JAUNDICE (icterus/icteretia) yellowish discoloration of tissue resulting from deposition of bilirubin usually presented on the skin or on the sclera

ra part of the eye SERUM HYPERBILIRUBINEMIA elevated serum bilirubin Causes: liver disease and hemolytic disorder serum bilirubin at least 3.0 mg/dl (51 mol/L)---> icteric sclera (jaundice) normal serum bilirubin: 1.0 mg/dl

BILIRUBIN PRODUCTION AND METABOLISM 250-300 MG BILIRUBIN PER DAY 70-80% o Breakdown of senescent of RBC (main source) 20-30% o Prematurel destroyed erythroid cells o Turnover of Hemoproteins (e.g. mygolobin)
o Cytochromes

There may be no apparent jaundice if serum bilirubin is between 1.0 - 3.0 mg/dl Sclera is more frequently involved because it has high elastin content (+) affinity for bilirubin as serum bilirubin levels rise: skin will become icteric/ darker yellow or even green
DIFFERENTIAL DIAGNOSIS: yellowish skin 1. Carotenoderma - yellow color imparted to skin by presence of carotene with ingestion of excessive amounts of vegetables and fruits with carotene (e.g. excessive drinking of carrot juices) yellow palms, soles, forehead, nasolabial fold, except the eyes 2. Quinacrine treatment - can cause scleral icterus 3. Excessive exposure to phenols some of the phenol compounds (e.g. cleaning agents) are absorbed in the skin coloring the skin yellow. BILIRUBINURIA darkening of urine due to renal excretion of conjugated bilirubin another sensitive indicator of increased serum bilirubin dark yellow, tea-colored, coca cola colored, patis colored urine Two types of bilirubin 1. Unconjugated/Indirect bilirubinor B1 2. Conjugated/Direct Bilirubin or B2

FORMATION OF BILIRUBIN occurs in reticuloendothelial cells in liver and spleen REACTIONS: 1. OXIDATION.

Oxidative cleavage of bridge of porphyrin group to open heme ring catalyzed by enzyme heme oxygenase
2. REDUCTION. Reduction of central methylene bridge of bilirubin - catalyzed by cytosolic enzyme bilirubin reductase. pero ang sabi sa Harrisons: reduction
the central methylene bridge of biliverdin and converts it to bilirubin catalyzed by biliverdin reductase

3. TRANSPORTATION IN BLOOD Bilirubin formed in reticuloendothelial cells is insoluble in water If it remained insoluble will not be ecreted in the urine hyperbilirubinemia Therefore, to be transported in blood, bilirubin must be solubilised in the process of conjugation. Reversible, noncovalent binding to albumin: renders bilirubin soluble transport in blood 4. HEPATIC UPTAKE unconjugated bilirubin + albumin
transported to liver

SY 2011-2012

Subject: Medicine Topic: Jaundice and Abnormal Liver Span Lecturer: Dr. D. Gonzales Date of Lecture: Nov. 16, 2011 Transcriptionist: Glutinoids Pages: 6

SY 2011-2012

hepatic uptake w/o albumin (via carriermediated membrane transport protein in hepatocyte cytosol): unconjugated bilirubin coupled to Glutathione S- transferase B (formerly ligandin)

5. INTRACELLULAR BINDING (formerly Transport) Within endoplasmic reticulum: bilirubin is solubilized by conjugation to glucuronic acid forming Bilirubin Monoglucuronide and Diglucuronide the hepatocyte, bilirubin is kept in solution by binding as a non substrate ligand to several Glutathione s- transferases 6. CONJUGATION conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridinediphosphate (UDP) glucuronosyltransferase 7. EXCRETION bilirubin glucoronides are excreted across the canalicular membrane into the bile canaliculi by ATP dependent transport process mediated by canalicular membrane protein, multidrug resistance associated protein 2 (MRP2) The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the proximal small bowel. Conjugated bilirubin is NOT taken up by the intestinal mucosa. In distal ileum and colon: conjugated bilirubin is hydrolyzed to unconjugated bilirubin, catalyzed by bacterial-glucuronidases The unconjugated bilirubin is reduced by normal gut bacteria to urobilinogens (colorless tetrapyrroles)
EXCRETION FORMS: 80-90% o urobilinogens: excreted in feces either unchanged or oxidized to orange derivatives urobilins o urobilins give the brown, green, or yellow color of the stool. o Obstruction to the flow of bile acholic stools: pale or clay

colored of stool indicating deficiency of bile (no bile or bilrubin coloring is emptied into the intestine) o Thus, acholic stools are manifestation of cholestasis 10-20%: o passively absorbed, enter venous blood and re-excreted by liver small fraction < 3 mg/dl: o escapes hepatic uptake: filters across renal glomerulus and excreted in urine MEASUREMENT OF SERUM BILIRUBIN Test: Van den Bergh Method

In this assay, bilirubin is exposed to diazotized sulfanilic acid, splitting into two relatively stable dipyrrylmethene azopigments that absorb maximally at 540 nm, allowing for photometric analysis. Normal Serum Bilirubin: < 1 mg/dl (17 mol/L) Direct Reacting: 30% o reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol. o provides approximate determination of conjugated bilirubin in serum o 0.3 mg/dL (5.1 mol/L) Total serum bilirubin = conjugated bilirubin + unconjugated bilirubin o the amount that reacts after the addition of alcohol. Indirect fraction: 70% o difference between total and direct bilirubin o provides estimate of unconjugated bilirubin in serum
UNEXPLAINED ENIGMAS IN JAUNDICED PATIENTS WITH LIVER DISEASE can now be explained by prolonged half-life of albumin 1. Patients with conjugated hyperbilirubinemia should have bilirubinuria during the recovery phase of their disease. But some patients with conjugated hyperbilirubinemia do not exhibit bilirubinuria during the recovery phase because bilirubin is bound to

albumin and therefore not filtered by renal glomeruli. 2. Elevated serum bilirubin levels decline more slowly than expected in some patients who otherwise appear to be recovering satisfactorily. Late in recovery phase of hepatobiliary disorders - all conjugated bilirubin may be in albumin linked form Its value in serum falls slowly because of long half-life of albumin MEASUREMENT OF URINE BILIRUBIN unconjugated bilirubin: o always bound to albumin in serum o not found in urine o not filtered in kidney conjugated bilirubin: o filtered at glomerulus o majority reabsorbed by proximal tubules o small fraction excreted in urine

Whether hyperbilirubinemia is predominantly conjugated or unconjugated in nature Whether other biochemical liver tests are abnormal o test for excretory function: ALT, AST, ALKAPHOS o test for synthetic function: Albumin and Prothrombin time

DISORDERS OF BILIRUBIN METABOLISM leading to UNCONJUGATED HYPERBILIRUBINEMIA Familial Defects in Hepatic Excretory Functions Dubin-Johnson syndrome (DJS) Rotors syndrome Benign Recurrent Intrahepatic Cholestasis (BRIC) Progressive Familial Intrahepatic Cholestasis (FIC)

Any bilirubin found in urine conjugated bilirubin bilirubinuria signifies liver disease
EVALUATION OF JAUNDICE (see figure on
the last page)

Hyperbilirubinemia may result from: Overproduction of bilirubin Impaired uptake, conjugation or excretion of bilirubin Regurgitation of unconjugated bilirubin from damaged hepatocytes or bile ducts (caused by: stones, tumors , worms, and stricture of lumen)

UNCONJUGATED HYPERBILIRUBINEMIA hemolytic disorders: serum bilirubin rarely exceeds 5 mg/dL higher levels: coexistent renal or hepatocellular dysfunction or in acute hemolysis

CRIGLER-NAJJAR TYPE I

in unconjugated bilirubin in serum results from:

o overproduction o impaired uptake o impaired conjugation

o Exceptionally rare condition in neonates o complete absence of bilirubin UDP glucuronosyl transferase activity unable to conjugate and excrete bilirubin
o characterized by severe jaundice o (bilirubin > 20 mg/dL) + neurologic o impairment 2 kernicterus

in conjugated bilirubin o due to decreased excretion into bile ductules or backward leakage of pigments
Initial Steps: To determine

o frequently leads to death in infancy or childhood

o only effective treatment: orthotopic liver transplantation

o altered excretion of bilirubin into bile ducts

CRIGLER-NAJJAR TYPE II o more common than type I

Rotors Syndrome o (+) problem with hepatic storage of bilirubin

o mutation in bilirubin UDP glucuronosyl transferase gene causes reduced but not completely absent enzyme activity o patients live to adulthood, serum b bilirubin: 6-25 mg/dl o -Treatment: phenobarbital-induces UDP glucuronosyl transferase activity
o (+) marked jaundice but survives into o adulthood

o *both presents with asymptomatic jaundice, typically in 2nd generation of life o *differentiation possible but clinically unnecessary due to their benign nature

Benign Recurrent Intrahepatic Cholestasis (BRIC) o Rare disorder characterized by recurrent attacks of pruritus and jaundice o Familial recessive pattern of inheritance o Jaundice and pruritus may be debilitating and prolonged o BRIC type 2- mutation in bile salt excretory protein (BSEP)

o with intercurrent illness (surgery) kernicterus

GILBERTS SYNDROME o marked by impaired conjugation of o bilirubin due to reduced bilirubin UDP o glucuronosyl transferase activity o mild unconjugated hyperbilirubinemia < 6 mg/dL o serum bilirubin levels may fluctuate and jaundice often identified only during periods of fasting o very common: 3-7%, male predominance 2-7:1

Progressive Familial Intrahepatic Cholestasis (FIC) o Phenotypically related syndromes

o Byler disease: progressive FIC type I

presents in early infancy as cholestasis, initially episodic; mutation in FIC1 gene

CONJUGATED HYPERBILIRUBINEMIA

o Type2: mutation in protein sister of p- glycoprotein, major bile canalicular exporter of bile acids ( BSEP bile salt excretory protein) o Type 3: associated with mutation of MDR3- protein essential for normal hepatocellular excretion of phospholipids across the bile canaliculus
associated with high serum levels of gamma glutamyl transferase activity

Dubin-Johnson Syndrome
o defect is a point mutation in the gene for o canalicular multispecific organic anion o transporter

ELEVATION OF SERUM BILIRUBIN WITH OTHER LIVER TEST ABNORMALITIES mainly to differentiate between primary hepatocellular process and intra-or extrahepatic cholestasis o History o Physical Examination o Laboratory Tests

o (+) arthralgia/myalgia before jaundice: suggest hepatitis o (+) RUQ pain with jaundice/chills: choledocholithiasis and ascending cholangitis
PHYSICAL EXAMINATION General assessment: o should include nutritional status temporal and proximal muscle wasting: suggests long standing disease re: pancreatic CA/cirrhosis

HISTORY complete history is perhaps the single most important part of the evaluation of a patient with unexplained jaundice

Stigmata of chronic liver diseases : o spider nevi o Dupuytrens contractureshand/hypothenar atrophy o palmar erythema o Parotid gland enlargement o Testicular atrophy o Gynecomastia o Caput medusae
Enlarged left supraclavicular node (Virchows node) or periumbilical nodule (Sister Mary Josephs nodule): o suggests abdominal malignancies

QUESTIONS: Use or exposure to any chemical or medication o herbal/vitamin preparations

o anabolic steroids Possible parenteral exposures: transfusions, IV and intranasal drug use, tattoos Sexual activity/exposure Recent travel history Exposure to people with jaundice Exposure to possibly contaminated foods Occupational exposure to hepatotoxins Alcohol consumption Duration of jaundice Presence of accompanying symptoms: arthralgias myalgia rash anorexia weight loss abdominal pain fever pruritus change in urine change in stool

Jugular venous distention o sign of right sided heart failure o suggests hepatic congestion (characterized by increased JVP and positive Hepatojugular Reflex) Right-sided pleural effusion in absence of clinically apparent ascites: o advanced cirrhosis Abdominal examination: should focus on: o size and consistency of liver o spleen - whether palpable/enlarged o presence of ascites Enlarged left liver lobe + enlarged spleen: o maybe seen in cirrhosis Grossly enlarged nodular liver or obvious abdominal mass: o suggests malignancy enlarged tender liver: o viral or alcaholic hepatitis less often - acute liver congestion Severe RUQ tenderness with inspiratory arrest (POSITIVE Murphy's Sign): o cholecystitis or occasionally ascending cholangitis ascites + jaundice: o suggests either cirrhosis or malignancy with peritoneal spread

suggest particular diagnoses:

LABORATORY TESTS helpful in initial evaluation of unexplained jaundice includes: o Total and direct serum bilirubin with fractionation o Aminotransferases o Alkaline phosphatase Low Albumin: suggestive of a chronic process (Chronic Liver Disease

Wilsons disease Autoimmune hepatitis CHOLESTATIC CONDITIONS THAT MAY PRODUCE JAUNDICE I. Intrahepatic A. Viral Hepatitis 1. Fibrosing cholestatis hepatitis hepatitis B and C 2. Hepatitis A, Epstein-Barr virus, cytomegalovirus B. Alcoholic hepatitis C. Drug toxicity 1. Pure cholestasis - anabolic and contraceptive steroids 2. Cholestatic hepatitis chlorpromazine, erythromycin estolate 3. Chronic cholestasis chlorpromazine and prochlorperazine D. Primary biliary cirrhosis E. Primary sclerosing cholangitis F. Vanishing bile duct syndrome 1. Chronic rejection of liver transplants 2. Sarcoidosis 3. Drugs G. Inherited 1. Benign recurrent cholestasis H. Cholestasis of pregnancy I. Total parenteral nutrition J. Nonhepatobiliary sepsis K. Benign postoperative cholestasis L. Paraneoplastic syndrome M. Venoocclusive disease N. Graft-versus-host disease II. Extrahepatic A. Malignant 1. Cholangiocarcinoma 2. Pancreatic cancer 3. Gallbladder cancer 4. Ampullary cancer 5. Malignant involvement of the porta hepatis lymph nodes B. Benign 1. Choledocholithiasis 2. Primary sclerosing cholangitis 3. Chronic Pancreatitis 4. AIDS cholangiopathy HEPATOMEGALY Palpable Liver without hepatomegaly o Right diaphragm displaced downwards (e.g. emphysema, asthma) o Subdiaphragmatic lesions (e.g. abscess) o Aberrant lobe of the liver (Riedels lobe) o Extremely thin or relaxed abdominal muscles o Occasionally present in normal persons o True Hepatomegaly

Normal Albumin: suggestive of a more acute process Elevated Prothrombin Time: indicates either Vitamin K deficiency due to prolonged jaundice and malabsorption of Vitamin K or significant hepatocellular dysfunction o FAILURE of Prothrombin time to be corrected with Vitamin K indicates severe hepatocellular injury Enzyme tests: o ALT, AST, Alkaline Phosphatase o helpful in differentiating between hepatocellular process and cholestatic process (+) hepatocellular process: generally have a disproportionate rise in aminotransferase compared to alkaline phosphatase (+) cholestatic process: disproportionate rise in alkaline phosphatase compared to aminotransferases Bilirubin: can be prominently elevated in both hepatocellular and cholestatic conditions: not necessarily helpful in differentiation All jaundiced patients: should have additional blood tests ALBUMIN and PROTHROMBIN TIME to assess liver function.
HEPATOCELLULAR CONDITIONS THAT MAY PRODUCE JAUNDICE Viral Hepatitis o Hepatitis A, B, C, D, and E o Epstein-Barr virus o Cytomegalovirus o Herpes simplex Alcohol Drug toxicity o Predictable, dose-dependent (acetaminophen) o Unpredictable, idiosyncratic (isoniazid) Environmental toxins o Vinyl chloride o Jamaica bush tea- pyrrolizidine alkaloids o Kava Kava o Wild mushrooms - Amanita phylloides or A. verna

 Vascular congestion (e.g. CHF, hepatic vein thrombosis) Bile duct obstruction (e.g. lesion in common duct hepatomegaly biliary cirrhosis)

o Cirrhosis - except late stage ---> small liver Tumors - primary, metastatic Cysts - polycystic disease, congenital hepatic fibrosis

Infiltrative disorders FALSELY INCREASED LIVER SPAN o Bone Marrow and abnormal dullness over normally reticuloendothelial cells resonant lung field Extramedullary hematopoeisis Consolidation (pneumonia) Leukemia Pleural Effusion Lymphoma Atelectasis/ Fibrosis o Fat FALSELY DECREASED LIVER Fatty liver (alcohol, diabetes or SPAN toxins) o Glycogen (diabetes, esp. after abnormal hyperresonance insulin excess) Pneumothorax o Amyloid Emphysema o Iron (hemochromatosis and hemosiderosis) Inflammatory disorders o Hepatitis - drugs, infectious EVALUATION OF JAUNDICED PATIENT

CAUSES OF ISOLATED HYPERBILIRUBINEMIA

I. Indirect hyperbilirubinemia A. Hemolytic disorders 1. Inherited a. Spherocytosis, elliptocytosis Glucose-6-phosphate dehydrogenase and pyruvate kinase deficiencies b. Sickle cell anemia 2. Acquired a. Microangiopathic hemolytic anemias b. Paroxysmal nocturnal hemoglobinuria c. Spur cell anemia d. Immune hemolysis B. Ineffective erythropoiesis 1. Cobalamin, folate, thalassemia, and severe iron deficiencies

C. Drugs 1. Rifampicin, probenecid, ribavirin D. Inherited conditions 1. Crigler-Najjar types I and II 2. Gilbert's syndrome II. Direct hyperbilirubinemia A. Inherited conditions 1. Dubin-Johnson syndrome 2. Rotor's syndrome

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