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Synonyms and keywords: Liver failure; fulminating hepatic failure
- The original definition of Acute liver failure by Trey and Davidson was in 1959.
- In the late 1980s and early 1990s, more terminologies of Acute liver failure proposed.
- Term of Acute-on-chronic Liver failure suggested by Jalan and willimas in 2002.
Three forms are recognized:
- Acute liver failure -when liver failure occurs rapidly. The most reliable signs of severe acute liver injury are prolonged international normalized ratio ([INR] ≥ 1.5) and any degree of hepatic encephalopathy, in patients without preexisting liver disease and the illness duration is less than 26 weeks.
- Chronic liver failure - When liver failure occurs as a result of cirrhosis. It usually means that the liver has been failing gradually for some time (more than 26 weeks), possibly for years. This is called chronic liver failure or End-stage Liver Disease (ESLD).
- Acute on Chronic Liver Failure - when acute hepatic decompensation observed in patients with preexisting chronic liver disease within 4 weeks, characterized by one or more extrahepatic organ failures and with a significantly increased risk of death.
- Hepatic injury results in hepatocyte necrosis which occurs due to ATP depletion causing cellular swelling and cell membrane disruptions. Most cases of Acute liver failure (except acute fatty liver of pregnancy and Reye syndrome) will have massive hepatocyte necrosis and/or apoptosis which ultimately result in liver failure. Secondary multi-organ failure occurs after hepatic failure.
- Cause-specific pathophysiologies:
- Immune-mediated hepatocellular injury: :
- Direct hepatocellular injury:
- Toxic metabolites: Acetaminophen, metabolic disorders
- Acetaminophen is predominantly metabolized in the liver through glucuronidation and sulfation, with a small amount metabolized by the cytochrome P450 system. Its metabolite, N-acetyl-p-benzoquinone imine (NAPQI), generated via the P450 pathway is subsequently conjugated by glutathione. In the setting of acetaminophen overdose, glutathione stores may become depleted, resulting in direct hepatocyte injury via NAPQI
- Toxins of Amanita phalloides(amatoxins, phallotoxins, and virotoxins) which inhibit RNA polymerases, cause necrosis of the liver, also partly in the kidney, with the cellular changes causing the fragmentation and segregation of all nuclear components.
- Toxic metabolites: Acetaminophen, metabolic disorders
- Ischemic hepatocellular injury:
- Secondary multiorgan failure is often a result of the initial massive proinflammatory response in reaction to pathogen‐specific molecular patterns (PAMPs) from heterotropic viruses as well as a response to damage‐associated molecular patterns (DAMPs), such as histones, DNA, and high mobility group box‐1 proteins released from injured cells upon hepatocyte death secondary to toxic etiologies which generating a systemic inflammatory response syndrome( SIRS) followed by a compensatory anti‐inflammatory response leading to immune cell dysfunction and sepsis. Dysregulation of systemic vascular tone leads to low systemic vascular resistance, causing hypotension and peripheral vasodilation results in poor pulmonary oxygen exchange, impaired tissue oxygen delivery, and lactic acidosis. Cerebrovascular and renovascular tone are most affected, resulting in cerebral hyperperfusion and hepatic encephalopathy along with functional renal failure. In the brain, altered blood-brain barrier occurs secondary to inflammatory mediators leading to microglial activation, accumulation of glutamine secondary to ammonia crossing the BBB, and subsequent oxidative stress leading to depletion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP). This ultimately leads to astrocyte swelling and cerebral edema and hepatic encephalopathy.
- To put it in the short statement,Acute liver failure results in hemodynamic instability. It is initially associated with hypovolemia due to a combination of poor oral intake and increased fluid loss. As Acute liver failure progresses, the release of circulatory cytokines and inflammatory mediators cause systemic vasodilation and worsens hypotension. The end results are low systemic vascular resistance, systemic hypotension, and increased cardiac output resembling septic shock. These hemodynamic changes lead to decreased peripheral tissue oxygenation and eventually multiorgan failure.
- Chronic liver failure is the result of Cirrhosis which is is an advanced stage of liver fibrosis that is accompanied by distortion of the hepatic vasculature.
- The pathogenesis of Acute-on-chronic liver failure is unclear but many theories are proposed in such as neutrophilic dysfunction that increases the risk of infections, circulating changes, oxidative stress, and toxin hypothesis.
|Category||Etiology of Acute liver failure|
- Acetaminophen hepatotoxicity is the most common cause of ALF in the U.S. and Europe. It results from excessive ingestion of acetaminophen either from suicidal ideations or inadvertent use of supratherapeutic doses for pain control. Increased production of the toxic metabolite N-acetyl-p-benzoquinone imine causes hepatic injury. Acetaminophen toxicity is dose-related with typically at least 10 gram/day required to cause ALF.
- Drug-induced liver injury is the cause of about 50% of ALF cases in the U.S. Many over-the-counter medications, weight loss medications, and prescription medications can lead to acute liver injury. Liver injury from drugs could be dose-dependent and predictable (acetaminophen toxicity) or idiosyncratic and unpredictable (carbamazepine, valproate).
- Viral hepatitis is the most common cause of acute liver failure worldwide and is the predominant cause of ALF in developing countries. The most common viruses are hepatitis A, B, and E infections as well as other rare viral causes including herpes simplex virus, epstein-barr virus, cytomegalovirus, and parvoviruses.
- Amanita phalloides is the most common mushroom to cause hepatotoxicity. History of recent mushroom ingestion should be obtained in patients who present with severe gastrointestinal (GI) symptoms such as nausea, vomiting, abdominal cramping, and diarrhea. Symptoms usually start within 6 to 12 hours of mushroom ingestion. The diagnosis of mushroom poisoning is made clinically because no blood test is available to confirm the diagnosis.
Causes of chronic liver failure
- Chronic liver failure usually occurs in the context of cirrhosis. Cirrhosis must be differentiated from other causes of abnormal liver function tests. In patients with stable cirrhosis, decompensation may occur due to various causes:
- Increased alcohol intake
- Bleeding from esophageal varices or dehydration
- Acute liver failure is a distinctive syndrome that is not confused with other conditions. The major differential diagnosis is in the cause of acute liver failure, whether viral (hepatitis A, B, C, D or E), autoimmune, metabolic (Wilson disease), drug-induced or idiopathic.
Epidemiology and Demographics
- Acute liver failure affects approximately 2,000–3,000 Americans each year.Acute liver failure was responsible for 3.3% of US liver transplants in 2017.Drug-induced hepatotoxicity occurs for more than 50% of acute liver failure cases including Acetaminophen toxicity (42%) and idiosyncratic drug reactions. Nearly 15% of cases remain of indeterminate etiology.
- Chronic liver disease and Cirrhosis are the 12(th) leading cause of death in the United States.
- Risk factors for acute liver failure
Natural History, Complications and Prognosis
- Patients who develop severe acute liver injury without preexisting chronic liver disease, often demonstrate significant liver dysfunction with coagulopathy (defined as an international normalized ratio (INR)≥1.5) and are designated as acute liver failure (ALF) when any degree of hepatic encephalopathy (HE) is present.
Clinical features in Hepatic failure and complications
Kidney and adrenal
- High output state
- Subclinical myocardial injury
- Hepatocardiac syndrome
prognosis of Acute liver failure
- The prognosis in patients with acute liver failure is highly variable and depends on the etiology, subtypes (hyperacute, acute,...), age, and the degree of coagulopathy. Determining the prognosis for these patients is vital. The overall mortality of ALF is currently between 30% to 40%. Liver transplantation has dramatically improved short-term survival in patients with acute liver failure. Still, 25% to 45% of patients will survive with medical treatment.
- Identification of patients who will eventually require liver transplantation should be addressed through continuous medical assessment. The most widely accepted prognostic tool for patients who present with ALF is King's College Criteria (KCC) .Although his scoring system is generally quite accurate in predicting poor prognosis and, along with clinical judgment, is useful for ensuring timely transfer to a liver transplant center in adults, but data suggest they may not reliably predict outcomes in the pediatric population.
Prognosis of chronic liver failure
- Patients with compensated cirrhosis have a median survival of 6–12 years. Decompensation and end stage liver disease occurs in 5%–7% annually; median survival then declines to 2 years.
- Several retrospectives studies have reported in patients with end-stage liver disease, the MELD score to have similar predictive value to the king's college criteria for mortality associated with ALF.
History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | Chest X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies | Clinical prediction rules
History and symptoms
- History of alcohol use:
- History of illicit drug use
- History of unprotected sexual intercourse
- History of recent travel
Past Medical history
- History of infections:
- History of autoimmune disorders:
- History of blood transfusions
- History of current or prior depression (including assessment of suicidality), anxiety, psychosis, or other mental illness.
- History of menstrual irregularities
- History of use of all medications used over the last 6 months, including prescription medications, over-the-counter agents, herbal supplements, wild mushrooms, or other alternatives/complementary therapies;
- Liver failure may present with
- Increase in abdominal girth due to ascites
- Signs of upper gastrointestinal bleeding:
- Symptoms due to hepatic encephalopathy:
- Muscle cramps due to reduction in effective circulating plasma volume
- Lower extremity edema
- Complete physical examination should be performed.
Appearance of the patient
- Blood pressure may be normal, low or high.
- Hypothermia or hyperthermia may be present
- Tachycardia with regular or iregularpulse may be present
- Icteric sclera
- Dilated pupils, sluggishly responsive to light
- Ophthalmoscopic exam may be abnormal with findings of papilledema
Signs of liver disease may be seen such as:
- Fluid collection in the abdomen (ascites)
- Abdominal tenderness
- A palpable liver in the epigastrium (hepatomegaly- feel with inspiration, relocate during expiration)
Physical examination of back is usually normal
- Jerking movement of the limbs (asterixis) is highly suggestive of hepatic encephalopathy
- Attention deficit and slow information processing
- Abnormal paper and pencil tests
- Altered mental status may be seen
- Scoring on Glasgow coma scale may be low
- Clonus may be present
- Positive (abnormal) Babinski reflex
- Bilaterally muscle weakness may be seen
- Examination cranial nerves is usually normal, but features of raised ICP(unequal and fixed pupils) may be seen.
- Prolonged prothrombin time(INR>1.5)
- Elevated aminotransferase level
- Elevated bilirubin level
- low platelet count
- Elevated ammonia level
- Elevated serum Cr, BUN
- Elevated amylase and lipase
- Acidosis or alkalosis
- Elevated LDH level
- laboratory tests are recommended for establishing an etiology and determining the prognosis of Acute liver failure:
- Imaging is not required for diagnosis but it is useful in the correct clinical context, for example:
- Abdominal ultrasound with Doppler to confirm portal and hepatic vein patency
- CXR for evaluation of lungs
- Non-contrast computed tomography (CT) scan of the head for patients with Hepatic encephalopathy
The most important part of the management of hepatic failure involves the timely diagnosis of it. Making a timely diagnosis in a patient who presents with liver dysfunction and an altered mental state remains the single most important management step for the clinician, as a delay can lead to substantial morbidity and mortality. Although there is no proven therapy for ALF, understanding the progression of ALF, from loss of hepatocytes to the development of multiorgan failure, helps the clinician in disease-specific complication management.
The management of Hepatic failure should involve
- Specific Treatment
- Supportive and symptomatic management
- Management of complications
- Emergency therapies
- Liver transplantation
1. Specific treatment:
- Identification of the etiology and initiation of specific treatment.
- Oral NAC: 140 mg/kg loading dose, then 70 mg/kg every 4 hours until discontinued by hepatology or transplantation surgery attending physician
- IV NAC: 150 mg/kg loading dose, then 50 mg/kg IV over 4 hours, then 100 mg/kg IV over 16 hours as a continuous infusion until discontinued by hepatology or transplantation surgery attending physician
- Charcoal: via NGT every 4 hours alternating with silymarin
- Penicillin G: 1 g/kg/day IV and
- NAC (Dosing as for acetaminophen overdose.),
- Silymarin: 300 mg PO/NGT every 12 hours,
- Legalon-SIL: 5 mg/kg/day IV (given in 4 divided doses) or 5 mg/kg IV loading dose followed by 20 mg/kg/day via continuous infusion
- Acyclovir: 10 mg/kg IV every 8 hours (using IBW) adjusted for kidney function
- Ganciclovir: 5 mg/kg IV every 12 hours (using IBW) adjusted for kidney function
Hepatitis B virus infection
- Delivery of the fetus
2. Supportive and symptomatic management
- Timely transfer to the critical care unit
- Check clinical status continuously
- Fluid restriction
- IV H2 Blockers or PPI
- Prevention of hypoglycemia
- Avoid sedation
- 12 hourly electrolytes and coagulation studies
3. Management of Complications:
Treatment of Hepatic encephalopathy:
- Reduce protein intake:
Traditionally it has been presumed that excessive protein intake leads to increased generation of ammonia, which, in the setting of severe liver impairment, will accumulate and worsen the hepatic encephalopathy. While very large protein loads (such as gastrointestinal hemorrhage, because blood is rich in protein) are known to precipitate encephalopathy, the need for patients with chronic liver disease patients to be protein restricted has been disproven. Indeed, because chronic liver disease is a catabolic state, a protein restricted diet would lead to protein malnutrition and a negative nitrogen balance.
- Correction of hypokalemia:
Lactulose is a compound that will cause osmotic diarrhea, thus lessening the time available for intestinal bacteria to metabolize protein into ammonia within the bowel. Further, it acidifies the environment in the lumen of the bowel. This promotes the conversion of lumenal ammonia (NH3) to ammonium (NH4+) which, by which virtue of its net charge, should be less readily absorbed into the bloodstream from the bowel lumen. Despite this theoretical and appealing mechanism, a meta-analysis of randomized controlled trials by the international Cochrane Collaboration found benefit, but suggests there is little evidence for its preferred use to treat hepatic encephalopathy. Indeed, any drug (laxative) which speeds up transit through the bowel thereby lessening the time available for bacteria to metabolize protein into ammonia, works just as well.
- Lactulose can be given rectally for patients who cannot take oral medications. One regimen is 300 mL (200 gm) of lactulose syrup (10 gm/15 ml) in 1 L of water which is retained for 1 hour, with the patient in the Trendelenburg position.
Antibiotics may be given to kill bacteria present in the bowel thereby decreasing bacterial conversion of protein to ammonia (and other toxic substances) there. Although effective, neomycin, a non-absorbable aminoglycoside antibiotic, is essentially contraindicated; it has been found that a proportion of the ingested dose is indeed absorbed due to increased gut permeability, thus increasing the risk of renal failure and hearing loss (i.e. two of the potential side effects of neomycin). The former side-effect, in particular, is especially worrisome given the already increased likelihood of renal failure in cirrhosis and portal hypertension (i.e. hepatorenal syndrome). Metronidazole has also been studied.
Rifaximin , receieved orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo. Multiple clinical trials have demonstrated that rifaximin at a dose of 400 mg taken orally 3 times a day was as effective as lactulose or lactilol at improving hepatic encephalopathy symptoms. Similarly, rifaximin was as effective as neomycin and paromomycin. Rifaximin was better tolerated than both the cathartics and the other nonabsorbable antibiotics. A number of concerns remain regarding rifaximin's role in the treatment of hepatic encephalopathy. It remains to be determined if rifaximin can improve severe encephalopathy symptoms as rapidly as lactulose. There are also concerns regarding the cost-effectiveness of the medication.
A meta-analysis of randomized controlled trials by the international cochrane collaboration found benefit from flumazenil. The doses of flumazenil varied around a median of 2 milligrams over 10 minutes: flumazenil was given as a continuous infusion (12 trials), preceded by bolus injections in two trials. One trial used only bolus injections. Patients received flumazenil at a total dose ranging from 0.2 to 19.5 milligram (median 2 milligram). The median duration of treatment was 10 minutes (range one minute to 72 hours)'. However, the benefit was short.
Hepatic coma is considered an absolute contraindication to the use of the following medications:
Treatment of cerebral edema:
The goal in the management of ICH is to lower the ICP to less than 20 to 25 mm Hg and maintain the cerebral perfusion pressure above 50 to 60 mm Hg. This is mainly performed by increasing the mean arterial pressure (MAP) and decreasing the ICP by the methods mentioned below:
- IV mannitol at the dose of 0.5 to 1.0 g/kg
- Hypertonic saline delayed the development of ICH
- Hyperventilation decreases ICP
- Hypothermia decreases ICP
- Seizure control
- Avoid hyperthermia
Treatment of hepatorenal syndrome:
Because of the high mortality associated with hepatorenal syndrome, emphasis is on prevention in patients who are at risk for the condition. Strategies for avoiding hepatorenal syndrome include appropriate and non-aggressive use of diuretics, identification and early treatment of infection and hemorrhage, and avoidance of other toxins that can affect both the liver and kidney.
The definitive treatment for hepatorenal syndrome is liver transplantation, and all other therapies can best be described as bridges to transplantation. These treatment strategies include the following:
All major studies showing improvement in renal function in patients with hepatorenal syndrome have involved expansion of the volume of the plasma with albumin given intravenously  One regimen is 1 gm albumin per kg of body weight intravenously on day one followed by followed by 20-40 grams daily.
Midodrine and octreotide
Midodrine is an alpha-agonist and octreotide is an analog of somatostatin. The medications are respectively systemic vasoconstrictors and inhibitors of vasodilators, and were not found to be useful when used individually in the treatment of the hepatorenal syndrome. However, one study of 13 patients with hepatorenal syndrome showed significant improvement when the two were used together (with midodrine given orally, octreotide given subcutaneously and both dosed according to blood pressure), with three patients surviving to discharge. A nonrandomized, observational study used "100 μg subcutaneously TID, with the goal to increase the dose to 200 μg subcutaneous TID" and "midodrine administration started at 5, 7.5, or 10 mg TID orally, with the goal to increase the dose to 12.5 or 15 mg if necessary" and found that "octreotide/midodrine treatment appears to improve 30-day survival".
The vasopressin analogue ornipressin was found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome, but has been limited by ischemic complications. Terlipressin is a vasopressin analogue that has been found in one study to be useful for improving renal function in patients with hepatorenal syndrome with a lesser incidence of ischemia. Neither medication is available for use in North America.
Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunts (TIPS) involve decompression of the high pressures in the portal circulation by placing a small stent between a portal and hepatic vein. They have also been shown to improve renal function in patients with hepatorenal syndrome.
Liver dialysis involves extracorporeal dialysis to remove toxins from the circulation. The molecular adsorbents recirculation system (MARS) has shown some utility as a bridge to transplantation in patients with hepatorenal syndrome.
Other agents used in treatment include
Management of Coagulopathy
- Routine correction of thrombocytopenia or elevated INR by plasma infusion, in the absence of bleeding, is not indicated in acute liver failure, because of the low incidence of bleeding manifestations in ALF and the risk of volume expansion with plasma replacement. In addition, INR is an important prognostic indicator in ALF, correction of coagulopathy would alter the INR and interfere in the assessment of prognosis.
- Routine administration of vitamin K (5 to10 mg subcutaneously)
- plasma or clotting factor replacement therapy in clinically significant bleeding or the need for a procedure with a high bleeding risk such as ICP monitor insertion. Recombinant activated factor VII is used if INR is still high to correct coagulopathy in these patients.
- Patients with thrombocytopenia with platelet count less than 50,000 cells/mm3 with clinically significant bleeding should receive platelet transfusion. In the absence of bleeding, there is no need to initiate platelet transfusion.
Management of metabolic abnormalities
- Intravenous glucose should be administered for the prophylaxis and treatment of hypoglycemia.
- Electrolyte abnormalities should be promptly identified and corrected urgently.
- Enteral feeding should be started at the earliest in patients who are unlikely to resume oral nutrition within 5 days. Parenteral feeding should be considered when enteral feeding cannot be instituted or is contraindicated, though parenteral feeding is associated with an increased risk of infections. Both of them reduce stress-related gastric ulcers.
- Serum ammonia levels should be monitored and protein load should be adjusted accordingly.
Treatment of hemodynamic instabilty
4. Emergency therapies
- Extracorporeal system to bridge liver transplantation or regenerating of the native liver and removing toxic substances:
- Artificial support systems: are extracorporeal devices that have either charcoal or other adherent particles in an extracorporeal circuit to help with detoxification. Unfortunately, randomized control trials have not shown conclusive benefits with these devices in patients and further study is needed.
- Bioartificial systems use cryopreserved cells and they are able to not only detoxify but also perform synthetic liver functions.
5. Liver transplantation
- Early consultation with liver transplant specialists and transfer of patients to a liver transplant center when necessary
Severe hepatic failure is considered an absolute contraindication to the use of the following medications:
- Conjugated estrogens/bazedoxifene
- Doxorubicin Hydrochloride
The ALFSG index is a newer option that may be more accurate.
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