Classical anatomic landmarks in the average 1400-1800 gram adult liver. Structure The liver is encased in a fibroelastic capsule called Glisson's capsule and is grossly separated into right and left lobes. Glisson's capsule contains blood vessels, lymph vessels, and nerves. The two liver lobes consist of many smaller units called lobules. The lobules contain the liver cells (hepatocytes) that line up together in plates. The hepatocytes are considered to be the functional units of the liver. Liver cells are capable of cell division and readily reproduce when needed to replace damaged tissue.
The liver is nothing more than an array of cells between the portal and caval venous systems. This shows the direction of flow. The liver gets about 80% of its blood supply from the portal veins and 20% from the hepatic arterial system. The IDEAL three-dimensional diagram: Hexagonal Hepatic “LOBULE” From the point of view of anatomy, physiology, and pathology, you must clearly understand the DIRECTION is: Portal vein Sinusoids Central vein Hepatic Veins IVC Crucially important concept worth repeating. KNOW the difference between an acinus and a lobule. The best tip to understanding liver disease is to understand the direction of blood flow. TOXIC injuries generally do more damage in the part of the liver closest to the PORTAL vein, and HYPOXIC injuries generally do more damage in the parts of the liver around the CENTRAL vein, i.e., centrolobular necrosis.
The classical view of liver tissue from a liver biopsy, H&E stained. The FIRST part of the lobule, i.e., portal triad is the FIRST to get blood flow, so it is also the FIRST to get the brunt of general toxic effects, and the LAST to get the brunt of ischemic effects. The LAST part of the lobule, central vein!
Bilirubin Biotransformation Bilirubin is a product of red blood cell breakdown. When a red blood cell has lived out its 120-day life span, the cell membrane becomes fragile and ruptures. Hemoglobin is released and is acted upon by circulating phagocytic cells to form free bilirubin. Free bilirubin binds to plasma albumin and circulates in the bloodstream to the liver. Free bilirubin is considered unconjugated in that, although it is bound to albumin, the binding is reversible. Once in the liver, bilirubin releases from albumin and, because free bilirubin is lipid soluble, moves easily into the hepatocytes. Once inside the hepatocytes, bilirubin is rapidly bound to another substance, usually glucuronic acid, and is now considered conjugated. Conjugated bilirubin is water soluble, not lipid soluble. Most conjugated bilirubin is actively transported into the bile canaliculi. From there it is delivered along with the other components of bile to the gallbladder or small intestine. A small amount of conjugated bilirubin does not go to the intestine as a bile component, however, but rather is absorbed back into the bloodstream. Therefore, in the bloodstream, there is always a small amount of conjugated bilirubin present, along with unconjugated bilirubin on its way to the liver. Once in the intestine, conjugated bilirubin is acted upon by bacteria and changed into urobilinogen. Most urobilinogen enters the bloodstream and is excreted by the kidneys in the urine, some is excreted in the stool, and some is recycled back to the liver in the enterohepatic (intestinal to liver) circulation. Figure shows the steps involved in the conjugation and excretion of bilirubin. The conjugation of bilirubin is essential for its excretion. Without conjugation, bilirubin cannot be excreted by either the kidneys or the intestines. The handling of bilirubin by the liver is a form of metabolic detoxification. Without conjugation, unconjugated bilirubin would build up in the bloodstream to toxic levels.
- Coinfection with HIV and Hepatitis C is a significant problem, especially among injection drug users In the United States it estimated that 240,000 persons are infected with both HCV and HIV. Studies estimate that as many as 25-30% of HIV positive people in the United States are coinfected with HCV and up to 10% of HCV positive person are infected with HIV. In urban areas of the US, up to 90% of person who acquired HIV infection from injection drug use also have HCV. HCV accelerated in the setting of HIV: Increased risk for cirrhosis HCV frequently “drives prognosis” in co-infected pts: making treatment more difficult
HAART - Highly Active Antiretroviral Therapy
Biochemical profile of Jaundice MUHAMMAD MUSTANSAR
JAUNDICEDR MUHAMMAD MUSTANSAR
LiverLiver• Largest internal organ• Weighs about 1400-1800 gram• Located on right side underribcage• Ability to regenerate• Has over 500 vital functions• Involved in many digestive,vascular and metabolicactivities
Introduction• Bilirubin is the orange-yellow pigment derived fromsenescent red blood cells.• It is a toxic waste product in the body.• It is extracted and biotransformed mainly in the liver, andexcreted in bile and urine.• It is a bile pigment• Elevations in serum and urine bilirubin levels are normallyassociated with Jaundice.
Erythrocytes become “old” as they lose their flexibilityand become pikilocytes (spherical), increasingly rigidand fragile. Once the cell become fragile, they easilydestruct during passage through tight circulationspots, especially in spleen, where the intra-capillaryspace is about 3 micron as compared to 8 micron ofcell sizeRBCs useful life span is 100 to 120 days,Afterwhich they become trapped and fragment in smallercirculatory channels, particularly in those of the spleen.For this reason, the spleen is sometimes called the “redblood cell graveyard.”Dying erythrocytes are engulfed and destroyed bymacrophages.
Formation of Bilirubin• Primary site of synthesis:-SPLEEN: The Graveyardof Red Blood Cells• Secondary site of synthesis:-LIVER & BONE MARROW
An average personproduces about 4mg/kg of bilirubinper day. The daily bilirubinproduction from allsources in manaverages from 250to 300 mg.TOTAL BILIRUBINHEMOGLOBINFROM SENESCENTRBC’S DESTROYED INRETICULOENDOTHELIALCELLS OFLIVER, SPLEEN &BONE MARROWRBC PRECURSORSDESTROYED IN THEBONE MARROW85% 15%CATABOLISM OFHEME-CONTAININGPROTEINS (MYOGLOBIN,CYTOCHROMES &PEROXIDASES)
Extravascular Pathway for RBC Destruction(Liver, Bone marrow,& Spleen)HemoglobinGlobinAmino acidsAmino acid poolHeme BilirubinFe2+ExcretedPhagocytosis & LysisRecycled
• The globin is recycled or converted into amino acids, whichin turn are recycled or catabolized as required.• Heme is oxidized, with the heme porphyrin ring beingopened by the endoplasmic reticulum enzyme, hemeoxygenase.• The oxidation occurs on a specific carbon producingequimolar amounts of the biliverdin, iron , and carbonmonoxide (CO). This is the only reaction in the body that isknown to produce CO.• Most of the CO is excreted through the lungs, with theresult that the CO content of expired air is a direct measureof the activity of heme oxygenase in an individual.
III IVI IIOxidation Heme OxygenaseIn the first reaction, abridging methylenegroup is cleaved byheme oxygenase toform Linear Biliverdinfrom Cyclic Hememolecule.Fe 2+ is released fromthe ring in this process.
• In the next reaction, a secondbridging methylene (betweenrings III and IV) is reduced bybiliverdin reductase,producing bilirubin.II IIIIII IVIVIIIIReduction Biliverdin Reductase
• biliverdin causing a change in the color of the moleculefrom blue-green (biliverdin) to yellow-red (bilirubin).• The latter catabolic changes in the structure of tetrapyrrolesare responsible for the progressive changes in color of ahematoma, or bruise, in which the damaged tissue changesits color from an initial dark blue to a red-yellow and finallyto a yellow color before all the pigment is transported out ofthe affected tissue.• Peripherally arising bilirubin is transported to the liver inassociation with albumin, where the remaining catabolicreactions take place.• biliverdin causing a change in the color of the moleculefrom blue-green (biliverdin) to yellow-red (bilirubin).• The latter catabolic changes in the structure of tetrapyrrolesare responsible for the progressive changes in color of ahematoma, or bruise, in which the damaged tissue changesits color from an initial dark blue to a red-yellow and finallyto a yellow color before all the pigment is transported out ofthe affected tissue.• Peripherally arising bilirubin is transported to the liver inassociation with albumin, where the remaining catabolicreactions take place.
Bilirubin is not very water-soluble, so most of it is carried to the liver bound toalbumin.
In cells of the liver, bilirubin undergoes modification toincrease its water solubility so that it can be excreted moreeasily.a.Bilirubin is conjugated to twomolecules of glucuronic acid, creatingbilirubin diglucuronide.b. Bilirubin diglucuronide is transportedout of the hepatocytes into the bilecanaliculi and is thus excreted in bile.In cells of the liver, bilirubin undergoes modification toincrease its water solubility so that it can be excreted moreeasily.a.Bilirubin is conjugated to twomolecules of glucuronic acid, creatingbilirubin diglucuronide.b. Bilirubin diglucuronide is transportedout of the hepatocytes into the bilecanaliculi and is thus excreted in bile.
In Blood• The bilirubin synthesized inspleen, liver & bone marrowis unconjugated bilirubin.• It is hydrophobic in nature soit is transported to the liveras a complex with theplasma protein, albumin.Unconjugated bilirubin– Lipid soluble– : limits excretion– 1 gm albumin binds 8.5mg bilirubin– Fatty acids & drugs candisplace bilirubin– Indirect positive reactionin van den Bergh testUnconjugated bilirubin– Lipid soluble– : limits excretion– 1 gm albumin binds 8.5mg bilirubin– Fatty acids & drugs candisplace bilirubin– Indirect positive reactionin van den Bergh test
Role of Blood Proteins in theMetabolism of Bilirubin1. AlbuminDissolved in Blood
BloodLiverLigandin(-) chargeLigandin(-) chargeLigandin Prevents bilirubin fromgoing back to plasma
In Endoplasmic ReticulumIn the microsomes of the endoplasmic reticulum,unconjugated bilirubin is converted to water solublemono- or di- conjugates by sequential covalentcoupling with glucuronic acid.
Bilirubin is conjugated ina two step process toform bilirubin mono- &di- glucuronide
Conjugation with GlucoronatesBILIRUBIN DIGLUCORONIDE
In the Intestine• In the small intestine, conjugated bilirubins are poorlyreabsorbed, but are partly hydrolyzed back to unconjugatedbilirubin by catalytic action of bacterial ß-glucuronidases.• In the distal ileum and colon, anaerobic flora mediate furthercatabolism of bile pigments:a) hydrolysis of conjugated bilirubin to unconjugated bilirubin bybacterial β-glucuronidases;b) multistep hydrogenation (reduction) of unconjugated bilirubin toform colorless urobilinogens; andc) oxidation of unconjugated bilirubin to brown coloredmesobilifuscins.
• Urobilinogens is a collectiveterm for a group of 3tetrapyrroles;– Stercobilinogen (6H)– Mesobilinogen (8H)&,– Urobilinogen (12H)• Upto 20 % of urobilinogenproduced daily is reabsorbedfrom the intestine & enters theentero-hepatic circulation.Urobilinogen Structure
• Most of the reabsorbed urobilinogen is taken up by the liver& is re-excreted in the bile.• A small fraction (2 % - 5 %) enters the general circulation &appears in the urine.• In the lower intestinal tract, the 3 urobilinogensspontaneously oxidize to produce the corresponding bilepigments;– Stercobilin– Mesobilin &– Urobilin;which are orange-brown in color and are the majorpigments of stool.
SYMPTOMSSYMPTOMSo Yellowing of the skin, scleras (white of the eye), andYellowing of the skin, scleras (white of the eye), andmucous membranes (jaundice)mucous membranes (jaundice)o Detectable when total plasma bilirubin levels exceedDetectable when total plasma bilirubin levels exceed2mg/100mL2mg/100mLAHHH!!! I have symptomsof hyperbilirubinemia!!!
Clinical SignificanceHyperbilirubinemia & Types of Jaundice• Hyperbilirubinemia : Increased plasma concentrationsof bilirubin (> 3 mg/dl) occurs when there is animbalance between its production and excretion.• Recognized clinically as jaundice.• Also known as icterus, a yellow discoloration of theskin, sclerae and mucous membrane.
• Jaundice becomes clinically evident when the serumbilirubin level exceeds 2.5mg/dL.• Several types of Jaundice:– Hemolytic– Hepatocellular– Obstructive• Symptoms:– Yellow discoloration of the skin, sclerae and mucousmembranes– Itching (pruritus) due to deposits of bile salts on the skin– Stool becomes light in color– Urine becomes deep orange and foamy
Different Causes of Jaundice• Excessive Production of Bilirubin• Reduced Hepatocyte Uptake• Impaired Bilirubin conjugation• Impaired Bile Flow
Prehepatic (hemolytic) jaundice• Results from excess productionof bilirubin (beyond the liversability to conjugate it) followinghemolysis• Excess RBC lysis is commonlythe result of autoimmunedisease; hemolytic disease of thenewborn (Rh- or ABO-incompatibility); structurallyabnormal RBCs (Sickle celldisease); or breakdown ofextravasated blood• High plasma concentrations ofunconjugated bilirubin (normalconcentration ~0.5 mg/dL)
Hepatic jaundice• Impaired uptake, conjugation,or secretion of bilirubin• Reflects a generalized liver(hepatocyte) dysfunction• In this case,hyperbilirubinemia is usuallyaccompanied by otherabnormalities in biochemicalmarkers of liver function
What is Hepatitis?• Inflammation of the liver• Caused by viruses, alcohol, medications, andother toxins• This training will focus on viral hepatitis Hepatitis A Virus (HAV)Hepatitis A Virus (HAV) Hepatitis B Virus (HBV)Hepatitis B Virus (HBV) Hepatitis C Virus (HCV)Hepatitis C Virus (HCV) Hepatitis D Virus (HDV)Hepatitis D Virus (HDV) Hepatitis E Virus (HEV)Hepatitis E Virus (HEV) Hepatitis F Hepatitis G (not confirmed yet).These viruses all affect the liver but otherwise are unique
Acute Hepatitis• Hepatitis can be defined as a constellation ofsigns & symptoms resulting frominflammation & hepatic cell necrosis• In a previously asymptomatic individual theterm “acute” is applied• Virus is the most common cause ofhepatitis.– Only occasionally can bacterial infections likesyphilis or TB be considered• Most cases of acute hepatitis are sub-clinical& usually undiagnosed
Hepatitis A (HAV)Hepatitis A (HAV)At one time, hepatitis A was referred to as "infectious hepatitis" because it could bespread from person to person like other viral infections. Infection with hepatitis A viruscan be spread through the ingestion of food or water, especially where unsanitaryconditions allow water or food to become contaminated by human waste containinghepatitis Found in the stool (feces) of persons infectedFound in the stool (feces) of persons infectedwith hepatitis A viruswith hepatitis A virus HAV is usually spread by “fecal-oralHAV is usually spread by “fecal-oraltransmission”transmission”– Putting something in the mouth (food,Putting something in the mouth (food,water, hands) that has been contaminatedwater, hands) that has been contaminatedwith the stool of a person with hepatitis Awith the stool of a person with hepatitis A– Most infections come from contact with aMost infections come from contact with ahousehold member or sex partner who hashousehold member or sex partner who hashepatitis Ahepatitis A Highly infectious and stable in environment forHighly infectious and stable in environment formonthsmonths
Signs and Symptoms of HAV• jaundice• fatigue• abdominal pain• loss of appetite• nausea• diarrhea• feverAdults have signs and symptoms moreoften than childrenIncubation Period: 15-50 days(average 28 days)
Hepatitis B (HBV)Hepatitis B (HBV)Type B hepatitis was at one time referred to as "serum hepatitis," because it wasthought that the only way hepatitis B virus (HBV) could spread was through bloodor serumAbout 6-10% of patients with hepatitis B develop chronic HBV infection (infectionlasting at least six months and often years to decades) and can infect others aslong as they remain infected. Patients with chronic hepatitis B infection also are atrisk of developing cirrhosis, liver failure and liver cancer. HBV is spread throughHBV is spread throughunprotected sex with an infectedunprotected sex with an infectedpersonpersonby sharing drugs, needles, or "works"by sharing drugs, needles, or "works"when using drugswhen using drugsthrough needlesticks or sharpsthrough needlesticks or sharpsexposures on the jobexposures on the jobfrom an infected mother to her babyfrom an infected mother to her babyduring birthduring birth The best way to protect against HBV isThe best way to protect against HBV isvaccinationvaccination
HBV Structure & AntigensDane particleDane particleHBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)HBcAg = inner core protein (a single serotype)HBeAg = secreted protein; function unknown
There are 4There are 4 open reading framesopen reading frames derived from the same strand (thederived from the same strand (theincomplete + strand)incomplete + strand)• SS - the 3 polypeptides of the surface antigen (- the 3 polypeptides of the surface antigen (preS1, preS2 and SpreS1, preS2 and S --produced from alternative translation start sites.produced from alternative translation start sites.• CC - the core protein- the core protein• PP - the polymerase- the polymerase• XX - a transactivator of viral transcription (and cellular genes?).- a transactivator of viral transcription (and cellular genes?).HBx is conserved in all mammalian (but not avian) hepadnaviruses.HBx is conserved in all mammalian (but not avian) hepadnaviruses.Though not essential in transfected cells, it is required for infectionThough not essential in transfected cells, it is required for infectionin vivo.in vivo.Open Reading Frames
Type C hepatitis was previously referred to as "non-A, non-B hepatitis,Patients with chronic hepatitis C infection are at risk for developing cirrhosis, liverfailure, and liver cancer.The hepatitis C virus (HCV) usually is spread by shared needles among drugabusers, blood transfusion, hemodialysis, and needle sticks. Approximately 90% oftransfusion-associated hepatitis is caused by hepatitis CHepatitis C (HCV)Preventing HCV InfectionPreventing HCV Infection There isThere is nono vaccinevaccine Best prevention is behaviorBest prevention is behaviorchangechange Do not shoot drugsDo not shoot drugs Do not share personal itemsDo not share personal itemssuch as razors or toothbrushessuch as razors or toothbrushes Avoid tattoos or body piercingAvoid tattoos or body piercing
Symptoms of HCV• jaundice• fatigue• dark urine• abdominal pain • loss of appetite• nausea80% of persons have no signs or symptoms80% of persons have no signs or symptomsIncubation Period: 14-180 days (average 45 days)Incubation Period: 14-180 days (average 45 days)• HCV disease does not appear to accelerate HIV diseaseHCV disease does not appear to accelerate HIV disease• Higher toxicity fromHigher toxicity from Highly Active Antiretroviral TherapyHighly Active Antiretroviral Therapy((HAART)HAART)• As people live longer with HIV, manyAs people live longer with HIV, many more HIV deaths aremore HIV deaths arecaused by HCV-related end stage liver diseasecaused by HCV-related end stage liver disease• There is still a lot of research to be done on these effectsThere is still a lot of research to be done on these effectsPotential Co-Infection Effect ofPotential Co-Infection Effect of HCVHCV on HIV Diseaseon HIV Disease
Types D, E, F, and G HepatitisTypes D, E, F, and G HepatitisThere also are viral hepatitis types D, E, F (not confirmed yet), and G. The mostimportant of these at present is the hepatitis D virus (HDV), also known as the delta virusor agent. It is a small virus that requires concomitant infection with hepatitis B to survive.HDV cannot survive on its own because it requires a protein that the hepatitis B virusmakes (the envelope protein, also called surface antigen) to enable it to infect liver cells.Hepatitis D OverviewHepatitis D OverviewCaused by hepatitis D virus (HDV)Caused by hepatitis D virus (HDV)Coined “Delta Hepatitis”Coined “Delta Hepatitis”Rarely seen in the United StatesRarely seen in the United StatesFoundFound onlyonly in persons infected with HBVin persons infected with HBVand has similar routes of transmission as HBVand has similar routes of transmission as HBVPrevention is vaccination for HBVPrevention is vaccination for HBVHepatitis E OverviewHepatitis E OverviewCaused by hepatitis E virusCaused by hepatitis E virusPrimarily a disease of importPrimarily a disease of importVery similar to hepatitis A with fecal-oral transmissionVery similar to hepatitis A with fecal-oral transmissionTransmitted like HAV with the same symptomsTransmitted like HAV with the same symptomsNo vaccination available
HbsAHbsAggAnti-Anti-HHBsBsAnti-Anti-HHBcBcHBeHBeAgAgAnti-Anti-HHBeBeInterpretationInterpretation++ -- IgMIgM ++ -- Acute HBV, high infectivityAcute HBV, high infectivity++ -- IgGIgG ++ -- Chronic HBV, high infectivityChronic HBV, high infectivity++ -- IgGIgG -- ++ Late-acute or chronic HBV infection, lowLate-acute or chronic HBV infection, lowinfectivityinfectivity++ ++ ++ +/-+/- +/-+/- Heterotypic anti-HBs with HBsAg;Heterotypic anti-HBs with HBsAg;usually indicates chronic HBV carrierusually indicates chronic HBV carrierstatestate-- -- IgMIgM +/-+/- +/-+/- Acute HBV infection (anti-HBc window)Acute HBV infection (anti-HBc window)-- ++ IgGIgG -- +/-+/- Recovery from HBV infectionRecovery from HBV infection-- -- IgGIgG -- +/-+/- Low-level HBsAg carrier or remote pastLow-level HBsAg carrier or remote pastinfectioninfection-- ++ -- -- -- Immunization for HBV (with HBsAg)Immunization for HBV (with HBsAg)
Alcoholic Hepatitis• An acute or chronic illness involving the liverwith necrosis, inflammation & scarring• 95% develop a fatty liver which is a reversibleprocess• Encephalopathy & death 20%• 30% go on to cirrhosis within 6 mo• 50% of those abstaining for 6 mo recovercompletely
Alcoholic HepatitisSymptoms• Most patients are symptomatic. The mostcommon complaints are:– Anorexia, nausea, vomiting– Abdominal pain (RUQ)– Fever (due to infection or inflammation of liver)– Weight loss due to anorexia– Jaundice is usually mild– Diarrhea which is due to portal hypertension
• Hemolytic jaundice arises as aconsequence of excessive destructionof RBCs.• – This overloads the capacity of the REsystem to metabolize heme.• – Failure to conjugate bilirubin toglucuronic acid causes accumulation ofbilirubin in the unconjugated form in theblood.
• Hepatocellular jaundice arises fromliver disease, either inherited oracquired.• – Liver dysfunction impairs conjugation ofbilirubin.• – Consequently, unconjugated bilirubinspills over into the blood.• –In addition, urobilinogen is elevated inthe urine.
Ongoing liver damage with liver cell necrosisfollowed by fibrosis and hepatocyteregeneration results in cirrhosis. Thisproduces a nodular, firm liver. The nodulesseen here are larger than 3 mm and, hence,this is an example of "macronodular"
Obstructive jaundiceDefinition :Is a conditioncharacterized byYellow discolorationof the skin , sclera &mucous membrane asa result of an elevatedSr. Bilirubin conc. dueto an obstructive cause.
Posthepatic(Obstructive) jaundice• Caused by an obstruction ofthe biliary tree.• Plasma bilirubin is conjugated,and other biliary metabolites,such as bile acids accumulatein the plasma.• Characterized by pale coloredstools (absence of fecalbilirubin or urobilin), and darkurine (increased conjugatedbilirubin).• In a complete obstruction,urobilin is absent from theurine.
• • Obstructive jaundice, as the name implies,is caused by blockage of the bile duct by agallstone or a• tumor (usually of the head of the pancreas).• – This prevents passage of bile into the intestineand consequently conjugated bilirubin builds upin the blood.• – Patients with this condition suffer severeabdominal pain associated with theobstruction (if due togallstone) and their fecesare gray in color due to lack of stercobilin.
Pre-hepatic Hepatic Post hepaticcause Excessive break downOf RBC’sMalaria,HSGilbert SyndromeInfectiveLiver DamageBile Duct ObstructionSerum Bilirubin unconjugated Both conj+unconj. conjugatedUrine bilirubin AbsentAchloric jaundiceBilirubinemia +Deep yellow urineAs in hepatic jaundice++UrineurobilinogenIncreasesBecause of increasedstercobilinogenDecreasesBecause of decreasedstercobilinogenAbsent(-)Fecalstercobilinogen20-250mg/dayMarkedly increasedDark brown stoolReducedPale coloured stoolAbsentclay colored stoolFecal fat 5-6% normal Increased 40-50%Bulky,pale greasy foulsmelling faecesAs hepatic jaundiceLiver functions normal Impaired SGOT/SGPT NormalAlkaline phosphatase++Vonden burg test Indirect+ biphasic Direct+
Neonatal Jaundice• Common, particularly in premature infants.• Transient (resolves in the first 10 days).• Due to immaturity of the enzymes involved in bilirubinconjugation.• High levels of unconjugated bilirubin are toxic to thenewborn – due to its hydrophobicity it can cross theblood-brain barrier and cause a type of mentalretardation known as kernicterus• If bilirubin levels are judged to be too high, thenphototherapy with UV light is used to convert it to awater soluble, non-toxic form.
• If necessary, exchange blood transfusion is used to removeexcess bilirubin• Phenobarbital is oftentimes administered to Mom prior toan induced labor of a premature infant – crosses theplacenta and induces the synthesis of UDP glucuronyltransferase• Jaundice within the first 24 hrs of life or which takes longerthen 10 days to resolve is usually pathological and needsto be further investigated
CLINICAL FEATURES• Severe unconjugated hyperbilirubinemia at birthPrior to phototherapy:• Kernicterus• Death in infancy
Phototherapy•Phototherapy is usually not neededunless the bilirubin levels rise veryquickly or go above 16-20 mg/dl inhealthy, full term babies.• During phototherapy, thetreatment of choice forjaundice, babies are placedunder blue lights that convertthe bilirubin into compoundsthat can be eliminated fromthe body.
Bilirubin Toxicity - Kernicterus• Kernicterus or brain encephalopathy refers to the yellowstaining of the deep nuclei (i.e., the kernel) of the brainnamely, the basal ganglia.• It is a form of permanent brain damage caused byexcessive jaundice.• The concentration of bilirubin in serum is so high that it canmove out of the blood into brain tissue by crossing the fetalblood-brain barrier.• This condition develops in newborns with prolongedjaundice due to:– Polycythemia– Rh incompatibility between mother & fetus
Isolated increased serum bilirubinRuling out of hemolysis, subsequent fractionation of the bilirubinPossibility of thefollowing syndromes:• Dublin-Johnson• RotorPossibility of following syndromesbased on the bilirubin concentration:• Gilbert’s - <3 mg/dl• Crigler-Najjar (Type I) - >25 mg/dl• Crigler-Najjar (Type II) - 5 to 20 mg/dl• Lucey-Driscoll - Transiently ~ 5 mg/dlAlgorithm for differentiating the familial causes ofHyperbilirubinemiaConjugated Unconjugated
Crigler-Najjar Syndrome (Type I)• Crigler-Najjar Syndrome (Type I) is a rare genetic disordercaused by complete absence of UDP-glucuronyltransferase and manifested by very high levels ofunconjugated bilirubin.• It is inherited as an autosomal recessive trait.• Most patients die of severe brain damage caused bykernicterus within the first year of life.• Early liver transplantation is the only effective therapy.
Crigler-Najjar Syndrome (Type II)• This is a rare autosomal dominant disorder.• It is characterized by partial deficiency of UDP-glucuronyltransferase.• Unconjugated bilirubin is usually 5 – 20 mg/dl.• Unlike Crigler-Najjar Type I, Type II respondsdramatically to Phenobarbital & a normal life can beexpected.
Gilbert’s Syndrome• Gilbert’s syndrome is also called as familial non-hemolyticnon-obstructive jaundice.• mild unconjugated Hyperbilirubinemia.• It affects 3% – 5% of the population. It is often misdiagnosedas chronic Hepatitis.• The concentration of Bilirubin in serum fluctuates between 1.5& 3 mg/dl.• In this condition the activity of hepatic glucuronyltransferase islow as a result of mutation in the bilirubin-UDP-glucuronyltransferase gene(UGT1A1).
Dubin-Johnson Syndrome• It is a benign, autosomal recessivecondition characterized by jaundicewith predominantly elevatedconjugated bilirubin and a minorelevation of unconjugated bilirubin.• Excretion of various conjugatedanions and bilirubin into bile isimpaired, reflecting the underlyingdefect in canalicular excretion.• The Liver has a characteristicgreenish black appearance and liverbiopsy reveals a dark brown melanin-like pigment in hepatocytes andkupffer cells.
Rotor’s Syndrome• It is another form of conjugated hyperbilirubinemia.• It is similar to dubin-johnson syndrome but withoutpigmentation in liver.