Neonatal Hyperbilirubinemia

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Neonatal Hyperbilirubinemia
Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). 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 μmol/L) and on the face at about 4 to 5 mg/dL (68 to 86 μmol/L). With increasing bilirubin levels, jaundice seems to advance in a head-to-foot direction, appearing at the umbilicus at about 15 mg/dL (258 μmol/L) and at the feet at about 20 mg/dL (340 μmol/L). Slightly more than half of all neonates become visibly jaundiced in the first week of life. Consequences of hyperbilirubinemia: Hyperbilirubinemia may be harmless or harmful depending on its cause and the degree of elevation. Some causes of jaundice are intrinsically dangerous whatever the bilirubin level. But hyperbilirubinemia of any etiology is a concern once the level is high enough. The threshold for concern varies by age (see Fig. 1: Metabolic, Electrolyte, and Toxic Disorders in Neonates: Risk of hyperbilirubinemia in neonates ≥ 35 wk gestation. mg/dL (>308 μmol/L). Kernicterus (see Metabolic, Electrolyte, and Toxic Disorders in Neonates: Kernicterus) is the major consequence of neonatal hyperbilirubinemia. Although it is now rare, kernicterus still occurs and can nearly always be prevented. Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei, caused by either acute or chronic hyperbilirubinemia. Normally, bilirubin bound to serum albumin stays in the intravascular space. However, bilirubin can cross the blood-brain barrier and cause kernicterus 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

), degree of prematurity, and health

status; however, in term infants, the threshold typically is considered to be a level > 18

Competitive binders include drugs (eg, sulfisoxazole

, ceftriaxone

, aspirin

) and free fatty acids and hydrogen ions (eg, in fasting, septic, or acidotic infants).

Fig. 1

Risk of hyperbilirubinemia in neonates ≥ 35 wk gestation.

Risk is based on total serum bilirubin levels. (Adapted from Bhutani VK, Johnson L, Sivieri EM: Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 103 (1):6–14, 1999.)

Pathophysiology
The majority of bilirubin is produced from the breakdown of Hb 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. The conjugated bilirubin is excreted in bile into the duodenum. In adults, conjugated bilirubin is reduced by gut bacteria to urobilin and excreted. Neonates, however, have sterile digestive tracts. They do have the enzyme βglucuronidase, which deconjugates the conjugated bilirubin, which is then reabsorbed by the intestines and recycled into the circulation. This is called enterohepatic circulation of bilirubin (seePerinatal Physiology: Bilirubin metabolism). Mechanisms of hyperbilirubinemia: 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

Etiology
Classification: There are several ways to classify and discuss causes of hyperbilirubinemia. Because transient jaundice is common among healthy neonates

(unlike adults, in whom jaundice always signifies a disorder), hyperbilirubinemia can be classified as physiologic or pathologic. It can be classified by whether the hyperbilirubinemia is unconjugated, conjugated, or both. It also can be classified by mechanism (see Table 1: Metabolic, Electrolyte, and Toxic Disorders in Neonates: Causes of Neonatal Hyperbilirubinemia ).

Causes: Most cases involve unconjugated hyperbilirubinemia. Some of the most common causes of neonatal jaundice include
• • • • Physiologic hyperbilirubinemia Breastfeeding jaundice Breast milk jaundice Pathologic hyperbilirubinemia due to hemolytic disease

Liver dysfunction (eg, caused by parenteral alimentation causing cholestasis, neonatal sepsis, neonatal hepatitis) may cause a conjugated or mixed hyperbilirubinemia. Physiologic hyperbilirubinemia occurs in almost all neonates. Shorter neonatal RBC life span increases bilirubin production; deficient conjugation due to the deficiency of UGT decreases clearance; and low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation. Bilirubin levels can rise up to 18 mg/dL by 3 to 4 days of life (7 days in Asian infants) and fall thereafter. Breastfeeding jaundice develops in one sixth of breastfed infants in the first week of life. Breastfeeding increases enterohepatic circulation of bilirubin in some infants who have decreased milk intake and who also have dehydration or low caloric intake. The increased enterohepatic circulation also may result from reduced intestinal bacteria that convert bilirubin to nonresorbed metabolites. Breast milk jaundice is different from breastfeeding jaundice. It develops after the first 5 to 7 days of life and peaks at about 2 wk. It is thought to be caused by an increased concentration of β-glucuronidase in breast milk, causing an increase in the deconjugation and reabsorption of bilirubin. Pathologic hyperbilirubinemia in term infants is diagnosed if

• • •


Jaundice appears in the first 24 h, after the first week of life, or lasts > 2 wk Total serum bilirubin (TSB) rises by > 5 mg/dL/day TSB is > 18 mg/dL Infant shows symptoms or signs of a serious illness

Some of the most common pathologic causes are
• Immune and nonimmune hemolytic anemia

• • • •

G6PD deficiency Hematoma resorption Sepsis Hypothyroidism

Table 1

Causes of Neonatal Hyperbilirubinemia
Mechanism
Increased enterohepatic circulation

Causes
Breast milk (breast milk jaundice) Breastfeeding failure (breastfeeding jaundice) Drug-induced paralytic ileus (Mg sulfate or morphine

) Fasting or other cause for hypoperistalsis Hirschsprung's disease Intestinal atresia or stenosis, including annular pancreas Meconium ileus or meconium plug syndrome Pyloric stenosis* Swallowed blood Overproduction Breakdown of extravascular blood (eg, hematomas; petechiae; pulmonary, cerebral, or occult hemorrhage) Polycythemia due to maternofetal or fetofetal transfusion or delayed umbilical cord clamping Overproduction due to hemolytic anemia Certain drugs and agents in neonates with G6PD deficiency (eg, acetaminophen

, alcohol, antimalarials, aspirin

,bupivacaine

, corticosteroids, diazepam

,nitrofurantoin

, oxytocin

, penicillin, phenothiazine, sulfonamides) Maternofetal blood group incompatibility (eg, Rh, ABO) RBC enzyme deficiencies (eg, of G6PD or pyruvate kinase) Spherocytosis Thalassemias (α, β–γ) Undersecretion due to biliary obstruction α1-Antitrypsin deficiency* Biliary atresia* Choledochal cyst* Cystic fibrosis* (inspissated bile) Dubin-Johnson syndrome and Rotor's syndrome* (seeApproach to the Patient with Liver Disease: DubinJohnson syndrome) Parenteral nutrition Tumor or band* (extrinsic obstruction) Undersecretion due to metabolicendocrine conditions Crigler-Najjar syndrome (familial nonhemolytic jaundice types 1 and 2—see Approach to the Patient with Liver Disease: Crigler-Najjar Syndrome) Drugs and hormones Gilbert syndrome (see Approach to the Patient with Liver Disease: Gilbert Syndrome) Hypermethioninemia Hypopituitarism and anencephaly Hypothyroidism Lucey-Driscoll syndrome Maternal diabetes

Prematurity Tyrosinosis Mixed overproduction and undersecretion Asphyxia Intrauterine infections Maternal diabetes Respiratory distress syndrome Sepsis Severe erythroblastosis fetalis Syphilis TORCH infections

*Jaundice may also occur outside the neonatal period. TORCH = toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex. Adapted from Poland RL, Ostrea EM Jr: Neonatal hyperbilirubinemia. In Care of the High-Risk Neonate, ed. 3, edited by MH Klaus and AA Fanaroff. Philadelphia, WB Saunders Company, 1986.

Evaluation
History: History of present illness should note age of onset and duration of jaundice. Important associated symptoms include lethargy and poor feeding (suggesting possible kernicterus), which may progress to stupor, hypotonia, or seizures and eventually to hypertonia. Patterns of feeding can be suggestive of possible breastfeeding failure or underfeeding. Therefore, history should include what the infant is being fed, how much and how frequently, urine and stool production (possible breastfeeding failure or underfeeding), how well the infant is latching on to the breast or taking the nipple of the bottle, whether the mother feels that her milk has come in, and whether the infant is swallowing during feedings and seems satiated after feedings. Review of systems should seek symptoms of causes, including respiratory distress, fever, and irritability or lethargy (sepsis); hypotonia and poor feeding (hypothyroidism, metabolic disorder); and repeated episodes of vomiting (intestinal obstruction). Past medical history should focus on maternal infections (toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex [TORCH] infections), disorders that can cause early hyperbilirubinemia (maternal diabetes), maternal Rh factor and blood group (maternofetal blood group incompatibility), and a history of a prolonged or difficult birth (hematoma or forceps trauma). Family history should note known inherited disorders that can cause jaundice, including G6PD deficiency, thalassemias, and spherocytosis, and also any history of siblings who have had jaundice.

Drug history should specifically note drugs that may promote jaundice (eg, ceftriaxone

, sulfonamides, antimalarials). Physical examination: Overall clinical appearance and vital signs are reviewed. The skin is inspected for extent of jaundice. Gentle pressure on the skin can help reveal the presence of jaundice. Also, ecchymoses or petechiae (suggestive of hemolytic anemia) are noted. The physical examination should focus on signs of causative disorders. The general appearance is inspected for plethora (maternofetal transfusion); macrosomia (maternal diabetes); lethargy or extreme irritability (sepsis or infection); and any dysmorphic features such as macroglossia (hypothyroidism) and flat nasal bridge or bilateral epicanthal folds (Down syndrome). For the head and neck examination, any bruising and swelling of the scalp consistent with a cephalohematoma are noted. Lungs are examined for rales, rhonchi, and decreased breath sounds (pneumonia). The abdomen is examined for distention, mass (hepatosplenomegaly), or pain (intestinal obstruction). Neurologic examination should focus on signs of hypotonia or weakness (metabolic disorder, hypothyroidism, sepsis). Red flags: The following findings are of particular concern:
• Jaundice in the first day of life TSB > 18 mg/dL Rate of rise of TSB > 0.2 mg/dL/h (> 3.4 μmol/L/h) or > 5 mg/dL/day Conjugated bilirubin concentration > 1 mg/dL (> 17 μmol/L) if TSB is < 5 mg/dL or >20% of TSB (suggests neonatal cholestasis) Jaundice after 2 wk of age Lethargy, irritability, respiratory distress

• • •
• •

Interpretation of findings: Evaluation should focus on distinguishing physiologic from pathologic jaundice. History, physical examination, and timing can help (see Table 2:Metabolic, Electrolyte, and Toxic Disorders in Neonates: Physical Findings in Neonatal Jaundice ), but typically TSB and conjugated serum bilirubin levels are measured.

Timing: Jaundice that develops in the first 24 to 48 h, or that persists > 2 wk, is most likely pathologic. Jaundice that does not become evident until after 2 to 3 days is more consistent with physiologic, breastfeeding, or breast milk jaundice. An exception is undersecretion of bilirubin due to metabolic factors (eg, Crigler-Najjar syndrome, hypothyroidism, drugs), which may take 2 to 3 days to become evident. In such cases,

bilirubin typically peaks in the first week, accumulates at a rate of < 5 mg/dL/day, and can remain evident for a prolonged period of time. Because most neonates are now discharged from the hospital or nursery within 48 h, many cases of hyperbilirubinemia are detected only after discharge.

Table 2

Physical Findings in Neonatal Jaundice
Findings
General examination Fever, tachycardia, respiratory distress First 24 h Accumulates > 5 mg/dL/day (> 86μmol/L/day) Lethargy, hypotonia May appear in the first 24–48 h Can be prolonged (> 2 wk) Macrosomia 24–48 h Can accumulate > 5 mg/dL Petechiae First 24 h Accumulates > 5 mg/dL Hemolytic states (eg, maternofetal blood group incompatibility, RBC enzyme deficiencies, hereditary spherocytosis, thalassemias, sepsis) Plethora First 24 h Accumulates > 5 mg/dL Head and neck examination Bilateral slanting palpebral fissures, flat nasal bridge, macroglossia, flattened occiput Cephalohematoma 24–48 h Can accumulate > 5 mg/dL Macroglossia 24–48 h Hypothyroidism Birth trauma First 2–3 days Down syndrome (possible duodenal atresia, Hirschsprung's disease, intestinal obstruction, wide spacing between 1st and 2nd toes) Maternofetal or fetofetal transfusion, delayed umbilical cord clamping Maternal diabetes Hypothyroidism, metabolic disorder Pneumonia, TORCH infection, sepsis

Timing of Jaundice

Cause

Can be prolonged (> 2 wk) Abdominal examination Abdominal distention, decreased bowel sounds Possible delayed manifestation (2–3 days or later) Intestinal obstruction (eg, cystic fibrosis, Hirschsprung's disease, intestinal atresia or stenosis, pyloric stenosis, biliary atresia)

TORCH = toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex.

Testing: Diagnosis is suspected by the infant's color and is confirmed by measurement of serum bilirubin. Noninvasive techniques for transcutaneous measurement of bilirubin levels in infants are being used increasingly, with good correlation with serum bilirubin measurements. Risk of hyperbilirubinemia is based on age-specific TSB levels. A bilirubin concentration > 10 mg/dL (> 170 μmol/L) in preterm infants or > 18 mg/dL in term infants warrants additional testing, including Hct, blood smear, reticulocyte count, direct Coombs' test, TSB and direct serum bilirubin concentrations, and blood type and Rh group of the infant and mother. Other tests, such as blood, urine, and CSF cultures to detect sepsis and measurement of RBC enzyme levels to detect unusual causes of hemolysis, may be indicated by the history and physical examination. Such tests also may be indicated for any neonates with an initial bilirubin level > 25 mg/dL (> 428 μmol/L).

Treatment
Treatment is directed at the underlying disorder. In addition, treatment for hyperbilirubinemia itself may be necessary. Physiologic jaundice usually is not clinically significant and resolves within 1 wk. Frequent formula feedings can reduce the incidence and severity of hyperbilirubinemia by increasing GI motility and frequency of stools, thereby minimizing the enterohepatic circulation of bilirubin. The type of formula does not seem important in increasing bilirubin excretion. Breastfeeding jaundice may be prevented or reduced by increasing the frequency of feedings. If the bilirubin level continues to increase > 18 mg/dL in a term infant with early breastfeeding jaundice, a temporary change from breast milk to formula may be appropriate; phototherapy also may be indicated at higher levels. Stopping breastfeeding is necessary for only 1 or 2 days, and the mother should be encouraged to continue expressing breast milk regularly so she can resume nursing as soon as the infant's bilirubin level starts to decline. She also should be assured that the

hyperbilirubinemia has not caused any harm and that she may safely resume breastfeeding. It is not advisable to supplement with water or dextrose because that may disrupt the mother's production of milk. Definitive treatment involves
• • Phototherapy Exchange transfusion

Phototherapy: This treatment remains the standard of care, most commonly using fluorescent white light. (Blue light is most effective for intensive phototherapy.) Phototherapy is the use of light to photoisomerize unconjugated bilirubin into forms that are more water-soluble and can be excreted rapidly by the liver and kidney without glucuronidation. It provides definitive treatment of neonatal hyperbilirubinemia and prevention of kernicterus. Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 25 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at > 72 h (see Fig. 1: Metabolic, Electrolyte, and Toxic Disorders in Neonates: Risk of hyperbilirubinemia in neonates ≥ 35 wk gestation. ). Phototherapy is not indicated for conjugated

hyperbilirubinemia. Because visible jaundice may disappear during phototherapy, though serum bilirubin remains elevated, skin color cannot be used to evaluate jaundice severity. Blood taken for bilirubin determinations should be shielded from bright light, because bilirubin in the collection tubes may rapidly photo-oxidize. Exchange transfusion: This treatment can rapidly remove bilirubin from circulation and is indicated for severe hyperbilirubinemia, which most often occurs with immunemediated hemolysis. Small amounts of blood are withdrawn and replaced through an umbilical vein catheter to remove partially hemolyzed and antibody-coated RBCs as well as circulating Igs. These then are replaced with uncoated donor RBCs. Only unconjugated hyperbilirubinemia can cause kernicterus, so if conjugated bilirubin is elevated, the level of unconjugated rather than total bilirubin is used to determine the need for exchange transfusion. Specific indications are serum bilirubin ≥ 20 mg/dL at 24 to 48 h or ≥ 25 mg/dL at > 48 h and failure of phototherapy to result in a 1- to 2-mg/dL (17- to 34-μmol/L) decrease within 4 to 6 h of initiation or at the first clinical signs of kernicterus regardless of bilirubin levels. If the serum bilirubin level is > 25 mg/dL when the neonate is initially examined, preparation for an exchange transfusion should be made in case intensive phototherapy fails to lower the bilirubin level. An alternative approach uses the weight of the neonate in grams divided by 100 to determine the bilirubin level (in mg/dL) at which exchange transfusion is indicated. Thus, a 1000-g neonate would receive an exchange transfusion at a bilirubin level of ≥ 10 mg/dL, and a 1500-g neonate would receive an exchange transfusion at a bilirubin level of ≥ 15 mg/dL.

Most often, 160 mL/kg (twice the infant's total blood volume) of packed RBCs is exchanged over 2 to 4 h; an alternative is to give 2 successive exchanges of 80 mL/kg each over 1 to 2 h. To do an exchange, 20 mL of blood is withdrawn and then immediately replaced by 20 mL of transfused blood; this procedure is repeated until the total desired volume is exchanged. For critically ill or premature infants, aliquots of 5 to 10 mL are used to avoid sudden major changes in blood volume. The goal is to reduce bilirubin by nearly 50%, with the knowledge that hyperbilirubinemia may rebound to about 60% of pretransfusion level within 1 to 2 h. It is also customary to lower the target level by 1 to 2 mg/dL in conditions that increase the risk of kernicterus (eg, fasting, sepsis, acidosis). Exchange transfusions may need to be repeated if bilirubin levels remain high. Finally, there are risks and complications with the procedure, and the success of phototherapy has reduced the frequency of exchange transfusion.

Key Points
• • • • • Neonatal jaundice is caused by increased bilirubin production, decreased bilirubin clearance, or increased enterohepatic circulation. Some jaundice is normal in neonates. Risk varies with postnatal age, TSB value, prematurity, and health of the neonate. Treatment depends on cause and degree of elevation. Definitive treatments include phototherapy and exchange transfusion.

KERNICTERUS
(Bilirubin Encephalopathy) Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei. Normally, bilirubin bound to serum albumin stays in the intravascular space. However, bilirubin can cross the blood-brain barrier and cause kernicterus when serum bilirubin concentration is markedly elevated; serum albumin concentration is markedly low (eg, in preterm infants); or bilirubin is displaced from albumin by competitive binders (eg,sulfisoxazole

, ceftriaxone

, and aspirin

; free fatty acids and hydrogen ions in fasting, septic, or acidotic infants).

In preterm infants, kernicterus may not cause recognizable clinical symptoms or signs. Early symptoms in term infants are lethargy, poor feeding, and vomiting. Opisthotonos, oculogyric crisis, seizures, and death may follow. Kernicterus may result in intellectual disability, choreoathetoid cerebral palsy, sensorineural hearing loss, and paralysis of upward gaze later in childhood. It is unknown whether minor degrees of kernicterus can cause less severe neurologic impairment (eg, perceptual-motor problems, learning disorders). There is no reliable test to determine the risk of kernicterus, and the diagnosis is made presumptively. A definite diagnosis can be made only by autopsy. There is no treatment once kernicterus develops; it can be prevented by treating hyperbilirubinemia (see Metabolic, Electrolyte, and Toxic Disorders in Neonates: Neonatal Hyperbilirubinemia).
Last full review/revision December 2009 by Nicholas Jospe, MD

http://www.merckmanuals.com/professional/sec19/ch274/ch274b.html

Content last modified December 2009

HYPERBILIRUBINEMIA Definition: Hyperbilirubinemia is one of the most common problems encountered in newborns. Jaundice is observed during the first week of life in approximately 60% of term infants and 80% of preterm infants. It results from the deposition of unconjugated bilirubin pigment in the skin and mucus membranes. Hyperbilirubinemia is defined as a total serum bilirubin level greater than 5 mg/dL. It is difficult to predict the level of serum bilirubin by examination alone. The primary concern of hyperbilirubinemia is the neurotoxic and cell injury that may result from high levels. Risk factors for Neonatal Hyperbilirubinemia 1. Race- Asian, Native Americans, Mediterranean 2. Complications during pregnancy 3. Non-optimal Breast feeding 4. Birth Trauma, bruising, and cephalahematomas 5. Infections and sepsis 6. Prematurity 7. Genetic factors such as G6PD deficiency and a family history of sibling who was jaundiced as a neonate 8. Drug exposure 9. Blood type incompatibility Causes of Hyperbilirubinemia: 1. Increased bilirubin production a. Hemolytic causes- increased unconjugated bilirubin,

i. Coombs positive- Rh, ABO, or minor antigen incompatibility ii. Coombs negative- RBC membrane defects (spherocytosis, elliptocytosis), RBC enzyme defects (G6PD, pyruvate kinase deficiency), drugs (streptomycin, vitamin K), hemoglobinopathies, sepsis b. Non-hemolytic causes- increased unconjugated bilirubin, i. Extravascular sources- cephalohematoma, bruising, swallowed blood, CNS hemorrhage ii. Polycythemia- delayed cord clamping, fetal-maternal transfusion, twintwin transfusion iii. Exaggerated enterohepatic circulation- cystic fibrosis, ileal atresia, pyloric stenosis, breast feeding jaundice, Hirschsprung’s disease 2. Decreased bilirubin conjugation- increased unconjugated bilirubin a. Physiologic jaundice b. Crigler-Najjar syndrome types 1 and 2- decreased conjugation c. Gilbert syndrome-decreased liver uptake d. Hypothyroidism 3. Impaired bilirubin excretion a. Biliary obstruction- biliary atresia, choledochal cyst, PSC, gallstones, neoplasm, Dubin-Johnson syndrome, Rotor’s syndrome b. Infection- sepsis, UTI, TORCH c. Metabolic disorder- alpha1-antitrypsin deficiency, cystic fibrosis, galactosemia, glycogen storage disease, hypothyroidism d. Chromosomal abnormality- Turner’s syndrome, trisomy 18/21 e. Drugs- aspirin, acetaminophen, rifampin, alcohol, corticosteroids Jaundice and Breastfeeding a. Breastfeeding jaundice occurs during the first week of life due to inadequate breastfeeding. The subsequent dehydration and reduced caloric intake can increase the intensity of jaundice in the neonate. Frequent feedings, rooming-in with night feedings, and discouraging dextrose or water supplementation may help reduce the incidence of breastfeeding jaundice. b. Breast milk jaundice occurs later in the newborn period, usually between the 6th through 14th day of life. Breast milk jaundice is the prolongation of the normal neonatal increased enterohepatic circulation of bilirubin, which is caused by a factor in human milk that promotes intestinal absorption. Physiologic Jaundice: Physiologic jaundice follows a regular pattern in healthy term neonates, usually peaking between the 2nd and 4th day of life to 5-6 mg/dL and then declining over the first week. The increased synthesis and enterohepatic circulation of bilirubin and the transient limitation of bilirubin conjugation in the liver of newborn infants cause it. Kernicterus: Kernicterus is the neurologic consequences of the deposition of unconjugated bilirubin in the basal ganglia and various brainstem nuclei. This occurs when the serum unconjugated bilirubin level exceeds the binding capacity of albumin, allowing unconjugated lipid-soluble bilirubin to cross the blood-brain barrier. Low albumin, infections, acidosis and prematurity may enhance the deposition of bilirubin in the brain. In the acute phase, clinical signs in neonates include lethargy, hypotonia, and poor suck. Later there is hypertonia of the

extensor muscles, opisthotonus, and torticollis. Bilirubin encephalopathy can lead to developmental and motor delays, movement disorders, sensorineural deafness, and mild mental retardation. Treatment of Hyperbilirubinemia 1. Prevention a. Increase oral intake, breast feeding instructions and support b. Early diagnosisi. Detect hemolysis by measuring Carbon Monoxide exhaled ii. Arrange follow-up after early discharge to check neonate c. Synthetic metalloporphyrins may inhibit production of bilirubin (not approved for use) 2. Phototherapy 3. Exchange Transfusion
References:

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Porter ML and Dennis BL. Hyperbilirubinemia in the Term Newborn. American Family Physician. 2002; 65(4): 599-606. Gartner LM and Herschel M. Jaundice and Breastfeeding. Pediatric Clinics of North America. Apr 2001; 48(2): 389-399. American Academy of Pediatrics Subcommittee on Neonatology Neonatal Jaundice and Kernicterus. Pediatrics. Sep 2001; 108(3): 763-765. Behrman: Nelson Textbook of Pediatrics, 16th ed (2002). Philadelphia: W.B. Saunders Company. Dennery Phyllis, Seidman Daniel, and Stevenson David. Neonatal Hyperbilirubinemia NEJM Vol 344 No. 8 Feb 22, 2001 pg 581 American Academy of Pediatrics. Hyerbilirubinemia in the Newborn Period. Pediatrics July 2004 Watchko J. Vigintiphobia Revisited Pediatrics June 2005 Maisel J. A primer on phototherapy for the jaundiced newborn. Contemporary Pediatrics June 2005 Newman T.B. et al. Outcomes among Newborns with Total Serum Bilirubin Levels of 25 mg per Deciliter or More. NEJM May 4, 2006 NEJM May 4, 2006

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10. Watchko J. Neonatal Hyperbilirubinemia-What are the Risks? 11. Maisels. M. Phototherapy for Neonatal Jaundice. 12. Harb R. and Thomas D. Conjugated Hyperbilirubinemia.

NEJM Feb 28, 2008 Pediatrics in Review Marach 2007

http://pedclerk.bsd.uchicago.edu/Hyperbilirubinemia.html
Anatomy and Physiology of the liver Human liver development begins during the third week of gestation and does not acheive mature architecture until about 15 years of age. It reaches its largest relative size, 10% of fetal weight, around the ninth week. It is about 5% of body weight in the healthy neonate. The liver is about 2% of body weight in the adult. It weighs around 1400g in an adult female and about 1800g in the male.* The liver is located in the right upper quadrant of the abdomen, just below the diaphragm. It is almost completely behind the rib cage but the lower edge may be palpated along the right costal margin during inspiration. A connective tissue layer called

Glisson's capsule covers the surface of the liver. The capsule extends to invest all but the smallest the vessels within the liver. *The falciform ligament attaches the liver to the abdominal wall and diaphragm and divides the liver into a larger right lobe and a smaller left lobe. In 1957, the french surgeon Claude Couinaud described 8 liver segments. Since then radiographic studies describe an average of twenty segments based on distribution of blood supply*. Each segment has its own independent vascular and biliary branches. Surgeons utilize these independent segments when performing liver resection for tumor or transplantation. There are at least three reasons why segmental resection is superior to simple wedge resection. First, segmental resection minimizes blood loss because vascular density is reduced at the borders between segments. Second, it results in improved tumor removal for those cancers which are disseminated via intrasegmental branches of the portal vein. Third, segmental resection spares normal liver allowing for repeat partial hepatectomy*. Each segment of the liver is further divided into lobules. Lobules are usually represented as discrete hexagonal aggregations of hepatocytes. The hepatocytes assemble as plates which radiate from a central vein. Lobules are served by arterial, venous and biliary vessels at their periphery. This model is useful for teaching purposes but more closely resembles the adult pig lobule than the human. Human lobules have little connective tissue separating one lobule from another. The paucity of connective tissue makes it more difficult to identify the portal triads and the boundaries of individual lobules. Central veins are easier to identify due to their large lumen and because they lack connective tissue that invests the portal triad vessels. Lobules consist of hepatocytes and the spaces

Phagocytosis Lobules consist of hepatocytes and the spaces between them. Sinusoids are the spaces between the plates of hepatocytes. Sinusoids receive blood from the portal triads. About Red blood cell (RBC) lifespan is about 120 days. Reticuloendothelial (macrophage) cells 25% of total cardiac output enters the sinusoids via terminal portal and arterial vessels. in the spleen, liver and bone marrow are primarily responsible for clearing pathogens and Seventy-five percentare the blood flowing into the liver comes through the portal vein; debris. Kupffer cells of reticuloendothelial cells resident in the liver sinusoids that the remaining 25% is oxygenated blood that is pass through. Hundreds of millionsblood scavange damaged RBCs and bacteria as they carried by the hepatic artery. The of mixes, passes throughthe reticuloendothelial the hepatocytes and drains into the like RBCs are removed by the sinusoids, bathes system every minute. Kupffer cells central vein. About 1.5 liters of blood exit the liver everyand iron. Iron is recycled, globin is other macrophages lyse RBCs into heme, globin minute. further catabolized into polypeptide components for reuse and heme is processed to bilirubin. About 85% of bilirubin is derived from lysis of RBCs, the rest comes from the breakdown of other hemoproteins like myoglobin, cytochromes and peroxidases. Kupffer cells like all macrophages release bilirubin into the blood. In the blood, bilirubin binds to albumin. The albumin/bilirubin compound is small enough to pass through the endothelial fenestrae and into the space of Disse where it contacts the hepatocyte. Hepatocytes cleave bilirubin from albumin and absorb the bilirubin. In the hepatocyte cytoplasm, bilirubin is conjugated to glucouronic acid. Bilirubin uridine diphosphate glucuronyl transferase (UDPGT) catalyzes the bonding of glucuronic acid and bilirubin to produce water-soluble bilirubin. Water soluble conjugated bilirubin is secreted into canaliculi along with water, electrolytes, bicarbonate, bile acids, salts, cholesterol and phospholipids. This combination is called bile and serves as a detergent to keep bile soluble in the biliary tract. Bile drains from the canaliculi>canal of Hering>bile ducts>common hepatic duct>gallbladder>common bile duct>ampulla of vater>duodenum.* In the duodenum, bile salts attach to fat globules forming smaller micelles that collect fatty acids and glycerol. The micelles travel to the jejunum where they deliver their cargo to the intestinal epithelium. Inside the epithelial cells glycerol and fatty acids are rejoined to form triglycerides. Finally triglycerides are joined to cholesterol and proteins are added to the surface; creating a chylomicron. Lipid management*

The liver receives a variety of lipid forms including: chylomicrons remnants, very low density lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL) and fatty acids. Large lipoprotein molecules are broken into smaller units by the lytic action of lipoprotein lipase (LPL) expressed on endothelium of vessels. Circulating lipoproteins small enough to enter the space of Disse attach to receptors on the hepatocyte. These lipoprotein remnants are held near the heptocyte surface and exposed to hepatic lipase compounds. Low Density Lipoprotein receptors transfer the lipoprotein fragments into the hepatocyte by the process of endocytosis.



Chylomicrons are the product of intestinal packaging of dietary fats. Chylomicrons are produced in the duodenal villi and secreted into the lymph lacteals for delivery to the thoracic duct>subclavian vein>superior vena cava>right ventricle>lungs>Left ventricle>aorta>hepatic artery>sinusoid.Chylomicrons range from 75-1200nm in diameter. They contain 98% lipids and 2% protein. Chylomicrons are degraded in the blood by contact with LPL. Chylomicrons become smaller and more dense as fatty acids are stripped off. Loss of fatty acids results in chylomicron remnants of various sizes and density when they finally reach the liver. Hepatic lipase expressed by the hepatic sinusoidal endothelium and hepatocytes continues the remnant degradation. Very low density lipoproteins (VLDL) are synthesized primarily in the hepatocyte. VLDLs range from 30-80nm. They contain 90% lipids and 10% protein.Their purpose is to transport triglycerides made in the liver into plasma for use or storage outside the liver. Low density lipoprotein (LDL) is formed from VLDLs in the plasma by the action of lipase. LDL diameter is about 20nm. They contain 70% lipids and 30% protein. LDLs distribute cholesterol throughout the body. Cholesterol is an important constituent of: VLDL, cell membranes, hormones, bile etc. High density lipoprotein (HDL) are small lipoprotein particles (5-15nm) formed in the liver and intestine. They range from 5-15nm in diameter. They contain 50% lipids and 50% protein. HDLs collect cholesterol & lipoprotein fragments from the blood and blood vessel plaques and return them to the liver for repurposing. Fatty acids are linear hydrocarbon chains that are the major constituents of dietary lipoproteins (triglycerides). The liver degrades lipoproteins with hepatic lipase or synthesizes fatty acids from carbohydrate sources. When carbohydrate energy sources are low fatty acids are oxidized for energy.









Carbohydrate management: When energy intake exceeds energy output the body stores the surplus glucose as glycogen or triglyceride. When energy output exceeds energy intake the body reacts by releasing stored energy as glucose and fatty acids. Glucose is the preferred energy source for most tissues but the body maintains very limited supplies of free circulating glucose. Certain tissues like the brain, RBCs, lens and cornea use glucose almost exclusively. To supply these tissues when blood glucose drops the liver lyses glycogen. Glycogen is a complex molecule composed of thousands of glucose units. Hepatocytes and myocytes store glucose as intracellular glycogen granules. The liver is central to blood glucose management because the liver is the only organ that can store and release glucose into the blood for use by other organs. After a meal the liver removes excess blood glucose and stores up to 8% of its weight as glycogen. Myocytes can store about 1-2% of total muscle mass as glycogen but once glucose enters a myocyte it must be used or stored by that myocyte. The liver uses three metabolic processes to manage carbohydrates and insure adequate blood glucose:

• • •

Glycogenesis - excess glucose, fructose, and galactose are converted to glycogen and stored in the liver. Glycogenolysis - the liver breaks down stored glycogen to maintain blood glucose levels when there is a decrease in carbohydrate intake. Gluconeogenesis - the liver can synthesize glucose from lactic acid, some amino acids and glycerol. When glucose is low the liver can derive energy from the metabolism of fatty acids which can conserve available glucose.

Protein management: Dietary protein is denatured by stomach acids and digested into amino acids in the small intestine. Amino acids are absorbed by the small intestine and delivered to the liver via the portal circulation. Up to 50% of the livers' energy requirements can be supplied by amino acid oxidation. The liver uses dietary amino acids and amino acids resulting from normal tissue breakdown to produce its own proteins and enzymes as well as plasma proteins. Plasma proteins produced by hepatocytes include: albumin, fibrinogen, prothrombin, a-fetoprotein, a2-macroglobin, hemopexin, transferrin, complenent components C3,C6 andC1, a1-antitrypsin, caeruloplasmin.*




About 15-17 g of albumin is synthesized by the normal liver daily.* Patients with decompensated cirrhosis produce only about 4 g per day. a-fetoprotein peaks about 16 weeks gestation and disappears a few weeks after birth. It may reappear in association with chronic hepatitis and a number of carcinomas a1-antitrysin deficiency is inherited a2-macroglobin functions as a protease inhibitor. It is active in the inhibition of thrombin and plasmin. hemopexin transports heme in the plasma protecting tissues from the actions of heme. transferrin transports heme to bone marrow for incorporation into erythroid precursors. complement components assist the immune system raise an immune response. caeruloplasmin is the major copper carrying plasma protein.


• • • • •

Biotransformation Hepatocytes protect the body from injury by biotransforming toxins, drugs and hormones. The liver employs enzymes to make substances more water soluble, so they can be excreted from the body in the urine and feces. In Phase 1 biotransformation the cytochrome P450 enzymes alter the target molecule by adding or exposing functional groups such as -OH or -COOH. Phase 2 biotransformation enzymes add sugars, amino acids, sulfates or acetyl groups to the functional group which makes them more water soluble. Vitamins The liver also plays an important role in vitamin and mineral storage. About 80% of the body's vitamin A stores are concentrated in fat droplets within the stellate cells of the liver. In pathological conditions like hepatic fibrosis or liver cirrhosis the stellate cells lose vitamin A, transform into fibroblasts or myofibroblasts and begin producing large amounts of collagen and adhesive glycoproteins.* Normal vitamin A reserves are enough to prevent deficiency for about 10 months. The liver also contains about a year supply of B12. Vitamin D stores equal about 3-4 months. Small amounts of Vitamins E and K and Vitamin C are stored in the liver to facilitate liver functions.

http://www.rnceus.com/ld/ldanat.html

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