critical care in acute liver failure || investigation and diagnostic pathways

48 © 2013 Future Medicine4848 www.futuremedicine.com

Heather PattonHeather Patton is a transplant hepatologist and Assistant Clinical Professor of Medicine at the University of California, San Diego (UCSD; CA, USA). Her clinical and research interests are in complications of cirrhosis and she is the Primary Investigator for the UCSD site of the North American Consortium for the Study of End Stage Liver Disease (NACSELD). She has developed an evidence-based protocol for the management of acute liver failure for the UC San Diego Health System.

Robert G GishRobert G Gish, MD, is the Medical Director of the Center for Hepatobiliary Disease and Abdominal Transplantation (CHAT), the Chief of Clinical Hepatology, and a Professor of Clinical Medicine at the University of California, San Diego (CA, USA). His clinical research focuses on viral hepatitis, liver cancer, end-stage liver disease, liver transplant, bioartificial liver, and public policy related to liver transplantation and viral hepatitis. He has a quarter century of experience as a clinician and clinical investigator. He has published over 100 articles in peer-reviewed journals, and given thousands of lectures on liver disease in the USA and a dozen other countries.

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© 2013 Future Medicine

doi:10.2217/EBO.12.325

49

Investigation and diagnostic pathways

Heather Patton & Robert G GishOnce a diagnosis of acute liver failure (ALF) has been established (see Chapter 1), the next key steps in patient evaluation are to determine the etiology of ALF, when possible, and to assess the patient’s prognosis (in particular, the need for liver transplant). Concurrent with these diagnostic evaluations, the patient requires diligent monitoring for development of complications so that these may be identified and managed in a timely fashion. This chapter will present an approach to the diagnostic evaluation of the ALF patient organized according to those studies aimed at: determining the diagnosis; establishing a prognosis; and following progression and monitoring for complications. This chapter is designed to help facilitate a rapid and accurate assessment of these patients given that their condition may evolve quickly and, in cases where a treatable etiology can be identified, medical management may increase the likelihood of overall survival for those patients who are not liver transplant candidates, and of transplant-free survival where a transplant can be offered.

Investigations aimed at determining the etiology of acute liver failure 50

Diagnostic studies aimed at determining prognosis 59

Diagnostic studies aimed at monitoring clinical progress of the ALF patient 60

Chapter 4

Patton & Gish

50 www.futuremedicine.com

Investigations aimed at determining the etiology of acute liver failureThe preponderant causes of acute liver failure (ALF) vary geographically, largely according to the prevalence of hepatotropic viruses and population

patterns of medication use and abuse, as well as drug abuse. Thus, the resources dedicated to diagnostic evaluation may vary regionally according to the most common etiologies observed in the local population [1]. For example, in developing countries, viral etiologies are predominantly the causal agents of ALF whereas in the USA and western Europe, drug-induced liver injury accounts for the majority of cases (see Chapter 3).

The attainment of a thorough history from patients with ALF may be challenging and, in some cases, impossible due to encephalopathy. As mental status changes can evolve quickly, medical personnel should interview patients as soon as possible so as not to miss the window of opportunity to obtain important historical details from the ALF patient. Family and other close contacts may serve as important sources of information in cases where patients have severe encephalopathy. The key aspects of history relevant to ALF are detailed below:

nPast medical history: relevant elements include history of autoimmune diseases, thrombotic disorders, psychiatric disease, cardiovascular disease, malignancy, pain syndromes and immunocompromised status;

nTiming of onset of symptoms: time course from first symptoms, which may be nonspecific, such as fatigue or malaise, and the onset of jaundice and subsequently altered mental status;

nAcetaminophen (paracetamol) product use: most ingestions resulting in ALF exceed 10 g/day with exceptional cases of severe injury reported in those with exposures as low as 3–4 g/day;

nReview of all medication exposures from the last 3–6 months: the most common classes of drugs implicated in drug-induced liver injury are anticonvulsants, antimicrobials and nonsteroidal anti-inflammatory agents. Specific questions about over-the-counter, herbal/natural/supplemental agents should also be asked, recognizing that patients may not consider

As drug-induced liver injury is the predominant cause of acute liver failure (ALF) in the USA and

western Europe, drug history in cases of ALF must include: acetaminophen-containing products, antibiotics, anticonvulsants, and nonsteroidal anti-inflammatory agents taken within the past 6 months.

Severe transaminitis (aspartate amino-transferase/alanine aminotransferase

>1000 U/l) without significant jaundice should raise concern for acetaminophen overdose, early viral hepatitis and shock liver, while with a severe hepatitis accompanied by a dramatically elevated bilirubin, a diagnosis of autoimmune hepatitis should be considered.

Investigation & diagnostic pathways

51www.futuremedicine.com

this history to be relevant and/or may be reluctant to share this history with healthcare providers;

nAlcohol and drug use: both remote and recent use with details regarding type, quantity, route and duration;

nTravel history: particularly to regions endemic for hepatotropic viruses, such as Asia, the Middle East, Africa and Central and South America [101,102];

nRisk factors for hepatitis A and E: ingestion of fecally contaminated food or drinking water, close household contact with infected family members or sexual partners, and travel to endemic locations;

nRisk factors for hepatitis B, C and D, and HIV: injection drug use, sexual activity, needle stick exposures, snorted drugs with shared paraphernalia, and tattoos (especially when obtained in countries where unsterilized needles and knives are commonly reused in tattoo shops);

nExposure to mushrooms from the Amanita genus: most common in Europe though also reported in northern Africa, Asia, and parts of the USA (Pacific Northwest, Pennsylvania, New Jersey, Ohio and Texas). Typical symptoms include nausea, vomiting, abdominal pain and diarrhea occurring within hours to a day of ingestion.

The initial diagnostic studies in patients with ALF need to be fairly extensive so as to arrive at a determination of etiology and prognosis as quickly as possible. The following comprehensive diagnostic studies are recommended:

nAcetaminophen level: should be obtained as soon as possible with any measurable level raising the concern about toxicity;

nToxicology screen: for drugs of abuse and blood alcohol levels;

nViral hepatitis serologies: the most common hepatotropic virus infections associated with ALF should be routinely tested (see section on diagnostic evaluation of hepatotropic viruses);

nAbdominal ultrasound with Doppler: to assess liver size, contour, vascular patency, and presence of intrahepatic mass or hemorrhage;

nHIV-1, HIV-2: given potential impact on type and severity of liver disease as well as transplant candidacy;

nCeruloplasmin level and 24-h urine copper: additional studies are warranted if clinical suspicion for Wilson’s disease (WD) is high (see later);

Patton & Gish


nPregnancy test: in women of childbearing potential. Pregnancy-associated cases of ALF typically present in the third trimester; thus, patients will be aware and confirmatory testing not indicated;

nMarkers of autoimmune liver disease: autoantibodies and immunoglobulin levels;

nTransjugular liver biopsy [2]: indicated if autoimmune hepatitis, metastatic liver disease, WD, herpes simplex hepatitis [3], or infiltrative disease (lymphoma, leukemia) are suspected.

Acetaminophen (ACM)-induced hepatotoxicity is the predominant cause of ALF in the USA and UK. ACM overdose may either be intentional (suicide attempt) or due to the inadvertent consumption of supratherapeutic quantities of analgesic agents. ACM hepatotoxicity is the exemplar of the hyperacute variant of ALF. Salient diagnostic features of ACM-induced hepatotoxicity include:

nVery high serum aminotransferase levels (aspartate aminotrans-ferase [AST] and alanine aminotransferase [ALT], typically >1000 IU/l) with low bilirubin levels [4]. Aminotransferase levels in excess of 3500 IU/l are highly suggestive of ACM;

nMost commonly, after intentional major overdose, patients will have detectable levels of ACM while with unintentional overdose, it is more likely that intake may have been staggered, resulting in ACM levels that are low or even undetectable. However, it is important to be aware that even with intentional overdose some cases will present after a delay when ACM will be undetectable;

nRapidly progressive course with early onset of multiorgan failure;

nPancreatitis;

nFeatures of unintentional overdose include use of multiple ACM-containing products and use of narcotic ACM preparations [5];

nFeatures of intentional overdose include larger total doses and concomitant consumption of alcohol and/or other drugs.

Cases of occult ACM overdose (undetectable ACM level in a patient unaware of having taken an overdose and/or unable to provide a history of ACM use due to severe hepatic encephalopathy) may be identified through an assay that detects acetaminophen-containing protein adducts that are released into the plasma by dying hepatocytes [6]. Importantly, these adducts are not found in cases of ACM use not associated with



hepatotoxicity. Presently, the ACM adduct assay is not routinely available for clinical use. Thus, clinicians need to rely on adjunctive evidence of ACM overdose as reviewed earlier.

In the developing world, acute viral hepatitis is the predominant cause of ALF. Hepatitis E is the primary cause of ALF in India, Pakistan, China, and Southeast Asia [7]. The most commonly observed viral causes for ALF (hepatitis A, B and E) should be tested for in all patients presenting with ALF with the following serologies:

nAnti-hepatitis A virus (HAV) IgM;

nHepatitis B virus (HBV) surface antigen (HBsAg); if positive, reflex to HBV DNA, HBeAg and anti-HBe;

nAnti-HBV core (HBc) IgM; if positive, reflex to HBV DNA quant;

nAnti-hepatitis E virus (HEV) IgM; if positive, a subsequent order needs to be placed for blood and stool PCR testing for HEV to confirm infection.

Historically, patients with ALF from acute hepatitis B infection and those with ALF from an acute exacerbation of chronic hepatitis B infection could not be distinguished from each other unless historical or histological evidence of chronicity was available. However, data from the Acute Liver Failure Study Group (ALFSG) published this year reported that those with acute HBV infection had much higher IgM anti-HBc titers, lower viral loads (HBV DNA) and better prognosis in comparison to those with acute exacerbation of chronic HBV infection [8]. While felt to be quite rare, cases of ALF from acute hepatitis C virus (HCV) infection have been reported in Japan and India; thus, testing for anti-HCV and HCV RNA may be considered. Other uncommon but documented viral causes of ALF that may be tested in specific clinical settings include the following (shown in parentheses are serological markers of acute rather than chronic/historical infection):

nHerpes simplex virus (HSV) 1 and 2 antibody (IgM antibody-positive or HSV DNA-positive with negative IgG antibody);

nAnti-varicella zoster virus (VZV; fourfold rise in antibody titer over 10–14 days);

nHuman herpesvirus 6 (HHV-6; IgM antibody-positive with negative IgG antibody or PCR-positive with negative IgG antibody);

nEpstein–Barr virus (EBV; IgM of viral capsid antigen [VCA] and/or IgM early antigen with negative antibody to nuclear antigen [NA], or PCR-positive with negative IgG to VCA and NA);

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nCytomegalovirus (CMV; PCR-positive with negative IgG antibody or IgM antibody >1:8 with negative IgG antibody);

nParvovirus B19 (PCR-positive with negative IgG antibody or IgM antibody-positive with negative IgG antibody).

Herpes virus infection is most commonly reported in patients who are immunosuppressed or during pregnancy (particularly the third trimester) but has also been reported very rarely in healthy individuals.

Approximately one quarter of patients with autoimmune hepatitis (AIH) present acutely with jaundice, a small subset of whom progress to ALF. Features suggestive of AIH include young age, female gender, Caucasian race, negative viral serologies, history-negative for drug and alcohol use, and high transaminases (ALT and AST often elevated to ≥1000 IU/l) with a high total bilirubin level (often ≥20 mg/dl). Recommended studies for evaluation of autoimmune hepatitis include:

nAnti-nuclear antibody (ANA);

nF-actin (smooth muscle) antibody;

nAnti-LKM-1 antibody, especially in children and young adults;

nQuantitative immunoglobulins.

Note that autoantibodies may be absent in up to 30%; thus, liver biopsy should be strongly considered if there is any degree of clinical suspicion for AIH (Figure 4.1) [9]. Histological features of AIH presenting with ALF from the USA ALF registry were: massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%) [9].

Ischemic hepatitis (‘shock liver’) results from arterial hypoxemia and/or impaired hepatic perfusion. While this is not an unusual diagnosis among critically ill patients, it is an uncommon cause for liver failure (4.4% of patients enrolled in the AFLSG) [10]. Echocardiogram should be obtained in cases where ischemic hepatitis is suspected as patients with congestive hepatopathy are at increased susceptibility for ischemic hepatitis. Typical clinical features of ischemic hepatitis include:

nRapid and significant transaminitis (ALT may reach or exceed 1000 IU/ml);

nElevated lactate dehydrogenase (LDH) levels;

nMarkers of muscle necrosis;

nAcute kidney injury.



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Episodes may be precipitated by cardiac events, such as congestive heart failure, myocardial infarction, cardiopulmonary arrest and cardiac arrhythmias, as well as non-cardiac events, such as sepsis and seizures. Typically, there is early recovery of hepatic function.

While WD is a rare cause for ALF both in the USA and Europe (2–3% in the USA ALFSG) [11], early recognition is important as this is universally fatal without liver transplantation [12].

Suspicion for WD should be heightened in the following:

nAge 5–40 years;

nCoombs-negative hemolytic anemia with high indirect-reacting bilirubin;

nRapidly progressive acute renal failure (due to renal tubular damage from copper);

nDecreased uric acid level;

nHigh total bilirubin (mg/dl) to alkaline phosphatase (IU/l) ratio (>2.0);

nNormal or very low alkaline phosphatase.

Note that while ceruloplasmin is recommended as the screening test for WD, levels may be normal in 15% of cases, may be elevated as an acute phase reactant, and may be decreased in up to 50% of patients with ALF from causes other than WD. Thus, in cases of suspected WD, other diagnostic studies to confirm diagnosis may include:

nKayser–Fleischer rings (Figure 4.2) may be observed in approximately 50% of WD patients with an acute presentation;

nUrinary copper levels;

nTransjugular liver biopsy with copper quantification;

Acute Budd–Chiari syndrome (BCS; hepatic vein thrombosis) is a rare cause of ALF that classically presents with:

nAbdominal pain;

nAscites;

nSignificant hepatomegaly.

Abdominal ultrasound with Doppler is the initial diagnostic test of choice. If nondiagnostic, other imaging studies such as computed tomography, magnetic resonance imaging, or venography may be obtained (Figure 4.3). Transjugular liver biopsy demonstrates central hepatic congestion, necrosis, portal central bridging and interhepatocyte hemorrhage. Note that



percutaneous liver biopsy should not be attempted in this setting as intractable peritoneal hemorrhage may ensue due to hepatic outflow obstruction. Once diagnosed with BCS, further investigations are required to identify an underlying hypercoagulable state (polycythemia, genetic disorders of coagulation, paroxysmal nocturnal hemoglobinuria, malignancy) as precipitant for the acute thrombosis as this may impact transplant candidacy.

A rare complication seen in late pregnancy (typically third trimester), ALF poses threat to both mother and fetus. However, prompt recognition of acute fatty liver of pregnancy and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome offers the opportunity for good outcomes with rapid delivery. Diagnostic features of these pregnancy-related causes of ALF include:

nJaundice, coagulopathy and thrombocytopenia;

nHypertension and proteinuria (features of pre-eclampsia) are frequently present;

nHepatic steatosis (may be identified on ultrasound);

nIntrahepatic hemorrhage, hepatic rupture may rarely occur with these.

While there are cases in which a causative etiology cannot be established (so-called seronegative disease or indeterminate cause), this is a diagnosis of exclusion. Causes implicated in patients with seronegative disease include toxic exposures, autoimmune disease, and viral infections yet to be identified. Seronegative disease has a tendency to follow a subacute course and to have particularly low rates of spontaneous survival with supportive medical care [1]. Review of indeterminate cases by the US ALFSG identified several cases with ACM-protein adducts as well as several others with histology consistent with AIH, demonstrating the potential usefulness of the ACM-protein adduct assay and transjugular liver biopsies in these seronegative cases. Finally, while the diagnostic laboratories and imaging

Figure 4.2. Kayser–Fleischer ring: copper deposition in Descemet’s membrane of the cornea.

These rings can be either dark brown, golden, or reddish-green, are 1–3 mm wide, and appear at the corneal limbus. With rare exceptions, they are diagnostic of Wilson’s disease.Reproduced from [103].

M30 antigen: the M30 antigen is a caspase cleaved neoepitope of cytokeratin 18,

indicative of apoptotic hepatocyte cell death. This biomarker is detected with an ELISA assay and, in combination with other clinical variables, may perform well as an indicator of prognosis in ALF [23,26].

Patton & Gish


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discussed are often critical at arriving at a determination for the cause of ALF, there are limitations in the performance characteristics of all of these tests; some of the potential problems with these diagnostics are shown in Box 4.1.

Diagnostic studies aimed at determining prognosisThere is perhaps no greater responsibility for a transplant hepatologist than to determine whether the ALF patient will require liver transplantation. The consequences of an inaccurate judgment mean that either a precious resource is consumed unnecessarily and an individual is left requiring lifelong immunosuppressant therapy or that a (typically) young and otherwise healthy young person dies without having had the opportunity for a life-saving intervention. There are no laboratory or clinical variables or prognostic models that have been proven to predict with 100% accuracy the need for liver transplant among patients with ALF. However, as reviewed in Chapter 10, there are several laboratory measures and models that have been devised towards this end. The recommended diagnostic studies to determine prognosis are:

nArterial blood gas (ABG; arterial pH) [13];

nArterial ammonia level [14,15];

nArterial lactate [16];

nSerum phosphorus level [17,18];

nFactor V level [19];

na-fetoprotein [20].

ABG should be obtained early following fluid resuscitation in order to determine arterial pH and lactate, both of which are components of the King’s College Hospital (KCH) criteria [13], widely used to determine need for liver transplant listing in the UK and the USA. Other variables included in the KCH criteria are routinely obtained on hospital admission and during routine clinical

Hepatomegaly in ALF may be seen with acute viral hepatitis, acute Budd–Chiari syndrome,

congestive heart failure and malignant infiltration of the liver.

Box 4.1. Diagnostic pitfalls in acute liver failure.

� Nodular contour to liver on imaging (may be seen in ALF and not indicative of cirrhosis in this setting)� Undetectable acetaminophen level when

there is a delay in presentation after ACM ingestion (may be detected with ACM protein adduct assay)� Absent skin lesions in suspected herpes

simplex virus infection (may be present in only 50% of cases)� Low ceruloplasmin levels in cases not due to

WD or normal ceruloplasmin levels in cases with WD� Negative autoantibodies in suspected AIH

(up to 30%)

ALF: Acute liver failure; ACM: Acetaminophen; AIH: Autoimmune hepatitis; WD: Wilson’s disease.

Patton & Gish


follow-up (INR, bilirubin and creatinine). Other criteria applied frequently in northern Europe are the Clichy–Villejuif [21] which require determination of coagulation Factor V concentration. In addition to these scoring systems, so-called supplemental markers of prognosis include serum lactate level [16], phosphate [17], serum Gc Globulin [22] and a-fetoprotein [20]. While not routinely monitored in patients with chronic liver disease, there is a body of literature supporting the prognostic significance of arterial ammonia in patients with ALF [14,15]. Recent data from the US ALF

Registry proposed new criteria, the ALFSG index, comprised of coma grade, INR, levels of bilirubin and phosphorus, and measurements of the apoptosis biomarker M30 [23]. Note that while transjugular liver biopsy has been proposed to facilitate diagnosis of the underlying etiology of ALF in certain clinical scenarios, liver histology is not felt to provide an accurate estimate of prognosis (e.g., due to parenchymal collapse, estimation of percentage hepatocyte necrosis is prone to error).

Diagnostic studies aimed at monitoring clinical progress of the ALF patientThe potential complications of ALF include coagulopathy with bleeding, cerebral edema with intracranial hypertension (ICH), infection, hypoglyce-mia, hypo- and hyper-phosphatemia and acute kidney injury/renal failure. There have been two recent publications evaluating thromboelastogram (TEG) in patients with ALF, recognizing that prothrombin time alone reflects only one aspect of the coagulation process that is affected by liver fail-ure [24,25]. Further data are needed to determine if use of TEG in this patient population allows for reduced blood product transfusions with equivalent patient outcomes with respect to bleeding and thrombotic complications.

Development of cerebral edema and ICH are recognized to be the most serious complications of ALF given the potential for uncal herniation. There is no consensus regarding the use of intracranial pressure monitors; and practices vary widely among centers in their use (although the clinical useful-

ness of this monitoring is readily apparent). Other means of monitoring for evidence of ICH are listed in Table 4.1; note that con-tinuous EEG monitoring, transcranial

Gc globulin: a multifunctional protein synthesized in the liver, the main physiologic

activity of which is felt to be actin binding and actin scavenging, levels of which are profoundly reduced in ALF [27].

Thromboelastogram: provides a global assessment of coagulation incorporating the cumulative effect of the interactions at various levels between plasma components (clotting proteins) and cellular components (platelets, red and white blood cells, and microparticles) of coagulation. This functional assay allows for dynamic assessment of different stages of clot formation (initial clot formation, rate of fibrin formation and cross-linking, maximal clot strength, and fibrinolysis) [24,25].

Diagnostic criteria for acetaminophen-induced hepatotoxicity include any ingestion >4 g,

detectable acetaminophen level, and aspartate aminotransferase >1000 IU/l [5].



Doppler ultrasound, and intraocular ultrasonography are not widely available and their clinical utility in ALF remains to be determined. A baseline head CT should be considered with repeat imaging for patients who progress to Grade III–IV encephalopathy. If antibiot-ics are not given prophylacti-cally (and data have not yet demonstrated survival ben-efit with prophylactic antibi-otics), surveillance cultures are recommended. Blood glucose levels should be rou-tinely monitored for hypo-glycemia. Renal failure is common in ALF and may contribute to mortality; thus, careful monitoring of renal function and manage-ment of hemodynamic derangement should be undertaken. At present, there are no data in patients with ALF on biomarkers of acute kidney injury, such as cystatin C and neutrophil gelatinase-associated lipocalin, that may facilitate a more rapid detection of acute kidney injury, although both appear promising in patients with cirrhosis and those undergoing liver transplant.

Financial & competing interests disclosure

The authors have no relevant affiliations or finan-cial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, con-sultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.

Neutrophil gelatinase-associated lipocalin (NGAL): a small protein expressed in the renal

tubules, renal expression of Neutrophil gelatinase-associated lipocalin is dramatically increased in kidney injury from a variety of causes, and NGAL is released into both urine and plasma. NGAL levels rise within 2 h of the insult, making NGAL attractive as an early biomarker of kidney injury (with data supporting its use in AKI in the setting of cirrhosis and liver transplantation) [28,29].

Table 4.1. Recommended studies to monitor complications in the acute liver failure patient.

Complication Test(s)

Bleeding Serial INR, fibrinogen and platelet count measurementThromboelastogram†

Cerebral edema/intracranial hypertension

Serial pupillary and neurological examinationsAssessment for non-convulsant seizure activity (intermittent or continuous EEG monitoring†)Jugular bulb oxygen saturation†

Near-infrared spectrophotometry†

Transcranial Doppler ultrasonography†

Intraocular ultrasonography†

Intracranial pressure monitorsComputed tomography brain scan

Infection Serial surveillance cultures and chest radiography

Hypoglycemia Serial measurements of blood glucose

Acute kidney injury/renal failure

Serial creatinine levels Measurement of urine outputNeutrophil gelatinase-associated lipocalin†

Cystatin C†

†These items are not considered standard of care and/or may not yet have data demonstrating utility in the acute liver failure patient population.INR: International normalized ratio.

Patton & Gish


Summary.

� As mental status changes can evolve quickly in acute liver failure (ALF), medical personnel should interview patients as soon as possible so as not to miss the window of opportunity to obtain important historical details from the ALF patient; family and other close contacts may serve as important sources of information in cases where patients have severe encephalopathy.� While it is prudent to cast a wide diagnostic net early in ALF so as to arrive at an etiologic

diagnosis as quickly as possible, an understanding of predominant causes in a given geographic region can help to tailor diagnostic resources based on most likely cause.� Drug-induced liver injury (predominantly from acetaminophen) is the most common cause of

ALF in the USA and western Europe; however, it is recommended to test for acute infection with the hepatotropic viruses most commonly implicated in ALF (hepatitis A, E and B viruses) in all patients.� Imaging studies may be diagnostic for Budd–Chiari Syndrome and helpful for diagnosis of

complications such as intrahepatic hemorrhage or rupture in pregnancy-associated ALF but may be falsely interpreted as showing cirrhosis in the setting of ALF (nodular contour may be seen related to parenchymal collapse).� Transjugular liver biopsy may be indicated when there is clinical concern for diagnosis of

autoimmune hepatitis, herpes hepatitis, or infiltrative liver disease (lymphoma) or in cases of seronegative disease.� In addition to standard laboratory tests obtained routinely upon hospital admission

(comprehensive metabolic panel, complete blood cell count, and prothrombin time/INR), diagnostic studies obtained to help assess prognosis in ALF may include (following fluid resuscitation) an arterial blood gas, arterial levels of ammonia and lactate, serum phosphorus, factor V level and a-fetoprotein.� Diagnostic studies important in monitoring for complications include an in-depth assessment of

coagulation profile (such as with a thromboelastogram), serial neurologic examinations (as well as more sophisticated testing for cerebral edema, where available), surveillance cultures and close monitoring of glucose and renal function (urine output and serum creatinine pending development of more sensitive indicators of acute kidney injury in this population).

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critical care in acute liver failure || investigation and diagnostic pathways

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