‘AACN Glial issue Volume 10, Number 4, pp. 423-441 (© 1999, AACN Differentiation and Diagnosis of Jaundice Patti L. Hass, RN, MSN [Bilirubin metabolism is a complex and fascinating example of the body's ability to discard, renew, and recycle vital elements, Jaundice is the warning sign for derangements in this system, As is true of pain, jaundice Is a powerlul impetus for visiting a healthcare provider. Usually associated with hepatitis by a nonclinician, the origins of jaundice can range from benign to fatally malignant, Patients may have any number of idiopathic or nosocomial conditions that can contribute to an icteric state. This raview delineates the steps of bilirubin metabolism, enumerates the sources of bilirubin derangement, and examines elements of patient condition and therapeutics that can contribute to hyperbilirubineria and jaundice. (KEYWORDS: jaundice, bilirubin, hyperbilirubinemia, ioterus) OThe Production of Bilirubin Bilirubin production begins with the destruc- tion of aged red blood cells (RBCs), which accounts for 80% of the compound heme (protoporphyrin). Immature ceils of erytiro- poiesis released from the spleen or bone marrow and other heme-containing organic compounds such as cytochromes and myo- globin make up the remaining 20%. Degra- dation of senescent RBCs begins with changes in the cell’s osmotic gradient, re- duced production of adenosine triphos: phate, and formation of methemoglobin in- side the erythrocyte.! Macrophages in the spleen select these aged and dysfunctional cells for destruction. The mononuclear phagocytes break down the RBCs and re- lease the compounds heme and globin, the two component parts of the hemoglobin molecule. Globin is reduced to its base amino acids and recycled into circulation. Heme is further degraded into iron and biliverdin, a pigment, The iron is recycled into the’ iron pool. Enzymes in the macrophages of the liver (Kupffer cells), spleen, and bone marrow reduce biliverdin to unconjugated bilirubin. ‘The unconjugated form of bilirubin is not water soluble but binds tightly to circulating albumin as a means of transport to the liver.? In the liver, the sinusoidal channels bathe the hepatocytes in portal blood. Here, albu- From the Department of Outcomes and Case Man- agement, University Health System, San Antonio, iL. Hass, RN, MSN, Depart- iyement, University 1X Reprint requests to P: ment of Outcom Health System, 4502 Medi 78229-4493, 433434 = HASS AACN Clinical Issues min releases the unconjugated bilirubin, and it crosses the cell membrane into the cyto- plasm of the hepatocyte where it is again bound for transport inside the cell toward the conjugation process.34 Che Conjugation Process Conjugation is necessary before bilirubin can move into the canaliculi of the liver toward the biliary tree. Once in the hepatocyte, glu- curonic acid combines with the lipid-soluble bilirubin and converts it into a water-soluble form that allows it to be excreted in bile. This conjugated bilirubin is expressed as ei- ther diglucuronide or monoglucuronide. Monoglucuronide accounts for a lesser amount of conjugated bilirubin in the adult, but this disproportion narrows when the amount of circulating unconjugated bilirubin is increased, as in hemolysis. It is estimated that between 200 and 300 mg of bilirubin is, formed each day from the breakclown of ap- proximately 6 g of hemoglobin.5¢ O&xcretion of Bilirubin ‘The excretion of conjugated bilirubin (diglu- curonide and monoglucuronide) from the hepatocyte takes place through an energy- dependent, carrier-mediated process. Failure of the hepatocyte to excrete conjugated bilirubin quickly enough can cause reflux of the conjugated form into the circulation,” It then binds with albumin to form delta biliru- bin; the importance of this substance will be discussed in the Laboratory Evaluations sec- tion, Once in the bile can: bilirubin combines with biliary cholesterol, phospholipids, bile acids, bile salts, and bi- carbonate, The resultant bile flow moves through the right and left hepatic ducts that join to form the common hepatic duct, then join again with the cystic duct of the gall- bladder to form the common bile duct, Bile fills a normally functioning gallbladder to a capacity of approximately 50 mL during fast- ing and empties during 2 meal. In 85% to 90% of people, the common bile duct joins with the pancreatic duct at the ampulla of ‘Vater. Bile flow continues through the com- uli, conjugated mon bile duct toward the sphincter of Oddi, where it empties into the duodenum. The re- mainder of the population has pancrea and biliary drainages that empty separately into the duodenum.' Obstruction at any of these points impedes the flow of bile. Because the conjugated form of bilirubin is water soluble, it traverses most of the length of the small intestine without real sorption, protecting the enterohepatic circu- lation from a reload of bilirubin, Bacteria in the distal small bowel and colon reduce the bilirubin conjugates to urobilinogens, some of which are reabsorbed into the enterohep- ulation for excret or re-excretion by the liver. Further oxida- tion of urobilinogen in the colon converts the substance to urobilin and stercobilin, which cannot be reabsorbed and is excreted in feces, providing the character tation of stool.5# Unconjugated bilirubin that is tightly bound to albumin is not cleared through the glomerulus and thus is not excreted in urine, Conjugated bilirubin may be excreted in urine, because it is water-soluble and is no longer bound to a large plasma protein. The small amount that is cleared in the urine is responsible for the usual yellow color of urine. The dark urine typically seen in ob- structive jaundice is the result of the clear- ance of water-soluble conjugated bilirubin through the kidney when it cannot be ex- creted through the bowel. CMechanisms for Hyperbilirubinemia and Jaundice Derangement in bilirubin metabolism is identified by the location of the anomaly: prehepatic or hepatobiliary. In the past, medical hyperbilirubinemia referred to the prehepatic or hematologic basis for jaundice, and the surgical form referred to an obstruc- tion of the outflow of bile from the liver. Hy- perbilirubinemia can also be described as unconjugated or conjugated. Narrowing the focus of derangement by location guides the investigation for the type of disorder. Faulty prehepatic metabolism includes those conditions that increase the load of bilirubin on the liver and overwhelm the conjugation process. Prehepatic dysfunctionVol. 10, No. 4 November 1999 JAUNDICE = 435 also refers to a failure of the albumin trans- port of unconjugated bilirubin into the hepa- tocyte. A poor nutritional state or any condi- tion that leads to plasma protein loss, as with burns, can account for unconjugated hyper- bilirubinemia and jaundice. Portocaval shunting allows unconjugated bilirubin to circumvent the liver. An increase in unconju- gated bilirubin can also be seen when there is drug competition for binding sites on al- bumin. Hepatobiliary dysfunction involves the in- tracellular mechanisms for conjugation or the flow of bile through the biliary tree, Any condition that impairs hepatic blood flow can impair function of the organ, affecting the enzymatic processes of the hepatocytes. Congestive heart failure and ischemic or hy- poxemic events can result in this type of dysfunction, ‘There are occasional circumstances of un- conjugated hyperbilirubinemia that are miti- gated by factors well past the point of he- patic bilirubin excretion. Therefore, the term is not exclusively a reference to prehepatic disease? Perhaps most helpful, hyperbilirubinemia can be categorized by the type of dysfunc- tion as erythropoietic, hepatocellular, or cholestatic, Erythropoiesis is the process of RBC formation. Mature cells live 120 days; immature cells or those with faulty cell walls or function may degrade sooner. This occurs at the same time that normal senescent RBC degradation is occurring, Premature clestruc- tion of RBCs or any condition that con- tributes to bilirubin release and adds to the load that must be processed by the liver is a form of erythropoietic dysfunction. Condi- tions that lead to the destruction of faulty RBCs and the release of bilirubin into the circulation are seen in Table 1. Causes for the excessive destruction of RBCs from ex- traneous causes are listed in Table 2. Hepatocellular dysfunction refers to faulty biochemical processes that fail to support bilirubin uptake into the hepato- cyte, bind to intracellular protein, undergo conjugation, or are excreted into bile path- ways. The dysfunction can be an alteration in hepatocyte cell membrane or the failing or absence of intracellular enzymatic processes, as seen in Table 3.58 TABLE 1 = Prehepatic Dyserythropoiesis Red Blood Cells Are Released Into Circulation Prematurely or Have a Defect in Structure That Leads to Early Demise of the Cell® * Sickle cell anemia + Thallesemia + Folate deticiency *Pernicious anemia + Iron deficiency anemia + Sideroblastic anemia + Erythropoietic porphyria + Spherooytosis, + Lead poisoning Cholestatic dystunction includes obstruc- tive problems that are intrahepatic or extra- hepatic and refers to the failure of bile to flow from the hepatic collection system to the duodenum." Examples are listed in Ta- bles 4 and 5. Overlap in these distinctions can be found when disease states affect bilirubin metabolism several ways. Hepatitis, for ex- ample, adversely affects intracellular biliru- bin metabolism through an acute-phase in- flammatory process intrahepatic), by rearrangement of liver architecture (cholestatic), and by failure later in the di ease in the synthesis of albumin and other plasma proteins (erythropoietic).4 TABLE 2 ® Prehepatic Hemolysis Destruction of Red Blood Cells Not Directly Related to the Condition of the Cell Itself * Acquired hemolytic anemia * Inherited hemolytic anemia + Thermal injury * Injection of venom isseminated intravascular coagulation + Prosthetic heart valve + Hemodialysis, + Pyruvate kinase deficiency + Extravasation of red blood cells (intracorporeal hemorrhage, as in bone fractures, retroperitoneal bleeding, crush injury or multiple trauma)" * Intra-aortic balloon pump436 = -HASS TABLES ® Hepatocellular Sources for Bilirubin, Derangement** Dysfunctional uptake—unconjugated bilirubin is unable to enter the hepatocyte. ‘+ Impedance by certain drugs—ritampin, probenecid + Reflux of unconjugated bilirubin from the hepatocyte Dysfunctional conjugation—anomaly in the formation of diglucuronide (BDG) and monogluouronide (BMG). * Crigler-Najjar Type |. Rare and fatal genetically transmitted disease, there is No conjugation activity in the hepatocyte. * Crigler-Najjar Type Il. Less severe than type |, there is minimal conjugation activity in the hepatocyte but response to therapy. * Gilberts disease. Usually benign, there is evidence of multitactoral derangement that may involve cellular reflux of bilirubin and impaired excretion. AACN Clinical Issues Dysfunction of bilirubin storage and excretion from the hepatocyte. * Dubin-Johnson syndrome + Rotor syndrome Damage to hepatocytes or hepatic architecture from chronic or acute disease. * Cirrhosis, hepatitis + Tuberculosis'* + Epstein-Barr, cytomegalovirus varicella + Drug and environmental toxins + Acetaminophen overdose + Autoimmune disease ‘+ Metabolic disorders (alpha ,-antitrypsin deficiency, Wilson's disease) CNeonatal Jaundice Neonatal jaundice can occur through the overproduction or underexcretion of biliru- bin, inherent or nosocomially induced errors in metabolism, or a combination of these factors. Physiologic jaundice describes the constellation of elements that contribute to jaundice in the healthy, term neonate in whom no disease can be identified. Some degree of jaundice can occur from the nor- mal transitional functions surrounding birth. For example, meconium stool is high in bilirubin and also contains an enzyme that disconjugates it. The released bilirubin is ef- fectively cleared by the placenta prenatally. Because little or no intestinal flora has yet developed that converts urobilinogen to uro- bilin, more is absorbed through the intestinal wall. At birth, a delayed passage of meco- nium stool allows reabsorption of disconju- gated bilirubin into the enterohepatic circu- lation of the neonate. Excretion of bilirubin can be adversely af= fected by prematurity, sepsis, hepatic hy- poperfusion, and reabsorption of intestinal bilirubins Maternal-fetal blood incompatibil: ity results in the premature destruction of RBCs, as does birth trauma or the induction of labor. Drugs, such as sulfonamides, ceftri- axone, and moxalactam, can affect the bind- ing of bilirubin to albumin and delay its transport to the liver. Other drugs linked to hyperbilirubinemia in the neonate are pan curonium bromide and chloral hydrate. Of interest is the phenomenon of uncon- jugated hyperbilirubinemia found in exclu- sively breast-fed infants.” Although there are suggestions that this may be related to caloric intake, intestinal flora, fluid intake, weight loss, or some yet-to-be identified substance in breast milk, « definitive mecha- nism remains unknown. Treatment of neonatal jaundice is in- tended to reduce unconjugated bilirubin and assist in its metabolism, because it correlates more closely with the development of biliru- bin encephalopathy (kernicterus) than does an elevation in total bilirubin, Methods to promote transport, conjugation, and excre-Vol. 10, No. 4 November 1999 JAUNDICE = 437 TABLE 4 ® Intrahepatic Cholestasis'® The Interruption of Bile Excretion From the Canalicular Membrane to the Main Intrahepatic Ducts + Medications—anabolic and contraceptive steroids, chlorpromazine, haloperidol, erythromycin, captopril, semisynthetic penicillins, carbamazepine, nonsteroidal anti-inflammatory drugs, nitrofurantoin, oral hypoglycemics, and antithyroid medications. * Cholestasis of pregnancy’ + Idiopathic benign recurrent cholestasis, * Congenital cystic disease of the liver, (Carol's disease) * Acquired cystic disease (hydatid cyst from the Echinococcus granulosus tapeworm)* + Sepsis + Total parenteral nutrition + Hodgkin's disease imary biliary cirrhosis + Primary or metastatic cancers of the liver tion of bilirubin include early and trequent feedings that inhibit reabsorption from the intestinal tract and promoting choleresis (the movement of bile through the biliary tree). Phototherapy changes circulating bilirubin to a more water-soluble form that can be ex- creted in bile or urine, Exchange transfusion precludes the antigenic response of blood in- compatibility. Frequent breastfeeding pat- terns promote stooling and rid the intestinal tract of meconium. Interruption of the en- terohepatic reabsorption of bilirubin from the intestine includes the administration of bind- ing agents such as cholestyramine or acti- vated charcoal, Prenatal maternal administra tion of phenobarbital or diphenythydantoin can enhance the synthesis of conjugated bilirubin in the hepatocytes of a fetus with low levels of the conjugating enzyme BGT CHyperbilirubinemia and Clinically Evident Jaundice Jaundice refers to the staining of skin and ‘mucous membranes with the pigment biliru- bin. Jaundice and icterus are both derived from words meaning yellow. An examiner's skill and experience, the light source, the length of time the patient has had jaundice, and the source of the jaundice are all factors that influence the observer's ability to clini cally detect jaundice. Hyperbilirubinemia is usually manifest and detectable as jaundice when blood levels are at least 2 to 3 mg/dL.!4 Because of the affinity of bilirubin for albumin, tissues or fluids that have a high protein content demonstrate a yellow cast first, as clo exudates. The sclera, frenulum of the tongue, soft palate, tunica media of the blood vessels, and skin all contain elastic ti sue to which bilirubin binds tightly. With a half-life of albumin at about 14 days, jaun- dice in the patient recovering from hepato- cellular or cholestatic disease may last well beyond the normalization of results of biliary laboratory tests. Other disorders that can pro- duce discoloration of tissues do not stain the sclera, thus making differentiation possible.s Conjugated bilirubin is more water solu ble and produces a more profound and gen- eralized coloration as it stains extravascular fluids and urine in patients with hepatocellu- lar or cholestatic disease. A darkening of the urine is noted before changes in the sclera, skin, or stool, because the bi quickly cleared from the kidneys. Scleral icterus is often not noted by the affected per- son but is brought to the person’s attention by an acquaintance. When there is an ob- struction to the normal passage of bile, the stools lose normal pigmentation; therefore, pale or clay-colored stools are found most often in patients with cholestatic disease, The development of jaundice is highly iable from disease to clisease. The pre- va TABLES # Extrahepati Cholestasis. * Biliary disease, including cholelithiasis, choledocholithiasis, biliary stricture, cho- langiocarcinoma, cholangitis. * Surgical complication such as retained common bile duct stone, migratory surgical clip, alteration in blood supply to pericholic organs. * Pancreatic disease, including pancreatitis, pancreatic pseudocyst, and cancer at the head of the panoreas. + Small and large bowel disease, including diverticulitis, irtable bowel syndrome, Crohn's disease, ulcerative colitis,438 = HASS hepatic or erythropoietic diseases usually produce jaundice in a shorter time. Hepato- cellular diseases also produce some degree of jaundice but in a longer time or only in the later stages. Cholestatic diseases variably produce jaundice, depending on the degree of obstruction and length of time during which it has occurred." A complete obstruc- tion of the common bile duct produces ele- vated levels of bilirubin that level off, even when the obstruction persists. Acute phase illnesses with a rapid increase in serum bilirubin also tend to include icterus as part of the clinical picture. OPhysical Assessment of the Patient With Jaundice ‘A thorough history, findings in a physical examination, and results of routine labors tory studies elucidate for the clinician a provisional diagnosis in most cases of jaun- dice. Patients are likely to report the sud- den onset of jaundice but dismiss other suggestive symptoms. Cachexia, nausea, changes in stool character, and right upper quadrant pain may exist for a far longer time without prompting intervention (au- thor’s observation). Few cases of jaundice represent a true medical emergency. The history should in- clude length of time and severity of symp- toms, history of familial disease, recent travel or exposure to toxins, medications, and pre- vious surgeries or injuries, especially of the abdominal cavity or biliary tree, Reports of abclominal pain should be care~ fully investigated. Severe pain with fever, ors, and hypotension should suggest ascend- ing cholangitis with imminent septicemia, an emergent condition, The elderly person may have nonclassic pain or absence of pain, even when there is clearly disease. Symp- toms related to clsease of the hepatobiliary system may be vague or diffuse and may not correlate with the severity of the disease. A significant pancreatic pseudocyst. may not cause pain but leaves the patient with a fee!- ing of fullness in the right upper quadrant of the epigastrium. Carcinoma of the pancreas may be described as a dull, constant ache that is relieved by hunching the back for- ward. Obstructions of the biliary tee may AACN Clinical Issues appear as sudden, excruciating pain that can radiate from the right upper quadrant, to the back. Careful questioning often re veals a procirome of nebulous gastrointesti nal symptoms: weight loss, early satiety, loss of appetite, changes in bowel habit, or fatigue.s20.21 An assessment of drug use, past or pre- sent, should be elicited, When a history of in- haled or ingested illicit crugs is present, a high index of suspicion should be main- tained regarding the possibility of intra- venous use, An estimation of alcohol use or abuse can be obtained using the CAGE ques- tioning technique; two or more responses correlate with excessive alcohol intake or al- coholism. ‘The questions are: Have you wanted to cult back on your drinking? Have you been annoyed by another's comments about your drinking? Have you ever felt guilty about your drinking? Have you ever needed an eye opener in the morning? Over- the-counter medications or “health foods” can contain compounds that promote cholestasis or result in hepatocellular disease. Pruritus is reported in most patients experiencing cholestatic jaundice and malignant diseases On physical examination, the shape and contour of the abdomen should be ob- served. Courvoisier’s siga is a markedly dis- tended gallbladder that is both visible and palpable and can accompany neoplastic conditions of the biliary tree. These gradu- ally obstructing lesions of the common bile duct allow a normal gallbladder to overfill, whereas a sudden obstruction of the duct with a diseased gallbladder, as in choledo- cholithiasis, does not, The liver should be palpated for smoothness or nodularity and the liver's span estimated. The clinician should observe for the constellation of signs of alcoholic liver disease: ascites, ca- put medusae, palmar erythema, and spider hemangiomas, Cholecystitis causes a pa- tient to halt inspiration suddenly when the fingers of the examiner are “hooked” over the lower edge of the liver—a positive Mur- phy’s sign, Laboratory Evaluation Laboratory evaluation of the patient with jaundice cannot provide direct answers about the nature of the derangement; usu-Vol. 10, No. 4 November 1999 JAUNDICE = 439 ally, the results must be considered as a whole for analysis. Although secretory com- ponent, a biliary protein, has been found to increase in mechanical cholestasis of rats,22 no single test in general use delineates whether cholestatic jaundice is caused by an intrahepatic or extrahepatic process. ‘The transaminases are the standard-bear- ers for the evaluation of liver dlisease, be- cause these enzymes are released directly from damaged hepatocytes. Aspartate aminotransferase (AST) and alanine amino- transferase (ALT) are found in higher con- centrations in the liver, but AST activity is in- creased! in the presence of alcohol. For th reason, an AST-ALT ratio higher than 2:1 should suggest alcohol involvement. Less specific is alkaline phosphatase (ALP), which is released from several body tissues but has a hepatic isoenzyme. When released from the liver cell into the bile canaliculi, ALP can squeeze through tight junctions be- tween hepatocytes or directly cross the cell membrane to enter the sinusoidal blood. Like ALP, y-glutamyl transpeptidase (GTP) plays a less significant role; it can confirm the hepatic origin of ALP and is often ele- vated in the presence of alcoholic liver dis- ease or acute alcohol ingestion 5# Measurement of total bilirubin levels can be low, normal, or high in the presence of significant hepatobiliary disease because of the liver’s reserve ability to conjugate up to 1,500 mg of bilirubin; the usual daily output is one third that amount, Quantification of the total does not discern between conju- gated and unconjugated bilirubin; “fractiona- tion” is necessary to differentiate the amounts of each. Indirect bilirubin is circ lating unconjugated bilirubin and accounts for more than 90% of the measured total. The indirect fraction is measured by sub- acting the direct amount from the total amount. This process requires the addition of another chemical to differentiate this frac- tion from the whole; thus, it is referred to as lirect. Direct bilirubin is conjugated biliru- bin plus delta bilirubin (conjugated bilirubin. that has entered the circulation and com- bined with albumin)? The testing process for conjugated bilirubin is direct, because it produces a measurable color change in vitro without the addition of other agents. Be- cause the direct measure includes delta bilirubin, it is not a true reflection of circulat- ing conjugated bilirubin but is a highly sug- gestive clue to hepatobiliary disease, be- cause there can be an increase in this fraction without a significant increase in the total. An elevation in either of the compo- nents can produce jaundice, however, The complete blood count and differen- tial cell count heralds erythropoietic prob- Jems, such as anemia, spherocytosis, or the leukocytosis of an acute inflammation. Pro- thrombin time may be elevated when there is a decrease in the amount of vitamin K, as in cholestatic jaundice or when there is fail- ure in utilization of adequate levels of vita- min K, as with parenchymal liver disease Fecal and urine studies are less direct and more variable and are not generally included in a routine work-up.& Other Studies Ultrasonography has taken the place of the oral cholecystogram to view mechanical ob- structions of the gallbladder or common bile duct, because it is faster to perform, does not involve radiation, and is without gastroin- testinal side effects. Sonograms can provide views of single or multiple echogenic stones and determine whether there is dilation of bile ducts. Thickening of the gallbladder wall and pericholecystic fluid collections found in chronic inflammation can also be demonstrated on ultrasound. Computerized tomography (CT) scanning is less specific for gallstones butt is more use- ful to pinpoint the location of biliary ob- struction in the absence of dilated ducts ancl is more specific for the identification of pan- creutic mass lesions that can also cause ob- struction and cholestasis. When neoplastic disease is suspected, CT scanning can iden- tify simultaneously the possible sites of metastatic implants within the abdominal cavity. Scintigraphy of the hepatobiliary system involves the injection of a radionucleotide whose uptake and excretion in the liver are competitive with naturally occurring orga ions This method been of the most use in determining the site of partial obstruction in nonicteric cholestatic conditions, such as with acute acalculus cholecystitis and chole- cystic sludge.440 = HASS Endoscopic retrograce cholangiopancre- atography is increasingly popular, because it provides diagnostic and therapeutic pos- sibilities for patients with extrahepatic ob- structive cholestasis. Well tolerated by pa- tients, ERCP enables the examiner to visualize the esophagus, stomach, proximal duodenum, common bile duct and pancre- atic ampulla directly. Sphincterotomy of a strictured duct, stent placement, stone re- moval, and biopsy can be performed through the instrument. Percutaneous cholangiography does not have the same therapeutic potential, has a slightly higher morbidity rate, and’ requires an invasive technique through the liver. Simultaneous liver biopsy may be helpful in the demon- stration of infiltrative or diffuse liver disease and when cholestasis is suspected to be in- trahepatic. It is not an early diagnostic tool in the evaluation of jaundice.420 Implications for Practice Critically ill patients undergo numerous inva- sive techniques and are exposed to multiple pharmacologic agents in the course of their care. Many of these factors can exacerbate existing liver disease and promote cholesta- sis. Jaundice is consistent with morbidity and mortality in these patients, particularly as a result of sepsis.2 In one study of patients with viral-induced cirthosis, bilirubin was the sole prognosticator for survival, indepen- dent of demographics and comorbidit An influx of endotoxin activates Kupffer cells in the liver to release cytokines, inter- leukins, tumor necrosis factor, and other in- flammatory mediators, unless the cells have endured insult. Obstructive cholestasis shown to inhibit Kupffer cell functioning and is linked to the translocation of bacteria from the gut. The appearance of systemic it flammatory response syndrome and multiple organ failure without a source of infection may be the sequelae of an interrupted im- mune response of the gut related to biliary dysfunction. Although hepatocellular dam- age from previous or chronic hepatitis or cir- thosis may cause jaundice, patients with pre- existing liver disease should be investigated for new-onset biliary obstruction when there is new-onset jaundice. Patients with he- AACN Clinical Issues molytic clisease and worsening bilirubinemia should be evaluated for cholelithiasis and common duct stones, particularly when. there is concomitant renal disease or when transfusions are administered.25 The administration of total parenteral nu- trition, transfusions, and many drugs can procluce some degree of hyperbilirubinemia, with or without jaundice, Efforts to use en- tert! nutrition earlier in the clinical course preserve the gut barrier defense and pro- mote biliary tree drainage.2 Meticulous maintenance of invasive access sites. mini mizes the opportunity for pathogens to mi grate and allows Kupffer cells to manage the acute-phase illness, Efforts to limit blood col- lection and the judicious administration of blood cellular components helps to preserve native cells and decrease the bilirubin load. Sources of bleeding should be rapidly identi- fied and hemostasis achieved.” OSummary Although many biochemical processes of the liver remain to be identified, there are algo- rithms to aid in the diagnosis of human he- patobiliary disease with jaundice.20 Based on abnormal test results that often clo not mani- fest until significant damage has occurred, hepatic transplantation has become one an- swer to organ failure, It is hoped! that earlier detection and intervention, with considera tion of environmental, traumatic, and genetic causal factors will decrease the morbidity and mortality associated with hepatobiliary system dysfunction and hyperbilirubinemia, References 1, McCance KL, Huether SE. In Brotmiller WG, ed, Pathophysiology: The Biological Basis for Disease in Adults and Children. St. Louis: CV Mosby; 1990, Zucker SD, Goessling W, Gollan JL. Kinetics of bilirubin transfer between serum albumin and__membrine ve J Biol Chem 1995;270:1974. 3. Gourley GR. Bilirubin metabolism and ker- nicterus, Adv Pecliatr 1997;44:173-229. 4, Sherlock 5, Dooley J. Diseases of the Liver ana Biliary System. 10th ed, Oxford, UK: Black- well Science; 1997.Vol. 10, No. 4 November 1999 JAUNDICE = 441 5. 6 10. rt 12, 13, 14, 7. . Moseley RH, A molecular bat Ostrow JD, ed. Bile Pigments and Jaundice. New York: Marcel Dekker; 1986. Johnson PJ, McFarlane IG. The Laboratory In- vestigation’ of Liver Disease, Philadelphia: Builliere Tindall; 1989. for jaundice and intrahepatic and extrahepatic cholestasis. Hepatology 1997;26:1682-1683. Traber PG, Gumucio JJ. Approach to the pa- tient with jaundice. in Yamado T, ed. Text- book of Gastroenterology. Philadelphia: JB Lippincott; 1991:810-828. Bimbaum A, Suchy FJ. ‘The intrahepatic cholangiopathies. Semin Liver Dis 1998;18: 263-269. ‘Truner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998;339:1217-12: Emmick RH Jr, Petersen SR. Evaluation of pancreatic injury after blunt abdominal trauma, Ann Emerg Med! 1996;27:658-661 Sort P, Mas A, Salmeron JM, Bruguera M, Rodes J. Recurrent liver involvement in heat- stroke, Liver 1996;16:335-337. Lee TM, Kuo SH, Lee YT. Case report: Re versible systolic heart failure and deep dice in hyperthyroidism. Am J Med Sci 1996;312:246-248, Caroli-Bose FX, Conio M, Maes B, Chevallier P, Hastier P, Delmont JP. Abdominal tubercu- losis involving hepatic hilar lymph nodes: A cause of portal vein thrombosis and port hypertension, J Clin Gastroenterol 197,25: 541-543.16. . Arazi G, Dufour PH, Puech F. Jaundice in- duced by hyperemesis gravidarum. Int J Gy- naecol Obstet 1998;61:181-183. . Herline AJ, Fisk JM, Debelak JP, Shull HJ Jr, Chapman WC. Surgical clips: A cause of kite recurrent gallstones. Am Surg 198;6+ 815-848. Maisels MJ, Kring E. Length of s 101:995-998. 18. 20, 21. 22. 23, ). Hernandez-Z: Katz SK, Gordon KB, Roenigk HH. The cuta- neous manifestations of gastrointestinal dis- Prim Care 1996;23:455~476, MA, Saab, S. The clinical detection of is: Observations of multiple ex- aminers. Mil Med 1997;8:560-563. Frank BB, et al, Clinical evaluation of jaun- dice. JAMA 1989;262:3031-3034 Reisman Y, et al. Physician's working diagno- compared to the Euricterus Real Life D: iagnostic Tool rial in three jaunclice data- bases: Euricterus Dutch, independent prospective and independent retrospective, Hepatogastroenterology _1997;44:1367-1375. Versland MR, Wu GY, Gorelick FS, Larkin JM. Serologic assay for secretory component dis- tinguishes mech: from _ hepatocellular choles in humans. Dig Dis Sci 1997;42:2246-2253. Welsh FK, Ramsclen CW, MacLennan K, et al Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice. ‘Ann Surg 1998;227:203-212. Gentilini P, et al. Long course and prognostic factors of virus-induced cirthosis of the liver. Am J Gastroenterol 1997;92:66-72. Lazaidis KN, Kamath PS. 28-year-old man with renal insufficiency and jaundice. Mayo Clinic Proc 1997;72:1057-1060. Wright HR, Gear AJ, Morgan RF, Edlich RF. Asymptomatic jaundice after fasting: A diag- nostic dilemma. J Emerg Med 1997;15: 781-784, . Michalopoulos A, Alivizatos P, Geroulanos $. Hepatic dysfunction following cardi surgery: Determinants and consequences. Hepatogastroenterology 1997344:779-783. Fragile fossils (transcrip). The New Explorers. Arts & Entertainment Network, 1999. vals A, Del Razo LM, Aguiar C, argas GG, Borja VH, Cebrian ME, Al