A J Aundice Pres Entation By Doc GP - WordPress
A J a u n dic e P re s e n ta tio n B yDo c G P
The symptoms of jaundice as described iscaused by the deposition of bilirubin inthe tissues secondary to increasedbilirubin levels in the blood. Jaundice is not a disease in itself, butrather a sign that occurs in manydifferent diseases in which there is anelevated plasma bilirubin. Jaundice then is usually a symptom ofan underlying disorder.
Usually the concentration of bilirubin in the bloodmust exceed 2-3mg/dL for the coloration to beeasily visible. The color of the skin and sclerae varydepending on the level of bilirubin. When the bilirubin level is mildly elevated, theyare yellowish. When the bilirubin level is high, they tend to bebrown. The classic definition of jaundice is a serumbilirubin level greater than 2.5 to 3 mg per dL(42.8 to 51.3 µmol per L) Normal range of serum bilirubin is 5-17 m mol/l Jaundice is clinically obvious at 50 m mol/l
Jaundice occurs when there is 1) too much bilirubin being produced for the liver toremove from the blood. (For example, patients withhemolytic anemia have an abnormally rapid rate ofdestruction of their red blood cells that releases largeamounts of bilirubin into the blood), 2) a defect in the liver that prevents bilirubin from beingremoved from the blood, converted to bilirubin/glucuronicacid (conjugated) or secreted in bile, or 3) blockage of the bile ducts that decreases the flow ofbile and bilirubin from the liver into the intestines. (Forexample, the bile ducts can be blocked by cancers,gallstones, or inflammation of the bile ducts). The decreased conjugation, secretion, or flow of bile thatcan result in jaundice is referred to as cholestasis:however, cholestasis does not always result in jaundice.
Jaundice
Bilirubin and Jaundice Jaundice (yellow color of skin, whites of the eyes)may occur when blood levels of bilirubin exceednormal (icterus). Jaundice may be characterized by an increase inunconjugated (indirect) bilirubin, conjugated (direct) bilirubin, or both. Accumulation of bilirubin (usually unconjugated) inthe brain (kernicterus) may result in death. When conjugated bilirubin increases, it may beexcreted, giving a deep yellow-red color to theurine.
CLASSIFICATION Jaundice is usually classified into threemajor forms as described below. However, in clinical practice jaundice isoften more complex than indicated inthis simple classification since theaccumulation of bilirubin may be due todefects at more than one step in themetabolism of bilirubin.
1- PREHEPATIC or HEMOLYTICJAUNDICE usually due to excesshemolysis of red blood cells for whatever cause. 2- HEPATIC or HEPATOCELLULARJAUNDICE 3- POST HEPATIC or OBSTRUCTIVEJAUNDICE
Hemolytic jaundice The liver has the capacity to conjugate and excrete over3000 mg bilirubin per day, whereas the normalproduction of bilirubin is only 300 mg/day. This excess capacity allows the liver to respond toincreased heme degradation with a correspondingincrease in conjugation and secretion of bilirubindiglucuronide. However, massive lysis of red blood cells (forexample, in patients with sickle cell anemia ormalaria) may produce bilirubin faster than the livercan conjugate it. More bilirubin is excreted into the bile, the amount ofurobilinogin entering the enterohepatic circula tionis increased, and urinary urobilinogen is increased.Unconjugated bilirubin is elevated in blood
Hepatocellular jaundice: Damage to liver cells (for example, inpatients with cirrhosis or hepatitis) causes adecrease in both bilirubin uptake andproduction of conjugated bilirubin.Unconjugated bilirubin occurs in the bloodand increased urobilinogen in the urine. Theurine is dark in color and stools are a pale,clay color. Plasma levels of AST (SGOT) andALT (SOPT) are elevated and the patientexperiences nausea and anorexia.
Obstructive jaundice: In this instance jaundice is not due tooverproduction of bilirubin, but results fromobstruction of the bile duct. For example, thepresence of a hepatic tumor or bile stones mayblock the bile ducts, preventing passage ofbilirubin into the intestine. Patients withobstructive jaundice experience GI pain,nausea, and produce stools that are a pale,clay color. The liver “regurgitates”conjugated bilirubin into the blood, which isexcreted in the urine. [ Prolonged obstruction of the bile duct can leadto liver damage and a subsequent rise inunconjugated bilirubin.]
Table of the causes of jaundiceJaundicePre-hepaticCauseCaused by anything which causes an increased rate ofhemolysis (breakdown of RBC’s).Malaria (in tropical countries)Genetic diseases, such as glucose 6-phosphatedehydrogenase deficiency.Defects in bilirubin matabolism. HepaticAcute hepatitisHepatotoxicityAlcoholic liver disease.Less common causes include:Primary Biliary CirrhosisGilbert’s syndromeMetastatic carcinomaNeonatal jaundice
Infiltrative diseases ofthe liverDiseases in which the liver is filled with cells orsubstances that don’t belong there. Example:Most commonMetastatic cancer to the liver (usually fromcancers within the abdomen).UncommonIron (hemochromatosis)alpha-one antitrypsin (alpha-one antitrypsindeficiency)Copper (Wilson’s disease). Inflammation of the bile Diseases causing inflammation of the bile ducts, forexample, primary biliary cirrhosis or sclerosingductscholangitis and some drugs, can stop the flow of bileand elimination of bilirubin and lead to jaundice.Blockage of the bileductsMost common:gallstonespancreatic cancerLess common:cancers of the liver and bile ducts
Post-hepaticCaused by an interruption to the drainage of bile in thebiliary system.Most common causes:Gallstones in the common bile ductPancreatic cancer in the head of the pancreas.Other causes:Strictures of the common bile duct, ductal carcinomaPancreatitisPancreatic pseudocystsMirizzi’s syndrome NORMALOBSTRUCTIVE
Developmental Rare instances in which the bile ducts do not developabnormalities of normally and the flow of bile is interrupted. These diseasesusually are present from birth though some of them may firstbile ductsbe recognized in childhood or even adulthood.Examples are:Cysts of the bile duct (choledochal cysts)Caroli’s disease
PregnancyIntrahepaticcholestasis ofpregnancyCholestasis ofpregnancy Bile pools in the gallbladder because of the pressure in theabdomen with pregnancy.Occur during the third trimesterIs often accompanied by itching, the itching can be severe,but there is treatment (ursodeoxycholic acid or ursodiol).Pregnant women with cholestasis usually do well althoughthey may be at greater risk for developing gallstones.There appears to be an increased risk to the fetus fordevelopmental abnormalities.It has been hypothesized that it is the increased estrogensduring pregnancy that are responsible for the cholestasis ofpregnancy.
Pre-eclampsiaPreviously called toxemia of pregnancyOccurs during the second half of pregnancyIt may result inhigh blood pressurefluid retentiondamage to the kidneysanemia ,reduced numbers of platelets due to destruction ofred blood cells and platelets.It often causes problems for the fetus.Although the bilirubin level in the blood is elevated in preeclampsia, it usually is mildly elevated, and jaundice isuncommon. Treatment of pre-eclampsia usually involvesdelivery of the fetus as soon as possible if the fetus ismature. Acute fatty liverof pregnancy Unclear causeOften is associated with pre-eclampsiaOccurs late in pregnancy and results in failure of the liver.There is an increased risk of infant death. Jaundice iscommon, but not always present in AFLP.Treatment usually involves delivery of the fetus as soon aspossible.
Causes of JaundicePRE-HEPATIC– Physiologic Jaundice/Neonatal Jaundice– Hemolytic Anemia– Hemolysis caused by genetic diseases, such as glucose 6phosphate dehydrogenase deficiency– Hereditary RBC Disorders ex. Sickle cell anemia, spherocytosis– Hemolysis in Malaria– Splenomegaly– Ineffective erythropoiesis– Side effects of drugs– Defects in bilirubin metabolism– Kidney failure– Erythroblastosis fetalis– Transfusions– Diseases of small blood vessels ex. microangiopathic hemolysis– Poisons ex. Snake venom– Artificial heart valves
Causes of JaundiceINTRA-HEPATIC– Hepatitis– Hepatotoxicity– Hypoxic– Autoimmune– Alcoholic liver disease ex. cirrhosis– Primary biliary cirrhosis– Failure of conjugation eg. Crigler-Najjar– Gilbert’s Syndrome– Metastatic Carcinoma.– Neonatal Jaundice– Starvation– Side effects of drugs– Circulating infections
Causes of JaundicePOST-HEPATIC allstonesPancreatic cancer in the head of the pancreas.Srictures of the common bile ductDuctal CarcinomaPancreatitisPancreatic pseudocystsMirizzi’s SyndromeBirth defectsinfections that damage the bile ductsSide effects of drugsPhysical injury.Pregnancy
Examples of hyperbilirubinemiaA. Hemolytic anemiaB. HepatitisC. Biliary duct stoneexcesshemolysis unconjugated bilirubin(in blood) conjugated bilirubin(released to bile duct) unconjugated bilirubin(in blood) conjugated bilirubin(in blood) unconjugated bilirubin(in blood) conjugated bilirubin(in blood)
Hepatobiliary System &Jaundice1.Overload bilirubin thatthe liver can’t remove2.Defect in the liver thatprevents removalbilirubin from blood,subsequent conjugation orsecretion into bile.3.Bile duct obstruction4.The decreasedconjugation, secretion, orflow of bile that can resultin jaundice is referred toas cholestasis: however,cholestasis does not
Not all causes of jaundice are the direct result of liverdisease (e.g. extravascular hemolysis and extrahepaticbile duct obstruction). Most diseases resulting in jaundice are acquired withviral hepatitis representing the most common cause inadults and physiologic jaundice of the newborn, themost common cause in children. A few genetic diseases also directly involve the liver(e.g. Gilbert syndrome, Wilson’s disease).
Causes of Jaundice Jaundice occurs when there is 1) Too much bilirubin being produced for theliver to remove from the blood. (For example,patients with hemolytic anemia have anabnormally rapid rate of destruction of their redblood cells that releases large amounts of bilirubininto the blood). 2) A defect in the liver that prevents bilirubinfrom being removed from the blood, convertedto bilirubin/glucuronic acid (conjugated) orsecreted in bile. 3) Blockage of the bile ducts that decreases theflow of bile and bilirubin from the liver into theintestines. (For example, the bile ducts can beblocked by cancers, gallstones, or inflammation ofthe bile ducts). The decreased conjugation, secretion, or flow of bilethat can result in jaundice are collectively referredto as cholestasis: *remember that cholestasis doesnot always result in jaundice.
Clinical diagnosis
Evaluation of Jaundice
Jaundice - Laboratory Tests
Hemolytic Anemia ("Indirect"), Hepatitis ("Mixed"), BiliaryDuct Stones ("Direct")
Evaluation Protocol
Additional detail for those who want todelve deeper into the issue of Jaundice,follows.
Genetic disorders causing jaundice There are several rare genetic disorderspresent from birth that give rise to jaundice. Crigler-Najjar syndrome is caused by a defect inthe conjugation of bilirubin in the liver due to areduction or absence of the enzyme responsiblefor conjugating the glucuronic acid to bilirubin. Dubin-Johnson and Rotor’s syndromes arecaused by abnormal secretion of bilirubin intobile. The only common genetic disorder that maycause jaundice is Gilbert’s syndrome whichaffects approximately 7% of the population.
Jaundice can be caused by a malfunction inany of the three phases of bilirubinproductionPREHEPATIC CAUSESINTRAHEPATIC CAUSESPOSTHEPATIC CAUSES
Pre hepatic JaundicePrehepatic/hemolytic jaundice,where too many red blood cellsare broken down.
Normally, the human body produces about 4 mgper kg of bilirubin per day from the metabolismof heme. Approximately 80 percent of the heme moietycomes from catabolism of red blood cells, withthe remaining 20 percent resulting fromineffective erythropoiesis and breakdown ofmuscle myoglobin and cytochromes. Bilirubin is transported from the plasma to theliver for conjugation and subsequent excretion.
The liver has the capacity to conjugateand excrete over 3000 mg bilirubin perday, whereas the normal production ofbilirubin is only 300 mg/day. This excess capacity allows the liver torespond to increased heme degradationwith a corresponding increase inconjugation and secretion of bilirubindiglucoronide.
The conditions that lead to pre hepatic jaundice include: 1) rapid destruction of red blood cells (referred to ashemolysis), 2) a defect in the formation of red blood cells that leadsto the over-production of hemoglobin in the bone marrow(called ineffective erythropoiesis), or 3) absorption of large amounts of hemoglobin whenthere has been much bleeding into tissues (e.g., fromhematomas, collections of blood in the tissues). Some of the situations that cause hemolytic crises orand pre hepatic jaundice are listed in the next slide.
Prehapatic jaundice may result when there is excessive heme degradation asoccurs in the hemolytic anemias in which there is a reduced abnormalhalf life of RBC, and haemolysis due to:Intrinsic factors1. Membrane disorders( e.g. Spherocytosis)2. Enzyme abnormalitiesGlucose-6-phosphate dehydrogenase deficiency3. Autoimmune disordersParasite invasion (malaria), bacterial4. Defect in Hb structure(e.g. Sickle cell disease, thalassemias)Extrinsic factors5. DrugsChemical haemolysis
With severe hemolysis, more bilirubin isreleased into the blood than can betransported to and conjugated in the liver. Unconjugated and total bilirubinincrease and may produce jaundiceand kernicterus.
Prehepatic Jaundice occurs when there is toomuch bilirubin being produced for the liver toremove from the blood, as a result ofhemolytic crises for what ever cause. Prehepatic jaundice results when there isbilirubin production beyond the disposalability of the liver. (For example, patients with hemolytic anemiahave an abnormally rapid rate of destruction oftheir red blood cells that releases large amountsof bilirubin into the blood).
Pre-hepatic jaundice results from theinability of the liver to handle anincreased bilirubin load, due to thesaturation of the enzyme glucuronyltransferase. When the enzyme glucuronyltransferase becomes saturatedconjugation of bilirubin stops resultingin excessive unconjugated bilirubin inthe blood resulting in jaundice As a result of this, the unconjugatedbilirubin is elevated in blood.
The yellow discolouration is less marked than thatseen in hepatic and extra-hepatic aetiologies, but it maybe difficult to observe clinically. Total serum bilirubin is increased and it ispredominantly unconjugated. There is no urinary bilirubin. Serum aminotransferases, alkaline phosphatase,albumin and globulin are all within the normal range,because there is no damage of liver cells. Hemolytic crisis may be confirmed by lowhemoglobin and elevated reticulocyte counts
Pre-HepaticJaundiceClinicalFeatures Due to excess production ofbilirubin by hemolysis orblood disease Jaundice not typically severe Increase in blood indirect( bilirubin unconjugatedplasma bilirubin Normal urobilinogen in urine Normal stercobilin withnormal stool color AP. ALT, AST - normal
Positive Signs for Pre-Hepatic Jaundice Lack of bile in the urineRapid onset of jaundice (acute hemolysis)Jaundice with feverJaundice with splenomegalyYellow skin color of a lighter degree than seems indicated for degree of bilirubinemiaAnemia with microspherocytosisAnemia with positive Coombs TestIncreased urobilinogen in urine or stool especially when urine lacks bile.Absence of bradycardia, itching, or hemorrhagic tendencyFamilial history of jaundice -.especially if cured by splenectomyCholelithiasis at an early age - or similar history in relativesFrank reticulocytosis with jaundiceAbnormal rouleau formationIncrease in RBC fragilityHyperbilirubinemia of indirect Van den Berg type with negative or low direct typeHepatic function tests normal in a jaundiced patientColor of stools darker than usualBone marrow showing normoblastic hyperplasiaHistory of "abdominal crisis" with jaundicePositive blood culture with a hemolytic organismIngestion of chemical with a known hemoltyic effectiveTransfusion reactionJaundice in heart failure
Glucose 6 Phosphate Dehydrogenase is of special interest, and soa few notes are included here. Deficiencies of certain enzymes of the pentose phosphate pathwayare major causes of hemolysis of red blood cells, resulting in onetype of hemolytic anemia. The principal enzyme involved is glucose-6-phosphatedehydrogenase (G6PD). G6PD deficiency is an inherited disease characterized byhemolytic anemia caused by the inability to detoxify oxidizingagents.
G6PD deficiency is the most common diseaseproducing enzyme abnormality in humans,affecting more than 200 million individualsworldwide. More than 200 million people in the world mayhave genetically determined low levels of thisenzyme. A mutation present in some populations causesa deficiency in G6PD, with consequentimpairment of the generation of NADPH. This X-linked enzyme deficiency is, in fact, afamily of deficiencies caused by over 400different mutations in the gene coding forG6PD.
The impairment in G6PD deficiency ismanifested as red cell hemolysis when thesusceptible individual is subjected to oxidants,such as the anti-malarial primaquine, aspirin,or sulfonamides, or when the susceptibleindividual has eaten fava beans. The life span of many individuals with G6PDdeficiency is somewhat shortened as a result ofcomplications arising from chronic hemolysis.
Hepatic Jaundice
In the hepatocyte, the unconjugated bilirubin isconjugated with a sugar via the enzymeglucuronosyltransferase and is then soluble inthe aqueous bile. Unconjugated bilirubin is insoluble in water butsoluble in fats. Therefore, it can easily crossthe blood-brain barrier or enter the placenta. Hepatic jaundice results from failure in thefunction of hepatocytes to take up, metabolizeor excrete bilirubin.
Etiology of intrahepatic hyperbilirubinemiaUnconjugated Types:Gilbert’s Syndrome: hypofunction liver enzyme: bilirubin-glucoronosideglucuronosyl transferase (5% US population!)Crigler-Najjar syndrome: complete absence bilirubin-glucuronoside glucuronosyltransferase Wilson Disease:defect in serum ceruloplasmin leading to abnormalcopper metabolism
In Gilbert- & Crigler Najjar - syndrome there is arespiratory hypofunction of bilirubin-glucuronosideglucuronosyl transferase to absence: no complex formation,no excretion of bilirubin into bile duct!
Gilbert's syndrome Gilbert’s Syndrome is a common and benign, hereditary disorder thataffects approximately 5-7% of the U.S. population.This inherited disorder is thought to be due to an inborn error of bilirubinmetabolism that causes a mild reduction in the activity ofglucuronosyltransferase - the enzyme responsible for conjugating theglucuronic acid to bilirubin.The increase in bilirubin in the blood usually is mild and infrequentlyreaches levels that cause jaundice.It manifests itself during periods of stress, fasting or illness withsymptoms such as mild jaundice, weakness, fatigue, nausea andabdominal pain.There is a slight to moderate increase in the indirect fraction of serumbilirubin but all other liver function values are within normal limits.These changes are usually transient in nature and their is no need topursue treatment or liver biopsy.
Crigler-Najjar Syndrome A rare genetic defect (autosomalrecessive) where there is the inability toform bilirubin glucoronide. This is due to the abs
Causes of Jaundice PRE-HEPATIC – Physiologic Jaundice/Neonatal Jaundice – Hemolytic Anemia – Hemolysis caused by genetic diseases, such as glucose 6-phosphate dehydrogenase deficiency – Hereditary RBC Disorders ex. Sickle cell anemia, spherocytosis – Hemolysis in Malaria – Splenomegaly – Ineffective erythropoiesis – Side effects .
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