JC66 (Surgery) - Liver transplant

Question 1

Causes of acute liver failure

Answer 1

→ Viral hepatitis
→ Drug-induced, eg. paracetamol, halothane, isoniazid
→ Herbs and health food products
→ Metabolic, eg. pregnancy, Reye syndrome, Wilson’s disease
→ Cardiovascular, eg. shock, heatstroke

Question 2

Acute liver failure

Cardiovascular manifestations and treatment

Answer 2

Hypotension - monitor, echocardiogram

Intravascular volume depletion - fluid resuscitation

Vasodilation - Vasopressors

Low CO and RV failure - Inotropic support

Question 3

Acute liver failure

Respiratory manifestations and treatment

Answer 3

Acute lung injury and ARDS
Higher risk of aspiration pneumonitis

Oxygen support, early tracheal intubation, mechanical ventilation

Question 4

Acute liver failure

Metabolic and renal manifestations
Treatment

Answer 4

Hypoglycaemia - serial biochemical test and glucose supplement

Hyponatremia - fluid management

Renal dysfunction, lactic acidosis, hyperammonemia - renal replacement therapy

Impaired drug metabolism - review drugs

Question 5

Acute liver failure

CNS manifestations and treatment

Answer 5

Hepatic encephalopathy

• neurological exam, serum ammonia, EEG and psychomotor test
• Lactulose, rifaximin, BCAA, LOLA
• Endotracheal intubation if high-grade encephalopathy

Cerebral edema and intracranial hypertension

• Osmotherapy by mannitol, hypertonic saline
• Temperature control
• Rescue therapy - Indomethacine, thiopentone

Seizures: phenytoin or short-acting benzodiazepines

Question 6

Define the pertinent features of stages of Hepatic encephalopathy

Answer 6

0: Normal consciousness, no clinical features, normal EEG
1: Inverted sleep pattern, confusion, euphoria + tremor, apraxia + normal EEG
2: Lethargic, Disinhibition + Flapping tremor, hyporeflexia, dysarthria + Slow EEG
3: Arousable, incoherent speech + Flapping tremor, Hyperreflexia, Babinski + Abnormal EEG
4. Coma, not arousable + Decerebrate position + Abnormal EEG

Question 7

Outline the King’s criteria for liver transplant for acute liver failure

Answer 7

Acetaminophen:

• pH < 7.3 or all 3 of following
• Grade III, IV encephalopathy + PT > 100s/ INR > 6.5 + Serum creatinine >300

Non-acetaminophen:

• PT > 100s/ INR > 6.5 or ANY 3 of following
• Age under 10 or over 45
• NOT hepatitis A or B, halothane, idiosyncratic drug reaction, Wilson’s disease
• Period of jaundice to encephalopathy > 7 days
• PT > 50s/ INR > 3.5
• Serum bilirubin > 300

Question 8

Liver transplant for fulminant liver failure

Indications

Answer 8

Indications:

1. Liver failure:
   - acute liver failure
   - acute-on-chronic liver failure
   - chronic liver failure with worsening liver function (INR, bilirubin, albumin) and cirrhotic complications
2. Metabolic diseases, eg. haemochromatosis, Wilson’s disease
3. Small, unresectable HCC:
   → Not meeting hepatectomy criteria: unilobar, no portal vein invasion, no distant mets, 15min ICG retention >14%
   → Meeting UCSF criteria: single ≤6.5cm or max 3 each ≤4.5cm with total ≤8cm

Question 9

Liver transplant for fulminant liver failure

Contraindications

Answer 9

Contraindications:
□ Acute liver failure with uncontrolled infection, Cerebral edema with coning

□ Unfit patient status: severe cardiopulmonary disease, AIDS, uncontrolled sepsis

□ Extra-hepatic malignancy: metastatic HCC or other incurable extrahepatic malignancies

□ Active alcohol or other substance misuse

Question 10

Define acute-on-chronic liver failure

Answer 10

Acute hepatic insult resulting in jaundice (serum bilirubin > 90) and coagulopathy (INR > 1.5)

Complicated in 4 weeks by ascites and/or encephalopathy

In a patient previously diagnosed or undiagnosed with chronic liver disease

Question 11

List complications of liver cirrhosis

Answer 11

• HCC
• Portal hypertension: Hypersplenism, esophageal varices, ascites and SBP, hernia and hydrocele
• Liver dysfunction: Hepato-pulmonary syndrome, Hepato-renal syndrome, Bleeding tendency, Immunosuppression, Malnutrition, Encephalopathy, jaundice

Question 12

Indication for liver transplant in chronic liver failure

Answer 12

Worsening liver function:

• High INR
• High bilirubin
• Low albumin

Complications of cirrhosis appear

Question 13

2 major Prognostic indices for transplantation

Answer 13

□ Model for end-stage liver disease (MELD)

□ Child-Pugh score

Question 14

Interpret following biochemical pattern for most likely cause of liver failure

 Very high aminotransferase (>3500IU/L)
 Low bilirubin (anicterus in early stages)
 High INR

Answer 14

Paracetamol poisoning

Question 15

Interpret following biochemical pattern for most likely cause of liver failure

 Very high aminotransferase (25-250× ULN)
 Elevated serum LDH

Answer 15

Ischemic liver injury

Question 16

Interpret following biochemical pattern for most likely cause of liver failure

 Coombs-negative haemolytic anaemia
 Aminotransferase <2000IU/L, AST:ALT >2
 Rapidly progressive renal failure
 Low uric acid levels

Answer 16

Wilson disease

Note that neurologic WD may be confused with HE. Features suggestive of neurologic WD including presence of dysarthria, dystonia, tremors or Parkinsonism

Question 17

Interpret following biochemical pattern for most likely cause of liver failure

 High aminotransferase (1000-200IU/L)
 ALT > AST levels
 HBsAg+, IgM anti-HBc+

Answer 17

Fulminant hepatitis B

Question 18

First-line investigations for acute liver failure

Answer 18

Blood:
→ Basics: CBC, RFT, ABG, arterial ammonia
→ Liver panel: LFT, PT/INR, (factor V)
→ Toxicology: serum paracetamol, blood/urine toxicology
→ Viral serology: anti-IgA IgM, HBsAg, IgM anti-HBc, IgM anti-HEV (esp if pregnant), anti-HSV, anti-VZV, IgM anti-CMV, monospot test
→ Autoimmune serology: ANA, anti-smooth muscle, anti-LKM, anti-SLA, Ig pattern

□ Imaging: USG for Budd-Chiari syndrome, portal hypertension, hepatic steatosis

□ Transjugular liver Bx if still unknown cause (percutaneous C/I due to bleeding risk)

Question 19

Child-Pugh score and classification

• Define metrics measured for total score
• Function
• Any use for transplantation?

Answer 19

Considers HE, ascites, bilirubin, albumin and PT/INR

Predict prognosis from class A to C

NOT used for transplantation because

• Limited differentiation: only 8 levels between Child B and C with same scores for different bilirubin and encephalopathy severity
• Subjective assessment in ascites and encephalopathy
• Variability of PT/albumin in different labs

Question 20

MELD score

• Define metrics measured for total score
• Function
• Any use for transplant?

Answer 20

Based on bilirubin, INR and serum Cr

Excellent in predicting 3mo mortality

Clinically important for prioritization of chronic liver disease patients for transplant

• ≤14 → does NOT benefit from LT
• 15-17 → equivocal benefit
• ≥18 → definitely beneficial

Question 21

Pre-liver transplantation evaluations for recipient and donor

Answer 21

Recipient

□ ABO/Rh blood typing: only require ABO matching, does NOT require HLA matching

□ Serology for viral: CMV, EBV, varicella, HIV, hep A-C
Serology for auotimmune and metabolic hepatita

□ Cardiopulmonary evaluation: ECG, cardiac stress testing, echocardiogram, lung function test

□ Cancer screening: CT/MRI abdomen, colonoscopy, Pap smear, mammography, PSA as indicated

□ Hepatic imaging: triphasic contrast CT abdomen for vascular anatomy and HCC

□ Upper endoscopy if previous variceal haemorrhage

Question 22

2 sources of liver for transplantation

Answer 22

Living donor liver transplant (LDLT)

Deceased donor liver transplant (DDLT)

Question 23

Pre-requisites for Living donor liver transplant

Answer 23

 Age 18-60y (arbitrary, depends on LFT)

 No HBV, HCV, HIV infection

 No medical diseases

 Altruistic (ensure informed consent)

 Remnant liver ≥30% of total liver vol

 Remnant liver regenerates to almost 100% within 3mo (otherwise danger)

Question 24

Pre-requisites for deceased donor liver transplant

Answer 24

 Brainstem death
 No HBV, HCV, HIV infection*
 No extracranial malignancy

*HIV-positive graft livers may be considered in HIV-positive recipients

Question 25

Living donor liver transplant (LDLT)

• define differences between transplant to child or to adult

Answer 25

Liver is divided by the Cantlie’s line (i.e. from IVC to gallbladder, Middle hepatic vein as landmark)

Left lobe (1/3) transplantation
 For adult to child (left lat. segment)
 From large body sized adult to small body sized adult (<60kg)

Right lobe (2/3) transplantation
 For adult to adult
 Right liver graft with middle hepatic vein
 ↑risk for donor but ↑recipient survival

Question 26

Deceased donor liver transplant

• Procedures to extract, preserve and insert liver

Answer 26

Organ procurement operation
 In situ flushing by cannulating IMV or aorta and pour in preservation solution (HTK solution or UW University of Wisconsin) at 4oC
 Total hepatectomy of graft liver

Organ transplantation operation
 Usually orthotopic
 Total hepatectomy of diseased liver
 Orthotopic placement of graft liver with anastomosis of suprahepatic/infrahepatic IVC, portal vein, hepatic artery and bile duct

Question 27

Living donor liver transplant

Recipient benefits and costs

Answer 27

Recipient benefits:

• Life saving (5y survival of 85%)
• Life improvement
• Earlier and planned operation
• Healthy graft

Cost:
- Small-for-size graft

Question 28

List donor morbidities after living donor liver transplant

Answer 28

Surgical:
- Scar, wound infection, hemorrhage, Pressure ulcer, DVT and PE

Liver:
- Cholestasis, Biliary injury, Portal hypertension

Social:
- Financial (missed work, missed school…)

Question 29

Deceased donor liver transplant

Possible complications?

Answer 29

Technical complications
 Bleeding
 Reperfusion injury due to accumulated toxins in GI → endotoxaemia and ↓BP
 Air embolism
 Anastomotic stenosis
 Graft failure due to eg. poor anastomosis, long cold ischaemia time

Question 30

Liver transplant early complications

Answer 30

Primary graft non-function: hepatocellular dysfunction due to prolonged cold-ischaemia time

Anastomotic complications
→ Eg. hepatic artery thrombosis, portal vein thrombosis, biliary leak or strictures

Acute cellular rejection: first 5-10d, but can occur at any point after LT (usu ≤6w)

Infection: post-operative bacterial infections, opportunistic pathogens due to high-dose immunosuppression

Question 31

Causative pathogens of post-liver transplant infections

Answer 31

0-1mo: post-operative bacterial infections, eg. abdominal/intrahepatic abscesses, cholangitis, wound infection, pneumonia, C. diff colitis

1-6mo: opportunistic pathogens due to high-dose immunosuppression
e.g. CMV, varicella-zoster, Epstein-Barr, RSV, HHV-6, TB

> 6mo: usually with community-acquired infections

Question 32

Late complications after liver transplant

Answer 32

Recurrence of primary liver disease: most commonly HBV and HCV

Immunosuppression-related complications:
→ Infections
→ Metabolic syndrome
→ CNI-related renal impairment
→ Metabolic bone disease
→ De novo malignancy: most commonly skin cancer (0.9-3.2%)
→ Hyperuricaemia and gout: ↓uric acid excretion by CyA and tacrolimus

Question 33

Post-liver transplant management

Answer 33

Immunosuppressants: usu prefer tacrolimus ± steroids

Antimicrobials: antibiotics, anti-fungal and anti-viral

Question 34

Antimicrobial prophylaxis after liver transplant

Types of drugs used against selective pathogens?

Answer 34

→ CMV prophylaxis: valacyclovir, acyclovir

→ PCP prophylaxis: septrin, inhaled pentamidine

→ Antifungal prophylaxis: fluconazole

→ Hepatitis B antiviral if anti-HBc +ve

Question 35

List 5 classes of immunosuppressants with examples for post-liver transplant

Answer 35

Calcineurin inhibitor (CNI): cyclosporine, tacrolimus

Steroids (avoid if possible): hydrocortisone, prednisone, prednisolone

mTOR inhibitors: everolimus

Antimetabolites: eg. MMF

Antibody therapy: anti-thymocyte globulin, muromonab-CD3 (OKT3, anti-CD3), basiliximab, daclizumab (anti-IL-2)

Question 36

Side effects of mTOR inhibitors

Answer 36

mTOR inhibitors: everolimus

S/E:
↑risk of hepatic artery thrombosis, should NOT be used <30d post-LT;
hyperlipidaemia (for sirolimus)

Question 37

Side effects of anti-metabolites

Answer 37

Antimetabolites: eg. MMF

S/E: leukopenia