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Flashcards in Congenital Liver Disease Deck (22)
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A pediatric patient, less than 10 years, comes in complaining of jaundice, right upper quadrant pain and a palpable RUQ mass. What are you thinking?

*choledochal cyst
*The biliary tree can demonstrate a variety of structural abnormalities.
*One of the most common is choledochal cyst, which is a dilation of the biliary tree.
*Most cases present before the age of 10 years with jaundice and abdominal pain.
*The classic triad of presenting symptoms, seen in 40% of patients, is jaundice, abdominal pain, and a right upper quadrant mass.


what is jaundice and why are you concerned about it in the neonate?

Jaundice (icterus) refers to yellowish pigmentation of the skin and sclerae, and is due to abnormally high levels of bilirubin in the blood (hyperbilirubinemia).
*Jaundice is a common finding in the newborn period.
*The differential diagnosis of neonatal jaundice is long, and includes both completely innocuous causes and serious disorders requiring prompt recognition and therapy.
*Thus, the correct diagnosis of neonatal jaundice is very important.


What is physiologic jaundice? is it worrisome?

*Think of it as a symptom, that can be worsened by events like birth trauma, sepsis and hypoxia. However, those things are already "done" at birth. physiologic jaundice is common and not emergent.
*Many newborns experience a period of physiologic jaundice, which is related to an inability to adequately conjugate bilirubin.
*These infants have an elevated level of unconjugated bilirubin.
*The mechanism for conjugation of bilirubin is not mature until approximately 2 weeks of age. Additionally, during this time, increased bilirubin production occurs because of the breakdown of fetal red blood cells.
*prematurity is another factor that worsens physiologic jaundice
*Additionally, breast milk contains beta-glucuronidases, which deconjugate bilirubin glucuronides in the gut, also contributing to increased jaundice.
*Physiologic jaundice is usually self-limited but phototherapy can be used. Phototherapy transforms bilirubin into isomers, which can be excreted in bile and urine.


When you see elevated levels of conjugated bilirubin, what need you do to exclude problematic causes?

*Elevated levels of conjugated bilirubin in the neonate occur in approximately 1 in 2500 live births.
*Etiologies to be excluded include:
* infection (viral and bacterial),
*metabolic disorders (including alpha-1 antitrypsin deficiency, cystic fibrosis and metabolic storage disorders),
*bile duct obstruction (especially extrahepatic biliary atresia),
*and medication effects.
*Once these etiologies have been excluded, patients may fall into the category of idiopathic neonatal hepatitis; this classification is continually diminishing as specific etiologies are identified and defined.


what is the treatment for Biliary Atresia?

In the neonate setting = BA = biliary atresia
*Treatment includes hepatoportoenterostomy, also known as the Kasai Procedure.
*In this procedure, the extrahepatic biliary system is excised and a loop of small bowel is connected to the hepatic hilum to allow for bile drainage. The success of this procedure decreases after day of life 60.
*Therefore bile duct obstruction should be considered and excluded in all infants with persistent neonatal cholestasis.


What is Biliary Atresia?

Biliary Atresia is an important cause of neonatal cholestasis.

*Two forms are described. The perinatal form is more common and accounts for 65-90% of cases. In this disorder, the extrahepatic biliary tree is normal at birth and undergoes progressive destruction.
*Patients are usually of normal birth weight and have normal post birth weight gain; however, they develop late onset jaundice with progressively acholic stools.
*Most commonly, atresia of the entire extrahepatic biliary system is present.
*Proposed etiologies include infection, toxin, autoimmune destruction (in a neonate? huh.), and underlying genetic lesions.
*Histological findings on liver biopsy include: cholestasis in hepatocytes, canaliculi, and bile ducts; portal fibrosis with prominent bile duct proliferation; variable inflammation.
*These histologic findings are suggestive of BA; however, definitive diagnosis requires a cholangiogram to assess the patency of the biliary tree.


How do you arrive at a dx of biliary atresia?

*Histological findings on liver biopsy include: cholestasis in hepatocytes, canaliculi, and bile ducts; portal fibrosis with prominent bile duct proliferation; variable inflammation.
*These histologic findings are suggestive of BA; however, definitive diagnosis requires a cholangiogram to assess the patency of the biliary tree.


what is the less common cause and presentation of biliary atresia?

*most common cause is normal at birth with subsequent destruction
*The less common embryonic/fetal form of biliary atresia (10-35% of cases) probably represents a congenital structural anomaly of the biliary tree, and is usually associated with other congenital anomalies. In this form, infants develop progressive jaundice immediately after birth.


What can happen after the Kasai procedure?

The success of the procedure is limited by intrahepatic progression of disease and infection. Patients often progress to cirrhosis and require liver transplantation for long-term survival. Biliary atresia is the number one pediatric disorder requiring liver transplantation.


If you can't find a definite etiology, what is the dx of exclusion for neonatal liver problems?

25-40% of infants with conjugated hyperbilirubinemia continue to have an undiagnosed etiology and may be categorized as having idiopathic neonatal hepatitis.
*Over 85% of cases are sporadic and 10-15% familial.
*Patients usually exhibit hepatomegaly and conjugated hyperbilirubinemia without a definable etiology.
*Findings on liver biopsy show cholestasis, prominent giant cell transformation of hepatocytes, minimal inflammation, and normal bile ducts.


You see: *Findings on liver biopsy show cholestasis, prominent giant cell transformation of hepatocytes, minimal inflammation, and normal bile ducts.

you should be thinking idiopathic neonatal hepatitis.


What's up with TPN (Total Parenteral Nutrition) hepatopathy?

TPN (Total Parenteral Nutrition) hepatopathy is seen in the context of disease requiring more than short-term administration of TPN.
*The most common contexts are gastrointestinal diseases, such as congenital anatomic defects of the GI tract and necrotizing enterocolitis.
*The risk and severity are roughly proportional to duration of TPN therapy.
*Biopsy findings are similar to, and can be indistinguishable from, those in biliary atresia. The majority of cases will resolve once TPN is discontinued, but some patients can progress to cirrhosis.


What genetic condition can lead to unconjugated hyperbilirubinemia?

Unconjugated hyperbilirubinemia:
-Crigler –Najjar Syndrome: A genetic mutation leads to lack of (Type I) or decrease in (Type II) UDP-glucuronyltransferase (UGT1A1), which normally conjugates bilirubin to glucuronic acid, thus making water-soluble bilirubin glucuronides, which are excreted in bile.
*Bile contains only trace amount of unconjugated bilirubin.
*Serum unconjugated bilirubin levels are extremely high in these conditions
* Type I is fatal without liver transplantation. Patients with Type II have jaundice, but are otherwise asymptomatic, and can have a normal life expectancy.


What is the disorder that causes CYCLICAL unconjugated hyperbilirubinemia?

-Gilbert Syndrome: Patients have mild, benign fluctuating levels of serum bilirubin due to a decrease in UGT1A1 activity. Patients experience episodic jaundice, often during periods of physiologic stress such as illness.


What is a genetic disorder that causes CONJUGATED hyperbilirubinemia?

-Dubin-Johnson Syndrome: Results from hereditary defect in excretion of bilirubin glucuronides across the canalicular membrane due to absence of multidrug resistance protein 2.
*Patients may have episodic jaundice, but most have normal life expectancy.


what types of glycogen storage disorders are caused by liver problems? (STEP)

-Glycogen storage disorders: Enzyme defects result in abnormal accumulation of glycogen in hepatocytes and other organs. These are classified by enzyme defect and location of accumulated glycogen. The liver is involved in Types I, III, IV, VI, and IX. Other disorders of carbohydrate metabolism include galactosemia and fructosemia.


Which Lysosomal storage disorders are found in liver problems? (STEP)

-Lysosomal storage disorders
-Lipid: Wolman Disease, defect in cholesterol ester storage
-Sphingolipidoses: Niemann Pick Disease (sphingomyelin) and Gaucher Disease (glucosyl ceramide)
-Oligosaccharidoses: abnormal glycoprotein degradation, including Farber and Fabry Diseases (ceramide accumulation)


A patient with a seemingly benign febrile condition suddenly tanks and dies. You suspect Reye syndrome. What metabolic problems can cause this?

-Defects in fatty acid oxidation may clinically resemble Reye Syndrome
* resulting in rapid childhood death from seemingly innocuous febrile illness.
*Examples include carnitine deficiency, and defects in acyl-CoA-dehydrogenases.


What is reye syndrome?

Reye Syndrome is a now rare disorder related to mitochondrial dysfunction.
*Most cases were seen in association with salicylate use in children with viral infection and fever. Initial fever and upper respiratory illness with initial recovery were followed by acute onset vomiting, delirium and progression to coma and death.
*Mechanism of disease was related to mitochondrial injury, especially in liver, brain, and skeletal muscle. Patients accumulated fat in liver, kidneys, myocardium and skeletal muscle. Cerebral edema was common.
*Treatment included supportive measures, hydration, and monitoring of intracranial pressure. This disorder is now rare, probably do to decreased salicylate use in children.


What are the benign neoplasms to consider in the neonate? (liver)

Benign Neoplasms in neonate liver
-Mesenchymal Hamartoma: Benign infantile neoplasm with 85% presenting at < 2 years. Symptoms include nontender, abdominal enlargement over days to months with associated vomiting, decreased appetite, and respiratory distress. Alpha fetoprotein levels are not increased, in contrast to hepatoblastoma.
*Surgical resection is the treatment of choice.
*Pathology shows a multicystic lesion composed of an admixture of primitive, but histologically benign, mesenchyme, bile ducts, and cords of hepatocytes.

*Other benign primary hepatic neoplasms include:
-Hepatocellular adenoma
-Focal nodular hyperplasia


What is the most common malignant neoplasm of the liver in children?

-Hepatoblastoma accounts for 27% pediatric liver tumors and 47% of malignant pediatric liver tumors.
*90% of cases present before age 5 yrs. A male to female ratio of 2:1 is reported.
*The tumor recapitulates hepatogenesis and, unlike hepatocellular carcinoma, arises in an otherwise normal liver (ie: not in the context of underlying chronic liver disease).
*Histological subtypes include epithelial and mesenchymal histology.
*Symptoms include an enlarged abdomen, anorexia, weight loss, nausea, vomiting, and pain.
*Most cases (90%) have an elevated alpha-fetoprotein level (tumor marker); beta-hCG may be elevated as well.
*Activation of the Wnt/Beta catenin pathway is present
*There is an increased incidence in Beckwith-Wiedemann Syndrome and Familial Adenomatous Polyposis, and 80% of cases show activation of the Wnt/beta-catenin signaling.
*Treatment consists of preoperative chemotherapy and surgical resection. The most important prognostic factor is stage at time of resection.


What other malignancy in the child liver should you be worried about if there is a concurrent congenital liver problem?

-Hepatocellular Carcinoma is primarily a malignancy of adults but also occurs in children, usually at an older age than hepatoblastoma (> 5 yrs). It usually presents in the background of chronic liver disease, such as congenital hepatitis B infection or metabolic disease. As in hepatoblastoma, serum alpha-fetoprotein is elevated.