Paediatric liver disorders

Question 1

Management of neonatal jaundice

Answer 1

Assessment:
Review obstetric history, including the mother’s ABO blood group and Rhesus status and the gestational age at birth and use of instrumentation/bruising
Age of onset and duration of jaundice
Feeding history
Number of wet nappies (assess hydration)
Ask specifically about the presence of dark urine and pale stools
Signs of illness (e.g. lethargy, fever, vomiting, weight loss)
Family history of relevant illnesses (e.g. G6PD deficiency, hereditary spherocytosis)
Ask whether close family have had similar symptoms

Examine: 
Look for signs of illness (e.g. fever)  
Appropriate weight gain 
Evidence of bruising (e.g. cephalhaematoma) 
Examine under bright natural light 

Risk Factors for Neonatal Jaundice:
Gestational age < 38 weeks
Previous sibling with neonatal jaundice requiring phototherapy
Exclusive breastfeeding
Visible jaundice within 24 hours of life

Measuring Bilirubin:
Serum bilirubin measurements for babies:
In the first 24 hours of life
Gestational age < 35 weeks

Babies with a gestational age > 35 weeks and who are > 24 hours old:
Transcutaneous bilirubinometer
If this is unavailable, use serum bilirubin
If transcutaneous bilirubinometer gives a reading >250 micromol/L, measure serum bilirubin to check the result
Use serum bilirubin if bilirubin levels are at or above the relevant treatment thresholds for their age, and for all subequent measurements

INTERVENTION:
Use the bilirubin threshold table or treatment threshold graphs to determine whether the baby needs:
No intervention
Phototherapy
Exchange blood transfusion
If the baby is clinically well, gestational age > 38 weeks and are >24 hours old with a bilirubin level that is within 50 micromol/L of the phototherapy threshold = repeat bilirubin measurements
Within 18 hours for babies with risk factors for neonatal jaundice
Within 24 hours for babies with no risk factors

During phototherapy
Repeat serum bilirubin measurement 4-6 hours after initiating phototherapy
Repeat serum bilirubin measurement every 6-12 hours when the serum bilirubin in stable or falling
STOP phototherapy once the serum bilirubin is at least 50 micromol/L below the threshold
Check for rebound hyperbilirubinaemia by repeating serum bilirubin measurement 12-18 hours after stopping phototherapy
Encourage short breaks (up to 30 mins) for breastfeeding, nappy changing and cuddling

Consider intensified phototherapy if:
Serum bilirubin level is rising rapidly (> 8.5 micromol/L per hour)
Serum bilirubin level within 50 micromol/L of the threshold for exchange transfusion after 72+ hours following birth
Bilirubin level fails to respond to phototherapy (within 6 hours)
Reduce the intensity of phototherapy once the serum bilirubin is > 50 micromol/L below the threshold for exchange transfusion

Assessment of Underlying Disease: 
        Measure serum bilirubin 
        Haematocrit 
        Blood group 
        DAT  
        Find out whether the mother received prophylactic anti-D immunoglobulin during pregnancy 
        FBC and blood film  
        Blood G6PD levels  
        LFT 
        Sepsis screen if infection is suspected  

Other treatments:
IVIG - used alongside intensified phototherapy in cases of rhesus haemolytic disease or ABO haemolytic disease where the serum bilirubin continues to rise by > 8.5 micromol/L per hour Exchange Transfusion
Used if above the threshold on the graph or if the baby is showing signs of bilirubin encephalopathy
Double-volume exchange transfusion is used to treat babies
During exchange transfusion, do NOT stop phototherapy
Measure serum bilirubin within 2 hours

ADVICE
Reassure that neonatal jaundice if common, usually transient and harmless
Breastfeeding can continue as per usual
Encourage frequent breastfeeding (e.g. every 3 hours) and to wake the baby up to feed

Question 2

Characteristics of biliary atresia

Answer 2

Progressive fibrosis and obliteraiton of the extrahepatic and intrahepatic biliary tree

Question 3

What is the major complication of biliary atresia?

Answer 3

Without intervention, chronic liver failure develops and death occurs within 2 years

Question 4

Presentation of biliary atresia

Answer 4

Mild jaundice
Pale stools (colour may fluctuate but becomes increasingly pale as the disease progresses)
Normal birthweight
Faltering growth
Hepatomegaly
Splenomegaly due to portal hypertension

Question 5

Investigations for biliary atresia

Answer 5

Raised conjugated bilirubin
Abnormal LFT
Fasting abdominal ultrasound may show contracted or absent gallbladder, but may be normal
DIagnosis is confirmed by a cholangiogram (either ERCP or operative)
- This will fail to outline the normal biliary tree structure
Liver biopsy will initially demonstrate neonatal hepatitis
- Features of extrahepatic biliary obstruction will develop with time

Question 6

Management of biliary atresia

Answer 6

Surgical intervention is recommended ASAP (ideally within the first 60 days of life)
Kasai hepatoportoenterostomy - involves ligating the fibrous ducts above the join with the duodenum and joining and end of the duodenum directly to the porta hepatis of the liver
Liver transplantation is considered if the Kasai procedure is unsuccessful

Question 7

Complications of biliary atresia, and how to manage them

Answer 7

Growth failure
Portal hypertension
Cholangitis
Ascites

Ursodeoxycolic acid promotes bile flow
During the first year of life, either breast milk or medium-chain triglyceride-enriched formula is given with monthly monitoring and nutritional status
Fat-soluble vitamins are given to all children with the condition - levels should be monitored and the dose adjusted accordingly
All patients within the first year of life should receive prophylactic antibiotics to prevent cholangitis (usually co-trimoxazole)

Question 8

Choledochal cysts

Answer 8

Cystic dilatations of the extrahepatic biliary system

May be detected antenatally

Question 9

Choledochal cyst presentation

Answer 9

May present with neonatal jaundice

In older children, it is more likely to present with abdominal pain, a palpable mass, jaundice or cholangitis

Question 10

How are choledochal cysts diagnosed?

Answer 10

Ultrasound or MRCP

Question 11

Complications of choledochal cysts

Answer 11

Cholangitis

Malignancy

Question 12

Treatment of choledochal cysts

Answer 12

Surgical excision of the cyst with the formation of a Roux-en-Y anastomosis to the biliary duct

Question 13

Features of neonatal hepatitis syndrome

Answer 13

Prolonged jaundice and hepatic inflammation

Babies may have low birth weight or faltering growth

Question 14

Alagille syndrome mode of inheritance

Answer 14

Rare autosomal dominant

Question 15

Clinical features of Alagille syndrome

Answer 15

Triangular facies
Skeletal abnormalities
Congenital ehart disease (usually peripheral pulmonary stenosis)
Renal tubular disorders
Defects in the eye
Infants may be profoundly cholestatic with severe pruritus and faltering growth

Question 16

Investigations for Alagille syndrome

Answer 16

Identifying gene mutations

Question 17

Management of Alagille syndrome

Answer 17

Nutrition and fat-soluble vitamins
Some will require liver transplant
Most survive to adulthood

Question 18

Progressive familial intrahepatic cholestasis

Answer 18

Autosomal recessive

Affects bile salt transport

Question 19

Clinical features of progressive familial intrahepatic cholestasis

Answer 19

Jaundice
Intense pruritus
Faltering growth
Rickets
Diarrhoea (sometimes)
Hearing loss (sometimes)
Older children may present with gallstones

Question 20

How is progressive familial intrahepatic cholestasis diagnosed?

Answer 20

Identifying mutations in bile salt transport genes

Question 21

Treatment of progressive familial intrahepatic cholestasis

Answer 21

Nutritional support and fat-soluble vitamins

FIbrosis usually progresses and liver transplant is often needed

Question 22

Alpha-1 antitrypsin deficiency mode of inheritance

Answer 22

Autosomal recessive

Question 23

How does alpha-1 antitrypsin deficiency cause disease?

Answer 23

Abnormal folding of alpha-1 antitrypsin protein is associated with accumulation of the protein within hepatocytes leading to liver disease in infancy and childhood
The lack of circulating alpha-1 antitrypsin leads to emphysema, as neutrophile elastase is not neutralised

Question 24

Clinical features of alpha-1 antitrypsin deficiency

Answer 24

Prolonged neonatal jaundice
Bleeding (less common) due to vitamin K deficiency (haemorrhagic disease of the newborn)
Hepatomegaly
Splenomegaly develops with cirrhosis and portal hypertension

Question 25

Investigations for alpha-1 antitrypsin

Answer 25

Measure alpha-1 antitrypsin in the plasma | Can be diagnosed antenatally

Question 26

Prognosis for alpha-1 antitrypsin deficiency

Answer 26

50% will have a good prognosis Remainder develop liver disease and may require transplantation Pulmonary disease is less significant in childhood, but is likely to develop in adult life

Question 27

Management of alpha-1 antitrypsin deficiency

Answer 27

Advise against smoking and to avoid pollution Advise against drinking alcohol/limiting alcohol consumption Pulmonary manifestations are treated similarly to COPD (varying combinations of bronchodilators, ICS, pulmonary rehabilitation and vaccination) Liver manifestations are managed similarly to other liver diseases (may include monitoring for coagulopathy, diuretics for ascites, OGD to detect/manage varices, liver transplantation)

Question 28

Clinical features of galactosaemia

Answer 28

``` WHEN FED MILK: Poor feeding Vomiting Jaundice Hepatomegaly ``` ``` If untreated: Liver failure Cataracts Developmental delay A rapidly fatal course with shock, haemorrhage and DIC due to Gram-negative sepsis may occur ```

Question 29

Investigations for galactosaemia

Answer 29

Galactose in the urine | Measuring galactose-1-phosphate-uridyl transferase in red cells

Question 30

Management of galactosaemia

Answer 30

Galactose-free diet prevents liver disease | Ovarian failure and learning difficulties may occur later

Question 31

Clinical features of viral hepatitis

Answer 31

``` Nausea Vomiting Abdominal pain Lethargy Jaundice (30-50% do not develop jaundice) Large, tender liver Splenomegaly Elevated transaminases NORMAL coagulation ```

Question 32

What kind of virus is Hepatitis A

Answer 32

RNA virus

Question 33

How is Hep A transmitted?

Answer 33

Faeco-oral Vaccination required if travelling to endemic areas

Question 34

Clinical features of Hepatitis A infection

Answer 34

May be symptomatic Most affected children have mild illness and recover clinically and biochemically within 2-4 weeks Some may develop prolonged cholestatic hepatitis or fulminant hepatitis Chronic liver disease does not occur

Question 35

Investigations for Hepatitis A

Answer 35

Anti-Hep A IgM antibodies

Question 36

Management of Hepatitis A infection

Answer 36

Supportive Close contacts should be vaccinated within 2 weeks of onset of illness Unvaccinated patients with recent exposure to hepatitis A should have normal intramuscular immunoglobulin or the hepatitis A vaccine

Question 37

What kind of virus is Hepatitis B?

Answer 37

DNA virus

Question 38

How is Hepatitis B transmitted?

Answer 38

Perinatal transmission from carrier mothers or horizontal spread within families Inoculation with infected blood via blood transfusion, needle stick injuries or renal dialysis Sexually transmitted

Question 39

Clinical features of Hepatitis B infection

Answer 39

Infants who contract Hep B are asymptomatic but at least 90% become chronic carriers Older children who contract HBV may be asymptomatic or have features of acute viral hepatitis: - Most will resolve spontaneously - 1-2% develop fulminant liver failure - 5-10% become chronic carriers

Question 40

Investigations for HBV infection

Answer 40

HBV antigens and antibodies IgM HBcAb (IgM antibodies against hepatitis B core antigen) are positive in acute infection HBsAg (hepatitis B surface antigen) is suggestive of ongoing infection

Question 41

Management of HBV infection

Answer 41

None for acute HBV - Supportive - Anti-viral therapy with/without liver transplant (lamivudine, entecavir, tenofovir disoproxil) Chronic - Supportive (usually asymptomatic) - Interferon or antiviral monotherapy (e.g. entecavir, peginterferon alpha, tenofovir disoproxil, lamivudine) is recommended in some patients

Question 42

What is the long-term risk with chronic HBV

Answer 42

30-50% of asymptomatic carrier children will develop chronic HBV liver disease, which may progress to cirrhosis There is a long-term risk of hepatocellular carcinoma

Question 43

Prevention of long-term liver disease secondary to chronic HBV

Answer 43

ALL pregnant women should have antenatal screening for HBsAg Babies of all HBsAg-positive mothers should receive hepatitis B vaccination Hepatitis B immunoglobulin is also given if the mother was HBeAg-positive Other members of the family should also be vaccinated

Question 44

What type of virus is hepatitis C?

Answer 44

RNA virus Prevalence is high amongst IVDUs

Question 45

How is HCV transmitted?

Answer 45

Vertical transmission is the most common cause of HCV transmission in children Transmission is much more comon if there is co-infection with HIV Rarely causes acute infection Most become chronic carriers

Question 46

Potential complications of HCV infection

Answer 46

20-25% lifetime risk of progression to cirrhosis or hepatocellular carcinoma

Question 47

Management of HCV infection

Answer 47

Treatment decisions are based on the genotype of the HCV Pegylated interferon Ribavirin New drugs are particularly effectie (e.g. sofosbuvir) NB: treatemnt is not undertaken until >3 years of age because verticaly acquired infections may resolve spontaneously

Question 48

Hepatitis D

Answer 48

Defective RNA virus Depends on hepatitis B virus for replication (coinfection or superinfection) Cirrhosis develops in 50-70% of those that develop HDV infection

Question 49

Hepatitis E

Answer 49

RNA virus Faeco-oral transmission usually from contaminated water Causes mild self-limiting illness in most people Can also be transmitted by blood transfusion or eating contaminated pork It is particularly dangerous in pregnant women - it causes fulminant hepatic failure with a high mortality rate

Question 50

What is seronegative hepatitis?

Answer 50

When a viral hepatitis is suspected but not identified, it is called a seronegative hepatitis

Question 51

Acute liver failure (fulminant hepatitis)

Answer 51

Characterised by the development of massive hepatic necrosis with subsequent loss of liver function This can be with or without hepatic encephalopathy Uncommon but has a high mortality

Question 52

Causes of acute liver failure

Answer 52

``` <2 years old: Infection (most commonly HSV) Metabolic disease Seronegative hepatitis Drug-induced Neonatal haemochromatosis ``` ``` >2 years: Seronegative hepatitis Paracetamol overdose Mitochondrial disease WIlson's disease Autoimmune hepatitis ```

Question 53

Clinical features of acute liver failure (fulminant hepatitis)

Answer 53

``` Jaundice Encephalopathy (features include irritability, confusion and drowsiness)- older children may be aggressive Coagulopathy Hypoglycaemia Electrolyte disturbance ```

Question 54

Complications of acute liver failure

Answer 54

Cerebral oedema Haemorrhage from gastritis or coagulopathy Sepsis Pancreatitis

Question 55

Investigations for acute liver failure

Answer 55

``` Bilirubin may be normal Massively elevated transaminases High ALP Abnormal coagulation High plasma ammonia IMPORTANT: acid-base balance, blood glucose and coagulation should be monitored at all times EEG - may show acute hepatic encephalopathy CT - may show cerebral oedema ```

Question 56

Management of acute liver failure

Answer 56

Early referral to a national paediatric liver centre Steps to stabilising the child: Maintaining blood glucose >4mmol/L with IV destrose Preventing sepsis with broad-spectrum antibiotics and antifungals Preventing haemorrhage with IV vitamin K and H2 antagonists/PPIs Prevent cerebral oedema by fluid restriction and mannitol diuresis Management is dependent on the suspected cause of acute liver failure ``` Features of poor prognosis: Shrinking liver Rising bilirubin Falling transaminases Worsening coagulopathy Coma ```

Question 57

Causes of chronic liver disease in older children

Answer 57

``` Post-viral hepatitis B and C Autoimmune hepatitis and sclerosing cholangitis Drug-induced (NSAIDs) Cystic fibrosis Wilson's disease Fibropolycystic liver disease Non-alcoholic fatty liver disease Alpha-1 antitrypsin deficiency ```

Question 58

What is the mean age of presentation of autoimmune hepatitis and sclerosing cholangitis?

Answer 58

7-10 years | More common in girls

Question 59

How can autoimmune hepatitis and sclerosing cholangitis present?

Answer 59

Acute hepatitis Fulminant hepatic failure Chronic liver disease Autoimmune features (e.g. skin rash, arthritis, haemolytic anaemia, nephritis)

Question 60

Investigations for autoimmune hepatitis and sclerosing cholangitis

Answer 60

``` Elevated total protein Hypergammglobulinaemia (IgG > 20) Positive autoantibodies Low serum complement (C4) Typical histology ```

Question 61

Autoimmune hepatitis may occur in association with:

Answer 61

IBD Coeliac disease Other autoimmune diseases

Question 62

Management of autoimmune hepatitis and sclerosing cholangitis

Answer 62

Most children with autoimmune hepatitis will respond to prednisolone and azathioprine Sclerosing cholangitis is treated with urseodexoycholic acid Liver transplants may be considered in severe cases

Question 63

What is the most common liver manifestation of CF?

Answer 63

``` Hepatic steatosis (fatty liver) Steatosis does not tend to progress and treatment involves ensuring optimal nutritional support ``` Progressive biliary fibrosis can result from thick tenacious bile with abnormal bile acid concentration Cirrhosis and portal hypertension will develop in 20% of children by mid-adolescence

Question 64

Hepatic investigations for CF

Answer 64

Liver histology will include fatty liver, focal biliary cirrhosis or focal nodular cirrhosis

Question 65

Management of hepatic manifestations of CF

Answer 65

Supportive therapy (endoscopic treatment of varices, nutritional) Ursodeoxycholic acid Liver transplant may be considered

Question 66

How is Wilson's disease inherited?

Answer 66

Autosomal recessive

Question 67

How does the basic gene defect in Wilson's cause disease?

Answer 67

Reduced synthesis of caeruloplasmin (copper-binding protein) Defective excretion of copper in the bile This leads to a build up of copper in the liver, brain, kidney and cornea

Question 68

Presentation of Wilson's disease

Answer 68

Patients could present with any form of liver disease (e.g. acute hepatitis, fulminant hepatisi, cirrhosis, portal hypertension) Neuropsychiatric features are more comon in 10-20 year olds. Features include: Deterioration in school performance Mood and behaviour change Extrapyramidal signs such as incoordination, tremor and dysarthria Renal tubular dysfunction, rickets and haemolytic anaemia may also occur Kayser-Flesicher rings are unlikely to be seen before 7 years of age

Question 69

Investigations of Wilson's disease

Answer 69

Low serum caeruloplasmin Low serum copper Increased urinary copper excretion (NB: increases further on administration of penicillamine (copper chelator)

Question 70

How is the diagnosis of Wilson's disease confirmed?

Answer 70

Elevated hepatic copper on liver biopsy or the identification of a gene mutation

Question 71

Management of Wilson's disease

Answer 71

Zinc - blocks intestianl copper resorption Trientine - increases urinary copper excretion May need symptomatic treatment for tremor, dystonia and speech impediment Pyridoxine (vitamin B6) - given to prevent peripheral neuropathy NB: neurological improvement may take up to 12 months Liver transplantation considered in children wtih end-stage liver disease

Question 72

What are ciliopathies (fibrocystic liver disease)?

Answer 72

Range of conditions affecting the development of the intrahepatic biliary tree

Question 73

How do fibrocystic liver diseases present?

Answer 73

Presentation is with liver cystic disease/fibrosis and renal disease Hepatosplenomegaly Abdominal distension Portal hypertension NB: liver function is normal at an early stage Liver histology - large bands of hepatic fibrosis containing abnormal bile ductules

Question 74

Complications of fibrocystic liver disease

Answer 74

Portal hypertension with varices Recurrent cholangitis Cystic renal disease may co-exist, causing hypertension and renal dysfunction

Question 75

What is the most common cause of chronic liver disease in high-income countries?

Answer 75

Non-Alcoholic fatty liver disease

Question 76

What is non-alcoholic fatty liver disease?

Answer 76

A spectrum ranging from simple fatty deposition (steatosis) through to inflammation (steatohepatitis), fibrosis, cirrhosis and end-stage liver failure It may be associated wtih metabolic syndrome or obesity Usually asymptomatic May be linked to insulin resistance

Question 77

How is non-alcoholic fatty liver disease diagnosed?

Answer 77

Often made after the incidental finding of an echogenic liver on ultrasound or mildly elevated transaminases Liver biopsy may reveal marked steatosis with or without inflammation or fibrosis

Question 78

Management of non-alcoholic fatty liver disease

Answer 78

Weight loss (and bariatric surgery) Treatment of insulin resistance and diabetes Statins Vitamin E and C Ursodeoxycholic acid (improved bile flow)

Question 79

Complications of chronic liver disease

Answer 79

Nutrition: Effective nutrition is ESSENTIAL Fat Malabsorption Long-chain fat is NOT effectively absorbed without bile Medium-chain triglyceride containing milk (specialist formula) is required in children who are persistently cholestatic (NOTE: these do NOT require bile micelles for absorption) Fat-soluble vitamins (ADEK) should be supplemented Protein Malnutrition Results from poor intake and high catabolic rate of the diseased liver Protein intake should NOT be restricted unless the child is encephalopathic Anorexia Unwell children may not eat or drinks so will require an NG tube or parenteral feeding Pruritus: Associated with cholestasis Difficult to manage and leads to excoriation MANAGEMENT Loose cotton clothing Keep nails short Emollients Medication Phenobarbital (stimulates bile flow) Cholestyramine (bile salt resin to absorb bile salts) Ursodeoxycholic acid (oral bile acid that solubilises the bile) Rifampicin (enzyme inducer) ``` Encephalopathy: Occurs in end-stage liver disease May be precipitated by: GI haemorrhage Sepsis Sedatives Renal failure Electrolyte imbalance ``` Presentation: Infants: irritability, sleepiness Older children: abnormalities in mood, sleep rhythm, intellectual performance and behaviour Plasma ammonium may be elevated EEG is abnormal MANAGEMENT (BMJ Best Practice) Supportive (frequent monitoring of neurological and mental status) Identify and correct precipitating factors (e.g. GI bleeding, infections, electrolyte disturbances, drugs) Reducing nitrogenous load Dietary protein restriction (be careful about worsening protein-caloric malnutrition) Nitrogenous load from the gut can be reduced using non-absorbable disaccharides (e.g. lactulose) or antibiotics (e.g. rifaximin) Cirrhosis and Portal Hypertension: Cirrhosis is defined as extensive fibrosis with regenerative nodules May be secondary to hepatocellular disease or chronic bile duct obstruction (biliary cirrhosis) Main pathophysiological effects of cirrhosis: Diminished liver function Portal hypertension with splenomegaly, varices and ascites Hepatocellular carcinoma may develop Children with compensated liver disease may be asymptomatic if liver function is adequate (normal LFTs and not jaundiced) ``` CLINICAL FEATURES Jaundice Palmar/plantar erythema Telangiectasia Spider naevi Malnutrition Hypotonia Portal hypertension (caput medusae, splenomegaly) ``` INVESTIGATIONS Screening for causes of chronic liver disease Upper GI endoscopy (to check for varices) Abdominal ultrasound (may show shrunken liver with gastric/oesophageal varices) Liver biopsy ``` As cirrhosis decompensates: Elevation of aminotransferases Elevation of ALP Fall in plasma albumin Prolonged prothrombin time ``` Oesophageal Varices: Consequences of portal hypertension Diagnosed by upper GI endoscopy Acute bleeding is treated conservatively with blood transfusions and H2 antagonists or omeprazole If bleeding persists, other options may be considered: Octreotide infusion Vasopressin analogues Endoscopic band ligation Sclerotherapy Portocaval shunts may be inserted before liver transplantation Ascites: Factors contributing to ascites include hypoalbuminaemia, sodium retention, renal impairment and fluid redistribution MANAGEMENT Sodium and fluid restriction Diuretics Refractory ascites: albumin infusion, paracentesis Spontaneous Bacterial Peritonitis: Should be considered if there is undiagnosed fever, abdominal pain, tenderness or an unexplained deterioration in hepatic or renal function Diagnostic paracentesis should be performed and sent for WCC, differential and culture More than 250 neutrophils/mm3 is diagnostic of spontaneous bacterial peritonitis MANAGEMENT: broad-spectrum antibiotics Renal Failure: Can occur secondary to renal tubular acidosis, acute tubular necrosis or functional renal failure (hepatorenal syndrome)

Question 80

Indications for liver transplantation

Answer 80

Severe malnutrition unresponsive to intensive nutritional therapy Complications refractory to medical management (bleeding varices, resistant ascites) Failure of growth and development Poor quality of life

Question 81

Contraindications to liver transplantation

Answer 81

Sepsis Untreatable cardiopulmonary disease Untreatable cerebrovascular disease

Question 82

Complications of liver transplantation

Answer 82

``` Primary non-function of the liver Hepatic artery thrombosis Biliary leaks and stricture Rejection SEPSIS (main cause of death) ``` 80% 20-year survival Most deaths occur in the first 3 months