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Hepatic failure

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Fulminant hepatic failure

Definition Aetiology
Pathogenesis Pathophysiology
Clinical features Diagnosis
Investigations Management
Liver transplantation Prognosis

Definition

Clinical syndrome developing as a result of massive necrosis of liver cells or following any other cause of sudden and severe impairment of hepatic function, occuring in patients without pre-existing liver disease. 

  • Hyperacute
    • encephalopathy within 7 days of onset of jaundice
    • very high risk of cerebral oedema
  • Acute
    • jaundice to encephalopathy: 8-28 days
    • high risk of cerebral oedema
  • Subacute
    • jaundice to encepalopathy: 5-26 weeks
    • low risk of cerebral oedema

Aetiology

  • acute viral hepatitis: A/B/C/D/E (70% of cases worldwide). HAV relatively rare cause of FHF in UK. Viral replication has usually ceased by the time of presentation in patients with FHF in association with HBV and therefore infection of the graft is not a problem in patients undergoing transplantation. Non-A, non-B hepatitis predominant cause of late onset FHF, accounting for 90% of cases in one series. Hepatitis E often benign and self-limiting, however, FHF has been reported in up to 2.85% of men and 22% of pregnant women, in whom it is usually fatal. HCV not a significant cause
  • paracetamol (acetoaminophen poisoning)
  • drugs eg rifampicin, isoniazid, MAOIs, gold, valproate, co-trimoxazole, phenytoin, halothane
  • acute fatty liver of pregnancy
  • Weil's disease
  • almost any cause of acute hepatitis
  • lymphoma (usually high grade): may be present with FHF
  • ischaemic hepatitis
  • acute Budd-Chiari
  • Wilson's disease

Pathogenesis

  • Fulminant viral hepatitis probably due to host immune factors: in fulminant hepatitis B humoral Ab response may be enhanced - significantly faster rate of clearance of HBsAg in patients with fulminant hepatitis compared with patients with severe uncomplicated hepatitis. Also, on admission anti-HBs Ab found in 40% of patients with fulminant hepatitis where as it is very rarely detected in uncomplicated hepatitis at this time. No differences in HBV specific DNA polymerase in the 2 groups of patients.
  • For all aetiologies there is an increased incidence in females, which has been attributed to a generally more pronounced antibody response to immunological challenge compared to that in males.
  • Halothane hepatitis probably also immune mediated
  • Paracetamol OD: hepatic necrosis is due to the formation of reactive intermediary products of paracetamol metabolism. These bind to intracellular proteins and interfere with cellular metabolism.

Pathophysiology

Wide variety of agents, including ammonia, free fatty acids, mercaptans, phenols, bile acids and aromatic amino acids combine to produce hepatic encephalopathy by several different mechanisms:

  • direct cellular effect
  • indirect: cause metabolic derangement
  • conversion to false neurotransmitters
  • alteration of permeability of BBB: allows entry of toxic metabolites into the brain and thus contributes to cerebral oedema - major cause of death: present in 32% of patients at PM.

Ammonia currently thought to be the main pathophysiological agent

Other possible aetiological mechanisms include the presence of benzodiazepine agonists (hepatic coma can be reversed temporarily by flumazenil) and altered GABA status

Clinical features

  • Encephalopathy
    • Grade I: Euphoric, occasionally depressed, fluctuant mild confusion, slowness of mentation and affect, untidy, slurred speech, reversal of sleep pattern, may have asterixis alone
    • Grade II: Accentuation of I, drowsy, inappropriate behaviour, possible to hold conversation
    • Grade III: Sleeps most of the time but is rousable, unable to converse coherently. May be manifest as extreme agitation or irritability with violence to self/others
    • Grade IV: Unrousable, may respond to noxious stimuli
  • +/- jaundice: often not present if onset of coma rapid
  • foetor hepaticus
  • flapping tremor
  • slurred speech
  • constructional apraxia
  • liver
    • may be enlarged initially
    • later decreases in size
  • cutaneous stigmata of liver diseases generally absent
    • spider naevi occasionally evident in protracted but fulminant disease.
  • haemodynamic disturbances
    • similar to those with sepsis.
    • sinus tachycardia usual but some patients with a viral aetiology have a relative or absolute bradycardia which may reflect myocardial involvement by the virus.
    • profound but variable vasodilatation so hypotensive crises are a frequent problem
  • arrhythmias
    • rare
    • usually due to a definable precipitating event (eg electrolyte disturbance, acidosis, hypoxia, direct cardiac irritation by lines)
  • speed of onset may give clues to aetiology. Illness of < 1 week before development of encephalopathy characteristic of hepatotoxic cause.
  • pre-terminal state
    • grade IV encephalopathy
    • hyperventilation common
    • pupils dilated and sluggish
    • hypertonic and grasp reflexes readily elicited
    • +/- decorticate/decerebrate postures
    • loss of oculovestibular reflex (other brainstem reflexes, including oculocephalic may disappear transiently in patients who ultimately survive)
    • +/- hypotension, arrythmias and respiratory arrest
    • hypothermia
    • areflexia
  • renal failure
    • renal failure requiring intervention seen mainly but not exclusively in patients with FHF secondary to paracetamol poisoning
    • hyperkalaemia rarely a problem and when present usually indicates concurrent rhabdomyolysis

Cerebral oedema

  • common but onset difficult to determine. Related to acuteness of presentation (24% in hyperacute cases and 9% in subacute). Papilloedema seldom present and bradycardia with pyrexia and hypotension common in fulminant hepatic failure. Often respiratory arrest and brain death due to tentorial herniation is first sign
  • keys to recognition are:
    • hypertension (bursts of systolic pressure > 200 mmHg, or a sustained systolic pressure > 150 mmHg)
    • rarely bradycardia
    • any pupillary changes including sluggishness, and cerebral "posturing".
    • hypotension is a late complication
  • early diagnosis requires excellent nursing. Pupillary responses may need to be checked as frequently as every 10 mins.
  • may be associated with or shortly followed by respiratory arrest if not recognised promptly and treated
  • major cause of death
  • in contra-distinction cerebral oedema only rarely occurs in patients with decompensated chronic liver disease, regardless of the depth of coma

Diagnosis

  • in jaundiced patient diagnosis is usually obvious
  • consider diagnosis in sick patients in whom an underlying diagnosis is lacking, particularly when coma or metabolic acidosis are present. Best screening test for hepatic aetiology is PT or INR
  • consider occult paracetamol poisoning in patients with unexplained metabolic acidosis and marked oliguria with a normal or near normal urea (creatinine will be raised).

Investigations

  • AST & ALT > 40 x normal initially. Fall with progression of damage
  • complex alterations in fluid and electrolyte balance. Often aggravated by renal failure. Hypokalaemia occurs early and can be life-threatening.
  • may be wild fluctuations in blood glucose. Hypoglycaemia is a consequence of increased circulating insulin, impaired gluconeogenesis and an inability to mobilise liver glycogen
  • hypophosphataemia and hypomagnesaemia common in patients who are passing urine. Should be corrected
  • respiratory alkalosis due to hyperventilation, may be exacerbated by metabolic alkalosis due to hypokalaemia/failure to alkalinize urine - exacerbated by continuous gastric aspiration/accumulation of basic compounds. +/- lactic acidosis ? due to both failure of hepatic gluconeogenesis (and therefore hepatic lactate clearance) and increased anaerobic metabolism due to peripheral circulatory failure. In the case of the latter circulatory failure may be secondary to severe relative hypovolaemia and in these patients aggressive fluid replacement may lead to dramatic improvement in acid-base status. In any patient with FHF or decompensated chronic liver disease the presence of a metabolic acidosis that does not respond to volume loading is associated with a very poor outlook
  • ­ ammonia. Risk of cerebral oedema correlated with magnitude of rise
  • ± widespread abnormalities of haemostatic mechanisms including thrombocytopaenia, multiple clotting factor deficiencies (with notable exception of factor VIII) and DIC
  • blood cultures:
    • markedly increased susceptibility to bacterial infections (bacteraemia in 30%, fungaemia in 10%)
    • pyrexia and leucocytosis often absent
    • significantly more common in patients with renal failure.
    • respiratory (47%) or urinary tract origin most common
    • Gram +ve most common in first week, gram -ve in second week and fungal infection in third week
  • ECG: multiple VEs, heart block, bradycardia common
  • EEG: hepatic encephalopathy has characteristic pattern
  • HAV IgM, HBcAb (IgM) - high sensitivity and specificity for acute infection with these 2 viruses. Assay for antibody to hepatitis C not very useful as it is rarely positive in the acute stages of the disease. Usually becomes positive for the first time only 3-6 months after the onset. The presence of HB IgM Ab to core Ag usually required for diagnosis as surface antigen is rapidly cleared

Prevention

  • lamivudine for patients with hepatitis B treated with steroids (to prevent acute liver failure on withdrawal of steroids)

Management

  • NB Early liason with and transfer to specialist unit before patient develops grade IV coma. 90% of patients in grade III coma progress to grade IV.
  • N-acetylcysteine of benefit in patients following paracetamol overdose even when there is evidence of encephalopathy and coagulopathy. Results in less hypotension and less cerebral oedema. Infusion results in increased cardiac output, oxygen delivery and consumption in patients with FHF. Mechanism of action is not clear.
  • Attention to metabolic homeostasis important

Coma

  • lactulose - aim to produce 2 soft motions/day - diarrhoea aggravates any abnormality of fluid and electrolyte balance. Reduces colonic production of ammonia in addition to having a laxative effect.

Nutrition

  • NB insulin resistance occurs in severe acute hepatitis.
  • Resting energy expenditure 1700 kcal/day with nitrogen loss of 7g/day (but heavily dependent on whether or not dialysis employed)
  • Enteral feeding does not increases ammonia and should not be witheld. Feeding regime does not need to be modified for liver failure
  • No role for branch amino acids in patients with acute or chronic liver failure (may have a role in subclinical liver failure in outpatients)

Cardiovascular

  • fluid balance and haemodynamics unusually difficult to assess clinically
  • optimize oxygen delivery and consumption and maintain adequate MAP
  • CVP often misleading - probably because of raised portal venous pressure
  • insertion and subsequent management of these intravascular devices (eg Swan-Ganz catheters) does not appear to be accompanied by noticeably greater morbidity than in other groups of patients despite the presence of coagulopathy
  • fluid overload best dealt with by ultrafiltration/CVVH as these patients do not usually respond to diuretics
  • vasodilatation predicts a poor BP response to dopamine and dobutamine which is confirmed in practice. Norepinephrine and epinephrine (starting dose 0.1 mcg/kg/min) usually raise systemic BP but may increase pulmonary AV shunting and although they increase oxygen delivery they may decrease consumption.

GI haemorrhage

  • 50% due to acute erosions in stomach and oesophagus. H2 blockers - almost completely prevent GI haemorrhage
  • (+/- lung/retroperitoneal haemorrhage/epistaxis)

Coagulopathy

  • FFP only necessary if spontaneous bleeding occurs (approx 5% patients). Prophylactic use not associated with any reduction in morbidity or mortality. Avoidance of FFP has advantage that PT remains valid prognostic marker. Once decision has been made to proceed with transplantation FFP can be given
  • risk of bleeding seems to correlate less with PT and more with thrombocytopaenia and the presence of overt DIC.
  • platelet infusions are indicated in severe thrombocytopaenia.

Respiratory problems

  • early intubation, as soon as gag reflex lost or patient develops grade III/IV encephalopathy
  • facilities for rapid intubation and ventilation must be available - respiratory arrest may occur at any time.
  • IV midazolam or propofol can be used for intubated patients who require sedation. Sedatives should not be used in patients who are not intubated.
  • muscle relaxants to prevent coughing, which can result in a prolonged rise in ICP
  • treat infection
  • ARDS occurs only rarely in FHF but is almost inevitably a preterminal event

Renal failure

  • manage along conventional lines (correct hypovolaemia, ensure adequate MAP etc)
  • continuous renal replacement therapy preferable to intermittent dialysis as fluid shifts associated with latter may exacerbate cerebral oedema
  • despite the profound coagulopathy all forms of extracorporeal circulation remain very prone to thrombosis and anti-coagulation for haemofiltration almost always necessary. Fortunately frank bleeding is rare.
  • patients with FHF have profoundly low levels of anti-thrombin III. It has recently been shown that its replacement (to control levels) markedly reduces the amount of heparin required for effective dialysis with a possible reduction in bleeding episodes. Very expensive and therefore should be reserved for problem cases
  • prostacyclin may have the dual effect of preventing thrombosis in the extra-coporeal circuit and improving oxygen delivery.

Cerebral oedema

Monitoring

  • ICP measurement
    • consider insertion of extradural catheter in grade III/IV encephalopathy to allow rapid treatment of rises in ICP before pupillary abonormalities develop
    • cerebral perfusion pressure should be maintained at > 50 mmHg
  • Jugular bulb saturation
    • appears to be useful in guiding management in conjunction with clinical indicators of cerebral irritability
    • persistent or repeated abnormal results may indicate need for ICP monitoring

Treatment of high ICP

  • electively intubate patients in grade III/IV encephalopathy and sedate with opiates/propofol
  • nurse at 15° head-up with head in neutral position
  • keep patient as static as possible as all forms of medical and nursing intervention raise ICP by as much as 40 mmHg once oedema has developed
  • keep Na normal. Note that patients are generally not sodium overloaded
  • mannitol as soon as there is evidence of raised ICP. Give 0.5 g/kg as bolus over 10 mins. Patient can be re-dosed until osmolarity of 320 mOsm/l is reached. In patients who are oliguric commence CVVHD aiming for "diuresis" of 300 ml of ultrafiltrate for each 100 ml of mannitol. Use of mannitol in patients who are not in renal failure associated with improved outcome
  • cerebral blood flow (CBF) high in patients with grade IV encephalopathy. Routine hyperventilation not recommended.
  • as last resort in patients with intractable cerebral oedema (ie cerebral oedema in the presence of renal failure unresponsive to 3 cycles of mannitol and ultrafiltration): thiopentone as a 15 minute infusion to a dose of 250 mg followed by continuous infusion. Propofol has similar effects and has the advantage of not being dependent on liver metabolism for termination of its effect
  • hypothermia decreases ICP, improves cerebral blood flow, decreases ammonia
  • prophylactic dexamethasone of no use

Pancreatitis

  • common but rarely presents a clinical problem

Infection

  • very low threshold for administration of antibiotics
  • late rise in INR is usually a pointer to uncontrolled sepsis and anti-fungals should be introduced if a comprehensive regime of antibacterials is already being used.
  • use of prophylactic antibiotics controversial. In a small study use of IV cefuroxime combined with enteral decontamination associated with decrease in documented infections and a non-significant increase in survival

Plasmaphoresis

  • High volume plasmaphoresis associated with improvement in conscious level, haemodynamics and reduction in arterial ammonia concentrations
  • Disadvantage is that possible hepatic growth factors are removed along with hepatotoxic mediators
  • Randomized clinical trial currently in progress examining its role in survival and as a bride to transplantation.

Artificial liver support

As yet no system has been shown to alter long term outcome

Liver transplantation

Patients with anticipated survival of < 80% and no contraindication to transplantation should be placed on waiting list as soon as possible. Multi-organ failure is major contraindication to transplantation. Cerebral perfusion pressure <40 mmHg is a relative contraindication.

Criteria for transplantation in FHF:

Non-paracetamol related:

Encephalopathy and THREE of the following:

  • age < 10 yrs or > 40 yrs
  • aundice for > 7 days prior to the development of encephalopathy
  • serum bilirubin > 300 mcmol/l
  • INR > 3.8 or PT > 50 seconds
  • aetiology: non A non B or drug induced

OR INR > 6.5 (PT > 100)

Paracetamol related cases:
  • pH < 7.3 following volume resuscitation and >24 h post ingestion OR
  • PT > 100 (INR >6.5), creatinine > 300 mcmol/l, grade III/IV encephalopathy within a 24 h time frame

Strongly consider transplantation in paracetamol related cases if arterial lactate >3.5 mmol/l after early fluid resuscitation.

Heterotopic transplants may be more appropriate for FHF but are technically difficult. With this technique the donor liver is placed in an ectopic site and the patient's own liver is left in-situ. The theory is that as the patient's own liver will recover fully if she survives the acute illness the transplanted liver can be removed after 2-3 months, thus sparing the patient a lifetime of immunosuppression. Use of a partial graft from a live donor may be possible in heterotopic grafting. Technically difficult

Correct clotting abnormalities before transfer to theatre. Usually requires 12 units of FFP and ultrafiltration.

On return from theatre patients are still at risk from raised ICP for 24 hrs. Postoperative bleeding frequent but usually minimal. Occasionally severe DIC occurs on reperfusion of graft. If severe intra-abdominal bleeding occurs the rise in intra-abdominal pressure may result in impaired renal function.

Graft function best assessed by monitoring PT. Presence of metabolic acidosis or hypoglycaemia following transplantation of great concern as it is indicative of primary graft dysfunction
Aspergillosis may account for up to 1/2 fatal infections in immediate post-op period

Transfer of patients with FHF

Aids to safe transport:

  • continuous oxygen
  • patient should be intubated if there is any doubt about ability to maintain airway
  • at least 1 reliable venous access
  • sitting posture
  • monitor pupils and (if possible) BP
  • monitor blood glucose
  • medical escort capable of performing intubation in sub-optimal conditions
  • concentrated glucose and mannitol solutions available

The coma grade often deteriorates by about 1 point/hour during transit

Prognosis

Without transplantation

  • up to 80% die
  • in specialist units approx 30% survive
  • spur cells in peripheral blood indicate poor prognosis
  • presence of jaundice for at least 1 wk prior to onset of encephalopathy associated with poor prognosis

Following transplantation

  • up to 80% 1 year survival. Markedly improved in comparison to results a few years ago at which time in-hospital mortality was 30-40% (cf 10% overall for liver transplantation). Improvement probably due to improved preoperative monitoring, particularly the inclusion of routine ICP monitoring, and a better appreciation of the risk factors for sudden cardiac death.
  • long term prognosis is good

Further reading

Lidofsky SD. Fulminant hepatic failure. Crit Care Clin, 1995; 11:415-430

Sizer E, Wendon J, Bernal W. Acute liver failure in the ICU. In Vincent J-L (ed), Yearbook of Intensive Care and Emergency Medicine 2003. Springer-Verlag, Berlin pp 847-857


 

©Charles Gomersall, August, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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