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An approach to jaundice

excerpts from harrison... reference from sheila sherlock and kuntz

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An approach to jaundice

  1. 1.  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!!!!
  2. 2.  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
  3. 3.  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.
  4. 4.  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)
  5. 5. 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
  6. 6.  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)
  7. 7.  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
  8. 8. Heme oxygenase – microsome Biliverdin reductase-- cytosol
  9. 9. 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
  10. 10. 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
  11. 11. * • 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
  12. 12.  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)
  13. 13. 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
  14. 14.  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
  15. 15.  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
  16. 16.  Tatoos, alcohol history, sexual promiscuity  Family history- hemolytic anemias, congenital hyperbilirubinemias, wilson disease  Recent travel history  Occupational history- rats
  17. 17.  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
  18. 18.  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
  19. 19.  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.
  20. 20.  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
  21. 21.  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)
  22. 22. 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
  23. 23.  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
  24. 24.  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%
  25. 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, 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
  26. 26.  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
  27. 27.  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
  28. 28. 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%
  29. 29.  Aspartate transaminase AST/SGOT  Alanine transaminase ALT/SGPT  Alkaline phosphatase with 5’ nucleotidase  Gamma glutamyl transpeptidase  Lactate dehydrogenase
  30. 30.  Tissues of high metabolic activity  Heart, liver, s.m, kidney, brain  Though cytosolic, 80% in liver- mitochondrial  AST:ALT > 2 in ALD(mitochondrial damage)
  31. 31.  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
  32. 32.  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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36.  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
  37. 37. Hep A IgM antibody assay HbsAg & anti- Hbc assay HCV RNA load Anti- HEV IgM assay CMV,EBV assay
  38. 38. 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.
  39. 39. AMA + VE USG Dilated ducts Extra-hepatic cholestasis Normal ducts Intra-hepatic cholestasis CT/MRCP Serology, AMA, drugs MRCP/liver biopsy Liver biopsy negative
  40. 40.  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.
  41. 41.  sensitivity of 63-96% & a specificity of 93- 100% to detect biliary obstruction  Non-calcified cholestrol gall stones can be easily missed on CT
  42. 42.  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.
  43. 43.  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
  44. 44.  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
  45. 45.  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
  46. 46.  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
  47. 47.  Infections: › HBV,HCV- fibrosing cholestatic hepatitis › EBV, CMV,HAV  Drugs: › trimethoprim,sulfamethaxozole, › Penicillin group, › cimetidine
  48. 48. 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)
  49. 49.  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
  50. 50.  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
  51. 51.  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
  52. 52.  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
  53. 53.  Jaundice after B.M. transplantation › GVH disease › Veno-occlusive disease  P.falciparum malaria  Sickle cell disease  Weil’s disease
  54. 54.  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.
  55. 55. 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

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