harrison 19th edition, refernce from shiela sherlock, kuntz

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