Hepatomegaly
Christina Bales
INTRODUCTION
Hepatomegaly is an important physical examination finding, which may reflect intrinsic liver disease or a wide array of systemic diseases. Determination of liver size may be achieved with a combination of techniques, including palpation, percussion, and auscultation. Among these, palpation is the most common approach. It is accomplished by applying gentle manual pressure to the right lower abdominal wall and advancing superiorly until the inferior border of the liver is appreciated with the fingertips. Extension of the liver below the xiphoid process and/or below the right costal margin in the midclavicular line by more than 3 cm in neonates or more than 2 cm in older children may suggest hepatomegaly. However, several pitfalls in this technique must be considered. Increased lung expansion, accumulation of air or liquid in the pleural or subdiaphragmatic space, and a narrow chest cavity (e.g., scoliosis or pectus excavatum) may all result in inferior displacement of the liver without actual hepatic enlargement. Presence of the Riedel lobe, a normal anatomic variant in which the right lobe of the liver extends far below the right costal margin, may also confound the examination. Thus, determination of the liver span is recommended. The span is measured by ascertaining the upper border via chest wall percussion and the lower border via one or more of the three aforementioned techniques. Auscultation is performed by placing the stethoscope below the xiphoid and “scratching” superiorly from the right lower quadrant until the lower edge of the liver causes a change in the transmitted sound. In neonates, the normal liver span is 4.5 to 5 cm. By 12 years of age, it measures 7 to 8 cm in boys and 6 to 7 cm in girls.
The differential diagnosis for pediatric hepatomegaly is expansive and is best organized by considering six broad mechanisms of liver enlargement (all beginning with the letter “I” for ease of recall): Infection, Inflammation (noninfectious), Inappropriate accumulation of fat, Infiltration, I mpaired outflow of blood or bile, and Inborn errors of metabolism resulting in abnormal cellular storage:
DIFFERENTIAL DIAGNOSIS LIST
Infection (Infectious Hepatitis)
Viral Infections
Hepatitis A to E
Epstein-Barr virus (EBV) (infectious mononucleosis)
Cytomegalovirus (CMV)
Herpesvirus
Varicella
Enterovirus
Adenovirus
Rubella
HIV
Bacterial Infections (± sepsis or abscess)
Bartonella henselae (“cat-scratch” disease)
Salmonella typhi
Streptococcus
Staphylococcus
Tularemia
Brucellosis
Listeria monocytogenes
Actinomycosis
Ehrlichiosis
Tuberculosis
Spirochete Infections
Treponema pallidum (syphilis)
Borrelia burgdorferi (Lyme disease)
Leptospirosis
Rickettsial Infections
Rickettsia rickettsii (Rocky Mountain spotted fever)
Coxiella burnetii (Q fever)
Fungal Infections
Aspergillus
Histoplasmosis
Coccidioidomycosis
Candidiasis
Parasite/Amoeba Infections
Entamoeba histolytica
Toxocariasis
Schistosomiasis
Clonorchis sinensis
Leishmaniasis
Plasmodium falciparum (Malaria)
Inflammation (Noninfectious Hepatitis)
Autoimmune hepatitis (AIH)
Primary sclerosing cholangitis
Juvenile idiopathic arthritis (JIA)
Systemic lupus erythematosus
Radiation
Giant cell hepatitis (neonatal)
Toxins
Organic (e.g., Amanita phalloides mushroom)
Drugs (e.g., acetaminophen overdose)
Alcohol
Inappropriate Accumulation of Fat
Obesity (nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH))
Diabetes mellitus
Ethanol (chronic use)
Drugs (e.g., corticosteroids, valproic acid)
Parenteral nutrition (PN)
Protein malnutrition (kwashiorkor)
Celiac disease
Reye syndrome
Infiltration (Tumors and Other Cellular Infiltrates)
Tumors
Hepatoblastoma
Hepatocellular carcinoma
Hemangioma
Hemangioendothelioma
Metastasis (e.g., neuroblastoma)
Cellular Infiltrates
Extramedullary hematopoiesis (e.g., in sickle-cell disease)
Leukemia
Lymphoma
Langerhans cell histiocytosis (LCH)
Hemophagocytic lymphohistiocytosis (HLH)
Malignant histiocytosis
Impaired Outflow of Blood
Veno-occlusive disease (VOD)
Budd-Chiari syndrome
Congenital hepatic vein web/stenosis
Congestive heart failure
Constrictive pericarditis
Bile (extrahepatic cholestasis)
Biliary atresia
Choledochal cyst
Choledocholithiasis
Biliary ascariasis
Bile (intrahepatic cholestasis)
PFIC
Alagille syndrome
Nonsyndromic bile duct paucity
Cystic fibrosis
Inborn Errors of Metabolism of Lipids and Sphingolipids
Niemann-Pick disease
Gaucher disease
Wolman disease
Cholesteryl ester storage disease
Mucolipidoses
Fatty acid oxidation disorders
Proteins
Tyrosinemia
α-1 Antitrypsin deficiency
Carbohydrates
Mucopolysaccharidoses (e.g., Hunter, Hurler)
GM1 Gangliosidosis
Glycogen storage disease
Hereditary fructose intolerance
Galactosemia
Peroxisomes (e.g., Zellweger syndrome)
Metals
Iron (primary and secondary hemochromatosis)
Copper (Wilson disease)
DIFFERENTIAL DIAGNOSIS DISCUSSION
Viral Infection
It is not uncommon for children with viral syndromes to have modest hepatomegaly with mild elevations in transaminase levels. In most cases, the course is benign, and only observation for resolution of the infection is required. Certain hepatotropic viruses (listed above) may cause a more significant acute hepatitis, associated with tender hepatomegaly, jaundice, and marked elevations in liver transaminases. In rare cases, these findings may herald the onset of fulminant liver failure, and close observation with monitoring of liver synthetic parameters, including prothrombin time/international normalized ratio (PT/INR), albumin, and glucose levels, is warranted. Viral hepatitis is discussed in further detail in Chapter 45, “Jaundice.”
HIV Infection
HIV-related cholangiopathy, typically associated with CMV, Microsporidia or Cryptosporidia superinfection, is the most common hepatic manifestation of advanced HIV infection. Patients may present with abdominal pain, diarrhea, icterus or jaundice, and hepatomegaly. Widespread implementation of HAART therapy has reduced the incidence of this complication. The course of chronic
HBV and HCV infection may be more severe in the setting of HIV coinfection. HIV infection is discussed in further detail in Chapter 70, “Sexually Transmitted Diseases.”
HBV and HCV infection may be more severe in the setting of HIV coinfection. HIV infection is discussed in further detail in Chapter 70, “Sexually Transmitted Diseases.”
Liver Abscess
Etiology
In the United States and other developed countries, pediatric liver abscess is a rare phenomenon, primarily caused by bacteria. Staphylococcus, anaerobes, and gram-negative rods are the predominant culprits. Parasitic agents, including Entamoeba histolytica and Echinococcus granulosa, predominate in underdeveloped nations, where liver abscess is more common. Risk factors for liver abscess in the pediatric population include:
Immunodeficiency (e.g., chronic granulomatous disease, history of bone marrow transplant)
Congenital biliary obstruction (e.g., biliary atresia, choledochal cyst)
Inadvertent portal vein cannulation with umbilical vein catheterization of the neonate
Liver transplantation
Inflammatory bowel disease
Clinical Features
Patients may present with fever, pain/tenderness in right upper quadrant, anorexia, nausea, vomiting, and, occasionally, jaundice. Signs can be subtle, particularly in the immunocompromised patient, and a high index of suspicion may be required.
Evaluation
The white blood cell count, alanine aminotransferase (ALT), aspartate aminotrans-ferase (AST), and alkaline phosphatase levels are usually increased. Blood cultures identify a bacterial organism in 50% of cases. Amebic infection can be diagnosed with indirect hemagglutination (90% sensitivity) or IgG enzyme immunoassay (99% sensitive). Ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) are useful imaging modalities.
Treatment
Initial therapy involves empiric broad-spectrum intravenous antibiotic therapy. A typical regimen includes triple therapy with ampicillin, a β-lactamase inhibitor, and metronidazole. CT- or ultrasound-guided percutaneous aspiration with or without drain placement is generally advocated for abscesses ≥5 cm in diameter. Open surgical drainage is indicated in cases of spontaneous abscess rupture or failed percutaneous drainage.
Autoimmune Hepatitis
Etiology
Autoimmune hepatitis is a progressive inflammatory disease that is likely caused by dysregulated immune reactions to host liver antigens. Genetic and environmental factors have been implicated.
Clinical Features
Autoimmune hepatitis is more prevalent in female patients. A personal history or family history of other autoimmune disease may be elicited. The clinical presentation may mimic acute viral hepatitis. A subset of these patients will develop progression to acute liver failure within weeks of initial manifestations. The presentation may also be more insidious. In these cases, vague constitutional symptoms, such as fatigue, anorexia, and headache, predominate with or without relapsing icterus/jaundice. Approximately 10% of patients remain asymptomatic until signs of portal hypertension evolve. Given the highly varied presentation, AIH should be considered in the differential diagnosis of both acute and chronic hepatitis, as well as more advanced cirrhosis.
Evaluation
Physical examination may reveal signs of acute hepatitis, including fever, icterus/jaundice, and tender hepatomegaly, or stigmata of chronic liver disease, including splenomegaly, ascites, dilated abdominal wall veins, spider nevi, and palmar erythema. In addition to transaminase elevation with or without conjugated hyperbilirubinemia, laboratory studies often reveal an elevated globulin fraction (i.e., total protein to albumin ratio). Levels of autoantibodies, including antinuclear, antismooth muscle, and anti-liver-kidney-microsomal antibodies, may be elevated. Liver biopsy is necessary to establish the diagnosis, and classically reveals interface hepatitis with plasma cell involvement. The PT/INR and albumin level should be evaluated in all patients to ensure preservation of liver synthetic function.