Jaundice, Types and how to detect

1. Jaundice
Dr Sarath Krishnan M P
Junior Resident/Biochemistry
AIIMS Rishikesh
1

2. Learning objectives!!!
• Case Scenario
• Introduction
• Bilirubin metabolism
• Epidemiology
• Aetiology
• Approach to a jaundice case
• Jaundice and COVID-19
• Recent updates
• Summary
2

3. CASE I
• A 27 years old male presented to medicine
OPD with complaints of Fatigue, Malaise, and
yellow discolouration of skin and eyes. He
gave history of being diagnosed with Malaria
5 days back and was on Primaquine.
• On Examination –There was Pallor(++),
Icterus(++), Pulse was 100/min. Temperature
102°F, Liver and spleen were palpable.
• Blood and Urine investigation were as follows:
 Hb-7 gm%
 TLC-14000 mm3 esp. polymorphs.
 Serum bilirubin- 7 mg%.
 Van den Bergh- Indirect positive.
 The colour of the urine was brownish black
 Urine- Hb+ and Urobilinogen +
3

4. CASE II
• A 45 year old woman gave history of
loss of appetite, Nausea and Fatigue
for 8 days. She also gave history of
abdominal pain for past two days.
O/E there was tenderness in the
right upper quadrant.
• Laboratory investigations showed;
 Serum Total bilirubin 5.0 mg%
 Direct bilirubin 2.0 mg%
 Indirect bilirubin 3.0 mg%
 Serum AST-40 IU/L
 Serum ALT-115 IU/L
 Serum ALP-20 Units (KA)
4

5. CASE III
• A 40 year old , fat female , presented to
emergency department with pain in the
right side of abdomen, intolerance to fatty
foods, yellowing of eyes and passage of
clay coloured stools.
• Laboratory investigations revealed
Serum Total bilirubin-20mg%, Direct
Bilirubin-16mg%, ALP-800U(KA),
SGPT-90IU/L
Urine Colour-deep yellow, Bilirubin-++,
Urobilinogen absent
Stools Clay coloured, Stercobilinogen-
absent
5

6. What is Jaundice???
• Yellowish discolouration of Sclera (Icterus)/ Skin and Mucous
membrane
• D/t Hyperbilirubinemia
• Not a disease, but a SIGN
• Clinically detectable: Plasma Bilirubin ~ 3mg/dl or 50μmol/L
6

7. 7

8. Sites to be examined
• Upper bulbar conjunctiva (Elastin)
• Base of tongue
• Mucous membrane of palate (specially soft palate)
• Palms and soles
• General skin surface
8

9. Is all yellowish discolouration jaundice???
Differential diagnosis
• Carotenoderma
• Drug – Quinacrine
• Excessive exposure to Phenols
9

10. Culprit???
• BILIRUBIN
10

11. Extravascular pathway for RBC
destruction
11

12. 12
Haem (from Hb, Mb and Cyt)
Fe,CO2 Haem oxygenase
Biliverdin
Biliverdin reductase
Bilirubin

13. An average person
produces about 4mg/kg of
bilirubin per day
13
Total bilirubin

14. Bilirubin processing
14

15. Fate of bilirubin
15

16. Bilirubin Fractions
• Unconjugated bilirubin (α – Bilirubin)
• Monoconjugated bilirubin (β – Bilirubin)
• Di – conjugated bilirubin (γ – Bilirubin)
• A fraction irreversibly bound to protein (δ – Bilirubin)
16

17. Serum bilirubin
• Total bilirubin(0.3-1.2mg/dl) is found in blood
17
Conjugated bilirubin (0.0-0.2mg/dl)
• Soluble in water so excreted by kidney.
Unconjugated Bilirubin
• Insoluble in water so bound to albumin in blood.

18. • Jaundice is latent when serum bilirubin is in between 1-3mg/dl
• Unconjugated hyperbilirubinemia – Direct bilirubin <15% of TB
• Conjugated hyperbilirubinemia – Direct bilirubin >15% of TB
18

19. δ – Bilirubin/ Biliprotein
• Cholestasis prevents excretion of conjugated bilirubin into bile
• Enters the plasma Filtered by Kidneys Excreted in Urine
• Some monoconjugated bilirubin can become covalently bound to
albumin
19

20. • This protein bound conjugated bilirubin - δ-Bilirubin/ Biliprotein
• Normally present in very small amount
• Increase in cholestasis
• Half life is longer--12-14days( Like Albumin)
• Normally half life of conjugated bilirubin is 2-4 hrs
20

21. Significance of δ-bilirubin
• As it is irreversibly bound to albumin it is not filtered at the
glomerulus and its half life reflects that of albumin
• Consequently it remains in plasma long time, giving rise to
conjugated hyperbilirubinemia in the absence of bilirubinuria
• Particularly evident in recovery phase of Cholestasis
• Delta bilirubin=TB-(DB+IB)
21

22. Causes of hyperbilirubinemia
Increase in
unconjugated bilirubin
only
Increase in conjugated
bilirubin only
Increase in both bilirubin
Haemolytic disease Cholestasis Intrahepatic /Liver
disorders
Genetic disorders- Crigler
Najjar and Gilbert’s
syndrome
Genetic disorders- Dubin
Johnson syndrome and
Rotor’s syndrome
Neonatal jaundice 22

23. Congenital hyperbilirubinemias
Crigler-Najjar syndrome
• AR
• Type I-Total absence of UDP
glucuronyl transferase
• Type II- Partial deficiency of UDP
GT
• Unconjugated bilirubin>20mg/dl
• Kernicterus
• Death -1yr of life
Gilbert’s syndrome
• AD inheritance
• Males
• Defective uptake of bilirubin by
the liver
• Unconjugated bilirubin~3mg/dl
• Harmless, No Rx
23

24. Dubin-Johnson syndrome
• AR
• Defective excretion of conjugated
bilirubin into BILE
• Mutation in gene encoding MOAT
protein
• Black liver jaundice
Rotor syndrome
• AR
• Exact cause??
• Abnormal excretion
• Harmless, No Rx
24

25. Algorithm for differentiating the familial
causes of hyperbilirubinemia
25

26. Epidemiology
• Prevalence of jaundice varies with age and sex.
• 20% of new-borns develop jaundice in the first week of life.
• Infancy/ childhood: Congenital defects/ Bilirubin uptake disorders/
Hemolytic disorders/ Conjugation defects.
• School aged children: Hepatitis A
• Old aged: CBD stones/ ALD/ Neoplasm of liver
26

27. Aetiology and Investigations
HEMOLYTIC/ PRE-HEPATIC JAUNDICE
HEPATIC JAUNDICE
POST HEPATIC/ OBSTRUCTIVE/ SURGICAL JAUNDICE
27

28. Hemolytic/ Pre-hepatic jaundice
• Excess production of bilirubin due to excess breakdown of RBC
• Indirect bilirubin
28

29. Causes of Hemolytic jaundice
Hemolytic disorders
INHERITED
• Spherocytosis, Elliptocytosis
• G6PD deficiency
• Pyruvate kinase deficiency
• Sickle cell anemia
Acquired
• Microangiopathic hemolytic anemia
• PNH
• Spur cell anemia
• Immune hemolysis
• Parasitic infections
29

30. Ineffective erythropoiesis
• Cobalamin/ Folate deficiency
• Severe Iron deficiencies
• Thalassemia
Drugs
• Rifampicin
• Ribavirin
• Probenecid
Increased bilirubin production
• Massive blood transfusion
• Resorption of hematoma
30

31. Classical signs and symptoms
• Anaemia
• Splenomegaly
• Dark coloured urine
31

32. Lab findings
• Serum: Increased unconjugated bilirubin
• Urine: Bilirubin = Absent
Urobilinogen = Increases
• Stool: Faecal Urobilinogen increases
• Rest LFT usually remains normal
32

33. Hepatic jaundice
• Ability to conjugate or excrete bilirubin is affected
• Both conjugated and unconjugated bilirubin are elevated
(BIPHASIC)
33

34. Causes of Hepatic jaundice
Viral hepatitis
34
Features HAV HBV HCV HDV HEV
Transmission Feco-oral Parentral,
Sexual,
Perinatal
Parentral Parentral,
Sexual,
Perinatal
Feco-oral
Carrier None 0.1-30% 1.5-3.2% Variable None
Chronicity None Occasional Common Common None
Cancer None + + +/- None
Prognosis Excellent Worsen with
age
Moderate A/c-Good
C/c-Poor
Good

35. • Other viruses: Epstein Barr/ CMV/ HSV
Alcoholic hepatitis
Drug toxicity
• Acetaminophen
• Isoniazid
Environmental toxins – Vinyl chloride/ Alkaloids/ Wild mushrooms
35

36. Wilson’s disease
Autoimmune hepatitis
Inherited conditions
• Indirect hyperbilirubinemia – Gilbert syndrome/ Crigler- najjar
syndrome/ Lucey-Driscoll syndrome
• Direct hyperbilirubinemia – Dubin Johnson syndrome/ Rotor
syndrome
36

37. Classical signs and symptoms
• Loss of appetite
• Hepatomegaly
• Spider naevi
• Palmar erythema
37

38. Lab findings
• Serum: Both conjugated and unconjugated bilirubin increased
• Urine: Bilirubin = Present
Urobilinogen = Decreased
• Faecal Stercobilinogen/ Faecal Urobilinogen: Decreased
• Enzymatic test: AST, ALT – Highly raised
ALP,GGT – slightly raised
• AST and ALT > ALP and GGT
• Plasma Albumin is low but plasma globulins are raised
38

39. 39
Disorders Bilirubin Aminotransferas
es
Alkaline
phosphatase
Albumin
Acute
hepatocellular
necrosis(Viral and
drug hepatitis,
hepatotoxins)
Both fractions
may be elevated
Bilirubinuria
Elevated often
>500IU
ALT>AST
Normal to <3x
normal elevation
Normal
Chronic
hepatocellular
disorders
Both fractions
may be elevated
Bilirubinuria
Elevated, but
usually <300IU
Normal to <3x
normal elevation
Often decreased
Alcoholic
hepatitis,
Cirrhosis
Both fractions
may be elevated
Bilirubinuria
AST/ALT >2
suggests alcoholic
hepatitis or
Cirrhosis
Normal to <3x
normal elevation
Often decreased

40. POST HEPATIC/ OBSTRUCTIVE/
SURGICAL JAUNDICE
• Bilirubin formation rate is normal
• Conjugation is normal
• Intrahepatic/ extrahepatic condition leading obstruction to the flow
of bile
40

41. Causes of Obstructive jaundice
Intrahepatic causes
• Viral hepatitis
• Alcoholic hepatitis
• Drug toxicity:
1.Pure cholestasis: Anabolic/ Contraceptive steroids
2.Cholestatic hepatitis: Chlorpromazine/ Erythromycin
3.C/c Cholestasis: Prochloperazine
• Primary biliary cirrhosis 41

42. • Primary sclerosing cholangitis
• Vanishing bile duct syndrome
• Inherited conditions
1.Progressive familial intrahepatic cholestasis
2.Benign recurrent cholestasis
• Cholestasis of pregnancy
• Non hepato-biliary sepsis
42

43. Extrahepatic causes
• Malignant
a. GB Cancer
b. Cholangiocarcinoma
c. Pancreatic cancer
d. Ampullary carcinoma
• Benign
a. Choledocolithiasis
b. Post operative biliary
strictures
c. Chronic pancreatitis
d. AIDS Cholangiopathy
43

44. Classical signs and symptoms
• Pale/ Clay coloured stools
• Dark urine
• Xanthelasma and Xanthomas
44

45. Lab findings
• Serum: Direct bilirubin increased
• Urine: Bilirubin – Present
Urobilinogen – Absent
• Faecal Stercobilinogen: Trace to absent
• Enzymatic test: AST, ALT – Slightly increase
ALP, GGT – Highly increased
• If ALP and GGT levels rise proportionately about as high as the
AST and ALT levels, this indicates a cholestatic problem. 45

46. 46
Disorder Bilirubin Aminotransf
erases
ALP Albumin
Intra and
extra hepatic
cholestasis
Both fractions
may be
elevated
Normal to
moderate
elevation
Elevated,
often >4x
normal
elevation
Normal,
unless
chronic
Infiltrative
diseases,
Partial bile
duct
obstruction
(Obstructive
jaundice)
Bilirubinuria
Elevated
direct bilirubin
Rarely
>500IU
Elevated,
often >4x
normal
elevation
Fractionate or
confirm liver
origin with
5’nucleotidas
e or GGT
Normal

47. Radiological investigation
Mainly in Obstructive jaundice
• Plain radiographs
• USG abdomen
• CECT abdomen
• MRI - MRCP
47

48. CASE I
• A 27 years old male presented to medicine
OPD with complaints of Fatigue, Malaise, and
yellow discolouration of skin and eyes. He
gave history of being diagnosed with Malaria
5 days back and was on Primaquine.
• On Examination –There was Pallor(++),
Icterus(++), Pulse was 100/min. Temperature
102°F, Liver and spleen were palpable.
• Blood and Urine investigation were as follows:
 Hb-7 gm%
 TLC-14000 mm3 esp. polymorphs.
 Serum bilirubin- 7 mg%.
 Van den Bergh- Indirect positive.
 The colour of the urine was brownish black
 Urine- Hb+ and Urobilinogen +
48

49. CASE II
• A 45 year old woman gave history of
loss of appetite, Nausea and Fatigue
for 8 days. She also gave history of
dark coloured urine for past two
days. O/E there was tenderness in
the right upper quadrant.
• Laboratory investigations showed;
 Serum Total bilirubin 5.0 mg%
 Direct bilirubin 2.0 mg%
 Indirect bilirubin 3.0 mg%
 Serum AST-40 IU/L
 Serum ALT-115 IU/L
 Serum ALP-20 Units (KA)
49

50. CASE III
• A 40 year old , fat female , presented to
emergency department with pain in the
right side of abdomen, intolerance to fatty
foods, yellowing of eyes and passage of
clay coloured stools.
• Laboratory investigations revealed
Serum Total bilirubin-20mg%, Direct
Bilirubin-16mg%, ALP-800U(KA),
SGPT-90IU/L
Urine Colour-deep yellow, Bilirubin-++,
Urobilinogen absent
Stools Clay coloured, Stercobilinogen-
absent
50

51. CASE IV
• A full-term infant was jaundiced and
his plasma bilirubin concentration
was 10 mg/dL 2 days after delivery.
Further testing showed that this was
predominantly unconjugated
bilirubin. The baby was otherwise
well, and within 5 days the plasma
bilirubin concentration decreased to
2.1 mg/dL.
51

52. 52

53. Physiological mechanisms of neonatal
jaundice
Increased bilirubin
production
Decreased clearance Increased reabsorption by
EHC
Higher erythrocyte mass Defective uptake D/t high levels of β-
glucuronidase
Shorter RBC lifespan(90days
vs 120days)
Defective conjugation:
Decreased UGT activity
Decrease in intestinal
bacteria
Increased ineffective
erythropoiesis
Decreased gut motility
Increased turnover of Non-Hb
heme proteins
53

54. Characteristics of physiological jaundice
• First appears between 24-72hrs of age
• Max intensity seen on 4-5th day in term and 7th day in preterm
neonates
• Does not exceed 15mg/dl
• Clinically undetectable after 14 days
• No Rx is required but baby should be observed closely for signs of
worsening jaundice
54

55. Kramer’s rule
55

56. CASE V
• Rh negative mother delivers a baby who
develops jaundice immediately after
birth.
• General Examination reveals Heart
rate 80/min, Icterus +, Irritability
present
• Laboratory Investigations
 Serum Total Bilirubin 10mg%
 Indirect 7 mg%
 Direct 3 mg%
 Alkaline Phosphatase 50 U/L
 Urine Urobilinogen +++
 Faeces Stercobilinogen +++
56

57. Pathological neonatal jaundice-Rh
incompatibility
57

58. Breastfeeding failure jaundice Vs Breast
milk jaundice
Diagnosis Timing Pathophysiology
Breastfeeding failure
jaundice
First week of life Lactation failure
result in:
• Decreased
bilirubin
elimination
• Increased EHC
• Suboptimal
breastfeeding
• Signs of
dehydration
Breast milk jaundice Starts at 3-5days;
peaks at 2 weeks
High levels of β-
glucuronidase in
breast milk
deconjugate intestinal
bilirubin
Adequate
breastfeeding
58

59. Jaundice in pregnancy
• Metabolic, synthetic and excretory functions of liver affected by
increased levels of oestrogen and progesterone in pregnancy
• Elevated level of bilirubin in pregnancy is always pathological
• Unconjugated bilirubin do not have deleterious effect on
neurodevelopmental status of offspring
59

60. Causes of jaundice in pregnancy
• Unique to pregnancy
• Intrahepatic cholestasis of pregnancy
• Acute fatty liver of pregnancy
• HELLP syndrome
• Severe hyperemesis gravidarum
• Coincidental to pregnancy
• Viral hepatitis
• Cholelithiasis
• Congenital disorders of bilirubin
metabolism
• Cirrhosis
• Hemolytic cause
60

61. Management
Depends on the underlying cause of jaundice
1. Expectant management at home with rest
2. IV Fluids/medications/ antibiotics/ blood transfusions
3. Drug/toxin which cause jaundice should be discontinued
4. Newborn jaundice: Phototherapy/ Exchange transfusion
5. Obstructive jaundice: Surgical management
61

62. Prevention
Not possible to prevent all causes which cause jaundice
1. Stick to the RDA of alcohol consumption
2. Maintain normal BMI
3. Vaccination for Hep A & B
4. Minimize the risk for developing Hep C
62

63. Tests for serum bilirubin
• Diazo method
• Spectrophotometric method
• Peroxidase method
• Diazo-peroxidase method
• HPLC
• Transcutaneous bilirubinometer
63
Enzymatic method

64. Van Den Bergh reaction
• Serum Bilirubin Diazotized sulphanilic acid
(Ehrlich diazo reagent)
Azobilirubin(Red)
• Direct bilirubin-reading is taken at one minute
2nd reading at 30 mts-Total Bilirubin
(By Adding activator/accelerator)
• Measure absorbance at 600nm
64

65. Central lab
Total bilirubin
Method: Photometric test using 2,4-Dichloroaniline(DCA)
Kit: DiaSys
Direct bilirubin
Method: DPD method-3,5 Dichlorophenyldiazonium
tetrafluoroborate
Kit: Medicon Hellas
65

66. 66
Diagnostic algorithm of patient with jaundice

67. Covid-19 and Jaundice
67

68. Recent advances
68

69. 69
Summary

70. References
• Harrisons Principles of Internal Medicine-20th edition
• Teitz Textbook of Clinical Biochemistry-7th edition
• Nelson Textbook of Pediatrics - 21st Edition
70

71. Thank you
71