JAUNDICE & ABNORMAL LIVER SPAN

Dina C. Gonzales, MD, MHPEd, FPCP, FPSG, FPSDE (11-25-2013) Internal Medicine
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Dont memorize. What you do is to picture or understand the problem. ~Dean Dra. Gonzales

JAUNDICE
BILIRUBIN PRODUCTION AND METABOLISM 250-300 mg of bilirubin/day is produced 70-80% Breakdown of senescent of RBC (main source) 20-30% Prematurely destroyed erythroid cells Turnover of hemoproteins (e.g. mygolobin, cytochromes) REMEMBER: Normal RBC lifespan = 120 days 1. FORMATION OF BILIRUBIN Occurs in reticuloendothelial cells in liver and spleen Reactions: 1. OXIDATIVE cleavage of -bridge of porphyrin group of hemoglobin to open the heme ring Catalyzed by enzyme heme oxygenase 2. REDUCTION of central methylene bridge of bilirubin Catalyzed by cytosolic enzyme bilirubin reductase Bilirubin formed in reticuloendothelial cells Insoluble in water Reversible non-covalent binding to albumin (conjugation) Renders bilirubin soluble and can be transported in blood 2. HEPATIC UPTAKE AND INTRACELLULAR BINDING

Icterus or ictericia Yellowish discoloration of tissue resulting from deposition of bilirubin 2 main pathophysiologic mechanisms of jaundice: Cholestasis Hepatocellular disease SERUM HYPERBILIRUBINEMIA Elevated serum bilirubin Causes: Liver disease Hemolytic disorder Icteric Sclera (Jaundice) At least 3.0 mg/dL High elastin content in sclerae (+) affinity for bilirubin As serum bilirubin levels rise: Skin will become icteric or even green DIFFERENTIAL DIAGNOSIS OF YELLOWISH SKIN 1. Carotenoderma Yellow color imparted to skin by presence of carotene with ingestion of excessive amounts of vegetables and fruit (carrots, squash) with carotene Yellow palms, soles, forehead, nasolabial folds 2. Quinacrine treatment Quinacrine is an anti-malarial drug, though used rarely nowadays Can cause scleral icterus 3. Excessive exposure to phenols Seen in factory workers BILIRUBINURIA Darkening of urine 2 renal excretion of conjugated bilirubin Another sensitive indicator of increased serum bilirubin

*Albumin is the main carrier protein in the blood, and is produced by the liver

Within the hepatocyte, bilirubin is kept in solution by binding as a non-substrate ligand to several glutathione s-transferases

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3. CONJUGATION In the endoplasmic reticulum Bilirubin is solubilized by conjugation to glucuronic acid forming BILIRUBIN MONOGLUCURONIDE and DIGLUCURONIDE Conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine-diphosphate (UDP) glucuronosyltransferase (UGT)
DEFINITION OF TERMS Complete absence of Bilirubin Crigler-Najjar Type I UDP glucoronosyltransferase Mutation in Bilirubin UDP Crigler-Najjar Type II glucoronosyltransferase Reduced activity of Bilirubin Gilberts syndrome UDP glucoronosyltransferase

*The pancreas and the biliary tree *Periampullary malignancy any malignancy involving the duodenum, ampulla of Vater, pancreas, bile duct, and gallbladder would present with conjugated hyperbilirubinemia and obstructive jaundice

4. EXCRETION Bilirubin glucoronides are excreted across the canalicular membrane into the bile canaliculi by ATP dependent transport process mediated by canalicular membrane protein called multidrug resistance associated protein-2 (MRP2)
EXCRETION FORMS UROBILINOGENS excreted in feces either unchanged or oxidized to orange derivatives called UROBILINS Passively absorbed, enter venous blood and re-excreted by liver Escapes hepatic uptake, filters across renal glomerulus and excreted in urine

80-90% 10-20% Small fraction (<3 mg/dl)

ORGANS OF BILIRUBIN METABOLISM

MEASUREMENT OF SERUM BILIRUBIN Normal Serum Bilirubin (Van den Bergh Method) <1 mg/dl (17 mol/L) Direct Reacting: 30% provides approximate determination of conjugated bilirubin in serum 0.3 mg/dL (5.1 mol/L) Total Serum Bilirubin Conjugated bilirubin + unconjugated bilirubin The amount that reacts after the addition of alcohol. Indirect fraction: Difference between total and direct bilirubin Provides estimate of unconjugated bilirubin in serum UNEXPLAINED ENIGMAS IN JAUNDICED PATIENTS WITH LIVER DISEASE Can be explained by prolonged half-life of albumin 1. Some patients with conjugated hyperbilirubinemia do not exhibit bilirubinuria during the recovery phase of their disease because a certain fraction of conjugated bilirubin is still 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 1. Unconjugated bilirubin Always bound to albumin in serum Not filtered in kidney Not found in urine 2. Conjugated bilirubin Filtered at glomerulus Majority reabsorbed by proximal tubules Small fraction excreted in urine
*Any bilirubin found in urine is conjugated bilirubin *Bilirubinuria signifies liver disease

All diseases that involve the liver itself may give you hepatocellular cause of hyperbilirubinemia If the affectation is after the liver (i.e. gallbladder, CBD, pancreas), the cause would be cholestatic Therefore, a patient with pancreatic carcinoma would have cholestatic hyperbilirubinemia, and the type of bilirubin seen in the blood is the conjugated form The liver is normal, and all bilirubin are being conjugated Meanwhile, a patient with hemolysis, G6PD deficiency, or hemophilia usually has unconjugated hyperbilirubinemia Excess hemolysis produces an increase in raw materials for bilirubin production Then, since the liver cannot conjugate the excess materials, unconjugated bilirubin fills the bloodstream

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EVALUATION OF JAUNDICE
CONDITION CAUSE Overproduction of bilirubin (excess raw materials) Impaired uptake, conjugation or excretion of bilirubin Regurgitation of unconjugated bilirubin from damaged hepatocytes or bile ducts Overproduction Impaired uptake Impaired conjugation Due to decreased excretion into bile ductules or backward leakage of pigments

Frequently leads to death in infancy or childhood Only effective treatment: Orthotopic liver transplantation 2. CRIGLER-NAJJAR TYPE II More common than type I Mutation in bilirubin UDP glucuronosyl transferase gene causes reduced but not completely absent enzyme activity Patients live to adulthood Serum bilirubin: 6-25 mg/dL Treatment: Phenobarbital Induces UDP glucuronosyl transferase activity (+) marked jaundice but survives into adulthood with intercurrent illness (surgery) Kernicterus 3. GILBERTS SYNDROME Marked by impaired conjugation of bilirubin due to reduced bilirubin UDP glucuronosyl transferase activity Mild unconjugated hyperbilirubinemia < 6 mg/dL Serum bilirubin levels may fluctuate and jaundice often identified only during periods of fasting Very common 3-7% Male predominance (2-7:1) CONJUGATED HYPERBILIRUBINEMIA Both present with asymptomatic jaundice Bilirubin measurement is abnormal, but all other workups are normal Typically in 2nd generation of life and differentiation possible but clinically unnecessary due to their benign nature 1. DUBIN-JOHNSON SYNDROME Defect is a point mutation in the gene for canalicular multi-specific organic anion transporter (+) altered excretion of bilirubin into bile ducts 2. ROTORS SYNDROME (+) problem with hepatic storage of bilirubin 3. BENIGN RECURRENT INTRAHEPATIC CHOLESTASIS (BRIC) Rare disorder characterized by recurrent attacks of pruritus and jaundice Familial recessive pattern of inheritance Jaundice and pruritus may be debilitating and prolonged Pruritus is one cardinal symptom of obstructive jaundice. It is due to the deposition of bile pigment in the skin. Other symptoms include acholic stool, and tea-colored urine BRIC type 2 mutation in bile salt excretory protein (BSEP)

Hyperbilirubinemia

Increase () in unconjugated bilirubin Increase () in conjugated bilirubin

Initial steps are to determine: 1. Whether hyperbilirubinemia is predominantly conjugated or unconjugated in nature 2. Whether other biochemical liver tests are abnormal DISORDERS OF BILIRUBIN METABOLISM LEADING TO UNCONJUGATED HYPERBILIRUBINEMIA
DISORDER I. Increased () bilirubin production II. Decreased () Hepatic Bilirubin Clearance III. Hereditary Defects in Bilirubin Conjugation MANIFESTED AS Hemolysis Ineffective erythropoesis Decreased Hepatic uptake Impaired conjugation Physiologic neonatal jaundice Acquired conjugation defects Crigler-Najjar Type I Crigler-Najjar Type II Gilbert syndrome

DISORDERS OF BILIRUBIN METABOLISM LEADING TO MIXED OR PREDOMINANTLY CONJUGATED HYPERBILIRUBINEMIA Familial Defects in Hepatic Excretory Function Dubin-Johnson syndrome (DJS) Rotors syndrome Benign Recurrent Intrahepatic Cholestasis (BRIC) Progressive Familial Intrahepatic Cholestasis (FIC) UNCONJUGATED HYPERBILIRUBINEMIA Hemolytic disorders: serum bilirubin rarely exceeds 5 mg/dL Higher levels: coexistent renal or hepatocellular dysfunction or in acute hemolysis (Antigenantibody reaction secondary to blood transfusion) 1. CRIGLER-NAJJAR TYPE I Exceptionally rare condition in neonates Complete absence of bilirubin UDP glucuronosyl transferase activity Unable to conjugate and excrete bilirubin Characterized by severe jaundice (bilirubin > 20 mg/dL) + neurologic impairment 2 kernicterus

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4. PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS (FIC) Phenotypically related syndromes Byler disease/Progressive FIC Type 1 Presents in early infancy as cholestasis, initially episodic; mutation in FIC1 gene Type 2 mutation in protein sister of pglycoprotein, major bile canalicular exporter of bile acids (BSEP bile salt excretory protein) Type 3 associated with mutation of MDR3protein essential for normal hepatocellular excretion of phospholipids across the bile canaliculus Associated with high serum levels of gamma glutamyl transferase activity ELEVATION OF SERUM BILIRUBIN WITH OTHER LIVER TEST ABNORMALITIES Mainly to differentiate between primary hepatocellular process and intra- or extra-hepatic cholestasis History Physical Examination Laboratory Tests ALT AST ALP HISTORY Complete history is perhaps the single most important part of the evaluation of a patient with unexplained jaundice Questions: Use or exposure to any chemical or medication (herbal/vitamin preparations, 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 Factory workers Insecticides Lysol users Alcohol consumption Duration of jaundice Presence of accompanying symptoms Arthralgias, abdominal pain, myalgia, fever, rash, pruritus, anorexia, change in urine color, weight loss, change in stool These suggest particular diagnoses: (+) arthralgia/myalgia before jaundice suggests hepatitis (+) RUQ pain together with jaundice/chills suggests choledocholithiasis and ascending cholangitis IMPORTANT: Note the history for the pattern relationships through time.

PHYSICAL EXAMINATION General assessment Should include nutritional status, including height and weight Temporal and proximal muscle wasting: suggests long standing disease (i.e. pancreatic CA/cirrhosis) Stigmata of chronic liver diseases: SPIDER NEVI

*A patient presenting with jaundice (eyes), and spider angiomata. To confirm spider angiomata, press or blanch on the red lesion, remove the pressure, and it will fill up from the center to the periphery.

PALMAR ERYTHEMA

GYNECOMASTIA CAPUT MEDUSA

*Gynecomastia, and large caput medusa, seen in chronic liver disease

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 DUPUYTRENS CONTRACTURES

*Palmar erythema, hypothenar atrophy, and Dupuytrens contracture

*Ascites and small caput medusa (collaterals)

PAROTID GLAND ENLARGEMENT TESTICULAR ATROPHY CONSIDERATIONS Suggests abdominal malignancies Sign of right sided heart failure: Suggests hepatic congestion Advanced cirrhosis Maybe seen in cirrhosis Suggests malignancy Viral or alcoholic hepatitis Less often: Acute liver congestion Cholecystitis or occasionally ascending cholangitis Suggests either cirrhosis or malignancy with peritoneal spread (+) cholestatic process Disproportionate rise (4x or more) in alkaline phosphatase compared to aminotransferases BILIRUBIN Can be prominently elevated in both hepatocellular and cholestatic conditions Not necessarily helpful in differentiation
FINDINGS Low albumin Normal albumin CONSIDERATIONS Suggests chronic process (i.e. cirrhosis, CA) Suggestive of more acute process (i.e. viral hepatitis, choledocholithiasis) Indicates either Vitamin K deficiency due to prolonged jaundice and malabsorption of Vitamin K or significant hepatocellular dysfunction Indicates severe hepatocellular injury

ABNORMAL P.E. FINDINGS Enlarged left supraclavicular node (Virchows node) or periumbilical nodule (Sister Mary Josephs nodule) Jugular venous distention Right-sided pleural effusion in absence of clinically apparent ascites Enlarged left liver lobe + enlarged spleen Grossly enlarged nodular liver or obvious abdominal mass Enlarged tender liver Severe RUQ tenderness with inspiratory arrest (Positive MURPHYs sign) Ascites + jaundice

LABORATORY TESTS Helpful in initial evaluation of unexplained jaundice Includes: Total and direct serum bilirubin with fractionation Aminotransferases (ALT and AST) Alkaline phosphatase Albumin Prothrombin time NOTE: Albumin and prothrombin time assess the synthetic function of the liver. In liver disease, albumin is low and prothrombin time is prolonged. All jaundiced patients should have additional blood tests ALBUMIN and PROTHROMBIN TIME to assess liver function ENZYME TESTS ALT, AST, Alkaline Phosphatase Helpful in differentiating between hepatocellular process and cholestatic process (+) hepatocellular process Generally have a disproportionate rise in aminotransferase compared to alkaline phosphatase Check the ALT:AST Ratio If more than 2 and AST is higher, it would connote alcoholic liver disease.

Elevated PROTIME

Failure of PROTIME to correct with parenteral Vitamin K

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HEPATOCELLULAR CONDITIONS THAT MAY PRODUCE JAUNDICE

HEPATOCELLULAR CONDITION Viral Hepatitis Alcohol Drug toxicity (anticonvulsants, anti-arrhythmic drugs, etc.) Environmental toxins Wilsons disease Autoimmune hepatitis ETIOLOGY Hepatitis A, B, C, D, and E Epstein-Barr virus Cytomegalovirus Herpes simplex Predictable, dose-dependent, e.g., acetaminophen Unpredictable, idiosyncratic, e.g., isoniazid Vinyl chloride Jamaica bush tea pyrrolizidine alkaloids Wild mushrooms Amanita phylloides -

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 Benign recurrent cholestasis H. Cholestasis of pregnancy I. Total parenteral nutrition J. Nonhepatobiliary sepsis K. Benign postoperative cholestasis L. Paraneoplastic syndrome M. Veno-occlusive disease N. Graft-versus-host disease
*NOTE: Viral hepatitis cause both cholestatic and hepatocellular jaundice

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

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
*EXTRAHEPATIC Any malignant lesion that can obstruct the bile ducts (stones, tumor, nodes, strictures)

ABNORMAL LIVER SPAN

HEPATOMEGALY Upon percussion and palpation, the normal liver span is 8 to 12 cm; greater than 12 would mean hepatomegaly. Palpable Liver without hepatomegaly 1. Right diaphragm displaced downwards (e.g. emphysema, asthma) 2. Subdiaphragmatic lesions (e.g. abscess) 3. Aberrant lobe of the liver (Riedels lobe) 4. Extremely thin or relaxed abdominal muscles 5. Occasionally present in normal persons Vascular congestion e.g. CHF, hepatic vein thrombosis Bile duct obstruction e.g. lesion in common duct hepatomegaly biliary cirrhosis Infiltrative disorders A. Bone Marrow and reticuloendothelial cells a. Extramedullary hematopoeisis b. Leukemia c. Lymphoma B. Fat Fatty liver (alcohol, diabetes or toxins) C. Glycogen (diabetes, esp. after insulin excess) D. Amyloid E. Iron (hemochromatosis and hemosiderosis) Inflammatory disorders A. Hepatitis drugs, infectious B. Cirrhosis except late stage small liver Tumors Primary Metastatic Cysts Polycystic disease Congenital hepatic fibrosis FALSELY INCREASED LIVER SPAN: 1. Consolidation (pneumonia) 2. Pleural effusion 3. Atelectasis/fibrosis FALSELY DECREASED LIVER SPAN: 1. Pneumothorax 2. Emphysema
PERCUSSION TIPS Upon percussion, anything that gives dullness in the upper part of the chest (whether mass or fluid) would give a falsely increased liver span; while anything that gives hyperresonance in the lungs would give a falsely decreased liver span. For example, a patient with pneumothorax will have resonant chest lung fields; thus the clinician will not be able to appreciate the dullness of the liver, and would falsely declare a decrease in liver span.

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*IMPORTANT. Learn, understand, and familiarize with.

*Image taken from past transcription *ERCP Endoscopic Retrograde Cholangiopancreatography *MRCP Magnetic resonance Cholangiopancreatography

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BASIS REMARKS Latest PPT; Past PPT & Transcript RECORDINGS + NOTES + DEVIATIONS 8-10% CREDITS Aubrey-cordings The third in the series of Justice League Handouts, with Batman and The Flash. Deviations were made to facilitate better reading.

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