Jaundice in children: Difference between revisions
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*[[Infants]] usually [[Appearance|appear]] well. | *[[Infants]] usually [[Appearance|appear]] well. | ||
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| align="center" style="background:#DCDCDC;" + |'''[[Pathological]] [[jaundice|jaundice<ref name="pmid30422525" />]]''' | | align="center" style="background:#DCDCDC;" + |'''[[Pathological]] [[jaundice|jaundice<ref name="pmid30422525" />]][[Jaundice in children#cite%20note-pmid30422525-1|<span class="mw-reflink-text">[1]</span>]]''' | ||
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*Seen anytime from the first few hours of [[life]]. | *Seen anytime from the first few hours of [[life]]. | ||
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==Pathophysiology== | ==Pathophysiology== | ||
*[[Jaundice]] is caused by high [[concentrations]] of [[bilirubin]] in the [[bloodstream]] | *[[Jaundice]] is caused by high [[concentrations]] of [[bilirubin]] in the [[bloodstream]], a condition known as [[Hyperbilirubinemia]]. | ||
*[[Hyperbilirubinemia]] can result from abnormalities in the [[metabolism]] of [[bilirubin]] which could occur at any stage from its [[production]] which is as a result of the excessive [[breakdown]] of [[red blood cells]], defects in its [[hepatic]] [[metabolism]], and its post [[hepatic]] transport. | *[[Hyperbilirubinemia]] can [[result]] from [[abnormalities]] in the [[metabolism]] of [[bilirubin]] which could occur at any stage from its [[production]] which is as a [[result]] of the excessive [[breakdown]] of [[red blood cells]], [[Defect|defects]] in its [[hepatic]] [[metabolism]], and its post [[hepatic]] [[Transporter|transport]]. | ||
*[[Hemoglobin]] from the [[breakdown]] of effete [[red blood cells]] is composed of [[heme]] and [[globin]]. [[Globin]] is further dismantled into its component [[amino acids]] and [[recycled]] while [[heme]] is split into [[iron]] and [[biliverdin]] by the [[enzyme]], [[heme oxygenase]] in the [[reticuloendothelial]] [[system]]. [[Iron]] is transferred to [[ferritin]] and used again to make [[hemoglobin]] while [[biliverdin]] is converted to [[bilirubin]] by [[biliverdin reductase]]. <ref name="pmid30422525">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume= | issue= | pages= | pmid=30422525 | doi= | pmc= | url= }} </ref> | *[[Hemoglobin]] from the [[breakdown]] of effete [[red blood cells]] is composed of [[heme]] and [[globin]]. [[Globin]] is further dismantled into its component [[amino acids]] and [[recycled]] while [[heme]] is split into [[iron]] and [[biliverdin]] by the [[enzyme]], [[heme oxygenase]] in the [[reticuloendothelial]] [[system]]. [[Iron]] is transferred to [[ferritin]] and used again to make [[hemoglobin]] while [[biliverdin]] is converted to [[bilirubin]] by [[biliverdin reductase]]. <ref name="pmid30422525">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume= | issue= | pages= | pmid=30422525 | doi= | pmc= | url= }} </ref> | ||
*[[Water]]-insoluble [[bilirubin]] becomes coupled to [[albumin]] and transported into [[hepatic]] [[cells]] for conjugation. | *[[Water]]-insoluble [[bilirubin]] becomes coupled to [[albumin]] and transported into [[hepatic]] [[cells]] for [[conjugation]]. | ||
*This [[albumin]]-[[bilirubin]] compound is broken down and the | *This [[albumin]]-[[bilirubin]] compound is broken down and the [[unconjugated bilirubin]] enters the [[cytosol]] of [[hepatocytes]] to be [[Conjugated bilirubin|conjugated]] to [[glucuronic acid]] in the [[endoplasmic reticulum]] by the [[enzyme]], [[Uridine diphosphate glucuronyltransferase|uridine diphosphate glucuronyltransferase (UDPGT)]].<ref name="pmid31334972">{{cite journal| author=| title=StatPearls | journal= | year= 2020 | volume= | issue= | pages= | pmid=31334972 | doi= | pmc= | url= }} </ref> | ||
*This conjugated form of [[bilirubin]] is secreted into [[bile]] and then into the [[small intestine]] after being stored in the [[gall bladder]]. Subsequently reaches the [[colon]] where it is acted upon by [[bacterial]] [[flora]] and deconjugated to [[urobilinogen]]. Most are [[excreted]] into [[feces]] as the brown pigment, [[stercobilin]], and the rest is [[reabsorbed]] into the [[blood]], converted to yellow [[urobilin]] which is eventually excreted into the [[urine]]. | *This [[Conjugated bilirubin|conjugated]] form of [[bilirubin]] is [[Secretion|secreted]] into [[bile]] and then into the [[small intestine]] after being stored in the [[gall bladder]]. Subsequently reaches the [[colon]] where it is acted upon by [[bacterial]] [[flora]] and deconjugated to [[urobilinogen]]. Most are [[excreted]] into [[feces]] as the [[brown]] [[pigment]], [[stercobilin]], and the rest is [[reabsorbed]] into the [[blood]], converted to yellow [[urobilin]] which is eventually excreted into the [[urine]]. | ||
*[[Hyperbilirubinemia]] whether conjugated or unconjugated gives a clue as to the defective point in the [[metabolism]] of [[bilirubin]]. | *[[Hyperbilirubinemia]] whether [[Conjugated bilirubin|conjugated]] or [[Unconjugated bilirubin|unconjugated]] gives a clue as to the [[Defect|defective]] point in the [[metabolism]] of [[bilirubin]]. | ||
==Causes== | ==Causes== | ||
*Causes of [[jaundice]] in [[children]] can be classified as follows: | *[[Causes]] of [[jaundice]] in [[children]] can be [[Classification|classified]] as follows: | ||
{{familytree/start}} | {{familytree/start}} | ||
{{familytree| | | | | | | A01 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |A01=Causes of [[jaundice]] in [[children]]}} | {{familytree| | | | | | | A01 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |A01=Causes of [[jaundice]] in [[children]]}} |
Revision as of 22:09, 22 December 2020
Jaundice in children Microchapters |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ifeoma Anaya, M.D.[2]
Synonyms and keywords: Jaundice in kids, hyperbilirubinemia
Overview
The word 'Jaundice' was derived from the French word for yellow which is jaune. Jaundice may be classified into two broad categories based on its time of onset and cause such as physiologic and pathologic jaundice. Jaundice is caused by high concentrations of bilirubin in the bloodstream, a condition known as hyperbilirubinemia. Hyperbilirubinemia can result from abnormalities in the metabolism of bilirubin which could occur at any stage from its production which is a result of excessive breakdown of red blood cells, defects in its hepatic metabolism, and its post hepatic transport. Pathologic causes of jaundice can be classified into causes of conjugated and unconjugated hyperbilirubinemia. Differentials for jaundice are very limited however, some skin discolorations in healthy individuals can look like jaundice in certain circumstances. The prevalence of jaundice varies among patient populations. In infants born at term, 60% will develop jaundice in their first-week of life which rises to 80% in preterms. Common risk factors in the development of jaundice in children are a family history of jaundice, family history of a child born with jaundice, hyperthyroidism in mother, medication use by the mother etc. It is essential for every clinician to note that jaundice is not always a benign condition therefore, extensive investigation of a child with jaundice is necessary to prevent severe complications. Symptoms of jaundice in children may include the yellowish discoloration of skin, sclera, and mucous membrane. A useful technique in assessing the severity of jaundice is by using the principle of skin discoloration progressing in a cephalo-caudal direction in newborns. Laboratory findings include measuring the serum bilirubin from a blood sample. The total and conjugated portions are measured and the unconjugated fraction is measured by subtracting the conjugated fraction from the total. Echocardiography can detect cardiac abnormalities in patients with Alagille syndrome and biliary atresia. Ultrasonography of the abdomen is used to screen for biliary atresia, choledochal cysts, or cholestatic workup in the setting of conjugated hyperbilirubinemia. Treatment options include phototherapy, intravenous immunoglobulin (IVIG), and exchange transfusion. Pharmacological options are also there. Surgery is the mainstay of therapy or the definitive treatment for most obstructive causes of conjugated hyperbilirubinemia. Several etiologies may be generally difficult to prevent however, the prevention of complications from jaundice is equally crucial. Parents should be educated on how to recognize jaundice very early in a neonate so as to present promptly for the management.
Historical Perspective
- The word 'Jaundice' was derived from the French word for yellow which is jaune.[1]
- Very early records of Icterus neonatorum dates back to the medical records of the Providence Lying-in Hospital in the late 19th century. A feature observed amongst several neonates in the first week of life and attributed to breastfeeding.
- Icterus gravis, a more dire presentation was better understood in the 1940s when advances in immunology and genetics led to the discovery of the Rh group of red cell antigens. It explained its recurrent nature in families after a first child becomes affected. These advances also led to the development of effective treatment modalities along with screening methods such as maternal serology and amniocentesis in the perinatal period.
- An increase in birth rates during the Baby Boom period of the 1960s enabled the completion of clinical trials that led to the development of the Rh-immune antiglobulin, following a corresponding rise in the rate of neonatal jaundice. With screening and immunoglobulin prophylaxis, Rh erythroblastosis subsequently became very rare.[2]
- The idea behind the development of phototherapy was first discovered at Rochford General Hospital, Essex in the 1950s. Babies carried out to the warm sunshine with the aim of having a timeout from the incubator literarily became less yellow than before. Subsequently, lab results further confirmed this discovery. [3]
Classification
- Jaundice may be classified into two broad categories based on its time of onset and cause as shown in the table below:
Type of Jaundice | Details |
---|---|
Physiologic jaundice |
|
Pathological jaundice[1][1] |
Pathophysiology
- Jaundice is caused by high concentrations of bilirubin in the bloodstream, a condition known as Hyperbilirubinemia.
- Hyperbilirubinemia can result from abnormalities in the metabolism of bilirubin which could occur at any stage from its production which is as a result of the excessive breakdown of red blood cells, defects in its hepatic metabolism, and its post hepatic transport.
- Hemoglobin from the breakdown of effete red blood cells is composed of heme and globin. Globin is further dismantled into its component amino acids and recycled while heme is split into iron and biliverdin by the enzyme, heme oxygenase in the reticuloendothelial system. Iron is transferred to ferritin and used again to make hemoglobin while biliverdin is converted to bilirubin by biliverdin reductase. [1]
- Water-insoluble bilirubin becomes coupled to albumin and transported into hepatic cells for conjugation.
- This albumin-bilirubin compound is broken down and the unconjugated bilirubin enters the cytosol of hepatocytes to be conjugated to glucuronic acid in the endoplasmic reticulum by the enzyme, uridine diphosphate glucuronyltransferase (UDPGT).[4]
- This conjugated form of bilirubin is secreted into bile and then into the small intestine after being stored in the gall bladder. Subsequently reaches the colon where it is acted upon by bacterial flora and deconjugated to urobilinogen. Most are excreted into feces as the brown pigment, stercobilin, and the rest is reabsorbed into the blood, converted to yellow urobilin which is eventually excreted into the urine.
- Hyperbilirubinemia whether conjugated or unconjugated gives a clue as to the defective point in the metabolism of bilirubin.
Causes
- Causes of jaundice in children can be classified as follows:
Causes of jaundice in children | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Physiologic | Pathologic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Unconjugated hyperbilirubinemia | Conjugated hyperbilirubinemia | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Hemolytic | Non-hemolytic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
•Rh incompatibility •ABO incompatibility •Hemoglobinopathies (Thalassemia) •Hematomas •Polycythemia •Sepsis | •Crigler-Najjar syndrome I and II •Gilbert syndrome •Breast milk jaundice | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Infectious | Obstructive | Drugs | Genetic/Metabolic | Storage disorders | Endocirnopathies | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
•Viral •Bacterial •Parasitic | •Biliary atresia •Choledochal cyst •Inspissated bile syndrome •Neonatal sclerosing cholangitis •Congenital hepatic fibrosis •Intrinsic/extrinsic mass | •Ceftriaxone •Isoniazid •Erythromycin •Rifampin •Sulfa drugs •Parenteral nutrition •Methotrexate | •Alpha 1 antitrypsin deficiency •Alagille syndrome •Cystic fibrosis •Tyrosinemia •Galactosemia •Rotor syndrome •Trisomy 18 and Trisomy 21 | •Gaucher's disease •Niemann-pick disease •Glycogen storage diseases •Mucolipidoses | •Hypopituitarism •Hypothyroidism •McCune Albright syndrome | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differentiating Jaundice in children from other Diseases
- Alternative diagnosis for jaundice are limited however, some skin discolorations in healthy individuals can reemble jaundice in certain circumstances.
- Use of the antimalarial and antihelminthic drug, Quinacrine can cause yellowish discoloration of the skin of individuals who take it.
- Excessive consumption of fruits and vegetables high in carotenes such as carrots and sweet potatoes can cause a skin discoloration termed as Carotenoderma.
- The above differentials spare the mucous membranes and sclera. [1][4]
Epidemiology and Demographics
- The prevalence of jaundice varies among patient populations.
- In infants born at term, 60% will develop jaundice in their first-week life. This rises to 80% in preterms. [1]
- 5-10% of neonates will require being admitted for the treatment of pathological jaundice. [5]
- Causes of jaundice also vary with age groups. In newborns, immature hepatic conjugation, hemolysis, and certain congenital disorders are top causes while Hepatitis A infection is a cause seen more in older children.
- Death rate is 0.28 per 1 million live births. [4]
Age
- Patients of all age groups may develop jaundice.
- It is more commonly observed in newborns and the elderly populations. [4]
Gender
- Gender preference can be observed in the etiology of jaundice.
- An example is the documented male preponderance of Glucose-6-Phosphate dehydrogenase (G6PD) deficiency with an incidence of 4.5% males to 0.5% in females. [6]
Race
- Racial predilection for jaundice is observed in a cause of unconjugated hyperbilirubinemia, Gilbert syndrome.
- A genetic mutation in the gene responsible for the production of the enzyme, UDPGT is its cause. Diagnosis is made only when alternative explanations have been ruled out. Symptoms are triggered by stressful situations like dehydration, illness.
- It has a prevalence of 5-10% in Caucasian and Asian populations. [6]
Risk Factors
- Common risk factors in the development of jaundice in children are:
- Family history of jaundice
- Family history of a child born with jaundice
- Hyperthyroidism in mother
- Medication use by mother
- Gestational Diabetes Mellitus (GDM)
- Race (Asian)
- Age >25 years
- ABO incompatibility
- Rh incompatibility
- Exclusive breastfeeding
- Inability to breastfeed adequately
- Primiparity
- Oxytocin use during labor
- Prematurity
- Weight loss(child)
- Male gender
- Polycythemia
- Hematoma in spleen or liver, cephalhematoma, causing excessive hemolysis with red blood cell breakdown
- Trisomy 21
- G6PD deficiency
- Congenital infection (TORCHES) [7] [1]
Natural History, Complications and Prognosis
- It is essential for every clinician to note that jaundice is not always a benign condition therefore, extensive investigation of a child with jaundice is necessary to prevent severe complications.
- In the setting of very high unconjugated bilirubin levels, a rare complication known as Bilirubin-induced neurological dysfunction (BIND) is observed.
- Elevated levels of unconjugated bilirubin crosses the immature blood-brain-barrier of neonates binding to glial tissue and brainstem nuclei.
- Lack of colonic bacteria in neonates also predisposes them to this outcome due to increased enterohepatic reabsorption of deconjugated bilirubin.
- Bilirubin encephalopathy, a catastrophic neurologic outcome known as Kernicterus or death are likely complications if treatment is either delayed or not promptly instituted.
- Early symptoms of kernicterus are:
- As the illness progresses, more severe symptoms are:
- Seizures
- Muscular spasms
- Cerebral palsy
- Learning problems
- Loss of hearing
- Complications from the causes of conjugated hyperbilirubinemia include:
- Liver failure
- Malabsorption of fat and fat-soluble vitamins from cholestasis
- Portal hypertension
- Cirrhosis
- Progression to hepatocellular carcinoma (HCC)
- Cholangiocarcinoma in patients with choledochal cyst
- Post Kasai procedure ascending cholangitis
- Prognosis is promising with prompt diagnosis and treatment. However, conjugated hyperbilirubinemia from obstructions of the hepatic and biliary tree have poorer outcomes. [4]
Diagnosis
Symptoms
- Symptoms of Jaundice in children may include the following:
- Skin, sclera, and mucous membrane discoloration.
- Time of onset and duration
- Progression. Involvement up to what body part?
- Poor feeding
- Irritability
- Fever
- Pruritus
- Rash
- Pains in the joints
- Recent travel history
- Diarrhea
- Urine and stool color change
- Anorexia
- Weight loss
- Body pains like abdominal discomfort/pains?
Physical Examination
- Patients appear yellow on the skin, mucous membranes, and/or sclera. A useful technique in assessing the severity of jaundice is by using the principle of skin discoloration progressing in a cephalo-caudal direction in newborns.
- If discoloration has progressed to the thigh level, samples for urgent serum bilirubin should be taken.
- This method is not necessary for infants who are already receiving phototherapy and those with darker colored skin.
- Other findings on examination are:
- Irritable infant
- Fever
- Rash
- Examine urine and stool
- Small or large for age
- Lymph node enlargement
- Muscle spasms
- Unconsolable cry
- Cardiac murmurs
- Hepatomegaly
- Splenomegaly
- Ascites
Laboratory Findings
- Measuring the level of bilirubin.
- Serum bilirubin from a blood sample. The total and conjugated portions are measured and the unconjugated fraction is measured by subtracting the conjugated fraction from the total.
- Knowing the type of hyperbilirubinemia will guide further workup in identifying the cause of jaundice. Conjugated or mixed hyperbilirubinemia gives a speculation of hepatic or post-hepatic etiology.
- Transcutaneous bilirubinometer. The accuracy of this can be altered by skin thickness and color.
- Bilimeter
- Complete blood count with differentials and smear
- Blood and Rh group
- G6PD levels
- Newborn screening for:
- To assess liver synthetic function:
- Liver function tests
- Alpha 1 antitrypsin levels and phenotype
- Viral serologies
- Serum ammonia
- Blood cultures
- Urinalysis
- Urine microscopy, culture, and sensitivity
- Stool microscopy, culture, and sensitivity
- TORCH screening
- Serum ferritin
- Serum ceruloplasmin
- Autoimmune antibodies
Electrocardiogram
- There are no ECG findings associated with Jaundice in children.
- It may be used to monitor cardiac rhythms during treatment.
X-ray
- Chest radiograph can reveal cardiomegaly in individuals with Alagille syndrome.
Echocardiography and Ultrasound
- Echocardiography can detect cardiac abnormalities in patients with Alagille syndrome and biliary atresia.
- Ultrasonography of the abdomen is used to screen for biliary atresia, choledochal cysts or cholestatic workup in the setting of conjugated hyperbilirubinemia.[6]
CT scan
- CT scan of the abdomen is used to screen for biliary atresia, choledochal cysts, or cholestatic workup in the setting of conjugated hyperbilirubinemia.
MRI
- MRI is used to screen for biliary atresia, choledochal cysts, or cholestatic workup in the setting of conjugated hyperbilirubinemia.
Other Imaging Findings
- Other imaging modalities used for screening for cholestatic workup include the following:
- Magnetic resonance cholangiopancreatography (MRCP)
- Endoscopic retrograde cholangiopancreatography (ERCP)
- Hepatobiliary scintigraphy with technetium-labeled iminodiacetic acid analog (HIIDA)
- Percutaneous transhepatic cholangiography (PTC)
Other Diagnostic Studies
- Diagnostic laparoscopy with/without treatment
- Liver biopsy
Treatment
Medical Therapy
- Treatment of Jaundice is usually tailored towards the underlying etiology whether it a hematologic disease or a hepatobiliary pathology.[4]
- Treatment options include the following:
- Phototherapy: Usually first line in neonates with severe hyperbilirubinemia to prevent neurologic sequelae.
- Intravenous immunoglobulin(IVIG): helpful in hemolytic diseases and can be used in place of phototherapy and/or exchange transfusion.
- Exchange transfusion: When the above options become inadequate to reduce levels of rising bilirubin or at the slightest clue of bilirubin encephalopathy, an exchange transfusion is done usually in the NICU/PICU and should be closely followed up for complications like:[1]
- Cardiac arrhythmias
- Sepsis
- Hyperkalemia
- Hypocalcemia
- Necrotising enterocolitis
- Exchange transfusion also removes hemolytic antibodies from Rh isoimmunization and ABO incompatibility.
- Pharmacologic remedies such as:
- Patients with pruritus especially older kids can be treated with warm baths or given antihistamines. Cholestyramine can be used in severe cases of pruritus. [4]
- Appropriate antiviral, antibacterial and antiparasitic therapy for jaundice of viral, bacterial and parasitic etiology respectively.
Surgery
- Surgery is the mainstay of therapy or the definitive treatment for most obstructive causes of conjugated hyperbilirubinemia.
- Examples of procedures for common disorders are:
- Choledochoentersotomy for choledochal cyst
- Hepatoportoenterostomy or the Kasai procedure for biliary atresia[8]
- Irrigation of the biliary tract for inspissated bile
- Surgical drainage for common bile duct perforation
- Timing of procedure with regards to the age of the child, nutritional support in the form of vitamins, and caloric replacements are extremely essential for the success of the procedure.
Prevention
- Several etiologies may be generally difficult to prevent however the prevention of complications from jaundice is equally crucial.
- Parents should be educated on how to recognize jaundice very early in a neonate so as to present promptly for management. Some phone apps and an icterometer are novel means of accurately detecting jaundice.[1]
- Appropriate vaccinations should be received prior to international travels.
- Prescribed medications should be taken in recommended dosages.
- Herbal medications should be avoided unless a physician clears it as safe.
- Smoking, use of illicit drugs, and excess alcohol intake should be avoided in children and pregnant women.
- Proper hand washing for pregnant mothers.
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "StatPearls". 2020. PMID 30422525.
- ↑ Mittendorf R, Williams MA (1991). "Rho(D) immunoglobulin (RhoGAM): how it came into being". Obstet Gynecol. 77 (2): 301–3. doi:10.1097/00006250-199102000-00029. PMID 1846439.
- ↑ Weiss EM, Zimmerman SS (2013). "A tale of two hospitals: the evolution of phototherapy treatment for neonatal jaundice". Pediatrics. 131 (6): 1032–4. doi:10.1542/peds.2012-3651. PMID 23650299.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "StatPearls". 2020. PMID 31334972.
- ↑ Mishra S, Agarwal R, Deorari AK, Paul VK (2008). "Jaundice in the newborns". Indian J Pediatr. 75 (2): 157–63. doi:10.1007/s12098-008-0024-7. PMID 18334797.
- ↑ 6.0 6.1 6.2 Chee YY, Chung PH, Wong RM, Wong KK (2018). "Jaundice in infants and children: causes, diagnosis, and management". Hong Kong Med J. 24 (3): 285–292. doi:10.12809/hkmj187245. PMID 29807950.
- ↑ Mojtahedi SY, Izadi A, Seirafi G, Khedmat L, Tavakolizadeh R (2018). "Risk Factors Associated with Neonatal Jaundice: A Cross-Sectional Study from Iran". Open Access Maced J Med Sci. 6 (8): 1387–1393. doi:10.3889/oamjms.2018.319. PMC 6108787. PMID 30159062.
- ↑ Kelly DA, Davenport M (2007). "Current management of biliary atresia". Arch Dis Child. 92 (12): 1132–5. doi:10.1136/adc.2006.101451. PMC 2066090. PMID 17878208.