Liver Disorders

Hepatology encompasses a wide range of conditions, from common disorders, such as viral and autoimmune hepatitis, to relatively rare disorders, such as genetic and metabolic disorders that cause neonatal cholestasis. Key areas to aid in the care of pediatric patients with acute and chronic liver disease, cholestasis, and post-liver transplantation are discussed in this section.

The following topics are addressed in this section:

• Liver Anatomy

• Jaundice, Cholestasis, and Biliary Atresia

• Acute and Chronic Hepatitis and Liver Failure

• Cirrhosis

• Liver Transplantation

Liver Anatomy

The Couinaud classification of liver anatomy divides the liver into eight functionally independent segments. Each segment has its own vascular inflow, outflow, and biliary drainage. In the center of each segment is a branch of the portal vein, hepatic artery, and bile duct. In the periphery of each segment is vascular outflow through the hepatic veins. The liver is also divided into the left lobe (segments 2-4), right lobe (5-8), and caudate lobe.

(Source: RANZCRPart1 Wiki 2015.)

Hepatic Circulation: The liver receives inbound blood supply through two sources:

• The hepatic artery carries oxygenated blood from the general circulation.

• The portal vein carries deoxygenated blood and nutrients from the small intestine.

Blood from both the hepatic artery and portal vein mix in the liver sinusoids, which are fenestrated to allow substrates to pass between the blood and hepatocytes. Deoxygenated blood exists the hepatic circulation through the hepatic vein and joins systemic circulation through the inferior vena cava.

Jaundice, Cholestasis, and Biliary Atresia

Jaundice

Jaundice is a clinical sign of hyperbilirubinemia (unconjugated and/or conjugated bilirubin). Patients with jaundice present with yellow discoloration of the skin and eye sclera. Jaundice can be caused by a variety of disorders, including bilirubin overproduction, impaired bilirubin conjugation, biliary obstruction, and hepatic inflammation.

Neonatal jaundice: Although jaundice is common in neonates, it is usually related to unconjugated hyperbilirubinemia, as seen in physiological jaundice, breastfeeding jaundice, and hemolytic conditions such as ABO incompatibility. Jaundice related to a rise in conjugated bilirubin in the blood is less common.

Cholestasis

Cholestasis is defined as direct or conjugated bilirubin ≥1 mg/dL. The terms conjugated and direct bilirubin are often used interchangeably, but they are not exactly equivalent. Direct bilirubin includes both conjugated bilirubin and delta bilirubin (conjugated bilirubin bound to albumin).

Causes of cholestasis include the following:

• massive hepatocellular necrosis

• impaired bile acid and subsequent bile formation at the hepatocellular level (bile acid synthesis defects)

• impaired bile flow at the hepatocellular-canaliculi transmembrane level or impaired bile flow secondary to bile duct dysfunction (bile duct dysfunction may be caused by processes that affect the small intrahepatic bile ducts or the extrahepatic biliary track and the common bile duct as it courses toward the ampulla of Vater in the second portion of the duodenum)

Neonatal Cholestasis: Neonatal cholestasis is generally defined as conjugated hyperbilirubinemia ≥1 mg/dL that occurs in the newborn period or shortly thereafter (within the first 3 months of life). Prevalence of neonatal cholestasis in term infants is 1:2500. Cholestasis results from diminished bile formation, excretion, or both, which can be caused by a number of disorders, most commonly biliary atresia. Typically, diseases that cause neonatal cholestasis manifest before 2 months of age.

Causes of neonatal cholestasis:

• Biliary atresia (BA) is the most common identifiable cause of cholestasis in infancy. BA is a progressive, idiopathic, fibro-obliterative disease of the intra- and extrahepatic biliary tree and is also the most common indication for liver transplantation in childhood. Most patients have isolated BA. Syndromes and congenital anomalies associated with BA include the following:

  • BA with laterality: situs inversus, asplenia or polysplenia, malrotation, cardiac defects

  • BA with anomalies without laterality: imperforate anus, renal and cardiac defects

• Other common causes of neonatal cholestasis are listed in the following table:

Evaluation and Diagnosis of Neonatal Cholestasis

Neonates with jaundice from cholestasis: Always evaluate the eyes for the presence of yellow (icteric) sclera. Skin color might make recognition of jaundice relatively challenging. Jaundice in infants age 2 weeks or older should be investigated further with measurement of unconjugated and conjugated bilirubin levels, as cholestasis at this age is never normal.

Initial laboratory studies in most infants with cholestasis should include:

• comprehensive metabolic panel (CMP)

• complete blood count with differential (CBC/diff)

• prothrombin time/international normalized ratio (PT/INR)

• aspartate aminotransferase (AST), alanine aminotransferase (ALT)

• total protein/albumin

• total and direct bilirubin

• gamma-glutamyl transferase (GGT)

Clinical questions: Consider the following questions in the evaluation of a neonate with cholestasis:

• Questions related to history:

  • Is the patient clinically stable? If not, then evaluate for sepsis and metabolic disorders.

  • Is the patient lethargic? If yes, it could be an indication of underlying metabolic disorder, sepsis, or acute liver failure.

  • Has the neonate developed ascites? If yes, consider gestational alloimmune liver disease (GALD), Niemann-Pick disease type C, or hemophagocytic lymphohistiocytosis (HLH).

  • Is the patient gaining weight adequately? If yes, an underlying metabolic disease is unlikely. On the contrary, neonates with BA usually appear well and not in distress and generally thrive during the first weeks of life.

  • Are stools acholic? If yes, strongly consider BA, choledochal cyst, common bile duct obstruction by gallstone, or external compression.

• Questions related to laboratory test results:

  • Is the patient coagulopathic with an INR >2? If yes, consider GALD, tyrosinemia, sepsis, HSV hepatitis, or viral hepatitis on the differential.

  • Is the GGT normal or low? If normal or low, consider genetic disorders such as progressive familial intrahepatic cholestasis (PFIC), bile acid synthetic defects (BASD), and arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome.

Imaging

• Abdominal ultrasound is necessary to evaluate for choledochal cyst, biliary tract malformations, gallstones, or external compression of the biliary tract leading to neonatal cholestasis.

• Abdominal Doppler is used to evaluate for hepatic vasculature patency and presence of congenital portosystemic shunts.

• Hepatobiliary iminodiacetic acid (HIDA) scan, also known as hepatobiliary scintigraphy, is a nuclear medicine scan used to assess the integrity of the hepatobiliary system. When used with phenobarbital for five days prior to the study, HIDA scan is highly sensitive (>95%) for BA. Given the need for timely diagnosis of BA, the 5 days required for this strategy is often avoided and more formal diagnosis with intra-operative cholangiogram is replacing this diagnostic tool.

• Intra-operative cholangiogram is the gold-standard testing for the diagnosis of BA. This is a surgical procedure during which the operator localizes the gall bladder and injects contrast within it to attempt to define the anatomy of the biliary tree while radiographs are performed. In BA, no biliary tree is identifiable.

Management of neonatal cholestasis: Treatment of patients with neonatal cholestasis depends on etiology, as follows:

• Biliary atresia: treated with the Kasai procedure before 90 days of life (earlier surgery is associated with better outcomes) as well as nutritional support with formula rich in medium-chain triglyceride oil and supplementation of fat-soluble vitamins

• Choledochal cyst (abnormal dilatation of the biliary tree): The five different types of choledochal cysts are based on the location of the dilatation (extrahepatic, intrahepatic, or both) and are treated as follows:

  • Type I, II, or IV cyst: Treatment is surgical resection due to the significant risk of malignancy.

  • Type III cyst: Cyst requires treatment when symptomatic and could be managed with sphincterotomy or endoscopic resection in the absence of neoplasia.

  • Type V cyst: Patients commonly experience recurrent cholangitis and sepsis; treatment is mainly supportive, but type V cysts can be difficult to manage and some patients eventually require liver transplantation.

(Source: Surgical Resection of a Type IVa Choledochal Cyst. Oncohema Key 2017.)

• HSV hepatitis: Treat with intravenous acyclovir.

• GALD: Treat with exchange transfusion and intravenous immune globulin (IVIG).

• Metabolic disorders: Each metabolic disorder requires a different treatment plan; patients may present in metabolic decompensation and be clinically unstable. Hence, initial management should include:

  • Discontinuation of feeds

  • Maintenance of glucose infusion rate (GIR) with dextrose infusion

  • Replacement of electrolytes

  • Correction of metabolic acidosis or alkalosis while evaluating the patient for the underlying metabolic disorder

• Neonatal acute liver failure: Provide treatment in a tertiary center where liver transplantation evaluation can be initiated.

Acute and Chronic Hepatitis and Liver Failure

Hepatitis refers to inflammation of the liver. Hepatitis is classified as either acute or chronic, based on the duration of abnormal liver enzymes or bilirubin levels.

Diagnosis: Suspect hepatitis in any patient who presents with cholestasis, generalized symptoms (e.g., fatigue, vague abdominal pain, weight loss, petechiae), or both. Hematemesis, hematochezia, and melena are unusual initial presentation symptoms of hepatitis.

• First evaluate for liver failure by assessing liver synthetic function with international normalized ratio (INR). If INR is >2, or >1.5 and the patient has signs of hepatic encephalopathy (see Stages of Hepatic Encephalopathy in Pediatric Patients), and the INR does not correct with subcutaneous vitamin K administration, the patient is experiencing liver failure.

• Initial evaluation should include a detailed history, physical exam, and laboratory testing to identify underlying etiology for hepatitis and to evaluate electrolyte levels and renal function.

• Patterns of liver enzyme elevation can suggest particular diagnoses. Additional laboratory testing as indicated in the tables below can assist in making a diagnosis. Biopsy is useful when the underlying condition is unclear based on laboratory testing and to assess for fibrosis or cirrhosis.

Acute Hepatitis

Acute hepatitis connotes new onset (<6 months) of liver inflammation and elevated liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT]). The following table describes laboratory testing and clinical features based on the underlying etiology:

Acute Liver Failure

Acute liver failure refers to the development of severe acute liver injury with encephalopathy and impaired synthetic function (INR ≥1.5) in a patient without cirrhosis or preexisting liver disease. Although reports of the time course that differentiates acute liver failure from chronic liver failure varies, a commonly used cutoff is an illness duration of <26 weeks.

Diagnosis: In children, diagnosis of acute liver failure requires the following criteria:

• onset of hepatic failure within 8 weeks of onset of clinical liver disease in a patient with no previous evidence of chronic liver disease

• biochemical evidence of acute liver injury, generally as elevated AST, ALT, and/or total and conjugated bilirubin

• coagulopathy not corrected by vitamin K (prothrombin time [PT] ≥15 seconds or INR ≥1.5)

• clinical evidence of encephalopathy required for patients with an INR >1.5 but <2.0 but not required if coagulopathy is severe (PT ≥20 seconds or INR ≥2.0)

Evaluation: Clinical questions that arise during evaluation of acute liver failure in a child include the following:

• Is this a reversible condition?

• Is there treatment for the underlying condition?

• Does the patient need liver transplantation to survive?

Management: Patients with acute liver failure should be managed in the intensive care unit (ICU) at a tertiary hospital that can provide pediatric liver transplantation as a treatment option. Otherwise, the patient needs to be transferred to a transplant center before they become unstable. Management involves three arms:

• Maintain clinical stability until transplantation or recovery of hepatic synthetic function; avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and benzodiazepines.

• Initiate workup to identify underlying etiology for fulminant acute liver failure.

• Initiate liver transplantation evaluation workup.

Chronic Hepatitis

Chronic hepatitis refers to inflammation of the liver with elevation of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) that lasts at least 6 months. The following table describes the diagnosis and management of chronic hepatitis based on etiology.

Cirrhosis

Cirrhosis represents the late stage of progressive hepatic fibrosis, with distortion of hepatic architecture and nodule formation. It is considered irreversible in late stages, and the only treatment option is liver transplantation.

Patients with cirrhosis develop portal hypertension and related complications such as ascites (most common), spontaneous bacterial peritonitis, upper (and rarely lower) gastrointestinal (GI) bleeding, encephalopathy, hepatopulmonary syndrome, portopulmonary syndrome, and hepatorenal syndrome.

• Ascites: Most patients with decompensated cirrhosis develop ascites. Abdominal discomfort, abdominal distention, and diffuse dullness on exam with positive fluid wave should raise suspicion.

  • First-line treatment consists of daily sodium restriction and diuretics (spironolactone and furosemide).

  • Second-line treatment is paracentesis and the transjugular intrahepatic portosystemic shunt (TIPS) procedure.

  • In children with poor weight gain, a balance between the palatability of a low-sodium diet and growth must be weighed.

  • If sodium restriction is followed, restrict to 2-4 mEq/kg/day. Fluid restriction is not recommended unless sodium level is below 125 mEq/L.

  • Ascites may be complicated by spontaneous bacterial peritonitis (SBP). Patients with ascites and fever should undergo paracentesis to guide diagnosis and treatment. Neutrophil count >250 cells per mm² in the peritoneal fluid is diagnostic of bacterial peritonitis; a positive peritoneal fluid culture will help narrow antibiotic coverage. The most common pathogen is Escherichia coli. Blood culture should also be obtained. Intravenous treatment for 5-7 days is required. SBP can precipitate renal failure and may indicate poor long-term prognosis.

• Upper GI bleeding (presenting with hematemesis/melena or maroon stools/bright-red blood per rectum necessitates ICU care and consultation with gastroenterology or hepatology.

  • First, stabilize a hemodynamically unstable patient by repleting intravascular volume.

  • Start octreotide drip and intravenous (IV) proton pump inhibitor (PPI).

  • Obtain blood culture and start patient on IV ceftriaxone for 5-7 days.

  • Obtain GI consultation for upper endoscopy to evaluate source of bleeding within 24 hours of presentation.

• Encephalopathy is not well studied in children and is more challenging to diagnose than in adults. Consider hepatic encephalopathy if a patient is sleepier during daytime and up at night (reversal of sleep cycle); is more irritable or fussy; or is slow to respond, nonresponsive, or comatose.

  • Initial workup should include evaluation for infectious causes, electrolyte abnormalities, other complications of cirrhosis (e.g., SBP or GI bleeding), or other medications.

  • Usually, encephalopathy resolves with correction of the underlying cause. Patients with stage III and IV hepatic encephalopathy (see Stages of Hepatic Encephalopathy in Pediatric Patients) should be treated in the ICU setting.

• Hepatopulmonary syndrome is rare in children.

  • Patients present with dyspnea, hypoxia (oxygen saturation <96%), and orthodeoxia (hypoxemia is worse in the upright position and resolves with recumbency).

  • The syndrome is caused by right-to-left shunting at the lungs and resolves with liver transplantation.

• Portopulmonary syndrome is pulmonary hypertension in the setting of portal hypertension.

  • Patients present with dyspnea, fatigue, and peripheral edema.

  • Severity affects liver transplantation candidacy.

  • Patients should be treated for pulmonary hypertension with vasodilators in consultation with cardiology and pulmonology.

• Hepatorenalsyndrome can develop in patients with ascites and usually is a result of kidney hypoperfusion in the setting of splanchnic vasodilation in portal hypertension. SBP can trigger hepatorenal syndrome.

  • Avoiding nephrotoxic agents such as NSAIDs is crucial.

  • Also consider discontinuing diuretics, repleting intravascular volume with albumin infusions, and treating underlying trigger.

Management of cirrhosis:

• Avoid NSAIDs and other nephrotoxic medications that increase the risk for severe renal injury and significant decline in renal function.

• Avoid benzodiazepines and opioids because metabolism and clearance are impaired in cirrhotic patients and may lead to oversedation and compromise of respiratory drive. These drugs also affect the clinical and neurological exam and interfere with the clinician’s ability to follow the progression of encephalopathy.

• Restrict sodium to 2­-4 mEq/kg/day, to reduce risk of fluid retention, iatrogenic ascites, or worsening existing ascites.

• Patients with ascites and fever are presumed to have SBP until proven otherwise.

Liver Transplantation

Liver transplantation is the treatment of choice in patients with acute liver failure or chronic liver failure with decompensated cirrhosis. Decompensated cirrhosis is defined by bleeding esophageal varices, ascites, hepatopulmonary syndrome, hepatorenal syndrome, portopulmonary hypertension, and SBP. In children, unique indications for liver transplantation include metabolic liver disease, severe failure to thrive, metabolic bone disease, and intractable pruritus.

Observed 20- and 30-year survival in pediatric liver transplant recipients was 73% and 58%, respectively, in patients transplanted in 1997-2006. Projected survival in in patients receiving transplants in 2007-2018 is 84% and 80%, respectively.

Biliary atresia (BA) is the most common reason for liver transplantation in pediatric patients. Long-term outcomes depend on long-term complications, primarily from immunosuppression and surgical complications, including opportunistic infections, chronic kidney disease, hypertension, metabolic syndrome, diabetes, increased cardiovascular risk, chronic rejection, disease recurrence, malignancy (post-transplant lymphoproliferative disease, skin malignancies), biliary strictures, and portal vein or hepatic vein stenosis.

When patients with liver transplant present to the emergency department with fever, a thorough physical exam and workup for infectious causes should be completed. Keep in mind that these patients are immunocompromised, have had surgery (hence anatomy might be slightly different), and may have other chronic conditions due to exposure to long-term immunosuppressant medications. Consultation with a primary liver transplantation team is essential for optimal management.