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The onset of jaundice usually prompts a patient to seek medical attention. Jaundice is a common medical finding in both inpatient and outpatient settings. Diagnosing the etiology of jaundice is an important training problem for third year medical students because accurate diagnosis requires prudent selection and interpretation of common diagnostic studies. Also, learning use of appropriate management strategies for jaundice is important because of its impact on patient morbidity and on health care cost.

The causes of hepatobiliary disease are many and can be quite overwhelming to the internal medicine clerk. A thorough understanding of a systematic approach to hyperbilirubinemia/jaundice is by far preferable to random knowledge of highly specific etiologies. The liver responds pathologically to injury in characteristic ways and knowledge of these patterns can also be very useful in differential diagnosis. Several etiologies of liver disease such as acute/chronic viral hepatitis and alcohol-induced liver disease are sufficiently common as to require specific attention. In addition, many liver diseases can result in cirrhosis and its complications and, therefore, understanding this end-stage development is important.



Describe and discuss:

  • anatomy, physiology, and pathophysiology of the hepatobiliary system
  • the biochemistry of hemoglobin synthesis, structure, and degradation
  • the role of the liver in conjugating bilirubin


  • complete medical history
  • basic physical examination
  • basic communication skills, including patients from diverse backgrounds
  • ability to examine a peripheral blood smear


Apply Medical Knowledge in the Clinical Encounter

1.     Describe and discuss pathophysiologic mechanisms that lead to jaundice including:

  • excess bilirubin production
  • decreased uptake and conjugation of bilirubin
  • intrahepatic cholestasis
  • hepatocellular disease
  • extrahepatic obstruction

(See differential diagnosis for a list of diseases caused by these mechanisms.)

2.     Describe and discuss epidemiology, pathophysiology, symptoms, signs, and typical clinical course of hepato-biliary diseases including:

  • steatosis (fatty liver)
  • hepatitis
  • cirrhosis
  • infiltrative liver disease
  • intrahepatic cholestasis
  • extrahepatic cholestasis (obstructive jaundice))
  • alcohol-induced liver disease
  • portal hypertension
  • ascites
  • spontaneous bacterial peritonitis
  • hepatic encephalopathy
  • the hepatorenal syndrome
  • cholelithiasis and cholecystitis
  • the clinical syndrome of “ascending cholangitis”
  • autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis

3.     Describe and discuss common causes of drug-induced liver injury.

4.     Describe and discuss the importance of distinguishing the type of bilirubin in each type of jaundice (unconjugated or conjugated) and why a urine dip stick test for urobilinogen is useful.

5.     Describe and discuss which type of bilirubin elevation (unconjugated or conjugated) goes with each of the 5 major pathophysiologic causes of jaundice.

6.     Describe and discuss genetic considerations in liver disease (i.e. hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, Gilbert’s syndrome).

7.     Describe and discuss laboratory tests including:

  • the use of serum markers of liver injury (e.g. AST, ALT, GGT, Alk Phos) and function (e.g. bilirubin, ALB, PT/INR) in the diagnostic evaluation of hepatobiliary disease
  • which transaminase (AST vs ALT) is more specific for liver disease
  • what is meant by the “AST/ALT split” and why that may be important
  • two other sources of AST in the body
  • the clinical significance of asymptomatic, isolated elevation of AST, ALT, GGT, and/or Alk Phos
  • how to interpret a Direct Coombs test
  • the analysis of ascitic fluid and its use in the diagnostic evaluation of liver disease
  • tests that can help support a diagnosis of intrascular hemolysis

8.     Describe the time course that it takes for liver disease to affect:

  • transaminases
  • prothrombin time
  • albumin

9.     Discuss the indications for and risks of paracentesis and liver biopsy.

10.  Discuss which causes of jaundice are treated medically and which are treated surgically.

11.  Discuss the importance of being able to reverse a prolonged prothrombin time with parenteral vitamin K in helping to refine the differential diagnosis of a conjugated hyperbilirubinemia.

12.  Identify which method of parenteral vitamin K administration (IV, IM, or SC) is associated with anaphylaxis and discuss why that route should be avoided.

13.  Identify and discuss medications that can cause jaundice.

14.  Discuss the importance of recognizing an elevated alkaline phosphatase level in some patients with jaundice.

15.  Describe how to distinguish between alkaline phosphatase elevations from bone disease and liver disease.

16.  Discuss the indications for and utility of hepatobiliary imaging studies, including:

  • ultrasound
  • computed tomography
  • percutaneous transhepatic cholangiography
  • endoscopic retrograde cholangiopancreatography (ERCP)
  • magnetic resonance cholangiopancreatograpy (MRCP)
  • nuclear medicine studies

17.  Describe and discuss the distinctions between acute and chronic hepatitis.

18.  Discuss the indications for and efficacy of hepatitis A and B vaccinations.



1.     obtain, document and present an age-appropriate medical history that differentiates among etiologies of disease, including:

  • jaundice, discolored urine, pruritis, light-colored stool, unintentional weight loss, fever, nausea, emesis, diarrhea, altered mental status, abdominal pain, increased abdominal girth, edema, rectal bleeding, hematemesis
  • DM
  • an alcohol and drug use history, taken in a non-judgmental way, showing compassion for the patient
  • prescription, over-the-counter, and illicit drug use
  • transfusions and other sources of potential blood-born pathogen exposure
  • consumption of uncooked shellfish and other food items potentially contaminated with fecal matter
  • sexual history
  • vaccination history
  • family history of liver diseases

2.     Perform a physical exam to establish the diagnosis and severity of disease, including:

  • assessment of the size of a patient’s liver and spleen on physical exam
  • identification of signs of hepatic disease on physical exam
  • complete abdominal examination including findings consistent with ascites (e.g. bulging flanks, shifting dullness, fluid wave)
  • findings compatible with chronic alcohol use and portal hypertension (e.g. palmar erythema, spider angiomas, gynecomastia, testicular atrophy, Dupuytren’s contracture, muscle wasting, splenomegaly, ascites, edema, caput medusa, hemorrhoids)
  • findings compatible with hepatic (portosystemic) encephalopathy (e.g. disturbances of consciousness and behavior, fluctuating neurologic signs, asterixis)

3.     Generate a differential diagnosis recognizing specific history and physical exam findings that suggest a specific etiology. It is necessary to:

  • recognize physical exam findings related to jaundice and distinguish true jaundice from caroteneima
  • recognize a patient with scleral icterus on physical exam
  • recognize signs of intravascular hemolysis and explain why that would be important to determine the cause of jaundice.
  • recognize which kind of jaundice (unconjugated or conjugated) in which it is important to look for signs of intravascular hemolysis
  • recognize findings from a peripheral blood smear as intravascular hemolysis
  • recognize dark urine and pale stools as an important finding to help determine the type of bilirubin that is causing the jaundice
  • recognize the importance of identifying a small cirrhotic liver and how this relates to the differential diagnosis of jaundice
  • understand the importance of eliciting the findings of fever and peritoneal signs in a patient with jaundice and how that affects the treatment plans
  • be able to demonstrate shifting dullness and the fluid wave test to look for ascites

4.     Recommend when to order diagnostic and laboratory tests and be able to interpret them, both prior to and after initiating treatment based on the differential diagnosis. Consider test cost and performance characteristics as well as patient preferences. Laboratory and diagnostic tests should include, when appropriate:

  • CBC
  • electrolytes, BUN/Cr, GLC
  • ALB, TP, total bilirubin, direct bilirubin, PT/INR, AST, ALT, Alk Phos
  • hepatitis serology
  • ascitic fluid ALB, amylase, cell counts, staining, cultures, and the serum-ascites albumin gradient (SAAG)

5.     Define the indications for and interpret (with consultation) the results of:

  • ultrasound
  • nuclear medicine studies
  • CT
  • MRI
  • magnetic resonance cholangiopancreatography (MRCP)
  • endoscopic retrograde

6.     Perform selected procedures.

  • Assist in performing a paracentesis after explaining the procedure to the patient.
  • Perform a urine dipstick to look for urobilinogen.
  • Take a patient’s temperature.

7.     Identify the patient’s problem from all of the problems listed in the differential diagnosis by combining scientific knowledge, information obtained in the clinical encounter and collective experience with similar patients.

  • Perform the diagnostic evaluation of asymptomatic, isolated elevation of the transaminases and/or Alk Phos.
  • Perform the diagnostic evaluation of patients with jaundice and unconjugated or conjugated hyperbilirubinemia.
  • Determine when to obtain consultation from a gastroenterologist, hepatologist, or biliary surgeon.
  • Use a cost-effective approach based on the differential diagnosis.
  • Access and utilize appropriate information systems and resources to help delineate issues related to liver disease.

8.     Communicate the diagnosis to the patient.

9.     Record, present, research, critique, and manage clinical information.

10.  Access and use appropriate information systems and resources to help delineate issues related to jaundice.


Develop a Management Plan

Make decisions about what to include from the following items and explain why each item selected should be included:

1.     Perform basic management of:

  • steatosis
  • hepatitis
  • cirrhosis
  • intra- and extra hepatic cholestasis
  • acute cholecystitis
  • ascites
  • portal hypertension
  • spontaneous bacterial peritonitis
  • hepatic encephalopathy

2.     Discuss preventive measures, including counseling and educating patients about sexual activity.

3.     Consider treatment measures such as appropriate prescribing as well as appropriate use of consultants and referral to specialists.

4.     Provide psychological support if indicated.

5.     Access and utilize appropriate information systems to ascertain information about health system and community resources.

6.     Plan for follow-up.

7.     Formulate a prognosis and communicate it to the patient in a caring and compassionate manner.

8.     Communicate the treatment plan and follow-up plan to patient.

9.     Consider the cost-effectiveness of the management plan.

10.  Discuss the public health role physicians play in the prevention of viral hepatitis.

11.  Appreciate the difficulties patient face with alcohol abstinence.


Differential Diagnosis

The 5 major pathophysiologic causes of jaundice

Excess bilirubin production

  • hereditary spherocytosis/other RBC membrane defects
  • hemoglobin disorders – hemoglobinopathies
  • cytoplasm/enzyme disorders – G6-PD deficiency triggered by oxidative stress
  • pyruvate kinase difficiency
  • autoantibodies – autoimmune hemolytic anemia (Coomb’s positive)
  • abnormalites in the circulation/mechanical stresses – Artificial heart valves, Kasabach-Merritt syndrome, Hemolytic uremic syndrome (HUS), DIC, TTP, malaria

Decreased uptake and conjugation of bilirubin

  • Gilbert’s syndrome
  • Crigler-Najjar syndrome

Intrahepatic cholestasis, including problems at the:

  • intracellular level – hepatitis
  • canalicular level – estrogen
  • ductule level – phenothiazine exposure
  • septal ducts – primary biliary cirrhosis
  • intralobular ducts – cholangiocarcinoma

Hepatocellular disease

  • Viral hepatitis A, B, C, D, E
  • toxins – ETOH, drugs (tyelenol), solvents, heavy metals, mushrooms
  • infiltration: fatty liver, amyloid, sarcoid, hemachromatosis, Wilsons, Tb, fungal, lymphoma
  • autoimmune – Primary biliary cirrhosis, PSC

Extrahepatic obstruction

  • gallstones
  • strictures
  • masses (abscess, neoplasm)