Jaundice: A Comprehensive Guide to Differential Diagnosis

Jaundice, clinically recognized as hyperbilirubinemia, manifests as a yellowish discoloration of body tissues due to an excessive buildup of bilirubin. This bilirubin accumulation signals either increased bilirubin production or impaired excretion. Normal serum bilirubin levels are typically below 1 mg/dL. However, jaundice becomes visually apparent, particularly as scleral icterus (yellowing of the sclera of the eyes), when serum bilirubin levels exceed 3 mg/dL. As bilirubin levels continue to rise, the skin progressively changes color, ranging from a lemon yellow to a greenish hue, especially in chronic cases, where the green tint is attributed to biliverdin. This article provides an in-depth review of jaundice, focusing on differential diagnosis, evaluation, and the crucial role of an interprofessional healthcare team in patient care.

Objectives:

Define the underlying causes and mechanisms of jaundice.
Detail the methodologies for history taking and physical examination in patients presenting with jaundice.
Review current treatment strategies and management options for jaundice.
Underscore the importance of interprofessional collaboration in enhancing jaundice management and patient outcomes.

Access free multiple choice questions on this topic.

Introduction

Jaundice, medically termed hyperbilirubinemia,¹ is characterized by the yellowing of body tissues resulting from an abnormal accumulation of bilirubin. This accumulation occurs when bilirubin production exceeds excretion, indicating an underlying issue in bilirubin metabolism. Normal serum bilirubin levels are less than 1 mg/dL; however, clinical jaundice, noticeable as scleral icterus (yellowing of the eye sclera), becomes apparent when bilirubin levels surpass 3 mg/dL. The sclera’s high elastin content contributes to its affinity for bilirubin.² As serum bilirubin levels escalate, the skin discoloration intensifies, progressing from lemon yellow to apple green, especially in long-standing conditions, with the green color stemming from biliverdin.³

Bilirubin exists in two forms: unconjugated (indirect) and conjugated (direct). An elevation in either form can lead to jaundice. Icterus is a critical clinical indicator not only for liver disease but also for various other systemic insults.⁴

It’s important to differentiate true jaundice from carotenoderma, a condition where the skin yellows due to high carotene intake, but characteristically spares the sclerae. Carotenoderma is typically seen in individuals with diets rich in carotene-containing foods.⁵

Etiology: Unpacking the Causes of Jaundice

Understanding the etiology of jaundice is crucial for effective differential diagnosis. Jaundice can be broadly categorized based on whether the hyperbilirubinemia is conjugated or unconjugated, which helps narrow down the potential causes.

CONJUGATED HYPERBILIRUBINEMIA⁶

Conjugated hyperbilirubinemia indicates an issue with bilirubin excretion after it has been processed by the liver. The causes can be further classified into defects in transport, intrahepatic issues, and extrahepatic obstructions.

Defects in Canalicular Organic Anion Transport⁷

Dubin-Johnson syndrome: This rare genetic disorder impairs the liver’s ability to secrete conjugated bilirubin into bile, leading to chronic or intermittent jaundice.

Defects in Sinusoidal Reuptake of Conjugated Bilirubin
Rotor syndrome: Another benign genetic condition, Rotor syndrome, is characterized by impaired hepatic uptake and storage of conjugated bilirubin, resulting in jaundice.

Decreased Intrahepatic Excretion of Bilirubin⁸

This category encompasses conditions that directly affect the liver’s ability to excrete bilirubin, including:

Hepatocellular diseases:
- Viral hepatitis (A, B, D, C, E): These viral infections cause liver inflammation and damage, impairing bilirubin processing and excretion.
- Alcoholic hepatitis: Liver damage from chronic alcohol abuse leads to impaired liver function and jaundice.
- Cirrhosis: Advanced liver scarring from various causes disrupts liver function and bilirubin metabolism.
- Nonalcoholic steatohepatitis (NASH): Liver inflammation and damage associated with fat accumulation in the liver, often linked to metabolic syndrome.
- Infections: Epstein-Barr virus (EBV), Cytomegalovirus (CMV), Herpes simplex virus (HSV) can cause hepatitis and jaundice.
- Genetic and Autoimmune Disorders: Wilson’s disease, autoimmune hepatitis disrupt liver function.
Cholestatic liver diseases:
- Primary biliary cholangitis (PBC): An autoimmune disease that destroys small bile ducts in the liver, leading to bile buildup and jaundice.
- Primary sclerosing cholangitis (PSC): Chronic inflammation and scarring of bile ducts inside and outside the liver, causing cholestasis and jaundice.
Infiltrative diseases: Conditions like amyloidosis, lymphoma, sarcoidosis, and tuberculosis can infiltrate the liver, disrupting its normal function and causing jaundice.
Systemic conditions: Sepsis and hypoperfusion states can lead to liver dysfunction and jaundice.
Total parenteral nutrition (TPN): Prolonged TPN can sometimes lead to cholestasis and jaundice.
Drug-induced liver injury and toxins: Medications (oral contraceptives, rifampin, probenecid, steroids, chlorpromazine), herbal remedies (Jamaican bush tea, kava kava), and toxins (arsenic) can induce cholestatic jaundice.
Hepatic crisis in sickle cell disease: Sickle cell crises can sometimes involve the liver, leading to jaundice.
Pregnancy: Intrahepatic cholestasis of pregnancy is a condition characterized by impaired bile flow and jaundice during pregnancy.

Extrahepatic Cholestasis (Biliary Obstruction)⁹

Obstruction of the bile ducts outside the liver prevents conjugated bilirubin from flowing into the intestine, leading to its buildup in the blood. Common causes include:

Choledocholithiasis: Gallstones in the common bile duct are a frequent cause of biliary obstruction and jaundice.
Tumors: Cholangiocarcinoma (bile duct cancer) and pancreatic cancer (especially head of pancreas) can obstruct bile flow.
Extrahepatic biliary atresia: A congenital condition in infants where the bile ducts outside the liver are blocked or absent.
Pancreatitis: Acute and chronic pancreatitis can cause bile duct obstruction due to inflammation or compression.
Bile duct strictures: Narrowing of the bile ducts, often from previous surgery or inflammation.
Parasitic infections: Infections like Ascaris lumbricoides and liver flukes can obstruct bile ducts.

UNCONJUGATED HYPERBILIRUBINEMIA

Unconjugated hyperbilirubinemia arises from an increase in bilirubin production that overwhelms the liver’s capacity to conjugate it, or from impaired hepatic uptake or conjugation.

Excess Production of Bilirubin

Hemolytic anemias: Increased destruction of red blood cells releases large amounts of heme, which is converted to bilirubin.
Extravasation of blood in tissues: Large hematomas can lead to increased bilirubin production as the body breaks down the blood.
Dyserythropoiesis: Ineffective red blood cell production in the bone marrow can lead to increased bilirubin levels.

Reduced Hepatic Uptake of Bilirubin
Certain drugs can interfere with the liver’s ability to take up bilirubin.

Impaired Conjugation[¹⁰, ¹¹](#article-23802.r10, #article-23802.r11)
Genetic disorders:
- Crigler-Najjar syndrome type 1 and 2: These are inherited disorders characterized by a deficiency in the enzyme UDP-glucuronosyltransferase, which is essential for bilirubin conjugation. Type 1 is severe with complete enzyme deficiency, while type 2 is less severe with partial deficiency.
- Gilbert syndrome: A common, benign genetic condition causing mild deficiency in UDP-glucuronosyltransferase, often leading to mild, fluctuating unconjugated hyperbilirubinemia, especially during stress, fasting, or illness.
Hormonal factors:
- Hyperthyroidism: Thyroid hormone imbalances can affect bilirubin metabolism.
- Estrogens: High estrogen levels can sometimes impair bilirubin conjugation.

Epidemiology of Jaundice

The prevalence of jaundice varies significantly across different populations, with newborns and the elderly being more frequently affected.¹²

Age is a critical factor in the etiology of jaundice. Neonatal jaundice is common, affecting approximately 60% of term and 80% of preterm newborns in the first week of life. Physiological jaundice in newborns is primarily due to the immaturity of the hepatic conjugation process.¹³ Other causes in infants and children include congenital disorders, hemolysis, and defects in bilirubin uptake or conjugation. Hepatitis A is a leading cause of jaundice in children.[¹⁴, ¹⁵](#article-23802.r14, #article-23802.r15) In contrast, elderly populations are more likely to experience jaundice due to bile duct stones, drug-induced liver disease, and malignant biliary obstruction.

Gender also plays a role in the epidemiology of certain causes of jaundice. Men have a higher incidence of alcoholic and non-alcoholic cirrhosis, chronic hepatitis B, pancreatic cancer, and sclerosing cholangitis.¹⁶ Conversely, women are more prone to gallbladder stones, primary biliary cholangitis, and gallbladder cancer.¹⁷

Kernicterus, or Bilirubin-Induced Neurologic Dysfunction (BIND), a severe complication of untreated jaundice in neonates, is rare but carries a high risk of mortality or long-term neurological damage. The mortality rate associated with kernicterus is estimated at 0.28 deaths per million live births.¹⁸

Pathophysiology: Mechanisms of Bilirubin Metabolism and Jaundice

To understand jaundice, it is essential to grasp the normal pathway of bilirubin metabolism, which can be divided into prehepatic, hepatic, and posthepatic phases.[¹⁹, ⁴](#article-23802.r19, #article-23802.r4)

PREHEPATIC PHASE: Bilirubin Production

Production: Bilirubin is the end product of heme breakdown, originating primarily from senescent or defective red blood cells (RBCs). In the reticuloendothelial system (spleen, liver, bone marrow), heme is converted to bilirubin through a two-step enzymatic process:

Heme → Biliverdin → Bilirubin (unconjugated, water-insoluble due to strong hydrogen bonding)

HEPATIC PHASE: Liver Uptake and Conjugation

Hepatocellular uptake: Unconjugated bilirubin, being insoluble in water, is transported in the bloodstream bound to albumin. This albumin-bilirubin complex is delivered to the liver. Hepatocytes facilitate the uptake of bilirubin by breaking the albumin bond at the liver cell membrane. Bilirubin then enters the hepatocytes via carrier-mediated transport and binds to intracellular proteins, preventing its efflux back into the plasma.
Conjugation of bilirubin: Inside the endoplasmic reticulum of hepatocytes, unconjugated bilirubin undergoes conjugation with glucuronic acid. This process, catalyzed by UDP-glucuronosyltransferase, converts bilirubin into conjugated bilirubin, which is water-soluble and can be excreted in bile.

POSTHEPATIC PHASE: Bile Secretion and Excretion

Bile secretion from hepatocytes: Conjugated bilirubin is actively secreted into bile canaliculi, then into bile ducts, and stored in the gallbladder. Bile is released into the small intestine via the ampulla of Vater.
Intestinal metabolism and Renal transport: Conjugated bilirubin, due to its water solubility and larger molecular size, is not readily reabsorbed by the intestinal mucosa. In the colon, bacteria deconjugate and metabolize bilirubin into urobilinogens. Approximately 80% of urobilinogens are excreted in feces, contributing to its brown color as stercobilin. The remaining 10-20% undergo enterohepatic circulation, where they are reabsorbed and returned to the liver. A small fraction of urobilinogens escapes hepatic uptake and is excreted by the kidneys, giving urine its yellow color.

Disruptions in each phase of bilirubin metabolism lead to different types of jaundice. Prehepatic issues typically result in elevated unconjugated bilirubin, while posthepatic problems cause conjugated hyperbilirubinemia. Hepatic phase impairments can lead to elevations in both unconjugated and conjugated bilirubin levels. Increased urinary excretion of urobilinogen can indicate increased bilirubin production, enhanced urobilinogen reabsorption from the colon, or decreased hepatic clearance of urobilinogen.

Histopathology of Cholestasis

Histopathological examination of liver tissue can reveal patterns of cholestasis, which are indicative of impaired bile flow. There are four recognized patterns of intrahepatic cholestasis:²⁰

Cytoplasmic cholestasis: Characterized by fine yellow bile pigment within the cytoplasm of hepatocytes.
Canalicular cholestasis: Bile accumulation is observed within the bile canaliculi.
Ductular cholestasis: Bile buildup in the periportal bile ductules of Hering, often associated with severe obstruction and sepsis.
Ductal cholestasis: Presence of bile casts within the portal bile ducts, indicating obstruction in larger ducts.

These histopathological changes are thought to result from the detergent effects of retained bile acids, which can damage liver cells and bile duct epithelia.

Toxicokinetics of Bilirubin

The serum bilirubin level reflects a balance between bilirubin production and hepatic excretion. After bilirubin reaches the colon and is metabolized by bacteria into urobilinogen, most urobilinogen is converted to stercobilin and excreted in feces. A small fraction (10-20%) is reabsorbed in the gut via beta-glucuronidase enzymes, participating in enterohepatic circulation and re-excretion by the liver. Only minimal urobilinogen (less than 3 mg/dL) escapes hepatic uptake and is filtered into the urine.⁴

Due to its lipid solubility, unconjugated bilirubin can cross the blood-brain barrier. While the brain has protective mechanisms, including an enzyme on the inner mitochondrial membrane that aids in bilirubin oxidation, newborns are particularly vulnerable. In neonates, the blood-brain barrier is not fully developed, and elevated serum bilirubin levels can lead to kernicterus, causing irreversible neurological damage or even death. Newborns are also at higher risk because of the absence of mature colonic bacteria and higher levels of beta-glucuronidase, leading to increased enterohepatic reabsorption of unconjugated bilirubin and hyperbilirubinemia.²¹

History and Physical Examination: Key Steps in Differential Diagnosis

A thorough history and physical examination are paramount in the differential diagnosis of jaundice.

History

Patients may present with a range of symptoms beyond the characteristic yellowing of the skin, including pruritus (itching). Asymptomatic presentation is also possible. A detailed history should include inquiries about:

Medications, alcohol, and toxin exposure: To identify drug-induced liver injury or toxic hepatitis.
Risk factors for hepatitis: Travel history, risky sexual behaviors, history of intravenous drug use, to assess risk for viral hepatitis.
HIV status.
Personal and family history: Inherited disorders (Gilbert’s, Crigler-Najjar, Dubin-Johnson, Rotor syndrome) or hemolytic disorders.
Duration of jaundice: Acute onset versus chronic jaundice helps narrow the differential.
Associated symptoms: Joint pain (arthralgia), rash, muscle pain (myalgia), changes in urine and stool color. Arthralgias and myalgias preceding jaundice may suggest viral or drug-induced hepatitis.

Further pertinent historical details include:

Fever and chills: Suggestive of cholangitis.
Severe right upper quadrant abdominal pain: Also indicative of cholangitis or biliary obstruction.
Anorexia and malaise: Common in hepatitis.
Significant weight loss: Raises suspicion for malignancy causing biliary obstruction.
History of ulcerative colitis or Crohn’s disease: Increases the likelihood of primary sclerosing cholangitis (PSC).

Physical Examination

The physical examination begins with a general assessment of the patient’s overall condition and nutritional status. Temporal and proximal muscle wasting may indicate malignancy or cirrhosis.²³ Look for stigmata of chronic liver disease, such as spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren’s contractures, parotid gland enlargement, and testicular atrophy. Palpable lymph nodes (especially left supraclavicular and periumbilical) may suggest malignancy. Jugular venous distension may indicate right-sided heart failure and hepatic congestion.

Abdominal examination should assess for hepatomegaly, splenomegaly, and ascites. Jaundice with ascites often points towards cirrhosis or malignancy with peritoneal spread. Right upper quadrant tenderness with a palpable gallbladder (Courvoisier’s sign) suggests obstruction of the common bile duct, typically due to malignancy.²⁴

Figure 1: Scleral Icterus, a key clinical sign in diagnosing jaundice, is evident as yellowing of the sclera of the eye.

Figure 2: Urine Color in Jaundice. Jaundice often leads to dark or tea-colored urine due to increased bilirubin excretion.

Figure 3: Visible Jaundice. Yellowish discoloration of the skin is a hallmark symptom of jaundice.

Evaluation: Laboratory and Imaging in Jaundice Diagnosis

Following history and physical examination, liver function tests (LFTs) are the most critical initial laboratory investigations.[²⁵, ²⁶](#article-23802.r25, #article-23802.r26)

Liver Function Tests (LFTs)

LFTs assess serum levels of:

Aspartate transaminase (AST)
Alanine transaminase (ALT)
Alkaline phosphatase (ALP)
Gamma-glutamyltransferase (GGT)
Serum albumin
Total protein
Bilirubin (total, direct, and indirect)

Interpreting LFT patterns is crucial for differential diagnosis:

Hepatocellular pattern: Disproportionately elevated AST and ALT compared to ALP suggests hepatocellular injury.
- AST/ALT ratio >2:1 is suggestive of alcoholic liver disease.
- Very high AST and ALT (in the thousands): Indicates acute hepatocellular injury, possibly due to viral hepatitis, toxins (acetaminophen overdose), or ischemic hepatitis.
Cholestatic pattern: Markedly elevated ALP (more than 5 times normal) with relatively normal or mildly elevated transaminases (<2 times normal) suggests biliary obstruction. Elevated GGT along with ALP confirms hepatic origin of ALP elevation, differentiating it from bone disease.
Isolated hyperbilirubinemia: Normal AST, ALT, and ALP levels suggest jaundice is not due to hepatocellular or biliary injury. Consider pre-hepatic causes (hemolysis) or inherited disorders of bilirubin metabolism (Gilbert, Crigler-Najjar, Dubin-Johnson, Rotor syndrome).

Serum Bilirubin Fractionation

Measuring both conjugated (direct) and unconjugated (indirect) bilirubin is essential to classify the type of hyperbilirubinemia and guide differential diagnosis.

Additional Liver Function Tests

Albumin and Prothrombin Time (PT): These assess liver synthetic function. Albumin reflects chronic liver function, while PT is a more acute marker. Failure of PT to correct with parenteral vitamin K suggests severe hepatocellular dysfunction.

Based on initial LFT results, further investigations can be tailored.

Hepatocellular Workup: If a hepatocellular cause is suspected, additional tests include:

Viral hepatitis serologies (hepatitis A, B, C, E).
Autoimmune antibodies (antinuclear antibody (ANA), anti-smooth muscle antibody, anti-liver kidney microsomal antibody (anti-LKM1)).
Serum ceruloplasmin (to rule out Wilson’s disease).
Ferritin and iron studies (to assess for hemochromatosis).

Cholestatic Workup: For suspected cholestasis, imaging studies are crucial:

Abdominal ultrasound: Initial imaging modality to detect biliary dilatation and gallstones.
CT scan: Provides more detailed imaging of the liver, bile ducts, and pancreas, helpful for identifying tumors or structural abnormalities.
Magnetic resonance cholangiopancreatography (MRCP): Non-invasive, highly sensitive for visualizing bile ducts and detecting obstructions.
Endoscopic retrograde cholangiopancreatography (ERCP): Invasive procedure, both diagnostic and therapeutic, for visualizing and treating bile duct obstructions (stone removal, stent placement).
Percutaneous transhepatic cholangiography (PTC): Invasive, used when ERCP is not feasible, involves direct puncture of bile ducts through the skin to visualize and decompress obstructed ducts.
Endoscopic ultrasound (EUS): Useful for imaging the pancreas and distal bile duct, and for obtaining tissue biopsies.

Treatment and Management of Jaundice

The primary approach to jaundice treatment is to address the underlying cause, whether it’s hepatobiliary or hematological.

Symptomatic Management: Pruritus

Pruritus (itching) is a common and distressing symptom of cholestatic jaundice. Management strategies depend on severity:

Mild pruritus: Warm baths or oatmeal baths can provide relief. Antihistamines may help reduce itching.
Moderate to severe pruritus: Bile acid sequestrants like cholestyramine or colestipol are often effective in binding bile acids in the intestine and reducing systemic levels. Other options include rifampin, naltrexone, sertraline, or phenobarbital, although these are generally less effective or have more side effects.
Liver transplantation: In intractable cases of pruritus unresponsive to medical therapies, liver transplantation may be considered.

Liver Transplantation

Jaundice, particularly when associated with hepatic decompensation, can be an indication for liver transplant evaluation, depending on the severity and etiology of liver injury.

Differential Diagnosis of Jaundice

The Differential Diagnosis For Jaundice is broad, encompassing various conditions affecting bilirubin metabolism. It’s crucial to distinguish jaundice from other causes of skin yellowing, like carotenoderma, where sclerae are spared and serum bilirubin levels are normal. Quinacrine use can also cause skin yellowing in some patients.²⁹

Key differentials in jaundice include:

Prehepatic jaundice: Hemolytic anemias, Gilbert syndrome, Crigler-Najjar syndrome.
Hepatocellular jaundice: Viral hepatitis, alcoholic hepatitis, NASH, autoimmune hepatitis, drug-induced liver injury, cirrhosis.
Cholestatic jaundice: Biliary obstruction (choledocholithiasis, tumors, strictures), primary biliary cholangitis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy.

A systematic approach using history, physical exam, LFTs, and imaging is essential for accurate differential diagnosis.

Prognosis of Jaundice

The prognosis of jaundice is highly variable and depends entirely on the underlying etiology.

Conditions associated with a generally excellent prognosis include:

Jaundice from hematoma resorption.
Physiological jaundice of the newborn.
Breastfeeding jaundice and breast milk jaundice.
Gilbert syndrome.
Choledocholithiasis (if treated successfully).

Conversely, jaundice due to malignant biliary obstructions and cirrhosis typically carries a poorer prognosis.³⁰

Complications of Jaundice

The primary complication of jaundice is related to the neurotoxicity of unconjugated bilirubin. In neonates, high levels of unconjugated bilirubin can cross the immature blood-brain barrier, leading to kernicterus or Bilirubin-Induced Neurologic Dysfunction (BIND), causing permanent neurological damage.²¹ In adults, while kernicterus is rare due to a mature blood-brain barrier, persistent jaundice indicates significant underlying disease that can lead to various complications depending on the cause (e.g., liver failure, biliary sepsis, complications of malignancy).

Consultations

Complex or undiagnosed cases of jaundice often require specialist consultation. Gastroenterologists and hepatologists are frequently consulted to aid in diagnosis and management.³¹

Deterrence and Patient Education

Preventing jaundice often involves addressing modifiable risk factors for liver disease. Patient education is crucial and should emphasize:

Caution with herbal medications: Many herbal supplements can be hepatotoxic and cause liver damage leading to jaundice. Always consult a physician before using herbal remedies.³²
Avoidance of liver toxins: Limit or avoid alcohol consumption, smoking, and intravenous drug use, which are major risk factors for liver disease.
Medication safety: Adhere to recommended dosages of prescribed medications and be aware of potential hepatotoxicity.
Early medical attention: Seek prompt medical evaluation for any signs of jaundice or unexplained symptoms.
Safe sex practices: To prevent viral hepatitis B and C transmission.
Vaccinations: Get vaccinated against hepatitis A and B, especially before traveling to endemic areas.

Pearls and Other Key Considerations

The initial evaluation of jaundice should always start with a thorough history and physical examination.
Classifying jaundice by etiology (prehepatic, hepatic, posthepatic) and type (conjugated vs. unconjugated) is essential for guiding diagnosis.
The basic mechanisms underlying jaundice include increased bilirubin production, decreased hepatic uptake, impaired conjugation, and impaired biliary excretion.
Treatment is directed at the underlying cause of jaundice.

Enhancing Healthcare Team Outcomes

Effective management of jaundice requires a collaborative interprofessional healthcare team. A healthcare system focused on prevention and early intervention can significantly improve patient outcomes. Many causes of jaundice are preventable through vaccinations, safe practices, and health education.

Physicians, nurses, and pharmacists play critical roles in jaundice management. Clinicians are responsible for accurate diagnosis and treatment planning. Nursing staff are vital for patient monitoring, education, and ensuring treatment adherence. Pharmacists contribute by reviewing medications for potential hepatotoxicity or drug interactions, verifying appropriate dosing, and providing medication counseling.

Interprofessional collaboration ensures comprehensive patient care, improves diagnostic accuracy, optimizes treatment strategies, and enhances patient outcomes in jaundice management.[Level 5]

Review Questions

[Link to review questions on StatPearls]

Disclosures

Disclosure: Abel Joseph declares no relevant financial relationships with ineligible companies.

Disclosure: Hrishikesh Samant declares no relevant financial relationships with ineligible companies.

References

[List of references as in the original article]

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