Hepatobiliary Surgery JC066: I Need A New Liver: Liver Transplantation

Question 1

Questions related to liver transplantation

Answer 1

1. What are disease indications for liver transplantation?
2. When should liver transplantation be performed?
3. What are sources of liver graft?
4. How is it being performed?
5. What are the post-operative complications and medications?
6. How successful is liver transplantation in the long run?

Question 2

Indications for liver transplantation

Answer 2

1. Fulminant hepatic failure
2. Acute-on-chronic liver failure
3. Chronic liver failure
4. Metabolic diseases
5. Small unresectable HCC

Question 3

1. Fulminant hepatic failure

Answer 3

• Severe liver injury, potentially reversible in nature with onset of hepatic encephalopathy **within 8 weeks of first symptoms (usually jaundice) in **absence of pre-existing liver disease

Causes:
1. Drug intoxication
- paracetamol
- halothane

2. Food poisoning
   - Amanita phalloides (mushroom)
3. Hepatitis
   - Hep A, E
   - Acute Hep B
4. Wilson’s disease

Question 4

Clinical features of Acute hepatic failure

Answer 4

Clinical features:
1. Brain
- hepatic encephalopathy
- cerebral edema
- intracranial hypertension

2. Lung
   - acute lung injury
3. Liver
   - loss of metabolic function
   - hypoglycaemia
   - lactic acidosis
   - hyperammonaemia
   - coagulopathy
4. BM
   - suppression
5. Leukocytes
   - impaired function —> high risk of sepsis
6. Heart
   - high output state
7. Pancreas
   - pancreatitis
8. Adrenal
   - inadequate glucocorticoid production —> hypotension
9. Kidney
   - dysfunction / failure
10. Portal hypertension
11. Systemic inflammatory response

Question 5

Management of Acute liver failure

Answer 5

Nursed in ***ICU
1. Organ support

2. ***Metabolic support
   - hypoglycaemia
   - hypoNa
3. Monitor consciousness level
   - indication for liver transplantation
4. ***Coagulopathy
   - beware of procedures
5. ***Antibiotic prophylaxis

Question 6

Hepatic encephalopathy

Answer 6

• may progress ***rapidly within days
• monitor closely + protect airway

Grading (0-4) on 3 aspects:
1. Consciousness / Intellect
- forgetfulness, irritability (grade 1)
- lethargic (grade 2)
- somnolent, aggressive (grade 3)
- coma (grade 4)

2. Clinical features
   - apraxia (grade 1)
   - flapping tremor (grade 2)
   - babinski +ve (grade 3)
   - decerebrate (grade 4)
3. EEG
   - slow 5 cps triphasic waves (grade 1-3)
   - slow 2-3 cps delta waves (grade 4)

Subclinical (between 0 and 1): Normal Consciousness / Intellect + EEG except Psychomotor testing abnormality

Question 7

Indication for Liver transplantation

Answer 7

King’s college criteria
- Irrespective of grade of encephalopathy
- PT >100s (INR >6.5)
or 3 of following:
- Age <10 / >40
- Duration of jaundice before encephalopathy >7 days (indicate low reversibility)
- PT > 50s (INR >3.5)
- Bilirubin > 300 umol/L
- Non-A, Non-B, Halothane or Idiosyncratic drug reaction, Wilson’s disease

For paracetamol poisoning:
- pH <7.3
or
- PT >100 + Creatinine >300 + Grade 3/4 encephalopathy

Question 8

When NOT to transplant in Acute liver failure

Answer 8

1. ***Uncontrolled infection
   - e.g. severe bronchopneumonia, fungal septicaemia
2. Cerebral edema + ***coning
   - may become vegetative state even after operation

Question 9

Acute-on-chronic liver failure

Answer 9

Acute hepatic insult manifesting as:
- **Jaundice (serum bilirubin >90) + Coagulopathy (INR >1.5)
- Complicated within 4 weeks by **Ascites / Encephalopathy in a patient with ***previously diagnosed / undiagnosed chronic liver disease

Causes:
- Acute exacerbation / Flare of chronic Hep B
- Cirrhosis with acute deterioration
—> hepatic function ***decompensation (e.g. variceal bleeding)
—> death

Question 10

Chronic liver failure

Answer 10

Causes:
- Cirrhosis (of any etiology)
—> **Hep B
—> **Hep C
—> **Alcoholism
—> **Primary biliary cirrhosis
—> Secondary biliary cirrhosis (chronic bile duct obstruction due to iatrogenic disease, biliary atresia in paediatrics —> ***longstanding biliary obstruction)
—> Autoimmune hepatitis
—> Budd-Chiari syndrome

Question 11

***Clinical features of Chronic liver failure

Answer 11

1. Malaise
2. Jaundice
3. Ascites
4. Infection (spontaneous bacterial peritonitis)
5. Bleeding esophageal varices
6. Coma

Laboratory abnormalities:
1. ↑ INR
2. ↑ Bilirubin
3. ↓ Platelet
4. ↓ Serum albumin
5. ↓ WBC (∵ hypersplenism)
(6. ↑ NH3, ↓ Urea)

Question 12

Complications of Cirrhosis

Answer 12

1. HCC
2. Portal hypertension
   - Varices in stomach, esophagus —> Bleeding
   - **Ascites —> Infection (spontaneous bacterial peritonitis) + Hernia, Hydrocele
   - **Hypersplenism
   - ***Encephalopathy
3. Liver dysfunction
   - **Hepatopulmonary syndrome (↑ liver production / ↓ liver clearance of vasodilators, possibly involving nitric oxide —> **microscopic intrapulmonary arteriovenous dilatations —> **overperfusion relative to ventilation, leading to **VQ mismatch + hypoxemia)

• Ascites —> Infection (spontaneous bacterial peritonitis) + Hernia, Hydrocele
• ↓ Protein synthesis —> Malnutrition, **Immunosuppression, **Bleeding tendency
• ↓ Elimination of wastes —> **↑ Bilirubin, **Encephalopathy, **Hepatorenal syndrome (∵ activation of **RAAS due to portal hypertension —> renal vasoconstriction)

Question 13

When to transplant in Chronic liver failure

Answer 13

1. Worsening of liver function
2. ↑ INR, ↑ Bilirubin, ↓ Albumin
3. Complications of cirrhosis (esophageal bleeding, intractable ascites, unresectable HCC, spontaneous bacterial peritonitis)

Question 14

Sources of donor liver grafts

Answer 14

1. Living donor liver transplantation
2. Deceased donor whole graft liver transplantation
3. Deceased donor split liver transplantation
4. Deceased donor reduced size liver transplantation
5. Sequential liver transplantation

Demand for liver transplant: 15-20 per million population per year
HK brain dead organ donation rate: 4-6 per million population per year

Question 15

Diagnosis of brain death

Answer 15

1. ***Fixed + dilated pupils, not responding to light
2. Absent corneal reflexes
3. No motor response to painful stimuli
4. No reflex activity except spinal cord reflex
5. No oculocephalic reflex (doll’s eyes)
6. No vestibulo-ocular reflexes
7. No gag / cough reflex to bronchial stimulation
8. No respiratory movements if mechanical ventilation stopped to ensure pCO2 >60 mmHg

Question 16

Prerequisite for Liver donation

Answer 16

1. ***No HBV, HCV, HIV infection
2. ***No extracranial malignancy

Question 17

Transplantation procedure

Answer 17

1. Brainstem dead patient
2. Organ harvesting
   - in-situ flushing (to cannulate aorta with cold organ preservation solution)
   - **University of Wisconsin solution at 4oC
   —> HES (Hydroxyethyl starch): support colloidal pressure
   —> Lactobionate: prevent cell swelling
   —> Glutathione: inhibit oxygen free-radical generation
   —> Adenosine: enhance ATP synthesis after reperfusion
   —> Allopurinol: inhibit oxygen free-radical generation
   —> others
   or
   - **HTK solution (Histidine-Tryptophan-Ketoglutarate)
   —> little K content (lower chance of cardiac arrhythmia)
3. Orthotopic liver transplantation: Anastomosis
   - Suprahepatic + Infrahepatic IVC
   - Hepatic artery
   - Portal vein
   - Bile duct
   - Hepaticojejunostomy / Duct-to-duct anastomosis

Question 18

Technical complications of Liver transplantation

Answer 18

1. ***Bleeding (∵ deranged liver function —> coagulopathy)
2. ***Reperfusion injury (flushing of endotoxins, sudden ↑ right heart strain —> right heart failure)
3. Air embolism
4. Anastomosis stenosis
5. ***Graft failure

Question 19

Who gets the brain-dead organ first?

Answer 19

• According to urgency
• Patients with ***Fulminant liver failure will get first
• Chronic liver failure patients are prioritised according to liver function grading

Question 20

Liver function grading

Answer 20

1. Child-Pugh classification
2. MELD (Model for End-stage Liver Disease) score —> **better depictor for mortality
   - Serum bilirubin level
   - INR
   - Serum creatinine level
   —> Cut-off value: **>=15 (already shows significant survival benefit)

Question 21

Liver donation

Answer 21

Full function of liver required: ***>=1/3 of normal liver

Dead donor:
- One Liver will be split into Right + Left lobe for 2 patients
- along Cantlie’s line (middle hepatic vein) (X Falciform ligament: divide Left lateral and Left medial segment)

• Right (2/3 of liver): including RHV + MHV, for Adult
• Left (1/3 of liver): for Young adults / children

Living donor:
Left liver donation:
- From large body size to small body size recipient
- Limited applicability

Right liver donation:
- From small body size to large body size recipient
- Expands applicability of living donor liver transplantation

Question 22

Living donor liver transplantation (LDLT)

Answer 22

Currently, LDLT and DDLT has comparable outcomes (even for high MELD score —> i.e. no need to wait for deceased donor graft)

Prerequisite:
- <60 yo
- **No HBV, HCV, HIV infection
- **No medical diseases
- Altruistic (no conflict of interest)
- Remnant liver ***>=30% total liver volume (∵ avoid liver failure in donor)
- Remnant liver regenerates to almost 100% in 3 months

Cost and Benefits:
Recipient benefit:
- life saving
- life improvement
- **earlier operation (no need to wait for graft)
- **planned operation
- healthy graft

Recipient cost
- small-for-size graft (smaller than whole graft)

Donor cost:
- mortality ~0.5%
- **morbidity ~15%
—> wound infection, cholestasis, biliary injury, haemorrhage, DVT, PE, pressure ulcer, portal hypertension, scar, financial burden, school
- surgical scar
- **long term morbidity?

Donor benefit:
- satisfaction

Question 23

Post-op medication for recipients

Answer 23

1. Immunosuppressants (lifelong)
   - **IL-2 receptor antagonists (Simulect) (during the operation)
   - Steroid
   - Cyclosporine, FK506 (Tacrolimus, prone to develop seizure after surgery) (after induction during operation) (Calcineurin inhibitor)
   - Sirolimus, Everolimus (anti-tumour effect as well —> for HCC) (mTOR inhibitor)
   - **Mycophenolate mofetil (as an adjunct)
2. Antibiotics
3. Antifungals
4. Antivirals

Current practice of immunosuppression:
- ***Avoid steroid
- Try to ↓ dosage of immunosuppressants

Question 24

Risk of immunosuppressants

Answer 24

1. ↑ risk of opportunistic **infection
   - e.g. CMV, TB
2. ↑ risk of ***malignancy
3. Drug specific **SE
   - Steroid: moon face, osteonecrosis, impaired glucose tolerance
   - Cyclosporine: **hairy face (hirsutism), **gum hypertrophy, **nephrotoxicity
   - Tacrolimus (FK506): **neurotoxicity (idiosyncratic), **nephrotoxicity
   - Mycophenolate mofetil: **leukopenia
   - Sirolimus: **hyperlipidaemia

From JC077:
1. Prednisolone: Cushingoid facies, **hyperglycaemia, HL, peptic ulcers, HT
2. Cyclosporine: **nephrotoxicity, HT, HL, **gum hypertrophy, gout
3. Tacrolimus: **nephrotoxicity, HT, **new onset DM, tremors, GI upsets
4. Mycophenolate mofetil: diarrhoea, vomiting, **anaemia, **leukopenia, viral infections
5. Rapamycin: synergistic nephrotoxicity with CNIs, proteinuria, HL, impaired wound healing, interstitial pneumonitis
6. Azathioprine: GI upsets, **hepatotoxicity, anaemia, leukopenia, thrombocytopenia

Question 25

Long-term outcome of Liver transplantation

Answer 25

- 5-year survival 85% - Good QOL - Gainful employment - ***Recurrence of original disease (e.g. HCC) possible - ***Transmission of disease from donor to recipient possible

Question 26

Summary

Answer 26

1. Improve brain-dead donor organ donation rate 2. Use every liver graft (even HBV e.g. HBV donor to HBV recipient) / Split into 2 grafts 3. Explore possibility of Non-heart beating donor 4. Improve donor safety 5. Improve recipient survival 6. Audit and Research

Question 27

SpC Interactive tutorial: Portal Hypertension

Answer 27

Portal hypertension: - Pathologic increase in portal pressure - Resulting from obstruction of portal blood draining from splanchnic circulation back to systemic circulation Normal direction of flow splanchnic circulation: - Left gastric vein (aka Coronary vein) + Splenic vein + Inferior mesenteric vein —> join Superior mesenteric vein —> Main portal vein —> R + L portal vein —> Liver —> R + M + L Hepatic vein —> IVC - Short gastric vein / Vasa brevia —> Lower esophagus —> Systemic circulation

Question 28

Definition of Portal hypertension

Answer 28

Pathologic increase in portal pressure ***Portal pressure gradient (PPG): >5 mmHg - PPG = Portal vein P - IVC P - PPG >10mmHg —> Ascites - PPG >12mmHg —> Variceal bleeding - PPG 6-10mmHg —> Subclinical portal hypertension (detected in surveillance imaging)

Question 29

Etiologies of Portal hypertension

Answer 29

1. Pre-hepatic (20%) - ***Malignant invasion of portal vein (e.g. ***Head of pancreatic cancer, ***HCC) - Congenital absence of portal vein - Thrombophlebitis of umbilical vein 2. Hepatic (80%) - ***Cirrhosis —> Viral cirrhosis —> Alcoholic cirrhosis —> Autoimmune hepatitis causing cirrhosis —> PBC, PSC —> Biliary atresia —> Wilson’s disease - Congenital hepatic fibrosis 3. Post-hepatic - Cardiac cirrhosis (RH failure e.g. constrictive pericarditis) - IVC obstruction - Budd-Chiari syndrome (Hepatic vein obstruction) - Venule obstruction (i.e. in Sinusoid level) —> Hepatic veno-occlusive disease

Question 30

***Pathophysiology of Portal hypertension

Answer 30

Cirrhotic liver —> ***Architectural disturbances (fibrosis, scarring, vascular thrombosis inside liver etc.) + ***Functional alterations (contraction of vascular smooth muscle + stellate cells) —> Increased hepatic resistance —> Portal hypertension —> ***Splanchnic arterial vasodilatation (splanchnic arteries try to dilate to increase blood flow to liver) —> Increased portal blood inflow —> Portal hypertension (vicious cycle) —> ***Effective hypovolaemia (low BP) —> Activation of endogenous vasoactive system —> contraction of vascular smooth muscle (in liver?) —> Portal hypertension (vicious cycle) —> ***Na retention, Hypervolaemia, Increased cardiac index —> Increased portal blood flow —> Portal hypertension (vicious cycle)

Question 31

Long-term outcome of Portal vein thrombosis

Answer 31

1. Cavernous transformation - New vessel development across blocked portal vein 2. Collaterals formation - Pre-existing vessel (usually not engorged / dilated) between portal and systemic circulation —> Engorged + Open during portal hypertension - Thin wall veins —> cannot support large volume of portal blood flowing through them —> rupture may occur (esp. for varices located at GEJ —> massive bleeding) - ↑ Variceal wall tension may be cause of rupture

Question 32

Clinical features of Portal hypertension

Answer 32

Back pressure effect: Viscera: - Splenomegaly - Ascites - Hepatomegaly (if post-hepatic cause) Blood vessels: - Dilatation of pre-existing collaterals between portal and systemic circulation —> Venous hum —> Around umbilicus: Caput medusae (∵ umbilical vein join the left portal vein —> normally obliterated after birth) —> Lower end of esophagus: Esophageal varices —> Rectum and anal canal: Rectal varices —> Extraperitoneal / Retroperitoneal surfaces: Silent (seen only on imaging)

Question 33

Diagnosis of Portal hypertension

Answer 33

1. Clinical - Manifestations of portal hypertension 2. Measurement of portal pressure - Cannulation of branch of mesenteric vein at laparotomy - Wedge hepatic venous pressure (balloon inflated: Portal pressure, deflated: IVC pressure) - Percutaneous transhepatic cannulation of portal vein (by interventional radiologist)

Question 34

CT images of Cirrhosis

Answer 34

Liver: - Shrunken liver: left lateral section not covering stomach, large potential space between liver and anterior abdominal wall (normally no space) - Nodular surface - Recannulisation of umbilical vein (pathognomonic) Spleen: - Splenomegaly: enlargement beyond mid-axillary line

Question 35

Esophageal varices

Answer 35

Diagnosis: 1. Barium swallow (obsolete, showing spiral shape filling defect) 2. Upper endoscopy - 4 columns: 2, 5, 7, 10 o’clock - no correlation between degree of portal HT and number of columns - Active bleeding from varices - Blood clot on varices indicating recent bleeding - Esophageal varices only and absence of other bleeding source in stomach / duodenum Clinical features: 1. Haematemesis 2. Melena (Fresh / Old) 3. Shock 4. Hepatic encephalopathy / coma (∵ ↑ nitrogen products) Treatment aim: 1. Stop bleeding 2. Restore / Maintain normal BP, pulse, urine output, haematocrit —> maintain organ function (including liver) 3. Prevent hepatic coma in case of cirrhosis (∵ blood breakdown product in gut absorbed into portal blood may predispose to hepatic coma)

Question 36

***Treatment of Esophageal variceal bleeding

Answer 36

1. ABC - ETT intubation if coma / haematemesis clot - 2 Large bore cannula - IV fluid + blood replacement (if large blood loss + high rate of loss) 2. ***Terlipressin / Vasopressin + Nitroglycerin (counteract Vasopressin’s vasoconstriction in heart / gut) 3. Upper endoscopy - active bleeding still seen —> ***Sengstaken-Blakemore tube (if you don’t know how to do intervention) / ***Injection Sclerotherapy / ***Banding - active bleeding not seen (i.e. bleeding stopped) —> Continue supportive treatment 4. Correct bleeding tendency - ***FFP infusion - ***Platelet concentrates infusion 5. Anti-hepatic coma treatment - ***Lactulose - ***Rifaximin (0% bioavailability —> high concentration in large bowel —> kill all gut flora converting blood products into toxic substance) - Neomycin (nephrotoxic) - Enema (rarely used since patient cannot hold enema) 6. Antibiotic - ∵ Immunocompromised 7. Definitive treatment (if not done yet) - ***Injection Sclerotherapy / ***Banding 8. Re-bleeding - ***TIPS - ***Surgery (Shunt, Devascularisation) - ***Liver transplantation 9. No re-bleeding - Reassess by endoscopy every 2 months (***Propranolol (decrease portal BP) +/- Isosorbide mononitrate) Risk of emergency endoscopic treatment of bleeding varices: 1. Aspiration pneumonia 2. Prolonged hypotension 3. Serious complications (10-20%) - e.g. Malposition of gastric balloon 4. Procedure related mortality (2%)

Question 37

Sengstaken-Blakemore tube

Answer 37

- 3 lumens —> Gastric balloon —> Esophageal balloon (seldom need to inflate if gastric ballon can already stop bleeding) —> Gastric aspiration channel - Inflate gastric balloon —> Stop bleeding by compression of GEJ —> Interruption of blood flow from gastric veins to azygos vein - Inflation of gastric balloon by 200ml - Traction by 1 pound weight - NOT exceed ***24 hours - Efficacy 90% Problems: 1. Incorrect position of gastric balloon - Esophagus —> ***Perforation of esophagus (causing mediastinitis) - Trachea —> ***Perforation of trachea - Inadequate traction —> Continue bleeding - Inadequate size —> Slipping out of esophagus —> ***Asphyxia, laceration of esophagus —> 1 pound weight should be <=15 cm from ground (∵ esophagus length is ~25cm) 2. Patient’s saliva cannot empty into stomach —> ***Aspiration of saliva into trachea 3. Too heavy + prolonged traction —> ***GEJ necrosis Confirmation of position of gastric balloon: 1. Plain X-ray 2. Radioopaque contrast in gastric balloon 3. Endoscopy (best way ∵ direct vision)

Question 38

Medical therapy

Answer 38

1. Terlipressin (Vasopressin analogue) (70-75% effective) 2. Octreotide (65%) 3. Somatostatin (65%) 4. Vasopressin (50%) Vasopressin: - lower portal BP by constricting splanchnic arterioles - may induce ***Ischaemia to small bowel —> abdominal pain - may induce ***myocardial ischaemia - ***Nitroglycerin used to counteract vasoconstrictive SE (not advocated now)

Question 39

Prevent recurrent bleeding after stabilisation

Answer 39

1. Injection sclerotherapy / Banding —> Obliteration of esophageal varices - Via endoscopy - Fine need puncture of varices / para-variceal areas (no difference) - Sclerosants: Ethanolamine oleate / Sodium tetradecyl sulphate - Fibrin glue for gastric varices (not for esophageal varice due to risk of chemical mediastinitis) 2. Creation of shunt between portal vein (or its branches) to IVC (or its branches) (Radiologically / Surgically) —> Reduction of portal BP Radiological shunt: - Transjugular intrahepatic porto-systemic shunt (TIPS) (stenting between hepatic vein and portal vein) - Risk: HE Surgical shunt: - ***Total shunt: Porto-caval shunt (all portal blood now go into IVC) - ***Selective shunt: Mesenterico-caval shunt / Spleno-renal shunt (only shunt part of portal blood away —> lower risk of HE / liver atrophy) - Risks: —> ***Hepatic encephalopathy (∵ nitrogenous products diverted away from liver) —> ***Liver atrophy (∵ gut hormone no longer goes to liver) - Advantage of selective shunt: —> Maintain blood supply to liver + prevent liver atrophy / HE 3. Division / Detachment of blood vessels around the GEJ (i.e. Devascularisation) —> Reduction of blood flow to stomach + esophagus 4. Liver transplantation if liver irreversibly damaged by disease Choices: 1. Injection sclerotherapy / Banding - ALL cases 2. Surgical shunt - Recurrence of bleeding after Injection sclerotherapy / Banding - Child A 3. Radiological shunt - Recurrence of bleeding after Injection sclerotherapy / Banding - In preparation for liver transplantation (∵ anatomy not altered) 4. Devascularisation - Recurrence of bleeding after Injection sclerotherapy / Banding - Child C 5. Liver transplantation - Child C