Bilirubinuria - Causes, Symptoms, Diagnosis, and Treatment

Introduction

Bilirubinuria is a condition in which there is a presence of bilirubin in the urine. It is detected using a standardized urine dipstick, known as urine analysis worldwide. Bilirubin and other metabolites are the reason for the characteristic coloring in bile and stool; its presence in the urine is not normal, and if at all present, it should be water-soluble and excreted by the kidney. Bilirubin exists as either a conjugated, direct, unconjugated, or indirect form in the body. Unconjugated bilirubin is fat-soluble in water and cannot be excreted. Unconjugated hyperbilirubinemia is characterized by acholuric jaundice as urine is not darkened by urinary bilirubin, and bilirubin is not detected in the urine.

What Is the Cause of Bilirubinuria?

Bilirubin metabolism takes place in three phases:

• Prehepatic.

• Intrahepatic.

• Post-hepatic.

After it is conjugated, bilirubin becomes water soluble in the liver. It is excreted through the biliary and cystic ducts to pass through the duodenum. Hence hyperbilirubinemia occurs when the disease process affects the hepatic and posthepatic phases of bilirubin metabolism. Intrahepatic causes of conjugated hyperbilirubinemia:

1. Hepatocellular disease:

• Viral hepatitis.
• Hemochromatosis.
• Wilson disease.
• Autoimmune hepatitis.
• Non-alcoholic steatohepatitis.
• Alcoholic liver disease.

2. Hereditary causes:

• Rotor syndrome.
• Dubin-Johnson syndrome.

3. Primary biliary cirrhosis.

4. Ischemic hepatitis.

5. Sarcoidosis.

6. Pregnancy.

7. Sepsis.

8. Drug-induced liver disease.

9. Extrahepatic causes of conjugated hyperbilirubinemia:

• Biliary stricture.
• Gallstones.
• Biliary atresia.
• Choledochal cyst.
• Cholangitis.
• Intrahepatic malignancy.
• Chronic pancreatitis.

What Is the Epidemiology of Bilirubinuria?

The incidence and prevalence of bilirubinuria are estimated at 3.9 % to 6.9 % in individuals with chronic liver disease. Bilirubinuria can also be present in individuals with acute liver and biliary disease. In addition, it is observed in people with unrelated systemic illnesses.

What Is the Pathophysiology of Bilirubinuria?

Pathophysiology of bilirubinuria depends on the phases of metabolism of bilirubin which include:

• Prehepatic: The body produces 4 mg of bilirubin from heme metabolism. Out of the total heme generated, 80 % is obtained from the catabolism of red blood cells and 20 % from ineffective erythropoiesis by breaking down muscle myoglobin. Heme is then converted to biliverdin which is transformed into bilirubin and transported to the liver for conjugation.

• Hepatic: The released bilirubin reaches the hepatocyte, is insoluble, and is bound to albumin. When it reaches the hepatocyte, the albumin-bilirubin bond is broken, and the bilirubin is taken by the hepatocyte having a carrier-membrane transport. In the hepatocyte, the unconjugated bilirubin is taken to the endoplasmic reticulum and conjugated with sugar by the enzyme glucuronosyltransferase and then becomes soluble in bile. The conjugated bilirubin is excreted into the bile. The canalicular excretion of bilirubin is the rate-limiting step of bilirubin metabolism. The presence of conjugated bilirubin in the blood is a sign of hepatocellular dysfunction when there is obstruction of the bile duct.

• Posthepatic: The soluble bilirubin is transported by the biliary and cystic ducts to the gallbladder and gets stored, or it may enter the duodenum. The colonic bacteria metabolize the bilirubin in the intestine into urobilinogen, most of which gets excreted in feces as stercobilin. The remaining urobilinogen is excreted in the urine as urobilin, which gives the urine its unique color, and whatever remains undergoes enterohepatic circulation.

How Is Bilirubinuria Diagnosed?

A medical history involving assessment of any condition related to hepatobiliary diseases such as pregnancy, fatty liver, viral hepatitis, alcoholic liver disease, celiac disease, right-sided heart failure, and thyroid disease should be obtained. All over-the-counter and prescribed medications, including dietary supplements and vitamins, should be recorded as they alter liver functions. Bilirubinuria is detected in individuals taking Phenazopyridine or Etodolac (nonsteroidal anti-inflammatory drugs). Surgical history is also recorded, especially if the individual has an extensive abdominal past surgical history. Family history is recorded to see if there are any inherited diseases (rotor syndrome and Dubin-Johnson syndrome). Social history with an emphasis on alcohol consumption may contribute to hepatic dysfunction. Risk factors for viral hepatitis, such as intravenous drug use, needle stick injury, and high-risk sexual activity, should be discussed. Psychological stress is also a cause of bilirubinuria.

Weight loss and constitutional symptoms are associated with obstructive malignancy and immune deficiency, which may lead to biliary obstruction from opportunistic infections. Individuals with biliary obstruction may have dark brown urine, pruritus, or light-colored stools.

Physical Examination:

A detailed skin and ocular examination are done to check for jaundice and scleral icterus. Warning signs for chronic liver disease such as caput-medusae, palmar erythema, spider nevi, and gynecomastia and as well as signs of hepatic congestion include:

• Palpable hepatomegaly.

• Increased jugular venous pressure.

• Abdominal ascites.

Evaluation:

Bilirubinuria is evaluated using a standard urinalysis. A chemical strip with diazonium salt reacts with bilirubin in the urine. The bilirubin produces a red azo dye. False negatives can be assessed with urinary nitrates, acidic urine with a pH below 5.5, and antibiotic usage, which is known to decrease intestinal flora. And oxidation by vitamin C. False positives can be detected by highly colored substances such as Phenazopyridine, Indicans, and Chlorpromazine Etodolac metabolites which give a reddish color to urine.

What Is the Treatment for Bilirubinuria?

The treatment for bilirubinuria is focused on different clinical etiologies. Liver biopsy, blood tests, and clinical history will help detect the cause. ERCP (endoscopic retrograde cholangiopancreatography) is a diagnostic and therapeutic procedure performed in individuals with bilirubinuria caused by a common bile duct obstruction.

What Are the Complications of Bilirubinuria?

Unconjugated bilirubin may cross the blood-brain barrier, also as it is lipid soluble. As a result, it can penetrate neuronal and glial membranes, leading to a spectrum of diseases called biliary encephalopathy. Morbidity and mortality related to conjugated hyperbilirubinemia and bilirubinuria are due to the underlying diseases.

What Is the Prognosis for Bilirubinuria?

The prognosis for bilirubinuria depends on the etiology. For example, benign conditions such as gallstones or biliary stricture have a better prognosis than malignant biliary obstruction or any disease leading to liver cirrhosis.

Conclusion:

Bilirubinuria is one of the earliest signs of pathology in the liver. People must consult their healthcare provider before using any herbal supplements, which may be toxic to the liver. It is essential to refrain from excessive alcohol consumption and intravenous drugs. Individuals should consult a physician and enquire about vaccines before traveling to hepatitis-endemic areas.