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 NecrosisAminotransferasesLactic Dehydrogenase

CholestasisAlkaline PhosphataseGamma Glutamyl TranspeptidaseBilirubin

Hepatic Synthetic ActivityProthrombin timeAlbumin

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.

AminotransferasesAST 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 Steatosis / steatohepatitis cirrhosis

Etiology of mild ALT/AST elevations

Nonhepatic Hemolysis Myopathy Thyroid disease Strenuous exercise

Time Course of ALT

1 2 3 40 Weeks

5000

1000

ALT(U/L)

Ischemia/ToxinViral/Drug

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 bilirubin3.4-15.4 uml0.2-1 mg/dL

Direct bilirubin5.1 uml0.3 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

HEPATOCELLULAR NECROSIS

Toxin/Ischemia Viral Hepatitis

Alcohol

Aminotransferases 50-100x 5-50x 2-5x

AP 1-3x 1-3x 1-10x

Bilirubin 1-5x 1-30x 1-30x

Prothrombin time

Prolonged & unresponsive to Vitamin K in severe disease

Albumin Decreased in subacute/chronic disease

Characteristic Biochemical Patterns:

BILIARY OBSTRUCTIONComplete Partial

Pancreatic CA Hilar tumor, PSC

Aminotransferases 1-5x 1-5xAP 2-20x 2-20xBilirubin 1-30x 1-5xProthrombin time

Often prolonged & responsive to parenteral vitamin K

Albumin Usually normal, decreased in advanced disease

Characteristic Biochemical Patterns:

Characteristic Biochemical Patterns:

HEPATIC INFILTRATION

Aminotransferases 1-3x

AP 1-20x

Bilirubin 1-5x (often normal)

Prothrombin time Usually normal

Albumin Usually normal

History & PELaboratory tests

Isolated elevationOf bilirubin

Bilirubin & otherLiver tests elevated

Isolated elevation of bilirubin

Indirect hyperbilirubinemia(Direct < 15%)

Direct hyperbilirubinemia(Direct > 15%)

Drugs: Rifampicin Probenecid

Inherited disorders:Gilbert’s syndrome

Hemolytic disordersIneffective erythropoieisis

Inherited disorders:Dubin-Johnson syndrome

Rotor’s syndrome

Bilirubin & other liver testselevated

Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase

Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST

Hepatocellular pattern

1. Viral serologies Hepatitis A IgM Hepatitis B surface antigen & core antibody Hepatitis C RNA2. Toxicology screen Acetaminophen level3. 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

Results (-)

Results (-)

Results (-) AMA (+)

Cholestatic pattern

Ultrasound

Dilated ductsExtrahepatic cholestasis

Ducts not dilatedIntrahepatic cholestasis

CT/ERCPSerologic testing: AMA Hepatitis serologies Hepatitis A, CMV, EBVReview drugs

ERCP/ Liver biopsy Liver biopsy