Liver Failure
Liver failure is the inability of the liver to perform its normal synthetic and metabolic function as part of normal physiology.
Two forms are recognised, acute and chronic.
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease (such as jaundice), and indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells). The complications are hepatic encephalopathy and impaired protein synthesis (as measured by the levels of serum albumin and the prothrombin time in the blood). The 1993 classification defines hyperacute as within 1 week, acute as 8–28 days and subacute as 4–12 weeks.[1] It reflects the fact that the pace of disease evolution strongly influences prognosis. Underlying etiology is the other significant determinant of outcome

Acute
- Cerebral edema and encephalopathy
- Coagulopathy
- Hyponatraemia (shift in sodium transport from Na/K ATPase inhibition
- Hypoglycaemia
- Lactic acidosis (failure of Cory cycle)
Historically mortality has been unacceptably high, being in excess of 80%.[19] In recent years the advent of liver transplantation and multidisciplinary intensive care support have improved survival significantly. At present overall short term survival with transplant is more than 65%.[20]
Several prognostic scoring systems have been devised to predict mortality and to identify who will require early liver transplant. These include King's College Hospital criteria, MELD score, APACHE II, and Clichy criteria.

What are the indications for liver Tx

•        End-stage liver disease with MELD >17

o   Alcoholic liver disease: 25% have HCV. 6 months of abstinence is required to ensure that liver dysfunction is not reversible.

o   HBV: recurrence has largely been overcome by high-dose HBV Ig and lamivudine

o   HCV:  recurrence of HCV infection is almost universal and 25% develop recurrent cirrhosis.

o   Non-alcholic steatohepatitis (NASH -fatty liver disease): associated with obesity and adult-onset DM. Probably represents the majority of cases classified as cryptogenic cirrhosis. Leads to steatosis and steaotohepatitis. Recurrence after Tx is possible

o   PBC- Treat with Usrodeoxycholic acid to slow progression of disease. After Tx the recurrence rate is about 15% at 5 years.

o   PSC: Associated with UC. Tx before colecetomy as liver failure makes a poor candidate for colectomy.

o   Biliary atresia – Portoenterostomy is treatment of choice for children less than 3 months. This fails eventually so that 75% require a LTx by 6 years of age. Recurrent cholangitis, growth failure and port HT leading to Variceal haemorrhage are indications for Tx.

o   Inherited metabolic disorders causing liver failure – alpha1-AT deficiency, Wilson’s disease, type I glycogen storage disease, tyrosinaemia.

•        Fulminant hepatic failure: encephalopathy within 8 weeks of onset

•        Patients with HCC and liver disease with Milan Criteria

•        Metabolic diseases of liver where liver is structurally and functionally normal, but transplantation replaces an enzyme which is deficient or dysfunctional – haemphila A or B, familial hypercholesterolaemia, Niemann-Pick, Oxalosis, familial amyloid polyneuropathy.

What are the contra-indications to LTx

•        Inability to withstand the operation due to cardiac or pulmonary disease. Surgical correction of cardiac disease may be difficult because of liver failure

•        Active substance misuse

•        Lack of social support

•        Recent intracranial haemorrhage

•        Active sepsis and extra-hepatic malignancy

o   Renal insufficiency increases the risk but is not a contra-indication

o   HIV no longer contraindication

•        Portal vein thrombosis is no longer a contra-indication – Can be overcome by eversion endarterectomy or portal vein, bypass using donor iliac vein to SMV. If SMV is also thrombosed then anastomosis to IVC or Aorta can be used to achieve inflow to liver.

What are the techniques for increasing available organs for liver transplantation

•        Split liver transplantation

o   Adult livers are typically too large to fit into a child.

o   Splitting of right lobe (VI-VIII), left lobe (II-IV) or left lateral section (II/III) will reduce the liver to appropriate size.

o   Originally the splitting was performed ex-vivo and the remaining liver discarded.

o   Techniques evolved to allow both portions of liver (usually left lateral segment for child and right tri-segment for adult) to be used

o   The right and left lobes were then split for two adult recipients.

o   Donors for split liver transplantation must be ideal donors (15-50 years, ICU stay <3days, BMI <27, MAP >60, Na,160, GGT <50 and no steatosis.

o   The survival for adult recipients of split livers is still inferior

•        Living donor liver Tx

o   Originally used to allow adult to donate left lateral segment to child

o   For adult to adult Tx, the right lobe (V –VIII) is donated leaving the IVC by taking the right hepatic vein with the graft.

o   The donor morbidity is greater than living renal donor. Mortality is 1-.01% with significant risk of complications including bile leaks. .

o   Reduced liver volume appears to be insufficient for patients with advanced liver

What is auxillary liver Tx

•        Donor allograft is placed heterotopically leaving the native liver in place

o   For fulminant hepatic failure where the chance of recovery is reasonable. If native liver recovers, immunosuppression is stopped and liver allograft will atrophy

o   Used for enzymatic deficiency when the liver functions well in other respects.

 What is end-stage liver disease

•        A liver that has minimal function and no potential for recovery

What is the MELD score

•        Model for End stage liver disease

•        Integer value based on Creatinine, bili, INR.

•        When MELD score exceeds 17 the mortality on the liver Tx waiting list exceeds the mortality of the transplant procedure in the same patient population

•        Patients with MELD score of <17 do not receive absolute survival benefit from LTx.

•        Implantation of MELD in organ allocation has resulted in reduced death rate on waiting list

•        MELD criteria disadvantage patients with HCC who may benefit from LTx despite lower MELD score

What are the King’s College criteria

•        Fulminant liver failure is progression to encephalopathy within 8 weeks of onset of symptoms in a previously healthy person

•        Before liver transplantation the mortality was 80%.

•        The King’s College Criteria predict the requirement for liver Tx.

o   Paracetamol-induced liver failure –

                        pH <7.3 (irrespective of encephalopathy)

            OR       Cr>300 and PT>50s in patient with grade III or IV encephalopathy.

o   Non-Paracetamol –

                  PT >50s (irrespective of encephalopathy grade)

OR       Any three of

                        Age (<10  >40)

                        Bili >300

                        PT>25s

                        Jaundice >7d

                        idiopathic/idiosyncratic/Halothane hepatitis.

What are the Milan Criteria

• The Milan criteria were used to select HCC patients for transplantation to define a group with a good outcome

Milan criteria

            Single tumour < 5cm

OR       2-3 tumours each <3cm with no vascular invasion nor extrahepatic disease

• These criteria are very restrictive and so only 5-10% of patients with HCC are candidates

Expanded criteria were defined (such as UCSF – single nodules <6.5, 3 or fewer tumours largest <4.5 and sum of tumours less than 8cm) which produce slightly worse outcome than Milan criteria.

The MELD has been amended to give priority for patients with HCC within Milan criteria

What are the complications of a liver Tx

Immediate

•        Bleeding – often associated with coagulopathy preceeding surgery or which develops during the anhepatic phase. 10% of liver Tx return to theatre for bleeding. Oliguria is significant sign.

•        Primary non-function

o   Occurs in 5% of Tx

o   Patient does not regain consciousness or has a short period of lucidity followed by coma. Transaminase >5000, INR >2.5, low levels of factor V. Patients should be listed as status 1 for re-transplantation

•        Hyper-acute rejection – very uncommon. Even ABO incompatible Transplants have a low incidence. HLA matching is not required and does not influence outcome through hyperacute, acute or chronic rejection

Early

•        General: Respiratory failure, MI, DVT, PE, renal failure

•        Bile leak or obstruction (occurs 10-30% post Tx). Bile duct depends on hepatic artery for viability. Biliary complication should prompt evaluation for hepatic artery thrombosis or stenosis.

o   Bile leak – biliary peritonitis requires laparotomy operative repair using Roux-en-Y hepatico-jejunostomy. Contained biloma can be drained percutaneously. ERCP can be used to diagnose and treat (by stenting) most bile leaks. If ERCP fails or there is a Roux-en-Y anastomosis then PTC and transhepatic stenting is used.

o   Stricture – Via ERCP or PTC balloon dilatation and stent placement is attempted. After failed dilatation, operative repair may be attempted.

•        Hepatic artery thrombosis (5%) – Sudden rise in transaminase, biliary problem or heptic necrosis may be first features detected. Duplex, MRA, CT or conventional angio used for diagnosis.

o   Risk factors: small donor compared to recipient, reconstructive arterioplasty, acute rejection in first week, CMV positive donor to negative recipient, smoking.

o   May be associated with post-operative hyper-coagulable state due to lack of production of PC/PS and ATIII. FFP is often given.

o   If thrombosis is identified in the first week then thrombecomy should be attempted, which is successful in 50% of cases.

o   Late thrombosis does not always lead to graft failure.

•        Portal vein thrombosis (3%)

o   Risk factors – portal vein thrombosis or portal vein surgery.

o   A previous spelno-renal shunt should be disconnected by ligating the left renal vein at its origin from IVC (which will not compromise the function of left kidney) to increase flow through the portal vein.

o   Patient develops ascities and symptoms of portal HTN. Diagnosis with Duplex, MRA or CT with portal venous phase.

o   If identified in the immediate post-op period then thrombectomy should be performed.

•        IVC or hepatic vein thrombosis/obstruction

o   Rare complication more common with piggy-back technique. Presents with ascities and renal dysfunction.

o   Diagnosis requires cavography and can be treated with angioplasty or stening

•        Intra-abdominal sepsis (5%)

o    Diffuse or localized peritonitis from leaking biliary anastomosis. Percutaneous drain for controlled leak or collection with surgical drainage for larger leaks or patient not responding to percutaneous drain.

•        Impaired consciousness – Due to encephalopathy, cerebral infarcts from hypotension, air embolus with patent foramen ovale, CNI causing seizure.

•        Acute rejection – less common cause of graft failure than HA thrombosis or PNF. Episodes of rejection do not influence long-term outcome (unlike kidney).

o   Findings of low grade fever, leucocytosis, eosinophila, rising transaminases, bilirubin, should prompt a biopsy.

o   Histolgical findings are portal lymphocytosis (T cells), endothelitis and bile duct infiltration and damage.

o   Differentiation from HCV recurrence can be difficult. 

Late

•        Chronic rejection

o   Attack on bile ducts which are obliterated (vanishing bile duct syndrome – absent in 15 of 20 bile ducts examined).

o   Rising ALP and Bili

o   Obliteration of small and medium-sized arteries.

What is the immunosuppression for a LTx

•        CNI (calcineurin inhibitor – e.g. cyclosporin)  is considered imperative.

•        Induction with Ab preparations may reduce the need for steroids or CNI

•        Anti-infective prophylaxis is used – TMP-SMX, ganciclovir and Fluconazole.

What is the treatment for acute rejection in LTx

•        Pulse steroids for 3 days

•        Increase CNI dose or add MMF(purine antagonist - mycophenolate mofetil)

•        If none of the above effective use OKT3 or ATG

Liver Transplant General Procedure:

Virtually all liver transplants are done in an orthotopic fashion, that is, the native liver is removed and the new liver is placed in the same anatomic location. The transplant operation can be conceptualized as consisting of the hepatectomy (liver removal) phase, the anhepatic (no liver) phase, and the postimplantation phase. The operation is done through a large incision in the upper abdomen. The hepatectomy involves division of all ligamentous attachments to the liver, as well as the common bile duct, hepatic artery, hepatic vein and portal vein. Usually, the retrohepatic portion of the inferior vena cava is removed along with the liver, although an alternative technique preserves the recipient's vena cava ("piggyback" technique).

The donor's blood in the liver will be replaced by an ice-cold organ storage solution, such as UW (Viaspan) or HTK until the allograft liver is implanted. Implantation involves anastomoses of the inferior vena cava, portal vein, and hepatic artery. After blood flow is restored to the new liver, the biliary (bile duct) anastomosis is constructed, either to the recipient's own bile duct or to the small intestine. The surgery usually takes between five and six hours, but may be longer or shorter due to the difficulty of the operation and the experience of the surgeon.