This is the first in a series on the critical care of the liver patient. You know hepatic failure is bad, so let's discuss the optimal way to care for these patients. Today, we are going to concentrate on Acute Liver Failure (ALF).
Tasneem Pirani
Hepatology and Intensive Care at King's College Hospital. Trained in gastroenterology and intensive care.
Tasneem's Paper
Anaesthesia – 2023 – Van Eldere – Liver intensive care for the general intensivist
Four Main Presentations
- Acute Liver Failure
- Cirrhosis with Acute Decompensation
- Acute on Chronic Liver Failure (ACLF)
- Liver dysfunction secondary to critical illness or Cirrhotic with Non-Liver Critical Illness
Acute Liver Failure
This is defined as a rare and life-threatening clinical syndrome that results after a catastrophic liver insult in an individual both without underlying chronic liver disease and presenting with jaundice, coagulopathy (INR > 1.5) and with an alteration of consciousness due to hepatic encephalopathy. Patients who present without hepatic encephalopathy are considered as having acute liver injury [From Van Eldere et al.]
Jaundice, coagulopathy, and alterations of consciousness, i.e. hepatic encephalopathy (no change in mental status = injury, not failure) in a patient without chronic liver disease. Another prerequisite for defining cases of ALF is the absence of previous severe fibrotic or cirrhotic chronic liver disease. Specific exceptions are the acute de novo presentation of autoimmune hepatitis and Budd-Chiari syndrome. In these conditions, an underlying chronic disease will not have been recognised or diagnosed previously, and there should be no clinical or histological evidence of cirrhosis. Wilson disease is another exception category; a clinical scenario when there is a clear chronic liver disease with splenomegaly, albeit frequently undiagnosed. The precipitant event is often a viral infection, [14] or in adolescents, non-compliance with therapy. Nevertheless, these patients are considered as having ALF since they share the poor prognosis, a common clinical picture of acute failure of the liver, and present with significant coagulopathy and encephalopathy. [from EASL guidelines]
ALF is in contrast to…
Cirrhosis with Acute (Liver) Decompensation
Patients with chronic liver failure or cirrhosis with GI hemorrhage, ascites, hepatic encephalopathy; jaundice or a combination thereof.
Lacks extra-hepatic organ failure
First presentation of cirrhosis or first decompensation after longstanding cirrhosis
not eligible for transplant
key is to prevent progression to ACLF
Acute on Chronic Liver Failure (ACLF)
an episode of acute decompensation in a cirrhotic patient, accompanied by extra-hepatic organ failure involving short term mortality [Chronic Liver Failure Consortium]
Critical Care of the Cirrhotic with Non-Liver Illness
Liver dysfunction secondary to critical illness
Differential of ALF
If Transaminitis in the 1000's (20x the upper limit of normal)
- Viral
- Toxin
- Drug
- Hypoxic/Ischemic (Heart Failure)
- Heat Shock
Presentations of Individual Etiologies of Acute Liver Failure
Transaminase levels > 5000 U/L
Only 3 categories of hepatic insult commonly produce a transaminase level > 5000 U/L: (1) a toxic event, such as acetaminophen toxicity; (2) ischemic hepatopathy; and (3) infection by atypical viruses such as HSV (Mayo Clin Proc, Vol. 81, pg. 1097).
Acetaminophen
POD-induced hepatotoxicity is characterised by extreme elevations of serum aminotransferase (usually >10,000 IU/L) and normal bilirubin levels. Metabolic acidosis, elevated serum lactate, hypoglycaemia and acute kidney injury (AKI) can occur in early stages of clinical evolution.
Ecstasy-induced liver injury
hyperacute presentation resulting from or associated with severe hyperthermia with multiple organ involvement, profound coagulopathy and severe rhabdomyolysis. This clinical picture is identical to other forms of heat shock related liver injury [EASL Guidelines]
Heat Shock
Environmental or Drug Induced
Drug-Induced
The classes of drugs most frequently associated with ALF are antituberculosis drugs (especially isoniazid [61]), antibiotics (especially nitrofurantoin and ketoconazole), anti-epileptics (especially phenytoin and valproate), non-steroidal anti-inflammatory drugs, and a wide group of other medication such as propylthiouracil and disulfiram [EASL Guidlines]
Viral hepatitis
The following hepatic viruses can cause ALF: hepatitis B virus (HBV), hepatitis A virus (HAV) and HEV. HBV is the most common viral cause of severe ALI and ALF, due to either de novo infection, delta superinfection or reactivation in a patient with previous HBV infection.
Other Viral Infections and Auto-Immune are rare
Budd-Chiari syndrome
An acute Budd-Chiari syndrome is characterised by abdominal pain, ascites and hepatomegaly. Diagnosis is made based on imaging of the liver. Testing for hypercoagulable conditions and screening for underlying malignancies are necessary [EASL Guidelines]
Wilson disease
The classic presentation of acute Wilson disease includes HE in young patients (<20 years) with a Coombs negative haemolytic anaemia, and high bilirubin to alkaline phosphatase ratio. In 50% of cases, Kayser-Fleischer rings are present. There is often renal dysfunction and serum uric acid level is low. Serum caeruloplasmin can be very low but may be normal or increased in the acute situation [[EASL Guidelines]
Mushroom poisoning
Mushroom poisoning, usually by amanita phalloides (the most toxic of the mushroom species regarding hepatotoxicity), can cause ALF. Although it occurs very rarely, recent mushroom ingestion should always be sought in a patient with ALI or ALF. There is no routine laboratory test to identify the toxins. Severe gastrointestinal symptoms with profuse vomiting and diarrhea within hours or a day after ingestion is suggestive for mushroom poisoning. The development of acute renal failure, secondary to volume depletion, normally precedes the development of liver failure. Prognosis should be judged in a similar way to the models for other hyperacute syndromes, such as paracetamol.[EASL Guidelines]
Pregnancy related ALF
There are two hepatic emergencies which occur in the third trimester of pregnancy: haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and acute fatty liver of pregnancy (AFLP). HELLP should be differentiated from atypical haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. AFLP is characterised by extensive hepatic steatosis and usually presents with abdominal pain and malaise. Transaminases are relatively low. Hypoglycaemia is common, and elevated urate levels are also seen as maybe polyuria and polydipsia. Other organ failures occur, including pancreatitis. Maternal mortality is around 20%. Prompt delivery of the baby in both these emergency scenarios offers a good outcome, and emergency LTx is rarely needed. Persistent elevation of lactate levels in the presence of severe HE potentially best identifies patients at greatest risk of death or LTx.
When liver failure occurs specifically in pregnancy, consideration should also be given to liver rupture associated with pre-eclampsia. This normally presents as sudden onset of right upper quadrant pain and requires distinction from pulmonary embolus. Management is normally conservative but may require laparotomy and packing if rupture through the capsule causes significant bleeding. Extensive subcapsular haematoma may result in ischaemic compression of liver parenchyma and rarely compression of the hepatic veins, resulting in a syndrome similar to Budd-Chiari [EASL Guidelines]
Ask on History [from EASL]
Drugs – history spanning up to 6 months previous
○ Paracetamol and other over the counter products that contain paracetamol
○ Herbal therapies and food supplements
○ Anabolic steroids
Immunosuppressants/chemotherapy or history of cancer past five years?
Recreational drugs use
○ Drug, frequency of use and source
Alcohol
○ Detailed history on quantity, duration, previous abstinence and support to achieve this
Psychiatric history
○ Formal diagnosis and previous treatment history, previous suicide attempts, inpatient treatment, community support and age at diagnosis
Travel history
○ Location, duration and activities undertaken
Occupation
Recent dietary history
○ New food, especially mushrooms
○ New supplements
○ Uncooked meats and shellfish
Pregnancy
○ Previous history of pre-eclampsia or hyperemesis
○ Natural or assisted conception
Previous episodes of jaundice including childhood jaundice
Family history of liver disease or genetic disorders (e.g. haemochromatosis)
Investigations
Labs
CBC, Chemistry, LFTS, COAGs, Lactate, and Blood Gas as per Tasneem
If they are sick and jaundiced, I would add the following up-front
- Ammonia
- Fibrinogen
- Lipase
- Serum Tox Screen
For Etiology:
Tox Screen
- Urine Drug Screen
- Aspirin and Acetaminophen serum levels
Serological screen for virus infections
•HBsAg, anti-HBc IgM (HBV DNA), (reflex HDV, if positive for HBV)
•anti HAV IgM
•anti-HEV IgM
•anti-HSV IgM, anti VZV IgM, CMV, HSV, EBV, parvovirus and VZV PCR
Possibly Autoimmune markers: ANA, ASMA, anti-soluble liver antigen, globulin profile, ANCA, HLA typing
Hyperacute presentations consist of severe coagulopathy, markedly increased serum transaminases and initially only moderate, if any, increase in bilirubin. In contrast, subacute/subfulminant presentations often have a milder increase in serum transaminases, deep jaundice and mild to moderate coagulopathy. Patients with subacute ALF often also have splenomegaly, ascites, and a shrinking liver volume. Once HE develops, these patients have a very low chance of spontaneous survival. In contrast, hyperacute presentations have a much greater chance of spontaneous recovery, despite having significant extrahepatic organ failure. [from EASL Guidelines]
Strict I/Os
which should be happening on all of your crit care patients
Imaging
- Liver ultrasound ± CT abdomen (triple phase) – main questions to ask include liver architecture and volume, presence of ascites, blood supply in and out of the liver, features of portal hypertension, splenomegaly, evidence of visceral ischaemia or pancreatitis, lymphadenopathy and any evidence of malignancy
- Chest X-ray
- CT brain if evidence if altered GCS
- EKG
Crit Care Management of Acute Liver Failure
Neuro – Hepatic Encephalopathy
Ammonia correlates with severity of HE in ALF (but not in CLD) [15963970 ]
hyperreflexia, clonus, dilated pupils
Do not treat with standard hepatic encephalopathy meds for ALF
Intubation
Osmotic Therapies
Hypertonic was better on secondary outcomes (rebound ICP and renal failure) than mannitol in this RCT [10.1159/000520229]
ICP Bundle
(Sedation, HOB Up, No Neck ties, Avoid Hyperthermia)
CRRT if ammonia > 150 (probably if >100), but patient must have already established hepatic encephalopathy to not ruin transplant list ranking
ICP Monitoring
Do transcranial dopplers have a role?
Evidence for ONSD is mixed.
Pulmonary
May need to treat them as a high ICP patient on the ventilator
Card/Circ
MAP goals as normal in ALF
may shoot for higher MAP if suspicion of ICP Elevation
They recommend starting with NORepi
Echo for hepatic cardiomyopathy
Renal
CRRT with high UF rates if Ammonia 100-150 micromol/L if the patient is in overt HE
Only some patients can tolerate citrate anti-coagulation (and need scrupulous monitoring of Ca if you do it)
ID
Consider empiric antibiotics for ALF, consider anti-fungals if signs of not gaining source control (beta-D-glucan)
C-reactive protein may be falsely low in cirrhotics
Endo
Frequent FS to screen for hypoglycemia
Fluids/Lytes/Nutrition
Enteral feeds, unless ammonia is spiking
Adequate fluids, keep sodium high for ICP
HEME
Elevated INR represents synthetic function of liver and not bleeding risk
Vitamin K supplementation doesn't negatively affect the ability to track progression, but Plasma does
Target normal fibrinogen (>100)
Use visco-elastic testing if available
The patients who bleed: low fibrinogen, elevated aPTT, low platelets (sepsis and/or renal failure are also contributory)
NAC
In all cases of ALF, start and continue for 5 days or when INR<1.5
Extra-Corporeal Liver Therapies
MARS
The Molecular Absorbent and Recirculating System (MARS®) system utilises a hollow fibre, double-sided, albumin-impregnated dialysis membrane, designed to extract protein-bound toxins into the albumin dialysate.
Initial reports suggested improvements in both systemic and cerebral haemodynamic parameters and improvements in HE in patients with ALF
Tasneem recommends only in acetaminophen overdose early in course, but King's doesn't use it at all.
Prometheus system
which separates plasma and treats it over adsorbent columns, has reported benefit in AoCLF but has not been studied in ALF
Extracorporeal Liver Assist Device (ELAD®) system
which utilises hepatoblastoma cell lines, has been studied in various contexts and shows some benefit in physiology and biochemical parameters
Plasma Exchange
RCT positive in ALF [J Hepatology 206;64:69]
Plasma exchange (PE) in patients with ALF, undertaken on the first 3 days of admission to critical care, has been shown to have physiological and biochemical benefits, and to decrease ICP in case series [308,309].
High Volume Plasma for Liver Failure
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962432/
10.1097/LVT.0000000000000231
ECMO for Hemodynamics in ALF
vs. our perceptions of dismal outcome in cirrhotics, these pts have a better prognosis
Referral Criteria
Acute Liver Failure
For ANY patient presenting with ALF, early discussion and advice from specialist center is encouraged.
Especially consider for:
Acetaminophen induced ALF if:
Arterial pH < 7.30 or HCO3 < 18
INR > 3.0 on day 2 or > 4.0 thereafter
Oliguria and/or acute kidney injury
Altered level of consciousness
Hypoglycaemia
Elevated arterial lactate (> 4 mmol.l−1) unresponsive to fluid resuscitation
Non-acetaminophen induced ALF if:
pH < 7.30 or HCO3 < 18 mmol.l−1
INR > 1.8
Oliguria/renal failure or Na < 130 mmol.l−1
Encephalopathy, hypoglycaemia or metabolic acidosis
Bilirubin > 300 umol.l−1
Shrinking liver size
EASL Guidelines
- EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure DOI:https://doi.org/10.1016/j.jhep.2016.12.003
Additional New Information
More on EMCrit
- IBCC – Acute Liver Failure
- IBCC – Acute on Chronic Liver Failure (ACLF)
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