This document discusses jaundice and approaches to evaluating its underlying causes. It defines jaundice as yellowish discoloration from bilirubin deposition. Liver enzymes, imaging like ultrasound and CT, and procedures like ERCP can help differentiate causes like viral hepatitis, alcoholic liver disease, autoimmune conditions, and obstructive jaundice. A careful history, exam, and pattern of lab and imaging abnormalities can often reveal the etiology of jaundice. A liver biopsy may be needed in some unclear cases to establish a diagnosis.

2.  Jaundice a.k.a icterus
› Jaune,jaunesse-french- yellow
› Ikterus -greek-yellow bird, oriole(
genus- icterus)
 Jaundice could be cured if pt
looked at the bird- people
thought so!!!!

3.  Yellowish discolouration of tissues resulting
from deposition of bilirubin.
 Normal - < 1 mg/dl ( 17 µmol/l)
 0.2 – 0.9 mg/dl– 95% of normal popn.
 Jaundice seen if values exceeds 3 mg/dl

4.  High affinity to elastin rich tissues.
 Sclera, skin, frenulum of tongue, ear drum
etc…
 Best seen at upper sclera, palate,
undersurface of tongue
 Clearly seen in daylight; difficult to see if
room has fluorescent lighting.

5.  Long standing jaundice: yellow to greenish
hue– due to biliverdin, oxidation product of
bilirubin
 Shades of jaundice:
› Rubin jaundice - reddish shade ( hepatitis)
› Flavin jaundice - lemon yellow with red hue ( hemolysis)
› Verdin jaundice - greenish yellow( obstruction)
› Melas jaundice - grayish or brackish green ( prolonged obstn)

6. 1. Carotenemia – carrots and mangoes –mainly
seen in palms, soles, forehead, nasolabial
folds- sclera sparing
2. Lycopaenemia – excessive tomatoes
3. Acriflavin,Fluorescine,Picric acid staining
4. Quinacrine, busulfan

7.  Next sensitive indicator- darkening of urine
 Tea or cola colored urine
 d/d:
› dehydration, fluid deprivation
› sulfasalazine use ( orange- yellow colored urine)
› other colored urines( rifampicin-orange, porphyria-
red, melanuria- dark, ochranosis- black)

8.  Total bilirubin – 250-300 mg/day
 70-80% -- senescent RBCs, remaining from
premature destruction of RBCs, myoglobin,
cytochromes
 Reticulo-endothelial cells of spleen and liver

9. Heme oxygenase – microsome
Biliverdin reductase-- cytosol

10. 1
• Hepatocyte (HC) uptake of UCB
• Alb+UCB dissociates and UCB enters HC
2
• Intracellular binding
• Several of Glutathione-s-transferases-LIGANDINS
3
• Conjugation in ER of Hepatocyte (HC)
• Formation of mono and di glucuronides BMG, BDG
• UDP Glucuronosyl transferase is energy dependent
4
• Excretion in into biliary canaliculi (MRP-2,MRP-3)
• Rate limiting step in metabolism

11. 1
• CB enters to duodenum; not taken up by int. mucosa
• Distal ileum, colon- hydrolysed by β- glucuronidases to UCB
• UCB- acted on by gut bact to urobilinogens( UBG)
2
• 80-90% UBG– unchanged/ reduced(stercobilin)– excreted in faeces
• 10-20% Enters EHC- liver
3
• UBG in liver– enters circulation– oxidised to urobilin
• Excreted in kidneys

12. *
• Urobilinogen/ urobilin– normally present– in traces
• If increased---hepatocellular injury
*
• UCB– not filtered or secreted in kidneys
• Always nil in urine
*
• CB– filtered and re-absorbed by proximal tubules
• Not normally present– if present, abnormal

13.  Van der bergh reaction
 Bilirubin exposed to diazotised sulfanilic acid
 Dipyrrylmethene azopigments- absorbs light at 540 nm
› Direct fraction - measured directly,
› Total fraction - measured after adding alcohol,
› Indirect - difference between two
 Normal 1 mg/dl. Upto 15% maybe direct
 Delta fraction/ Bili-protein-- CB with albumin. T1/2 is 14
days( normal is 4 hrs)

14. Properties Unconjugated Conjugated
Normal serum fraction 85% 15%
Water solubility (polarity) 0 (non polar) + (polar)
Affinity to lipids (Kernicterus) +++ 
Renal excretion Nil +
Vanden Berg Reaction Indirect Direct
Temporary Albumin Binding +++ 0
Irreversible Delta Bilirubin 0 ++
14

16.  Is it isolated elevation of serum bilirubin ?
 If so, is the↑unconjugated or conjugated fraction?
 If not,is it accompanied by other liver test abnormalities ?
 Is the disorder hepatocellular or cholestatic?
 If cholestatic, is it intra- or extrahepatic?
Answers can be sought by careful history, physical
examination, lab tests and radiological procedures

18.  Duration of jaundice – Acute / Chronic
 Painful/painless jaundice
 Accompanying symptoms- fever,
dyspepsia,arthralgia, myalgia, rash, weight
loss,loss of appetite,back pain,
 Exposure to medications- OTC/ prescribed/
alternative
 Parenteral exposures- transfusions, iv abuse

19.  Tatoos, alcohol history, sexual promiscuity
 Family history- hemolytic anemias,
congenital hyperbilirubinemias, wilson
disease
 Recent travel history
 Occupational history- rats

20.  G/E:
› Anemia- hemolysis/ca/cirrhosis
› Gross wgt loss- ca/severe malabsorption
› Hunched up position- pancreatic ca
› Primary sites- breast,colon,stomach, thyroid, lung
› Lymph node- virchow/ sister mary joseph nodules
 Fetor hepaticus, flapping tremor-impending hepatic coma
 Skin changes: scratch marks, melanin pigmentation,
xanthoma of eyelids- chronic cholestasis

21.  Stigmata of chronic liver disease –spider nevi, palmar
erythema, gynecomastia, caput medusa, dupuytrens
contractures, parotid enlargement or testicular atrophy.-
advanced alcoholic cirrhosis
 Bruising, purpuric spots- clotting defects-
thrombocytopenia of cirrhosis
 Ankle edema- cirrhosis, IVC obstn due to hepatic,
pancreatic malignancy

22.  Abdominal examination- Size and consistency of liver and
spleen
 A grossly enlarged nodular liver or an obvious abdominal mass
suggests malignancy
 Small liver- severe hepatitis/cirrhosis
 An enlarged tender liver could signify
› viral or alcoholic hepatitis;
› an infiltrative process such as amyloidosis; or, less often,
› an acutely congested liver secondary to right-sided heart failure.

23.  Choledocholithiasis- GB area may be tender;
murphy sign +
 Palpable, visibly enlarged GB- pancreatic ca
 Splenomegaly- hemolytic states, hodgkin’s,
portal HT
 Ascites- cirrhosis/ abd malignancy

25.  Look for serum bilirubin
› If < 1 mg%--- normal,
› if > 2.5 mg %--- elevated.
 If isolated elevation of bilirubin, check for
direct fraction
› direct < 15% -- indirect ( Pre-hepatic)
› direct > 15% -- direct ( hepatocellular and obst)

26. Hemolysis- inherited or acquired
SB rarely > 5 mg%
If above, check for c0-existent renal,
hepatic dysfunction or r/o sickle cell
crisis
Chronic hemolysis- high incidence of
gallstones-- obstruction
Rifampicin, probenecid,
ribavirin,flavaspidic acid– decreases
hepatic uptake of bilirubin for
conjugation

27.  Criggler-najjar type 1:- AR pattern
Complete absence of UDPGT activity
Mutation in 3’ domain of the gene
No conjugation at all
Severe jaundice ( UCB > 20 mg/dl)
Kernicterus, leading to death in infancy
No response to phenobarbital

28.  Criggler- najjar type 2 (arias syndrome):
More common than type 1
Mutations in gene cause activity reduction(< 10 %)
SB values in range of 6-25 mg/dl
Survive to adulthood: kernicterus in stress
Enzyme activity induced by phenobarbital
Inheritance not clear; both AD with variable
penetrance and AR
Responds to phenobarbital- ↓ in bilirubin conc by >
25%

29.  Gilbert syndrome:
 3-7 % of popn; M:F = 2-7:1
 enzyme activity upto 30 %
 SB always < 6 mg/dl
 mutation in promoter region of gene, not coding
 jaundice precipitated by fasting, fever, alcohol
 AR pattern
 Also called constitutional hepatic dysfunction/ familial
nonhemolytic jaundice
 Phenobarbital- normalizes serum bilirubin
 Fasting test, nicotinic acid test, phenobarbital test, thin
layered chromatography- diagnostic tests

31.  Dubin-johnson syndrome:
 AR; MRP-2 gene mutation
Liver, macroscpically is greenish-black; (black
liver jaundice), in section, liver cells contain
brown pigment
Chronic, intermittent jaundice with conj.
Hyperbilirubinemia and bilirubinuria

32.  Rotor syndrome:
 probable autosomal recessive inheritance
 similar to dubin-johnson in presentation, but no
brown pigment
deficiency of the major hepatic drug re-uptake
transporters OATP1B1 and OATP1B3

33. Dubin-johnson Rotor
Liver cells contain brown pigment No such pigment
Non-visualisation of GB in OCG GB visualised
BSP clearance delayed; reflux of
conjugated BSP in 90 mins
BSP clearance delayed; no reflux of
conjugated BSP
Total urinary coproporphyrin N Total urinary coproporphyrin elevated
Fraction of isomer 1 > 80% Fraction of isomer 1 < 70%

35.  Aspartate transaminase AST/SGOT
 Alanine transaminase ALT/SGPT
 Alkaline phosphatase with 5’ nucleotidase
 Gamma glutamyl transpeptidase
 Lactate dehydrogenase

36.  Tissues of high metabolic activity
 Heart, liver, s.m, kidney, brain
 Though cytosolic, 80% in liver-
mitochondrial
 AST:ALT > 2 in ALD(mitochondrial damage)

37.  Cytosolic, more specific for liver
 30-50 times in infectious/toxic hepatitis
 Mod. Increase in hepatocellular disease
 Synthesis more sensitive to pyridoxal-5-
phosphate; def. in alcoholics--- lower ALT
levels

38.  ALP-
› non-specific, in placenta, ileal mucosa, kidney,
bone and liver
› rises in obst. Jaundice, SOL liver, cholestasis
› Isolated elevation– bone lesion; elevation along
with 5’-nucleotidase—liver lesion
› Isolated elevation in preg– N in 3rd trimester

39. GGT
› Increased in cholestasis, hepatocellular disease
› Confirms raised ALP of hepato-biliary origin
› Isolated rise in alcohol abuse; monitor cessation of alcohol
consumption in chronic alcoholic
LDH
› Cytosolic enzyme
› ALT:LDH > 1.5– acute viral hepatitis
› ALT:LDH < 1.5– ischemic hepatitis, para toxicity

40. Liver enzymes Normal Range Value
Alkaline phosphatase 25-100 u/L Dx of Obstructive Jaundice
Aspartate transaminase
(AST/SGOT)
14-20 u/l(m)
10-36 u/l(f)
Early Dx and follow up
Alanine transaminase
(ALT/SGPT)
10-40 u/l(m)
7-35 u/I(f)
AST/ALT > 2 in ALD
Gamma glutamyl
transpeptidase (GGT)
7-47 u/L (m)
5-25 u/l(f)
Very sensitive in ALD
Albumin 3.5-5.0 g/dL Assess severity of disease
Prothrombin time (PT) 12-16 s Assess severity of disease
40

41. Abnormal LFT Non hepatic causes
Albumin
Nephrotic syndrome
Malnutrition, CHF
ALP
Bone disease, Pregnancy,
Malignancy , Adv age
AST MI, Myositis, I.M.injections
Bilirubin
Hemolysis, Sepsis,
Ineffective erythropoiesis

43.  Wilson’s disease occurs primarily in young adults; severe liver d in
childhood+f/h of liver d+ neuropsyciatric disturbances -
ceruloplasmin assay(↓d); ↑ hepatic cu and urinary cu
 Autoimmune hepatitis is typically seen in young to middle-aged
women- ANA assay, SMA assay
 alcoholic hepatitis –AST:ALT atleast 2:1, and the AST level rarely
exceeds 300 U/L
 viral hepatitis and toxin --aminotransferase levels >500 U/L, with the
ALT greater than or equal to the AST

44. Hep A IgM antibody
assay
HbsAg &
anti- Hbc assay
HCV RNA load
Anti- HEV IgM assay
CMV,EBV assay

45. Conventional Drugs Natural Substances
Acetaminophen, Alpha-methyldopa Vitamins, Hypervitaminosis A
Amiodarone, Dantrolene, Diclofenac Niacin, Cocaine, Mushrooms
Disulfiram, Fluconazole, Glipizide Aflatoxins, Herbal remedies
Glyburide, Isoniazid, Ketaconazole Senecio, crotaliaria,
Labetalol, Lovastatin, Nitrofurantoin Pennyroyal oil, Chapparral,
Thiouracil, Troglitazone, Trazadone Germander, Senna, Herbal mix.

46. AMA + VE
USG
Dilated ducts
Extra-hepatic
cholestasis
Normal ducts
Intra-hepatic
cholestasis
CT/MRCP
Serology,
AMA, drugs
MRCP/liver
biopsy
Liver
biopsy
negative

47.  USG – valuable but operator dependant
 sensitivity of 55-91% & specificity of 82-95% for biliary obstruction
 Besides it can differentiate intrahepatic from extrahepatic cholestasis,
US can also detect the associated abnormalities such as portal
hypertension, focal lesions & fatty liver.

48.  sensitivity of 63-96% & a specificity of 93-
100% to detect biliary obstruction
 Non-calcified cholestrol gall stones can be
easily missed on CT

49.  not only permits direct visualization of the
biliary tree but also allows therapeutic
intervention
 gold standard test for the evaluation of
extrahepatic biliary disease causing jaundice.

50.  direct contrast visualization of the biliary tree is obtained
via a percutaneous needle puncture of the liver
 useful if there is high biliary obstruction e.g. a tumour at
the bifurcation of the hepatic ducts
 also permits therapeutic intervention such as stent
insertion to bypass a ductal malignancy

51.  MRCP is superior to US & CT in detecting
biliary obstruction.
 It has a sensitivity of 82-100% & a specificity of
92-98% to detect biliary obstruction

52.  Relatively low risk, it is needed in only a minority of cases
with hepatic dysfunction
 Major indications include
› chronic hepatitis,
› cirrhosis,
› unexplained liver enzyme abnormalities,
› hepatosplenomegaly of unknown aetiology,
› suspected infiltrative disorder,
› suspected granulomatous disease

54.  Choledocholithiasis- m.c.c
 P.S.C and IgG4 cholangitis- stricturing of biliary tree– later
responds to glucocorticoids
 AIDS cholangiopathy- infection of bile duct epithelium by
CMV, cryptosporidia
 Mirrizi syndrome- gall stone impacted in cystic duct/GB
neck---compression of CBD
 Pancreatic, GB, ampullary ca, cholangio carcinoma;
ampullary-highest surgical cure rate; others poor prognosis

56.  Infections:
› HBV,HCV- fibrosing cholestatic hepatitis
› EBV, CMV,HAV
 Drugs:
› trimethoprim,sulfamethaxozole,
› Penicillin group,
› cimetidine

57. 57
 Anabolic steroids (testosterone, norethandrolone)
 Antithyroid agents (methimazole)
 Azathioprine (Immunosuppressive drug)
 Chlorpromazine HCI (Largactil)
 Clofibrate, Erythromycin estolate
 Oral contraceptives (containing estrogens)
 Oral hypoglycemics (especially chlorpropamide)

58.  Primary biliary cirrhosis
› Auto-immune, middle aged women
› Destruction of interlobular bile ducts
› Diag by AMA.
 Primary sclerosing cholangitis
› Destruction of larger bile ducts
› Diag by p-ANCA; MRCP/ERCP- segmental strictures

59.  Vanishing bile duct/ adult bile ductopenia
› ↓d no. of bile ducts in liver specimen
› Seen in patients
 Chronic rejection after liver transplant
 GVH disease after bone marrow transplant
 Sarcoidosis, chlorpromazine

60.  Progressive familial intra-hepatic cholestasis (PFIC)
› PFIC1- AR-ATP8B1-childhood
› PFIC2- ABCB11
› PFIC3- MRP-3
 Benign recurrent intra-hepatic cholestasis(BRIC)
› BRIC1-ATP8B1
› BRIC2-ABCB11
› AR pattern; in adulthood; considered benign because
does’nt lead to cirrhosis or ESLD

61.  Cholestasis of pregnancy-
› 2nd & 3rd trimester-
› resolves after delivery
 TPN, benign post-operative cholestasis
 Para-neoplastic syndrome
› HL, MTC,RCC(stauffer’s syndrome)
 Cholestasis in ICU
› Sepsis
› Ischemic hepatitis ( shock liver)
› TPN jaundice

62.  Jaundice after B.M. transplantation
› GVH disease
› Veno-occlusive disease
 P.falciparum malaria
 Sickle cell disease
 Weil’s disease

63.  Jaundice is a hallmark of liver disease.
 Through clinical examination and history
becomes vital in all cases.
 Classified as pre hepatic, hepatocellular and
cholestatis although overlaps do occur.
 Biochemical and radiological evaluation helps in
making a diagnosis.

64. 1. Harrison’s principles of Internal Medicine-19th edition
2. Sherlock’s diseases of Biliary system- 12th edition
3. A manual of Lab. and Diagnostic tests – 9th edition- Frances
fischbach, Marshall.B.Dunning
4. Medscape articles –www.medscape.com