*Definition and Overview -
Jaundice is a clinical sign characterized by a yellowish discoloration of the
skin, sclerae (whites of the eyes), and mucous membranes. It results from
elevated levels of bilirubin—a yellow pigment produced during the breakdown of
red blood cells—in the bloodstream and tissues. Bilirubin normally passes
through the liver, where it is conjugated (made water-soluble) and excreted
into bile. When any step in this process is disrupted, unconjugated or
conjugated bilirubin accumulates, leading to visible yellowing.
1. Physiology and Pathophysiology
- Bilirubin Production
- Senescent red blood cells
are broken down in the spleen and reticuloendothelial system.
- Hemoglobin is metabolized
into unconjugated (indirect) bilirubin, which is lipid-soluble and
travels bound to albumin in plasma.
- Hepatic Uptake and
Conjugation
- In the liver, hepatocytes
take up unconjugated bilirubin.
- Through the action of
UDP-glucuronyl transferase, unconjugated bilirubin is converted into
conjugated (direct) bilirubin, which is water-soluble.
- Excretion
- Conjugated bilirubin is
secreted into bile canaliculi, flows into the biliary tree, and
ultimately reaches the intestine.
- Intestinal bacteria convert
it into urobilinogen; some is reabsorbed and excreted in urine, while
most is eliminated in feces as stercobilin.
- Points of Disruption
- Pre-hepatic (Hemolytic): Excessive breakdown of
red blood cells produces more unconjugated bilirubin than the liver can
handle.
- Hepatic: Intrinsic liver disease
(e.g., viral hepatitis, alcoholic liver injury, genetic enzyme defects)
impairs uptake, conjugation, or both.
- Post-hepatic
(Obstructive/Cholestatic): Blockage of bile ducts prevents excretion
of conjugated bilirubin into the gut (e.g., gallstones, pancreatic head
tumors, strictures).
2. Classification of Jaundice
A.
Pre-hepatic (Unconjugated, Indirect)
- Mechanism: Hemolysis or
ineffective erythropoiesis overwhelms the liver’s conjugating capacity.
- Typical findings: Elevated
indirect (unconjugated) bilirubin on labs; normal alkaline phosphatase
(ALP); normal gamma‐glutamyl transferase (GGT); no dark urine
(unconjugated bilirubin is not water-soluble, so it isn’t excreted in
urine).
- Common causes:
- Hemolytic anemias (e.g.,
sickle cell disease, autoimmune hemolysis)
- Hereditary conditions
(e.g., Gilbert syndrome, Crigler–Najjar syndrome)
- Transfusion reactions,
malaria, snake bites (in endemic areas)
B.
Hepatic (Mixed or Predominantly Indirect or Direct)
- Mechanism: Dysfunction at
hepatocyte level, affecting uptake, conjugation, or excretion.
- Lab pattern: Elevated both
direct (conjugated) and indirect bilirubin (though proportions vary). ALP
and GGT may be mildly elevated or normal. Transaminases (AST/ALT) often
elevated if there is hepatocellular damage.
- Common causes:
- Viral hepatitis (A, B, C,
E, etc.)
- Alcoholic liver disease
- Nonalcoholic fatty liver
disease (NAFLD/NASH)
- Drug-induced liver injury
(e.g., acetaminophen overdose, certain antibiotics)
- Genetic syndromes (e.g.,
Dubin-Johnson, Rotor syndrome)
C.
Post-hepatic (Obstructive or Cholestatic, Predominantly Conjugated)
- Mechanism: Physical
obstruction of bile flow from the liver to the duodenum.
- Lab pattern: Predominant
elevation of direct (conjugated) bilirubin. Markedly increased ALP and
GGT. Dark urine (conjugated bilirubin is water-soluble and spills over
into urine), pale or clay‐colored stools (reduced stercobilinogen).
- Common causes:
- Gallstones in common bile
duct (choledocholithiasis)
- Cholangiocarcinoma,
pancreatic head carcinoma
- Primary sclerosing
cholangitis (PSC), primary biliary cholangitis (PBC)
- Biliary strictures or
post-surgical biliary injury
3. Clinical Presentation
- General Signs and Symptoms
- Yellow discoloration: First noticed in sclerae,
then skin/mucous membranes as bilirubin levels rise above approximately
2.5–3 mg/dL.
- Dark urine: If conjugated bilirubin
exceeds renal threshold (typically >2 mg/dL), urine may turn dark
amber or tea-colored.
- Pale stools: In obstructive forms,
lack of stercobilin in bile leads to clay-colored or pale stools.
- Pruritus (itching): Often intense in
cholestatic forms due to bile salt deposition in the skin.
- Systemic or Underlying
Disease Features
- Pre-hepatic: Signs of hemolysis—fatigue,
pallor, tachycardia, splenomegaly, elevated lactate dehydrogenase (LDH),
low haptoglobin, reticulocytosis.
- Hepatic: Malaise, anorexia,
nausea/vomiting, right upper quadrant (RUQ) discomfort or pain,
hepatomegaly or a tender liver. Features of chronic liver disease (e.g.,
ascites, spider angiomas, palmar erythema) in long-standing cases.
- Post-hepatic: Severe colicky or
constant RUQ/epigastric pain (e.g., due to gallstone obstruction), weight
loss and anorexia if malignant, palpable non-tender gallbladder in
carcinoma (“Courvoisier’s sign”).
- Associated Findings
- Fever and chills: May suggest ascending
cholangitis if infection of biliary tree is present (Charcot triad:
fever/chills, RUQ pain, jaundice).
- Coagulopathy: Advanced liver disease or
obstruction can impair vitamin K metabolism, leading to prolonged
prothrombin time (PT)/INR.
- Fatigue and weight loss: Especially in chronic
viral hepatitis or malignancies.
4. Diagnostic Evaluation
- Laboratory Tests
- Serum Bilirubin
Fractionation:
Distinguish unconjugated versus conjugated dominance.
- Liver Function Tests (LFTs):
- AST/ALT: Markedly raised
in acute hepatocellular injury (e.g., viral hepatitis).
- ALP and GGT: Markedly
raised in cholestatic/obstructive patterns.
- Albumin and PT/INR:
Assesses synthetic function; hypoalbuminemia and prolonged INR indicate
severe or chronic liver disease.
- Hemolysis Workup (if
pre-hepatic suspected): Reticulocyte count, haptoglobin, LDH,
peripheral smear, Coombs test (if autoimmune cause suspected).
- Viral Serologies: Hepatitis A IgM,
Hepatitis B surface antigen/IgM core antibody, Hepatitis C antibody/RNA,
and others (E, D) depending on epidemiology and risk factors.
- Autoimmune Markers (if
cholestatic or hepatic autoimmune suspected): ANA, anti–smooth muscle
antibody (ASMA), anti–mitochondrial antibody (AMA), IgG4 levels.
- Metabolic and Genetic Tests: Ceruloplasmin (Wilson
disease), alpha-1 antitrypsin levels and phenotype, ferritin/transferrin
saturation (hemochromatosis), tests for Gilbert/Crigler–Najjar as
indicated.
- Imaging Studies
- Abdominal Ultrasound (first-line):
- Detects biliary dilation
(“double-duct” sign), gallstones, masses in liver or pancreas.
- Assesses hepatic size,
texture (fatty infiltration, cirrhosis), and spleen size.
- Magnetic Resonance
Cholangiopancreatography (MRCP): Non-invasive imaging of biliary tree to
localize strictures, stones, or tumors.
- Computed Tomography (CT)
Scan:
Useful when malignancy (e.g., pancreatic carcinoma) is suspected or to
evaluate complications in hepatitis (e.g., liver abscesses).
- Endoscopic Retrograde
Cholangiopancreatography (ERCP): Both diagnostic and therapeutic—can identify
obstructing stones or strictures and allow sphincterotomy, stone removal,
or stent placement.
- Liver Biopsy: Reserved for unclear
hepatic processes when serology and imaging are inconclusive (e.g.,
autoimmune hepatitis, infiltrative disorders).
- Other Specialized Tests
- Endoscopic Ultrasound (EUS): For detailed evaluation
of pancreas head lesions or small biliary stones missed by transabdominal
ultrasound.
- Percutaneous Transhepatic
Cholangiography (PTC): In cases where ERCP is not feasible (e.g.,
altered gastrointestinal anatomy).
- Genetic Testing: Confirm inborn errors
like Crigler–Najjar, Dubin-Johnson, or Rotor syndrome if suspected from
family history and lab patterns.
5. Common Etiologies and Risk Factors
- Pre-hepatic (Hemolytic)
- Hereditary: Sickle cell
disease, thalassemias, hereditary spherocytosis, G6PD deficiency.
- Autoimmune: Autoimmune
hemolytic anemia (warm or cold agglutinin types).
- Infections/Toxins: Malaria (in
endemic regions), certain snake venoms, toxins causing red cell
destruction.
- Transfusion Reactions:
Acute or delayed hemolytic transfusion reactions.
- Hepatic
- Viral Hepatitis:
- Hepatitis A/E: Often
acute, self-limited, sometimes fulminant in elderly or those with liver
disease.
- Hepatitis B/C/D: Can be
acute or chronic; chronic infection predisposes to cirrhosis and
hepatocellular carcinoma.
- Alcoholic Liver Disease:
- Spectrum from steatosis to
alcoholic hepatitis to cirrhosis; often accompanied by AST:ALT ratio
>2:1.
- Non-Alcoholic Fatty Liver
Disease (NAFLD)/Non-Alcoholic Steatohepatitis (NASH)
- Strongly linked to
metabolic syndrome (obesity, diabetes, dyslipidemia).
- Drug-Induced Liver Injury: Acetaminophen overdose,
certain antibiotics (e.g., isoniazid), statins, anti-tubercular drugs.
- Genetic/Metabolic:
- Wilson’s disease (copper
overload)
- Hemochromatosis (iron
overload)
- Alpha-1 antitrypsin
deficiency
- Gilbert syndrome (benign,
mild unconjugated hyperbilirubinemia, often asymptomatic)
- Crigler–Najjar syndrome (severe
unconjugated hyperbilirubinemia in infancy)
- Post-hepatic
(Obstructive/Cholestatic)
- Gallstones: Most common cause of
extrahepatic obstruction; risk factors summarized by “4 Fs”: female, fat,
forty, fertile.
- Malignancies:
- Cholangiocarcinoma (bile
duct cancer)
- Pancreatic head carcinoma
(Courvoisier’s sign: palpable, nontender gallbladder + jaundice)
- Ampullary carcinoma
- Primary Sclerosing
Cholangitis (PSC): Chronic progressive fibro-obliterative
disease of intrahepatic and extrahepatic bile ducts; associated with
ulcerative colitis.
- Primary Biliary Cholangitis
(PBC):
Chronic autoimmune cholestatic disease affecting small intrahepatic bile
ducts; strongly associated with AMA positivity.
- Biliary Strictures or
Injury:
Postoperative (e.g., post-cholecystectomy), traumatic.
6. Management and Treatment
A.
General Measures
- Identify and Treat
Underlying Cause:
The primary goal is to correct the specific etiology—stop hemolysis, treat
viral hepatitis, relieve obstruction, or discontinue hepatotoxic
medications.
- Supportive Care: Maintain hydration,
correct electrolyte imbalances, provide nutritional support (especially
protein if there is significant hepatic dysfunction), and manage pruritus.
B.
Pre-hepatic Jaundice
- Treat Hemolysis:
- Autoimmune hemolysis:
Corticosteroids or immunosuppressive therapy; in refractory cases,
splenectomy.
- Enzyme deficiencies (e.g.,
G6PD): Avoid precipitating agents, manage infections promptly.
- Sickle cell crisis:
Hydroxyurea, hydration, pain control, exchange transfusion if needed.
C.
Hepatic Jaundice
- Viral Hepatitis:
- Hepatitis A/E: Usually
supportive (antiemetics, rest); rarely need hospitalization for acute
liver failure.
- Hepatitis B: Antiviral
therapy (e.g., tenofovir, entecavir) if severe or chronic.
- Hepatitis C: Direct-acting
antivirals (DAAs) such as sofosbuvir-ledipasvir regimens, based on
genotype and liver fibrosis stage.
- Alcoholic Hepatitis: Abstinence from alcohol,
nutritional supplementation (thiamine, folate), corticosteroids in severe
cases (Maddrey’s discriminant function >32).
- NAFLD/NASH: Lifestyle
modifications—weight loss through diet and exercise, control of diabetes
and dyslipidemia; Vitamin E or pioglitazone in selected NASH patients.
- Drug-Induced: Discontinue offending
drug; N-acetylcysteine for acetaminophen overdose; treat acute liver
failure in ICU or transplant center if indicated.
- Autoimmune Hepatitis: Prednisone ± azathioprine
to achieve remission; monitor LFTs and IgG levels.
- Genetic Disorders:
- Wilson’s disease: Chelation
therapy (penicillamine, trientine) and zinc acetate.
- Hemochromatosis:
Phlebotomy; chelation (deferoxamine) if severe.
- Alpha-1 antitrypsin
deficiency: Supportive; liver transplant in end-stage disease.
D.
Post-hepatic (Obstructive) Jaundice
- Gallstone Obstruction
(Choledocholithiasis):
- ERCP with sphincterotomy
and stone extraction; if unsuccessful, percutaneous transhepatic
cholangiography (PTC) for drainage.
- Cholecystectomy after
resolution of acute obstruction to prevent recurrence.
- Benign Strictures: Endoscopic balloon
dilatation with or without stenting; surgical reconstruction if
refractory.
- Malignant Obstruction:
- Decompression by
ERCP-guided biliary stent placement (plastic or metal stent).
- Surgical resection if
early-stage (e.g., Whipple procedure for resectable pancreatic head
carcinoma).
- Palliative options:
Percutaneous transhepatic biliary drainage (PTBD), photodynamic therapy
or radiofrequency ablation for cholangiocarcinoma.
- Cholangitis (Ascending):
- Emergent broad-spectrum
antibiotics covering Gram-negative rods and anaerobes (e.g.,
piperacillin-tazobactam, ceftriaxone + metronidazole).
- Urgent biliary
decompression (ERCP or PTBD) once stabilized.
7. Complications and Prognosis
- Acute Liver Failure (in fulminant hepatic
causes)
- Encephalopathy,
coagulopathy, cerebral edema; high mortality without liver transplant.
- Chronic Liver Disease
- Progression to cirrhosis,
portal hypertension, variceal bleeding, ascites, hepatic encephalopathy,
hepatocellular carcinoma.
- Cholangitis / Sepsis
- Untreated biliary
obstruction can lead to ascending cholangitis, sepsis, and multi-organ
failure.
- Nutritional Deficiencies
- Chronic cholestasis can
cause fat‐soluble vitamin deficiency (A, D, E, K).
- Pruritus and Quality of Life
- Severe pruritus in
cholestatic jaundice often requires medications (e.g., cholestyramine,
rifampin, sertraline, or UVB phototherapy).
Prognostic
Factors
- Underlying cause (e.g.,
Gilbert syndrome has excellent prognosis; acute fulminant hepatitis may
require transplant).
- Degree and duration of
bilirubin elevation; rapid progression of coagulopathy or encephalopathy
suggests poor outcome.
- Presence of comorbidities
(e.g., HIV/HCV co-infection, alcoholic cirrhosis).
8. Prevention and Patient Education
- Vaccination
- Hepatitis A vaccine for
travelers to endemic regions or high-risk groups.
- Hepatitis B vaccine for all
infants and unvaccinated adults at risk (healthcare workers, hemodialysis
patients, sexual exposure).
- Lifestyle Modifications
- Moderation or abstinence
from alcohol; limit hepatotoxic substances.
- Healthy diet and regular
exercise to prevent NAFLD/NASH.
- Avoidance of drugs and
herbal supplements known to cause liver injury.
- Safe Practices
- Safe blood
transfusion/screening to prevent transfusion-transmitted viral hepatitis.
- Use of barrier protection
and safe needle practices to reduce risk of hepatitis B/C.
- Screening in High-Risk
Populations
- Periodic LFTs and
ultrasound for patients with chronic hepatitis B/C to detect early
cirrhosis or hepatocellular carcinoma.
- Family screening for
hereditary conditions when indicated (e.g., hemochromatosis, Wilson’s
disease).
- Prompt Evaluation of
Symptoms
- Early medical attention for
unexplained jaundice, dark urine, clay-colored stools, severe abdominal
pain, or pruritus to detect reversible causes.
9. Summary
- Jaundice is a hallmark of disrupted
bilirubin metabolism, appearing yellowish once serum bilirubin exceeds
roughly 2.5–3 mg/dL.
- It is classified by site of
dysfunction: pre-hepatic (hemolytic), hepatic (hepatocellular or
metabolic), and post-hepatic (cholestatic/obstructive).
- History and physical exam, combined with laboratory
tests (bilirubin fractions, liver enzymes, hemolysis workup) and imaging
(ultrasound, MRCP, ERCP as needed), usually pinpoint the cause.
- Management involves treating
the underlying cause (e.g., antivirals for hepatitis, ERCP for
obstructive stones), providing supportive measures, and preventing
complications.
- Preventive strategies
include vaccination (hepatitis A/B), safe practices to avoid
blood-borne infections, lifestyle changes for metabolic and
alcoholic liver disease, and early evaluation of symptoms.
By
understanding the mechanisms, forms, and appropriate workup of jaundice,
clinicians can tailor investigations and interventions—ranging from simple
observation in mild Gilbert syndrome to urgent biliary decompression in
ascending cholangitis—to optimize outcomes and prevent long-term sequelae.
