Selasa, 28 Agustus 2018

Jaundice – Conjugated Hyperbilirubinemia

The presence of jaundice in a child can be a useful indicator of occult pathology. The finding of icterus should set in motion a careful diagnostic search to elucidate the cause. The ultimate goal, to identify precisely the cause of the clinical syndrome, may rest in some cases with the longitudinal caregiver. In all cases, however, the emergency physician at first visit must separate patients whose admission can be temporized from those who require urgent intervention and/or immediate hospitalization.

PATHOPHYSIOLOGY

Unconjugated bilirubin is largely a product of converted heme from senescent red blood cells. Unconjugated bilirubin is transported from extrahepatic reticuloendothelial cells to the liver, bound to albumin. Albumin is detached as the bilirubin gains entry into the hepatocyte. In the liver cell, bilirubin is conjugated with glucuronide by the action of uridine diphosphate glucuronyl transferase. The soluble conjugated diglucuronide then is secreted across the canalicular membrane into the bile. In the intestine, as a result of the activity of bacterial flora, bilirubin is converted to urobilinogen. A portion of urobilinogen is reabsorbed into the portal circulation and is taken up by the liver cells, only to be reexcreted into the bile. A small percentage of urobilinogen escapes into the systemic circulation and is excreted in the urine. The unabsorbed urobilinogen is excreted in the stool as fecal urobilinogen.

In hepatocellular disease, the damaged liver may be unable to excrete the conjugated bilirubin produced in normal amounts. Or, in the absence of hepatic damage, regurgitation into the plasma of conjugated bilirubin may result from functional cholestasis, disruption of the hepatic architecture, or extrahepatic biliary obstruction. In most instances of jaundice primarily related to hepatic disease, the plasma exhibits elevated concentrations of unconjugated and conjugated bilirubin. Overt mechanical obstruction of bile excretion leads to raised plasma levels of conjugated bilirubin, and only as secondary liver damage occurs do unconjugated bilirubin levels rise.

DIFFERENTIAL DIAGNOSIS

Conjugated hyperbilirubinemia is defined by a conjugated bilirubin level higher than 1 mg per dL if the total bilirubin is less than 5 mg per dL or the conjugated bilirubin level represents more than 20% of the total bilirubin if the total bilirubin is higher than 5 mg per dL. Conjugated hyperbilirubinemia, indicating cholestasis, is considered pathological. Cholestatic jaundice may be congenital or acquired. The differential diagnosis includes a variety of structural defects, infections, hepatotoxins, inborn errors of metabolism, and familial syndromes (Table 41.1). Although only a few diseases commonly cause conjugated hyperbilirubinemia (Table 41.2), all are serious. In addition, several less common conditions are important considerations because they are life threatening (Table 41.3).



EVALUATION AND DECISION

It is convenient to divide the approach to patients with conjugated hyperbilirubinemia by age, focusing first on those younger than 8 weeks old and then on those who are older (Fig. 41.1). A majority of children who eventually develop lifethreatening or chronic liver disease initially present in the first 2 months of life. Early physician recognition may lead to successful treatment and a more favorable prognosis.


Infants Younger than 8 Weeks

In the perinatal period, infants develop conjugated hyperbilirubinemia in response to a variety of conditions that may not be encountered in older patients. The increased sensitivity to insult is a result of different patterns of hepatic enzyme activity and liver immaturity with regard to bile formation. Many systemic or hepatic insults may produce perinatal cholestasis (Table 41.1). However, a small number of disorders account for the overwhelming majority of perinatal cholestasis. They include idiopathic neonatal hepatitis, biliary atresia, 1-antitrypsin deficiency, cystic fibrosis, tyrosinemia, galactosemia, choledochal cyst, and perinatal infections. These disorders can be separated by the tempo of the presentation and the appearance of the infant.

The tempo of cholestasis is most abrupt with the infections acquired in utero and during the birthing process. Infected patients are more likely to present shortly after birth. Those who have congenital infections will have a low birth weight. They present with cholestatic jaundice, irritability, jitteriness, and/ or seizures. On examination, microcephaly, hepatomegaly, splenomegaly, and petechiae may be seen with the perinatal TORCHS complex. These include perinatal infections from toxoplasmosis, other infections, rubella, cytomegalovirus (CMV), herpes simplex, and syphilis. Jaundice may be one of the first signs of bacteremia without apparent focus of infection or bacterial sepsis in the first few days of life. Hyperbilirubinemia may occur antecedent to blood cultures becoming positive and may precede findings of anorexia, vomiting, abdominal distension, fever, hepatomegaly, or alterations in respiratory pattern or sensorium. The precise mechanism of jaundice that complicates bacteremia and sepsis is not completely understood. Jaundice may also be an early diagnostic sign of urinary tract infection in the neonatal period. An increase in the conjugated bilirubin fraction may be seen in patients who have afebrile, otherwise asymptomatic urinary tract infection.

The tempo of icterus is subacute with the other common causes of conjugated hyperbilirubinemia. The metabolic and hepatic disorders have variable symptoms at onset. However, the manifestations are far less acute than those seen in the infectious states. Infants with galactosemia, tyrosinemia, and fructose intolerance may appear ill in the emergency department due to metabolic derangement or secondary infection. However, they have had an antecedent history of failure to thrive, developmental delay, and inconstant jaundice. Unexplained fatality in the sibship or unexplained pulmonary, gastrointestinal, neurologic, or psychiatric disturbance in other family members may provoke diagnostic consideration.

The tempo of hepatic and biliary tree disorders is chronic. Those with biliary atresia have intermittent, mild conjugated hyperbilirubinemia during the first 6 to 8 weeks of life. They feed well and thrive. Their stools may be intermittently pigmented early on and become permanently without pigment only after 4 to 6 weeks. They have a benign appearance and with the exception of jaundice and hepatomegaly seem otherwise well. Those patients without a precise anatomic, genetic, or infectious cause of cholestasis are considered to have idiopathic neonatal cholestasis or neonatal hepatitis syndrome. They have onset of their jaundice from 1 to 30 days, with a mean of 7 days. Initially, their stool color is normal, but the stools may become acholic after several weeks. The presence of acholic stools may make it difficult to differentiate between obstructive jaundice causing hepatocellular disease and that caused by obstruction of the biliary tree.

The priorities for the emergency physician are to diagnose medically treatable infections, identify metabolic disorders for which effective therapy is available, and detect extrahepatic obstructive lesions that are amenable to surgical correction. The evaluation begins with cultures of cerebrospinal fluid, blood, urine, and stool. Infants should also have complete blood cell and platelet counts, coagulation studies, hepatic enzymes (aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyl transpeptidase), ammonia, albumin, total protein, alkaline phosphatase, electrolytes, blood urea nitrogen, creatinine, and blood sugar tests. Urine should be obtained for urinalysis and tested for reducing substances. A right upper quadrant ultrasound should be performed in order to identify anatomic abnormalities such as a choledochal cyst. If cystic fibrosis is suspected, schedule the patient for a sweat chloride iontophoresis or testing for common genetic variants in the cystic fibrosis transmembrane conductance regulator gene. Additional studies of blood and urine that they may find useful include 1-antitrypsin, TORCHS and hepatitis B virus serology, serum amino acids, thyroid function tests, red blood cell galactose 1-phosphate uridyltransferase activity, and urine examination for cytomegalovirus.

Inpatient observation is appropriate in this age group because the diagnosis can rarely be established in the emergency department. Empiric therapy for sepsis or urinary infection is often warranted, pending culture results.

Children Older than 8 Weeks

In the evaluation of conjugated hyperbilirubinemia beyond infancy, it is necessary to know if there has been exposure to contagion or a potential for sexual or vertical transmission of infections such as hepatitis or human immunodeficiency virus. Other risk factors for hepatitis (e.g., needle sticks, hemodialysis, transplant, transfusion of blood products, or factor use) need to be evaluated. The physician should pursue possible exposure to industrial toxins or foods previously implicated in hepatic injury (e.g., carbon tetrachloride, yellow phosphorus, tannic acid, alcohol, mushrooms of the Amanita species). The emergency physician must inquire about use of acetaminophen, salicylates, nonsteroidal anti-inflammatory drugs, iron salts, erythromycin estolate, ceftriaxone, rifampin, nitrofurantoin, oxacillin, tetracycline, trimethoprim-sulfamethoxazole, ketoconazole, diphenylhydantoin, isoniazid, and chlorpromazine. The presence of prior episodes of jaundice, acholic stools, and/or abdominal pain may suggest an underlying disorder, predisposing the patient to obstruction of the biliary tree. Other historical points include the presence of fever, arthralgia, arthritis, conjunctivitis, rash, pruritus, vomiting, diarrhea, weight loss, color of the urine, abnormal bruising or spontaneous bleeding, and changes in mental status. An examination that focuses on ongoing physical signs of liver disease may result in greater accuracy in clinical evaluation of the older jaundiced patient. These signs include skin changes (spider angiomata, excoriations, palmar erythema) and peripheral edema. The abdominal examination should include observations of the venous pattern, presence of ascites, mass, or peritoneal irritation. There should be an estimation of liver size, contour, and tenderness, as well as an estimate of spleen size. The clinician should exclude cardiovascular dysfunctions such as hypoxemia, systemic venous congestion, and low cardiac output. Observations should be made of mental status and neuromuscular changes. Patients with cystic fibrosis, 1-antitrypsin deficiency, Wilson’s disease, or inflammatory bowel disease tend to have symptoms that remit and relax. However, slow progression is the rule. Patients with 1-antitrypsin deficiency may have onset of respiratory or hepatic complaints at any age. Similarly, infants who have failure to thrive from cystic fibrosis may develop obstruction at any age in the extrahepatic or intrahepatic ducts and, transiently or persistently, may exhibit jaundice. Patients with ulcerative colitis and Crohn’s disease may become symptomatic intermittently with episodes of cholestasis. The degree of hepatic derangement and expression of neurologic abnormality is variable with Wilson’s disease. Before the diagnosis is entertained, patients typically exhibit dysarthria, tremors, rigidity, or psychic disturbances. Rarely, younger patients without prodromal events have acute jaundice and hepatomegaly and progress to hepatic failure. Biliary calculi and acute inflammation of the gallbladder are uncommon causes of conjugated hyperbilirubinemia in the pediatric population. However, a subset of patients is predisposed to these complications. Cholelithiasis may complicate any of the hemolytic anemias, particularly in patients with sickle hemoglobinopathies. These patients have increased incidence of both liver and gallbladder disease. Liver or gallbladder dysfunction accounts for jaundice when more than 10% of an elevated bilirubin in a patient with sickle cell disease is conjugated. Cholecystitis may accompany a variety of acute focal infections, such as pneumonia or peritonitis, and may occur in the course of bacterial sepsis. In this event, shock and hyperpyrexia may divert the clinician from the deranged biliary system. In less severe cases, fever, nausea, vomiting, abdominal distension, and right upper quadrant pain are prominent features of cholecystitis. Right upper quadrant abdominal mass, pain, and jaundice constitute the classic triad in the diagnosis of choledochal cyst. The clinical recognition may be delayed until there is a complication, such as cholangitis. An acute, painful right upper quadrant mass associated with jaundice may also occur in the course of acute hydrops of the gallbladder from Kawasaki disease or systemic streptococcal infection. In the previously healthy child, the most common cause of conjugated hyperbilirubinemia is acute hepatitis . The illness may be abrupt in onset, with fever, urticaria, and arthralgia as primary manifestations. More often, the illness is insidious. Viral hepatitis is characterized by low-grade fever and gastrointestinal complaints such as anorexia, malaise, nausea, vomiting, and abdominal pain before the jaundice. Liver enlargement with hepatitis (A, B, C, and non-A, non-B, non-C), varicella, herpesvirus, Coxsackievirus, echovirus, Epstein-Barr virus, and adenovirus infection is inconstant. Hepatic tenderness is a more reliable finding. Rarely, ascites can accompany hepatitis virus infection. Splenomegaly is the rule with Epstein-Barr virus but is unusual with the other agents. On occasion, hepatitis may be associated with a distinctive erythematous papular eruption localized to the limbs (Gianotti-Crosti syndrome). Toxic hepatitis, unlike viral hepatitis, does not have a prolonged prodrome. Acute nausea, vomiting, and malaise are followed in 1 to 2 days by alterations in mental status and deterioration of liver function. Most patients with toxic hepatitis will have an identifiable exogenous precipitant. Children with fulminant hepatic failure typically experience anorexia, nausea, vomiting, malaise, and fatigue—all symptoms indistinguishable from those expected with viral hepatitis. The patient’s jaundice becomes more profound and vomiting becomes protracted. Hyperexcitability, mania, and subtle psychomotor abnormalities may be seen. Coagulopathy, ascites, and sudden decrease in liver size are often the prelude to the development of frank neuromuscular signs. The objectives of the emergency physician are to render supportive care to those icteric patients with infectious and metabolic derangements and to identify those cases in which jaundice is caused by mechanical obstruction or hepatic failure. The impression based on a targeted history, physical examination, and clinical algorithms can be bolstered with the following laboratory examinations: complete blood cell count, platelet count, coagulation profile, prothrombin time, total and direct bilirubin, hepatic enzymes, alkaline phosphatase, electrolytes, blood urea nitrogen, and creatinine. Urinalysis, culture, and toxicologic screen should be considered. Chest and abdominal radiographs are indicated when there are pulmonary parenchymal complaints or significant abdominal findings. Other laboratory tests that are often available immediately and that may provide useful information in specific circumstances are serum ammonia, albumin, total protein, lipid profile, pH, and carbon dioxide. If available, abdominal sonography or computed tomography may be helpful occasionally. In no circumstance will results of several important blood and urine tests be of immediate use. Such studies, which are appropriate, include antinuclear antibody, fetoprotein, and serum for bile acids, ceruloplasmin, protein electrophoretic pattern, polymerase chain reaction assays or serologic evidence of recent infection (e.g., Epstein-Barr virus, mycoplasmal or hepatitis profiles). Urinary analysis includes assessment of organic acids and copper. These investigations may be helpful, however, to the longitudinal caregiver who must maintain a vigilant watch over the jaundiced patient. Children older than 8 weeks with conjugated hyperbilirubinemia should be admitted to the hospital at the time of their presentation in all cases in which life-threatening conditions may exist (Table 41.3). Inpatient treatment is also suggested when intravenous fluids are necessary to treat symptomatic hypoglycemia or electrolyte imbalance and when operative intervention may prove necessary. Icteric patients who have been diagnosed previously with confidence and who have exacerbation of their symptoms may require admission to reappraise their status. The physician may also be influenced to admit the patient when social factors or geographic barriers inhibit consistent observations. Admission is also indicated for patients who require further diagnostic intervention, such as hepatobiliary scintigraphy, endoscopic retrograde cholangiopancreatography, or liver biopsy to arrive at a definitive diagnosis.

Suggested Readings

Crain EF, Gershel JC. Urinary tract infections in febrile infants younger than 8 weeks of age. Pediatrics 1990;86:363–367.

Emerick KM, Whitington PF. Neonatal liver disease. Pediatr Ann 2006;35: 280–286.

Garcia FJ, Nager AL. Jaundice as an early diagnostic sign of urinary tract infection in infancy. Pediatrics 2002;109:846–851.

Jacquemin E, Lykavieris P, Chaoui N, et al. Transient neonatal cholestasis: origin and outcome. J Pediatr 1998;133:563–567.

Moyer V, Freese DK, Whitington PF, et al. Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2004;39:115–128.


Suchy FJ. Approach to the infant with cholestasis. In: Suchy FJ, Balistreri WF, Sokol RJ, eds. Liver disease in children, 3rd ed. New York, NY: Cambridge University Press, 2007:187–194.

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