Hepatic failure: Difference between revisions

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{{CMG}} {{AE}} [[User:Roghayeh Marandi|Roghayeh Marandi]][mailto:parastoo@aol.in]
 


'''''Synonyms and keywords:''''' Liver failure; fulminating hepatic failure
'''''Synonyms and keywords:''''' Liver failure; fulminating hepatic failure
==Overview==
==Overview==
'''Liver failure''' is the inability of the [[liver]] to perform its normal [[protein synthesis|synthetic]] and [[metabolism|metabolic]] function as part of normal physiology.
'''Liver failure''' is the inability of the [[liver]] to perform its normal [[protein synthesis|synthetic]] and [[metabolism|metabolic]] function as part of normal [[physiology]].
 
==Historical Perspective==
* The original definition of [[Acute liver failure]] by Trey and Davidson was in 1959.<ref name="pmid18452113">{{cite journal |vauthors=Riordan SM, Williams R |title=Perspectives on liver failure: past and future |journal=Semin. Liver Dis. |volume=28 |issue=2 |pages=137–41 |date=May 2008 |pmid=18452113 |doi=10.1055/s-2008-1073113 |url=}}</ref>
* In the late 1980s and early 1990s, more terminologies of [[Acute liver failure]] proposed.<ref name="pmid3529410">{{cite journal |vauthors=Bernuau J, Rueff B, Benhamou JP |title=Fulminant and subfulminant liver failure: definitions and causes |journal=Semin. Liver Dis. |volume=6 |issue=2 |pages=97–106 |date=May 1986 |pmid=3529410 |doi=10.1055/s-2008-1040593 |url=}}</ref><ref name="pmid8101303">{{cite journal |vauthors=O'Grady JG, Schalm SW, Williams R |title=Acute liver failure: redefining the syndromes |journal=Lancet |volume=342 |issue=8866 |pages=273–5 |date=July 1993 |pmid=8101303 |doi=10.1016/0140-6736(93)91818-7 |url=}}</ref>
* Term of Acute-on-[[chronic Liver failure]] suggested by Jalan and willimas in 2002.<ref name="pmid11867872">{{cite journal |vauthors=Jalan R, Williams R |title=Acute-on-chronic liver failure: pathophysiological basis of therapeutic options |journal=Blood Purif. |volume=20 |issue=3 |pages=252–61 |date=2002 |pmid=11867872 |doi=10.1159/000047017 |url=}}</ref>
 
==Classification==
==Classification==
Two forms are recognised:<ref>O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. ''[[The Lancet|Lancet]]'' 1993;342:273-5. PMID 8101303.</ref>
Three forms are recognized:
* '''[[Acute liver failure]]''' - development of [[hepatic encephalopathy]] (confusion, stupor and coma) and decreased production of [[protein]]s (such as [[human serum albumin|albumin]] and [[coagulation|blood clotting proteins]]) within four weeks of the first symptoms (such as [[jaundice]]) of a liver problem. "Hyperacute" liver failure is said to be present if this interval is 7 days or less, while "subacute" liver failure is said to be present if the interval is 5-12 weeks.
* '''[[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.<ref name="pmid31498101">{{cite journal |vauthors=Stravitz RT, Lee WM |title=Acute liver failure |journal=Lancet |volume=394 |issue=10201 |pages=869–881 |date=September 2019 |pmid=31498101 |doi=10.1016/S0140-6736(19)31894-X |url=}}</ref><ref name="pmid30485882">{{cite journal |vauthors=Rajaram P, Subramanian R |title=Acute Liver Failure |journal=Semin Respir Crit Care Med |volume=39 |issue=5 |pages=513–522 |date=October 2018 |pmid=30485882 |doi=10.1055/s-0038-1673372 |url=}}</ref>
* '''Chronic liver failure''' usually occurs in the context of '''[[cirrhosis]]''', itself potentially the result of many possible causes, such as excessive [[alcoholic beverage|alcohol]] intake, [[hepatitis B]] or [[hepatitis C|C]], autoimmune, hereditary and metabolic causes (such as [[hemochromatosis|iron]] or [[Wilson's disease|copper]] overload or [[non-alcoholic fatty liver disease]]).
** [[Acute liver failure]] was further classified depending on the interval between the onset of [[jaundice]] and the onset of [[encephalopathy]] into: "Hyperacute " (interval0-7 days), [["Acute"]] (interval 8-28days), [["sub-acute"]] (interval 29days to 12 weeks), [["late -onset"]] (interval 12 -26 weeks).<ref name="pmid8101303">{{cite journal |vauthors=O'Grady JG, Schalm SW, Williams R |title=Acute liver failure: redefining the syndromes |journal=Lancet |volume=342 |issue=8866 |pages=273–5 |date=July 1993 |pmid=8101303 |doi=10.1016/0140-6736(93)91818-7 |url=}}</ref><ref name="pmid3082735">{{cite journal |vauthors=Gimson AE, O'Grady J, Ede RJ, Portmann B, Williams R |title=Late onset hepatic failure: [[clinical]], [[serological]] and [[histological]] features |journal=Hepatology |volume=6 |issue=2 |pages=288–94 |date=1986 |pmid=3082735 |doi=10.1002/hep.1840060222 |url=}}</ref>
 
* '''[[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.<ref name="pmid23474284">{{cite journal |vauthors=Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, Durand F, Gustot T, Saliba F, Domenicali M, Gerbes A, Wendon J, Alessandria C, Laleman W, Zeuzem S, Trebicka J, Bernardi M, Arroyo V |title=Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis |journal=Gastroenterology |volume=144 |issue=7 |pages=1426–37, 1437.e1–9 |date=June 2013 |pmid=23474284 |doi=10.1053/j.gastro.2013.02.042 |url=}}</ref>
 
==Pathophysiology==
*[[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]].
 
The [[pathophysiology]] of [[ALF]] can be divided into cause‐specific [[liver]] injury [[Pathophysiology|pathophysiologie]]s and [[pathophysiology]] related to the occurrence of secondary multi-organ failure.
'''
*Cause-specific pathophysiologies''':<ref name="pmid31840297">{{cite journal |vauthors=Dong V, Nanchal R, Karvellas CJ |title=Pathophysiology of Acute Liver Failure |journal=Nutr Clin Pract |volume=35 |issue=1 |pages=24–29 |date=February 2020 |pmid=31840297 |doi=10.1002/ncp.10459 |url=}}</ref>
**[[Immune]]-mediated hepatocellular injury: :
*** Hepatotrophic [[virus]] family([[HAV]], [[HBV]], [[HCV]])
**[[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 450|cytochrome P450 system]]. Its [[metabolite]], N-acetyl-p-benzoquinone imine ([[NAPQI]]), generated via the [[Cytochrome 450|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 [[virotoxin|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.<ref name="pmid9604278">{{cite journal |vauthors=Vetter J |title=Toxins of Amanita phalloides |journal=Toxicon |volume=36 |issue=1 |pages=13–24 |date=January 1998 |pmid=9604278 |doi=10.1016/s0041-0101(97)00074-3 |url=}}</ref>
**[[Ischemic]] [[hepatocellular]] injury:
*** [[Shock]]
*** [[SIRS]]
 
 
* 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 [[Antiinflammatory|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]]<ref name="pmid22796239">{{cite journal |vauthors=Chung RT, Stravitz RT, Fontana RJ, Schiodt FV, Mehal WZ, Reddy KR, Lee WM |title=Pathogenesis of liver injury in acute liver failure |journal=Gastroenterology |volume=143 |issue=3 |pages=e1–e7 |date=September 2012 |pmid=22796239 |pmc=3641754 |doi=10.1053/j.gastro.2012.07.011 |url=}}</ref>. [[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]].<ref name="pmid18328931">{{cite journal |vauthors=Schuppan D, Afdhal NH |title=Liver cirrhosis |journal=Lancet |volume=371 |issue=9615 |pages=838–51 |date=March 2008 |pmid=18328931 |pmc=2271178 |doi=10.1016/S0140-6736(08)60383-9 |url=}}</ref>
 
* The [[pathogenesis]] of [[Acute-on-chronic liver failure]] is unclear but many theories are proposed in such as [[Neutrophil|neutrophilic]] dysfunction that increases the risk of [[infection]]s, [[circulating]] changes, [[oxidative stress]], and [[toxin]] [[hypothesis]].


==Causes==
==Causes==
===Drugs===
Causes for [[Acute liver failure]]<ref name="pmid18318440">{{cite journal |vauthors=Lee WM, Squires RH, Nyberg SL, Doo E, Hoofnagle JH |title=Acute liver failure: Summary of a workshop |journal=Hepatology |volume=47 |issue=4 |pages=1401–15 |date=April 2008 |pmid=18318440 |pmc=3381946 |doi=10.1002/hep.22177 |url=}}</ref><ref name="pmid16820551">{{cite journal |vauthors=Watkins PB, Kaplowitz N, Slattery JT, Colonese CR, Colucci SV, Stewart PW, Harris SC |title=Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial |journal=JAMA |volume=296 |issue=1 |pages=87–93 |date=July 2006 |pmid=16820551 |doi=10.1001/jama.296.1.87 |url=}}</ref>:
*[[Carfilzomib]]
{| class="wikitable"
*[[Caspofungin acetate]]
|+
*[[Cefadroxil]]
!Category
*[[Ceftazidime]]
!Etiology of Acute liver failure
*[[Chlordiazepoxide]]
|-
*[[Dactinomycin]]
|'''Viruses'''
*[[Didanosine]]
|
*[[Diflunisal]]
* [[Hepatitis A virus]]
*[[Efavirenz]]
* Hepatitis B virus ± delta virus
*[[Fulvestrant]]
* [[Hepatitis E virus]]
*[[Gemcitabine]]
* [[Herpes simplex virus]]
*[[Indinavir]]
* [[Varicella-zoster virus]]
*[[Interferon gamma]]
* [[Cytomegalovirus]]
*[[Ixabepilone]]
* [[Epstein-Barr virus]]
*[[Meropenem]]
* [[Human herpesvirus 6|Human herpesvirus-6]]
*[[Micafungin sodium]]
* [[Adenovirus]], [[Coxsackie B virus]]
*[[Oxaprozin]]
* [[hemorrhagic fever virus]]
*[[Oxazepam]]
|-
*[[Sorafenib]]
|'''Drugs'''
*[[Sulfasalazine]]
|
*[[Zafirlukast]]
* [[Idiosyncratic reactions]]
**[[Isoniazid]]
**[[Nonsteroidal anti-inflammatory drugs]]
**[[Carbamazepine]]
*Dose-dependent hepatotoxicity
**[[Acetaminophen]]
**[[sulfonamides]]
**[[tetracycline]]
*Antibiotics
**[[Amoxicillin-clavulanate]]
**[[ciprofloxacin]]
**[[nitrofurantoin]] 
**[[Dapsone]]
**[[Trimethoprim-sulfamethoxazole]] 
**[[Efavirenz]]
**[[Didanosine]]
**[[Abacavir]]
* Herbal supplements
**[[ma huang]]
**[[kava kava]]
**[[Herbalife]]
|-
|'''Metabolic diseases'''
|
* [[Wilson disease]]
* [[Reye syndrome]]
* [[Acute fatty liver of pregnancy]]
|-
|'''Toxins'''
|
* [[Amanita phalloides]] toxin
* Bacillus cereus toxin
* [[Cyanobacteria]] Toxin
* Organic Solvents(eg; [[Carbon tetrachloride]])
* [[Yellow phosphorus]]
|-
|'''Vascular diseases'''
|
* [[Right heart failure]]
* [[Budd-Chiari syndrome]]
* [[Ischemic hepatitis]]
|-
|'''Malignant Infiltration'''
|
* Metastatic breast cancer
* [[Lymphoma]]
|-
|'''Autoimmune disease'''
|
* [[Autoimmune hepatitis]]
|-
|'''Indeterminate'''
|
* Unknown
|}
 
===[[Drug-induced]] [[acute liver injury]]===
*[[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]] [[NAPQI|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 [[OTC|over-the-counter medication]]s,  weight loss medications, and [[prescription medication]]s can lead to acute liver injury. [[Liver injury]] from drugs could be [[dose-dependent]] and predictable ([[acetaminophen]] toxicity) or [[Idiosyncratic drug reaction|idiosyncratic]] and unpredictable ([[carbamazepine]], valproate).
 
===[[Viral hepatitis]]===
*[[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]], [[Hepatitis B|B]], and [[Hepatitis E Virus|E]] infections as well as other rare [[viral]] causes including [[herpes simplex virus]], [[epstein-barr virus]], [[cytomegalovirus]], and [[parvoviruses]].
 
===[[Mushroom poisoning]]===
*[[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 test]]s. In patients with stable [[cirrhosis]], [[decompensation]] may occur due to various causes:
* [[Constipation]]
* [[Infection]]
* Increased alcohol intake
* [[Medication|Medications]]
* [[Bleeding]] from [[esophageal varices]] or [[dehydration]]
 
==Differential Diagnosis==
*[[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]], [[Hepatitis B|B]], [[Hepatitis C|C]], [[Hepatitis D|D]] or [[Hepatitis E Virus|E]]), [[autoimmune]], [[metabolic]] ([[Wilson disease]]), [[drug-induced]] or [[idiopathic]].<ref name="pmid31753252">{{cite journal |vauthors=Chayanupatkul M, Schiano TD |title=Acute Liver Failure Secondary to Drug-Induced Liver Injury |journal=Clin Liver Dis |volume=24 |issue=1 |pages=75–87 |date=February 2020 |pmid=31753252 |doi=10.1016/j.cld.2019.09.005 |url=}}</ref><ref name="pmid18852631">{{cite journal |vauthors=Murray KF, Hadzic N, Wirth S, Bassett M, Kelly D |title=Drug-related hepatotoxicity and acute liver failure |journal=J. Pediatr. Gastroenterol. Nutr. |volume=47 |issue=4 |pages=395–405 |date=October 2008 |pmid=18852631 |doi=10.1097/MPG.0b013e3181709464 |url=}}</ref>
 
==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.<ref name="pmid30811890">{{cite journal |vauthors=Kim WR, Lake JR, Smith JM, Schladt DP, Skeans MA, Noreen SM, Robinson AM, Miller E, Snyder JJ, Israni AK, Kasiske BL |title=OPTN/SRTR 2017 Annual Data Report: Liver |journal=Am. J. Transplant. |volume=19 Suppl 2 |issue= |pages=184–283 |date=February 2019 |pmid=30811890 |doi=10.1111/ajt.15276 |url=}}</ref>[[Drug-induced]] [[hepatotoxicity]] occurs for more than 50% of [[acute liver failure]] cases including [[Acetaminophen]] toxicity (42%) and [[idiosyncratic drug reaction]]s. Nearly 15% of cases remain of indeterminate etiology.<ref name="pmid18318440">{{cite journal |vauthors=Lee WM, Squires RH, Nyberg SL, Doo E, Hoofnagle JH |title=Acute liver failure: Summary of a workshop |journal=Hepatology |volume=47 |issue=4 |pages=1401–15 |date=April 2008 |pmid=18318440 |pmc=3381946 |doi=10.1002/hep.22177 |url=}}</ref><ref name="pmid16317692">{{cite journal |vauthors=Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM |title=Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study |journal=Hepatology |volume=42 |issue=6 |pages=1364–72 |date=December 2005 |pmid=16317692 |doi=10.1002/hep.20948 |url=}}</ref><ref name="pmid22675278">{{cite journal |vauthors=Patton H, Misel M, Gish RG |title=Acute liver failure in adults: an evidence-based management protocol for clinicians |journal=Gastroenterol Hepatol (N Y) |volume=8 |issue=3 |pages=161–212 |date=March 2012 |pmid=22675278 |pmc=3365519 |doi= |url=}}</ref>
* [[Chronic liver disease]] and [[Cirrhosis]] are the 12(th) leading cause of death in the United States.<ref name="pmid23583430">{{cite journal |vauthors=Asrani SK, Larson JJ, Yawn B, Therneau TM, Kim WR |title=Underestimation of liver-related mortality in the United States |journal=Gastroenterology |volume=145 |issue=2 |pages=375–82.e1–2 |date=August 2013 |pmid=23583430 |pmc=3890240 |doi=10.1053/j.gastro.2013.04.005 |url=}}</ref>
[[File:Etiology of ALF in Adults.jpg|200px|thumb|Left|]]
 
==Risk factors==
*Risk factors for [[acute liver failure]]
**Chronic [[alcohol abuse]]
**Poor [[nutritional]] status
**Female sex
**Age >40 years
**[[Pregnancy]]
**Chronic [[hepatitis B]]
**[[Chronic pain]] and [[narcotic]] use
**[[Complementary]] and [[alternative medicine]] [[hepatotoxicity]]
**[[Acetaminophen]] and [[antidepressant]] therapy
**Chronic [[hepatitis C]]
**[[HIV]] and [[hepatitis C]] [[coinfection]]
 
==Screening==
Not applicable
 
==Natural History, Complications and Prognosis==
 
===Natural History===
*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.<ref name="pmid28440304">{{cite journal |vauthors=Koch DG, Speiser JL, Durkalski V, Fontana RJ, Davern T, McGuire B, Stravitz RT, Larson AM, Liou I, Fix O, Schilsky ML, McCashland T, Hay JE, Murray N, Shaikh OS, Ganger D, Zaman A, Han SB, Chung RT, Brown RS, Munoz S, Reddy KR, Rossaro L, Satyanarayana R, Hanje AJ, Olson J, Subramanian RM, Karvellas C, Hameed B, Sherker AH, Lee WM, Reuben A |title=The Natural History of Severe Acute Liver Injury |journal=Am. J. Gastroenterol. |volume=112 |issue=9 |pages=1389–1396 |date=September 2017 |pmid=28440304 |pmc=5587371 |doi=10.1038/ajg.2017.98 |url=}}</ref>
 
===Clinical features in Hepatic failure and complications===
 
===Brain===
*[[Hepatic encephalopathy]]
*[[Cerebral edema]]
*[[Intracranial hypertension]]
*[[Seizures]]
 
===Liver===
*Loss of [[metabolic]] function
*[[Hypoglycemia]]
*[[Hyperammonemia]]
*[[Coagulopathy]]
*[[Lactic acidosis]]
 
===Kidney and adrenal===
*[[Hepatorenal syndrome]]
*[[Hepatoadrenal syndrome]]
*[[Electrolyte abnormalities]]
 
===System===
*[[Systemic inflammatory response syndrome|Systemic inflammatory response]]
*[[Immunosuppression]]
*[[Catabolic state]]
 
===Heart===
*High output state
*Subclinical [[myocardial]] injury
*Hepatocardiac syndrome
 
===Pancreas===
*[[Pancreatitis]]
 
===Lungs===
*Acute lung injury
*[[Acute respiratory distress syndrome]]([[ARDS]])
*[[Hepatopulmonary syndrome]]
 
===Bone marrow===
*Frequent suppression
*[[Anemia]]
*[[Thrombocytopenia]]
 
===Prognosis===
===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%.<ref name="pmid18318440">{{cite journal |vauthors=Lee WM, Squires RH, Nyberg SL, Doo E, Hoofnagle JH |title=Acute liver failure: Summary of a workshop |journal=Hepatology |volume=47 |issue=4 |pages=1401–15 |date=April 2008 |pmid=18318440 |pmc=3381946 |doi=10.1002/hep.22177 |url=}}</ref> [[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.<ref name="pmid26819519">{{cite journal |vauthors=Mendizabal M, Silva MO |title=Liver transplantation in acute liver failure: A challenging scenario |journal=World J. Gastroenterol. |volume=22 |issue=4 |pages=1523–31 |date=January 2016 |pmid=26819519 |pmc=4721985 |doi=10.3748/wjg.v22.i4.1523 |url=}}</ref>
*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 [[outcome|outcomes]] in the pediatric population.<ref name="pmid22906509">{{cite journal |vauthors=Sundaram V, Shneider BL, Dhawan A, Ng VL, Im K, Belle S, Squires RH |title=King's College Hospital Criteria for non-acetaminophen induced acute liver failure in an international cohort of children |journal=J. Pediatr. |volume=162 |issue=2 |pages=319–23.e1 |date=February 2013 |pmid=22906509 |pmc=3504621 |doi=10.1016/j.jpeds.2012.07.002 |url=}}</ref><ref name="pmid22675278">{{cite journal |vauthors=Patton H, Misel M, Gish RG |title=Acute liver failure in adults: an evidence-based management protocol for clinicians |journal=Gastroenterol Hepatol (N Y) |volume=8 |issue=3 |pages=161–212 |date=March 2012 |pmid=22675278 |pmc=3365519 |doi= |url=}}</ref><ref name="pmid20827368">{{cite journal |vauthors=McDowell Torres D, Stevens RD, Gurakar A |title=Acute liver failure: a management challenge for the practicing gastroenterologist |journal=Gastroenterol Hepatol (N Y) |volume=6 |issue=7 |pages=444–50 |date=July 2010 |pmid=20827368 |pmc=2933761 |doi= |url=}}</ref><ref name="pmid26819519">{{cite journal |vauthors=Mendizabal M, Silva MO |title=Liver transplantation in acute liver failure: A challenging scenario |journal=World J. Gastroenterol. |volume=22 |issue=4 |pages=1523–31 |date=January 2016 |pmid=26819519 |pmc=4721985 |doi=10.3748/wjg.v22.i4.1523 |url=}}</ref>
 
===Prognosis of chronic liver failure===
 
*Patients with compensated [[cirrhosis]] have a median survival of 6–12 years. Decompensation and [[End stage liver failure|end stage liver disease]] occurs in 5%–7% annually; median survival then declines to 2 years.<ref name="pmid25390468">{{cite journal |vauthors=Potosek J, Curry M, Buss M, Chittenden E |title=Integration of palliative care in end-stage liver disease and liver transplantation |journal=J Palliat Med |volume=17 |issue=11 |pages=1271–7 |date=November 2014 |pmid=25390468 |pmc=4229716 |doi=10.1089/jpm.2013.0167 |url=}}</ref>
 
* Several retrospectives studies have reported in patients with [[End stage liver failure|end-stage liver disease]], the [[MELD score]] to have similar predictive value to the king's college criteria for [[mortality]] associated with [[ALF]].
 
==Diagnosis==
 
[[Hepatic failure history and symptoms|History and Symptoms]] | [[Hepatic failure physical examination|Physical Examination]] | [[Hepatic failure laboratory findings|Laboratory Findings]] | [[Hepatic failure electrocardiogram|Electrocardiogram]] | [[Hepatic failure chest x ray|Chest X Ray]] | [[Hepatic failureCT|CT]] | [[Hepatic failure MRI|MRI]] | [[ echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Hepatic failure other imaging findings|Other Imaging Findings]] | [[Hepatic failure other diagnostic studies|Other Diagnostic Studies]] | [[Hepatic failure Clinical prediction rules|Clinical prediction rules]]
 
==History and symptoms==
 
=== Social history ===
*History of [[alcohol]] use:
**Amount
**Duration
*History of illicit [[:Category:Drugs|drug]] use
*History of unprotected [[intercourse|sexual intercourse]]
*History of recent travel
 
=== Past Medical history ===
*History of [[Infection|infections]]:<ref name="pmid21877109">{{cite journal |vauthors=Flores YN, Lang CM, Salmerón J, Bastani R |title=Risk factors for liver disease and associated knowledge and practices among Mexican adults in the US and Mexico |journal=J Community Health |volume=37 |issue=2 |pages=403–11 |year=2012 |pmid=21877109 |doi=10.1007/s10900-011-9457-4 |url=}}</ref>
**[[Hepatitis B]]
**Hepatitis [[Hepatitis C|C]]
*History of [[Autoimmunity|autoimmune disorders]]:
**[[autoimmune hepatitis]]
**[[Crohn's disease]]
*History of [[Blood transfusion|blood transfusions]]
* History of current or prior depression (including assessment of suicidality), anxiety, psychosis, or other mental illness.
 
=== Menstrual history ===
*History of [[Menstrual disorder|menstrual irregularities]]
 
=== Family history ===
*[[Family history]] of liver disease:
**[[Wilson's disease]]
**[[hemochromatosis]]
 
=== Medication history ===
*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;
 
===Symptoms===
*Liver failure may present with<ref name="pmid25230084">{{cite journal |vauthors=Bloom S, Kemp W, Lubel J |title=Portal hypertension: pathophysiology, diagnosis and management |journal=Intern Med J |volume=45 |issue=1 |pages=16–26 |year=2015 |pmid=25230084 |doi=10.1111/imj.12590 |url=}}</ref>
**[[Jaundice]]  
**Increase in abdominal girth due to [[ascites]]  
**[[Itch|Pruritus]]  
**Signs of [[upper gastrointestinal bleeding]]:
***[[Hematemesis]]
***[[Hematochezia]]
***[[Melena]]
**Symptoms due to [[hepatic encephalopathy]]:
***[[Altered mental status]]
***[[Confusion]]
***Sleep disturbances
**Muscle cramps due to reduction in effective circulating plasma volume
**Lower extremity [[edema]]
 
==Physical Examination==
 
*Complete physical examination should be performed.
 
===Appearance of the patient===
*Patients with hepatic failure have any degree of Hepatic encephalopathy.<ref name="pmid23006457">{{cite journal| author=Bleibel W, Al-Osaimi AM| title=Hepatic encephalopathy. | journal=Saudi J Gastroenterol | year= 2012 | volume= 18 | issue= 5 | pages= 301-9 | pmid=23006457 | doi=10.4103/1319-3767.101123 | pmc=3500018 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23006457  }} </ref><ref name="pmid22348593">{{cite journal| author=Salam M, Matherly S, Farooq IS, Stravitz RT, Sterling RK, Sanyal AJ et al.| title=Modified-orientation log to assess hepatic encephalopathy. | journal=Aliment Pharmacol Ther | year= 2012 | volume= 35 | issue= 8 | pages= 913-20 | pmid=22348593 | doi=10.1111/j.1365-2036.2012.05038.x | pmc=3616137 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22348593  }} </ref>
 
*[[Confusion|confused]]
*[[Drowsiness|drowsy]]
*[[irritable]]
*[[unconscious]]
 
===Vital signs===
In patients with hepatic failure [[vital signs]] include:<ref name="pmid28835821">{{cite journal| author=Wannhoff A, Nusshag C, Stremmel W, Merle U| title=Slow ventricular tachycardia presenting with acute liver failure. | journal=SAGE Open Med Case Rep | year= 2017 | volume= 5 | issue=  | pages= 2050313X17718100 | pmid=28835821 | doi=10.1177/2050313X17718100 | pmc=5528920 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28835821  }} </ref>
*[[Blood pressure]] may be normal, low or high.
*[[Hypothermia]] or [[hyperthermia]] may be present
*[[Tachycardia]] with regular or iregular[[pulse]] may be present
*[[Tachypnea]]
 
===Skin===
Signs of [[Liver diseases|liver disease]] may be seen, such as:<ref name="pmid25755383">{{cite journal| author=Dogra S, Jindal R| title=Cutaneous manifestations of common liver diseases. | journal=J Clin Exp Hepatol | year= 2011 | volume= 1 | issue= 3 | pages= 177-84 | pmid=25755383 | doi=10.1016/S0973-6883(11)60235-1 | pmc=3940632 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25755383  }} </ref>
*[[Yellow skin]]
*Protracted and disabling [[pruritus]]
*[[Spider angioma|Spider angiomas]]
*[[Palmar erythema]]
 
===HEENT===
*[[Icterus (medicine)|Icteric]] [[sclera]]<ref name="pmid25755383" />
*[[Mydriasis|Dilated pupils]], sluggishly responsive to light<ref name="pmid22067133">{{cite journal| author=Shawcross DL, Wendon JA| title=The neurological manifestations of acute liver failure. | journal=Neurochem Int | year= 2012 | volume= 60 | issue= 7 | pages= 662-71 | pmid=22067133 | doi=10.1016/j.neuint.2011.10.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22067133  }} </ref>
*[[Ophthalmoscopy|Ophthalmoscopic]] exam may be abnormal with findings of [[papilledema]]<ref name="pmid1615943">{{cite journal| author=Crippin JS, Gross JB, Lindor KD| title=Increased intracranial pressure and hepatic encephalopathy in chronic liver disease. | journal=Am J Gastroenterol | year= 1992 | volume= 87 | issue= 7 | pages= 879-82 | pmid=1615943 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1615943  }} </ref>
 
===Neck===
[[Physical examination]] of neck is usually normal but in Hepatic failure due to CHF,[[Jugular vein distention]] may be seen.
 
===Lungs===
*[[Tachypnea]]
*[[Hypoxia]]
 
===Heart===
[[Physical examination]] of [[heart]] is usually normal unless the cause of hepatic failure is Heart disease such as [[Right heart failure]].
 
===Abdomen===
Signs of liver disease may be seen such as:
* Fluid collection in the [[abdomen]] ([[ascites]])<ref name="pmid4579401">{{cite journal| author=Losowsky MS, Scott BB| title=Ascites and oedema in liver disease. | journal=Br Med J | year= 1973 | volume= 3 | issue= 5875 | pages= 336-8 | pmid=4579401 | doi= | pmc=1586440 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4579401  }} </ref>
* [[Abdominal tenderness]]<ref name="pmid14627332">{{cite journal| author=Riley TR, Koch K| title=Characteristics of upper abdominal pain in those with chronic liver disease. | journal=Dig Dis Sci | year= 2003 | volume= 48 | issue= 10 | pages= 1914-8 | pmid=14627332 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14627332  }} </ref>
*A palpable [[liver]] in the [[epigastrium]] ([[hepatomegaly]]- feel with [[inspiration]], relocate during [[expiration]])<ref name="pmid15618841">{{cite journal| author=McCormick PA, Nolan N| title=Palpable epigastric liver as a physical sign of cirrhosis: a prospective study. | journal=Eur J Gastroenterol Hepatol | year= 2004 | volume= 16 | issue= 12 | pages= 1331-4 | pmid=15618841 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15618841  }} </ref>
 
===Back===
[[Physical examination]] of back is usually normal
 
===Genitourinary===
* [[Small testicles]]
* [[Oliguria]]
*signs of [[renal dysfunction]]
 
===Neuromuscular===
*J[[Jerking|erking movement]] of the [[limbs]] ([[asterixis]]) is highly suggestive of hepatic encephalopathy<ref name="pmid27089111" />{{#ev:youtube|Or65nOrcz1A}}
*[[Attention deficit]] and slow information processing<ref name="pmid24357348">{{cite journal| author=Nabi E, Bajaj JS| title=Useful tests for hepatic encephalopathy in clinical practice. | journal=Curr Gastroenterol Rep | year= 2014 | volume= 16 | issue= 1 | pages= 362 | pmid=24357348 | doi=10.1007/s11894-013-0362-0 | pmc=3918211 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24357348  }} </ref>
*Abnormal paper and pencil tests<ref name="pmid24357348">{{cite journal| author=Nabi E, Bajaj JS| title=Useful tests for hepatic encephalopathy in clinical practice. | journal=Curr Gastroenterol Rep | year= 2014 | volume= 16 | issue= 1 | pages= 362 | pmid=24357348 | doi=10.1007/s11894-013-0362-0 | pmc=3918211 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24357348  }} </ref>
*[[Altered mental status]] may be seen<ref name="pmid23474970">{{cite journal| author=Rahimi RS, Elliott AC, Rockey DC| title=Altered mental status in cirrhosis: etiologies and outcomes. | journal=J Investig Med | year= 2013 | volume= 61 | issue= 4 | pages= 695-700 | pmid=23474970 | doi=10.2310/JIM.0b013e318289e254 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23474970  }} </ref>
*Scoring on [[Glasgow coma scale]] may be low
*[[Clonus]] may be present<ref name="pmid22067133">{{cite journal| author=Shawcross DL, Wendon JA| title=The neurological manifestations of acute liver failure. | journal=Neurochem Int | year= 2012 | volume= 60 | issue= 7 | pages= 662-71 | pmid=22067133 | doi=10.1016/j.neuint.2011.10.006 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22067133  }} </ref>
*[[Hyporeflexia]]<ref name="pmid13134644">{{cite journal| author=ADAMS RD, FOLEY JM| title=The neurological disorder associated with liver disease. | journal=Res Publ Assoc Res Nerv Ment Dis | year= 1953 | volume= 32 | issue=  | pages= 198-237 | pmid=13134644 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=13134644  }} </ref>
*Positive (abnormal) [[Plantar reflex|Babinski reflex]]<ref name="pmid28680841">{{cite journal| author=Djiambou-Nganjeu H| title=Hepatic Encephalopathy in Liver Cirrhosis. | journal=J Transl Int Med | year= 2017 | volume= 5 | issue= 1 | pages= 64-67 | pmid=28680841 | doi=10.1515/jtim-2017-0013 | pmc=5490964 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28680841  }} </ref>
*[[Bilateral|Bilaterally]] [[muscle weakness]] may be seen<ref name="pmid23006457">{{cite journal| author=Bleibel W, Al-Osaimi AM| title=Hepatic encephalopathy. | journal=Saudi J Gastroenterol | year= 2012 | volume= 18 | issue= 5 | pages= 301-9 | pmid=23006457 | doi=10.4103/1319-3767.101123 | pmc=3500018 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23006457  }} </ref>
*Examination [[cranial nerves]] is usually normal, but features of raised ICP(unequal and fixed pupils) may be seen.
 
===Extremities===
* [[Athetosis]] (writhing, sinuous movements of the digits and [[extremities]]) may be present
 
==Laboratory Findings==
*Prolonged [[prothrombin time]](INR>1.5)
*Elevated [[aminotransferase]] level
*Elevated [[bilirubin]] level
*low [[platelet count]]
*Elevated [[ammonia]] level
*Elevated [[Cr|serum Cr]], [[BUN]]
*Elevated [[amylase]] and [[lipase]]
*[[Hypoglycemia]]
*[[Hypokalemia]]
*[[Hypophosphatemia]]
*[[Acidosis]] or [[alkalosis]]
*Elevated [[LDH]] level
 
 
*laboratory tests are recommended for  establishing an etiology and determining the [[prognosis]] of [[Acute liver failure]]:
<br />
{| class="wikitable"
|+
|
* [[Liver function tests]]
* [[Complete blood count]] with differential
* [[Prothrombin time]]/[[international normalized ratio]]
* [[Comprehensive metabolic panel]]
* [[Magnesium]] level
* [[Phosphorus]] level
* [[Amylase]] and [[lipase]] levels
* [[Toxicology screen]] (including acetaminophen and salicylate levels)
* Factor V level<ref name="pmid8675171">{{cite journal |vauthors=Izumi S, Langley PG, Wendon J, Ellis AJ, Pernambuco RB, Hughes RD, Williams R |title=Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure |journal=Hepatology |volume=23 |issue=6 |pages=1507–11 |date=June 1996 |pmid=8675171 |doi=10.1002/hep.510230630 |url=}}</ref>
* [[Alpha-fetoprotein|a-fetoprotein]] level
* Arterial [[lactate]] level
* Arterial [[blood gas]] level
* Arterial [[ammonia]] level (in patients with stage 2 or greater hepatic encephalopathy)
* [[Viral hepatitis]] serologies: [[Hepatitis B]] surface antigen (hepatitis delta immunoglobulin (Ig)G if the surface antigen is positive), [[Hepatitis B]] core IgM, [[Hepatitis A]] IgM, [[Hepatitis E]] IgG (if positive, ribonucleic acid testing should be ordered in select patients), [[Hepatitis C]] antibody
* HIV antibody
* Blood and [[urine culture]]s
* [[Urinalysis]]
* [[Blood type]]
* Serum [[pregnancy]] test (for patients with childbearing potential)
* Thromboelastogram
* Diagnostic transjugular liver biopsy
|}
 
===Imaging===
*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]]
 
==Treatment==
 
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'''<br>
#'''Supportive and symptomatic management'''<br>
#'''Management of complications'''<br>
#'''Emergency therapies'''<br>
#'''[[Liver transplantation]]'''<br>
 
==1. Specific treatment:==
*Identification of the etiology and initiation of specific treatment.
 
==='''[[Acetaminophen]] intoxication'''===
*Oral [[NAC]]: 140 mg/kg [[loading dose]], then 70 mg/kg every 4 hours until discontinued by [[hepatology]] or transplantation surgery attending physician
**Or
*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
 
==='''[[Amanita phalloides]]'''([[mushroom poisoning]])===
*[[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
 
==='''[[Herpes simplex virus infection]]'''===
*[[Acyclovir]]: 10 mg/kg IV every 8 hours (using IBW) adjusted for kidney function
 
==='''[[Cytomegalovirus infection]]'''===
*[[Ganciclovir]]: 5 mg/kg IV every 12 hours (using IBW) adjusted for kidney function
 
==='''[[Autoimmune hepatitis]]'''===
*[[Methylprednisolone]]
 
==='''[[Hepatitis B]] virus infection'''===
*[[Entecavir]] (taken on an empty stomach) or [[tenofovir]] at standard renal adjusted doses
 
==='''[[Acute fatty liver of pregnancy]] /[[HELLP]]'''===
*Delivery of the fetus
 
==2. Supportive and symptomatic management==
*Timely transfer to the critical care unit
*Check clinical status continuously
*Fluid restriction
*IV [[H2-receptor blockers|H2 Blockers]] or [[PPI]]
*[[Antibiotics]]
*Prevention of [[hypoglycemia]]
*Avoid [[sedation]]
*12 hourly [[electrolyte]]s and [[coagulation]] studies
 
==3. Management of Complications:==
 
==Treatment of [[Hepatic encephalopathy]]:==
 
Even minimal [[hepatic encephalopathy]] may benefit from treatment.<ref name="pmid17326150">{{cite journal |author=Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R |title=Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy |journal=Hepatology |volume=45 |issue=3 |pages=549-59 |year=2007 |pmid=17326150 |doi=10.1002/hep.21533}}</ref>
 
* 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.<ref>{{cite journal |author=Córdoba J, López-Hellín J, Planas M, et al |title=Normal protein diet for episodic hepatic encephalopathy: results of a randomized study |journal=J. Hepatol. |volume=41 |issue=1 |pages=38–43 |year=2004 |pmid=15246205 |doi=10.1016/j.jhep.2004.03.023}}</ref> Indeed, because [[chronic liver disease]] is a [[catabolic]] state, a [[protein]] restricted diet would lead to protein [[malnutrition]] and a negative [[nitrogen]] balance.


==Prognosis==
* Correction of [[hypokalemia]]:
The King's College criteria (KCC) may be used.
Concomitant [[hypokalemia]] should be corrected as [[hypokalemia]] increases renal [[ammonia]] production and may promote conversion of [[ammonium]] into [[ammonia]] which can cross the [[blood-brain barrier]].<ref name="pmid5958605">{{cite journal |author=Artz SA, Paes IC, Faloon WW |title=Hypokalemia-induced hepatic coma in cirrhosis. Occurrence despite neomycin therapy |journal=Gastroenterology |volume=51 |issue=6 |pages=1046-53 |year=1966 |pmid=5958605 |doi=}}</ref>
 
* [[Lactulose]]:
[[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]] (NH<sub>3</sub>) to [[ammonium]] (NH<sub>4</sub><sup>+</sup>) 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]].<ref>{{cite journal |author=Als-Nielsen B, Gluud L, Gluud C |title=Nonabsorbable disaccharides for hepatic encephalopathy |journal=Cochrane Database Syst Rev |volume= |issue= |pages=CD003044 |year= |pmid=15106187}}</ref> 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.<ref name="pmid4682313">{{cite journal |author=Kersh ES, Rifkin H |title=Lactulose enemas |journal=Ann. Intern. Med. |volume=78 |issue=1 |pages=81-4 |year=1973 |pmid=4682313 |doi=}}</ref><ref name="pmid240347">{{cite journal |author=Ratnaike RN, Hicks EP, Hislop IG |title=The rectal administration of lactulose |journal=Australian and New Zealand journal of medicine |volume=5 |issue=2 |pages=137-40 |year=1975 |pmid=240347 |doi=}}</ref><ref name="pmid3301614">{{cite journal |author=Uribe M, Campollo O, Vargas F, et al |title=Acidifying enemas (lactitol and lactose) vs. nonacidifying enemas (tap water) to treat acute portal-systemic encephalopathy: a double-blind, randomized clinical trial |journal=Hepatology |volume=7 |issue=4 |pages=639-43 |year=1987 |pmid=3301614 |doi=}}</ref> 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]].<ref name="pmid11467622">{{cite journal |author=Blei AT, Córdoba J |title=Hepatic Encephalopathy |journal=Am. J. Gastroenterol. |volume=96 |issue=7 |pages=1968-76 |year=2001 |pmid=11467622 |doi=10.1111/j.1572-0241.2001.03964.x}}</ref>
 
* [[Antibiotic|Antibiotics]]:
[[Antibiotic|Antibiotics]] may be given to kill [[bacteria]] present in the [[bowel]] thereby decreasing [[Bacteria|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 insufficiency|renal failure]] in [[cirrhosis]] and [[portal hypertension]] (i.e. [[hepatorenal syndrome]]). [[Metronidazole]] has also been studied.<ref name="pmid7035298">{{cite journal |author=Morgan MH, Read AE, Speller DC |title=Treatment of hepatic encephalopathy with metronidazole |journal=Gut |volume=23 |issue=1 |pages=1-7 |year=1982 |pmid=7035298 |doi=}}</ref>
 
* [[Rifaximin]]:
[[Rifaximin]] , receieved orphan drug status in 2005 for the treatment of [[hepatic encephalopathy]]. In contrast to [[neomycin]], its tolerability profile is comparable to [[placebo]].<ref name="pmid10741936">{{cite journal |author=Williams R, James OF, Warnes TW, Morgan MY |title=Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study |journal=European journal of gastroenterology & hepatology |volume=12 |issue=2 |pages=203-8 |year=2000 |pmid=10741936 |doi=}}</ref> 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.<ref name="pmid8325041">{{cite journal |author=Bucci L, Palmieri GC |title=Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy |journal=Current medical research and opinion |volume=13 |issue=2 |pages=109-18 |year=1993 |pmid=8325041 |doi=}}</ref> Similarly, [[rifaximin]] was as effective as [[neomycin]] and [[Paromomycin sulfate|paromomycin]].<ref name="pmid1751811">{{cite journal |author=Pedretti G, Calzetti C, Missale G, Fiaccadori F |title=Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial |journal=The Italian journal of gastroenterology |volume=23 |issue=4 |pages=175-8 |year=1991 |pmid=1751811 |doi=}}</ref> [[Rifaximin]] was better tolerated than both the cathartics and the other nonabsorbable [[Antibiotic|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.
 
* [[Benzodiazepine]] receptor [[antagonists]]:
A [[meta-analysis]] of [[randomized controlled trials]] by the international [[Cochrane Collaboration|cochrane collaboration]] found benefit from [[flumazenil]].<ref name="pmid15106178">{{cite journal |author=Als-Nielsen B, Gluud LL, Gluud C |title=Benzodiazepine receptor antagonists for hepatic encephalopathy |journal=Cochrane database of systematic reviews (Online) |volume= |issue=2 |pages=CD002798 |year=2004 |pmid=15106178 |doi=10.1002/14651858.CD002798.pub2}}</ref> 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.
 
* L-[[ornithine]]-L-[[aspartate]]:
L-[[ornithine]]-L-[[aspartate]] stimulates the [[urea cycle]], and has shown encouraging results in [[randomized controlled trials]].<ref>{{cite journal |author=Poo J, Góngora J, Sánchez-Avila F, Aguilar-Castillo S, García-Ramos G, Fernández-Zertuche M, Rodríguez-Fragoso L, Uribe M |title=Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study |journal=Ann Hepatol |volume=5 |issue=4 |pages=281-8 |year=2006 |pmid=17151582}}</ref><ref name="pmid17151582">{{cite journal |author=Poo JL, Góngora J, Sánchez-Avila F, et al |title=Efficacy of oral L-ornithine-L-aspartate in cirrhotic patients with hyperammonemic hepatic encephalopathy. Results of a randomized, lactulose-controlled study |journal=Annals of hepatology : official journal of the Mexican Association of Hepatology |volume=5 |issue=4 |pages=281-8 |year=2006 |pmid=17151582 |doi=}}</ref><ref name="pmid9625322">{{cite journal |author=Stauch S, Kircheis G, Adler G, et al |title=Oral L-ornithine-L-aspartate therapy of chronic hepatic encephalopathy: results of a placebo-controlled double-blind study |journal=J. Hepatol. |volume=28 |issue=5 |pages=856-64 |year=1998 |pmid=9625322 |doi=}}</ref>


====Contraindicated medications====
====Contraindicated medications====
{{MedCondContrAbs|MedCond = Hepatic coma|Bumetanide|Metolazone}}
==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:<ref name="pmid20049084">{{cite journal |vauthors=Plauth M, Schuetz T |title=Hepatology - Guidelines on Parenteral Nutrition, Chapter 16 |journal=Ger Med Sci |volume=7 |issue= |pages=Doc12 |date=November 2009 |pmid=20049084 |pmc=2795384 |doi=10.3205/000071 |url=}}</ref>
*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 [[death|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 [[upper gastrointestinal bleeding|hemorrhage]], and avoidance of other toxins that can affect both the liver and kidney.<ref name="pmid26159272">{{cite journal| author=Cavallin M, Fasolato S, Marenco S, Piano S, Tonon M, Angeli P| title=The Treatment of Hepatorenal Syndrome. | journal=Dig Dis | year= 2015 | volume= 33 | issue= 4 | pages= 548-54 | pmid=26159272 | doi=10.1159/000375346 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26159272  }}</ref>
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:<ref name="pmid24356549">{{cite journal| author=Fabrizi F, Aghemo A, Messa P| title=Hepatorenal syndrome and novel advances in its management. | journal=Kidney Blood Press Res | year= 2013 | volume= 37 | issue= 6 | pages= 588-601 | pmid=24356549 | doi=10.1159/000355739 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24356549  }}</ref>
===Albumin===
All major studies showing improvement in renal function in patients with hepatorenal syndrome have involved expansion of the volume of the [[blood plasma|plasma]] with [[human serum albumin|albumin]] given intravenously <ref name="Guevara" /><ref name="Terli" /> One regimen is 1 gm albumin per kg of body weight intravenously on day one followed by followed by 20-40 grams daily.<ref name="pmid15084697">{{cite journal |author=Ginès P, Cárdenas A, Arroyo V, Rodés J |title=Management of cirrhosis and ascites |journal=N. Engl. J. Med. |volume=350 |issue=16 |pages=1646-54 |year=2004 |pmid=15084697 |doi=10.1056/NEJMra035021}}</ref>
===Midodrine and octreotide===
[[Midodrine]] is an alpha-agonist and octreotide is an [[Analog (chemistry)|analog]] of [[somatostatin]]. The medications are respectively systemic [[vasoconstrictors]] and [[Inhibitor|inhibitors]] of [[vasodilator]]s, and were not found to be useful when used individually in the treatment of the [[hepatorenal syndrome]].<ref>Pomier-Layrargues G, Paquin SC, Hassoun Z, Lafortune M, Tran A.  Octreotide in hepatorenal syndrome: a randomized, double-blind, placebo-controlled, crossover study.  ''Hepatology'' 2003 Jul;38(1):238-43.</ref> However, one study of 13 patients with hepatorenal syndrome showed significant improvement when the two were used together (with [[midodrine]] given orally, [[octreotide]] given [[subcutaneous]]ly and both dosed according to [[blood pressure]]), with three patients surviving to discharge.<ref name="Angeli">Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, Amodio P, Sticca A, Caregaro L, Maffei-Faccioli A, Gatta A.  Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide.  ''Hepatology'' 1999 Jun;29(6):1690-7.  PMID 10347109</ref> 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".<ref name="pmid17235705">{{cite journal |author=Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA |title=Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome |journal=Dig. Dis. Sci. |volume=52 |issue=3 |pages=742-8 |year=2007 |pmid=17235705 |doi=10.1007/s10620-006-9312-0}}</ref>
===Vasopressin analogues===
The [[Vasopressin#Pharmacology|vasopressin analogue]] [[ornipressin]] was found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome,<ref name="Guevara">Guevara M, Gines P, Fernandez-Esparrach G, Sort P, Salmeron JM, Jimenez W, Arroyo V, Rodes J.  Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.  ''Hepatology'' 1998 Jan;27(1):35-41.  PMID 9425914  </ref><ref>Gulberg V, Bilzer M, Gerbes AL.  Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine.  ''Hepatology'' 1999 Oct;30(4):870-5.  PMID 10498636 </ref> but has been limited by [[ischemia|ischemic]] complications<ref name="Guevara" />. [[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]].<ref name="Terli">Ortega R, Gines P, Uriz J, Cardenas A, Calahorra B, De Las Heras D, Guevara M, Bataller R, Jimenez W, Arroyo V, Rodes J.  Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.  ''Hepatology'' 2002 Oct;36 (4 Pt 1):941-8.  PMID 12297842</ref> Neither medication is available for use in North America.
===Transjugular intrahepatic portosystemic shunt===
[[Image:TIPS.jpg|thumb|right|200 px|TIPS, shown in progress here, has been shown to improve renal function in individuals with HRS if portal pressures decrease after the procedure.]]
[[Transjugular intrahepatic portosystemic shunt]]s ([[TIPS]]) involve decompression of the high pressures in the [[portal hypertension|portal]] circulation by placing a small stent between a [[portal vein|portal]] and [[hepatic vein]].  They have also been shown to improve renal function in patients with hepatorenal syndrome.<ref>Wong F, Pantea L, Sniderman K.  Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome.  ''Hepatology''. 2004 Jul;40(1):55-64.  PMID 15239086.</ref><ref>Guevara M, Rodes J. Hepatorenal syndrome. ''Int J Biochem Cell Biol.'' 2005 Jan;37(1):22-6. PMID 15381144.</ref>
===Liver dialysis===
[[Liver dialysis]] involves extracorporeal dialysis to remove toxins from the circulation.  The [[Liver dialysis#Liver dialysis devices|molecular adsorbents recirculation system]] (MARS) has shown some utility as a bridge to transplantation in patients with hepatorenal syndrome.<ref>Mitzner SR, Stange J, Klammt S, Risler T, Erley CM, Bader BD, Berger ED, Lauchart W, Peszynski P, Freytag J, Hickstein H, Loock J, Lohr JM, Liebe S, Emmrich J, Korten G, Schmidt R. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective, randomized, controlled clinical trial. ''Liver Transpl.'' 2000 May;6(3):277-86. PMID 10827226.</ref>
===Hemodialysis===
[[Renal replacement therapy]] may be required to 'bridge' the patient to [[liver transplantation]], although the condition of the patient may dictate the modality used.<ref>Witzke O, Baumann M, Patschan D, Patschan S, Mitchell A, Treichel U, Gerken G, Philipp T, Kribben A.  Which patients benefit from hemodialysis therapy in hepatorenal syndrome?  ''J Gastroenterol Hepatol.'' 2004 Dec;19(12):1369-73.  PMID 15610310</ref>
===Other medications===
Other agents used in treatment include
* [[Pentoxifylline]],
* [[Acetylcysteine]],<ref>Holt S, Goodier D, Marley R, Patch D, Burroughs A, Fernando B, Harry D, Moore K.  Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. ''Lancet''. 1999 Jan 23;353(9149):294-5.  PMID 9929029</ref>
* [[Misoprostol]].<ref>Clewell JD, Walker-Renard P.  Prostaglandins for the treatment of hepatorenal syndrome.  ''Ann Pharmacother.'' 1994 Jan;28(1):54-5.  PMID 8123962</ref>
==Management of Coagulopathy<ref name="pmid31498101">{{cite journal |vauthors=Stravitz RT, Lee WM |title=Acute liver failure |journal=Lancet |volume=394 |issue=10201 |pages=869–881 |date=September 2019 |pmid=31498101 |doi=10.1016/S0140-6736(19)31894-X |url=}}</ref>==
*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.<ref name="pmid31498101">{{cite journal |vauthors=Stravitz RT, Lee WM |title=Acute liver failure |journal=Lancet |volume=394 |issue=10201 |pages=869–881 |date=September 2019 |pmid=31498101 |doi=10.1016/S0140-6736(19)31894-X |url=}}</ref>
==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]].<ref name="pmid20049084">{{cite journal |vauthors=Plauth M, Schuetz T |title=Hepatology - Guidelines on Parenteral Nutrition, Chapter 16 |journal=Ger Med Sci |volume=7 |issue= |pages=Doc12 |date=November 2009 |pmid=20049084 |pmc=2795384 |doi=10.3205/000071 |url=}}</ref>
*[[Serum]] [[ammonia]] levels should be monitored and protein load should be adjusted accordingly.
==Treatment of hemodynamic instabilty==
*Invasive [[hemodynamic]] monitoring
*[[Colloid]], [[crystalloid fluids]], and blood products
*[[Vassopressor]]
==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 system|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
==Contraindicated medications==


{{MedCondContrAbs|MedCond =Severe hepatic failure|Carvedilol|Conjugated estrogens/bazedoxifene|Diclofenamide|Dronedarone|Nebivolol|Rosuvastatin|Simvastatin|Spironolactone|Hydrochlorothiazide|Doxorubicin Hydrochloride}}
{{MedCondContrAbs|MedCond =Severe hepatic failure|Carvedilol|Conjugated estrogens/bazedoxifene|Diclofenamide|Dronedarone|Nebivolol|Rosuvastatin|Simvastatin|Spironolactone|Sulfamethoxazole/Trimethoprim|Hydrochlorothiazide|Doxorubicin Hydrochloride|Tipranavir}}
The ALFSG index is a newer option that may be more accurate.<ref name="pmid22885329">{{cite journal| author=Rutherford A, King LY, Hynan LS, Vedvyas C, Lin W, Lee WM et al.| title=Development of an accurate index for predicting outcomes of patients with acute liver failure. | journal=Gastroenterology | year= 2012 | volume= 143 | issue= 5 | pages= 1237-43 | pmid=22885329 | doi=10.1053/j.gastro.2012.07.113 | pmc=PMC3480539 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22885329  }} </ref>
The ALFSG index is a newer option that may be more accurate.<ref name="pmid22885329">{{cite journal| author=Rutherford A, King LY, Hynan LS, Vedvyas C, Lin W, Lee WM et al.| title=Development of an accurate index for predicting outcomes of patients with acute liver failure. | journal=Gastroenterology | year= 2012 | volume= 143 | issue= 5 | pages= 1237-43 | pmid=22885329 | doi=10.1053/j.gastro.2012.07.113 | pmc=PMC3480539 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22885329  }} </ref>



Latest revision as of 19:22, 28 September 2020

Hepatic failure
ICD-10 K72.9
DiseasesDB 5728
MeSH D017093

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Roghayeh Marandi[2]


Synonyms and keywords: Liver failure; fulminating hepatic failure

Overview

Liver failure is the inability of the liver to perform its normal synthetic and metabolic function as part of normal physiology.

Historical Perspective

Classification

Three forms are recognized:

Pathophysiology

The pathophysiology of ALF can be divided into cause‐specific liver injury pathophysiologies and pathophysiology related to the occurrence of secondary multi-organ failure.




Causes

Causes for Acute liver failure[13][14]:

Category Etiology of Acute liver failure
Viruses
Drugs
Metabolic diseases
Toxins
Vascular diseases
Malignant Infiltration
Autoimmune disease
Indeterminate
  • Unknown

Drug-induced acute liver injury

Viral hepatitis

Mushroom poisoning

Causes of chronic liver failure

Differential Diagnosis

Epidemiology and Demographics

Risk factors

Screening

Not applicable

Natural History, Complications and Prognosis

Natural History

Clinical features in Hepatic failure and complications

Brain

Liver

Kidney and adrenal

System

Heart

  • High output state
  • Subclinical myocardial injury
  • Hepatocardiac syndrome

Pancreas

Lungs

Bone marrow

Prognosis

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%.[13] 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.[22]
  • 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.[23][19][24][22]

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.[25]

Diagnosis

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

Social history

Past Medical history

Menstrual history

Family history

Medication history

  • 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;

Symptoms

Physical Examination

  • Complete physical examination should be performed.

Appearance of the patient

  • Patients with hepatic failure have any degree of Hepatic encephalopathy.[28][29]

Vital signs

In patients with hepatic failure vital signs include:[30]

Skin

Signs of liver disease may be seen, such as:[31]

HEENT

Neck

Physical examination of neck is usually normal but in Hepatic failure due to CHF,Jugular vein distention may be seen.

Lungs

Heart

Physical examination of heart is usually normal unless the cause of hepatic failure is Heart disease such as Right heart failure.

Abdomen

Signs of liver disease may be seen such as:

Back

Physical examination of back is usually normal

Genitourinary

Neuromuscular

Extremities

Laboratory Findings



Imaging

Treatment

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

  1. Specific Treatment
  2. Supportive and symptomatic management
  3. Management of complications
  4. Emergency therapies
  5. Liver transplantation

1. Specific treatment:

  • Identification of the etiology and initiation of specific treatment.

Acetaminophen intoxication

  • Oral NAC: 140 mg/kg loading dose, then 70 mg/kg every 4 hours until discontinued by hepatology or transplantation surgery attending physician
    • Or
  • 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

Amanita phalloides(mushroom poisoning)

  • 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

Herpes simplex virus infection

  • Acyclovir: 10 mg/kg IV every 8 hours (using IBW) adjusted for kidney function

Cytomegalovirus infection

  • Ganciclovir: 5 mg/kg IV every 12 hours (using IBW) adjusted for kidney function

Autoimmune hepatitis

Hepatitis B virus infection

Acute fatty liver of pregnancy /HELLP

  • Delivery of the fetus

2. Supportive and symptomatic management

3. Management of Complications:

Treatment of Hepatic encephalopathy:

Even minimal hepatic encephalopathy may benefit from treatment.[43]

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.[44] Indeed, because chronic liver disease is a catabolic state, a protein restricted diet would lead to protein malnutrition and a negative nitrogen balance.

Concomitant hypokalemia should be corrected as hypokalemia increases renal ammonia production and may promote conversion of ammonium into ammonia which can cross the blood-brain barrier.[45]

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.[46] 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.[47][48][49] 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.[50]

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.[51]

Rifaximin , receieved orphan drug status in 2005 for the treatment of hepatic encephalopathy. In contrast to neomycin, its tolerability profile is comparable to placebo.[52] 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.[53] Similarly, rifaximin was as effective as neomycin and paromomycin.[54] 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.[55] 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.

L-ornithine-L-aspartate stimulates the urea cycle, and has shown encouraging results in randomized controlled trials.[56][57][58]

Contraindicated medications

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:[59]

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.[60]

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:[61]

Albumin

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 [62][63] One regimen is 1 gm albumin per kg of body weight intravenously on day one followed by followed by 20-40 grams daily.[64]

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.[65] 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.[66] 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".[67]

Vasopressin analogues

The vasopressin analogue ornipressin was found in a number of studies to be useful in improvement of renal function in patients with hepatorenal syndrome,[62][68] but has been limited by ischemic complications[62]. 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.[63] Neither medication is available for use in North America.

Transjugular intrahepatic portosystemic shunt

TIPS, shown in progress here, has been shown to improve renal function in individuals with HRS if portal pressures decrease after the procedure.

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.[69][70]

Liver dialysis

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.[71]

Hemodialysis

Renal replacement therapy may be required to 'bridge' the patient to liver transplantation, although the condition of the patient may dictate the modality used.[72]

Other medications

Other agents used in treatment include

Management of Coagulopathy[5]

  • 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.[5]

Management of metabolic abnormalities

Treatment of hemodynamic instabilty

4. Emergency therapies

5. Liver transplantation

  • Early consultation with liver transplant specialists and transfer of patients to a liver transplant center when necessary

Contraindicated medications

Severe hepatic failure is considered an absolute contraindication to the use of the following medications:

The ALFSG index is a newer option that may be more accurate.[75]

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