An Approach to the Patient with Suspected Liver Disease JAUNDICE AND ASCITES An Approach to the Patient with Suspected Liver Disease

Objectives: 1. discuss the pathophysiology of jaundice and ascites 2. do a complete history and physical examination on a patient with liver disease 3. know the significance of liver-laboratory tests 4. evaluate a patient with liver disease

Hyperbilirubinemia 1. overproduction of bilirubin 2. impaired uptake, conjugation, or excretion of bilirubin 3. regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia

Evaluating a patient with jaundice 1. determine whether conjugated or unconjugated hyperbilirubinemia 2. determine presence of other abnormal laboratory tests

In a patient with jaundice, a careful history, physical examination, and review of standard laboratory tests should permit a physician to make an accurate diagnosis in 85% of cases. Franz Ingelfinger, MD 1958

Causes of Jaundice 1. viral hepatitis 2. alcohol-induced liver disease 3. chronic active liver disease 4. drug-induced liver disease 5. gallstones and their complications 6. carcinoma of the pancreas 7. primary biliary cirrhosis 8. sclerosing cholangitis

Clinical History Related to viral hepatitis Blood transfusions IV drug use Sexual practices Contact with jaundiced persons Needle stick exposure Work in renal dialysis unit Body piercing/tattoos Travel to endemic areas

Clinical History Medication related Review all prescription medications Over-the-counter drugs Use of vitamins, especially vit A Herbal preparations Food supplements Home remedies purchased in health food store

Clinical History Alcohol use Detailed quantitative history of both recent and previous alcohol from patient and family members History of withdrawal symptoms CAGE criteria Evidence of alcohol associated illnesses (pancreatitis, perpheral neuropathy)

Quantification of alcohol intake 1 oz whiskey contains 10-11 g alcohol 1 12-oz beer contains 10-11 g alcohol 4 oz red wine contains 10-11g alcohol Ingestion of >3 units/day everyday or 21 units/week every week is excessive. Threshold for alcohol-induced hepatic injury appears to be 30 gm for women and 60 gm for men if ingested >10 yrs

CAGE criteria 1. has the patient tried to cut back on alcohol use? 2. does the patient become angry when asked about his alcohol intake? 3.does the patient feel guilty about his alcohol use? 4. does the patient need an eye opener in the morning?

Clinical History Miscellaneous Pruritus Evolution of jaundice Recent changes in menstrual cycle History of anemia Symptoms of biliary tract disease Family history of liver disease, gallbladder disease Occupational history

Physical Examination General inspection Scleral icterus Pallor Wasting Needle tracks Skin excoriations Ecchymosis/petechiae Muscle tenderness and weakness Lymphadenopathy Evidence of congestive heart failure

Physical Examination Peripheral stigmata of liver disease Spider angiomata Palmar erythema Gynecomastia Dupuytren’s contracture Parotid enlargement Testicular atrophy Paucity of axillary and pubic hair

Physical Examination Abdominal examination Hepatomegaly Splenomegaly Ascites Prominent abdominal collateral veins Bruits and rubs Abdominal masses Palpable gallbadder

Liver Liver span is about 10-12 cm in men, and 8-11 cm in women Normal liver is non-tender, sharp-edged, smooth and not hard, left lobe not palpable Modest hepatomegaly in viral hepatitis, chronic hepatitis, cirrhosis Marked enlargement in tumors, fatty liver, severe congestive heart failure Pulsatile liver in tricuspid regurgitation

Spleen Normally not palpable Enlarged in portal hypertension because of cirrhosis Splenomegaly also seen in infections, leukemias, lymphomas, infiltrative disorders, hemolytic disorders, etc

Gallbladder Not normally palpable Palpable in 25% of cancer of the head of the pancreas (Courvoisier’s law) Palpable in about 30% of cholecystitis, usually because of stone impacted in neck of gallbladder Palpable in the RUQ at the angle formed by the lateral border of the rectus abdominis muscle and the right costal margin

Ascites Assessed on physical examination by: Shifting dullness Fluid wave Puddle sign Bulging flanks

Both shifting dullness and fluid wave test will not uniformly detect fluid less than 1000 ml Both tests have a sensitivity of about 60% when compared with ultrasound Confirmation of presence of ascites by imaging procedures Tests can be spuriously positive in obese patients

Causes of ascites: 1. cirrhosis 2. congestive heart failure 3. nephrosis 4. disseminated carcinomatosis

Laboratory findings Because many of the clinical features of liver injury are non-specific, the history and physical examination are routinely supplemented by “liver function” tests, which are so widely available that they have become a standard and esssential component of the evaluation.

Biochemical Liver Tests Hepatocellular Necrosis Aminotransferases Lactic Dehydrogenase Cholestasis Alkaline Phosphatase Gamma Glutamyl Transpeptidase Bilirubin Hepatic Synthetic Activity Prothrombin time Albumin

Aminotransferases Increased levels results from leakage from damaged tissues, released from damaged hepatocytes following injury or death AST not exclusive for liver, also found in heart, muscle, kidney, brain, pancreas and erythrocytes. Confirm liver injury by doing ALT which is almost exclusive to liver

Aminotransferases Acute elevations to >1000 IU reflect severe hepatic necrosis and usually seen in viral hepatitis, toxin-induced hepatitis and hepatic ischemia. AST/ALT >2 with AST level of <300IU is suggestive of alcohol-induced liver disease. Higher AST levels in viral hepatitis, ischemia and other liver injuries.

Aminotransferases AST and ALT levels Poorly correlates with the extent of hepatocyte injury Not predictive of outcome Azotemia can lower AST level Persistent elevation of AST from macroenzyme complex with albumin

Etiology of mild ALT/AST elevations ALT predominant Chronic hepatitis B & C Acute hepatitis A & E Steatosis / steatohepatitis Medications / toxins autoimmune hepatitis AST predominant Alcohol-related liver disease cirrhosis

Etiology of mild ALT/AST elevations Nonhepatic Hemolysis Myopathy Thyroid disease Strenuous exercise

Time Course of ALT Ischemia/Toxin 5000 Viral/Drug ALT (U/L) 1000 0 Weeks 1 2 3 4

Lactic Dehydrogenase (LDH) Wide tissue distribution Massive but transient elevation in ischemic hepatitis Sustained elevation with elevated alkaline phosphatase in malignant infiltration of the liver

Alkaline Phosphatase Major sources: bone and liver Others: intestine, placenta, adrenal cortex, kidney and lung Increased levels because of increased synthesis and release from damaged cells Marked increase in infiltrative hepatic disorders or biliary obstruction

Alkaline Phosphatase Marked increases seen in ductular injury – intrahepatic cholestasis, infiltrative process, extrahepatic biliary obstruction, biliary cirrhosis, malignancy and organ rejection Lesser increase in viral hepatitis, cirrhosis and congestive hepatopathy

Gamma Glutamyl Transpeptidase (GGTP) Wide distribution Not found in bone Main use: determine if elevation in AP is liver rather than bone in origin Induced by alcohol and drugs GGTP/AP ratio > 2 suggests alcohol abuse Isolated elevations are non-specific, most cases not associated with clinically significant liver disease

5 ‘ Nucleotidase Wide distribution Significant elevations in liver disease Sensitivity comparable to AP detecting obstruction, infiltration, cholestasis

Measurement of serum bilirubin (van den Bergh reaction) Direct fraction = conjugated bilirubin = B1 - fraction that reacts with diazotized sulfanilic acid in the absence of an accelerator Total bilirubin - amount that reacts with diazotized sulfanilic acid in the presence of an accelerator Indirect fraction = unconjugated bilirubin = B2 - the difference between total and direct fraction

Normal serum bilirubin Total bilirubin 3.4-15.4 uml 0.2-1 mg/dL Direct bilirubin 5.1 uml 0.3 mg/dL

Bilirubin Serum bilirubin level normally almost unconjugated Bilirubin in urine is conjugated thus indicative of hepatobiliary disease In chronic hemolysis with normal liver, levels usually not more than 5 mg/dl Magnitude of elevation useful prognostically in alcoholic hepatitis and acute liver failure

Urine bilirubin Bilirubin found in the urine is conjugated bilirubin Unconjugated bilirubin is bound to albumin in the serum; it is not filtered by the kidney; and is not found in the urine

Prothrombin Time Most important predictor of outcome in acute liver failure Useful in monitoring hepatic synthetic function Useful indicator of liver failure in both acute and chronic hepatic injury provided that cholestasis with malabsorption of Vit K has been excluded

Albumin Half life of 20 days Less useful than prothrombin time in monitoring acute liver disease because of long half life Correlates with prognosis in chronic liver disease- used for grading system

Characteristic Biochemical Patterns: HEPATOCELLULAR NECROSIS Toxin/Ischemia Viral Hepatitis Alcohol Aminotransferases 50-100x 5-50x 2-5x AP 1-3x 1-10x Bilirubin 1-5x 1-30x Prothrombin time Prolonged & unresponsive to Vitamin K in severe disease Albumin Decreased in subacute/chronic disease

Characteristic Biochemical Patterns: BILIARY OBSTRUCTION Complete Partial Pancreatic CA Hilar tumor, PSC Aminotransferases 1-5x AP 2-20x Bilirubin 1-30x Prothrombin time Often prolonged & responsive to parenteral vitamin K Albumin Usually normal, decreased in advanced disease

Characteristic Biochemical Patterns: HEPATIC INFILTRATION Aminotransferases 1-3x AP 1-20x Bilirubin 1-5x (often normal) Prothrombin time Usually normal Albumin

History & PE Laboratory tests Isolated elevation Of bilirubin Bilirubin & other Liver tests elevated

Isolated elevation of bilirubin Direct hyperbilirubinemia (Direct > 15%) Indirect hyperbilirubinemia (Direct < 15%) Drugs: Rifampicin Probenecid Inherited disorders: Dubin-Johnson syndrome Rotor’s syndrome Inherited disorders: Gilbert’s syndrome Hemolytic disorders Ineffective erythropoieisis

Bilirubin & other liver tests elevated Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST

Hepatocellular pattern Results (-) Viral serologies Hepatitis A IgM Hepatitis B surface antigen & core antibody Hepatitis C RNA 2. Toxicology screen Acetaminophen level 3. Ceruloplasmin (if patient less than 40 yrs of age) 4. ANA, SMA, LKM, SPEP Additional virologic testing: CMV DNA, EBV capsid antigen Hepa D antibody (if indicated) Hepa E IgM (if indicated) Liver biopsy

Extrahepatic cholestasis Ducts not dilated Intrahepatic cholestasis Cholestatic pattern Ultrasound Results (-) AMA (+) Dilated ducts Extrahepatic cholestasis Ducts not dilated Intrahepatic cholestasis Serologic testing: AMA Hepatitis serologies Hepatitis A, CMV, EBV Review drugs CT/ERCP ERCP/ Liver biopsy Liver biopsy