THSCSA THSCSA ediatric Resident Curriculum for the PICU ediatric Resident Curriculum for the PICU Fulminant Hepatic Fulminant Hepatic Failure & Failure & Liver Transplantation Liver Transplantation
UTHSCSA Pediatric Resident Curriculum for the PICU Fulminant Hepatic Failure & Liver Transplantation.
Dec 17, 2015
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Fulminant Hepatic Fulminant Hepatic Failure &Failure &Liver TransplantationLiver Transplantation
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Fulminant Hepatic FailureFulminant Hepatic Failure
DefinitionDefinition - - Altered mental status Altered mental status with coagulopathy in setting of with coagulopathy in setting of acute liver disease. Hepatic acute liver disease. Hepatic encephalopathy occurring within 8 encephalopathy occurring within 8 weeks of onset of illness defines weeks of onset of illness defines FHF.FHF.
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EtiologyEtiology
• Viral hepatitisViral hepatitis– Hepatitis A - Hepatitis A -
rarelyrarely– Hepatitis B - Hepatitis B -
appx 1% of hep Bappx 1% of hep B– Hep C -- probably Hep C -- probably
not, but ??not, but ??– Hep D -- delta Hep D -- delta
agent coinfects agent coinfects with Hep Bwith Hep B
– Hep EHep E– CMV, HSVCMV, HSV
• Toxins Toxins – Carbon Carbon
tetrachloridetetrachloride– PhosphorusPhosphorus– Amanita Amanita
phalloidesphalloides (antidote (antidote penicillin and penicillin and silybin)silybin)
– Industrial Industrial cleaning cleaning solventssolvents
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EtiologyEtiology
• DrugsDrugs– AcetaminophenAcetaminophen– Acetaminophen Acetaminophen
in Tx doses with in Tx doses with alcoholalcohol
– Idiosyncratic Idiosyncratic reaction -- reaction -- halothane, halothane, sulfonamides, sulfonamides, phenytoin, and phenytoin, and others.others.
VascularVascular— Heart failure -- Heart failure --
centrolobular centrolobular necrosisnecrosis
— Sinusoidal Sinusoidal obstruction obstruction secondary to secondary to metastatic dzmetastatic dz
— Budd ChiariBudd Chiari— Veno-occlusive Veno-occlusive
diseasedisease
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PathologyPathology
• Viral, toxicViral, toxic -- -- hepatocellular necrosis, hepatocellular necrosis, diffuse, extensive, resulting in caseating diffuse, extensive, resulting in caseating necrosis.necrosis.
• CardiacCardiac -- -- similar, with particularly severe similar, with particularly severe centrolobular necrosis from higher centrolobular necrosis from higher intravascular pressure and watershed effect. intravascular pressure and watershed effect. Blood flows from portal triad (hepatic artery Blood flows from portal triad (hepatic artery and portal vein) to central veins to hepatic and portal vein) to central veins to hepatic vein. With poor cardiac output, splanchnic vein. With poor cardiac output, splanchnic flow markedly decreased, resulting in flow markedly decreased, resulting in markedly decreased portal flow, which is a markedly decreased portal flow, which is a large proportion of flow to liver.large proportion of flow to liver.
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PathologyPathology
• Fatty liver of pregnancy and Reye’s Fatty liver of pregnancy and Reye’s show microvesicular collections of fat show microvesicular collections of fat in hepatocytes and much less necrosis.in hepatocytes and much less necrosis.
• Special stains -- iron in Special stains -- iron in hemochromatosis, copper in Wilson’s, hemochromatosis, copper in Wilson’s, etc.etc.
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Clinical PresentationClinical Presentation
• Typically -- nonspecific symptoms, Typically -- nonspecific symptoms, nausea, malaise, jaundice, altered mental nausea, malaise, jaundice, altered mental status, coma -- all over a few days.status, coma -- all over a few days.
• The altered mental status occasionally The altered mental status occasionally precedes clinical jaundice.precedes clinical jaundice.
• Mental status changes often start with Mental status changes often start with agitation, delusions, irritability before agitation, delusions, irritability before progressing to lethargy, stupor, and progressing to lethargy, stupor, and coma.coma.
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Clinical PresentationClinical Presentation
• Laboratory --Laboratory --• Transaminases usually high (>1000)Transaminases usually high (>1000)•Bilirubin -- usually mixed Bilirubin -- usually mixed
hyperbilirubinemiahyperbilirubinemia•Ammonia -- usually elevatedAmmonia -- usually elevated•Coagulopathy with prolonged PT, PTT, Coagulopathy with prolonged PT, PTT,
decreased factorsdecreased factors• Low level DICLow level DIC• Low level fibrinolysisLow level fibrinolysis•Respiratory alkalosisRespiratory alkalosis•Metabolic acidosis, increased lactateMetabolic acidosis, increased lactate
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Hepatic EncephalopathyHepatic Encephalopathy
EtiologyEtiology
Etiology uncertain. Etiology uncertain.
Suggested mechanisms:Suggested mechanisms:
Depressed neural energy Depressed neural energy metabolism -- but autopsied metabolism -- but autopsied animals show no changes of animals show no changes of ischemiaischemia
Decreased hepatic clearance of Decreased hepatic clearance of neuro toxic substancesneuro toxic substances
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Hepatic EncephalopathyHepatic Encephalopathy
NeurotoxinsNeurotoxins• Ammonia -- correlates poorly with Ammonia -- correlates poorly with
encephalopathyencephalopathy• Amino acids --aromatic and straight chain aa Amino acids --aromatic and straight chain aa
are increased in liver failure -- tryptophan may are increased in liver failure -- tryptophan may be preferentially transported into CNS be preferentially transported into CNS
• Methionine, mercaptansMethionine, mercaptans• Gamma aminobutyric acid (GABA) -- this is an Gamma aminobutyric acid (GABA) -- this is an
inhibitory neurotransmitter. GABA receptor is inhibitory neurotransmitter. GABA receptor is site of benzodiazepine action. GABA levels and site of benzodiazepine action. GABA levels and endogenous benzodiazepines are elevated in endogenous benzodiazepines are elevated in hepatic failure. Enteric bacteria produce GABA hepatic failure. Enteric bacteria produce GABA and this may be absorbed across gut. and this may be absorbed across gut. Flumazenil anecdotally improves Flumazenil anecdotally improves encephalopathy.encephalopathy.
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Hepatic EncephalopathyHepatic Encephalopathy
Grading SystemGrading System
• Grade 0Grade 0 -- Normal -- Normal
• Grade IGrade I -- Altered spatial orientation, -- Altered spatial orientation, sleep patterns, and affectsleep patterns, and affect
• Grade IIGrade II -- Drowsy but arousable, -- Drowsy but arousable, slurred speech, confusion, and asterixisslurred speech, confusion, and asterixis
• Grade IIIGrade III-- Stuporous but responsive to -- Stuporous but responsive to painful stimulipainful stimuli
• Grade IVGrade IV-- Unresponsive, with or -- Unresponsive, with or without decorticate or decerebrate without decorticate or decerebrate posturingposturing
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Hepatic EncephalopathyHepatic Encephalopathy
Cerebral EdemaCerebral Edema
• Etiology uncertain -- Correlated with Etiology uncertain -- Correlated with degree of encephalopathy. Occurs in 50 - degree of encephalopathy. Occurs in 50 - 85% of patients with late grade 3 to 85% of patients with late grade 3 to grade 4 encephalopathy.grade 4 encephalopathy.
• Evidence of altered blood brain barrierEvidence of altered blood brain barrier• Impaired cellular Na+K+ -ATP pump Impaired cellular Na+K+ -ATP pump
resulting in glial cell edemaresulting in glial cell edema• Inappropriate cerebral vasodilatationInappropriate cerebral vasodilatation
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Hepatic EncephalopathyHepatic Encephalopathy
Cerebral EdemaCerebral Edema
Signs of increased ICP (may not be Signs of increased ICP (may not be present until late)present until late)– Increased muscle toneIncreased muscle tone– Increased DTRsIncreased DTRs– Dilated sluggish pupilsDilated sluggish pupils– HyperventilationHyperventilation– Cushing reflex (very late)Cushing reflex (very late)
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Hepatic EncephalopathyHepatic Encephalopathy
TreatmentTreatment
•Protect airway -- Most patients with Protect airway -- Most patients with grade III to IV should be intubated.grade III to IV should be intubated.
•Avoid precipitants:Avoid precipitants:– Excessive protein load -- particularly Excessive protein load -- particularly
in form of GI bleedin form of GI bleed– CNS depressantsCNS depressants– InfectionInfection– Electrolyte abnormalities Electrolyte abnormalities – Respiratory alkalosisRespiratory alkalosis
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Hepatic EncephalopathyHepatic Encephalopathy
TreatmentTreatment
•Prevent hypotension Prevent hypotension • Lactulose -- although not shown to Lactulose -- although not shown to
work well in FHF and felt to be less work well in FHF and felt to be less effective than in chronic liver effective than in chronic liver disease.disease.
•Branch chain amino acids -- Branch chain amino acids -- theoretically appealing but studies theoretically appealing but studies are mixed results -- most authors are mixed results -- most authors feel they are not helpful.feel they are not helpful.
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Hepatic EncephalopathyHepatic Encephalopathy
TreatmentTreatment•Beware and intervene for cerebral edemaBeware and intervene for cerebral edema• ICP monitoring -- somewhat controversial because ICP monitoring -- somewhat controversial because
studies have not shown altered outcome and risk studies have not shown altered outcome and risk is significant because of coagulopathy. Reasons is significant because of coagulopathy. Reasons favoring monitoring:favoring monitoring:– Intracranial hypertension is erratic and can develop Intracranial hypertension is erratic and can develop
rapidly with few clinical signsrapidly with few clinical signs– Monitoring allows for early detection and minute-to-Monitoring allows for early detection and minute-to-
minute titration of therapyminute titration of therapy– Cerebral perfusion pressure is prognostic sign and Cerebral perfusion pressure is prognostic sign and
would spare poor risk patients a transplant (CPP < would spare poor risk patients a transplant (CPP < 50 for 2 hrs)50 for 2 hrs)
– Allows management of intraoperative eventsAllows management of intraoperative events
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Hepatic EncephalopathyHepatic Encephalopathy
TreatmentTreatment
Consider ICP monitoring ifConsider ICP monitoring if
– Grade 3 - 4 with posturingGrade 3 - 4 with posturing
– PT corrected to < 20, platelets PT corrected to < 20, platelets correctedcorrected
– Patient is listed for transplant and Patient is listed for transplant and felt to be a candidate for felt to be a candidate for transplanttransplant
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Hepatic EncephalopathyHepatic Encephalopathy
TreatmentTreatment• MannitolMannitol -- shown to be effective in improving -- shown to be effective in improving
outcomeoutcome• HyperventilationHyperventilation -- probably useful for acute -- probably useful for acute
spikes in ICP. Has not been shown to be spikes in ICP. Has not been shown to be effective in hepatic failure. Concerns about effective in hepatic failure. Concerns about effect on cerebral perfusion warrant effect on cerebral perfusion warrant consideration.consideration.
• Elevation of headElevation of head -- ?? What is effect on CPP? -- ?? What is effect on CPP? Keep head midline, perhaps 20 - 30 degrees of Keep head midline, perhaps 20 - 30 degrees of elevation.elevation.
• Pentobarbital coma, hypothermiaPentobarbital coma, hypothermia -- unproven, -- unproven, occasionally may be indicated.occasionally may be indicated.
• SteroidsSteroids -- no good, may worsen outcome -- no good, may worsen outcome
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Hepatic EncephalopathyHepatic Encephalopathy
TreatmentTreatment
Get better liverGet better liver
oror
Get liver betterGet liver better
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CoagulopathyCoagulopathy
• Decreased production of liver clotting Decreased production of liver clotting factors (all but factor VIII), fibrinogen, factors (all but factor VIII), fibrinogen, ATIII, thrombocytopenia (splenic ATIII, thrombocytopenia (splenic sequestration, low level DIC, other)sequestration, low level DIC, other)
• PT/PTT prolongedPT/PTT prolonged• Factors V and VII often followed as Factors V and VII often followed as
they are relatively labilethey are relatively labile• Factor VIII normal or increased if just Factor VIII normal or increased if just
liver failure, decreased in DICliver failure, decreased in DIC• Euglobulin clot lysis time abnormal in Euglobulin clot lysis time abnormal in
primary fibrinolysisprimary fibrinolysis
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CoagulopathyCoagulopathy
ManagementManagement• Avoid bleedingAvoid bleeding• GI prophylaxisGI prophylaxis• Avoid nasal intubationAvoid nasal intubation• Beware with surgical procedures, line Beware with surgical procedures, line
placement, etc.placement, etc.• FFP -- Not shown to be effective in changing FFP -- Not shown to be effective in changing
bleeding risk (?). Most authors discourage bleeding risk (?). Most authors discourage routine attempts at normalizing PT. Use for routine attempts at normalizing PT. Use for active bleeding and procedures.active bleeding and procedures.
• Antifibrinolytics (Amicar) may be considered if Antifibrinolytics (Amicar) may be considered if bleeding and primary fibrinolysis is occurring. bleeding and primary fibrinolysis is occurring. Caution with DIC.Caution with DIC.
• Maintain platelet count >50K, or 100K if Maintain platelet count >50K, or 100K if bleedingbleeding
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Metabolic ConsiderationsMetabolic Considerations
• HypoglycemiaHypoglycemia -- decreased hepatic glycogen -- decreased hepatic glycogen stores, impaired gluconeogenesis results in stores, impaired gluconeogenesis results in hyperinsulin state and insulin resistance. hyperinsulin state and insulin resistance. There is impaired glucose homeostasis and There is impaired glucose homeostasis and hypoglycemia.hypoglycemia.
glucagon, glucagon, insulininsulin secondary to decreased secondary to decreased hepatic clearance, leads to decreased hepatic clearance, leads to decreased insulin/glucagon ratio, which favors catabolism.insulin/glucagon ratio, which favors catabolism.
• Aromatic amino acidsAromatic amino acids are increased, probably are increased, probably because of decreased hepatic clearance.because of decreased hepatic clearance.
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Metabolic ConsiderationsMetabolic Considerations
• Branch chain amino acids are cleared into skeletal Branch chain amino acids are cleared into skeletal muscle and are not elevated, so AAA > BCAAmuscle and are not elevated, so AAA > BCAA
• AAA and BCAA compete for entry to CNS. AAA, AAA and BCAA compete for entry to CNS. AAA, particularly tryptophan is converted to serotonin particularly tryptophan is converted to serotonin and other possible false neurotransmitters.and other possible false neurotransmitters.
• Supplementing BCAA theoretically may improve Supplementing BCAA theoretically may improve encephalopathy, but studies give mixed results encephalopathy, but studies give mixed results and most authorities feel the evidence does not and most authorities feel the evidence does not favor their use for this indication.favor their use for this indication.
• BCAA may also be more readily available for BCAA may also be more readily available for nutrition since the hyperinsulin state favors nutrition since the hyperinsulin state favors uptake by muscle, which is not true for other AA. uptake by muscle, which is not true for other AA. Evidence indicates less catabolism and less muscle Evidence indicates less catabolism and less muscle wasting with use of BCAA.wasting with use of BCAA.
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Hemodynamic EffectsHemodynamic Effects
• Increased cardiac outputIncreased cardiac output• Decreased systemic vascular Decreased systemic vascular
resistanceresistance• Decreased oxygen extraction ratio Decreased oxygen extraction ratio
and decreased consumption despite and decreased consumption despite increased deliveryincreased delivery
• Oxygen consumption often becomes Oxygen consumption often becomes supply dependent.supply dependent.
• Lactic acidosis secondary to anaerobic Lactic acidosis secondary to anaerobic metabolism ensues.metabolism ensues.
• Lactic acidosis has been shown to Lactic acidosis has been shown to herald a poor prognosis.herald a poor prognosis.
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Renal EffectsRenal Effects
Renal failure commonRenal failure commonPrerenal azotemiaPrerenal azotemiaAcute tubular necrosisAcute tubular necrosisHepatorenal syndromeHepatorenal syndrome
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Hepatorenal SyndromeHepatorenal Syndrome Etiology uncertainEtiology uncertain -- prominent theory is that -- prominent theory is that
low SVR results in “arterial underfilling” and low SVR results in “arterial underfilling” and subsequent increase in renin, aldosterone, subsequent increase in renin, aldosterone, ADH, and norepinephrine resulting in renal ADH, and norepinephrine resulting in renal arteriole vasoconstriction. Renal vasodilatory arteriole vasoconstriction. Renal vasodilatory prostaglandins are important to attenuate prostaglandins are important to attenuate this, so that when NSAIDS are given this this, so that when NSAIDS are given this compensation is lost. NSAIDS are known compensation is lost. NSAIDS are known precipitants of hepatorenal syndrome.precipitants of hepatorenal syndrome.
Diagnosis Diagnosis -- in absence of hypovolemia see -- in absence of hypovolemia see very low urine sodium, normal urine sediment. very low urine sodium, normal urine sediment. Exclude other causes. Exclude other causes.
TreatmentTreatment -- recover hepatic function, -- recover hepatic function, otherwise the renal failure is very recalcitrant. otherwise the renal failure is very recalcitrant. Dialysis as needed and indicated. Dialysis as needed and indicated.
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Respiratory EffectsRespiratory Effects
Respiratory failure can occur by several Respiratory failure can occur by several mechanisms:mechanisms:
•Neurogenic pulmonary edemaNeurogenic pulmonary edema• Fluid overload because of Fluid overload because of
hyperaldosterone and increased ADH hyperaldosterone and increased ADH with conservation of salt and waterwith conservation of salt and water
•ARDS secondary to sepsis or MSOFARDS secondary to sepsis or MSOF•Also, some have suggested capillary Also, some have suggested capillary
leak affecting pulmonary and CNS leak affecting pulmonary and CNS vasculaturevasculature
•Hepatopulmonary syndromeHepatopulmonary syndrome
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Hepatopulmonary syndromeHepatopulmonary syndrome
•Hypoxemia associated with chronic Hypoxemia associated with chronic liver disease. liver disease.
• Thought to be secondary to Thought to be secondary to intrapulmonary vascular dilatations intrapulmonary vascular dilatations with a-v shunting as well as diffusion with a-v shunting as well as diffusion block because of dilated capillaries.block because of dilated capillaries.
•Sometimes, but not always resolves Sometimes, but not always resolves with transplantwith transplant
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Infectious Disease IssuesInfectious Disease Issues
• Impaired host defenses --Impaired host defenses --
•Defective opsonic activityDefective opsonic activity• Impaired PMN functionImpaired PMN function• Impaired cell and humoral immunityImpaired cell and humoral immunity•Decrease clearance of enteric Decrease clearance of enteric
organisms by hepatic RESorganisms by hepatic RES•Ascites -- good culture mediumAscites -- good culture medium• Invasive lines, ETT, etcInvasive lines, ETT, etc
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Infectious Disease IssuesInfectious Disease Issues
• Infection riskInfection risk: : 80% of patients had documented 80% of patients had documented bacterial or fungal invasive infections, with a bacterial or fungal invasive infections, with a suspicion of infection in half the remaining patients. suspicion of infection in half the remaining patients. 25% had blood stream infection, with a respiratory 25% had blood stream infection, with a respiratory source predominating in the remainder.source predominating in the remainder.
• OrganismsOrganisms: : Predominantly gram positive (strep Predominantly gram positive (strep and staph), gram negatives also occur. 30% have and staph), gram negatives also occur. 30% have fungal infection.fungal infection.
• Prophylactic antibioticsProphylactic antibiotics have not been shown to have not been shown to change outcome and most authors recommend change outcome and most authors recommend meticulous surveillance and aggressive intervention meticulous surveillance and aggressive intervention with antibiotics when infection suspected.with antibiotics when infection suspected.
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Fulminant Hepatic FailureFulminant Hepatic Failure
TherapyTherapy
““Authors tend to publish isolated cases Authors tend to publish isolated cases with a favorable outcome attributed to a with a favorable outcome attributed to a given therapy, but not to publish cases in given therapy, but not to publish cases in which therapy has failed. In fact it might which therapy has failed. In fact it might be argued that the best future one can be argued that the best future one can wish for a sufferer from SAHF (sudden wish for a sufferer from SAHF (sudden acute hepatic failure) is to undergo a new acute hepatic failure) is to undergo a new treatment and have his case published -- treatment and have his case published -- ‘be published or perish!’ “‘be published or perish!’ “
Benhanou, 1972Benhanou, 1972
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Fulminant Hepatic FailureFulminant Hepatic Failure
TherapyTherapy• Tried but failed --Tried but failed --
• Insulin and glucagon to stimulate Insulin and glucagon to stimulate regenerationregeneration
•Prostaglandin EProstaglandin E•CorticosteroidsCorticosteroids•HemofiltrationHemofiltration•Charcoal hemoperfusionCharcoal hemoperfusion•Plasma exchangePlasma exchange
• Liver transplantationLiver transplantation -- -- best results. Greater than best results. Greater than 60% one year survival in adult patients with acute liver 60% one year survival in adult patients with acute liver failure. Only 10% of patients are deemed candidates failure. Only 10% of patients are deemed candidates and successfully supported until transplantation.and successfully supported until transplantation.
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Fulminant Hepatic FailureFulminant Hepatic Failure
TherapyTherapy• ELAD (extracorporeal liver assist device)ELAD (extracorporeal liver assist device) -- --
most acute liver failure is thought to be most acute liver failure is thought to be recoverable if patient survives long enough. recoverable if patient survives long enough. Most patients either die or have regeneration Most patients either die or have regeneration and normal liver function. Goal would be to:and normal liver function. Goal would be to:
•Support patient while awaiting recovery - Support patient while awaiting recovery - thus avoiding transplant and its risks - thus avoiding transplant and its risks - short and long termshort and long term
•Stabilize patient while awaiting transplantStabilize patient while awaiting transplant• ELAD seems promising in animal studies and ELAD seems promising in animal studies and
has been used on a few patients with has been used on a few patients with encouraging results. Not yet a proven therapy.encouraging results. Not yet a proven therapy.
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Criteria for Predicting Death and Criteria for Predicting Death and Need for Liver TransplantationNeed for Liver Transplantation
• Depends on etiologyDepends on etiology
• For Acetaminophen poisoningFor Acetaminophen poisoning– pH < 7.3 (irrespective grade of pH < 7.3 (irrespective grade of
encephalopathy)encephalopathy)– or or PT > 100 seconds and serum PT > 100 seconds and serum
creatinine > 3.4 in patients with grade creatinine > 3.4 in patients with grade III or IV encephalopathyIII or IV encephalopathy
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Criteria for Predicting Death and Criteria for Predicting Death and Need for Liver TransplantationNeed for Liver Transplantation• All other etiologiesAll other etiologies
– PT > 100 seconds (irrespective of grade of PT > 100 seconds (irrespective of grade of encephalopathy)encephalopathy)
• OR OR any 3 of the following any 3 of the following– Age < 10 years or > 40Age < 10 years or > 40– Liver failure caused by non-A, non-B Liver failure caused by non-A, non-B
hepatitis, halothane, or idiosyncratic drug hepatitis, halothane, or idiosyncratic drug rxnrxn
– Jaundice for > 10 days prior to Jaundice for > 10 days prior to encephalopathyencephalopathy
– PT > 50 secondsPT > 50 seconds– Serum bilirubin > 17.5Serum bilirubin > 17.5
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United Network for Organ Sharing (UNOS)United Network for Organ Sharing (UNOS)
Status 1 - most urgent levelStatus 1 - most urgent level
Rapid development of grade 3 - 4 Rapid development of grade 3 - 4 encephalopathyencephalopathy
Prothrombin time > 25 secProthrombin time > 25 sec On vasopressors or ventilatory supportOn vasopressors or ventilatory support Have primary graft non-functionHave primary graft non-function Are expected to live less than 7 days Are expected to live less than 7 days
without a transplantwithout a transplant Inborn error of metabolism with Inborn error of metabolism with
metabolites that are toxic to the CNSmetabolites that are toxic to the CNS
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Transplantation in FHFTransplantation in FHF
ContraindicationsContraindications
Uncontrolled sepsisUncontrolled sepsis Multi-organ system failureMulti-organ system failure Irreversible brain damageIrreversible brain damage
By neurologic examBy neurologic exam Imaging studiesImaging studies Sustained ICP > 50, orSustained ICP > 50, or CPP < 40 for 1 - 2 hoursCPP < 40 for 1 - 2 hours
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Fulminant Hepatic FailureFulminant Hepatic Failure
Recommended ReadingsRecommended Readings
• Lee WM. Acute Liver Failure. N Engl J Med Lee WM. Acute Liver Failure. N Engl J Med 1993;329:1862 - 1872.1993;329:1862 - 1872.
• Caraceni P, and Van Thiel DH. Acute Liver Caraceni P, and Van Thiel DH. Acute Liver Failure. Lancet 1995;345:163-9.Failure. Lancet 1995;345:163-9.
• Riordan SM, and Williams R. Treatment of Riordan SM, and Williams R. Treatment of Hepatic Encephalopathy. N Engl J Med Hepatic Encephalopathy. N Engl J Med 1997;337:473-9.1997;337:473-9.
• Whitington PF, et al. Pediatric Liver Whitington PF, et al. Pediatric Liver Transplantation. Seminars in Liver Transplantation. Seminars in Liver Disease 1994; 14:303-317.Disease 1994; 14:303-317.
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