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TAS Hepatology > Neonatal Liver Disease ✅ > Flashcards

Neonatal Liver Disease ✅ Flashcards

1
Q

What proportion of term babies have transient jaundice 3-5 days after birth?

A

Around 2/3

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2
Q

What is often the underlying mechanism of unconjugated jaundice in neonates?

A

Immaturity of the hepatic enzyme glucuronosyltransferase

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3
Q

What is the enzyme glucuronosyltransferase responsible for?

A

Glucuronidation of bilirubin

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4
Q

What can cause unconjugated jaundice in the neonatal period?

A
  • Breastmilk jaundice
  • Haemolysis
  • Sepsis
  • Hypothyroidism
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5
Q

What is often the underlying mechanism in conjugated jaundice in neonates?

A

Hepatic dysfunction due to a number of potential causes

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6
Q

What should be measured in babies with significant jaundice?

A

Bilirubin level with fractional breakdown of the conjugated and unconjugated components

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7
Q

What are Crigler-Najjar types I and II?

A

Rare autosomal recessive disorders which cause intensive unconjugated hyperbilirubinaemia in the first days of life, which persists after

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8
Q

What is the underlying problem in Crigler-Najjar syndrome type I?

A

No UDP-glucuronosyltransferase

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9
Q

What is the problem with hyperbilirubinaemia in Crigler-Najjar syndrome type I?

A

It is very severe despite phototherapy, and may result in kernicterus

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10
Q

How is a diagnosis of Crigler-Najjar syndrome type I made?

A

DNA analysis

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11
Q

How is Crigler-Najjar syndrome type 1 acutely treated?

A

Exchange transfusion

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12
Q

What is the long term treatment for Crigler-Najjar syndrome type I?

A

Liver transplantation

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13
Q

Can Crigler-Najjar syndrome type I be treated with phenobarbital?

A

No, there is no response to phenobarbital

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14
Q

How does Crigler-Najjar syndrome type II differ from type I?

A

In type II, some UDP-glucuronosyltransferase is present, so hyperbilirubinaemia is less severe

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15
Q

How is Crigler-Najjar syndrome type II managed?

A

Phenobarbital (causes marked decreased in serum bilirubin)

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16
Q

How does phenobarbital help in Crigler-Najjar syndrome type II?

A

It causes cytochrome P450 enzyme induction

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17
Q

What are likely to be helpful in the future management of Crigler-Najjar syndrome?

A

Therapies based on gene and cell transfer techniques

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18
Q

What is conjugated hyperbilirubinaemia defined as in neonates?

A

Serum conjugated bilirubin of greater than 25% of the total, or >25µmol/L

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19
Q

What is the most common cause of conjugated neonatal jaundice?

A

Cholestasis

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20
Q

What causes neonatal cholestasis?

A

Impairment of bile excretion caused by defects in intrahepatic production or transmembrane transport of bile, or mechanical obstruction to bile flow

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21
Q

What do the biochemical features of cholestasis reflect?

A

Retention of components of bile within the serum (bilirubin, bile acids, and/or cholesterol)

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22
Q

How to patients with conjugated jaundice classically present?

A
  • Jaundice
  • Pale (acholic) stool
  • Dark urine
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23
Q

Why does conjugated jaundice present with pale stools?

A

As no bilirubin reaches the GI tract

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24
Q

Why does conjugated jaundice present with dark urine?

A

Due to excretion of water-soluble conjugated bilirubin in the urine

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25
Q

What is the most common cause of neonatal liver disease?

A

Biliary atresia

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26
Q

How does biliary atresia present?

A
  • Conjugated jaundice
  • Acholic stools
  • Hepatomegaly
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27
Q

What is bile essential for?

A

Carrying waste from the liver and promoting absorption of fats and fat-soluble vitamins

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28
Q

What does biliary atresia result in if not corrected?

A

Chronic liver failure

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29
Q

How is biliary atresia surgically corrected?

A

The Kasai portoenterostomy - attaching porta hepatis to a loop of small intestine

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30
Q

What is the purpose of the Kasai portoenterostomy?

A

To allow diversion of bile from the residual small bile ducts

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31
Q

How effective is the Kasai portoenterostomy?

A

Up to 60% will achieve biliary drainage (bilirubin <20µmol/L) within 6 months

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32
Q

What is the prognosis for children with biliary atresia who have undergone a successful Kasai portoenterostomy?

A

Most will reach adolesence with a good quality of life (but with cirrhosis/evidence of portal hypertension) without undergoing liver transplantation

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33
Q

Which congenital infections are associated with conjugated jaundice and hepatomegaly?

A
  • CMV
  • Toxoplasmosis
  • Rubella
  • Syphilis
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34
Q

What other infections can cause cholestasis?

A

Any infection acquired around the time of birth, e.g. herpes simplex, varicella zoster, or any bacterial infection

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35
Q

Why can bacterial infections or infections acquired around the time of birth cause cholestasis?

A

As hepatic bile flow is very sensitive to circulating endotoxins

36
Q

What are the roles of the liver?

A
  • Amino acid metabolism
  • Protein synthesis
  • Carbohydrate metabolism
  • Lipid metabolism
  • Manufacture of blood coagulation proteins
37
Q

What are the (relatively) common genetic diseases affecting the liver presenting with conjugated hyperbilirubinaemia?

A
  • Alpha-1-antitrypsin deficiency
  • Alagille syndrome
  • Tyrosinaemia type 1
  • Niemann-Pick disease
  • Progressive familial intrahepatic cholestasis
38
Q

What is the inheritance of alpha-1-antitrypsin deficiency?

A

Autosomal recessive

39
Q

What gene is affected in alpha-1-antitrypsin deficiency?

A

SERPINA1 gene

40
Q

What are the alleles of SERPINA1 gene?

A

M, S, and Z

41
Q

What is the most common genetic mutation in the SERPINA1 gene causing alpha-1-antitrypsin deficiency?

A

Z-amino acid substitution

42
Q

When does alpha-1-antitrypsin deficiency present?

A

Neonatal period

43
Q

How does alpha-1-antitrypsin deficiency present?

A
  • Conjugated jaundice
  • Acholic stools
  • IUGR
  • Variable hepatomegaly
44
Q

What are the sequelae of alpha-1-antitrypsin deficiency?

A

Hepatitis, cirrhosis, and liver failure

Risk of malignant transformation of cirrhosis

45
Q

How is alpha-1-antitrypsin deficiency managed?

A
  • Liver transplantation for chronic liver disease
  • Family screening
  • Alcohol and smoking advice
46
Q

What is the inheritance of Alagille syndrome?

A

Autosomal dominant with incomplete penetrance

47
Q

What is the genetic defect in Alagille syndrome?

A

Defects in the JAG1 gene

48
Q

Where is the JAG1 gene located?

A

Chromosome 20

49
Q

What does the JAG1 gene code for?

A

The ligand Notch1

50
Q

Where is Notch1 expression found?

A

Many organs, e.g. liver, kidney, heart

51
Q

How does Alagille syndrome present?

A
  • Cardiac problems
  • Renal problems
  • Dysmorphic features
  • Butterfly vertebrae in the thoracic spine
52
Q

What are the characteristic facies of Alagille syndrome?

A
  • Broad forehead
  • Hypertelorism
  • Deep set eyes
  • Small pointed chin
53
Q

What are butterfly verterae?

A

When there is fusion of the anterior arch of the vertebral body

54
Q

How is Alagille syndrome managed?

A
  • Supportive with vitamins
  • Medications to control intense pruritis
  • May need transplantation for chronic liver disease
55
Q

What is the inheritance of tyrosinaemia type 1?

A

Autosomal recessive

56
Q

What is the problem in tyrosinaemia type I?

A

Defect of fumaryl acetoacetase, the terminal enzyme in tyrosine degradation, leading to accumulation of toxic metabolites

57
Q

How do patients with tyrosinaemia type I present?

A

Acute liver failure

58
Q

What is a key feature of tyrosinaemia type I?

A

Hepatocyte dysplasia

59
Q

What are patients with tyrosinaemia type I at risk of?

A

HCC

60
Q

How is tyrosinaemia managed?

A
  • Dietary restriction
  • Nitisone
  • Liver transplantation (prevents development of HCC)
61
Q

What is the inheritance of Niemann-Pick disease?

A

Autosomal recessive

62
Q

What genes are involved in Niemann-Pick disease?

A

NPC1 or NPC2

63
Q

What do NPC1 and NPC2 genes do?

A

Encode intracellular lipid trafficking proteins

64
Q

What do mutations in NPC1 and NPC2 genes in Niemann-Pick disease lead to?

A

Accumulation of intracellular unesterified cholesterol in many tissues, e.g. the brain

65
Q

How does Niemann-Pick disease present?

A
  • Hepatosplenomegaly
  • Hydrops fetalis
  • Ascites
  • Developmental of neurological impairment, becoming more obvious with age
66
Q

What feature is pathognomonic of Niemann-Pick disease?

A

Loss of upwards gaze due to vertical supranuclear opthalmoplegia

67
Q

What are the other neurological features of Niemann-Pick disease?

A
  • Ataxia
  • Seizures
  • Severe developmental delay
  • Dementia
68
Q

What is the management of Niemann-Pick disease?

A
  • Liver and bone marrow transplantation

- Miglustat

69
Q

How does miglustat work?

A

It inhibits the first step in glycosphingolipid synthesis

70
Q

What is the evidence for glycosphingolipid?

A

Clinical trials and observational studies suggest it delays progression of neurological symptoms

71
Q

What is the inheritance of progressive familial intrahepatic cholestasis?

A

Autosomal recessive

72
Q

What genes are affected in progressive familial intrahepatic cholestasis?

A

PFIC-1 and PFIC-2

73
Q

How does progressive familial intrahepatic cholestasis present?

A
  • Jaundice
  • Hepatomegaly
  • Pancreatitis
  • Pruritis
  • Steatorrhoea
  • Faltering growth
  • Early progression to cirrhosis
74
Q

What feature is characteristic of progressive familial intrahepatic cholestasis?

A

Low/normal serum GGT discordant with the degree of cholestasis

75
Q

What is the other biochemical feature of progressive familial intrahepatic cholestasis?

A

Low/normal serum cholesterol

76
Q

How is progressive familial intrahepatic cholestasis treated?

A

Treatment is supportive
Biliary diversion is considered
Progressive liver cirrhosis eventually lead to need for liver transplantation

77
Q

What is the purpose of biliary diversion in progressive familial intrahepatic cholestasis?

A

Aid excretion of bile salts

78
Q

What are the main endocrine causes of jaundice in a neonate presenting with conjugated hyperbilirubinaemia?

A
  • Hypothyroidism

- Hypopituitarism

79
Q

What is the mechanism of the development of jaundice in pituitary hormone insufficiency?

A

Not fully established, but known that thyroid hormone and cortisol affect the bile acid-independent bile flow

80
Q

What effect does cortisol have on bile?

A

Can influence bile formation and reduce bile flow

81
Q

How is cortisol measurement used in the assessment of hypopituitarism?

A

Low level raises suspicions, and is an indication for performing a short synacthen test

82
Q

How does growth hormone affect bile?

A

Modulates bile acid synthesis and is important for bile acid formation

83
Q

What does the clinical presentation of hypopituitarism depend on?

A
  • Patients age

- The specific hormone deficiencies

84
Q

Are the specific hormone deficiencies in hypopituitarism single or multiple?

A

Can be either

85
Q

What are the potential presenting features of hypopituitarism?

A
  • Hypoglycaemia
  • Hyponatraemia
  • Prolonged jaundice
  • In males, small genitalia and undescended testes
86
Q

What condition should be considered whenever a diagnosis of congenital hypopituitarism is diagnosed?

A

Septo-optic dysplasia

87
Q

What do patients with septo-optic dysplasia have?

A
  • Neuroendocrine deficiency
  • Optic nerve hypoplasia
  • Midline brain defects including agenesis of septum pellucidum

TAS Hepatology (10 decks)

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