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

2. 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

3. 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

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

5. 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

6. 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

7. 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

8. 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

9. 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)

10. Quantification of alcohol intake
1 oz whiskey contains g alcohol
1 12-oz beer contains 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

11. 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?

12. 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

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

14. 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

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

16. 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

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

18. 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

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

20. 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

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

22. 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.

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

24. 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

25. 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.

26. 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

27. 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

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

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

30. 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

31. 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

32. 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

33. 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

34. 5 ‘ Nucleotidase Wide distribution
Significant elevations in liver disease
Sensitivity comparable to AP detecting obstruction, infiltration, cholestasis

35. 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

36. Normal serum bilirubin
Total bilirubin
uml
0.2-1 mg/dL
Direct bilirubin
5.1 uml
0.3 mg/dL

37. 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

38. 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

39. 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

40. 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

41. 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

42. 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

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

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

45. 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

46. 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

47. 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

48. 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