DR JAWAD ALI RESIDENT MEDICINE KRL HOSPITAL ISLAMBAD

DEFINITION

Acute liver failure refers to the rapiddevelopment of severe acute liverinjury with impaired syntheticfunction and encephalopathy in aperson who previously had a normalliver or had well-compensated liverdisease.

DEVELOPMENT OF ENCEPHALOPATHY WITHIN 7 DAYS OF ONSET OF JAUNDICE

HYPER-ACUTE

DEVELOPMENT OF ENCEPHALOPATHY WITHIN 2 TO 28 DAYS OF ONSET OF JAUNDICE

ACUTE

DEVELOPMENT OF ENCEPHALOPATHY WITHIN 5 TO 56 WEEK OF ONSET OF JAUNDICE

SUBACUTE

Hepatitis virusesAlthough hepatitis A is the most common form of acute viral hepatitis, it is rare for acute infection to progress to ALF. Hepatitis B is probably the most common viral cause of ALF.

Hepatitis C virus does not appear to be a significant cause of ALF.

Other viral etiologies of ALF include hepatitis delta virus coinfection or superinfection, hepatitis E (especially in pregnant women in endemic areas), Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and varicella zoster.

CAUSES/ETIOLOGY

Acetaminophen is the most common toxinassociated with ALF in most reports . Most casesoccur after ingestion of large doses in an attemptto commit suicide.

AMINATA FUNGAL TOXIN

ISONIAZIDE

HALOTHANE

TOXINS AND DRUGS

Vascular causes of ALF include portalvein thrombosis, Budd-Chiarisyndrome (hepatic vein thrombosis),veno-occlusive disease, and ischemichepatitis.

VASCULAR

A number of metabolically-related disorders have been associated with ALF including Wilson's disease, acute fatty liver of pregnancy, and Reye's syndrome.

METABOLIC

ALF has also been reported in patientswith malignant infiltration of the liver,heat stroke, sepsis, and autoimmunehepatitis.

MISCILLANEOUS

SIGNS:

JAUNDICE

HEPATIC ENCEPHALOPATHY

FETOR HEPATICUS

ASTEREXIS

CONSTRUCTIONAL APRAXIA

SIGNS OF CHRONIC LIVER DISEASE

CLINICAL PRESENTATION

BLOOD:

BLOOD CP

URINE R/E

LFTS

PT/APTT

BSR

PARACETAMOL LEVELS

HEPATITIS PROFILE

CMV AND EBV SEROLOGY

INVESTIGATIONS

FERITIN

ALPHA 1 ANTITRYPSIN

CERULOPLASMIN

AUTOANTIBODIES (ANTI SMA, AMA, ANTI LKM, ANA)

BLOOD C/S

URINE C/S

ASCITIC FLUID R/E AND C/S

MICROBIOLOGY

CXR

ABDOMINAL USG

DOPLER USG OF PORTAL VEIN

CT SCAN BRAIN

RADIOLOGY

EEG

EVOKED POTENTIALS

NERUROPHYSIOLOGY

• ENCEPHALOPATHY

• SEPSIS

• GI BLEED

• CEREBRAL EDEMA

• AKI

• PULMONARY

• METABOLIC

COMPLICATIONS

HEPATIC ENCEPHALOPATHY —

Hepatic encephalopathy is a major complication of ALF, although the precise mechanism remains unclear.

The most widely accepted theory is related to increased production of ammonia from nitrogenous substances within the gut lumen.

lactulose, although its use in acute liver failure is controversial.

it should not be administered orally or per nasogastric tube to patients with advanced encephalopathy unless endotracheal intubation is performed.

.

COMPLICATIONS

Cerebral edema develops in 75 to 80 percent of patients with grade IV encephalopathy.

The precise mechanism by which it occurs in ALF is incompletely understood.

Possible contributing factors include osmotic derangement in astrocytes

changes in cellular metabolism and alterations in cerebral blood flow

CEREBRAL EDEMA

The consequences of cerebral edema includeelevated intracranial pressure (ICP) and brainstemherniation, which are the most common causes ofdeath in ALF.

Cerebral edema also can lead to ischemic andhypoxic injury to the brain.

The classic signs of elevated ICP include systemichypertension, bradycardia, and irregularrespirations (referred to as Cushing's triad).

CEREBRAL EDEMA

invasive means of monitoring intracranial pressure have been recommended, and are routinely used by more than one-half of liver transplantation programs

MONITORING OF ICP

Four types of catheters have been used to measure ICP: epidural, subdural, parenchymal, and intraventricular:

Epidural catheters are placed outside the dura mater

Subdural catheters are placed beneath the dura mater

Parenchymal catheters are placed directly into the brain parenchyma

Intraventricular catheters are placed within a cerebral ventricle

ICP MONITORING

An epidural ICP monitor should be placed in patients with grade IV encephalopathy or

in patients in whom grade III encephalopathy is rapidly progressing.

Before an ICP monitor is placed, any existing coagulopathy should be corrected.

TREATMENT

Three parameters should be followed during intracranial pressure monitoring:

Intracranial pressure

Cerebral perfusion pressure (CPP)

Cerebral oxygen consumption

Cerebral perfusion pressure is the difference between mean arterial pressure and intracranial pressure

Cerebral oxygen consumption is a function of cerebral blood flow and the oxygen gradient between arterial and jugular venous blood.

ICP MONITORING

The goals of therapy are to maintain the ICP below 20 mmHg and the CPP above 50 mmHg.

These goals can be accomplished using a combination of interventions:

Patients should be placed in an environment with minimal sensory stimulation since stimulation

Placement of a nasogastric tube can cause gagging and thus their use should be minimized

Similarly, endotracheal suction should be minimized.

ICP TREATMENT

Overhydration can elevate ICP. Thus, thefluid status of patients with ALF should beclosely monitored.

The head of the patient's bed should beelevated to 30 degrees. However, bedelevation can also reduce cerebralperfusion. Thus, patients should remainsupine if the CPP falls below 50 mmHg withbed elevation.

ICP TREATMENT

If no response or relapse is noted, hyperosmotic agentssuch as mannitol (0.5 to 1 g/kg) or

hypertonic saline (3 percent) should be administered asan intravenous bolus and then on an as-needed basis.

ICP TREATMENT

If no response or relapse is noted after mannitol administration

pentobarbital coma should be induced using a bolus of 3 to 5 mg/kg intravenously.

Dexamethasone has not proven to be effective in the treatment of cerebral edema caused by ALF and should not be administered

ICP TREATMENT

Prophylactic phenytoin

The observation that patients with acute liver failure may have subclinical seizure activity provided the rationale for a controlled trial of seizure prophylaxis using phenytoin.

SEIZUREPROPHYLAXIS

Acute renal failure complicates ALF in approximately 30 to 50 percent of patients.

The frequency of acute renal failure is higher (up to 75 percent) for etiologies of ALF that are known to independently damage the kidneys, such as acetaminophen intoxication

ACUTE RENAL FAILURE

Treatment of acute renal failure should focus on prevention because, once established, the renal failure is usually progressive and associated with a grave prognosis without liver transplantation. Among the preventive measures are ensuring arterial perfusion by maintaining an adequate systemic blood pressure, identifying and treating infections promptly, and avoiding the use of nephrotoxic agents

TREATMENT OF AKI

Patients with ALF are at increased risk of infection and sepsis from a wide variety of causes.

The most common sites of infection are the respiratory and urinary tracts and blood .

Localizing signs of infection, such as fever and sputum production, are frequently absent and the only clues to an underlying infectious process may be worsening of encephalopathy or renal function.

Thus, an aggressive approach to diagnosing and treating infections is necessary. This includes a low threshold for obtaining frequent blood, urine, and sputum cultures, and diagnostic radiographs, or for performing a diagnostic paracentesis.

INFECTION AND SEPSIS

The role of prophylactic antibiotics is controversial.

Empiric broad spectrum antibiotics should be considered in the following patients

Presence of or the rapid progression to advanced stages of encephalopathy

Refractory hypotension

Presence of systemic inflammatory response syndrome

ANTIBIOTICS

Common metabolic disturbances in ALF includeacid-base and electrolyte disorders,hypophosphatemia, and hypoglycemia. Amongthe acid-base disorders, alkalosis is morefrequently encountered than acidosis in the earlystages of ALF, and is frequently a mixedrespiratory and metabolic abnormality. As ALFprogresses, patients typically develop metabolicacidosis (due to lactic acidosis) with respiratoryalkalosis.

METABOLIC DISTURBANCES

Correction of hypokalemia, if present, is an

essential component of therapy.

Hypokalemia increases renal ammoniaproduction; in addition, the often concurrentmetabolic alkalosis may contribute by promotingammonia entry into the brain by promoting theconversion of ammonium (NH4+),

a charged particle which cannot cross the blood-brain barrier, into ammonia (NH3) which can.

METABOLIC DERANGEMENTS

Hyponatremia is more frequently seen in patients with subfulminant hepatic failure. Tissue hypoperfusion, leading to enhanced release of antidiuretic hormone, and impaired renal function combine to limit free water excretion.

METABOLIC DERANGEMENT

Hypophosphatemia is especially common in patients with acetaminophen-induced ALF and those with intact renal function.

METABOLIC DERANGEMENT

Prophylactic administration of fresh frozen plasma is usually not recommended since it has not been proven to influence mortality, it can interfere with assessments of liver function, and it may worsen cerebral edema. Fresh frozen plasma (FFP) is indicated only in the setting of active hemorrhage or prior to invasive procedures, such as placement of intracranial pressure monitors.

COAGULOPATHY

Small pilot studies have demonstrated that recombinant human factor VIIa (rFVIIa) has been associated with improvement or normalization of the serum prothrombin time and control of bleeding in such patients

COAGULOPATHY

Pulmonary edema and pulmonary infections areencountered in approximately 30 percent ofpatients with ALF.

Mechanical ventilation may be required to ensureadequate oxygenation.

However, extreme caution must be used withpositive end-expiratory pressure in patients withALF since PEEP can worsen cerebral edema.

PULMONARY COMPLICATIONS

A number of specific interventions have been studied butare unhelpful for ALF and should generally not be used.

Glucocorticoids, increase the risk of sepsis, although theymay have a potential role in severe autoimmune hepatitis.

Hepatic regeneration therapy using insulin and glucagon.

UNHELPFUL TREATMENT

Artificial hepatic assist devices —There has been a strong interest in developing an artificial hepatic assist device for ALF that would operate on the same basic principles as hemodialysis for renal failure.

The major difference between the two is that the liver performs an incredibly large number of diverse and vital synthetic functions compared to the kidneys. As a result, developing a machine that performs the functions of the liver is inherently more difficult than developing one that performs the excretory functions of the kidneys.

Extracorporeal assist devices currently under development use hepatocytes from human or nonhuman cell lines to provide synthetic capability.

NEWER APPROACHES

Auxiliary liver transplantation —

Auxiliary liver transplantation involves placement of a graft adjacent to the patient's native liver (auxiliary heterotopic liver transplantation) or in the hepatic bed

There are also reports of auxiliary liver grafts being reused in second recipients with chronic liver disease .

NEWER APPROACHES

Xenotransplantation —The role of

xenotransplantation (transplantation of a nonhuman organ) in the treatment of ALF is currently being reexamined.

Prior to 1992, only 33 xenotransplants had been performed in humans

The longest graft survival was only nine months.

Despite the initial disappointing results, this approach is being reevaluated because of advances in immunosuppression and the ability to manipulate donor antigen expression

NEWER APPROACHES

only therapy proven to improve patient outcome in ALF is orthotopic liver transplantation, which is associated with one-year survival rates of greater than 80 percent, this is in contrast to patients with ALF who are managed with supportive medical therapy alone, in whom survival is much lower

PROGNOSIS

THANK YOU