1. Approach to the Jaundiced Patient
Dr. Ümit Akyüz
Yeditepe University
Division of Gastroenterology

2. Jaundice
A yellowing of the skin, sclerae(공막), and other tissues caused by excess circulating bilirubin

3. Bilirubin Metabolism
Formation: About 250 to 350 mg of bilirubin forms daily; 70 to 80% derives from the breakdown of senescent RBCs. The remaining 20 to 30% (early-labeled bilirubin) comes from other heme proteins located primarily in the bone marrow and liver. The heme moiety of Hb is degraded to iron and the intermediate product biliverdin by the enzyme heme oxygenase. Another enzyme, biliverdin reductase, converts biliverdin to bilirubin.
Plasma transport: Because of internal hydrogen bonding, bilirubin is not water-soluble. Unconjugated (indirect-reacting) bilirubin is therefore transported in the plasma bound to albumin
Liver uptake: Uptake of bilirubin is via active transport and is rapid
Conjugation: Free bilirubin concentrated in the liver is conjugated with glucuronic acid to form bilirubin diglucuronide, or conjugated (direct-reacting) bilirubin. This reaction, catalyzed by the microsomal enzyme glucuronyl transferase, renders the bilirubin water-soluble

4. indirect reacting bilirubin
The fraction of serum bilirubin which has not been conjugated with glucuronic acid in the liver cell; so called because it reacts with the Ehrlich diazo reagent only when alcohol is added; increased levels are found in hepatic disease and haemolytic conditions.

5. Biliary excretion: Conjugated bilirubin is secreted into the bile canaliculus (모세담관) with other bile constituents. In the intestine, bacterial flora deconjugate and reduce bilirubin to compounds called stercobilinogens . The kidney can excrete bilirubin diglucuronide but not unconjugated bilirubin. This explains the dark urine typical of hepatocellular or cholestatic jaundice and the absence of urinary bile in hemolytic jaundice
Abnormalities at any of these steps can result in jaundice. Increased formation, impaired liver uptake, or decreased conjugation can cause unconjugated hyperbilirubinemia. Impaired biliary excretion produces conjugated hyperbilirubinemia. In practice, both liver disease and biliary obstruction create multiple defects, resulting in a mixed hyperbilirubinemia

6. Diagnostic Approach to Jaundice
Symptoms and Signs
-Mild jaundice without dark urine : unconjugated hyperbilirubinemia caused by hemolysis or Gilbert's syndrome rather than hepatobiliary disease
-More severe jaundice or dark urine clearly indicates a liver or biliary disorder.
-Signs of portal hypertension (문맥고압증), ascites, or skin and endocrine changes usually imply a chronic rather than an acute process
-Patients often notice dark urine before skin discoloration; thus, the onset of dark urine better indicates the duration of jaundice
-Nausea and vomiting preceding jaundice most often indicate acute hepatitis or common duct obstruction by a stone; abdominal pain or rigors favor the latter

7. Laboratory Findings
Mild hyperbilirubinemia with normal aminotransferase and alkaline phosphatase levels usually reflects hemolysis or Gilbert's syndrome rather than liver disease
Aminotransferase elevations > 500 U suggest hepatitis or an acute hypoxic episode; disproportionate increases of alkaline phosphatase suggest a cholestatic or infiltrative disorder
Low albumin and high globulin levels indicate chronic rather than acute liver disease

8. DISORDERS OF BILIRUBIN METABOLISM
Unconjugated Hyperbilirubinemia :
-Hemolysis
-Gilbert's syndrome : defects in the liver's uptake of plasma bilirubin (우성유전)
-Crigler-Najjar syndrome : glucuronyl transferase deficiency
-Primary shunt hyperbilirubinemia: This rare, familial benign condition is associated with overproduction of early-labeled bilirubin.

9. Noncholestatic Conjugated Hyperbilirubinemia
-Dubin-Johnson syndrome: Asymptomatic mild jaundice characterizes this rare autosomal recessive disorder. The basic defect involves impaired excretion of various organic anions as well as bilirubin, but bile salt excretion is unimpaired.
-Rotor's syndrome: This rare disorder is similar to Dubin-Johnson syndrome, but the liver is not pigmented and other subtle metabolic differences are present

10. CHOLESTASIS
-A clinical and biochemical syndrome that results when bile flow is impaired
-Etiology :Bile flow may be impaired at any point from the liver cell canaliculus to the ampulla of Vater(바터팽대부) . The most common intrahepatic causes are hepatitis, drug toxicity, and alcoholic liver disease. Less common causes include primary biliary cirrhosis(담즙성간경변), cholestasis of pregnancy, metastatic carcinoma, and numerous uncommon disorders.The most common extrahepatic causes are a common duct stone and pancreatic cancer. Less common causes include benign stricture of the common duct (usually related to prior surgery), ductal carcinoma, pancreatitis or pancreatic pseudocyst, and sclerosing cholangitis(경화성 담관염)

11. -Pathophysiology : interference with microsomal hydroxylating enzymes, which leads to the formation of poorly soluble bile acids; impaired activity of Na+,K+-ATPase, which is necessary for canalicular bile flow; altered membrane lipid composition and fluidity; interference with the function of microfilaments (thought to be important for canalicular function); and enhanced ductular reabsorption of bile constituents. Because bile salts are needed for absorption of fat and vitamin K, impaired biliary excretion of bile salts can produce steatorrhea(지방변) and hypoprothrombinemia(저프로트롬빈혈증 ). In long-standing cholestasis (eg, primary biliary cirrhosis), concomitant Ca and vitamin D malabsorption may result in osteoporosis or osteomalacia(골연화증)

12. Symptoms and Signs
-Jaundice, dark urine, pale stools, and generalized pruritus(소양증)
Diagnosis :
-Intrahepatic and extrahepatic cholestasis must be differentiated. Intrahepatic cholestasis is suggested by symptoms of hepatitis, heavy alcohol ingestion, recent use of potentially cholestatic drugs, or signs of chronic hepatocellular disease (eg, spider nevi, splenomegaly, ascites). Extrahepatic cholestasis is suggested by biliary or pancreatic pain, rigors(오한), or a palpable gallbladder.
-Laboratory tests
-Imaging studies
-Liver biopsy

13. Treatment
-In intrahepatic cholestasis, treating the underlying cause usually suffices
-Extrahepatic biliary obstruction usually requires intervention: surgery, endoscopic extraction of ductal stones, or insertion of stents and drainage catheters for strictures (often malignant) or partially obstructed areas

14. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

15. Jaundiced Emergencies
Acetaminophen Toxicity
Fulminant Hepatic Failure
Ascending Cholangitis

16. Jaundice Unrelated to Intrinsic Liver Disease
Hemolysis (usually T. bili < 4)
Massive Transfusion
Resorption of Hematoma
Ineffective Erythropoesis
Disorders of Conjugation
Gilbert’s syndrome
Intrahepatic Cholestasis
Sepsis, TPN, Post-operation

17. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

22. HBV Serology + - HBSAg HBcAb IgM IgG HBSAb Acute HBV Resolved HBV
Chronic HBV
HBV vaccinated

23. Acute Hepatitis C Plateau phase = 57 days HCV RNA Anti-HCV10 20 30 40 50 60 70 80 90
100
Infection Day 0
HCV RNA Day 12
HCV Antibody Day 70
From DL Thomas

24. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

25. Alcoholic Liver Disease
The history is the key – 60 grams/day
Gynecomastia, parotids, Dupuytren’s
Lab clues: AST/ALT > 2, MCV > 94
AST < 300
Alcoholic hepatitis:
Anorexia, fever, jaundice, hepatomegaly
Treatment:
Abstinence
Nutrition
Consider prednisolone or pentoxifylline

26. Alcoholic Liver Disease
Discriminant Function Formula:
DF = [4.6 x (PT – control)] + bilirubin
Consider treatment for DF > 32
Prednisolone 40 mg/day x 28 days
contraindications: infection, renal failure, GIB
Pentoxifylline 400 mg PO tid x 28 days

27. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

28. Autoimmune Hepatitis Widely variable clinical presentations
Asymptomatic LFT abnormality (ALT and AST)
Severe hepatitis with jaundice
Cirrhosis and complications of portal HTN
Often associated with other autoimmune dz
Diagnosis:
Compatible clinical presentation
ANA or ASMA with titer 1:80 or greater
IgG > 1.5 upper limits of normal
Liver biopsy: portal lymphocytes + plasma cells

29. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

30. Drug-induced Liver Disease
Hepatocellular
acetaminophen, INH, methyldopa, MTX
Cholestatic
chlorpromazine, estradiol, antibiotics
Chronic Hepatitis
methyldopa, phenytoin, macrodantin, PTU
Hypersensitivity Reaction
Phenytoin, Augmentin, allopurinol
Microvesicular Steatosis
amiodarone, IV tetracycline, AZT, ddI, stavudine

31. Acetaminophen Toxicity
Danger dosages (70 kg patient)
Toxicity possible > 10 gm
Severe toxicity certain > 25 gm
Lower doses potentially hepatotoxic in:
Chronic alcoholics
Malnutrition or fasting
Dilantin, Tegretol, phenobarbital, INH, rifampin
NOT in acute EtOH ingestion
NOT in non-alcoholic chronic liver disease

33. Acetaminophen Toxicity
Day 1:
Nausea, vomiting, malaise, or asymptomatic
Day 2 – 3:
Initial symptoms resolve
AST and ALT begin to rise by 36 hours
RUQ pain, tender enlarged liver on exam
Day 4
AST and ALT peak > 3000
Liver dysfunction: PT, encephalopathy, jaundice
Acute renal failure (ATN)

34. Acetaminophen Toxicity Treatment
Activated charcoal if < 4 hours from ingestion
Administer as a single dose 1 mg/kg PO or NG
Does not adversely effect NAC efficacy
N-Acetylcysteine (NAC)
140 mg/kg loading dose PO or NG
70 mg/kg q 4 hours PO or NG X 17 doses
Continue longer until INR < 2.0 and improved
OK to DC if acetaminophen levels undetectable and normal AST at 36 hours

35. Acetaminophen Toxicity Treatment
Indications for NAC therapy:
Above the line on the nomogram
Serum concentration > 10 mcg/ml and unknown time of ingestion
Repeated excessive doses, risk factors for acetaminophen hepatoxicity, and serum concentration > 10 mcg/ml
Evidence of hepatoxicity and a history of excessive acetaminophen dosing

37. Fulminant Hepatic Failure
Definition:
Rapid development of hepatic dysfunction
Hepatic encephalopathy
No prior history of liver disease
Most common causes:
Acetaminophen
Unknown
Idiosyncratic drug reaction
Acute HAV or HBV (or HDV or HEV)

38. Fulminant Hepatic Failure
Close glucose monitoring IV glucose
Avoid sedatives - give PO lactulose
Avoid nephrotoxins and hypovolemia
Vitamin K SQ
Do not give FFP unless active bleeding, since INR is an important prognostic factor
GI bleed prophylaxis with PPI
Transfer all patients with FHF who are candidates to a liver transplant center

39. 5,6741 Liver Transplants in 2003 Indications:
Hepatitis C %
Alcoholic Liver Disease %
Cirrhosis of unknown etiology %
Hepatocellular Carcinoma %
Fulminant Hepatic Failure %
Primary Sclerosing Cholangitis %
Primary Biliary Cirrhosis %
Metabolic Liver Disease %
Autoimmune Hepatitis %
Hepatitis B %

40. Liver Transplantation: Contraindications
ABSOLUTE
active alcohol or drug abuse
HIV positivity
extrahepatic malignancy
uncontrolled extrahepatic infection
advanced cardiopulmonary disease
RELATIVE
Age over 65
poor social support
poorly controlled mental illness

41. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

42. Obstructive Jaundice CBD stones (choledocholithiasis) vs. tumor
Clinical features favoring CBD stones:
Age < 45
Biliary colic
Fever
Transient spike in AST or amylase
Clinical features favoring cancer:
Painless jaundice
Weight loss
Palpable gallbladder
Bilirubin > 10

44. Ascending Cholangitis
Pus under pressure
Charcot’s triad: fever, jaundice, RUQ pain
All 3 present in 70% of patients, but fever > 95%
May also present as confusion or hypotension
Most frequent causative organisms:
E. Coli, Klebsiella, Enterobacter, Enterococcus
anaerobes are rare and usually post-surgical
Treatment:
Antibiotics: Levaquin, Zosyn, meropenem
ERCP with biliary drainage

45. Ascending Cholangitis Indications for Urgent ERCP
Persistent abdominal pain
Hypotension despite adequate IVF
Fever > 102
Mental confusion
Failure to improve after 12 hours of antibiotics and supportive care

46. Obstructive Jaundice Malignant Causes
Cancer of the Pancreas
Cancer of the Bile Ducts (Cholangiocarcinoma)
Ampullary Tumors
Portal Lymphadenopathy

48. New Onset Jaundice Viral hepatitis Alcoholic liver disease
Autoimmune hepatitis
Medication-induced liver disease
Common bile duct stones
Pancreatic cancer
Primary Biliary Cirrhosis (PBC)
Primary Sclerosing Cholangitis (PSC)

49. Primary Biliary Cirrhosis
Cholestatic liver disease (ALP)
Most common symptoms: pruritus and fatigue
Many patients asx, and dx by abnormal LFT
Female:male ratio 9:1
Diagnosis:
Compatible clinical presentation
AMA titer 1:80 or greater (95% sens/spec)
IgM > 1.5 upper limits of normal
Liver biopsy: bile duct destruction
Treatment: Ursodeoxycholic acid 15 mg/kg

50. Primary Sclerosing Cholangitis
Cholestatic liver disease (ALP)
Inflammation of large bile ducts
90% associated with IBD
but only 5% of IBD patients get PSC
Diagnosis: ERCP (now MRCP)
No autoantibodies, no elevated globulins
Biopsy: concentric fibrosis around bile ducts
Cholangiocarcinoma: 10-15% lifetime risk
Treatment: Liver Transplantation

51. Diagnosis of Immune-Mediated Liver Disease
LFT
Serology
Quantitative Immunoglobulins
Biopsy
AIH
ALT
ANA
ASMA
IgG
Portal inflammation
Plasmacytes
Piecemeal necrosis
PBC
ALP
AMA
IgM
Bile duct destruction
granulomas
PSC
none
normal
Periductal concentric fibrosis

52. Unusual Causes of Jaundice
Ischemic hepatitis
Congestive hepatopathy
Wilson’s disease
AIDS cholangiopathy
Amanita phalloides (mushrooms)
Jamaican bush tea
Infiltrative diseases of the liver
Amyloidosis
Sarcoidosis
Malignancy: lymphoma, metastatic dz

53. Wilson’s Disease Autosomal recessive – copper metabolism
Chronic hepatitis or fulminant hepatitis
Associated clinical features:
Neuropsychiatric disease
Hemolytic anemia
Physical exam: Kayser-Fleischer rings
Diagnosis: ceruloplasmin, urinary Cu
Treatment: d-penicillamine

54. Critical Questions in the Evaluation of the Jaundiced Patient
Acute vs. Chronic Liver Disease
Hepatocellular vs. Cholestatic
Biliary Obstruction vs. Intrahepatic Cholestasis
Fever
Could the patient have ascending cholangitis?
Encephalopathy
Could the patient have fulminant hepatic failure?

55. Evaluation of the Jaundiced Patient HISTORY
Pain
Fever
Confusion
Weight loss
Sex, drugs, R&R
Alcohol
Medications
pruritus
malaise, myalgias
dark urine
abdominal girth
edema
other autoimmune dz
HIV status
prior biliary surgery
family history liver dz

56. Evaluation of the Jaundiced Patient PHYSICAL EXAM
BP/HR/Temp
Mental status
Asterixis
Abd tenderness
Liver size
Splenomegaly
Ascites
Edema
Spider angiomata
Hyperpigmentation
Kayser-Fleischer rings
Xanthomas
Gynecomastia
Left supraclavicular adenopathy (Virchow’s node)

57. Evaluation of the Jaundiced Patient LAB EVALUATION
AST-ALT-ALP
Bilirubin – total/indirect
Albumin
INR
Glucose
Na-K-PO4, acid-base
Acetaminophen level
CBC/plt
Ammonia
Viral serologies
ANA-ASMA-AMA
Quantitative Ig
Ceruloplasmin
Iron profile
Blood cultures

58. Evaluation of the Jaundiced Patient
Ultrasound:
More sensitive than CT for gallbladder stones
Equally sensitive for dilated ducts
Portable, cheap, no radiation, no IV contrast
CT:
Better imaging of the pancreas and abdomen
MRCP:
Imaging of biliary tree comparable to ERCP
ERCP:
Therapeutic intervention for stones
Brushing and biopsy for malignancy

59. Yes
Yes
Treat

60. Unknown Case #1 59 year old male lawyer
Nausea, vomiting, lethargy, chronic back pain
Drinks 3-4 scotch and water/day
PMH: HTN, hypercholesterolemia
Meds: Prinivil, Lipitor, Vicodin
VSS afebrile, jaundice, no stigmata cirrhosis
A/O, no asterixis no edema, no ascites
sl RUQ tender, liver span 18 cm, no palp spleen
AST 3246, ALT 4620, ALP 105, bili 5.2

61. Unknown Case #2 38 year old female manager of Mi Pueblo
3 days of episodic severe RUQ pain
2 days of fever/chills/rigors
Daughter noticed yellow eyes today
PMH: DM, HTN
Meds: glipizide, HCTZ
BP 110/64 HR 112, temp 101.8
Jaundice, no stigmata of cirrhosis
RUQ tender to palp, no spleen, no ascites
AST 602, ALT 654, ALP 256, bili 5.2

62. Unknown Case #3 64 year old female bartender
1 month history of fatigue, anorexia, arthralgias
1 week history of jaundice
No abdominal pain, no fever, 5 lb wt. loss
Denies EtOH “I never liked the stuff”
PMH: none PSH: none meds: rare Motrin
AST 256, ALT 302, ALP 162, bili 8.6
alb INR TP plt 256

63. Yes
Yes
Treat