to bacterial translocation can inhibit platelet function
  • Coagulation factors
    • Reduced synthesis of fibrinogen, Factors II, V, VII, IX, X and XI leads to reduced coagulation
    • Reduces synthesis of Protein C and S and antithrombin III leads to reduced anticoagulant effects
    • Factor VIII levels are raised in cirrhosis (made by endothelium)
    • Vitamin K deficiency due to cholestatic liver disease (bile salts are required for fat-soluble Vit K absorption), malnutrition and antibiotic use further reduces functional levels of Factor II, VII, IX and X; Protein C and Protein S)
  • Fibrinolysis
    • Failure of the liver to clear tPA leads to enhanced fibrinolysis
    • Decreased hepatic production of antifibinolytic proteins also promotes fibrinolysis (e.g. alpha-2 antiplasmin and thrombin activatable fibrinolysis inhibitor (TAFI)

Clinical features

• Chief complaints – Nausea, vomiting, fatigue, diarrhoea, RUQ/epigastric pain, pruritis, inappropriate bleeding or ALOC
• HxPC – Eating out, raw oysters, drug intake (esp. paracetamol, herbal, antibiotics, anticonvulsants, statins), mushroom intake, travel
• PMHx – Chronic hepatitis, blood products, HIV status, dyslipidaemia, obesity, T2DM, depression and pain medication use
• SHx – IVDU, chronic alcohol abuse, promiscuous, travel

Drugs

• Paracetamol
• Alcohol
• Vitamin A
• Isoniazid
• Propylthiouracil
• Phenytoin
• Valproate
• Statins – 3% of patients have mild transaminitis and clinically significant hepatotoxicity is rare

Herbal remedies

• Black cohosh – Menopausal Sx – Hepatic necrosis and bridging fibrosis
• Chaparral – Antioxidant – Cholestasis, chronic hepatitis, cholangitis, cirrhosis
• Comfrey 0 Wound healing – Hepatic veno-occlusive disease
• Echinacea – Respiratory – Acute cholestatic autoimmune hepatitis
• Kava – Anxiolytic – Acute and chronic hepatitis, cholestasis, fulminant hepatic failure
• Kombucha – Weight loss, wellbeing – Acute liver failure, acute renal failure
• Ma huang – Weight loss – Acute hepatitis
• Mistletoe – HTN, insomnia, epilepsy, asthma, infertility, urinary disorders – Acute hepatitis
• Noni juice – Health tonic, subacute hepatic failure, acute hepatitis
• Prostata – Cholestatic hepatitis
• Senna – Laxative – Acute hepatitis, acute cholestatic hepatitis, acute liver failure
• Skullcap – Sedative – Hepatic veno-occlusive disease, cholestasis, hepatitis
• St Johns Wort – Anti-depressant – Cytochrome P450 induction, serotonin syndrome
• Valerian – Sedative – Hepatisis

Acute vs chronic vs fulminant

• Acute hepatitis 
  • Nausea, vomiting, RUQ pain +- fever, jaundice, enlarged tender liver
  • Usually viral infection, toxins (alcohol or paracetamol)
• Chronic hepatitis
  • Abdominal pain, distension, abnormal bleeding, lower body oedema, encephalopathy, ascites, electrolyte derangement, examination findings of chronic hepatitis
• Acute fulminant liver failure
  • Potential final common pathway of both acute and chronic liver disease
  • Coagulopathy, encephalopathy, abnormal fluid shifts and hepatorenal syndrome

Acute liver failure

• Complex multisystem illness after significant liver insult
• O’Grady definitions
  • Hyperacute: Onset of encephalopathy within 7 days of jaundice
  • Acute: Encephalopathy 8-28 days from onset of jaundice
  • Subacute: Encephalopathy 4-26 weeks after jaundice

Acute liver failure – Hyperacute

• Onset of encephalopathy within 7 days of jaundice
• Most commonly paracetamol, ischaemic, viral, toxins
• Greatest degree of coagulopathy, encephalopathy, organ dysfunction and cerebral oedema
• Greatest chance of spontaneous survival

Acute liver failure – Subacute

• Onset of encephalopathy 4-26 weeks from jaundice
• More frequently seronegative, idiopathic or drug-related e.g. NSAIDs
• Jaundice is inevitable but transaminitis is less pronounced
• Carries lower risk of cerebral oedema and intracranial hypertension
• Once poor prognostic criteria are reached, likelihood of effective liver regeneration and recovery are low
• Very poor prognosis overall without liver transplantation
• Hepatitis B and paracetamol are common causes

Acute hepatitis – Viral

• Hepatitis A
  • Faecal-oral transmission. Mostly from asymptomatic children to adults
  • May be associated with improper food handling and oyster consumption
  • Incubation period 15-50 days with prodromal nausea, vomiting, malaise
  • No chronic component
  • Only 0.35% of Hep A infections cause acute liver failure (but constitutes 10% of cases)
  • Diagnosed by anti-HAV IgM

Lab studies

• Hepatitis A serology
  • HepA IgM indicates acute infection
  • HepA total antibody (IgM + IgG) – Assume immunity
  • HepA PCR is available
  • Infectious 2 weeks prior and 1 week after jaundice
  • Treat close contacts with NHIG (but not vaccination)

Acute hepatitis – Viral

• Hepatitis B
  • Sexually, blood transfusion, needles or perinatal
  • Incubation 1-3 months
  • Infectious for 5-15 weeks after onset of symptoms
  • If develop chronic hepatitis B will be infectious indefinitely
  • Chronic infection in only 6-10% of patients (adults) vs. 90% of infants and 30% of children under age 5
  • Presentation of acute phase is like Hepatitis A
  • Causes 25-75% of acute liver failure from acute viral hepatitis
  • Reactivation of HepB causing acute hepatitis is increasingly seen with steroid use or immunosuppression

Acute hepatitis – Viral

• Hepatitis B
  • Preicteric phase
    • Incubation period 2 months
    • Arthritis, fevers, rash, low serum complement due to circulating HBsAg and anti-HBsAb complexes
  • Acute hepatitis B
    • Occurs in 25% of exposures
    • High levels of anti-HBcAg IgM
    • Rarely fulminant
  • Chronic hepatitis B
    • 10% of exposures (1-3% of healthy adults; 5-10% of immunocompromised adults and 90% of neonates)
    • Risk highest the younger the time of exposure
    • Defined by presence of HBsAg on two occasions 6 months apart with no other evidence of acute disease
    • Anti-HBcAg IgG
    • HBeAg positive or negative

Phases of chronic HepB

• Phase 1
  • Immune tolerance
  • 20-40 years
  • High levels of viral replication
  • Normal ALT
  • HBeAg antibodies absent
  • No treatment required
  • Most patients progress to active disease
• Phase 2
  • Immune clearance
  • Vigorous immune response, elevated ALT and viral DNA
  • Repeated inflammation leads to fibrosis/cirrhosis
  • 30-40% of patients suffer cirrhosis
  • 5-10% of patients each year seroconvert HBeAg to anti-HBeAg Ab

Phases of chronic HepB

• Phase 3
  • Immune control
  • Viral replication suppressed
  • Inflammation reduces and ALT falls
  • Associated with development of seroconversion (anti-HBeAg)
  • Can stay in this phase indefinitely but can reactivate
• Phase 4
  • Immune escape
  • Virus mutates and loses ability to produce HBeAg
  • Get replication and renewed inflammatory response
  • ALT persistently elevated; HBeAg negative
  • Elevated viral DNA
  • 8-10% progress to cirrhosis each year
  • Require long-term viral suppression therapy

HepB Serology

• HBsAb
  • Appears weeks to months after infection
  • Indicates immunity and recovery OR immunity following vaccination
• HBsAg
  • Appears before onset of symptoms
  • Peaks during clinical disease
  • Present in:
    • Acute infection
    • Chronic infection (if present >6 months)
    • Carrier state
• Anti-HBc IgM
  • Acute infection. Not produced by vaccination. 
• Anti-HBc IgG
  • Chronic infection. Not produced by vaccination

HepB Serology

• HBeAg
  • Detected acutely and indicates high infectivity and active viral replication
• HBeAb
  • Fall over time once virus has cleared. May indicate lower replication levels but Hep B PCR can detect true viral loads to discern this
• HepB PCR
  • Very sensitive method to detect DNA to detect viral replication
• HepB pre-core mutants
  • If mutations occur in genome in pre-core region, virus produces a non-detectable e Antigen giving false negative HBeAg results. In this instance, the HBeAb will be ineffective.

Acute hepatitis – Viral

• Hepatitis C
  • Primarily blood-borne
  • Mostly asymptomatic acutely but >75% go on to suffer chronic hepatitis C
  • 1-5% of chronic hepatitis C cases will die from cirrhosis or liver cancer
  • Very rarely causes acute hepatitis
  • Hepatitis C serology
    • If positive, suggests infection at some point in time
    • HepC PCR detects ongoing replication which is often the clinical question
    • 6-8 week window period

Acute hepatitis – Viral

• Hepatitis D
  • Uncommon and seen in those with pre-existing chronic Hepatitis B (superinfection)
  • Can result in rapidly progressive fulminant liver failure
  • Mostly seen in association with IVDU
• Hepatitis E
  • Particularly prevalent form (like HepA) in India and Asia
• CMV, HSV, Coxsackie, EBV can all cause hepatitis but unlikely to be significant in otherwise healthy host

Acute hepatitis – Toxic

• Drugs make up 15-25% of acute liver failure causes
• Paracetamol
  • Causes >40% of liver failure in US and 1/3 of deaths due to toxic ingestion
  • Nausea, vomiting, abdominal pain with signs of liver failure at 48-72 hours
  • 28% of patients with paracetamol overdose will develop liver failure
  • Likelihood of liver failure depends upon:
    • Time of presentation
    • Dose ingested
    • Baseline health status
    • Glutathione depletion e.g. malnutrition
    • Chronic alcohol ingestion
    • Enzyme-inducing agents

Acute hepatitis – Toxic

• Alcohol
  • Asymptomatic – reversible fatty liver – acute alcoholic hepatitis – cirrhosis
  • Diagnosis of alcoholic liver disease carries 35% 5-year survival rate
  • Consistent heavy alcohol use (10SD/day) is thought to be required to develop significant alcoholic liver disease
  • Other non-hepatic features can provide clues: Malnutrition, stocking-glove peripheral neuropathy, pityriasis rosea and cardiomyopathy
• Mushrooms
  • Important but rate cause of fulminant liver failure

Acute hepatitis – Seronegative

• Diagnosis of exclusion once no identifiable viral or drug cause found
• Prognosis is not as good as if identifiable virus found
• May be an acute autoimmune form, although these will often lack IgG or anti-smooth muscle or liver kidney autoantibodies
• Fulminant Wilson’s disease
  • Cirrhosis with thrombocytopaenia, Kayser-Fleischer rings and non-immune-mediated haemolysis
• HELLP
• Heat shock injury
• Ischaemic
• Budd-Chiari syndrome
  • Hepatic vein obstruction

Acute on chronic hepatic failure

• Most common precipitants are sepsis, variceal bleeding, intoxication, dehydration, HCC and portal vein thrombosis
• Ascitic tap >250 PMN/mm3 suggests bacterial infection
• Hepatic encephalopathy in this setting rarely causes cerebral oedema (unlike acute hepatic failure)

Chronic hepatitis and cirrhosis

• HepB, HepC, NASH or alcoholic hepatitis most commonly
• Asymptomatic period of gradual replacement of liver parenchyma with fibrotic scar tissue ultimately leading to cirrhosis
• Ascites
  • Can lead to sympathetic pleural effusion with respiratory compromise
  • Bulging flanks is 80% sensitive but only 50% specific
  • Fluid thrill 60% sensitive and 90% specific
  • Need 1500mL for flank dullness
• SBP
  • Survival rate after first episode is 68% at 1 month and 30% at 6 months
  • 30% of ascitic patients will develop SBP in a given year
  • Easily missed on hx and examination

Chronic hepatitis and cirrhosis

• Hepatorenal syndrome
  • Complication of cirrhosis that often accompanies SBP
  • Acute renal failure with histologically normal kidneys in presence of pre-existing chronic or acute hepatic failure
  • Type 1
    • Progressive oliguria and doubling of serum creatinine over 2 weeks
    • Marker of extreme morbidity and mortality (median survival 2 weeks without medical treatment)
  • Type 2
    • Gradual impairment in renal function

Chronic hepatitis and cirrhosis

• Hepatic encephalopathy
  • Accumulation of nitrogenous waste products normally metabolised by the liver with subsequent intracerebral accumulation of glutamine and cerebral oedema
    • Clear relationship in acute liver failure between higher grades of coma and arterial ammonia level (150-200)
  • Suggests liver unable to metabolise usual nitrogenous waste and/or supply of nitrogenous waste has increased
  • Sources of increased supply include proteinaceous meal or GI bleeding
  • Progressive liver disease, constipation, hypo/hyperglycaemia, alcohol withdrawal, sepsis and iatrogenic interventions can all compromise metabolic capacity of liver
  • Common complication of transjugular intrahepatic portosystemic shunt (TIPS)
    • Performed to alleviate portal hypertension and variceal bleeding but subsequently reduces hepatic metabolism of nitrogenous wastes by reducing hepatic blood flow
  • Adding or removing antibiotics can change intestinal flora and alter the guts ability to metabolise proteins
  • Rate of onset has large bearing on severity (as in chronic liver disease, adaptation occurs to prevent cerebral oedema)

Chronic hepatitis and cirrhosis

• Hepatic encephalopathy (modified Parsons-Smith scale)
  • Stage I – General apathy – GCS 15
  • Stage 2 – Lethargy, drowsiness, variable orientation, asterixis – GCS 11-15
  • Stage 3 – Stupor with hyperreflexia, extensor plantar reflexes – GCS 8-11
  • Stage 4 – Coma – GCS <8
• Hepatic encephalopathy is a diagnosis of exclusion and must rule out spontaneous/traumatic ICH, hyponatraemia, Wernicke-Korsakoff, hyper/hyponatraemia, drug intoxication (e.g. accumulation of opioids/benzo’s), renal failure, sepsis and GI bleeding

Hepatic failure

• Progression is varied and often depends on comorbid HIV status, diabetes, obesity, ongoing IVDU and alcohol use
• Survival rate <30%
• Most common causes of presenting acute liver failure are paracetamol overdose (46%), indeterminate (14%), other drugs (11%), Hep B (7%) and autoimmune hepatitis
• Clinical hallmarks are hepatic encephalopathy, coagulopathy and hepatorenal syndrome
• Cerebral oedema and raised ICP are the most ominous complications
• Other findings are hypoglycaemia, hypotension and relative adrenal insufficiency
• Transfer to a transplant centre may be indicated

Other syndromes

• Gilbert’s
  • Familial liver disorder with raised LFT’s and bilirubin
  • Does not cause cirrhosis or affect liver function
• Wilson’s, haemochromatosis, alpha-1 AT deficiency are all familial disorders that can lead to chronic liver disease and liver failure
• Autoimmune hepatitis is progressive, chronic disease
• Primary biliary cirrrhosis has a chronic course

Venous thrombosis

• Rare but important causes of liver disease as potentially treatable
• Portal vein thrombosis
  • Associated with hypercoagulable states including Protein C/S deficiency, antithrombin III deficiency, Factor V Leiden, abdominal trauma, sepsis, pancreatitis, cirrhosis and hepatocellular carcinoma
  • Presents with abdominal pain, ascites and splenomegaly
• Hepatic vein thrombosis (Budd-Chiari syndrome)
  • Abdominal pain, hepatomegaly and ascites
  • Seen in coagulopathies, polycythaemia vera, paroxysmal nocturnal haemoglobinuria and congenital webs of the vena cava

Lab studies

• Bilirubin
  • Unconjugated (indirect) = haemolysis or failed hepatic conjugation
  • Conjugated (direct) = Obstructive (intra- or extrahepatic)
• Transaminases
  • Levels in hundreds suggest mild injury while levels in thousands suggest extensive acute hepatic necrosis
  • Levels <5x ULN suggests alcohol liver disease and NASH
  • Marked elevations commonly seen with acute viral hepatitis
  • May be near normal in end-stage cirrhosis
  • AST:ALT >2 in alcoholic hepatitis as alcohol stimulates AST production
  • ALT is more specific for liver injury than AST
  • Elevations 3-5x normal and ALP up to 2x ULN in diabetic or obese patients suggests NASH
  • AST elevations can be due to paracetamol, NSAIDs, ACEi, nicotinic acid, isoniazid, sulfonamides, erythromycin, griseofulvin and fluconazole
  • Cholestatic picture: AST increases before ALT and levels usually no higher than 5xULN

Lab studies

• GGT
  • Stimulated by alcohol consumption
  • Slightly more sensitive than ALP for obstructive liver disease
  • Also elevated by drugs that induce hepatic microsomal enzyme activity e.g. phenobarbital and warfarin, phanytoin
  • Also may rise in acute or chronic pancreatitis, acute MI, uraemia, COPD, RA, DM
  • Elevation in hepatitis suggests an alcoholic cause
• ALP
  • Elevations >4x ULN strongly suggest cholestasis
  • Minor elevations in all hepatobiliary disease
  • Also derived from bone, placenta, intestine, kidneys and leukocytes
  • Rises up to 2x in pregnancy
  • If GGT not also raised, consider ALP from alternative site

Lab studies

• Prothrombin time
  • Common complication of advancing cirrhosis but also seen in acute hepatitis and exacerbations of chronic compensated liver disease
  • If present with acute viral hepatitis, suggests widespread hepatocellular necrosis
  • Some correlation between prolongation and clinical outcome in fulminant liver disease
  • Vitamin K deficency from another cause can be distinguished by delivery of Vit K 10mg IM and >30% reduction in prothrombin time over 24 hours
• Albumin
  • Half-life of 3 weeks so does not acutely decrease in fulminant liver disease
  • May also be low in malnourished states or protein-losing enteropathy

Lab studies

• Ascitic tap
  • Old classification
    • Exudate >30g/L protein vs. transudate <30g/L protein
  • Serum-ascites albumin gradient (SAAG)
    • >=11g/L = Portal HTN with 99% accuracy
      • DDx: CCf, Budd-chiari, portal vein thrombosis
    • <11g/L
      • Peritoneal carcinomatosis, tuberculous peritonitis, pancreatic ascites, biliary ascites and nephrotic syndrome
  • WCC >1000 or neutrophils >250 diagnoses SBP
  • Can have up to 500 WCC/mm3 if no symptoms to suggest SBP and predominant lymphocytes
  • Low glucose and high protein also indicate infection
  • Gram stain and culture results are falsely negative 30-40% of the time so should start empiric antibiotics in ED
  • Culture sensitivity is improved by 10mL of fluid for each BC bottle and transferring fluid to culture bottles at the bedside
    • Posiive culture in 80% if in blood culture bottle vs. 50% in urine jar

Treatment

• Ascites
  • Mild-moderate ascites managed with salt-restricted diet, diuretics (spironolactone 50-200mg per day and/or amiloride 5-10mg per day)
  • Frusemide can lead to overdiuresis
  • De Alwis suggests frusemide 40mg/spironolactone 100mg mane then uptitrate
  • Fluid restriction not required unless Na <120/125
  • Above regime 90% effective in achieving acceptable ascitic levels
  • Large volume refractory ascites requires paracentesis
    • Considered safe from bleeding perspective unless there is evidence of fibrinolysis (three-dimensional bruising or oozing from IV sites) or DIC
    • Albumin 6-8mg/L of fluid removed once >5L removed
    • Midline or LLQ safest options (avoid inferior epigastric vessels and midline relatively avascular)
    • Can use 3.8cm metal needle and leave in for up to an hour (18G preferred if therapeutic)
    • Do not continually manually aspirate as leads to bowel/omentum clogging needle

Treatment

• SBP
  • Need to sample if new diagnosis ascites or those with ascites who develop fever, encephalopathy, abdominal pain or GI bleeding
  • Emergency physician clinical exam only 75% sensitive for SBP
  • Diagnosis = Positive culture and PMN >250 without intra-abdominal source
  • If PMN >250 or clinical suspicion high – treat empirically while awaiting Gram stain and culture
  • Clinical examination cannot differentiate secondary BP from spontaneous BP
    • If perforation has occurred, ascitic tap will show PMN >250, multiple organisms on Gram stain + 2 out of:
      • Total protein >10g/L
      • LDH > ULN for serum
      • Glucose <5
    • These criteria are only 50% sensitive for non-perforated secondary bacterial peritonitis
  • Most common bugs are E. coli, Klebsiella and Streptococcus pneumoniae
  • Empirical treatment Ceftriaxone 1g daily OR IV fluoroquinolone (ineffective if receiving prophylactic fluoroquinolone) or oral fluoroquinolone in mild cases with close follow-up
    • Add metronidazole if suspect secondary bacterial peritonitis (or just PipTaz)

Treatment

• Hepatic encephalopathy
  • Identify any precipitants (if no clear precipitant, treat as sepsis with Ceftriaxone 1g daily or Cefotaxime 1g q8h
  • Lactulose
    • Can reduce blood ammonia levels by 50% by:
      • Reduced intestinal production and absorption of ammonia
      • Facilitates movement of ammonia from small bowel to colon
      • Also inhibits glutamine-dependent ammonia production in gut wall
    • Initial dose of 30mL q1-2 hourly until a bowel movement via PO or NG then 3-4 times daily
    • 300mL in 700mL of water as enema retained for one hour in Trendelenberg position every 2 hours as required
    • Once risk of aspiration reduced and HE improving can convert to target 2-4 loose bowel motions per day starting at 30-40mL BD PO
  • Rifaximin
    • Oral non-absorbed antibiotic 550mg PO BD allows 58% risk reduction in HE
    • As effective as lactulose in moderate to severe HE and effective even in those already on lactulose
  • If acute (not chronic) liver failure need to monitor for cerebral oedema and manage as per usual

Treatment

• Coagulopathy
  • Needs to be treated if undergoing a procedure or has uncontrolled bleeding
  • The reality is, traditional coagulation screening does NOT provide a measure of the patients actual propensity to both bleed and/or thrombose
  • Liver disease results in a complex hybrid of procoagulant and anticoagulant forces and are often prone to both bleeding and clotting
  • ROTEM (or TEG) is the most reliable method of measuring aberrations requiring correction in an actively bleeding patient with hepatic coagulopathy
    • Vitamin K 10mg IV or PO
    • FFP or Prothrombinex
    • Cryoprecipitate or Fibrinogen concentrate for fibrinogen deficiency
    • Platelets can be replaced
    • TXA for hyperfibrinolysis

Disposition

• Acute hepatitis
  • Admit elderly, pregnant women, those that do not respond adequately to supportive care, bilirubin >20mg/dL, PT >50% above noral, hypoglycaemia, hypoalbuminaemia or GI bleeding
• Those with advanced cirrhosis are at high risk of falls and subsequent bleeds. Must be ambulatory or be closely supervised if considering discharge
• Should involve gastroenterology and transplant specialists in decisions

Pain control in hepatic disease

• Paracetamol up to 2g daily has been shown to be safe in the short-term
• Gabapentin and pregabalin are safe options
• Fentanyl and tramadol are the safest of the opioids but should be avoided if possible and given small doses with increased dosing intervals
• Propofol and fentanyl are good options for sedation/GA/analgesia required

Prognosis in acute liver failure

• Spontaneous recovery with encephalopathy
  • Grade I to II – 65-70%
  • Grade III – 40-50%
  • Grade IV – <20%
• Patients <10 or >40 have worse likelihood of spontaneous recovery
• Transplant-free survival >50% if paracetamol, HepA, ischaemia, pregnancy—related
• Transplant-free survival <25% if HepB, autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, cancer or indeterminate cause
• Liver histology not useful for prognostication but has role in identifying underlying cause

Prognosis in acute liver failure

• O’Grady criteria (King’s College Criteria)
  • Paracetamol-related (all within 24 hours of ingestion)
    • Acidodis (pH <7.3) irrespective of encephalopathy OR
    • Grade III/IV encephalopathy with both a PT >100 (INR >6) and Creatinine >300
    • Specificity of 90%; survival without transplant of patients meeting criteria = 15%
    • Sensitivity as low as 60%; may fail to detect patients who will die without transplant
  • Non-paracetamol-related
    • INR >6 (PT >100) OR
    • Encephalopathy with any 3 of the following:
      • Age <10 or >40
      • Bili >300
      • Time from jaundice to encephalopathy >7 days
      • Aetiology: Either non-A, non-B (seronegative) or drug-induced
      • INR > 3.5 (PT >50)

Prognosis in acute liver failure

• Modified King’s
  • Addition of
    • Lactate >3.5 at 4 hours
    • pH <7.3 or lactate >3 at 12 hours
  • Attempts to improve sensitivity (to 91%)

Prognosis in acute liver failure

• French criteria (Clichy)
  • Encephalopathy (coma or confusion) and one of:
    • Age <30 with Factor V level <20% or
    • Factor V level <30% if greater than 30 years old
  • PPV of mortality 82% and NPV of mortality was 98%
• MELD (Model for End-stage Liver Disease)
  • Similar to King’s College criteria w.r.t. mortality prediction
  • Originally designed prospectively for chronic liver disease

When to transfer to transplant centre

• In paracetamol-induced liver failure
  • INR >3 at 48 hours or >4.5 at any time
  • Oliguria or creatinine >200
  • pH <7.3 after resuscitation
  • SBP <80
  • Hypoglycaemia
  • Severe thrombocytopaenia
  • Encephalopathy of any degree

Criteria for transplant in chronic liver disease

• MELD
  • Childs Pugh B or C
    • Bili >300
    • Albumin <28
    • INR >1.7
    • Hepatic encephalopathy
    • Refractory ascites
  • Comorbidities
    • Hepatorenal syndrome
    • Variceal bleeding
    • SBP
    • Hepatocellular carcinoma

MARS

• Extracorporeal liver replacement device (molecule absorbent recirculating system)
• Overall patient survival 60%

Pneumobilia and portal venous gas

• Portal venous gas = Peripheral
  • Children: NEC, umbilical vein catheterization
  • Adults: Ischaemic bowel, IBD, paralytic ileus, intra-abdominal sepsis of any cause
• Common bile duct gas = Central
  • Recent biliary instrumentation eg. ERCP
  • Incompetent Sphincter of Oddi
  • Biliary-enteric surgical anastomosis
  • Infection (cholangitis, emphysematous cholecystitis, liver abscess

Jaundice

• Unconjugated
  • Overproduction of bilirubin
    • Extravascular haemolysis, haematoma, intravascular haemolysis, dyserythropoiesis
  • Impaired bilirubin uptake by liver
    • Hepatic failure, portosystemic shunt, medications (rifampicin), CCF
  • Impaired conjugation of bilirubin
    • Gilbert, Crigler-Najjar, advanced cirrhosis, hyperthyroidism, ethinyl oestradiol

Jaundice

• Conjugated
  • Hepatocellular
    • Viral hepatitis, alcoholic hepatitis, NASH, autoimmune liver disease, drugs, carcinoma, lymphoma/sarcoid, Budd-Chiari, metabolic
  • Intrahepatic cholestasis
    • PBC, alcoholic hepatitis, NASH, viral hepatitis, steroids, antibiotics, lymphoma/sarcoid, pregnancy
  • Biliary obstruction
    • Choledocholithiasis, pancreatic tumor, cholangiocarcinoma, PSC, pancreatitis, benign strictures

Last Updated on June 13, 2022 by Andrew Crofton