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Robbins Liver & Biliary > Jaundice and Cholestasis (inc causes) > Flashcards

Jaundice and Cholestasis (inc causes) Flashcards

1
Q

What are the two major functions of bile?

A

Emulsification of dietary fat through detergent action of bile salts

Elimination of bilirubin, excess cholesterol, xenobiotics and other waste products that aren’t hydrophilic (can’t enter urine)

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2
Q

Can both conjugated and unconjugated bilirubin accumulate systemically?

A

Yes

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3
Q

How hydrophilic is unconjugated bilirubin?

A

Virtually not at all

Cannot be excreted by the kidneys even at high serum concentrations

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4
Q

If unconjugated bilirubin isn’t complexed with albumin in the blood for transport, what complications does it cause?

A

Can diffuse into tissues, and in newborns/foetuses can cross the BBB causing neuronal toxicity

Thus in haemolytic disease of the newborn (erythroblastosis foetalis) unconjugated bilirubin accumulates in the developing brain causing severe neurological damage (kernicterus)

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5
Q

What are the potential outcomes of kernicterus?

A

Acute bilirubin encephalopathy (ABE)

Chronic bilirubin encephalopathy (CBE)

Subtle bilirubin encephalopathy (SBE)

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6
Q

Describe acute bilirubin encephalopathy

A

Lethargy

Hypertonia or hypotonia

High pitched cry

Fever

Seizures

Death

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7
Q

Describe chronic bilirubin encephalopathy’s symptoms

A

Movement disorders (cerebral palsy or dystonia)

Auditory neuropathy

Oculomotor impairments (nystagmus, strabismus, and/or corticovisual impairment)

Impaired digestive function

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8
Q

Describe subtle bilirubin encephalopathy’s symptoms

A

Mild forms of the same symptoms of chronic bilirubin encephalopathy

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9
Q

Can acute bilirubin encephalopathy be treated?

A

Yes

Reduce bilirubin levels and symptoms will reduce and no sequelae should result

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10
Q

Can chronic or subtle bilirubin encephalopathy be treated?

A

Hyperbilirubinaemia can be treated, but not the neuronal damage

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11
Q

What is the protein that normally conjugates bilirubin?

A

Uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1)

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12
Q

Is UGT1A1 active in the foetus/newborn?

A

No, inactive

Though levels are the same as in the maternal liver

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13
Q

Why is hyperbilirubinaemia dangerous in the foetus/newborn?

A

UGT1A1 inactive (maternal liver performs this function for the foetus) and is inactive several months after birth

BBB not complete, can cross into the brain

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14
Q

Is jaundice in a newborn a negative prognostic marker?

A

Not normally

New research shows that physiologic jaundice is within the reference range in the first week of life for healthy term babies, particularly those breastfed

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15
Q

What areas of the brain does unconjugated bilirubin typically enter?

A

Cranial nerve nuclei

Basal ganglia

Hippocampus

Cerebellum can also be affected

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16
Q

How can hyperbilirubinaemia be treated?

A

Exchange transfusion if not refractory to treatment (replacing baby’s blood with citrate phosphate dextrose (CPD) banked O- (important because all antibodies may not be removed) blood that does not contain bilirubin

Phototherapy

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17
Q

What is the mortality rate of exchange transfusion in the treatment of hyperbilirubinaemia kernicterus?

A

3 in 1000 (high)

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18
Q

Which conditions can lead to unconjugated hyperbilirubinaemia?

A

Excess production of bilirubin (hapmolytic anaemia, ineffective erythropoiesis eg pernicious anaemia or thalassaemia)

Reduced hepatic uptake (drug interference with membrane carrier systems)

Impaired conjugation (physiologic jaundice of the newborn, breast milk, Crigler-Najjar type I and II, Gilbert Syndrome, diffuse liver disease eg cirrhosis)

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19
Q

Which conditions can lead to conjugated hyperbilirubinaemia?

A

Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)

Impaired bile flow

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20
Q

What is the primary pathology in Crigler-Najjar syndrome?

A

Absent UGT1A1 activity in Type I

Decreased UGT1A1 activity in Type II

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21
Q

How does conjugated bilirubin differ from unconjugated bilirubin?

A

Water soluble

Nontoxic

Only loosly binds to albumin

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22
Q

Does conjugated bilirubin ever much bind to albumin?

A

In prolonged conjugated hyperbilirubinaemia there is a fraction that binds to albumin

This is called the bilirubin delta fraction

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23
Q

What are the normal serum bilirubin levels in a normal adult?

A

0.3 - 1.2 mg/dL

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24
Q

With what bilirubin levels does jaundice typically become noticeable?

A

2.0 - 2.5 mg/dL

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25
Q

What are the 5 mechanisms by which jaundice can develop?

A

Excessive extrahepatic production of bilirubin

Reduced hepatocyte uptake

Impaired conjugation

Decreased hepatocellular excretion

Impaired bile flow

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26
Q

Can you have both conjugated and unconjugated bilirubin in excess?

A

Yes

Typically only occurs though when conjugated hyperbilirubinaemia is present first

Mechanism unknown, could be from competition for hepatic clearance between conjugated and unconjugated

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27
Q

Is it useful to know the serum bilirubin level of both conjugated and unconjugated?

A

No

Typically only one will be raised and that is the one that you must investigate to investigate the cause

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28
Q

What is the normal survival time for babies with Criggler-Najjar syndrome type I (absent UGT1A1) that are not given a liver transplant?

A

18 months

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29
Q

What happens to unconjugated bilirubin in individuals with Crigler-Najjar syndrome type II?

A

UGT1A1 that is present is only able to convert bilirubin to monoglucuronidated bilirubin

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30
Q

How is Crigler-Najjar syndrome type II treated?

A

Phenobarbitals can induce hypertrophy of the endoplasmic reticulum

Exchange transfusion

Phototherapy

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31
Q

How is phototherapy effective in the treatment of jaundice?

A

Causes the formation of water-soluble bilirubin isomers that can be secreted in bile without conjugation

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32
Q

What is the efficacy of phototherapy dependant on?

A

Dose, ie:

Duration of being under the light (don’t go towards the light)

Intensity of the light

Age

Amount of skin exposed to the light

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33
Q

Why is age an important factor in the efficacy of phototherapy in reducing jaundice?

A

Because after the ages of 3-4 the ratio of skin surface area to body mass is reduced

34
Q

What is a typical length of dose of phototherapy in Crigler-Najjar syndrome type I sufferers?

A

10-16 hours per day

35
Q

What is Gilbert syndrome?

A

Benign inherited condition with decreased UGT1A1 activity

36
Q

Is Gilbert syndrome a cause of major morbidity?

A

No

Usually innocuous

37
Q

What symptoms characterise Gilbert syndrome?

A

Jaundice

Abdominal cramps, fatigue, malaise sometimes

38
Q

Are physical symptoms in Gilbert syndrome proportional to serum bilirubin levels?

A

No

39
Q

What proportion of Gilbert syndrome patients are asymptomatic?

A

30%

40
Q

How much bilirubin is typically produced by a healthy adult per day?

A

250 - 400 mg

41
Q

What drugs can cause unconjugated hyperbilirubinaemia while used?

A

Rifampicin

Rifamycin

Probenecid

Flavaspidic acid

Bunamiodyl (cholecystographic agent)

42
Q

What is Lucey-Driscoll syndrome?

A

The heightened presence of beta-glucuronidases in breast milk

43
Q

What is the genetic basis of Gilbert syndrome?

A

Homozygous insertion of extra bases into the 5’ promoter region of the UGT1 gene, leading to reduced transcription

44
Q

What is a complication of a Gilbert diagnosis

A

The patient may become distressed about the diagnosis, but it’s important to assure them that they are relatively well and their life will not change at all

45
Q

Are the syndromes (ie Gilbert, Crigler Najjar etc) that cause hyperbilirubinaemia all autosomal dominant or recessive?

A

Autosomal recessive

46
Q

How can you summarise the mechanism by which a conjugated hyperbilirubinaemia is caused?

A

Reduction in the rate of secretion of conjugated bilirubin into the bile or the flow of bile into the intestine produce a conjugated bilirubinaemia due to reflux of conjugates back into plasma

47
Q

Is the colour of urine most afected in conjugated or unconjugated hyperbilirubinaemia?

A

Conjugated

Unconjugated is too strongly bound to albumin, due to its hydrophobic nature, to pass into the urine

48
Q

Does a conjugated hyperbilirubinaemia directly cause any morbidity or mortality?

A

No

Any morbidity or mortality is associated with the disease process causing the conjugated hyperbilirubinaemia

49
Q

What are the two broad categories of diseases that cause conjugated hyperbilirubinaemia?

A

Acute or chronic hepatocellular dysfunction

Diseases that prevent flow of bile into the intestine

50
Q

What can cause acute or chronic hepatocyte dysfunction leading to conjugated hyperbilirubinaemia?

A

Infection (hep A-E, CMV, EBV, sepsis)

Inflammation (drugs, halothane, alcoholic hepatitis, haemochromatosis, Wilson disease, autoimmune hepatitis)

Metabolic dysfunction (ischaemia, a1-antitrypsin deficiency, preeclampsia, Reye syndrome, acute fatty liver of pregnancy)

Inborn errors of metabolism (Dubin-Johnson syndrome, Rotor syndrome, benign recurrent cholestasis)

51
Q

What diseases can block the flow of bile, and cause conjugated hyperbilirubinaemia?

A

Damage to intrahepatic bile ducts or portal tracts

Damage to or obstruction of larger bile ducts

Diffuse infiltrative diseases

Diseases that interfere with biliary secretion of bilirubin

52
Q

What conditions cause conjugated hyperbilirubinaemia through damage to intrahepatic bile ducts or portal tracts?

A

Primary biliary cirrhosis

Veno-occlusive disease

Sclerosing cholangitis

53
Q

What diseases cause conjugated hyperbilirubinaemia through damage to or obstruction of larger bile ducts?

A

Bile duct cancers

Extrinsic compression of the bile duct

Tumours

Acute pancreatitis

Post-surgical strictures

54
Q

What diffuse infiltrative diseases cause conjugated hyperbilirubinaemia?

A

Granulomatous disases

Sarcoidosis

Lymphoma

Amyloidosis

Diffuse malignancy

55
Q

What diseases cause conjugated hyperbilirubinaemia through interference of biliary secretion of bilirubin?

A

Chlorpromazine

Erythromycin

Oestrogens

Anabolic steroids

56
Q

What blood tests are useful in hyperbilirubinaemia?

A

CBC (screen for haemolysis)

LFT (ALT and AST levels)

Serology for Hep viruses (anti-HCV, HBsAg, anti-HBcAb)

Alkphos (if elevated -> obstruction)

Fractionated bilirubin

etc

57
Q

What is Dubin-Johnson syndrome?

A

Defect in hepatocellular excretion of bilirubin glucuronides across the canalicular membrane due to the absence of MRP2 (multidrug resistance protein 2)

58
Q

What symptoms do Dubin-Johnson patients experience?

A

Chronic or recurrent jaundice of fluctuating intensity

Most are symptomatic however

59
Q

What is Rotor syndrome?

A

Rare form of asymptomatic conjugated hyperbilirubinaemia

60
Q

What is the cause of Rotor syndrome?

A

Unknown

61
Q

What symptoms are associated with Rotor syndrome?

A

None besides jaundice

62
Q

What would you expect to happen to the stool and urine in conjugated hyperbilirubinaemia?

A

Stools would become pale due to less conjugated bilirubin entering the gut

Urine would become dark as the water soluble conjugated bilirubin enters it

63
Q

What history questions would you ask a patient with jaundice?

A

Blood transfusions, IV drug use, piercings, tattoos, sexual activity, contacts jaundiced?, family history, alcohol, all medications

64
Q

What would you be looking for in examination of a patient with jaundice?

A

Signs of chronic liver disease

Signs of encephalopathy

Signs of lymphadenopathy

Hepatosplenomegaly

Palpable gall bladder

65
Q

What does it tell you when a patient has a palpable gall bladder but painless jaundice?

A

A cause other than gallstones

This is Courvoisier’s law

66
Q

Do problems with bilirubin production or clearance cause abnormal LFT’s?

A

No

Abnormal LFTs indicate cholestasis

67
Q

What does glucose-6-phosphate dehydrogenase do?

A

G6PD maintains NADPH levels in RBCs

NADPH then maintains glutathione levels, which protects against oxidative damage

68
Q

How common is G6PD deficiency?

A

Most common enzyme deficiency

Present in 400 million people worldwide

69
Q

Why are RBCs most vulnerable to G6PD deficiency?

A

G6PD is the RBCs only source of NADPH

Other cells have other methods of getting NADPH

70
Q

What can G6PD cause?

A

Haemolytic anaemia

71
Q

What can trigger a haemolytic event in a G6PD deficient patient?

A

Oxidative stresses

Exposure to fava beans

Ketoacidosis

72
Q

What are symptoms of a haemolytic attack in G6PD deficient patients?

A

Weakness

Jaundice

Tachycardia

Haematuria

73
Q

How long does a typical haemolytic event last in G6PD dficiency?

A

8 - 14 days

74
Q

Why is there a limit to the length of a haemolytic period in G6PD deficient patients?

A

The episode kills mostly old RBCs which have less G6PD

New RBC populations have compensatory higher G6PD levels and are less vulnerable to oxidative damage

75
Q

What are the two varieties of G6PD deficiency?

A

Gd(med) in mediterranean

Gd(A-) in africa

Also called white and black G6PD deficiency

76
Q

How can G6PD deficiency be managed?

A

Patient education, to avoid substances that cause oxidative stress

77
Q

What must lab tests show in order for cholestasis to be diagnosed?

A

Either bile salts or conjugated bilirubin must be elevated (ie, provably being retained)

78
Q

What are typical symptoms of cholestasis?

A

Scleral icterus

Cutaneous jaundice

Evidence of scratching or excoriation if they have severe bile acid retention

Xanthomas (small white papules on skin of trunk or areas of friction like creases of hands, elbows or neck, caused by cholesterol)

79
Q

What are the two broad groups of causes of cholestasis?

A

Hepatocellular cholestasis

Obstructive cholestasis

80
Q

What are typical lab findings in cholestasis?

A

^ Bilirubin

^ Serum bile salts

^ Alkphos, ^ GGT

81
Q

What is a very important consequence of cholestasis?

A

Malabsorption of the fat soluble vitamins (A, D, E, K)

Treat by administration of them

Robbins Liver & Biliary (6 decks)

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