Dubin-Johnson syndrome is an autosomal recessive disorder characterized by intermittent mild jaundice, caused predominantly by a conjugated hyperbilirubinemia (bilirubin 2 to 5 mg/dL Reduced hepatic bilirubin clearance can be due to defective 1) unconjugated bilirubin uptake and intrahepatic storage, 2) conjugation of glucuronic acid to Inherited disorders with defective UDPGT function are associated with unconjugated hyperbilirubinemia; in severe cases (e.g. [15] Common laboratory findings for cholestasis: alkaline phosphatase , gamma-glutamyltransferase , and direct bilirubin. Do you have updated information on In some individuals, inherited conditions may also give rise to higher than normal levels of bilirubin in urine. Inherited disorders of bilirubin metabolism: Gilbert Syndrome: The Gilbert syndrome is characterized by unconjugated hyperbilirubinemia with serum bilirubin less than 3.0 mg/dL. The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. [1] It is a biochemical marker of cholestasis and hepatocellular dysfunction. Serum bilirubin is generally between 25 mg/dL, but can be as high as 2025 mg/dL, and bilirubinuria is frequently observed. Mentioned in: Erythroblastosis Fetalis, 79(3):378-86. According to the severity of UGT1A1 enzyme deficiency, inherited unconjugated hyperbilirubinemia can be classified into Crigler-Najjar syndrome type I (CNS1), Crigler-Najjar syndrome type II (CNS2), and Gilbert syndrome (GS). The underlying bio-chemical disturbance of jaundice is defined by direct or indirect hyperbilirubinemia. Inherited Conditions (Bilrubin in Urine) Dubin-Johnson Syndrome is a rare inherited condition that prevents the liver from conjugating bilirubin, which results marked levels of bilirubin in urine as one of the symptoms. The clinical manifestation of hyperbilirubinemia is relatively mild; transient jaundice is the primary symptom. Mostly it means an increased severity of the disease or poor control of the disease. Four inherited hyperbilirubinemias: Crigler-Najjar, Gilbert, Dubin-Johnson and Rotor syndromes. Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, Moreover, the problem of jaundice is potentiated in cases of inherited UDP glucuronosyltransferase promoter polymorphism associated with Gilbert syndrome [14, 15]. There will also be a rise in ALP and GGT levels. 5 GS occurs as a result of one of several identified mutations in the UGT1A1 gene, 6 leading to a reduction in enzyme activity to approximately one-third normal. Rotor syndrome (also known as Rotor type hyperbilirubinemia) is a rare cause of mixed direct (conjugated) and indirect (unconjugated) hyperbilirubinemia, relatively benign, autosomal recessive bilirubin disorder characterized by non-hemolytic jaundice due to the chronic elevation of predominantly conjugated bilirubin.. Rotor type hyperbilirubinemia is a distinct yet similar With the exception of Crigler-Najjar syndrome type I, inherited hyperbilirubinemia syndromes do not require medical management. PKU is an inherited disease in which the body cannot metabolize a protein called phenylalanine. Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. This hyperbilirubinemia is often caused by an underlying hepatic or hematologic derangement, but can also be a benign finding. Jaundice may be present by the 2nd or 3rd day of life that usually clears by the 7th day of life. Unconjugated hyperbilirubinemia. How is this test done? Pathogenesis of neonatal jaundice includes physiologic process of bilirubin accumulation or pathological mechanism. Tx: Phototherapy vs None. BILIRUBIN METABOLISM 4. DubinJohnson syndrome is a rare disorder characterized by mild, predominantly conjugated hyperbilirubinemia. Transient familial hyperbilirubinemia is an inherited disorder. Inherited disorders associated with conjugated hyperbilirubinemia; Intrahepatic cholestasis of pregnancy; Liver biochemical tests that detect injury to hepatocytes; Malnutrition in children in resource-limited countries: Clinical assessment; Noninvasive assessment of hepatic fibrosis: Overview of serologic tests and imaging examinations Gilberts Syndrome. Here are a few syndromes that are easy to mix up: Crigler-Najjar, Gilbert, Dubin-Johnson, and Rotor syndromes. In children and neonates with this condition, the first diagnosis to be ruled out is inherited disorders such as Crigler-Najjar syndrome or Gilbert syndrome. Bilirubin is a natural by-product of the breakdown of red blood cells, however, a high level of bilirubin may indicate a problem with the liver. Hyperbilirubinemia is a condition in which there is a build up of bilirubin in the blood, causing yellow discoloration of the eyes and skin, called jaundice. [Guideline] Dani C, Pratesi S, Raimondi F, Romagnoli C, for the Task Force for Hyperbilirubinemia of the Italian Society of Neonatology. Pediatr Res. Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. If anemia and high bilirubin levels coexist, the diagnosis is probably related to the increased production of this substance. Less frequently, neonatal hyperbilirubinemia may result from a inherited hemolytic disorder such as hereditary spherocytosis, glucose-6-phosphate dehydrogenase deficiency or a hemoglobinopathy such as thalassemia. Bilirubin is a yellow substance that the body creates when it replaces old Since bilirubin is produced during the breakdown process of red blood cells, increased destruction commonly leads to an elevated bilirubin level. Benign Neonatal Hyperbilirubinemia (Physiologic Jaundice of Newborn) Cause: Immature UDP-Glucuronosyltransferase. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Jaundice is usually first seen 4872 hours postpartum in neonatal hyperbilirubinemia. Hyperbilirubinemia Symptoms. Gilberts syndrome is mainly due to the genetic defect in the gene which causes the deficiency of UDP glucouronyl transferase.. Pathologic hyperbilirubinemia in term infants is diagnosed if. Gilbert syndrome is an inherited genetic condition in which a person has slightly high levels of bilirubin pigment, because the liver does not process it properly. Hyperbilirubinemia - Hyperbilirubinemia is an excess accumulation of bilirubin in the blood; another term for jaundice. Gilbert syndrome is a relatively mild condition characterized by periods of elevated levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). Inherited disorders causing excessive bilirubin production, reduced glucuronidation, defective canalicular excretion, or abnormal reuptake can cause hyperbilirubinemia. Yellowing of the skin and whites of the eyes. The most common inherited cause of unconjugated hyperbilirubinemia, it occurs in 3-7% of the worlds population. Normal Transition Seen in Newborn. These conditions may first become apparent during the early years of childhood. Hemolytic disorders are either inherited or acquired. [2] The breakdown of heme molecules in This leads to fluctuating levels of bilirubin in the blood, sometimes causing levels to be high (hyperbilirubinemia). The direct Coombs test is usually positive. This rare inherited liver disorder is caused by deficiency of the enzyme glucuronyl transferase (UGT1A1), which catalyzes the conjugation of bilirubin (mainly to bilirubin diglucuronide) to render bilirubin water soluble. These include disorders resulting in predominantly unconjugated hyperbilirubinemia (Crigler-Najjar syndrome types I and II, and Gilbert syndrome) and those resulting in predominantly conjugated hyperbilirubinemia (Dubin-Johnson syndrome, Rotor syndrome, and benign recurrent intrahepatic cholestasis). Inherited disorders of bilirubin metabolism involve four autosomal recessive syndromes: Gilbert, Crigler-Najjar, Dubin-Johnson and Rotor, among which the first two are characterized by unconjugated and the second two by conjugated hyperbilirubinemia. 79 (3):378-86. . Pathologic elevation of conjugated or direct bilirubin (concentration higher than 2 mg/dL or more than 20% of total bilirubin) is termed conjugated hyperbilirubinemia. Italian guidelines for the management and treatment of neonatal cholestasis. It usually causes very severe hyperbilirubinemia and kernicterus, leading to death within eighteen months after birth. Newborn jaundice occurs when a baby has a high level of bilirubin in the blood. An autosomal recessive inherited disorder characterized by unconjugated hyperbilirubinemia, resulting in harmless intermittent jaundice. This condition results from increased production, impaired hepatic uptake, or decreased conjugation of bilirubin. This type of jaundice is characterized by an increased conjugated bilirubin >1.5 mg/dL (24 mol/L). A new elevation of bilirubin in patients with chronic hepatitis (even if its mild) should be taken seriously. Hypercalcemia - Elevated blood calcium level greater than 10.5mg/dL; a consequence of hyperparathyroidism, cancers, dehydration, or diuretics. Patients with hyperbilirubinemia generally have a good prognosis. van Dijk R, Beuers U, Bosma PJ. Neonatal jaundice is a yellow discoloration of the skin and mucous membranes as a result of raised bilirubin levels occurring in the first 28 days of life. Glucose-6-phosphate Dehydrogenase Deficiency The association of hyperbilirubinemia with G6PD deficiency is clear: of the infants who develop the syndrome or go on to develop kernicterus there is a disproportionate number with G6PD deficiency several times the percentage in the general population and rising in some studies to 20-30% of readmissions for hyperbilirubinemia. There is a risk of the development of kernicterus. Reduced hepatic bilirubin clearance can be due to defective 1) unconjugated bilirubin uptake and intrahepatic storage, 2) conjugation of glucuronic acid to Does this test pose any risks? Hyperbilirubinemia is a common finding in neonates. The result is an impairment in OBJECTIVES: Hereditary spherocytosis (HS) is the most common inherited hemolytic disease among people of Northern European decent. Bilirubin Metabolism and Related Disorders. Gene replacement Hepatocellular injury Crigler-Najjar syndrome, Type I), patients die in infancy or around the age of puberty from bilirubin induced brain damage. It occurs when the body does not properly break down (metabolize) a certain form of bilirubin. G6PD deficiency can lead to an increased risk and earlier onset of hyperbilirubinemia, 24, 25 which may require phototherapy or exchange transfusion. Bilirubin is a waste product that is created during the destruction of old red blood cells. Gilbert syndrome is inherited as an autosomal recessive trait. The hyperbilirubinemia that can occur when using indinavir or atazanavir is similar to that of the inherited condition called Gilberts syndrome, which can affect as much as 10 percent of some Caucasian population groups. It also decreases the amount of In Crigler-Najjar syndrome, jaundice is apparent at birth or in infancy. Newborns in low- and middle-income countries are typically at a greater risk of severe jaundice, or neonatal hyperbilirubinemia, because of the This increase bilirubin is the unconjugated one which is accumulated in the liver. Monarchs tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. What is bilirubin? Liver enzymes are frequently checked during inpatient hospitalization, and elevated serum bilirubin is a common finding. [1] Approximately 80% of the bilirubin is derived from hemoglobin metabolism. Various defects in the gene coding for the enzyme cause complete (type 1) or partial (type 2) inactivation of the enzyme. Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. 14. Prolonged jaundice is defined as a serum bilirubin level higher than 85 mol/L (5 mg/dl), which persists at postnatal 14 days in term infants and 21 days following the birth in preterm infants. autosomal recessive defect in bilirubin glucuronidation and is the most common inherited disorder of bilirubin conjugation leading to recurrent episodes of unconjugated hyperbilirubinemia. Abstract. Gilberts syndrome is the most common inherited cause of unconjugated hyperbilirubinemia. Gilbert's syndrome is an inherited (genetic) liver disorder that affects the bodys ability to process bilirubin. Low levels of bilirubin in the newborn is common and does not cause any trouble and will resolve on its own in the first week of life. 2018;98(6):354361. detoxification. Conjugated hyperbilirubinemia results from inherited disorders in canalicular transport of conjugated bilirubin, such as Dubin-Johnson syndrome and Rotor syndrome. Gunn rats are an animal model of Crigler-Najjar syndrome, Type I. Gilberts syndrome is an inherited liver condition in which your liver cant fully process a compound called bilirubin. Conjugated hyperbilirubinemia is defined as a measure of direct reacting bilirubin of >1.0 mg/dL, if the total serum bilirubin (TSB) is 5.0 mg/dL, or more than 20% TSB. Bile duct scarring. Inherited disorders of bilirubin clearance. The most frequent sign of Gilbert syndrome is an occasional yellowish tinge of the skin and the whites of the eyes as a result of slightly higher levels of bilirubin in the blood. The term Jaundice comes from the French word jaundice, which means yellow; thus a jaundiced baby is one whose skin color appears yellow due to bilirubin. Type 1(Congenital non-hemolytic jaundice), There is severe deficiency of UDP glucuronyl transferase. infectious causes, inherited metabolic conditions, and sepsis. Conjugated hyperbilirubinemia. Gilbert syndrome occurs in 2%-10% of general population, while others are rare. Fasting or eating a very low-calorie diet. Hyperbilirubinemia. Common causes include, but are not limited to, the following. Certain rare inherited diseases. Too much bilirubin in infants could lead to jaundice. Hyperbilirubinemia can also be caused by impaired bilirubin conjugation due to polymorphisms and mutations in genes involved in bilirubin metabolism (eg, UGT1A1). Biliverdin is The most important cause is idiopathic neonatal hepatitis and biliary atresia. ICD-10-CM E80.4 is grouped within Diagnostic Related Group(s) (MS-DRG v 39.0): 441 Disorders of liver except malignancy, cirrhosis or alcoholic hepatitis with mcc; Bilirubin is yellow liquid waste that occurs naturally as the body breaks down old red blood cells. Questions to Consider. The serum bilirubin level required to cause jaundice varies with skin tone and body region, but jaundice usually becomes visible on the sclera at a level of 2 to 3 mg/dL (34 to 51 micromol/L) and on the face at about 4 to 5 mg/dL (68 to 86 micromol/L). While the unconjugated Jaundice in an infant or older child may reflect accumulation of either unconjugated or conjugated bilirubin and could be related to inherited bilirubin disorders. All are inherited disorders in which there is a high bilirubin but there are important differences. In-Depth Information. With hyperbilirubinemia, the excessive buildup of bilirubin can manifest with symptoms of jaundice, including: 1. Your liver breaks down MRCP Revision Guides. The genesis of significant neonatal hyperbilirubinemia [total serum bilirubin (TSB) 17 mg/dL (291 mol/L)] is characterized by etiologic heterogeneity, environmental modulation, and the interaction of multiple gene loci (2-6).Comprehensive reviews of specific genetic contributors to neonatal jaundice have been published and suggest that in addition to inherited A 68-year-old man with Gilbert's syndrome was referred for evaluation of fatigue and pancytopenia. Several inherited disorders may interfere with the processing of bilirubin by the liver, including Gilbert syndrome, Crigler-Najjar syndrom, Dubin-Johnson syndrom or Rotor syndrome, according to MedlinePlus, a publication of the National Institutes of Health 2. Hereditary hyperbilirubinemia refers to the condition where levels of bilirubin are elevated, for reasons that can be attributed to a metabolic disorder. Neonatal jaundice is treated by phototherapy. Its prevalence rate in white populations, where it has been studied most, is estimated at 10%. Neonates with HS can develop significant hyperbilirubinemia, but we suspect that HS is underrecognized as a cause of neonatal jaundice.METHODS: We used electronic record repositories of Intermountain Healthcare to Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. Unconjugated hyperbilirubinemia refers to increased levels of unconjugated bilirubin. Cause: Mild UDP-Glucuronosyltransferase Defect. There is a defect in the conjugation. Takes 14 Weeks to Reach Adult Levels. Jaundice may not be apparent until adolescence. Bilirubin has an orange-yellow tint, and hyperbilirubinemia causes yellowing of the skin and whites of the eyes (jaundice). Hyperbilirubinemia in Myelodysplastic Syndromes. Low levels of bilirubin in the newborn is common and does not cause any trouble and will resolve on its own in the first week of life. Gilberts syndrome is an inherited disorder that runs in families (which means that it is hereditary). 2016 Mar. Jaundice appears in the first 24 hours, after the first week of life, or lasts > 2 weeks. Other articles where hyperbilirubinemia is discussed: blood group: Blood groups and disease: Hyperbilirubinemia (an increased amount of bilirubin, a breakdown product of hemoglobin, in the blood) may lead to neurological deficits. Infants with a cephalohematoma or excessive bruising may develop Unconjugated hyperbilirubinemia can result from increased production, impaired conjugation, or impaired hepatic uptake of bilirubin, a yellow bile pigment produced from hemoglobin during erythrocyte destruction. (See Epidemiology .) Gilbert syndrome occurs in 2%-10% of general popula-tion, while others are rare. Neonates with HHA and co-inherited variants impairing bilirubin conjugation are at increased risk of bilirubin-associated toxicity. Neonatal jaundice can be classified as: Unconjugated hyperbilirubinemia. Serum bilirubin levels may rise up to 30 mg/dL. Bilirubin in the urine is indicative of the presence of conjugated hyperbilirubinemia. Which form of hyperbilirubinemia is caused by an inherited absence of UDP-glucuronyl transferase? Abstract. 3. It has a prevalence of 26%. Abstract. Menkes disease (MD) is an inherited X-linked recessive disorder that affects many systems in the body. 2016 Mar. It is estimated that one in every 10,000 to 15,000 babies is born with PKU in the U.S. Hyperbilirubinemia and Jaundice. Darkening of urine, sometimes to a brownish tone. Disturbances in the bilirubin metabolisms result in accumulation of bilirubin in the liver and blood, and consequently cause hyperbilirubinemia detected by routine serum biochemistry test, or called jaundice clinically. Classification These two categories may represent different mechanisms causing jaundice. In people with Gilbert syndrome, bilirubin levels may increase due to: Illness, such as a cold or the flu. Indir-ect hyperbilirubinemia typically results from increased Inherited conditions can lead to hemolytic anemia. Excess bilirubin is known as hyperbilirubinemia. Inherited disorders of hyperbilirubinemia may be caused by increased bilirubin production or decreased bilirubin clearance. They are both problems in liver enzymes that conjugate bilirubin. (hyperbilirubinemia). Pharmacology and Therapeutics. Low levels of bilirubin are often not a concern. It is caused by either a genetic mutation or a deletion of certain key gene fragments. [QxMD MEDLINE Link]. A condition where there is a high level of bilirubin in the blood. Thalassemia is an inherited disease, meaning that at least one of the parents must be a carrier for the disease. Other, rare causes of discolored nails include the "yellow nail syndrome," an inherited condition that results in slow-growing, yellowing, (Hyperbilirubinemia) Jaundice or hyperbilirubinemia in adults is caused by an underlying disease or condition. Exposing the skin of newborns to light of 450nm causes conversion of bilirubin to a more polar, water soluble isomer that can be excreted in bile without conjugation. By definition, bilirubin levels in Gilbert syndrome are lower than 6 mg/dL, though most patients exhibit levels lower than 3 mg/dL. Excretion of conjugated bilirubin is impaired in a number of acquired conditions (such as alcoholic and viral hepatitis, biliary obstruction, cholestasis of pregnancy) and in inherited disorders (such as Dubin-Johnson syndrome, Rotor syndrome, benign recurrent intrahepatic cholestasis). Reduced hepatic bilirubin clearance can be due to defective (i) unconjugated bilirubin uptake and intrahepatic storage, (ii) conjugation of glucuronic acid to bilirubin (e.g., Gilbert syndrome, Crigler-Najjar syndrome, Lucey-Driscoll syndrome, breast milk Inherited Hyperbilirubinemia. Jaundice is a common symptom of inherited or acquired liver diseases of various causes. Expanded newborn screening, including infectious and metabolic diseases, was also negative. The pathological jaundice may be acquired or inherited. For example, sickle cell anemia leads to crescent-shaped rather than normal disc-shaped red blood cells. Why does bilirubin increase in blood?Damage to the liver. For this reason, many medical specialists consider that the bilirubin analysis in blood is very useful to evaluate the presence or not of possible liver damage.Conditions of the gallbladder or pancreas. But bilirubin (particularly direct bilirubin) not only increases when there is a problem in the liver.Hemolytic anemia. What causes high bilirubin?Gallstones. Gallstones happen when substances like cholesterol or bilirubin harden in your gallbladder. Gilberts Syndrome. Gilberts syndrome is a genetic liver condition that causes your liver to not process bilirubin properly.Liver dysfunction. Hepatitis. Bile duct inflammation. Intrahepatic cholestasis of pregnancy. Hemolytic anemia. Examination revealed scleral icterus. Jaundice develops due to increase the level of bilirubin and deposition under the skin and cause the yellow discoloration of the skin. Inherited disorders of bilirubin clearance. Various defects in the gene coding for the enzyme cause complete (type 1) or partial (type 2) inactivation of the enzyme. If the liver is the source of the issue, pale, clay-colored stools can be present. An inherited autosomal recessive disorder characterized by the presence of mild jaundice due to abnormalities in the bilirubin transportation from the liver parenchyma to the biliary system. Etiologies of inherited bilirubin metabolism disorders causing indirect hyperbilirubinemia. Affected infants are often born prematurely and may have non-specific symptoms such as hypothermia, hypoglycemia, and prolonged jaundice. Hyperbilirubinemia is a biochemical finding but jaundice is a clinical finding for increased bilirubin levels in the blood. The combination of the two gene mutations has been shown to significantly increase the incidence of hyperbilirubinemia in a dose-dependent manner . This child was presented with indirect hyperbilirubinemia (jaundice without high coloured urine) suggestive of hemolysis of long standing duration. 2. Jaundice can be a hallmark seen in many, although not all, causes of indirect hyperbilirubinemia. The test is done with a blood sample. Bilirubin levels rapidly build up in the body. They result from abnormal uptake, conjugation or excretion of bilirubin due to inherited defects. Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). Inherited disorders of bilirubin metabolism result in hyperbilirubinemia. Occurs when ,serum bilirubin >2 mg/dl Yellowing of the skin, scleras (white of the eye), and mucous membranes (jaundice) A sufficient elevation of bilirubin produces jaundice. Crigler-Najjar syndrome is a severe condition characterized by high levels of a toxic substance called bilirubin in the blood (hyperbilirubinemia). The hemolysis suggests a following differential diagnosis Hereditary spherocytosis or other RBC membrane defects. The high levels are poisonous to the brain and can cause death. Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). Bilirubin is produced when red blood cells are broken down. Crigler-Najjar Syndrome: Enzyme deficiency: UDP glucuronyl transferase. (5) Elevated level of bilirubin in infants. Pediatrics 2004;114: e130-e153. If jaundice is due to cholestasis, there will be a rise in total bilirubin, most of which will be conjugated. Gilbert syndrome is associated with a defect in bilirubin uptake and the genetic mechanism is not fully understood. Increased bilirubin productionImpaired bilirubin uptakeImpaired bilirubin conjugation G-6-PD deficiency Autoimmune hemolytic anemia Inherited hemoglobinopathy Introduction. It is thought to be caused by an increased concentration of beta-glucuronidase in breast milk, causing an increase in the deconjugation and reabsorption of bilirubin. Patients with this type of illness have a defective UGT1A1 gene which causes the liver to have difficulties eliminating bilirubin from the bloodstream. In some individuals, jaundice may only be apparent when triggered by one of these conditions. Hyperbilirubinemia can be reversed by discontinuing atazanavir. Increased bilirubin production may be associated with hemolysis, ineffective erythropoiesis, or resorption of a hematoma. This inherited chronic Jaundice disorder results in conjugated hyperbilirubinemia secondary to a defect in the canalicular transport of organic anions. 1) Bilirubin is produced from the catabolism of protoporphyrin IX by a microsomal enzyme in a two reaction step. The first step involves the opening of the tetrapyrrole ring to form biliverdin. Isolated conjugated hyperbilirubinemia: Consider testing for inherited hyperbilirubinemia (e.g., Dubin-Johnson syndrome, Rotor syndrome) in consultation with a specialist. Article Details. Jaundice occurs when bilirubin starts to build up in the blood. Pediatr Res. Newborns have transient hyperbilirubinemia that normally resolves in 12 weeks, but can be prolonged or exacerbated by breast-feeding, delayed UGT1A1 maturation, or