Jaundice

H
Dr.Mohamed Elmaghraby
Assistant Lecturer of Pediatrics
AL Hussein University Hospital
Al Azhar University
Case scenario
5 years old boy presented with yellow
eyes, pale skin and dark urine.
What’s your differential diagnosis ???
Definition of Jaundice:
 Yellow discoloration of the sclera, skin and mucous membranes due to
increased bilirubin level more than normal according to the patient age.

 Jaundice usually becomes clinically apparent when the serum total

bilirubin concentration is greater than 2 to 3 mg/dL (34 to 51
micromol/L),

Forms of bilirubin:
-Bilirubin occurs in plasma in two forms:

1. unconjugated bilirubin: tightly bound to albumin.

2. Conjugated bilirubin: the only fraction to appear in urine.
Conjugated hyperbilirubinemia

 Defined as serum conjugated bilirubin concentration >0.5 mg/dL (8.6

micromol/L).

 More commonly, the conjugated component is estimated by measuring

"direct" bilirubin, which is elevated if it is >1 mg/dL (17 micromol/L) if the
total bilirubin is 5 mg/dL (85 micromol/L) or more than 20 percent of the
total bilirubin if the total bilirubin is >5 mg/dL (85 micromol/L).

 Elevation in conjugated (or direct) bilirubin is an abnormal finding that

requires further evaluation.
Unconjugated hyperbilirubinemia

 Defined as hyperbilirubinemia without an increase in the

conjugated component.

 Thus, it is hyperbilirubinemia in which conjugated bilirubin is

<1mg/dl (17 micromol/L) if the total bilirubin is 5 mg/dL (85
micromol/L) or less than 20 percent of the total bilirubin if the
total bilirubin is >5 mg/dL (85 micromol/L).
CAUSES OF UNCONJUGATED HYPERBILIRUBINEMIA

 Unconjugated hyperbilirubinemia is caused by one of three basic

pathophysiologic mechanisms :

1- Bilirubin overproduction.

2- Impaired hepatic bilirubin uptake.

3- Impaired hepatic bilirubin conjugation.

* After the neonatal period, the most common causes of unconjugated

hyperbilirubinemia are hemolytic processes resulting in bilirubin
overproduction.
Bilirubin overproduction
Extravascular hemolysis
Extravasation of blood into tissues
Hypersplenism
Intravascular hemolysis
Inherited red blood cell disorders
Glucose-6-phosphate dehydrogenase deficiency*
Sickle cell disease*
Thalassemia
Hereditary spherocytosis
Hereditary elliptocytosis
Infection: malaria, bacterial sepsis*
Autoimmune hemolytic anemia
Microangiopathic hemolytic anemia
Drug induced hemolytic anemia (eg, cephalosporins, penicillins, trimethoprim-sulfamethoxazole) ¶
Impaired hepatic bilirubin uptake
Heart failure
Portosystemic shunts
Some patients with Gilbert syndrome
Certain drugs: Rifamycin, probenecid, flavaspadic acid, bunamiodyl
Impaired bilirubin conjugation
Inherited
Crigler-Najjar syndrome
Gilbert syndrome*
Acquired
Neonates: physiologic hyperbilirubinemia,* breast-milk jaundice*
Hyperthyroidism (mechanism unclear)
Certain drugs: Ethinyl estradiol, gentamicin (above therapeutic range), novobiocin, antiretroviral drugs
Liver diseases
Chronic persistent hepatitis
Advanced cirrhosis
Wilson disease
Bilirubin overproduction
 Bilirubin overproduction can result from increased breakdown of
haemoglobin and other heme-containing proteins, typically due to
extravascular or intravascular hemolysis or sometimes due to abnormal
erythropoiesis.

 In patients with normal liver function, the liver efficiently conjugates and
excretes the excess haemoglobin.

 As a result, the serum bilirubin concentration caused by hemolysis will

rarely exceed 4 mg/dL (68.4 micromol/L).

 However, haemolysis can lead to severe hyperbilirubinemia in patients

with concurrent liver disease, even if mild.
Extravascular hemolysis : is mainly caused by:

1- Extravasation of blood into tissues (hematomas, pulmonary blood,

and other collections of extravasated blood).

2- Hypersplenism of various causes (including splenic sequestration in

sickle cell disease).

Intravascular hemolysis:
* In most populations, the most common noninfectious causes of
intravascular hemolysis in children are inherited red blood cell
disorders:

1- Hemoglobinopathies (eg, sickle cell disease and related disorders).

2- Disorders of hemoglobin chain synthesis (the thalassemias).
3- Erythrocyte membrane defects (hereditary spherocytosis, hereditary
elliptocytosis, and related disorders).
4- Erythrocyte enzyme deficiencies (eg, glucose-6-phosphate
dehydrogenase deficiency).
Impaired hepatic bilirubin uptake
-Impaired delivery of bilirubin to the liver and disorders affecting
bilirubin uptake by hepatocytes result in reduced hepatic bilirubin
uptake and therefore increased levels of circulating unconjugated
bilirubin.

Reduced hepatic blood flow :

-Conditions causing reduced hepatic blood flow and delivery of
bilirubin to hepatocytes include heart failure and portosystemic
shunts. The hyperbilirubinemia caused by these disorders is
predominantly unconjugated.

Drugs :
-Administration of several drugs can impair bilirubin uptake.
-Such effects will usually resolve within 48 hours of drug
discontinuation.
Impaired bilirubin conjugation
 Gilbert syndrome and Crigler-Najjar syndrome types I and II are
among the inherited disorders that cause decreased or absent uridine
glucuronoyl transferase (UGT) activity, an enzyme responsible for
bilirubin conjugation with glucuronic acid.

Gilbert syndrome
Gilbert syndrome is a common cause of unconjugated
hyperbilirubinemia in adolescents and adults. Individuals with this
condition have reduced bilirubin-UGT activity.

Crigler-Najjar syndrome
Crigler-Najjar syndrome types I and II are characterized by the
absence or deficiency of the enzyme bilirubin-UGT, respectively. Type I
is the more severe form, which presents soon after birth and is
associated with severe morbidity and mortality. Type II is the milder
form and typically presents in infancy or later childhood but may appear
as late as adolescence.
DIAGNOSTIC APPROACH
 The initial laboratory evaluation of a child presenting with jaundice
should begin with measurement of the total serum bilirubin with
fractionation (conjugated and unconjugated bilirubin), followed by
serum alanine aminotransferase and aspartate aminotransferase,
complete blood count with reticulocyte count, and microscopic
examination of the blood smear.

 These tests will help to categorize the jaundice by answering the

following questions:

• Are there signs or symptoms of sepsis?

* Jaundice with fever, toxic appearance, or abnormal white blood cell
count suggests sepsis and calls for prompt evaluation and empiric
treatment with antibiotics if indicated.
• Is the jaundice caused by hyperbilirubinemia?
* Jaundice usually becomes clinically apparent when the serum total
bilirubin concentration is greater than 2 to 3 mg/dL (34 to 51 micromol/L),
but the threshold varies among patients.

* If the serum bilirubin level is not elevated, the patient's yellow-appearing

skin is not true jaundice and is probably due to carotenemia, which also can
be distinguished from jaundice during a physical examination because there
is no scleral icterus in carotenemia.

 Is the hyperbilirubinemia unconjugated?

* If hyperbilirubinemia is present, the next step is to determine whether it is
unconjugated or conjugated.

● Unconjugated : The hyperbilirubinemia is unconjugated if there is only a

small conjugated component (ie, conjugated bilirubin < 1 mg/dL if total
bilirubin > 5mg/dl, or less than 20 percent of the total bilirubin if the total
bilirubin is >5 mg/dL).
● Conjugated : Hyperbilirubinemia with a large conjugated component
(conjugated bilirubin >1 mg/dL, or more than 20 percent of the total bilirubin)
indicates a very different set of diagnostic possibilities.
 Is the patient anemic?

* If the hyperbilirubinemia is unconjugated and the child is well-

appearing, the presence or absence of anemia will determine the likely
diagnostic possibilities.

* Unconjugated hyperbilirubinemia with anemia.

* Unconjugated hyperbilirubinemia without anemia.
HISTORY AND PHYSICAL EXAMINATION
 The differential diagnosis of unconjugated hyperbilirubinemia is
broad and requires a thorough history and physical examination as
part of the initial evaluation.

History
 A general clinical history is the first step in the evaluation of the child
with unconjugated hyperbilirubinemia. Attention should focus on the
following historical details:

1- Age of the patient at first presentation.

2- History of inherited disorder (including liver diseases and hemolytic
disorders), including a family history of jaundice or anemia
3- History of medication/toxic exposure.
4- Dietary history (appetite, carotene intake, fava bean ingestion if
glucose-6-phosphate dehydrogenase deficiency is suspected).
5- Travel history
Physical examination
* General appearance
 A toxic appearance suggests sepsis or other serious underlying
condition.

* Skin and sclerae

• The sclerae and skin should be examined closely under adequate light.
In patients with dark skin, the palms and soles are less pigmented and
may be easier to evaluate for jaundice or pallor .

● In patients with mild hyperbilirubinemia (eg, 2 to 3 mg/dL), jaundice may

be subtle and seen only in the sclerae.

● Jaundice should be distinguished from carotenemia. In carotenemia, the

sclerae are not discolored and the skin color is characteristically more
yellow-orange rather than yellow and more noticeable over the palms and
soles; serum bilirubin is normal.

● Pallor and/or vital sign changes, such as tachycardia and hypotension,

may indicate anemia secondary to hemolysis or blood loss.
● Large areas of bruising or hematoma formation suggest
extravascular hemolysis as the cause of the unconjugated
hyperbilirubinemia.

• Abdomen

● Hepatomegaly or liver tenderness suggests the possibility of

hepatitis (eg, viral or druginduced), which can cause
hyperbilirubinemia due to hepatocellular dysfunction.

● Splenomegaly may indicate a hypersplenic state such as splenic

sequestration in sickle cell disease, portal hypertension, or
autoimmune hemolysis as may occur in systemic lupus
erythematosus.
LABORATORY TESTING
 The serum total bilirubin measurement with fractionation is the first test
in the evaluation of the patient with jaundice.

 Transcutaneous bilirubin devices provide useful measures of bilirubin

levels in neonates but do not distinguish between conjugated and
unconjugated bilirubin.

 This technique has not been validated in older infants and children and
is not recommended for use beyond the neonatal period.

 If unconjugated hyperbilirubinemia is confirmed, further testing is

warranted to determine the underlying etiology.

* This includes complete blood count and reticulocyte count. Serum

aminotransferases should also be measured.
* Elevated values suggest the presence of liver disease, and
measurement of the prothrombin time and partial thromboplastin time
may be warranted.
Unconjugated hyperbilirubinemia with anemia
and/or hemolysis

 For patients with anemia and/or evidence of hemolysis, a peripheral

blood smear should be examined microscopically and a direct
antiglobulin (Coombs) test should be performed to look for evidence of
autoimmune hemolysis.

 Sickle cells, spherocytes, or elliptocytes suggest a specific red blood cell

disorder.

 Helmet cells or fragmented cells are diagnostic of a microangiopathic

hemolytic anemia, as may be seen in hemolytic-uremic syndrome.

 Testing for glucose-6-phosphate dehydrogenase deficiency should be

considered in children with appropriate risk factors. Boys of African or
Mediterranean descent are most likely to have symptomatic disease,
which may be triggered by infection or exposure to certain drugs (eg,
sulfamethoxazole and some antimalarial agents).
Unconjugated hyperbilirubinemia without anemia
or hemolysis

 Patients without anemia or evidence of hemolysis who have no

laboratory abnormality other than a serum unconjugated bilirubin level
less than 5 mg/dL probably have Gilbert syndrome .

 Confirmation of the diagnosis can be made by detecting a reduction in

hepatic bilirubin-uridine glucuronoyl transferase (UGT) activity, which is
approximately 30 percent of normal .

 However, this test is not necessary to establish the diagnosis of Gilbert

syndrome if the patient is otherwise healthy and has no evidence of
hemolysis or liver disease.

 Children with serum unconjugated bilirubin levels well above 5 mg/dL

should be evaluated for Crigler Najjar syndrome.
Other results
 Patients who do not have unconjugated hyperbilirubinemia fall into
the following categories:

* Yellow-appearing skin without hyperbilirubinemia:

 The most likely cause is carotenemia.

 Carotenemia is usually found in infants and toddlers whose diets
consist of large amounts of strained yellow vegetables, particularly
carrots.
 Unlike jaundice, the sclerae are not discolored.
 In carotenemia, the skin color is characteristically more yellow-
orange rather than yellow and more noticeable over the palms and
soles.
 Although the diet is a major cause of carotenemia in childhood,
other causes include nephrotic syndrome, diabetes mellitus,
anorexia nervosa, liver disease, and hypothyroidism.
Conjugated hyperbilirubinemia:

 The finding of hyperbilirubinemia with a large conjugated component

calls for a different approach to the work-up.

 The causes of conjugated hyperbilirubinemia are largely distinct from

those of unconjugated hyperbilirubinemia, although some cases may
have mixed mechanisms.

 Causes of conjugated hyperbilirubinemia include biliary obstruction

(eg, gallstones), liver disease causing hepatocellular dysfunction (eg,
hepatitis, sepsis, or hepatotoxic drugs), and several inherited
disorders (eg, Dubin-Johnson or Rotor syndrome).

 Some disorders, including sickle cell disease, can present with either
unconjugated or conjugated hyperbilirubinemia, depending upon the
presence of infection, biliary obstruction, or hepatocyte injury that
prevents efficient conjugation and clearance of bilirubin.
Hepatitis
DEFINITION:

 It is an inflammatory process of the hepatocytes characterized by

degeneration and regeneration with loss of hepatic architecture

TYPES:
 a) Acute: less than six months duration
 b) Chronic: more than six months.
ETIOLOGY:
Infections:
* 1. Viral:
 Hepatotropic: A, B, C, D, E viruses
 Non hepatotropic:
* Infect the liver in the course of other systemic illness:
 Epstein-Barr virus (EBV).
 Cytomegalovirus (CMV).
 Rubella Varicella & Measles viruses.
* 2. Bacterial
  As a part of generalized septicemia
  Liver abscess.
  Leptospirosis.
* 3. Protozoal: Amoebic hepatitis.
Drugs and Toxins:
  Anti T.B. e.g. Isoniazid.
  Antimetabolites.
  Anticonvulsant (valporic acid).
  Irradiation.
  Chlorpromazine.
  Halothane.
  Total parenteral nutrition.
Immunological Disorders:
  As a part of: SLE & JRA
  auto immune hepatitis (lipoid hepatitis)
Metabolic Causes:
  Alpha antitrypsine deficiency
  Galactosemia
  Tyrosinemia
  Hemosiderosis
  Hemochromaosis (Wilson disease).
Vascular Causes
  Hepatic vein thrombosis
  Hepatic artery thrombosis
 HEPATITIS A VIRUS INFECTION

Mode of transmission:

 Feco- oral route.

Incubation period:

 2-6 Ws (average 4 week).

Clinical Picture:
Pre-Icteric phase (Prodromal): (1-2 w)
  Fever.
  Headache.
  Malaise.
  Absolute anorexia.
  Others: Nausea, vomiting, lethargy.
* This phase can be passed unnoticed by the parents.
Icteric phase: (2-3 w)
  Jaundice.
  Dark urine.
  Abdominal pain
  Soft, enlarged tender liver.
Convalescence phase: (1-2 w)
 After which the child becomes nearly normal.
Investigations:

 Serum level of direct and indirect bilirubin: Raised.

 Serum transaminases (ALT & AST): Marked elevation.
 Urine contains both bilirubin (dark color) & Urobilinogen.

 IgM Anti- HAV:

* Detected at the onset of the symptoms.
* Disappears within 4 months.

 IgG anti-HAV:
* Appears at 8 weeks and persists for life.
Treatment:
 There is no specific therapy for acute viral hepatitis.
 Most children are managed at home except if liver cell failure is suspected.

Prevention:
 Period of infectivity:
* Contagious for about 7 days before and 7 days after the onset of jaundice.

 Period of isolation from school:

* Patient should be excluded from school and child care centers, from the
appearance of dark color urine and appearance of jaundice till 7 days after.

 1. Careful hand washing after changing diapers and before preparation of

food.
 2. Fly control.
 3. Intramuscular immunoglobulin may be indicated in pre and post exposure.
 4. Hepatitis A vaccine is now available to be given at 18 months old.
 5. Contacts are immunized with immunoglobulin or the vaccine.
SUMMARY AND RECOMMENDATIONS

 Jaundice is the clinical finding caused by hyperbilirubinemia; it

usually becomes apparent at serum bilirubin concentrations above
2 mg/dL, which is twice the upper limit of normal.

 A patient with a jaundiced appearance but normal serum bilirubin

most likely has carotenemia, which also can be distinguished from
jaundice during a physical examination.

 In most jaundiced infants and children, the hyperbilirubinemia is

exclusively or primarily unconjugated. This can be caused by
bilirubin overproduction (eg, hemolysis), impaired hepatic bilirubin
uptake (eg, reduced hepatic blood flow or certain drugs), or
impaired bilirubin conjugation (eg, Gilbert or Crigler-Najjar
syndromes) .
 Ill-appearing infants and children with jaundice should be evaluated
promptly for sepsis, as well as for other possible causes of their
hyperbilirubinemia. Sepsis can cause hyperbilirubinemia through
several mechanisms, including intravascular haemolysis (bilirubin
overproduction).

 Gilbert syndrome is a common cause of unconjugated

hyperbilirubinemia, particularly in adolescents and adults. It is a
heritable defect in bilirubin glucuronidation and presents with mild
transient elevations of unconjugated bilirubin, often triggered by an
intercurrent illness.

 After sepsis is excluded, the diagnostic evaluation should establish

whether the hyperbilirubinemia is unconjugated. If so, the next steps
are:

* If anemia is present, evaluate for hemolysis and then for specific

hemolytic disorders.
* If there is no anemia, the patient should be evaluated for the possibility
of underlying liver disease, versus inherited disorders of impaired
bilirubin conjugation (Gilbert or Crigler-Najjar syndrome)
 Hepatitis A virus (HAV) infection occurs worldwide. HAV is spread
via the fecal oral route. The majority of patients who acquire the
illness have had personal contact with an infected person.

 HAV infection in children is typically an acute, self-limited illness

associated with nonspecific symptoms, such as fever, malaise,
anorexia, vomiting, nausea, abdominal pain or discomfort, and
diarrhea. During the prodromal period, aminotransferases are
typically elevated. Jaundice (conjugated hyperbilirubinemia) usually
occurs one week after onset of symptoms, along with choluria
(bilirubin in the urine) and mild hepatomegaly.

 HAV disease tends to be more severe when acquired at older ages.

Among younger children (under six years of age) with HAV infection,
only one-third develop symptomatic hepatitis and this often lasts
less than two weeks. In contrast, most older children and adults with
HAV infection are jaundiced and have hepatomegaly, and they are
usually symptomatic for several weeks.
 The diagnosis of acute HAV infection is made by the detection of
anti-HAV immunoglobulin M (IgM) in a patient with the typical clinical
presentation. This antibody is positive at the onset of symptoms,
peaks during the acute or early convalescent phase of the disease,
and remains positive for approximately four to six months.

 Hepatitis A vaccine is part of the recommended childhood and

adolescent immunization schedule. It is recommended as a two-
dose series for all children beginning at one year of age and also for
specific high-risk groups, including international travelers and
patients with chronic liver disease.

 HAV infection in children is usually a minor and self-limited infection

requiring no specific therapy. The usual supportive measures for
fever and diarrhea may be undertaken. Patients rarely require
hospitalization, except for those who develop acute liver failure.
Thank You