Dr. Eduardo Martinez

Foie gras (pronounced /fwɑːˈɡrɑː/ in English; French for "fat liver") is a food product made of the liver of a duck or goose that has been specially fattened.

Metabolic◦ Carb metabolism◦ Protein and lipoprotein metabolism◦ Fatty acid metabolism◦ Biotransformation of drugs

Storage◦ Glycogen◦ Vitamins A, D, E, and K◦ Iron and copper

Immunological function s◦ Synthesis of immunoglobulins◦ Phagocytosis by Kupffer cells◦ Filtration of bacteria◦ Degradation of endotoxins

Excretion of bilirubin and urea formation Haematological functions

◦ Blood reservoir◦ Haematopoiesis in the foetus

• Syndrome that leads to MOF and deatho Previously normal liver may fail within days

• High grade encephalopathy, survival is <20%

• Early death:o cerebral oedema, CVS collapse

• Late death:o Sepsis , MOF

• ALF: Sd. defined byo Encephalopathyo Coagulopathyo Jaundiceo Individual with previously normal liver

• Fulminant Hepatic Failureo Potentially reversible conditiono Consequence of severe liver injuryo Encephalopathy appears within 8 wks. of

initial Sx.o Absence of pre-existing liver ds.

• King’s classification:o Hyperacute: encephalopathy within <7 days

Paracetamol, ischaemic, viral, toxinso Acute: 8-28 dayso Subacute: 5-26 weeks

Seronegative, idiopathic, drug-related Different etiology Poorer prognosis

Cause Agent Responsible

Viral Hepatitis Hep. A, B, D, E, CMV, HSV, seronegative hepatitis (14-25% in UK)

Drug-related Dose-related, e.g.paracetamol; idiosyncratic reactions, e.g. anti-TB, statins, recreational drugs, anticonvulsants, NSAIDs, many others

Toxins Carbon tetrachloride, amanita phalloides

Vascular events Iscahemic hepatitis, veno-occlusive disease, Budd-Chiari, heatstroke

Other Pregnancy-related liver disease, Wilson’s disease, lymphoma, carcinoma, trauma

• Most common causes:o Worldwide:

Hepatotrophic viruses A-Eo UK

Paracetamol overdose Seronegative or non-A-E hepatitis Idiosynchratic drug rxs. or Wilson’s ds.

• Identify the etiologyo Hx., examination, viral and autoimmune

profiles• Bloods

o FBC, EUC, CMP, coags, LFTs, drug levels• Abdo USG and CT

o Vascular pattern, ascitis, splenomegaly

• Liver Bx.o Done by transjugular routeo Mays suggest specific Dx.o Watch for sample from healthy livero >50% necrosis assoc. with poor prognosiso Need to reverse coagulopathy before doing

it

• Hepatic encephalopathyo alteration in mental status and cognitive function

occurring in the presence of liver failure • Liver failure leads to:

o portal HTN o splachnic vasodilationo Hypoalbuminaemiao Reduced plasma oncotic pressureo Leads to ascitis and organ oedema

• Decreased intravascular volumeo Kidneys try to “compensate” and retain Na+

and water making oedema worse• Also,• Gut-derived toxins reach the liver

o Ammonia levels are often higho Correlation between ammonia and

symptoms is poor

• Depend on the severity, which depends on:o Etiologyo Speed of onset of symptoms

• Non-specifico N&V, abdo pain

• Neurologicalo Confusion, agitation, coma

Grade Level of Consciousness Personality and Intellect Neurologic Signs Electroencephalogram (EEG) Abnormalities

0 Normal Normal None None

Subclinical

Normal Normal Abnormalities only on psychometric testing None

1 Day/night sleep reversal, restlessness

Forgetfulness, mild confusion, agitation, irritability

Tremor, apraxia, incoordination, impaired handwriting

Triphasic waves (5 Hz)

2 Lethargy, slowed responses Disorientation to time, loss of inhibition, inappropriate behavior

Asterixis, dysarthria, ataxia, hypoactive reflexes

Triphasic waves (5 Hz)

3 Somnolence, confusion Disorientation to place, aggressive behavior Asterixis, muscular rigidity, Babinski signs, hyperactive reflexes

Triphasic waves (5 Hz)

4 Coma None Decerebration Delta/slow wave activity

• Mortality is higher for Grade III/IVo Mostly due to cerebral oedema o Occurs in 80% of pts. w/ALF

Due to lack of equilibration of osmotic gradient 30% of those have cerebellar tonsil and/or

temporal lobe herniation causing deatho We’re now better at treating cerebral

oedema

• Elevated ICPo HTN, bradycardia, blown pupils: occur lateo CTB won’t tell youo ICP monitor is best way of knowing

• CVS changeso Similar to sepsiso Might be due to infection

• Renal failureo Oligurico Poor prognosis

Except with paracetamol overdose where it has a good prognosis

• Impaired immunityo Decreased complement synthesis, Kupffer

cell dysfunction, poor neutrophil adhesion and superoxide production

• Increased susceptibility to infectiono 80% of pts. have bacteriologically proven

infectionso Major sepsis is contributor to death in 20%

of cases Staph. aureus 70% of gram (+) E. Coli most common gram (-) C. albicans in 30% of pts.

• Pts. need HDU/ICU• Need CVC and continuous IBP

monitoring and IDC• Baseline ABG and lactate

o Lactate >3mmo/L after adequate resus has same sensi. and speci. for death as The King’s College Hospital criteria

• Early indicators of prognosis in fulminant hepatic failure.

O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Gastroenterology. 1989 Aug;97(2):439-45.

• King’s Collage Hospital Criteriao Originally devised as prognostic criteria to predict

patient survival without liver transplanto Now used as selection criteria for potential liver

transplant recipients

• Patients with paracetamol toxicityo pH <7.3 (7.25 if given NAC) Or all three of the following:o Prothrombin time >100so Serum creatinine level >300

μmol/lo Grade III or

IVencephalopathy

• Other patientso Prothrombin time >100

seconds orThree of the following variables:

o Age <10 yr or >40 yro Jaundice >7 days before

encephalopathyo PT > 50so Bilirubin > 300mmol/L

Positive predictive value for ICU death without transplantation of 0.98

Negative predictive value of 0.82

• Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group.

Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH et al.

Critical Care Medicine 2007; 35: 2498-508

• Adult U.S. Acute Liver Failure Study Groupo Data from

23 liver transplant centers >1,110 pts.

o In 2005 convened to review literature on management Care of pts. w/high ICPs Compare practices of different centers

• Admit to hospital and HDU/ICU o When evidence of ALF

E.g.: INR>1.5o D/W:

Physician Intensivist Nearest transplant center Regarding best time to refer

• Etiology-specific treatmento Studies only for paracetamol overdoseo NAC regardless of time of overdose

IV if Grade I encephalopathy Hypotension Any other reason PO NAC is not tolerated

o HELLP or acute fatty liver of pregnancy Tx. Is immediate delivery

• NACo 150mg/kg IV in 200ml NS over 15-60minso 50mg/kg IV over 4hrso 100mg/kg IV over 16hrs

Total dose: 300mg/kg over 20hrso Infusion recommended until there is

evidence of improved hepatic function rather than time or paracetamol levels

• Hepatic encephalopathy and hyperammonaemia

• Infections• Sedation and analgesia• Bleeding diathesis• Nutrition• Seizures• Circulatory dysfunction

• Standard treatment:o Lactulose

Watch for: Abdo distension Oesophageal varices will need a scope Avoid intravascular depletion

o Non-absorbable ATBs Neomycin not recommended by ALFSG

because of nephrotoxicity

• Infection is one of main causes of death in ALF

• Most common sites:o Lungo Urinary tracto Blood

• Most common M.O.o Gram (+) cocci: Staph aureuso Gram (-) rods: E. colio Fungi: candida

• Empirical ATBs are recommended by ALFSG when:o Surveillance cultures reveal significant isolateso Advanced stage (III/IV) encephalopathyo Refractory hypotensiono SIRS

• 3rd gen. Cephalosporin or Timentin, Vancomycin, Fluconazole

• Agitation contributes to raised ICP• Propofol vs. Benzos

o Both increase GABA neurotransmission, therefore may exacerbate encephalopathy

o Propofol decreases ICP and wears off quickly• Opioids

o Shorter acting are preferableo When there is concommitant ARF, avoid morphine

or pethidine due to metabolite accumulation

• Pts. with ALF are by definition coagulopathico Low plts. and fibrinogen, Vit. K deficiento Spontaneous bleeding is rare

• Very difficult to obtain complete correction• ALFSG recommends aiming for:

o INR 1.5o Plts. 50,000

• Prophylactic FFP not recommendedo Obscures the trend of PT as prognostic marker

• Cryo recommended when fibrinogen low• When FFP fails to correct PT/INR, then

recombinant factor VIIa can be giveno Should be given before planned procedureso Avoid in patients with risk of thrombotic

complication MI, DVTs, etc.

• UGI bleeding o reduced by H2 antagonists or PPIs

• TEDS and Scuds

• ALF is a catabolic stateo Negative nitrogen balanceo Immunodeficiency

• Enteral nutrition when possibleo Hi-calo Avoid free water and hypo-osmolarity

• TPN when:o Specific contraindication for enteral feeds

• Nonconvulsive seizure activity is commono Prophylactic antiepileptics not recommendedo EEG when:

Grade II/IV encephalopathy Sudden neuro deterioration Myoclonus To titrate use of barbiturates

• Tx.o Phenytoino Propofol, midaz, barbiturates

• Correct hypovolaemia before starting vasopressors

• Pressors needed for hypotension and low CPPo Norad is first line, can give high dose dopamineo Adrenaline may compromise HBFo Vasopressin not recommended because directly

causes cerebral vasodilation and high ICPs• Medium doses of steroid may improve

pressor response

• Raised ICP due to cerebral oedema is one of major causes of M&M

• CTB for Grade III/IVo To rule out anything else, i.e. bleed

• ICP monitoro Grade III/IV encephalopathyo To optimize CPPo Not routine

• Aim foro ICP<25mmHgo CPP 50-80

• General recommendationso Keep it quiet , minimize chest physio and

ETT suctioning, head at 30oo Don’t treat spontaneous hyperventilation,

keep PaCO2 35-40mmHg, treat fever aggressively with physical measures

• Specific managemento Manitol: first line therapyo Hypertonic Salineo Induced hypothermiao Barbiturate comao Indomethacin: 25mg IV over 1min.

• When to intubate:o Respiratory failureo Airway protection in advanced

encephalopathyo Agitationo Imminent ICP monitor placement

• Pts. w/ALF often develop ALI/ARDSo Follow ARDSNet protocolo Avoid high PEEP

Use the minimum needed

• Indicated for:o Renal failureo Fluid overloado Metabolic derangementso Need to create space for IV colloids, i.e.

FFP• CRRT preferred over IRRT

o HD instability common

• Use citrate over heparino Monitor ionized calcium

• Use bicarb buffer over lactate or citrate buffero Liver won’t be able to convert them to

HCO3-• Avoid hyponatraemia

o May exacerbate cerebral oedema

Orthotopic liver transplant is the definitive treatment for patients who meet the criteria◦ or·tho·top·ic (ôrth-tpk)adj.In the normal or

usual position 1 yr. and 5 yr . survival of patients

undergoing OLT for ALF is about 20% lower than elective cases for cirrhotic patients

Auxiliary liver transplantation is and alternative

Absolute contraindications◦ Overwhelming sepsis◦ Refractory hypotension◦ AIDS◦ Uncontrolled raised ICP with likely permanent

damange

MARS: molecular absorption and recirculation system◦ Adaptation of haemodialysis◦ Blood is dialysed against 20% albumin

Shown to improve encephalopathy, renal function and haemodynamic parameters

◦ The efficacy of this technique has not yet been studied