Materiały źródłowe

• #1 Neonatal Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532930/

  Neonatal jaundice is a clinical manifestation of elevated total serum bilirubin, termed neonatal hyperbilirubinemia, which results from bilirubin that is deposited into an infant’s skin. […] The two types of neonatal hyperbilirubinemia are unconjugated hyperbilirubinemia and conjugated hyperbilirubinemia. In most neonates, unconjugated hyperbilirubinemia is the cause of clinical jaundice. However, some infants have conjugated hyperbilirubinemia, which is always pathologic and signifies an underlying medical or surgical etiology. […] When neonatal jaundice is clinically identified, the underlying etiology of neonatal hyperbilirubinemia must be determined. Unconjugated hyperbilirubinemia is diagnosed by assessing bilirubin levels with a transcutaneous measurement device or blood samples for total serum bilirubin. Conjugated hyperbilirubinemia is typically diagnosed through laboratory studies, including serum aminotransferase, prothrombin time, urine cultures, tests for inborn errors of metabolism, and, in some cases, imaging studies.

• #2 British Journal Of Midwifery – Bilirubin in the newborn: Physiology and pathophysiology

  https://www.britishjournalofmidwifery.com/content/clinical-practice/bilirubin-in-the-newborn-physiology-and-pathophysiology/

  Physiological jaundice is common in the first week of life, occurring in around 60% of term and 80% of preterm infants (Ng and How, 2015; Mitra and Rennie, 2017). […] It is the result of rising levels of bilirubin, which eventually binds to tissues such as the skin and sclera, producing clinically recognisable jaundice around day 3 or 4 (Mitra and Rennie, 2017; Rankin, 2017). […] Bilirubin is produced during the breakdown of red blood cells, and in newborn infants there is a transitional imbalance between its production and elimination, resulting in an excess of bilirubin. […] This normal imbalance that produces physiological jaundice can, however, be exacerbated by factors that result in pathological jaundice, which can result in neurological damage, dysfunction, and death (Ng and How, 2015).

• #3 Neonatal Hyperbilirubinemia – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/metabolic-electrolyte-and-toxic-disorders-in-neonates/neonatal-hyperbilirubinemia

  Normally, bilirubin bound to serum albumin stays in the intravascular space. However, unconjugated bilirubin can cross the blood-brain barrier and cause CBE in certain situations: When serum bilirubin concentration is markedly elevated […] When serum albumin concentration is markedly low (eg, in preterm infants) […] When bilirubin is displaced from albumin by competitive binders. […] Hyperbilirubinemia can be caused by one or more of the following processes: Increased production […] Decreased hepatic uptake […] Decreased conjugation […] Impaired excretion […] Impaired bile flow (cholestasis) […] Increased enterohepatic circulation. […] The majority of bilirubin is produced from the breakdown of hemoglobin into unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to albumin in the blood for transport to the liver, where it is taken up by hepatocytes and conjugated with glucuronic acid by the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT) to make it water-soluble.

• #4 British Journal Of Midwifery – Bilirubin in the newborn: Physiology and pathophysiology

  https://www.britishjournalofmidwifery.com/content/clinical-practice/bilirubin-in-the-newborn-physiology-and-pathophysiology/

  Most bilirubin is produced during the breakdown of senescent red blood cells, with bilirubin being produced as a result of the breakdown of the haem component of haemoglobin. […] This occurs in phagocytic monocytes and macrophages in various tissues of the body (Mitra and Rennie, 2017), and first results in a form of bilirubin called unconjugated bilirubin. […] This is lipid-rather than water-soluble, so is transported to the liver for metabolism bound to albumin (Blackburn, 2017). […] In the liver it undergoes conjugation (it is combined with glucuronic acid by the enzyme glucuronyl transferase) to produce conjugated bilirubin, which is more water-soluble and can thus be excreted in urine and bile (Mitra and Rennie, 2017; Rankin, 2017). […] Mutations in this enzyme that reduce its function can result in Gilbert and Crigler-Najjar syndromes, which are characterised by hyperbilirubinaemia due to reduced functioning of the liver’s bilirubin-conjugating ability and the resulting build-up of unconjugated bilirubin (Wong and Stevenson, 2015; Chang et al, 2017). […] As the liver conjugating system also requires oxygen and glucose to function efficiently, hypoxia and hypoglycaemia may also slow down this process and increase the risk of hyperbilirubinaemia (Blackburn, 2017; Rankin, 2017).

• #5 Neonatal jaundice – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/neonatal-jaundice/

  Pathological neonatal jaundice can be caused by multiple mechanisms: increased production of bilirubin (e.g., conditions with increased hemolysis), decreased hepatic uptake (e.g., due to liver immaturity), decreased conjugation (e.g., Crigler-Najjar syndrome), impaired excretion (e.g., conditions with cholestasis, gastrourinary malformations), and increased enterohepatic circulation (e.g., conditions with decreased intestinal motility, breastfeeding jaundice). […] Unconjugated hyperbilirubinemia is caused by short lifespan of erythrocytes in the newborn, insufficient hepatic bilirubin metabolism due to immature UDP-glucuronosyltransferase, and enterohepatic circulation of bilirubin. […] Hyperbilirubinemia can be caused by increased production of bilirubin, decreased hepatic uptake, decreased conjugation, impaired excretion, and increased enterohepatic circulation.

• #6 Hyperbilirubinemia in the Term Newborn | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0215/p599.html

  Hyperbilirubinemia is one of the most common problems encountered in term newborns. […] Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL (86 mol per L) per day or is higher than 17 mg per dL (290 mol per L), or an infant has signs and symptoms suggestive of serious illness. […] Neonatal hyperbilirubinemia, defined as a total serum bilirubin level above 5 mg per dL (86 mol per L), is a frequently encountered problem. […] Jaundice typically results from the deposition of unconjugated bilirubin pigment in the skin and mucus membranes. […] Unconjugated hyperbilirubinemia, the primary focus of this article, is the most common form of jaundice encountered by family physicians. […] The causes of neonatal hyperbilirubinemia can be classified into three groups based on mechanism of accumulation: bilirubin overproduction, decreased bilirubin conjugation, and impaired bilirubin excretion.

• #7 Bilirubin metabolism & pathophysiology of neonatal jaundice – IJMPO

  https://www.ijmpo.com/html-article/20301

  Jaundice is a visible yellowish color change in skin and sclera, secondary to elevated serum bilirubin which accumulates in the skin. […] In the new born, jaundice is visible during the 1st week of life in 60% of full term and 80% preterm infants. […] Bilirubin metabolism in a neonate is in transitional state from fetus to adult. […] Mostly, neonatal jaundice or bilirubin toxicity is result of a combination of events. […] Increased rate of bilirubin production (neonatal rate of 6-8 mg/kg/d cf. adult rate of 3-4 mg/kg/d) leads to increased UCB load. […] Inability of liver to clear sufficient bilirubin from plasma. […] Reduced activity of transferase enzyme (Y protein or ligandin or glutathione S transferase B) leads to decreased uptake by hepatocyte. […] Decreased conjugation due to deficiency (1% of adult of UGT1A1 Competition / blockade of transferase enzyme (developmental (particularly in preterm babies), drugs / substances requiring glucuronic acid conjugation for excretion).

• #8 Infant jaundice – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/infant-jaundice/symptoms-causes/syc-20373865

  Infant jaundice occurs because the baby’s blood contains an excess of bilirubin (bil-ih-ROO-bin), a yellow pigment of red blood cells. […] Infant jaundice usually occurs because a baby’s liver isn’t mature enough to get rid of bilirubin in the bloodstream. In some babies, an underlying disease may cause infant jaundice. […] Excess bilirubin (hyperbilirubinemia) is the main cause of jaundice. Bilirubin, which is responsible for the yellow color of jaundice, is a normal part of the pigment released from the breakdown of „used” red blood cells. […] A newborn’s immature liver often can’t remove bilirubin quickly enough, causing an excess of bilirubin. Jaundice due to these normal newborn conditions is called physiologic jaundice, and it typically appears on the second or third day of life.

• #9 Neonatal jaundice – Knowledge @ AMBOSS

  https://www.amboss.com/us/knowledge/neonatal-jaundice/

  Neonatal jaundice is one of the most common conditions occurring in newborn infants and is characterized by elevated levels of bilirubin in the blood (total serum bilirubin concentration 5 mg/dL or 85.5 mol/L). […] The most common cause of neonatal jaundice is a physiological rise in unconjugated bilirubin, which results from hemolysis of fetal hemoglobin and an immature hepatic metabolism of bilirubin. […] Physiological neonatal jaundice is harmless and occurs in most infants between the second and the eighth day of life. […] Pathologic neonatal jaundice can be conjugated or unconjugated and is typically a symptom of an underlying disease. […] Hyperbilirubinemia can cause drowsiness and poor feeding in the newborn, and in severe cases, unconjugated bilirubin can cross the blood-brain barrier and cause permanent neurological damage (kernicterus).

• #10 Neonatal jaundice – Wikipedia

  https://en.wikipedia.org/wiki/Neonatal_jaundice

  In newborns, jaundice tends to develop because of two factors: the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature metabolic pathways of the liver, which are unable to conjugate and so excrete bilirubin as quickly as an adult. This causes an accumulation of bilirubin in the blood (hyperbilirubinemia), leading to the symptoms of jaundice.[citation needed] […] Mechanisms involved in physiological jaundice include: […] Relatively low activity of the enzyme glucuronosyltransferase which normally converts unconjugated bilirubin to conjugated bilirubin that can be excreted into the gastrointestinal tract. Before birth, this enzyme is actively down-regulated, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus. After birth, it takes some time for this enzyme to gain function.

• #11 Bilirubin metabolism & pathophysiology of neonatal jaundice – IJMPO

  https://www.ijmpo.com/html-article/20301

  Jaundice is a visible yellowish color change in skin and sclera, secondary to elevated serum bilirubin which accumulates in the skin. […] In the new born, jaundice is visible during the 1st week of life in 60% of full term and 80% preterm infants. […] Bilirubin metabolism in a neonate is in transitional state from fetus to adult. […] Mostly, neonatal jaundice or bilirubin toxicity is result of a combination of events. […] Increased rate of bilirubin production (neonatal rate of 6-8 mg/kg/d cf. adult rate of 3-4 mg/kg/d) leads to increased UCB load. […] Inability of liver to clear sufficient bilirubin from plasma. […] Reduced activity of transferase enzyme (Y protein or ligandin or glutathione S transferase B) leads to decreased uptake by hepatocyte. […] Decreased conjugation due to deficiency (1% of adult of UGT1A1 Competition / blockade of transferase enzyme (developmental (particularly in preterm babies), drugs / substances requiring glucuronic acid conjugation for excretion).

• #12 Neonatal hyperbilirubinemia – McMaster Pathophysiology Review

  https://www.pathophys.org/neonatal-hyperbilirubinemia/

  More than 80% of newborns will exhibit jaundice, the clinical sign of hyperbilirubinemia, in the first few days of life. Hyperbilirubinemia can be benign at low levels but is harmful to the brain at higher levels. […] Bilirubin is the product of red blood cell breakdown, specifically heme degradation. Bilirubin in this state is not water-soluble, and must become water-soluble to be excreted in bile. […] Several factors specific to the neonates physiology contribute to physiologic hyperbilirubinemia: Increased production: Fetal erythrocytes have a higher rate of turnover; per kilogram, newborn infants produce twice the daily adult amount of bilirubin. Decreased clearance: Newborns have relatively low UDP-glucuronyltransferase activity (increases until approximately 14 weeks). They also have slow intestinal motility in the first few days as feeding becomes established, and this increases small amounts of bilirubin reuptake by the enterohepatic circulation.

• #13 Newborn jaundice: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001559.htm

  Newborn jaundice occurs when a baby has a high level of bilirubin in the blood. Bilirubin is a yellow substance that the body creates when it replaces old red blood cells. The liver helps break down the substance so it can be removed from the body in the stool. […] A high level of bilirubin makes a baby’s skin and whites of the eyes look yellow. This is called jaundice. […] When the baby is growing in the mother’s womb (uterus), the placenta removes bilirubin from the baby’s body. The placenta is the organ that grows during pregnancy to feed the baby. After birth, the baby’s liver starts doing this job. But, it may take some time for the baby’s liver to be able to do this efficiently. […] Severe newborn jaundice may occur if the baby has a condition that increases the number of red blood cells that need to be replaced in the body, such as:

• #14 Phototherapy for Jaundice: Background, Indications, Contraindications

  https://emedicine.medscape.com/article/1894477-overview

  Jaundice refers to the yellow appearance of the skin that occurs with the deposition of bilirubin in the dermal and subcutaneous tissue. Normally in the body, bilirubin is processed through the liver, where it is conjugated to glucuronic acid by the enzyme uridine diphosphate glucuronyl transferase (UGT) 1A1. This conjugated form of bilirubin is then excreted into the bile and removed from the body via the gut. When this excretion process is low following birth, does not work efficiently, or is overwhelmed by the amount of endogenously produced bilirubin, the amount of bilirubin in the body increases, resulting in hyperbilirubinemia and jaundice. […] Jaundice in the newborn can occur from an underlying pathological condition, such as isoimmune hemolysis or an RBC enzyme deficiency. However, it is more commonly due to the normal physiological inability of the newborn infant to process bilirubin adequately due to the combined effects of increased RBC turnover and a transient deficit in bilirubin conjugation in the liver.

• #15 Breast Milk Jaundice (Nursing) Article

  https://www.statpearls.com/articlelibrary/nursingarticle/18589

  Infant jaundice, also known as hyperbilirubinemia, is a frequently encountered clinical problem in neonates. Estimates are that between 60-80% of all term or late-term, healthy newborns exhibit physiologic jaundice with no cause found (idiopathic). […] The two common mechanisms for this are breastfeeding jaundice and breast milk jaundice. […] Breast milk jaundice was first described in 1963 when it was noted that some breastfed infants had prolonged, unconjugated hyperbilirubinemia that persisted beyond the third week of life. […] However, it can persist for 8-12 weeks of life before resolution. Infants with breast milk jaundice often have higher peaks of serum bilirubin and an overall slower decline than infants without it, leading to longer resolution time. […] The exact etiology of breast milk jaundice has not been determined (idiopathic). […] Most of the proposed etiologies of late-onset breastmilk jaundice beginning at 4 to 5 days or later, involve the factors present in the human breast milk itself.

• #16 Neonatal jaundice – Wikipedia

  https://en.wikipedia.org/wiki/Neonatal_jaundice

  In newborns, jaundice tends to develop because of two factors: the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature metabolic pathways of the liver, which are unable to conjugate and so excrete bilirubin as quickly as an adult. This causes an accumulation of bilirubin in the blood (hyperbilirubinemia), leading to the symptoms of jaundice.[citation needed] […] Mechanisms involved in physiological jaundice include: […] Relatively low activity of the enzyme glucuronosyltransferase which normally converts unconjugated bilirubin to conjugated bilirubin that can be excreted into the gastrointestinal tract. Before birth, this enzyme is actively down-regulated, since bilirubin needs to remain unconjugated in order to cross the placenta to avoid being accumulated in the fetus. After birth, it takes some time for this enzyme to gain function.

• #17 Breast Milk Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537334/

  After conjugation and excretion from hepatocytes, the bilirubin passes to the small intestine, where it gets converted to stercobilin by gut flora and subsequently excreted via the stool. […] Infants have a decreased concentration of gut flora needed for this process than adults, leading to a higher concentration of bilirubin remaining within the intestinal tract. […] Neonates have significantly higher activity of the enzyme -glucuronidase and a more permeable gut wall, leading to overall higher concentrations of unconjugated bilirubin and increased enterohepatic circulation. […] Basic and clinical studies were conducted and are still ongoing to investigate breast milk jaundice’s pathophysiology by studying breast milk’s effect on the processes discussed above.

• #18 Hyperbilirubinemia in the Term Newborn | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0215/p599.html

  Hyperbilirubinemia is one of the most common problems encountered in term newborns. […] Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL (86 mol per L) per day or is higher than 17 mg per dL (290 mol per L), or an infant has signs and symptoms suggestive of serious illness. […] Neonatal hyperbilirubinemia, defined as a total serum bilirubin level above 5 mg per dL (86 mol per L), is a frequently encountered problem. […] Jaundice typically results from the deposition of unconjugated bilirubin pigment in the skin and mucus membranes. […] Unconjugated hyperbilirubinemia, the primary focus of this article, is the most common form of jaundice encountered by family physicians. […] The causes of neonatal hyperbilirubinemia can be classified into three groups based on mechanism of accumulation: bilirubin overproduction, decreased bilirubin conjugation, and impaired bilirubin excretion.

• #19 Neonatal hyperbilirubinemia (jaundice) continued

  https://www.utmb.edu/Pedi_Ed/CoreV2/Neonatology/Neonatology24.html

  These are uncommon and result from biliary obstruction or the impairment of hepatic uptake, conjugation, or canalicular transport of bilirubin. The hyperbilirubinemia may be unconjugated or conjugated, depending on whether the etiology is inadequate conjugation or inadequate biliary secretion. […] This type of disorder should be suspected if jaundice is prolonged beyond the first week of life. […] Note also that babies who are exclusively breastfed may have an exaggerated course of physiologic jaundice possibly related to increased enterohepatic recirculation of bilirubin.

• #20 Hyperbilirubinemia in the Term Newborn | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0215/p599.html

  Hyperbilirubinemia is one of the most common problems encountered in term newborns. […] Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL (86 mol per L) per day or is higher than 17 mg per dL (290 mol per L), or an infant has signs and symptoms suggestive of serious illness. […] Neonatal hyperbilirubinemia, defined as a total serum bilirubin level above 5 mg per dL (86 mol per L), is a frequently encountered problem. […] Jaundice typically results from the deposition of unconjugated bilirubin pigment in the skin and mucus membranes. […] Unconjugated hyperbilirubinemia, the primary focus of this article, is the most common form of jaundice encountered by family physicians. […] The causes of neonatal hyperbilirubinemia can be classified into three groups based on mechanism of accumulation: bilirubin overproduction, decreased bilirubin conjugation, and impaired bilirubin excretion.

• #21 Hemolytic causes of neonatal jaundice: diagnosis and treatment – Bahr – Pediatric Medicine

  https://pm.amegroups.org/article/view/6462/html

  Jaundice is very common in newborns. Hemolysis is a major component in the pathophysiology of hyperbilirubinemia, and newborns with severe hemolysis appear to be at greater risk of developing bilirubin neurotoxicity. […] As will be discussed, hemolysis is a major component in the pathophysiology of hyperbilirubinemia and newborns with hemolysis appear to be at greater risk of developing bilirubin neurotoxicity. […] The risk of developing bilirubin neurotoxicity appears to be increased in neonates with a predominantly hemolytic etiology for their hyperbilirubinemia. […] Increased hemolysis is associated not only with classic choreoathetotic cerebral palsy, but also with neurologic abnormalities and lower IQ. […] Although there is to date no evidence demonstrating higher levels of UB in hemolyzing neonates, it is generally accepted that hemolysis is a potential factor increasing the risk for bilirubin-related brain damage.

• #22 Hemolytic causes of neonatal jaundice: diagnosis and treatment – Bahr – Pediatric Medicine

  https://pm.amegroups.org/article/view/6462/html

  Hemolytic conditions continue to top the list of identified etiologies of hyperbilirubinemia and ABE in modern times. […] The Subcommittee on Hyperbilirubinemia of the American Academy of Pediatrics (AAP), in its 2004 guideline, emphasizes the high risk of developing hyperbilirubinemia associated with hemolysis. […] The practical aspects of both increased risk for hyperbilirubinemia and neurotoxicity in association with hemolysis are manifest in the recommendations of the 2004 AAP guideline, in which a more aggressive approach is adopted in babies with hemolysis than in those without an obvious hemolytic condition. […] Hemolysis is defined as an abnormally short RBC lifespan. […] When neonatal jaundice is found to be the result of hemolysis, caregivers should be aware that: (I) the TSB level can rise rapidly; (II) the hyperbilirubinemia might be slow to fall even with intensive phototherapy; and (III) the hyperbilirubinemia is likely to rebound after phototherapy is discontinued.

• #23 Neonatal jaundice pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Neonatal_jaundice_pathophysiology

  Bilirubin is the catabolic product of the heme which is the main component of the red blood cells. Bilirubin is formed in the liver and spleen then it passes through several process in order to be metabolized. Metabolism processes include hepatic uptake, conjugation, clearance and excretion of the bilirubin in the bile. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. The pathological jaundice may be acquired or inherited. Acquired neonatal jaundice include Rh hemolytic disease, ABO incompatibility disease, and hemolytic disease due to G6PD enzyme deficiency. Inherited neonatal jaundice is due to defect of one of the processes of bilirubin metabolism and it concludes some inherited syndromes. Inherited neonatal jaundice include Gilbert’s syndrome, Crigler-Najjar syndrome type I and II, Lucey-Driscoll syndrome, Dubin-Johnson syndrome, and Rotor syndrome.

• #24 Hemolytic causes of neonatal jaundice: diagnosis and treatment – Bahr – Pediatric Medicine

  https://pm.amegroups.org/article/view/6462/html

  Jaundice is very common in newborns. Hemolysis is a major component in the pathophysiology of hyperbilirubinemia, and newborns with severe hemolysis appear to be at greater risk of developing bilirubin neurotoxicity. […] As will be discussed, hemolysis is a major component in the pathophysiology of hyperbilirubinemia and newborns with hemolysis appear to be at greater risk of developing bilirubin neurotoxicity. […] The risk of developing bilirubin neurotoxicity appears to be increased in neonates with a predominantly hemolytic etiology for their hyperbilirubinemia. […] Increased hemolysis is associated not only with classic choreoathetotic cerebral palsy, but also with neurologic abnormalities and lower IQ. […] Although there is to date no evidence demonstrating higher levels of UB in hemolyzing neonates, it is generally accepted that hemolysis is a potential factor increasing the risk for bilirubin-related brain damage.

• #25 Breast Milk Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537334/

  Several studies have shown that mutations in the coding region of the UGT1A1 gene increase the risk of developing breast milk jaundice. […] Before discussing the mechanism for breast milk jaundice, it is crucial to understand neonatal bilirubin metabolism and why neonates, in general, are affected by hyperbilirubinemia. Newborns have markedly increased bilirubin production compared to their adult counterparts, secondary to a higher blood volume and hemoglobin concentration, a shorter red blood cell lifespan, and liver enzymes’ physiological immaturity. […] The conjugation process occurs within the hepatocyte by bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme. UGT1A1 gene codes this enzyme production. Therefore those with genetic mutations in this gene are unable to conjugate bilirubin adequately.

• #26 Jaundice in infants and children: causes, diagnosis, and management | HKMJ

  https://www.hkmj.org/abstracts/v24n3/285.htm

  Gilbert syndrome results from a mutation in the UGT1A1 gene promotor region. […] Such mutation may produce structural or functional enzymatic deficiencies, possibly resulting in impaired bilirubin conjugation and hyperbilirubinaemia. […] The disease is characterised by inflammatory sclerosing cholangiopathy affecting the entire biliary tract. […] Its aetiology remains largely unknown and the most widely accepted theory is that unknown exogenous factors trigger a series of self-limiting inflammatory events in a genetically predisposed individual during the embryonic or perinatal period. […] Current evidence suggests that genetics play an important role in the pathogenesis of BA. […] The diagnosis of BA should be confirmed by direct visualisation of the fibrotic biliary tract. […] The management of individual diagnoses will be discussed below.

• #27 British Journal Of Midwifery – Bilirubin in the newborn: Physiology and pathophysiology

  https://www.britishjournalofmidwifery.com/content/clinical-practice/bilirubin-in-the-newborn-physiology-and-pathophysiology/

  Most bilirubin is produced during the breakdown of senescent red blood cells, with bilirubin being produced as a result of the breakdown of the haem component of haemoglobin. […] This occurs in phagocytic monocytes and macrophages in various tissues of the body (Mitra and Rennie, 2017), and first results in a form of bilirubin called unconjugated bilirubin. […] This is lipid-rather than water-soluble, so is transported to the liver for metabolism bound to albumin (Blackburn, 2017). […] In the liver it undergoes conjugation (it is combined with glucuronic acid by the enzyme glucuronyl transferase) to produce conjugated bilirubin, which is more water-soluble and can thus be excreted in urine and bile (Mitra and Rennie, 2017; Rankin, 2017). […] Mutations in this enzyme that reduce its function can result in Gilbert and Crigler-Najjar syndromes, which are characterised by hyperbilirubinaemia due to reduced functioning of the liver’s bilirubin-conjugating ability and the resulting build-up of unconjugated bilirubin (Wong and Stevenson, 2015; Chang et al, 2017). […] As the liver conjugating system also requires oxygen and glucose to function efficiently, hypoxia and hypoglycaemia may also slow down this process and increase the risk of hyperbilirubinaemia (Blackburn, 2017; Rankin, 2017).

• #28 Breast Milk Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537334/

  Breast milk jaundice is a type of jaundice that occurs in neonates due to breastfeeding. It happens within the first week of life due to the abnormal accumulation of bilirubin, causing a yellowish discoloration to the neonate’s skin known as jaundice. […] The exact etiology of breast milk jaundice has not been determined. Most of the proposed etiologies involve the factors present in the human breast milk itself. Other hypotheses suggest potential genetic mutations present in the affected neonates. […] Some human breast milk factors that may be related to breast milk jaundice’s etiology include pregnane-3a,20-diol, interleukin IL1, -glucuronidase, epidermal growth factor, and alpha-fetoprotein. […] The presence of pregnane-3a,20-diol, is thought to inhibit bilirubin’s conjugation, which in turn impedes bilirubin excretion.

• #29 Breast Milk Jaundice (Nursing) Article

  https://www.statpearls.com/articlelibrary/nursingarticle/18589

  Infant jaundice, also known as hyperbilirubinemia, is a frequently encountered clinical problem in neonates. Estimates are that between 60-80% of all term or late-term, healthy newborns exhibit physiologic jaundice with no cause found (idiopathic). […] The two common mechanisms for this are breastfeeding jaundice and breast milk jaundice. […] Breast milk jaundice was first described in 1963 when it was noted that some breastfed infants had prolonged, unconjugated hyperbilirubinemia that persisted beyond the third week of life. […] However, it can persist for 8-12 weeks of life before resolution. Infants with breast milk jaundice often have higher peaks of serum bilirubin and an overall slower decline than infants without it, leading to longer resolution time. […] The exact etiology of breast milk jaundice has not been determined (idiopathic). […] Most of the proposed etiologies of late-onset breastmilk jaundice beginning at 4 to 5 days or later, involve the factors present in the human breast milk itself.

• #30 Breastfeeding Jaundice and Breast Milk Jaundice

  https://www.birthinjuryhelpcenter.org/birth-injuries/help-center/jaundice-breastfeeding/

  Infant jaundice stems from excessive bilirubin in the blood. This happens when there’s too much bilirubin in the baby’s blood. […] In most cases, the baby’s liver can process the bilirubin and eliminate it from the body, but in some cases, the liver may not be mature enough to do this effectively, leading to jaundice. […] A newborn (especially preterm newborns) has an underdeveloped liver with limited function, which leads to slower metabolism of bilirubin. […] Breastfeeding jaundice usually occurs in the first week of life while the baby and mother are in the early stages of learning how to breastfeed. […] Breastfeeding jaundice is the result of the baby not receiving enough milk to lower their bilirubin levels. […] The cause of breast milk jaundice is currently unknown, but doctors believe it is linked to some type of substance in the breast milk that inhibits the liver’s ability to break down and process bilirubin.

• #31 Breast Milk Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK537334/

  Several studies have shown that mutations in the coding region of the UGT1A1 gene increase the risk of developing breast milk jaundice. […] Before discussing the mechanism for breast milk jaundice, it is crucial to understand neonatal bilirubin metabolism and why neonates, in general, are affected by hyperbilirubinemia. Newborns have markedly increased bilirubin production compared to their adult counterparts, secondary to a higher blood volume and hemoglobin concentration, a shorter red blood cell lifespan, and liver enzymes’ physiological immaturity. […] The conjugation process occurs within the hepatocyte by bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme. UGT1A1 gene codes this enzyme production. Therefore those with genetic mutations in this gene are unable to conjugate bilirubin adequately.

• #32 Breast Milk Jaundice (Nursing) Article

  https://www.statpearls.com/articlelibrary/nursingarticle/18589

  Some factors in human breast milk that may be related to the etiology of breast milk jaundice include proteins and enzymes thought to inhibit the conjugation of bilirubin that allows for its excretion. […] Studies have shown that the activity of this enzyme within formula milk is negligible, but it is considerable in human breast milk. […] Several studies have shown that mutations in the coding region of the UGT1A1 gene increase the risk of developing breast milk jaundice. […] Mutations in this gene’s regulatory region are known to cause Crigler-Najjar and Gilbert syndrome, two syndromes known to cause persistent hyperbilirubinemia. […] The frequency of breast milk jaundice within the United States is thought to be 20-30% for neonates from 3 to 4 weeks of age whose feeding is predominantly via breastfeeding. […] The international frequency of breast milk jaundice is not extensively reported but is thought to be similar to the frequency in the United States.

• #33 Hyperbilirubinemia and Neonatal Infection

  https://jpp.mums.ac.ir/article_2026.html

  Hyperbilirubinemia is a common and in most cases benign problem in first mouth of life which is often physiologic and intervention is not usually necessary. Jaundice may develop serious complications like kernicterus and lifelong disability. […] One of these factors is infection which is a serious clinical problem among newborns. The incidence rate of hyperbilirubinemia due to infection is unknown. It is well known that clinical manifestations of neonatal infection pretends as a wide spectrum, ranging from nonspecific signs and symptoms to severe illness as well as poor feeding, fever, vomiting, renal failure and respiratory distress. Hyperbilirubinemia may be the only manifestation of infection, especially UTI within neonatal period. […] Bacterial infection has been well-documented as a cause of neonatal jaundice in previous studies but the prevalence rate, jaundice presentation time and the differences between the jaundice associated with infection and other types of jaundice was unknown yet.

• #34 Hyperbilirubinemia and Neonatal Infection

  https://jpp.mums.ac.ir/article_2026.html

  The aim of this study was to determine the incidence rate, symptoms, and age at presentation, predisposing factors, characteristics, the severity of jaundice associated with infection and complications and the etiology of infection among neonates with hyperbilirubinemia in the first month- of life. […] Neonatal infection was found in approximately 10% of jaundiced newborns. The most common infection associated with neonatal jaundice was UTI (77.9%), Sepsis (16.8%) and pneumonia (5.3%), in order. […] The mechanism of jaundice in neonatal pneumonia is not well known. This partially may be related to the congestion of liver affected by pneumonia. Mean bilirubin value was significantly higher in sepsis subgroup as compared with noninfectious subjects. The mechanism of jaundice in neonatal sepsis maybe related to liver involvement by infection or hemolysis, although this mechanism is not well known. Conjugated hyperbilirubinemia can be associated with cholestasis secondary to bacterial infection. The mechanism in which infection causes cholestasis is not clear, but possible mechanisms include microcirculatory changes in the liver, direct effects from bacterial products, and/or from endotoxin-induced mediators.

• #35 Prolonged Jaundice in Newborn | IntechOpen

  https://www.intechopen.com/chapters/78011

  Intrahepatic or extrahepatic biliary obstructions, viral infections, inborn diseases of metabolism and endocrine disorders can lead to hyperbilirubinemia. […] Biliary atresia is the most common cause of neonatal cholestasis, and affected infants may appear healthy for a considerable time. […] Prolonged jaundice is seen in approximately 10% of infants with congenital hypothyroidism. Decreased UGT activity is blamed for the pathophysiology of hyperbilirubinemia seen in congenital hypothyroidism. […] Galactosemia is one of the etiologies of prolonged conjugated hyperbilirubinemia as a hereditary and metabolic disease. […] In the neonatal period, infections can be accompanied by jaundice. Particularly, urinary tract infections, and sepsis are common causes of jaundice. […] Prolonged jaundice can become an intensive care problem, if not noticed early. Extreme hyperbilirubinemia (TB of 25 to 30 mg/dL) can cause bilirubin encephalopathy, Kernicterus, which is usually characterized by the deposition of unconjugated bilirubin in brain cells.

• #36 Jaundice in newborns could be an evolutionary safeguard against death from sepsis

  https://theconversation.com/jaundice-in-newborns-could-be-an-evolutionary-safeguard-against-death-from-sepsis-97049

  In newborn babies, jaundice is so common as to be termed physiological. […] But it now looks as though this jaundice is not merely one of the pitfalls of entering the world. New research just published in Scientific Reports, in which we have been involved, suggests that it is one of the gifts of evolution. Humans may develop jaundice as newborns to protect from something even more serious: sepsis. […] Richard began wondering if the bilirubin was directly linked to the infection, and if it was part of the babys bodys attempt to clear the sepsis (in this case the baby survived). […] Richard realised that the biggest threat to their life after surviving delivery would probably be overwhelming sepsis in the first few days exactly when the bilirubin level rises naturally. Could jaundice be an evolutionary mechanism to protect against this?

• #37 Jaundice in newborns could be an evolutionary safeguard against death from sepsis

  https://theconversation.com/jaundice-in-newborns-could-be-an-evolutionary-safeguard-against-death-from-sepsis-97049

  The results of this project have just been published. Our team have shown that even modest concentrations of bilirubin reduced by one third the growth of Gram-positive Streptococcus agalactiae. […] It feels like were discovering something new about the physiology of newborn babies. Its the excitement of being a clinician scientist: taking an idea from a real patient into the laboratory and testing then developing it to hopefully help future patients. When newborn babies develop jaundice in future, well still need to treat it carefully. But quite possibly we will also be thankful that its protecting them from something potentially life-threatening.

• #38 Neonatal Hyperbilirubinemia – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/metabolic-electrolyte-and-toxic-disorders-in-neonates/neonatal-hyperbilirubinemia

  Hyperbilirubinemia is an elevated serum bilirubin concentration, causing jaundice (a yellow discoloration of the skin and eyes). […] Almost all hyperbilirubinemia in the immediate neonatal period is unconjugated, which is also termed indirect bilirubin; conjugated bilirubin is termed direct bilirubin. […] Neurotoxicity is the major negative consequence of neonatal hyperbilirubinemia. An acute encephalopathy can be followed by a variety of neurologic impairments, including cerebral palsy and sensorimotor deficits; cognition is usually spared. Chronic bilirubin encephalopathy (CBE), formerly known as kernicterus, is the most severe form of neurotoxicity. […] CBE is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei, caused by either acute or chronic hyperbilirubinemia.

• #39 Infant jaundice – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/infant-jaundice/symptoms-causes/syc-20373865

  An underlying disorder may cause infant jaundice. In these cases, jaundice often appears much earlier or much later than does the more common form of infant jaundice. […] High levels of bilirubin that cause severe jaundice can result in serious complications if not treated. […] Bilirubin is toxic to cells of the brain. If a baby has severe jaundice, there’s a risk of bilirubin passing into the brain, a condition called acute bilirubin encephalopathy.

• #40 Hyperbilirubinemia in the Term Newborn | AAFP

  https://www.aafp.org/pubs/afp/issues/2002/0215/p599.html

  Kernicterus refers to the neurologic consequences of the deposition of unconjugated bilirubin in brain tissue. […] The precise role of bilirubin in the development of kernicterus is not completely understood. […] If the serum unconjugated bilirubin level exceeds the binding capacity of albumin, unbound lipid-soluble bilirubin crosses the blood-brain barrier. […] The exact bilirubin concentration associated with kernicterus in the healthy term infant is unpredictable. […] Conjugated hyperbilirubinemia is never physiologic, and it may indicate the presence of a potentially serious underlying disorder.

• #41 Neonatal Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532930/

  Pathologic jaundice in neonates is related to increased production of bilirubin in the RES, impaired hepatic uptake, deficient conjugation of bilirubin, and enhanced enterohepatic circulation of bilirubin. […] In severe hyperbilirubinemia, unbound, unconjugated bilirubin crosses the blood-brain barrier and binds to the brainstem, hippocampus, cerebellum, globus pallidus, and subthalamic nuclei. […] These mechanisms are implicated in the pathogenesis of bilirubin toxicity that clinically manifests as bilirubin-induced neurologic dysfunction (BIND) and bilirubin encephalopathy.

• #42 Neonatal Hyperbilirubinemia – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/metabolic-electrolyte-and-toxic-disorders-in-neonates/neonatal-hyperbilirubinemia

  Normally, bilirubin bound to serum albumin stays in the intravascular space. However, unconjugated bilirubin can cross the blood-brain barrier and cause CBE in certain situations: When serum bilirubin concentration is markedly elevated […] When serum albumin concentration is markedly low (eg, in preterm infants) […] When bilirubin is displaced from albumin by competitive binders. […] Hyperbilirubinemia can be caused by one or more of the following processes: Increased production […] Decreased hepatic uptake […] Decreased conjugation […] Impaired excretion […] Impaired bile flow (cholestasis) […] Increased enterohepatic circulation. […] The majority of bilirubin is produced from the breakdown of hemoglobin into unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to albumin in the blood for transport to the liver, where it is taken up by hepatocytes and conjugated with glucuronic acid by the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT) to make it water-soluble.

• #43 Newborn jaundice: MedlinePlus Medical EncyclopediaLock

  https://medlineplus.gov/ency/article/001559.htm

  Things that make it harder for the baby’s body to remove bilirubin may also lead to more severe jaundice, including: […] Babies who are born too early (premature) are more likely to develop jaundice than full-term babies. […] A very high level of bilirubin can damage the brain. This is called kernicterus. The condition is almost always diagnosed before the level becomes high enough to cause this damage. Treatment is usually effective.

• #44 Newborn Jaundice: Pathological, Prevention, Signs of Recovery

  https://www.medicinenet.com/newborn_jaundice_neonatal_jaundice/article.htm

  The complications associated with neonatal jaundice occur when bilirubin levels reach toxic levels, and the bilirubin gets into the central nervous system and damages the brain. The brain toxicity can either be reversible (early acute bilirubin encephalopathy) or the damage may be permanent and irreversible (kernicterus).

• #45 Neonatal Jaundice – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK532930/

  Pathologic jaundice in neonates is related to increased production of bilirubin in the RES, impaired hepatic uptake, deficient conjugation of bilirubin, and enhanced enterohepatic circulation of bilirubin. […] In severe hyperbilirubinemia, unbound, unconjugated bilirubin crosses the blood-brain barrier and binds to the brainstem, hippocampus, cerebellum, globus pallidus, and subthalamic nuclei. […] These mechanisms are implicated in the pathogenesis of bilirubin toxicity that clinically manifests as bilirubin-induced neurologic dysfunction (BIND) and bilirubin encephalopathy.

• #46 neonatal jaundice, classification and diagnosis

  https://labpedia.net/liver-part-4-neonatal-jaundice-classificationand-and-diagnosis/

  Neonatal jaundice appears in the early days of the newborn. […] If jaundice persists beyond 14 days, it indicates some pathological cause. This may be a hemolytic disease of the newborn that starts in utero and causes jaundice, anemia, and hepatosplenomegaly in mature infants. […] The early diagnosis and the significance of unconjugated hyperbilirubinemia are the potentials for developing Kernicterus. […] Kernicterus is the bilirubin staining of the central nervous system and basal ganglia with death or permanent neurologic or mental abnormalities. […] The damage to the brain is called Kernicterus. […] In kernicterus, there is yellowness of the subthalamic nucleus, hippocampus, thalamus, putamen, cerebellar nuclei, cranial nerves, and globus pallidus. […] The most common cause is the hemolytic disease of the newborn (HDN).

• #47 Jaundice – Wikipedia

  https://en.wikipedia.org/wiki/Jaundice

  While most cases of newborn jaundice are not harmful, when bilirubin levels are very high, brain damage kernicterus may occur leading to significant disability. Kernicterus is associated with increased unconjugated bilirubin (bilirubin which is not carried by albumin). Newborns are especially vulnerable to this damage, due to increased permeability of the blood-brain barrier occurring with increased unconjugated bilirubin, simultaneous to the breakdown of fetal hemoglobin and the immaturity of gut flora. […] Jaundice in newborns is usually transient and dissipates without medical intervention. In cases when serum bilirubin levels are greater than 421 mg/dl (68360 mol/L), infant may be treated with phototherapy or exchanged transfusion depending on the infant’s age and prematurity status.

• #48 Neonatal Hyperbilirubinemia – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/metabolic-electrolyte-and-toxic-disorders-in-neonates/neonatal-hyperbilirubinemia

  Hyperbilirubinemia is an elevated serum bilirubin concentration, causing jaundice (a yellow discoloration of the skin and eyes). […] Almost all hyperbilirubinemia in the immediate neonatal period is unconjugated, which is also termed indirect bilirubin; conjugated bilirubin is termed direct bilirubin. […] Neurotoxicity is the major negative consequence of neonatal hyperbilirubinemia. An acute encephalopathy can be followed by a variety of neurologic impairments, including cerebral palsy and sensorimotor deficits; cognition is usually spared. Chronic bilirubin encephalopathy (CBE), formerly known as kernicterus, is the most severe form of neurotoxicity. […] CBE is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei, caused by either acute or chronic hyperbilirubinemia.

• #49 Oli Health Magazine Organization – International Scientific Research Academy

  https://www.olihealthmagazine.org/neonatal-jaundice_H91.html

  Kernicterus Is a complication of untreated hyperbilirubinaemia (high level of bilirubin in the Blood). In newborn babies with hyperbilirubinaemia, the bilirubin can cross the membrane (thin layer of tissue) That separates the brain and the blood. The bilirubin causes yellow staining of the brain, and can damage the brain and spinal cord. This may result in short-term or long-term brain damage, or even death. […] Brain damage caused by high levels of bilirubin is also called bilirubin encephalopathy.

• #50 Prolonged Jaundice in Newborn | IntechOpen

  https://www.intechopen.com/chapters/78011

  Intrahepatic or extrahepatic biliary obstructions, viral infections, inborn diseases of metabolism and endocrine disorders can lead to hyperbilirubinemia. […] Biliary atresia is the most common cause of neonatal cholestasis, and affected infants may appear healthy for a considerable time. […] Prolonged jaundice is seen in approximately 10% of infants with congenital hypothyroidism. Decreased UGT activity is blamed for the pathophysiology of hyperbilirubinemia seen in congenital hypothyroidism. […] Galactosemia is one of the etiologies of prolonged conjugated hyperbilirubinemia as a hereditary and metabolic disease. […] In the neonatal period, infections can be accompanied by jaundice. Particularly, urinary tract infections, and sepsis are common causes of jaundice. […] Prolonged jaundice can become an intensive care problem, if not noticed early. Extreme hyperbilirubinemia (TB of 25 to 30 mg/dL) can cause bilirubin encephalopathy, Kernicterus, which is usually characterized by the deposition of unconjugated bilirubin in brain cells.

• #51 CASE STUDY INVESTIGATION | The Effect of Neonatal Jaundice on Infants’ Auditory Mechanism in Nigeria – American Academy of Audiology

  https://www.audiology.org/news-and-publications/audiology-today/articles/case-study-investigation-the-effect-of-neonatal-jaundice-on-infants-auditory-mechanism-in-nigeria/

  Jaundice is a common condition that requires medical attention in newborns worldwide. The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. […] In some cases, however, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death in newborns, and lifelong neurologic sequelae in infants who survive including hearing loss. […] Biochemically, hyperbilirubinamia is the major cause of neonatal jaundice, but it could be mitigated by the use of some drugs (phenobarbitols, dexamethasone, and clofibrates) that causes the production of uridine diphosphate glucuronyl transferase (UDPGT), an enzyme that helps to convert the bilirubin to water soluble bilirubin (conjugated bilirubin). This is because if unconjugated bilirubin is not converted, it could pass through the brain barrier membrane and cause neurotoxicity which results in auditory nerve damage thereby giving rise to hearing loss.

• #52 Neonatal Hyperbilirubinemia – Pediatrics – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pediatrics/metabolic-electrolyte-and-toxic-disorders-in-neonates/neonatal-hyperbilirubinemia

  Hyperbilirubinemia is an elevated serum bilirubin concentration, causing jaundice (a yellow discoloration of the skin and eyes). […] Almost all hyperbilirubinemia in the immediate neonatal period is unconjugated, which is also termed indirect bilirubin; conjugated bilirubin is termed direct bilirubin. […] Neurotoxicity is the major negative consequence of neonatal hyperbilirubinemia. An acute encephalopathy can be followed by a variety of neurologic impairments, including cerebral palsy and sensorimotor deficits; cognition is usually spared. Chronic bilirubin encephalopathy (CBE), formerly known as kernicterus, is the most severe form of neurotoxicity. […] CBE is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei, caused by either acute or chronic hyperbilirubinemia.

• #53 Bilirubin metabolism & pathophysiology of neonatal jaundice – IJMPO

  https://www.ijmpo.com/html-article/20301

  Jaundice is a visible yellowish color change in skin and sclera, secondary to elevated serum bilirubin which accumulates in the skin. […] In the new born, jaundice is visible during the 1st week of life in 60% of full term and 80% preterm infants. […] Bilirubin metabolism in a neonate is in transitional state from fetus to adult. […] Mostly, neonatal jaundice or bilirubin toxicity is result of a combination of events. […] Increased rate of bilirubin production (neonatal rate of 6-8 mg/kg/d cf. adult rate of 3-4 mg/kg/d) leads to increased UCB load. […] Inability of liver to clear sufficient bilirubin from plasma. […] Reduced activity of transferase enzyme (Y protein or ligandin or glutathione S transferase B) leads to decreased uptake by hepatocyte. […] Decreased conjugation due to deficiency (1% of adult of UGT1A1 Competition / blockade of transferase enzyme (developmental (particularly in preterm babies), drugs / substances requiring glucuronic acid conjugation for excretion).

• #54 Severe neonatal hyperbilirubinemia secondary to combined RhC hemolytic disease, congenital hypothyroidism and large adrenal hematoma: a case report | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03594-7

  Neonatal hyperbilirubinemia is the most widespread disease in the neonatal period. Hemolytic disease of the newborn(HDN) is a prevalent cause of severe hyperbilirubinemia that frequently results in severe jaundice, the prevalence rate is about 12.9%. Alloimmune HDN predominantly affects the Rhesus (Rh), A, B, AB, and O blood groups, whereas minor blood group incompatibilities (Kell, Duffy, MNS, P, and Diego systems) can also cause irreversible damage. About 35% cases of HDN were reported caused by minor blood group incompatibility. Congenital hypothyroidism(CHT) is another cause of hyperbilirubinemia, yet it usually leads to mild to moderate jaundice and persistent jaundice. There are few reports of severe jaundice induced by CH, the prevalence rate is about 0.3%. Adrenal hemorrhage in newborn infants is an uncommon occurrence that can cause jaundice duo to extravascular hemolysis, with the incidence proportion of about 0.17%0.3%. A case of special hyperbilirubinemia coupled with RhC hemolytic disease, congenital hypothyroidism caused by DUOX2 gene mutation, and large adrenal hemorrhage are described.

• #55

  https://www.childrensmedicalassociation.com/caring-for-your-newborn-with-jaundice

  Caring For Your Newborn with Jaundice […] The term jaundice comes from the French word jaune, meaning yellow, and refers to a yellow discoloration of the skin and the whites of the eyes (sclera) from the deposition of the pigment called bilirubin. Bilirubin largely comes from the breakdown of hemoglobin, the protein that carries oxygen in the red blood cells. With neonatal jaundice, increase in bilirubin load resulting in hyperbilirubinemia is due to either/both an increase in bilirubin production or a decrease in bilirubin clearance. […] Most neonatal jaundice is normal, unconjugated, and related to natural breakdown of fetal hemoglobin, immaturity of the newborn liver to efficiently metabolize bilirubin, low intake/dehydration from breast feeding, and reabsorption of bilirubin from the intestinal tract during sluggish elimination of stool. […] Because severely elevated total bilirubin 25 mg/dl allows bilirubin to cross into the brain, which may cause brain damage (bilirubin-induced neurologic dysfunction or BIND, formerly known as kernicterus), and elevated direct bilirubin above 2mg/dl or 20% of the total may indicate a problem with the conjugation or excretion of bilirubin anyplace within the liver/biliary system (cholestasis), which must be identified/treated quickly to minimize liver damage. […] Risk factors for more severe hyperbilirubinemia include prematurity; maternal diabetes; race (Asians and Native Americans); male sex; trisomy 21 (Down Syndrome); blood in the scalp following vaginal delivery (cephalohematoma); hemolysis (abnormal breakdown of blood cells, e.g., one such cause is if the baby and mom have different blood types – ABO and/or Rh – and antibodies against the babys blood type cross the placenta and attack red blood cells in the baby); oxytocin induction; breast feeding; delayed passage of meconium; gene mutations; and a history of siblings who had neonatal jaundice. […] If your newborns examination is abnormal, if the jaundice continues past two weeks, or if there is cholestasis, we will request additional labwork to assess hemolysis, liver function, metabolic disorders, or the presence of infection. […] For newborns with persistent or pathological jaundice, we will enlist the help of a pediatric gastroenterologist to help manage the evaluation and your babys ongoing care.

• #56 Narrative review of the epidemiology of neonatal jaundice – Hansen – Pediatric Medicine

  https://pm.amegroups.org/article/view/6073/html

  Jaundice in the newborn has a reported incidence between 60% to more than 90%. Bilirubin, the molecule that causes the color of jaundice, is the end product of disassembly of heme-containing molecules, primarily hemoglobin. Therefore, conditions that increase hemolysis will increase bilirubin production and cause jaundice. Common conditions in the newborn are blood group incompatibilities and congenital hemolytic anemias. A family history of NJ increases the likelihood of jaundice in the present newborn, and is one of several examples of genetic conditions that contribute. Endocrine and metabolic conditions contribute, the most common being maternal diabetes. An increased incidence is seen in infants of Southeast Asian mothers, while African infants have a lower incidence unless they suffer from G-6-PD-deficiency. Drugs taken by the mother during pregnancy may impact on hepatic metabolism of bilirubin in the newborn, often by reducing the incidence of jaundice, and the same may happen with certain drugs given to the newborn. Birth trauma, through extravasation of blood, will increase bilirubin production and jaundice. Preterm infants have immature bilirubin metabolism and a higher incidence of jaundice. Breast-fed infants have an increased incidence of jaundice, which may also last longer. […] Extreme NJ, associated with risk of kernicterus spectrum syndrome, has an estimated worldwide incidence of 99/100,000 or more, thus affecting 130,000 or more infants each year and calling for increased vigilance and preparedness for rapid therapeutic intervention.

• #57 Severe neonatal hyperbilirubinemia secondary to combined RhC hemolytic disease, congenital hypothyroidism and large adrenal hematoma: a case report | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03594-7

  Neonatal hyperbilirubinemia is the most widespread disease in the neonatal period. Hemolytic disease of the newborn(HDN) is a prevalent cause of severe hyperbilirubinemia that frequently results in severe jaundice, the prevalence rate is about 12.9%. Alloimmune HDN predominantly affects the Rhesus (Rh), A, B, AB, and O blood groups, whereas minor blood group incompatibilities (Kell, Duffy, MNS, P, and Diego systems) can also cause irreversible damage. About 35% cases of HDN were reported caused by minor blood group incompatibility. Congenital hypothyroidism(CHT) is another cause of hyperbilirubinemia, yet it usually leads to mild to moderate jaundice and persistent jaundice. There are few reports of severe jaundice induced by CH, the prevalence rate is about 0.3%. Adrenal hemorrhage in newborn infants is an uncommon occurrence that can cause jaundice duo to extravascular hemolysis, with the incidence proportion of about 0.17%0.3%. A case of special hyperbilirubinemia coupled with RhC hemolytic disease, congenital hypothyroidism caused by DUOX2 gene mutation, and large adrenal hemorrhage are described.

• #58 Severe neonatal hyperbilirubinemia secondary to combined RhC hemolytic disease, congenital hypothyroidism and large adrenal hematoma: a case report | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03594-7

  Further examination confirmed our suspicion, congenital hypothyroidism is the second factor in his bilirubin increase. Thyroid hormones revealed that the TSH of baby was 13.334mIU/L, which increased to 16mIU/L over two weeks of oral administration of euthyroxine. An epidemiological survey in Iran conducted that hypothyroidism is responsible for around 4.2% of hyperbilirubinemia. Although the large portion of CH manifestations are protracted jaundice, several large-sample studies have shown that congenital hypothyroidism can produce severe hyperbilirubinemia, prompting transfusion exchange. […] The activity of uridine diphosphate glucuronyl transferase (UGT) in neonatal liver cells deminishes when there is a paucity of thyroxine. This is the main cause of hypothyroidism-induced jaundice. In contrast, newborns with congenital hypothyroidism, intestinal peristalsis slows down, and meconium excretion is delayed, augmenting the intestinal hepatic circulation of bilirubin and aggravating jaundice.

• #59 Severe neonatal hyperbilirubinemia secondary to combined RhC hemolytic disease, congenital hypothyroidism and large adrenal hematoma: a case report | BMC Pediatrics | Full Text

  https://bmcpediatr.biomedcentral.com/articles/10.1186/s12887-022-03594-7

  In addition to Anti C isoimmunization and CH, ultrasound of the adrenal glands and subsequent abdominal MRI reported that the child had a dominant right adrenal hemorrhage, which contributed to the overall rise in serum bilirubin. Neonatal adrenal hemorrhage is infrequent, with incidence proportion of about 0.17%0.3%. Adrenal hemorrhage can occur in neonates owing to the relatively large size and distinctive vascularity, making them vulnerable to asphyxia, infection, birth injury, and abnormal blood coagulation. […] This is the third example of hyperbilirubinemia with hemolytic disease and adrenal hematoma that has also been associated with congenital hypothyroidism to our knowledge. It was challenging to treat such a complicated jaundice. Our experience can potentially be used as a guide for future clinical practice.

• #60 Mechanism of bilirubin elimination in urine: insights and prospects for neonatal jaundice

  https://www.degruyterbrill.com/document/doi/10.1515/cclm-2020-1759?srsltid=AfmBOoq8ZDwoCMUr16rAOptG9QuTpnWzOCyGTeo93bPsqsGPkU–JLk9

  Despite a century of research, bilirubin metabolism and the transport mechanisms responsible for homeostasis of bilirubin in serum remain controversial. […] Emerging evidence on the hepatic membrane transporters and inherited disorders of bilirubin metabolism have contributed to a greater understanding of the various steps involved in bilirubin homeostasis and its associated excretory pathways. […] New insights gained speculate that a proportion of conjugated bilirubin is excreted via the renal system, as an alternative to the intestinal excretion, even in normal physiological jaundice with no associated pathological concerns. […] Finally, this paper discusses the clinical relevance of targeting the altered renal excretory pathway, as bilirubin in urine may hold diagnostic importance in screening for neonatal jaundice.

• #61 Mechanism of bilirubin elimination in urine: insights and prospects for neonatal jaundice

  https://www.degruyterbrill.com/document/doi/10.1515/cclm-2020-1759?srsltid=AfmBOoq8ZDwoCMUr16rAOptG9QuTpnWzOCyGTeo93bPsqsGPkU–JLk9

  Despite a century of research, bilirubin metabolism and the transport mechanisms responsible for homeostasis of bilirubin in serum remain controversial. […] Emerging evidence on the hepatic membrane transporters and inherited disorders of bilirubin metabolism have contributed to a greater understanding of the various steps involved in bilirubin homeostasis and its associated excretory pathways. […] New insights gained speculate that a proportion of conjugated bilirubin is excreted via the renal system, as an alternative to the intestinal excretion, even in normal physiological jaundice with no associated pathological concerns. […] Finally, this paper discusses the clinical relevance of targeting the altered renal excretory pathway, as bilirubin in urine may hold diagnostic importance in screening for neonatal jaundice.

• #62 Phototherapy for Jaundice: Background, Indications, Contraindications

  https://emedicine.medscape.com/article/1894477-overview

  This type of nonpathologic jaundice is referred to as physiologic jaundice of the newborn. […] In most infants with physiologic jaundice, bilirubin concentrations do not rise to a point that requires treatment. However, in some infants with exaggerated physiologic jaundice, and in many infants with pathologic jaundice, bilirubin in the blood reaches very high concentrations that put the infant at risk for acute and chronic bilirubin encephalopathy (kernicterus). In these cases, treatment aimed at decreasing bilirubin concentration is required in order to avoid kernicterus. […] Effective treatments to decrease bilirubin levels in infants with severe jaundice include phototherapy and exchange transfusion. […] At its most basic, phototherapy refers to the use of light to convert bilirubin molecules in the body into water soluble isomers that can be excreted by the body. The absorption of light by normal bilirubin (4Z,15Z-bilirubin) results in the creation of 2 isomeric forms of bilirubin: structural isomers and configurational isomers. The main structural isomer of bilirubin is Z-lumirubin. The main configurational isomer of bilirubin is 4Z,15 E -bilirubin. Configurational isomerization is reversible, and structural isomerization is irreversible. Both the configurational and structural isomers of bilirubin are less lipophilic than normal bilirubin and can be excreted into bile without undergoing glucuronidation in the liver.

• #63 Phototherapy for Jaundice: Background, Indications, Contraindications

  https://emedicine.medscape.com/article/1894477-overview

  The absorptions of light by bilirubin also results in the generation of excited-state bilirubin molecules that react with oxygen to produce colorless oxidation products, or photooxidation products. This process occurs more slowly than configurational or structural isomerization. […] Mechanism of phototherapy: Blue-green light in the range of 460-490 nm is most effective for phototherapy. The absorption of light by the normal bilirubin (4Z,15Z-bilirubin) generates configuration isomers, structural isomers, and photooxidation products. The 2 principal photoisomers formed in humans are shown. Configurational isomerization is reversible and much faster than structural isomerization. Structural isomerization is slow and irreversible. Photooxidation occurs more slowly than both configurational and structural isomerization. Photooxidation products are excreted mainly in urine.

• #64 Neonatal hyperbilirubinemia – McMaster Pathophysiology Review

  https://www.pathophys.org/neonatal-hyperbilirubinemia/

  Phototherapy involves exposing the skin to blue wavelengths of light. At this frequency, light induces a conformational change in the fat-soluble unconjugated bilirubin deposited in the skin and subcutaneous tissues, rendering it water soluble. This form of bilirubin can be then excreted in bile and urine without needing to be conjugated by hepatocytes. […] Intravenous immunoglobulin G (IVIG) can be used in Rh and ABO hemolytic disease, and has been demonstrated to significantly reduce the need for exchange transfusion.

• #65 Phototherapy for Jaundice: Background, Indications, Contraindications

  https://emedicine.medscape.com/article/1894477-overview

  The absorptions of light by bilirubin also results in the generation of excited-state bilirubin molecules that react with oxygen to produce colorless oxidation products, or photooxidation products. This process occurs more slowly than configurational or structural isomerization. […] Mechanism of phototherapy: Blue-green light in the range of 460-490 nm is most effective for phototherapy. The absorption of light by the normal bilirubin (4Z,15Z-bilirubin) generates configuration isomers, structural isomers, and photooxidation products. The 2 principal photoisomers formed in humans are shown. Configurational isomerization is reversible and much faster than structural isomerization. Structural isomerization is slow and irreversible. Photooxidation occurs more slowly than both configurational and structural isomerization. Photooxidation products are excreted mainly in urine.

• #66 British Journal Of Midwifery – Bilirubin in the newborn: Physiology and pathophysiology

  https://www.britishjournalofmidwifery.com/content/clinical-practice/bilirubin-in-the-newborn-physiology-and-pathophysiology/

  Physiological jaundice is common in the first week of life, occurring in around 60% of term and 80% of preterm infants (Ng and How, 2015; Mitra and Rennie, 2017). […] It is the result of rising levels of bilirubin, which eventually binds to tissues such as the skin and sclera, producing clinically recognisable jaundice around day 3 or 4 (Mitra and Rennie, 2017; Rankin, 2017). […] Bilirubin is produced during the breakdown of red blood cells, and in newborn infants there is a transitional imbalance between its production and elimination, resulting in an excess of bilirubin. […] This normal imbalance that produces physiological jaundice can, however, be exacerbated by factors that result in pathological jaundice, which can result in neurological damage, dysfunction, and death (Ng and How, 2015).

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