Internal Medicine/Jaundice

Introduction to Jaundice
Jaundice, characterized by the yellow discoloration of the skin, sclerae (the white part of the eyes), and mucous membranes, is a common clinical sign. This discoloration arises from elevated levels of bilirubin in the blood and body tissues. Bilirubin is a pigment formed during the breakdown of heme molecules from aging red blood cells (RBCs). The liver normally processes bilirubin and excretes it in bile. Jaundice can signal a range of underlying medical conditions, some of which can be benign, while others may be life-threatening.

Evaluation of Jaundice
Understanding the underlying causes of jaundice is critical for its evaluation. Various factors can contribute to hyperbilirubinemia, the main mechanism behind jaundice:

Causes of Hyperbilirubinemia


 * Hemolysis: Conditions that accelerate the destruction of red blood cells can lead to increased bilirubin levels. Examples include hemolytic-uremic syndrome, paroxysmal nocturnal hemoglobinuria, and parasitic infections such as malaria.
 * Ineffective Erythropoiesis: Certain medical conditions, including deficiencies in cobalamin (vitamin B12), folate, and iron, can result in ineffective erythropoiesis, contributing to hyperbilirubinemia.
 * Resorption of Hematomas and Massive Blood Transfusions: The resorption of hematomas and the infusion of large volumes of blood through transfusions can release hemoglobin and bilirubin into circulation.
 * Impaired Hepatic Uptake or Conjugation of Bilirubin: Some drugs, such as rifampin and probenecid, can cause unconjugated hyperbilirubinemia by interfering with hepatic bilirubin uptake.

Laboratory Tests for Evaluation

Evaluating jaundice involves a comprehensive assessment, including a detailed medical history, physical examination, and specific laboratory tests. Key laboratory tests in the assessment of jaundice include:


 * Bilirubin with Fractionation
 * Alanine Aminotransferase (ALT)
 * Aspartate Aminotransferase (AST)
 * Alkaline Phosphatase
 * Prothrombin Time
 * Albumin Levels

Isolated Elevation of Bilirubin

Jaundice can present with an isolated elevation of bilirubin, and this can provide valuable diagnostic information:


 * Indirect Hyperbilirubinemia (Direct Bilirubin <15%): Potential causes of this presentation include hemolytic disorders, ineffective erythropoiesis, conditions leading to increased bilirubin production (e.g., massive blood transfusion), and specific drugs (e.g., rifampin, probenecid).
 * Direct Hyperbilirubinemia (Direct Bilirubin >15%): Inherited disorders such as Dubin-Johnson syndrome and Rotor syndrome can lead to this type of hyperbilirubinemia.

Hepatocellular Pattern vs. Cholestatic Pattern

Differentiating between a hepatocellular pattern and a cholestatic pattern is crucial in diagnosing the underlying cause of jaundice:


 * Hepatocellular Pattern: Elevations of ALT and AST that are disproportionate to alkaline phosphatase levels suggest various hepatocellular diseases.
 * Cholestatic Pattern: When alkaline phosphatase levels are out of proportion to ALT and AST elevations, this pattern indicates conditions affecting bile flow within the liver.

Dilated Ducts vs. Extrahepatic Cholestasis

Further evaluation of jaundice depends on whether it is related to dilated ducts (intrahepatic cholestasis) or extrahepatic cholestasis. Imaging tests such as computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), and liver biopsy may be necessary to determine the cause accurately.

Causes of Intrahepatic and Extrahepatic Cholestasis
Intrahepatic Cholestasis: This section explores conditions that lead to intrahepatic cholestasis. Causes encompass viral hepatitis, drug-induced liver injury, autoimmune hepatitis, inherited disorders, and more. The diagnosis often requires serologic testing in combination with a liver biopsy.

Extrahepatic Cholestasis: Malignant and benign causes of extrahepatic cholestasis are discussed. Malignant causes include various cancers such as pancreatic, gallbladder, and cholangiocarcinoma. Benign causes consist of choledocholithiasis, primary sclerosing cholangitis, chronic pancreatitis, and more.

Global Considerations: Infections remain a leading cause of jaundice in developing countries. Various infections, including malaria, leptospirosis, hepatitis viruses (A to E), Epstein-Barr virus (EBV), cytomegalovirus (CMV), viral hemorrhagic fevers (e.g., Ebola virus), yellow fever, dengue fever, and various parasitic diseases can lead to liver involvement and jaundice. Bacterial infections, even those not directly involving the liver and bile ducts, may lead to jaundice, particularly in the context of sepsis.

Evaluation of Intrahepatic Cholestasis
Viral Hepatitis: Intrahepatic cholestasis can be attributed to various forms of viral hepatitis, including hepatitis B and C. In particular, fibrosing cholestatic hepatitis is a severe form that can arise in patients with hepatitis B and C. This condition can lead to significant liver dysfunction and jaundice.

Drug-Induced Liver Injury: A broad range of drugs can cause intrahepatic cholestasis. It's crucial to distinguish between pure cholestasis and cholestatic hepatitis. Anabolic and contraceptive steroids, chlorpromazine, erythromycin estolate, imipramine, tolbutamide, sulindac, cimetidine, and erythromycin estolate are some of the drugs associated with cholestatic hepatitis. Some cases of cholestasis may persist even after discontinuing the offending drug.

Autoimmune Hepatitis: Autoimmune hepatitis, while typically presenting with hepatocellular patterns of injury, can occasionally manifest as a cholestatic variant. Diagnosing this condition involves serologic testing and liver biopsy.

Inherited Disorders: Intrahepatic cholestasis can also result from inherited conditions such as progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC). These genetic disorders often manifest in childhood and can lead to progressive cholestasis. Different types of PFIC are associated with specific genetic mutations.

Cholestasis of Pregnancy: This condition typically occurs in the second and third trimesters of pregnancy and usually resolves after delivery. The exact cause is unknown, but it is believed to have genetic predispositions and can be triggered by estrogen administration.

Evaluation of Extrahepatic Cholestasis
Malignant Causes: Extrahepatic cholestasis can result from various malignancies, including pancreatic, gallbladder, ampullary cancers, and cholangiocarcinoma. Cholangiocarcinoma, in particular, is challenging to diagnose and often associated with primary sclerosing cholangitis (PSC). Some of these malignancies may have poor prognoses due to late-stage diagnoses.

Choledocholithiasis: This is one of the most common causes of extrahepatic cholestasis. It can present with a wide range of symptoms, from mild discomfort to severe ascending cholangitis with jaundice and sepsis. Diagnosis and management often involve imaging studies and endoscopic interventions.

Primary Sclerosing Cholangitis (PSC): This autoimmune disease primarily affects larger bile ducts, leading to strictures and fibrosis. Diagnosis involves cholangiography (MRCP or ERCP) to identify characteristic segmental strictures. Approximately 75% of patients with PSC also have inflammatory bowel disease.

AIDS Cholangiopathy: In HIV-infected individuals, cholangiopathy can occur due to infections like CMV or cryptosporidia. It may resemble PSC in its cholangiographic appearance. These patients often have significantly elevated alkaline phosphatase levels but may not present with jaundice.

Other Causes: Less common causes of extrahepatic cholestasis include chronic pancreatitis, Mirizzi's syndrome, parasitic diseases (e.g., ascariasis), and more.

Global Considerations
In developing countries, infections remain a leading cause of jaundice. Various infectious agents can lead to liver involvement and jaundice, including parasites like schistosomiasis, fascioliasis, opisthorchiasis, and ascariasis. Bacterial infections, especially in sepsis, can also result in cholestasis.