Harrison's Practice: Jaundice

Harrison's Practice

Jaundice

Definition

Yellowish discoloration of tissue, also called icterus, resulting from the deposition of bilirubin, which occurs only in the presence of serum hyperbilirubinemia.
Jaundice is not usually detected until the serum bilirubin level exceeds 3.0 mg/dL.
Bilirubin is an end product of hemoglobin catabolism.
- To facilitate its excretion in the bile, bilirubin is conjugated within the liver to glucuronic acid.
- Jaundice can result from an excess of unconjugated bilirubin:
  - From hemolysis, abnormalities of conjugation, or impaired hepatic uptake of bilirubin
  - Unconjugated bilirubin is also referred to as indirect bilirubin (definition comes from original chemical reactions used for determining bilirubin levels).
- Jaundice can also result from an excess of conjugated bilirubin (usually accompanied by a smaller excess of unconjugated bilirubin).
  - From liver or biliary disease
  - Conjugated bilirubin is also referred to as direct bilirubin.
Although usually a sign of significant disease, many persons have a congenital predisposition to mild jaundice (e.g., Gilbert’s syndrome) that is not pathologic.

Epidemiology

Liver and biliary diseases are the leading cause of jaundice in most populations.
Hemolysis sufficient to cause jaundice is the second major etiologic category.
Prevalence of inherited hyperbilirubinemia
- Gilbert’s syndrome
  - Common
  - 3–7% of population
- Crigler-Najjar type I
  - Exceptionally rare
- Crigler-Najjar type II
  - Somewhat more common than type I
- Conjugated hyperbilirubinemia
  - Found in 2 rare inherited conditions: Dubin-Johnson syndrome and Rotor’s syndrome
- Vanishing bile duct syndrome and adult bile ductopenia
  - Rare
Age
- Jaundice can affect all age groups.
- Some disorders typically present in certain age groups.
  - Crigler-Najjar type I
    - Found in neonates
  - Primary biliary cirrhosis
    - Predominantly middle-aged women
  - Autoimmune hepatitis
    - Typically seen in young to middle-aged women
  - Dubin-Johnson syndrome and Rotor’s syndrome
    - Patients present with asymptomatic jaundice, typically in second decade of life.
Sex
- Predisposition by sex occurs in certain disorders.
  - Primary biliary cirrhosis
    - Predominantly middle-aged women
  - Gilbert’s syndrome
    - Male-to-female ratio 2–7:1

Mechanism

Bilirubin is a product of hemoglobin metabolism.
- Its serum level reflects a balance between:
  - Input from production of bilirubin
  - Hepatic/biliary removal of pigment
- Bilirubin is conjugated within the liver to glucuronic acid.
  - Only conjugated bilirubin can be excreted into bile.
  - It then passes into the intestines where it turns the stool dark.
  - Intestinal flora also degrades bilirubin into urobilinogen, which is reabsorbed and excreted in the urine, turning it dark as well.
  - Unconjugated bilirubin binds to serum proteins and does not follow the above pathways.
    - Thus, in cases of unconjugated bilirubinemia, neither dark stools nor the presence of urobilinogen occur.
Hyperbilirubinemia may result from:
- Overproduction of bilirubin, which results in an increase in unconjugated bilirubin (e.g., from massive hemolysis)
- Impaired uptake, conjugation, or excretion of bilirubin
  - In physiologic neonatal jaundice, hepatic physiologic processes are incompletely developed at birth.
- Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts
- Obstruction of bile ducts as in cancer or stones results in an increase primarily in conjugated bilirubin.

Symptoms & Signs

History

Perhaps the most important part of evaluation
Important considerations include:
- Exposure to any chemical or medication
  - Physician-prescribed or over-the-counter, including herbal and vitamin preparations, anabolic glucocorticoids
- Possible parenteral exposures, including:
  - Transfusions
  - Intravenous and intranasal drug use
  - Tattoos
- Sexual activity
- Recent travel history
- Exposure to anyone with jaundice
- Exposure to contaminated foods
- Occupational exposure to hepatotoxins
- Alcohol consumption
- Duration of jaundice
- Presence of any accompanying symptoms; while not specific for any 1 condition, can suggest a particular diagnosis.
  - Arthralgias
  - Myalgias
  - Rash
  - Anorexia
  - Weight loss
  - Abdominal pain
  - Fever
  - Pruritus
  - Changes in color of urine and stool
- History of arthralgias and myalgias predating jaundice
  - Suggests hepatitis, either viral or drug-related
- Jaundice associated with sudden onset of severe right upper quadrant pain and shaking chills
  - Suggests choledocholithiasis and ascending cholangitis

Physical examination

Nutritional assessment
- Temporal and proximal muscle wasting
  - Suggests long-standing diseases such as pancreatic cancer or cirrhosis
Yellowing of the sclerae is usually the first detectable sign of jaundice.
- Scleral icterus can usually be detected when the serum bilirubin exceeds 3.0 mg/dL.
- Ability to detect scleral icterus is made more difficult if examining room has fluorescent lighting.
- If examiner suspects scleral icterus, a second place to examine is underneath tongue.
Skin examination for icterus
- As serum bilirubin levels rise, skin will eventually become yellow in light-skinned patients and even green if process is long-standing.
- Green color is produced by oxidation of bilirubin to biliverdin.
Darkening of urine
- Patients often describe urine as tea- or cola-colored.
- Sensitive indicator of increased serum bilirubin
- Due to renal excretion of conjugated bilirubin
- Bilirubinuria indicates:
  - Elevation of direct serum bilirubin fraction
  - Presence of liver disease
Stigmata of chronic liver disease
- Commonly seen in advanced alcoholic (Laennec’s) cirrhosis and occasionally in other types of cirrhosis
  - Spider nevi
  - Palmar erythema
  - Gynecomastia
  - Caput medusae
  - Dupuytren’s contractures
  - Parotid gland enlargement
  - Testicular atrophy
Enlarged left supraclavicular node (Virchow’s node) or periumbilical nodule (Sister Mary Joseph’s nodule)
- Suggests abdominal malignancy
Jugular venous distention
- Sign of right-sided heart failure
- Suggests hepatic congestion
Right pleural effusion
- In absence of clinically apparent ascites, may be seen in advanced cirrhosis
Abdominal examination
- Should focus on:
  - Size and consistency of liver
  - Whether spleen is palpable and, therefore, enlarged
  - Whether ascites is present
- Enlarged left lobe of liver, felt below xiphoid, and enlarged spleen
  - Seen in cirrhosis
- Grossly enlarged nodular liver or obvious abdominal mass
  - Suggests malignancy
- Enlarged tender liver
  - Viral or alcoholic hepatitis
  - Less often, acutely congested liver secondary to right-sided heart failure
- Severe right upper quadrant tenderness with respiratory arrest on inspiration (Murphy’s sign) suggests:
  - Cholecystitis
  - Occasionally, ascending cholangitis
- Ascites in presence of jaundice
  - Suggests either advanced cirrhosis or malignancy with peritoneal spread

Differential Diagnosis

Other causes of skin yellowing

Carotenoderma
- Yellow color is imparted to skin by presence of carotene.
- Occurs in healthy individuals who ingest excessive amounts of vegetables and fruits that contain carotene, e.g., carrots, leafy vegetables, squash, peaches, and oranges
- Pigment is concentrated on palms, soles, forehead, and nasolabial folds.
  - Sclerae are spared from discoloration.
  - Unlike jaundice, where yellow coloration of skin is uniformly distributed over body
Use of quinacrine
- Causes yellow discoloration of skin in 4–37% of treated patients
- Can cause discoloration of sclerae
Excessive exposure to phenols

Isolated indirect (unconjugated) hyperbilirubinemia

Physiologic neonatal jaundice
Hemolytic disorders
- Inherited disorders include:
  - Spherocytosis
  - Sickle cell anemia
  - Deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase
  - Serum bilirubin rarely exceeds 86 μmol/L (5 mg/dL).
- Acquired hemolytic disorders include:
  - Microangiopathic hemolytic anemia (e.g., hemolytic-uremic syndrome)
  - Paroxysmal nocturnal hemoglobinuria
  - Spur cell anemia
  - Immune hemolysis
Ineffective erythropoiesis
- Cobalamin, folate, thalassemia, and severe iron deficiencies
Drugs
- Rifampicin, probenecid, ribavirin
Inherited conditions
- Crigler-Najjar syndrome type I
  - Characterized by severe jaundice [bilirubin > 342 μmol/L (> 20 mg/dL)] in neonates
- Crigler-Najjar syndrome type II
  - Serum bilirubin levels range from 103–428 μmol/L (6–25 mg/dL)
- Gilbert’s syndrome
  - Marked by impaired conjugation of bilirubin due to reduced bilirubin uridine diphosphate glucuronosyltransferase activity
  - Patients have mild unconjugated hyperbilirubinemia with serum levels almost always < 103 μmol/L (6 mg/dL).
  - Serum levels may fluctuate.
  - Jaundice often identified only during periods of fasting

Isolated direct (conjugated) hyperbilirubinemia

Found in 2 rare inherited conditions
- Dubin-Johnson syndrome
- Rotor’s syndrome
Differentiating between syndromes possible but clinically unnecessary, due to their benign nature

Causes of elevation of both conjugated and unconjugated bilirubin (percent of conjugated bilirubin usually >50%)

Hepatocellular diseases

Viral hepatitis
- Hepatitis A, B, C, D, and E
- Epstein-Barr virus (EBV)
- Cytomegalovirus (CMV)
- Herpes simplex
Drug toxicity
- Classified as either predictable or unpredictable
- Predictable reactions are dose-dependent and affect all patients who ingest toxic dose; classic example is acetaminophen hepatotoxicity.
- Unpredictable or idiosyncratic drug reactions are not dose-dependent and occur in few patients.
- Many drugs can cause idiosyncratic hepatic injury.
Environmental toxins include:
- Industrial chemicals such as vinyl chloride
- Herbal preparations containing pyrrolizidine alkaloids (e.g., Jamaica bush tea) and kava kava
- Mushrooms Amanita phalloides or Amanita verna that contain highly hepatotoxic amatoxins
Wilson disease
Autoimmune hepatitis
Alcoholic hepatitis
- Can be differentiated from viral and toxin-related hepatitis by pattern of aminotransferase in serum

Hepatic cirrhosis from any cause

Excessive use of alcohol is by far the leading cause of cirrhosis.
End-stage cirrhosis from any cause

Cholestatic conditions

When the pattern of the liver tests suggests a cholestatic disorder, the next step is to determine whether it is intra- or extrahepatic, which can be difficult.
- History, physical examination, and laboratory tests often not helpful
- Next appropriate test is an ultrasound.
  - Absence of biliary dilatation suggests intrahepatic cholestasis.
  - Biliary dilatation suggests extrahepatic cholestasis.
  - False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing cholangitis.

Intrahepatic cholestasis

Diagnosis often is made by serologic testing in combination with percutaneous liver biopsy.
List of possible causes is long and varied.
A number of conditions that typically cause a hepatocellular pattern of injury can also present as cholestatic variants.
- Hepatitis B and C can cause cholestatic hepatitis (fibrosing cholestatic hepatitis) with histologic features that mimic large duct obstruction.
- A disease variant has been reported in patients who have undergone solid organ transplantation.
- Hepatitis A, alcoholic hepatitis, EBV, and CMV may present as cholestatic liver disease.
Drug-induced cholestasis
- Usually reversible after eliminating offending drug
- May take many months to resolve
- Most commonly associated drugs are anabolic and contraceptive steroids.
- Reported with chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, and erythromycin estolate, trimethoprim, sulfamethoxazole, and penicillin-based antibiotics such as ampicillin, dicloxacillin, and clavulinic acid
- Rarely, may be chronic and associated with progressive fibrosis despite early discontinuation of drug
- Chronic cholestasis is associated with chlorpromazine and prochlorperazine.
Primary biliary cirrhosis
- Progressive destruction of interlobular bile ducts
PSC
- Characterized by destruction and fibrosis of larger bile ducts
- In 95% of patients, both intra- and extrahepatic ducts are involved.
- May involve only intrahepatic ducts and present as intrahepatic cholestasis
Vanishing bile duct syndrome and adult bile ductopenia are seen:
- In patients who develop chronic rejection after liver transplantation
- In patients who develop graft-versus-host disease after bone marrow transplantation
- In rare cases of sarcoidosis
- In patients taking certain drugs, including chlorpromazine
- Idiopathically
Familial forms of intrahepatic cholestasis
- Familial intrahepatic cholestatic syndromes, I–III
- Benign recurrent cholestasis
Cholestasis of pregnancy
- Occurs in second and third trimesters
- Resolves after delivery
- Cause unknown
- Probably inherited
- Can be triggered by estrogen administration
Other causes include:
- Total parenteral nutrition (TPN)
- Nonhepatobiliary sepsis
- Benign postoperative cholestasis
- Infiltrative disease
  - Tuberculosis
  - Lymphoma
  - Amyloid
- Paraneoplastic syndrome is associated with a number of different malignancies, including:
  - Hodgkin’s disease
  - Medullary thyroid cancer
  - Hypernephroma
  - Renal sarcoma
  - T cell lymphoma
  - Prostate cancer
  - Several GI malignancies
- Patients may develop cholestasis in intensive care unit.
  - Major considerations should be sepsis, shock liver, and TPN jaundice.
- Jaundice occurring after bone marrow transplantation most likely is due to venoocclusive disease or graft-versus-host disease.

Malignant causes of extrahepatic cholestasis

Pancreatic and gallbladder tumors
Ampullary carcinoma
Cholangiocarcinoma
- Most commonly associated with PSC
- Exceptionally difficult to diagnose because appearance often identical to PSC
Hilar lymphadenopathy due to metastases from cancers causing obstruction of extrahepatic biliary tree

Non-neoplastic (benign) causes of extrahepatic cholestasis

Choledocholithiasis
- Most common cause of extrahepatic cholestasis
- Wide range of presentation
  - Mild right upper quadrant discomfort with only minimal elevations of enzyme tests
  - Ascending cholangitis with jaundice, sepsis, and circulatory collapse
PSC may occur with clinically important strictures limited to extrahepatic biliary tree.
Chronic pancreatitis rarely causes strictures of distal common bile duct, where it passes through head of pancreas.
AIDS cholangiopathy
- Usually due to infection of bile duct epithelium with CMV or cryptosporidia
- Has cholangiographic appearance similar to that of PSC
- Patients do not typically present with jaundice.
Mirizzi syndrome
Parasitic disease (ascariasis)

Diagnostic Approach

History (focus on medication/drug exposure)
Physical examination
Lab tests [bilirubin with fractionation, alanine aminotransferase (ALT), aspartate (AST), alkaline phosphatase, prothrombin time, and albumin]
If bilirubin and other liver tests are elevated, look at the pattern of abnormalities.
- Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase
  - Viral serologies: hepatitis A IgM, hepatitis B surface antigen and core antibody, hepatitis C RNA
  - Toxicology screen: acetaminophen level
  - Ceruloplasmin (if patient < 40 years of age)
  - Antinuclear antibody, smooth muscle antibody, liver–kidney microsomal antibody, serum protein electrophoresis
    - If results are negative: additional virologic testing [e.g., CMV DNA, EBV capsid antigen, hepatitis D antibody (if indicated), hepatitis E IgM (if indicated)]
  - Liver biopsy (if additional virologic testing was negative)
- Cholestatic pattern: alkaline phosphatase out of proportion to ALT/AST
  - Obtain an abdominal ultrasound.
  - If ultrasound shows dilated ducts, extrahepatic cholestasis: CT/endoscopic retrograde cholangiopancreatography (ERCP)
  - If ultrasound shows ducts not dilated, intrahepatic cholestasis: serologic testing for antimitochondrial antibody, hepatitis serologies, hepatitis A, CMV, EV; review of drugs
    - If results negative: ERCP/liver biopsy
    - If antimitochondrial antibody positive: liver biopsy
In evaluating jaundice in patients with chronic hemolysis
- High incidence of pigmented (calcium bilirubinate) gallstones increases likelihood of choledocholithiasis as alternative explanation for hyperbilirubinemia.

Laboratory Tests

Serum bilirubin

van den Bergh method
- Direct fraction provides approximate determination of conjugated bilirubin in serum.
- Total serum bilirubin is the amount that reacts after addition of alcohol.
- Indirect fraction is difference between total and direct bilirubin.
  - Provides estimate of unconjugated bilirubin in serum
Normal serum bilirubin concentration usually 17 μmol/L (< 1 mg/dL)
- Up to 30%, or 5.1 μmol/L (0.3 mg/dL), of total may be direct-reacting (conjugated) bilirubin.
- Total serum bilirubin concentrations are 3.4–15.4 μmol/L (0.2–0.9 mg/dL) in 95% of normal population.
In normal persons or those with Gilbert’s syndrome
- Almost 100% of serum bilirubin is unconjugated.
- < 3% is monoconjugated bilirubin.
In general, hyperbilirubinemia associated with hepatocellular and biliary disease is >50% direct (conjugated) bilirubin.
- In hemolysis, hyperbilirubinemia is usually largely (indirect) unconjugated bilirubin.
In jaundiced patients with hepatobiliary disease
- Part of direct-reacting bilirubin fraction includes conjugated bilirubin that is covalently linked to albumin.
- Albumin-linked bilirubin fraction (delta fraction or biliprotein) represents important fraction of total serum bilirubin in patients with cholestasis and hepatobiliary disorders.
- Prolonged half-life of albumin-bound conjugated bilirubin explains 2 previously unexplained enigmas in jaundiced patients with liver disease:
  - Some patients with conjugated hyperbilirubinemia do not exhibit bilirubinuria during recovery phase of disease because bilirubin is bound to albumin and not filtered by renal glomeruli.
  - Elevated serum bilirubin level declines more slowly than expected in some patients who otherwise appear to be recovering satisfactorily.
- Late in recovery phase of hepatobiliary disorders, all conjugated bilirubin may be in albumin-linked form.
  - Value in serum falls slowly because of long half-life of albumin.
Bilirubin levels in some specific disorders of isolated indirect hyperbilirubinemia
- Crigler-Najjar syndrome type I
  - Characterized by severe jaundice [bilirubin > 342 μmol/L (> 20 mg/dL)]
- Crigler-Najjar syndrome type II
  - Serum bilirubin levels range from 103–428 μmol/L (6–25 mg/dL)
- Gilbert’s syndrome
  - Mild unconjugated hyperbilirubinemia with serum levels almost always < 103 μmol/L (6 mg/dL)
  - Serum levels may fluctuate.
- Hemolytic disorders
  - Serum bilirubin rarely exceeds 86 μmol/L (5 mg/dL).

Urine bilirubin

Bilirubinuria
- Implies presence of liver disease
Conjugated bilirubin
- Filtered by glomerulus
- Majority is reabsorbed by proximal tubules.
- Small fraction is excreted in urine.
  - Any bilirubin found in urine is conjugated bilirubin.
Unconjugated bilirubin
- Always bound to albumin in serum
- Not filtered by kidney
- Not found in urine

Urine dipstick test (Ictotest)

Gives same information as fractionation of serum bilirubin
Very accurate
False-negative test
- Possible in prolonged cholestasis due to predominance of conjugated bilirubin covalently bound to albumin

Enzyme tests

ALT
AST
Alkaline phosphatase
Helpful in differentiating between hepatocellular process and cholestatic process
- Critical step in determining what additional workup is indicated
- Bilirubin can be prominently elevated in both; not necessarily helpful in differentiating between the two.
- Hepatocellular process
  - Generally disproportionate rise in aminotransferases compared with alkaline phosphatase
- Cholestatic process
  - Disproportionate rise in alkaline phosphatase compared with aminotransferases
- Degree of aminotransferase elevation
  - Occasionally helpful in differentiating between hepatocellular and cholestatic processes
  - ALT and AST values < 8 times normal may be seen in either hepatocellular or cholestatic liver disease.
  - Values ≥25 times normal seen primarily in acute hepatocellular diseases
Alcoholic hepatitis
- AST:ALT ratio typically at least 2:1
- AST rarely exceeds 300 U/L
Acute viral hepatitis and toxin-related injury severe enough to produce jaundice
- Typically aminotransferases > 500 U/L
- ALT ≥ AST
Jaundice from cirrhosis
- Normal or only slight elevations of aminotransferases
AIDS cholangiopathy
- Patients usually present with greatly elevated serum alkaline phosphatase levels, mean of 800 IU/L, but bilirubin often is near normal.

Albumin and prothrombin time

Perform in all jaundiced patients to assess liver function.
Low albumin
- Suggests chronic process such as cirrhosis or cancer
Normal albumin
- Suggests more acute process such as viral hepatitis or choledocholithiasis
Elevated prothrombin time indicates either:
- Vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or
- Significant hepatocellular dysfunction
Failure of prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury.

Further testing in hepatocellular disease

Appropriate testing for acute viral hepatitis, including:
- Hepatitis A IgM antibody
- Hepatitis B surface antigen and core IgM antibody
- Hepatitis C viral RNA
  - Can take many weeks for hepatitis C antibody to become detectable; unreliable if acute hepatitis C suspected
Depending on circumstances, the following studies may be indicated:
- Hepatitis D
- Hepatitis E
- EBV
- CMV
- Drug levels (acetaminophen)
Ceruloplasmin
- Initial screening test for Wilson disease
Iron, transferrin, and ferritin
- Screen for hemochromatosis
Testing for autoimmune hepatitis
- Usually includes antinuclear antibody and measurement of specific immunoglobulins (anti-smooth muscle and liver-kidney microsomal antibodies)
Antimitochondrial antibody
- Found in 95% of patients with primary biliary cirrhosis
Alpha-1-antitrypsin activity
- Screens for deficiency in this enzyme

Imaging

Ultrasound
- Appropriate when pattern of liver tests suggests cholestatic disorder
  - Helps distinguish intrahepatic from extrahepatic cholestasis
- Inexpensive
- No ionizing radiation
- Can detect dilation of intra- and extrahepatic biliary tree with high degree of sensitivity and specificity
  - Absence of biliary dilatation suggests intrahepatic cholestasis.
  - Presence of biliary dilatation indicates extrahepatic cholestasis.
    - Rarely identifies site or cause of obstruction
    - Distal common bile duct particularly difficult to visualize because of overlying bowel gas
- False-negative results occur in patients with:
  - Partial obstruction of common bile duct
  - Cirrhosis or primary sclerosing cholangitis (PSC), where scarring prevents intrahepatic ducts from dilating
- Appropriate next tests include:
  - CT
  - ERCP
CT
- Better than ultrasonography for the following:
  - Assessing head of pancreas
  - Identifying choledocholithiasis in distal common bile duct
    - Particularly when ducts not dilated
ERCP
- "Gold standard" for identifying choledocholithiasis
- Used to make diagnosis of primary sclerosing cholangitis
  - Pathognomonic findings are multiple strictures of bile ducts with dilatations proximal to strictures.
  - Approximately 75% of patients with PSC have inflammatory bowel disease
- Technique
  - Side-viewing endoscope introduced perorally into duodenum
  - Ampulla of Vater visualized and catheter advanced through ampulla
  - Injection of dye allows visualization of common bile duct and pancreatic duct.
- Success rate for cannulation of common bile duct
  - 80–95%, depending on operator’s experience
- Therapeutic interventions
  - Removal of common bile duct stones
  - Placement of stents
- In patients in whom ERCP is unsuccessful
  - Transhepatic cholangiography can provide same information
Magnetic resonance cholangiopancreatography
- Now widely available, noninvasive technique for imaging the bile and pancreatic ducts
- It has replaced ERCP as the initial diagnostic test in cases where the need for intervention is felt to be small.

Diagnostic Procedures

Percutaneous liver biopsy
- Only indicated when confronted with hepatocellular disease of unknown type
- Histologic findings
  - Hepatitis B and C can cause cholestatic hepatitis (fibrosing cholestatic hepatitis), which has histologic features that mimic large duct obstruction.
  - Vanishing bile duct syndrome and adult bile ductopenia
    - Decreased number of bile ducts seen in liver biopsy specimens
    - Histologic picture similar to that found in primary biliary cirrhosis
  - Intrahepatic cholestasis
    - Diagnosis often made by serologic testing in combination with percutaneous liver biopsy

Treatment Approach

Definitive treatment depends on cause of jaundice.

Specific Treatments

Specific therapies depend on etiology of jaundice.
Some specific therapies include:
- Gilbert’s syndrome
  - Benign condition; usually does not require treatment
- Crigler-Najjar type I
  - Only effective treatment is orthotopic liver transplantation.
  - Gene therapy and allogeneic hepatocyte infusion are experimental approaches that look promising for the future.
- Crigler-Najjar type II
  - Administration of phenobarbital can reduce serum bilirubin levels.
- Choledocholithiasis
  - PSC may occur with clinically important strictures limited to extrahepatic biliary tree.
  - In cases where there is a dominant stricture, patients can be effectively managed with serial endoscopic dilatations.
  - See Choledocholithiasis for details.
- Physiologic neonatal jaundice
  - Treatment options include phototherapy and exchange transfusion.
- Drug-induced cholestasis
  - Usually reversible after eliminating offending drug
  - May take many months to resolve
- Hepatitis: see

Monitoring

Serum bilirubin should be monitored to ensure that the level is not increasing.
Serum bilirubin as well as other liver test abnormalities should be checked after treatment to ensure a return to normal levels.

Complications

Physiologic neonatal jaundice
- Risk for bilirubin encephalopathy (kernicterus) with rapidly rising unconjugated bilirubin, or absolute values > 340 µmol/L (20 mg/dL)
- Consequences range from appreciable neurologic deficits to death.
Crigler-Najjar syndrome type I
- Neurologic impairment due to kernicterus, often leading to death in infancy or childhood
Crigler-Najjar syndrome type II
- Susceptibility to kernicterus under stress of intercurrent illness or surgery
In chronic hemolysis
- High incidence of pigmented gallstones increasing the likelihood of choledocholithiasis
Choledocholithiasis
- Can progress to ascending cholangitis with jaundice, sepsis, and circulatory collapse
Drug-induced cholestasis
- Rarely, may be chronic and associated with progressive fibrosis despite early discontinuation of drug
Other disorders
- For complications from other specific hepatocellular and cholestatic conditions, see specific disease.

Prognosis

Prognosis is related to the underlying disorder.
Gilbert’s syndrome
- No different from general population
Crigler-Najjar syndrome type I
- Death typically in infancy or childhood
Crigler-Najjar syndrome type II
- Patients live into adulthood
- Susceptibility to kernicterus under stress of intercurrent disease or surgery

Prevention

Prevention with hepatitis A vaccine or hepatitis B vaccine
Avoidance of drugs or toxins that cause predictable hepatocellular injury

ICD-9-CM

774.6 Unspecified fetal and neonatal jaundice
782.4 Jaundice, unspecified, not of newborn