Overview
When the level of direct bilirubin (a type of pigment in the bile) in your body is too high, more than 2mg/dL or making up more than 20% of total bilirubin, it is called conjugated hyperbilirubinemia. This is an indication that something might be wrong in the liver, like a blockage or cellular damage. Generally, 80% of bilirubin comes from the breakup of hemoglobin, a protein in your red blood cells that carries oxygen.
Bilirubin is made through a series of steps. First, heme (a part of hemoglobin) is turned into something called biliverdin. Then, it is changed into a form of bilirubin that isn’t soluble or dissolvable in water, called unconjugated bilirubin. Finally, in the liver, it is joined with something called glucuronate to form conjugated bilirubin, which is soluble in water.
A key player in this process is an enzyme called heme oxygenase. It breaks down heme into biliverdin and is found in large amounts in cells that are known to destroy old and damaged red blood cells. Once it becomes unconjugated bilirubin, it mainly attaches to albumin, a protein in your blood. Albumin keeps the bilirubin within your blood vessels and carries it to the liver cells.
Unconjugated bilirubin has properties that make it insoluble in water, and it is this type of bilirubin that can cause problems like Kernicterus, a type of brain damage. To get rid of bilirubin from the body, it must be changed into a form that can dissolve in water by breaking specific bonds in its structure. This change, happening in liver cells, is facilitated by an enzyme called UGT and it’s vital for removing bilirubin from your body.
After this change, bilirubin (now conjugated) is pushed into tiny tubes in the liver that lead to your gut, a process that involves a protein called MRP2. Once in your gut, bacteria further break bilirubin down into urobilinogen. Half of this goes back into circulation and is removed by your kidneys, while the other half is altered into something called stercobilinogen and leaves the body through the feces.
Lastly, lab tests can tell the difference between the two types of bilirubin (conjugated and unconjugated) due to their differing properties acquired after the change in the liver. Total bilirubin includes both types, but the majority of it, over 90%, is of the unconjugated kind.
Causes
There are several conditions that typically affect adults, like:
– Gallstones and pancreatitis
– Cancer in the pancreas or bile duct
– Swollen lymph nodes around the liver
– Scarring or narrowing of the bile duct due to procedures
– A specific type of chronic liver disease
– Complications from AIDS that affect the bile ducts
– Bile duct cysts
– Dysfunction of a bile duct muscle
– Parasites or a type of tumor related to white blood cells
– Small sacs near the small intestine
– A condition which causes blockage in the bile ducts
There are also problems that can happen within the liver, such as:
– Various types of viral hepatitis
– Alcoholic and non-alcoholic fatty liver disease
– Cirrhosis
– Lack of blood flow to the liver
– Damage from drugs and toxins
– Autoimmune disease affecting the liver
– Systemic infections
– Complications after surgery
– Sickle cell disease and Budd-Chiari syndrome
– Parasites or other factors that causes liver damage
– Special cases during pregnancy or after organ transplantation
– Some inherited conditions or diseases like Sarcoidosis and Amyloidosis
Children and infants can also experience:
– Blockage in the bile ducts
– Cysts in the bile ducts
– Unexplained liver inflammation in newborns
– Rare genetic disorders like tyrosinemia, Gaucher disease, and others
– Lack of a specific protein (alpha-1-antitrypsin)
– Severe infections
– Certain congenital infections
Also, older children and adolescents can get:
– Cysts in the bile ducts
– An autoimmune condition affecting the liver
– Two specific types of chronic liver diseases
– An inherited disorder causing copper to build-up in the liver
– Severe infections
Risk Factors and Frequency
Conjugated hyperbilirubinemia, an irregularity commonly seen due to liver-related diseases or other illnesses affecting the liver, varies in occurrence depending on the specific health condition causing it.
In some countries, certain parasitic infections like clonorchiasis and ascariasis can cause issues in the bile ducts. Other infections, like malaria, might result in a type of anemia that increases the amount of indirect bilirubin in the body, leading to the formation of pigment gallstones that can obstruct the bile flow.
- The demographic distribution of conjugated hyperbilirubinemia is associated with the specific disease causing it, resulting in variations based on age, sex, and race.
- For instance, children may encounter this condition due various causes, such as a bile duct disorder known as biliary atresia, and neonatal hepatitis.
- In young adults presenting neurological signs along with liver disease, the possibility of a genetic disorder called Wilson’s disease should be considered.
Signs and Symptoms
Hyperbilirubinemia is a condition where there’s too much bilirubin in your blood. The first step in dealing with it is trying to figure out what caused it, what symptoms it’s causing, and what complications can happen because of it. Symptoms could vary depending on the specific condition causing hyperbilirubinemia. These might include things like yellow skin, itching, changes in mental state, tiredness, feeling generally ill, loss of appetite, nausea, vomiting, weight changes, shortness of breath, diarrhea, swelling in the stomach or lower extremities, bruising, fever, muscle aches, chills, vomiting blood, dark urine, changes in stool appearance, and issues with menstrual cycles.
To get a better understanding of the patient’s condition, healthcare professionals usually ask about when the symptoms started, how long they’ve lasted, how they’ve developed over time, how severe they are, any other symptoms that are occurring, and anything that makes the symptoms better or worse. For example, a fever and stomach pain might indicate gallstones. Symptoms like weight loss could point to cancer or chronic infections. Itching could mean there’s cholestasis (blockage in the bile ducts) or liver issues. If someone is pregnant, this can sometimes lead to harmless recurrent cholestasis or acute fatty liver disease of pregnancy.
Knowing past medical and surgical history is also important. This could help to identify potential causes of hyperbilirubinemia. For instance, severe heart failures or certain infections could lead to liver congestion. Certain conditions could also lead to an increase in bilirubin. Things like diabetes, skin pigmentation, hypogonadism, arthritis, heart problems, liver disease, and thyroid disease could potentially affect the liver. Furthermore, a history of getting transfused blood could be a risk factor for viral hepatitis.
Physicians also need to know about any medication someone is taking. Many common medications could potentially cause liver damage, like painkillers, antibiotics, antiviral medicines, tuberculosis treatments, anti-inflammatory drugs, steroids, epilepsy medicines, cancer medications, some anesthesia drugs, etc. Being exposed to certain toxic substances, whether at work or elsewhere, could also lead to liver damage. For example, people who’ve been exposed to certain types of mushrooms or certain industrial chemicals might be at risk. In children and teenagers, using aspirin while they have a viral infection could potentially cause a serious condition called Reye’s syndrome.
Family history can provide valuable information as well. For instance, a history of yellowing of the skin (jaundice) in the family could suggest an inherited disorder related to bilirubin metabolism; a family history of early-onset pancreatic cancers might increase a person’s risk for it.
People’s lifestyle factors like intravenous drug use, unsafe sexual practices, and exposure to infected individuals may increase the risk for viral hepatitis. Alcohol use is particularly important, especially if consumption is beyond a certain limit.
Lastly, healthcare professionals will do a physical exam. You might notice your urine has turned a brownish color with hyperbilirubinemia. This is because the kidneys can filter out the bilirubin, causing the color change. Your skin, white parts of your eyes, and bodily secretions might turn a yellow or green color if there’s enough raised bilirubin. The physical exam focuses on checking for these changes and figuring out what’s causing them. The healthcare professional will feel your abdomen to see if there are any abnormal lumps or bumps, which could indicate tumors. They might also check for a tender liver, fluid build-up in your abdomen (ascites), and other signs of various conditions, such as chronic liver disease or hemochromatosis, a condition in which the body absorbs too much iron. Usually, stool that is light gray in color might signify biliary stasis or obstruction.
Testing
Finding the root cause of high levels of bilirubin in your blood, also known as conjugated hyperbilirubinemia, involves a careful examination of your medical history and physical condition. Possible causes of this condition include blockages in your bile ducts, liver damage, unusual liver conditions, or inherited diseases. Certain tests can help medical professionals diagnose the problem:
A Serum Bilirubin test can help doctors distinguish between different types of jaundice (which occurs when parts of your body turn yellow due to bilirubin). Higher levels of a specific type of bilirubin may indicate liver damage or an issue with your liver’s ability to detoxify this substance. For newborns, high bilirubin levels can indicate an infection or require a more detailed examination of the liver and bile ducts.
Urine tests, complete blood count (CBC), and tests for enzymes produced by the liver (such as AST and ALT) provide additional information about liver function and possible damage. If AST and ALT are high, it could mean the liver is injured due to factors like toxins or reduced blood supply. If a patient’s AST to ALT ratio is 2:1 or more, it could indicate liver damage caused by alcohol.
The Prothrombin Time/INR and Albumin tests assess how well your liver can produce certain proteins. If these levels are abnormal, it might mean you have serious liver disease, in which case a liver transplant might be necessary.
Doctors may also check for viral hepatitis, or conduct a blood alcohol test, a serum acetaminophen test (Tylenol), or a drug screening if they suspect toxins, alcohol, or drugs could be the cause of liver damage. Other likely causes of liver disease, such as inflammation of the bile ducts or an autoimmune disease, can be identified with specific antibody tests.
Genetic and iron studies may be done if the doctor suspects a condition such as hemochromatosis, which leads to iron buildup and can damage key organs.
Aside from these tests, doctors could also use imaging techniques such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) to get a detailed view of the liver and bile ducts and look for any signs of obstruction or damage.
Lastly, a liver biopsy, where a small sample of liver tissue is taken for further examination, might be done if all other tests do not reveal the cause of the problem. A biopsy can also help doctors predict how the disease will progress and decide on the best treatment options.
Treatment
Conjugated hyperbilirubinemia, which is not a disease but a sign of various diseases, requires different treatment strategies depending on its cause. Treatment can aim to either cure the disease causing hyperbilirubinemia or to provide relief from symptoms. A common approach is to stop any medication that could harm the liver while figuring out the cause of the hyperbilirubinemia. This is crucial because continuous exposure to harmful substances or drugs can worsen liver damage and may even cause death.
Here are some treatment suggestions based on the common causes of hyperbilirubinemia:
Gallstones: If a patient cannot undergo surgery or decides against it, they can be given oral bile salts (like ursodeoxycholic acid) or undergo a procedure known as extracorporeal shock wave lithotripsy (ESWL). Ursodeoxycholic acid helps dissolve cholesterol stones by reducing cholesterol in the bile. However, once the patient stops taking this medication, about half of them experience a comeback of gallstones within five years. On the other hand, ESWL is a technique that uses shock waves to break up gallstones. It can’t be used in certain conditions, including gallbladder infection, gallstone-induced pancreatitis, and in patients who are pregnant, have a blood clotting disorder, or are taking blood thinners. Unfortunately, the recurrence of gallstones after ESWL is quite high – about 70%.
Pancreatic Cancer: The best treatment options typically include chemotherapy, radiation therapy, and surgery such as the Whipple procedure.
Biliary Tract Obstruction due to Cancer: Procedures like endoscopic stenting or endoscopic biliary drainage can be employed to alleviate symptoms of hyperbilirubinemia caused by this obstruction.
Related Conditions
Elevated levels of conjugated bilirubin, a substance produced by the liver, is usually a reflection of an underlying medical issue, not a disease itself. Consequently, several different conditions may be the root cause.
Some of these conditions can affect people of all ages, but are most commonly seen in adults; they can be related to issues both within the liver (intrahepatic) and outside the liver (extrahepatic). They include but aren’t limited to:
- Issues with the bile duct such as bile duct stones or cancer, or strictures after a procedure
- Pancreatitis which is inflammation in the pancreas
- Various infections, infestations, or diseases including AIDS cholangiopathy, sarcoidosis, Budd-Chiari syndrome
- Conditions causing liver damage like viral Hepatitis, alcoholic Hepatitis, cirrhosis, toxins
- Genetic disorders affecting bilirubin metabolism like Rotor syndrome, Caroli disease
There are also certain causes of elevated conjugated bilirubin levels that are unique to infants:
- Biliary atresia where the bile ducts are damaged or absent
- Choledochal cyst, an abnormal bile duct growth
- Sepsis, a life-threatening infection causing whole-body inflammation
- Metabolic diseases like Gaucher disease, Niemann-Pick disease
Lastly, the following conditions could cause similar symptoms specifically in older children and teenagers:
- Choledochal cyst
- Autoimmune hepatitis
- Diseases that cause damage to bile ducts within the liver such as Primary biliary cirrhosis, Primary sclerosing cholangitis
- Wilson’s disease, a rare inherited disorder
Prognosis
Conjugated hyperbilirubinemia is a symptom of a disease, not a disease itself. So, the outlook really depends on the disease causing this symptom. Diseases related to the liver and bile duct system that are cancerous often have a poorer outlook. On the other hand, non-cancerous causes like infections, toxins, or non-cancerous duct blockages, usually have a better outcome if they are treated quickly.
In some health conditions, like primary biliary cholangitis and alcoholic hepatitis, high bilirubin levels can indicate a higher risk of death in the short term. However, a high bilirubin level itself doesn’t directly lead to an increased risk of early death.
Possible Complications
Conjugated hyperbilirubinemia isn’t a disease by itself, but a symptom that shows when there’s an illness inside the body. The complications of conjugated hyperbilirubinemia can vary based on what is causing it. However, there are some issues that can arise simply due to the high levels of bilirubin, a substance produced by the liver. Don’t worry too much, though! While this might sound alarming, conjugated bilirubin can’t cause kernicterus, a type of brain damage, or other similar toxic effects. It’s not able to bind significantly to our nervous system tissues.
One condition that can develop from this is cholestasis, which can lead to the body not absorbing fats properly. When this happens, it becomes important to monitor levels of vitamins that are soluble in fat, and take steps to correct them if needed. Also, in babies born with low birth weight, being exposed to high levels of conjugated bilirubin for a long time can make their teeth have a greenish color, which is a complication that occurs later.
Another problem can be infections in what we call the hepatobiliary systems, which is a fancy term for the parts of the body that produce and transport bile, like the liver and gall bladder. These infections can develop into very serious conditions like sepsis or septic shock, inflammation of the lining of the abdomen, or gall bladder rupture.
If the cause of the hyperbilirubinemia is a cancer, other complications can happen. These include infections, pain, severe weight loss or malnutrition, blood clots, uncontrollable vomiting and, in the worst cases, death.
Common Risks:
- Cholestasis leading to fat malabsorption
- Greenish pigmentation of teeth in low birth weight infants
- Infections in the hepatobiliary systems
- Sepsis or septic shock
- Peritonitis (inflammation of abdomen lining)
- Gall bladder rupture
- Complications due to malignancy
- Uncontrollable vomiting and, in severe cases, death
Prevention and Education
It can be frustrating for both the patient and the healthcare provider when it’s difficult to make an accurate diagnosis. This is often the case because the early symptoms might be unclear or minor, leading to a delayed diagnosis. This delay can miss the chance for early treatment. It’s crucial for patients, particularly those with a family history of liver and gallbladder cancers, to learn how to identify the initial symptoms of jaundice.
Furthermore, most of the causes of conjugated hyperbilirubinemia, a condition where there’s too much bilirubin in the blood resulting in yellowing of the skin and eye whites, are linked to long-term health issues. Hence, having a strong support network is critical to help the patient better manage the medical condition and enhance the effectiveness of the treatment.
