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Reference interval bilirubin - examples
Types of bilirubin found in plasma
Why measure bilirubin ?
When should bilirubin be measured ?
Interpretation of bilirubin values
Physiological classification of jaundice
Physiological jaundice of newborns
Treatment for hyperbilirubinemia/jaundice in newborns
Action limits for treatment of newborns with jaundice ?
Bilirubin is the yellow breakdown product of the degradation of the heme group of hemoglobin. It is transported in blood from its site of production – the reticuloendothelial system – to the liver, where it is biotransformed before excretion in bile. Jaundice, the pathological yellow discoloration of skin, is due to abnormal accumulation of bilirubin in the tissues, and is always associated with elevated blood concentration of bilirubin (hyperbilirubinemia).
Most bilirubin is the product of heme catabolism from hemoglobin in aged erythrocytes removed from the circulation to reticuloendothelial sites in the spleen, liver and bone marrow (Fig. 17). The remainder is derived from inefficient erythropoiesis and from catabolism of other heme-containing proteins, such as myoglobin, catalases and the cytochromes. This unconjugated bilirubin is released into the circulation where it is rapidly bound to albumin for transport to the liver. After release from albumin, unconjugated bilirubin is transported into hepatocytes where it combines enzymatically with glucuronic acid, producing bilirubin glucuronides (i.e. conjugated bilirubin), which are excreted in bile to the intestines. The action of colonic bacteria deconjugates bilirubin and converts the resulting unconjugated bilirubin to the final excretory product, urobilinogen, that passes from the body in feces. A small proportion of urobilinogen is reabsorbed into the blood circulation and back to the liver for re-excretion (enterohepatic circulation of bilirubin) or to be excreted in urine by the kidneys.
Several factors peculiar to neonatal physiology contribute to jaundice at this age :
- Increased red cell destruction and therefore increased bilirubin production
- Immature liver and therefore reduced ability to conjugate bilirubin
- Increased enterohepatic circulation of bilirubin
- Lack of intestinal bacterial flora to convert bilirubin to excretion products
In neonates, much of the conjugated bilirubin in the intestines is hydrolyzed back to unconjugated bilirubin. This unconjugated bilirubin is reabsorbed into the blood stream by way of the enterohepatic circulation, adding an additional bilirubin load to the already overstressed liver .
Types of bilirubin found in plasma
- Unconjugated (indirect) bilirubin (bound to albumin). It is water-soluble and non-toxic. This fraction normally comprises around 90 % of total bilirubin
- Unconjugated (indirect) free bilirubin (i.e. not bound to albumin). It is poorly soluble in water and is potentially toxic as it can pass the lipid membranes and cause kernicterus. This fraction normally comprises <0.1 % of all unconjugated bilirubin
- Conjugated (direct) bilirubin (bound to glucuronic acid) is water-soluble and non-toxic. This fraction normally comprises around 10 % of total bilirubin
- Delta (δ) bilirubin is covalently bound to plasma proteins to form a conjugated bilirubin-protein complex. It is water-soluble, non-toxic and appears in serum when hepatic excretion of conjugated bilirubin is impaired in patients with hepatobiliary disease 
Total bilirubin is typically defined as unconjugated plus conjugated. As δ-bilirubin is usually low (0 – 2 % of total bilirubin) and difficult to measure, it is most often not included in the total bilirubin calculation.
Why measure bilirubin?
Monitoring neonatal jaundice is one of the most common reasons for measuring bilirubin concentration. Most newborns have some degree of jaundice, although it is usually mild, benign and resolves without treatment during the second week of life. The potential neural toxicity of bilirubin requires that jaundiced newborns be monitored to identify those who might, without treatment, develop severe hyperbilirubinemia, which is associated with risk of acute bilirubin encephalopathy or kernicterus (See note at the end of this chapter) .
In older infants, children and adults bilirubin should be measured when there is a suspicion of jaundice and/or liver or biliary-tract disease.
When should bilirubin be measured?
In newborns when there are signs and symptoms of hyperbilirubinemia [23, 186]:
- Yellow staining of the skin (jaundice)
- Dark urine
- Poor sucking/feeding
- Distinctive high-pitched cry
In adults when there is suspicion of e.g. liver or biliary-tract disease, hemolytic anemia or jaundice.
Interpretation of bilirubin values
Increased bilirubin and the resulting jaundice can be attributed to disturbances at any of the steps along the metabolic pathway outlined above. It is helpful in the differential diagnosis of jaundice to know if the increase in total bilirubin is due to a predominant increase in conjugated or unconjugated bilirubin.
For example, increase in unconjugated bilirubin suggests that jaundice is due to either increased bilirubin production from heme or reduced ability of liver cells to conjugate bilirubin. Both of these mechanisms operate in physiological neonatal jaundice. Increased bilirubin production also explains the jaundice that can occur in those with any form of hemolytic anemia (called hemolytic jaundice). Reduced ability of liver cells to conjugate bilirubin explains the jaundice that occurs in Gilbert’s syndrome, a genetic disorder characterized by an inherited deficiency of the enzyme required for bilirubin conjugation .
Increase in conjugated bilirubin, on the other hand, implies that conjugated bilirubin is not being excreted in bile as efficiently as normal, and instead is spilling into blood. This can be due to impairment of conjugated bilirubin delivery from hepatocyte to bile canaliculi or reduced bile flow (cholestasis) within the liver (called hepatocellular jaundice or cholestatic jaundice); or obstruction of bile flow through the biliary tract (called obstructive jaundice).
Physiological classification of jaundice
Unconjugated hyperbilirubinemia in newborns [4, 23]
Increased production of unconjugated bilirubin from heme:
- Hemolytic disease:
- Red cell incompatibility
- Due to Rhesus (Rh) incompatibility; for example, Rh(–) mother, Rh(+) fetus and blood type ABO incompatibility, mother (O) and infant (A or B)
- Breast-feeding jaundice:
- Due to α-glucuronidase in breast milk, which hydrolyzes conjugated to unconjugated bilirubin in the intestines
- Ineffective erythropoiesis:
- Rapid turnover of increased red blood cell mass in neonates
Decreased uptake of unconjugated bilirubin across the hepatocyte membrane:
- Competitive inhibition
- Gilbert’s syndrome
- Sepsis, fasting
Decreased biotransformation (conjugation):
- Physiological jaundice
- Inhibition (drugs)
- Hereditary (Crigler-Najjar syndrome)
- Hepatocellular dysfunction
- Gilbert’s syndrome
Conjugated hyperbilirubinemia (cholestasis) [4, 23]
Decreased secretion of conjugated bilirubin into canaliculi:
- Hepatocellular disease:
- Cholestasis (intrahepatic)
- Extrahepatic obstruction
- Dubin-Johnson syndrome
- Roter syndrome
- Extrahepatic obstruction:
- Primary biliary cirrhosis
- Bile-duct paucity
Physiological jaundice of newborns
Neonates are physiologically predisposed to jaundice, due to increased breakdown of hemoglobin and limited hepatic function. Low concentration of albumin increases the risk of rising free unconjugated bilirubin, which in turn increases the risk of neurotoxicity and resulting acute bilirubin encephalopathy (kernicterus) [186, 188]. (See note at the end of this chapter).
In full-term infants jaundice usually develops after 24 hours of life and peaks on day 3 or 4 . It may be noticeable as yellow discoloration of the sclera at levels of about 34 – 51 µmol/L (2 – 3 mg/dL)  and of the skin at higher levels (jaundice).
Premature babies are more likely to develop jaundice than full-term babies. In preterm infants it usually begins 48 hours after birth, peaks on day 5 and may last 2 weeks . Neonates need treatment if the total bilirubin level is too high or is rising too quickly.
Physiological jaundice is generally mild and not harmful, but bilirubin concentrations above 170 µmol/L (10 mg/dL), coupled with prematurity, low serum albumin, acidosis, and substances that compete for the binding sites of albumin (e.g. aspirin) may increase the risk of kernicterus .
Treatment for hyperbilirubinemia/jaundice in newborns
- Phototherapy to convert bilirubin to products that can bypass the liver’s conjugating system and be excreted in bile or in urine without further metabolism 
- Exchange transfusion to remove bilirubin mechanically
- Pharmacological agents given to interfere with heme degradation and bilirubin production, accelerate the normal metabolic pathways for bilirubin appearance, or inhibit the enterohepatic circulation of bilirubin
Action limits for treatment of newborns with jaundice?
Guidelines for the use of phototherapy and exchange transfusion in term and near-term infants with a gestational age of 35 weeks or more are provided by the American Academy of Pediatrics . These guidelines, however, are not evidence-based but primarily the product of expert opinion. The use of phototherapy in infants with low birth weight is prophylactic and based on either birth weight or gestational age . The time-honored bilirubin concentration of 340 µmol/L (20 mg/dL), which was considered critical and required action (intensive phototherapy, exchange transfusion), is now being abandoned and replaced . It is now recommended to monitor the increase in total bilirubin concentration from time of birth until the time of discharge from hospital (36 – 73 hours). A plot of total bilirubin concentration versus time (hours) should be made and compared with the similar plot found in the guideline from the American Academy of Pediatrics, Subcommittee of Hyperbilirubinemia  to guide implementation of phototherapy.
Note: The American Academy of Pediatrics, Subcommittee of Hyperbilirubinemia  recommends that in infants the term “acute bilirubin encephalopathy” be used to describe the acute manifestations of bilirubin toxicity seen in the first weeks after birth and that the term “kernicterus” be reserved for the chronic and permanent clinical sequelae of bilirubin toxicity.
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Effective Date January 20th, 2023 (last updated January 20th, 2023)
ABOUT THIS POLICYRadiometer values your privacy and the protection of your personal data. This policy (“Policy”) explains how Radiometer its affiliates, subsidiaries or related companies, a full list of which can be located here (together, “Radiometer”, “our”, “us”, or “we”), collects, uses, shares, transfers and processes data collected from or about you.
“Personal Data” is any information that can be used to directly or indirectly identify an individual or that can be reasonably expected to link to an individual. This can include items such as name, address, telephone number, credit card details, email address, ID number, Internet Protocol (“IP”) address of an electronic device used by an individual, or other identifying code (even absent of other identifying information). Statistical and non-identifiable metric data are not considered Personal Data.
The Radiometer subsidiary, affiliate or related company with which you interact is, where applicable, the data controller (or equivalent under applicable law) responsible for the processing of your Personal Data. You can find a list of the relevant legal entities that act as data controllers in Appendix 1 to this Policy.
SCOPEThis Policy describes the types of Personal Data that we may collect, process or disclose about you and how you may govern this processing by exercising applicable legal rights. This Policy applies to both online and offline information collection, including your use of websites or subdomains operated by us, any mobile applications, when we provide products and/or services to you or notify you about prospective items of interest and in other situations where you interact with us in-person, by telephone or by mail where this Policy is posted or referenced.
There may be occasion where you have been provided with a circumstance-specific privacy notice that is separate from this policy, such as privacy notices for specific activities such as Recruitment. To the extent you were provided with a different notice, those notices apply and govern our interactions with you. If you provide Personal Data about parties other than yourself, you are responsible for ensuring their knowledge of how we will process their personal data, and, where applicable, obtaining any necessary consents required in advance.
We are committed to processing Personal Data in accordance with applicable laws. Please note that if you do not wish to provide your Personal Data to us, some products and/or services may become unavailable to you. Your use of any or all these platforms indicates you have been notified of our collection, use, transfer, and disclosure of your information as described in this Policy to the extent permitted by applicable law.Read more