Madhu D. Hardasmalani
• Jaundice within the first 24 hours of life is NEVER normal.
• Urinary tract infections can be associated with the onset of unconjugated hyperbilirubinemia after a week of age.
• Conjugated hyperbilirubinemia is never normal at any age, consider hemolytic disease with unconjugated hyperbilirubinemia beyond the neonatal period.
• Acute cholangitis should be suspected in any patient with fever and jaundice who has had surgical correction of biliary atresia
Hemoglobin released from red blood cells is broken down into heme, and reduced to unconjugated (indirect) bilirubin which is then bound to serum albumin. Unconjugated bilirubin is converted to water-soluble conjugated (direct) bilirubin in the liver and stored in the gallbladder as bile. Bile is released into the intestines to assist in digestion and cholesterol metabolism as well as absorption of lipids and fat-soluble vitamins. Hyperbilirubinemia can be due to an increase in either unconjugated bilirubin or conjugated bilirubin levels. Conditions causing increased red blood cell destruction or decreased conjugation lead to unconjugated hyperbilirubinemia. Conditions that impair secretion of bile from liver or gallbladder result in conjugated hyperbilirubinemia.
The patient’s age and the type of hyperbilirubinemia, whether direct or indirect, are important factors in determining the cause and treatment.
NEONATAL UNCONJUGATED HYPERBILIRUBINEMIA
The most common causes of indirect/unconjugated hyperbilirubinemia in the first week of life are physiologic jaundice, breast milk jaundice, and hemolysis.
Physiologic neonatal jaundice becomes visible by second or third day peaking by the fourth day and decreasing by seventh day of life. Physiologic jaundice is due to increased production of bilirubin following breakdown of fetal RBCs combined with limited conjugation of bilirubin by the liver. In full-term infants, 6% to 7% have indirect bilirubin levels greater than 12.9mg/dL and less than 3% will have levels greater than 15mg/dL.1
Breast milk jaundice is a common cause of neonatal unconjugated hyperbilirubinemia. It is due to beta-glucuronidases and nonesterified fatty acids in breast milk that inhibit enzymes which conjugate bilirubin. Bilirubin levels peak at 2 to 3 weeks of life, may remain elevated for 3 weeks to 2 months and then resolve.
Birth trauma resulting in cephalhematomas, bruising that leads to excessive red cell breakdown, and maternal-fetal blood group incompatibility such as Rh/ABO incompatibility can cause excessive red cell destruction and resultant hyperbilirubinemia.2 Erythrocyte enzymatic defects such as G6PD and pyruvate kinase deficiency decrease RBC life span and cause hemolysis. Infections can impair hepatic conjugation leading to unconjugated hyperbilirubinemia. Disorders of hepatic uptake and conjugation such as Gilberts and Crigler–Najjar syndrome also lead to unconjugated bilirubinemia. In infants with pyloric stenosis, 10% to 25% develop jaundice due to impaired conjugation which corrects rapidly after surgery. Endocrine disorders such as congenital hypothyroidism cause impaired conjugation leading to jaundice.2 (Fig. 73-1).
FIGURE 73-1. Neonatal unconjugated hyperbilirubinemia.
NEONATAL UNCONJUGATED HYPERBILIRUBINEMIA
History, including prenatal and perinatal with identification of maternal blood type if possible, should be obtained. Family history should include a search for liver diseases, metabolic abnormalities or hemolytic anemia. The presence of lethargy, fever/hypothermia and poor feeding in an icteric neonate should alert the physician to the possibility of sepsis. Urinary tract infections are associated with the onset of unconjugated hyperbilirubinemia after a week of age. In addition to scleral icterus, hepatomegaly, splenomegaly, cephalhematoma, and large areas of ecchymosis may be identified on a carefully performed physical examination.
Initial studies include total and direct bilirubin to confirm the diagnosis. If hemolysis or anemia is suspected, a complete blood count with reticulocyte count, direct antibody test, blood type, serum albumin, and urine for reducing substances should be obtained. Testing for G6PD should be considered if suggested by ethnic or geographic origin. If serious bacterial infection is suspected, a full sepsis workup should be performed with prompt administration of antibiotics.
MANAGEMENT AND COMPLICATION
Bilirubin level, chronologic age, gestational age, and clinical status of the patient are all considerations in the management. The goal is to prevent kernicterus which results from the deposition of bilirubin in the brain primarily in the basal ganglia. Kernicterus is associated with long-term impairment of coordination, hearing, and learning disabilities with initial symptoms consisting of poor feeding, lethargy, ensuing opisthotonus, seizures, and death. The icteric newborn needs to be well hydrated and enterally fed to promote bilirubin excretion. When bilirubin rises significantly, phototherapy and or exchange transfusion may be indicated. The American Academy of Pediatrics guideline for the initiation of phototherapy in infants of 35 or more weeks’ gestation is available on their website.3 It is important to remember that premature infants and those with significant comorbidity require treatment at lower bilirubin levels.
For jaundiced breast-fed infants, interruption of breastfeeding should be discouraged. Phototherapy should be considered in these infants while continuing breastfeeding, making sure the baby is well hydrated.
Due to the risk of kernicterus, neurotoxicity, and encephalopathy, exchange transfusion must be considered when bilirubin levels are >20 mg/dL. Careful monitoring is necessary especially for electrolyte or acid-base disturbance and infection.
NEONATAL CONJUGATED HYPERBILIRUBINEMIA
Direct hyperbilirubinemia is defined as a direct bilirubin concentration >2 mg/dL, or if the direct concentration is greater than 20% total bilirubin. Neonatal direct hyperbilirubinemia is always abnormal and indicates hepatobiliary dysfunction. The most common causes of conjugated hyperbilirubinemia in neonates are biliary atresia, extrahepatic biliary obstruction, neonatal hepatitis, and metabolic disorders.4Neonatal hepatitis has multiple etiologies including viral, bacterial, idiopathic, and in association with total parenteral nutrition. TORCH infections (toxoplasmosis, rubella cytomegalovirus, hepatitis B, or HIV) are the most common infectious causes. Urinary tract infections can also cause conjugated hyperbilirubinemia in neonates. Neonatal hepatitis presents with prolonged jaundice, vomiting, and poor feeding. Symptoms usually appear in the first few weeks of life but may appear as late as 2 to 3 months. Physical examination may reveal, hepatomegaly, altered mental status, or signs of a bleeding diathesis in addition to jaundice.5 Urinary tract infections can also cause conjugated hyperbilirubinemia in neonates. Alpha 1-antitrypsin deficiency is the most common hereditary cause of both acute and chronic liver disease, as well as the most common inherited disorder leading to liver transplantation.4 Patient presentation is highly variable and range from symptoms indistinguishable from idiopathic neonatal hepatitis to portal hypertension in older children. Diagnosis is based on alpha 1-antitrypsin (Pi) phenotype, and liver biopsy.5
DIAGNOSIS AND ANCILLARY TESTIN
Patient history should include a detailed prenatal and perinatal history. Family history should include the presence of childhood liver disorders and metabolic illnesses. Parents should be questioned about the presence of pale stools which raises the suspicion for cholestasis. Scleral icterus, hepatomegaly, and or splenomegaly may be present on physical examination (Fig. 73-2).
FIGURE 73-2. Neonatal conjugated hyperbilirubinemia.
Diagnosis and identification of the pathologic cause is essential. Initial studies should include complete blood cell and platelet counts, coagulation studies, liver profile, and chemistry panel. TORCH titers, thyroid function tests, alpha 1-antitrypsin and sweat test for cystic fibrosis should also be considered. Urine should be obtained for urinalysis and culture as well as for detecting reducing substances. A right upper quadrant ultrasound should be performed to identify anatomic abnormalities such as a choledochal cyst.
MANAGEMENT AND COMPLICATION
Most neonates with direct hyperbilirubinemia require in-hospital admission and consultation with pediatric gastroenterologist. Patients should be monitored closely for complications particularly coagulopathy and cholestasis.
HYPERBILIRUBINEMIA BEYOND THE NEONATAL PERIO
In children and adolescents, unconjugated hyperbilirubinemia is most commonly caused by hemolytic processes resulting in the overproduction of bilirubin. Included in the differential are sickle cell disease, hereditary spherocytosis, and G6PD deficiency. If hemolysis is not evident, liver injury must be considered. Causes of hepatocellular injury include viral and drug related hepatitis. Although autoimmune hepatitis and Wilson disease are less common causes of jaundice, these should be considered.
Conjugated hyperbilirubinemia beyond the neonatal period is caused by biliary obstruction or hepatocellular injury. The most common causes of biliary obstruction are cholelithiasis, tumor, or choledochal cyst.4
In addition to bilirubin levels, consider CBC with smear and liver function tests. In case of conjugated hyperbilirubinemia, liver ultrasound is the appropriate imaging study.
Hepatitis A and B vaccines have significantly decreased the incidence of hepatitis in children.6,7 Most children with viral hepatitis have minimal and nonspecific symptoms; however, it is important to establish a diagnosis and etiology as postexposure prophylaxis is available for some variants.
DIAGNOSIS AND ANCILLARY TESTIN
In children, hepatitis presents clinically with a prodrome of nonspecific symptoms including malaise, anorexia, nausea, vomiting, low-grade fever, and epigastric or right upper abdominal pain followed by the acute onset of scleral icterus and jaundice. Physical examination reveals tender hepatomegaly. Furthermore, mild splenomegaly is present in up to 50% of cases.8 Extra hepatic signs and symptoms such as arthritis, arthralgia, rash may be associated in some cases of hepatitis B. The icteric phase usually lasts for 1 to 4 weeks.
Elevated levels of AST/ALT are diagnostic of hepatocellular injury. Elevated conjugated bilirubin levels indicate liver disease. Serum ceruloplasmin levels should be obtained in patients older than 5 years to rule out Wilson disease. Indicators of hepatic function may be abnormal including ammonia, prothrombin time, and glucose. Serodiagnostic testing should be obtained for hepatitis A, B, C, CMV, and EBV with further testing as indicated. Table 73-1 reviews the symptoms, spread, risks, and management of the various types of viral hepatitis.
Characteristics and Management of Viral Hepatitis
Management is supportive care. The majority of patients can be managed at home. Indications for hospitalization include dehydration, direct bilirubin levels greater than 20 mg/dL, liver transaminase levels greater than 3000 units per liter, or an abnormal prothrombin time.
FULMINANT HEPATIC FAILURE
Fulminant hepatic failure is an acute or chronically progressive event with the loss of vital hepatic functions resulting in hyperbilirubinemia, hypoglycemia, coagulopathy, hypoproteinemia, and encephalopathy. Acute fulminant liver failure has a mortality approaching 60% to 80% without liver transplant.9
The causes of fulminant hepatic failure include infection, metabolic derangements, ischemia, malignancy, and toxin exposure. In neonates, it is thought to have an infectious (such as HSV) or metabolic (such as Wilson disease) source. In children, fulminant hepatic failure is most commonly a complication of viral hepatitis or toxin induced (mushrooms) or pharmacologic exposure (acetaminophen, anticonvulsants).
An uncommon but severe cause of liver failure is Reye syndrome. Reye syndrome occurs following a viral illness (most commonly, influenza B) with vomiting and rapid onset of hepatic dysfunction, encephalopathy, and cerebral edema. Antecedent treatment with aspirin has been associated with Reye syndrome. The hallmark is elevated levels of liver transaminases and blood ammonia. Prothrombin time is elevated greater than 50% of the control value. Direct hyperbilirubinemia rarely exceeds 2 mg/dL. The management is supportive. Increased intracranial pressure from cerebral edema is the major cause of mortality and morbidity.3
DIAGNOSIS AND ANCILLARY TESTIN
By history, most patients have an unremarkable medical history with no preexisting liver disease. The majority of patients have nonspecific complaints including nausea, vomiting, anorexia, and abdominal pain, particularly right upper quadrant. As failure progresses, jaundice develops and is often the symptom prompting medical attention. With the onset of coagulopathy, bruising and bleeding may occur. Hemorrhage can be significant, especially if it occurs from gastric and esophageal varices resulting from portal hypertension. Patients may also have a characteristic breath odor, “fetor hepaticus.” Encephalopathy correlates with the severity of liver dysfunction and can progress from simple fatigue and drowsiness to unresponsiveness secondary to cerebral edema and elevated intracranial pressure.
Coagulopathy is the first indicator of liver disease. Prolonged PT suggests impending liver failure. Transaminases and bilirubin levels are increased initially. However as the number of viable hepatocytes decrease serum transaminase levels fall while bilirubin levels continue to rise. Other markers of hepatic dysfunction such as hypoalbuminemia and hyperammonemia are usually seen. Hypoglycemia is a common complication and serum glucose must be monitored closely. As hepatorenal syndrome occurs in 75% of the cases,8 monitoring of renal function and urine output is necessary. Liver biopsy shows patchy or confluent necrosis of hepatocytes, without evidence of hepatic regeneration.
Treatment is supportive with close monitoring often in an intensive care unit. Consistent monitoring of the following is imperative: coagulation studies, ammonia, blood glucose, total bilirubin, complete blood count, and serum electrolytes. Intravenous dextrose may be necessary for the treatment of persistent hypoglycemia. Ascites should be managed either by direct paracentesis or with 25% IV albumin administration. Patients must be closely monitored for any signs of encephalopathy. In cases of increased intracranial pressure secondary to cerebral edema, intracranial pressure monitoring, mechanical ventilation, and mannitol should be considered. Coagulopathy is managed with the administration of vitamin K.10
Prognosis is based on the underlying cause of liver failure and the stage of hepatic encephalopathy. Poor prognosis is associated with
1. Jaundice > than 5 days before the onset of encephalopathy.
2. PT > than 50 seconds.
3. Serum bilirubin > than 17.5mg/dL.
Although the liver is capable of regeneration, in fulminant hepatic failure, the injury/insult may be so significant and widespread that regeneration does not occur.
BILIARY TRACT DISEAS
Biliary tract abnormalities seen in infancy include biliary atresia, choledochal cyst, and the potentially life-threatening disorder associated with both, that is acute cholangitis. Acute biliary-tract disease in childhood includes cholelithiasis, cholecystitis, and hydrops of the gallbladder.
Biliary atresia is the most common surgically treated cause of cholestasis and conjugated hyperbilirubinemia in the neonatal period. It occurs in 1:10 000 to 1:18 000 births in European Americans, with a higher incidence in Asian Americans, especially Asian American females. This disorder is characterized by obliteration of the extrahepatic biliary system resulting in obstructed bile flow.11
Although the etiology has not clearly been identified, theories suggest that biliary atresia is due to congenital malformation of the biliary pustular system. However, viruses such as cytomegalovirus have also been implicated.
DIAGNOSIS AND ANCILLARY TESTIN
Direct hyperbilirubinemia as a result of biliary atresia usually occurs within 2 to 3 weeks of age. Parents will report stools that are light yellow, gray, or acholic. Hepatomegaly occurs early and the liver is firm on physical examination. Splenomegaly is common and indicates progressive cirrhosis. A high index of suspicion is key to making the diagnosis because if diagnosis is delayed beyond 2 months of age, then irreversible biliary cirrhosis develops.
Initial laboratory studies will reveal conjugated hyperbilirubinemia. If the diagnosis is delayed, other serologic abnormalities occur resulting from hepatic damage and poor nutrition. Visualization of the biliary tree, by nuclear medicine hepatobiliary studies (DISIDA) scan, can determine if there is presence of obstruction and can help define abnormalities. Liver biopsy is a conclusive diagnostic test in greater than 90% of cases; however, intraoperative cholangiography definitively demonstrates patency of the extrahepatic biliary tract.10
Once suspected, surgical intervention is necessary for definitive diagnosis and therapy. The operative procedure is hepatoportoenterostomy (Kasai procedure). Early surgical intervention is imperative because success is time dependant with maximum benefit obtained if surgery is performed before 3 months of age. If uncorrected, two-thirds of patients will develop liver failure. Supportive treatment includes caloric and nutritional supplementation with fat soluble vitamins (A, D, E, K) and ursodeoxycholic acid.
Choledochal cysts are congenital bile duct anomalies. The cystic dilatations can involve intra/extra hepatic biliary tree or both. The incidence is higher in Asian countries than in Western countries.12 Fifty percent of cases are seen in Japan where the incidence is 1/1000 (12). Complications include cholangitis, pancreatitis, and hepatocellular damage. Cholangiocarcinoma is the most dangerous complication with an incidence of 5% to 28%.13
DIAGNOSIS AND ANCILLARY TESTING
Infants typically present with conjugated hyperbilirubinemia, acholic stools, and hepatomegaly. Children diagnosed after infancy typically present with intermittent biliary obstruction or recurrent bouts of pancreatitis.14
Liver function tests with hyperbilirubinemia, elevated serum amylase and lipase in case of associated pancreatitis can be seen. Abdominal ultrasonography is the test of choice. Abdominal CT scan and MRI help delineate the anatomy of the lesion and surrounding structures.
Referral to pediatric surgeon and gastroenterologist is indicated. Surgical excision of the entire cyst is the treatment of choice.
Acute cholangitis is a complication associated with surgical correction of biliary atresia or removal of choledochal cyst. The typical presentation consists of triad of fever, right upper quadrant tenderness, and worsening jaundice. Elevated serum transaminases and bilirubin along with leukocytosis are commonly seen. Prompt recognition and institution of antibiotics is imperative as morbidity and mortality associated with this disorder is significant.
CHOLELITHIASIS AND CHOLECYSTITIS
Acute cholecystitis is relatively uncommon condition in children. It is typically a complication of cholelithiasis. Cholelithiasis in young children is usually associated with hemolytic anemia such as sickle cell disease and spherocytosis. Gallstones can also develop as a result of abdominal surgery, sepsis, necrotizing enterocolitis, parenteral nutrition, or disorders with enhanced biliary enterohepatic circulation such as cystic fibrosis or Crohn disease.15In adolescents, cholelithiasis is more common in females than male and is seen secondary to obesity, oral contraceptive use, and or pregnancy.
Acalculus cholecystitis or inflammation of the gallbladder in the absence of stones is more common in children than cholelithiasis and is associated with enteric bacterial infections such as salmonella, shigella, viral infections, and parasitic infestations like giardiasis.16
DIAGNOSIS AND ANCILLARY TESTING
Patients present with colicky abdominal pain usually in the right upper quadrant or epigastric region. Pain may radiate to the right shoulder or back and is usually associated with vomiting. Cholecystitis usually presents as a triad of fever, right upper abdominal pain, and leukocytosis.
Abdominal ultrasound is commonly used to diagnose gallbladder disease as it is noninvasive and easily available. Ultrasound can detect stones, thickened gallbladder wall, sludge, and dilated bile ducts. Laboratory tests are typically nonspecific. Leukocytosis may be seen with cholecystitis. Serum bilirubin levels may be increased but usually do not exceed 4 mg/dL. Serum transaminases may be mildly elevated.
Treatment of cholelithiasis include discontinuation of oral intake, IV hydration, and pain control. Patients with a good response can be managed as outpatients with oral medications and surgical follow-up. Febrile patients with cholecystitis require hospital admission and IV antibiotics, usually ampicillin and gentamicin, plus clindamycin or metronidazole. Complications of cholecystitis include gallbladder perforation, bile peritonitis, pancreatitis, sepsis, and abscess/fistula formation.16
HYDROPS OF THE GALLBLADDE
Gallbladder hydrops is an acute noninfectious process leading to an enlarged gallbladder without gallstones. It occasionally occurs as a complication of viral gastroenteritis, Kawasaki disease, streptococcal pharyngitis, mesenteric adenitis, or nephrotic syndrome. Patients present with abdominal pain, elevation in liver enzymes, and possibly hepatomegaly. Ultrasound is diagnostic. This condition resolves when the underlying cause is treated. NSAIDs can be given for pain control.14,16
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