Hepatology Flashcards
What are steps of bilirubin metabolism??
🔹Product of haem metabolism ➡️ transport with albumin to the hepatocytes
🔹 Hepatocyte uptake ➡️ membrane receptor carriers or by simple passive diffusion.
🔹 Conjugation with glucuronic acid by esterification to make it water soluble (enzyme – bilirubin uridine diphosphate glucuronosyltransferase – UGT)
🔹Secretion of conjugates against a concentration gradient through the canalicular membrane into the bile
What percentage of Neonatal jaundice??
30–50% of normal term neonates experience jaundice; few have significant underlying disease
Risk factor of significant hyper billirubinemia??
🔹Gestational age <38 weeks
• A previous sibling with neonatal jaundice requiring phototherapy
• Mother’s intention to breastfeed exclusively
• Visible jaundice in the first 24 hours of life
What are the risk factor for kernectrus??
🔹A serum bilirubin level >340 μmol/l in babies with a gestational age ≥37 weeks
🔹A rapidly rising bilirubin level >8.5 μmol/l per h
🔹 Clinical features of acute bilirubin encephalopathy
which jaundice that is considered always pathological and cannot be attributed to physiological jaundice??
Jaundice within the first 24 h of life
What is the incidence of Breast-milk jaundice and what are the types??
• Occurs in 0.5–2% of neonates
• Early onset: develops after day 4
• Late onset: develops around day 7,
Why Kernicterus occurs??
🔹 high levels of unbound, lipid-soluble, unconjugated bilirubin
🔹Albumin-bound bilirubin may also cross the blood–brain barrier if damage has occurred because of asphyxia, acidosis, hypoxia, hypoperfusion, hyperosmolality or sepsis in the newborn
What are the Inherited disorders of unconjugated hyperbilirubinaemia and what are the mode of inheritance ❓
🔅This spectrum of disease depends on the degree of bilirubin UGT deficiency.
🔅Liver function tests and histology are normal.
🔅Autosomal recessive inheritance. Both Gilbert syndrome and Crigler–Najjar type II can also have autosomal dominant transmission
What is the genetic cause of Gilbert syndrome❓
• Mild deficiency (≥50% decrease of UGT activity) occurring in 7% of population
• Polymorphism with TA repeats in the promoter region (TATA box) in white individuals compared with exon mutations in Asian individuals on chromosome 2q37
What are the characteristics and Management of Crigler - Najjar type 1 and type 2 ❓
🔅Crigler–Najjar type II
• Moderate deficiency
• May require phototherapy and phenobarbital
🔅Crigler–Najjar type I
• Severe deficiency of UGT
• High risk of kernicterus
• Requires life-long phototherapy or even liver transplantation
What are the Causes of early onset breast milk jaundice??
relative caloric deprivation, decreased volume and frequency of feeding with resultant mild dehydration and delayed passage of meconium
What are the Causes of late onset breast milk jaundice??
substances in maternal milk, such as β-glucuronidases, and nonesterified fatty acids, may inhibit normal bilirubin metabolism
When is the peak incidence of breast milk jaundice and when does it disappear??
• Jaundice peaks around the end of the second week • May overlap with physiological jaundice or be protracted for 1–2 months
How to confirm the diagnosis of late onset of breast milk jaundice
• Diagnosis is supported by a drop in serum bilirubin (≥50% in 1–3 days) if breastfeeding is interrupted for 48 hours
Is there any correlation between the enzyme level and bilirubin in individual with Gilbert syndrome ❓
🔅Correlation between hepatic enzyme activity and serum bilirubin levels is unpredictable because up to 40% of patients with Gilbert syndrome have a reduced red blood cell lifespan
What is the Clinical presentation of gilbert syndrom ❓
▪️ Higher incidence of neonatal jaundice and breast-milk jaundice
▪️ Usually presents after puberty with an incidental finding of elevated bilirubin on blood tests or jaundice after a period of fasting or intercurrent illness
▪️More common in males
What is the treatment for Gilbert syndrome ❓
.
No treatment required
1} Increased production of unconjugated bilirubin from haem
🧡Haemolytic disease (hereditary or acquired)
🔺Isoimmune haemolysis : • Rh incompatibility • ABO incompatibility
🔺 Red cells membrane abnormalities : Congenital spherocytosis • Hereditary elliptocytosis • Infantile pyknocytosis
🔺Erythrocyte enzyme defects: • Glucose-6-phosphate dehydrogenase deficiency • Pyruvate kinase deficiency
🔺Haemoglobinopathy: • Sickle cell anaemia • Thalassaemia • Others
🧡Polycythaemia: • Diabetic mother • Fetal transfusion (recipient) • Delayed cord clamping
🧡Sepsis
🧡 Microangiopathy:
• Haemolytic–uraemic syndrome • Haemangioma
🧡Ineffective erythropoiesis
🧡Drugs Infection
🧡Enclosed haematoma
2} Decreased delivery of unconjugated bilirubin (in plasma) to hepatocyte
🔺Right-sided congestive heart failure
🔺 Portacaval shunt
3} Decreased bilirubin uptake across hepatocyte membrane
🔺Presumed enzyme transporter deficiency
🔺 Competitive inhibition:
• Breast-milk jaundice
• Lucy–Driscoll syndrome
• Drug inhibition (radiocontrast material)
Miscellaneous:
• Hypothyroidism • Hypoxia • Acidosis
4} Decreased storage of unconjugated bilirubin in cytosol (decreased Y and Z proteins)
Competitive inhibition
Fever
5}Decreased biotransformation (conjugation)
Physiological jaundice
Inhibition (drugs)
Hereditary (Crigler–Najjar):
• Type I (complete enzyme deficiency) • Type II (partial deficiency) Gilbert disease
Hepatocellular dysfunction
6} Enterohepatic recirculation
🔺 Intestinal obstruction:
• Ileal atresia
• Hirschsprung disease
• Cystic fibrosis
• Pyloric stenosis
🔺Antibiotic administration
🔺Breast-milk jaundice
What are the definition of conjugated hyperbilirubinaemia ❓❓
•and what are the Top causes ❓❓
Biochemical definition is direct bilirubin >20% of total
®️Top causes :
• ‘Idiopathic’ neonatal hepatitis (40%)
• Extrahepatic biliary atresia (25–30%)
• Intrahepatic cholestasis syndromes (20%), e.g. Alagille syndrome, progressive familial intrahepatic cholestasis (PFIC)
• α1-Antitrypsin deficiency (7–10%)
What is Idiopathic neonatal hepatitis associated with and what are histological finding ❓❓
• Diagnosis of exclusion
• Associated with low birthweight or prematurity
📍📍 Histology
• Hepatocellular swelling (ballooning), focal hepatic necrosis and multinucleated giant cells
• Bile duct proliferation and bile duct plugging are usually absent
What is the incidence of Biliary atresia (BA) and what are the associations ❓❓
• Incidence: 1 per 16 000 live births • Slight female preponderance • Exact pathogenesis is unknown
• 25% associated with other congenital malformations
How biliary atresia is diagnosed ❓❓
• Hepatobiliary ultrasound (fasting) – will show absent gallbladder or irregular outline and triangular cord sign
• Radionuclide imaging (phenobarbital priming) – no excretion indicates possible biliary atresia; excretion indicates that it is not biliary atresia
• Liver biopsy – expanded portal tracts with bile duct proliferation, bile plugs and fibrosis
• Gold standard for diagnosis is exploratory and operative cholangiography
What is management of Biliary atresia ❓❓
Portoenterostomy (Kasai operation) should be offered to all children unless there is decompensated liver disease
• Fat-soluble vitamin supplementation is essential
• Role of choleretic agents such as phenobarbital and ursodeoxycholic acid and steroids is unproven
What is the mode of inheritance of Alagille syndrome (arteriohepatic dysplasia) ❓❓❓
• Autosomal dominant • Incidence is 1 per 100 000 live births • Defect of the JAG1 gene on chromosome 20p12
What are the Clinical features Alagille syndrome ❓❓
♀️Intrahepatic biliary hypoplasia
♀️ Characteristic facies (may not be prominent at birth): • Broad forehead • Deep-set eyes • Mild hypertelorism • Small chin
♀️ Skeletal abnormalities:
• Thoracic hemivertebrae/‘butterfly’ vertebrae
♀️ Eye findings:
• Posterior embryotoxon
• Retinal changes
♀️Cardiac disease:
• Peripheral pulmonary artery stenosis
• Other congenital cardiac malformations
♀️ Intrauterine growth retardation and faltering growth with severe malnutrition occur in 50%
♀️Others:
• Renal disease
• Delayed puberty or hypogonadism
• Learning disability, learning difficulties or psychosocial dysfunction
• Vascular abnormalities
• Hypothyroidism and pancreatic insufficiency
• Recurrent otitis media, chest infection • Hypercholesterolaemia
What are the Clinical features of Progressive familial intrahepatic cholestasis ❓❓
🔺neonatal hepatitis,
🔺faltering growth
🔺 pruritis
🔺progressive liver disease
What are the characteristics ot Type 1 progressive familial intrahepatic cholestasis (PFIC) ❓❓
• Byler disease
• Mutation of the FIC1 gene on chromosome 18q21-22
🔺Pancreatitis
🔺persistent diarrhoea
🔺short stature
🔺sensorineural hearing loss
What are the genetic causes of PFIC type 2 and 3 and what are the characteristics ?❓❓
Type 2.
• Mutations on chromosome 2q24, bile salt export pump (BSEP) gene • Normal GGT
Type 3
• Mutations in the P-glycoprotein MDR-3 gene (ABCB4)
• Elevated GGT
• Bile phospholipids 15% of normal
what are the Most common inherited cause of conjugated jaundice and what are the genetic causes and mode of inheritance ❓❓
🔅α1-Antitrypsin deficiency
• Autosomal recessive
• Mutation at the protease inhibitor (Pi) locus on chromosome 14
➡️The most common disease phenotype is PiZZ, homozygous for a point mutation in which glutamic acid is replaced by glycine at position 342.
This causes abnormal folding of the α1-antitrypsin molecule so that it becomes trapped in the endoplasmic reticulum, causing liver damage
What are the Clinical presentation of A2 antitrypsin deficiency ❓❓
➿Associated with intrauterine growth retardation
➿Hepatomegaly at presentation is common
➿Cholestasis may be severe enough to produce totally acholic stools
How to Diagnose is α1-Antitrypsin ❓❓
• Low α1-antitrypsin levels
• Phenotype (Pi) by isoelectric focusing
What is treatment of 1 antitrypsin deficiency and what is the prognosis ❓❓
🔺Replacement with recombinant α1-antitrypsin is not helpful because abnormal protein continues to accumulate in the endoplasmic reticulum
• Prognosis – 50% of children presenting with neonatal hepatitis develop chronic liver disease with half of them requiring a liver transplantation in the first 10 years of life.
What are the infectious Causes of conjugated jaundice❓❓
🔺🔺Bacterial
• Urinary tract infection
• Septicaemia
• Syphilis
• Listeriosis
• Tuberculosis
🔺🔺Parasitic
• Toxoplasmosis
• Malaria
🔺🔺 Viral
• Cytomegalovirus
• Herpes simplex virus
• Human herpesvirus type 6
• Herpes zoster virus
• Adenovirus • Parvovirus
• Enterovirus
• Reovirus type 3 •
Human immunodeficiency virus
• Hepatitis B virus • Hepatitis A
• Rotavirus
What are the Metabolic disorders that lead to conjugated hyperbilirubinaemia ❓❓❓
💲💲💲Carbohydrate metabolism
• Galactosaemia
• Fructosaemia
• Glycogen storage type 4
• Congenital disorders of glycosylation
💲💲💲Protein metabolism (amino acid)
• Tyrosinaemia
• Hypermethioninaemia
• Urea cycle defects (arginase deficiency)
💲💲💲 Lipid metabolism
• Niemann–Pick disease (type C)
• Wolman disease
• Cholesterol ester storage disease
💲💲💲Bile acid disorders
💲💲💲Fatty acid oxidation defects
💲💲💲 Disorders of oxidative phosphorylation
💲💲💲 Zellweger syndrome Other mitochondrial disorders
What are Endocrine disorders that leads to conjugated hyperbilirubinaemia ❓❓❓
Hypothyroidism
Hypopituitarism (with or without septo-optic dysplasia)
What are the Metals and toxins that can lead to conjugated hyperbilirubinaemia ❓❓
Inspissated bile syndrome
Biliary tree disorders
Biliary atresia Mucus plug Bile duct stenosis/stricture Spontaneous perforation of common bile duct Neonatal sclerosing cholangitis Caroli disease Compression of bile duct by a mass Inflammatory pseudotumour at porta hepatis
♂️Neonatal haemochromatosis
♂️Copper-related cholestasis
♂️ Parenteral nutrition
♂️Drugs
What are the Immunological disorders that causes conjugated hyperbilirubinaemia ❓❓
Neonatal lupus erythematosus
Giant cell hepatitis with Coombs test-positive haemolytic anaemia Graft-versus-host disease
Adenosine deaminase deficiency
What are the Vascular anomalies that leads to conjugated hyperbilirubinaemia ❓❓
Haemangoendothelioma
Congenital portacaval anomalies
Idiopathic
Familial
Non-familial (good prognosis)
Miscellaneous
• Hypoperfusion of liver • Dubin–Johnson syndrome
What are the causes of conjugated hyperbilirubinaemia ❓❓
1️⃣Infections
2️⃣Metabolic disorders
3️⃣Endocrine disorders
4️⃣Chromosomal disorders
5️⃣Metals and toxins
6️⃣ Haematological disorders
7️⃣ Inspissated bile syndrome
8️⃣Biliary tree disorders
9️⃣Immunological disorders
1️⃣0️⃣Vascular anomalies
1️⃣1️⃣ Miscellaneous
• Hypoperfusion of liver
• Dubin–Johnson syndrome
What are the Haematological disorders that cause congugated hyperbilirubinaemia ❓❓
Haemophagocytic lymphohistiocytosis
Langerhans cell histiocytosis
What are the Investigation for type 1 PFIC ❓
• Normal γ-glutamyltransferase (GGT), serum cholesterol
• Elevated serum bile salts, sweat chloride
• Low chenodeoxycholic acid in bile
What is clinical features of Acute infective hepatitis ❓
Prodromal symptoms
Tender hepatomegaly
• Splenomegaly
• Lymphadenopathy
• Rash
• Jaundice
What are the Causes of acute infective hepatitis ❓❓
🔺Viruses
- Hepatotropic viruses
Hepatitis A /Hepatitis B /Hepatitis C Hepatitis D Hepatitis E
-Non-hepatotropic viruses
Paramyxovirus (measles)
Togavirus (rubella)
Enterovirus > Echovirus / Cosackievirus
Flavivirus > Marbug virus /Ebola virus
Arenavirus (Lassa fever)
Parvovirus B19
Adenovirus
Herpesvirus > Her 1, 2- CMV - EBV - VZV- HV6
🔺Bacterium
Bartonella hensele/Quintana spp.
Brucella melitensis
Legionella pneumophila
Leptospira ictohaemorrhagica
Listeria monocytogenes
Mycobacterium tuberculosis
Salmonella typhi
🔺Protozoa
Toxoplasma gondii
🔺Helminths
-Cestodes (tapeworms)
Echinococcus multilocularis
Echinococcus granulosus
-Nematodes (roundworms)
Ascaris lumbricoides
Toxocara canis
Toxocara catis
-Trematodes (flukes)
Schistosoma mansoni
Schistosoma japonicum
Fasciola hepatica
What is the Incubation period for Hepatitis A virus ❓and how long is the Infectivity period ❓
➿Incubation period 2–6 weeks
➿ Infectivity from faecal shedding begins during the prodromal phase, peaks at the onset of symptoms and then rapidly declines. Shedding may persist for up to 3 months
What are Morbidity and mortality of HAV associated with:
• Fulminant hepatic failure
• Prolonged cholestasis
Confirmation of diagnosis relies on detection of: • Anti-HAV IgM – indicator of recent infection; peak levels occur during acute illness or early convalescent phase; persists for 4–6 months after infection • Anti-HAV IgG – appears early; peaks during convalescent phase; persists lifelong, conferring protection
• Supportive symptomatic treatment and adequate hydration. Complete recovery is usual within 3–6 months
• Active immunization with a formaldehyde-inactivated vaccine is available • Passive immunization with human normal immunoglobulin offers up to 6 months of protection and is effective if given within 2–3 weeks of exposure
Mechanism of drug-induced liver disease• Direct hepatotoxicity – usually dose dependent • Adverse drug reaction – unpredictable and idiosyncratic
Spectrum of drug-induced liver disease
• Enzyme induction without disease • Acute hepatitis/hepatocellular necrosis (most common) – paracetamol, methyldopa, isoniazid, halothane, phenytoin
• Cholestasis – erythromycin, co-trimoxazole • Granulomatous hepatitis – carbamazepine • Drug-induced chronic hepatitis – methyldopa, nitrofurantion • Fatty liver – microvesicular (aspirin, valproate, tetracycline) or macrovesicular (amiodarone) • Fibrosis – methotrexate, vitamin A, actinomycin D • Vascular disorders – sinusoidal dilatation (oestrogen) or veno-occlusive disease (6mercaptopurine)
• Hepatic tumours – oral contraceptives
Diagnosis of drug-induced liver disease is usually based on circumstantial evidence and exclusion of other causes. Withdrawal of the causative drug is the most effective treatment. Specific therapy is available for paracetamol (N-acetylcysteine).
ACUTE LIVER FAILURE
Acute liver failure or fulminant hepatitis is rare in childhood. The mortality rate is 70% without appropriate management or liver transplantation. It is the indication for liver transplantation in about 10–20% of paediatric recipients in major transplant centres. The 1-year survival rate is in the range 60–70%.
It is a multisystemic disorder, defined as: • Severe impairment of liver function (INR >2 and unresponsive to vitamin K) • ± encephalopathy (not essential to make diagnosis) • Associated hepatocellular necrosis • No previous underlying recognizable liver disease
The most common causes of acute liver failure are: • In the neonate: • Neonatal haemochromatosis • Disseminated herpes simplex infection • Haemophagocytic lymphohistiocytosis • Metabolic causes • In the older child:• Viral hepatitis • Metabolic causes • Paracetamol toxicity • Autoimmune hepatitis • Wilson disease • Idiopathic
What are the Clinical features of HAV ❓❓
• Usually asymptomatic; <5% of infected people have an identifiable illness • Symptomatic infection increases with age of acquisition
What is the type of HAV ❓
• Picornavirus family, RNA virus.
What is prevelance of HAV ❓❓
• The most common form of acute viral hepatitis, accounting for 20–25% of all clinically apparent hepatitis worldwide
• Fulminant hepatic failure
• Prolonged cholestasis
What ®️Extrahepatic complications of HAV ❓❓
🔺Neurological involvement – Guillain–Barré syndrome, transverse myelitis, postviral encephalitis, mononeuritis multiplex
🔺Renal disease – Acute interstitial nephritis, mesangioproliferative glomerulonephritis, nephrotic syndrome, acute renal failure
🔺Acute pancreatitis
🔺Haematological disorders – autoimmune haemolytic anaemia, red cell aplasia, thrombocytopenic purpura
Acute liver failure or fulminant hepatitis is rare in childhood. The mortality rate is 70% without appropriate management or liver transplantation.
multisystemic disorder, defined as: • Severe impairment of liver function (INR >2 and unresponsive to vitamin K) • ± encephalopathy (not essential to make diagnosis) • Associated hepatocellular necrosis • No previous underlying recognizable liver disease
the neonate: • Neonatal haemochromatosis • Disseminated herpes simplex infection • Haemophagocytic lymphohistiocytosis • Metabolic causes • In the older child:• Viral hepatitis • Metabolic causes • Paracetamol toxicity • Autoimmune hepatitis • Wilson disease • Idiopathic
Causes of neonatal acute liver failure
Perinatal herpes simplex virus infection Neonatal haemochromatosis Galactosaemia Tyrosinaemia Haemophagocytic lymphohistiocytosis Septicaemia Mitochondrial cytopathies Congenital disorders of glycosylation Severe birth asphyxia
Biochemistry of acute liver failure❓❓
• ↑ prothrombin time (does not improve with parenteral vitamin K)
• ↑ direct and indirect bilirubin
• ↑ aminotransferase activities (AST), then ↓ as patient deteriorates • ↑ serum ammonia
What are the Clinical stages of hebatic Encephalopathy❓❓:
💙 May be absent or difficult to recognize in children
• Stage 1 – mild confusion/anxiety, disturbed or reversal of sleep rhythm, shortened attention span, slowing of ability to perform mental tasks (simple addition or subtraction). In young children, irritability, altered sleep pattern, unexplained bursts of excessive crying
• Stage 2 – drowsiness, confusion, mood swings with personality changes, inappropriate behaviour, intermittent disorientation of time and place, gross deficit in ability to perform mental tasks. In young children, excessive sleepiness, inability to interact with or recognize parents, lack of interest in favourite toys or activities
• Stage 3 – pronounced confusion, delirious but arousable, persistent disorientation of time and place, hyperreflexia with a positive Babinski sign
• Stage 4 – comatose with or without decerebrate or decorticate posturing, response to pain present (stage 4a) or no response to pain (stage 4b)
Renal insufficiency/failure as association with acute liver failure ❓❓:
• 10–15% have renal failure, 75% have renal insufficiency as a result of hepatorenal syndrome, direct kidney toxicity or acute tubular necrosis
• 50% require haemodialysis or haemofiltration support
Cardiovascular complications of fulminant hepatic failure ❓❓:
• Early hyperdynamic circulation with decreased peripheral vascular resistance
• Late haemodynamic circulatory failure as a result of falling cardiac output, depression of brainstem function or cardiac arrhythmias
What are Pulmonary complications of liver disease :
• Aspiration, intrapulmonary shunting, atelectasis, infection, intrapulmonary haemorrhage, respiratory depression or pulmonary oedema
Coagulopathy:
• Vitamin K deficiency:
• ↓ synthesis of clotting factors
• ↑ fibrinolysis and ↓ clearance of activated factors and fibrin degradation products
• Thrombocytopenia (correlates with risk of haemorrhage)
Why Infections are common in liver disease ❓❓:
• Poor host defences, poor respiratory effort, multiple invasive lines and tubes
What other complication of severe liver disease ❓❓
🔹 Adrenal hyporesponsiveness
🔹pancreatitis
🔹aplastic anaemia
What are the steps of Management of acute liver failure❓❓
💙 involves management of complications, and elucidation and treatment of the cause:
♀️Discuss/refer to a liver centre
♀️No sedation unless patient is on assisted ventilation
♀️Ventilate for respiratory failure, agitation with grade I or II encephalopathy or severe encephalopathy (grade III or IV)
• No coagulation support unless bleeding or for invasive procedures ♀️Monitoring should involve:
• Continuous oxygen saturation monitoring
• At least 6-hourly – neurological observations/vital signs (may need invasive monitoring)/urine output/blood glucose (maintain >4 mmol/l)
• At least 12-hourly – acid–base/electrolytes/prothrombin time (PT)/partial thromboplastin time
(PTT), INR (international normalized ratio)
• Gastric pH (>5)
• Daily or more often – haemoglobin and platelet count
♀️Fluid balance:
• 75% maintenance with 0.45% (or less) saline with dextrose
• Maintain circulating volume with colloid, crystalloids or blood products as appropriate
♀️• Haemofiltration if there is renal failure
♀️ Coagulation:
• Fresh frozen plasma when bleeding
• Keep platelet count >50 × 109/dl
♀️ Drugs:
• H2-receptor blockers or proton pump inhibitors (prevent gastrointestinal bleed)
• Lactulose to achieve two or three stools per day
• N-Acetylcysteine as experimental for non-paracetamol-induced acute liver failure
• Intravenous broad-spectrum antibiotics and antifungals as prophylaxis
♀️Nutrition:
• Enteral feeding (1–2 g protein/kg per day)
• Parenteral nutrition is rarely indicated
What are Specific therapies for selected conditions
• Paracetamol toxicity – N-acetylcysteine (100 mg/kg per day)
• Hereditary tyrosinaemia – NTBC
• Neonatal haemochromatosis – iron chelation and antioxidant cocktail/N-acetylcysteine (100 mg/kg per day intravenous infusion)/selenium (3 g/kg per day intravenous)/desferrioxamine (30 mg/kg per day intravenous)/prostaglandin E1 (0.4–0.6 g/kg per hour intravenous)/vitamin E (25 U/kg per day intravenous/oral)
• Mushroom poisoning – benzylpenicillin (1 000 000 U/kg per day) or thiotic acid (300 mg/kg per day)
• Hepatic support with liver assist devices such as molecular adsorbent recirculating system (MARS) is still under investigation
• Emergency liver transplantation
With overdosage, gluthathione is depleted and NAPQI (N-acetyl-p-benzoquinone imine) is not detoxified
Acute ingestion of 150 mg/kg is likely to cause significant hepatotoxicity
Triphasic clinical course: • Stage 1 (0–24 h) – nausea, vomiting, anorexia • Stage 2 (24–48 h) – liver enlarged and tender from hepatic necrosis • Stage 3 (48–96 h) – acute liver failure • If patient survives stage 3, resolution of liver dysfunction within 4 days to 2 weeks
Prognosis is bad if: • Arterial pH <7.3 • PTT >100 s or INR >6.6, creatinine >300 μmol/l, grade III–IV encephalopathy (all three)
• Management:• Discuss with a liver centre • N-Acetylcysteine infusion 100 mg/kg per day until INR <1.5
What are the mode of inheritance and the genetic cause of Wilson disease❓❓
🔺An autosomal recessive disease with incidence of 1 in 50 000; 🔺caused by a mutation of the ATP7B gene at 13q14.3 (most common H1069Q).
What are the Clinical presentation of the Wilson disease ❓❓
🔺Asymptomatic: family screening
🔺Hepatic (5–12 years):
• Insidious onset with vague symptoms followed by jaundice
• Abnormal liver function tests
• Acute hepatic failure
• Acute hepatitis
• Chronic liver disease
• Cirrhosis and portal hypertension
🔺 Neurological (second decade):
• Deteriorating school/work performance
• Mood/behaviour changes
• Incoordination (e.g. deterioration of handwriting)
• Resting and intention tremors
• Dysarthria, excessive salivation
• Dysphagia
• Mask-like facies
• Others: • Sunflower cataracts • Acute haemolytic anaemia • Renal, cardiac, skeletal abnormalities
How can we diagnose Wilson disease ❓❓❓
• ↓ total serum copper
• ↓ plasma ceruloplasmin (<200 mg/l)
• ↑ urinary copper (>5 μmol/24 h [baseline], >25 μmol/24 h [after penicillamine challenge])
• Liver copper concentration (>250 μg/g dry weight of liver)
• Mutation analysis
• Kayser–Fleischer rings
Treatment
• Penicillamine 20 mg/kg per day (gradually increased from 5 mg/kg per day) • Pyridoxine 10 mg/week • Other drugs include: triethylene tetramine dihydrochloride (trientine), zinc sulphate/acetate, tetrathiomolybdate
• Liver transplantation: • fulminant hepatic failure • chronic, progression of hepatic dysfunction despite treatment
What is the pathophysiology of Chronic liver diseases of childhood❓❓
🔹lead to cirrhosis and/or cholestasis.
🔹 The resulting fibrosis and regenerative nodular formation distort the liver architecture and compress hepatic vascular and biliary structures, resulting in portal hypertension and a vicious cycle of events that worsen the hepatic injury.
What are the type of liver disease ❓❓
• Compensated – may be asymptomatic
• Decompensated – presence of liver synthetic failure and occurrence of complications
• End-stage –
🔺a persistent rise in bilirubin,
🔺prolongation of the INR >1.3,
🔺persistent fall in serum albumin to <35 g/l,
🔺faltering growth despite intensive nutritional support,
🔺severe hepatic complications such as chronic hepatic encephalopathy, refractory ascites, intractable pruritus or recurrent variceal bleeding despite appropriate medical management
What are the management of Malnutrition and growth failure associated with chronic liver disease ❓❓
• Specialized formula (↓ Na+, ↑ MCT [medium-chain triglyceride]) • Supplement vitamins A, D, K and E
• ↑ caloric density of enteral feeds
• Continuous nocturnal nasogastric or nasojejunal feeds
• Parenteral nutritional support
What is definition of Portal hypertension and what it is contribution to mortality and morbidity of chronic liver disease ❓❓
• Major cause of morbidity and mortality (30–50%)
• Portal vein pressure >5 mmHg or portal vein to hepatic vein gradient >10 mmHg
Ascites
• 50% of patients will die within 2 years of developing ascites • Treatment: • Step 1 – sodium restriction (1–2 mmol/kg per day) • Step 2 – spironolactone • Step 3 – ± chlorthiazide/furosemide and fluid restriction
• Spontaneous bacterial peritonitis can occur insidiously and causes high mortality
What are the complication of portal hypertension ❓❓
• Splenomegaly → hypersplenism
• Oesophageal, gastric and rectal varices
• Ascites
• Encephalopathy
Coagulopathy
• Vitamin K malabsorption/deficiency • Vitamin K-dependent coagulation protein deficiencies (factors II, VII, IX and X) • Hypofibrinogenaemia and dysfibrinogenaemia • Thrombocytopenia • Consumption coagulopathy• Parenteral vitamin K and transfusion of fresh frozen plasma (prothrombin time >40 s) or platelets (<40 × 109/l)
What are the Factors that predict bleeding in portal hypertension varesis ❓❓
• Portal vein–hepatic vein gradient >12 mmHg
• Large, tense varices
• Red weal marks, red spots on varices
• Severity of underlying liver disease
Hepatopulmonary syndrome
• Triad of:
• Liver dysfunction
• Intrapulmonary arteriovenous shunts
• Arterial hypoxaemia – arterial oxygen pressure <9.3 kPa (70 mmHg) in room air and an alveolar/arterial gradient of >20 mmHg (2.7 kPa)
When Should hepatopulmonary syndrome be suspected ❓
increasing history of breathlessness, cyanosis, clubbing and platypnoea
Platypnoea and orthodeoxia occur because
the intrapulmonary arteriovenous shunts occur predominantly in the bases of the lung. Therefore, when sitting up or standing, blood pools at the bases of the lung with resultant increased arteriovenous shunting
Site and extent of shunt is assessed by:
• Arterial blood gas analysis • Technetium-99m-labelled macroaggregated albumin ([99mTc]MAA) study • Contrast echocardiogram
Portopulmonary hypertension
• Mean pulmonary artery pressure >25 mmHg, pulmonary capillary wedge pressure <15 mmHg in the absence of any secondary causes of pulmonary hypertension
Comparison of hepatopulmonary syndrome and portopulmonary hypertension
💛Hepatopulmonary syndrome
Intrapulmonary vasodilatation
Alveolar arterial gradient >2.7 kPa (20 mmHg)
Normal mean pulmonary artery pressure
Perform shunt fraction study Trial of 100% O2
Often reversible with liver transplantation
Poor prognosis: PaO2 <9.3 kPa (300 mmHg) on 100%O2
Histology: pulmonary artery normal
💛Portopulmonary hypertension
Intrapulmonary vasoconstriction
Alveolar arterial gradient usually normal
Mean pulmonary artery pressure >25 mmHg
Perform right heart catheterization
Vasodilator therapy trial
May not reverse with liver transplant
Poor prognosis: pulmonary artery pressure >45 mmHg
Histology: pulmonary artery abnormal; concentric medial hypertrophy
Hepatorenal syndrome
• Diagnostic criteria: • Oliguria: urine output <1 ml/kg per day • Factorial excretion sodium <1% • Urine:plasma creatinine ratio <10 • ↓ glomerular filtration rate, ↑ creatinine • Absence of hypovolaemia • Other kidney pathology excluded
• Type 1 rapidly progressive with poor prognosis • Type 2 less precipitous loss of renal function
Causes of chronic liver disease in children Onset in infancy
Structural
• Extrahepatic biliary atresia
• Alagille syndrome, biliary hypoplasia
• Choledochal cyst, tumours, stones
Storage/metabolic diseases
• Carbohydrate defects: galactosaemia, fructosaemia, glycogen storage III and IV
• Amino acid defects: tyrosinaemia, urea cycle disorders
• Metal storage defects
• Lipid storage diseases: Gaucher disease, Niemann–Pick type C
• Fatty acid oxidation defects
• Peroxisomal disorders
• Zellweger syndrome
• Mitochondrial disorders
• Progressive familiar intrahepatic cholestasis syndrome
• Total parenteral nutrition-associated cholestasis
• Cystic fibrosis liver disease
Haematological: Langerhans cell histiocytosis
Infection/inflammation
• Neonatal hepatitis
• Hepatitis B and hepatitis C
Onset in childhoodAll of the above and:
Autoimmune liver disease • Autoimmune hepatitis • Autoimmune sclerosing cholangitis
Sclerosing cholangitis Drugs/toxins (e.g. chemotherapy-induced veno-occlusive disease) Fibropolycystic disorders
Chronic hepatic venous outflow obstruction: • Hepatic vein thrombosis • Budd–Chiari syndrome • Veno-occlusive disease • Cardiac cirrhosis
Autoimmune hepatitis has a 75% female preponderance. Other autoimmune disorders are present in 20% and 40% of first-degree relatives may also have autoimmune disease.
Clinical presentation is variable:
• Acute hepatitis • Insidious onset • Portal hypertension
Diagnostic criteria are based on:
• Serum non-organ-specific autoantibodies • Type 1: • Anti-nuclear antibody (ANA) • Anti-smooth muscle antibody (SMA)
• Type 2: • Anti-liver–kidney microsomal (LKM-1) • Up to 20% may not have antibodies detectable at presentation
• Serum biochemistry: • ↑ aminotransferases
• Serum IgG: • >1.5 × normal• Liver histology • Absence of: • Markers of viral infection and metabolic disease • Excessive alcohol consumption • Use of hepatotoxic drugs
Treatment of Autoimmune hepatitis involves:
• Corticosteroids • Azathioprine for poor response or as steroid sparing • Liver transplantation for fulminant hepatic failure or failure of medical therapy
Response to therapy (International Autoimmune Hepatitis Group) is defined as follows:
• Marked improvement of symptoms and return of serum aspartate/alanine aminotransferase (AST/ALT), bilirubin and immunoglobulin levels to completely normal within 1 year and sustained for at least a further 6 months on maintenance therapy, ±
• Liver biopsy specimen during this period showing minimal activity,
or
• Marked improvement of symptoms together with at least 50% improvement of all liver test results during the first month of treatment, with AST/ALT levels continuing to fall to less than twice the upper limit of normal within 6 months during any reduction towards maintenance therapy, ±
• Liver biopsy within 1 year showing minimal activity
What is the prognosis of Autoimmune hepatitis ❓
Hepatitis B (a DNA hepadnavirus)
Relapses are common (occurring in 40%). IgG levels and autoantibody titres correlate with disease activity
What is the prevelance of HBV and what is modes of transmission ❓❓
Worldwide prevalence of 5% (chronic carriers)
• Transmission:
• Perinatal – hepatitis B ‘e’ antigen (HBeAg)-positive mothers have a 70–90% risk of transmission to their offspring • Horizontal
What is the Clinical presentation of HBV
Symptomatic acute hepatitis: • Complete resolution occurs in 90% • Lifelong immunity
• Asymptomatic chronic infection (hepatitis B surface antigen [HBsAg] positive for at least 6 months): • 90% progress to chronic liver disease
Three stages –
immune tolerance, immune clearance and residual non-replicative infection
Treatment
• Immunomodulation – interferon-α, pegylated interferon
• Antivirals – lamivudine, famciclovir, adefovir
• Not much paediatric experience
• 50% of patients seroconvert with therapy (adult data)
• Liver transplantation
Hepatitis C infection
(an RNA flavivirus)
Prevelance of HCV ❓❓
Worldwide prevalence is 3%
What is clinical presentation of HCV
Usually asymptomatic but leads to cirrhosis over years
Serology:
• Anti-HCV antibody positive • HCV RNA positive in two consecutive samples
Treatment:
• Interferon-α monotherapy • Interferon-α/ribavirin combination therapy • Paediatric experience is minimal • 70% of patients seroconvert with therapy (adult data)
Non alcoholic chronic liver disease ❓
Most common cause of paediatric liver disease; prevalence ranges from at least 3% in children overall to about 50% in obese childre
What are the association of NACLD
Associated with obesity although it can occur in non-obese children
Spectrum of disease from
simple steatosis to non-alcoholic steatohepatitis (NASH) to advanced fibrosis and cirrhosis
What is the presentation of NAFLD ❓
Asymptomatic or may present with abdominal pain, hepatomegaly and acanthosis nigricans. An elevated ALT with an enlarged echogenic liver on ultrasonography, in the setting of being overweight or obese and/or evidence of insulin resistance, is highly suggestive, but is not conclusive, for NAFLD
What is the definitive diagnostic investigation and what are the histopathological types ❓❓
Liver biopsy is the ultimate standard for the diagnosis and semiquantitative analysis of injury in NASH
• Type 1 NASH (adult pattern) – steatosis with ballooning degeneration and/or perisinusoidal fibrosis in the absence of portal features
• Type 2 NASH – steatosis along with portal inflammation and/or fibrosis in the absence of ballooning degeneration and perisinusoidal fibrosis. Central vein is consistently spared, portal inflammation was predominantly lymphocytic. Type 2 NASH is more common and associated with younger age and obesity
No proven drug therapy. Management consists of (1) diagnosis and treatment of related metabolic disturbances such as diabetes and hyperlipidaemia, (2) targeting IR by weight loss (healthy lifestyle: diet and exercise) or pharmacotherapy and (3) control of the secondary processes promoting to oxidative stress, inflammation, apoptosis and hepatic fibrosis by using hepatoprotective agents such as antioxidants
Indications for transplantation
• Acute liver failure
• Decompensated chronic liver disease
• Liver-based metabolic diseases
• Liver tumours
Relative contraindications
• Severe systemic sepsis
• Malignant hepatic tumours with extrahepatic involvement
• Severe, irreversible extrahepatic disease (e.g. structural brain damage, severe cardiopulmonarydisease not correctable with surgery)
• Severe systemic oxalosis with cardiac involvement (haemodynamic instability)
• Mitochondrial cytopathies with multisystem involvement
• Giant cell hepatitis with Coombs test-positive haemolytic syndrome
Type of graft
Procedure
Whole liver
Segmental graft
• Orthotopic
• Auxiliary
Lifelong immunosuppression is required with
Calcineurin inhibitors:
• Ciclosporin
• Tacrolimus
Renal sparing drugs: • Mammalian target of rapamycin (mTOR) inhibitor • Sirolimus (mTOR inhibitor) • Mycophenolate mofetil • Azathiaprine • Interleukin-2 receptor antibodies – basiliximab, daclizumab • Others – anti-thymocyte globulin, OKT3
Steroids
What is the usual site of variceal bleeding ❓❓
The junction between the mucosal and submucosal varices in the lower 2–5 cm of the oesophagus
Causes of portal hypertension Prehepatic (portal vein occlusion) General factors
▪️Developmental malformation
▪️Septicaemia
▪️Thrombophilia
• Myeloproliferative disorders
• Paroxysmal nocturnal haemoglobinuria
• Protein C deficiency
• Protein S deficiency
• Antithrombin III deficiency
• Factor V Lieden mutation
• Anti-phospholipid antibodies
• Factor II gene mutation (G20210A)
• Homocysteinaemia
Local factors
• Umbilical sepsis, catheterization, infusion of irritant solutions
• Intra-abdominal sepsis and portal pyaemia
• Abdominal trauma
• Structural lesions
• Cholangitis/choledochal cyst • Pancreatitis • Malignant disease/lymphadenopathy • Splenectomy
Intrahepatic Presinusoidal
• Hepatoportal sclerosis • Neoplasia • Hepatic cyst
Sinusoidal • Chronic liver disease and congenital hepatic fibrosisPostsinusoidal • Veno-occlusive disease
Posthepatic portal hypertension ❓❓
• Budd–Chiari syndrome
• Chronic constrictive pericarditis
• Right ventricular failure
How are the Prevention and management of oesophageal variceal bleeding❓❓
• Sclerotherapy
• Variceal ligation
• Surgical portosystemic shunts
• Transjugular intrahepatic portosystemic shunt (TIPS)
• Oesophageal transection and devascularization
• Pharmacotherapy, e.g. propranolol
Postoperative complications
• Early: • Graft failure (primary non-function) • Surgical (intra-abdominal haemorrhage, hepatic artery thrombosis, portal vein thrombosis • Drug side effects (renal failure, hyperglycaemia, hypertension)
• After first week: • Acute rejection • Biliary leaks and strictures • Persistent wound drainage• Sepsis • Late: • Epstein–Barr virus infection • Side effects of immunosuppression (renal failure, hyperglycaemia, hyperlipidaemia) • Post-transplantation lymphoproliferative disease • Graft rejection • Late biliary strictures, hepatic artery thrombosis or portal vein thrombosis • Recurrent disease (HBV infection, malignant hepatic tumours) • New autoimmune hepatitis
Bilirubin
• Conjugated (direct) hyperbilirubinaemia: • Specific to liver disease • Conjugated fraction >20% of total bilirubin is indicative of hepatic dysfunction
AST is produced in the cytosol and mitochondria of the liver, heart, skeletal muscle, kidney, pancreas and red cells
• ALT is found in the cytosol of liver and muscle cells and so is more liver specific
In isolated AST or ALT elevations, a normal creatine kinase level is helpful in ruling out muscle pathologies
• ALT:AST ratio >1 is suggestive of fibrosis in some liver pathologies such as steatohepatitis and chronic hepatitis C
• There is no correlation between the enzyme levels and the severity of disease
Chylothorax
• Effusion of lymph into the pleural space as a result of either: • Underlying congenital abnormality of the pulmonary lymphatics • Iatrogenic abnormality after cardiothoracic surgery
Conjugated (direct) hyperbilirubinaemia what it indicates❓❓
Specific to liver disease
Conjugated fraction >20% of total bilirubin is indicative of hepatic dysfunction
Where are ALT and AST produced ❓❓
- AST is produced in the cytosol and mitochondria of the liver, heart, skeletal muscle, kidney, pancreas and red cells
- ALT is found in the cytosol of liver and muscle cells and so is more liver specific
How to exclude muscle disease is a cause of elevated AST AND ALT and is the level correlate with disease severity ❓❓
In isolated AST or ALT elevations, a normal creatine kinase level is helpful in ruling out muscle pathologies
• ALT:AST ratio >1 is suggestive of fibrosis in some liver pathologies such as steatohepatitis and chronic hepatitis C
• There is no correlation between the enzyme levels and the severity of disease
Where ALP cab be found ❓❓
Found in liver, kidney, bone, placenta and intestine
• Reflects biliary epithelial damage
Where QGGT FOUND
brainPresent in biliary epithelia, hepatocytes, renal tubules, pancreas, , breast and small intestine
GGT
Normal levels in newborns are five to eight times higher than those of adults but reach adult values by 9 months
Ggt
Most sensitive test for hepatobiliary disease but cannot differentiate between extra- and intrahepatic biliary disease
GgtMay be normal in
familial intrahepatic cholestasis, bile acid synthesis disorders, ARC (arthrogryposis, renal and cholestasis) syndrome and very advanced liver disease
Albumin concentration
• Long half-life (15–20 days), so it is not decreased in acute liver injury • Levels <35 g/dl in chronic liver disease suggest decompensation
Prothrombin time (PT)
• Prolongation of PT >3 s above normal or INR >1.3 may indicate vitamin K deficiency • Failure of INR to normalize after a parenteral dose of vitamin K (1 mg/year of age up to a maximum of 5 mg) suggests liver failure
Cirrhosis (early)
biliary atresia, sclerosing cholangitis, congenital hepatic fibrosis
Haematological Infection
Immune Metabolic Proliferative thalassaemia, spherocytosis, sickle cell anaemia infectious mononucleosis, TORCH, malaria, septicaemia
juvenile rheumatoid arthritis, systemic lupus erythematosus, immunodeficiency states
α1-antitrypsin deficiency, tyrosinaemia, cystic fibrosis leukaemia, lymphoma, Langerhans cell histiocytosis
Storage diseases Gaucher (long term), Niemann–Pick, mucopolysaccharidoses
What are causes of hepatomegaly ❓❓– SHIRTS –
💛structural
Extrahepatic biliary atresia, choledochal cyst, intrahepatic biliary hypoplasia, polycystic disease, congenital hepatic fibrosis
💛Storage/metabolic
Defective lipid metabolism – Gaucher disease, Niemann–Pick disease, hyperlipoproteinaemias,
cholesteryl ester storage disease, carnitine deficiency, mucolipidoses
Defective carbohydrate metabolism – diabetes mellitus, glycosyltransferase deficiency (types 1, 3,
4 and 6), hereditary fructose intolerance, galactosaemia, Cushing syndrome,
mucopolysaccharidoses
Defective amino acid/protein metabolism – tyrosinaemia (type 1), urea cycle enzyme disorders
Defective mineral metabolism – Wilson disease, juvenile haemochromatosis
Defective electrolyte transport – cystic fibrosis
Defective nutrition – protein calorie malnutrition, total parenteral nutrition
Deficiency of protease – α1-antitrypsin deficiency
Defective bile flow – progressive familial intrahepatic cholestasis syndrome
💛H – haematological
Hemoglobinopathies - leukaemias
💛Heart/vascular
Congestive cardiac failure, constrictive pericarditis, obstructed inferior vena cava, Budd–Chiari syndrome
💛I – infection
Viral infection – congenital rubella, cytomegalovirus (CMV) infection, Coxsackievirus, echovirus,
hepatitis A, B, C, D and E viruses, infectious mononucleosis
Bacterial infections – neonatal septicaemia, Escherichia coli urinary tract infection, tuberculosis, syphilis
Parasitic infections – hydatid disease, malaria, schistosomiasis, toxoplasmosis, visceral larva migrans
Fungal infection – coccidioidomycosis
💛Inflammatory
Autoimmune liver disease
Inflammatory bowel disease associated liver disease
💛R – reticuloendothelial Non-Hodgkin lymphoma, Hodgkin disease, Langerhans cell histiocytosis
💛Rheumatological Systemic juvenile chronic arthritis, systemic lupus erythematosus
💛T – tumour/hamartoma
Primary hepatic neoplasms – hepatoblastomas, hepatocellular carcinoma (hepatoma) Secondary deposits – neuroblastoma, Wilms tumour, gonadal tumours
💛 Vascular malformation/benign neoplasm – infantile haemangioendothelioma, cavernous haemangioma
💛Trauma Hepatic haematoma
Diagnosis by antenatal ultrasound scan allows antenatal drainage by insertion of intercostal drains, which may reduce the risk of pulmonary hypoplasia and facilitate resuscitation after birth
• Ventilatory support may be required postnatally, along with intermittent intercostal drainage • Volume of chyle can be reduced by using a medium-chain triglyceride milk formula or avoidingenteral feeds for up to several weeks as the underlying abnormality resolves with time; protein and lymphocyte depletion may complicate this
• Surgical treatment is needed for the small number of cases that do not resolve spontaneously
Acute pancreatitis
• Defined clinically as the sudden onset of abdominal pain associated with a rise in amylase or lipase of at least three times the upper limit in the blood or urine
• Rare in children
Presents with epigastric or back pain. May have prominent nausea and vomiting. Less commonly there may be fever, tachycardia, hypotension, jaundice, and abdominal signs such as guarding, rebound tenderness and a decrease in bowel sounds
The most common cause of familial pancreatitis: • Mutations in cationic trypsinogen gene (e.g. PRSS1) enhance trypsin activation • Mutations in the SPINK1 (serine protease inhibitor Kazal type 1) gene result in an abnormal
pancreatic secretory trypsin inhibitor • Mutations of the CFTR (cystic fibrosis transmembrane conductance regulator) gene, which reduces the pancreatic fluid secretion capacity, increase the risk of keeping activated trypsin in the pancreas for a longer period of time
Acute pancreatitis scoring system for children that predicts severity of disease and mortalityinclude the following parameters: • Age (<7 years) • Weight (<23 kg) • Admission white blood cell count (>18.5 × 109/l) • Admission lactate dehydrogenase (>2000 IU/l) • 48-hour trough Ca2+ (<8.3 mg/dl) • 48-h trough albumin (<2.6 g/dl) • 48-hour fluid sequestration (>75 ml/kg per 48 h) • 48-hour rise in urea (>5 mg/dl) • Each criterion is assigned a value of 1 point, cumulative score predicts the outcome of patients • 0–2 points – 8.6% severe, 1.4% death • 2–4 points – 38.5% severe, 5.8% death • 5–7 points – 80% severe, 10% death
The mainstay of current treatment is analgesia, intravenous fluids, pancreatic rest and monitoring for complications
Surgical management is limited to debridement of infected necrotic pancreas or cholecystectomy or endoscopic sphincterotomy in the presence of gallstones
enteral nutrition significantly reduced mortality, multiple organ failure, systemic infections and the need for operative interventions compared with total parenteral nutrition
Antibiotics are usually not necessary unless in severe pancreatic necrosis • Octreotide infusions may reduce pancreatic secretions in those with pancreatic fluid sequestration
Causes of acute pancreatitis
• Idiopathic • Pancreatitis associated with systemic illness • Trauma • Structural abnormalities of pancreas, pancreatic or common bile duct • Medications (valproate, L-asparaginase, prednisolone, azathioprine, 6-mercaptopurine, furosemide, phenytoin)
• Infections (mainly viral, e.g. mumps, enterovirus, Epstein–Barr virus, hepatitis A, CMV, rubella, Cosackievirus, rubeola, measles, influenza)
• Gallstones • Familial (PRSS1, SPINK1 or CFTR mutation) • Post-endoscopic retrograde cholangiopancreatography • Metabolic: • Diabetic ketoacidosis • Hypercalcaemia • Hypertriglyceridaemia
• Cystic fibrosis
Local
SystemicOedema Shock
Inflammation Fat necrosis
Phlegmon
Pancreatic necrosis Sterile
Infected Abscess Haemorrhage
Fluid collections Pseudocysts
Duct rupture and strictures Extension to nearby organs
Pulmonary oedema Pleural effusions
Acute renal failure, coagulopathy Haemoconcentration
Bacteraemia, sepsis Distant fat necrosis
Vascular leak syndrome Multiorgan system failure Hypermetabolic state Hypocalcaemia Hyperglycaemia
The mainstay of current treatment is analgesia, intravenous fluids, pancreatic rest and monitoring for complicationsSurgical management is limited to debridement of infected necrotic pancreas or cholecystectomy or endoscopic sphincterotomy in the presence of gallstonesAntibiotics are usually not necessary unless in severe pancreatic necrosis • Octreotide infusions may reduce pancreatic secretions in those with pancreatic fluid sequestration
Chronic pancreatitis
• Defined as a complex process beginning with acute pancreatitis and progressing to end-stage fibrosis as the result of recurrent and chronic inflammatory processes
Cystic fibrosis is the most important cause of chronic pancreatitis in children. CFTR mutationassociated pancreatitis can be divided into four mechanistic subtypes, where CFTRsev is the severe CFTR mutation phenotype and CFTRm-v is the mild or variable CFTR mutation
Faecal elastase <100 μg/g is suggestive of severe exocrine pancreas insufficiency • Invasive pancreatic stimulation tests are the standard for assessment of pancreatic insufficiency but are not usually indicated
• Chronic pancreatitis with calcifications can be identified on abdominal radiography or by transabdominal ultrasonography. When present, the diagnosis of chronic pancreatitis can be made with 90% confidence
Genetic testing for PRSS1, SPINK1, CFTR and other mutations can be performed if there is history of recurrent acute pancreatitis, unexplained chronic pancreatitis or presence of a positive family history of hereditary pancreatitis
What is the prognosis of Idiopathic neonatal hepatitis and what are Factors predicting poor prognosis ❓❓
• Severe jaundice beyond 6 months
• Acholic stools
• Familial occurrence
• Persistent hepatosplenomegaly
*** 90% do well with no long-term liver disease
What are the anotomical variation of Biliary atresia ❓❓
• Anatomical variants:
• Type I – obliteration of the common bile duct
• Type II – obliteration is extended to the common hepatic duct
• Type III – obliteration of the entire extrahepatic biliary tree (most common form)
What are the prognosis of Biliary atresia of kasai operation ❓❓
• Between 70 and 80% achieve partial bile flow with 50% becoming jaundice free after surgery
• Ascending bacterial cholangitis follows the first year of surgery in 45–50%
• It is a progressive disease even with a successful Kasai operation, although prognosis may be better if procedure is performed within 8 weeks of birth
• Majority (80%) require liver transplantation by 20 years of age
What is the function of vitamin K ❓❓
vitamin K functions as a cofactor for γ carboxylation of glutamic acid, which allows the calcium binding that is required for the activation of factors II, VII, IX, X and proteins C, S and Z of the coagulation cascade
What is management of Neonatal haemochromatosis❓❓
✔️iron chelation and
✔️antioxidant cocktail/
N-acetylcysteine (100 mg/kg per day intravenous infusion)/
selenium (3 g/kg per day intravenous)/
desferrioxamine (30 mg/kg per day intravenous)/
prostaglandin E1 (0.4–0.6 g/kg per hour intravenous)/
vitamin E (25 U/kg per day intravenous/oral)
What are the Chromosomal disorders and genetic defects that leads to conjugated hyperbilirubinaemia ❓❓
Down syndrome
Trisomy E
Patau syndrome
Leprechaunism
Other genetic–metabolic defects
✔️α1-Antitrypsin deficiency
✔️Cystic fibrosis
✔️Familial cholestasis syndromes
• Alagille syndrome
• Byler syndrome (PFIC-1)
• Bile salt export protein defect (BSEP defect, PFIC-2)
• Multidrug-resistant 3 deficiency (MDR-3, PFIC-3)
• Hereditary cholestasis with lymphoedema (Aagenaes syndrome)
In long-standing disease, varices around the common bile duct may cause portal hypertensive biliopathy resulting in bile duct dilatation and obstructive jaundice
Extrahepatic portal hypertension: • variceal banding or sclerotherapy• portacaval or mesoportal shunt
