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Jaundice Dorota Mańkowska -Wierzbicka, MD, PhD Jaundice Definition Accumulation of yellow pigment in the skin and other tissues (Bilirubin) Jaundice definition It arises from the abnormal accumulation of bilirubin in body tissues, which occurs when the serum bilirubin level exceeds 3 mg/dL or 50 umol/L.1 Excess bilirubin causes a yellow tinting to the skin, sclera, and mucous membranes. Jaundice The presence of jaundice can indicate a transient hepatitis, biliary obstruction, or progressive deterioration in a patient awaiting liver transplantation. Thus, the appropriate management of the patient with jaundice depends on localizing the site and nature of the problem. Jaundice Hyperbilirubinemia is defined as a total bilirubin level greater than 1.5 mg/dL, an unconjugated level greater than 1 mg/dL, or a conjugated bilirubin level greater than 0.3 mg/dL. Jaundice Jaundice- Causes Of Hyperbilirubinemiaunconjugated Hemolysis Ineffective erythropoesis Neonatal causes Uridine diphosphate glucuronoyltransferase deficiencies Gilbert syndrome Crigler-Najjar syndromes Miscellaneous causes (drugs, hypothyroidism, thyrotoxicosis, pulmonary infarct, fasting) Gilbert Syndom Defective UDPG Transferase Uridine diphosphate glucuronoyltransferase Usually asymptomatic Serum BR < 3 mg% ↑ BR-monoglucuronide Benign Crigler –Najjar Syndrome Type I No UDPGT No BR conjugation Neonatal kernicterus, death Autosomal recessive Crigler–Najjar Syndrom Type II Reduced UDPGT activity Jaundice, 2d-3d decade of life Mostly monoglucuronide in bile Usually benign Treatment: Phenobarbital, induces more UDPGT Jaundice- Causes Of Hyperbilirubinemiaconjugated Congenital causes Rotor syndrome Impaired biliary excretion of conjugated BR. Jaundice appearing in childhood. Autosomal recessive. Uncommon.Benign Dubin-Johnson syndrome Defective transporter for conjugated BR. Uncommon. Benign. Conjugated BR in blood & urine Choledochal cysts Familial disorders Benign recurrent intrahepatic cholestasis Cholestasis of pregnancy Jaundice- Causes Of Hyperbilirubinemiaconjugated Hepatocellular defects Alcohol abuse Viral infection Cholestatic Primary biliary cirrhosis Primary sclerosing cholangitis Biliary obstruction Pancreatic disease Jaundice- Causes Of Hyperbilirubinemiaconjugated Systemic disease Infiltrative disorders Postoperative complications Renal disease Sepsis Drugs Jaundice Unconjugated hyperbilirubinemia exists if more than 80% to 85% of the total bilirubin is unconjugated. Conjugated hyperbilirubinemia exists if greater than 30% of the total bilirubin level is conjugated. Overproduction of bilirubin results in unconjugated hyperbilirubinemia. Mild hyperbilirubinemia may require blood or urine tests for detection, as jaundice usually does not become apparent until the bilirubin level exceeds 3 mg/dL. Pathophysiologic classification of Jaundice Hemolytic Jaundice Hepatic Jaundice Obstructive Jaundice Hemolytic Jaundice Pathogenesis Overproduction Hemolysis (intra and extra vascular) inherited or genetic disorders acquired immune hemolytic anemia (Autoimmune hemolytic anemia) nonimmune hemolytic anemia (paroxysmal nocturna Hemoglobinruia) Ineffective erythropoesis Overproduction may overload the liver with UB Hemolytic Jaundice Symptoms weakness, Dark urine, anemia, Icterus, splenomegaly Lab UB↑ ↑ without bilirubinuria fecal and urine urobilinogen↑ ↑ hemolytic anemia hemoglobinuria (in acute intravascular hemolysis) Reticulocyte counts↑ ↑ Hepatic Jaundice Due to a disease affective hepatic tissue either congenital or acquired diffuse hepatocellular injury Hepatic Jaundice Pathogenesis Impaired or absent hepatic conjugation of bilirubin Familiar or hereditary disorders • decreased GT activity (Gilbert‘s syndrome) hereditary absence or deficiency of UDPGT (Grigler-Najjar Syndrome) Dubin-Johnson Syndrome Rotor syndrome Acquired disorders hepatocellular necrosis intrahepatic cholestasis (Hepatitis, Cirrhosis, Drug-related) Hepatocellular defects Viral hepatitis Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis G Hepatocellular defects Alcohol Liver abuse steatose (fatty liver) Hepatitis Cirrhosis of the liver Obstructive Jaundice Pathogenesis it is due to intra- and extra hepatic obstruction of bile ducts intrahepatic Jaundice: Hepatitis, PBC, Drugs Extra Hepatic Biliary Obstruction: Stones, Stricture, Inflammation, Tumors, (Ampulla of Vater) Cholestasis PBC PSC Biliary obstruction Pancreatic disease PBC The clinical features include jaundice, pruritus, steatorrhea, xanthomas, and osteopenia. In advanced disease, signs of portal hypertension will occur with esophageal varices, ascites, and other conditions. Primary biliary cirrhosis is a chronic progressive cholestatic disorder typically, although not exclusively, found in women in the fourth to fifth decade of life. PBC laboratory abnormalities: a characteristic isolated alkaline phosphatase elevation out of proportion to other liver function tests, Elevated serum IgM, cholesterol, antimitochondrial antibody (AMA) . PBC laboratory abnormalities: a characteristic isolated alkaline phosphatase elevation out of proportion to other liver function tests, Elevated serum IgM, cholesterol, antimitochondrial antibody (AMA) . PSC Progressive cholestatic liver disease, which is found mostly in men of middle age. Inflammation of both intrahepatic and extrahepatic bile ducts Clinically, patients present with recurrent abdominal pain, fever, and intermittent jaundice and later with symptoms of portal hypertension. Characteristic narrowing or "beading" occurs in the hepatic ducts, as demonstrated by cholangiogram. PSC vs. UC Chronic inflammatory bowel diseases, such as ulcerative colitis or Crohn , are associated in 30% to 75% of primary sclerosing cholangitis patients Of all patients with ulcerative colitis, 5% to 10% will have primary sclerosing cholangitis. Obstructive Jaundice symptoms Pruritus Jaundice may vary in intensity Chill+fever+gall bladder enlargement →stone+cholangitis Obstructive Jaundice Lab Findings Serum Bilirubin↑ ↑ Feceal urobilinogen↓ ↓ (incomplete obstruction) Feceal urobilinogen absence (complete obstruction) urobilinogenuria is absent in complete obstructive jaundice bilirubinuria ↑ ALP ↑ , GGTP ↑ cholesterol ↑ Evaluation to the patient with jaundice The investigation of a patient with jaundice begins with a thorough review of the history of presentation, medication use, past medical history, physical examination, and evaluation of liver function tests. Evaluation to the patient with jaundice Several questions must be answered initially: 1. Is the elevated bilirubin conjugated or unconjugated? In general, most jaundiced patients will not have an isolated unconjugated hyperbilirubinemia. 2. If the hyperbilirubinemia is unconjugated, is it caused by increased production, decreased uptake, or impaired conjugation? 3. If the hyperbilirubinemia is conjugated, is the problem intrahepatic or extrahepatic? 4. Is the process acute or chronic? Evaluation to the patient with jaundice Patients with conjugated hyperbilirubinemia usually have acquired disease- identify an intrahepatic or an obstructive cause. Acute disease usually can be differentiated from chronic disease by the patient's history, physical examination (xanthelasma, spider angioma, ascites, or hepatosplenomegaly), and laboratory tests (hypoalbuminemia, thrombocytopenia, and an uncorrectable prolongation of the prothrombin time). Evaluation to the patient with jaundice Chronic cholestasis may arise from such diseases as cirrhosis, primary sclerosing cholangitis, primary biliary cirrhosis, secondary biliary cirrhosis, or carcinoma or from drugs. Patients with chronic cholestasis usually do not have hepatitis or gallstones. Evaluation to the patient with jaundice The presence of fever, right upper quadrant pain, tenderness, hepatomegaly, and newonset bilirubinuria usually indicates acute disease. Patients older than 50 years of age with asymptomatic cholestasis and mild hepatomegaly may have carcinoma of the pancreas or biliary tree. Evaluation to the patient with jaundice Women aged over 30 years of age are more likely to have choledocholithiasis. Gallstones cholelithiasis the formation or presence of stones in the gallbladder or common bile duct. chole = bile, lith = stone, iasis = condition Gallstones biliary colic: pain associated with gallstones that have entered the common bile duct. choledocholithiasis the presence of gallstones in the common bile duct. cholecystitis inflammation of the gallbladder. cholangitis inflammation of the bile ducts. cholecystectomy : surgical removal of the gallbladder. Gallbladder Disorders Risk factors for cholelithiasis a. Age b. Family history, also Native Americans and persons of northern European heritage c. Obesity, hyperlipidemia d. Females, use of oral contraceptives e. Conditions which lead to biliary stasis: pregnancy, fasting, prolonged parenteral nutrition f. Diseases including cirrhosis, ileal disease or resection, sickle-cell anemia, glucose intolerance Gallbladder Disorders Manifestations of cholelithiasis a. Many persons are asymptomatic b. Early symptoms are epigastic fullness after meals or mild distress after eating a fatty meal c. Biliary colic (if stone is blocking cystic or common bile duct): steady pain in epigastric or RUQ of abdomen lasting up to 5 hours with nausea and vomiting d. Jaundice may occur if there is obstruction of common bile duct Gallbladder Disorders Manifestations of acute cholecystitis a. Episode of biliary colic involving RUQ pain radiating to back, right scapula, or shoulder; the pain may be aggravated by movement, or deep breathing and may last 12 – 18 hours b. Anorexia, nausea, and vomiting c. Fever with chills Evaluation to the patient with jaundice An adult with asymptomatic, isolated unconjugated hyperbilirubinemia who is not taking any drugs and has no evidence of hemolysis probably has Gilbert syndrome and can be monitored with bilirubin determinations for 12 months. If no abnormality develops, no further evaluation is needed. Evaluation to the patient with jaundice Fever, leukocytosis, and hypotension point to ascending cholangitis Asterixis, confusion, or stupor may indicate severe hepatocellular dysfunction or fulminant hepatocellular failure Clinical symptoms Fever Chills Weight loss Flu like symptoms Abdominal pain Anorexia Nausea, and vomiting Pruritus Physical examination General appearance cachexia, muscle wasting, palmar erythema, Dupuytren contracture, abnormal nails, parotid enlargement, or xanthelasmas, gynecomastia, spider nevi, or dilated veins. Physical examination The size and consistency of the liver shrunken, nodular liver - cirrhosis, a palpable mass - an abscess or malignancy. If the liver span is greater than 15 cm- fatty infiltration, congestion, other infiltrative diseases, or malignancy. Liver tenderness may denote acute disease but is generally not helpful. The presence of a friction rub or bruit suggests malignancy. Clinical examination Spider angioma, palmar erythema, and distended abdominal veins Ascites in the presence of jaundice (cirrhosis, malignancy and severe acute disease, such as viral or alcoholic hepatitis) Splenomegaly (infections, infiltrative diseases, viral hepatitis, or cirrhosis) A palpable, distended gallbladder suggests malignant biliary obstruction. Asterixis in fulminant hepatic failure and end-stage liver disease. Patients with biliary colic or infection may have fever. Laboratory tests TB (conjugated, unconjugated) AspAT, AlAT GGTP AP TP + (albumin, gammaglobulin) Prothrombin Laboratory tests TCh AMA 5’-NT LAP Alfa1-antitrypsin Iron levels Ceruloplasmin Alfa-fetoprotein (AFP) Antinuclear antibody Noninvasive tests US CT Radionuclide imaging is an excellent means of detecting cystic duct obstruction. It is the test of choice if acute cholecystitis is suspected, but it has little value in differentiating intrahepatic from extrahepatic causes of cholestasis. Invasive tests ERCP - endoscopic retrograde cholangiopancreatography PTC - percutaneous transhepatic cholangiography liver biopsy ERCP ERCP is 90% successful regardless of the presence or absence of ductal dilation and can localize the site of obstruction in more than 90% of patients. It is particularly helpful in diagnosing patients with common duct stones. Because it has therapeutic capabilities, it allows some patients to avoid surgery. ERCP is also helpful if a stricture due to chronic pancreatitis is suspected. PTC PTC visualizes the biliary tree in 90% to 100% of patients with dilated ducts and localizes the site of obstruction in 90% of cases. It locates the obstruction in 50% to 90% of patients without dilated ducts, as determined by ultrasound. PTC is less expensive than ERCP and often is easier to perform. The patient must have a prothrombin time of less than 16 seconds, a platelet count greater than 50,000, and no ascites. Minor complications occur in 30% of patients. Major complications, including sepsis, bleeding, biliary leak, pneumothorax, arteriovenous fistula, hematoma, abscess, and peritonitis, occur in 1% to 10% of patients who undergo PTC.