AN APPROACH TO JAUNDICE

KATHIRAVAN.A.RPOST GRADUATE

INTERNAL MEDICINE, KMC

ETYMOLOGY 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!!!!

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

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.

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)

Differential diagnosis1. Carotenemia – carrots and mangoes –

mainly seen in palms, soles, forehead, nasolabial folds- sclera sparing

2. Lycopaenemia – excessive tomatoes3. Acriflavin,Fluorescine,Picric acid

staining4. Quinacrine, busulfan

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)

Bilirubin metabolism 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

Bilirubin handling

Heme oxygenase – microsomeBiliverdin reductase-- cytosol

Bilirubin inside hepatocyte

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

Bilirubin in intestine

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

Bilirubin in kidneys

*•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

How to measure? 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)

Bilirubin – And its natureProperties 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 DirectTemporary Albumin Binding +++ 0

Irreversible Delta Bilirubin 0 ++14

Bilirubin- in a nutshell

Approach– questions? 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

History 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

Tatoos, alcohol history, sexual promiscuity

Family history- hemolytic anemias, congenital hyperbilirubinemias, wilson disease

Recent travel history Occupational history- rats

Physical examination 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

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

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.

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

Lab. tests 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)

Hemolysis- inherited or acquiredSB rarely > 5 mg%If above, check for c0-existent renal, hepatic dysfunction or r/o sickle cell crisisChronic hemolysis- high incidence of gallstones-- obstruction

Rifampicin, probenecid, ribavirin,flavaspidic acid– decreases hepatic uptake of bilirubin for conjugation

Syndromes Criggler-najjar type 1:- AR pattern

Complete absence of UDPGT activityMutation in 3’ domain of the geneNo conjugation at allSevere jaundice ( UCB > 20 mg/dl)Kernicterus, leading to death in infancyNo response to phenobarbital

Criggler- najjar type 2 (arias syndrome):More common than type 1Mutations in gene cause activity reduction(< 10 %)SB values in range of 6-25 mg/dlSurvive to adulthood: kernicterus in stressEnzyme activity induced by phenobarbitalInheritance not clear; both AD with variable

penetrance and ARResponds to phenobarbital- ↓ in bilirubin conc by >

25%

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, alcoholAR patternAlso called constitutional hepatic dysfunction/ familial

nonhemolytic jaundicePhenobarbital- normalizes serum bilirubinFasting test, nicotinic acid test, phenobarbital test, thin

layered chromatography- diagnostic tests

Isolated elevated BR with direct >15%

Dubin-johnson syndrome: AR; MRP-2 gene mutationLiver, macroscpically is greenish-black;

(black liver jaundice), in section, liver cells contain brown pigment

Chronic, intermittent jaundice with conj. Hyperbilirubinemia and bilirubinuria

Rotor syndrome: probable autosomal recessive inheritance similar to dubin-johnson in presentation,

but no brown pigmentdeficiency of the major hepatic drug re-

uptake transporters OATP1B1 and OATP1B3

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%

Liver enzymes Aspartate transaminase AST/SGOT Alanine transaminase ALT/SGPT Alkaline phosphatase with 5’

nucleotidase Gamma glutamyl transpeptidase Lactate dehydrogenase

AST/SGOT Tissues of high metabolic activity Heart, liver, s.m, kidney, brain Though cytosolic, 80% in liver-

mitochondrial AST:ALT > 2 in ALD(mitochondrial

damage)

ALT/SGPT 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

Others 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

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 alcoholicLDH› Cytosolic enzyme› ALT:LDH > 1.5– acute viral hepatitis› ALT:LDH < 1.5– ischemic hepatitis, para toxicity

Liver Function Tests (LFT)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

Non Hepatic causes of abnormal LFTAbnormal LFT Non hepatic causes

Albumin Nephrotic syndromeMalnutrition, CHF

ALP Bone disease, Pregnancy,Malignancy , Adv age

AST MI, Myositis, I.M.injections

Bilirubin Hemolysis, Sepsis, Ineffective erythropoiesis

Hepatocellular patternAST/ALT ↑d; ALP N

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

Acute viral hepatitis

Hep A IgM antibody assay

HbsAg & anti- Hbc assay

HCV RNA load

Anti- HEV IgM assay

CMV,EBV assay

Hepato toxic drugsConventional Drugs Natural SubstancesAcetaminophen, 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.

Cholestatic patternALP↑d; out of proportion to ALT/AST

AMA + VE

USG

Dilated ductsExtra-hepatic cholestasis

Normal ductsIntra-hepatic cholestasis

CT/MRCP

Serology, AMA, drugs

MRCP/liver

biopsyLiver

biopsy

negative

Imaging procedures- USG 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.

CT sensitivity of 63-96% & a specificity of

93-100% to detect biliary obstruction Non-calcified cholestrol gall stones

can be easily missed on CT

ERCP 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.

PTC 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

MRCP 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

Liver Biopsy 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

Extra-hepatic cholestasis

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

Intra-hepatic cholestasis

Infections:› HBV,HCV- fibrosing cholestatic hepatitis› EBV, CMV,HAV

Drugs: › trimethoprim,sulfamethaxozole,› Penicillin group,› cimetidine

Drugs causing Cholestasis

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)

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

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

Familial forms 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

Other causes 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

Jaundice after B.M. transplantation› GVH disease› Veno-occlusive disease

P.falciparum malaria Sickle cell disease Weil’s disease

Take home!! 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.

References1. Harrison’s principles of Internal Medicine-19th edition2. Sherlock’s diseases of Biliary system- 12th edition3. A manual of Lab. and Diagnostic tests – 9th edition-

Frances fischbach, Marshall.B.Dunning4. Medscape articles –www.medscape.com

Thank u!!!