Acute liver failure: diagnostics, intensive care, treatment and prognosis

Acute Liver Failure

Acute liver failure is defined as progressive liver disease with encephalopathy and INR > 1.5 in a person without previously known liver disease. In the following text, the English abbreviation ALF (Acute Liver Failure) is used.

The condition is characterized by rapid deterioration of the liver’s synthetic capacity and results in coagulopathy and encephalopathy that develop within days to weeks. ALF is often preceded by nausea and vomiting. The condition is often complicated by multiple organ failure (MODS) with vasoplegic cardiovascular failure, kidney failure, and cerebral edema, as liver necrosis triggers the inflammation cascade. Resuscitation with fluids (crystalloids, albumin), vasopressors (norepinephrine), and adequate oxygenation (O2, ventilator) prevents further ischemic organ damage and stimulates hepatocyte regeneration. There is a high risk of hypoglycemia, and blood glucose levels must be closely monitored and treated. Patients with acute liver failure may initially appear unaffected but can deteriorate rapidly with the development of multiple organ failure.

The classification of ALF is crucial as the time frame for the onset of symptoms affects prognosis. O’Grady’s classification can be used as follows:

1. Hyperacute liver failure. Encephalopathy develops within 7 days of the onset of jaundice. This condition carries the greatest risk of cerebral edema.
2. Acute liver failure – development of encephalopathy from 8 to 28 days after jaundice. (Considerable risk of cerebral edema).
3. Subacute liver failure – development of encephalopathy 28 days to 12 weeks after jaundice. (Low incidence of cerebral edema).

The incidence of cerebral edema is highest in the hyperacute group, and the prognosis without liver transplantation is worst in the subacute group. When ALF has a toxic cause, such as an overdose of acetaminophen, poisoning with Amanita phalloides (death cap mushroom), or ischemia, encephalopathy may appear before visible jaundice and nausea. ALF is a condition where severity depends on how many hepatocytes are destroyed.

Acute-on-chronic liver failure assumes an underlying liver disease and is defined as an acute worsening of a chronic liver disease, often in connection with a triggering factor. The condition is relatively common, affecting 3–7 percent of patients with liver cirrhosis each year. Decompensation episodes that reverse can occur, but about 30 percent progress to a more severe stage with multiple organ system failure. In cases of multi-organ failure requiring intensive care, mortality is high. In the following text, the English abbreviation ACLF (Acute-on-Chronic Liver Failure) is used.

Causes of Acute Liver Failure

The cause of ALF varies between different parts of the world. In developing countries, viral hepatitis predominates. In Europe and the USA, drug-induced liver injury is the most common cause. Within Europe, the etiology of ALF varies; in Spain, viral hepatitis is the most common cause of ALF, while in Scandinavia and the UK, drug-induced ALF (primarily acetaminophen) predominates. In 11% of patients in Sweden, the cause of liver failure is not found (17% in the UK). These are called cryptogenic liver failure or NANBNC hepatitis (non-A non-B non-C hepatitis).

In Sweden, 42% of ALF is caused by acetaminophen, 15% by other drugs, 3% by HAV, 4% by HBV, and 25% by other causes, such as ischemic hepatitis, autoimmune hepatitis, Budd-Chiari syndrome, malignancy, mushroom poisoning, Wilson’s disease, pregnancy-induced liver failure (1-3% HELLP – Hemolysis Elevated Liver enzymes and Low Platelets), AFLP. Causes of ALF can overlap with causes of ACLF (acute-on-chronic liver failure).

Viral Hepatitis

• Hepatitis A, B, C, D, and E
• Herpes simplex 1 and 2
• Human herpesvirus 6 (HHV-6)
• Epstein-Barr virus (EBV)
• Cytomegalovirus (CMV)
• Varicella-zoster virus (VZV)
• Parvovirus B19
• Adenovirus (children)

Drugs and Substances That Can Cause ALF

• Acetaminophen
• Other drugs; (idiosyncrasies or direct toxic effects), e.g., NSAIDs, tricyclic antidepressants (TCA), SSRIs, neuroleptics, valproate, carbamazepine, phenytoin, disulfiram, tuberculosis drugs, antifungals, amiodarone, lisinopril, verapamil, sulfasalazine, chemotherapy drugs, etc.
• Inhalation anesthetics like sevoflurane, desflurane
• Illegal drugs – cocaine and ecstasy
• Internet drugs – new psychoactive substances with unclear effects are constantly emerging on the market.
• Alcohol – in the context of ACLF.

Toxins

• Mushroom poisoning – death cap and destroying angel mushrooms (Amanita virosa, Amanita phalloides). Amatoxin and phallotoxin.
• Certain herbal medicines
• Organic solvents – carbon tetrachloride, perchloroethylene, acetone, etc.
• Elements – phosphorus, copper, lead, iron
• Insecticides

Immunological Causes

• Autoimmune hepatitis: ANA, SMA, AMA
• Heatstroke: often in combination with a drug that causes hyperactivity and/or disturbed thermoregulation.
• GVHD after bone marrow or intestinal transplantation

Bacterial Infections

• Sepsis
• Food poisoning (Bacillus cereus, etc.)
• Liver abscess – sepsis, tropical diseases, etc.
• Miliary TB

Metabolic Conditions

• Wilson’s disease (copper accumulation in the liver)
• Hemochromatosis
• Pregnancy-induced liver failure
  • AFLP (acute fatty liver of pregnancy)
  • HELLP (hemolysis elevated liver enzymes and low platelets) in preeclampsia.
• Reye’s syndrome – affects children after a viral infection

Circulatory-Associated Causes

• Arterial ischemia/anoxia – low or temporarily halted perfusion in advanced left ventricular failure, circulatory arrest, severe bleeding, etc.
• Venous stasis – hepatic vein thrombosis, right ventricular failure, pulmonary embolism, etc.
• Thrombosis – hepatic artery
• Intravenous leiomyomatosis

Malignant Infiltration of the Liver

• Hepatocellular carcinoma (HCC)
• Cholangiocarcinoma
• Lymphoma
• Non-Hodgkin lymphoma
• Hodgkin’s disease
• Leukemia
• Malignant melanoma
• Malignant histiocytosis
• Metastasis

Symptoms and Clinical Findings in Acute Liver Failure

The clinical presentation of acute liver failure varies depending on how quickly the condition develops (compare hyperacute, acute, and subacute liver failure). Regardless of the original cause, ALF produces symptoms that differ from those seen in chronic liver disease (see later ACLF).

Often, non-specific symptoms such as fatigue and nausea develop in a previously healthy individual. This is followed by jaundice and lethargy, which can quickly progress to coma, sepsis, and multiple organ failure (MODS). The progressive liver damage causes the primary symptoms and leads to multiple complications in various organs and systems (activation of both pro- and anti-inflammatory cytokines, SIRS).

Differential Diagnoses

• Sepsis with MODS
• Drug overdose (narcotics)
• Circulatory failure with secondary severe liver damage
• Cerebral edema in herpes encephalitis with concurrent liver damage (compare primary herpes hepatitis)

Investigation and Testing in ALF

Must be done quickly as the patient’s condition can deteriorate rapidly.

Diagnosis of ALF – probable etiology based on history and other available information (possibly liver biopsy). History: Obtain a detailed history as early as possible to avoid missing the “window” before potential encephalopathy complicates or prevents the patient from providing their own history. Obtain history from relatives. Previous illnesses such as autoimmune diseases, thromboembolism, psychiatric illnesses, cardiovascular diseases, malignancies, pain syndromes, impaired immune function, etc.

Further routine procedures include:

• Prognostication and transplant assessment
• Hemodynamic monitoring to detect complications early (ICU patient)

Observe underlying contributing causes:

• The goal is to identify treatable etiology for ALF to improve survival among those who are not transplant candidates and those who could have been transplanted but were not operated on.
• Onset of symptoms over time (to determine whether liver failure is hyperacute, acute, or subacute). Time of first symptoms (which may be non-specific such as fatigue and nausea). Time of jaundice and altered mental status.
• Compilation of all drug exposures in the last 3-6 months. Note any overconsumption of acetaminophen. Of particular interest are antiepileptics, antibiotics, NSAIDs. Note any intoxication events.
• Herbal medicines
• Drug use, especially intravenous drug use, but not limited to it.
• Alcohol
• Travel history: Endemic areas for viral hepatitis.
• Risk factors for hepatitis A and E. Whether the patient consumed food or water that may have been contaminated, lived with infected family members, or had sexual partners with possible infection.
• Risk factors for hepatitis B, C, D, and HIV: intravenous drug use, drug paraphernalia, risky sexual activities, tattoos (especially if performed in countries where needles are not routinely sterilized).
• Mushroom exposure from the genus Amanita (death cap, destroying angel). These are most common in Europe but also occur in North Africa, Asia, and parts of the USA.

Testing

• S-acetaminophen
• Toxicology screening in urine (amphetamine, ecstasy, etc.) + other acute intoxication tests in serum according to local routines (ethanol, S-salicylate, etc.). If strong suspicion, special testing for synthetic internet drugs (urine/blood)
• S-Fe, S-TIBC, and S-ferritin (hemochromatosis)
• Ceruloplasmin, (24h urine copper – Wilson’s disease)
• Arterial blood gases + intensive care tests including coagulation tests and liver function tests, etc.
• Blood cultures (aerobic + anaerobic)
• Urine culture and microscopic urine analysis
• Autoantibodies: ANA (antinuclear antibodies), SMA (smooth muscle antibodies), and AMA (mitochondrial antibodies)
• Alpha-1-antitrypsin

Hepatitis Serology

• Anti-HAV IgG, IgM
• HbsAg: if positive: take HBV-DNA quantitative, anti-HDV, (HBeAg, anti-HBE)
• Anti-HBc IgM: if positive, HBV-DNA quantitative
• Anti-HCV: if positive, take HCV-RNA quantitative (sometimes it is recommended to take HCV-RNA directly as Anti-HCV may be negative early).
• Anti-HEV IgG: if positive, PCR HEV in blood and stool.
• Anti-EB IgG, IgM (Epstein-Barr)
• Anti-HSV 1 and 2 (Herpes Simplex)
• Anti-VZV (Varicella zoster virus)
• Anti-CMV IgG, IgM
• HIV serology
• (Parvovirus B19 IgG, IgM)

Clinical Examinations

• Liver ultrasound with Doppler to assess liver parenchyma and blood flow to and from the liver
• CT abdomen to rule out ascites and malignancy
• Echocardiography
• Chest X-ray
• CT brain

Prognostic Assessment

Hepatologists (O’Grady et al.) at King’s College Hospital in London developed prognostic criteria (1989) for indications for liver transplantation. Many have attempted to evaluate the performance of the KCH criteria. The largest meta-analyses have found that the KCH criteria for non-acetaminophen-induced liver damage have a sensitivity of 68% and a specificity of 82%. The KCH criteria have a sensitivity of 58% and specificity of 95% for acetaminophen-induced liver damage. The balance is difficult between missing patients who would have survived with transplantation and patients who would have survived without transplantation.

King’s College Criteria for Liver Transplantation in ALF

In acetaminophen-induced liver damage:

• Arterial pH < 7.30 after fluid resuscitation
• or all of the following:
• INR > 6.5
• S-creatinine > 300 μmol/l
• Encephalopathy grade 3/4

In non-acetaminophen-induced liver damage:

• INR > 6.5 or at least three of the following:
• NANB (unknown)/drug/halothane etiology
• Onset of encephalopathy > 7 days after jaundice onset
• Age < 10 or > 40 years
• INR > 3.5
• S-bilirubin > 300 μmol/l

MELD Score

A tool for prognosticating short-term survival (months) is the Model of End-Stage Liver Disease score (MELD), which is calculated based on values of bilirubin, INR, and serum creatinine. It is used to assess the need for liver transplantation.

Click here for a link to the MELD calculator

The formula for MELD is: = 9.57 x log e(creatinine mg/dL*) + 3.78 x log e (bilirubin mg/dL**) + 11.20 x log e (INR) + 6.4

* Creatinine 1 mg/dL = 88.4 μmol/L. ** Bilirubin: 1 mg/dL = 17.1 μmol/L

Three-month survival of liver failure is at:

• MELD score 20: > 90%
• MELD score 30: 60%
• MELD score 40: 10%

Care Level

A patient with ALF and Encephalopathy grade 2 (Modified Parsons-Smith Scale) (Equivalent to GCS 11-14) is cared for in an intensive care unit. Patients in this group may be referred to a transplant center for liver transplantation assessment. If the patient develops encephalopathy grade 3-4, transport between hospitals becomes difficult or impossible due to the high risk of brain herniation.

Care responsibility
At a transplant center, the patient is assessed by a team of:

1. Hepatologist
2. Transplant surgeon
3. ICU physician and transplant anesthesiologist.

West Haven grading of Hepatic Encephalopathy

Treatment of ALF

The goal of medical treatment is to support vital functions and create conditions for hepatocyte regeneration and optimize the patient for potential liver transplantation.

• Acetylcysteine infusion as follows: 350 mg/kg in 100 ml NaCl 0.9% over 15 minutes followed by 50 mg/kg in 100 ml NaCl 0.9% over 4 hours. Then 100 mg/kg in 200 ml NaCl 0.9% over 24 hours. The treatment should start at the referring hospital. Evidence shows that acetylcysteine is effective even in non-acetaminophen-induced liver damage if encephalopathy grade < 3 and the patient is an adult. Treatment with acetylcysteine lasts a maximum of 5 days. Start acetylcysteine infusion according to protocol as soon as possible.
• Early initiation of continuous venovenous hemofiltration (CRRT), preferably with CVVH settings and high flow rates.
• Monitor arterial ammonia levels.
• Sodium levels should be kept high to reduce the risk of cerebral edema. If encephalopathy grade > 3, S-Sodium levels between 145-155 mmol/l are recommended.
• In case of hypoglycemia, which is common in ALF, 10-20% glucose solution IV. ALF is a catabolic state. Enteral nutrition is recommended without protein restriction (1-1.5 g/kg/day). A caloric intake of 600-800 kcal/day for the first week is considered sufficient. Vitamin deficiencies are common in ALF and must be replaced.
• Vitamin K (phytomenadione) 10 mg x 1-2 IV.
• Ulcer prophylaxis (omeprazole) with injection Pantoloc 40 mg x 1 IV.
• Lactulose is no longer recommended in ALF due to the risk of dehydration.
• Antibiotic prophylaxis with, for example, Meronem and antifungals. Primarily Ecalta (anidulafungin) as it has minimal liver impact (200 mg on day 1, then 100 mg per day).
• Antiviral treatment for confirmed viral hepatitis. If ALF is suspected to be caused by hepatitis B, treatment must be initiated immediately, and this will likely also apply to hepatitis C now that new non-toxic antivirals are available.
• Seizure prophylaxis can be considered if the patient is on a ventilator and EEG is not available.

Medical Management of Acute Liver Failure

Monitoring

The patient usually requires invasive monitoring. Coagulopathy in liver failure includes both pro- and antithrombotic components. The INR value in liver failure is rarely associated with an increased risk of bleeding. Thromboelast ography (TEG) can be helpful (normal in 45%, hypercoagulable in 35%, and hypocoagulable in 20%). Plasma administration should be avoided if possible as it complicates further assessment of liver failure progression. Factor concentrates like octaplex increase the risk of thrombotic complications. Plasma, fibrinogen, and platelets are recommended only in cases of active bleeding or when placing a parenchymal monitor for measuring intracranial pressure (ICP). Temporary correction of coagulation lasts 2-6 hours, and thrombotic complications are possible during this time.

Arterial line, CVP line, NGT, urinary catheter with hourly urine output measurement. Hemodynamic monitoring with, for example, PICCO in cases of circulatory instability, which is common in ALF. PA catheter may be considered.

ICP monitoring may be necessary (highest risk of cerebral edema in hyperacute and acute ALF).

Daily testing: (some tests are performed multiple times per day, ordered on a case-by-case basis)

Hgb, WBC, platelets, CRP, Procalcitonin, Sodium, Potassium, Phosphate, Magnesium, Calcium, Creatinine, Urea, Albumin, Liver function tests, INR, P-amylase, a-PTT, Antithrombin III, fibrinogen, D-dimer, TEG, repeated arterial blood gases: blood glucose, lactate, ammonia levels are monitored. Daily blood cultures.

Special Monitoring and Treatment

In ALF, the two most common causes of death are:

1. Sepsis with MODS
2. Cerebral edema with brain herniation (previously the most common cause of death (before 1990))

Survival in patients with ALF has greatly improved over the past 4 decades. This has been achieved through improved medical management and liver transplantation when necessary. This applies primarily to the hyperacute and acute groups of ALF. In the subacute group, survival remains low without transplantation. The natural course of ALF has changed, with sepsis now occurring later in the course and fewer patients developing cerebral edema with increased intracranial pressure. In patients with subacute onset, even low-grade encephalopathy may indicate a very poor prognosis, while in patients with hyperacute onset, survival with medical management can be high even in patients with high-grade encephalopathy.

CNS

Cerebral edema with intracranial hypertension affects 20% of patients with ALF (2004-2008). It is most common in hyperacute and acute ALF. Hyperammonemia and high concentrations of organic osmolytes in astrocytes are central to the pathophysiology. Systemic inflammation and recurrent infections, together with hyperammonemia, accelerate the development of cerebral edema. Both clinical symptoms and CT brain scans are non-specific. Persistent ICP above 30 mm Hg can be expected to lead to decreased consciousness, agitation, systolic hypertension, increased muscle tone with extension spasms, hyperventilation, and abnormal pupil reactions. Rapid progression to deterioration is common.

EEG – continuous EEG is recommended in the literature for non-convulsive status.

Encephalopathy – grade according to the following 

Patients with ALF can progress from encephalopathy grade 1 to grade 3 or 4 with severe intracranial pressure increase within a few hours. It is therefore important to regularly assess the degree of encephalopathy. Pupil checks should be performed every hour if the patient is unstable.

ICP monitoring may be considered in the following cases: (highest risk of cerebral edema in hyperacute and acute ALF).

1. If arterial ammonia levels exceed 150 μmol/l for more than 24 hours.
2. In case of severe hyponatremia (less than 130 mmol/l)
3. Abnormal pupil reflexes or seizures
4. Encephalopathy grade 3-4 or when the patient is intubated.
5. Three of four SIRS criteria
6. ALF patient requiring vasopressor support and developing renal failure

A neurosurgeon places the ICP monitor if necessary (a parenchymal monitor can be placed epidurally to minimize bleeding risk). The patient receives plasma, platelets, and fibrinogen immediately before the procedure. Coagulation targets are ordered on a case-by-case basis. Testing for INR, a-PTT, fibrinogen, platelets, TEG, and possibly multiplate before the procedure. Aim for ICP below 20 mmHg and CPP above 55 mmHg.

Measures to prevent high ICP:

1. Maintain high tonicity (S-Na 145-155 mmol/l)
2. Early CRRT with high flow rates (CVVH settings). Monitor ammonia levels.
3. Elevate head of bed to 30 degrees.
4. Normovolemia
5. Normoventilation with adequate oxygenation (PaO₂>12 kPa).
6. Blood glucose 6-8 mmol/l
7. Normal temperature
8. Adequate sedation: Short-acting agents like propofol/ultiva facilitate assessment of wakefulness.

If ICP/CPP problems arise: (buying time for life-saving urgent liver transplantation)

1. Increase sedation: induces hypometabolic vasoconstriction in the brain
2. Administer hypertonic saline or mannitol (hypertonic saline is preferred because the BBB is less permeable to, for example, rescueflow due to its higher polarity compared to mannitol) (reflection coefficient 1.0 for hypertonic saline compared to 0.9 for mannitol).
3. CRRT with high-flow CVVH. Reduces circulating ammonia. Avoid disequilibrium by adding sodium to dialysis fluids to match the patient’s S-Na (should be 145-155) or administering hypertonic saline IV.
4. Induce mild hypothermia: (however, this can have other negative consequences such as impaired coagulation, etc.)
5. Hyperventilation to buy time.
6. NSAIDs (indomethacin 0.5 mg/kg IV) may be considered in manifest intracranial hypertension with documented cerebral hyperemia.
7. Barbiturates are not recommended in ALF with high ICP but may be tried in therapy-resistant intracranial hypertension.

Respiration

Early elective intubation with mechanical ventilation may be necessary even before transport to the transplant center. However, it is common for the patient to arrive non-intubated to facilitate assessment. The literature recommends intubation at Encephalopathy grade > 2. Note that these patients have a high aspiration risk. Sedate patients with short-acting agents (remifentanil /propofol) to facilitate assessment even after intubation. PEEP levels below 10 mmHg and normoventilation are recommended.

Circulation

Hemodynamic instability is common in ALF. It is characterized by pronounced vasodilation with hypotension and a hyperdynamic increase in cardiac output. At the microcirculatory level, oxygen uptake is impaired with abnormal shunting. Hyperlactatemia is common. The literature recommends:

1. Maintain MAP > 65 mmHg
2. Administer volume. Albumin first, crystalloids second, avoid starch solutions.
3. If vasopressors are needed for adequate MAP, norepinephrine is the first choice.
4. Terlipressin can be added if necessary.
5. Extend circulatory monitoring if necessary (PICCO, Swan-Ganz, etc.).
6. In cases of therapy-resistant hypotension, hydrocortisone may be tried.

Kidneys

Renal failure is a common complication of ALF. The cause is considered multifactorial, including sepsis, SIRS, hypovolemic renal hypoperfusion, drug-induced nephrotoxicity (e.g., aminoglycosides, radiographic contrast agents, and acetaminophen), cadmium release from necrotic liver, and finally intra-abdominal hypertension. Prevention of renal failure is important by removing nephrotoxins, limiting the use of intravenous contrast, maintaining adequate MAP, and ensuring adequate circulating volume.

The literature recommends the following in cases of renal failure as a complication of ALF:

1. Maintain MAP > 70 mmHg (slightly higher than the recommendation above).
2. Avoid positive fluid balance if possible.
3. Measure intra-abdominal pressure.
4. In cases of oliguria despite optimal plasma volume and MAP, early initiation of CRRT is recommended, preferably in CVVH mode. (In our practice, CVVHDF with 0 in dialysate).

Coagulopathy

Monitor coagulation status with extended specific testing. Use TEG and possibly “multiplate” for graphical monitoring. Platelet concentrate and fibrinogen may be needed before invasive procedures.

Coagulopathy in liver failure causes both pro- and antithrombotic effects. Plasma should be avoided if possible, as it complicates further assessment of liver failure progression. The PT value in liver failure is rarely associated with increased bleeding risk. Instead, thromboelastometry is monitored. Platelet levels in patients not yet undergoing surgery should be kept above 30 (higher if there is an increased bleeding risk) to reduce the risk of intracerebral bleeding. Plasma, fibrinogen, and platelets are recommended only in cases of active bleeding and invasive procedures with high bleeding risk, such as the placement of a parenchymal monitor for intracranial pressure (ICP) measurement. A central venous catheter (CVC) can be placed without coagulation optimization if a puncture site is easily located using ultrasound guidance. Factor concentrates may increase the risk of thrombotic complications and are given only in cases of life-threatening bleeding. Temporary correction of coagulation lasts 2–6 hours, during which time there is a risk of thrombotic complications. Thromboprophylaxis with low molecular weight heparin is recommended unless there are clinical signs of bleeding. Individual dose adjustment may be needed based on prolonged a-PTT.

Infection Control

This patient group is very susceptible to infections, and a severe infection within a few days is more the rule than the exception. ALF patients are highly susceptible to bacterial and fungal infections. There should be a low threshold for starting antibiotics in ALF, but prophylactic antibiotics have unfortunately not been shown to improve survival. Classical signs of infection such as fever and leukocytosis are often absent. CRP and procalcitonin may be of value, but no inflammation parameter can be fully trusted. The practice is nevertheless prophylactic broad-spectrum antibiotics with Meronem and antifungal agents, preferably anidulafungin (Ecalta) as it has low liver toxicity and does not need dose adjustment for liver or renal failure. An alternative is Mycamine (Micafungin), which does require dose adjustment in severe liver failure. Another well-established antifungal agent is Ambisome (Amphotericin B). Infection control recommends Ecalta as the first choice in severe liver failure (of course, treatment should be guided by culture results with resistance testing).

MARS (Molecular Adsorbent Recycling System)

A French controlled multicenter study (Saliba, Camis, Durand et al.) on ALF could not demonstrate increased survival with MARS. The majority of patients received only one treatment as they were transplanted within 24 hours. A subgroup analysis showed a trend towards increased survival in acetaminophen-induced ALF. Transplant-free survival was significantly longer in patients who received at least three MARS treatment sessions.

A Finnish study on ALF (Kantola et al.) (113 patients between 2001-2007 compared with a control group of 47 patients between 1995-2001) showed a survival benefit with MARS even in transplanted patients treated before transplantation. However, the improvement was considered a result of advancements in intensive care, anesthesia, and surgical techniques rather than MARS itself. The RELIEF study, conducted on the AoCLF patient group, also did not show increased survival with MARS. However, the improvement in encephalopathy grade was significant.

High-Volume Plasmapheresis (Plasma Exchange)

Preliminary studies show promising results. Sixteen percent of body weight is exchanged with plasmapheresis daily for three days (Fin Stolze Larsen, Copenhagen). A study is soon to be published that, according to the abstract, shows a 20% survival benefit in a group that was not transplanted but was treated with high-volume plasmapheresis. This may become the first temporary liver support system to show a significant survival benefit in ALF.

”Urgent Call” for Liver Transplantation

In ALF or in cases of early retransplantation after liver transplantation, there is an option within the framework of Scandiatransplant to place the patient on the liver transplantation waiting list with a request for “urgent call.” Urgent call means that the patient has priority for the first suitable (blood group-compatible) donor in the Nordic region. This priority exists for three days. If two “urgent patients” are listed simultaneously, the one listed first has priority. Once the three days have expired, the transplanting clinic can issue an appeal, which is usually respected.

Note that “urgent call” cannot be used for patients with chronic liver failure. Indications for urgent retransplantation may include “primary non-function” (the transplanted liver is not functioning well), arterial thrombosis, portal vein thrombosis, or severe rejection. There is no defined time interval after transplantation for this, and it is assessed on a case-by-case basis. Listing the patient on the waiting list as urgent call is done by the responsible transplant surgeon.

References

• Acute Liver Failure Lancet 2010;376:190-201. W Bernal, G Auzinger, Julia Wendon.
• Acute Liver Failure NEJM 369;26 NEJM.ORG December 26, 2013 W Bernal, J Wendon.
• Critical Care in Acute Liver Failure (Roger Williams and Julia Wendon) 2013. Future Medicine. ISBN: 978-1-78084-257-8
• Acute hepatic failure (PACT 2012) Chris Willars and Julia Wendon.

Acute upon Chronic Liver Failure – ACLF

The triggering causes of acute decompensation in a chronic condition vary between countries. In Europe, infections and alcohol predominate, but nearly half of the cases lack a detectable etiology.

Triggering Causes in Patients with Known Liver Disease and Previous Liver Failure

• Bacterial infection: 33%
• Alcohol: 25%
• GI bleeding: 13%
• Multiple causes: 13%
• No detectable cause: 44%

Clinical Course and Prognosis

The clinical picture varies depending on the underlying diagnosis and how quickly the condition develops, but it differs from symptoms seen in chronic liver disease. The progressive liver damage causes primary symptoms and leads to multiple complications across several organs, with activation of both pro-inflammatory and anti-inflammatory mechanisms. It is crucial to characterize the progression of liver failure and determine if there is a primarily treatable cause (e.g., virus, autoimmune disease, fungal toxin, infection).

Liver failure often starts with non-specific symptoms such as fatigue and nausea in a previously healthy individual. This is followed by jaundice and lethargy, which can quickly progress to coma, sepsis, and multiple organ failure (MODS). Assessing the etiology and character of the progression (classification according to O’Grady) is essential, as the time for symptom development is linked to prognosis.

Classification ACLF

Classification of Organ Failure and 3-Month Mortality

• Grade 1: Encephalopathy grade 3–4 plus kidney failure, or severe kidney failure with creatinine >178, or failure in one organ system + kidney failure
  3-Month Mortality: 41%
• Grade 2: Failure in two organ systems excluding the kidneys
  3-Month Mortality: 52%
• Grade 3: Failure in three or more organ systems
  3-Month Mortality: 79%

Mortality in ACLF is primarily determined by the number of failing organs and the extent to which the underlying liver disease has progressed and impacted the patient’s overall condition. Direct complications from portal hypertension, such as bleeding esophageal varices, can also be critical for a fatal outcome.

Interventions Against Encephalopathy in ACLF

• Medications with direct or indirect sedative effects are discontinued/reduced (also in ALF).
• Lactulose is dosed until bowel movements occur, initially 30 ml every other hour.
• Rifaximin 550 mg x2 tablet via tube (in consultation with a hepatologist).
• Metronidazole 200–400 mg x2 IV (in consultation with a hepatologist).

Cerebral edema with intracranial hypertension affects approximately 20% of patients with ALF, usually in the hyperacute and acute forms, but is rare in ACLF. Both clinical symptoms and brain CT are non-specific. Persistent ICP above 30 mmHg may lead to decreased consciousness, agitation, systolic hypertension, increased muscle tone with posturing, hyperventilation, and abnormal pupil response.