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Approach to the Jaundiced Patient. Dr. Ümit Akyüz Yeditepe University Division of Gastroenterology. Jaundice. A yellowing of the skin, sclerae ( 공막 ), and other tissues caused by excess circulating bilirubin. Bilirubin Metabolism.

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approach to the jaundiced patient

Approach to theJaundiced Patient

Dr. Ümit Akyüz

Yeditepe University

Division of Gastroenterology

  • A yellowing of the skin, sclerae(공막), and other tissues caused by excess circulating bilirubin
bilirubin metabolism
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
indirect reacting bilirubin

The fraction of serumbilirubin which has not been conjugated with glucuronic acid in the liver cell; so called because it reacts with the Ehrlichdiazo reagent only when alcohol is added; increased levels are found in hepaticdisease and haemolyticconditions.

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
diagnostic approach to jaundice
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

laboratory findings
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
disorders of bilirubin metabolism
  • Unconjugated Hyperbilirubinemia :


-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.

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


-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)
-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)
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


-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

new onset jaundice
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)
jaundiced emergencies
Jaundiced Emergencies
  • Acetaminophen Toxicity
  • Fulminant Hepatic Failure
  • Ascending Cholangitis
jaundice unrelated to intrinsic liver disease
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
new onset jaundice1
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)
acute hepatitis c
Acute Hepatitis C

Plateau phase = 57 days














Infection Day 0

HCV RNA Day 12

HCV Antibody Day 70

From DL Thomas

new onset jaundice2
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)
alcoholic liver disease
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
alcoholic liver disease1
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
new onset jaundice3
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)
autoimmune hepatitis
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
new onset jaundice4
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)
drug induced liver disease
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
acetaminophen toxicity
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
acetaminophen toxicity1
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)
acetaminophen toxicity treatment
Acetaminophen ToxicityTreatment
  • 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
fulminant hepatic failure
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)
fulminant hepatic failure1
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
5 6741 liver transplants in 2003 indications
5,6741 Liver Transplants in 2003Indications:
  • Hepatitis C 29%
  • Alcoholic Liver Disease 15%
  • Cirrhosis of unknown etiology 8%
  • Hepatocellular Carcinoma 7%
  • Fulminant Hepatic Failure 6%
  • Primary Sclerosing Cholangitis 5%
  • Primary Biliary Cirrhosis 4%
  • Metabolic Liver Disease 4%
  • Autoimmune Hepatitis 3%
  • Hepatitis B 3%
liver transplantation contraindications
Liver Transplantation:Contraindications
    • active alcohol or drug abuse
    • HIV positivity
    • extrahepatic malignancy
    • uncontrolled extrahepatic infection
    • advanced cardiopulmonary disease
    • Age over 65
    • poor social support
    • poorly controlled mental illness
new onset jaundice5
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)
obstructive jaundice
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
ascending cholangitis
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
ascending cholangitis indications for urgent ercp
Ascending CholangitisIndications 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
obstructive jaundice malignant causes
Obstructive JaundiceMalignant Causes
  • Cancer of the Pancreas
  • Cancer of the Bile Ducts (Cholangiocarcinoma)
  • Ampullary Tumors
  • Portal Lymphadenopathy
new onset jaundice6
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)
primary biliary cirrhosis
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
primary sclerosing cholangitis
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
unusual causes of jaundice
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
wilson s disease
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
critical questions in the evaluation of the jaundiced patient
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?
evaluation of the jaundiced patient history



Weight loss

Sex, drugs, R&R




malaise, myalgias

dark urine

abdominal girth


other autoimmune dz

HIV status

prior biliary surgery

family history liver dz

Evaluation of the Jaundiced PatientHISTORY
evaluation of the jaundiced patient physical exam

Mental status


Abd tenderness

Liver size




Spider angiomata


Kayser-Fleischer rings



Left supraclavicular adenopathy (Virchow’s node)

Evaluation of the Jaundiced PatientPHYSICAL EXAM
evaluation of the jaundiced patient lab evaluation

Bilirubin – total/indirect




Na-K-PO4, acid-base

Acetaminophen level



Viral serologies


Quantitative Ig


Iron profile

Blood cultures

Evaluation of the Jaundiced PatientLAB EVALUATION
evaluation of the jaundiced patient
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